The impact of local treatment of the prostate in patients with...

FACULTY OF MEDICINE AND HEALTH SCIENCES

Academic Year 2015 - 2016

The impact of local treatment of the prostate in patients with newly diagnosed metastatic

prostate cancer.

Miet VANDEMAELE

Promotor: Prof. Dr. P. Ost

Dissertation presented in the 2nd Master year in the programme of

Master of Medicine in Medicine

“The author and the promotor give the permission to use this thesis for consultation and to copy parts

of it for personal use. Every other use is subject to the copyright laws, more specifically the source must

be extensively specified when using results from this thesis.”

Date

11/04/2016

Miet Vandemaele Prof. Dr. Piet Ost

The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. p. 5

I. Acknowledgements

This thesis has been a long process and a challenge in many ways, and I would like to express

my gratitude for the people who helped make this dissertation possible.

First of all, I would like to thank my promotor, prof. Dr. Piet Ost, for his supervision. His

constructive feedback made the writing of this thesis possible, and transformed it into a valuable

learning process.

A special thanks goes out to my family and friends, for reading and rereading this thesis many

times. Their encouragements supported me throughout the entire process of this thesis and their

input has been a great help.

p. 6 The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer.


II. Abstract

1. Abstract

Goal of this thesis: The evolutions in screening tactics and treatment have had a positive impact

for men diagnosed with metastatic prostate cancer. However, survival rates are still dramatic.

This thesis takes a critical look at the arguments and current evidence to investigate if local

treatment of the prostate improves the survival rate or clinical outcomes of patients with newly

diagnosed metastatic prostate cancer.

Methods: A literature research was performed in Ovid. 4511 articles were found with a search

strategy including men with newly diagnosed mPCa, undergoing local treatment (whether or

not combined with systemic treatment), compared to systemic treatment alone, with outcomes

including overall survival rate (OS), disease specific survival rate (DSS), progression free (or

failure free) survival rate, toxicity, and biochemical response. 63 articles remained after

reviewing title and abstract, and were assessed by full text, to ultimately select 9 studies. These

studies were assessed for quality with a ‘modified Delphi technique’, leaving only two studies

that met the threshold: a retrospective cohort study by Culp et al. investigating radiotherapy and

radical prostatectomy, and a case-control study by Heidenreich et al. looking at radical

prostatectomy.

Results: Both studies indicate an OS benefit for metastatic prostate cancer patients treated with

radiotherapy (RT) or radical prostatectomy (RP), compared to systemic therapy alone. Culp et

al. showed an prolonged DSS rate for RP and RT independently, Heidenreich et al. confirmed

this for RP. The absolute DSS found by Heidenreich et al. was not significantly better than in

the control group. Culp et al. performed subgroup analysis for age, PSA level and M stage, with

results following the trend of the previous outcomes. They also identified factors independently

associated with worse survival rates: age ≥ 70 yr, cT4 disease, PSA ≥ 20 ng/ml, high-grade

disease, and pelvic lymphadenopathy.

Conclusion: Adding surgery or radiotherapy to systemic treatment in mPCa patients seems a

promising approach. There is a profit in both overall survival and disease specific survival for

local treatments added to systemic therapy, compared to systemic therapy alone. It was not

possible to distinguish which local therapy is the most beneficial, or to identify what patients


could profit most. Furthermore, because of the lack of comparative or randomised trials and the

many limitations in the included studies, adding local treatment cannot be recommended at this

time as a new standard of care. There are several prospective trials in the near future that could

provide more conclusive evidence, and make more validated recommendations.

2. Nederlandstalig abstract

Doel van deze thesis: De voorbije jaren is de prognose voor mannen met gemetastaseerde

prostaat kanker positief geëvolueerd. Vooral een betere screening en nieuwe therapieën hebben

hieraan bijgedragen. Toch zijn de overlevingskansen nog steeds bedroevend. In deze thesis

wordt een overzicht gegeven van de argumenten en evidentie in de bestaande literatuur die de

lokale behandeling van de prostaattumor ondersteunen, om uit te wijzen of er een verbeterde

overleving of klinische uitkomst is in patiënten met primair gemetastaseerde prostaatkanker.

Methode: Op basis van een zoekstrategie werd literatuur geselecteerd in Ovid. Inclusiecriteria

waren patiënten met nieuw gediagnosticeerde prostaat kanker, behandeld met lokale therapie,

al dan niet gecombineerd met systemische behandeling, met als controlegroep enkel

systemische therapie. De beoogde uitkomsten waren totale overleving (overall survival OS),

ziektespecifieke overleving (disease specific survival DSS), overleving zonder recidiveren

(failure free survival FFS), toxiciteit en biochemische respons. 63 artikels werden weerhouden

na selectie op titel en abstract. Hiervan werden 9 studies geselecteerd na lezen van de volledige

tekst: deze werden beoordeeld op kwaliteit door middel van een ‘modified Delphi technique’.

Twee studies werden uiteindelijk weerhouden: een retrospectieve cohort studie door Culp et al.

die zowel radiotherapie als een chirurgische aanpak onderzocht, en een case-control studie door

Heidenreich et al. die enkel prostatectomie bekeek.

Resultaten: In beide studies was er een OS voordeel bij behandeling met radiotherapie (RT) of

radicale prostatectomie (RP), in vergelijking met enkel een systemische aanpak. Culp et al.

toonden een betere DSS rate aan voor zowel RT als RP, Heidenreich et al. bevestigden dit voor

RP. De absolute DSS die Heidenreich et al. waarnamen, was niet significant beter voor de

geopereerde patiënten, in vergelijking met de controle groep. Culp et al. voerden een analyse

uit op subgroepen gebaseerd op leeftijd, PSA level, en M stagering: de resultaten waren

gelijkaardig aan die van de volledige groep. De auteurs vonden ook enkele factoren die


onafhankelijk geassocieerd zijn met een slechtere overlevingskans: leeftijd ≥ 70 jaar, cT4

ziekte, PSA ≥ 20 ng/ml, hooggradige maligniteit, en aangetaste lymfeklieren in het bekken.

Conclusie: Lokale therapie onder de vorm van radiotherapie of chirurgie lijkt een meerwaarde

te zijn in patiënten met primair gemetastaseerde PCa. Er is een voordeel in totale overleving en

ziektespecifieke overleving in vergelijking met patiënten die enkel systemisch behandeld

worden. Het is niet mogelijk om op basis van deze thesis een besluit te maken over de meest

voordelige lokale therapie, of over de eigenschappen die een patiënt meest geschikt maken voor

deze aanpak. Door het gebrek aan gerandomiseerde en prospectieve onderzoeken, en de

verschillende tekortkomingen in de huidige evidentie, kan op dit moment de toevoeging van

lokale behandeling niet aanbevolen worden als nieuwe standaardtherapie. Er zijn momenteel

verscheidene prospectieve trials gepland, die binnen afzienbare tijd voor sterkere bewijzen

kunnen zorgen, en meer onderbouwde adviezen zullen formuleren.


III. Contents

I. Acknowledgements ......................................................................................................................... 5

II. Abstract ........................................................................................................................................... 7

1. Abstract ........................................................................................................................................... 7

2. Nederlandstalig abstract .................................................................................................................. 8

III. Contents ..................................................................................................................................... 11

IV. Abbreviations ............................................................................................................................ 13

V. Introduction ................................................................................................................................... 14

1. Epidemiology and incidence of prostate cancer ............................................................................ 14

2. Outcome and survival of PCa ........................................................................................................ 14

3. Metastatic prostate cancer ............................................................................................................. 15

3.1. Epidemiology and incidence ................................................................................................. 15

3.2. Survival and outcome ............................................................................................................ 16

3.3. Treatment of metastatic prostate cancer ................................................................................ 18

3.4. The use of local therapy in PCa ............................................................................................ 19

a. Delaying Local progression .................................................................................................. 20

b. Preventing further metastasis and inhibiting growth of existing metastases and progression

of the disease ................................................................................................................................. 20

c. Benefit for local treatment in PCa and other malignancies ................................................... 21

d. Improved response to systemic therapy ................................................................................ 22

4. Local treatment in metastatic PCa ................................................................................................. 22

VI. Materials and methods .............................................................................................................. 23

1. Research question and PICO ......................................................................................................... 23

2. Article selection............................................................................................................................. 23

3. Qualitative synthesis ..................................................................................................................... 25

VII. Results ....................................................................................................................................... 27

1. Study description ........................................................................................................................... 27

2. Outcomes ....................................................................................................................................... 27

2.1. Overall survival ..................................................................................................................... 28

a. Survival rates ......................................................................................................................... 28

b. Subset analysis by Culp et al. ................................................................................................ 29

2.2. PCa-specific survival............................................................................................................. 30

a. Survival rates ......................................................................................................................... 30

b. Subset analysis by Culp et al. ................................................................................................ 31

2.3. FFS in Heidenreich et al. ....................................................................................................... 32

VIII. Discussion ................................................................................................................................. 33


1. Diversity of patients and selection bias ......................................................................................... 33

1.1. Selection criteria .................................................................................................................... 33

1.2. Number of included patients.................................................................................................. 34

2. Data collection ............................................................................................................................... 35

3. Identification of patients ................................................................................................................ 35

4. Outcomes ....................................................................................................................................... 37

5. Other Literature ............................................................................................................................. 38

6. Future studies ................................................................................................................................. 40

7. Limitations of this thesis................................................................................................................ 40

IX. Conclusion ................................................................................................................................. 43

X. Bibliography .................................................................................................................................. 44

XI. Appendix ...................................................................................................................................... i

1. Distribution of mPCa ........................................................................................................................ i

2. Description of the 9 selected studies selected by literature search ................................................. iii

3. Patient characteristics Heidenreich et al. ........................................................................................ iv

4. Patient characteristics Culp et al. ..................................................................................................... v

5. Subset analysis by Culp et al. ......................................................................................................... vi

6. Future studies ................................................................................................................................ viii


IV. Abbreviations

PCa Prostate cancer

mPCa Metastatic prostate cancer

PSA Prostate-specific antigen

SEER study The Surveillance, Epidemiology and End

Results study

TNM Classification of Malignant Tumours:

- T describes the size of the original

(primary) tumour and whether it has

invaded nearby tissue

- N describes nearby (regional) lymph

nodes that are involved

- M describes distant metastasis

RT Radiotherapy

BT Brachytherapy *

RP Radical prostatectomy

NSR No surgery or radiotherapy (control group)

OS Overall survival

DSS Disease specific survival (PCa specific

survival): the time from start to treatment to

disease progression or disease related death

ADT Androgen deprivation therapy

SHR Subhazard ratio

LT Local treatment

* Culp et al. only mention brachytherapy (BT), but different forms of radiotherapy are

included in the study. The term BT is used in Results to be consistent with the original study.


