Post on 14-Jul-2020
Position Statement – Testing for ovarian
cancer on asymptomatic women
Technical Report
February 2019
Position Statement – Testing for ovarian cancer in asymptomatic women: Technical Report was prepared and
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Cancer Australia
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© Cancer Australia 2019.
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Cancer Australia, 2019. Position Statement – Testing for ovarian cancer in asymptomatic women: Technical Report,
Cancer Australia, Surry Hills, NSW.
Position Statement – Testing for ovarian cancer in asymptomatic women: Technical Report can be downloaded from
the Cancer Australia website: canceraustralia.gov.au/resources
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iii Technical Report – Testing for ovarian cancer in asymptomatic women
Contents
Executive summary ......................................................................................................................................... 1
Population screening ............................................................................................................................................ 1 Surveillance in women at high risk of ovarian cancer .................................................................................... 1 Ongoing clinical studies........................................................................................................................................ 3 Emerging technologies ......................................................................................................................................... 3
1 Background ......................................................................................................................................... 4
Current Position Statements ................................................................................................................................. 4 Australian framework for population screening .............................................................................................. 4
2 Aim, objective and scope ................................................................................................................. 6
Aim……. ................................................................................................................................................................... 6 Objective ................................................................................................................................................................. 6 Scope of the review .............................................................................................................................................. 6
3 Methodology ....................................................................................................................................... 7
Clinical questions and PICOS criteria ................................................................................................................. 7 3.1.1 Population screening ............................................................................................................... 7 3.1.2 Surveillance of women at high risk ........................................................................................ 8
Search for clinical evidence ................................................................................................................................ 9 3.1.3 Search strategy ......................................................................................................................... 9 3.1.4 Study eligibility ......................................................................................................................... 10 3.1.5 Study selection ........................................................................................................................ 10 3.1.6 Quality appraisal of included evidence ............................................................................ 10
Search for clinical guidance ............................................................................................................................. 11 3.1.7 Search strategy ....................................................................................................................... 11 3.1.8 Eligibility criteria ....................................................................................................................... 11 3.1.9 Guideline selection ................................................................................................................. 11
Search for definitions of high risk population .................................................................................................. 11 3.1.10 Search strategy ....................................................................................................................... 12
Search for emerging technologies for screening or surveillance ............................................................... 12 3.1.11 Search strategy ....................................................................................................................... 12 3.1.12 Eligibility criteria ....................................................................................................................... 12
4 Results ................................................................................................................................................. 13
Review of evidence for population screening .............................................................................................. 13 4.1.1 Identified studies of screening effectiveness/harms ........................................................ 13 4.1.2 Data extraction – clinical studies ......................................................................................... 27 4.1.3 Data extraction – systematic reviews and HTAs ............................................................... 38
Review of evidence for surveillance of women at high risk ........................................................................ 47 4.1.4 Identified studies of surveillance effectiveness/harms .................................................... 47 4.1.5 Data extraction – clinical studies using ROCA-based CA125 evaluation ................... 59 4.1.6 Data extraction – clinical studies using single threshold CA125 .................................... 65 4.1.7 Data extraction – systematic reviews and HTAs ............................................................... 75
Review of clinical guidance .............................................................................................................................. 75 4.1.8 Identified guidelines ............................................................................................................... 75 4.1.9 Guidance relating to population screening ..................................................................... 77 4.1.10 Guidance relating to surveillance in women at high risk ................................................ 81
Review of definitions of high risk of ovarian cancer ..................................................................................... 84
Technical Report – Testing for ovarian cancer in asymptomatic women iv
4.1.11 Identified guidance that defines high risk .......................................................................... 84 4.1.12 Definitions of high risk of ovarian cancer ........................................................................... 84 4.1.13 Comparison of definitions with current Cancer Australia definition ............................. 88
Review of emerging technologies ................................................................................................................... 90
5 Synthesis of findings .......................................................................................................................... 95
Population screening .......................................................................................................................................... 95 5.1.1 Current clinical evidence ...................................................................................................... 95 5.1.2 Post-literature review publication – outcomes by histology ........................................... 97 5.1.3 Ongoing clinical studies......................................................................................................... 98 5.1.4 Impact of recent findings on evidence-informed guidance ......................................... 98 5.1.5 Emerging technologies .......................................................................................................... 98
Surveillance in women at high risk .................................................................................................................... 98 5.1.6 Current clinical evidence ...................................................................................................... 98 5.1.7 Ongoing clinical studies....................................................................................................... 102 5.1.8 Impact of recent findings on evidence-informed guidance ....................................... 102 5.1.9 Definitions of high risk of ovarian cancer ......................................................................... 102 5.1.10 Emerging technologies ........................................................................................................ 102
Appendices .................................................................................................................................................. 103
Appendix A Australian criteria for assessment of population screening ....................................... 103
Appendix B Literature search details .................................................................................................. 105
B.1 Clinical evidence .................................................................................................................. 105 B.2 Guidelines and position statements .................................................................................. 107 B.3 Emerging technologies ........................................................................................................ 110
Appendix C Evidence hierarchy ......................................................................................................... 111
Appendix D Included studies ............................................................................................................... 112
D.1 Population screening ........................................................................................................... 112 D.2 Surveillance in women at high risk ..................................................................................... 114
Appendix E Additional data extraction ............................................................................................. 116
E.1 Additional data extraction for population screening ................................................... 116 E.2 Additional data extraction for surveillance studies........................................................ 120
Appendix F Quality assessment .......................................................................................................... 122
Appendix G Membership of the Working Group .............................................................................. 130
Abbreviations and acronyms .................................................................................................................... 131
References……. ........................................................................................................................................... 134
v Technical Report – Testing for ovarian cancer in asymptomatic women
Tables
Table 1.1.1 2009 Cancer Australia guidance for ovarian cancer screening and surveillance ........................... 4
Table 3.1.1 PICOS criteria and additional considerations for population screening ............................................. 7
Table 3.1.2 PICOS criteria and additional considerations for surveillance of women at high risk ....................... 9
Table 3.2.1 Inclusion and exclusion criteria .................................................................................................................. 10
Table 3.2.2 Critical appraisal tools for specific study designs ................................................................................... 11
Table 4.1.1 Characteristics of included studies for population screening ............................................................. 15
Table 4.1.2 Cancer types included in primary and secondary analyses of the primary outcome in
PLCO and UKCTOCS – OC-specific mortality ......................................................................................... 20
Table 4.1.3 Terminology and definitions of select outcomes – PLCO and UKCTOCS .......................................... 21
Table 4.1.4 Key statistical analysis methods for mortality outcomes – population screening ............................ 22
Table 4.1.5 Key characteristics of systematic reviews relating to population screening for ovarian
cancer............................................................................................................................................................ 24
Table 4.1.6 Death due to ovarian cancer – primary outcome in PLCO and UKCTOCS ..................................... 27
Table 4.1.7 Death due to ovarian cancer – primary outcome analyses accounting for delayed
effects of screening in UKCTOCS .............................................................................................................. 29
Table 4.1.8 OC-specific mortality excluding prevalent cases, for ROCA triage versus no screening –
UKCTOCS ....................................................................................................................................................... 30
Table 4.1.9 All-other-cause mortality – PLCO and UKCTOCS ................................................................................... 30
Table 4.1.10 Mode of cancer detection in screening groups – PLCO and UKCTOCS .......................................... 31
Table 4.1.11 Ovarian cancer incidence – PLCO and UKCTOCS ............................................................................... 32
Table 4.1.12 Sensitivity of screening strategies – PLCO and UKCTOCS ..................................................................... 32
Table 4.1.13 False-positive surgery rates – PLCO and UKCTOCS ................................................................................ 33
Table 4.1.14 Cancer stage at diagnosis, all modes of detection – PLCO and UKCTOCS .................................... 34
Table 4.1.15 FIGO staging of ovarian cancer ............................................................................................................... 34
Table 4.1.16 Low versus high volume tumours at diagnosis, all modes of detection – UKCTOCS ....................... 35
Table 4.1.17 Complications associated with screening tests – PLCO and UKCTOCS ............................................ 37
Table 4.1.18 Complications associated with unnecessary surgery – PLCO and UKCTOCS .................................. 37
Table 4.1.19 Summary of evidence table from Henderson 2017 – effect on disease-specific mortality ........... 41
Table 4.1.20 Summary of evidence table from Henderson 2017 – harms ................................................................ 44
Table 4.1.21 Conclusions from systematic reviews relating to population screening for ovarian cancer ......... 46
Table 4.2.1 Characteristics of included studies using ROCA – surveillance of women at high risk of
ovarian cancer ............................................................................................................................................. 49
Table 4.2.2 Characteristics of included studies using single threshold CA125 – surveillance of women
at high risk of ovarian cancer .................................................................................................................... 50
Table 4.2.3 Inclusion/exclusion criteria – surveillance studies ................................................................................... 54
Table 4.2.4 Details of screening strategies – surveillance studies ............................................................................ 56
Table 4.2.5 Terminology and definitions – surveillance studies ................................................................................. 56
Table 4.2.6 Key characteristics of systematic reviews relating to surveillance of women at high risk .............. 58
Table 4.2.7 Mode of cancer detection – UKFOCSS Phase II ..................................................................................... 60
Table 4.2.8 False positive surgery rates – UKFOCSS Phase II ...................................................................................... 60
Table 4.2.9 Cancer stage at diagnosis – UKFOCSS Phase II ...................................................................................... 62
Technical Report – Testing for ovarian cancer in asymptomatic women vi
Table 4.2.10 Mode of cancer detection – CGN/GOG ............................................................................................... 64
Table 4.2.11 False-positive surgery rates – CGN/GOG ................................................................................................ 65
Table 4.2.12 Cancer stage at diagnosis – CGN/GOG ................................................................................................ 65
Table 4.2.13 Outcomes from PLCO RCT for women with at least one first degree relative with breast or
ovarian cancer ............................................................................................................................................. 66
Table 4.2.14 Outcomes from PLCO RCT for women with a personal history of breast cancer ............................ 67
Table 4.2.15 Mode of cancer detection – UKFOCSS Phase I ...................................................................................... 68
Table 4.2.16 Sensitivity of screening, with and without occult cancers – UKFOCSS Phase I ................................. 69
Table 4.2.17 False-positive surgery rates – UKFOCSS Phase I ...................................................................................... 70
Table 4.2.18 Cancer stage at diagnosis – UKFOCSS Phase I....................................................................................... 71
Table 4.2.19 Proportion of cancers diagnosed at ≥ Stage IIIC – UKFOCSS Phase I ................................................ 72
Table 4.2.20 Mode of cancer detection – UK-Netherlands-Norway study .............................................................. 73
Table 4.2.21 Cancer stage at diagnosis – UK-Netherlands-Norway study ............................................................... 73
Table 4.2.22 Key characteristics of systematic reviews relating to surveillance of women at high risk .............. 75
Table 4.3.1 Included clinical practice guidelines ....................................................................................................... 76
Table 4.3.2 Included position statements and other guidance ............................................................................... 77
Table 4.3.3 Relevant guidance from clinical practice guidelines – women at average risk ............................. 78
Table 4.3.4 Relevant guidance from other sources – women at average risk...................................................... 79
Table 4.3.5 Relevant guidance from clinical practice guidelines – surveillance of women at high risk .......... 82
Table 4.3.6 Relevant guidance from other sources – surveillance of women at high risk .................................. 83
Table 4.4.1 Definitions of women at high risk of ovarian cancer from guidelines and position
statements ..................................................................................................................................................... 84
Table 4.4.2 Definitions of women at high risk of ovarian cancer from included clinical studies........................ 87
Table 4.4.3 Current risk definition in Cancer Australia Position Statements............................................................ 89
Table 4.5.1 Potential ovarian cancer screening methodologies identified in literature search ........................ 92
Table 5.2.1 Identification of possible OC and diagnosis verification – surveillance studies............................. 121
Table AppA.1 Australian criteria for deciding whether a new screening program should be introduced
in a defined target population ............................................................................................................... 103
Table AppB.1 Search strategy to identify clinical evidence ...................................................................................... 105
Table AppB.2 Medline search string for ovarian cancer screening .......................................................................... 105
Table AppB.3 Medline search string for ovarian cancer surveillance in women at high risk ............................... 106
Table AppB.4 Study selection for the review of ovarian cancer population screening ....................................... 106
Table AppB.5 Study selection for the review of ovarian cancer surveillance in women at high risk ................. 107
Table AppB.6 Search strategy to identify guidelines and position statements ....................................................... 107
Table AppB.7 Medline search strings for guidelines and position statements ........................................................ 108
Table AppB.8 Selection for the review of guidelines and position statements ....................................................... 109
Table AppB.9 Search strategy to identify emerging technologies ........................................................................... 110
Table AppC.1 Designations of levels of evidence for interventional studies ........................................................... 111
Table AppD.1 Clinical trials of population screening for ovarian cancer ................................................................ 112
Table AppD.2 Systematic reviews of population screening for ovarian cancer .................................................... 113
Table AppD.3 Clinical studies of surveillance in women at high risk of ovarian cancer ....................................... 114
Table AppD.4 Systematic reviews of surveillance in women at high risk of ovarian cancer ................................ 115
Table AppE.1 ICD-10 codes interrogated for UKCTOCS study .................................................................................. 116
Table AppE.2 Case identification and verification – diagnosis or death due to OC ............................................ 117
Table AppE.3 Cancer stage at diagnosis, by tumour type grouping – UKCTOCS ................................................. 119
vii Technical Report – Testing for ovarian cancer in asymptomatic women
Table AppE.4 ROCA triage protocol – UKFOCSS Phase II ........................................................................................... 120
Table AppF.1 Systematic review quality assessment – Buhling 2017 ........................................................................ 122
Table AppF.2 Systematic review quality assessment – Guirguis-Blake 2017 ............................................................ 123
Table AppF.3 Systematic review quality assessment – Henderson 2017 .................................................................. 124
Table AppF.4 Systematic review quality assessment – Bloomfield 2014 .................................................................. 125
Table AppF.5 Systematic review quality assessment – Reade 2013 ......................................................................... 127
Table AppF.6 Systematic review quality assessment – Auranen 2011...................................................................... 128
1 Technical Report – Testing for ovarian cancer in asymptomatic women
Executive summary
Cancer Australia’s Position Statements on ‘Population screening and early detection of ovarian
cancer in asymptomatic women’ and ‘Surveillance of women at high or potentially high risk of
ovarian cancer’ were developed in 2009. Since that time, the evidence base for screening and
surveillance has grown, and the findings have been incorporated in recent clinical guidelines.
The objective of this high-level review is to identify and appraise recent clinical evidence and
recent national and international guidelines on ovarian cancer screening and surveillance. The
findings of the high-level review will be used to inform an update of the 2009 Cancer Australia
Position Statements.
Population screening
The Cancer Australia Position Statement on population screening refers to two large randomised
controlled trials (RCTs) of cancer antigen 125 (CA125) and transvaginal ultrasound (TVUS) in
asymptomatic women at average risk, namely the Prostate, Lung, Colorectal and Ovarian Cancer
Screening Trial (PLCO) and the United Kingdom Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS). At the time, only preliminary results were available from these trials, and the final,
longer term results were much anticipated.
Since 2009, there have been 15 full text publications from these two large, well-conducted RCTs,
and there is ongoing debate about the relative strengths and weaknesses of each trial in light of
the inherent difficulties in designing and analysing a screening trial for a relatively rare and
heterogeneous cancer. Although disease-specific mortality is the key outcome for ovarian cancer,
false positive rates are also highly relevant as the screening strategy necessitates surgical removal
of ovaries for confirmation of diagnosis.
Based on a priori analyses, the evidence to date, which has adequate power to detect differences
in mortality, indicates there is no mortality benefit associated with population screening with any of
the implemented strategies. Pre-specified and post hoc secondary analyses are suggestive that a
delayed mortality benefit may be attributable to screening in the UKCTOCS study, but longer-term
follow up is necessary to confirm this. A post-hoc analysis of the PLCO trial was identified
subsequent to the literature search in this Review – no stage shift or mortality benefit was found for
Type II tumours, which were less likely to be detected by screening than other tumour types. Such
an analysis is yet to be report for the UKCTOCS trial. Follow up of UKCTOCS to 2018 has received
funding, and plans to continue to 2024 are reported. At that time, it may be necessary to re-
evaluate whether population screening is justified.
Overall, the current evidence does not support the implementation of screening in asymptomatic
women at average risk of ovarian cancer. Accordingly, recent national and international
guidelines do not recommend population screening for ovarian cancer based on the technologies
that have been trialled to date.
Surveillance in women at high risk of ovarian cancer
The Cancer Australia Position Statement on surveillance in high-risk women refers to two multicentre
prospective cohort studies that were underway at the time – the United Kingdom Familial Ovarian
Cancer Screening Study (UKFOCSS), and the Cancer Genetics Network and Gynecologic
Oncology Group (CGN/GOG) collaborative study.
Technical Report – Testing for ovarian cancer in asymptomatic women 2
Since 2009 there have been 10 full text publications relating to six studies of surveillance in women
at high risk of ovarian cancer: four prospective cohort studies (UKFOCSS Phase I, UKFOCSS Phase II,
CGN/GOG, UK-Netherlands-Norway study), one prospective cohort survey (Fox Chase Cancer
Centre study), and a post hoc analysis of a high-risk subgroup from the PLCO population screening
RCT (PLCO-HR). As random assignment to a no-surveillance arm is considered unethical in high-risk
women, no studies included a no-surveillance comparator group, instead relying on historical
controls or before/after comparisons within a cohort. While such comparisons may be considered
valid, and are likely the best approach available to investigate the effectiveness of surveillance,
the results of these studies should be considered in light of the inherent design flaws and inevitable
confounding that limit the opportunity to demonstrate statistically robust improvements in
outcomes. The low incidence rate for ovarian cancer also means that even in the largest studies,
the number of events are small, especially when subgroups such as stage at diagnosis are
examined, further reducing the certainty of the outcomes. Interpretation of the results of these
surveillance studies also requires consideration of the fact that risk-reducing salpingo-
oophorectomy (RRSO) is recommended as optimal management.
The PLCO-HR subgroup analysis overcomes many of the limitations described above. However, it
was not feasible to identify women in this study post hoc according to the usual array of criteria
that define high risk, and the more readily discernible group of women with a personal history of
breast cancer or family history of breast or ovarian cancer was used instead. Consequently, the
overall disease-specific risk in this subgroup would have been lower than in a typical high-risk
population.
The few surveillance studies that reported on mortality did not find any improvements associated
with surveillance. The PLCO subgroup analysis, however, did find significant improvements in
disease-specific survival with surveillance in a population with a higher-than-average risk, and an
absolute reduction in advanced-stage cancers. Stage shift trends were also discernible in the other
surveillance trials, and were statistically significant in the UKFOCSS trials. Event numbers were low in
all surveillance studies of high-risk cohorts, so it is not clear whether the failure to demonstrate a
corresponding improvement in mortality is due to limited statistical power or a fundamental failure
to improve mortality outcomes as a result of surveillance (i.e. early detection may not result in
improved mortality). Furthermore, these studies were limited by the lack of a balanced comparator
group (PLCO excepted), so the current lack of a demonstrated mortality benefit is not evidence
that surveillance cannot improve survival outcomes.
While stage shift may be of interest as a surrogate outcome for mortality, reduced volume of
disease is also a patient-relevant outcome in itself, with implications regarding rates of post-surgical
residual disease. So while the evidence may not be resounding for the use of surveillance as first-
line management in high-risk women, it appears there may be a role for surveillance of those
women wishing to postpone RRSO to complete childbearing or delay surgically induced
menopause. This suggests surveillance may be considered appropriate for some women to support
decision making around the timing of RRSO. This is likely to be a decision made at the clinical level,
but the evidence to date does not support a shift in current management recommendations
across all high-risk women.
No clinical practice guidelines or other guidance was identified that incorporates all recent
evidence relating to surveillance in women at high risk of ovarian cancer. In general, routine
surveillance is not recommended; however, some guidance documents advise that despite a lack
of strong evidence, surveillance using CA125 and TVUS may be considered in particular high-risk
populations from the age of 30 or 35, so long as patients are informed about the limited value of
these tools as an effective surveillance measure.
3 Technical Report – Testing for ovarian cancer in asymptomatic women
Ongoing clinical studies
The only ongoing study identified in the search of clinical trial databases was the long-term follow
up of UKCTOCS, which will use an updated classification of peritoneal cancers to reflect the revised
classification of tumours of the reproductive system from the World Health Organization (WHO) in
2014. After reclassification of these peritoneal cancers, the primary outcomes of UKCTOCS and
PLCO will be more closely aligned. The next censorship for UKCTOCS is planned for December 2018,
and final censorship for December 2024.
Although several clinical studies of new biomarkers and molecular screening tests were identified in
clinical trial databases, the viability of the clinical studies could not be verified. Several entries had
the following warning: “The recruitment status of this study is unknown. The completion date has
passed and the status has not been verified in more than two years.”
Emerging technologies
Given the absence of a single marker or screening device that is effective for ovarian cancer,
research is likely to increasingly aim to identify new markers and combinations of markers in
prediction models.
A number of methodologies were identified that are either currently available for prognosis or
diagnosis of ovarian cancer, or that are in clinical or scientific development for screening for
ovarian cancer. However, none of these technologies are likely to be introduced/recommended in
the short- to medium-term.
The recent Evidence Synthesis of screening for ovarian cancer prepared for the US Preventative
Services Task Force of the Agency for Healthcare Research and Quality (AHRQ; Henderson et al
2017) also identified no ongoing randomised trials of ovarian cancer screening using new screening
tools. The authors noted that while some tools in development may hold promise for the future (e.g.
microRNA), currently there are no new screening tools (i.e. biomarkers, instruments) exhibiting levels
of test performance beyond what is observed for the screening tools evaluated in trials.
In their recent review of the evolving paradigms in research and care for ovarian cancer, the
National Academies of Science, Engineering and Medicine (NASEM) claim that it is highly unlikely
that a single biomarker or imaging modality will be sufficient to aid in the early detection of all
ovarian cancer subtypes, given the marked heterogeneity of ovarian cancers and the incomplete
understanding of early disease development for each subtype (NASEM 2016). The authors note that
“while research on refining current methods may be fruitful, distinct multimodal approaches will
likely be needed to detect each of the various subtypes at their earliest stages”.
Technical Report – Testing for ovarian cancer in asymptomatic women 4
1 Background
Current Position Statements
In 2009, Cancer Australia developed Position Statements on ‘Population screening and early
detection of ovarian cancer in asymptomatic women’, and ‘Surveillance of women at high or
potentially high risk of ovarian cancer’. Table 0.1 lists the guidance provided in each Position
Statement.
Table 0.1 2009 Cancer Australia guidance for ovarian cancer screening and surveillance
Topic Statements
Population screening and early detection of ovarian cancer in asymptomatic women
There is currently no evidence that any test, including pelvic examination, CA125 or other biomarkers, ultrasound
(including transvaginal ultrasound), or combination of tests, results in reduced mortality from ovarian cancer.
There is no evidence to support the use of any test, including pelvic examination, CA125, or other biomarkers, ultrasound
(including transvaginal ultrasound), or combination of tests, for routine population based screening for ovarian cancer.
Further validation in large clinical trials is required before current or new biomarkers could be recommended for routine
use in a population screening setting.
Surveillance of women at high or potentially high risk of ovarian cancer
Ovarian cancer surveillance is not recommended for women at high or potentially high risk.
Evidence shows that ultrasound or CA125, singly or in combination, is not effective at detecting early ovarian cancer.
The most effective risk reducing strategy for ovarian cancer is bilateral salpingo-oophorectomy.
Definition of potentially high risk women
The category of potentially high risk of ovarian cancer covers less than 1% of the female population. As a group, lifetime
risk of ovarian cancer ranges between 1 in 30 and 1 in 2. This risk is more than 3 times the population average. Individual
risk may be higher or lower if genetic test results are known.1 Women who have had a genetic fault identified through
testing are regarded as being at high risk. Women have been defined as being at potentially high risk of developing
ovarian cancer1 if they:
Are at high or potentially high risk of breast cancer
Have one 1° relative diagnosed with epithelial ovarian cancer in a family of Ashkenazi Jewish ancestry2
Have one woman in the family with ovarian cancer at any age, and another with breast cancer before the
age of 50, where the women are 1° or 2° relatives of each other
Have two 1° or 2° relatives on the same side of the family diagnosed with epithelial ovarian cancer,
especially if one or more of the following features occurs on the same side of the family:
o additional relative(s) with breast or ovarian cancer
o breast cancer diagnosed before the age of 40
o bilateral breast cancer
o breast and ovarian cancer in the same woman
o breast cancer in a male relative
Have three or more 1° or 2° degree relatives on the same side of the family diagnosed with any cancers
associated with hereditary non-polyposis colorectal cancer (HNPCC): colorectal cancer (particularly if
diagnosed before the age of 50), endometrial cancer, ovarian cancer, gastric cancer, and cancers
involving the renal tract
Are a member of a family in which the presence of a high-risk ovarian cancer gene mutation has been
established.
Source: Cancer Australia website
Australian framework for population screening
The framework used to guide decision makers regarding the implementation of population
screening for cancer and other chronic diseases in Australia is outlined in Appendix A. The
Australian framework takes into account:
the need for a strong evidence base in making a decision about the introduction of a
screening program including evidence of the safety, reproducibility and accuracy of the
screening test and the efficacy of treatment; and
1 National Breast Cancer Centre 2006. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health
professionals. National Breast Cancer Centre, Camperdown, NSW. 2 High-risk ovarian and breast cancer mutations are more common in people of Ashkenazi Jewish ancestry.
5 Technical Report – Testing for ovarian cancer in asymptomatic women
the requirement that a screening program offers more benefit than harm to the target
population.
The framework does not address surveillance in high risk populations, but it is necessary to consider
these patients when planning the coverage of screening programs.
Technical Report – Testing for ovarian cancer in asymptomatic women 6
2 Aim, objective and scope
Aim
The overall aim of this project is to provide the Australian community with up-to-date evidence-
based information on:
1. population screening and early detection of ovarian cancer in asymptomatic women, and
2. surveillance of women at high or potentially high risk of ovarian cancer.
Objective
The objective of this high-level review is to identify and appraise recent clinical evidence and
recent national and international guidelines on ovarian cancer screening and surveillance. The
findings of the high-level review will be used to inform an update of the 2009 Cancer Australia
Position Statements.
Scope of the review
The high level review includes the following components:
a review of the highest level clinical evidence for ovarian cancer screening and surveillance,
published from 2009 onwards
a review of clinical practice guidelines, position statements, and other evidence-based
guidance from Australia and other countries, published from 2011 onwards
a review of emerging technologies with potential for screening or surveillance.
7 Technical Report – Testing for ovarian cancer in asymptomatic women
3 Methodology
This section of the Technical Report describes the methodology used to identify and review recent
clinical evidence and guidelines on population screening for ovarian cancer and surveillance of
women at high or potentially high risk of ovarian cancer; the research questions, the PICOS criteria
used to guide the selection of eligible studies, the methodology used to search the published
literature and select relevant evidence and guidance.
Clinical questions and PICOS criteria
3.1.1 Population screening
3.1.1.1 Clinical question for population screen
The research question to focus the high-level review of the literature for ovarian cancer population
screening is:
What is the effectiveness (health benefits and harms) of routine population-based
screening for ovarian cancer?
3.1.1.2 PICOS criteria for population screening
PICOS criteria were developed to assist with evidence selection using information from the
literature. As shown in Table 0.1, these criteria define the following four elements in detail:
the target population for the intervention
the intervention being considered
the appropriate comparator
the outcomes that are most relevant to assess safety and effectiveness
the setting for the intervention.
Additional considerations are also noted (e.g. frequency of screening, duration of follow-up).
Table 0.1 PICOS criteria and additional considerations for population screening
PICOS criterion Description
Population Asymptomatic women who are at population risk of ovarian cancer.
Exclude children and adolescents, aged < 18 years, pregnant women, and symptomatic women.
Intervention Ovarian cancer screening using:
Pelvic examination
CA125
Other biomarkers (e.g. HE4)
Transvaginal ultrasound
Combination of above
Exclude examination or testing for diagnosis.
Comparator Usual care i.e. no population-based ovarian cancer screening.
Technical Report – Testing for ovarian cancer in asymptomatic women 8
PICOS criterion Description
Outcomes Detection outcomes
Ovarian cancer incidence
o all diagnoses
o by cancer site/grade/histology/stage
Number of interval cancers in screening group
Number of surgeries performed to detect one case of ovarian cancer
Rate of false-positive screening tests
Sensitivity
Mortality
Ovarian cancer specific mortality
o Time to ovarian cancer specific mortality
All-cause mortality
Adverse events
Complications associated with unnecessary surgery
QoL
Measures of worry or anxiety related to ovarian cancer risk
Quality of life (assessed using validated instruments)
Economic outcomes
Economic analysis (cost-effectiveness, cost-benefit, cost-minimisation)
Setting Developed countries, primary care outpatient setting (or similar)
Exclude settings not applicable to primary care
Additional considerations Frequency of screening/testing
Duration of follow-up
o stratify outcomes by follow-up time point (e.g. follow-up of 1-2 years versus >2 years) or use latest
reported time point for all outcomes
Menopausal status of women
Abbreviations: QoL, quality of life.
3.1.2 Surveillance of women at high risk
3.1.2.1 Clinical question for surveillance of women at high risk
For the review of surveillance in women at high risk of ovarian cancer, the research question is:
What is the effectiveness (health benefits and harms) of surveillance of women who
are at high or potentially high risk of ovarian cancer?
3.1.2.2 PICOS criteria for surveillance of women at high risk
PICOS criteria were developed to assist with evidence selection using information from the
literature. As shown in Table 0.2, these criteria define the following four elements in detail:
the target population for the intervention
the intervention being considered
the appropriate comparator
the outcomes that are most relevant to assess safety and effectiveness
the setting for the intervention.
Additional considerations are also noted (e.g. frequency of screening, duration of follow up).
9 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.2 PICOS criteria and additional considerations for surveillance of women at high risk
PICOS criterion Description
Population Asymptomatic women who are at high or potentially high risk of ovarian cancer
Exclude children and adolescents, aged < 18 years, pregnant women, and symptomatic women
Intervention Ovarian cancer screening using:
Pelvic examination
CA125
Other biomarkers (e.g. HE4)
Transvaginal ultrasound
Combination of above
Exclude examination or testing for diagnosis
Comparator Usual care, including the option of risk-reducing surgery (salpingo-oophorectomy) i.e. no surveillance in
women at high or potentially high risk of ovarian cancer
Outcomes Detection outcomes
Ovarian cancer incidence
o all diagnoses
o by cancer site/grade/histology/stage
Number of interval cancers in screening group
Number of surgeries performed to detect one case of ovarian cancer
Rate of false-positive screening tests
Sensitivity
Mortality
Ovarian cancer specific mortality
o Time to ovarian cancer specific mortality
All-cause mortality
Adverse events
Complications associated with unnecessary surgery
Complications associated with prophylactic surgery
QoL
Measures of worry or anxiety related to ovarian cancer risk
Quality of life (assessed using validated instruments)
Economic outcomes
Economic analysis (cost-effectiveness, cost-benefit, cost-minimisation)
Setting Developed countries, primary care outpatient setting (or similar)
Additional considerations Frequency of screening/testing
Duration of follow-up
o stratify outcomes by follow-up time point (e.g. follow-up of 1-2 years versus >2 years) or use latest
reported time point for all outcomes
Menopausal status of women
Study definition of high or potentially high risk
Search for clinical evidence
3.1.3 Search strategy
A comprehensive search of peer-reviewed scientific literature was undertaken 17 – 20 October
2017 for original publications of individual studies, health technology assessments (HTAs) or
systematic reviews providing clinical evidence of the effectiveness and safety of ovarian cancer
population screening, and surveillance of women at high or potentially high risk.
Briefly, the search strategy included:
a search of the Medline electronic database (using the Ovid interface),
a targeted search of the websites of peak cancer bodies and HTA agencies,
a search of clinical trial registries, and
Technical Report – Testing for ovarian cancer in asymptomatic women 10
snowballing for any additional relevant studies that might not have been identified in the
formal literature search (e.g. hand-searching reference lists; chasing up studies mentioned in
clinical practice guidelines).
The search strategy, including the websites targeted and Medline search string, is shown in
Appendix B (Section B.1).
3.1.4 Study eligibility
Study eligibility was based on the PICO criteria outlined above in Section 0, together with the
inclusion and exclusion criteria shown in Table 0.1. Eligible studies include RCTs, systematic reviews
and meta-analyses – that is, Level I and Level II evidence as described in the NHMRC Evidence
Hierarchy (Appendix C). For surveillance of women at high risk of ovarian cancer, lower levels of
evidence (Level III-1 or III-2) were eligible for inclusion, with prospective cohort studies taking priority
over retrospective studies.
In order to focus on recent developments (since publication of the Cancer Australia Position
Statements on ovarian cancer screening and surveillance), only studies published from 2009
onwards were considered for inclusion.
Table 0.1 Inclusion and exclusion criteria
Item Inclusion criteria Exclusion criteria
Publication types Published journal articles
Health technology assessments
Clinical trials
Conference abstracts
Letters and editorials
Opinion pieces and commentaries
Study types and
designs
Systematic reviews
Meta-analyses
Randomised controlled trials
Non-randomised trials
Single arm studies
Diagnostic studies
Study language English language articles only –
Publication date From 1 January 2009 –
3.1.5 Study selection
3.1.5.1 Population screening
The Medline search identified 248 unique records, of which 17 met the eligibility criteria for the
review. Appendix B (Section B.1.2) outlines the selection process. An additional seven records were
identified through targeted searches of websites and snowballing.
3.1.5.2 Surveillance in women at high risk
The Medline search identified 290 unique records, of which 11 met the eligibility criteria for the
review. The selection process is outlined in Appendix B (Section B.1.2). No additional records were
identified through targeted searches of websites and snowballing.
3.1.6 Quality appraisal of included evidence
Although formal assessment of the risk of bias associated with the included studies is out of scope
for the current work, the principles for assessing the risk of bias was based on one of the critical
appraisal tools listed in Table 0.2 that is appropriate for the study design.
11 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.2 Critical appraisal tools for specific study designs
Level Study design Development Critical appraisal tool
I SR AMSTAR, Canada AMSTAR
II/III-1 RCTs/quasi-RCTs Cochrane Collaboration Risk of Bias (RoB) tool for RCTs
III-2 Non-randomised experimental trials,
cohort studies with concurrent control
group
Scottish Intercollegiate Guidelines
Network (SIGN)
Methodology Checklist 3 for
Cohort Studies
Search for clinical guidance
3.1.7 Search strategy
A comprehensive search was undertaken 17 – 20 October 2017 to identify national and
international clinical guidance (clinical practice guidelines and position statements) regarding
population screening for ovarian cancer in asymptomatic women, and surveillance of women at
high risk of ovarian cancer.
Briefly, the search strategy included:
a search of the Medline electronic database (using the Ovid interface),
a search of clinical practice guideline databases, and
a targeted search of the websites of peak cancer bodies.
The search strategy, including the websites targeted and Medline search string, is shown in
Appendix B (Section B.2.1).
3.1.8 Eligibility criteria
Clinical practice guidelines and position statements were considered eligible if they provided
evidence-informed guidance on ovarian cancer screening and surveillance. Guidance developed
through a consensus process was only considered eligible in cases where evidence was found to
be insufficient. Guidelines published prior to 2011 were not eligible for inclusion on the basis that
they may not reflect current practice.
3.1.9 Guideline selection
The Medline search identified 200 unique records, of which nine met the eligibility criteria for the
review. The selection process is outlined in Appendix B (Section B.2.2). An additional 11 guidance
documents were identified through searches of clinical practice guideline databases and targeted
searches of websites.
Search for definitions of high risk population
Criteria for defining the population of women with an elevated risk of ovarian cancer typically
includes family history and genetic mutation status. The definition used in the 2009 Cancer Australia
Position Statement is shown in Table 0.1. A review of definitions used in clinical studies, clinical
practice guidelines, position statements and by peak cancer organisations will allow an assessment
of whether the definition requires any adaptation for the updated Cancer Australia Position
Statement.
Technical Report – Testing for ovarian cancer in asymptomatic women 12
3.1.10 Search strategy
A full and comprehensive, evidence-based assessment of the definition of the high-risk population
is beyond the scope of this Evidence Review and a specific search for definitions was not
undertaken. When searching for clinical studies and clinical guidance for other sections of the
report, the websites of peak cancer authorities were scanned for a definition of the population
considered to be at high or potentially high risk of ovarian cancer. Additionally, clinical studies,
guidelines and position statements considered eligible for inclusion in earlier sections of the report
were reviewed for criteria to define women with an elevated risk of ovarian cancer.
Search for emerging technologies for screening or surveillance
3.1.11 Search strategy
A targeted scanning search was undertaken 30 October – 3 November 2017 to identify promising
new tests and biomarkers for ovarian cancer.
Briefly, the search strategy included:
a targeted search of the websites of HTA agencies
a targeted search of the websites of peak cancer bodies
a targeted search of horizon scan websites
a targeted search of 2016 and 2017 abstracts from key cancer conferences
a targeted search of clinical trial registries
a general web search
snowballing (e.g. hand-searching reference lists; chasing weblinks).
The search strategy, including the websites targeted, is shown in Appendix B (Section B.3.1).
3.1.12 Eligibility criteria
Tests/biomarkers were included if they were considered:
emerging – not yet available for use within the healthcare system but in development and
expected to be registered or launched within the next 2 years, or
new – tests that have been available for use for 5 years or less but not yet considered for use,
or are in the early phases of adoption.
13 Technical Report – Testing for ovarian cancer in asymptomatic women
4 Results
Review of evidence for population screening
4.1.1 Identified studies of screening effectiveness/harms
The literature searches identified a total of 24 eligible records for ovarian cancer population
screening: 19 clinical study publications/unpublished reports and five systematic reviews.
4.1.1.1 Key clinical studies
The 19 eligible clinical study publications and unpublished reports are listed in Appendix D (Section
D.1.1). They describe two RCTs:
The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial
United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).
For the PLCO trial, primary and secondary outcomes are reported in three publications, and two
publications describe post hoc analyses. One study that reports the results of the initial round of
screening was published prior to the 2009 cut-off date for the literature review, but this is also shown
in Appendix D. An additional two records describing study design were identified during a directed
search. The Cancer Data Access System website, hosted by the National Cancer Institute, is a
repository of information for this trial, and a link to the main page for this resource is also included.
For the UKCTOCS trial, primary and secondary outcomes are reported across five publications, and
an additional three publications describe post hoc analyses (two relate to cost-effectiveness).
Directed searching also identified a study protocol for the trial and another for the ongoing long
term follow up (entitled ‘Detailed Project Description’), which provides a brief overview of the
design of the original trial, mortality results so far, and the rationale for extending follow up.
Study characteristics
The study characteristics of the two RCTs of population screening are shown in Table 0.1. Key
differences between the trials include the following:
Menopausal status
PLCO – not excluded, but older participants (at least 55 years)
UKCTOCS – excluded pre-menopausal
Women with a high risk of ovarian cancer
PLCO – not excluded
UKCTOCS – excluded
Cancer antigen 125 (CA125) interpretation
PLCO – cutoff value of 35 U/mL
UKCTOCS – Risk of Ovarian Cancer Algorithm (ROCA) to analyse longitudinal CA125
(individual risk factors for each woman inform the ROCA in the calculation of personal risk)
Technical Report – Testing for ovarian cancer in asymptomatic women 14
Screening strategies
PLCO – single screening group with simultaneous CA125 and transvaginal ultrasonography
(TVUS) testing for first four years, then CA125 only for the final two years
UKCTOCS – two screening groups:
o TVUS only
o CA125 only unless levels elevated, then TVUS
Number of screening rounds
PLCO – 6
UKCTOCS – 7-11
15 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.1 Characteristics of included studies for population screening
Item PLCO UKCTOCS
Country and setting United States – 10 screening centres under contract to the
National Cancer Institute
United Kingdom – 13 regional centres in NHS Trusts in England, Wales, and Northern Ireland, with the Queen Mary
University of London as the coordinating centre between 2001 and 2004 and then University College London from 2004
onwards
Trial number NCT00002540 NCT00058032
Inclusion criteria Women 55 to 74 years of age
Menopausal status not a criterion
Post-menopausal women, defined as either (a) >12 months amenorrhoea following a natural menopause or
hysterectomy, or (b) >12 months of HRT commenced for menopausal symptoms
50 to 74 years of age
Exclusion criteria Previous diagnosis of lung, colorectal, or ovarian
cancer
Previous oophorectomy (dropped in 1996)
Current tamoxifen use (dropped in 1999)
Increased risk of familial ovarian cancer not a criterion
Previous ovarian malignancy
History of bilateral oophorectomy
Active non-ovarian malignancy3
Increased risk of familial ovarian cancer4
Participation in other ovarian cancer screening trials
Study design RCT with two groups, randomised 1:1
CA125 and TVUS
no screening
RCT with three groups, randomised 1:1:2 respectively to:
multimodal screening (ROCA triage to repeat CA125 and/or TVUS)
TVUS
no screening
Period of study
Start date 16 Nov 1993 Apr 2001
Recruitment period Nov 1993 to Jul 2001 17 Apr 2001 to 29 Sep 20055
Randomisation period Nov 1993 to Jul 2001 1 Jun 2001 to 21 Oct 2005
Maximum no. of
annual screening
rounds
6 annual screening rounds
4 with CA125 plus TVUS, followed by
2 with CA125 only
Compliance per round:
CA125, 73-85%; TVUS, 78-84%
7-11 annual screening rounds, depending on date of randomisation (protocol change in 2008 increased number of
screening rounds from 6 to a maximum of 11)
Compliance across all rounds:
ROCA triage, 80.8%; TVUS, 78.0%
End of screening date NR, but planned for Sep 2006 (see Appendix E,
FigureAppE.1.1)
31 Dec 20116
3 Women who have a past history of malignancy are only eligible if (a) they have no documented persistent or recurrent disease and (b) have not received treatment for >12 months. The intention is to minimise false
positive CA125 results due to advanced stages of previously diagnosed malignancy. This exclusion did not include premalignant disease such as cervical intraepithelial neoplasia or use of tamoxifen to prevent
breast cancer recurrence. 4 Women with increased risk of familial ovarian cancer were eligible to enter the separate trial, the United Kingdom Familial Ovarian Cancer Screening Study (UKCTOCS) – the inclusion criteria for this study are listed in
the study characteristics table for studies of ovarian cancer surveillance in the following section of the current Report. 5 Of 1,243,282 women invited to participate, 205,090 were recruited and 202,638 (16.3%) were randomised. 6 The original trial protocol specified six annual screens and follow-up for 7 years from randomisation. In 2008, an analysis of overall and cause-specific standardised mortality in the no-screening group showed a lower
than expected mortality rate. Screening in the TVU and CA125 (±TVU) groups was therefore extended to Dec 31, 2011, resulting in women being offered 7–11 screens depending on the year of randomisation.
