Download chapter 2: active surveillance for prostate cancer

SELECTION OF MEN FOR ACTIVE SURVEILLANCE
IN LOW RISK PROSTATE CANCER
Lih-Ming Wong
M.B., B.S. University of Melbourne, Australia
F.R.A.C.S. Urology, Royal Australasian College of Surgeons
Thesis submitted in total fulfillment of the requirements of the degree
of Masters of Surgery (552AA).
December 2013
Department of Surgery, Austin Hospital
Faculty of Medicine, Dentistry and Health Sciences
University of Melbourne
Victoria
Australia
Produced on archival quality paper
1
Abstract
Aims:
Active surveillance (AS) is a management strategy that aims to avoid overtreatment of indolent prostate cancer, monitor for development of more
aggressive disease, and intervene within the window of curability. Interest in AS
has increased as large randomized screening trials suggest many men with
prostate cancer are over-diagnosed and over-treated.
Suitability of men for AS is determined by criteria that were found to predict
"insignificant tumours", defined as tumours of volume <0.5ml. However,
amongst the published literature on AS, variations in eligibility criteria exist
between individual institutions. The primary aim of this thesis was to examine
the ability of certain published AS eligibility criteria to include only men with
insignificant tumours, and avoid selection of men with more aggressive disease.
Methods:
To investigate eligibility criteria for AS, data on men who were suitable for AS
but underwent upfront radical prostatectomy was analysed. Initially, a database
from Addenbrookes Hospital, Cambridge, United Kingdom was utilized.
Subsequently, a collaboration of radical prostatectomy data between
Addenbrookes Hospital, United Kingdom; Vancouver Prostate Centre, Canada;
and Royal Melbourne Hospital, Australia was formed.
First, the Cambridge database was used to assess a National Institute for Health
and Clinical Excellence (NICE) guideline. Here, it had previously been stated
“men with low-risk localised prostate cancer who are considered suitable for
radical treatment should first be offered active surveillance”. Subsequently, the
combined database was utilized to examine two of the commonly used AS
criteria (Sunnybrook Toronto and European Prostate Cancer Research
International: Active Surveillance (PRIAS)). Here, the number of men suitable for
2
AS according to each criteria, and proportions of men with upgrading and
upstaging at radical prostatectomy were described. Multivariate logistical
regression was done to identify predictors of more aggressive, or high-risk,
disease, and analysis to create a predictive model for both indolent and high-risk
disease performed.
Results
When reviewing the NICE guideline, their definition of low risk prostate cancer,
was applied to the Cambridge radical prostatectomy database (n=700) and
39.2% of men (n=275) deemed suitable. In this group of NICE low risk patients,
30.6% (n=84/275) of men had features of more aggressive disease (Gleason sum
≥7, pathological stage ≥ pT3) at upfront radical prostatectomy.
In selecting men for AS, application of more stringent criteria was found to
effectively halve the number of men suitable for AS (Sunnybrook criteria n=800,
compared to PRIAS criteria n=410). The proportion of men with increase in
Gleason grade (≥7) was 42.7-50.6%, and increase in stage was 12.4-17.6%.
Predictors of high-risk disease included increasing age, cT2, increasing PSA and
number of positive cores. More men in Cambridge, compared to Vancouver and
Melbourne, were found to have pT3 disease (26% versus 12%). To assist
selection of men in the UK for AS, from the Cambridge data, we generated a
nomogram predicting high-risk features in patients who meet the Sunnybrook
Toronto criteria (AUC of 0.72).
Conclusions
In selecting men for AS, a proportion of them will harbour undiagnosed high-risk
disease. Using more stringent criteria may reduce this number but at the cost of
including fewer men who may benefit from AS. Predictive models may assist
with selection of men but the future likely lies in better tests, be it imaging or
biomarkers, to be performed at time of selection and during the course of AS.
3
Author’s Declaration
This is to certify that:
i)
the thesis comprises only my original work towards the masters
except where indicated in the Preface
ii)
due acknowledgement has been made in the text to all other material
used
iii)
the thesis is 14,882 words in length, exclusive of tables, figures,
bibliographies and appendices.
Signature:
Lih-Ming Wong
4
Preface, Acknowledgements & Dedication
Multi-author published work is included in this thesis for which I declare that I
contributed >50% of the content of the work, and am the “primary author”.
Communications arising from this Thesis and the co-authors involved are listed
in the section below.
Writing of the initial draft, and subsequent editing in response to collaborators
and editors, was performed by myself. I would also like to acknowledge the
contribution of others who actively collaborated in various work as below:

Acquisition of data – The robotic assisted radical prostatectomy database at
Addenbrookes Hospital had been commenced by Dr Naomi Sharma and
updated by Dr Richard Johnston and myself. Dr Niall Corcoran, my principle
collaborator for work presented in chapter 5, had access to the
prostatectomy databases from The Vancouver Prostate Centre, Canada; and
the Australian Prostate Cancer Centre@Epworth, Melbourne, Australia.

Analysis and Interpretation of data – I am grateful for the assistance of Dr
Richard Johnston and Dr Niall Corcoran who assisted me with statistical
analysis and interpretation of the data in chapters 4 and 5.

Drafting of manuscript – I would like to acknowledge the help of Professor
David Neal and Dr Niall Corcoran who were the primary editors of my work.
Other co-authors who were closely involved with drafting manuscripts were
Dr Nimish Shah, Dr Richard Johnston and Dr Anne Warren. The remaining coauthors are listed with the publications included in Appendix B.
Finally, I would like to dedicate this work to my loving and supportive wife
Olivia. Her patience and organizational skills have been invaluable in helping me
complete this thesis.
5
My supervisors for this thesis were:
Supervisors:
Professor Damien Bolton
University of Melbourne Department of Surgery and Ludwig Institute for Cancer
Research
Austin Hospital, Melbourne.
Associate Professor Nathan Lawrentschuk
University of Melbourne Department of Surgery and Ludwig Institute for Cancer
Research
Austin Hospital, Melbourne.
External supervisor:
Associate Professor Antonio Finelli
Princess Margaret Hospital
3rd Floor Rm. 130
610 University Ave
Toronto, Ontario
Canada M5G 2M9
[email protected]
Advisory committee:
Professor Neil E. Fleshner
Princess Margaret Hospital
3rd Floor Rm. 130
610 University Ave
Toronto, Ontario
Canada M5G 2M9
[email protected]
These studies were performed with institutional research and ethics review
board approval.
6
Communications arising from this Thesis
Communications published during the research period of this thesis
(arising directly from this thesis).
International multicentre study examining selection criteria for active surveillance in
men undergoing radical prostatectomy. British Journal of Cancer, 2012; 107: 14671473
http://dx.10.1038/bjc.2012.400
Wong L, Neal DE, Johnston RB, Shah N, Sharma N, Warren AY, Hovens CM,
Goldenberg SL, Gleave ME, Costello AJ, Corcoran NM.
General application of the National Institute for Health and Clinical Excellence (NICE)
guidance for active surveillance for men with prostate cancer is not appropriate in
unscreened populations. British Journal of Urology Int. 2012;110(1):24-27.
http://dx.doi.10.1111/j.1464-410X.2011.10730.x.
Wong, L, Johnston, RB, Sharma, N, Shah, N, Warren, AY, Neal, DE.
Other communications published during the research period of this thesis
(related to this thesis).
The role of 1.5 Tesla magnetic resonance imaging in staging of prostate cancer. ANZ
Journal of Surgery. Article first published online: 6 MAR 2013.
http://dx.doi.org/10.1111/ans.12094
Johnston R, Wong L, Warren A, Shah N, Neal DE.
7
Peer reviewed presentations and prizes arising from this thesis.
Prizes:
European Association of Urology Annual Congress, Paris. 2012
Best Poster, Poster Session 91
An international multi-center study examining re-classification rates of patients with
prostate cancer suitable active surveillance who underwent radical prostatectomy.
Wong L, Neal DE, Johnston R, Warren A, Shah N, Hovens CH, Goldenberg L, Gleave
ME, Costello AJ, Corcoran NM.
Presentations:
2012
European Association of Urology Annual Congress, Paris.
An international multi-center study examining re-classification rates of patients with
prostate cancer suitable active surveillance who underwent radical prostatectomy.
(Extended podium presentation, Best Poster, Poster Session 91.)
Wong L, Neal DE, Johnston R, Warren A, Shah N, Hovens CH, Goldenberg L, Gleave
ME, Costello AJ, Corcoran NM.
American Urologic Association Annual Meeting, Atlanta.
An international multi-center study examining re-classification rates of patients with
prostate cancer suitable active surveillance who underwent radical prostatectomy.
Wong L, Neal DE, Johnston R, Warren A, Shah N, Hovens CH, Goldenberg L, Gleave
ME, Costello AJ, Corcoran NM.
8
Canadian Urologic Association Annual Meeting, Banff.
An international multi-center study examining re-classification rates of patients with
prostate cancer suitable active surveillance who underwent radical prostatectomy.
Wong L, Neal DE, Johnston R, Warren A, Shah N, Hovens CH, Goldenberg L, Gleave
ME, Costello AJ, Corcoran NM.
2011
British Urologic Association Society Annual Meeting, Liverpool.
Correlation of National Institute of Health and Clinical Excellence (NICE) 'low-risk'
prostate cancer (CaP) in Britain with radical prostatectomy specimens. Is active
surveillance in our population realistic?
BJUI. 2011; 108. 33
DE Neal, LM Wong, R Johnston, N Shah, K Wadhwa
9
Table of Contents
ABSTRACT
2
COMMUNICATIONS ARISING FROM THIS THESIS
7
LIST OF TABLES
12
LIST OF FIGURES.
13
CHAPTER 1: BACKGROUND – PROSTATE CANCER
14
PROSTATE CANCER EPIDEMIOLOGY
RISK FACTORS FOR PROSTATE CANCER
DIAGNOSIS OF PROSTATE CANCER
PROSTATE CANCER STAGING
PROSTATE CANCER SCREENING
MODELS TO PREDICT PROGNOSIS OF MEN DIAGNOSED WITH PROSTATE CANCER.
MANAGEMENT OF LOW RISK PROSTATE CANCER
14
16
19
21
22
25
25
CHAPTER 2: ACTIVE SURVEILLANCE FOR PROSTATE CANCER
27
DEFINITION
ELIGIBILITY AND INCLUSION CRITERIA
THE ROLE OF BIOPSY
THE ROLE OF PROSTATE SPECIFIC ANTIGEN
RESEARCH PROBLEM AND HYPOTHESES
JUSTIFICATION AND CLINICAL IMPACT OF THE RESEARCH
27
27
29
29
30
31
CHAPTER 3: PATIENTS AND METHODS
32
THESIS OVERVIEW:
DATA SOURCES AND VARIABLES:
IDENTIFICATION OF STUDY PATIENTS:
OUTCOMES MEASURED IN THE THESIS:
STATISTICAL METHODS USED IN THE THESIS:
ETHICS STATEMENT:
32
32
34
34
35
35
CHAPTER 4: GENERAL APPLICATION OF THE N.I.C.E. GUIDANCE FOR ACTIVE
SURVEILLANCE (AS) FOR MEN WITH PROSTATE CANCER IS NOT APPROPRIATE IN
UNSCREENED POPULATIONS
36
SUMMARY:
INTRODUCTION:
PATIENTS AND METHODS:
RESULTS:
DISCUSSION
CONCLUSIONS:
DISCLOSURES:
ACKNOWLEDGEMENTS:
36
37
38
39
41
42
43
43
10
CHAPTER 5: AN INTERNATIONAL MULTI-CENTRE STUDY EXAMINING SELECTION
CRITERIA FOR ACTIVE SURVEILLANCE IN MEN UNDERGOING RADICAL
PROSTATECTOMY
44
SUMMARY:
INTRODUCTION:
PATIENTS AND METHODS:
RESULTS:
DISCUSSION
CONCLUSIONS:
44
46
47
48
60
65
GENERAL DISCUSSION:
67
THESIS SUMMARY:
THESIS LIMITATIONS
FUTURE DIRECTIONS FOR AS:
67
69
71
CONCLUSION:
80
SUMMARY OF CLINICAL IMPLICATIONS:
80
REFERENCES:
81
APPENDIX A: LIST OF VARIABLES
94
APPENDIX B: PUBLISHED MANUSCRIPTS FROM THESIS
95
11
List of Tables
Table 1-1: Autopsy prevalence of prostate cancer in the world....................................... 17
Table 1-2: The 2009 TNM (tumour, node, metastasis) classification.(46) .................. 21
Table 2-1: Published eligibility criteria for active surveillance........................................ 28
Table 3-1: Data sources used in the thesis ................................................................................. 32
Table 4-1: NICE risk groups for localized prostate cancer ................................................. 39
Table 4-2: Pre-operative characteristics of patients satisfying NICE low risk
criteria. ..................................................................................................................................................... 40
Table 4-3: Frequency of unfavourable histopathology subgroup within NICE low
risk group, on analysis of the prostatectomy specimen. ...................................................... 40
Table 4-4: Comparison between groups with favourable and unfavourable final
histology. ................................................................................................................................................. 41
Table 5-1: Patient baseline characteristics – men who underwent upfront radical
prostatectomy but were suitable for active surveillance .................................................... 49
Table 5-2: Pathological results from radical prostatectomy for patients suitable
active surveillance ............................................................................................................................... 51
Table 5-3: Data (combined 3 centres) restricted to year ≥2003 and number of cores
≥8. ................................................................................................................................................................ 54
Table 5-4: Multivariable logistic regression for predictors of high-risk disease (*)
disease, for combined 3 centres, Sunnybrook Toronto and PRIAS selection criteria.
