ANZGOG – 0701
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Transcript of ANZGOG – 0701
NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre
Symptom Benefit Study
Measuring the Benefit of Palliative Chemotherapy in women with platinum refractory/ resistant
ovarian cancer
ANZGOG – 0701
NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre
Study Background
• The aim is to develop a method to measure the benefit of chemotherapy, which takes into account BOTH subjective and objective responses
• Document time to symptom progression as an additional endpoint as well as symptom benefit
• Better insight into patterns of care and reasons for treatment with platinum resistant or refractory ovarian cancer
• Develop a prognostic index that better defines outcomes and test in a separate group
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Objective
• Stage 1: To determine the symptoms and aspects of HRQL that are rated most severe, troublesome in patients and identify best instruments to use in stage 2
• Stage 2: To determine the proportion of women benefiting from palliative chemotherapy as defined by a clinically significant improvement in HRQL scores and improvement of symptoms and time to symptom progression.
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Makhija S et al. ProcASCO 2007;Abstract 5507
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REGISTER
Target Population
>18yrs
platinum resistant/ refractory epithelial ovarian cancer
ECOG 0-3
Able to commence treatment within 2wks of registration
Ability to complete QoL formsindependently
During Trial
Stage1• Complete QoL questionnaires at each cycle
• 20 subjects will participate in additional QoL telephone interviews
Stage2
Determine the optimal QoL forms from Stage1Longer follow-upPrognostic data collected at baseline
Data Collection
4 Treatment
cycles or
Disease progression
Proposed longer
follow-up for Stage 2
Study Schema
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Lung Cancer as a Model
Close parallels between platinum resistant/ refractory ovarian cancerand recurrent NSCLC and SCLC in terms of response rates and survival
Copyright © American Society of Clinical Oncology
von Pawel, J. et al. J Clin Oncol; 17:658 1999
Fig 1. Survival in weeksTOPOTECAN VS. CAV
Symptom improvement compared with baseline in patients with SCLC treated with i.v. topotecan or CAV
Symptom i.v. topotecan % CAV % p value
Anorexia 32 16 0.042
Chest pain 25 17 0.371
Cough 25 15 0.160
Dyspnea 28 7 0.002
Fatigue 23 9 0.032
Hemoptysis 27 33 0.706
Hoarseness 33 13 0.043
Insomnia 33 19 0.085
Interference with daily activities 27 11 0.023
Jassem et al.
2002 [33]Osoba et al.
1985 [36]Fernandez et al.
1989 [38]Hardy et al.
1989 [39]Ellis et al.
1995 [34]Tummarello et al.
1995 [37]Cullen et al.
1988 [35]
Regimen GP BEP PVM/I MVbP MVbP PMVb MIP
Overall response (%) 41 44 42 21 32 33 56
Overall symptom improvement (%)a — — — 67 69 54 —
Symptom improvement (%)
Anorexia — — 50 — — — 58
Cough 44 68 45 71 66 40 70
Dyspnea 36 31 78 65 59 66 46
Hemoptysis 75 78 91 — — 100 92
Malaise — 53 — — 53 62 —
Pain — 68 47 63 60 39 77
Weight loss — 44 89 — — 30 —
Non Small Cell Lung Cancer – Studies Gralla Oncologist 2004; 9:14-24
LCSS in relation to standard efficacy measures- Maximum Improvementfrom baseline LCSS items- 2nd line therapy
De marinis et al JTO 3;1 2008
LCSC in relation to standard efficacy measures
De marinis et al JTO 3;1 2008
Lung Cancer Studies
● Confirm that Symptom Benefit is a valid and valuable endpoint
● Correlation of Symptom Benefit with Response and SD
● Instruments sensitive to detect symptom benefit● Provides complimentary efficacy data
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Current status