Technical Report – Testing for ovarian cancer in asymptomatic women 16
Item PLCO UKCTOCS
Person-years Screening: 371,833
No screening: 374,976
ROCA triage: 345,572
TVUS: 327,775
No screening: 1,097,089
End of follow-up 31 Dec 2012 Dec 2024
Length of follow up From randomisation through to
13 years of follow-up or
28 Feb 2010
whichever comes first.
From randomisation through to censorship
Dec 2014 (up to 14 years – 1 analysis)
Extended follow up, planned reporting:
Dec 2018 (up to 18 years)7
Dec 2024 (up to 24 years)
Participants randomised
Screening (method 1) Screening: 39,105 ROCA triage: 50,640
Screening (method 2) – TVUS: 50,639
Control No screening: 39,111 No screening: 101,359
Participants analysed
Screening (method 1) Screening: 34,253 ROCA triage: 50,624 (complete follow-up 50,084)
Screening (method 2) – TVUS: 50,623 (complete follow-up: 50,060)
Control No screening: 34,304 No screening: 101,299 (complete follow-up: 100,149)
Baseline characteristics The authors note that baseline characteristics were
balanced between study groups.
The authors note that baseline characteristics were balanced between study groups.
Median follow up
(years)
Primary analysis (28 Feb 2010)
12.4 (range 10.9-13.0)
Extended follow up (31 Dec 2012)
Screening: 14.72 (IQR 13.1, 16.4)
No screening: 14.65 (IQR 12.8, 15.7)
Primary analysis (31 Dec 2014)
11.1 (IQR 10.0–12.0)
7 Taken from NHS 2016 Detailed Project Description.
17 Technical Report – Testing for ovarian cancer in asymptomatic women
Item PLCO UKCTOCS
Screening methods CA125 interpretation
Threshold: ≥35 U/mL
Group 1 – CA125 + TVUS8
First 4 rounds of annual screening
CA125 and TVUS
Subsequent rounds (up to 2)
CA125 only
Bimanual examination of the ovaries was originally part of
the screening procedures but was discontinued in
December 1998 because no cancers were detected solely
by ovarian palpation.
CA125 interpretation
Risk of Ovarian Cancer Algorithm (ROCA)9
Group 1 – ROCA triage
Multimodal screening (MMS): annual serum CA125, with repeat CA125 alone or with TVUS, depending on results:
Level I screen
CA125 ROCA
Normal ROC – resume annual CA125 screening
Intermediate ROC – repeat CA125 in 12 weeks
Elevated ROC – Level II screen in 6-8 weeks, or earlier where suspicion is high
Level II screen
TVUS and repeat CA125 ROCA
Scan & ROC normal – resume annual CA125 screening
Scan normal but ROC elevated – repeat Level II scan in 12 weeks (sooner where suspicion is high)
Scan unsatisfactory (irrespective of ROC) – repeat Level II scan in 12 weeks (sooner where suspicion is high)
Scan abnormal (irrespective of ROC) – referral for clinical assessment with a view to surgery
Group 2 – TVUS
Annual TVUS scan, with repeat TVUS scans depending on results:
Level I screen
Scan normal – resume annual screening
Scan unsatisfactory – repeat scan in 12 weeks
Scan abnormal – repeat scan in 6-8 weeks (earlier where suspicion is high) = Level II
Level II screen
Scan normal – resume annual screening
Scan unsatisfactory – repeat scan in 6-8 weeks (earlier where suspicion is high) and triaged based on findings to
annual screening or clinical assessment
Scan abnormal – referral for clinical assessment with a view to surgery
8 Although TVUS was included in the first four screening rounds only, this intervention is referred to as CA125 +TVUS.
9 The first ROC determination is based on the absolute CA125 level and age-specific risk; subsequent ROC determinations are based on the absolute CA125 level and the rate of change in CA125.
Technical Report – Testing for ovarian cancer in asymptomatic women 18
Item PLCO UKCTOCS
UKCTOCS: strategies for ROCA ±TVUS (multimodal) and TVUS (ultrasound) screening
Source: NHS 2016 Figure 4, p11
Positive-screen follow-up
actions
Abnormal results for either test precipitated notification in
writing to the participant and their physician for standard
diagnostic and follow up procedures. If requested, referral
physicians were provided with standard-of-practice
guidelines for diagnostic procedures by the local PLCO
screening centre.
In both groups, women with persistent abnormalities had clinical assessment and additional investigations within the
NHS by a trial clinician.
On finding an adnexal abnormality, further evaluation was undertaken by a designated clinician, and included clinical
evaluation and investigations (serum CA125, repeat TVS and Doppler studies, CT/ MRI of the abdomen and pelvis and
occasionally assessment of other tumour markers) as appropriate. They had the option of conservative management in
cases where the features of the cyst were felt to be associated with a lower risk of EOC; the history included previous
hysterectomy/major pelvic surgery which could be responsible for the ultrasound appearance; or the participant was
asymptomatic and did not have other clinical findings suggestive of malignancy. The management plan took account
of the views of the individual woman, any significant comorbidity, the specific morphological features of the detected
lesion and history of a previous hysterectomy or major pelvic surgery that could be responsible for false-positive
ultrasound appearances. If surgery was not undertaken following clinical assessment, the women usually underwent
conservative management with follow-up and subsequent return to annual screening.
Comparator arm Usual care (no screening). Usual care (no screening).
Key outcomes reported Mortality due to OC
Ovarian cancer incidence
Cancer stage
Survival
Potential harms of screening
Mortality due to OC
Ovarian cancer incidence
Cancer stage
Physical morbidity due to surgical intervention attributable to screening
Psychological consequences of screening
Abbreviations: CT, computed tomography; EOC, epithelial ovarian cancer; HRT, hormone replacement therapy; IQR, interquartile range; MMS, multimodal screening; MRI, magnetic resonance imaging; NHS,
National Health Service; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RCT, randomised controlled trial; ROC, risk of ovarian cancer; ROCA, Risk of Ovarian Cancer
Algorithm; TVS/TVUS, transvaginal ultrasound; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
19 Technical Report – Testing for ovarian cancer in asymptomatic women
Cancer types included
Table 0.2 shows the ICD-10 codes for the three types of cancer included in the two RCTs of
population screening: ovarian cancer, fallopian tube cancer (FTC) and primary peritoneal cancer
(PPC). The UKCTOCS study included an additional category (undesignated) for cancers that were
either ovarian, tubal or peritoneal in origin, but could not be further delineated during the
interrogation of medical records.
The PLCO trial lists C56.9 as the ICD-10 code used for ovarian cancer while the UKCTOCS trial lists
the higher level code C56, under which sit C56.1 (left ovary), C56.2 (right ovary) and C56.9
(unspecified ovary). As described below, ascertainment of outcome in the PLCO trial involved
investigating all diagnoses of PLCO cancers, mostly via notifications from mailed surveys. Although
not stated, presumably all cancers described by respondents as ovarian were investigated,
regardless of which ICD-10 code may have been attributed to the malignancy. So it appears that
the use by the study authors of the specific C56.9 code to define ovarian cancer does not reflect
any limitation on the types of ovarian cancer included in this study.
The key difference between the trials regarding cancer types is the classification of borderline
tumours:
Invasive versus borderline epithelial ovarian tumours
PLCO – excludes epithelial ovarian borderline tumours (classified as false positives)
UKCTOCS – includes epithelial ovarian borderline tumours (classified as malignancies)
Nomenclature in this report:
ovarian cancer including borderline tumours – ovarian (all)
ovarian cancer excluding borderline tumours – ovarian (invasive).
Non-epithelial ovarian tumours
PLCO – does not specify inclusion or exclusion of non-epithelial ovarian tumours. In the current
Report, it is assumed that these tumours were not excluded in the PLCO trial, and that
reference to ‘primary invasive neoplasms of the ovary’ would include these cancers.
UKCTOCS – it is clearly stated that non-epithelial ovarian tumours are included as ovarian
cancer.
Cancer types included in analyses of the primary outcome
The primary analysis of the primary outcome in the UKCTOCS trial was restricted to ovarian cancers
and FTCs. The authors note that most peritoneal cancers are likely to be classified as tubal and
ovarian cancer ‘once wider acceptance of the World Health Organization (WHO) 2014 revision has
occurred’. Consequently, they also specified a secondary analysis of the primary outcome that
included all three cancer types.
The primary outcome in the PLCO trial included all three cancer types: invasive ovarian cancers,
FTCs and PPCs. In the report of extended follow up, an additional analysis was performed that
excluded peritoneal cancer, making this analysis more comparable to the primary outcome in the
UKCTOCS trial.
Technical Report – Testing for ovarian cancer in asymptomatic women 20
Table 0.2 Cancer types included in primary and secondary analyses of the primary
outcome in PLCO and UKCTOCS – OC-specific mortality
Code ICD-10 descriptor 1 analysis 2 analysis
PLCO UKCTOCS PLCO ext.
follow up
UKCTOCS
Ovarian
C5610 Malignant neoplasm of ovary
Fallopian tube
C57.0 Malignant neoplasm of fallopian tube
Peritoneal
C48.1/48.2 Malignant neoplasm of specified parts of
peritoneum/peritoneum, unspecified
Primary site undesignated
– Unable to delineate if primary site ovary or
fallopian tube or peritoneum
N/A N/A
Borderline tumours included as malignancy No Yes No Yes
Abbreviations: OC, ovarian cancer; N/A, not applicable; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; UKCTOCS,
United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Note: in the UKCTOCS study, ascertainment of outcome was performed on any women with one of 19 ICD-10 codes, who were reviewed for
re-classification into primary cancers of the ovary (C59), fallopian tube (C57.0), peritoneum (C48.1, C48.2), or undesignated (unclear whether
primary site is ovarian, tubal or peritoneal). In the PLCO study, ascertainment of outcome was performed on any women with any cancer
diagnosis. After censorship for the primary analysis (Feb 28th, 2010), no endpoint verification was performed, and the trial ascertained deaths
primarily through the National Death Index.
Notifications and ascertainment of outcomes
Key differences between the trials in the methods used to identify incident cancers and deaths
include the following:
Main sources for identification of ovarian cancer or death
PLCO – questionnaires mailed to participants (annual study update),11 supplemented with
searches of the National Death Index or, where possible, population-based cancer registries.
UKCTOCS – dataset linkage via NHS numbers allowed searches of cancer/death registries and
notifications by trial regional centres and treating hospitals. Supplemented with two mailed
questionnaires (3-5 years after randomisation and in April 2014).
Trigger for review of medical records for outcome verification
PLCO – ovarian cancer diagnosis or death indicated in returned questionnaire (annual study
update), or discovered in search of cancer or death registries.
UKCTOCS – discovery of any of 19 ICD-10 codes (Appendix E; Section E.1) in the linked cancer
or death registry records or medical records.
Definitions of select outcomes
A selection of definitions used in the two trials are shown in Appendix E (Section E.1). The key
differences between the two trials are:
10 C56.1, C56.2 and C56.9 are the three codes for malignant neoplasm of ovaries. While the PLCO study publication refers only to C56.9, the
mode of outcome ascertainment indicates all ovarian cancers would have been included. 11 Although one could expect substantially complete endpoint identification using the NDI, the PLCO trial uses an active approach as the
primary follow-up process to obtain more timely information and to promote contact with participants so as to enhance acquiring consent
and clinical follow-up information should a participant develop cancer or die.
21 Technical Report – Testing for ovarian cancer in asymptomatic women
Definition of prevalent cancers
PLCO – the terms ‘prevalent cancers’ or ‘prevalent screen’ are not used, but the number
diagnosed after the first round of screening were reported.
UKCTOCS – the term ‘prevalent cases’ is used, but does not refer to women diagnosed after
the first round of screening, but to women in the ROCA triage group estimated to have had
cancer prior to randomisation (backwards extrapolation of the ROCA).
Definition of false positives
PLCO – borderline ovarian cancers are false positives.
UKCTOCS – borderline ovarian cancers are malignancies (post hoc calculations also present
some results here for UKCTOCS with borderline ovarian cancer excluded i.e. false positive).
PLCO – any woman who proceeded to clinical assessment after a screen positive test but was
not diagnosed with ovarian cancer was regarded as a false positive, regardless of whether
surgery was undertaken (i.e. includes conservative management). However, false positives
who underwent surgery as part of the diagnostic workup were reported.
UKCTOCS – only women who underwent surgical intervention after a screen positive test but
were not diagnosed with ovarian cancer were regarded a false positive.
Table 0.3 Terminology and definitions of select outcomes – PLCO and UKCTOCS
Study ID Terminology
PLCO Cancers
True positives – diagnosed as a result of investigations initiated after a screening test with a positive result and without a
lapse in the diagnostic evaluation exceeding 9 months.
Prevalent cases – terminology not used, but category reported (detected as baseline screen).
Incident cases – terminology not used, but category reported (detected by screening at 1-5 years).
Interval cancers – cancers not detected by screening and diagnosed within 12 months of the woman’s last expected
screening examination.
Other Diagnoses
False positives – positive screening examination result that did not result in cancers detected by screening.
UKCTOCS Cancers
True positive – terminology not used.
Prevalent cases – cancers detected at first round of screening were not reported. Prevalent cases, defined as women
with ovarian cancer before screening started, were identified in the ROCA triage group for inclusion in a pre-specified
analysis by estimating whether the CA125 change point would have occurred prior to randomisation.
Incident cases – terminology not used, but screen positives was used to describe all screen-detected cancers, which
would include incident and prevalent cases.
Interval cancers (false negatives) – terminology not used, but category reported (detected in screen negatives < 1 year
from last test of screening episode).
Other diagnoses
False positive – benign adnexal pathology or normal adnexa in women who had screen-positive surgery.
Abbreviations: CA, cancer antigen; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROCA, Risk of Ovarian Cancer
Algorithm; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Key statistical methods
The statistical analysis methods used for the primary outcome are shown in Table 0.4. The key
difference is the statistical test pre-specified in the statistical analysis plan for the for the primary
analysis:
PLCO – weighted log-rank test
UKCTOCS – Cox proportional hazard model.
Technical Report – Testing for ovarian cancer in asymptomatic women 22
The implications of these choices are discussed in Section 4.1.2.1 (data extraction) and Section
5.1.1 (synthesis of findings).
Table 0.4 Key statistical analysis methods for mortality outcomes – population screening
Analysis PLCO UKCTOCS
Participants included in
primary analysis
Intention to screen population, excluding women
with a pretrial history of bilateral oophorectomy
(eligible for enrolment only after a change in
protocol in 1996).
Modified intention to screen – all randomly
allocated women except for those who we later
came to know had a bilateral oophorectomy,
ovarian cancer, or exited the registry before
recruitment.
Primary outcome –
OC-specific mortality
Included cancers:
ovarian
fallopian tube
primary peritoneal
Primary analysis
weighted log-rank test
The test statistic was a weighted log-rank statistic
with weights linear in cumulative mortality. Choice
of this combination of boundary and weights was
based on power computation conducted using
simulation methods. For early termination with a
negligible effect, a stochastic curtailment
procedure was implemented. This procedure
makes allowance for non-proportional hazards,
frequently encountered in a screening trial.
Included cancers – primary analysis:
ovarian
fallopian tube
Included cancers – secondary analysis:
ovarian
fallopian tube
primary peritoneal
Primary analysis
Cox proportional hazards model
Prespecified secondary analysis
Royston-Parmar (RP) model
The RP method can model proportional and non-
proportional hazards due to delayed effects.
Post hoc analysis
weighted log-rank test
The pre-specified analytic approach did not take
into account the inherent delay from
randomisation to diagnosis and then death. Other
screening trials (such as the PLCO Trial) addressed
this delay by using a weighted log-rank test for the
primary outcome analysis. In view of this
precedent, it was decided to perform a single post
hoc analysis of the primary outcome, applying the
weighted log-rank test with the same choice of
weights proportional to pooled ovarian cancer
mortality as that used in the primary PLCO trial
analysis.
Subgroup analysis of primary
outcome –
OC-specific mortality,
excluding prevalent cases
NR Included cancers:
ovarian
fallopian tube
Excludes prevalent cases – CA125 change point
estimated to have occurred prior to
randomisation, indicating the cancer was present
before screening began.
Prespecified subgroup analysis
Royston-Parmar (RP) model
Abbreviations: CA, cancer antigen; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; UKCTOCS,
United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Ongoing studies of population screening
The only ongoing study identified in the search of clinical trial databases was the long-term follow
up of UKCTOCS. As described in the NHS 2016 report (Detailed Project Description for the long-term
follow up of UKCTOCS), the primary outcome will remain unchanged from the original RCT, but the
classification of peritoneal cancers will be updated to reflect the new criteria in the WHO 2014
definition. This process will involve re-examination of all cancers diagnosed as PPC, and it is
expected that cases evaluated using the WHO 2003 criteria are likely to be re-classified as primarily
ovarian or tubal cancers. Stage as per International Federation of Gynecology and Obstetrics
(FIGO) 2014 will also be re-assessed.
23 Technical Report – Testing for ovarian cancer in asymptomatic women
After reclassification of these peritoneal cancers, the primary outcomes of UKCTOCS and PLCO will
be more closely aligned, as the PLCO trial analysed all three primary cancer types together
(ovarian, tubal and peritoneal). The next censorship for UKCTOCS is planned for December 2018,
and final censorship for December 2024. A major secondary outcome for the long-term follow-up is
cost-effectiveness of screening.
4.1.1.2 Key systematic reviews and HTAs
Three systematic reviews examined screening of asymptomatic women for ovarian cancer (Buhling
2017; Henderson 2017; Reade 2013). An additional two systematic reviews examined routine pelvic
examination screening for gynaecologic cancers (including ovarian cancer) and other
gynaecologic conditions (Guirguis-Blake 2017; Bloomfield 2014). The list of citations for the published
systematic reviews is shown in Appendix D (Section D.1.2).
Characteristics of systematic reviews and included studies
The key characteristics and quality of the identified systematic reviews is summarised in Table 0.5.
The systematic review by Henderson et al (2017) was prepared for the US Preventative Services Task
Force of the Agency for Healthcare Research and Quality (AHRQ) and provides a comprehensive
assessment of screening for ovarian cancer in asymptomatic women, published up to January
2017. This good quality systematic review includes the PLCO and UKCTOCS RCTs, as well as two
smaller RCTs published in 1999 and 2007. The authors comment that the rarity of ovarian cancer
necessitated a focus on mortality from ovarian cancer rather than on overall mortality from all-
causes because the effects of screening on overall mortality would be minor given that ovarian
cancers represent a very small proportion of deaths overall. Because ovarian cancer is rare, large
trials are necessary to evaluate effects of screening on ovarian cancer morbidity and mortality in
average-risk women.
Technical Report – Testing for ovarian cancer in asymptomatic women 24
Table 0.5 Key characteristics of systematic reviews relating to population screening for ovarian cancer
Study ID
Qualitya
Study aim Literature
search
Study eligibility Included studies (no. of
patients)
Intervention &
comparator
Outcomes of interest
Screening for ovarian cancer
Henderson
2017
Good
quality
To update the previous
systematic review and inform the
USPSTF OC screening guidance.
The review addresses two
questions: 1). Does screening for
OC in asymptomatic women
using a single test or combined
algorithm (such as, but not limited
to, testing for serum CA125 and
ultrasonography) reduce all-
cause or disease-specific
morbidity and mortality? 2). What
are the harms of screening for
OC, including harms of the
screening test and of diagnostic
evaluation?
Narrative synthesis of results, with
grading of the overall body of
evidence for each question using
an adaptation of a system based
on GRADE. Prepared for AHRQ.
Medline,
PubMed
Publisher-
Supplied
Records,
Cochrane
Collaboration
Registry of
Controlled
Trials;
reference lists
Search Jan
2003 to Jan
2017
Inclusion
RCTs
asymptomatic women aged 45+ with
average (or unknown) risk of OC
reported health outcomes
primary care setting (including obstetrics
and gynaecology practices)
English language articles
Exclusion
screening explicitly in high-risk populations
reported screening accuracy and cancer
detection rates without reporting
morbidity, mortality or quality of life
screening tests not evaluated in clinical
trials
specialty practice settings, such as
oncology
4 RCTs, published in 17 articles
(N=293,587)b:
UKCTOCS, Jacobs 2016
(N=202,546; UK; good quality)
PLCO, Buys 2011 (N=68,557;
US; good quality)
QUEST, Andersen 2007
(N=549; US; fair quality)
UK Pilot, Jacobs 1999
(N=21,935; UK; good quality)
Intervention
Any screening for OC
(alone or as part of a
clinical examination).
Includes (but not
limited to): testing for
CA125, TVUS, and
combined screening
approaches or
algorithms
Comparator
Usual care or no
screening
Different screening
methods or programs
Question 1
OC-specific mortality
all-cause mortality
cancer-related morbidity
quality of life
Question 2
surgery rate
FP screening results
complications of diagnostic
surgical procedures
health and psychological
effects of screening tests
Buhling
2017
Fair quality
To systematically analyse the
effect of TVUS in an
asymptomatic female population
as an annual screening
procedure with regard to
mortality data.
Studies evaluated descriptively
on their strengths and
weaknesses considering methods
and results.
PubMed,
Medline,
Embase
Search to
Dec 2015
Inclusion
RCTs with ethical approval
≥1 population-based intervention
screening group with annual TVS, ≥1 group
of post-menopausal women aged 45+
follow-up ≥3 years
no current symptoms associated with OC
no personal history of OC
English language articles
Exclusion
inaccurate description of methodology &
results
history of bilateral oophorectomy
OC diagnosed before registration
Jadad score <3/5
3 RCTs (N=363,341)b:
PLCO, Buys 2011 (N=68,557;
USA, 1993-2001)
UKCTOCS, Jacobs 2016
(N=202,546; UK, 2001-2014)
SCSOCS, Kobayashi 2008
(N=82,487; Japan, 1985-2002)
Intervention
Annual TVUS ± CA125
Comparator
Usual care
Overview of outcomes
reported in included studies;
for example:
compliance
repeat testing
need for clinical evaluation
cancers detected
diagnostic performance
(sensitivity, specificity, PPV,
FP rate, surgeries to detect
one cancer)
deaths due to OC or other
causes
relative mortality reduction
stage at diagnosis
25 Technical Report – Testing for ovarian cancer in asymptomatic women
Study ID
Qualitya
Study aim Literature
search
Study eligibility Included studies (no. of
patients)
Intervention &
comparator
Outcomes of interest
Reade
2013
Good
quality
To determine the risks and
benefits of OC screening in
asymptomatic women, with a
focus on mortality and
unnecessary surgery and its
consequences.
Evaluated confidence in effect
estimates using GRADE system for
each outcome. Meta-analysis of
some outcomes.
Medline,
Cinahl,
Embase,
CENTRAL;
reference
lists;
contacted
expert for
ongoing or
unpublished
trials
Search to
Feb 2012
Inclusion
RCTs
asymptomatic women at high or low risk of
OC
any language articles
10 RCTs:
Parkes 1994 (N=7124 c; UK)
Tabor 1994 (N=950 c;
Denmark)
Jacobs 1999 (N=21,935 c; UK)
Taylor 2004 (N=432 c; USA)
ROCA trial, Menon
2005(N=13,472 c; UK)
Johnson 2006 (N=522 c; USA)
QUEST trial, Andersen 2007
(N=592 c; UK)
SCSOCS trial, Kobayashi 2008
(N=82,487 c; Japan)
UKCTOCS trial, Menon 2009
(N=202,638 c; UK)
PLCO trial, Buys 2011
(N=78,216 c; USA)
Intervention
Any form of screening
for OC
Comparator
No intervention, usual
care, or education
regarding signs &
symptoms of OC
all-cause mortality
OC-specific mortality
surgeries performed to
detect one case of OC
FP screening tests
complications associated
with unnecessary surgery
OC diagnosed at an
advanced stage
worry or anxiety related to
OC risk
quality of life
Screening for gynaecologic cancers (including ovarian cancer)
Guirguis-
Blake 2017
Good
quality
To support the USPSTF in creating
its recommendation on the
periodic screening pelvic
examination.
The review addresses three
questions: 1) What is the direct
evidence for the effectiveness of
the pelvic examination in
reducing all-cause mortality,
cancer- and disease- specific
morbidity and mortality, and
improving quality of life? 2) What
are the test performance
characteristics of the pelvic
examination in screening for
gynecologic cancers and other
gynecologic conditions? 3) What
are the adverse effects of
screening using the pelvic
examination?
Qualitative synthesis prepared for
AHRQ.
Medline,
PubMed,
Cochrane
Central
Register of
Controlled
Trials;
reference
lists; grey
literature;
suggestions
from experts;
clinical trials
databases
Search to
Jan 2016
Inclusion
age ≥18 years, general unselected
females, asymptomatic, not pregnant,
women with or without hysterectomy, post-
menopausal women
primary care outpatient setting (or similar
applicable to primary care)
gynaecologic cancers and other
gynaecologic conditions
reported outcomes of interest
reported screening accuracy of the pelvic
examination in a single encounter or as a
periodic program of screening
English language articles
developed countries
Exclusion
studies conducted solely in symptomatic
populations
studies rated as poor quality
cervical cancer, gonorrhea, chlamydia
For OC
4 studies in total (N=26,432):
1 RCT (good quality)
PLCO
3 prospective diagnostic
accuracy studies (fair quality):
Adonokis 1996
Grover 1995
Jacobs 1988
Intervention
Pelvic examination
(external inspection,
internal speculum
examination, bimanual
examination,
rectovaginal
examination) ± other
tests for screening
Comparator
No pelvic examination;
reference standard
all-cause mortality
cancer-specific mortality or
morbidity for included
cancers
disease-specific morbidity
for included conditions
quality of life
diagnostic accuracy
(sensitivity, specificity,
likelihood ratios, PPV, NPV)
unnecessary diagnostic
workup or treatment
physical pain/discomfort
psychological harms
Technical Report – Testing for ovarian cancer in asymptomatic women 26
Study ID
Qualitya
Study aim Literature
search
Study eligibility Included studies (no. of
patients)
Intervention &
comparator
Outcomes of interest
Bloomfield
2014
Fair quality
To evaluate the benefits and
harms of routine screening pelvic
examination in asymptomatic,
nonpregnant adult women for
indications other than sexually
transmitted infection screening
before provision of hormonal
contraception and cervical
cancer screening.
Findings summarised in narrative
and tabular form.
Medline;
Cochrane
databases;
reference
lists;
suggestions
from expert
panel and
peer
reviewers
Search to
Jan 2014
Inclusion
asymptomatic, nonpregnant, average-risk
women
outpatient settings
reported outcomes of interest
screening for noncervical cancer, PID, or
other gynecologic conditions
English language, full text articles
Exclusion
cervical cancer screening
For OC
3 diagnostic accuracy cohort
studies (N=5633 patients; high
quality):
Grover 1995
Jacobs 1988
Adonakis 1996
Intervention
Pelvic examination
Comparator
No pelvic examination;
reference standard
diagnostic accuracy
(sensitivity, specificity, PPV,
NPV)
mortality or morbidity from
pathologic conditions
direct procedure-related
harms (physical
pain/discomfort)
indirect harms (false
reassurance, over-
diagnosis, over-treatment)
ancillary benefits
Abbreviations: AHRQ, Agency for Healthcare Research and Quality; CA, cancer antigen; FP, false positive; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; NPV, negative
predictive value; OC, ovarian cancer; PID, pelvic inflammatory disease; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPV, positive predictive value; QUEST, Quality of life, Education, and
Screening Trial; RCT, randomised controlled trial; SCSOCS, Shizuoka Cohort Study of Ovarian Cancer Screening; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian
Cancer Screening; USA, United States of America; USPSTF, US Preventive Services Task Force.
a Quality was assessed using AMSTAR (see Appendix F).
b N refers to total number of patients included in the analysis.
c N refers to total number of patients randomised.
27 Technical Report – Testing for ovarian cancer in asymptomatic women
4.1.2 Data extraction – clinical studies
4.1.2.1 Mortality outcomes
Primary outcome – death due to ovarian cancer
Table 0.6 shows all deaths due to ovarian cancer (OC-specific death), regardless of mode of
cancer detection, in each group of the PLCO and UKCTOCS trials. The PLCO trial does not include
borderline tumours as ovarian cancer while UKCTOCS does. However, given the low malignant
potential of these tumours, mortality outcomes are not expected to differ with their inclusion or
exclusion. The PLCO trial included PPCs in all analyses, while UKCTOCS present data with
(secondary analysis) and without (primary analysis) peritoneal cancers, both of which are shown in
Table 0.6.
In women diagnosed with ovarian cancer throughout these trials, mortality was similar in the
screening and no-screening groups in both trials, with no statistical significance to the differences in
ovarian cancer death rates using the tests pre-specified for the primary analyses.
Table 0.6 Death due to ovarian cancer – primary outcome in PLCO and UKCTOCS
OC-specific
mortality
PLCO – primary analysis12
OC (invasive), FTC, PPC
Weighted log-rank test (0-13 y)
UKCTOCS – secondary analysis
OC (all), FTC, PPC
Cox proportional hazard (0-14 y)
UKCTOCS – primary analysis
OC (all), FTC
Cox proportional hazard (0-14 y)
CA125
+TVUS
No
screening
ROCA
triage
TVUS No
screening
ROCA
triage
TVUS No
screening
Participants, n 34,253 34,304 50,624 50,623 101,299 50,624 50,623 101,299
Person-years 381,574 382,502 548,533 548,825 1,097,089 548,533 548,825 1,097,089
Deaths, n 118 100 160 163 358 148 154 347
OC death rate
(per 10,000
person-years)13
3.1 2.6 2.9 3.0 3.3 2.7 2.8 3.2
Risk estimate
[95% CI]
RR 1.18
[0.82, 1.71]
– HR 0.89
[0.74, 1.08]
HR 0.91
[0.76, 1.09]
– HR 0.85
[0.70, 1.03]
HR 0.89
[0.73, 1.07]
–
% mortality
reduction [95%
CI], p value
NR – 11% [–8, 26]
p=0.23
9% [–9, 24]
p=0.31
– 15% [–3, 30]
p=0.10
11% [–7, 27]
p=0.21
–
Abbreviations: CA, cancer antigen; CI, confidence interval; FTC, fallopian tube cancer; HR, hazard ratio; NR, not reported; OC, ovarian
cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer
Algorithm; RR, risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
In ovarian cancer screening trials, there is an inherent delay between detection and death – as
only women without symptoms or a diagnosis of ovarian cancer can enter the study, the first
deaths will be observed after subsequent diagnosis and disease progression. Figure 0.1 shows
cumulative mortality results from the UKCTOCS trial, showing the no-screening group hazard rate
continuing to rise throughout the study period, the ROCA triage group hazard rate levelling off,
becoming substantially lower than that of the no-screening group at about 7 years, and the TVUS
hazard rate levelling off at about 9 years. The study authors note this appears to indicate a delayed
effect of screening.
12 Longer-term follow up to December 2012 extended the median by 2.3 years to 14.7 years (Pinsky 2016). This additional data was collected in
a subset of patients who re-consented to further follow up after Feb 2010. The number of patients in this group is not reported but the
mortality analysis (Pinsky 2016, Figure 1) shows the number at risk in the intervention arm fell from 12,805 to 2,631 in the last two years of follow
up (similar numbers reported for the control arm). The risk of ovarian cancer death at longer-term follow up was no different between arms,
either including PPC (RR 1.06 [95% CI 0.87, 1.30]) or excluding PPC (RR 1.08 [0.87, 1.33]). 13 Calculated post hoc for UKCTOCS
Technical Report – Testing for ovarian cancer in asymptomatic women 28
Figure 0.1 Kaplan-Meier cumulative OC-specific mortality with and without PPC – UKCTOCS
Ovarian (all), FTC, PPC Ovarian (all), FTC
Source: Jacobs 2016 Figure 2A and B.
Abbreviations: CI, confidence interval; FTC, fallopian tube cancer; HR, hazard ratio; MMS, multimodal screening; OC, ovarian cancer; PPC,
primary peritoneal cancer; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening; USS, ultrasound screening.
The Cox proportional hazard model used for the primary analysis in the UKCTOCS trial assumes a
constant hazard event rate over time, and was considered by the study authors, in retrospect, to
be a poor choice of test for the primary analysis of mortality in a screening trial. Therefore, the
decision was made by the UKCTOCS investigators to conduct a post hoc analysis using the same
method as the PLCO study (weighted log-rank test).
An additional analysis of the primary outcome using the Royston-Parmer flexible parametric model
was pre-specified in the UKCTOCS protocol, and it also accounts for delayed effects. However, the
relative merits of each approach are beyond the understanding of the current Review authors.
These additional prespecified and post hoc analyses are shown in Table 0.7.
Again, these analyses are shown both with and without PPCs. When PPCs are included, neither the
Royston-Parmer model or weighted log rank test found a statistically significant difference between
no screening and either of the screening groups in UKCTOCS. When women with PPCs were
excluded from the analysis, statistically significance was achieved, showing screening improved
mortality rates for the following:
Royston-Parmer model for the period 7-14 years from randomisation – ROCA triage better
than no screening, in the detection of invasive ovarian cancer, borderline ovarian cancer
and FTC (23% reduction in mortality [95% CI: 1%, 46%]).
Weighted log-rank test (0-14 years from randomisation) – ROCA triage better than no
screening in the detection of ovarian cancer, borderline ovarian cancer and FTC (22%
reduction in mortality [95% CI: 3%, 38%], p=0.023).
Weighted log-rank test (0-14 years from randomisation) – annual TVUS better than no
screening in the detection of ovarian cancer, borderline ovarian cancer and FTC (20%
reduction in mortality [95% CI: 0%, 35%], p=0.049).
29 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.7 Death due to ovarian cancer – primary outcome analyses accounting for
delayed effects of screening in UKCTOCS
OC-specific mortality UKCTOCS – secondary analysis
OC (all), FTC, PPC
UKCTOCS – primary analysis
OC (all), FTC
ROCA
triage
TVUS No
screening
ROCA
triage
TVUS No
screening
Participants, n 50,624 50,623 101,299 50,624 50,623 101,299
Deaths, n 160 163 358 148 154 347
Royston-Parmer model (pre-specified
analysis)
% reduction in mortality [95% CI]
p-value: 0-14 years
11% [–7, 28]
p=0.15
10% [–8, 27]
p=0.27
– 16% [–1, 33]
p=0.11
12% [–6, 29]
p=0.18
–
Split by time since randomisation
0-7 years 4% [–25, 27] 2% [–26, 26] – 8% [–20, 31] 2% [–27, 26] –
7-14 years 18% [–5, 40] 17% [–8, 38] – 23% [1, 46] 21% [–2, 42] –
Weighted log-rank test (post hoc
analysis)
% reduction in mortality [95% CI]
p-value: 0-14 years
18% [–1, 34]
p=0.064
17% [–3, 33]
p=0.097
– 22% [3, 38]
p= 0.023
20% [0, 35]
p=0.049
–
Abbreviations: CI, confidence interval; FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, Risk of
Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
These various analyses of mortality in the UKCTOCS trial are also illustrated in the form of forest plots
(Figure 0.2). A survival curve from the PLCO trial is shown in Appendix E (Section E.1).
Figure 0.2 Forest plot display of various mortality analyses for ROCA triage – UKCTOCS
ROCA triage TVUS
Source: NHS 2016, Figure 2, p8
Abbreviations: MMS, multimodal screening; NHS, National Health Service; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal
ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening; USS, ultrasound screening.
Subgroup analysis of primary outcome – exclusion of prevalent cases in UKCTOCS
The UKCTOCS study prespecified a subgroup analysis of the primary outcome excluding cases of
ovarian cancer deemed to have developed prior to randomisation (i.e. prevalent cases). The
UKCTOCS study publication did not define prevalent cases as those identified in the first round of
screening. Instead, the serial levels of CA125 were analysed in the ROCA triage group in order to
estimate the time at which they are likely to have started to rise, and women deemed to have had
rising CA125 levels prior to randomisation were designated as prevalent cases. By excluding these
cases from the ROCA triage group, the study investigators were intending to assess mortality for
incident cases only, which may be more representative of ongoing screening.
Baseline CA125 levels were also available in 517 of the 63014 women with ovarian cancer, and
along with CA125 levels at diagnosis, women in the no-screening group appearing to have had
14 Ovarian cancer, including borderline, or FTC (i.e. excludes PPC)
Technical Report – Testing for ovarian cancer in asymptomatic women 30
rising CA125 levels prior to randomisation were designated as prevalent cases. No analysis of this
type was performed for the TVUS group. This process excluded an average of 19% of the 338 cases
of cancer in the ROCA triage group and an average of 18% of the 630 cases in the no-screening
group (for all cancers, excluding PPCs).
The Royston-Parmer model was used to derive hazard ratios for cumulative mortality up to 14 years
after randomisation (Table 0.8). Significant improvements in mortality were observed in the ROCA
triage group compared with no screening, both with peritoneal cancers (16%) and without
peritoneal cancers (20%).
Table 0.8 OC-specific mortality excluding prevalent cases, for ROCA triage versus no
screening – UKCTOCS
OC-specific mortality excluding
prevalent cases
UKCTOCS – 2 analysis
OC (all), FTC, PPC
UKCTOCS – 1 analysis
OC (all), FTC
ROCA triage No screening ROCA triage No screening
Participants, n 50,561 101,191 50,561 101,183
Deaths, n 131 298 120 281
% mortality reduction [95% CI]
Royston-Parmer model
0-14 years 16% [–6, 35]
p=0.047
– 20% [–2, 40]
p=0.021
Abbreviations: CI, confidence interval; FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, Risk of
Ovarian Cancer Algorithm; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Note: BOLD indicates statistically significant result.
All-other-cause mortality
In both the PLCO and UKCTOCS trials, all-cause mortality, excluding that due to ovarian cancer,
was no different between the no-screening and screening groups (Table 0.9).
Table 0.9 All-other-cause mortality – PLCO and UKCTOCS
Mortality over period of study PLCO UKCTOCS
CA125 +TVUS No screening ROCA triage TVUS No screening
Participants, n 34,253 34,304 50,624 50,623 101,299
All-other-cause mortality15
Deaths, n 2,924 2,914 3,376 3,262 6,658
Person-years 381,574 382,502 548,533 548,825 1,097,089
Mortality per 10,000 person-years16 76.6 76.2 61.5 59.4 60.7
Risk estimate [95% CI] RR 1.01
[0.96, 1.06]
– RR 0.9917
[CI NR] p = 0.65
–
Abbreviations: CA, cancer antigen; CI, confidence interval; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer
Screening Trial; ROCA, Risk of Ovarian Cancer Algorithm; RR, risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom
Collaborative Trial of Ovarian Cancer Screening.
4.1.2.2 Detection outcomes
Mode of detection
Table 0.10 shows the detection outcomes for the screening arms in the PLCO and UKCTOCS trials.
To allow a meaningful comparison with PLCO, the UKCTOCS data are presented with peritoneal
cancers included but borderline tumours excluded. The results for UKCTOCS including all
malignancies as defined by that study (i.e. including borderline tumours and PPCs) are also shown.
15 Excludes ovarian cancer, FTC and PPC. In PLCO also excludes colorectal and lung cancers. 16 Calculated post hoc for UKCTOCS. 17 RR for combined CA125 (±TVUS) and TVUS groups versus no screening.
31 Technical Report – Testing for ovarian cancer in asymptomatic women
Cancers for all women randomised to screening who attended at least one screening round are
shown by the phase of study in which diagnosis occurred: during the screening phase, or after the
screening phase. A larger proportion of these diagnoses were made during the screening phase in
UKCTOCS (83-87%), compared with PLCO (59%).
For cancers diagnosed during the screening phase, the proportion that were screen-detected (i.e.
not interval cancers) was around three quarters in the UKCTOC ROCA triage group, around two
thirds in the PLCO screening group, and around half in the UKCTOCS TVUS group. The UKCTOCS
study further classifies interval cancers into those detected within a year of a negative test and
those detected at a delayed routine trial screen (i.e. over a year between prior negative test and
abnormal test leading to diagnosis). Approximately half of the interval cancers in both UKCTOCS
screening groups were detected at a delayed trial screen.
Table 0.10 Mode of cancer detection in screening groups – PLCO and UKCTOCS
Detection outcomes
n (%)
PLCO
OC (invasive), FTC, PPC
UKCTOCS
OC (invasive), FTC, PPC
UKCTOCS
OC (all), FTC, PPC
CA125 +TVUS ROCA triage TVUS ROCA triage TVUS
Total cancers diagnosed, N (%) 212 310 271 354 324
Never attended screening 24 3 11 3 13
All diagnoses in women who attended
at least one screening round 188 (100) 307 (100) 260 (100) 351 (100) 311 (100)
Diagnosed during screening phase18 110 (59) 255 (83) 226 (87) 294 (84) 277 (89)
Diagnosed after screening phase 78 (41) 52 (17) 34 (13) 57 (16) 34 (11)
During screening phase 110 (100) 255 (100) 226 (100) 294 (100) 277 (100)
Screen-detected 73 (66) 188 (74) 116 (51) 212 (72) 164 (59)
Prevalent screen 20 NR NR NR NR
Subsequent screens 53 NR NR NR NR
Not screen detected – interval
cancers 37 (34) 67 (26) 110 (49) 82 (28) 113 (41)
Detected < 1 year since previous
trial screen NR 31 61 41 63
Detected >1 year since previous
trial screen i.e. delayed trial screen NR 36 49 41 50
Note: N and % calculated post hoc for many data in this table, using data reported in study publications.