V. Introduction

1. Epidemiology and incidence of prostate cancer

In 2010, prostate cancer (PCa) was the highest 5-year prevalent cancer in Belgian men with

363.9/100,000 person years (adjusted to the world standard population), or 43,984 cases. [1, 2]

Prostate cancer is typically found in elderly men: more than 50% of the Belgian PCa patients

were 70 years or older in 2010. Despite this general elderly patient population, men older than

80 years have a significantly lower risk of diagnosis, and this number is dropping even further

since the latest recommendations against PCa screening. The risk of dying of PCa however,

keeps rising with age. [1-4]

Presently, most PCa are diagnosed by prostate biopsies after an abnormal PSA-test in

asymptomatic men. [3] The increased use of PSA-testing influenced not only the number of

PCa diagnoses, but also caused a stage migration and a relatively younger patient population.

The SEER (Surveillance, Epidemiology and End Results) study of the US National Cancer

Institute reports an increasing number of diagnosis of organ-confined PCa, but this evolution is

changing since the new screening recommendations. Decreased screening causes a reduction in

diagnosis of intermediate and high risk PCa, and a small increase in non-localized PCa. These

results give cause for concern that in future years the diagnosis of advanced disease may rise

again. [3-6]

2. Outcome and survival of PCa

The prognosis and survival of PCa patients has improved immensely during the last decade due

to earlier diagnosis and new therapies. Overdiagnosis and the detection of clinically

insignificant PCa have also contributed to the better outcomes. At present, the 5-year relative

survival rate for men with local and regional prostate cancer is 100%. [3, 5, 7, 8]

Prostate cancer has a remarkably high incidence-to-mortality ratio, meaning a large part of men

diagnosed with PCa will die of other, unrelated, causes. This is very clearly to see in the Belgian

PCa cases from 2004 to 2008: the 5-year observed survival rate is 77.6% and the 5-year relative

survival rate is 95.3%. Despite this optimistic ratio, PCa mortality is still considerable because


of its frequent occurrence: 9.3% of all cancer deaths in Belgian men in 2008 were caused by

PCa. [6, 9]

3. Metastatic prostate cancer

3.1. Epidemiology and incidence

Presently, about 4% of prostate cancer patients already have metastases at the moment of

diagnosis. The evolution in incidence is not exactly the same as for PCa in general. The SEER

program in the USA observed a decrease in stage IV PCa with distant metastasis at diagnosis:

incidence fell from 18.4 per 100,000 in 1988 to 6.7 per 100,000 in 2003, an average reduction

of 8.0% per year (Figure 1). As mentioned before: this evolution mostly is explained by

screening tactics and PSA-testing: diagnoses are made at an earlier stage. Again, this decline in

stage is combined with a younger age at moment of diagnosis. The proportion of men aged 60

or less at diagnosis rose from 8.5% in 1988 to over 15% in 2003. A distribution of mPCa for

age and other variables can be found in the Addendum (Addendum Table 1 and Addendum

Table 2). This evolution is less pronounced than the age shift in PCa in general, but still

significant. But there is reason for caution: as mentioned before, the new PCa screening tactics

may turn this evolution around. [4, 5, 8, 10]

Figure 1: Incidence of PCa, metastatic at first presentation (USA, 1975–2012) [10]


3.2. Survival and outcome

The SEER study in the USA registered a 25.0% survival for patients diagnosed with distant

metastasis in 1988, rising to 27.0% in 2001. A part of this improvement in survival is due to the

earlier detection and less advanced state, even in metastatic disease. But this small rise in

survival rate is hardly significant, especially when compared to the enormous progression for

prostate cancer in general. [5, 7, 8]

The age-adjusted survival rates in Belgium for 2004-2008 for different stages of PCa show how

both age and stage are important for prognosis: for stage I and II, all age groups have a 5-year

relative survival rate of practically 100%. [6] In stage III there is a difference in the different

age groups: patients between 15-74 years have a 5-year relative survival of almost 100%,

patients older than 75 have a rate of only 89.4%. [6]

Figure 2: PCa relative survival by stage (Belgium, 2004-2008) [6]

This difference only grows bigger in stage IV: the prognosis is poor for all age groups, but the

oldest patients have the most unfavourable predictions. Patients between 15 and 59 years have

a 5-year survival rate of 63.3%, between 60-74 years the rate decreases to 58.6%, and for

patients older than 75 years the rate has dropped to 40.4%. [6] The relative survival by age

group and stage for Belgian men in 2004-2008 can be seen in Figure 2 and Table 1, by Schutter

et al.


Table 1: PCa, relative survival by age group (Belgium, 2004-2008) [6]

Even with the most up-to-date therapies, survival rates are depressing for men diagnosed with

mPCa. Several studies recently investigated the progress of survival with the current standard

of care.

The SWOG-phase 3 trials (performed by the South West Oncology Group) confirm these

improved survival trends again in men with newly diagnosed M1 metastatic prostate cancer.

The overall survival of patients receiving similar ADT (Androgen Deprivation Therapy) was

compared before and after PSA testing became standard screening. After adjusting for other

risk factors it was found that overall survival improved significantly for all groups of men. It is

possible that the latest screening recommendations undo this survival profit. [4, 5]

An important insight on survival outcomes and prognostic factors for men with newly

diagnosed M1 disease, treated with standard-of-care therapy, can be found in the control arm

of the STAMPEDE trial. This ‘Systemic Therapy in Advancing or Metastatic Cancer:

Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial’

randomised and followed a cohort of PCa patients, of which 917 were newly diagnosed

metastatic patients. Outcome for this group was, as expected, not very good. Median FFS (FFS:

Failure Free survival: the time from start to treatment to disease progression or disease related

death) for the entire group was 11.2 months, median OS was 42.1 month (OS: Overall Survival:

the time from start of treatment to any cause of death). Two year estimate for FFS was 29%,

for overall survival 72%.

Several factors independently influenced these outcome rates: primary tumour stage, initial

Gleason sum score category, metastases grouping, age group, and WHO performance status are

associated with both OS and FFS. A lower two-year survival was observed in patients with

bone metastases and soft tissue metastases at the same time. A worsened FFS was seen in

patients with higher PSA level before starting ADT and in patients with higher primary tumour

stage. [7]


A significant evolution for survival of mPCa patients was adding chemotherapy to ADT.

Several RCT’s (CHAARTED, GETUG-15, STAMPEDE) showed that the addition of

docetaxel improved both failure-free and overall survival. The addition of docetaxel is now

recommended as the standard of care in men with newly diagnosed mPCa. [11]

The STAMPEDE and other randomised trials confirm the conclusions of other research and

studies. Survival of newly diagnosed prostate cancer has improved somewhat over the years,

mostly due to PSA screening and new treatments, but outcomes are still depressing. [5, 7, 8]

3.3. Treatment of metastatic prostate cancer

The most recent guidelines on the treatment of mPCa by the European Association of Urology

state that luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in

mPCa. They provide reversible androgen deprivation and can be used in intermittent therapy.

[12] Recently, adding docetaxel to ADT is recommended as the new standard of care for mPCa

patients. [11]

Other options are less frequently used, or only for specific indications (Table 2).

LHRH antagonists decrease testosterone levels without any testosterone surge, and they may

have an oncologic benefit compared with LHRH analogues. This has yet to be confirmed in

prospective trials. Anti-androgen monotherapy may be an option in locally advanced or M0

patients, but not in mPCa. Maximum androgen blockade with anti-androgens has a small

advantage over LHRH monotherapy for survival, but causes significant impairment of quality

of life. Intermittent androgen deprivation has equal oncologic efficacy when compared with

continuous ADT, in well-selected populations. For mPCa, there is no significant survival

advantage for early ADT compared with delayed ADT. [12]

Additional local treatments in mPCa are at present only used for relapsing mPCa, symptomatic

relief or palliative treatment. [12]


Table 2: indications for hormonal therapy in mPCa [12]

3.4. The use of local therapy in PCa

Local therapy of the prostate has long proven its worth in treatment of non-metastatic tumours.

From the moment the cancer expands beyond the prostate capsule, systemic treatment becomes

the standard of care. Local treatments are then only offered to reduce local symptoms and to

assist palliative care. [13] However, systemic treatment alone is often not sufficient. Many

patients with mPCa ultimately develop resistance to hormonal therapy, and will need alternative

or additional treatment. [14]

In many other metastatic cancers, studies have shown a positive influence of local treatment,

either radiotherapy or surgery, on survival rates, but its benefit in mPCa remains uncertain. [13-

15]. There are several possible theories why adding local therapy could improve survival rates:

delaying local progression, removal of a persistent source of possible metastasis, and an

improved response to systemic treatment through debulking and decreasing tumour burden. So

far, none of these theories are supported by extensive evidence. [14, 16]


a. Delaying Local progression

Local progression can cause serious morbidity with a strong impact on the quality of life of the

patient: ureteral and bladder outlet obstruction, perineal or bony pain, … [16, 17] Adding

prostatectomy or radiotherapy to ADT in N+ patients delays local progression compared to

ADT alone. [16] The profits of local therapy are very clear, but there is no evidence so far for

metastatic PCa. It is possible that surgery or radiation therapy in mPCa could have a positive

impact on survival rates by delaying local progression, instead of only relieving symptoms, as

it already does for N+ or locally confined PCa.

b. Preventing further metastasis and inhibiting growth of existing

metastases and progression of the disease

There are many studies describing the relationship between the primary tumour and its

metastases. Some argue that metastases are a result of progression of locoregional lymphatic

disease, and thus require early detection and cure. Others propose that cancer is a systemic

disease; local therapies are not as important as systemic therapy. [13-15, 18] Although none of

these hypotheses have been proven with RCT’s, they are more or less accepted and used to

explain the effect of local therapies in some malignancies.