...................................................................................................................................................................... 55
Table 5-5: Multivariable logistic regression for predictors of high-risk disease (*)
disease, for Cambridge cohort, Sunnybrook Toronto AS selection criteria................. 58
Table 5-6: Comparison between centres for rates of upgrading/upstaging using
Sunnybrook Toronto and PRIAS inclusion criteria for AS. ................................................. 61
Table 5-7: Comparison world wide of rates of PSA testing (*) ......................................... 63
12
List of Figures.
Fig 1-1: Trends in incidence rates for Prostate Cancer, Australia, 1982-2009.......... 14
Fig 1-2: Trends in incidence rates for Prostate Cancer, Great Britain, 1975-2010(8)
...................................................................................................................................................................... 15
Figure 1-3: Prostate cancer mortality rates, United States America.(9) ..................... 16
Figure 5-1: Nomogram to predict individual probability of high-risk prostate
cancer in UK men who meet the Sunnybrook Toronto criteria. ....................................... 57
Figure 5-2: ROC curve to assess performance of nomogram predicting probability
of high-risk prostate cancer in UK men satisfying Sunnybrook Toronto AS criteria.
...................................................................................................................................................................... 59
Figure 5-3. Calibration plot, comparing nomogram predicted probabilities to
actual proportions of high-risk disease ...................................................................................... 59
13
CHAPTER 1: BACKGROUND – PROSTATE CANCER
Prostate cancer epidemiology
In Australia, prostate cancer was estimated to be the most common cancer
diagnosed (excluding non-melanoma skin cancer) in 2012. In 2010, it was the
3rd most common cause of cancer deaths behind lung and bowel cancers (1).
The trend in incidence rates for prostate cancer has steadily increased between
1982-2009(2). Based on data from 2009, it was estimated 1 in 5 Australian men
would be diagnosed with prostate cancer. These statistics are similar to those
reported by other developed countries (3-5).
Global temporal trends in incidence of prostate cancer reflect utilization of
prostate specific antigen (PSA) testing. In countries with higher uptake of PSA
screening, such as Australia, Canada and United States of America (USA) (6),
rates increased dramatically in the 1990s followed by a decline due to fewer
prevalent cases (Fig 1-1). In contrast, in other developed countries such as the
United Kingdom and Denmark (7) with slower adoption of PSA screening,
incidence shows a steady increase (Fig 1-2).
Fig 1-1: Trends in incidence rates for Prostate Cancer, Australia, 1982-2009
Trends in incidence rates for Prostate cancer
(ICD10 C61), Australia, 1982–2009
Male ASI rate
Female ASI rate
250
Cases per 100,000
200
150
100
50
0
1980
1985
1990
1995
2000
2005
2010
2015
Year
14
Fig 1-2: Trends in incidence rates for Prostate Cancer, Great Britain, 19752010(8)
Trends in death rates from prostate cancer have declined in developed countries
(Fig 2). This is likely secondary to improvements in treatments with curative
intent (6, 7). The role of PSA screening in reduction of prostate cancer related
mortality, however, remains controversial.
15
Figure 1-3: Prostate cancer mortality rates, United States America.(9)
Risk factors for prostate cancer
The pathogenesis of prostate cancer is complex and multi-factorial. There are a
few established risk factors and many postulated ones.
16
Increasing age is a well-accepted risk factor for prostate cancer. It is rare for men
under the age of 40 to be diagnosed but the probability for a man to be
diagnosed with prostate cancer by the age of 70 is 1 in 8 (12.5%) in the USA (10),
and 1 in 5 in Australia(1). Interestingly, a discrepancy exists in probability of a
man diagnosed with prostate cancer and the probability of prostate cancer found
at autopsy. Autopsy series have found histological evidence of prostate cancer in
up to10% of men aged 20 (11) and 80% in 71-79 year olds (Table 1-1)(12). This
information illustrates how common prostate cancer is in the community but
also emphasizes the indolent natural history of many with the disease.
Table 1-1: Autopsy prevalence of prostate cancer in the world
Age (years)
US
US
White
Black
Japan
Spain
21-30
8
8
0
4
31-40
31
31
20
9
41-50
37
43
13
14
51-60
44
46
22
24
61-70
65
70
35
32
71-80
83
81
41
33
81-90
48
Adapted from: Haas, G.P., Delongchamps, N., Brawley, O.W., et al. The Worldwide
Epidemiology of Prostate Cancer: Perspectives from Autopsy Studies. Can J Urol.
2008;15(1):3866-3871.
Men with a positive family history of first-degree relatives are at increased risk
of developing prostate cancer. With one first-degree relative the risk is doubled,
and with ≥2 first-degree relatives, the risk is increased by 5-11 fold(13, 14). A
study of twins showed that concordance for prostate cancer was substantially
higher among monozygous twin pairs, 27.1%, than among dizygous twin pairs,
7.1%(15) suggesting a genetic component. A small proportion of men (5-10%)
will have dominantly inherited susceptibility genes with high penetrance, and
17
contribute 30-40% of early onset disease (16). Hereditary prostate cancer is
diagnosed on average 6-7 years earlier than sporadic disease but otherwise
clinically behaves like the sporadic form. As yet, no single gene has been
demonstrated to definitively cause cancer though several genes (such as HPC-1,
BRCA 1 and BRCA 2) have been shown to occur more frequently in men with
prostate cancer.
Ethnicity or race is an intricate blend of genetic and environmental factors. Men
of African descent in the USA have a consistently higher death rate from prostate
cancer than white males. This may reflect genetic susceptibility (17) though
socio-economic factors such as access to healthcare have also been shown to be
important(18). Furthermore, whilst incidence and mortality for AfricanAmerican men are consistently highest, the distribution in grade of prostate
cancer appears to be similar among races(19). The incidence of clinically
detected prostate cancer in South East Asian countries is lower than western
societies. However, epidemiological migration studies show that Japanese that
move to Hawaii adopt an increased risk of prostate cancer approaching that of
white American men(20). Thus observed differences between various races are
strongly influenced by environmental factors that potentially could be
modifiable.
Many exogenous factors that might affect risk of progression from latent to
clinical prostate cancer have been studied. Differences in diet between different
ethnicities have been explored extensively but overall, findings are mostly
observational, weak and inconsistent. Increased dietary fat in the western world
has been blamed been for elevated occurrence of many cancers, including
prostate. The Health Professionals Follow-up Study was a prospective cohort
study involving over 50,000 US men that showed a trend in the relationship
between higher total fat consumption and risk of advanced prostate cancer
(RR=1.79, p=0.06)(21). In particular, high alpha linolenic acid intake (vegetable
oils and meats) is thought to be associated with increased risk (21, 22), though
alpha linolenic acid probably only constitutes 1% of total fat intake (23).
Lycopene, the main carotenoid in tomatoes was initially shown to have negative
18
association with prostate cancer (24, 25) however these results were not
replicated in larger cohort studies(26). Similar inconsistency in evidence exists
with Vitamin E. The Alpha Tocopherol, Beta Carotene Trial suggested alpha
tocopherol supplementation could decrease prostate cancer risk (27) however
the randomized Selenium and Vitamin E Chemoprevention Trial (SELECT) found
no evidence of protection (28) and even increased risk with longer followup(29). The overall association of obesity to prostate cancer is weak, however it
has been observed that obese men tend to be diagnosed with more advanced,
higher grade disease(30). Finally, when considering dietary and lifestyle issues,
it should be remembered that many with prostate cancer have indolent disease
and like the general population, are more likely to die of cardiac disease. Thus a
simple “healthy heart” diet and exercise regime in itself is likely to improve the
quality of life for many men(31).
Diagnosis of prostate cancer
Currently, most prostate cancer is diagnosed using serum prostate specific
antigen (PSA), digital rectal examination followed by transrectal ultrasound
guided prostate biopsy.
PSA is a protease enzyme secreted by the prostatic epithelium which assists with
liquefaction of semen. Whilst it is for practical purposes organ-specific, it is not
cancer specific. Thus other conditions affecting the prostate such as benign
prostatic hypertrophy (BPH), inflammation of the prostate (prostatitis) and
infection can cause an elevation in PSA. PSA is used as a continuous parameter
with higher values associated with increased likelihood of prostate cancer being
present. However, cancer can be found at low PSA levels too (32). Since PSA was
first described in 1979 (33) and described as a serum marker for prostate cancer
in 1987 (34), it has been difficult to find a better biomarker for prostate cancer.
It is used for screening of prostate cancer, diagnosis, as well as in follow-up for
evaluation of treatment given.
19
Digital rectal examination (DRE) is an integral part of the clinical assessment for
prostate cancer. Most prostate cancers are anatomically located in the peripheral
zone of the gland, and hence may be palpated on DRE when their volume is 0.2ml
or larger. A suspicious DRE, independent of the PSA level, results in detection of
prostate cancer in about 18% of patients. Another limitation of its use is limited
reproducibility between examiners(35). It’s positive predictive value increases
with higher PSA (2-4ng/ml) to 30-48.6% (36, 37). An association between an
abnormal DRE and more aggressive Gleason score (>7) exists(37).
Standard transrectal ultrasound (TRUS) enables visualization of the prostate.
The classic hypoechoic lesion in the peripheral zone is not always seen and gray
scale TRUS is not able to visualize areas of prostate cancer reliably. Hence
systematic biopsies of different zones of the prostate are taken(38), in addition
to targeted biopsies of any suspicious lesions. Complications from prostate
biopsy include bleeding, sepsis(39), exacerbation of lower urinary tract
symptoms with possibly urinary retention, and impotence(40).
Prostate cancer found on core biopsy or operative specimens is graded on
histological appearance using the Gleason score. The current standard is the
ISUP 2005 Gleason score(41) and is the accepted grading system around the
world. Five classic different patterns of tumor growth (1-5) were described
originally by Donald Gleason in 1966 (42). These 5 patterns, designated as
grades, describe progressive loss of normal prostate glandular architecture with
pattern 5 being the worst grade. However, only grades 3-5 are now reported
because of the advent of immunohistochemistry staining for basal cells. Most
cases diagnosed with Gleason 1 or 2 in the original era are now referred to as
adenosis (41). The Gleason score is the sum of the two most common patterns
and ranges from 6 to 10, with 10 being the most aggressive. For needle biopsies,
the worst grade should always be incorporated into the Gleason score, even if
comprises <5% of the cancer.
Tumor grading of prostate cancer forms an integral part of determining disease
biology and prognosis. Prognosis is a prediction of the chance of survival or
20
recovery from the disease. In prostate cancer, biological potential to spread
outside the prostate to other organs is the limiting factor for curability. The
Gleason score, in use now for over 40 years, remains an important prognostic
indicator for prostate cancer(43, 44).
Most urologists incorporate the Gleason score, together with PSA and DRE
findings, into 3 broad risk categories:

low risk: Gleason score 6 and PSA <10ng/ml and cT1/cT2a

intermediate risk: Gleason score 7 or PSA 10-20ng/ml or cT2b

high risk: Gleason score ≥8 or PSA >20 or cT2c
These risk categories currently form the basis for determining prognosis in
prostate cancer(45).
Prostate cancer staging
The 2009 TNM (tumour, node, metastasis) classification for prostate cancer is
shown in Table 1-2 (46).
Table 1-2: The 2009 TNM (tumour, node, metastasis) classification.(46)
T - Primary tumour
Tx
T0
T1
T1a
Primary tumour cannot be assessed
No evidence of primary tumour
Clinically inapparent tumour not palpable or visible by imaging
Tumour incidental histological finding in 5% or less of tissue
resected
T1b
Tumour incidental histological finding in more than 5% of tissue
resected
T1c
Tumour identified by needle biopsy (e.g. because of elevated
prostate-specific antigen [PSA] level)
T2
Tumour confined within the prostate1
T2a
Tumour involves one half of one lobe or less
21
T2b
Tumour involves more than half of one lobe, but not both lobes
T2c
Tumour involves both lobes
T3
Tumour extends through the prostatic capsule2
T3a
Extracapsular extension (unilateral or bilateral) including
microscopic bladder neck involvement
T3b
Tumour invades seminal vesicle(s)
T4
Tumour is fixed or invades adjacent structures other than seminal
vesicles: external sphincter, rectum, levator muscles, and/or pelvic
wall
N - Regional lymph nodes3
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
M - Distant metastasis4
Mx
M0
M1
1
M1a
Distant metastasis cannot be assessed
No distant metastasis
Distant metastasis
Non-regional lymph node(s)
M1b
M1c
Bone(s)
Other site(s)
Tumour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is
classified as T1c.