Abbreviations: CA, cancer antigen; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROCA, Risk of
Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Incidence data are shown in Table 0.11, for the screening and no-screening groups of both trials.
Rates were similar between screening and no-screening groups.
18 Events up to one year after the last trial screen are included in the screening phase for UKCTOCS, and up to 9 months in the PLCO trial.
Technical Report – Testing for ovarian cancer in asymptomatic women 32
Table 0.11 Ovarian cancer incidence – PLCO and UKCTOCS
Detection outcomes
n (%)
PLCO
OC (invasive), FTC, PPC
UKCTOCS
OC (invasive), FTC, PPC
UKCTOCS
OC (all), FTC, PPC
CA125
+TVUS
No
screening
ROCA
triage
TVUS No
screening
ROCA
triage
TVUS No
screening
Total cancers detected,
N 212 176 310 271 583 354 324 645
Person-years 371,833 374,976 548 533 548,825 1,097,089 548 533 548,825 1,097,089
Incidence
Overall incidence per
10,000 person-years
[95% CI]
5.7
[NR]
4.7
[NR]
5.5
[4.8, 5.7]
4.7
[4.1, 5.3]
5.2
[4.8, 6.1]
6.2
[5.5, 6.8]
5.7
[5.1, 6.4]
5.7
[5.3, 6.2]
Risk estimate for
between-group
difference [95% CI]
RR 1.21
[0.99, 1.48] no statistical difference between groups no statistical difference between groups
Abbreviations: CA, cancer antigen; CI, confidence interval; NR, not reported; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and
Ovarian Cancer Screening Trial; ROCA, Risk of Ovarian Cancer Algorithm; RR, risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United
Kingdom Collaborative Trial of Ovarian Cancer Screening.
Sensitivity
Sensitivity estimates are shown for each of the screening groups in Table 0.12. Post hoc calculations
were performed to allow comparison between trials for invasive cancers. As expected, sensitivity is
reduced by the omission of borderline tumours in the UKCTOCS trial. The most sensitive test was the
UKCTOCS ROCA triage group.
Table 0.12 Sensitivity of screening strategies – PLCO and UKCTOCS
Outcome PLCO
OC (invasive),
FTC, PPC
UKCTOCS
OC (invasive), FTC, PPC OC (all), FTC PPC
CA125 +TVUS ROCA triage TVUS ROCA triage TVUS ROCA triage TVUS
Screen +ve
cancers, n 73 188 116 199 161 13 3
Interval cancers, n 37 67 110 38 60 3 3
Sensitivity % [95%
CI], n/N
66%
[NR]
73/
(73+37)
74%
[NR]
188/
(188+67)
51%
[NR]
116/
(166+110)
84%
[79, 88]
199/
(199+38)
73%
[66, 79]
161/
(161+60)
81%
[NR]
13/
(13+3)
50%
[NR]19
3/
(3+3)
Abbreviations: CA, cancer antigen; CI, confidence interval; FTC, fallopian tube cancer; NR, not reported; OC, ovarian cancer; PLCO,
Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm; RR,
risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Note: sensitivity rates shown without confidence intervals were calculated post hoc using data in table.
False positives
Definitions for screen positive and false positive differed between the two trials. In both trials,
women who had a screen-positive test followed by surgery and a finding of no cancer were
deemed false positives, but in the PLCO trial, those women who underwent clinical assessment
after a screen-positive test and did not have surgery (i.e. conservative management, deemed not
to require further investigation) were also considered false positives. In the PLCO trial, 3,285 women
had false-positive testing results, of which 1,080 had received surgery.
Table 0.13 shows the number of screen-positive surgeries with benign or normal pathology (false-
positive surgeries) and the number of screen-positive surgeries with ovarian cancer, FTC or PPC
(screen-positive cancers). For PLCO, borderline tumours were counted as false-positive surgeries
19 The primary study publication (Jacobs 2016) reports this result as 3/10 peritoneal cancers were screen detected. However, this denominator
of 10 includes 4 cancers detected over a year after the last screening episode – such cancers were not included in the calculations of
sensitivity for any other groups.
33 Technical Report – Testing for ovarian cancer in asymptomatic women
and for UKCTOCS they were screen-detected cancers. To allow a meaningful comparison of false-
positive rates between trials, post hoc calculations were performed re-classifying borderline
tumours in UKCTOCS as false positives, reducing the number of screen detected cancers by 34 in
the ROCA triage group and 50 in the TVUS group.
When all borderline tumours are classified as false positives, the false-positive surgery rate was the
same in PLCO and the TVUS screening group of UKCTOCS (both 14.8 false-positive surgeries per
screen-detected cancer, corresponding to a low positive predictive value ([PPV] of 6.3%20). The
lowest rate was substantially lower; at 2.9 per screen-detected cancer, the ROCA triage arm of
UKCTOCS trial had a PPV of 25.4%21, exceeding the standard goal of 10% PPV (no more than nine
false positive surgeries per case of screen-detected cancer (NASEM 2016)).
Table 0.13 False-positive surgery rates – PLCO and UKCTOCS
Outcome PLCO
OC (invasive), FTC, PPC
UKCTOCS
OC (all), FTC, PPC
UKCTOCS – reclassify borderline as
false positive as per PLCO22
OC (invasive), FTC, PPC
CA125 +TVUS ROCA triage TVUS ROCA triage TVUS
Screen-positive surgeries, n 1,153 700 1,798 700 1,798
False positive surgeries23 1,080 488 1,634 522 1,684
Screen-detected cancers 73 212 164 178 114
Number of surgeries to detect
one case of cancer
15.8
(1,153/73)
3.3
(700/212)
11.0
(1,798/164)
3.9
(700/178)
15.8
(1,798/114)
Number of false positive
surgeries per screen-detected
cancer
14.8
(1,080/73)
2.3
(488/212)
10.0
(1,634/164)
2.9
(522/178)
14.8
(1,684/114)
Person-years of screening 371,833 345,572 327,775 345,572 327,775
Number of false positive
surgeries per 10,000 screens
2924 14 50 15 51
Abbreviations: CA, cancer antigen; FTC, fallopian tube cancer; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer
Screening Trial; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS,
United Kingdom Collaborative Trial of Ovarian Cancer Screening.
4.1.2.3 Tumour characteristics
Table 0.14 shows stage at diagnosis in both the PLCO and UKCTOCS trials. In each study group, the
majority of cancers were late stage (Stage III or Stage IV); 77-78% in the PLCO study and 55-69% in
UKCTOCS. When borderline epithelial ovarian cancers were excluded, the proportion of late-stage
tumours in UKCTOCS was reduced to 62-75% – closer to levels in the PLCO trial. Results for UKCTOCS
were calculated post hoc from stage-at-diagnosis data reported in the Jacobs 2016 online
supplement for the following four cancer groups: (1) invasive epithelial ovarian/ tubal/
undesignated cancer;25 (2) non-epithelial ovarian cancer; (3) borderline epithelial ovarian cancer;
and (4) peritoneal cancer (reproduced in Appendix E.1, Table AppE.3).
20 Calculated post hoc from data in Table 0.13. 21 Calculated post hoc from data in Table 0.13. 22 Borderline tumours excluded in post hoc calculations by current Review authors: ROCA triage n = 34; TVU n = 50. 23 Of 3,285 with false-positive results, 1,080 underwent surgery as part of the diagnostic workup. 24 Calculated post hoc. 25 Shown for Stages Ia-c, IIa-c and IIIa-c.
Technical Report – Testing for ovarian cancer in asymptomatic women 34
Table 0.14 Cancer stage at diagnosis, all modes of detection – PLCO and UKCTOCS
Tumours by
stage, n (%)
PLCO
OC (invasive), FTC, PPC
UKCTOCS
OC (all), FTC, PPC
UKCTOCS
OC (invasive), FTC, PPC26
TVUS
No
screening
ROCA
triage TVUS
No
screening
ROCA
triage TVUS
No
screening
Total cancers
diagnosed 212 (100) 176 (100) 354 (100) 324 (100) 644 (100) 310 (100) 271 (100) 582 (100)
Stage at diagnosis
I 32 (15) 18 (10) 127 (36) 99 (31) 147 (23) 86 (28) 49 (18) 98 (17)
II 15 (7) 20 (11) 32 (9) 19 (6) 51 (8) 32 (10) 19 (7) 47 (8)
III 120 (57) 83 (47) 160 (45) 154 (48) 333 (52) 157 (51) 151 (56) 324 (56)
IV 43 (20) 54 (31)27 34 (10) 52 (16) 112 (17) 34 (11) 52 (19) 112 (19)
Unknown 2 (1) 1 (1) 1 (0) 0 (0) 2 (0) 1 (0) 0 (0) 1 (0)
Combined stages, known volume28
Early (I or II) 47 (22) 38 (22) 159 (45) 118 (36) 198 (31) 118 (38) 68 (25) 145 (25)
Late (III or IV) 163 (77) 137 (78) 194 (55) 206 (64) 445 (69) 191 (62) 203 (75) 436 (75)
Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC,
primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom
Collaborative Trial of Ovarian Cancer Screening.
Stage shift
The authors of the PLCO primary study publication concluded that screening did not result in a
stage shift for ovarian cancer diagnoses. They noted that the total number of advanced stage
cancers was greater in the screening group (n=163) than in the usual care group (n=137), and that
this was also the case when limiting the comparison to the screening phase of the trial. Considering
only screen-detected cancers in the screening group, 69% of cases were late stage compared to
the only ‘slightly higher’ 78% of the usual care group (no statistical analyses were reported).
The FIGO staging system classifies ovarian cancers according to the degree of spread, with early
stages confined to the ovaries or pelvis (Table 0.15). The UKCTOCS investigators have analysed
stage shift by comparing malignancies categorised according to the volume of metastatic
peritoneal disease, with cancers at Stage IIIa or less referred to as low volume and those more
advanced than Stage IIIa as high volume cancers.
Table 0.15 FIGO staging of ovarian cancer
Category Stage Characteristics of malignancy UKCTOCS
categories29
Early Stage I Confined to ovary
Low volume Stage II Spread to pelvis
Late
Stage III Peritoneal metastasis outside the pelvis
Stage IIIa Microscopic peritoneal metastasis (no macroscopic tumor)
Stage IIIb Macroscopic peritoneal metastasis (≤ 2 cm)
High volume Stage IIIc Macroscopic peritoneal metastasis (>2 cm and/or regional lymph node metastasis)
Stage IV Spread beyond abdominal organs
Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer
Screening.
Table 0.16 shows UKCTOCS data for all cancers except non-epithelial ovarian cancer and
borderline epithelial ovarian cancer. It is for this population that the sole statistical analysis
26 Data calculated post hoc for this group of cancers, using data from the Jacobs 2016 online supplement. 27 Difference between TVUS and no screening in number of Stage IV cancers is not statistically significant. 28 Calculated post hoc from data reported in this table. 29 Categorisation as low or high volume taken from the UKCTOCS primary study publication (Jacobs 2016).
35 Technical Report – Testing for ovarian cancer in asymptomatic women
regarding potential stage shift is reported in this study. The authors found that significantly more
tumours were of low volume in the ROCA triage group compared to the no-screening group.
A systematic review prepared for the AHRQ (Henderson 2017) notes that statistically significant
stage shifts were observed for early stage disease (Stages I and II) and even at the localised stage
(Stage I; p<0.005). This was readily confirmed in Review Manager by the current Review authors for
the data in the table below and also for the other tumour type groups shown above in Table 0.15. It
is not clear why this was not reported in the UKCTOCS study publication.
Table 0.16 Low versus high volume tumours at diagnosis, all modes of detection – UKCTOCS
Tumours by stage, n (%) UKCTOCS
OC (invasive epithelial only30), FTC, PPC
ROCA triage TVUS No screening
Total cancers, n (%) 299 (100) 259 (100) 574 (100)
Early vs late stage at diagnosis31
Stage I or II 108 (36) 58 (22) 137 (24)
Stage III or IV or unstaged 191 (64)32 201 (78) 437 (76)32
Low vs high volume at diagnosis33
Stage I or II or IIIa 119 (40) 62 (24) 149 (26)
Stage IIIb or IIIc or IV or unstaged 180 (60) 197 (76) 425 (74)
Between-group differences for low vs high volume
ROCA triage vs no screening p < 0.0001 – –
TVUS vs no screening – p=0.57 –
Note: one cancer in the ROCA triage group and one cancer in the no screening group could not be staged. These cancers were excluded
from the early vs late stage analyses but included as high-volume cancers in the Jacobs 2016 analysis of low vs high volume.
Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm;
TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Stage at diagnosis by phase of study
The PLCO study reported stage at diagnosis by phase of study (screening phase versus post-
screening phase). There was no significant association between study period and stage distribution;
76% of intervention group cases diagnosed during the screening phase of the study (years 0-5)
were Stage III or IV compared with 79% of those diagnosed during the post-screening phase.
4.1.2.4 Quality-of-life outcomes
The impact of an abnormal screen test result and surgery on anxiety, psychological morbidity
(Barrett 2014) and sexual functioning (Fallowfield 2017) was investigated in the UKCTOCS trial using
the following validated instruments:
State/Trait Anxiety Inventory (STAI) – score range 20 to 80
General Health Questionnaire 12 (GHQ-12) – score range 1 to 12, dichotomised with ≥4
signifying probable psychological morbidity
Fallowfield’s Sexual Activity Questionnaire (FSAQ) – 3 domains (range of scores): Pleasure
(0-18); Discomfort (0-6); Habit (0-3).
30 Excludes non-epithelial tumours as well as borderline tumours. 31 Data abstracted (with post hoc calculations) from results reported in Jacobs 2016 online supplement, Web Table 3. One tumour was not
able to be staged. 32 Includes one tumour not able to be staged. 33 Data abstracted (with post hoc calculations) from results reported in Jacobs 2016 study publication.
Technical Report – Testing for ovarian cancer in asymptomatic women 36
Each of the two screening interventions included two levels of follow-up testing:
ROCA triage
o Level 1 – repeat blood test
o Level 2 – repeat blood test and TVUS
TVUS
o Level 1 – repeat TVUS and by a senior ultrasonographer or consultant
o Level 2 – repeat TVUS or biopsy.
Among women recalled for repeat screening, the effect on anxiety was statistically significant
(mean difference 0.37 [95% CI: 0.23, 0.51; p< 0.01]) but with a range of scores from 20 to 80 with the
STAI, this was considered too small to be of clinical significance (the authors note the large size of
the study led to detection of very small changes). An effect on psychological morbidity was
evident when recalled for a Level 2 screen (chance of returning a GHQ-12 score ≥ 4: OR 1.28 [95%
CI: 1.18, 1.39)].
Surgery prompted by abnormal test results increased anxiety compared with routine screening, at
both 6 weeks (mean difference -1.1 [95% CI: -1.6, -0.59]) and 6 months (-1.23 [95% CI: -1.71, -0.75])
after surgery. Among women who returned to routine screening after surgery, anxiety levels
returned to normal after 6 months, but not surprisingly increased for women diagnosed with ovarian
cancer (3.21 [95% CI: 1.62, 4.80]).
Among women recalled for further tests, significant differences in sexual activity were found
between the ROCA triage group (n=12,810) and the annual TVUS group (n=10,156), with the TVUS
group having lower pleasure scores; mean difference -0.14, p=0.046 (instrument range 0-18).
Comparing all women in either screening group who were recalled for Level I screens only, those
recalled for Level II tests had significantly lower pleasure scores (-0.16, p=0.005).
The authors of these two studies concluded that screening for ovarian cancer does not increase
anxiety in general, especially when compared with the variation in anxiety levels that occur within
individuals. Psychological morbidity is slightly elevated by higher levels of secondary testing
following annual screening, and was unremitting for those diagnosed with ovarian cancer. They
found that ovarian cancer screening did not affect sexual activity and functioning unless a woman
had abnormal results and underwent repeated or higher level screening.
4.1.2.5 Safety outcomes
Complications associated with screening
In the PLCO trial, complications were reported separately for the two tests used in the single
screening group. The screening-related complication rate was higher for the CA125 blood test than
for TVUS, and is much higher than the rates in the UKCTOCS trial groups. It is possible that in the
PLCO trial, this outcome is actually the number of complications reported rather than the number
of women reporting complications. 34
34 The only data for this outcome is reported by the authors in the following statement: ‘Minor complications such as fainting and bruising
occurred at a rate of 58.3 per 10 000 women screened with CA125 and 3.3 per 10 000 women screened with transvaginal ultrasound’.
37 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.17 Complications associated with screening tests – PLCO and UKCTOCS
Screening-related complications PLCO UKCTOCS
CA125 TVUS ROCA triage TVUS
Participants, n (%) 34,253 34,253 50,624 50,623
Number of women reporting a complication NR NR 30 (<1%) 61 (<1%)
Number of women reporting complications per 10,000
women screened35 58.3 3.3 0.86 1.86
Abbreviations: CA, cancer antigen; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROCA, Risk of
Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.
Complications associated with unnecessary surgery
The proportion of women experiencing complications associated with false-positive surgery was
substantially greater in the PLCO study than in UKCTOCS. Insufficient information is available for the
PLCO study to compare the seriousness of the complications reported, which may account for
some of the difference.
Table 0.18 Complications associated with unnecessary surgery – PLCO and UKCTOCS
Unnecessary surgery outcomes PLCO UKCTOCS
CA125 +TVUS ROCA triage TVUS
Benign or normal pathology after screen positive surgery, n 1,080 488 1634
Number of women reporting complications 163 15 57
Number of complications reported36 222 NR NR
Proportion of women experiencing complications after
false-positive surgery, % [95% CI]
15%
[NR]
3.1%
[1.7, 5.0]
3.5%
[2.7, 4.5]
Complication rate associated with false-positive surgery,
(events per 100 surgical procedures) 20.6 NR NR
Abbreviations: CA, cancer antigen; CI, confidence interval; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer
Screening Trial; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of
Ovarian Cancer Screening.
Complication rates associated with surgery for benign or normal pathology were not reported for
the no screening groups of these trials. Major complications associated with ‘diagnostic
procedures’ was reported for PLCO, with 95/212 (45%) in the screening group and 91/176 (52%) in
the no-screening group experiencing at least 1 major complication (i.e. infection, blood loss, bowel
injury, cardiovascular events).
The UKCTOCS trial reported that outside of the trial, women had both ovaries or the only remaining
ovary removed for a range of indications and had benign pathology or normal adnexa, which
occurred at similar rates in all three study groups (0.8%-0.9%). Data for associated complication
rates for these surgeries were not available.
4.1.2.6 Economic analyses
Two economic analyses have been published on ovarian cancer population screening, both
evaluating the UKCTOCS trial. The study authors of both analyses conclude that longer follow up of
the UKCTOCS mortality data is necessary before screening could be recommended on economic
grounds.
35 For PLCO, this outcome may actually be the number of complications reported rather than the number of women reporting complications. 36 Some women reported more than one complication. In PLCO all complications are included in this analysis; in UKCTOCS only the most
serious complication was reported in women with more than one complication (i.e. the total number of complications associated with false-
positive surgery is not reported in UKCTOCS).
Technical Report – Testing for ovarian cancer in asymptomatic women 38
The authors of the model-based economic evaluation published by Kearns et al (2016) were from
the University of Sheffield and the University of Exeter. They based their model on information in the
public domain at the time, which included the primary study publication (Jacobs 2016).
The authors concluded the following:
Based on 11 years of follow-up we estimated that screening is not cost-effective, as
the mortality benefit is outweighed by the dis-benefits associated with both treating
false positives and earlier treatment of women with ovarian cancer. In contrast,
lifetime cost-effectiveness results are promising, with an estimated ICER comparing
[ROCA triage] with no screening of £8864 per [quality-adjusted life year] QALY (95%
confidence interval £2600 to £51,576).
They noted, however, that there was substantial uncertainty in the long-term effectiveness of ROCA
triage in reducing mortality, which is a key driver of cost-effectiveness (the non-significant effect on
mortality reported in the trial publication was used in the model).
The second economic evaluation was published by UKCTOCS investigators (Menon 2017), who
noted that the ‘long-lead time associated with establishing mortality benefit from ovarian cancer
screening has meant that the full benefits to be realised from such a programme have not been
established authoritatively’.
The following model estimates were reported:
Using a CA125–ROCA cost of £20, the within-trial results show [TVUS] to be strictly
dominated by [ROCA triage], with the [ROCA triage] vs [no screening] comparison
returning an incremental cost-effectiveness ratio (ICER) of £91,452 per life year
gained (LYG). If the CA125–ROCA unit cost is reduced to £15, the ICER becomes
£77,818 per LYG. Predictive extrapolation over the expected lifetime of the
UKCTOCS women returns an ICER of £30,033 per LYG, while Markov modelling
produces an ICER of £46,922 per QALY.
In the final conclusion they note the following:
Analysis suggests that, after accounting for the lead time required to establish full
mortality benefits, a national [ovarian cancer screening] programme based on the
[ROCA triage] strategy quickly approaches the current NICE thresholds for cost-
effectiveness when extrapolated out to lifetime as compared with the within-trial
ICER estimates.
A public health programme of screening for ovarian cancer could become cost-
effective within an NHS setting if the mortality benefit from screening continues to
increase over time. Any definitive conclusion as to whether [ROCA triage] could be
recommended on economic grounds would depend on the confirmation and size
of the mortality benefit at the end of ongoing follow-up of the UKCTOCS cohort.
When UKCTOCS long term follow up is reported, it is expected these analyses will be repeated.
4.1.3 Data extraction – systematic reviews and HTAs
The Henderson 2017 Evidence Synthesis prepared for the AHRQ is the most recent and
comprehensive of the published systematic reviews. The authors reanalysed the data reported in
the clinical trial publications to account for (1) the WHO revised classification of tumours of the
reproductive system37; (2) differences between RCTs in the calculation of false positive rates. The
37 In 2014, WHO revised the classification of tumours of the female reproductive system. Following these revisions, most cancers historically
classified as peritoneal cancer would be reclassified as ovarian and tubal cancers.
39 Technical Report – Testing for ovarian cancer in asymptomatic women
Evidence Synthesis considers data from four included RCTs: PLCO, UKCTOCS, UK Pilot, and QUEST.
The three larger trials (PLCO, UKCTOCS and the UK Pilot) were rated as good-quality. The smaller
QUEST trial, which only reported on psychological harms of screening, was rated as fair-quality. The
screening tests evaluated across the four trials were:
annual TVUS (UKCTOCS)
annual TVUS and CA125 serum testing (PLCO, QUEST)
annual CA125 testing (UK Pilot)
annual CA125 serum testing interpreted with an algorithm (ROCA) that incorporates changes
over time to inform triage and rescreening intervals (UKCTOCS).
The Shizuoka Cohort Study of Ovarian Cancer Screening and Shizuoka Cancer Registry (SCSOCS
trial) was not included in the Henderson 2017 Evidence Synthesis because health outcomes have
not been reported for that trial.
4.1.3.1 Mortality
The evidence summary in Table 0.19 relates to the Henderson 2017 Evidence Synthesis question:
Does screening for ovarian cancer in asymptomatic women using a single test or combined
algorithm (such as, but not limited to, testing for serum CA125 and ultrasonography) reduce all-
cause or disease-specific morbidity and mortality?
In summary, the three trials reporting mortality outcomes (PLCO, UKCTOCS, UK Pilot) had null
findings based on a priori per protocol statistical analyses testing four screening programs for
ovarian cancer. The PLCO and UKCTOCS were designed with statistical power to detect a 30 to 35
percent difference in mortality from this relatively rare but often fatal cancer, and had null findings
in primary analyses. The UK Pilot trial reported mortality outcomes, but was designed to examine the
feasibility of screening and was underpowered to detect a mortality difference.
The UKCTOCS investigators included statistical analyses suggestive of a possible long-term benefit
of the CA125 ROCA screening intervention on ovarian cancer mortality (excluding peritoneal
cancers) based on their observation that Kaplan-Meier cumulative mortality curves appear to
diverge approximately 10 years after randomisation. However, the Henderson 2017 Evidence
Synthesis did not focus on the secondary analysis because (1) they prioritised analyses with both
ovarian and peritoneal cancer included, since their presentation and treatment is not distinct in
clinical practice and because they are often difficult to distinguish pathologically; (2) they focused
on statistical tests that were specified a priori through publication of a protocol and trial registration,
using an intention-to-treat analysis of all participants, since these findings are more robust and
applicable to the implementation of a screening program and its cumulative effects; and (3) the
divergence of the trial arms later in the study period are more difficult to attribute to the original
randomised condition and screening per se, as the longer a study continues, the more
opportunities there are for measured and unmeasured differences in the study arms to accrue.
There were also substantially fewer women at risk included in the analyses beyond 10 years,
because women recruited into the study later have not yet accrued follow-up time for inclusion in
the analysis. Thus, data from the later years of the trial (>10 years) are based on incomplete data
and should be cautiously interpreted.
Henderson et al (2017) argue that differential reasons for censoring could lead to some divergence
in the ovarian cancer mortality curves as follow-up times lengthen. In the UKCTOCS trial, there were
no differences across arms in participant follow-up (censoring) or other causes of death, but there
may have been differences between arms and changes over time in the proportion of participants
Technical Report – Testing for ovarian cancer in asymptomatic women 40
in the trial with two ovaries intact. Those with both ovaries rather than just one, by definition, have
higher ovarian cancer risk. The usual-care screening arm may have had a net surplus of ovaries at
risk, despite a similar proportion of women at risk. Others have suggested that the potential
prophylactic effect of ovary and fallopian tube removal might influence the UKCTOCS results,
especially in the long term. To date, there is no overall difference in the incidence of ovarian
cancer by arm, suggesting that a prophylactic effect is not present, but as more years of follow-up
data are available for more of the enrolled participants, additional analysis of the cumulative
cancer incidence rate by study arm can be undertaken.
41 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.19 Summary of evidence table from Henderson 2017 – effect on disease-specific mortality
Test # studies (k),
sample size
(n) Design
Summary of Findings by Outcome Consistency/
Precision
Reporting Bias Quality Body of Evidence
Limitations
Assessment of
Strength of Evidence
for key question
Applicability
CA125 k=2
n=173,858
RCT
OC mortality (k=2, n=173,858). Screening with
CA125 did not result in improved OC mortality
compared with no screening (UKCTOCS HR, 0.89
[95% CI, 0.74 to 1.08], U.K. Pilot RR, 0.5 [95% CI,
0.22 to 1.11])
Reasonably
consistent
Reasonably
precise
Undetected Good Follow-up data
incomplete
beyond 10 years
for a substantial
proportion of trial
participants
Moderate Trial evidence from the UK, where
screening occurred in specialised
trial settings and cancer treatment
was provided through the NHS,
which is a more centralised health
system relative to the US. Study
enrolled mostly white women.
UKCTOCS began in 2001. FDA does
not support ROCA screening
algorithm.
TVUS k=1
n=151,922
RCT
OC mortality (k=1, n=151,922). TVUS screening
did not result in improved OC mortality
compared with usual care (UKCTOCS HR, 0.91
[95% CI, 0.76 to 1.09])
Consistency
NA
Reasonably
precise
Undetected Good Follow-up data
incomplete
beyond 10 years
for a substantial
proportion of trial
participants
Moderate Trial evidence from the UK, where
screening occurred in specialised
trial settings and cancer treatment
provided through the NHS, which is
a more centralised health system
relative to the US. Study enrolled
few nonwhite participants.
CA125
+ TVUS
k=1
n=68,557
RCT
OC mortality (k=1, n=68,557). No reduction
found in OC mortality from combined TVUS and
CA125 screening compared with usual care
(PLCO RR, 1.18 [95% CI, 0.82 to 1.71])
Consistency
NA
Reasonably
precise
Undetected Good Changes to
protocol, ovarian
palpation
dropped after
first 4 trial years
Moderate US multisite trial with usual care
control condition and referral to
community clinicians for screen
positives. Majority white, non-
Hispanic study participants. Trial
begun in 1993.
Abbreviations: CA, cancer antigen; CI, confidence interval; FDA, US Food and Drug Administration; HR, hazard ratio; NA, not applicable; NHS, National Health Service; OC, ovarian cancer; PLCO, Prostate, Lung,
Colorectal and Ovarian Cancer Screening Trial; QUEST, Quality of life, Education, and Screening Trial; RCT, randomised controlled trial; ROCA, risk of ovarian cancer algorithm; RR, risk ratio; TVUS, transvaginal
ultrasonography; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening, US, United States.
Technical Report – Testing for ovarian cancer in asymptomatic women 42
4.1.3.2 Stage shift and treatment findings
The Henderson 2017 Evidence Synthesis examined included studies for evidence of a cancer stage
or type shift. They focused the evaluation of stage shift on comparisons in the trial arms between
women diagnosed with localised disease (Stage I) and those with regional or distant disease
(stages II-IV).
Detection of a higher proportion of localised cancers in the screening arms compared with control
arms was reported in the two large trials. In UKCTOCS, a statistically significant (p<0.005) greater
proportion of cases was identified at the localised stage (Stage I) in the ROCA triage and TVUS
arms than in the control arm. The overall differences by arm and stage were also statistically
significant when comparing localised and regional cancers (stages I and II) to more advanced
stages (stages III and IV). However, this shift did not confer a statistically significant mortality benefit.
In PLCO, there was not a statistically significant difference in the proportion of cases identified at
the localised stage in the intervention versus usual care group. Furthermore, comparisons by stage
and arm also were not statistically different when comparing localised and regional cancer cases
to more advanced cancers. In addition, there were no differences in treatments (surgery plus
systemic therapy) by study arm in PLCO.
Overall, Henderson et al (2017) made the following observations:
‘The absence of a mortality benefit in these large, well-conducted trials has
generated a theory that late stage disease grows so rapidly that it cannot be
identified at an earlier stage. The stage shift in UKCTOCS trial would seem to counter
this, but the lack of mortality benefit may suggest that these “early stage” tumors
detected early are more aggressive tumor phenotypes that would not have
improved survival no matter when they were identified. Recent work to refine the
distinctions among ovarian cancer molecular, pathological, and clinical
characteristics highlight this point in noting that survival differences are more likely
attributable to type than to stage at diagnosis, with the most common Type II
cancers being particularly lethal regardless of stage, likely owing to microscopic
lesions that are not detectable before significant spread has occurred.’
4.1.3.3 Harms
Given evidence that there is no mortality benefit from routine ovarian cancer screening, Henderson
et al (2017) argue that the harms associated with screening merit extra consideration. Harms of
screening include surgery resulting from a false positive. These surgeries often result in the removal
of one or both ovaries and/or fallopian tubes, and can lead to major surgical complications.
The evidence summary in Table 0.20 relates to the question: What are the harms of screening for
ovarian cancer, including harms of the screening test and of diagnostic evaluation?
All four trials reported on the harms of ovarian cancer screening. False positive rates and surgical
harms were highest among screening programs including TVUS with or without CA125
measurement. Major surgical complications as estimated in the two largest trials occurred in
women with investigations from screening that did not lead to a cancer diagnosis, ranging from 3
to 15 percent of surgeries. The screening tests themselves resulted in minor complications, at rates
widely ranging based on study specific definitions from 0.86 to 58.3 per 10,000 screens/women for
CA125 test blood draws (e.g. fainting, bruising) and from 1.86 to 3.3 per 10,000 screens/women for
ultrasound testing (e.g. pain, discomfort, infection, bruising).
The UKCTOCS employed a more nuanced approach to CA125 testing and triage by using an
algorithm that assigns three levels of risk to direct surveillance and triage tests. This was aimed at
43 Technical Report – Testing for ovarian cancer in asymptomatic women
reducing rates of surgical investigation, which were lower in the ROCA triage arm than in the TVUS-
only arm of the trial. False positive surgery rates in the ROCA triage arm of UKCTOCS were markedly
lower than in PLCO (1% versus 3%), as were major complication rates for false positive surgery (just
over 3% in UKCTOCS versus 15% in PLCO). Henderson et al (2017) claim that differences in the study
settings could account in part for this difference, as all women referred for diagnostic testing in
UKCTOCS were seen at National Health Services tertiary care surgical centres, whereas diagnostic
testing in PLCO was conducted through referrals to women’s routine sources of care, and not
necessarily specialised tertiary care settings.
Technical Report – Testing for ovarian cancer in asymptomatic women 44
Table 0.20 Summary of evidence table from Henderson 2017 – harms
Test # studies (k),
sample size (n)
Design
Summary of Findings by Outcome Consistency/
Precision
Reporting Bias Quality Body of Evidence
Limitations
Assessment of
Strength of Evidence
for key question
Applicability
CA125 k=3
n=242,415
RCT
FP rate from screening (k=2, n= 173,858). FP
rates over multiple rounds of screening ranged
from 4.2% to 44.3%.
Complications from screening (k=2, n= 220,480).
Complications from CA125 testing were
generally minor and ranged from 0.86 per
10,000 screens to 58.3 per 10,000 women.
FP surgery (k=2, n=173,858). FP surgeries
occurred in 0.2% to 1% of those screened with
CA125.
Complications from FP surgery (k=2, n=173,858).
One larger trial (n=151,923) reported
complications in 3.1% of FP surgeries. One
smaller trial (n=21,935) reported no surgical
complications.
Psychological effects of screening (k=1, n=
13,413). Psychological harms were reported in a
subset of 1 trial. No statistically significant
differences were found in psychological
outcomes between the screening and no-
screening arms.
Reasonably
consistent or
NA
Reasonably
precise
Undetected Good Psychological
harms measured
only for subsets
of trial
participants.
Moderate (Low for
psychological
harms).
Trial evidence from the UK, where
screening occurred in specialised
trial settings and cancer treatment
was provided through the NHS,
which is a more centralised health
system relative to the US.
TVUS k=2
n=220,479
RCT
FP rate and complications from screening (k=1,
n= 151,922). FP rate of 11.9% was reported in the
initial screening round.
Complications from screening (k=2, n= 220,479).
Complications from screening with TVUS ranged
from 1.86 per 10,000 screens to 3.3 per 10,000
women.
FP surgery (k=1, n=151,922). FP surgeries
occurred in 3.2% of those screened with TVUS.
Complications from FP surgery (k=1, n= 151,922).
Complications occurred in 3.5% of FP surgeries.
Psychological effects of screening (k=1,
n=10,716). Psychological harms were reported
in a subset of 1 trial. No statistically significant
differences were found in psychological
outcomes between the screening and no-
screening arms.
Reasonably
consistent or
NA
Reasonably
precise
Undetected Good Psychological
harms measured
only for subsets
of trial
participants
Data on
cumulative FP
rate not
reported.
Moderate (Low for
psychological
harms).
Screening conducted in specialised
trial centers.
Treatment for cancer (in all study
arms) was through the centralised
NHS system in UK and in community
care settings in US.
45 Technical Report – Testing for ovarian cancer in asymptomatic women
Test # studies (k),
sample size (n)
Design
Summary of Findings by Outcome Consistency/
Precision
Reporting Bias Quality Body of Evidence
Limitations
Assessment of
Strength of Evidence
for key question
Applicability
CA125
+ TVUS
k=2
n=69,106
RCT
FP rate and complications from screening (k=1,
n=68,557). FP screening rate of 5.9% was
reported for the first round of screening and
9.8% for the entire screening program.
Complications from screening (see
complication rates for individual components).
FP rate for screen positive surgery (k=1,
n=68,557). FP surgeries occurred in 3.2% of those
screened.
Complications from FP surgery (k=1, n=68,557).
Complications occurred in 15.1% FP surgeries.
Psychological effects of screening (k=1, n=549).
Women with abnormal test results (n=32)
compared with women with no abnormal
results more likely to report cancer worry at 2
year follow-up (OR, 2.8 [95% CI, 1.1 to 7.2]).
Consistency
NA
Reasonably
precise
(except
psychological
harms
[imprecise])
Undetected Fair to
Good
Psychological
harms measured
only for subsets
of trial
participants.
Moderate (Low for
psychological
harms).
US-based, multisite trial.
Pragmatic trial with usual care
control condition and referral to
community clinicians for screen
positives.
Majority white, non-Hispanic
participants.
Abbreviations: CA, cancer antigen; CI, confidence interval; FP, false positive; NA, not applicable; NHS, National Health Service; OC, ovarian cancer; OR, odds ratio; RCT, randomised controlled trial; TVUS, transvaginal
ultrasonography; UK, United Kingdom; US, United States.
Technical Report – Testing for ovarian cancer in asymptomatic women 46
4.1.3.4 Conclusions from systematic reviews
Table 0.21 provides the conclusions reported in all of the published systematic reviews that assessed
screening interventions for ovarian cancer in asymptomatic women. Overall, the systematic reviews
were consistent in concluding that the body of evidence does not show a benefit for routine
screening over control in terms of a reduction in mortality; furthermore, the harms associated with
screening must be considered.
Table 0.21 Conclusions from systematic reviews relating to population screening for ovarian
cancer
Study ID
Qualitya
Intervention &
comparator
Conclusions
Screening for ovarian cancer
Henderson
2017
[AHRQ]
Good quality
Intervention
Any form of screening
for OC
Comparator
Usual care or no
screening
Since the previous review for the USPSTF, results from a large trial conducted in the UK were
published
OC mortality did not differ between control and intervention screening conditions in any of
the included trials, including two good-quality studies with adequate power to detect
differences
Harms of screening include surgery following a false positive test, often resulting in removal
of one or both ovaries and/or fallopian tubes, and the potential for major surgical
complications
Reports from the UKCTOCS of a potential delayed effect of screening on OC mortality
require further follow-up data to evaluate, but the causal mechanism for a delayed
screening effect is unclear
Major trials of promising OC screening tools have null findings to date among healthy
average-risk women, and there are considerable harms associated with screening
Buhling 2017
Fair quality
Intervention
Annual TVUS ± CA125
Comparator
Usual care
An annual palpation does not offer the beneficial effect that might be expected from
patients who undergo this examination
The development of new ultrasound machines with higher image resolution in combination
with a well-standardised algorithm for OC in upcoming years might provide an improvement
in mortality
The current studies do not show a benefit in screening an asymptomatic population
annually with TVUS, but a significant change was observed in the MMS group after 7–14
years of follow-up with a 28% reduction in mortality
Nevertheless, all three heterogeneous RCTs have weaknesses in their methods and therefore
do not reflect a general recommendation, but at the same time cannot disprove
Reade 2013
Good quality
Intervention
Any form of screening
for OC
Comparator
No intervention, usual
care, or education
RCTs evaluating screening [asymptomatic women for OC] do not show any benefit in
reduction of mortality or risk of diagnosis at an advanced stage
False-positive screening tests lead to unnecessary surgery and surgical complications, and
are associated with increased levels of worry for up to two years
This information should be considered for informed decision-making regarding OC screening
Screening for gynaecologic cancers (including ovarian cancer)
Guirguis-
Blake 2017
[AHRQ]
Good quality
Intervention
Pelvic examination
Comparator
No pelvic examination;
reference standard
There is no direct evidence on the overall benefits and harms of the pelvic examination as a
one-time or periodic screening test
There is limited evidence regarding the diagnostic accuracy and harms of the routine
screening pelvic examination to guide practice in asymptomatic primary care populations
Bloomfield
2014
Fair quality
Intervention
Pelvic examination
Comparator
No pelvic examination;
reference standard
No data supporting the use of pelvic examination in asymptomatic, average-risk women
were found
Low-quality data suggest that pelvic examinations may cause pain, discomfort, fear,
anxiety, or embarrassment in about 30% of women
Abbreviations: AHRQ, Agency for Healthcare Research and Quality; CA, cancer antigen; MMS, multimodal screening; OC, ovarian cancer;
RCT, randomised controlled trial; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian Cancer
Screening; USPSTF. United States Preventative Services Task Force.
a Quality was assessed using AMSTAR (see Appendix F).
47 Technical Report – Testing for ovarian cancer in asymptomatic women
Review of evidence for surveillance of women at high risk
4.1.4 Identified studies of surveillance effectiveness/harms
The literature searches identified a total of 11 eligible records for surveillance of women at high risk
of ovarian cancer; 10 clinical study publications and one systematic review.
4.1.4.1 Key clinical studies
The 10 eligible clinical study publications are listed in Appendix D (Section D.2.1). They describe five
cohort studies and one post hoc analysis of the PLCO RCT. These studies are referred to in this
Review as:
The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial – subgroup analysis
(PLCO-HR)
United Kingdom Familial Ovarian Cancer Screening Study – Phase I (UKFOCSS Phase I)
United Kingdom Familial Ovarian Cancer Screening Study – Phase II (UKFOCSS) Phase II)
o Partner study – Psychological evaluation of Familial Ovarian Cancer Screening (PsyFOCS)
Cancer Genetics Network and Gynecologic Oncology Group (CGN/GOG)
UK-Netherlands-Norway study
Fox Chase Cancer Centre
An additional record was found by directed searching – a protocol document for UKCTOCS
Phase II published online only.
A matched case-control study was also identified of 54 women with Lynch syndrome who
participated in any screening program using TVUS and CA125 for gynaecological cancers
(endometrial and ovarian; Stuckless 2013). This study, which found no improvement in early
detection, was excluded as it was retrospective.
A cohort study was identified that included women with increased risk of ovarian cancer within a
population screening trial (University of Kentucky Ovarian Cancer Screening Project; van Nagell
2011). Only true negatives were reported for this population, which is not an outcome of relevance
to this Review. Therefore, this study was not eligible for inclusion as a surveillance study (wrong
outcomes) nor as a population screening study (wrong study design – not an RCT).