A first reason for local therapy, is the assumption that the primary tumour and its metastases

are communicating systems, in a complex network with several molecular pathways. An

uncontrolled local tumour probably promotes the growth of its metastases, as well as creating

new ones. It should also be considered that the primary PCa can synthesise testosterone from

weak adrenal androgens, and be a source of intraprostatic androgen even after ADT. Therefore

attacking the primary tumour with local therapy, can have an effect on the linked metastases.

[13, 14]

The ‘tumour seeding’ theory states that the primary tumour is responsible for priming an

environment for metastatic growth. Consequently, metastasis can be prevented with local

therapy of the primary tumour. There could be no preparation of distant tissue for metastatic

cell arrival, and the amount of possible metastases could be reduced with local control of the

primary source. The continuous cycle of metastases becoming metastatic tumours themselves

might be avoided as well. [14, 15, 19, 20]


Another claim for additional local therapy is the abscopal effect: the phenomenon of regression

of distant disease after the primary tumour is treated locally. This effect is mostly attributed to

the activation of anti-tumour immunity, with a positive systemic effect. The local inflammation

caused by radiotherapy starts a cascade of immune reactions, leading to a targeted T-cell

response against both tumour and metastases. This immune response is empowered by

hormonal therapy. ADT has an effect on the gene expression in tumour cells, changing the

cellular and membrane environment. This modifies tolerance and enables the immune system

to recognise the tumour cells, an effect that is in its turn strengthened by local radiotherapy, and

leads to tumour cell death. [19]

c. Benefit for local treatment in PCa and other malignancies

There is plenty of evidence for the benefit of local treatment in other forms of PCa and other

tumours. Local control of the tumour has improved survival in patients with metastatic colon

cancer, renal cell carcinoma, glioblastoma, ovarian cancer. Decreasing the primary tumour

burden also has an effect of increasing response to systemic chemotherapy in breast cancer,

colon cancer, and ovarian cancer. Many studies suggest that metastatic PCa may react in a

similar way. [14, 16]

There are several studies confirming a positive impact of adding a local therapy to systemic

treatment in patients with locally advanced or lymph node positive PCa. Many studies and

reviews show a long lasting survival benefit in favour of the N+M0 patients receiving a local

treatment to the primary tumour, compared to those treated systemically only. At present, there

are three large prospective randomized phase III trials suggesting that, in patients with locally

advanced tumours with high risk of occult micrometastases, the 10-year outcome can be

improved by adding radiotherapy to androgen deprivation (D’Angelillo et al., 2015; Mottet et

al., 2012; Warde et al. 2011). [19]

The results for additional local therapy in similar metastatic malignancies or mPCa are

promising. Further research for the benefits of local therapy in metastatic prostate cancer is

certainly appropriate, based on this matching evidence in other fields.


d. Improved response to systemic therapy

Metastatic PCa appears to increase in heterogeneity as it progresses. The result is variable

androgen responsiveness, resistance to chemotherapy, proliferation, risk of metastasis…

Studies in N+ suggest that local treatment could eliminate some of this heterogeneity, and thus

improve the success of systemic therapy. It seems logical that this argument can be used for

M+ prostate cancer as well. [16] As mentioned before, the abscopal effect depends on an

improved response to systemic therapy as well. ADT and radiotherapy empower each other,

resulting in a more effective remedy. [19]

4. Local treatment in metastatic PCa

The last decades have meant an enormous progress for the treatment of prostate cancer, but

metastatic PCa still has dramatic survival rates. Even the newest recommendations for therapy

promise only small profit in survival rates. Survival and incidence rates show that in this group

of relatively young and otherwise healthy men, there is still a lot of potential health to gain.

Other options need to be explored, and additional local treatment is supported by many

arguments. However, these claims presented in literature are all theoretical, backed by evidence

in other malignancies or experiences in non-metastatic PCa.

The goal of this literature review is to summarise and critically review the existing data, and to

determine if there is conclusive evidence for a survival benefit for local treatment combined

with systemic treatment in newly diagnosed metastatic prostate cancer patients, compared to

systemic treatment alone.


VI. Materials and methods

1. Research question and PICO

The research question for this thesis is: “Does local treatment of the prostate improve the

survival rate or clinical outcomes of patients with primary metastatic prostate cancer.” This

question was framed in terms of population, interventions, controls, and outcome (PICO). The

result is as follows:

Patient: men with newly diagnosed metastatic (Tx, Nx, M+) prostate cancer (not metastatic

recurrence).

Intervention: Local treatment of the primary prostate cancer, whether or not combined with

systemic therapy. This local treatment includes, but is not restricted to: radiotherapy, radical

prostatectomy, and/or combinations.

Controls: treatment with systemic therapy alone, at present the standard-of-care for men with

newly diagnosed metastatic prostate cancer.

Outcome: Overall survival rate, progression free (or failure free) survival rate, toxicity,

biochemical response.

For each term, a selection of appropriate Mesh descriptors were selected, as well as relevant

text words to include suitable articles.

2. Article selection

Potential articles were then selected in the Ovid database, with Ovid MEDLINE, Ovid

MEDLINE in-process & other non-indexed citations and Ovid MEDLINE Daily Update as

selected resources. No limitations were set for publication language or publication year.

Using the search strategy: “(exp prostatic neoplasms/ or prostat* cancer.tw.) and (Neoplasms

metastasis/ or metast*.tw.) and (Local treatment.tw. or local therapy.tw. or Exp radiotherapy/

or radio?therapy.tw. or radiation therapy.tw. or exp prostatectomy/ or radical

prostatectomy.tw.)”, 4511 articles were found on 12/06/2015.


Other sources added 13 articles. The last articles were added on 6/02/2016. Additional studies

were identified through related citations and bibliographies of relevant articles, adding 2 new

articles. After removing 112 duplicates, title and abstract were reviewed for relevance to the

research question. The remaining articles (63) were assessed by full text. Studies were excluded

if they did not meet the PICO framework. Because of the small amount of research on this

subject, all types of studies (such as randomized controlled trials, cohort, case series etc.) were

included. Other sorts of publication types, such as reviews, commentaries, editorials, were

excluded. Articles without available full text were excluded as well. 9 studies were selected

based on full text.

The selection process can be seen in the PRISMA diagram below (Figure 3).

Figure 3: PRISMA Diagram for literature selection


3. Qualitative synthesis

Potential studies were identified from the selected articles, as described in the PRISMA

diagram. The 9 selected studies were assessed for quality with the “quality appraisal tool for

studies using a modified Delphi technique”, including assessment of study objectives,

interventions, outcome measures, statistical analysis, and more. The assessment tool uses

indicators of the overall quality and identifies the risk of bias, with items such as ‘selection of

consecutive cases’, ‘key outcomes measured before and after the intervention’, and

‘information provided on the loss to follow-up’. This ‘modified Delphi’ was the most

appropriate assessment tool, considering the variability of study designs.

A study with 14 or more positive responses is considered to be of acceptable quality. [21] Only

2 studies met this threshold: a retrospective cohort study by Culp et al. and a case-control study

by Heidenreich et al.

A brief description and the complete quality assessment for all 9 studies can be found

respectively in Addendum Table 3 and Table 3.


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re th

e e

ligib

ility c

riteria

(inclu

sio

n a

nd

exc

lusio

n c

riteria

) to e

ntry

the s

tud

y e

xplic

it an

d a

pp

rop

riate

?1

11

10

10

10

5. W

ere

partic

ipan

ts re

cru

ited

co

nsecu

tively

?0

00

00

01

00

6. D

id p

artic

ipan

ts e

nte

r the s

tud

y a

t a s

imila

r po

int in

the d

isease?

11

11

11

11

1

Inte

rven

tion

an

d c

o-in

terv

en

tion

7. W

as th

e in

terv

en

tion

cle

arly

describ

ed

in th

e s

tud

y?

01

00

01

00

1

8. W

ere

ad

ditio

nal in

terv

en

tion

s (c

o-in

terv

en

tion

s) c

learly

rep

orte

d in

the s

tud

y?

00

00

01

00

0

Ou

tco

me m

easu

res

9. A

re th

e o

utc

om

e m

easu

res c

learly

defin

ed

in th

e in

trod

uctio

n o

r meth

od

s s

ectio

n?

11

10

01

11

1

10. W

ere

rele

van

t ou

tco

mes a

pp

rop

riate

ly m

easu

red

with

ob

jectiv

e a

nd

/or s

ub

jectiv

e m

eth

od

s?

11

11

11

11

1

11. W

ere

ou

tco

mes m

easu

red

befo

re a

nd

afte

r inte

rven

tion

?1

11

11

11

11

Sta

tistic

al a

naly

sis

12. W

ere

the s

tatis

tical te

sts

used

to a

ssess th

e re

lev

an

t ou

tco

mes a

pp

rop

riate

?1

11

10

11

11

Resu

lts a

nd

co

nclu

sio

ns

13. W

as th

e le

ng

th o

f follo

w-u

p re

po

rted

?0

11

10

11

11

14. W

as th

e lo

ss to

follo

w-u

p re

po

rted

?1

11

00

10

11

15. D

oes th

e s

tud

y p

rov

ide e

stim

ate

s o

f the ra

nd

om

varia

bility

in th

e d

ata

an

aly

sis

of re

lev

an

t ou

tco

mes?