2
Invasion into the prostatic apex, or into (but not beyond) the prostate capsule, is not classified as
pT3, but as pT2.
3
Metastasis no larger than 0.2 cm can be designated pN1 mi.
4
When more than one site of metastasis is present, the most advanced category should be used.
Prostate cancer screening
Screening of prostate cancer with PSA was initially described in 1991 (47).
Its impact on the epidemiology of prostate cancer was discussed above. The
association of prostate cancer screening and mortality has been investigated in
22
two large randomized controlled trials. The Prostate Lung Colorectal and
Ovarian Screening Trial (PLCO) contained 75,000 men and after 13 years of
follow-up, found no mortality benefit for organized annual screening (48).
However, the study was deeply flawed as nearly half of the control arm
underwent screening, so ultimately can only really be considered a trial of
regular screening versus opportunistic screening. The European Randomized
Study of Screening for Prostate Cancer (ERSPC) was published at a similar time.
Across 8 European countries and involving over 150,000 men, at 11 years
follow-up, screening was found to have a relative reduction in risk of death of
21% (49). To prevent one death from prostate cancer at 11 years, 1055 men
would need to be screened and 37 cancers would need to be detected.
The most impressive results favouring population prostate cancer screening
come from Sweden. In 20,000 men, screening was found to decrease the relative
risk (RR) of dying from prostate cancer by nearly 50% (RR 0.56). To prevent one
prostate cancer death in this study, the number needed to be screened (NNS)
was 293 and the number needed to be treated (NNT) was 12 (50). It is thought
these results differ from the ERSPC because follow-up was longer (14 years
versus 11) and men were screened from a younger age (median age at baseline
was 56 years versus 60.8 years). As the natural history of prostate cancer is one
of long lead-time and long natural course, it is logical that the potential benefits
of screening would become more apparent with longer follow-up. The number
needed to screen and treat decreased in the subsequent ERSPC update (11 years
versus 9 years follow-up), further strengthening this theory (51).
The results from the Swedish Göteborg study (NNS 293, RR 0.56) are
comparable to screening studies for other cancers with similar length of follow
up. Breast cancer screening with mammography has reported a NNS of 337 with
a RR of 0.68-0.86 (depending on age)(52). A Cochrane review suggests the NNT
for mammography is 10 patients, over 10 years. Screening for colorectal cancer
with one flexible sigmoidoscopy between the ages of 55-64 was examined in a
large randomized trial of 170,432 patients in the United Kingdom. In people who
received sigmoidoscopy, the incidence of colorectal cancer was reduced by 23-
23
33% (depending on either intention-to-treat or per-protocol analyses). The NNS
to prevent one colorectal cancer diagnosis or death were 191 and 489
respectively (53).
Opinions on the public health impact of screening for prostate cancer are
polarized. The United States Preventative Services Task Force current
recommendation, released in May 2012, counsels against PSA-screening for
prostate cancer(54). They concluded that “many men are harmed as a result of
prostate cancer screening and few, if any, benefit”. Many urologists worry that if
PSA screening decreases or stops, men will present with more advanced disease,
outside the window of curability. A more balanced approach was taken in the
American Urological Association’s guideline on prostate cancer screening
released in May 2013, which was considerably different previous consensus
statement issued in 2009. The new guideline only recommends PSA testing for
men aged 55-69, with shared decision-making between doctor and patient to
discuss the potential harms of screening and treatment(55). A concern with this
guideline is the potential effect of ceasing PSA testing for men aged 45-55 years.
There is evidence that PSA in younger men, before the confounding effects of
benign prostatic hypertrophy (BPH) occur, can be a predictor of metastasis and
death from prostate cancer. Vickers and colleagues showed that for men in age
groups 45-49 and 51-55, those with PSA in the highest 10th centile contributed
to nearly 50% of the prostate cancer deaths and were at higher risk of metastasis
(1.6% and 5.2% respectively)(56).
Whilst the correlation between PSA screening and prostate cancer mortality
remains contentious, most agree that over diagnosis and over treatment of
prostate cancer is an issue. Concern over an elevated PSA almost invariably leads
to a prostate biopsy for diagnosis. Cancer found at biopsy may lead to treatment.
Procedures for both diagnosis and treatment are associated with potential for
considerable morbidity. As the natural history of prostate cancer has become
better understood, it has become apparent that a large proportion of men
diagnosed with prostate cancer are destined to die of other causes other than
prostate cancer (57-59). For men with low risk prostate cancer who were
24
observed, the calculated cumulative 10-year prostate cancer–specific mortality
has been reported to be 2.4%(59). In an older population with median age of 78
years, the 10 year prostate cancer–specific mortality was 8.3% corresponding 10
year risk of dying of competing causes 59.8% (60). If this is indeed the case,
many men may not radical treatment of their low risk prostate cancer.
Models to predict prognosis of men diagnosed with prostate cancer.
There have been many predictive models created to assist clinicians with
prognostication and management of patients worried about prostate cancer. The
Partin tables (61) were one of the first to estimate pathological staging using
PSA, DRE and Gleason score. The classifications suggested by D’Amico (low,
intermediate and high) showed significant differences in freedom from disease
at 10 years after radical treatment, are simple to remember, and still used today
by many urologists(62). Various on-line prediction tools from different
institutions around the world are available and easily accessible (63-67). They
can help predict presence of cancer for men deciding whether to have a prostate
biopsy(65, 67), and the risk of biochemical recurrence after different forms of
treatment(63). The UCSF-CAPRA score can predict likelihood of metastasis,
cancer-specific mortality and overall mortality(64). However, it is increasingly
being realized that the performance of these predictive models deteriorates
when applied to a different population from which they are derived from(68).
Management of low risk prostate cancer
Traditionally, prostate cancer when diagnosed was treated in a radical manner.
The term radical refers to the approach of treating the whole gland, either by
surgical removal (radical retropubic prostatectomy) or ablation by energy
source, most commonly radiotherapy. Radical retropubic prostatectomy involves
removal of the whole prostate gland between urethra and bladder, along with
the seminal vesicles and adjacent soft tissues to ensure a negative surgical
margin. Radiotherapy can be delivered using external beam or by brachytherapy
25
(implantation of radioactive seeds). Unfortunately, all treatments are potentially
associated with side effects. After surgery, erectile dysfunction rates are
reported to be between 29-100% though using improved nerve-sparing
techniques (69), this number more recently has been reported to be between 3186 (70). Stress urinary incontinence, the other long term concern with surgery, is
reported to be 14-31%(71) but lack of standardization in reporting makes this
somewhat difficult to interpret. The rate of men undergoing surgical procedure
post-prostatectomy for incontinence is around 5-6%(72).
With external beam radiotherapy (EBRT), erectile dysfunction rates are similar
to surgery with potential toxicity (≥grade 2) in the urinary tract (15.9%) and
bowel (11%)(73). Improved targeting techniques, such as intensity modulated
radiation therapy (IMRT), may decrease toxicity in surrounding organs but this
needs to be balanced against increased toxicity from dose escalation(74). In
addition, increased risk of developing secondary malignancies in the bladder and
rectum, has been seen following both external beam and brachytherapy
radiotherapy(75, 76). Brachytherapy involves careful selection of patients, with
consideration of prostate volume size and anatomical configuration of pubic
arch, do to greater risk short-term urinary obstruction (1.5-22%)(77). Longterm toxicity suggest possibility of lower erectile dysfunction rates (16%), with
chronic urinary (33.8%) and bowel (21%) problems also existing(78).
With the uptake of PSA screening, it is estimated that 81% of men with prostate
cancers now diagnosed have localized disease(10). However, the evidence from
the screening studies suggest that many men need to be diagnosed and treated
to prevent one death from prostate cancer. Thus many men are being exposed to
complications from biopsy (overdiagnosis) and treatment (overtreatment) with
significant ramifications on their quality of life. To minimize the harms of
overtreatment, the management of men with low-risk prostate cancer with
active surveillance was proposed. This involves the monitoring of men diagnosed
with low-risk prostate cancer with the intent to intervene radically if their
disease is found to worsen.
26
CHAPTER 2: ACTIVE SURVEILLANCE FOR PROSTATE CANCER
In this chapter, how active surveillance is currently conducted across different
institutions is summarized and the thesis research hypotheses and aims
presented.
Definition
Active surveillance (AS) involves the monitoring of men diagnosed with low-risk
prostate cancer with the intent to intervene radically if their disease is found to
worsen. By using AS, clinicians aim to minimize the harms associated with
overtreatment of men with indolent disease but still catch men with more
aggressive disease within the window of curability.
Eligibility and Inclusion criteria
The foundation for AS eligibility criteria is derived from work done by
Stamey(79) that was refined by Epstein(80). These studies examined men who
had radical prostatectomy and identified a subset of patients with potentially
biologically insignificant tumor. Stamey first provided evidence that tumors
<0.5ml, which formed 80% of his series, were unlikely to reach clinically
significant size. Epstein then showed that serum PSA level, PSA density, and
needle biopsy pathologic findings were accurate predictors of tumor extent(80).
When the literature is examined to see how AS is conducted globally, a variety of
eligibility criteria are found. As shown in Table 2-1, different institutions use
variations on the initial set of criteria proposed. It is also interesting to see how
these criteria are evolving. Dr Klotz and colleagues initially accepted (19951999) older men >70 years with PSA up to 15ng/ml, and Gleason scores
≤3+4(81) but since 2000, restricted inclusion to PSA <10ng/ml and Gleason sum
27
≤3+3. More recently, there have been publications suggesting that men with
Gleason score 3+4 can be followed on AS, though follow-up is still short (82, 83).
Most centres do not have an age cut off for AS, though consideration of comorbidities and life expectancy is essential when considering management of
any man with prostate cancer.
Table 2-1: Published eligibility criteria for active surveillance.
Institution
Clinical PSA
PSA
Biopsy
No. of
% of
stage
density
Gleason
positive
single
(ng/ml/
score
cores
core
(ng/ml)
ml)
Royal
≤T2a
≤15
-
≤3+4
-
-
≤T2a
≤10
-
≤3+3
-
-
PRIAS (86)
≤T2a
≤10
<0.20
≤3+3
2
-
MSKCC (87)
≤T2a
≤10
-
≤3+3
≤3
 50%
≤T2a
≤10
≤3+3
2
 20%
≤T2a
≤10
≤3+3
≤1/3 of
 50%
Marsden(84)
Sunnybrook
Hospital (85)
and PMCC
(88)
University of
Miami (89)
UCSF (90, 91)
-
total
John Hopkins
≤T2a
-
≤0.15
≤3+3
2
 50%
(91)
PRIAS: Prostate Cancer Research International: Active Surveillance originating from the
European Randomized study of Screening Prostate Cancer.
MSKCC: Memorial Sloan Kettering Cancer Center, New York.
PMCC: Princess Margaret Cancer Center, Toronto.
UCSF: University of California San Francisco.
28
The role of biopsy
As Gleason grade remains on the best predictors of prognosis for men with
prostate cancer, repeated transrectal ultrasound guided prostate biopsy
(TRUSPB) currently forms the foundation for monitoring men on AS.
There is consensus that the initial biopsy, also called the baseline or diagnostic
biopsy, should consist of a standard extended template of 10-12 cores with
laterally directed biopsies(92). With this template, the risk of clinical undergrading is estimated to be 20-30%(93), and thus men could be enrolled into AS
with more extensive disease than initially thought. To minimize this risk, some
centres recommend an immediate or early re-biopsy, the confirmatory biopsy,
before allowing patients to commence AS. Adamy and colleagues proposed the
confirmatory biopsy after finding that by performing re-biopsy within 3 months,
up to 35% of men may no longer be suitable candidates for AS(87).
The frequency of serial prostate biopsy varies between institutions. John
Hopkins requires patients to have yearly biopsies (91) whereas most others
have described repeating the biopsy at 2-3 year intervals(85, 94). With multiple
prostate biopsies, changes in histology are found. It is thought these changes
represent a combination of both tissue under-sampling and disease progression
(95). Currently, we are unable to differentiate between the two. Changes in
prostate cancer grade on serial biopsy have been described, with the risk of
grade progression being 22-30% with each biopsy round (96). The majority of
upgrading found was Gleason 3+4 disease.
The role of prostate specific antigen
Regular monitoring of prostate specific antigen (PSA) with digital rectal
examination (DRE) forms the other foundation of AS. Most series describe DRE
and PSA testing every 3 months, but this is an arbitrary time interval. Increase in
absolute PSA above 10ng/ml, the threshold for AS eligibility, is currently used to
29
trigger further investigation with biopsy, or magnetic resonance imaging (MRI),
rather than directly triggering progression to treatment(87).