An RCT was identified comparing screening modalities that triage women with CA125 testing,
either with or without the addition of HE4 testing (Karlan 2014). Positive predictive value was the
only outcome analysed, which is not eligible for inclusion in this Review, so this study was excluded.
Characteristics of included studies
Two of the six included studies used ROCA to evaluate CA125 levels:
UKFOCSS Phase II
CGN/GOG
The UKFOCSS Phase II evolved from the Phase I study, increasing the frequency of screening and
switching from single threshold to ROCA evaluation of CA125. The CGN/GOG study combined
data from the Cancer Genetics Network (CGN) and Gynecologic Oncology Group (GOG) studies,
which laid the groundwork for personalising the CA125 test with ROCA.
The characteristics of these studies are shown in Table 0.1.
Technical Report – Testing for ovarian cancer in asymptomatic women 48
The four other studies either used a single threshold for CA125 evaluation or were assumed to have
done so:
PLCO-HR
UKFOCSS Phase I
UK-Netherlands-Norway study
Fox Chase Cancer Centre study
The most recently published of these (PLCO-HR) is a post hoc analysis of high-risk women who
received routine annual screening in the PLCO population screening trial. Women in the UKFOCSS
Phase I trial also received annual screening with TVUS and single threshold CA125 testing. However,
between 2007 and 2009, phase II screening (ROCA once every 4 months, triaging to TVUS) was
introduced in response to concerns about the ability of annual screening to detect early-stage
disease.
An analysis of mostly published screening data from five cancer genetics centres in the UK, the
Netherlands and Norway was published in 2009 (UK-Netherlands-Norway). Information about the
screening interventions used, the definitions applied, and the cancers excluded were not reported
in detail, but it is assumed that a single threshold would have been used for CA125 evaluation.
A fourth study (Fox Chase Cancer Centre) did not report the details of screening, which served as a
control in an assessment of the impact of surgery on quality of life. However, the authors note that
screening options for high-risk women include serum CA125 evaluation and TVUS.
The characteristics of these five studies are shown in Table 0.2. The following sections include
information about eligibility criteria, details of the screening strategy, definitions used (e.g. interval
cancers, false positives), and methods for notification and ascertainment of outcomes.
49 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.1 Characteristics of included studies using ROCA – surveillance of women at high risk of ovarian cancer
Item UKFOCSS Phase II CGN/GOG
Main publication ID Rosenthal 2017 Skates 2017
CA125 interpretation ROCA ROCA
Country and setting 42 centres in the UK (52% were UKFOCSS Phase I participants) CGN: 25 sites across US (NCT-00039559)
GOG-0199: 112 across US and Australia (NCT-00043472)
Key inclusion criteria
(see Table 0.3 for full list of criteria)
aged ≥35 years; median 45.5 (range 34.2, 84.8)
lifetime risk of OC ≥10%
aged > 30 years
subject or family member with BRCA1/2 mutation, or
multiple ovarian and/or breast cancers in 1st or 2nd degree relatives
Only difference in eligibility criteria is that women without ovaries were
ineligible for GOG-0199 but could be screened for PPC in CGN (excluded
from the analysis in the CGN/GOG analysis of these two studies).
Key exclusion criteria
(see Table 0.3 for full list of criteria)
test negative for mutation in an affected family member test negative for mutation in an affected family member
Study design, N Prospective, multicentre cohort study Combined analysis of two prospective, multicentre cohort studies
conducted by the CGN and GOG.
Recruited (N) N = 4,531 N = 3,818
CGN, N = 2,359; GOG-0199, N = 1,459
Analysed (N) N = 4,348 N = 3,449
CGN, N = 1,991; GOG-0199, N= 1,458
Cancers included invasive OC (i.e. not borderline)
FTC
PPC
invasive OC (i.e. not borderline)
FTC
PPC
Period of study
Start date Jun 2007 CGN 2001
GOG-0199 2003
End of recruitment May 2012 CGN 2011
GOG-0199 2006
Person-years screened 13,728 Total: 13,080
CGN 6,979
GOG-0199 6,101
Censorship 1 year after last UKFOCSS screen38 CGN: not reported, but all women were followed for at least a year after
the last screening test
GOG-0199: open-ended annual questionnaires after 5 years of screening
38 Dates reported for last cancer notifications from NHS digital were February 28, 2016 (England/Wales), May 15, 2016 (Scotland), and April 19, 2016 (Northern Ireland); the last death notifications were received on
March 14, 2016 (all countries).
Technical Report – Testing for ovarian cancer in asymptomatic women 50
Item UKFOCSS Phase II CGN/GOG
Median follow up
(years)
4.8 (range 0.1, 8.7) CGN 2.9 (range 0, 10.3)39
GOG-0199 5.0 (range 0, 6.9)
Screening method
(see Screening strategies section below for details)
HR ROCA triage
High-risk ROCA40 every 4 months for possible triage to additional CA125
and/or TVUS, and
TVUS annually
HR ROCA triage
High-risk ROCA40 every 3 months for possible triage to additional CA125
and/or TVUS, and
TVUS annually
Positive-screen follow-up actions Referral to a local gynaecologist for clinical assessment. Follow up with gynaecological oncologist or study site principal
investigator.
Key outcomes reported diagnoses by mode of detection
false positive surgeries
stage at diagnosis
mortality (reported but not analysed)
sensitivity
QoL outcomes
diagnosis by mode of detection
false positive surgeries
stage at diagnosis
sensitivity
Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; OC, ovarian cancer; PPC, primary peritoneal cancer; QoL, quality of life;
ROCA, risk of ovarian cancer algorithm; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study; US, United States.
Table 0.2 Characteristics of included studies using single threshold CA125 – surveillance of women at high risk of ovarian cancer
Item PLCO-HR UKFOCSS Phase I UK-Netherlands-Norway Fox Chase Cancer Centre
Main publication ID Lai 2016 Rosenthal 2013 Evans 2009 Fang 2009
CA125 interpretation Single threshold CA125 with TVUS Single threshold CA125 with TVUS Single threshold CA12541 with TVUS NR42 (likely CA125 and or TVUS)
Country and setting US – 10 screening centres under
contract to the National Cancer
Institute.43
37 centres in the UK Five cancer genetics centres44 in
UK – Edinburgh and Manchester
The Netherlands – Leiden
Norway – Oslo and Bergen45
Family Risk Assessment Program at Fox
Chase Cancer Centre, Philadelphia,
US
39 ‘0’ years indicates women who enrolled but were never screened. 40 The high-risk ROCA incorporated the higher a priori risk in this population and different reference levels for risk stratification for post-menopausal compared with pre-menopausal women (higher baseline CA125 and
variability in pre-menopausal women). 41 This study did not describe screening in detail, which was conducted in one of five European centres. However, a publication reporting results from the Netherlands that was cited by Evans 2009 for further
information regarding screening protocols reports using a single threshold cut-off of 35 U/mL. 42 The authors make the comment that ‘screening options for high-risk women include serum CA125 evaluation and TVU’. The screening group serves as a control for surgery in this QoL study. 43 Screening centres were located at the University of Colorado Health Sciences Center in Denver, Colorado; Georgetown University in Washington, DC; the Pacific Health Research Institute in Honolulu, Hawaii; Henry
Ford Health System in Detroit, Michigan; the University of Minnesota in Minneapolis, Minnesota; Washington University School of Medicine in St. Louis, Missouri; the Cancer Institute of Brooklyn at Maimonides Medical
Center in Brooklyn, New York (discontinued in 1997); the University of Pittsburgh Cancer Institute in Pittsburgh, Pennsylvania; the University of Utah Health Sciences Center in Salt Lake City, Utah; Marshfield Medical
Research and Education Foundation in Marshfield, Wisconsin; and the University of Alabama at Birmingham in Birmingham, Alabama. 44 These centres were among 10 centres involved in a European Biomed project funded in 1995 (there were insufficient data and cancers in the other centres to increase power). 45 Screening in Norway was performed in several local hospitals.
51 Technical Report – Testing for ovarian cancer in asymptomatic women
Item PLCO-HR UKFOCSS Phase I UK-Netherlands-Norway Fox Chase Cancer Centre
Key inclusion criteria
(see Table 0.3 for full list of criteria)
Family history:
aged 55 to 74
at least one first degree relative with
breast cancer or OC
Personal history:
a personal history of breast cancer
prior to enrolment
there were 2,708 participants (3.5%
of enrolees) identified for inclusion in
this subgroup
Menopausal status not a criterion.
age ≥ 35 years
estimated ≥ 10% lifetime risk of
OC/FTC
surveillance start ‘at age 30 or 35
years’46
‘Usually at least a 10% lifetime risk’ of
OC
age ≥25 years and considering
RRSO due to family history or
known mutation
Key exclusion criteria
(see Table 0.3 for full list of criteria)
Previous diagnosis of lung,
colorectal, or ovarian cancer
Previous oophorectomy (dropped in
1996)
Current tamoxifen use (dropped in
1999)
bilateral salpingo-oophorectomy NR NR
Study design, N Post hoc analysis of prospective PLCO
RCT of population screening –
subgroup analysis of high-risk women.
Family history subgroup N=22,355;
28.6% of enrolees in population
screening study
Personal history subgroup N = 2,708;
3.5% of enrolees
Prospective cohort study (N = 3,563) Prospective cohort study (N = 3,532) Prospective cohort survey (N = 75)
imminent surgery (n =38)
continue screening (n = 37)
Cancers included invasive OC
FTP
PPC
(borderline excluded – false positive)
epithelial OC
FTC
PPC (separately)
Non-epithelial OC and borderline
ovarian tumours were excluded.
‘PPC (defined according to
recognised pathologic criteria) is
unlikely to be amenable to early-stage
detection using current techniques;
however, data are presented both
including and excluding PPC from the
screening performance analysis.’
invasive epithelial OC
borderline OC
(FTC and PPC not mentioned)
N/A
46 According to a cited article reporting results from a multicentre study in the Netherlands that contributed to this study: ‘the minimum age of entry into the surveillance programme was 35 years or 5 years earlier
than the youngest age at diagnosis of ovarian cancer in the family.’
Technical Report – Testing for ovarian cancer in asymptomatic women 52
Item PLCO-HR UKFOCSS Phase I UK-Netherlands-Norway Fox Chase Cancer Centre
Period of study
Start date Nov 1993 May 2002 Jan 1991 Dec 1999
End date Jul 2001 (end of recruitment) Jan 2008 Mar 200747 Sep 2004
Person-years screened Not reported for subgroups 11,366 NR N/A
Censorship After 13 years of follow-up, or 28 Feb
2010; whichever comes first.
Participants were followed for a
minimum of 10 years.
Censored 1 year after withdrawal or
last trial screen. However, subsequent
diagnoses to March 2011 were
reported as diagnoses > 365 days after
last trial screen (post-censorship).
66.2% of women transferred to
UKFOCSS Phase II, which started in Jun
2007, and were censored 365 days
after the first Phase II screen. No
cancers were detected within this first
year of increased screening, so
sensitivity was not artificially increased.
1 Mar 2007 N/A
Median follow up
(years)
NR for subgroups (minimum 10 years) NR.
11,366 women-years of screening
(mean, 3.2 years per woman)
up to 16 years 1 year
Screening method
(see Screening strategies section below
for details)
Annual screening for 4 years with both:
TVUS
CA125
followed by 2 years of screening with
TVUS only.
Single threshold cut-off:
≥35 U/mL
Annual screening with both:
TVUS
CA125
Single threshold cut-offs:
pre-menopausal – 35 U/mL
post-menopausal – 30 U/mL
Annual screening with both:
TVUS
CA125
It is assumed CA125 was analysed with
a single threshold, but no further
description of the screening strategy
was reported.
Not reported.
Positive-screen follow-up actions Abnormal results for either test
precipitated notification in writing to
the participant and their physician for
standard diagnostic and follow up
procedures. If requested, referral
physicians were provided with
standard-of-practice guidelines for
diagnostic procedures by the local
PLCO screening centre.
Guidelines for management of results
were provided, but management
remained at the discretion of
collaborating gynaecologists.
NR NR
47 This period of time was variously reported as being the screening period or the recruitment period. Actual length of screening and recruitment is unclear, and may not have ceased at censorship.
53 Technical Report – Testing for ovarian cancer in asymptomatic women
Item PLCO-HR UKFOCSS Phase I UK-Netherlands-Norway Fox Chase Cancer Centre
Key outcomes reported OC incidence
stage at diagnosis
mortality due to OC
all-cause mortality
diagnoses by mode of detection
false positive surgeries
sensitivity
stage at diagnosis
mortality
diagnoses by mode of detection
stage at diagnosis
mortality (comparison of BRCA1/2
carriers and non-carriers)
QoL using four instruments, two of
which are validated:
Medical Outcomes Survey (MOS)
Short-Form Health Survey (SF-36)
Center for Epidemiological Studies-
Depression scale (CES-D)
Abbreviations: CA, cancer antigen; FTC, fallopian tube cancer; N/A, not applicable; NR, not reported; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary
peritoneal cancer; QoL, quality of life; RCT, randomised controlled trial; RRSO, risk-reducing salpingo-oophorectomy; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKFOCSS, United Kingdom Familial
Ovarian Cancer Screening Study; US, United States.
Technical Report – Testing for ovarian cancer in asymptomatic women 54
Eligibility criteria
Table 0.3 Inclusion/exclusion criteria – surveillance studies
Study ID Inclusion/exclusion criteria including definition of high risk status
ROCA-based CA125 evaluation
UKFOCSS
Phase II
Inclusion criteria
The volunteer must be aged at least 35 years and should either have been affected by one of the following cancers or be
a first degree relative (FDR) of an affected family member (NB. Tubal & primary peritoneal cancers may be considered
equivalent to ovarian cancers)
Families with ovarian or ovarian & breast cancer
1) ≥2 individuals with OC who are FDR
2) One OC and 1 breast cancer <50 years who are FDR
3) One OC and 2 breast cancers <60 years who are FDR
4) Breast cancer in volunteer/ proband (≤45 years) and mother with both breast and ovarian cancer (in the same
person)
5) Breast cancer in volunteer/ proband (≤40 years) and sister with both breast and ovarian cancer (in the same person)
6) Criteria 1, 2, and 3 can be modified where paternal transmission is occurring (i.e. families where affected relatives are
related by second degree through an unaffected intervening male relative and there is an affected sister are
eligible).
Families with a known gene mutation
7) The family contains an affected individual with a mutation of one of the known OC predisposing genes e.g. BRCA1,
BRCA2, MLH1, MSH2, MSH6, PMS1 and PMS2.
Families with colorectal cancer (HNPCC or Lynch syndrome)
8) The family contains ≥3 individuals with a HNPCC related cancer#, who are FDR and ≥1 case is diagnosed before 50
years and the cancers affect ≥1 generation.
#HNPCC related cancers - colorectal, endometrial, small bowel, ureteric and renal pelvic cancers
Families with only breast cancer*
9) ≥4 breast cancers
10) 3 breast cancers related by FDR
a) one ≤30 years or
b) all ≤40 years or
c) one MBC (Male Breast Cancer) and one bilateral breast cancer
11) Breast cancer in volunteer/ proband (≤50 years) and
a) breast cancer in mother (age of onset being ≤30 years in one and ≤50 years in the other) or
b) bilateral breast cancer in mother (≤40 years onset) or
c) one MBC and one bilateral breast cancer
12) Two MBC (one <40 years) in the family and proband is a FDR of one of them.
Families with Ashkenazi Jewish ethnicity (additional criteria)*
Ashkenazi Jewish ethnicity and any one of the following:
13) Breast cancer (<40 years) or bilateral breast cancer (first cancer <50 years) in volunteer/ proband, irrespective of FH
(family history) of cancer
14) Breast cancer in volunteer/ proband (<50 years) and one FDR with breast cancer (<50years) or ovarian cancer (any
age) or MBC (any age)
15) Breast cancer in volunteer/ proband (<60 years) and one FDR with breast cancer (<40 years) or ovarian cancer (any
age) or MBC (any age)
16) One FDR with ovarian cancer (<50 years)
17) FDR with breast and ovarian cancer in the same woman (any age)
18) Two FDR with breast cancer (<40 years)
19) Two MBC (<60 years) in the family and proband is a FDR of one of them.
*Families in these categories negative on full BRCA1 and BRCA2 screening are ineligible.
Exclusion criteria
1) Past history of bilateral oophorectomy (women with one or both fallopian tubes still present are eligible)
2) Age <35 years
3) Women participating in other ovarian cancer research trials
4) Women who have tested negative for a pathological mutation found in an affected family member. Similarly, those
who obtain a negative result after recruitment need to be withdrawn
5) Breast cancer-only families (inclusion criteria 9-12) and Ashkenazi families (criteria 13-19) are not eligible if full gene
mutation screening has been done and no mutation found (such families are not thought to be at increased risk of
developing ovarian cancer)
6) Women should not be recruited if RRSO is imminent, but those with an intention to have RRSO at some (unspecified)
date in the future are eligible. Good clinical practice dictates that even if a woman is not recruited to UKFOCSS, she
should have a TVUS and CA125 performed shortly before RRSO to reduce the risk that an occult cancer only comes to
light at the time of surgery.
55 Technical Report – Testing for ovarian cancer in asymptomatic women
Study ID Inclusion/exclusion criteria including definition of high risk status
CGN/GOG Inclusion criteria
Eligibility criteria included the following, with “close relatives” defined as first- or second-degree blood relatives:
1. the subject or close relative (deleterious mutation in a first-degree relative confers a 50% prior probability of an
untested subject being a mutation carrier, while deleterious mutation in a second-degree relative confers a 25%
prior probability of an untested subject being a mutation carrier) had a known, deleterious BRCA1 or BRCA2
mutation; or
2. at least two ovarian or breast cancers (including DCIS) had been diagnosed among the subject or close
relatives within the same lineage; or
3. the subject was of Ashkenazi Jewish ethnicity, with one first-degree or two-second degree relatives with ovarian
or breast cancer; or
4. the subject was of Ashkenazi Jewish ethnicity and had a personal history of breast cancer; or
5. the probability of carrying a BRCA1 or BRCA2 mutation given family pedigree of breast and ovarian cancers as
calculated by BRCAPRO exceeded 20%.
When a diagnosis of breast cancer was required to meet any of these criteria, at least one breast cancer must have been
pre-menopausal or, if menopausal status was unknown at time of diagnosis, then age at diagnosis was required to be ≤50
years.
It has since become apparent that some of these women are now known to not be at increased risk for ovarian cancer –
e.g. women with a site-specific breast cancer family history whose families lack a deleterious BRCA1/2 mutation, but they
are nonetheless included in our analysis in line with the principle of “intention to treat.”
Exclusion criteria
The subject was excluded from study participation if she:
1. had a personal history of ovarian cancer, including low malignant potential cancers (LMP), or primary papillary
serous carcinoma of the peritoneum; or
2. had a close relative with a deleterious BRCA1/2 mutation and the subject had tested negative for the same
mutation; or
3. was less than 30 years of age; or
4. was currently pregnant or anticipating pregnancy during the study; or
5. was participating in other ovarian cancer early detection trials; or
6. had a current active malignancy (other than non-melanoma skin cancer); or
7. had been treated for metastatic malignancy within the prior five years (excluding hormonal therapies); or
8. had undergone intra-peritoneal surgery within the prior 3 months (laparoscopy or laparotomy); or
9. had a history of any medical conditions that would place the subject at risk related to phlebotomy, including but
not limited to hemophilia or other bleeding disorders, chronic infectious disease, emphysema or serious anemia.
Women who had clinical symptoms suggestive of ovarian cancer were also excluded.
Single threshold CA125 evaluation
PLCO-HR The current study defined a subgroup of participants who reported at least one first degree relative with breast cancer or
at least one first degree relative with ovarian cancer.
A separate subgroup of patients with a personal history of breast cancer prior to enrolment was also analysed.
Other inclusion and exclusion criteria as per the PLCO RCT for population screening.
UKFOCSS PI Inclusion criteria
The inclusion criteria originally defined a minimum 10% lifetime OC risk (Appendix, online only) on the basis of family history
or predisposing mutations, including LS-associated mutations. OC in the family was defined as epithelial OC, FTC, or PPC.
Exclusion criteria
Women were excluded if they had undergone bilateral salpingo-oophorectomy or were participating in
other OC screening trials.
UK-
Netherlands-
Norway
Inclusion criteria
Women assessed as being at increased risk of ovarian cancer (usually at least a 10% lifetime risk, requiring more than just a
single close relative with ovarian cancer). Screening started ‘at either 30 or 35 years of age’.
Exclusion criteria
None reported.
Fox Chase
Cancer
Centre
Inclusion criteria
Eligible women were ages 25 and older who were considering RRSO due to: 1) a family history of ovarian cancer, 2) a
family history suggestive of a hereditary breast/ovarian pattern, and/ or 3) the presence of a known disease-related gene
mutation in the family.
Exclusion criteria
None reported.
Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; DCIS, ductal carcinoma in situ; FDR, first degree relative; FTC, fallopian
tube cancer; GOG, Gynecologic Oncology Group; HNPCC, hereditary nonpolyposis colorectal cancer; MBC, male breast cancer; OC,
ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; RCT, randomised
controlled trial; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy; TVUS, transvaginal ultrasonography; UK,
United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
Technical Report – Testing for ovarian cancer in asymptomatic women 56
Screening strategies
Table 0.4 Details of screening strategies – surveillance studies
Study ID Screening strategies
ROCA-based CA125 evaluation
UKFOCSS
Phase II
ROCA every 4 months and annual TVUS (or within 2 months of an abnormal ROCA result). The ROCA was adjusted for the
high-risk population (HR ROCA).48
The first ROC value triaged women to one of the following three paths;
4-monthly routine screening (‘normal’)
TVUS within two months and repeat CA125 measurement after two months (‘intermediate’)*
referral for clinical assessment by collaborating centre gynaecologist (‘elevated’).
Subsequent TVUS and ROC results triggered one of the following paths;
return to routine screening
repeat CA125
repeat CA125 and TVUS
referral to rapid access gynaecologist, or
triage by coordinating centre study clinician if ROC was persistently intermediate or TVS unsatisfactory.
*from 13/05/2010 Intermediate results were sub-classified into High Intermediate and Low Intermediate.
In addition to this protocol, CA125 was repeated at coordinating centre clinicians’ discretion within 2 months if the ROC
was ‘normal’ but CA125 had increased by >50% since the prior test. Women referred but not undergoing surgery were, at
the coordinating centre clinicians’ discretion, transferred to ‘high-alert screening’, comprising repeat TVS and CA125 at 2,
6 and 10 months.
(Also see Table AppE.4 in Appendix E for a representation of the triage protocol.)
CGN/GOG ROCA every 3 months and annual TVUS
normal-risk women (<1% risk of having OC) returned in 3 months for the next CA125
those with an intermediate risk (1%–10%) were referred for TVUS
those with an elevated risk (>10%) received TVUS and evaluation by a gynaecologic oncologist or study site principal
investigator.
Single threshold CA125 evaluation
PLCO-HR In the screening arm, participants underwent a baseline pelvic ultrasound and serum CA125, with subsequent annual
pelvic ultrasound for an additional 3 years, and annual CA125 for 5 years. Abnormal screening was determined by a
CA125 greater than 35 U/mL, or any of the following abnormalities on pelvic ultrasound: ovarian volume greater than 10
mL, cyst volume greater than 10 mL, any solid area of papillary projection, or any cyst with mixed components.
UKFOCSS
Phase I
Annual TVUS and single threshold CA125 (cut-offs of 35 and 30 IU/mL in pre-menopausal and post-menopausal women,
respectively). Abnormalities triggered follow-up scans, but no further information was provided regarding timing or
combinations of tests performed during repeat screening. Protocols developed for Phase II of this study.
UK-
Netherlands-
Norway
This study did not describe screening in detail, which was conducted in one of five European centres. However, a
publication reporting results from the Netherlands that was cited by Evans 2009 for further information regarding screening
protocols reports using a single threshold cut-off of 35 U/mL.
Fox Chase
Cancer
Centre
Not described.
Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group; HR, high-risk; OC, ovarian cancer;
PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROC, risk of ovarian cancer; ROCA, risk of ovarian cancer algorithm;
TVUS, transvaginal ultrasonography; UK, United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
Terminology and definitions
Table 0.5 Terminology and definitions – surveillance studies
Study ID Definition
ROCA-based CA125 evaluation
UKFOCSS
Phase II
Cancers
True positive – invasive epithelial OC/FTC diagnosed after screen-positive surgery.
Prevalent cases – diagnosed at first screen.
Incident cases – diagnosed after subsequent screens. For women who transferred from Phase I to Phase II, their first
Phase II screen was classified as incident.
48 The high-risk ROCA incorporated the higher a priori risk in this population and different reference levels for risk stratification for post-
menopausal compared with pre-menopausal women (higher baseline CA125 and variability in pre-menopausal women).
57 Technical Report – Testing for ovarian cancer in asymptomatic women
Study ID Definition
Interval cancers (false negatives) – presenting clinically < 365 days after the last screen.
Occult cancers – found in RRSO specimens < 365 days after the last annual screen (these can be classified as either false
negative or true positive as they would have been either missed or detected at the next routine screening if RRSO had not
taken place).49
Other diagnoses
False positive – all other diagnoses (including borderline and benign tumours) from surgery prompted by abnormal test
results.
Screening-related surgery – Cases in which a non-concerning test result (e.g. simple ovarian cysts, transiently raised
CA125) had contributed to the decision to undergo surgery.
True negative – last screen was normal, and no diagnosis of OC/FTC was made in the subsequent 365 days.
RRSO – asymptomatic women who had normal screening tests in the year before surgery and the recruiting center
indicated RRSO as the reason for withdrawal from the study.
CGN/GOG Cancers
True positive – term used but not defined.
Prevalent cases – existing but undetected at screening initiation.
Incident cases – arose during rather than before screening initiation.
Interval cancers – term not used; referred to as ‘clinically detected’, and not defined.
Occult cancers – term used but not defined.
Other diagnoses
False positive – term used but not defined.
Single threshold CA125 evaluation
PLCO-HR Taken from definitions extracted from PLCO RCT for population screening:
Cancers
True positives – diagnosed as a result of investigations initiated after a screening test with a positive result and without a
lapse in the diagnostic evaluation exceeding 9 months.
Prevalent cases – terminology not used, but category reported (detected as baseline screen).
Incident cases – terminology not used, but category reported (detected by screening at 1-5 years).
Interval cancers – cancers not detected by screening and diagnosed within 12 months of the woman’s last expected
screening examination.
Other Diagnoses
False positives – positive screening examination result that did not result in cancers detected by screening.
UKFOCSS PI Cancers
True positive – invasive epithelial OC/FTC diagnosed after screen-positive surgery.
Prevalent cases – diagnosed at first screen.
Incident cases – diagnosed after subsequent screens.
Interval cancers (false negatives) – presenting clinically < 365 days after the last screen.
Occult cancers – found in RRSO specimens < 365 days after the last annual screen (these can be classified as either false
negative or true positive as they would have been either missed or detected at the next routine screening if RRSO had not
taken place).49
Other diagnoses
False positive – all other diagnoses (including borderline and benign tumours) from surgery prompted by abnormal test
results.
Screening-related surgery – Cases in which a non-concerning test result (e.g. simple ovarian cysts, transiently raised
CA125) had contributed to the decision to undergo surgery.
True negative – last screen was normal, and no diagnosis of OC/FTC was made in the subsequent 365 days.
UK-
Netherlands-
Norway
Interval cancers: occurring symptomatically within 12–14 months of a previously normal screening round.
Incidence cancers: detected either by CA125, ultrasound or both after the initial prevalent round of screening.
Fox Chase
Cancer
Centre
As this study is reporting QoL outcomes only, findings from screening are not reported.
Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; HR,
high-risk; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; QoL, quality of life; RCT, randomised
controlled trial; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy; UK, United Kingdom; UKFOCSS, United
Kingdom Familial Ovarian Cancer Screening Study.
49 The authors therefore reported screening performance using both these scenarios, on the assumption that the true sensitivity of screening in
a population not undergoing RRSO falls between these two estimates.
Technical Report – Testing for ovarian cancer in asymptomatic women 58
Notifications and ascertainment of outcomes
Key differences between the trials in the methods used to identify incident cancers and deaths
include the following:
Main sources for identification of ovarian cancer or death
UKFOCSS Phase I and II – women were flagged at cancer registries using unique health
number identifiers.
CGN/GOG and PLCO-HR – followed up with questionnaires sent to participants.
Trigger for review of medical records for outcome verification
UKCFOCSS Phase I and II – review of all surgical records.
CGN/GOG – review of all surgical specimens.
PLCO-HR – ovarian cancer diagnosis or death indicated in returned questionnaire (annual
study update), or discovered in search of cancer or death registries.
4.1.4.2 Key systematic reviews and HTAs
Only one systematic review (Auranen et al 2011) evaluated the role of surveillance in women at
high risk of ovarian cancer. The specific focus of this systematic review was on women belonging to
hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) families. The
citation details for this review is shown in Appendix D (Section D.2.2).
Characteristics of systematic reviews
The characteristics of the systematic review are summarised in Table 0.6.
Table 0.6 Key characteristics of systematic reviews relating to surveillance of women at
high risk
Study ID
Qualitya
Study aim Literature
search
Study eligibility Included studies (no.
of patients)
Intervention &
comparator
Outcomes of
interest
Auranen
2011
Poor
quality
To evaluate the
role of
gynaecological
cancer
surveillance in
women who
carry a HNPCC
mutation or
belong to a
family that fulfils
the criteria for
HNPCC.
PubMed; a
clinical trials
registry
Search to
Feb 2010
Inclusion
women: a)
belonging to families
fulfilling Amsterdam II
criteria but the
families have not
been tested for
mutations; b)
belonging to families
with a known
HNPCC mutation but
the women have not
been tested; c)
carrying an HNPCC
mutation
reported a result of
any gynecological
intervention
Exclusion
reported
interventions other
than surveillance
For OC
1 prospective cohort
study:
Renkonen-Sinisalo
2006 (N=175;
Finland)
1 prospective
observational studies:
Gerritzen 2009
(N=100;
Netherlands)
1 retrospective
observational studies:
Rijcken 2003 (N=41;
Netherlands)
Intervention
Gynaecological
cancer
surveillance
Comparator
Not specified
cancers
detected at
screening
stage at
screening
cancer
precursor
states at
screening
interval
cancers
detected
stage of
interval
cancers
Abbreviations: HNPCC, hereditary nonpolyposis colorectal cancer; OC, ovarian cancer.
a Quality was assessed using AMSTAR (see Appendix F).
59 Technical Report – Testing for ovarian cancer in asymptomatic women
4.1.5 Data extraction – clinical studies using ROCA-based CA125 evaluation
A combined analysis of the CGN and GOG-0199 studies (Skates 2011) was the foundation work for
the development of ROCA for use in high risk women, which takes into account different baseline
levels in pre-menopausal and post-menopausal women, among other factors. The Skates 2017
study publication (CGN/GOG) reports diagnosis by mode of detection, false positive and stage at
diagnosis. Phase II of the UKFOCSS trial implemented a very similar screening strategy using the
high-risk ROCA for triage to TVUS.
4.1.5.1 UKFOCSS Phase II
Phase II of the UKFOCSS trial was instigated in response to concerns that annual screening with
CA125 (single threshold) and TVUS in the Phase I trial was not increasing the proportion of early
stage diagnoses (see Section 4.1.6.2 for the results of Phase I). Changes were made to Phase II of
the trial in an attempt to achieve rigorous adherence to screening schedules and swifter action on
abnormal results, and thereby optimise early detection:
screening frequency increased to once every 4 months
protocol driven threshold for, and timing of, repeat tests
CA125 assayed in a single laboratory to reduce inter-assay variability
ROCA for evaluating serial CA125 values
collaborators prompted to organise scans and referrals via an Internet-based database,
modelled on the successful UKCTOCS database.
Participants were recruited from the Phase I trial (52%) or by de novo recruitment (48%).
A before/after screening comparison is presented by the study authors, comparing outcomes
within a year of screening to those over a year after the last screen.
Detection outcomes
Mode of detection
The mode of cancer detection is shown in Table 0.7. A total of 37 cancers were detected, of which
around half (19) were detected within a year of trial screening. Of those, most were screen
detected (13) and the others were occult (i.e. no incident diagnoses prompted by symptoms within
a year of screening). This is in contrast to diagnosis over a year after the last trial screen, for which
13 of 18 (72%) were symptom-prompted.
Only one prevalent cancer was detected in Phase II, in a de novo recruit to Phase II. This is in
contrast to the Phase I trial, in which 9 of 37 cancers were prevalent. As half the participants in
Phase II had received ongoing screening immediately prior during Phase I, this result is not surprising.
Consequently, the results of Phase II are presented aggregated for prevalent or incident screen-
detected cancers.
Technical Report – Testing for ovarian cancer in asymptomatic women 60
Table 0.7 Mode of cancer detection – UKFOCSS Phase II
Detection outcomes with HR ROCA triage OC (invasive), FTC, PPC
n (%)
N=4,348
Total cancers detected 37 (100)
Detected <365 days after last trial screen (prior to censorship) 19 (51)
Detected >365 days after last trial screen (post-censorship) 18 (49)
Detected by screening 13 (35)
First screen (prevalent) 1 (3)
Subsequent screens (incident screen-detected) 12 (32)
Detected by other means <365 days after last trial screen 6 (16)
Surgery prompted by symptoms (interval cancers) 0 (0)
Occult cancers – discovered at RRSO unrelated to test results 6 (16)
Detected >365 days after last trial screen 18 (49)
Surgery prompted by symptoms 13 (35)
Occult cancers – discovered at RRSO 2 (5)
Detected at annual screening performed locally 3 (8)
Incidence (detected < 365 days from last screen)
Overall annual incidence (%) based on 13,728 person-years of trial screening 0.14
Abbreviations: FTC, fallopian tube cancer; HR, high risk; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, risk of ovarian cancer
algorithm; RRSO, risk-reducing salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
Sensitivity
Occult cancers discovered during risk-reducing salpingo-oophorectomy (RRSO), unrelated to
screening, impacts on estimates of screening sensitivity. In an attempt to account for this, sensitivity
estimates were derived from modelling; the lower confidence interval for all screen detected
cancers of 75.3% was used as a conservative approximation of the proportion of occult cancers
that might have been screen detected had women not undergone RRSO.
Modelled sensitivity for ovarian cancer or FTC detection within 1 year was estimated at 94.7% (95%
CI: 74.0%, 99.9%).
False positives
Table 0.8 shows the number of false positive surgeries i.e. screen-positive surgeries resulting in any
diagnosis other than invasive ovarian cancer, FTC or PPC (borderline tumours were counted as
false positives). The number of false-positive surgeries per screen-detect cancer is substantially
higher in Phase II of UKFOCSS compared to Phase I (11.5 versus 2.4, respectively).
RRSO is currently recommended as optimal management for women at high risk of ovarian cancer,
but some women who would otherwise elect to have RRSO may decide to use surveillance if it
were recommended – especially prior to completion of childbearing. This impacts on the
implications of false positive surgery, as complications that may arise from false positive surgery
may also have occurred during prophylactic RRSO.
Table 0.8 False positive surgery rates – UKFOCSS Phase II
Outcome N (%)
Participants 4,348 (100)
Screen-positive surgeries 162 (3.7)
False positive surgeries 149 (3.4%)
Screen-detected cancers 13 (0.3%)
Number of surgeries to detect one case of cancer 12.5
Number of false positive surgeries per screen-detected cancer 11.5
Abbreviations: UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
61 Technical Report – Testing for ovarian cancer in asymptomatic women
Tumour characteristics
As described earlier in Table 0.15, FIGO staging of ovarian tumours is based on the degree of
spread, with early stage restricted to the ovaries or pelvis. The UKFOCSS Phase II study also reported
comparisons according to the volume of metastatic peritoneal disease, with cancers at Stage IIIa
or less referred to as low volume, and those more advanced than Stage IIIa as high volume
cancers. Table 0.9 shows all cancers diagnosed in this study by stage, and by detection mode.
Although a no-screening comparison group is not available, the authors note that a comparison
between diagnoses made during screening and after screening may be valid.
Screen-detected cancers are either prevalent or incident cases – these were shown combined as
only one case was detected at the prevalence screen.
Of 37 total diagnoses during the trial, 13 were screen detected, of which 5 (38.5%) were early stage
(95% CI: 13.9, 68.4) and 46% were low volume. Eighteen cancers were diagnosed >365 days after
the last UKFOCSS screen, most of which were flagged by symptoms. All of these post-censorship
diagnoses were late stage and high volume with the exception of one case found at Stage I during
RRSO unrelated to surgery (occult).
To investigate stage shift, the primary study publication reports a single statistical analysis,
comparing the proportion of high volume diagnoses made <365 days after the last screen (7/19;
36.8%) versus >365 days after the last screen (17/18; 94.4% [95% CI: 72.7, 99.9]), which was a
statistically significant difference (p<0.001).
Technical Report – Testing for ovarian cancer in asymptomatic women 62
Table 0.9 Cancer stage at diagnosis – UKFOCSS Phase II
OC (invasive), FTC, PPC
Diagnoses by stage, n (%) All diagnoses
Detected <365 days after last trial screen Detected >365 days after last trial screen
Screen
detected
Occult – RRSO
unrelated to
screening
Prompted by
symptoms
All screening
phase
Local
annual
screening
Occult
– RRSO
Prompted by
symptoms
All post-
screening
phase
Total cancers detected 37 (100) 13 (100)50 6 (100) 0 (100) 19 (100) 3 (100) 2 (100) 13 (100) 18 (100)
Stage I 7 (19) 2 (15) 4 (67) 0 (0) 6 (32) 0 (0) 1 (50) 0 (0) 1 (6)
Stage II 4 (11) 3 (23) 1 (17) 0 (0) 4 (21) 0 (0) 0 (0) 0 (0) 0 (0)
Stage IIIa 2 (5) 1 (8) 1 (17) 0 (0) 2 (11) 0 (0) 0 (0) 0 (0) 0 (0)
Stage IIIb/c 21 (57) 7 (54) 0 (0) 0 (0) 7 (37) 3 (100) 1 (50) 10 (77) 14 (78)
Stage IV 3 (8) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (23) 3 (17)
Early versus late stage
Early (I or II) 11 (30) 5 (38) 5 (83) 0 (0) 10 (53) 0 (0) 1 (50) 0 (0) 1 (6)
Late (III or IV) 26 (70) 8 (62) 1 (17) 0 (0) 9 (47) 3 (100) 1 (50) 13 (100) 17 (94)
Low versus high volume
Low volume (I or II or IIIa) 13 (35) 6 (46) 6 (100) 0 (0) 12 (63) 0 (0) 1 (50) 0 (0) 1 (6)
High volume (IIIb or IIIc or IV) 24 (65) 7 (54) 0 (0) 0 (0) 7 (37) 3 (100) 1 (50) 13 (100) 17 (94)
% low volume, <365 days vs >
365 days
p < 0.001
Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; RRSO, risk-reducing salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
50 Includes 1 case diagnosed in prevalence screen.
63 Technical Report – Testing for ovarian cancer in asymptomatic women
Mortality
Of the 37 women diagnosed with ovarian cancer, FTC or PPC, 5 (13%) were not alive at censorship
in March 2016.51 Of the 19 women diagnosed within a year of screening, 3 (16%) died. No survival
analysis was reported due to the low number of events observed.
Quality of life – PsyFOCS partner study
Outcomes from PsyFOCS, the partner study to UKFOCSS, used quality of life instruments to
investigate the impact of screening and reasons for withdrawal. All women entering Phase II of the
UKFOCSS trial were invited to participate in PsyFOCS, which used the following validated
instruments:
a revised Illness Perceptions Questionnaire (IPQ-R) – adapted to refer to ovarian cancer or
ovarian cancer risk52
the Hospital Anxiety and Depression Scale (HADS)
the Impact of Event Scale (IES) – used for ovarian cancer-specific distress.
Questionnaires were sent out at the following times:
T1 – one month before the first routine Phase II blood test
T2 – one week after women received their initial screening result
T3 –only for those recalled for further testing, sent one week after being returned to routine
screening
T4 – nine months after receiving a normal result or after return to routine screening following
recall for further tests due to an abnormal result.
Measures included cancer distress, general anxiety/depression, reassurance, and withdrawal from
screening.
Prior to screening
T1 was completed by 1,999 women, and these baseline psychological data were used in predictor
analyses of ovarian cancer-specific distress (Lancastle 2011; not reported here).
Factors associated with withdrawal from UKFOCSS Phase II prior to the first screen were investigated
(Lifford 2012); 110 of the 1,999 T1 survey respondents withdrew prior to their first Phase II screen, with
a majority (66%) deciding on RRSO. Logistic regression analysis of baseline (T1) findings from these
women and 1,868 women who continued with screening found the following were associated with
withdrawal prior to first screen:
prior annual (Phase 1) screening (OR=13.34, p<0.01)
past experience of recall for further tests (OR=2.37, p<0.01)
greater cancer-specific distress (OR=1.38, p<0.01)
belief in ageing as a cause of ovarian cancer (OR=1.32, p=0.05).
The authors concluded that both clinical and psychological factors were involved in the decision
to withdraw.
Impact of recall for further testing
Covariate analyses of data from all surveys (T1-T4) were used to indicate that women with
abnormal results reported significantly more ‘moderate cancer distress’ compared to women with
normal results (F=27.47, p≤0.001, η2=0.02) one week after their abnormal result, and were
51 It is assumed these women died from their disease, although this is not explicitly stated. This compares to 30% observed in the Phase I study. 52 Described in Lancastle 2011
Technical Report – Testing for ovarian cancer in asymptomatic women 64
significantly more likely to withdraw from screening (OR=4.38, p≤0.001). These effects were not
apparent at later follow up (once returned to routine screening, and nine months later). The effect
of screening results on general anxiety/depression or overall reassurance was not significant.