10

10

00

01

1

16. A

re a

dv

ers

e e

ven

ts re

po

rted

?0

10

00

10

01

17. A

re th

e c

on

clu

sio

ns o

f the s

tud

y s

up

po

rted

by

resu

lts?

11

11

11

11

1

Co

mp

etin

g in

tere

st a

nd

so

urc

e o

f su

pp

ort

18. A

re b

oth

co

mp

etin

g in

tere

st a

nd

so

urc

e o

f su

pp

ort fo

r the s

tud

y re

po

rted

?1

01

10

00

00

Tota

l1

31

31

41

14

14

10

12

13

Table 3: Modified Delphi quality assessment [13, 22-29]


VII. Results

1. Study description

The study selection process is outlined in the PRISMA diagram (Figure 3). Nine studies were

found through a literature search: 4 retrospective case series, 3 retrospective cohort studies, 1

case-control study and 1 prospective, controlled, non-randomized study. There was significant

variation in inclusion criteria, in additional local therapies in the intervention groups, and in

reporting of outcomes. (summary in Addendum Table 3). [13, 22-29]

Two studies were selected after quality assessment: Culp et al. (a retrospective cohort study),

and Heidenreich et al. (a case-control study) were considered to be of sufficient quality. Culp

et al. describe 8185 patients selected from the SEER database, consisting of population-based

cancer registries, between 2004-2010. Both radical prostatectomy (RP) and radiotherapy (RT)

are included. In the study only brachytherapy (BT) is mentioned, but different forms of

radiotherapy are included (the term BT will be used in Results to be consistent with the original

study). Heidenreich et al. selected two groups of patients: 23 patients with low volume

metastatic disease who were treated with RP, and a control group of 38 men initially treated

with ADT only. The patient characteristics of both studies can be found in the Addendum:

Addendum Table 4 and Addendum Table 5.

2. Outcomes

Outcomes in the selected studies are similar: OS (overall survival) and PCa-specific survival

(further referred to as disease specific survival [DSS], to be consistent with the original study)

are registered in both. Culp et al. also determined ‘factors associated independently with cause-

specific mortality’, Heidenreich et al. added FFS (failure free survival). The latter also reported

on complications of surgery and functional outcomes, describing feasibility of RP, that are not

relevant for this study: these results will not be described further. Other outcomes like toxicity

of radiotherapy or biochemical response were not registered in these studies.


2.1. Overall survival

a. Survival rates

Culp et al. reported 5-yr OS rates with a median follow-up of 16 months. The 5-yr OS was

significantly higher in patients who had local treatment: RP (67.4%; 95% confidence interval

[CI], 58.7–74.7) or BT (52.6%; 95% CI, 39.8–63.9) compared with NSR (no surgery or

radiotherapy) patients (22.5%; 95% CI, 21.1–23.9) ( p < 0.001). This result is confirmed in a

multivariable competing risks regression, showing adjusted subhazard ratios for RP, BT and

NSR. With non-local treatment as the reference group, radical prostatectomy and brachytherapy

have an adjusted SHR (subhazard ratio) of 0.38 (95 %CI: 0.27-0.53, p<0.001) and 0.68 (95%

CI: 0.49-0.93, p=0.018), respectively. (Table 4). Non-PCa caused deaths were seen in 15.7%

of the patients (1284 in total), but there was no significant difference among the various groups.

[22]

A second analysis was performed, excluding patients who died within 12 months from

diagnosis. This analysis was performed to reduce bias by excluding patients who might benefit

least from local therapy: patients with progressive disease, significant comorbidity, or history

of other primary malignancies. Results were similar to those for all patients: at a median follow-

up of 27 months (IQR: 18–42), 5-yr OS was still higher in patients undergoing RP (76.5%; 95%

CI, 67.0–83.7) or BT (58.2%; 95% CI, 44.5–69.7), compared with NSR patients (30.6%; 95%

CI, 28.9–32.4) ( p < 0.001). (Table 4) [22]

Heidenreich et al. compared radical prostatectomy with a control group of ADT. The local

treatment group had an overall survival rate of 91.3%, with a median follow-up of 40.6 months.

The control group was followed for a median time of 44.0 months, with an OS of 78.9%. The

p-value for comparing these groups was 0.048 (Table 5).


Table 4: Results from Culp et al.

5yr-OS, % adjusted SHR DSS 5 yr-probability (%)

all patients NSR 22.5; 95% [CI], 21.1–23.9 reference group 48.7

RP 67.4; 95% [CI], 58.7–74.7 0.38; 95 %[CI] 0.27-0.53 75.8

BT 52.6; 95% [CI], 39.8–63.9 0.68; 95%[CI] 0.49-0.93 61.3

2nd analysis NSR 30.6; 95% [CI], 28.9–32.4 reference group 46.9

RP 76.5; 95% [CI], 67.0–83.7 0.37; 95% [CI] 0.26–0.54 75.1

BT 58.2; 95% [CI], 44.5–69.7 0.57; 95% [CI] 0.37–0.87 64.5

p<0,001

p<0,05

p not significant/ no p-value

b. Subset analysis by Culp et al.

Culp et al. performed subset analysis to find out if overall survival is different among groups

based on age (<70 yr or ≥70 yr old) or PSA (<20 or ≥ 20 ng/ml).

For both age groups, OS rates were significantly higher for local treatment compared to the

NSR controls. In men <70 yr, 5-yr OS was 71.2% (95% CI, 61.6–78.9) for the RP group, 57.4%

(95% CI, 22.6–66.6) for the BT group, compared with 28.9% (95% CI, 26.6–31.3) for the

controls (p<0.001). In men ≥70 yr, 5-yr OS was 50.3% (95% CI, 30.1–67.5) for the RP group,

48.5% (95% CI, 30.0–64.7) for the BT group, compared with 18.1% (95% CI, 16.5–19.8) for

the controls (p<0.001). (Addendum Table 6 and Addendum Table 7)

In the subset analysis for PSA, OS rates were significantly higher in patients with additional

local treatment in both subgroups (<20 or ≥20ng/ml), compared to no local treatment. In men

with PSA <20 ng/ml, treatment with RP had a 5-yr OS rate of 77.1% (95% CI, 66.1-85.0), BT

had 71.2% (95% CI, 46.8–85.9), compared to 33.7% (95% CI, 30.4–37.1) for NSR (p<0.001).

The subgroup with PSA ≥20ng/ml, had 5-yr OS rate of 55.7% (95% CI, 37.1-70.9) for RP,

37.3% (95% CI, 21.4-53.2) for BT, compared to 19.8% (95% CI, 18.2-42.3) for NSR (p<0.001

and <0.05, respectively). (Addendum Table 6 and Addendum Table 7)

Another analysis was performed to determine if the outcomes of the different treatment are

influenced by the extent of metastatic disease, based on AJCC M stage (M1a-c). Although these

results reflect the trend of the previous outcomes, many were not significant. Patients treated

with RP had a significantly higher OS in M1b and M1c disease, compared to NSR patients. RP

in M1b had 5-yr OS rates of 70.1 % (95% CI, 58.1-79.2) compared to 22.9% (95% CI, 21.2-


24.6) in controls (p<0.001). RP in M1c had 60.7% (95% CI, 42.7-74.6) OS rates, compared to

18.6% (95% CI, 16.1-21.2) in controls (p<0.001). (Addendum Table 6 and Addendum Table

7)

In patients treated with BT, OS was significantly higher regardless of M stage. In M1a patients,

5-yr OS rates were 54.7% (95% CI, 8.6–86.2) for BT, compared to 35.1% (95% CI, 28.0–42.3)

for controls (p = 0.014). In M1b, 5-yr OS rates were 55.0% (95% CI, 31.1-64.5) for BT,

compared to 22.9% (95% CI, 21.2-24.6) for controls (p <0.001). In M1c, 5-yr OS rates were

53.4% (95% CI, 34.4-69.2) for BT, compared to 18.6% (95% CI, 16.1-21.2) for controls

(p<0.001). (Addendum Table 6 and Addendum Table 7)

The study tried to identify factors independently associated with lower survival rates in patients

with local treatments. These factors included age ≥ 70 yr, cT4 disease, PSA ≥ 20 ng/ml, high-

grade disease, and pelvic lymphadenopathy. Patients with none or only one of these factors (n

= 181 [48.4%]) had the highest OS (77.3%; 95% CI, 67.4–84.5) probability. Patients with two

factors (n = 116 [31.0%]) had a lower 5-yr OS (53.1%; 95% CI, 38.9–65.4), but this survival

rate is still better than for patients without local treatment. (Addendum Table 6 and Addendum

Table 7)

2.2. PCa-specific survival

a. Survival rates

In Culp et al. both RP or BT were each independently associated with improved DSS, with

predicted 5-yr DSS probabilities of 75.8% for RP and 61.3%, for BT, compared with 48.7% for

NSR patients. There was no significant difference in DSS between RP and BT. [22] The second

analysis on DSS, excluding patients who died within 12 months from diagnosis, showed similar

results: treatment with RP (subhazard ratio [SHR]: 0.37; 95% CI, 0.26–0.54; p < 0.001) or BT

(SHR: 0.57; 95% CI, 0.37–0.87; p = 0.01) was still each independently associated with

decreased DSS compared with NSR patients, with 5-yr DSS probabilities of 75.1%, 64.5%, and

46.9%, respectively. [22] (Table 4)

Heidenreich et al. found that the median DSS in the radical prostatectomy group was 47 (range

9-71) months, and 40.5 (19-75) months in the control group. An extra analysis on the control

group was performed with only the patients with a PSA < 1.0ng/ml after 6 months of ADT: this

adapted group had a median DSS of 44.3 (21-75) months. The p-value for comparing DSS was


not significant. The DSS rate was 95.6% and 84.2% for local treatment and controls,

respectively, with a p-value of 0.043. [26] (Table 5)

Table 5: Results from Heidenreich et al.