The evidence for use of PSA kinetics during AS to predict disease progression
remains controversial. PSA doubling time (PSA DT), the period of time it takes
for PSA to double in value, was suggested by the Toronto group as a trigger to
recommend treatment(85). They suggested a PSA DT <3 years cut-point for
triggering treatment, and this was calculated using a general linear mixed model
with at least eight PSA values, to account for PSA fluctuations between
measurements. When considering 5 prostate cancer specific deaths in their
Toronto cohort, it was noted all had a rapid PSA DT of < 1.6 years(97). However,
other institutions have been unable to show a correlation between PSA DT(98),
or PSA velocity(99), and adverse pathology at biopsy or radical prostatectomy.
Research problem and hypotheses
The primary aim of this thesis was to examine the ability of various published AS
eligibility criteria to select men with insignificant tumours and avoid including
men with more aggressive disease. Secondary objectives were to explore
potential differences between centres in our collaborative data pool, and to
create a predictive model for indolent and/or high-risk disease from the dataset.
The hypotheses of this thesis are as follows:
1. Criteria with increased stringency in selecting men for AS will reduce the
amount of upgrading and upstaging found at radical prostatectomy.
2. Active surveillance eligibility criteria may not be appropriate for all
populations of men, particularly those different to the original population
where the standards were derived from.
30
Justification and clinical impact of the research
This thesis addresses the need for continued refinement in the manner of which
men are selected for AS. The decision to embark on AS or have radical therapy is
a large fork in the treatment road for patients with prostate cancer, and worthy
of further investigation. Results from this investigation will be readily
generalizable and immediately applicable for many clinicians and their patients.
31
CHAPTER 3: PATIENTS AND METHODS
Thesis overview:
In this chapter, an overview including the data sources utilized, patient
identification and selection, and statistical methods will be presented. More
specific details of methods pertaining to each manuscript will be described in the
respective dedicated chapters.
For this thesis, two published manuscripts are included (Appendix B):
1. Assessment of the suitability of the National Institute for Health and
Clinical Excellence (NICE) guidelines for men with low risk prostate
cancer using a single institution database(100).
2. A study examining the effect of different AS eligibility criteria on different
populations of men, who were suitable for AS but underwent upfront
radical prostatectomy, utilizing a multi-institution database(68).
Data sources and variables:
The data sources utilized for this thesis are summarized in Table 3-1. For
Chapter 4, the radical prostatectomy database from Addenbrookes Hospital,
Cambridge, United Kingdom was analyzed. This data was prospectively collected
from initiation of the robotic assisted laparoscopic radical prostatectomy
program at Addenbrookes Hospital (2005-2010).
Table 3-1: Data sources used in the thesis
Chapter 3
Chapter 4
Data type:
Dates and Description
Radical prostatectomy
Addenbrookes Hospital Cambridge,
database
United Kingdom (2005-2010).
Radical prostatectomy
Collaboration between urology
database
departments:
32
a) Addenbrookes Hospital
Cambridge, United Kingdom
(2005-2010),
b) The Royal Melbourne Hospital,
Melbourne, Australia (20032010); and
c) The Vancouver Prostate
Centre, Vancouver, Canada
(1995-2010).
Men who had radical prostatectomy.
Data includes: pre-operative clinicopathological variables, surgical
margin status, and pathology from
final specimen.
For Chapter 5, collaboration between urology departments in Addenbrookes
Hospital (AH), Cambridge, United Kingdom; The Royal Melbourne Hospital
(RMH), Melbourne, Australia; and The Vancouver Prostate Centre (VPC),
Vancouver, Canada was formed. The RMH database (2003-2010) was
prospectively collected whereas the VPC database (1995-2010) was
predominantly retrospectively compiled. All 3 databases contained data on
radical prostatectomy and were pooled for analysis.
A summary list of all variables used in the thesis is provided in Appendix A.
Baseline variables are those present at time of diagnosis of prostate cancer.
These include age, year of diagnosis, family history of prostate cancer, DRE
findings, serum PSA, TRUS prostate findings (prostate volume, presence of
hypoechoic lesions, total number of cores taken), pathology from needle prostate
biopsy (number of positive cores involved, Gleason score, maximum percentage
of a single core involved, and location within prostate of where positive core(s)
33
were found). From radical prostatectomy, variables of interest were date of
surgery, positive margin status and final pathology (Gleason score, pT-stage, and
lymph node status).
Identification of study patients:
From the Addenbrookes Hospital database, in chapter 4, patients satisfying
National Institute for Health and Clinical Excellence (NICE) criteria for low risk
disease (PSA<10 and Gleason score ≤ 6 and cT1-2a) were identified.
In chapter 5, from the collaborative radical prostatectomy dataset, subsets of
patients with pre-operative parameters satisfying suitability for active
surveillance, as defined by Sunnybrook Toronto, and European Prostate Cancer
Research International: Active Surveillance (PRIAS) eligibility criteria (Table 21), were identified. The Sunnybrook criteria consist of PSA <10 ng/ml, clinical
stage ≤T2a and biopsy Gleason score ≤3+3. PRIAS criteria are more stringent and
in addition to the 3 features used by Sunnybrook, also require a PSA density of
<0.20 ng/ml/ml, and ≤ 2 positive cores of cancer.
Outcomes measured in the thesis:
For both chapter 4 and 5, the primary outcome was to examine the frequency of
men who were thought to have disease suitable for active surveillance, but in
fact were found to have more aggressive disease at radical prostatectomy.
Aggressive disease was defined as increase in Gleason grade (upgrading,
increase in Gleason score from 6 to ≥7) and or increase in T-stage (extraprostatic spread, ≥pT3).
In Chapter 5, using a larger data set, the effect of two different published AS
eligibility criteria on both upgrading and upstaging was examined. Furthermore,
comparison of data between the different institutions was possible. A secondary
aim of this project was to analyze our data to identify predictors of indolent
and/or high risk disease, and create a predictive model to assist with selection of
men suitable for AS.
34
Statistical methods used in the thesis:
For comparison between different groups, continuous variables were assessed
using ANOVA or the Student’s t-test (parametric data), Wilcox Mann-Whitney or
Kruskal-Wallis tests (non-parametric data); and chi-squared or Fisher's exact
tests used to determine differences between groups of categorical variables.
Univariate and multivariate analysis was performed using logistical regression.
Multivariate models were built with important clinico-pathological variables and
forward stepwise regression was used. Collinearity was assessed between
similar variables (e.g. PSA, prostate volume and PSA density). The number of
covariables for the multivariable model was carefully selected to avoid overfitting(101). Statistical analyses were performed using SPSS version 18.0 (IBM
Corporation, Armonk, NY, USA). All statistical tests were two sided with p<0.05
considered to be statistically significant.
Ethics statement:
For this thesis data was collaborated between 3 institutions. Ethics approval in
all three centres was obtained for data collection and covered retrospective
analysis of collected clinical information. With data sharing, patients’ personal
health information was de-identified. Records were kept in secure, password
encrypted electronic files.
35
CHAPTER 4: General application of the N.I.C.E. guidance for
active surveillance (AS) for men with prostate cancer is not
appropriate in unscreened populations
Summary:
Purpose:
To determine if National Institute for Health and Clinical Excellence (NICE)
guidelines for men with low risk prostate cancer (PCa) were generally applicable
in unscreened populations.
Patients and Methods:
Retrospective analysis of prospectively collected case series from a single
tertiary care centre in England. 700 consecutive men treated for prostate cancer
from 2005 by means of robotic assisted laparoscopic prostatectomy (RALP).
Patients satisfying NICE criteria for low risk disease (PSA<10 and Gleason score
≤ 6 and cT1-2a) had their pathological samples analyzed for advanced disease,
defined as extra capsular extension (ECE: pT3), seminal vesicle involvement
(SVI), Gleason sum 7, or 8-10 or node positive disease.
Results:
A total of 275 patients (n=275/700, 39.2%) met the NICE low risk criteria, but
pathologically advanced disease was found in 37.2% (n=102/275) of this group.
Seventy-one had ECE (25.8%), 10 had SVI (3.6%), 9 (3.3%) had Gleason score 7
(4+3), 12 had Gleason sum 8-10 (4.4%).
Conclusions:
The NICE guidance was developed largely on data from North America where
populations are highly screened using PSA testing. In the UK, many men with low
risk disease have undiagnosed high-risk disease and the general applicability of
the NICE guidance is questionable in unscreened populations.
36
We recommend that radical therapy be discussed concurrently with AS for men
in the UK with NICE low-risk criteria.
Introduction:
In February 2008, the National Institute for Health and Clinical Excellence (NICE)
guidelines for prostate cancer (PCa) were issued(102). A key recommendation
was that “men with low-risk localised prostate cancer (103) who are considered
suitable for radical treatment should first be offered active surveillance”.
Because there was concern that men in the UK might have more advanced
disease and because the wording might have implied that men should be advised
only to have active surveillance, subsequent clarification in May 2009 was
agreed with NICE and the British Association of Urological Surgeons (BAUS).
This clarification
(http://www.nice.org.uk/nicemedia/live/11924/44396/44396.pdf) noted that
all treatment options should be discussed with men with low risk PCa.
Recent data from the European Randomized Trials of Screening for prostate
cancer (ERSPC) (104) and the Goteberg Screening Study(105), have shown
clearly that screening using PSA testing decreased mortality from PCa, but that
there is considerable over-diagnosis and risks of over-treatment (106, 107).
Also it is clear that the likely benefit of radical treatment for PCa will be seen
only after 10 to 15 years due to the long natural history of most cases of PCa
(108, 109). More elderly men with co-morbidity, and with low volume Gleason
grade 6 disease, are at low risk of developing future problems from PCa. Various
methods of attempting to define “low risk” PCa have been developed. The
D’Amico method has the merit of being easy to apply and categorises men into
low, intermediate and high risk disease(110).
Because of these issues, more conservative approaches have been developed to
try to avoid unnecessary radical treatments whilst maintaining the patient
within a window of curability if subsequent treatment is required. Active
surveillance (AS) involves careful follow-up with PSA testing and forms one of
37
the arms of the ProtecT Trial(111, 112); AS (113-115) also involves additional
biopsies that are performed at subsequent time-points after diagnosis. The
rationale of performing additional biopsies is two-fold. Firstly, the initial biopsy
may miss areas of higher grade disease or may under-call the amount of cancer
present; secondly the tumour will eventually grow or may become less well
differentiated over time. Outcomes from AS studies have reported low PCa
mortality, but within 3 to 5 years about 30% of men have selected more radical
treatments. Furthermore, study cohorts have been small and mainly reported
from countries with high levels of underlying opportunistic PSA testing, or from
centres with high levels of private practice, where similar issues are likely to be
relevant.
Most research on active surveillance for PCa comes from PSA-screened
populations. In Britain, the rate of opportunistic PSA testing is 6%, and is rather
low in comparison (116, 117). It has been well demonstrated that repeated
rounds of screening or PSA testing results in stage migration (118, 119). We
hypothesised that in the UK where underlying rates of PSA testing are low, a high
proportion of men with “low risk” disease, will actually have features of
aggressive PCa and may not be suitable for active surveillance.
Patients and Methods:
We retrospectively analysed prospectively collected data on 700 consecutive
men treated for prostate cancer from 2005-2010 by means of robotic assisted
laparoscopic radical prostatectomy (RALP). PSA level was measured and clinical
stage assigned by the attending urologist according to the 2002 TNM staging
system. All patients had their biopsy and RALP specimens evaluated at our
institution by genitourinary pathologists according to protocols from the Royal
College of Pathologists.
Patients satisfying NICE criteria (Table 4-1) for low risk disease (PSA<10 and
Gleason score ≤ 6 and cT1-2a) where divided into those with favourable and
unfavourable final histopathology. The unfavourable histopathology subgroup
38
was defined as those with specimens with features of more advanced disease,
defined as extra capsular extension (ECE), seminal vesicle involvement (SVI),
Gleason sum 7 (4+3), Gleason sum 8-10 and node positive disease. We then used
the Student’s t-test and the Wilcox-Mann-Whitney test to compare these two
groups. Regression models were fitted to determine any independent variables
predicting unfavourable histopathology. We tested the regression models for
homogeneity of variance and normality using the Bartlett modification of the
Neyman-Pearson likelihood ratio test. Analyses were performed with SAS®
Visual Data Discovery (SAS Institute, Cary, NC).
Patients gave informed consent and the study had ethics approval from the
hospital ethics committee.
Table 4-1: NICE risk groups for localized prostate cancer
Risk stratification for men
with localised prostate
cancer.