The authors report the following conclusion:
‘Women participating in frequent ovarian screening who are recalled for an
abnormal result may experience transient cancer-specific distress, which may
prompt reconsideration of risk management options. Health professionals and policy
makers may be reassured that frequent familial ovarian screening does not cause
sustained psychological harm’.
Semi-structured interviews were also conducted with women who had taken part in the UKFOCSS
study (Lifford 2013; not reported here) to ‘gain an in-depth understanding of women’s experiences
of participating in ovarian cancer screening’. Overall, the authors found that most women
considered surveillance screening to be an acceptable risk management strategy.
Safety outcomes
The primary publication for the UKFOCSS Phase II study did not report adverse events of screening
or surgery.
4.1.5.2 CGN/GOG
Detection outcomes
Mode of detection
Of the 19 cancers detected in the CGN/GOG combined studies, 9 were screen-detected; 4 at
prevalence screening and 5 at subsequent screening. One interval cancer and 9 occult cancers
were also diagnosed during the study. The authors did not report annual incidence. It is not clear
whether such an estimate is valid for the combined studies, but was calculated here post hoc to
compare with the Phase II UKFOCSS study – both were 0.14%.
Table 0.10 Mode of cancer detection – CGN/GOG
Detection outcomes with HR ROCA triage OC (invasive), FTC, PPC
n (%)
N=3,449
Total cancers detected 19
Detected by screening 9 (47)
First screen (prevalent) 4
Subsequent screens (incident screen-detected) 5
Detected by other means 10 (53)
Surgery prompted by symptoms (interval cancers) 1
Occult cancers – discovered at RRSO unrelated to test results 9
Incidence
Overall annual incidence (%) based on 13,080 person-years of trial screening 0.1453
Abbreviations: CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; HR, high risk; OC, ovarian
cancer; PPC, primary peritoneal cancer; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy.
Sensitivity
Sensitivity was calculated as 83% based on 5 of the 6 incident cancers being screen detected. The
authors note that they focused sensitivity analysis on incident cases as they comprise the ‘best
metric for long-term screening’.
53 Calculated post hoc – annual incidence not reported in study publication.
65 Technical Report – Testing for ovarian cancer in asymptomatic women
This estimate does not take into account the 9 occult cancers discovered during 501 elective
RRSOs – had screening replaced these surgeries, a proportion of them may have been screen
detected. The UKFOCSS Phase I study accounted for the impact of occult cancers on sensitivity by
calculating upper and lower limits, and Phase II used modeling.
False positives
The false positive rate in the CGN/GOG was very high at 20.7 false positive surgeries performed for
every case of cancer detected.
Table 0.11 False-positive surgery rates – CGN/GOG
Outcome N (%)
Participants 3,449
Screen-positive surgeries 195
False positive surgeries 186
Screen-detected cancers 9
Number of surgeries to detect one case of cancer 21.7
Number of false positive surgeries per screen-detected cancer 20.7
Abbreviations: CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group.
Tumour characteristics
Table 0.12 shows the stage by diagnosis for all 19 cancers diagnosed in the CGN/GOG study. These
exclude borderline tumours. For incident cancers (both screen-detected and clinically detected), 3
of 6 (50%) were detected early (95% CI: 12%, 88%). Using historical rates, this represents a statistically
significant increase in early stage diagnosis compared to BRCA1 cases (10%; p=0.016) but not
normal risk cases (33.5%; p>0.1).
Table 0.12 Cancer stage at diagnosis – CGN/GOG
OC (invasive), FTC, PPC
Diagnoses by stage, n (%)
Screen-detected Occult – RRSO
unrelated to
screening
Prompted by symptoms
(clinically detected
incident cancer) Prevalent Incident
Total cancers detected 4 5 9 1
Stage I - - 5 -
Stage II - 3 - -
Stage III 3 2 3 1
Stage IV 1 - - -
Other 1 STIC54
Early versus late stage
Stage I/II 0 3 5 0
Stage III/IV 4 2 3 1
Source: data extracted from Table 2 in Skates 2017.
Abbreviations: CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; OC, ovarian cancer; PPC,
primary peritoneal cancer; RRSO, risk-reducing salpingo-oophorectomy.
Mortality
Mortality outcomes were not reported in this study.
4.1.6 Data extraction – clinical studies using single threshold CA125
4.1.6.1 PLCO-HR
This post hoc analysis of the PLCO RCT reported comparative results for two subgroups:
54 One lesion was reported as a serous tubal intraepithelial carcinoma (STIC) allocated Stage 0 and Grade 0.
Technical Report – Testing for ovarian cancer in asymptomatic women 66
women with a family history of breast or ovarian cancer (at least one first degree relative)
women with a personal history of breast cancer.
While these definitions are broader than the general definitions of high risk, it is of interest to
determine whether screening may be more effective in a population with a slightly elevated
overall risk compared to the general population.
All results reported in this study for women with a family history are shown in Table 0.13. A similar
number of cancers was diagnosed in each of the two study groups. While a higher proportion of
screened women were diagnosed with early stage cancers (Stages I or II), the difference was not
significant.
However, when classified as ≤Stage IIIb versus ≥Stage IIIc, a significant stage shift was observed in
screened versus unscreened women. The authors note this classification identifies women prior to
the ‘symptomatic phase’. The study authors conclude that these results indicate a trend towards
earlier stage diagnosis associated with screening, and a significant reduction in advanced bulky
disease at diagnosis.
Table 0.13 Outcomes from PLCO RCT for women with at least one first degree relative with
breast or ovarian cancer
OC (invasive), FTP, PPC
Outcomes
CA125 + TVUS
(N = 11,293)
No screening
(N = 11,062)
Risk ratio [95% CI]
Overall mortality NR NR 0.99 [0.93, 1.06]
Ovarian cancers detected, n 48 44 NR
OC-specific mortality, n 23 32 0.66 [0.39, 1.12]
OC-specific survival from enrolment55 NR NR 0.66 [0.47, 0.93]
Proportion diagnosed by stage
Diagnosed early (Stage I or II) 29% 17% p=0.085
Diagnosed prior to symptomatic phase (Stage I or II or IIIa/b) 48% 25% p=0.031
Abbreviations: CA, cancer antigen; CI, confidence interval; FTC, fallopian tube cancer; NR, not reported; OC, ovarian cancer; PLCO,
Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; RCT, randomised controlled trial; TVUS,
transvaginal ultrasonography.
OC-specific mortality and OC-specific survival from randomisation were both analysed, and while
a significant improvement in survival was observed for screened women (RR 0.66 [95% CI, 0.47 to
0.93]). Figure 0.1), this did not translate into a statistically significant improvement in disease-specific
mortality (RR 0.66 [0.39, 1.12]).
55 Cox proportional hazard regression test.
67 Technical Report – Testing for ovarian cancer in asymptomatic women
Figure 0.1 OC-specific survival in women with a family history of breast or ovarian cancer –
PLCO-HR
Source: Lai 2016, Figure 1.
Abbreviations: HR, high risk; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
All results reported in this study for women with a personal history of breast cancer are shown in
Table 0.14. The number of events in the subgroup of women with a personal history of breast
cancer were too low to allow statistical analysis. The numbers diagnosed and the numbers that
died due to their diagnosis are shown. When combined with the results for the family history
subgroup, survival results remained statistically significant.
Table 0.14 Outcomes from PLCO RCT for women with a personal history of breast cancer
OC (invasive), FTP, PPC
Outcomes
CA125 + TVUS
N = 1,351
No screening
N = 1,357
Risk ratio [95% CI]
Ovarian cancers detected, n 6 5 Insufficient events
OC-specific mortality 3 4 Insufficient events
Abbreviations: CA, cancer antigen; CI, confidence interval; OC, ovarian cancer; FTC, fallopian tube cancer; PLCO, Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; RCT, randomised controlled trial; TVUS, transvaginal ultrasonography.
The study authors note that while trials of screening efficacy must demonstrate a reduction in
disease-specific mortality, secondary endpoints ‘may be useful, and may be indicative of a
potential benefit to screening’. It was noted that the increase in early stage cancers was
associated with a significant reduction in the absolute number of Stage IIIc and IV cancers (i.e. not
only an increase in the detection of nonlethal subclinical malignancies), and that cancers in the
screened group were similar to cancers in the control group with regard to histology and grade
(data not reported). The authors consider this to suggest a direct correlation between stage shift
and survival, rather than a ‘length-biased sampling’ effect.
The study authors concluded that this study found significant differences in the number of patients
presenting with advanced bulky disease, and in survival (but not mortality) in those diagnosed with
ovarian cancer. They consider that further investigation is warranted to assess the screening of
women with an increased risk of ovarian cancer.
The rate of false positive surgery was not reported in this study.
Technical Report – Testing for ovarian cancer in asymptomatic women 68
4.1.6.2 UKFOCSS Phase I
This UK study was initiated in 2002 and screened women at high risk of ovarian cancer with annual
single threshold CA125 and TVUS. A before/after screening comparison is presented by the study
authors, comparing outcomes within a year of screening to those over a year after the last screen.
After data abstraction, post hoc calculations (proportions) were performed so that outcomes
could be presented similarly to the Phase II study results, facilitating between-study comparisons.
Detection outcomes
Mode of detection
A total of 37 cancers were detected,56 of which the majority were screen detected (n=22; 59%). A
large proportion of those were prevalent at the start of the trial (n=9; 41% of screen-detected
cancers). Consequently, results are shown separately for prevalent cancers, which may be
expected to have different characteristics to those detected during the screening phase.
Detection is shown by time from last screen (<365 days vs >365 days from last screen). This screening
refers to screening that took place within the trial. A majority of women in Phase I of this study
transferred to Phase II, and they were censored one year after the first Phase II screen. No cancers
were diagnosed in Phase II within a year of transferring from Phase I. Therefore, the group of women
with cancers detected >365 days since their last screen would consist of:
women who did not attend all scheduled annual screens during Phase I, and
those who left Phase I but did not join Phase II.
Three cancers were detected after symptom-prompted surgery within a year of screening (interval
cancers). Symptom-prompted surgery also formed the majority of instances of cancers detected
over a year after surgery (6 of 10).
The overall annual incidence of ovarian cancer or FTC or PPC was higher in Phase I (0.24%) than in
Phase II (0.14%). The higher number of prevalent cases in Phase I accounts for this difference.
Table 0.15 Mode of cancer detection – UKFOCSS Phase I
Detection outcomes
n (%) with CA125 single threshold
N=3,563
OC (invasive), FTC,
PPC
OC (invasive), FTC PPC
Total cancers detected 37 (100) 33 (100) 4 (100)
Detected <365 days after last trial screen (prior to censorship) 27 (73) 26 (79) 1 (25)
Detected >365 days after last trial screen (post censorship) 10 (27) 7 (21) 3 (75)
Detected by screening <365 days after last trial screen 22 (59) 22 (67) 0 (0)
First screen (prevalent) 9 (24) 9 (27) 0 (0)
Subsequent screens (incident screen-detected) 13 (35) 13 (39) 0 (0)
Detected by other means <365 days after last trial screen 5 (14) 4 (12) 1 (25)
Surgery prompted by symptoms (interval cancers) 3 (8) 2 (6) 1 (25)
Occult cancers – discovered at RRSO unrelated to test results 2 (5) 2 (6) 0 (0)
Detected >365 days after last trial screen 10 (27) 7 (21) 3 (75)
Surgery prompted by symptoms 6 (16) 6 (18) 0 (0)
Occult cancers – discovered at RRSO 2 (5) 1 (3) 1 (25)
Detected by screening locally 2 (5) 0 (0) 2 (50)
56 Phase II also detected a total of 37 cancers – this is not a data extraction error.
69 Technical Report – Testing for ovarian cancer in asymptomatic women
Detection outcomes
n (%) with CA125 single threshold
N=3,563
OC (invasive), FTC,
PPC
OC (invasive), FTC PPC
Incidence (detected < 365 days from last screen)
Overall annual incidence (%) based on 11,366 person-years of
screening 0.24 0.2357 0.009
Abbreviations: CA, cancer antigen; OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; RRSO, risk-reducing
salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
Sensitivity
As mentioned for Phase II of this study, occult cancers detected at RRSO, unrelated to screening,
impact on estimates of the sensitivity of screening. The Phase I study presented two analyses of
occult cancers; one treating them as false negatives (assumed all would have been detected in
the next round of screening) and the other treating them as true positives (assuming none would
be detected in the next round of screening), thus providing an upper and lower limit for the impact
of occult cancers on sensitivity. These analyses were also performed for subgroups according to
mutation status. While some estimates of sensitivity using the single threshold CA125 and TVUS for
annual screens are high, all have substantially wide confidence intervals.
Table 0.16 Sensitivity of screening, with and without occult cancers – UKFOCSS Phase I
Sensitivity estimated with two occult cancers
(diagnosed <365 days after last screen) either
excluded or included as a true positive
Prevalent Incident
OC (invasive), FTC
% [95% CI]
OC (invasive), FTC
% [95% CI]
OC (invasive), FTC, PPC
% [95% CI]
Total screened population, (N=3,563)
Occult – false negative 90.0 [55.5, 99.8] 81.3 [54.3, 96.0] 76.5 [50.1, 93.2]
Occult – true positive 100 [69.2, 100] 87.5 [61.7, 98.5] 82.4 [56.6, 96.2]
BRCA1/2 mutation carriers (n=538)
Occult – false negative 85.7 [42.1, 99.6] 76.9 [46.2, 95.0] No PPC
Occult – true positive 100 [59.0, 100] 91.7 [61.5, 99.8] No PPC
Unknown mutation status at enrolment (n=3,065)
Occult – false negative None 91.7 [61.5, 99.8] 75.0 [19.4, 99.4]
Occult – true positive None 100 [73.5, 100] 75.0 [19.4, 99.4]
LS mutation of family history (n=99)
Occult – false negative 100 [29.2, 100] 100 [2.5, 100]58 No PPC
Occult – true positive 100 [29.2, 100] 100 [2.5, 100] No PPC
Abbreviations: CI, confidence interval; OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; UKFOCSS, United
Kingdom Familial Ovarian Cancer Screening Study.
False positives
Table 0.17 shows the number of false positive surgeries i.e. screen-positive surgeries resulting in any
diagnosis other than invasive ovarian cancer, FTC or PPC (borderline tumours were counted as
false positives).
57 Calculated post hoc from 26 cancers detected <365 days from last screen. 58 As shown in Table 2 of Rosenthal 2013, all diagnoses in women with Lynch syndrome were detected at prevalent screen – it is unclear why
data are reported for incident cancers.
Technical Report – Testing for ovarian cancer in asymptomatic women 70
Table 0.17 False-positive surgery rates – UKFOCSS Phase I
UKFOCSS Phase I
Outcome
N (%)
Participants 3,563 (100)
Screen-positive surgeries 74
False positive surgeries 52
Screen-detected cancers (invasive OC, FTC, PPC diagnosed prior to censorship) 22
Number of surgeries to detect one case of cancer 3.4
Number of false positive surgeries per screen-detected cancer 2.4
Note: data calculated post hoc from the reported number of false positive surgeries and the number of screen-detected cancers.
Abbreviations: OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; UKFOCSS, United Kingdom Familial Ovarian
Cancer Screening Study.
Tumour characteristics
Cancer stage at diagnosis is shown for all three cancer types diagnosed to March 2011 (Table
0.18). When considering cancers diagnosed within a year of screening, around half were
diagnosed late (Stage III or IV = 52%; Stage IIIa or later = 44%), while cancers diagnosed over a year
after the last trial screen were almost all late stage/high volume (90%), with 6 of 10 diagnoses
prompted by symptoms.
When restricted to incident screen-detected cancers, the frequency of late stage diagnoses was
higher (69% Stage III or IV; 62% high volume). In the prevalent screen, however, the majority of
cancers (67%) were detected at an early stage (Stage I or II). It is noted that the numbers analysed
are low. A single statistical comparison was reported, for ovarian cancer or FTC diagnosed within a
year of screening versus over a year after screening, excluding PPCs and women with Lynch
syndrome. This analysis is described below.
71 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.18 Cancer stage at diagnosis – UKFOCSS Phase I
OC (invasive), FTC, PPC
Diagnoses by stage, n (%) All
diagnoses
Detected <365 days after last trial screen Detected >365 days after last trial screen
Prevalent
screen
Incident screen Occult – RRSO
unrelated to
screening
Prompted by
symptoms
(interval)
All <1 year
after last
screen
Screening after
trial
Occult – RRSO Prompted by
symptoms
All >1 year
after last
screen
Total cancers detected 37 9 13 2 3 27 2 2 6 10
Stage I 10 (27) 5 2 1 1 9 (33) 0 1 0 1 (10)
Stage II 4 (11) 1 2 1 0 4 (15) 0 0 0 0 (0)
Stage IIIa 2 (5) 1 1 0 0 2 (7) 0 0 0 0 (0)
Stage IIIb 6 (16) 1 4 0 0 5 (19) 1 0 0 1 (10)
Stage IIIc 13 (35) 1 4 0 1 6 (22) 1 1 5 7 (70)
Stage IV 2 (5) 0 0 0 1 1 (4) 0 0 1 1 (10)
Early versus late stage
Early (I or II) 14 (38) 6 (67) 4 (31)59 2 (100) 1 (33) 13 (48) 0 (0) 1 (50) 0 (0) 1 (10)
Late (III or IV) 23 (62) 3 (33) 9 (69) 0 (0) 2 (67) 14 (52) 2 (100) 1 (50) 6 (100) 9 (90)
Low versus high volume
Low volume (I or II or IIIa) 16 (43) 7 (78) 5 (38) 2 (100) 1 (33) 15 (56) 0 (0) 1 (50) 0 (0) 1 (10)
High volume (IIIb or IIIc or IV) 21 (57) 2 (22) 8 (62) 0 (0) 2 (67) 12 (44) 2 (100) 1 (50) 6 (100) 9 (90)
Data abstracted from Rosenthal 2013 Table 3, with post hoc calculations of proportions.
Abbreviations: OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; RRSO, risk-reducing salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
59 30.8%; 95% CI, 12.4% to 58.0%)
Technical Report – Testing for ovarian cancer in asymptomatic women 72
Table 0.19 shows the proportion of cancers that were Stage IIIc or later, which involves peritoneal
metastasis >2cm and/or regional lymph node metastasis, or spread beyond abdominal organs.
Proportions are shown for diagnoses made one year before and one year after the last screen trial.
Stepwise exclusion of primary peritoneal cases and women with Lynch syndrome is shown. For this
last comparison, diagnoses made within a year of screening were significantly less likely to be Stage
IIIc or Stage IV (Fisher’s test p=0.009).
Table 0.19 Proportion of cancers diagnosed at ≥ Stage IIIC – UKFOCSS Phase I
%, (n/N) or [95% CI] OC (invasive), FTC, PPC
(all 3 cancer types)
OC (invasive), FTC
(excl. PPC)
OC (invasive), FTC
(excl. PPC and Lynch
syndrome)
Detected <365 days after last trial screen 25.9%
(7/27)
23.1%
(6/26)
26.1%
[10.2, 48.4]
(6/23)
Detected >365 days after last trial screen 80.0%
(8/10)
85.7%
(6/7)
85.7%
[42.1, 99.6]
(6/7)
p=0.009
Abbreviations: CI, confidence interval; OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; UKFOCSS, United
Kingdom Familial Ovarian Cancer Screening Study.
Mortality
All-cause mortality and OC-specific mortality were censored in March 2011. Of the 37 women
diagnosed with ovarian cancer, FTC or PPC, 11 died as a result of their disease (30%)60. All deaths
were due to ovarian cancer or FTC, but the number of deaths in women diagnosed within a year
of screening was not reported. However, there was no difference in OC-specific mortality between
women diagnosed within a year of last screen and those diagnosed over a year after last screen
(log-rank [Mantel-Cox] p=0.233).
4.1.6.3 UK-Netherlands-Norway study
The UK-Netherlands-Norway study reported the combined data from ovarian cancer screening at
five cancer genetics centres. The details of the screening protocol were not described, and may
well have differed between sites. The authors suggest the screening strategy would have involved
CA125 and TVUS, and this is certainly the case for at least the Netherlands centre, which used a
single threshold cut-off for CA125 evaluation.
Within this single cohort study, the authors made comparisons between cancers detected at
prevalence screening and post-prevalence screening (incident and interval cancers) with a view
to detecting a survival difference or a stage shift. False positive surgery and RRSO were not
reported. No quality of life or adverse event outcomes were reported.
60 This rate is higher than that observed in Phase II (13%).
73 Technical Report – Testing for ovarian cancer in asymptomatic women
Detection outcomes
Table 0.20 Mode of cancer detection – UK-Netherlands-Norway study
Detection outcomes
n (%)
UK-Netherlands-Norway
OC (invasive, borderline)
CA125/TVUS
Total cancers detected 64 (100)
Prevalent screen-detected (first screen) 26 (41)
Incident screen-detected (subsequent screens) 27 (42)
Interval cases (<12–14 months from negative screen) 11 (17)
Total post-prevalent cases (incident, incl. interval cancers) 38 (59)
Abbreviations: CA, cancer antigen; OC, ovarian cancer; TVUS, transvaginal ultrasonography; UK, United Kingdom.
Tumour characteristics
Table 0.21 shows tumour stage by mode of detection (prevalent screen or post-prevalent screen)
for all cancers detected and also for all cancers in carriers of BRCA1/2 mutations. These groups
were not compared statistically, which is not surprising given the small sample sizes. The authors
noted that there is little difference in the number of late stage diagnoses (Stage III or IV) between
the prevalent and post-prevalent cases across all cancers, but when restricted to cancers in
women with BRCA1 or BRCA2 mutations, there is ‘some evidence of down staging’ (81% of
prevalent cases were late stage and 61% of post-prevalent cases were late stage).
Table 0.21 Cancer stage at diagnosis – UK-Netherlands-Norway study
OC (invasive, borderline)
Detection outcomes, n
All cancers All cancers BRCA1/2 carriers
Prevalent Post-prevalent Prevalent Post-prevalent
Total cancers detected 64 26 38 21 28
Stage I – borderline 5 4 1 0 0
Stage 1 – invasive 11 3 8 2 6
Stage II 7 2 5 2 5
Stage III or IV 41 17 24 17 17
Late stage diagnosis (% Stage III or IV)
Including borderline tumours 64 65 63 81 61
Excluding borderline tumours 70 77 65 N/A N/A
Abbreviations: OC, ovarian cancer; UK, United Kingdom.
Mortality
Kaplan–Meier survival analysis was used to compare survival to censorship61 in patients with
prevalent cases versus patients with post-prevalent cases. No difference was seen between
groups, either with borderline tumours included (log rank p=0.9363) or excluded (log rank
p=0.4428), or when restricted to patients with BRCA1/2 mutations (data not reported).
4.1.6.4 Fox Chase Cancer Centre
This prospective study surveyed women who were undergoing routine surveillance screening due
to an increased risk of ovarian cancer and were considering prophylactic RRSO. Participants
identified as either having surgery in the immediate future (N=38) were compared with those
choosing to continue with screening (N=37). Baseline characteristics were compared between
groups and were balanced overall.
61 Up to 16 years follow up, mean or median not reported.
Technical Report – Testing for ovarian cancer in asymptomatic women 74
Outcomes were assessed at 1 month, 6 months and 12 months after baseline assessment, which
was at surgery for women in the surgery group.
Quality of life
This study used the validated Medical Outcomes Survey (MOS) Short-Form Health Survey (SF-36)
and the Center for Epidemiological Studies-Depression scale (CES-D), which the authors note has
high reliability and internal validity and has been widely used. These two outcomes are reported
here. A further two instruments were also used: Sexual Activity Questionnaire and a 43-item
symptom checklist that was originally developed for the National Surgical Adjuvant Breast and
Bowel Project. Neither of these outcomes are reported here as they are not validated.
Short-Form Health Survey (SF-36)
Physical Component Summary (PCS) and Mental Component Summary (MCS) were analysed over
time from measures at baseline, 1 month, 6 months and 12 months, with surgery taking place at
baseline in the surgery group.
The surgery group reported significantly lower mean scores for physical wellbeing (PCS) at 1-month
follow-up compared with baseline (β=−5.61, p<0.02), whereas no such deficit was observed in the
screening group (Figure 0.2). No differences in MCS were observed between the two groups or
over time.
Figure 0.2 Mean PCS and MCS scores by group at each time point – Fox Chase Cancer
Centre
Source: Fang 2009, Figure 1.
Abbreviations: MCS, Mental Component Summary; PCS, Physical Component Summary.
The SF-36 subscales were also compared between the surgery and screening groups. At 1-month
follow up, women in the surgery group had significantly worse scores than at baseline for five
subscales: Physical Functioning, Role-Physical, Bodily Pain, Vitality, and Social Functioning. However,
these decrements were no longer apparent at 6-month and 12-month follow up. One exception
was bodily pain, with significantly lower scores, indicating greater pain, at 12-month assessment
(mean 69.00, SD 22.35) compared with baseline (mean 80.31, SD 22.51), β=−10.92, p=0.05.
Women in the screening group reported no significant decrements in these domains over time.
Center for Epidemiological Studies-Depression scale (CES-D)
No significant differences in depressive symptoms were observed over time or between the surgery
and screening groups.
75 Technical Report – Testing for ovarian cancer in asymptomatic women
The authors concluded that while deficits in physical functioning and other specific domains of
quality of life were observed following RRSO, they were short term, with most women recovering by
6 to 12 months after surgery.
4.1.7 Data extraction – systematic reviews and HTAs
The conclusions of the Auranen 2011 systematic review, which evaluated the role of
gynaecological cancer surveillance in women who carry a HNPCC mutation or belong to a family
that fulfils the criteria for HNPCC, are summarised in Table 0.22. As the literature search for this
systematic review was conducted in 2010, the results are not discussed any further in the current
report.
Table 0.22 Key characteristics of systematic reviews relating to surveillance of women at
high risk
Study ID
Qualitya
Intervention &
comparator
Conclusions
Auranen
2011
Poor quality
Intervention
Gynaecological
cancer surveillance
Comparator
Not specified
Currently available published studies on gynecological cancer surveillance in women with
HNPCC do not adequately allow for evidence-based clinical decisions.
No benefit was shown for OC surveillance. Of the five OCs diagnosed in the studies included
in the review, four were of endometrioid subtype and the subtype of the fifth patient was
not given. In the general population, approximately 15% of ovarian carcinomas are of
endometrioid subtype, and the majority are either serous or undifferentiated subtypes.
Abbreviations: HNPCC, hereditary nonpolyposis colorectal cancer; OC, ovarian cancer; TVUS, transvaginal ultrasound.
a Quality was assessed using AMSTAR (see Appendix F).
Review of clinical guidance
4.1.8 Identified guidelines
Nine clinical practice guidelines were identified with guidance relating to ovarian cancer
screening and/or surveillance, published from 2011 onwards (Table 0.1). The search also identified a
further 11 forms of guidance, which included position statements, regulatory safety
communications, committee opinions, policy recommendations, and practice bulletins (Table 0.2).
Technical Report – Testing for ovarian cancer in asymptomatic women 76
Table 0.1 Included clinical practice guidelines
Ref ID Title Developer/affiliation Brief description of
methodology
Paluch-
Shimon 2016
Prevention and screening in BRCA mutation
carriers and other breast/ovarian hereditary
cancer syndromes: ESMO Clinical Practice
Guidelines for cancer prevention and
screening
European Society of Medical
Oncology (ESMO)
Relevant literature selected by
expert authors. Levels of
evidence and grades as per
the Infectious Diseases Society
of America methodology
RACGP 2016 Guidelines for preventive activities in
general practice
Royal Australian College of General
Practitioners (RACGP)
Systematic review with quality
rating and grading using
NHMRC methodology
Llort 2015 SEOM clinical guidelines in hereditary breast
and ovarian cancer
Sociedad Española de Oncología
Médica (SEOM)
Used Infectious Diseases Society
of America-US Public Health
Service Grading System for
Ranking Recommendations in
Clinical Guidelines to determine
quality of evidence and
strength of recommendations
Singer 2015 Clinical Practice Guideline for the
prevention and early detection of breast
and ovarian cancer in women from HBOC
(hereditary breast and ovarian cancer)
families
Singer et al. (Austrian) NR
British
Columbia
2014
Genital tract cancers in females: ovarian,
fallopian tube, and primary peritoneal
cancers
Family Practice Oncology Network
and the Guidelines and Protocols
Advisory Committee
States that the guideline is
based on scientific evidence
current as of the effective date
Qaseem
2014
Screening Pelvic Examination in Adult
Women: A Clinical Practice Guideline From
the American College of Physicians
American College of Physicians (ACP) Systematic review and
evidence grading using GRADE
SIGN 2013 Management of epithelial ovarian cancer:
A national clinical guideline (SIGN 135)
Scottish Intercollegiate Guidelines
Network (SIGN)
Systematic review with quality
rating using SIGN criteria.
Graded using SIGN criteria.
Morgan 2012 NCCN Guidelines Insights. Ovarian Cancer,
Version 3.2012. Featured updates to the
NCCN Guidelines
National Comprehensive Cancer
Network (NCCN)
NR but evidence-based
NBOCC 2011 Recommendations for management of
women at high risk of ovarian cancer. A
clinical practice guideline developed by
National Breast and Ovarian Cancer Centre,
September 2011
National Breast and Ovarian Cancer
Centre (NBOCC)62
Systematic review and level of
evidence using NHMRC criteria
62 Now Cancer Australia.
77 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.2 Included position statements and other guidance
Ref ID Title Developer/affiliation Brief description of
methodology
AAFP 2017 Summary of Recommendations for Clinical
Preventive Services, July 2017
American Academy of Family
Physicians (AAFP)
Starting point is a review of
recommendations released by
USPSTF
ACOG 2017a Committee Opinion 716: The role of the
obstetrician-gynecologist in the early
detection of epithelial ovarian cancer in
women at average risk
American College of Obstetricians
and Gynecologists (ACOG)
Committee on Gynecologic
Practice and Society of
Gynecologic Oncology (SGO)
Not reported
ACOG 2017b Practice Bulletin No. 182: Hereditary breast
and ovarian cancer syndrome. Practice
Bulletin Number 182
American College of Obstetricians
and Gynecologists (ACOG)
Committee on Practice Bulletins–
Gynecology, Committee on
Genetics, and Society of
Gynecologic Oncology (SGO)
Systematic review and
evaluation and grading using
USPSTF criteria
ACR 2017 ACR Appropriateness Criteria Ovarian Cancer
Screening
American College of Radiology
(ACR)
Systematic review and
appropriateness rating using
RAND/UCLA Appropriateness
Method63
USPSTF 2017a
(draft)
Screening for ovarian cancer US Preventive Services Task Force
(USPSTF)
Systematic review with quality
rating using USPSTF criteria.
Graded using USPSTF criteria.
USPSTF 2017b Screening for Gynecologic Conditions With
Pelvic Examination US Preventive Services Task
Force Recommendation Statement
US Preventive Services Task Force
(USPSTF)
Systematic review with quality
rating using USPSTF criteria.
Graded using USPSTF criteria.
Zeimet 2017 AGO Austria recommendation on screening
and diagnosis of Lynch syndrome (LS)
Austrian Arbeitsgemeinschaft für
Gynäkologische Onkologie (AGO)
Not reported
FDA 2016 The FDA recommends against using screening
tests for ovarian cancer screening: FDA Safety
Communication
Food and Drug Administration (FDA) Not reported
GOC 2016 The Society of Gynecologic Oncology of
Canada (GOC) Opinion Statement regarding
the UK Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS) results
Society of Gynecologic Oncology
of Canada (GOC)
Not reported
Wilt 2015 Screening for cancer: advice for high-value
care from the American College of Physicians
American College of Physicians
(ACP)
Review of clinical practice
guidelines
Moyer 2012 Screening for Ovarian Cancer: U.S. Preventive
Services Task Force Reaffirmation
Recommendation Statement
US Preventive Services Task Force Systematic review
4.1.9 Guidance relating to population screening
All guidance published in 2016 and 2017 considered evidence from the primary publication of the
UKCTOCS trial (Jacobs 2016). None of the clinical practice guidelines (Table 0.3) or other forms of
guidance (Table 0.4) recommend routine screening for ovarian cancer in asymptomatic or
average-risk women.
Consistent with this formal guidance, Cancer Research UK states that, “There is no national
screening programme for ovarian cancer in the UK because there is no test that reliably picks up
ovarian cancer at an early stage.”64
Likewise, the American Cancer Society states that, “Researchers continue to look for new tests to
help diagnose ovarian cancer early but currently there are no reliable screening tests.”65
63 Fitch K. The Rand/UCLA appropriateness method user's manual. Santa Monica: Rand; 2001. 64 Taken from the Cancer Research UK website, accessed October 2017. 65 Taken from the American Cancer Society website, accessed October 2017
Technical Report – Testing for ovarian cancer in asymptomatic women 78
Table 0.3 Relevant guidance from clinical practice guidelines – women at average risk
Ref ID
Developer
Guidance type Recommendation/evidence statement Level of evidence/
Grade66
Evidence base
RACGP 2016 Evidence-based Lower risk women: those who have used the oral contraception or carried a
pregnancy to term (risk of about half the population average)
No screening for ovarian cancer.
NR Jacobs 2016 [UKCTOCS], GOC 2016, CA 2015, Moyer
2012, CA 2009, Schorge 2010
British Columbia
2014
Evidence-based Routine screening of females, whether of high or average risk, is not recommended.
Studies have consistently failed to identify any reduction in the morbidity or mortality
from ovarian cancer in females screened with currently available technology such as
TVUS or CA125. The potential harms of screening are substantial and include false
reassurance, high recall rates for false positive results, and surgery for benign
conditions with the associated surgical risks.
NR Barton 2012 [AHRQ], Buys 2011 [PLCO], Horsman 2007,
BC Cancer Agency (date unknown),
Qaseem 2014
ACP
Evidence-based ACP recommends against performing screening pelvic examination [for cancer,
pelvic inflammatory disease or other benign conditions] in asymptomatic,
nonpregnant, adult women.
Moderate quality
evidence
Strong
recommendation
Related to ovarian cancer
Buys 2011 [PLCO]
SIGN 2013 Evidence-based Screening for ovarian cancer in the general population should not be performed
outside the research setting.
Grade A Buys 2011 [PLCO], Menon 2009 [UKCTOCS initial
screening round]
Morgan 2012
NCCN
Evidence-based Screening for ovarian cancer is not recommended by the NCCN Ovarian Cancer
Panel or by any major organisation.
Category 2A Smith 2012, Buys 2011 [PLCO], Clarke-Pearson 2009
Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACP, American College of Physicians; CA, cancer antigen; CT, computed tomography; FDA, US Food and Drug Administration; FDG-PET,
18F-fluorodeoxyglucose positron emission tomography; GOC, Society of Gynecologic Oncology of Canada; MRI, magnetic resonance imaging; NA, not applicable; NCCN, National Comprehensive Cancer Network;
NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RACGP, Royal Australian College of General Practitioners; SIGN, Scottish Intercollegiate Guidelines Network; TVUS, transvaginal
ultrasonography; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening; US, United States; USPSTF, US Preventive Services Task Force.
NCCN: category I – high level of evidence with uniform consensus; category IIA – lower level of evidence with uniform consensus; category IIB – lower level of evidence without a uniform consensus but with no major
disagreement; and category III – any level of evidence but with major disagreement.
SIGN: Grade A: At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly
applicable to the target population, and demonstrating overall consistency of results; Grade B – A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating
overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+; Grade C – A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating
overall consistency of results; or Extrapolated evidence from studies rated as 2++; Grade D – Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+.
66 See table footnotes for description of different grading systems used.
79 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.4 Relevant guidance from other sources – women at average risk
Ref ID
Developer
Guidance type Recommendation/evidence statement Level of evidence/
Grade67
Evidence base
ACOG 2017a Committee Opinion Currently, there is no strategy for early detection of ovarian cancer that reduces
ovarian cancer mortality. The use of TVUS and tumour markers (such as CA125), alone
or in combination, for the early detection of ovarian cancer in average-risk women
have not been proved to reduce mortality, and harms exist from invasive diagnostic
testing (e.g. surgery) resulting from false positive tests.
NA AOG 2016, Jacobs 2016 [UKCTOCS], OCRF/BCWG
2016, Menon 2015 [UKCTOCS], Bristow 2013, Moyer
2012, Buys 2011 [PLCO], Moore 2011, Ueland 2011, Van
Gorp 2011, Menon 2009 [UKCTOCS], Partridge 2009,
Menon 2005 [UKCTOCS], Skates 2003, Jacobs 1989,
Bast 1983,
ACR 2017 Evidence-based Ovarian cancer screening [using ultrasound, CT, MRI and FDG-PET] is not
recommended for average-risk pre-menopausal women.
Usually not
appropriate
No evidence base to support
Ovarian cancer screening [using ultrasound, CT, MRI and FDG-PET] is not
recommended for average-risk post-menopausal women, as randomised controlled
trials have not demonstrated a definitive mortality benefit in this population.
Usually not
appropriate
Jacobs 2016 [UKCTOCS], Lu 2013, Reade 2013, Dodge
2012, Buys 2011 [PLCO], van Nagell 2011, Pickhardt
2010, Partridge 2009, Kobayashi 2008, van Nagell 2007,
Menon 2005, Kinkel 2005, Jacobs 1999.
USPSTF 2017a
(draft)
Evidence-based68 The USPSTF recommends against screening for ovarian cancer in asymptomatic
women.
TVUS and serum CA125 testing are the most commonly suggested screening
modalities. Annual screening with TVUS and serum CA125 testing in women does not
decrease ovarian cancer mortality. Screening for ovarian cancer can lead to
important harms, including major surgical interventions in women who do not have
cancer. Therefore, the harms of screening for ovarian cancer outweigh the benefits.
Grade D Henderson 2017 AHRQ Evidence Synthesis Number
157: [UKCTOCS, PLCO]
USPSTF 2017b Evidence-based69 No recommendation. The USPSTF concludes that the current evidence is insufficient to
assess the balance of benefits and harms of performing screening pelvic
examinations70 [for gynaecologic conditions] in asymptomatic, nonpregnant adult
women.
I Statement (see
legend)
Guirguis-Blake 2017 AHRQ Evidence Synthesis Number
147: [PLCO]
FDA 2016 Safety
Communication for
physicians
Do not recommend or use tests that claim to screen for ovarian cancer in the general
population of women. Be aware that testing higher risk asymptomatic patients for
ovarian cancer has no proven benefit and is not a substitute for preventive actions
that may reduce their risk.
NA NR
GOC 2016 Opinion statement Based on the results of the two large randomised phase three trials, the recent
UKCTOCS trial (December 2015) and the previously published PLCO trial (2011), GOC
does not recommend screening for “ovarian” cancer at this time.
NA Jacobs 2016, [UKCTOCS] Buys 2011 [PLCO]
67 See table notes for description of different grading systems used. 68 Retrieved from USPSTF website. 69 Retrieved from USPSTF website. 70 May include any of the following components, alone or in combination: assessment of the external genitalia, internal speculum examination, bimanual palpation, and rectovaginal examination.
Technical Report – Testing for ovarian cancer in asymptomatic women 80
Ref ID
Developer
Guidance type Recommendation/evidence statement Level of evidence/
Grade67
Evidence base
Wilt 2015 High-value care
advice
Clinicians should not screen average-risk women for ovarian cancer.
Based on a large RCT of screening, all organisations [ACOG, ACP, ACS, USPSTF]
recommend against pelvic examinations, CA125 blood tests, and TVUS for ovarian
cancer screening. Screening would lead to no benefits and would increase harms
and costs, including complications of invasive work-ups.
NA AAFP 2015; Smith 2015; Qaseem 2014; Moyer 2012;
Buys 2011 [PLCO]
AAFP 201271 Policy
recommendations
Asymptomatic women
The AAFP recommends against screening for ovarian cancer in women. (2012)
Grade: D
recommendation
[USPSTF]
Barton 2012 [AHRQ]; Danforth 2012 [AHRQ]; Buys 2011
[PLCO]; Menon 2009 [UKCTOCS initial screening
round]; Partridge 2009; Kobayashi 2008; Menon 2005;
Nelson 2004 [AHRQ]
Moyer 2012
USPSTF
Reaffirmation
Recommendation
Statement
Asymptomatic women without known genetic mutations that increase risk for ovarian
cancer – do not screen for ovarian cancer.
Grade D Barton 2012 [AHRQ]
Abbreviations: AAFP, American Academy of Family Physicians; ACOG, American College of Obstetricians and Gynecologists; ACP, American College of Physicians; ACS, American Cancer Society; AHRQ, Agency for
Healthcare Research and Quality; CA, cancer antigen; CT, computed tomography; FDA, US Food and Drug Administration; FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; GOC, Society of
Gynecologic Oncology of Canada; MRI, magnetic resonance imaging; NA, not applicable; NCCN, National Comprehensive Cancer Network; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian
Cancer Screening Trial; RACGP, Royal Australian College of General Practitioners; RCT, randomised controlled trial; SIGN, Scottish Intercollegiate Guidelines Network; SR, systematic review; TVUS, transvaginal
ultrasonography; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening; US, United States; USPSTF, US Preventive Services Task Force.
ACR: Usually not appropriate – The imaging procedure or treatment is unlikely to be indicated in the specified clinical scenarios, or the risk-benefit ratio for patients is likely to be unfavorable; May be appropriate – The
imaging procedure or treatment may be indicated in the specified clinical scenarios as an alternative to imaging procedures or treatments with a more favorable risk-benefit ratio, or the risk-benefit ratio for patients
is equivocal.
USPSTF: Grade A – The USPSTF recommends the service. There is high certainty that the net benefit is substantial; Grade B – The USPSTF recommends the service. There is high certainty that the net benefit is moderate,
or there is moderate certainty that the net benefit is moderate to substantial; Grade C – The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and
patient preferences. There is at least moderate certainty that the net benefit is small; Grade D – The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or
that the harms outweigh the benefits; I statement: Insufficient evidence. Read the Clinical Considerations section of the USPSTF Recommendation Statement. If the service is offered, patients should understand the
uncertainty about the balance of benefits and harms.