OS rate %

DSS [median (range)

in months] DSS rate %

FFS [median (range)

in months]

RP 91.3 47.0 (9-71) 95.6 38.6 (42-52)

controls 78.9 40.5 (19-75) 84.2 26.5 (12-48)

controls PSA < 1.0 ng/ml - 44.3 (21-75) - 32.4 (19-48)

p<0.001

p<0.05

p not significant/no p-value

b. Subset analysis by Culp et al.

The subset analysis was performed for DSS as well, with the same groups based on age (<70

yr or ≥70 yr old) or PSA (<20 or ≥ 20 ng/ml). DSS probabilities were significantly higher in

patients <70 yr, but not in the subgroup ≥70yr, compared to the NSR controls.

In the subset analysis for PSA, DSS probability was higher in patients with additional local

treatment in men with PSA <20 ng/ml, but for ≥20ng/ml, only RP patients had a significantly

improved DSS compared to NSR patients.

The analysis on subgroups of metastasis reflect the previous results. A significant higher DSS

was noted in patients treated with RP, regardless of M stage, and in patients with M1c disease

treated with BT.

The study tried to identify factors independently associated with decreased DSS in patients with

local treatments. These factors included age ≥ 70 yr, cT4 disease, PSA ≥ 20 ng/ml, high-grade

disease, and pelvic lymphadenopathy. Patients with one or none of these factors (n = 181

[48.4%]) had the highest DSS (89.9%) probability. Patients with two factors (n = 116 [31.0%])

had lower DSS probability (68.7%), but these survival rates are still better than for patients

without local treatment.

The subset analysis, as described by Culp et al., can be found in the Addendum (Addendum

Table 6 and Addendum Table 7).


2.3. FFS in Heidenreich et al.

Heidenreich et al. reported the median months of clinical progression free survival (further

referred to as Failure Free Survival or FFS). Biochemical progression or failure was defined as

a PSA increase to 0.2 ng/ml validated by two consecutive increases at two-week intervals, if

PSA decreased to undetectable serum levels postoperatively. If the postoperative PSA was still

detectable, biochemical progression was defined by two consecutive increases above the first

postoperative PSA, one week apart, resulting in 2.50% increases over the nadir. [26]

The RP group had a median FFS of 38.6 months (range 42-52), the control group had a median

FFS of 26.5 (12-48) months, and the adapted control group (cf. supra) had a median FFS of

32.4 (19-48) months. In the group treated with surgery, all patients had a serum testosterone of

<50ng/dl. In the control group, mean time between start of ADT and symptomatic progression

was 23 months (range 6-52). [26]


VIII. Discussion

Both studies are analogous in their outcomes, as described earlier in ‘Results’. Although these

studies have been assessed for quality, they still have limitations and flaws that should be looked

into before interpreting the results.

1. Diversity of patients and selection bias

1.1. Selection criteria

Methodology and inclusion criteria are significantly different in both studies.

Heidenreich et al. selected 23 patients for their intervention group, with biopsy proven PCa and

low volume metastatic disease who underwent RP. These men were eligible for surgery if they

met 6 inclusion criteria, concerning limited metastatic disease (osseous, lymphatic, visceral)

and possibility of resecting the tumour. The patients received flare-up prophylaxis with

bicalutamide and ADT with LHRH-analogues for at least 6 months. Men with a PSA decrease

to less than 1.0 ng/ml, remission or stable disease of osseous metastases and without the

development of new lymph node or visceral metastases, were considered candidates for surgery.

The control group was 38 men initially treated with androgen deprivation therapy only, and

followed until progression, development of castration resistant PCa or death. There is no

mention of other selection criteria for the control group. [26] The contrast in selection criteria

for both groups could cause serious bias. Although the intervention group was matched for

biological, clinical and oncologic parameters with the control group, it is very likely that

patients were overselected for local treatment.

Culp et al. identified cases from the SEER database between 2004 and 2010. Patients were

selected by age ≥ 35 years. At time of diagnosis, they had to be documented stage IV (M1a-c)

PCa, based on the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (sixth

edition) with either radiographic or pathologic confirmation of metastatic disease through the

Collaborative Staging System. Groups were based on no surgery or radiation therapy (NSR) or

definitive local therapy to the prostate: either radical prostatectomy (surgery site codes 50 or

70) or brachytherapy (radiation-specific codes 2, 3, or 4: respectively meaning radioactive

implants, radioisotopes, and beam radiation combined with 2 or 3). Within the local treatment

group, men were not excluded if they received adjuvant external-beam radiation therapy.


Relevant data (PSA, age, disease grade, marital status, race, …) was registered at time of

diagnosis, using the SEER coding guidelines. The limitations in selection criteria and data

analysis caused by this SEER coding are mentioned further. [22].

1.2. Number of included patients

In both studies, the number of patients with local treatment is (relatively or absolutely) low

(patient characteristics can be found in Addendum Table 4 and Addendum Table 5). Culp et al.

included a total of 8185 patients, but only 374 of them received additional local treatment: 4.6%

of the selected patients. The reason for adding local treatment was not registered. It is likely

that patients received extra treatment because of better underlying health, and being capable of

tolerating the extra burden. Another possibility is that patients with worse prognosis were

singled out for extra treatment, in the hopes to prolong their survival. Although both groups are

significantly similar in clinical and oncological parameters, selection bias in this study is likely

and could influence the results. [30]

Heidenreich et al. compared two groups, selected in a single institution: 23 patients were treated

with radical prostatectomy, and a control group of 38 patients initially received ADT only. The

intervention group and the control group were matched for biological, clinical and oncologic

data: as shown in Addendum Table 4, almost all p-values for comparing the groups are not

significant, meaning they are significantly similar for (almost) all parameters. However, both

groups have a low number of patients: the chance of statistical error in comparing these groups

is realistic. The diversity in the groups may not be statistically significant because of the lack

of power, but it may influence the outcomes of the study. Furthermore, the low number of

patients in itself and the single-institute selection could bias the results. This should be a point

of attention for future prospective studies: recruiting a sufficient number of patients in several

medical institutions will be necessary to avoid sampling bias. Statistical power should be

ensured by larger numbers as well.


2. Data collection

Culp et al. selected patients from the SEER database, using the SEER coding guideline to

identify suitable patients. Because of this coding, there was no detailed description of the used

interventions possible for selecting patients or analysis of interventions. There is no

specification of used techniques, or of dosage and timing of the therapies. This may have caused

a heterogeneity in the intervention group, influencing the outcomes.

Many relevant variables are not included or coded in the SEER database, and thus not reported

or analysed in this study. These variables are the already mentioned details of therapy, but also

additional interventions, patient performance status, site-specific EBRT codes and comorbidity

or adverse events. [22] These coding guidelines are a serious limitation for this retrospective

study. It’s difficult to define what the best local therapy is, or what patient might benefit most,

without these missing variables. It is also not possible to identify possible confounders that

could influence the results of the study, because of this limited SEER coding.

Data collection in both studies was also limited because of the relative short time of follow-up.

Culp et al. had a median follow-up of 16 months, Heidenreich et al. 40.6 and 44.0 months for

the intervention group and control group respectively. These short periods make it impossible

to evaluate long term outcomes or adversary events. It should also be noted that Heidenreich et

al. make no mention of the period of time for the survival rates: it is unclear if these rates are

calculated for median follow-up time or for the usual 1 or 5 year interval.

3. Identification of patients

Culp et al. performed a subset analysis, trying to mark out patients with better prospects

(Addendum Table 6 and Addendum Table 7). Subgroups were made based on age (<70 yr or

≥70 yr old), PSA (<20 or ≥ 20 ng/ml) or extent of metastatic disease (M1a-c). Several features

were found to be independently associated with decreased DSS, as described in Results: age ≥

70 yr, cT4 disease, PSA ≥ 20 ng/ml, high-grade disease, and pelvic lymphadenopathy. There is

an extra argument for the influence of T and N state: patients with advanced disease have more

potential of ‘leaving disease behind’ after local treatment. The positive effects of RP might be

undone. [22]


The identification of patients with mPCa who would benefit the most from definitive local

treatment, is also the subject of many research papers.

The factors associated with DSS as described by Culp et al. are very similar to those researched

in the STAMPEDE trials: primary tumour stage, initial Gleason sum score category, metastases

grouping, age group, and WHO performance status. As described in the introduction, these

features are found to have an influence on the survival outcomes and prognosis in newly

diagnosed mPCa patients. Unfavourable scores on these factors predict worse outcomes for

patients, compared to patients without these negative predictors. [7, 22]

The SWOG 8894 trial tried to identify the patients, treated with ADT, with the best long-term

survival odds. The authors suggest that this long-surviving subgroup in mPCa may benefit the

most from additional local treatment of the prostate. Of the patients with mPCa enrolled in the

SWOG 8894 trial, 7% was still alive after 15 years, despite their pessimistic initial presentation.

Several predictors of long-term success for local treatment are suggested: performance status,

diploid tumour, Gleason score, number of nodes involved, seminal vesicle invasion, and the

number of metastatic lesions. [16]

The factors found by Culp et al., associated with improved DSS in patients treated with local

therapy, seem similar to factors associated with overall condition and survival rates in mPCa

patients. The improved DSS in patients treated with local therapy could be (partially) explained

by these independent factors. It is suggested by some articles that only patients with good

overall condition or positive predictors could benefit most from additional therapy. However,

it is not unreasonable that patients with fast progressive mPCa could benefit from local therapy

as well, especially when they quickly evolve to castration-resistant mPCa.

To sum up, mPCa patients are a heterogeneous group with varying survival rates, influenced

by many independent factors. There is a lot of literature to support the suggestions made by

Culp et al. about what patient characteristics can influence the outcomes. It is important that

future prospective studies look carefully at these characteristics, to confirm their impact, and to

make precise recommendations on what patients could benefit the most from additional local

therapy. [7, 19, 22, 26]


4. Outcomes

The local treatments looked at in this thesis are radical prostatectomy and radiotherapy. Both

Culp et al. and Heidenreich et al. researched the effects of prostatectomy, radiotherapy was

researched by Culp et al. only. As mentioned before, the term brachytherapy is used in the

study, but in fact different forms of radiotherapy were included. Heidenreich et al. only looked

into surgery and made no comparison with radiotherapy.