Low risk
Intermediate risk
High risk
PSA
Gleason score
Clinical stage
< 10 ng/ml
and
≤6
and
T1-T2a
10–20 ng/ml
or
7
or
T2b-T2c
> 20 ng/ml
or
8-10
or
T3-T4
Results:
Of the total cohort, 39.2% (n=275/700) qualified as NICE low risk. The
preoperative parameters for this group are shown in Table 4-2. The median age
was 61 years (range 39-73 years), median PSA was 6.39ng/ml (0.5-9.9ng/ml)
with 78.2% having cT1 disease.
39
Table 4-2: Pre-operative characteristics of patients satisfying NICE low risk criteria.
Low risk
Total (n, %)
275 (275/700, 39.2%)
Age, years. (median, range)
61 (39-73)
PSA ng/ml (median)
6.39 (0.5 – 9.9)
Clinical stage
cT1a+b
4 (1.5%)
cT1c
211 (76.7%)
cT2a
60 (21.8%)
cT2b-3
0
The number of men with unfavourable histopathology (n=84/275, 30.6%) at
analysis of the prostatectomy specimen is shown in Table 4-3. Within this group,
71 men had extra-prostatic extension, 10 had seminal vesicle invasion and 21
had Gleason sum ≥ 7.
Table 4-3: Frequency of unfavourable histopathology subgroup within NICE low
risk group, on analysis of the prostatectomy specimen.
% (n)
Extra-prostatic extension
25.8% (71/275)
Seminal vesicle invasion
3.6% (10/275)
Gleason sum 4+3=7
3.3%; (9/275)
Gleason sum 8-10
4.4%; (12/275)
Lymph node positive disease
0%
40
In this low risk group, a comparison of pre-operative clinical and pathological
factors between favourable and unfavourable pathology at radical prostatectomy
was made. Significant differences between the groups are shown in Table 4-4.
Table 4-4: Comparison between groups with favourable and unfavourable final
histology.
Favourable
(n=191)
Unfavourable*
(n=84)
p-value
Age (years)
61 (39 -71)
62 (48-73)
P=0.04
PSA Density
0.116
0.143
P=0.01
% of total cores
with tumour
22%
34%
P<0.01
* extra capsular extension (ECE) OR seminal vesicle involvement (SVI) OR
Gleason sum 7(4+3) OR Gleason sum 8-10 OR node positive disease.
Discussion
This series comprises, for the British population, one of the largest radical
prostatectomy series examining pathological results and evaluating for preoperative predictors to guide management of PCa. Our results demonstrate that
approximately one third (30.6%) of patients identified as “low risk PCa” preoperatively, as defined by NICE, have features of more advanced disease. Thus,
the initial NICE guidance on AS for low risk PCa patients was confusing. By
stating “men with low-risk localised PCa who are considered suitable for radical
treatment should first be offered AS” a significant proportion of patients would
be undertreated. It is of interest to note, for a disease so prevalent in Britain,
(34,986 new cases a year in England and Wales)(120), most of the research used
to formulate the national guidelines was derived from overseas data. Decision
making tools derived from local populations would conceivably be more
accurate and assist with formulation of national guidelines.
41
Active surveillance has emerged as a method to manage the increasing incidence
of small localised, well-differentiated tumours found due to the stage migration
effect caused by screening. In a country where the underlying rate of
opportunistic PSA testing is only 6%, this must be taken into consideration. Our
results also highlight the fact that current sextant biopsy diagnosis is not
accurate in reflecting the true nature of PCa found on final pathology. The
combination of these two points suggests AS in the British population should be
approached with careful counselling.
AS protocols consider features such as number of cores involved with cancer
(≤2) and proportion of the core involved (<50% of any one core, <10mm of any
core) in addition to D’amico low risk group. With many of these variables being
continuous, nomograms such as Kattan’s(121) have been formulated to define
risk of progression whilst on AS for the individual. Our results support
consideration of age, PSA density, and percentage of total cores involved with
cancer, when discussing AS as a management option with the patient. The
ProtecT trial is comparing another conservative approach (Active Monitoring –
AM) in a randomised trial with surgery and radiotherapy. Data are derived from
cohort studies with the longest median follow-up being 8 years(85).
Limitations of our study include selection of a surgical cohort rather than all
newly diagnosed patients with PCa. The D'Amico risk group classification was
originally developed to estimate the risk of biochemical recurrence following
treatment for localized PCa. However, as NICE have applied this classification to
guide selection of men for AS, we have used it to select the correspondingly
defined specimens for features of advanced disease. The patients all derive from
a single tertiary centre, however, as the hospital serves a significant region of
England, we believe the data a good representation of the English population.
Conclusions:
In our radical prostatectomy cohort, 30.6% of men with low risk prostate cancer
at diagnosis actually had features of more advanced disease. Age, PSA density
and the number of cores involved are useful markers for aggressive disease.
42
These findings should be incorporated into discussions with men in the UK about
potential management options. We confirm that radical therapy should be
discussed as an alternative option to active surveillance from the outset for such
men. Lessons should be learnt from applying results from heavily screened
populations to the UK setting where PSA testing remains uncommon.
Disclosures:
DE Neal is one of the principal investigators for the ProtecT study, which is
funded by the National Institute for Health Research Health Technology
Assessment Programme (projects 96/20/06, 96/20/99), and the CAP study
(comparison arm of ProtecT study), which is funded by Cancer Research UK.
A.Y. Warren is an uropathologist member of the ProtecT study pathology group.
There were no conflicts of interest. There were no sources of funding for this
study. All authors had full access to the data and accept responsibility for the
integrity of the data and accuracy of the data analysis.
Acknowledgements:
Thank you to Dr Karan Wadhwa for assistance with data entry. We are grateful
to study volunteers for their participation and to staff at the Welcome Trust
Clinical Research Facility, Addenbrooke's Clinical Research Centre, Cambridge
for their help in conducting the study. We also acknowledge the support of the
NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant) and
the NCRI / MRC (ProMPT grant) for help with the bio-repository.
43
CHAPTER 5: An International multi-centre study examining
selection criteria for active surveillance in men undergoing
radical prostatectomy
Summary:
Purpose:
To examine, for men who were initially suitable for active surveillance (AS),
according to Sunnybrook Toronto and European Prostate Cancer Research
International: Active Surveillance (PRIAS) criteria, that underwent radical
prostatectomy:
1. the proportion of pathological re-classification(Gleason score ≥7, ≥pT3
disease),
2. predictors of high risk disease,
3. create a predictive model to assist with selection of men suitable for AS.
Patients and Methods:
From three centers in UK, Canada and Australia, data on men who underwent
radical prostatectomy was retrospectively reviewed (n=2329).
Multivariable logistic regression was performed to identify predictors of highrisk disease. A predictive model was generated by logistic regression analysis,
and performance characterized by ROC curves.
Results:
For men suitable for AS according to Sunnybrook Toronto (n=800) and PRIAS
(410) criteria, the rates for upgrading were 50.6%, 42.7%, and upstaging 17.6%,
12.4% respectively.
Significant predictors of high-risk disease were:
-
Sunnybrook Toronto criteria: increasing age, cT2 disease, centre of
diagnosis and number of positive cores
-
PRIAS criteria: increasing PSA and cT2 disease
Cambridge had a high pT3a rate (26% vs. 12%). To assist selection of men in the
UK for AS, from the Cambridge data, we generated a nomogram predicting high-
44
risk features in patients who meet the Sunnybrook Toronto criteria (AUC of
0.72).
Conclusions:
The proportion of pathological re-classification in our cohort was higher than
previously reported. Care must be used when applying AS criteria generated
from one population to another. With more stringent selection criteria, there is
less reclassification but also fewer men who may benefit from AS.
45
Introduction:
Treatment paradigms for small-volume, low-grade prostate cancer (PCa) are
currently moving away from radical treatments. The controversial US
preventative task force report (122) giving PSA screening a “D” rating, was
prompted by review of results from the Prostate, Lung, Colorectal, and Ovarian
(PLCO) Cancer Screening Trial (48) and European Randomized Study of
Screening for Prostate Cancer (ERSPC) (49) trial. These trials highlighted the
issues of over-diagnosis and over-treatment in the management of many men
with prostate cancer. In follow-up of over 3,500 patients across 7 active
surveillance (AS) case series, the cancer-specific survival for the cohort is 99.7%
(123), though median follow-up remains relatively short (2-7years). Active
surveillance has emerged as a safe management option and should be offered to
patients with low risk cancer (124, 125).
There are many different inclusion criteria for AS published in the literature
(Table 2-1). Whilst all are variations on the model developed by Epstein (80), the
discrepancies between them reflect the uncertainty in appropriate cut-offs to
distinguish indolent from high risk cancer. In addition, regional differences in the
underlying prevalence of PSA testing in the community alters the pre-test
probability for high-risk disease in defined ‘low-risk’ cohorts (126), which
potentially interferes with the performance of selection rules when applied to
populations distinct from which they were generated.
In our study, we examine application of AS selection rules to a combined
Australian, British and Canadian group of patients who underwent radical
prostatectomy. Our primary objective was to document the proportion of
pathological re-classification from prostate biopsy to radical prostatectomy.
Secondary aims included analysis for predictors of high-risk disease and creation
of a predictive model to assist with selection of men suitable for AS.
46
Patients and Methods:
Pooled data from Addenbrooke’s Hospital, Cambridge, United Kingdom (20052010); The Vancouver Prostate Centre, Canada (1995-2010); and the Australian
Prostate Cancer Centre@Epworth, Melbourne, Australia (2003-2010) were
retrospectively analysed. All patients had their radical prostatectomy (RP)
specimens discussed at centralised multidisciplinary meetings and evaluated by
dedicated genitourinary pathologists. Cambridge and Vancouver had routine
centralised review of biopsies. Ethics approval in all three centres covers the use
of collected clinical information for prognostic studies.
A summary of the literature review for published inclusion criteria used for AS is
shown in Table 2-1 (87, 89, 90, 127-130). In selecting which AS criteria to apply
to our series, we used the Sunnybrook Toronto criteria, described by Klotz et al
(128) in the first protocol-based AS prospective study, and those published from
the Prostate Cancer Research International: Active Surveillance (PRIAS)
originating from the ERSPC (86). Our cohort did not contain data for the amount
of cancer present in a biopsy core (length or percentage) as only Cambridge
consistently recorded this in their database so the PRIAS criteria were the
strictest applicable to our dataset.
Patients treated by means of RP who had pre-operative parameters appropriate
for inclusion for AS per these criteria, had final pathology analyzed for reclassification rates of upstaging, defined as ≥pT3, or upgrading, defined as
Gleason sum 7-10. Gleason 7 disease was subdivided into 3+4 and 4+3 groups.
High-risk disease was defined as ≥pT3 and/or Gleason sum ≥ 8. CAPRA-S scores,
a validated postsurgical score to predict prostate cancer recurrence using pretreatment and pathological data, for risk stratification were also calculated
(131). Lymph node involvement was not analyzed as across all centres, there
was no consistent policy regarding the performance of a pelvic lymph node
dissection in patients with low risk disease, and hence data collection was poor.
Differences between groups of continuous variables were determined by MannWhitney U or Kruskal-Wallis ANOVA tests. Pearson’s Chi-squared or Fisher’s
47
exact test was used to determine differences between groups of categorical
variables. To identify predictors of high-risk disease in patients selected for AS,
logistic regression models were fitted including parameters age, PSA, PSAD,
clinical stage, number of biopsy cores taken, number of positive biopsy cores and
centre of treatment as individual terms. Statistical analyses were performed
using SPSS version 18.0, IBM Corporation, New York USA), and all tests were
two-sided with significance assumed a p<0.05 unless otherwise stated.
To generate a clinically usable tool that predicted the presence of high-risk
disease in the Cambridge cohort that met the Sunnybrook Toronto criteria, all
factors found to be significant in multi-variate analysis were considered and the
most parsimonious model generated from these. Patients were randomly
assigned 70:30 to a learning and evaluation cohort. Logistic regression analysis
was then performed using all available potential predictors of high-risk disease
in the learning cohort, and a nomogram of the resulting equation generated
using Orange (http://orange.biolab.si. V2.0b, accessed Aug 5 2011). The
discriminative ability of our nomogram to predict high-risk disease was
characterised by generating receiver-operating characteristic (ROC) curves
based on the predicted probabilities of the evaluation cohort. The area under the
ROC curve (AUC) indicates the model’s ability to predict the outcome of interest
(i.e. high-risk prostate cancer). Most models predict with 70-80% accuracy,
which indicates correct predictions in 7 or 8 out of 10 cases. A Loess calibration
plot was used to assess the performance of our model across the entire range of
predicted values, as a tool may have excellent overall accuracy but may not
perform well in a specific range of predicted probabilities. A two component
(calibration and AUC calculation) decomposition Brier score was calculated, with
a lower Brier score indicating better discriminant properties (132).
Results:
Of the 2329 patients that had RP, 800 patients met the Sunnybrook Toronto
criteria for AS, and this number was reduced to 410 patients when the stricter
48
PRIAS criteria were applied. The pre-operative characteristics for these 2 groups
are shown, overall and by treatment centre, in Tables 5-1a and 5-1b.