71 AAFP guidance is dated 2017 but the relevant recommendation for asymptomatic women was developed in 2012.
81 Technical Report – Testing for ovarian cancer in asymptomatic women
4.1.10 Guidance relating to surveillance in women at high risk
Relevant guidance on surveillance of women at high or potentially high risk of ovarian cancer is
summarised below for clinical practice guidelines (Table 0.5) and other forms of guidance (Table
0.6).
None of the identified clinical practice guidelines incorporate the primary publications for
UKFOCSS, CGN/GOG or PLCO-HR, which were all published in 2016-2017. The recent American
College of Obstetricians and Gynecologists Practice Bulletin on hereditary breast and ovarian
cancer syndrome (HBOC; ACOG 2017b) incorporates evidence from UKFOCSS Phase II, but not
CGN/GOG or PLCO-HR. The recent American College of Radiology Appropriateness Criteria for
ovarian cancer screening (ACR 2017) incorporates the primary publication from PLCO-HR and
UKFOCSS Phase I, but not the UKFOCSS Phase II.
On the basis of the evidence considered, there was no strong support in guidelines for routine
surveillance of women at high risk. Five guidance documents advise that despite a lack of strong
evidence, surveillance with TVUS with or without CA125 may be considered in particular high-risk
populations (ACOG 2017b; ACR 2017; AGO 2017; Paluch-Shimon 2016; Llort 2015). One guideline
from Austria (Singer 2015) recommends annual TVUS and CA125 for the prevention and early
detection of ovarian cancer in women from HBOC families, noting that a potential benefit of
CA125 on the early detection of ovarian cancer has not been demonstrated.
Technical Report – Testing for ovarian cancer in asymptomatic women 82
Table 0.5 Relevant guidance from clinical practice guidelines – surveillance of women at high risk
Ref ID
Developer
Guidance type Recommendation/evidence statement Level of evidence/
Grade
Evidence base
Paluch-Shimon
2016
ESMO
Evidence-based Before risk-reducing salpingo-oophorectomy, 6-monthly, TVUS and measures of serum CA125 may
be considered from the age of 30; however, the limited value of these tools as an effective
screening measure should be communicated to individuals.
Studies without a
control group, case
reports, expert
opinion
Grade C
Menon 2015 [UKCTOCS post hoc analysis
of performance of a CA125 threshold
rule], Greene 2008
RACGP 2016 Evidence-based Higher risk women: family history of ovarian cancer, especially first-degree relatives and more than
one relative (risk of about 3 times the population average); presence of the genes BRCA1 or
BRCA2.
No screening for ovarian cancer.
NR Jacobs 2016 [UKCTOCS], USPSTF 2013,
Buys 2011 [PLCO]
Llort 2015
SEOM
Evidence-based Women with a BRCA1 or BRCA2 mutation who have not chosen salpingo-oophorectomy may
follow determination of CA125 and TVUS since age 35, but they should be informed that early
detection of ovarian cancer is not guaranteed.
IIC NR
Singer 2015 NR Female HBOC family members
Recommends TVUS and CA125 once a year. If applicable TVUS should be initiated 5 years prior to
the age at which the youngest family member has developed ovarian cancer. A potential benefit
of CA125 on the early detection of ovarian cancer has not been demonstrated.
NR NR
British Columbia
2014
Evidence-based Routine screening of females, whether of high or average risk, is not recommended. Studies have
consistently failed to identify any reduction in the morbidity or mortality from ovarian cancer in
females screened with currently available technology such as TVUS or CA125. The potential harms
of screening are substantial and include false reassurance, high recall rates for false positive
results, and surgery for benign conditions with the associated surgical risks.
NR Barton 2012, Buys 2011 [PLCO], Horsman
2007, BC Cancer Agency (date
unknown),
SIGN 2013 Evidence-based Screening for ovarian cancer in high risk groups should only be offered in the context of a
research study.
Grade D NCGSG 2009, Moller 2001, Taylor 2001,
Karlan 1999.
NBOCC 2011 Evidence-based For women at high/potentially high risk of ovarian cancer
Ovarian cancer surveillance is not recommended for women at high risk or potentially high risk.
Evidence shows that ultrasound or CA125, singly or in combination, is not effective at detecting
early ovarian cancer.
NR NBOCC 2009
Abbreviations: CA, cancer antigen; ESMO, European Society of Medical Oncology; HBOC, hereditary breast and ovarian cancer; NBOCC, National Breast and Ovarian Cancer Centre; NR, not reported; SEOM,
Sociedad Española de Oncología Médica; SIGN, Scottish Intercollegiate Guidelines Network; RACGP, Royal Australian College of General Practitioners; TVUS, transvaginal ultrasound.
ESMO: A – Strong evidence for efficacy with a substantial clinical benefit, strongly recommended, B – Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended, C –
Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, ...), optional, D – Moderate evidence against efficacy or for adverse outcome, generally not
recommended, E – Strong evidence against efficacy or for adverse outcome, never recommended.
SIGN: Grade A: At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly
applicable to the target population, and demonstrating overall consistency of results; Grade B – A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating
overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+; Grade C – A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating
overall consistency of results; or Extrapolated evidence from studies rated as 2++; Grade D – Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+.
83 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.6 Relevant guidance from other sources – surveillance of women at high risk
Ref ID
Developer
Guidance type Recommendation/evidence statement Level of evidence/
Grade
Evidence base
ACOG 2017b Evidence-based
Practice Bulletin
In women with BRCA mutations or who have a personal history of ovarian cancer, routine ovarian
cancer screening with measurement of serum CA125 level or TVUS is generally not recommended.
TVUS or measurement of serum CA125 level may be reasonable for short-term surveillance in
women at high risk of ovarian cancer starting at age 30-35 years until the time they choose to
pursue risk-reducing bilateral salpingo-oophorectomy, which is the only proven intervention to
reduce ovarian cancer-specific mortality.
NR Rosenthal 2017 [UKFOCSS Phase II],
NCCN 2016, Nelson 2013, Oei 2006,
Olivier 2006, Stirling 2005,
ACR 2017 Evidence-based Ovarian cancer screening with pelvic ultrasound may be appropriate for some pre-menopausal
women at increased risk for ovarian cancer; however, strong evidence is not available for this
clinical scenario.
May be
appropriate
Jacobs 2016 [UKCTOCS], Rosenthal 2013
[UKFOCSS Phase I, Buys 2011 [PLCO], van
Nagell 2011, van der Velde 2009,
Gaarenstroom 2006, Olivier 2006, Stirling
2005, Hogg 2004.
Ovarian cancer screening with pelvic ultrasound may be appropriate for some post-menopausal
women at increased risk for ovarian cancer; however, strong evidence is not available for this
clinical scenario.
May be
appropriate
Lai 2016 [PLCO-HR], Rosenthal 2013
[UKFOCSS Phase I], van der Velte 2009,
Lacey 2006, Gaarenstroom 2006, Olivier
2006, Stirling 2005, Hogg 2004.
Zeimet 2017
AGO
Consensus-based Women who wish to avoid the risks of surgery and premature menopause and who understand
the risk of ovarian and endometrial cancer and the lack of efficient screening for early detection
of both cancers might nevertheless choose observation. As an alternative, the patient should be
offered the possibility of an annual endometrium biopsy (pipelle eventually complemented by an
office-hysteroscopy) together with TVUS examination from age 30/35 years.
NR Koh 2014, Koornstra 2009, Lindor 2006
FDA 2016 Safety
Communication for
physicians
Do not recommend or use tests that claim to screen for ovarian cancer in the general population
of women. Be aware that testing higher risk asymptomatic patients for ovarian cancer has no
proven benefit and is not a substitute for preventive actions that may reduce their risk.
NA NR
Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACR, American College of Radiology; AGO, Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie; CA, cancer antigen; FDA, US
Food and Drug Administration; NA, not applicable; NBOCC, National Breast and Ovarian Cancer Centre; NR, not reported; TVUS, transvaginal ultrasound; US, United States.
ACR: Usually not appropriate – The imaging procedure or treatment is unlikely to be indicated in the specified clinical scenarios, or the risk-benefit ratio for patients is likely to be unfavorable; May be appropriate – The
imaging procedure or treatment may be indicated in the specified clinical scenarios as an alternative to imaging procedures or treatments with a more favorable risk-benefit ratio, or the risk-benefit ratio for patients
is equivocal.
Technical Report – Testing for ovarian cancer in asymptomatic women 84
Review of definitions of high risk of ovarian cancer
4.1.11 Identified guidance that defines high risk
Definitions of high risk populations were extracted from the guidance identified in Section 4.1.10,
and the studies identified in Section 4.1.4.
4.1.12 Definitions of high risk of ovarian cancer
Table 0.1 summarises the definitions of high risk that appear in identified clinical practice guidelines
and other position statements published from 2011 onwards. Table 0.2 summarises the criteria used
to recruit high risk women to the clinical studies that examined surveillance of women at high risk of
ovarian cancer.
In general, definitions include personal and family history of BRCA mutations, breast and ovarian
cancer, and Ashkenazi Jewish ancestry.
Table 0.1 Definitions of women at high risk of ovarian cancer from guidelines and position
statements
Ref ID/Developer
Country
Definition
Clinical practice guidelines
Paluch-Shimon 2016
ESMO
Europe
BRCA1 or BRCA2 germline mutation
Lynch syndrome genes: MLH1, MSH2, MSH6, EPCAM and PMS2 mutations
RAD51 mutation
BRIP1 mutation
RACGP 2016
Australia
‘Higher risk’ of OC:
Family history of OC, especially first-degree relatives and more than one relative (risk of about 3 times the
population average)
Presence of the genes BRCA1 or BRCA2
Also refers to breast cancer risk (see below), taken from Cancer Australia Familial Risk Assessment – Breast and
Ovarian Cancer (FRA-BOC) guidance.
Potentially high risk72 of breast cancer or carrying a mutation (<1% of the female population):
Women who are at potentially high risk of OC
Two first-degree or second-degree relatives on one side of the family diagnosed with breast or ovarian cancer,
plus one or more of the following features on the same side of the family:
o additional relative(s) with breast or ovarian cancer
o breast cancer diagnosed before age 40 years
o bilateral breast cancer
o breast and ovarian cancer in the same woman
o Ashkenazi Jewish ancestry
o breast cancer in a male relative
One first-degree or second-degree relative diagnosed with breast cancer aged <45 years plus another first-
degree or second-degree relative on the same side of the family with sarcoma (bone/soft tissue) aged <45
years
Member of a family in which the presence of a high-risk breast cancer gene mutation has been established
Llort 2015
SEOM
Spain
HBOC
BRCA1 or BRCA2 germline mutation
Mismatch repair (MMR) genes, RAD51D, BRIP1
Singer 2015
Austria
BRCA1 or BRCA2 germline mutation
72 More than three times the population average. Individual risk may be higher or lower if genetic test results are known.
85 Technical Report – Testing for ovarian cancer in asymptomatic women
Ref ID/Developer
Country
Definition
British Columbia 2014
Canada
For epithelial OC
personal or family history73 of cancer of breast, epithelial ovarian, fallopian tubes, primary peritoneal and/or
Lynch syndrome (also known as HNPCC)
personal or family history of confirmed breast cancer gene mutation (BRCA) 1 or 2
nulliparity and/or infertility
age
There may be other risk factors for ovarian cancer (e.g. use of fertility drugs, smoking); however, at present time
they are not well enough understood.
SIGN 2013
Scotland
Identifying women at high risk of developing ovarian cancer
Defining high risk groups using family history:
A woman is defined as being at high risk of ovarian cancer if she meets one of the following criteria:
she is a known carrier of relevant cancer gene mutations including BRCA1, BRCA2, MMR genes
she is an untested first degree relative of an individual with a mutation in BRCA1, BRCA2, RAD51C, RAD51D or
MMR genes
she is an untested second degree relative, through an unaffected man, of an individual with a mutation in
BRCA1, BRCA2, RAD51C, RAD51D or MMR genes
she has a first degree relative (mother, father, sister, brother, daughter or son) affected by cancer within a
family that meets one of the following criteria:
o two or more individuals with OC, who are first degree relatives of each other
o one individual with OC at any age, and one with breast cancer diagnosed under age 50 years, who are
first degree relatives of each other
o one relative with OC at any age, and two with breast cancer diagnosed under 60 years, who are
connected by first degree relationships
o three or more family members with colon cancer, or two with colon cancer and one with stomach,
ovarian, endometrial, urinary tract or small bowel cancer in two generations. One of these cancers must
be diagnosed under age 50 years and affected relatives should be first degree relatives of each other
o one individual with both breast and ovarian cancer
Defining high risk groups using genetic testing:
A high risk of ovarian cancer is associated with mutation in the tumour suppressor genes BRCA1 and BRCA2, in the
mismatch repair genes associated with HNPCC families, and rarely, in RAD51C and RAD51D.
NBOCC 2011
Australia
Definition of potentially high risk of ovarian cancer
Women have been defined as being at potentially high risk of developing OC if they:
Are a woman who is at high risk of breast cancer due to a gene fault e.g. in BRCA1 or BRCA2
Have one 1° or 2° relative diagnosed with epithelial OC in a family of Ashkenazi Jewish ancestry74
Have one 1° or 2° relative with OC at any age, and another with breast cancer before the age of 50, where
the women are 1° or 2° relatives of each other
Have two 1° or 2° relatives on the same side of the family diagnosed with epithelial OC, especially if one or
more of the following features occurs on the same side of the family:
1. additional relative(s) with breast or ovarian cancer
2. breast cancer diagnosed before the age of 40
3. bilateral breast cancer
4. breast and ovarian cancer in the same woman
5. breast cancer in a male relative
Have three or more 1° or 2° relatives on the same side of the family diagnosed with a family history suggestive
of Lynch syndrome (or HNPCC) e.g. colorectal cancer (particularly if diagnosed before the age of 50),
endometrial cancer, OC, gastric cancer, and cancers involving the renal tract
Are a member of a family in which the presence of a high-risk OC gene mutation has been established
If genetic test results are known, individual risk may be higher or lower. The category of potentially high risk of OC
covers less than 1% of the female population. As a group, lifetime risk of OC ranges between 1 in 30 and 1 in 2.
This risk is more than 3 times the population average.
73 Particularly in a patient’s close relatives, including: children, brothers, sisters, parents, aunts, uncles, grandchildren and grandparents on the
same side of the family. History of cancer in cousins and more distant relatives from the same side of the family may also be relevant. 74 High-risk ovarian and breast cancer gene mutations are more common in people of Ashkenazi Jewish ancestry.
Technical Report – Testing for ovarian cancer in asymptomatic women 86
Ref ID/Developer
Country
Definition
Other guidance
ACOG 2017b
United States
HBOC
Criteria for further genetic evaluation for HBOC:
Women affected with one or more of the following have an increased likelihood of having an inherited
predisposition to breast75 and ovarian, tubal, or peritoneal cancer and should receive genetic counseling and be
offered genetic testing:
breast cancer at age 45 years or less
breast cancer and have a close relative76 with breast cancer at age 50 years or less or close relative with
epithelial ovarian, tubal, or peritoneal cancer at any age
breast cancer at age 50 years or less with a limited or unknown family history77
breast cancer and have two or more close relatives with breast cancer at any age
breast cancer and have two or more close relatives with pancreatic cancer or aggressive prostate cancer
(Gleason score equal to or greater than 7)
two breast cancer primaries, with the first diagnosed before age 50 years
triple-negative breast cancer at age 60 years or less
breast cancer and Ashkenazi Jewish ancestry at any age
pancreatic cancer and have two or more close relatives with breast cancer; ovarian, tubal, or peritoneal
cancer; pancreatic cancer; or aggressive prostate cancer (Gleason score equal to or greater than 7)
Women unaffected with cancer, but with one or more of the following have an increased likelihood of having an
inherited predisposition to breast and ovarian, tubal, or peritoneal cancer and should receive genetic counseling
and be offered genetic testing:
a first-degree or several close relatives that meet one or more of the aforementioned criteria
a close relative carrying a known BRCA1 or BRCA2 mutation78
a close relative with male breast cancer
Genetic mutations associated with increased risk of ovarian cancer:
BRCA1 or BRCA2 germline mutation
Lynch syndrome MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM)
BRIP1
RAD51C
RAD51D
STK11
ACR 2017
United States
OC screening – High risk (pre-menopausal or post-menopausal)
personal history or family history or known or suspected genetic predisposition or elevated CA125
Zeimet 2017
AGO
Austria
Lynch syndrome genes: MLH1, MSH2, MSH6, PMS2
FDA 2016
United States
“…women at high risk of developing ovarian cancer, including those with BRCA mutations,….”
USPSTF 201279 Women with BRCA1 and BRCA2 genetic mutations, the Lynch syndrome (HNPCC), or a family history of OC are
at increased risk for OC
Women with an increased-risk family history should be considered for genetic counselling to further evaluate
their potential risks
“Increased-risk family history” generally means having 2 or more first- or second-degree relatives with a history
of ovarian cancer or a combination of breast and ovarian cancer
o For women of Ashkenazi Jewish descent, it means having a first-degree relative (or 2 second-degree
relatives on the same side of the family) with breast or ovarian cancer
USPSTF 201680 Women with high-risk genetic syndromes, including BRCA1 and BRCA2 gene mutations, Lynch syndrome
(hereditary nonpolyposis colon cancer), Li-Fraumeni syndrome, and Peutz-Jeghers syndrome, are at high risk for
ovarian cancer.
Women with a family history of ovarian cancer are also at increased risk.
Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACR, American College of Radiology; AGO, Austrian
Arbeitsgemeinschaft für Gynäkologische Onkologie; CA, cancer antigen; ESMO, European Society of Medical Oncology; FDA, Food and Drug
Administration; HBOC, hereditary breast and ovarian cancer; HNPCC, hereditary non-polyposis colorectal cancer; NBOCC, National Breast
and Ovarian Cancer Centre; OC, ovarian cancer; SEOM, Sociedad Española de Oncología Médica; SIGN, Scottish Intercollegiate Guidelines
Network; RACGP, Royal Australian College of General Practitioners.
75 Invasive and ductal carcinoma in situ breast cancer. 76 Close relative is defined as first degree (parent, sibling, offspring), second degree (grandparent, grandchild, uncle, aunt, nephew, niece,
half-sibling), or third degree (first cousin, great-grandparent or greatgrandchild). 77 Limited family history includes fewer than two first-degree or second-degree female relatives surviving beyond age 45 years. 78 Or carrying another known actionable deleterious mutation associated with hereditary breast and ovarian cancer syndrome. 79 Final Recommendation Statement: Ovarian Cancer: Screening. U.S. Preventive Services Task Force. Current as of September 2012; Accessed
October 2017. 80 Draft Recommendation Statement: Ovarian Cancer Screening. U.S. Preventive Services Task Force. Accessed December 2017.
87 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.2 Definitions of women at high risk of ovarian cancer from included clinical studies
Ref ID Definition
UKFOCSS Phase II The UKFOCSS inclusion criteria were devised to include all women who have a ≥10% life time risk of OC. This
corresponds to a BRCA carrier probability of ≥25% in the volunteer and ≥50% in the first degree relative (FDR) of
the volunteer.
The volunteer should either have been affected by one of the following cancers or be a FDR of an affected
family member:
Families with ovarian or ovarian and breast cancer
1. ≥2 individuals with OC who are FDR
2. One OC and one breast cancer <50 years who are FDR
3. One OC and two breast cancers <60 years who are FDR
4. Breast cancer in volunteer/proband (≤45 years) and mother with both breast and ovarian cancer (in the same
person)
5. Breast cancer in volunteer/proband (≤40 years) and sister with both breast and ovarian cancer (in the same
person)
6. Criteria 1, 2, and 3 can be modified where paternal transmission is occurring i.e. families where affected
relatives are related by second degree through an unaffected intervening male relative and there is an affected
sister are eligible.
Families with a known gene mutation
7. The family contains an affected individual with a mutation of one of the known OC predisposing genes e.g.
BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS1, PMS2.
Families with colorectal cancer (HNPCC or Lynch syndrome)
8. The family contains ≥3 individuals with a HNPCC related cancer81, who are FDR and ≥1 case is diagnosed
before 50 years and the cancers affect ≥1 generation.
Families with only breast cancer
9. ≥4 breast cancers
10. 3 breast cancers related by FDR: one ≤30 years, or all ≤40 years, or one male breast cancer (MBC) and one
bilateral breast cancer
11. Breast cancer in volunteer/proband (≤50 years) and: breast cancer in mother (age of onset being ≤30 years in
one and ≤50 years in the other), or bilateral breast cancer in the mother (≤40 years onset), or one MBC and one
bilateral breast cancer
12. Two MBC (one ≤40 years) in the family and the proband is a FDR of one of them.
Families with Ashkenazi Jewish ethnicity (additional criteria)82
13. Breast cancer (<40 years) or bilateral breast cancer (first cancer <50 years) in volunteer/proband, irrespective
of family history of cancer
14. Breast cancer in volunteer/proband (<50 years) and one FDR with breast cancer (<50 years) or OC (any age)
or MBC (any age)
15. Breast cancer in volunteer/proband (<60 years) and one FDR with breast cancer (<40 years) or OC (any age)
or MBC (any age)
16. One FDR with OC (<50 years)
17. FDR with breast and OC in the same woman (any age)
18. Two FDR with breast cancer (<40 years)
19. Two MBC (<60 years) in the family and proband is a FDR of one of them.
CGN/GOG Eligibility criteria included the following, with ‘close relatives’ defined as first- or second-degree blood relatives:
1. the subject or close relative (deleterious mutation in a FDR confers a 50% prior probability of an untested
subject being a mutation carrier, while deleterious mutation in a second-degree relative confers a 25% prior
probability of an untested subject being a mutation carrier) had a known, deleterious BRCA1 or BRCA2 mutation;
or
2. at least two ovarian or breast cancers (including DCIS) had been diagnosed among the subject or close
relatives within the same lineage; or
3. the subject was of Ashkenazi Jewish ethnicity, with one first-degree or two-second degree relatives with ovarian
or breast cancer; or
4. the subject was of Ashkenazi Jewish ethnicity and had a personal history of breast cancer; or
5. the probability of carrying a BRCA1 or BRCA2 mutation given family pedigree of breast and ovarian cancers as
calculated by BRCAPRO exceeded 20%.
When a diagnosis of breast cancer was required to meet any of these criteria, at least one breast cancer must
have been pre-menopausal or, if menopausal status was unknown at time of diagnosis, then age at diagnosis
was required to be ≤50 years.
It has since become apparent that some of these women are now known to not be at increased risk for OC – e.g.
women with a site-specific breast cancer family history whose families lack a deleterious BRCA1/2 mutation.
81 HNPCC cancers include colorectal, endometrial, ovarian, small bowel, ureteric and renal pelvic cancers. 82 Families in these categories negative on full BRCA1 and BRCA2 screening are ineligible.
Technical Report – Testing for ovarian cancer in asymptomatic women 88
Ref ID Definition
PLCO-HR The current study defined a subgroup of participants who reported at least one FDR with breast cancer or at least
one FDR with OC. A separate subgroup of patients with a personal history of breast cancer prior to enrolment was
also analysed.
The study population represents a heterogeneous group of patients, some with and some without genetic
mutations. As a whole, this may be construed as an intermediate or moderate risk group. Nonetheless, this was
seen as a clinically useful approach, as many patients with a positive family history will inquire about screening
but may not have the resources or desire to undergo genetic evaluation.
UKFOCSS Phase I Family history/mutation eligibility criteria
Eligibility was determined as follows: Participants were known carriers of one of the OC predisposing genes
(BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS1, PMS2) or FDRs (mother, sister, daughter) of an affected member of a
high-risk family. High-risk families were those fulfilling any of the following criteria:
The family contained two or more individuals with OC who were FDRs
The family contained one individual with OC and one individual with breast cancer diagnosed at age < 50
years who were FDRs
The family contained one individual with OC and two individuals with breast cancer diagnosed at age < 60
years who were connected by first-degree relationships
The family contained an affected individual with a mutation of one of the known OC predisposing genes
(BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS1, PMS2)
The family contained three individuals with colorectal cancer, at least one of whom was diagnosed at age <
50 years as well as one individual with OC, and all of these individuals were connected by first-degree
relationships
The first three criteria could be modified where paternal transmission occurred (i.e. families in which affected
relatives were related by second degree through an unaffected intervening male relative and in which the
proband had an affected sister were eligible)
UK-Netherlands-
Norway study
Women presenting to a cancer genetics centre had their family history documented, assessed and confirmed, as
far as practicable, by Clinical Genetic Services. Women assessed as being at increased risk of ovarian cancer
(usually at least a 10% lifetime risk, requiring more than just a single close relative with ovarian cancer) were
eligible to participate.
Fox Chase Cancer
Centre
Eligible women were ages 25 and older who were considering RRSO due to: 1) a family history of ovarian cancer,
2) a family history suggestive of a hereditary breast/ovarian pattern, and/ or 3) the presence of a known disease-
related gene mutation in the family.
Abbreviations: CGN/GOG, Cancer Genetics Network and Gynecologic Oncology Group; DCIS, ductal carcinoma in situ; FDR, first degree
relative; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial; RRSO, risk-reducing salpingo-
oophorectomy; UK, United Kingdom; UKFOCSS, UK Familial Ovarian Cancer Screening Study;
4.1.13 Comparison of definitions with current Cancer Australia definition
The definition of high or potentially high risk from the 2009 Position Statements for ovarian cancer
surveillance is reproduced below. This definition is taken from a 2006 National Breast Cancer Centre
document, and is similar (but not identical) to the definition used in the 2011 guideline from the
same centre (see Table 0.1).83
83 In 2008, National Breast Cancer Centre (NBCC), incorporating the Ovarian Cancer Program, changed its name to National Breast and
Ovarian Cancer Centre (NBOCC). In 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia.
89 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.3 Current risk definition in Cancer Australia Position Statements
Definition of high or potentially high risk women
The category of potentially high risk of ovarian cancer covers less than 1% of the female population. As a group, lifetime risk of ovarian
cancer ranges between 1 in 30 and 1 in 2. This risk is more than 3 times the population average. Individual risk may be higher or lower if
genetic test results are known.84 Women who have had a genetic fault identified through testing are regarded as being at high risk.
Women have been defined as being at potentially high risk of developing ovarian cancer185 if they:
Are at high or potentially high risk of breast cancer
Have one 1° relative diagnosed with epithelial ovarian cancer in a family of Ashkenazi Jewish ancestry86
Have one woman in the family with ovarian cancer at any age, and another with breast cancer before the age of 50, where
the women are 1° or 2° relatives of each other
Have two 1° or 2° relatives on the same side of the family diagnosed with epithelial ovarian cancer, especially if one or more
of the following features occurs on the same side of the family:
o additional relative(s) with breast or ovarian cancer
o breast cancer diagnosed before the age of 40
o bilateral breast cancer
o breast and ovarian cancer in the same woman
o breast cancer in a male relative
Have three or more 1° or 2° degree relatives on the same side of the family diagnosed with any cancers associated with
hereditary non-polyposis colorectal cancer (HNPCC): colorectal cancer (particularly if diagnosed before the age of 50),
endometrial cancer, ovarian cancer, gastric cancer, and cancers involving the renal tract
Are a member of a family in which the presence of a high-risk ovarian cancer gene mutation has been established
Source: Cancer Australia website
4.1.13.1 Family history criteria
Much of the family history criteria remain consistent with more recent guidance from other
jurisdictions. However, Ashkenazi Jewish ancestry could be extended to second degree relatives
(which is consistent with advice from NBOCC 2011 and USPSTF 201287).
In their review of the evolving paradigms in research and care for ovarian cancer, the National
Academies of Science, Engineering and Medicine (NASEM) recognises that relying on family history
alone may lead clinicians to overlook some women with germline mutations that put them at
higher risk for ovarian cancer (NASEM 2016). They claim that up to one-half of women with high risk
germline mutations do not have an apparent family history of breast or ovarian cancer. Also, family
history may not identify high risk for women with few female relatives, for women who were
adopted and do not know their biological family’s cancer history, or for women who otherwise do
not know the family health history of one or both parents.
4.1.13.2 Genetic testing criteria
In November 2017, two new Medical Benefits Schedule (MBS) items were listed for (i) genetic testing
of specific individuals affected by breast or ovarian cancer, and (ii) genetic testing of family
members of individuals who test positive according to the first item (i.e. ‘cascade testing’). For both
items, it is proposed that genetic testing be limited to the following genes: BRCA1, BRCA2, STK11,
PTEN, CDH1, PALB2, and TP53. While individuals known to have ovarian cancer are outside of the
scope of screening or surveillance, individuals who test positive following cascade testing represent
a subgroup of the population of women at increased risk of ovarian cancer.
As the introduction of an MBS item for cascade testing of BRCA1/2 and other specified mutations
might increase the number of women known to be at increased risk of ovarian cancer, it may be
worth considering whether the definition of high or potentially high risk could contain more explicit
advice about the genetic mutations that predispose to ovarian cancer (namely BRCA1/2, and
mutations associated with Lynch syndrome/HNPCC).
84 National Breast Cancer Centre 2006. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health
professionals. National Breast Cancer Centre, Camperdown, NSW. 85 National Breast Cancer Centre 2006. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health
professionals. National Breast Cancer Centre, Camperdown, NSW. 86 High-risk ovarian and breast cancer mutations are more common in people of Ashkenazi Jewish ancestry. 87 Note that the 2017 USPSTF Draft Recommendation Statement does not specifically mention Ashkenazi Jewish ancestry as a high risk
population.
Technical Report – Testing for ovarian cancer in asymptomatic women 90
The NASEM review of research and care for ovarian cancer (NASEM 2016) provides the following
examples of high-risk ovarian cancer susceptibility genes:
BRCA1, BRCA2 (HBOC syndrome)
MLH1, MSH2, MSH6, PMS2, EPCAM (Lynch syndrome)
TP53 (Li–Fraumeni syndrome)
STK11/LKB1 (Peutz–Jeghers syndrome, sex cord and mucinous tumours)
The American College of Obstetrics and Gynecology refers to several additional genetic mutations
associated with increased risk of ovarian cancer: BRIP1, RAD51C, RAD51D (ACOG 2017b).
4.1.13.3 Other criteria
The NASEM review of research and care for ovarian cancer (NASEM 2016) notes that the majority of
women with an ovarian cancer do not appear to have a known high-risk germline mutation or a
significant family history; as such, it is critical to also consider other potential risk factors. They state
that, “While several nongenetic factors are associated with either an increased or a decreased risk
for developing ovarian cancers, the patterns of association are inconsistent. For example, some risk
factors may affect risk in the same way for all subtypes, whereas other factors may increase risk for
some subtypes while decreasing risk for other subtypes. The strongest known risk factors to date are
those associated with the less common and less lethal subtypes”.
Review of emerging technologies
As discussed in earlier sections of the report, current approaches for early detection include
assaying for biomarkers (CA125), often in combination with imaging technologies. While the use of
these strategies in large screening trials has resulted in more ovarian cancers being detected at
earlier stages, to date these methods have not had a substantial impact on overall mortality.
The recent Evidence Synthesis of screening for ovarian cancer prepared for the US Preventative
Services Task Force of the AHRQ (Henderson 2017) notes the following:
“We identified no ongoing randomised trials of ovarian cancer screening using new
screening tools. While some tools in development may hold promise for the future
(e.g. microRNA), currently there are no new screening tools (i.e. biomarkers,
instruments) exhibiting levels of test performance beyond what is observed for the
screening tools evaluated in trials.
The UKCTOCS trialists are engaged in efforts to improve upon the ROCA algorithm,
adding other protein markers along with CA125 to new prediction models derived
using data from the UKCTOCS data. These models would require further validation
and testing to ascertain whether they truly represent improvements on the ROCA
algorithm that would potentially attain clinical benefits for ovarian cancer detection
and treatment. In any case, given the absence of a single marker or screening
device that is effective for ovarian cancer, research is likely to increasingly aim to
identify new markers and combinations of markers in prediction models.”
In the recent NASEM review of research and care for ovarian cancer (NASEM 2016), the committee
note that:
“Given the marked heterogeneity of ovarian cancers and the incomplete
understanding of early disease development for each subtype, it is highly unlikely
that a single biomarker or imaging modality will be sufficient to aid in the early
91 Technical Report – Testing for ovarian cancer in asymptomatic women
detection of all the subtypes. The committee concludes that current screening
strategies have not had a substantial impact on reducing mortality in the general
population and that while research on refining current methods may be fruitful,
distinct multimodal approaches will likely be needed to detect each of the various
subtypes at their earliest stages.”
The ensuing recommendation in the NASEM 2016 review is:
“Researchers and funding organisations should focus on the development and
assessment of early detection strategies that extend beyond current imaging
modalities and biomarkers and that reflect the pathobiology of each ovarian
cancer subtype.”
Table 0.1 identifies and notes methodologies that are either currently available for prognosis or
diagnosis of ovarian cancer, or that are in clinical or scientific development for screening for
ovarian cancer (including ongoing trials). These findings suggest that there are no screening tests
for ovarian cancer that are likely to be introduced/recommended in the short- to medium-term.
The 2009 Cancer Australia Position Statement on surveillance in women at high risk of ovarian
cancer, and the 2010 horizon scanning report by the Australian and New Zealand Horizon Scanning
Network (ANZHSN 2010), mentioned OvPlex™, a then commercially available blood test developed
by HealthLinx Limited (Australia) that was marketed as a test for the early detection of ovarian
cancer. OvPlex was based on measurement of CA125 as well as four other biomarkers: C-reactive
protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6) and interleukin 8 (IL-8). In the Position
Statement it was noted that no data from prospective controlled trials had been reported for the
test, and this appears to still be the case. In addition, OvPlex appears to no longer be commercially
available, and HealthLinx Limited changed its name to Manalto Limited88 in 2015.
As recently as 2016, the US Food and Drug Administration (FDA) noted that they were “not aware of
any valid scientific data to support the use of any test, including using a test cleared or approved
by FDA for other uses, as a screening tool for ovarian cancer.”89 The FDA has specifically
recommended against the use of tests marketed for screening of ovarian cancer, with the
following recommendations made to physicians:90
“Do not recommend or use tests that claim to screen for ovarian cancer in the
general population of women. Be aware that testing higher risk asymptomatic
patients for ovarian cancer has no proven benefit and is not a substitute for
preventive actions that may reduce their risk.
Consider referring women at high risk of developing ovarian cancer, including those
with BRCA mutations, to a genetic counsellor or gynaecologic oncologist, or other
appropriate health care provider for more specialised care.”
In particular, the FDA stated that the ROCA algorithm has been marketed in the United States with
no data to support its claims for ovarian cancer detection and improved cancer survival. Following
this statement from the FDA in September 2016, the company marketing the ROCA test temporarily
suspended its commercial availability in the United States.
88 According to its Annual Report released on 30 October 2017, Manalto Limited is an “integrated technology company focusing on social
media and e-commerce solutions for SMBs [small and medium-sized businesses] and enterprises.” 89 Accessed from the FDA website on 8 November 2017. 90 Accessed from the FDA website on 8 November 2017.
Technical Report – Testing for ovarian cancer in asymptomatic women 92
Table 0.1 Potential ovarian cancer screening methodologies identified in literature search
Test/ combination
Company
(Source)
Description Components Approval Approved/studied use Approved for screening
Currently marketed
ROMA
Fujirebio Diagnostics
Software algorithm and
two analytes
Serum
CA125, HE4
Other
Menopausal status
FDA Assess whether a pre-menopausal or post-menopausal woman who
presents with an ovarian adnexal mass is at high or low likelihood of
finding malignancy on surgery
No – specifically noted that it
should not be used for
screening
OVA1
Vermillion
Software algorithm and
five analytes
Serum
CA125, transthyretin,
apolipoprotein A-1, Β2-
microglobulin, transferrin
FDA Further assess the likelihood that malignancy is present when the
physician’s independent clinical and radiological evaluation does not
indicate malignancy
No – specifically noted that it
should not be used for
screening
Currently under clinical investigation
Longitudinal MROCA
(Simmons 2016)91
Longitudinal algorithm
and four analytes
Serum
CA125, HE4, MMP-7, CA72-4
- Early detection of ovarian cancer -
Requiring clinical investigation
Proseek® Multiplex
Oncology Plates
(Boylan 2017)92
Twelve proteins Serum
CA125, HE4, MK, KLK6, hK11,
CXCL13, FR-alpha, IL-6,
TNFSF14, FADD, PRSS8, FUR
- Screening for detecting early stage ovarian cancer in the general
population
Plasma API
(Miyagi 2017)93
Index Plasma
Amino acid profile
- Distinguish epithelial ovarian malignant tumours from benign growths -
Novel risk model I
for Type I OC
(Russell 2017)94
Algorithm and three
analytes
Serum95
CA125, fibronectin, Protein Z
Other
Age, interaction term
between age and fibronectin,
interaction term between age
and Protein Z
- Early detection and screening for ovarian cancer -
91 According to the authors this panel is “now under validation in a large blinded retrospective study utilising longitudinal cases and controls specimens from the UKCTOCS trial, to establish final parameters for the
MROCA and to assess both lead times and CA125 complementarity. If either lead time or complementarity advantage is noted for the MROCA over the CA125 ROCA, a prospective trial will be conducted to
validate the multi-marker panel, interpreted with the MROCA algorithm to determine clinical utility for this screening methodology.” 92 The authors note that “Additional studies using a larger cohort of patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early stage ovarian cancer
in the general population.” 93 The authors note that “a prospective clinical study is warranted to validate API for practical use in the future.”
93 Technical Report – Testing for ovarian cancer in asymptomatic women
Test/ combination
Company
(Source)
Description Components Approval Approved/studied use Approved for screening
Novel risk model II
for Type II OC
(Russell 2017)96
Algorithm and three
analytes
Serum97
CA125, fibronectin, CRP
Other
Age, age*fibronectin
- Early detection and screening for ovarian cancer -
Scientific development
Protein biomarkers
(Boylan 2014)
Normal Pap test Core
Proteome
Residual Pap fluid
153 proteins
- Identification of proteins in residual Pap fluid of women with normal
cytology to identify biomarkers for gynaecological diseases
-
Multiplex methylation-
specific PCR assay
(Zhang 2013)
Multiplex methylation-
specific PCR assay to
identify methylation status
of one of seven genes
found in cell-free serum
DNA
Serum
APC, RASSF1A, CDH1, RUNX3,
TFPI2, SFRP5, OPCML98
- Improve early detection of ovarian cancer -
Ongoing trials
DOvEEgene
(NCT02288676;
Registered 2014)
Molecular screening test NR - Screening test for the early diagnosis of cancer of the endometrium,
fallopian tubes and ovaries
-
Biomarker identification
[NCT01787656;
Registered 2013]
Phase II biomarker
validation study
Unique peptides/protein –
unspecified
A Novel Method of Screening for Ovarian Cancer Using Gynecologic
Fluids and Mucus.
AminoIndex
(NCT02178462;
Registered 2014)
Metabolomic profiling of
amino acids
NR - To discriminate gynaecologic cancer from benign disease or healthy
subjects
-
94 The authors note that the models “require further validation in a larger, independent sample set, containing samples from patients with benign ovarian tumours and other diseases in order to add confidence in
their utility as screening tools.” 95 Samples collected from UKCTOCS. 96 The authors note that the models “require further validation in a larger, independent sample set, containing samples from patients with benign ovarian tumours and other diseases in order to add confidence in
their utility as screening tools.” 97 Samples collected from the UKCTOCS. 98 Tumorigenic function in epithelial ovarian cancer: APC = an antagonist of the Wnt pathway, involved in cell migration and adhesion, transcriptional activation, and apoptosis; RASSF1A = inhibit the accumulation of
cyclin D1, induce cell cycle arrest; RUNX3 = suppress the proliferation and tumorigenicity; CDH1 = Key role in EMT, loss of function is thought to increase proliferation, invasion, and/or metastasis; TFP12 = a Kunitz-type
serine proteinase inhibitor that inhibits transformation and proliferation; SFRP5 = inactivation leads to oncogenic activation of Wnt pathway and contributes to cancer progression and chemoresistance; OPCML =
Inhibit the proliferation and tumour growth, negatively regulating receptor tyrosine kinases (Zhang et al 2013).
Technical Report – Testing for ovarian cancer in asymptomatic women 94
Test/ combination
Company
(Source)
Description Components Approval Approved/studied use Approved for screening
Lysophosphatidic acid
assay
(NCT00986206;
Registered 2009)99
Lysophosphatidic acid
assay
- - For the early detection of ovarian cancer (high risk women) -
Glycan analysis
(NCT00628654;
Registered 2008)
Glycan analysis - - Diagnosing cancer in women with ovarian epithelial cancer and in
healthy female participants
-
CA125 algorithm
(NCT00539162;
Registered 2007)
CA125 algorithm NR - Early detection of ovarian cancer in low risk women -
CAAb test
(NCT00327925;
Registered 2006)100
Ovarian cancer
associated antibodies test
- - Assess the effectiveness of the CAAb test with ovarian cancer patients
(primary purpose: screening)
-
Mesothelin
(NCT00155740;
Registered 2005)101
Mesothelin - - New tumour marker for ovarian cancer (primary purpose: screening) -
Abbreviations: CA, Cancer Antigen; CAAb, cancer associated antibodies; CRP, C-reactive protein; CXCL13, CXC motif chemokine 13; FADD, FAS-associated death domain protein; FR-alpha, folate receptor-alpha;
FUR, furin; HE4, human epididymis protein 4; hK11, kallikrein 11; IL-6, interleukin-6; KLK6, kallikrein 6; MK, midkine; MMP-7, matrix metalloproteinase-7; MROCA, multi-marker risk of ovarian cancer algorithm; NR, not
reported; OC, ovarian cancer; PCR, polymerase chain reaction; PRSS8, prostasin; ROMA, Risk of Ovarian Malignancy Algorithm; TNSF14, tumor necrosis factor superfamily member 14.