Both Heidenreich et al. and Culp et al. indicate an overall survival benefit for metastatic prostate

cancer patients treated with radiotherapy or radical prostatectomy, compared to systemic

therapy alone. They agree on a significant advantage for patients treated with RP compared

with no local treatment. Culp et al. studied radiotherapy as well, and found here too an OS

benefit compared to the controls without local treatment.

Both studies also compared DSS for local therapy and systemic treatment. Culp et al. showed

a prolonged DSS for RP and BT independently, but Heidenreich et al. found no significant

improvement in DSS for RP. The DSS rate however, found by Heidenreich et al., was

significantly better for the group treated with radical prostatectomy.

Heidenreich et al. looked also at FFS for RP. Patients treated with RP had a longer median time

before PSA elevation, compared to both the control group and the adapted control group. The

ranges of FFS of all three groups overlap each other, indicating that these results may not be

significantly different. There are several possible explanations for this overlap, but the small

number of patients is the most likely.

The possible differences between RP and BT have not been explored by Culp et al. Both

treatments were associated independently with increased OS and DSS, but they were only

compared with the controls, treated with systemic therapy. Comparing the outcomes for the

local treatments in this study is useless: patients were recruited from the SEER database, and

grouped by additional local treatment or no additional local treatment. The reason for additional

local treatment is unknown: it is very likely that the groups are significantly different in

characteristics and prognosis, thus influencing outcomes. The different local treatment groups

should be matched for clinical and oncological characteristics to look at possible differences in

survival.


The results of the studies are consistent with many literature reviews: adding local therapy

seems beneficial for mPCa patients. Of course, there are many limitations to consider: the

results of the studies may be significant, but they are not absolute. However, the consensus in

results in this thesis and the support of many other (not-selected) studies and literature reviews,

are more than enough reason to authorize further research and trials for additional local therapy

in men with mPCa.

5. Other Literature

Various systemic reviews were published recently to evaluate evidence on local treatments for

metastatic PCa: a short overview.

Arcangeli et al. (2016) reviewed 6 retrospective studies providing analysis of survival of

patients with locally advanced or metastatic PCa according to the treatment received. This

publication is limited by the heterogeneity and the shortage of published data, and presented

rather an overview of present knowledge than a systematic review. The conclusion of this

publication shows there is strong support for the benefit of local treatment in PCa, but this needs

to be validated by future studies. [19]

Aoun et al. (2014) provide an overview of the currently available literature about local control

of primary tumour and oligometastases in metastatic prostate cancer and salvage lymph node

dissection of clinical lymph node relapse after curative treatment of prostate cancer. The

conclusion of this comprehensive review is that local control of the primary tumour is still

experimental, but there is growing evidence of genetic and molecular research to support the

hypothesis. [14]

Bayne et al. performed a literature review in 2015 regarding the treatment of the primary tumour

in metastatic patients. Since they found no RCT comparing the combination of local therapy

and systemic therapy to systemic therapy alone, they analysed prospective studies of men with

locally advanced PCa and retrospective studies of occult node-positive PCa with additional

local treatment. The review concludes that treatment of the primary tumour in PCa is being

increasingly explored, with preclinical, translational and retrospective evidence to support

additional local treatment. There are some upcoming studies described to evaluate this new


approach and identify the metastatic patients most likely to benefit from additional local

treatment. [15]

Another literature review was performed by Ghadjar et al. in 2014. Screening population-based

data and retrospective series presented arguments to suggest that the use of local treatment of

the prostate in patients with primary metastatic prostate cancer may improve cancer-specific

survival and overall survival compared with treating these patients with androgen deprivation

therapy alone.

All these studies suggest several reasons why local treatment should be investigated further,

and many theories to prove why it could work. Most of them state some evidence as well for

survival benefits in patients treated with local therapy, but the results should be looked at

critically. Nearly all of these reviews are making conclusions out of the same group of studies:

retrospective case series or cohort studies selected out of population-wide databases (e.g. the

SEER database) are the most common source of input. Because of the limited amount of

existing data, few articles exclude studies based on quality assessments, to ensure a more

complete overview of the current evidence. This thesis only accepted two studies after quality

assessment, and still there are many limitations to consider. Despite the general consensus that

additional local therapy in mPCa patients is very likely to be beneficial, evidence is still very

poor. This thesis does not provide stronger evidence, but it gives a more critical look on existing

information and the current conclusions.


6. Future studies

There are many theories that support adding local therapy in mPCa, and the evidence in

literature is growing steadily. It is no surprise that many upcoming studies are trying to prove

the benefits of additional radiotherapy, prostatectomy, or both, for mPCa patients. A short

overview is presented in Addendum Table 8.

7. Limitations of this thesis

As described in the methodology, only one database was used for literature research: the Ovid

database. The literature search was not repeated. Even though a large number of articles was

found, the use of a single source could have limited the amount and variety of studies.

Another limitation is the small number of selected studies: only two articles are included in

results of this literature research. Although 9 articles were found through the literature research,

only two of them met the threshold score of the quality assessment (Table 3). Of the 9 articles,

many are deficient in the same categories: recruitment in more than one centre, consecutive

recruitment of participants, clearly describing the intervention, reporting of co-interventions,

reporting of adverse events, reporting of both competing interests and source of support.

Some of these deficiencies can be explained by the retrospective design: not all relevant data

was registered at the time the patient was actually treated, causing lacking information. Three

of the studies used the SEER database, and are limited in description of the intervention,

reporting of adverse events, and reporting of all co-intervention. A detailed description of other

SEER limitations is mentioned earlier for Culp et al. The retrospective and observational design

explains the flaws in recruitment: patients are recruited from existing databases, instead of

consecutively.

The quality of the studies themselves is important as well. Although both studies used were

included after a quality assessment, they have some limitations that could influence their results.

These limitations are described above, and should be regarded carefully before making any

recommendations based on the outcomes of this thesis. Both of the studies used in this thesis

are retrospective: Heidenreich et al. published a cohort study, Culp et al. a case-control study.


The level of evidence for these types of research, according to the Oxford Center for Evidence

Based Medicine, is IIb and IIIb, respectively.

To rate the quality of evidence of this thesis, the GRADE (Grading of Recommendations

Assessment, Development, and Evaluation) system was chosen and can be found in Table 6.

[31] The quality of evidence starts out as ‘low’, because of the observational study design. The

assessment is equal for OS and DSS, FFS is only described by Culp et al., and has a slightly

different score.

Table 6: GRADE analysis

GRADE Quality assesment

Quality

Importance

of outcome

no. of

studies Study design

Risk of

bias imprecision inconsistency indirectness

other

considerations

OS

2 observational

very

serious serious not serious serious none

●○○○

very low critical

DSS

2 observational

very

serious serious not serious serious none

●○○○

very low critical

FFS

1 observational

very

serious not serious not serious serious none

●○○○

very low critical

For all outcomes, there were sufficient reasons to lower the GRADE assessment to ‘very low’.

As described before, the risk of bias is very serious in both studies: it’s likely there is a bias in

selecting patients, and several limitations in data collection are reported. The down-rating for

imprecision is explained because of the low numbers in the intervention group and the lack of

confidence interval in the results of Heidenreich et al. This is less of a problem for FFS: this

outcome is only studied by Culp et al. Inconsistency gives little reason for concern: both of the

studies have similar results. The indirectness is serious: applicability of the results is difficult.

The sampled patients used by Heidenreich et al. are not representative for the population, and

Culp et al. do not describe details of the local therapies used in the intervention group. However,

combined with the hard outcomes and the direct comparisons between intervention and

controls, indirectness should only decrease by one level.

Together, all these flaws lower the level of evidence even more: from ‘low’ to ‘very low’. This

implies that the true effect of local therapy in mPCa is likely to be substantially different from

the results presented in this thesis.

Using the GRADE approach, a recommendation for the acquired evidence can be made for

local treatment in mPCa. Only Heidenreich et al. reported on feasibility of radical


prostatectomy, Culp et al. registered no adverse events, so the desirable effects (or lack of it)

are most taken into account. All 3 outcomes (OSS, DSS, FFS) are significantly better in the

intervention groups with local treatment, compared to systemic therapy alone. However,

considering the many limitations in the studies, local therapy in men with newly diagnosed

mPCa can only be conditionally recommended. Other or better studied alternatives should be

considered as well.


IX. Conclusion

Adding surgery or radiotherapy to systemic treatment in mPCa patients seems a promising

approach. There is a profit in both overall survival and disease specific survival for local

treatments added to systemic therapy, compared to systemic therapy alone.

Based on the selected articles, it was not possible to distinguish which local therapy is the most

beneficial, or to identify what patients could profit most. Furthermore, because of the lack of

comparative or randomised trials and the many limitations in the studies that were used, adding

local treatment cannot be recommended at this time as a new standard of care. This is confirmed

by a GRADE analysis and strength of recommendation.

There are many arguments in literature to endorse the research for additional local therapy in

mPCa. Several randomised prospective trials in the near future should provide more conclusive

evidence on the benefits of these treatments. These trials should pay careful attention to

specifications of the local therapies used and the identification of patients who could benefit

the most. It is to be expected that new recommendations will follow soon.


X. Bibliography

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guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-

update 2013. Eur Urol. 2014;65(1):124-37.

2. Henau K, Damme NV, Calay F, Slabbaert M, Thibaut L, Francart J, et al. Cancer incidence in

Belgium 2010. Brussels: Belgian Cancer registry, 2013 D/2013/11.846/1

3. Brawley OW. Prostate cancer epidemiology in the United States. World Journal of

Urology.30(2):195-200.

4. Barocas DA, Mallin K, Graves AJ, Penson DF, Palis B, Winchester DP, et al. Effect of the

USPSTF Grade D Recommendation against Screening for Prostate Cancer on Incident Prostate Cancer

Diagnoses in the United States. The Journal of urology. 2015;194(6):1587-93.