Table 5-1: Patient baseline characteristics – men who underwent upfront radical
prostatectomy but were suitable for active surveillance
a) Pre-operative characteristics for patients suitable for AS according to
Sunnybrook Toronto criteria – by centre
Cambridg
Melbourn
Vancouve
Total
e
e
r
Years of data
1995-2010
2005-2010
N (total RP)
2329
700
790
839
N (total AS)
800 (34.3%)
267 (40%)
187 (31%)
190 (32%)
61 (56.7-65)
61 (39-73)
60 (42-74)
61 (43-79)
6.4 (0.5-
5.5 (0.3-
5.5 (0.5-
5.8 (4.7-7.4)
10)
10)
10)
cT1
570 (71.3%)
206 (77%)
149 (80%)
109 (58%)
cT2a
230 (28.7%)
59 (23%)
38 (20%)
80 (42%)
0.1
0.108
0.114
0.11
PSA density*
(0.086-
(0.011-
(0.014-
(0.012-
Median (IQR)
0.151)
0.816)
0.315)
0.371)
10 (2-30)
12 (4-30)
11 (4-30)
8 (2-13)
2 (1-4)
2 (1-14)
3 (1-12)
2 (1-8)
2003-2010 1995-2010
Age (years)
Median (IQR)
PSA (ng/ml)
Median (IQR)
Clinical stage
Biopsy cores taken
Median (range)
Number of positive
cores
Median (IQR)
* not part of original Klotz criteria but reported for comparison to Van den
Bergh.
49
b) Pre-operative characteristics for patients suitable for AS according to PRIAS
criteria – by centre
N (total RP)
Cambridg
Melbourn
Vancouve
Total
e
e
r
2329
700
790
839
162
N (total AS)
410 (18%)
134 (19%) 114 (14%)
Age (years)
Median (IQR)
(19%)
62 (43-
60.5 (56.3-65)
PSA (ng/ml)
62 (45-70) 59 (48-73)
73)
6.3 (2.7-
5.6 (0.3-
5.4 (1.5-
5.6 (4.3-7)
10)
10)
0.4)
cT1
287 (70%)
109 (81%)
91 (80%)
87 (54%)
cT2a
123 (30%)
25 (19%)
23 (20%)
75 (46%)
PSA density*
0.1 (0.071-
0.99 (0.02-
0.1 (0.01-
0.1(0.01-
Median (IQR)
0.13)
0.19)
0.19)
0.2)
9 (2-24 - IQR)
12 (6-24)
10 (3-17)
8 (2-12)
1
1 (1-2)
2 (1-2)
2 (1-2)
Median (IQR)
Clinical stage
Biopsy cores taken
Median (range)
Number of positive
cores
Median (IQR)
The pathology results from radical prostatectomy, including proportions reclassified and final risk group, also divided by treatment centre, are shown in
Tables 5-2a and 5-2b.
50
Table 5-2: Pathological results from radical prostatectomy for patients suitable
active surveillance
a) Pathological results from radical prostatectomy for patients suitable for
Sunnybrook Toronto AS criteria.
Total
n
(Toronto)
Cambridge
Melbourne
Vancouver
800
280
248
272
p
Pathological GS
≤6
395 (47.8%)
157 (56%)
94 (38%)
144 (53%)
Upgrade
7
389 (48.6%)
117 (42%)
151 (61%)
121 (44%)
pT
Upstage
Margins
3+4
340 (87.4%)
108 (92%)
133 (88%)
99 (82%)
4+3
49 (12.6%)
9 (8%)
18 (12%)
22 (18%)
8-10
16 (2%)
6 (2%)
3 (1%)
7 (3%)
pT2
659 (82.4%)
205 (73%)
216 (87%)
238 (88%)
pT3/4
141 (17.6%)
75 (27%)
32 (13%)
34 (12%)
EPE
136 (17%)
73 (26%)
30 (12%)
32 (12%)
SVI
8 (1%)
2 (1%)
3 (1%)
3 (1%)
Negative
675 (84.4%)
239 (85%)
217 (88%)
219 (81%)
Positive
125 (15.6%)
41 (15%)
31 (12%)
53 (19%)
tumour
Median
5
5
3
10
(n=716)
Range
3-15
4-10
1.5-9
5-20
362 (45.3%)
135 (48%)
91 (37%)
136 (50%)
286 (35.8%)
65 (23%)
123 (50%)
98 (36%)
152 (19%)
80 (29%)
13 (13%)
38 (14%)
0-2
629 (78.6%)
208 (77.9%)
152 (82.3%)
143 (75.3%)
3-5
165 (20.6%)
58 (21.7%)
34 (18.2%)
44 (23.2%)
≥6
6 (0.8%)
1 (0.4%)
1 (0.5%)
3 (1.5%)
<0.001
0.049
<0.001
0.077
Percent
<0.001
Final Risk
Group*
Low
<0.001
Intermediate
High
CAPRA-S
0.42
51
b) Pathological results from radical prostatectomy for patients suitable for
PRIAS criteria.
Total
n
(PRIAS)
Cambridge
Melbourne
Vancouver
410
134
114
162
p
Pathological GS
≤6
235 (57.3%)
87 (65%)
53 (46%)
95 (58%)
Upgrade
7
166 (40.5%)
44 (33%)
59 (52%)
63 (39%)
3+4
138 (83.1%)
40 (91%)
52 (88%)
46 (73%)
4+3
28 (16.9%)
4 (9%)
7 (12%)
17 (27%)
8-10
9 (2.2%)
3 (2%)
2 (2%)
4 (3%)
pT
pT2
359 (87.6%)
115 (86%)
104 (91%)
140 (86%)
Upstage
pT3/4
51 (12.4%)
19 (14%)
10 (9%)
22 (14%)
EPE
48 (11.7%)
19 (14%)
9 (8%)
20 (12%)
SVI
4 (1%)
0 (0%)
1 (1%)
3 (2%)
Negative
364 (88.8%)
122 (91%)
103 (90%)
139 (86%)
Positive
46 (11.2%)
12 (9%)
11 (10%)
23 (14%)
tumour
Median
5
5
2
10
(n=367)
Range
2-10
0.2-80
0.3-37
1-70
219 (53.4%)
79 (59%)
52 (46%)
88 (54%)
mediate
133 (32.4%)
33 (25%)
51 (45%)
49 (30%)
High
53 (14.1%)
22 (16%)
11 (9%)
25 (16%)
0-2
346 (84.4%)
112 (89.6%)
76 (87%)
77 (79%)
3-5
60 (14.6%)
12 (9.6%)
10 (12%)
20 (20%)
≥6
4 (1%)
1 (0.8%)
1 (1%)
1 (1%)
Margins
0.005
0.023
0.43
0.27
0.3
Percent
<0.001
Final
Risk
Group*
Low
0.014
Inter-
CAPRA-S
0.2
* Risk group patterned on D’Amico system with pT and Gleason sum from radical
prostatectomy (instead of cT and biopsy Gleason sum)
52
Overall, for those satisfying Sunnybrook Toronto criteria, 50.6% were upgraded
to GS  7 and 17.6% upstaged to pT3/4. The reclassification rates for the PRIAS
group were 40.5% and 12.4% respectively. For both groups, the majority of GS
upgrading consisted of 3+4 disease (Sunnybrook Toronto=84%, PRIAS=79%). In
Cambridge, there was a relatively high rate of pT3a disease in the Sunnybrook
Toronto criteria group (26%), which decreased with PRIAS criteria (14%).
Melbourne had a relatively high rate of Gleason 7 disease in final pathology for
both Sunnybrook Toronto and PRIAS criteria groups (61% and 52%).
Given that study periods at different centres were different, to account for
changes in biopsy technique, pathological interpretation and treatment patterns
with time, we repeated the analysis in a restricted cohort (year ≥2003 and total
number of cores taken at biopsy ≥8) more reflective of contemporary practice.
Results of this sub-analysis for Sunnybrook Toronto and PRIAS inclusion criteria
are shown in Table 5-3 and were similar to the initial overall analysis with
similar proportions of GS upgrading (49.4% Sunnybrook Toronto, 41% PRIAS)
and pT3/4 upstaging (Sunnybrook Toronto 17.9% and PRIAS 11.3%).
Using standard reported clinico-pathological variables, we were unable to derive
a more accurate model that predicted indolent disease than the PRIAS criteria.
However, we were able to identify significant predictors for high-risk disease
(Table 5-4) by multivariate logistic regression analysis. For patients meeting the
Sunnybrook Toronto criteria, increasing age (OR 1.04, 1.01-1.07, p=0.02),
number of positive cores (OR 1.25, 1.14-1.37, p<0.001), the presence of palpable
disease (OR 1.54, 1.01-2.34, p=0.045) as well as the centre of diagnosis
(Cambridge versus Vancouver, OR 2.85, 1.68-4.84, p<0.001) were all significant
predictors of the presence of high-risk disease; whereas for patients meeting the
more stringent PRIAS criteria, only increasing PSA (OR 1.15, 1.01-1.31, p=0.043)
and the presence of palpable disease were significant (OR 1.85, 1.03-3.32,
p=0.04). Total number of cores taken was analyzed and not predictive.
53
Table 5-3: Data (combined 3 centres) restricted to year ≥2003 and number of cores
≥8.
Sunnybrook Toronto criteria
PRIAS
criteria
Years of data
2003-2010
2003-2010
N (total AS)
Age (years)
Median (IQR)
PSA (ng/ml)
Median (IQR)
Clinical stage
- cT1
644
310
61 (57-65)
61 (57-65)
0.55
5.8 (4.7-7.4)
5.6 (4.4-7.0)
0.018
467 (72.5%)
232 (74.8%)
177 (27.5%)
0.111 (0.082-0.147)
78 (25.2%)
0.098 (0.070.127)
10 (8-12)
10 (8-12)
2 (1-4)
1 (1-2)
0.48
0.8
- cT2a/cT2
PSA density*
Median (IQR)
Biopsy cores taken
- Median (range)
Number of positive cores
- Median (IQR)
p
0.45
<0.001
Centre (n, %)
-
Cambridge
267 (41.5%)
125 (40.3%)
-
Vancouver
190 (29%)
87 (28.1%)
-
Melbourne
187 (29%)
98 (31.6%)
Prostatectomy Gleason Score
-
≤6
311 (48.3%)
176 (56.8%)
-
7
318 (49.4%)
127 (41%)
3+4
273 (85.8%)
102 (80.3%)
4+3
45 (14.2%)
25 (19.7%)
-
8-10
15 (2.3%)
7 (2.2%)
-
pT2
529 (82.1%)
275 (88.7%)
-
pT3/4
115 (17.9%)
35 (11.3%)
-
No
533 (82.8%)
277 (89.4%)
-
Yes
111 (17.2%)
33 (10.6%)
-
No
637 (98.9%)
307 (99%)
-
Yes
7 (1.1%)
3 (1%)
0.24
pT
0.024
EPE
0.008
SVI
0.87
54
Table 5-4: Multivariable logistic regression for predictors of high-risk disease (*)
disease, for combined 3 centres, Sunnybrook Toronto and PRIAS selection criteria.
Toronto AS criteria
OR
95% CIs
PRIAS criteria
p
OR
95% CIs
Age
1.04 1.01- 1.07 0.02
1.02
0.97-1.07
0.47
PSA
1.08 0.98- 1.19 0.1
1.15
1.01-1.31
0.043
cT-stage
1.54 1.01-2.34
0.045
1.85
1.03-3.32
0.04
Total #Cores taken 0.94 0.88-1.01
0.085
0.95
0.87-1.04
0.25
# Positive cores
<0.001
0.91
0.51-1.61
0.75
1.25 1.14-1.37
p
Centre
Vancouver
1
1
Cambridge
2.85 1.68-4.84
<0.001
1.55
0.71-3.38
0.27
Melbourne
1.03 0.59-1.79
0.91
0.76
0.34-1.7
0.51
*high risk disease defined as: ≥ pT3 and/or Gleason sum ≥ 8
AS = active surveillance
CI = confidence interval
cT = clinical stage
PSA = prostate specific antigen
A number of subgroup analyses were undertaken to search for predictors of
more advanced disease. Examining for cancer present in a biopsy core
(percentage) as a predictor in only the Cambridge cohort did not yield a
significant result. Repeating multivariate logistic regression analyses limited by
year of surgery (≥2003) and number of biopsy cores taken (≥8) for high-risk
disease (≥pT3 or Gleason sum ≥ 8) or ≥pT3 alone, demonstrated similar
predictors to those found for the entire cohort. There were no significant
predictors of primary Gleason pattern 4 (as opposed to Gleason sum 8)
identified.