99 The ClinicalTrials.gov website notes that the recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years. 100 The ClinicalTrials.gov website notes that the recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years. 101 The ClinicalTrials.gov website notes that the recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
95 Technical Report – Testing for ovarian cancer in asymptomatic women
5 Synthesis of findings
Population screening
5.1.1 Current clinical evidence
The current clinical evidence for ovarian cancer screening in the general population indicates
there is no mortality benefit associated with screening with any of the implemented strategies,
based on a priori analyses in two large population screening trials: PLCO and UKCTOCS. In
summary, pre-specified and post hoc secondary analyses are suggestive that a delayed mortality
benefit may be attributable to screening in the UKCTOCS study, but longer-term follow up is
necessary to confirm this. Follow up to 2018 has received funding, and plans to continue to 2024
are reported.
The UKCTOCS statistical analysis plan nominated the Cox proportional hazard model for the primary
analysis of the primary outcome. This statistical approach assumes the hazard of disease-specific
death is proportional (i.e. constant) over time. However, there is an inherent delay in any potential
impact of screening on mortality due to the time from incident malignancy diagnosis through
disease progression to death. In the PLCO trial, a weighted statistic was chosen for the primary
analysis of the primary outcome because of ‘the presumed delay in effect of screening on ovarian
cancer mortality’. A weighted log-rank test was used, which differentially assigns weight to different
time points.
It is unclear why a method of analysis that relies on the proportional hazard assumption was chosen
for the primary analysis in the UKCTOCS trial. The authors of the primary study publication make the
following comment:
In retrospect, it would have been preferable to specify a primary analysis that was
weighted to reflect the predictable delay in mortality reduction in a screening trial
of this type.
They considered their failure to anticipate the late effect of screening in their statistical design as
the main limitation of the trial. The planned Cox proportion hazard statistic is reported as the
primary analysis, which found no mortality benefit to screening, so it was decided to perform a
single post hoc analysis using the weighted log-rank approach, which resulted in a statistically
significant reduction in ovarian cancer-specific mortality for the same population of tumours
analysed in the primary analysis (i.e. excluding peritoneal cancers).
When peritoneal cancers, which have very high mortality, are added to the weighted log-rank
analysis, statistical significance is lost. With the WHO definition of ovarian cancer having been
broadened in 2014 to include PPC, analyses including these cancers are more relevant for clinical
practice.
Another point of difference between the two RCTs is the treatment of borderline epithelial ovarian
cancers, which UKCTOCS included as malignancies but PLCO excluded as ‘low malignant
potential’ tumours. Since many of the detection outcomes were reported by cancer type in the
UKCTOCS study, a number of these outcomes were presented in this Review both with and without
these borderline tumours (post hoc calculations), which allows comparison of detection outcomes
and stage shift with the PLCO trial. Conversely, the systematic review by Buhling et al (2017)
examined the impact of re-classifying borderline tumours in the PLCO analysis as malignancies.
They found the risk ratio for ovarian cancer-specific death changed from 1.20 (p=0.0647) to a
Technical Report – Testing for ovarian cancer in asymptomatic women 96
statistically significant 1.22 (p=0.0463). They made the comment that borderline tumours ‘are
generally not malignant but have a high potential for transforming from benign to malignant’ and
this may be a reason to include them in the assessment of a screening process.
Stage shift was also investigated in this Review, as it is thought to be a necessary, although not
sufficient, requirement for reducing mortality. Some evidence of stage shift was reported in
UKCTOCS. The systematic review by Henderson et al (2017) conducted to inform U.S. Preventive
Services Task Force ovarian cancer screening guidance made the following observation about the
lack of a mortality benefit despite evidence of a stage shift:
‘The absence of a mortality benefit in these large, well-conducted trials has
generated a theory that late stage disease grows so rapidly that it cannot be
identified at an earlier stage. The stage shift in UKCTOCS trial would seem to counter
this, but the lack of mortality benefit may suggest that these “early stage” tumors
detected early are more aggressive tumor phenotypes that would not have
improved survival no matter when they were identified. Recent work to refine the
distinctions among ovarian cancer molecular, pathological, and clinical
characteristics highlight this point in noting that survival differences are more likely
attributable to type than to stage at diagnosis, with the most common Type II
cancers being particularly lethal regardless of stage, likely owing to microscopic
lesions that are not detectable before significant spread has occurred.’
This review also considered the following aspects of UKCTOCS that may have impacted on
mortality outcomes:
Data from the later years of the trial are based on incomplete data, with women randomised
late in the study yet to report full follow up (the current Review authors consider this data has
the potential to enhance screening-associated improvement in mortality if there is truly a
delayed mortality benefit in this trial).
The no-screening group may have had a surplus of ovaries, as removal of ovaries in false
positives will, over time, deplete the number of at-risk ovaries in the screening groups
(potentially prophylactic surgery in the screening groups would have the effect of decreasing
apparent mortality compared with the no-screening group).
The authors of the Henderson 2017 review also make the following comment:
Given the natural history of ovarian cancer, it is unclear how a screening
intervention aimed at identifying ovarian cancer and intervening at a more
treatable stage would have a delayed effect.
A delayed effect was expected by the PLCO trial investigators, who specified the weighted log-
rank test to account for non-proportional hazards. However, the length of the delay may be
puzzling (over 7 years). The current Review authors are not in a position to comment on this.
False positive rates are highly relevant in a screening strategy that necessitates surgical removal of
ovaries for confirmation of diagnosis. This is especially the case for population screening, the scale
of which will result in major negative impacts in a large number of women without elevated ovarian
cancer risk. The ROCA triage screening strategy reduced false positive rates substantially
compared to TVUS; when borderline tumours are considered false positives, ROCA triage resulted in
2.9 false positive surgeries per screen-detected cancer102 compared with 14.8 in the TVUS screening
groups in both the UKCTOCS and PLCO studies. Such unacceptably high rates of unnecessary
surgery with TVUS screening alone is likely to be a barrier to implementing population screening.
102 2.3 if borderline tumours are considered malignant.
97 Technical Report – Testing for ovarian cancer in asymptomatic women
However, another factor to be considered regarding the ROCA triage approach to screening,
should long term follow up suggest it does reduce mortality, is that around 20% of ovarian cancers
do not express CA125. This would result in these cancers evading screen detection, which is a
clinical limitation of the screening strategy in its current form.
Quality of life outcomes were examined in women taking part in UKCTOCS. The investigators found
that psychological morbidity is slightly elevated by higher levels of secondary testing following
annual screening, and that screening for ovarian cancer does not increase anxiety in general,
especially when compared with the variation in anxiety levels that occur within individuals. The
study authors did not appear to consider these findings to present a barrier to screening.
Overall, current evidence does not support the implementation of population screening. Results of
longer-term follow up in UKCTOCS will be reported in coming years, analysed with the pre-specified
Cox proportional hazard model, at which point it will be necessary to re-evaluate whether
population screening is justified.
5.1.2 Post-literature review publication – outcomes by histology
Type II tumours are the most common and most aggressive of the ovarian cancers with poorer
survival than other cancer types (Shih & Kurman 2004). Since the screening trials were initiated prior
to ‘a modern understanding of ovarian carcinogenesis’, neither specified Type II lesions as an
outcome of interest, and while the UKCTOCS study reported the proportion of diagnoses by
histological type for each of the study arms, neither screening trial reported outcomes by tumour
type. However, subsequent to the literature search for the current Review, a post hoc analysis of
the PLCO trial (Temkin 2017) was published that reports outcomes by tumour type. It should be
noted that around 20% of diagnoses are excluded from this retrospective analysis as they could not
be histologically characterised from limited information in earlier pathology reports.
In the PLCO screening arm, Type II tumours were less likely to be screen-detected than other
tumour types (sensitivity 64.8% versus 85.7%, respectively, p = 0.02). The majority of Type II tumours
were diagnosed post-screening (45.9%) or as interval cancers (15.7%). No stage shift was observed
for either Type II or other tumour types, with a majority of Type II tumours being diagnosed at a late
stage in both screening (85.8%) and non-screening (85.6%) arms. As expected, survival was
significantly different between Type II and other cancer type diagnoses (p<0.01), but no significant
difference was found in survival between the screening and non-screening groups for Type II
tumours (p = 0.74) or other cancer types (p = 0.32). The authors concluded that screening did not
result in a stage shift or mortality benefit for Type II cancers, and that:
‘The results of this study support the notion that non-Type II ovarian cancers tend to
remain in an early stage for some time, whereas Type II cancers tend to spread
rapidly and are more likely to be missed in the window of opportunity for early
detection afforded by a screening test.’
They noted the following:
‘Future studies of screening for ovarian cancer must incorporate a contemporary
understanding of the natural history of ovarian cancer and account for the diverse
biologic behaviour of the subtypes of this malignancy.’
The authors also noted that similar post hoc analyses of the UKCTOCS trial will be ‘crucial to a
modern understanding of the role of screening in ovarian cancer’.
Technical Report – Testing for ovarian cancer in asymptomatic women 98
5.1.3 Ongoing clinical studies
The only ongoing study identified in the search of clinical trial databases was the long-term follow
up of UKCTOCS, which will use an updated classification of peritoneal cancers to reflect the new
criteria in the WHO 2014 definition. After reclassification of these peritoneal cancers, the primary
outcomes of UKCTOCS and PLCO will be more closely aligned. The next censorship for UKCTOCS is
planned for December 2018, and final censorship for December 2024.
5.1.4 Impact of recent findings on evidence-informed guidance
All guidance published in 2016 and 2017 considered evidence from the primary publication of the
UKCTOCS trial (Jacobs 2016). None of the clinical practice guidelines or other forms of guidance
recommend routine screening for ovarian cancer in asymptomatic or average-risk women.
5.1.5 Emerging technologies
Given the absence of a single marker or screening device that is effective for ovarian cancer,
research is likely to increasingly aim to identify new markers and combinations of markers in
prediction models.
A number of methodologies were identified that are either currently available for prognosis or
diagnosis of ovarian cancer, or that are in clinical or scientific development for screening for
ovarian cancer. However, none of these are likely to be introduced/recommended in the short- to
medium-term.
The UKCTOCS trialists are engaged in efforts to improve upon the ROCA algorithm, adding other
protein markers along with CA125 to new prediction models derived using data from the UKCTOCS
trial. These models would require further validation and testing to determine whether they truly
represent improvements on the ROCA algorithm that would potentially attain clinical benefits for
ovarian cancer detection and treatment.
OvPlex™ was mentioned in the 2009 Cancer Australia Position Statement as a commercial blood
test for early detection of ovarian cancer. No data from prospective controlled trials have been
reported for the test and it no longer appears to be commercially available.
Surveillance in women at high risk
5.1.6 Current clinical evidence
5.1.6.1 Design of studies and nature of comparisons presented
Justification for screening typically requires demonstration of a mortality benefit, which in the case
of surveillance in high risk women presents particular challenges. Random assignment to a no-
screening arm is considered unethical in high-risk women, so no studies restricted to this population
included a no-screening comparator group. Consequently, historical controls are called upon in
these studies, or before/after comparisons are made within the cohort of screened women. In the
case of UKFOCSS, follow up after the last trial screening test prior to diagnosis or at the end of the
screening period of the study was censored at 365 days for the purpose of recording events
associated with screening, but follow up continued after that to capture events after the end of
screening. In the CGN/GOG study, prevalent and incident cancers are compared, with the latter
considered to represent ongoing screening.
While such comparisons may be considered valid, and are likely the best approach available to
investigate the effectiveness of surveillance, the results of these studies should be considered in light
of the inherent design flaws and inevitable confounding that limit the opportunity to demonstrate
99 Technical Report – Testing for ovarian cancer in asymptomatic women
statistically robust improvements in outcomes. The low incidence rate for ovarian cancer also
means that even in the largest studies, the number of events are small, especially when subgroups
such as stage at diagnosis are examined, further reducing the certainty of the outcomes.
Interpretation of the results of these surveillance studies also requires consideration of a number of
factors involved in the management of high-risk women, including the fact RRSO is recommended
as optimal management.
An exception was the PLCO post hoc analysis of a subgroup that included high-risk women. The
PLCO population screening study did not exclude high-risk women, and randomised women to
usual care, so the PLCO-HR subgroup analysis overcomes many of the limitations described above.
However, it was not feasible to identify women in this study post hoc according to the usual array of
criteria that define high risk, and the more readily discernible group of women with a personal
history of breast cancer or family history of breast or ovarian cancer was used instead.
Consequently, the overall disease-specific risk in this subgroup would have been lower than in a
typical high-risk population.
Therefore, the findings of these trials are described in detail to allow the reader to better
appreciate the data being compared, and to visualise possible trends that may not have statistical
significance, especially for stage-at-diagnosis results. This required post hoc calculations, using the
published data, of proportions or ratios not reported in the study publications (e.g. early versus late
stage diagnosis, proportions of diagnoses by stage, incidence rates).
5.1.6.2 Overview of UKFOCSS studies
The UKFOCSS study began in 2002 with annual screening using a single threshold CA125
measurement and TVUS. A change in protocol in 2007 (Phase II) introduced more frequent testing,
evaluating CA125 every 4 months using ROCA to triage for TVUS. These two phases of the study are
reported separately in the results section of this Review, grouped with studies using similar methods
of CA125 evaluation. The findings of both Phase I and Phase II studies are discussed together here,
then compared with the other studies.
Mortality outcomes in the UKFOCSS studies
Both phases of the UKFOCSS study compared outcomes for women diagnosed within a year of
their last trial screen with those diagnosed over a year since their last trial screen.103 No difference in
survival was found between these two groups in Phase I of the study, and was not analysed in
Phase II due to the low number of events. The potential implications of other findings on mortality
are discussed later in this section.
The authors of the current Review note that a simple comparison of the proportion of all women
diagnosed by any means who died due to their disease was much greater in Phase I (30%) than in
Phase II (13%). These studies had a similar number of participants (Phase I, N=3,563; Phase II,
N=4,531), and a similar number of person-years of screening (Phase I, 11,366; Phase II, 13,728). The
two studies differed substantially with regard to screening strategies, which likely underlies the
observed differences in overall disease-specific mortality. Another contributing factor may be the
proportion of women continuing surveillance from a prior screening study (Phase I, 0%; Phase II,
48%). Fewer prevalent cases might be expected in this group at the first Phase II screen. Indeed, no
cancer diagnoses were made in the first year of Phase II in any of these women from Phase I,
whereas the prevalence screen in Phase I found 9 of the 22 screen-detected cancers in that study
(41%).
103 Women in the latter group may have undergone screening locally after withdrawal from trial.
Technical Report – Testing for ovarian cancer in asymptomatic women 100
Stage at diagnosis in the UKFOCSS studies
Prevalent cases in Phase I were more likely to be early stage than subsequently diagnosed cancers.
The study authors noted that three of the six early stage prevalent cancers were in women with
Lynch syndrome, with all three diagnosed at Stage I. They noted the prognosis of Lynch syndrome
ovarian cancer is better than that for BRCA1/2 carriers, possibly because of earlier stage at
diagnosis. The authors speculated that Lynch syndrome-associated tumours may have a ‘longer
sojourn time, explaining the high proportion of early-stage disease in the prevalence screen’. The
single statistical analysis of stage shift in the Phase I study excludes diagnoses in women with Lynch
syndrome, providing a more conservative estimate of any potential increase in early stage
diagnosis in screened women.
In the Phase I study, significantly fewer women were diagnosed with very late-stage tumours (Stage
≥IIIc, p=0.009) if screened in the year before diagnosis.104 The authors, however, lamented the
disappointing results regarding detection of Stage I disease, which did not increase with screening.
Phase II of the UKFOCSS study also reported a single statistical analysis of stage shift, finding women
screened within a year of diagnosis had a significantly higher proportion of low volume disease,
defined as ≤Stage IIIa (corresponding to less macroscopic peritoneal metastasis outside the pelvis;
p<0.001). The study also reported that the proportion of all cases with zero residual disease after
surgery (an important prognostic factor in ovarian cancer) was higher in women diagnosed within
one year of screening compared with women from the same cohort in whom cancer was
diagnosed more than one year after screening was completed, but this finding was not significant
(p = 0.09).
Around one third of these low-volume diagnoses made within a year of the last screen were occult
cancers discovered during RRSO unrelated to screening, and the study authors do state that the
significantly lower proportion of ‘high-volume’ disease is associated with the ROCA-based
screening ‘alongside reminders of the effectiveness of RRSO’. They conclude that their overall
findings suggest a screening-mediated reduction in disease volume.
Harms of surveillance
The foremost harm of screening for ovarian cancer is false-positive surgery. The number of false-
positive surgeries per screen-detected cancer in the Phase II study was 11.5, substantially higher
than in Phase I (2.9) or the ROCA triage arm of the UKCTOCS population screening study (also 2.9;
Table 0.13).105 Value judgements around false positive surgery are complex in women at increased
risk of ovarian cancer, as prophylactic surgery is the currently recommended optimal management
strategy for high-risk women.
Quality-of-life outcomes
A number of studies investigated the emotional and psychological impact of screening and
reasons for withdrawal. Both clinical and psychological factors influenced the decision to withdraw,
and while recall for further testing was shown to cause moderate cancer distress, these effects
were transient and did not increase general anxiety or depression. Most women found surveillance
an acceptable risk management strategy.
Conclusions from the UKFOCSS studies
For screening to impact on survival, a stage shift is thought to be necessary, but it is not sufficient on
its own to reduce mortality. While encouraging, the clinical significance of the observed screening-
mediated reduction in disease volume in Phase II of UKFOCSS is uncertain, and the study authors
104 This analysis also excluded PPC. 105 Counting borderline tumours as false positives.
101 Technical Report – Testing for ovarian cancer in asymptomatic women
note it remains unknown whether these outcomes would translate into improved survival in
screened high-risk women. They also note that the high rate of compliance observed in the study
may not be maintained outside a trial.
The Phase II study authors conclude, however, that screening using ROCA every 4 months and TVUS
(at an interval determined by the ROCA), along with continual consideration of RRSO, appears to
be a better approach than symptom awareness alone. They note the high negative predictive
value of surveillance (not reported here) is ‘relevant to this population of women, who may
undergo screening to delay RRSO to complete childbearing or delay surgically induced
menopause’, which suggests surveillance may be considered appropriate for some women to
support decision making around the timing of RRSO. This is likely to be a decision made at the
clinical level, but the evidence to date does not support a shift in current management
recommendations across all high-risk women.
5.1.6.3 High-risk ROCA studies
CGN/GOG and UKFOCSS Phase II
The only other screening studies to use the ROCA in women at high risk of ovarian cancer is the
combined analysis of the CGN and GOG-0199 studies (CGN/GOG) and UKFOCSS Phase II. The
screening protocol for UKFOCSS Phase II drew from CGN/GOG, and they included similar numbers
of participants and a similar number of person-years of screening; overall incidence of ovarian
cancer was similar in the two studies, at 0.14% per year.106
No survival or mortality analyses were performed in these studies. Stage shift associated with
screening was analysed only for UKFOCSS Phase II, and was found to be significantly lower for high
volume diagnoses (> Stage IIIa). A trend towards earlier diagnosis was observed in CGN/GOG
when prevalent and incident screen-detected cancers were compared, but events were very few
(n=4 and n=5, respectively). False positive rates were substantially higher in the CGN/GOG study, at
21.7 surgeries to detect one case of cancer compared with 12.5 in the UKFOCSS study.
The authors of the CGN/GOG study are ‘exploring opportunities’ to pool their results with those from
other ROCA studies of high-risk women such as the UKFOCSS study, which could improve statistical
power for sensitivity and positive predictive value estimates.
5.1.6.4 Other CA125 single threshold studies
The UKFOCSS Phase I study is discussed earlier with Phase II in Section 5.1.6.2.
PLCO-HR
The post hoc analysis of a subgroup in PLCO with personal or familial histories has the powerful
strengths of study design and size (RCT), and while not completely applicable to the typically
defined high-risk group, does provide evidence that outcomes of screening in women at higher-
than-average risk of ovarian cancer are different to those for the general population. A significant
improvement in ovarian cancer-specific survival with screening is encouraging, as is the significant
reduction in advanced-stage disease (Stage IIIc or IV) relative to earlier-stage disease, and a
significant reduction in the absolute number of Stage IIIc and IV cancers. Whether this demarcation
in disease stage is clinically relevant is unclear, and ovarian cancer-specific mortality was not
significantly improved.
UK-Netherlands-Norway study
The main focus of this study was comparative survival among women diagnosed with ovarian
cancer who were BRCA1 carriers, BRCA2 carriers, or ‘other’. However, prevalent and incident
106 Post hoc calculation by authors of the current Review for CGN/GOG.
Technical Report – Testing for ovarian cancer in asymptomatic women 102
(including interval) diagnoses were also compared in this study, which found no difference in
mortality but a non-significant trend towards down staging when restricting the analysis to BRCA1/2
carriers.
5.1.6.5 Overall findings of surveillance studies
The few surveillance studies that reported on mortality did not find any improvements associated
with screening. The PLCO subgroup analysis, however, did find significant improvements in disease-
specific survival with screening in a population with a higher-than-average risk, and an absolute
reduction in advanced-stage cancers – a necessary finding for effective screening. Stage shift
trends were also discernible in the other surveillance trials, and were statistically significant in the
UKFOCSS trials. Event numbers were low in all surveillance studies of high-risk cohorts, so it is not
clear whether the failure to demonstrate a corresponding improvement in mortality is due to limited
statistical power or a fundamental failure to improve mortality outcomes in screened individuals
(i.e. early detection may not result in improved mortality). Furthermore, these studies were limited
by the lack of a balanced comparator group (PLCO excepted), so the current lack of a
demonstrated mortality benefit is not evidence that surveillance cannot improve survival
outcomes.
While stage shift may be of interest as a surrogate outcome for mortality, reduced volume of
disease is also a patient-relevant outcome in itself, with implications regarding rates of post-surgical
residual disease. So while the evidence may not be resounding for the use of surveillance as first-
line management in high-risk women, it appears there may be a role for surveillance of those
women wishing to postpone RRSO.
5.1.7 Ongoing clinical studies
No ongoing clinical studies were identified in this population.
5.1.8 Impact of recent findings on evidence-informed guidance
No clinical practice guidelines or other guidance was identified that incorporates all recent
evidence relating to surveillance in women at high risk of ovarian cancer. In general, routine
surveillance is not recommended; however, some guidelines advise that surveillance using CA125
and TVUS may be considered in particular high-risk populations from the age of 30 or 35, so long as
patients are informed about the limited value of these tools as an effective screening measure.
5.1.9 Definitions of high risk of ovarian cancer
The criteria for defining women at high or potentially high risk of ovarian cancer typically contain
elements that are already included in the 2009 Position Statements, such as a personal and family
history of breast and ovarian cancer, genetic mutations, and Ashkenazi Jewish ancestry.
The recent introduction of an MBS item for cascade testing of BRCA1/2 and other specified
mutations has the potential to increase the number of women known to be at increased risk of
ovarian cancer. As such, it may be expected that any definition of a high risk population explicitly
mentions BRCA1/2 and other genetic mutations that predispose to ovarian cancer (e.g. mutations
associated with Lynch syndrome/HNPCC).
5.1.10 Emerging technologies
As for population screening (Section 5.1.5), there are no new biomarkers or other technologies that
are likely to be introduced/recommended in the short- to medium-term for surveillance of women
at high or potentially high risk of ovarian cancer.
103 Technical Report – Testing for ovarian cancer in asymptomatic women
Appendices
Appendix A Australian criteria for assessment of population screening
The framework used to guide decision makers regarding the implementation of population
screening for cancer and other chronic diseases in Australia is based on the principles outlined in
Table AppA.1. The framework has been adapted from the 1968 WHO criteria but takes into
account:
the need for a strong evidence base in making a decision about the introduction of a
screening program including evidence of the safety, reproducibility and accuracy of the
screening test and the efficacy of treatment; and
the requirement that a screening program offers more benefit than harm to the target
population.
The decision to introduce a screening program needs to also consider whether the outcomes in the
research setting can be reproduced in population screening settings.
The Australian Population Screening Framework is not designed to address targeted testing of high
risk groups. In planning the coverage of screening programs, however, steps must be taken to
ensure that consideration is given to those at high risk of developing the disease being screened
for, and that policies are in place for the appropriate identification and management of individuals
in these high risk groups.
Table AppA.1 Australian criteria for deciding whether a new screening program should be
introduced in a defined target population
Requirement Criteria to be met
Condition The condition:
is an important health problem
has a recognisable latent or early symptomatic stage
The natural history of the disease or condition, including, where relevant, the relationship between the risk
marker and the disease and the development from latent to declared disease is adequately understood.
Test The test:
is highly sensitive
is highly specific
is validated
is safe
has a relatively high positive predictive value
has a relatively high negative predictive value
is acceptable to the target population including important sub groups such as target participants who are
from culturally and linguistically diverse backgrounds, Aboriginal and Torres Strait Islander people, people
from disadvantaged groups, and people with a disability
There are established criteria for what constitutes positive and negative test results, where a positive test result
means that the person needs further investigations, and a negative test result means the person is rescreened
at the usual interval, where applicable.
Assessment Systems should be in place for evidence based follow up assessment of all people with a positive screening test
regardless of rurality, ethnicity, socio economic status or disadvantage status.
Treatment The treatment must be effective, available, easily accessible and acceptable to all patients with the
recognised disease or condition.
Technical Report – Testing for ovarian cancer in asymptomatic women 104
Requirement Criteria to be met
Screening program The Screening Program must:
respond to a recognised need
be clinically, socially, legally and ethically acceptable to health professionals, consumers and the Australian
public
have a clear definition of the objectives of the program and the expected health benefits
have scientific evidence of screening program effectiveness
identify the target population who stand to benefit from screening
clearly define the screening pathway and interval
ensure availability of the organisation, infrastructure, facilities and workforce needed to deliver the screening
program
have measures available that have been demonstrated to be cost effective to encourage high coverage
have adequate facilities available for having tests and interpreting them
have an organised quality control program across the screening pathway to minimise potential risks of
screening
have a referral system for management of any abnormalities found and for providing information about
normal screening tests
have adequate facilities for follow-up assessment, diagnosis, management and treatment
have evidence based guidelines and policies for assessment, diagnosis and support for people with a
positive test result
have adequate resources available to set up and maintain a database of health information collected for
the program
integrate education, testing, clinical services and program management
have a database or systems available capable of providing a population register for people screened that
can issue invitations for initial screening, recall individuals for repeat screening, follow those with identified
abnormalities, correlate with morbidity and mortality results and monitor and evaluate the program and its
impact
plan evaluation from the outset and ensure that program data are maintained so that evaluation and
monitoring of the program can be performed regularly
be cost-effective
ensure informed choice, confidentiality and respect for autonomy
promote equity and access to screening for the entire target population including important sub groups such
as participants who are from culturally and linguistically diverse backgrounds, Aboriginal and Torres Strait
Islander people, people from disadvantaged groups, and people with a disability
ensure the overall benefits of screening outweigh the potential harms, including psychological, physical,
social, cultural, ethical and legal harms
Treatment and ongoing
management
Treatment and management considerations:
Ongoing management referral protocols must be established for individuals who have the disease or
condition detected through the screening program
There needs to be an established policy for the management of individuals who are identified at high risk of
developing the disease or condition
Source: Population based screening framework 2016 downloaded from Department of Health, Standing Committee on Screening in
September 2017.
105 Technical Report – Testing for ovarian cancer in asymptomatic women
Appendix B Literature search details
B.1 Clinical evidence
B.1.1 Search strategy
Table AppB.1 Search strategy to identify clinical evidence
Source of information Database/website Date limits and search terms
Electronic database Medline (Ovid)107 From 1 January 2009 to present.
See Table AppB.2 for search strings.
HTA websites AHRQ (https://www.ahrq.gov/)
CADTH (https://www.cadth.ca/)
EuroScan (http://www.euroscan.bham.ac.uk/)
HealthPACT (https://www.health.qld.gov.au/healthpact/html/tech-
evaluated)
MSAC (http://www.msac.gov.au/)
NICE (https://www.nice.org.uk/)
From 1 January 2009 to present.
Search terms will depend on the
complexity of the available search
engine. In the first instance, ‘ovarian
cancer’ combined with each
intervention.
Peak cancer authorities American Cancer Society (https://www.cancer.org/)
ASCO (http://www.asco.org/)
Cancer Care Ontario (https://www.cancercare.on.ca/)
Cancer Research UK (https://www.cancerresearchuk.org/)
EORTC (http://www.eortc.org/)
ESMO (http://www.esmo.org/)
IARC (http://www.iarc.fr/)
NCCN (https://www.nccn.org/)
NCI (https://www.cancer.gov/)
Society of Gynecologic Oncology (https://www.sgo.org/)
Search terms will depend on the
complexity of the available search
engine. In the first instance, ‘ovarian
cancer’ combined with each
intervention.
Clinical trial registries Australian New Zealand Clinical Trials Registry
(http://www.anzctr.org.au/)
ClinicalTrials.gov (https://clinicaltrials.gov/)
EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/ctr-
search/search)
World Health Organization International Clinical Trials Registry
Platform (http://apps.who.int/trialsearch/)
Recently completed (unpublished) and
ongoing trials only.
Search terms will depend on the
complexity of the available search
engine. In the first instance, ‘ovarian
cancer’ combined with ‘screen’ or
‘detection’.
Abbreviations: AHRQ, Agency for Healthcare Research and Quality; ASCO, American Society of Clinical Oncology; CADTH, Canadian
Agency for Drugs and Technologies in Health; EORTC, European Organization for Research and Treatment of Cancer; ESMO, European
Society for Medical Oncology; EuroScan, European Information Network on New and Changing Health Technologies; HTA, Health Technology
Assessment; IARC, International Agency for Research on Cancer; MSAC, Medical Services Advisory Committee; NCCN, National
Comprehensive Cancer Network; NCI, National Cancer Institute; NICE, National Institute for Health and Care Excellence.
Table AppB.2 Medline search string for ovarian cancer screening
String
no.
Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and
Ovid MEDLINE(R) 1946 to Present. Searched 17 Oct 2017
Records
1 exp Ovarian Neoplasms/ 80,829
2 (ovar$ adj5 (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ot. 52,495
3 exp Mass Screening/ 120,562
4 exp Early Detection of Cancer/ 18,961
5 screen$.ti,ab,ot. 649,445
6 1 or 2 87,296
7 or/3-5 695,334
8 6 and 7 4,465
9 Randomized Controlled Trial/ 496,904
107 Includes Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946
to Present
Technical Report – Testing for ovarian cancer in asymptomatic women 106
String
no.
Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and
Ovid MEDLINE(R) 1946 to Present. Searched 17 Oct 2017
Records
10 randomi#ed controlled trial.pt. 496,904
11 controlled clinical trial.pt. 99,253
12 randomi#ed.ab. 519,298
13 placebo.ab. 202,740
14 clinical trials as topic.sh. 195,527
15 randomly.ab. 298,737
16 trial.ti. 195,716
17 or/9-16 1,243,082
18 8 and 17 494
19 limit 18 to yr="2009 -Current" 309
Table AppB.3 Medline search string for ovarian cancer surveillance in women at high risk
String
no.
Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and
Ovid MEDLINE(R) 1946 to Present. Searched 17 Oct 2017
Records
1 (famil$ or heredit$ or BRCA or high$ risk or elevated risk or increased risk).ti,ot,ab. 1,502,735
2 exp Ovarian Neoplasms/ 80,829
3 (ovar$ and (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ot. 54,588
4 2 or 3 88,365
5 exp Mass Screening/ 120,562
6 (screen$ or surveillance or monitor or CA125 or CA-125 or CA 125 or human epididymis protein 4 or human
epididymal protein 4 or HE4 or HE 4 or transvaginal ultrasound or TVUS or tvs).ti,ot.
209,343
7 exp CA-125 antigen/ 4,580
8 5 or 6 or 7 273,813
9 1 and 4 and 8 700
10 limit 9 to yr="2009 -Current" 337
B.1.2 Study selection
Table AppB.4 Study selection for the review of ovarian cancer population screening
Screening of records identified in Medline search on 17 October 2017 Records
Total records from population screening search 309
Duplicates 61
Unique records screened 248
Reasons for exclusion:
Wrong population 47
Wrong intervention 80
Wrong/no comparator 0
Wrong outcomes 76
Wrong publication type 29
Wrong study type 2
Not in English 0
Not in humans 0
Total excluded 234
Included records from population screening search in Medline 14
Records identified in Medline search for guidelines 3
Included records for population screening 17
107 Technical Report – Testing for ovarian cancer in asymptomatic women
Table AppB.5 Study selection for the review of ovarian cancer surveillance in women at high risk
Screening of records identified in Medline search on 17 October 2017 Records
Total records from ovarian cancer surveillance search 337
Duplicates 47
Unique records screened 290
Reasons for exclusion:
Wrong population 22
Wrong intervention 185
Wrong/no comparator 5
Wrong outcomes 21
Wrong publication type 25
Wrong study type 19
Not in English 0
Not in humans 2
Total excluded at title/abstract review 279
Included records from ovarian cancer surveillance search in Medline 11
B.2 Guidelines and position statements
B.2.1 Search strategy
Table AppB.6 Search strategy to identify guidelines and position statements
Source of information Database/website Restrictions
Clinical practice
guideline databases
Australian Clinical Practice Guidelines Portal
(https://www.clinicalguidelines.gov.au/)
AHRQ's National Guideline Clearinghouse
(https://guideline.gov/)
Guidelines International Network
(http://www.g-i-n.net/library/international-guidelines-library)
SIGN (http://www.sign.ac.uk/)
NICE (https://www.nice.org.uk/)
Evidence-informed guidelines and
position statements published from 2011
onwards.
Search terms depend on complexity of
the search engine. In first instance try
‘ovarian cancer’.
Electronic databases Medline (Ovid) 108 Evidence-informed guidelines and
position statements published from 2011
onwards.
Peak cancer authorities American Cancer Society (https://www.cancer.org/)
ASCO (http://www.asco.org/)
Cancer Care Ontario (https://www.cancercare.on.ca/)
Cancer Research UK (https://www.cancerresearchuk.org/)
EORTC (http://www.eortc.org/)
ESMO (http://www.esmo.org/)
IARC (http://www.iarc.fr/)
NCCN (https://www.nccn.org/)
NCI (https://www.cancer.gov/)
Society of Gynecologic Oncology (https://www.sgo.org/)
Evidence-informed guidance/advice
published from 2011 onwards.
108 Includes Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946
to Present
Technical Report – Testing for ovarian cancer in asymptomatic women 108
To identify relevant guidance in the Medline database, a search string that includes broad terms
for the interventions was combined with a search filter for clinical practice guidelines and position
statements developed by the Canadian Agency for Drugs and Technologies in Health (CADTH).
Table AppB.7 Medline search strings for guidelines and position statements
String
no.
Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid
MEDLINE(R) 1946 to Present. Searched 17Oct 2017
Records
1 exp Ovarian Neoplasms/ 80,848
2 (ovar$ adj5 (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ab,kw. 85,947
3 exp Mass Screening/ 120,594
4 exp Early Detection of Cancer/ 18,974
5 screen$.ti,ab,kw. 651,580
6 1 or 2 108,203
7 (3 or 4 or 5) and 6 6,333
8 (famil$ or heredit$ or BRCA or high$ risk or elevated risk or increased risk).ti,ab,kw. 1,525,861
9 exp Ovarian Neoplasms/ 80,848
10 (ovar$ and (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ab,kw. 104,015
11 9 or 10 123,264
12 exp Mass Screening/ 120,594
13 (screen$ or surveillance or monitor or CA125 or CA-125 or CA 125 or human epididymis protein 4 or human
epididymal protein 4 or HE4 or HE 4 or transvaginal ultrasound or TVUS or tvs).ti,ab,kw.
922,898
14 exp CA-125 antigen/ 4,580
15 12 or 13 or 14 962,180
16 8 and 11 and 15 3,184
17 exp clinical pathway/ 6,128
18 exp clinical protocol/ 161,293
19 exp consensus/ 8,863
20 exp consensus development conference/ 11,567
21 exp consensus development conferences as topic/ 2,712
22 critical pathways/ 6,128
23 exp guideline/ 31,725
24 guidelines as topic/ 37,582
25 exp practice guideline/ 24,751
26 practice guidelines as topic/ 107,967
27 health planning guidelines/ 4,167
28 (guideline or practice guideline or consensus development conference or consensus development conference,
NIH).pt.
40,846
29 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 25,608
30 (standards or guideline or guidelines).ti,kf,kw. 95,422
31 ((practice or treatment* or clinical) adj guideline*).ab. 32,939
32 (CPG or CPGs).ti. 5,447
33 consensus*.ti,kf,kw. 21,539
34 consensus*.ab. /freq=2 21,193
35 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 17,345
36 recommendat*.ti,kf,kw. 35,508
37 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 46,971
38 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or
diagnosed or diagnosing)).ti,ab,kf,kw.
6,363
39 (algorithm* adj2 (pharmacotherap* or chemotherap* or chemotreatment* or therap* or treatment* or
intervention*)).ti,ab,kf,kw.
8,209
40 or/17-39 549,904
41 (7 or 16) and 40 469
42 limit 41 to yr="2011 -Current" 232
109 Technical Report – Testing for ovarian cancer in asymptomatic women
B.2.2 Selection of guidelines and position statements
Table AppB.8 Selection for the review of guidelines and position statements
Screening of records identified in bibliographic database searches on 17 October 2017 Records
Total records from guidelines search 232
Duplicates 32
Unique records screened 200
Title/abstract review exclusions:
Wrong population 4
Wrong intervention 134
Wrong outcomes 1
Wrong publication type 31
Wrong study type 11
Not in English 2
Not in humans 0
Total excluded at title/abstract review 183
Total records reviewed at full text 17
Full text review exclusions:
Superseded 2
Not in English 1
Wrong study type 5
Total excluded at full text review 8
Included records from Medline search for guidelines for ovarian cancer screening and surveillance 9
Records identified from other searches:
Medline search for studies of population screening 0
Medline search for studies of surveillance in women at high risk 2
Targeted and general web searches 11
Total guidelines and position statements 20
Technical Report – Testing for ovarian cancer in asymptomatic women 110
B.3 Emerging technologies
B.3.1 Search strategy
Table AppB.9 Search strategy to identify emerging technologies
Source of
information
Database/website Date limits and search terms
HTA websites AHRQ (https://www.ahtq.gov/)
CADTH (https://www.cadth.ca/)
EuroScan (http://www.euroscan.bham.ac.uk/)
HealthPACT (http://www.health.qld.gov.au/healthpact/html/tech-evaluated)
MSAC (http://www.msac.gov.au)
NICE (https://www.nice.org.uk/)
Published from 2009 onwards.
Search terms varied depending on
the complexity of the search
engine. Generally used ‘ovarian
cancer’.
Horizon scan
websites
ANZHSN (https://www.horizonscanning.gov.au/)
ISCRR (https://www.iscrr.com.au/evidence-data-and-research/evidence-
review-hub/horizon-scanning)
CADTH Horizon Scanning (http://www.cadth.ca/about-cadth/what-we-
do/products-services/horizon-scanning)
ECRI Institute (https://www.ecri.org/Pages/default.aspx)
The King’s Fund (http://www.kingsfund.org.uk/)
McGill Technology Assessment Unit (http://www.mcgill.ca/tau/)
The Medical Futurist (http://medicalfuturist.com/)
NICE Medtech Innovation Briefings (https://www.nice.org.uk/about/what-we-
do/our-orogrammes/nice-advice/medtech-innovation-briefings)
NIHR-DEC Horizon Scanning Programme
(https://www.oxfor.dec.nihr.ac.au/research/horizon-scanning-1)
NIHR-IO (https://www.io.nihr.ac.uk/)
NIHR-SATSU (https://www.york.ac.uk/satsu/
Search terms varied depending on
the complexity of the search
engine. Generally used ‘ovarian
cancer’.
Peak cancer
authorities
ACS (https://www.cancer.org/)
ASCO (http://www.asco.org/)
Cancer Care Ontario (https://www.cancercare.on.ca/)
Cancer Research UK (https://www.cancerresearchuk.org/)
EORTC (http://www.eortc.org/)
ESMO (http://www.esmo.org/)
IARC (http://www.iarc.fr/)
NCCN (https://www.nccn.org/)
NCI (https://www.cancer.gov/)
Society of Gynecologic Oncology (https://www.sgo.org/
Search terms varied depending on
the complexity of the search
engine. Generally used ‘ovarian
cancer’.
Clinical trial
registries
ANZCTR (https://www.anzctr.org.au/)
ClinicalTrials.gov (https://clinicaltrials.gov/)
EUCTR (https://www.clinicaltrialsregister.eu/ctr-search/search)
WHOICTRP (https://apps.who.int/trialsearch/
Recently completed or ongoing
trials
Search terms varied depending on
the complexity of the search
engine. Generally used ‘ovarian
cancer’ and the following terms:
screening, surveillance, detection,
test, diagnostic and biomarker.
Conference
abstracts
Key cancer conferences:
ASCO (http://ascopubs.org/jco/meeting)
ESMO (http://www.esmo.org/Conferences/Past-Conferences
Abstracts/commentary from 2016
and 2017 conferences
Searched ‘ovarian cancer’ and
‘screening’ or ‘biomarker’.
Abbreviations: ACS, American Cancer Society; AHRQ, Agency for Healthcare Research and Quality; ANZHSN, Australia and New Zealand
Horizon Scanning Network; ASCO, American Society of Clinical Oncology; CADTH, Canadian Agency for Drugs and Technologies in Health;
DEC, Diagnostic Evidence Co-operative; EORTC, European Organisation for Research and Treatment of Cancer; ESMO, European Society for
Medical Oncology; EUCTR, European Union Clinical Trials Register; HealthPACT, Health Policy Advisory Committee on Technology; HTA, Health
Technology Assessment; IARC, International Agency for Research on Cancer; IO, Innovation Observatory; ISCRR, Institute for Safety,
Compensation and Recovery Research; MSAC, Medical Services Advisory Committee; NCCN, National Comprehensive Cancer Network; NCI,
National Cancer Institute; NICE, National Institute for Health and Care Excellence; NIHR, National Institute for Health Research; SATSU, Science
and Technology Studies Unit; WHOICTRP, World Health Organization International Clinical Trials Registry Platform.