Fourteen sites open to recruitment
Twelve in Australia
Two in CanadaA further nine Australian sites are currently awaiting final ethics approval
Total recruitment
46
26 Australia
20 Canada
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Baseline Demographics
Symptom control/palliation + rising CA125 + radiological progression 28
Rising CA125 + radiological progression 9
Symptom control/palliation + rising CA125 6
Symptom Control + radiological evidence 1
Radiological Evidence only 1
Rising CA125 only 1
N = 46
Reason for treatment at enrolment
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Baseline Demographics cont’d
Major symptoms reported at baseline:
1. Pain
2. Fatigue
3. Abdominal Bloating
ECOG 0 = 17 (N = 45 - missing data for one patient)
1 = 26
2 = 2
3 = 0
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Previous lines of chemotherapy
1 x line 2 x lines 3 x lines 4 x lines 5 x lines 7 x lines
18 8 9 5 2 1
N = 43* Missing data on 3 x pts – awaiting response from sites
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Majority Platinum Resistant
Compliance
All questionnaires were completed to a very high compliance rate with few or no missing data
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Death/Disease Progression
1 x pt. has withdrawn consent
3 x pts. off study due to site error
NB. Due to centralised data entry, there is a time lag in receipt of CRFs
Cycle 2
Cycle 3
Cycle4
Deaths 4 1
Disease progression 1 6
Completed 34 22 14
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Stage 1 QoL Questionnaires
1. Symptom Representation Questionnaire
2. FACT-O (includes FOSI)
3. EORTC QLQ-C30
4. EORTC QLQ-OV28
5. Patient Data Form
6. Expected and Perceived Benefit Scale7. HAD Scale (Baseline & End of Treatment only)
8. Herth Hope Index (Baseline & End of Treatment only)
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Ovarian Symptom Benefit Study (OSBS)
Initial results and rationale for choosing the FACT-O and revising the
Patient DATA Form – Ovarian as the patient reported outcome measures (PRO)
for stage 2
Prepared by Madeleine King and Martin Stockler on behalf of the
Ovarian Symptom Benefit Study Team6 October 2009
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Background: What’s the problem?
• OSBS stage 1 uses 4 questionnaires to measure symptoms and/or quality of life:
items1. Symptom Representation Questionnaire (SRQ) 662. Pt Disease & Treatment Assessment (Pt DATA Form) 483. FACT-O (including 8 items of FOSI) 394. QLQ-C30 + Ov28 58
• The booklet was deliberately long and repetitive to corroborate findings and help determine the best subset of items for future studies
• Interviews with 10 patients indicated that they neither preferred nor disliked any particular questionnaires
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Substitutability of candidate questionnaires
• SRQ vs. Patient DATA Form– designed to measure clinically important aspects of QOL– similar layouts, 0 to 10 scales– single-item scoring (rather than multi-item or domain scoring)
• QLQ-C30/Ov28 vs. FACT-O – designed to measure quality of life (QOL) in cancer clinical trials– similar format and layout, similar response scales– multi-item domains & scoring (QLQ-C30 incl. some single
items)
• We decided to choose for OSBS stage 2– Either SRQ or Pt-DATA Form for individual symptoms – Either QLQ-C30/Ov28 or FACT-O for multi-dimensional QOL
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‘First filter’ analysis: aims & methods
Aim Determine which 4 PRO questionnaires to retain for stage 2
Analysis1. Prevalence of each possible symptom in the
‘Top Three Most Noticed Symptoms in the last week’ (as asked by the Symptom Representation Questionnaire).