55
We were unable to generate a nomogram predicting high-risk disease from the
whole cohort data because of difficulties modelling sampling error. To account
for sampling error, we used an index of prostate size to number of cores taken
however this did not significantly improve the performance of the model. As the
rate of pT3a was high in the Cambridge data, we performed logistic regression
analysis to identify predictors of ≥pT3a/GS≥8 disease specifically for the
Cambridge cohort alone (Table 5-5) and were able to formulate a predictive
model from this. When only Cambridge data was analysed for the nomogram,
PSAD was more predictive than PSA. From this analysis, a nomogram (Figure 51) was generated that predicts individual risk of high-risk disease in UK men
who meet the Sunnybrook Toronto criteria, based on age, PSA density, number
of positive biopsy cores and the presence or absence of palpable disease. The
logistic regression equation for the nomogram is also included to facilitate future
validation studies.
56
Figure 5-1: Nomogram to predict individual probability of high-risk prostate
cancer in UK men who meet the Sunnybrook Toronto criteria.
Instructions for use:
For a patient, each criteria (age, PSAD, number of positive cores and cT stage)
translates to a number of points – read off the top line. The total number of points
then corresponds to a probability of finding high-risk PCa if RP is performed.
Logistic regression equation for nomogram. Log(p/1-p) = - 7.051 + 0.059( age in
years) + 0.537(PSAD in units of 0.1 ng/ml/cm3) + 0.996(cT) + 0.218 (number of
positive cores).
57
Table 5-5: Multivariable logistic regression for predictors of high-risk disease (*)
disease, for Cambridge cohort, Sunnybrook Toronto AS selection criteria.
OR
95% CIs
p
Age
1.06
1
1.13
0.049
PSA density
1.71
1.03
2.83
0.037
cT
2.71
1.2
6.12
0.017
Positive cores
1.24
1.06
1.46
0.008
Assessment of the nomogram using a receiver-operating curve (ROC) to predict
the presence of high-risk disease in a randomly selected evaluation cohort
revealed reasonable accuracy (AUC of 0.72) (Figure 5-2). A calibration plot,
comparing nomogram predicted probabilities to actual proportions of high-risk
disease is shown in Figure 5-3. This shows our nomogram underestimates the
observed probability of high-risk disease. The two-component (calibration and
AUC calculation) decomposition Brier score was 0.199. External validation for
the nomogram generated from the Cambridge data, using Melbourne and
Vancouver data, showed an AUC of 0.68 and 0.55 respectively.
58
Figure 5-2: Receiver operating curve (ROC) to assess performance of
nomogram predicting probability of high-risk prostate cancer in UK men
satisfying Sunnybrook Toronto AS criteria.
AUC = 0.72
Figure 5-3. Calibration plot, comparing nomogram predicted probabilities to
actual proportions of high-risk disease
59
Discussion
It is clear that published inclusion criteria for AS (Table 2-1) vary in their
stringency. The criteria at John Hopkins Medical Institute are the strictest but
some centres elsewhere have accepted Gleason 7 (usually 3+4), PSA levels up to
15ng/ml, and all clinical T2 disease. Furthermore, not all centres use PSAD
(0.15-0.20), number of positive cores (2, ≤3 or 1/3 of total) and percentage
(20-50%) of single core involvement to enrol patients. It has been
demonstrated previously (93, 133, 134) that increases in stringency can
decrease the rates of adverse pathological features but will also substantially
decrease the number of men suitable for AS. Until the ProtecT trial reports (111),
we will not know the criteria that predict the most important outcome of AS,
namely death from prostate cancer.
Our paper reports combined results from Australian, British and Canadian
academic centres. These results are compared to the American (UCSF, n=331,
(93)) and European (Milan and Hamburg, n=2,455 and Milan, n=85, (134, 135))
cohorts where Sunnybrook Toronto and PRIAS inclusion criteria were also used
to select patients from a RP database (Table 5-6). Applying the Sunnybrook
Toronto criteria, we found a higher than previously reported rate of Gleason
score upgrading (50.6%) compared to Conti et al 31% and Suardi et al 38.1%.
However, similar to previous reports, the majority of GS upgrading was 3+4
disease (84%) and this may not translate into a major clinical problem. The rate
of upstaging (EPE/SVI) when using the Sunnybrook Toronto criteria (17%) was
similar to previous reports in the literature (14-15%). Using the stricter PRIAS
criteria, there was less upstaging and upgrading found compared to Sunnybrook
Toronto criteria. However our reclassification rates were markedly higher
(upgrading 42.7%, upstaging 12.7%) compared to those previously reported by
the Milan group using the PRIAS criteria (upgrading 7.1%, upstaging 2.4%)(134).
60
Table 5-6: Comparison between centres for rates of upgrading/upstaging using
Sunnybrook Toronto and PRIAS inclusion criteria for AS.
AS
Our data
Comparison centres
criteria
UCSF
Milan + Hamburg
Conti et al (136)
Suardi et al (137)
Sunny-
N=800
N=331
N= 2455
brook
GS upgrade 7
GS upgrade  7 =
GS upgrade 7 =
Toronto
=50.6%
31%
38.1%
7 (3+4) = 42.5%
7 (3+4) = 33.2%
7 (4+3) = 6.1%
No GS breakdown
7 (4+3) = 4.2%
8-10 = 2%
available for review.
8-10 = 0.7%
Rate of EPE = 17%
Rate of EPE = 14%
Rate of EPE = 15%
Rate of SVI = 1%
Rate of SVI = 3%
Rate of SVI = 3.2%
PRIAS
Suardi et al
(Milan)(138)
N=410
GS upgrade 7 =
N=85
42.7%
GS upgrade 7 =
Rate of EPE =
7.1%
11.7%
Rate of EPE = 1.2%
Rate of SVI = 1%
Rate of SVI = 1.2%
AS = active surveillance
PRIAS = Prostate Cancer Research International: Active Surveillance
UCSF = University of California, San Francisco
GS = Gleason sum
EPE = extra-prostatic extension
SVI = seminal vesicle invasion
61
The results of our sub-analysis, by year (≤2003) and number of biopsy cores
taken (≥8), demonstrated similar predictors to those found for the entire cohort.
This was not surprising given that the two cohorts with high rates of upstaging
(Cambridge) and upgrading (Melbourne) were the most contemporary with
higher median number of cores taken (Table 5-1).
Individually, each of our 3 centres had a relatively high rate of GS upgrading
(Table 5-2, Cambridge 44%, Vancouver 47%, Melbourne 62%). Possible reasons
for GS changes include sampling error on biopsy, inter-observer pathology
variation between biopsy and RP reports and differing geographic population
patterns of disease. The number of biopsy cores taken for each centre was:
Cambridge (median=12, IQR10-12), Melbourne (median=10, IQR8-13) and
Vancouver (median=8, IQR8-8). The standard extended core template for
prostate biopsy consists of 10-12 cores so particularly in Vancouver, biopsy
under-sampling could affect our results. To minimise biopsy sampling error,
Adamy and colleagues suggest immediate confirmatory biopsy (< 3months)
before commencing AS (87). There is potential for inter-observer variation
between pathology reporting of biopsies and radical prostatectomy specimens in
Melbourne. Here, community pathologists report approximately 50% of biopsies,
whereas all RP specimens are read by two specialist uro-pathologists. The
clinical significance of the Gleason sum upgrading found, 84% was Gleason 3+4
disease, remains to be elucidated. Results for carefully selected men on AS with
intermediate risk disease (Gleason sum 7 or CAPRA score 3-5) have been
published suggesting that within limited follow-up (4years), outcomes were
similar to men with GS 3+3 disease (83).
Cambridge had a high proportion of EPE in its Sunnybrook Toronto criteria
group compared to the other two centres (26% vs. 12%, p<0.001). As pathology
for biopsy and RP is centrally reviewed in Cambridge, and an extended template
used for biopsy, this high rate of pT3a disease could also be attributable to a low
uptake of PSA testing in the UK. Melia et al (139) compared worldwide rates of
PSA testing in 2005 and allowing for lack of standardized data, found rates of
62
PSA testing in the UK considerably lower than elsewhere (Table 5-7). At a similar
period in time (year 2000) the rate of PSA testing in the UK was 5.4 tests per 100
men per annum, compared to the USA (38% of black men, 31% of white men),
Italy (26.9%), Australia (23% and Canada (47.5%)(140).
Table 5-7: Comparison world wide of rates of PSA testing (*)
England and Wales
2001-2002
In men aged 45-84yrs old tested in general
practice, where there was no previous
diagnosis of prostate cancer: 5.4 tests per
100 men per annum.
USA
1998
In Medicare records: 38% of black men and
31% of white men aged ≥ 65 years had a test
Italy, Milan
1999–2000
26.9% in men aged ≥ 40 years
Rotterdam
1997–2000
Defined by PSA ≥ 3 ng/mL followed by
biopsy, in 2.9 years, general population rate
33 per 1000 person years, control arm of
screening study 20% or 73 per 1000 person
years
Australia, Sydney.
1999
23% aged 40–70 years consulting their GP
for any condition reported having had a PSA
test
Canada (140)
2001-2
Almost half of Canadian men over the age of
50 years (47.5%; 95% CI=46.4-48.5)
reported receiving PSA screening during
their lifetime.
*modified from Melia J et al, 2005 (139).
The few previously published predictive tools for AS selection have focused on
calculating likelihood of indolent, low-volume/low-grade or insignificant
prostate cancer (141-145) rather than high-risk features. Nakanishi et al’s
nomogram, using a cohort of 258 men from Canada and the USA, is specific for
63
men with a single positive biopsy core and uses age, PSAD and tumour length in
a core to predict indolent cancer (142). Most would agree that having only a
single positive core is too stringent a criterion for a program of AS. Kattan et al ‘s
nomogram to predict small, moderately differentiated, confined tumours (144)
was validated and updated by Steyerberg and colleagues (143). However its
generalizability is questionable as its data is based on sextant biopsies with most
centres now performing 10-12 core biopsies. A nomogram generated from an
Australian cohort was published (145) and for multiple probability cut-offs
predicting indolent prostate cancer, they gave coexisting rates of high-risk
disease.
To our knowledge, there has not been a nomogram derived from British data to
assist with selection of patients for AS. From our Cambridge data, we generated a
nomogram that predicts presence of high-risk disease in patients who satisfy the
Sunnybrook Toronto entry criteria for AS. Overall assessment of the
performance of our nomogram was good (AUC 0.72 and two-component Brier
score 0.199). However the calibration plot (Fig 5-3) suggests that our nomogram
consistently underestimates the observed proportion of high-risk disease for
nearly all predicted values. Unsurprisingly, the nomogram performed poorer
when we used the Melbourne (AUC 0.68) and Vancouver (0.55) data to
externally validate it. There is evidence that risk calculators are best applied to
the population from which they are generated (Bhojani et al., 2009)(146). An
ideal nomogram would also include information on previous biopsies, family
history of significant CaP and results of MRI imaging, however this was not
present in our dataset. Given the low rate of PSA testing in the UK and the high
rate of upstaging in our Cambridge cohort, our nomogram would be a reasonable
tool for counselling UK patients in regards to AS.
Our study has limitations. Being retrospective, data collected was reliant on
individual centres’ protocols and they did not all include information on tumour
volume. The use of additional criteria such as length or percentage of a single
core involved might reduce the amount of re-classification, but would likely
reduce the number of patients to whom AS could be offered. Data on lymph node
64
status was lacking as lymph node dissection for low-risk disease was according
to surgeon preference and not consistently performed or recorded. Lack of
follow-up data for cancer recurrence or death is significant, as having
pathological features of advanced disease on biopsy does not necessarily
translate to poorer outcomes after surgery. Using a surgical cohort includes
unforeseen biases in patient selection not addressed in AS criteria such as age,
co-morbidities, family history, patient anxiety for intervention, findings on
imaging or institutional bias towards type of treatment. The median age of our
cohort (61 years) is younger than that reported by AS cohorts (65 years)(129,
147). Being a multicentre study, multiple pathologists reported biopsies and
specimens and the effect of inter-observer variation was not calculated. We also
accept that given our study spanned a broad period of time, interpretive changes
in pathological grading and clinical staging of prostate cancer did occur(148).
Multiple surgeons performed the surgery though positive margin rates were
similar.
Conclusions:
Our study examined the rates of re-classification of men from Australia, Britain
and Canada who underwent RP who initially would have been suitable for AS, as
defined by the Sunnybrook Toronto and PRIAS criteria. Compared to previously
reported cohorts from Europe and North America using the same AS selection
criteria, we found significantly higher rates of upgrading and upstaging.
Care must be used when applying AS criteria generated from one population to
another distinct population. There is an onus on larger centres in individual
countries to assess the performance of different criteria on their population
prior to implementation in routine AS programs and generate predictive tools
from their own datasets. Use of increasingly stringent selection criteria may
reduce re-classification but this must be balanced against the exclusion of a
significant number of men from AS who may benefit from such an approach.
65
The acceptability of AS protocols would best be evaluated by ongoing
prospective studies. The development of novel serum or tissue markers, and
improved imaging to predict disease progression would help remove any
uncertainties physicians and patients have with AS.