5. Tangen CM, Hussain MH, Higano CS, Eisenberger MA, Small EJ, Wilding G, et al. Improved

overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial

experience (S8494, S8894 and S9346). The Journal of urology. 2012;188(4):1164-9.

6. Schutter HD, Adam M, Giusti F, Schillemans V, Gendt CD, Jegou D, et al. Cancer Survival in

Belgium. Belgian Cancer Registry, 2012 D/2012/11.846/1.

7. James ND, Spears MR, Clarke NW, Dearnaley DP, De Bono JS, Gale J, et al. Survival with

Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the

Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). Eur Urol. 2015;67(6):1028-38.

8. Cetin K, Beebe-Dimmer JL, Fryzek JP, Markus R, Carducci MA. Recent time trends in the

epidemiology of stage IV prostate cancer in the United States: analysis of data from the Surveillance,

Epidemiology, and End Results Program. Urology.75(6):1396-404.

9. Penson DF, Rossignol M, Sartor AO, Scardino PT, Abenhaim LL. Prostate cancer:

epidemiology and health-related quality of life. Urology.72(6 Suppl):S3-11.

10. Welch HG, Gorski DH, Albertsen PC. Trends in Metastatic Breast and Prostate Cancer —

Lessons in Cancer Dynamics. New England Journal of Medicine. 2015;373(18):1685-7.

11. Vale CL, Burdett S, Rydzewska LHM, Albiges L, Clarke NW, Fisher D, et al. Addition of

docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-

sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. The Lancet

Oncology. 2016;17(2):243-56.

12. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU

guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant

prostate cancer. European Urology.65(2):467-79.

13. Antwi S, Everson TM. Prognostic impact of definitive local therapy of the primary tumor in

men with metastatic prostate cancer at diagnosis: A population-based, propensity score analysis.

Cancer Epidemiology.38(4):435-41.

14. Aoun F, Peltier A, van Velthoven R. A comprehensive review of contemporary role of local

treatment of the primary tumor and/or the metastases in metastatic prostate cancer. BioMed Research

International.2014:501213.

15. Bayne CE, Williams SB, Cooperberg MR, Gleave ME, Graefen M, Montorsi F, et al.

Treatment of the Primary Tumor in Metastatic Prostate Cancer: Current Concepts and Future

Perspectives. Eur Urol. 2015.

16. Canby-Hagino ED, Swanson GP, Crawford ED, Basler JW, Hernandez J, Thompson IM.

Local and systemic therapy for patients with metastatic prostate cancer: should the primary tumor be

treated? Current Urology Reports.6(3):183-9.

17. Bott SR, Birtle AJ, Taylor CJ, Kirby RS. Prostate cancer management: 2. An update on locally

advanced and metastatic disease. Postgraduate Medical Journal.79(937):643-5.

18. Conde Moreno AJ, Ferrer Albiach C, Muelas Soria R, Gonzalez Vidal V, Garcia Gomez R,

Albert Antequera M. Oligometastases in prostate cancer: restaging stage IV cancers and new

radiotherapy options. Radiation Oncology.9:258.


19. Arcangeli S, Zilli T, de Bari B, Alongi F. “Hit the primary”: A paradigm shift in the treatment

of metastatic prostate cancer? Critical Reviews in Oncology-Hematology. 2016(97):231-7.

20. Ghadjar P, Briganti A, De Visschere PJ, Futterer JJ, Giannarini G, Isbarn H, et al. The

oncologic role of local treatment in primary metastatic prostate cancer. World Journal of

Urology.33(6):755-61.

21. Moga C, Guo B, Schopflocher D, Harstall C. Development of a quality appraisal tool for case

series studies using a modified Delphi technique. Institute of Health Economics. Alberta Canada.

2012.

22. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate

cancer benefit from definitive treatment of the primary tumor? A SEER-based study. European

Urology.65(6):1058-66.

23. Cho Y, Chang JS, Rha KH, Hong SJ, Choi YD, Ham WS, et al. Does Radiotherapy for the

Primary Tumor Benefit Prostate Cancer Patients with Distant Metastasis at Initial Diagnosis? PLoS

ONE [Electronic Resource]. 2016;11((1)):e0147191.

24. Fossati N, Trinh QD, Sammon J, Sood A, Larcher A, Sun M, et al. Identifying optimal

candidates for local treatment of the primary tumor among patients diagnosed with metastatic prostate

cancer: a SEER-based study. European Urology.67(1):3-6.

25. Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in clinically non-organ-confined

prostate cancer. Current Urology Reports.15(11):455.

26. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with

prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study.

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27. Qin XJ, Ma CG, Ye DW, Yao XD, Zhang SL, Dai B, et al. Tumor cytoreduction results in

better response to androgen ablation--a preliminary report of palliative transurethral resection of the

prostate in metastatic hormone sensitive prostate cancer. Urologic Oncology.30(2):145-9.

28. Satkunasivam R, Kim AE, Desai M, Nguyen MM, Quinn DI, Ballas L, et al. Radical

Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in

Metastatic Prostate Cancer: A SEER-Medicare Analysis The Journal of urology.194(2):378-85.

29. Wu RY, Wang GM, Xu L, Zhang BH, Xu YQ, Zeng ZC, et al. The feasibility and safety of

high-intensity focused ultrasound combined with low-dose external beam radiotherapy as

supplemental therapy for advanced prostate cancer following hormonal therapy. Asian Journal of

Andrology.13(3):499-504.

30. Giordano SH, Kuo Y-F, Duan Z, Hortobagyi GN, Freeman J, Goodwin JS. Limits of

observational data in determining outcomes from cancer therapy. Cancer. 2008;112(11):2456-66.

31. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1.

Introduction—GRADE evidence profiles and summary of findings tables. Journal of Clinical

Epidemiology. 2011;64(4):383-94.

The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum p. i

XI. Addendum

1. Distribution of mPCa

Addendum Table 1: mPCa distribution pt. 1 [8]

p. ii The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum

Addendum Table 2: mPCa distribution pt. 2 [8]

The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum p. iii

2. Description of the 9 selected studies selected by literature search

Stud

yty

pe o

f stu

dy

Dat

a so

urce

(stu

dy

inte

rval

)

No.

Of

patie

nts

incl

usio

n cr

iteria

type

of l

ocal

ther

apy

adde

d to

stan

dard

of c

are

treat

men

t in

cont

rol

arm

Med

ian

follo

w-u

p

time

Out

com

e

Ant

wi e

t al.

retro

spec

tive

coho

rt

stud

ySE

ER d

ata(

2004

-201

0)78

58

≥35y

rs, d

ocum

ente

d st

age

IV (M

1a-c

), p

atho

logi

cal o

r rad

iolo

gica

l

conf

irmat

ion

of m

etas

tasi

s, P

ca is

the

first

and

onl

y pr

imar

y tu

mou

r.RP

or b

rach

ythe

rapy

stan

dard

of c

are

Not

repo

rted

OS,

DSS

Cho

et a

l.

retro

spec

tive

case

serie

sYo

nsei

Can

cer c

ente

r14

0

dist

ant m

etas

tasi

s (M

1) a

t ini

tial d

iagn

osis

or w

ithin

1 m

onth

from

initi

al d

iagn

osis

, with

out o

ther

prim

ary

mal

igna

ncie

s, n

o RP

bef

ore

befo

re R

TRT

stan

dard

of c

are

34,0

mon

ths

(1,7

-

108,

8mo)

OS,

FFS

, tox

icity

Culp

et a

l.

retro

spec

tive

coho

rt

stud

ySE

ER d

ata

(200

4-20

10)

8185

≥35y

rs, d

ocum

ente

d st

age

IV (M

1a-c

), ra

diog

raph

ic o

r pat

holo

gica

l

conf

irmat

ion

of m

etas

tatic

dis

ease

RP o

r bra

chyt

hera

pyno

sur

gery

or R

T16

mon

ths

OS,

DSS

, cau

se-

spec

ific

mor

talit

y

Foss

ati e

t al.

retro

spec

tive

case

serie

sSE

ER d

ata

(200

4-20

11)

8197

age

35-9

0 yr

, mPC

a (M

1a-c

), ex

clus

ion

of u

nkno

wn

PSA

or G

leas

on

scor

e, e

xclu

sion

of o

nly

EBRT

RP a

nd p

elvi

c ly

mph

nod

e

diss

ectio

n or

bra

chyt

hera

pyO

bser

vatio

n or

AD

T

36 m

onth

s in

LT,

31

mon

ths

for N

LTD

SS a

fter 3

yea

rs

Grat

zke

et a

l.

retro

spec

tive

case

serie

s

Mun

ich

Canc

er C

ente

r

(199

8-20

10)

1538

new

ly d

iagn

osed

M+

Pca

RP

stan

dard

of c

are

with

out R

PN

ot re

porte

dO

S

Hei

denr

eich

et a

l.

retro

spec

tive

case

-

cont

rol s

tudy

Dep

artm

ent o

f Uro

logy

,

Uni

vers

ity A

ache

n

23 +

38

(con

trols

)

6 cr

iteria

for c

ytor

educ

tive

RP;

biop

sy p

rove

n PC

a, m

inim

al o

sseo

us

met

asta

ses

(3 o

r few

er h

ot s

pots

on

bone

sca

n), N

0, P

SA d

ecre

ase

to

≤1.0

1.0

ng/

ml a

fter n

eoad

juva

nt a

ndro

gen

depr

ivat

ion

ther

apy

cyto

redu

ctiv

e RP

stan

dard

of c

are

with

out l

ocal

ther

apy

OS,

DSS

, FFS

Qin

et a

l.

retro

spec

tive

case

serie

s

Fuda

n U

nive

rsity

Sha

ngha

i

Canc

er C

entre

(200

6-20

07)

146

new

ly d

iagn

osed

M+

Pca

TURP

AD

T +

anti-

andr

ogen

15 m

onth

sO

S, D

SS, F

FS

Satk

unas

ivam

et a

l.