2. Summary statistics and histograms describing the frequency distributions of items and domain scores for each symptom at baseline
3. Changes from baseline in item and domain scores
Data31 patients who completed QOL questionnaires at baseline (pre-C1) AND (pre-C2 (AND/OR) pre-C3) by Jul
‘09
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Results: Top 10 Symptoms of the ‘Three Most Noticed Symptoms in the last week’
at baseline Rank Symptom
No. who nominated this symptom in her
Top 3 (n=31)
1 Fatigue 17
2 Pain - general 11
3 Abdominal bloating 10
4 Sleep disturbance 9
5 Nausea and vomiting 8
6 Appetite 7
7 Shortness of breath 6
8 Bowel disturbances (including constipation) 6
9 Pain - abdominal 5
10 Urinary problems 3
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Coverage of Top 10 symptoms by candidate questionnaires
Symptom SRQ Pt DATA FACT-O FOSI QLQ-C30 QLQ-OV28
Fatigue 2 1 1 1 3 -
Pain - general 1 1 1 1 2 -
Abdominal bloating 1 1 1 1 - 1
Sleep disturbance 1 1 1 - 1 -
Nausea and vomiting 2 2 2 2 2 -
Appetite 1 2 1 - 1 1
Shortness of breath 1 1 - - 1 -
Bowel disturbances 1 3 1 - 2 3
Pain - abdominal - 1 1 1 - 1
Urinary problems 1 1 - - - 1
# items covering Top 10 12 15 9 6 12 9
Total # items in q’aire 24 18 39 8 30 28
% 50% 83% 23% 75% 40% 32%
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Detailed example of overlap Pain - general
Q’aire Item stem Response scale Scoring
SRQ Pain 0 = did not have the symptom10 = as bad as I can imagine
Single item
Pt-DATA Pain (all or anywhere) 0 = no trouble at all10 = worst I can imagine
Single item
FACT-O I have pain 0 = Not at all 1 = A little bit 2 = Somewhat 3 = Quite a bit 4 = Very much
One of 7 items in the Physical Wellbeing scale of the FACT
One of 8 items in the FOSI
QLQ-C30 Have you had pain? 1 = Not at all 2 = A little 3 = Quite a bit 4 = Very much
These two items form the pain scale of the QLQ-C30QLQ-C30 Did pain interfere with
your daily activities?
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Results at baseline (pre-cycle 1)• For each of the top 10 symptoms:
– we compared distributions and summary statistics for similar items
– No major ceiling or floor effects– Similar distributions for similar items
• Nothing to choose between questionnaires
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Change at Cycles 2 and 3
• For each of the top 10 symptoms: – we compared distributions and summary
statistics of change scores on similar items– Mean change ~0 with large SD reflecting
improvements in some women and deteriorations in others
– Comparable results across q’aires• Nothing to choose between questionnaires
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DecisionsRetain modified Pt DATA Form – Ovarian to measure key symptoms• Enhance coverage of the Top 10• Allow measurement of both current status and change• Modifications by developer and OSBS investigators
OSBS Recent Status Form (after each cycle) OSBS Change Form (after every 2nd cycle)
• Develop a separate Side Effects Form for net clinical benefitRetain FACT-O (including FOSI) to measure QOLFACT-O• Has fewer items: 39 (incl. 8 for FOSI) vs. 58 in the
QLQ-C30/Ov28• Provides summary scores: overall QOL, Trial Outcome Index,
FOSI• Overall QOL based on all itemsQLQ-C30• 22 sub scales• Duplication of single-item symptoms with Pt DATA Form• Global QOL based on 2 items
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Prognostic Modelvariables
No. of lines of therapy Performance status Volume of disease Sites of disease CA125 velocity LDH; Hb; Albumin; Platelets Inflammatory markers Grade; histological subtype
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Platinum Resistant Ovarian CancerPFS
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Platinum Resistant Ovarian CancerOS
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Platinum Resistant Ovarian CancerHypothetical Risk Groups
PFS
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Platinum Resistant Ovarian CancerHypothetical Risk Groups
OS
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Discussion Points
• Comments and questions of study and design- relatively fluid at present
• Comments on circulated CRF’s
• Which groups will join stage 2 study and when ? Feasibility; Time Frame; Trials
Translations
Funding arrangements in different groups
ECRF’s and scanning of HRQOL forms