111 Technical Report – Testing for ovarian cancer in asymptomatic women
Appendix C Evidence hierarchy
The levels of evidence hierarchy for interventions, developed by the National Health and Medical
Research Council (NHMRC), is shown in Table AppC.1.
Table AppC.1 Designations of levels of evidence for interventional studies
Level Intervention Screening intervention
Ia A systematic review of Level II studies A systematic review of Level II studies
II A randomised controlled trial A randomised controlled trial
III-1 A pseudo-randomised controlled trial (i.e. alternate
allocation or some other method)
A pseudo-randomised controlled trial (i.e. alternate
allocation or some other method)
III-2 A comparative study with concurrent controls: A comparative study with concurrent controls:
Non-randomised, experimental trialb Non-randomised, experimental trial
Cohort study Cohort study
Case-control study Case-control study
Interrupted time series with a control group
III-3 A comparative study without concurrent controls: A comparative study without concurrent controls:
Historical control study Historical control study
Two or more single-arm studyc Two or more single-arm study
Interrupted time series without a parallel control group
IV Case series with either post-test or pre-test/post-test
outcomes
Case series
Source: National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for developers of
guidelines. Canberra: National Health and Medical Research Council, 2009.
a A systematic review will only be assigned a level of evidence as high as the studies it contains, excepting where those studies are of Level II
evidence. Systematic reviews of Level II evidence provide more data than the individual studies and any meta-analyses will increase the
precision of the overall results, reducing the likelihood that the results are affected by chance. Systematic reviews of lower level evidence
present results of likely poor internal validity and thus are rated on the likelihood that the results have been affected by bias, rather than
whether the systematic review itself is of good quality. Systematic review quality should be assessed separately. A systematic review should
consist of at least two studies. In systematic reviews that include different study designs, the overall level of evidence should relate to each
individual outcome/result, as different studies (and study designs) might contribute to each different outcome.
b This also includes controlled before-and-after (pre-test/post-test) studies, as well as adjusted indirect comparisons (i.e. utilise A vs B and B vs
C, to determine A vs C with statistical adjustment for B).
c Comparing single-arm studies i.e. case series from two studies. This would also include unadjusted indirect comparisons (i.e. utilise A vs B and
B vs C, to determine A vs C but where there is no statistical adjustment for B).
Technical Report – Testing for ovarian cancer in asymptomatic women 112
Appendix D Included studies
D.1 Population screening
D.1.1 Clinical trials
Table AppD.1 Clinical trials of population screening for ovarian cancer
Trial Study ID Citation Main
outcome
PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening RCT
Primary and secondary outcomes
Pinsky
2016
Pinsky PF, Yu K, Kramer BS, Black A, Buys SS, Partridge E, et al. (2016). Extended mortality
results for ovarian cancer screening in the PLCO trial with median 15years follow-up.
Gynecologic Oncology. 143(2):270-5.
Mortality –
longer term
follow up
Primary
publication
Buys 2011 Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. (2011). Effect of
screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian
(PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 305(22):2295-303.
Mortality
Partridge
2009
Partridge E, Kreimer AR, Greenlee RT, Williams C, Xu JL, Church TR, et al. (2009). Results
from four rounds of ovarian cancer screening in a randomized trial. Obstetrics &
Gynecology. 113(4):775-82.
False positive
surgery, stage
at diagnosis
Buys
2005109
Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. (2005). Ovarian
cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer
screening trial: Findings from the initial screen of a randomized trial. American Journal of
Obstetrics and Gynecology. 193(5):1630-9.
Initial screen
Post hoc analyses
Pinsky
2013
Pinsky PF, Zhu C, Skates SJ, Black A, Partridge E, Buys SS, et al. (2013). Potential effect of
the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate,
Lung, Colorectal and Ovarian (PLCO) trial. International Journal of Cancer. 132(9):2127-
33.
Mortality
Nyante
2011
Nyante SJ, Black A, Kreimer AR, Duggan MA, Carreon JD, Kessel B, et al. (2011).
Pathologic findings following false-positive screening tests for ovarian cancer in the
Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Gynecologic
Oncology. 120(3):474-9.
Predictors of
false positive
results
Additional material
NIH –
National
Cancer
Institute
Cancer Data Access System. Online information for PLCO including a summary of trial
design, datasets and a list of study publications Accessed 31 Oct 2017
Data source
Prorok
2000
Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, Crawford ED, et al. (2000). Design of
the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Controlled
clinical trials. 21(6 Suppl):273S-309S.
Study design
Simpson
2000
Simpson NK, Johnson CC, Ogden SL, Gamito E, Trocky N, McGuire C, et al. (2000).
Recruitment strategies in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer
Screening Trial: the first six years. Controlled clinical trials. 21(6 Suppl):356S-78S.
Study design
109 This study was published prior to the 2009 date limit for the literature search, and was identified by hand searching.
113 Technical Report – Testing for ovarian cancer in asymptomatic women
Trial Study ID Citation Main
outcome
UKCTOCS: UK Collaborative Trial of Ovarian Cancer Screening RCT
Primary and secondary outcomes
Fallowfield
2017
Fallowfield L, Solis-Trapala I, Menon U, Langridge C, May S, Jacobs I, et al. (2017). The
effect of ovarian cancer screening on sexual activity and functioning: results from the UK
collaborative trial of ovarian cancer screening RCT. British Journal of Cancer. 116(8):1111-
7.
Adverse
effects of tests
Primary
publication
Jacobs
2016
Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. (2016). Ovarian
cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS): a randomised controlled trial. Lancet. 387(10022):945-56. Supplementary
appendix available.
Mortality
Barrett
2014
Barrett J, Jenkins V, Farewell V, Menon U, Jacobs I, Kilkerr J, et al. (2014). Psychological
morbidity associated with ovarian cancer screening: results from more than 23,000
women in the randomised trial of ovarian cancer screening (UKCTOCS). BJOG: An
International Journal of Obstetrics & Gynaecology. 121(9):1071-9.
Adverse
effects of tests
Sharma
2012
Sharma A, Apostolidou S, Burnell M, Campbell S, Habib M, Gentry-Maharaj A, et al.
(2012). Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-
detected ovarian masses: a prospective cohort study within the UK collaborative trial of
ovarian cancer screening (UKCTOCS). Ultrasound in Obstetrics & Gynecology. 40(3):338-
44.
False positive
surgery
Menon
2009
Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, et al. (2009).
Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer,
and stage distribution of detected cancers: results of the prevalence screen of the UK
Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncology. 10(4):327-
40.
Initial screen
Post hoc analyses
Menon
2017
Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, et al. (2017). The cost-
effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of
Ovarian Cancer Screening (UKCTOCS). British Journal of Cancer. 117(5):619-27.
Cost
effectiveness
Kearns
2016
Kearns B, Chilcott J, Whyte S, Preston L, Sadler S. (2016). Cost-effectiveness of screening
for ovarian cancer amongst postmenopausal women: a model-based economic
evaluation.[Erratum appears in BMC Med. 2017 Feb 3;15(1):31; PMID: 28158977]. BMC
Medicine. 14(1):200.
Cost
effectiveness
Menon
2015
Menon U, Ryan A, Kalsi J, Gentry-Maharaj A, Dawnay A, Habib M, et al. (2015). Risk
Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected
Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative
Trial of Ovarian Cancer Screening. Journal of Clinical Oncology. 33(18):2062-71.
Threshold
testing
Additional material
Jacobs
and
Menon
2015
Protocol for the United Kingdom Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS) Version 7.1, April 2015 Accessed 31 Oct 2017
Study design
NHS 2016 Detailed Project Description: Long term impact of screening on ovarian cancer mortality
in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Report. Accessed
31 Oct 2017.
Rationale for
extending
follow up
Abbreviations: PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RCT, randomised controlled trial; NHS, National Health
Service; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening.
D.1.2 Systematic reviews and HTAs
Table AppD.2 Systematic reviews of population screening for ovarian cancer
Study ID Citation
Buhling 2017 Buhling KJ, Lezon S, Eulenburg C, Schmalfeldt B. (2017). The role of transvaginal ultrasonography for detecting ovarian
cancer in an asymptomatic screening population: a systematic review. Archives of Gynecology & Obstetrics.
295(5):1259-68.
Guirguis-Blake
2017
Guirguis-Blake JM, Henderson JT, Perdue LA, Whitlock EP. (2017) Screening for Gynecologic Conditions With Pelvic
Examination: A Systematic Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 147. AHRQ
Publication No. 15-05220-EF-1. Rockville, MD: Agency for Healthcare Research and Quality.
Henderson 2017 Henderson JT, Webber E, Sawaya GF. (2017). Screening for Ovarian Cancer: An Updated Evidence Review for the U.S.
Preventive Services Task Force. Evidence Synthesis No. 157. AHRQ Publication No. 17-05231-EF-1. Rockville, MD: Agency
for Healthcare Research and Quality.
Technical Report – Testing for ovarian cancer in asymptomatic women 114
Study ID Citation
Bloomfield 2014 Bloomfield HE, Olson A, Greer N, Cantor A, MacDonald R, Rutks I, et al. (2014). Screening pelvic examinations in
asymptomatic, average-risk adult women: an evidence report for a clinical practice guideline from the American
College of Physicians. Annals of Internal Medicine. 161(1):46-53.
Reade 2013 Reade CJ, Riva JJ, Busse JW, Goldsmith CH, Elit L. (2013). Risks and benefits of screening asymptomatic women for
ovarian cancer: a systematic review and meta-analysis. Gynecologic Oncology. 130(3):674-81.
Abbreviations: HTA, health technology assessment; MA, meta-analysis; SR, systematic review.
D.2 Surveillance in women at high risk
D.2.1 Clinical studies
Table AppD.3 Clinical studies of surveillance in women at high risk of ovarian cancer
Study ID Citations Main outcome
UKFOCSS Phase II
Rosenthal
2017
Rosenthal AN, Fraser LSM, Philpott S, Manchanda R, Burnell M, Badman P, et al. (2017). Evidence of
Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom
Familial Ovarian Cancer Screening Study. Journal of Clinical Oncology. 35(13):1411-20.
Performance
characteristics
Additional material
Jacobs 2010 The UK Familial Ovarian Cancer Screening Study (UK FOCSS) Phase II. Study Protocol. Accessed 10
Nov 2017.
Study design
PsyFOCS
Lifford 2013 Lifford KJ, Clements A, Fraser L, Lancastle D, Brain K, Psy FMG. (2013). A qualitative study of women's
experiences of familial ovarian cancer screening. Psycho-Oncology. 22(11):2576-84.
Quality of life
Brain 2012 Brain KE, Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, et al. (2012). Psychological
outcomes of familial ovarian cancer screening: no evidence of long-term harm. Gynecologic
Oncology. 127(3):556-63.
Quality of life
Lifford 2012 Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, Phelps C, et al. (2012). Withdrawal from
familial ovarian cancer screening for surgery: findings from a psychological evaluation study
(PsyFOCS). Gynecologic Oncology. 124(1):158-63.
Quality of life
Lancastle
2011
Lancastle D, Brain K, Phelps C. (2011). Illness representations and distress in women undergoing
screening for familial ovarian cancer. Psychology & Health. 26(12):1659-77.
Quality of life
CGN/GOG
Skates 2017 Skates SJ, Greene MH, Buys SS, Mai PL, Brown P, Piedmonte M, et al. (2017). Early Detection of
Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women
at Increased Familial Risk - Combined Results from Two Screening Trials. Clinical Cancer Research.
23(14):3628-37.
Diagnostic
performance
PLCO-HR
Lai 2016 Lai T, Kessel B, Ahn HJ, Terada KY. (2016). Ovarian cancer screening in menopausal females with a
family history of breast or ovarian cancer. Journal of Gynecologic Oncology. 27(4):e41.
Mortality/
survival
UKFOCSS Phase I
Rosenthal
2013
Rosenthal AN, Fraser L, Manchanda R, Badman P, Philpott S, Mozersky J, et al. (2013). Results of
annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight
the need for strict adherence to screening schedule. Journal of Clinical Oncology. 31(1):49-57.110
Performance
characteristics
UK-Netherlands-Norway study
Evans 2009 Evans DG, Gaarenstroom KN, Stirling D, Shenton A, Maehle L, Dorum A, et al. (2009). Screening for
familial ovarian cancer: poor survival of BRCA1/2 related cancers. Journal of Medical Genetics.
46(9):593-7.
Survival in
BRCA1/2
carriers
Fox Chase Cancer Centre
Fang 2009 Fang CY, Cherry C, Devarajan K, Li T, Malick J, Daly MB. (2009). A prospective study of quality of life
among women undergoing risk-reducing salpingo-oophorectomy versus gynecologic screening for
ovarian cancer. Gynecologic Oncology. 112(3):594-600.
Quality of life
Abbreviations: CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer
Screening Trial; UK, United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
110 Online appendix referred to be not available.
115 Technical Report – Testing for ovarian cancer in asymptomatic women
D.2.2 Systematic review and HTAs
Table AppD.4 Systematic reviews of surveillance in women at high risk of ovarian cancer
Study ID Citations
Auranen 2011 Auranen A, Joutsiniemi T. (2011). A systematic review of gynecological cancer surveillance in women belonging to
hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstetricia et Gynecologica Scandinavica.
90(5):437-44.
Technical Report – Testing for ovarian cancer in asymptomatic women 116
Appendix E Additional data extraction
E.1 Additional data extraction for population screening
FigureApp E.1.1 shows a timeline for the PLCO trial published in 2000. As this is the sole source of
information regarding the date that screening ended in this trial, this figure is reproduced here.
FigureApp E.1.1 Timeline for PLCO trial
Source: Prorok 2000 Figure 2.
Abbreviations: PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
Table AppE.1 ICD-10 codes interrogated for UKCTOCS study
Code Description
C56 Malignant neoplasm of ovary
C57.0 Malignant neoplasm of fallopian tube
C57.4 Uterine adnexa, unspecified
C57.7 Other specified female genital organs
C57.8 Malignant neoplasm of overlapping lesion of female genital organs
C57.9 Malignant neoplasm of female genital organ, unspecified
C48.0 Retroperitoneum
C48.1 Specified parts of peritoneum
C48.2 Malignant neoplasm of peritoneum, unspecified
C48.8 Overlapping lesions of retroperitneum and peritoneum
C76.2 Malignant neoplasm of abdomen
C76.3 Malignant neoplasm of pelvis
C80 Malignant neoplasm without specification of site
D07.3 Carcinoma in situ of other/unspecified female genital organ
D28.2 Benign neoplasm of fallopian tube
D28.9 Benign neoplasm of female genital organ, unspecified
D36.9 Benign neoplasm of unspecified site
D39.1 Neoplasm of uncertain or unknown behaviour of ovary
D39.9 Neoplasm of uncertain or unknown behaviour of female genital organ, unspecified
Source: Jacobs 2016, supplementary appendix, p3.
Note: Medical records were obtained and interrogated for all women except those who had both an ICD10-C80 (malignant neoplasm of
uncertain origin) and another specific non-ovarian/ peritoneal cancer registration.
Abbreviations: ICD-10, International Statistical Classification of Diseases and Related Health Problems (10th revision); UKCTOCS, United
Kingdom Collaborative Trial of Ovarian Cancer Screening.
117 Technical Report – Testing for ovarian cancer in asymptomatic women
Table AppE.2 Case identification and verification – diagnosis or death due to OC
PLCO UKCTOCS
Identification of
possible cases of
ovarian cancer
Original analysis period (to 28 Feb 2010)
Incident cancers and deaths were ascertained primarily
through a mailed annual study update questionnaire
(ASU), which asked about type and date of cancer
diagnosed in the previous year.
Data pertaining to diagnosis and (at least initial)
treatment of all PLCO cancers were collected in both
the screened and control arms of the trial to enable
uniform staging and other prognostic criteria to be
applied. Incident cancers reported on the ASU were
verified by obtaining medical records and utilizing a
standardized abstracting process. Next of kin notified the
trial of deaths, which were verified by obtaining death
certificates; National Death Index (NDI) searches were
also used (screening centres compiled the information
necessary to search the NDI files, e.g. name, social
security number, date of birth). Population-based cancer
registries also were used when possible. Medical records
pertaining to diagnosed cancers were obtained by the
PLCO screening centers.
The screening centres actively tracked participants with
screening test abnormalities and actively sought,
collected, assembled, organized, and abstracted
medical record information related to diagnostic follow-
up and treatment.
Extended follow up (to 31 Dec 2012)
Going forward from the time of the original analysis
period, there was a structural change in the operation of
PLCO that affected the way cancer incidence and
mortality endpoints were ascertained. Specifically,
beginning in mid-2011, PLCO transitioned from a system
of follow-up performed at the individual screening
centers to a centralized approach in which Participants
were followed by a central data coordinating center
(CDCC). All participants were contacted, and those
willing to continue in the study were eligible for linkages
to the NDI and state cancer registries.
The coordinating centre (CC) was notified of new cases
of ovarian/fallopian tube cancer and possible ovarian
cancer by various sources. Volunteers’ NHS numbers
were used to link to various datasets and registries, and
the Health and Social Care Information Centre (HSCIC)
cancer registration and Death Certificates were two of
the most important sources of information.
Quarterly HSCIC updates were received electronically.
After each update, a query was run to identify potential
new cases of ovarian/tubal cancer. The query flags up a
list of the ICD-10 codes that could be related to a
diagnosis of ovarian or tubal cancer.
The cohort was also linked to the Hospital Episodes
Statistics (HES) administrative records in England. HES is a
comprehensive dataset of volunteers’ in- and out-
patient hospital admissions (2001-2009) and
corresponding disease codes (2003-2009). HES data on
the women was received by the CC in 2010. The clinical
diagnosis fields of the HES dataset were searched for any
of 19 relevant ICD-10 diagnosis codes (0, Table AppE.1).
For women who resided in England, data was also
obtained from the National Cancer Intelligence Network.
Another source of information was the trial regional
centres (RC), which would notify the CC of all new cases
of screen-detected OC, and possible OC, and forward
relevant medical notes to the UKCTOCS senior research
nurse or designated research associate. The RCs would
sometimes also notify the CC of screen negative and
control arm cases where these cases were known to
them. However, these volunteers did not always receive
treatment at the RC hospital and were therefore not be
identified through this method.
Other sources of notification were two postal follow-up
questionnaires (3-5 years after randomisation and April,
2014) and direct communication from trial participants,
their families, and physicians.
Verification of
diagnosis
Original analysis period (to 28 Feb 2010)
Data on the stage, histology, and grade of PLCO
cancers were abstracted by certified tumour registrars. In
addition, treatment information during the first year post-
diagnosis was abstracted.
Deaths potentially related to a PLCO trial cancer and
those of unknown or uncertain cause were reviewed by
at least 1 individual from a panel with appropriate
expertise (epidemiology, surgery, medicine, radiation
oncology); panel members were not otherwise affiliated
with the trial and reviewers were blinded to the
randomization group of the deceased participant.
Early on during the death review process, each death
had 2 independent reviews and discrepancies were
resolved by consensus after a third reviewer had
examined the records. After 2 years, the process was
streamlined. As a result, a primary reviewer considered
the record without having access to the death
certificate. If he or she recorded an underlying cause of
death different from that of the death certificate, a
second reviewer independently reviewed the record
together with the death certificate. Disagreement
between the reviewers resulted in another independent
Ascertainment of outcomes involved interrogating all
available data sources of women identified by the
notification process described above. All medical
records and notes related to cancer diagnosis/death
were obtained from the corresponding regional centres,
hospital(s) where treatment was received, GP surgeries,
hospices and cancer registries. For all screen-positive
surgeries, these included discharge summaries,
multidisciplinary team meeting notes, surgery notes, and
histopathology and/or cytology reports, along with
death certificates for cases of OC-specific death. 111
All data were reviewed by an outcomes review
committee (two pathologists and two gynaecological
oncologists) who were masked to the randomisation
group. They confirmed the final diagnosis, stage, and
morphology of any cancer and, when possible, they
classified invasive epithelial ovarian or tubal cancers into
Type I (low-grade serous, low-grade endometrioid,
mucinous, and clear cell cancers) or Type II (high-grade
serous, high-grade endometrioid, carcinosarcomas, and
undifferentiated carcinoma) cancers. Where it was not
possible to delineate whether the primary site was ovary,
fallopian tube, or peritoneum, the diagnosis was
classified as undesignated. Death due to ovarian cancer
111 This approach provided additional information for 99% (1757/1767) of women with regards to cancer diagnosis and 97% (876/900) with
regard to death diagnosis.
Technical Report – Testing for ovarian cancer in asymptomatic women 118
PLCO UKCTOCS
review, which was subsequently resolved by a meeting
or teleconference.
Extended follow up (to 31 Dec 2012)
Only mortality is reported to date for the extended
analysis. The trial ascertained deaths primarily through
the NDI, so medical records were not available to
perform endpoint verification. Therefore, for deaths
occurring after the original cut-off (Feb 28th, 2010), the
underlying cause of death from the NDI was used to
classify deaths as being from ovarian cancer or not and
no endpoint verification was performed.
Linkage with cancer registries to ascertain incident
ovarian cancers is ongoing, so complete incidence data
for the period after Feb 28th, 2010 are not currently
available.
was based on disease progression (appearance of new
lesions or increases in size of previously documented
lesions with imaging, clinical worsening, or rising
biomarker concentrations).
A final diagnosis was assigned by application of an
algorithm.
Abbreviations: ASU, annual study update; CC, coordinating centre; CDCC, central data coordinating center; GP, general practitioner; HES,
Hospital Episodes Statistics; HSCIC, Health and Social Care Information Centre; ICD, International Classification of Diseases; NDI, National
Death Index; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RC, regional centres; UKCTOCS,
United Kingdom Collaborative Trial of Ovarian Cancer Screening.
FigureApp E.1.2 Survival from randomisation in patients with ovarian (invasive), tubal or peritoneal
cancer – PLCO
Years from
randomisation 0 1 2 3 4 5 6 7 8 9 10 11 12 13
At risk
TVUS 212 210 207 201 195 183 168 153 140 125 95 69 47 16
No screening 176 176 173 167 160 148 135 123 114 98 72 54 35 15
Source: Buys 2011 online supplement, eFigure (last page).
Abbreviations: PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; TVUS, transvaginal ultrasonography.
119 Technical Report – Testing for ovarian cancer in asymptomatic women
Table AppE.3 Cancer stage at diagnosis, by tumour type grouping – UKCTOCS
Tumours by stage, n (%) UKCTOCS
OC (invasive), FTC, undesignated Peritoneal Non-epithelial ovarian Borderline epithelial ovarian
ROCA
triage TVUS
No
screening
ROCA
triage TVUS
No
screening
ROCA
triage TVUS
No
screening
ROCA
triage TVUS
No
screening
Total cancers detected, n 283 (100) 249 (100) 559 (100) 16 (100) 10 (100) 15 (100) 11 (100) 12 (100) 8 (100) 44 (100) 53 (100) 62 (100)
Stage at diagnosis
I 76 (27) 39 (16) 91 (16) 0 (0) 0 (0) 0 (0) 10 (91) 10 (83) 7 (88) 41 (93) 50 (94) 49 (79)
II 31 (11) 19 (8) 45 (8) 1 (6)112 0 (0) 1 (7)112 0 (0) 0 (0) 1 (13) 0 (0) 0 (0) 4 (6)
III 142 (50) 141 (57) 314 (56) 14 (88) 9 (90) 10 (67) 1 (9) 1 (8) 0 (0) 3 (7) 3 (6) 9 (15)
IV 33 (12) 50 (20) 108 (19) 1 (6) 1 (10) 4 (27) 0 (0) 1 (8) 0 (0) 0 (0) 0 (0) 0 (0)
Unknown 1 (0) 0 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)
Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; ROCA, risk of ovarian cancer algorithm; TVUS, transvaginal ultrasound; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening.
112 Stage IIb.
Technical Report – Testing for ovarian cancer in asymptomatic women 120
E.2 Additional data extraction for surveillance studies
Table AppE.4 ROCA triage protocol – UKFOCSS Phase II
Note: Figure should be read from left to right.
Results classification:
ROC N = Normal; I = Intermediate*; E = Elevated
Scans N = Normal; U = Unsatisfactory; A = Abnormal
Action:
RS = Routine Screening (i.e. 4-monthly CA125 and annual scan)
CD = Clinical Decision
Refer = Referral for clinical assessment by local study centre gynaecologist.
Clinical Decision = management at discretion of study clinicians at coordinating centre. Clinical decisions will be to (i) refer the woman to a
gynaecologist for further investigation, (ii) return to routine screening or (iii) undergo repeat CA125 and or ultrasound sooner than routine
screening.
*from 13/05/10 Intermediate results were sub-classified into High Intermediate and Low Intermediate. Actions following these results were as
follows: High Intermediate – scan within 2 months and repeat CA125 after 2 months; Low Intermediate – repeat CA125 after 2 months.
Source: Rosenthal 2017 online supplement, Figure A3
Abbreviations: CA, cancer antigen; CD, clinical decision; ROC, risk of ovarian cancer; ROCA, risk of ovarian cancer algorithm; RS, routine
screening; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
121 Technical Report – Testing for ovarian cancer in asymptomatic women
Table 0.1 Identification of possible OC and diagnosis verification – surveillance studies
Study ID Identification of possible cases of OC Verification of diagnosis
ROCA-based CA125 evaluation
UKFOCSS
Phase II
Participants were flagged (by their unique NHS number)
with relevant cancer registries, which provided cancer
and/or death data. Collaborators notified the coordinating
centre when women withdrew before routine screening
ended (June 30, 2011). Women were observed through
cancer registries with censorship that was based on date of
death, last notification from the registry, or last contact if
they were lost to registry follow-up. Participants were sent
health questionnaires in January 2011 and April 2013
specifically asking about surgery that involved removal of
fallopian tubes/ovaries and cancer diagnosis.
Whenever women underwent salpingo-oophorectomy, the
coordinating centre obtained documentation of
indication, operation notes, and histopathology/
cytopathology reports. These were reviewed by a
gynaecologic oncologist and pathologist (blinded to the
clinical and previous pathology data) and were classified
according to the ICD-10.
Specific ICD codes were not mentioned: included cancers
were described as invasive ovarian, fallopian tube or
primary peritoneal cancers.
CGN/GOG Questionnaires sent to participants. Each study had central review of all ovarian surgical
specimens, including all 501 RRSOs, by central pathologists.
Single threshold CA125 evaluation
PLCO-HR OC diagnosis or death indicated in returned questionnaire
(annual study update), or discovered in search of cancer
or death registries (see Appendix E, Table AppE.2) for more
information about the PLCO RCT).
Deaths potentially related to a PLCO trial cancer and those
of unknown or uncertain cause were reviewed by at least 1
individual from a panel with appropriate expertise
(epidemiology, surgery, medicine, radiation oncology);
panel members were not otherwise affiliated with the trial
and reviewers were blinded to the randomisation group of
the deceased participant.
UKFOCSS
Phase I
All women were flagged with the relevant national cancer
registry (National Health Service Information Centre for
Health and Social Care, General Registrar Office for
Scotland, and Northern Ireland Cancer Registry).
Whenever women underwent salpingo-oophorectomy, the
Coordinating Centre obtained documentation explaining
surgical indication, whether CA125 and/or scan results had
prompted surgery, the operation note, and histopathology
and cytopathology reports. These data were reviewed by
a gynaecologic oncologist and pathologist.
UK-
Netherlands-
Norway
Hospital notes and cancer and other registries were used
to establish date at death and current vital status as of 1
March 2007.
More information may be available in one of five cited
records of prior publications of these screening
programmes.
Fox Chase
Cancer
Centre
N/A (screening outcomes not reported as only QoL
outcomes measured)
N/A
Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group; HR, high-risk; N/A, not applicable;
NHS, National Health Service; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; QoL, quality of life;
RCT, randomised controlled trial; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy; UK, United Kingdom;
UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.
Technical Report – Testing for ovarian cancer in asymptomatic women 122
Appendix F Quality assessment
Table AppF.1 Systematic review quality assessment – Buhling 2017
Question Answer
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research
objectives to score a “yes.”
Yes
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements
should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks
the other’s work.
Yes
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used
(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the
search strategy should be provided. All searches should be supplemented by consulting current contents,
reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the
references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central
counts as 2 sources; a grey literature search counts as supplementary).
Yes
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
The authors should state that they searched for reports regardless of their publication type. The authors
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate
“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for
this purpose. If searching a source that contains both grey and non-grey, must specify that they were
searching for grey/unpublished lit.
No
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is
dead, select “no.”
No
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the
participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,
race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be
reported.
Note: Acceptable if not in table format as long as they are described as above.
Yes
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to
include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion
criteria); for other types of studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,
etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long
as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is
not acceptable).
No
Used Jadad scale
as inclusion criteria
but no individual
Jadad score
reported. Reported
strengths and
weaknesses of
each study, but
not in terms of risk
of bias.
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the
conclusions of the review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of
included studies.” Cannot score “yes” for this question if scored “no” for question 7.
No
123 Technical Report – Testing for ovarian cancer in asymptomatic women
Question Answer
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their
homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model
should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is
it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool
because of heterogeneity/variability between interventions.
No
Data not pooled,
likely due to
heterogeneity but
not stated (also no
obvious assessment
of heterogeneity)
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other
available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias
could not be assessed because there were fewer than 10 included studies.
No
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the
included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of
the included studies.
No
Not mentioned for
included studies
Table AppF.2 Systematic review quality assessment – Guirguis-Blake 2017
Question Answer
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research
objectives to score a “yes.”
Yes
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements
should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks
the other’s work.
Yes
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used
(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the
search strategy should be provided. All searches should be supplemented by consulting current contents,
reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the
references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central
counts as 2 sources; a grey literature search counts as supplementary).
Yes
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
The authors should state that they searched for reports regardless of their publication type. The authors
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate
“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for
this purpose. If searching a source that contains both grey and non-grey, must specify that they were
searching for grey/unpublished lit.
Yes
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is
dead, select “no.”
Yes
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the
participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,
race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be
reported.
Note: Acceptable if not in table format as long as they are described as above.
Yes
Technical Report – Testing for ovarian cancer in asymptomatic women 124
Question Answer
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to
include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion
criteria); for other types of studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,
etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long
as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is
not acceptable).
Yes
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the
conclusions of the review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of
included studies.” Cannot score “yes” for this question if scored “no” for question 7.
Yes
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their
homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model
should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is
it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool
because of heterogeneity/variability between interventions.
Yes
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other
available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias
could not be assessed because there were fewer than 10 included studies.
No
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the
included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of
the included studies.
No
Not mentioned for
included studies
Table AppF.3 Systematic review quality assessment – Henderson 2017
Question Answer
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research
objectives to score a “yes.”
Yes
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements
should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks
the other’s work.
Yes
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used
(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the
search strategy should be provided. All searches should be supplemented by consulting current contents,
reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the
references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central
counts as 2 sources; a grey literature search counts as supplementary).
Yes
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
The authors should state that they searched for reports regardless of their publication type. The authors
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate
“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for
this purpose. If searching a source that contains both grey and non-grey, must specify that they were
searching for grey/unpublished lit.
No
125 Technical Report – Testing for ovarian cancer in asymptomatic women
Question Answer
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is
dead, select “no.”
Yes
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the
participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,
race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be
reported.
Note: Acceptable if not in table format as long as they are described as above.
Yes
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to
include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion
criteria); for other types of studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,
etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long
as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is
not acceptable).
Yes
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the
conclusions of the review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of
included studies.” Cannot score “yes” for this question if scored “no” for question 7.
Yes
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their
homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model
should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is
it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool
because of heterogeneity/variability between interventions.
Yes
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other
available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias
could not be assessed because there were fewer than 10 included studies.
No
Publication bias
reported for studies
as undetected –
no test values were
given
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the
included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of
the included studies.
No
Not mentioned for
included studies
Table AppF.4 Systematic review quality assessment – Bloomfield 2014
Question Answer
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research
objectives to score a “yes.”
Yes
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements
should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks
the other’s work.
Yes
Technical Report – Testing for ovarian cancer in asymptomatic women 126
Question Answer
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used
(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the
search strategy should be provided. All searches should be supplemented by consulting current contents,
reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the
references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central
counts as 2 sources; a grey literature search counts as supplementary).
Yes
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
The authors should state that they searched for reports regardless of their publication type. The authors
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate
“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for
this purpose. If searching a source that contains both grey and non-grey, must specify that they were
searching for grey/unpublished lit.
No
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is
dead, select “no.”
No
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the
participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,
race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be
reported.
Note: Acceptable if not in table format as long as they are described as above.
Yes
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to
include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion
criteria); for other types of studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,
etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long
as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is
not acceptable).
Yes
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the
conclusions of the review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of
included studies.” Cannot score “yes” for this question if scored “no” for question 7.
No
Not explicit.
Limitations of
studies described
but not considered
in conclusions
particularly
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their
homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model
should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is
it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool
because of heterogeneity/variability between interventions.
No
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other
available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias
could not be assessed because there were fewer than 10 included studies.
No
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the
included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of
the included studies.
No
Not mentioned for
included studies
127 Technical Report – Testing for ovarian cancer in asymptomatic women
Table AppF.5 Systematic review quality assessment – Reade 2013
Question Answer
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research
objectives to score a “yes.”
Yes
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements
should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks
the other’s work.
Yes
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used
(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the
search strategy should be provided. All searches should be supplemented by consulting current contents,
reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the
references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central
counts as 2 sources; a grey literature search counts as supplementary).
Yes
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
The authors should state that they searched for reports regardless of their publication type. The authors
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate
“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for
this purpose. If searching a source that contains both grey and non-grey, must specify that they were
searching for grey/unpublished lit.
Yes
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is
dead, select “no.”
No
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the
participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,
race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be
reported.
Note: Acceptable if not in table format as long as they are described as above.
Yes
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to
include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion
criteria); for other types of studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,
etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long
as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is
not acceptable).
Yes
Quality assessment
for each outcome
investigated rather
than by individual
study
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the
conclusions of the review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of
included studies.” Cannot score “yes” for this question if scored “no” for question 7.
Yes
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their
homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model
should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is
it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool
because of heterogeneity/variability between interventions.
Yes
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other
available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publicat ion bias
could not be assessed because there were fewer than 10 included studies.
No
Not mentioned for
included studies
Technical Report – Testing for ovarian cancer in asymptomatic women 128
Question Answer
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the
included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of
the included studies.
No
Not mentioned for
included studies
Table AppF.6 Systematic review quality assessment – Auranen 2011
Question Answer
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research
objectives to score a “yes.”
Yes
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements
should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks
the other’s work.
Can’t answer
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used
(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the
search strategy should be provided. All searches should be supplemented by consulting current contents,
reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the
references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central
counts as 2 sources; a grey literature search counts as supplementary).
No
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
The authors should state that they searched for reports regardless of their publication type. The authors
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate
“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for
this purpose. If searching a source that contains both grey and non-grey, must specify that they were
searching for grey/unpublished lit.
No
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is
dead, select “no.”
No
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the
participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,
race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be
reported.
Note: Acceptable if not in table format as long as they are described as above.
Yes
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to
include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion
criteria); for other types of studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,
etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long
as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is
not acceptable).
No
Methodological
quality assessment
was based on
reporting of
outcome measures
only
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the
conclusions of the review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of
included studies.” Cannot score “yes” for this question if scored “no” for question 7.
No
129 Technical Report – Testing for ovarian cancer in asymptomatic women
Question Answer
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their
homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model
should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is
it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool
because of heterogeneity/variability between interventions.
No
No explanation of
why results not
pooled
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other
available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias
could not be assessed because there were fewer than 10 included studies.
No
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the
included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of
the included studies.
No
Not mentioned for
included studies
Technical Report – Testing for ovarian cancer in asymptomatic women 130
Appendix G Membership of the Working Group
A Working Group was established to provide expert input into the development of the position
statement. The Working Group comprised members with clinical, academic and community
knowledge and experience. A list of the member of the Working Group is provided in the table
below.
Name Area of expertise Role
Professor Lyndal
Trevena
General Practitioner, NSW Chair
Associate Professor
Jane Armes
Pathologist, Royal College of Pathologists of Australasia
representative, NSW
Member
Dr Cheryl Bass Clinical Radiologist, Australian and New Zealand College of
Radiologists representative, VIC
Member
Associate Professsor
Alison Brand
Gynaecological Oncologist, NSW Member
Dr Rachel Delahunty Medical Oncologist, VIC Member
Dr Susan Jordan Epidemiologist, QLD Member
Associate Professor
Judy Kirk
Clinical Geneticist, NSW Member
Ms Karen Livingstone Consumer, VIC Member
Ms Ann-Maree
Mulders
Consumer, NSW Member
Dr Larissa Roeske General Practitioner, Royal Australian College of General
Practitioners representative, VIC
Member
131 Technical Report – Testing for ovarian cancer in asymptomatic women
Abbreviations and acronyms
AAFP American Academy of Family Physicians
ACOG American College of Obstetricians and Gynecologists
ACP American College of Physicians
ACR American College of Radiology
ACS American Cancer Society
AGO Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie
AHRQ Agency for Healthcare Research and Quality
AMSTAR Assessing the Methodological Quality of Systematic Reviews
ANZHSN Australia and New Zealand Horizon Scanning Network
ASCO American Society of Clinical Oncology
CA cancer antigen
CAAb cancer associated antibodies
CADTH Canadian Agency for Drugs and Technologies in Health
CDCC central data coordinating centre
CGN Cancer Genetics Network
CGN/GOG Cancer Genetics Network and Gynecologic Oncology Group
CI confidence interval
CRP C-reactive protein
CT computed tomography
CXCL13 CXC motif chemokine 13
DCIS ductal carcinoma in situ
DEC Diagnostic Evidence Co-operative
EOC epithelial ovarian cancer
EORTC European Organisation for Research and Treatment of Cancer
ESMO European Society for Medical Oncology
EUCTR European Union Clinical Trials Register
EuroScan European Information Network on New and Changing Health Technologies
FADD FAS-associated death domain protein
FDA US Food and Drug Administration
FDG-PET 18F-fluorodeoxyglucose positron emission tomography
FDR first degree relative
FH family history
FIGO International Federation of Gynecology and Obstetrics
FP false positive
FR-alpha folate receptor-alpha
FTC fallopian tube cancer
FUR furin
GOC Society of Gynecologic Oncology of Canada
GOG Gynecologic Oncology Group
GP general practitioner
GRADE Grading of Recommendations Assessment Development and Evaluation
HADS Hospital Anxiety and Depression Scale
HBOC hereditary breast and ovarian cancer
HE4 human epididymis protein 4
HealthPACT Health Policy Advisory Committee on Technology
HES Hospital Episodes Statistics
hK11 kallikrein 11
HNPCC hereditary non-polyposis colorectal cancer
HR high risk
HRT hormone replacement therapy
HSCIC Health and Social Care Information Centre
HTA Health Technology Assessment
Technical Report – Testing for ovarian cancer in asymptomatic women 132
IARC International Agency for Research on Cancer
ICD International Classification of Diseases
ICD-10 International Statistical Classification of Diseases and Related Health Problems (10th revision)
ICER incremental cost-effectiveness ratio
IL-6 interleukin-6
IQR interquartile range
ISCRR Institute for Safety, Compensation and Recovery Research
KLK6 kallikrein 6
LMP low malignant potential
LS Lynch syndrome
LYG life year gained
MA meta-analysis
MBC male breast cancer
MBS Medical Benefits Schedule
MCS Mental Component Summary
MK midkine
MMP-7 matrix metalloproteinase-7
MMR mismatch repair
MMS multimodal screening ('ROCA triage')
MOS Medical Outcomes Survey
MRI magnetic resonance imaging
MROCA multi-marker risk of ovarian cancer algorithm
MSAC Medical Services Advisory Committee
NA not applicable
NASEM National Academies of Science, Engineering and Medicine
NBOCC National Breast and Ovarian Cancer Centre
NCCN National Comprehensive Cancer Network
NCI National Cancer Institute
NDI National Death Index
NHMRC National Health and Medical Research Council
NHS National Health Service
NICE National Institute for Health and Care Excellence
NIHR National Institute for Health Research
NPV negative predictive value
NR not reported
OC ovarian cancer
OR odds ratio
PCR polymerase chain reaction
PCS Physical Component Summary
PICOS population, intervention, comparator, outcomes, setting
PID pelvic inflammatory disease
PLCO Prostate Lung Colorectal and Ovarian Cancer Screening Trial
PPC primary peritoneal cancer
PPV positive predictive value
PRSS8 prostasin
PsyFOCS Psychological evaluation of Familial Ovarian Cancer Screening
QoL quality of life
QUEST Quality of life Education and Screening Trial
RACGP Royal Australian College of General Practitioners
RC regional centres
RCT randomised controlled trial
RoB risk of bias
ROC risk of ovarian cancer
ROCA risk of ovarian cancer algorithm
RP Royston-Parmar
RR risk ratio
133 Technical Report – Testing for ovarian cancer in asymptomatic women
RRSO risk-reducing salpingo-oophorectomy
RS routine screening
SCSOCS Shizuoka Cohort Study of Ovarian Cancer Screening
SEOM Sociedad Española de Oncología Médica
SIGN Scottish Intercollegiate Guidelines Network
STAI State/Trait Anxiety Inventory
SR systematic review
TVS/TVUS transvaginal ultrasound
UK United Kingdom
UKCTOCS UK Collaborative Trial of Ovarian Cancer Screening
UKFOCSS UK Familial Ovarian Cancer Screening Study
USPSTF United States Preventative Services Task Force
USS ultrasound screening (TVUS)
WHO World Health Organization
WHOICTRP World Health Organization International Clinical Trials Registry Platform
Technical Report – Testing for ovarian cancer in asymptomatic women 134
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