retro

spec

tive

coho

rt

stud

ySE

ER d

ata

(200

4-20

09)

4069

≥66

yrs,

mPC

a

RP, c

onfo

rmal

RT,

Inte

nsity

Mod

ulat

ed R

adia

tion

ther

apy

stan

dard

of c

are

with

out l

ocal

ther

apy

20 m

onth

sO

S, D

SS

Wu

et a

l.

pros

pect

ive,

cont

rolle

d an

d no

n-

rand

omize

d st

udy

Zhon

gsha

n H

ospi

tal o

f

Fuda

n U

nive

rsity

120

first

-tim

e pa

tient

s w

ith lo

cally

adv

ance

d (T

3-4,

N0-

1, M

0) o

r

met

asta

tic (M

+) P

ca

HIF

U, L

ow-d

ose

exte

rnal

beam

RT,

con

vent

iona

l-dos

e

exte

rnal

bea

m R

T

stan

dard

of c

are

with

out l

ocal

ther

apy

14,1

- 55

,1 m

onth

s O

S, D

SS, t

oxic

ity

Addendum Table 3: studies selected by full text assessment [13, 22-29]

p. iv The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum

3. Patient characteristics Heidenreich et al.

Addendum Table 4: patient characteristics by Heidenreich et al. [26]

The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum p. v

4. Patient characteristics Culp et al.

Addendum Table 5: patient characteristics by Culp et al. [22]

p. vi The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum

5. Subset analysis by Culp et al.

Addendum Table 6: Subset analysis by Culp et al. pt 1 [22]

The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum p. vii

Addendum Table 7: Subset analysis by Culp et al. pt 2 [22]

p. viii The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum

6. Future studies

Nam

e o

f the s

tud

y

typ

ep

op

ula

tion

/inclu

sio

n c

riteria

Inte

rven

tion

co

ntro

lsP

rimary

ou

tco

mes

sta

tus

A ra

nd

om

ised

stu

dy

ab

ou

t the e

ffect o

n s

urv

ival o

f ho

rmo

nal

thera

py

vers

us h

orm

on

al th

era

py

plu

s lo

cal e

xtern

al ra

dia

tion

thera

py

in p

atie

nts

with

prim

ary

dia

gn

osed

meta

sta

sis

ed

(M+

)

pro

sta

te c

an

cer (H

OR

RA

D) (IS

RC

TN

06890529)

Ran

do

mize

d c

on

trolle

d tria

lM

ulti-c

en

ter s

tud

y

LH

RH

an

alo

gu

e c

om

bin

ed

with

RT

of th

e

pro

sta

te (7

0 G

ray

)L

HR

H a

nalo

gu

esu

rviv

al

trial c

om

ple

ted

Ran

do

mize

d, P

hase II T

rial o

f Best S

yste

mic

Th

era

py

or B

est

Sy

ste

mic

Th

era

py

(BS

T) P

lus D

efin

itive T

reatm

en

t (Rad

iatio

n

or S

urg

ery

) of th

e P

rimary

Tu

mo

r in M

eta

sta

tic (M

1) P

rosta

te

Can

cer (P

C) (N

CT

01751438)

Ran

do

mize

d c

on

trolle

d tria

lM

ulti-c

en

ter s

tud

y

Best S

yste

mic

Th

era

py

(BS

T) +

Su

rgery

or R

ad

iatio

n T

hera

py

Best S

yste

mic

Th

era

py

(BS

T)

Pro

gre

ssio

n-F

ree S

urv

ival

recru

iting

patie

nts

ST

AM

PE

DE

: Sy

ste

mic

Th

era

py

in A

dv

an

ced

or M

eta

sta

tic

Pro

sta

te C

an

cer: E

valu

atio

n o

f Dru

g E

fficacy

- An

dro

gen

Su

pp

ressio

n-B

ased

Th

era

py

Alo

ne o

r Co

mb

ined

With

Zo

led

ron

ic A

cid

, Do

ceta

xel, P

red

nis

olo

ne, C

ele

co

xib,

Ab

irate

ron

e, E

nza

luta

mid

e a

nd

/or R

ad

ioth

era

py

in T

reatin

g

Patie

nts

With

Lo

cally

Ad

van

ced

or M

eta

sta

tic P

rosta

te C

an

cer

(NC

T00268476)

Ran

do

mize

d c

on

trolle

d tria

lM

ulti-c

en

ter s

tud

y

Arm

H : A

DT

+ ra

dio

thera

py

: two

rad

ioth

era

py

do

se-fra

ctio

natio

n

sch

ed

ule

s a

re p

erm

itted

. 36G

y in

6

fractio

ns o

f 6G

y, a

dm

inis

tere

d w

eekly

ov

er 6

co

nsecu

tive w

eeks o

r 55G

y in

20

fractio

ns o

f 2.7

5G

y, a

dm

inis

tere

d d

aily

,

five d

ay

s p

er w

eek, o

ver 4

co

nsecu

tive

weeks.

Arm

A (A

DT

(plu

s R

T fo

r

new

ly-d

iag

no

sed

no

n-

meta

sta

tic d

isease)

[co

ntro

l]): bila

tera

l

orc

hid

ecto

my

or L

HR

H

an

alo

gu

es to

ach

iev

e

castra

tion

lev

els

of

testo

ste

ron

e.

Ov

era

ll su

rviv

al

recru

iting

patie

nts

Lo

cal T

reatm

en

t With

Rad

ical P

rosta

tecto

my

for N

ew

ly-

dia

gn

osed

Meta

sta

tic P

rosta

te C

an

cer. (L

oM

P) (N

CT

02138721)

no

n-ra

nd

om

ized

para

llel

assig

nm

en

tM

ulti-c

en

ter s

tud

y

Rad

ical P

rosta

tecto

my

with

exte

nd

ed

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ic L

ym

ph

No

de D

issectio

n +

rou

tine

care

in m

eta

sta

tic p

rosta

te c

an

cer

rou

tine c

are

in m

PC

a

Castra

tion

Refra

cto

ry

Pro

sta

te C

an

cer

Pro

gre

ssio

n-F

ree

Su

rviv

al, T

ime

recru

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patie

nts

Pro

sp

ectiv

e E

valu

atio

n o

f Ste

reo

tactic

Bo

dy

Rad

ioth

era

py

for

Meta

sta

tic P

rosta

te C

an

cer (N

CT

02206724)

safe

ty s

tud

ysin

gle

gro

up

Ste

reo

tactic

bo

dy

rad

iatio

n o

f the

pro

sta

ten

o c

on

trols

Rad

iatio

n re

late

d to

xicity

no

t yet

recru

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ilot S

tud

y o

f Defin

itive T

hera

py

for N

ew

ly D

iag

no

sed

Men

With

Olig

om

eta

sta

tic P

rosta

te C

an

cer (N

CT

02716974)

safe

ty s

tud

ysin

gle

gro

up

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ste

mic

ho

rmo

nal a

nd

ch

em

oth

era

py

,

follo

wed

by

defin

itive lo

cal tu

mo

r co

ntro

l

with

pro

sta

tecto

my

+/- a

dju

van

t rad

iatio

n

thera

py

, an

d c

on

so

lidativ

e s

tere

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ctic

rad

iatio

n to

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om

eta

sta

tic le

sio

ns.

no

co

ntro

ls

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ty o

f the

mu

ltimo

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thera

py

no

t yet

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iting

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hase III o

f AD

T +

/- Lo

cal R

T +

/- Ab

irate

ron

e A

ceta

te in

Meta

sta

tic H

orm

on

e-n

aïv

e P

rosta

te C

an

cer. (P

EA

CE

1)

(NC

T01957436)

Pro

sp

ectiv

e R

an

do

mis

ed

Ph

ase III S

tud

yM

ulti-c

en

ter s

tud

y

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+ a

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tero

ne a

ceta

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pre

dn

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: AD

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; Arm

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AD

T +

ab

irate

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ne +

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A

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: AD

T

Ov

era

ll an

d p

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n-

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ival

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patie

nts

Imp

act o

f Rad

ical P

rosta

tecto

my

as P

rimary

Tre

atm

en

t in

Patie

nts

With

Pro

sta

te C

an

cer W

ith L

imite

d B

on

e M

eta

sta

ses

(g-R

AM

PP

) (NC

T02454543)

pro

sp

ectiv

e R

an

do

mis

ed

co

ntro

lled

trial

Mu

lti-cen

ter s

tud

yA

DT

+ R

P +

exte

nd

ed

lym

ph

ad

en

ecto

my

AD

TC

an

cer s

pecific

su

rviv

al

recru

iting

patie

nts

Testin

g R

ad

ical p

rosta

tecto

my

in m

en

with

olig

oM

eta

sta

tic

pro

sta

te c

an

cer th

at h

as s

pre

ad

to th

e b

on

e (T

Ro

Mb

on

e)

(ISR

CT

N15704862)

ran

do

mis

ed

co

ntro

lled

feasib

ility tria

lM

ulti-c

en

ter s

tud

yA

DT

+ R

P +

exte

nd

ed

lym

ph

ad

en

ecto

my

AD

T

feasib

ility to

ran

do

mis

e a

t

6 m

on

ths

no

t yet

recru

iting

Cy

tore

du

ctiv

e P

rosta

tecto

my

in T

reatin

g P

atie

nts

With

New

ly

Dia

gn

osed

, Meta

sta

tic P

rosta

te C

an

cer (N

CT

02458716)

ph

ase I s

afe

ty tria

lsin

gle

gro

up

RP

follo

wed

by

AD

Tn

o c

on

trols

Rate

of m

ajo

r peri-

op

era

tive c

om

plic

atio

ns

defin

ed

as C

lav

ien

-Din

do

gra

de III o

r hig

her

recru

iting

patie

nts

Addendum Table 8: overview of future trials

The impact of local treatment of the prostate in patients with newly diagnosed metastatic prostate cancer. - Addendum p. ix

The impact of local treatment of the prostate in patients with...

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