66
General Discussion:
Thesis summary:
The radical prostatectomy series reported in Chapter 4 was one of the largest
British cohorts reported at time of publication. The principal finding was 30.6%
of men defined as “low-risk prostate cancer” by NICE criteria had features of
more advanced disease at upfront radical prostatectomy. An earlier edition of
the NICE guidelines had suggested “men with low-risk localised prostate cancer
who are considered suitable for radical treatment should first be offered AS”.
This recommendation blurred the important distinction between definitions of
"low-risk" and "insignificant cancer". Whilst some features overlap (PSA <10,
cT1/cT2 and Gleason sum ≤6), the definition of "insignificant cancer" as
described by Epstein initially (80), also considers volume criteria such as PSA
density, millimeters of core involvement and number of positive cores.
The other key issue the manuscript raised was formulation of national guidelines
based on evidence from studies performed overseas. In the United Kingdom, the
uptake of PSA screening has been documented to be lower than countries such
as Canada, Australia and the USA (Table 5-6)(149). Thus when diagnosed with
prostate cancer, it is probable men in the UK have more advanced disease than
their counterparts in populations where screening is more prevalent.
In chapter 5, a collaboration of radical prostatectomy databases from 3 academic
centers in Cambridge, UK; Vancouver, Canada and Melbourne, Australia was
achieved. Once more, a cohort of men with clinical pathological features suitable
for active surveillance (AS) undergoing up-front radical prostatectomy was
examined. This time, eligibility criteria specified by AS cohorts in PRIAS and
Sunnybrook Toronto was investigated. By examining two different sets of
eligibility criteria, we demonstrated that the number of men considered suitable
for AS nearly halved (Sunnybrook Toronto, n=800; versus PRIAS, n=410) if the
more stringent criteria (PRIAS) was used. Differences in frequency of Gleason
67
score upgrading (42.7% versus 50.6%) and upstaging (12.4% versus 17.6%)
also reflected the stringency of inclusion criteria with less upgrading and
upstaging in the PRIAS criteria group. Thus, using more stringent AS criteria will
minimize the probability of missing aggressive disease. However, this comes at
the expense of excluding more men from AS, and exposing them to the morbidity
of radical treatment.
A benefit of the collaboration was we were able to further investigate the
hypothesis generated in chapter 4, that men in the UK, because of lower uptake
of PSA screening, have more advanced disease at diagnosis compared to other
countries. When assessing upgrading and upstaging in men suitable for AS using
the Sunnybrook Toronto criteria (Table 5-2a), the Cambridge cohort had
significantly more men with pT3/4 disease compared to the Melbourne and
Vancouver cohorts (27% vs 13% and 12% respectively, p<0.001). Most of this
upstaging consisted of extra-prostatic extension (pT3a) rather than seminal
vesicle invasion (pT3b). Interestingly, when the more stringent PRIAS criteria
were applied, the proportion of men from Cambridge with upstaging at radical
prostatectomy reduced and was similar to Melbourne and Vancouver (14%
versus 9% and 14%, p=0.43)(Table 5-2b).
In our multivariate analysis to examine for predictors of high-risk disease at
radical prostatectomy (defined as: ≥ pT3 and/or Gleason sum ≥ 8), for men
suitable for AS according to Toronto eligibility criteria, centre of diagnosis was a
significant variable. Men diagnosed with prostate cancer in Cambridge were 2.85
times more likely to have high-risk disease at radical prostatectomy than those
in Vancouver or Melbourne (OR 2.85, 95% C.I. 1.68-3.83, p<0.001)(Table 5-4).
Other statistically significant variables found included increasing age, PSA,
presence of cT2 disease, and number of positive cores.
With men in Cambridge being found to have to high rates of pT3a disease, a subanalysis using multivariable logistic regression in the Cambridge cohort alone
(Table 5-4b) was performed. We found increasing age, PSA density, clinical stage
and number of positive cores were all positive predictors of men having high-
68
risk disease in the Cambridge cohort. Based on this analysis, a graphical
nomogram (Figure 5-1), one of the first of its kind derived from a British
population, was generated to aid clinicians in the UK with counseling men
considering AS on their risk of harbouring high-risk disease. External validation
of our nomogram using the Melbourne and Vancouver sub-groups showed that
the nomogram did not perform as well in these populations (AUC 0.68 and 0.55)
compared to internal validation techniques (AUC 0.72). This may be related to
statistical methods of internal validation which tend to over-fit models and thus
over-estimate. However, the difference may be a real one as the populations used
for external validation were fundamentally different (due to different uptake of
screening) compared to the Cambridge one.
Thesis Limitations
A number of general limitations must be acknowledged regarding this thesis. The
studies herein reported in the thesis have all been analyzed retrospectively. As
there was no randomization of subjects and no control groups, unaccounted
confounders could potentially influence the findings reported. However, the AS
literature currently consists of single institution case series (some prospectively
collected), with the exception of the European PRIAS project(94). Results from
the ProtecT study, a randomized comparison between AS, radical prostatectomy
and conformal radiotherapy are eagerly awaited(150).
The retrospective nature of analysis particularly impacted the study reported in
chapter 5. As data from 3 different centres was collaborated, the data collected
was dependent on individual centres’ protocols. As a result, we were unable to
analyze data on biopsy core tumour volume (percentage or millimetres
involved) and lymph node pathology at radical prostatectomy due to
inconsistencies in collection of this information between centres. Furthermore,
being a multicentre study, multiple pathologists reported biopsies and radical
prostatectomy specimens, and the effect of inter-observer variation was unable
to be calculated. We also accept that the data collected on radical prostatectomy
spanned a broad period of time (e.g. Vancouver 1995-2010), with interpretive
69
changes in pathological grading (2005) and clinical staging of prostate cancer
occurring (1997) (151).
As this was a surgical cohort, unforeseen biases in patient selection such as age,
co-morbidities, family history, patient anxiety for intervention, findings on
imaging or institutional bias towards type of treatment may be present. The
median age of our cohort (61 years) is younger than that reported by AS cohorts
(65 years)(129, 147). Differences in surgical technique are also likely to exist
though there was no difference in the positive margin rate on comparison of the
3 centres.
The nomogram derived from the analysis of Cambridge data would benefit from
external validation using another UK cohort. Performance when using the
Melbourne and Vancouver data for external validation was poorer however this
may be a statistical phenomenon of internal validation. We are currently in the
process of using data from another British cohort, the ProtecT study (Prostate
testing for cancer and treatment)(150) to externally validate our nomogram.
Finally, the main outcomes measured in this thesis were upgrading and
upstaging. Follow-up data on cancer recurrence, cancer specific or overall
mortality was not available for our data set. However, there is evidence that
increased Gleason grade and presence of extra-prostatic extension are predictors
for prostate cancer recurrence(152).
70
Future directions for AS:
Standardization of patient selection and triggers for treatment
As has been highlighted in this thesis, variation on what different institutions
and guidelines define as criteria suitable for inclusion exists. Our results from
chapter 4 emphasize "low-risk" disease should not be confused with
"insignificant" disease, however the optimal definition for "insignificant disease"
still remains to be determined. Longer follow-up will enable validation of these
criteria, as more concrete end points such as biochemical recurrence after
treatment, metastatic disease and prostate cancer specific mortality appear.
Thus far, there have been very few deaths from prostate cancer reported in AS
series(153). Taking into account the limitation of relatively short follow-up, this
does suggest that inclusion criteria could potentially be broadened. There have
been some reports on the feasibility of AS in men with Gleason 3+4 disease(82,
83) though follow-up is even shorter in these groups. Another issue is the
allowable volume of Gleason 3+3 disease. When considering the role of tumor
volume in AS, we must reflect on the derivation of AS inclusion criteria. These
were developed from a definition of insignificant prostate cancer being ≤ 0.5ml
(79, 80), in a time when tumor volume was an important prognostic marker.
However, radical prostatectomy studies from the PSA-screening era, with tumors
detected earlier and being smaller, suggest final tumor volume is inferior to
pathological grade, stage and margin status in predicting biochemical recurrence
(154, 155). The concept of the 0.5ml “significant” threshold was challenged by a
report examining the tumor threshold volume in an organ-confined, no Gleason
4-5, more modern prostate cancer cohort. Here, Wolters et al suggested a larger
tumor volume threshold of 1.3ml for index tumor and 2.5ml for total tumor
should be considered (156). Thus more work is still required to scrutinize the
very foundations of how AS is defined.
71
Imaging
Transrectal ultrasound imaging of the prostate has been used to guide prostate
biopsy for nearly 25 years (157). Standard grayscale ultrasound is has low
sensitivity in detecting prostate cancer and hence most prostate biopsies are
taken in a systematic, but random and blinded, manner. Improvements to
grayscale ultrasound using power Doppler sonography (158) have not been
consistently demonstrated. In comparison, during the course of this thesis,
enthusiasm for utilization of multiparametric MRI as a diagnostic tool for
prostate cancer and utilization as part of AS has increased.
There have been significant improvements in prostate MRI techniques over the
past 3 decades. Previously, prostate MRI relied predominantly on morphologic
and signal changes present on T1- and T2-weighted images and suffered from
relatively poor sensitivity and specificity for detecting prostate cancer (159).
Current state-of-the-art prostate MRI consists of a multiparametric approach, in
which two or more functional sequences complement the morphologic
information provided by T2-weighted imaging. The newer stronger magnetic
fields of 3.0 Tesla MRI systems provide a higher signal-to-noise ratio compared
with 1.5 Tesla (T) systems. An endorectal coil (ERC) was traditionally required
with 1.5T systems, placed adjacent to the prostate, to augment the signal for
image generation. With newer 3.0T MRI systems, it is less certain if an ERC is still
required as patient discomfort can be significant.
It has been recommended in guidelines from the European Society of Urogenital
Radiology (ESUR) that MRI in prostate consists of multiparametric MRI (mpMRI)(160). The components of the mp-MRI approach are T2 weighted imaging
(T2WI); diffusion weighted imaging (DWI); dynamic contrast enhanced imaging
(DCEI) and MR spectroscopic imaging (MRSI)(161). High resolution T2WI
provides the best assessment of the prostate gland’s morphology, margins and
differentiation between peripheral and central zones. Prostate cancer lesions
typically appear as hypointense low signal (dark) in the peripheral zone. DWI
differentiates tumors from normal glandular tissue by assessing functional
72
information about tissue microstructure. By assessing how freely water protons
can move in space, tumours with higher cellular density and complex
microstructure restrict diffusion of water more, which is detectable on DWI.
There is also evidence to suggest that the results produced by DWI, the ADC
(apparent diffusion coefficient) map, not only are useful to differentiate between
benign and malignant tissue, but can subcategorize foci based on degree of
aggressiveness (Gleason score at biopsy or surgery)(162, 163). Tumour
angiogenesis, leading to vascular differences such as increased blood flow,
microvascular density and capillary leakiness are exploited by DCEI. Prostate
MRSI is the most technically challenging and time-consuming of the functional
imaging modalities. It examines the relative concentrations of metabolites in the
prostate, in particular choline (increased concentration in prostate cancer) and
citrate (reduced in prostate cancer). It has been shown that T2WI with at least 2
functional MRI techniques provides better characterization than T2WI with one
functional technique. DWI and MRSI add specificity to lesion characterization
whilst DCE has high sensitivity in cancer detection.
Results from MRI still require prostate biopsy to confirm presence of cancer and
degree of aggressiveness. The most common way of using MRI imaging to guide
prostate biopsy is the “cognitive” method. Cognitive-fusion simply entails the
biopsy operator aiming the needle towards the region where the reviewed MRI
demonstrates a lesion. The traditional random systematic sampling of prostate
zones is often taken at the same sitting. Direct “in-bore” (within the MRI tube)
MRI-guided biopsy represents the other extreme. MRI is used to both identify the
lesion and confirm correct biopsy needle localization. Only targeted cores are
taken so detection of insignificant cancers is reduced. However, this method is
both time consuming and expensive. Furthermore, the true false negative rate of
prostate mp-MRI is still unknown so systematic biopsies are still being
performed. Finally, MRI-TRUS fusion technology is also being explored. Images
from the MRI are digitally overlayed using software to real time ultrasound. This
technique does require specialized equipment and training but enables biopsies
to be taken in an office-outpatient setting. Results suggest more accurate
73
sampling of lesions and improved detection of cancer over standard systematic
TRUSPB (164, 165).
For active surveillance, the role prostate mp-MRI is rapidly evolving. In patients
in whom clinical suspicion for aggressive prostate cancer exists, usually with
discrepancy between PSA and prostate biopsy, MRI is used to evaluate presence
of an anterior tumour. The anterior zone is not typically sampled with standard
TRUSPB and can thus harbour significant cancers (166, 167). The main
limitations for prostate mp-MRI are cost, availability and expertise. With time,
one would expect each of these issues to improve. It is highly likely that in the
future, prostate mp-MRI will be utilized to aid selection for eligibility, monitor
for disease progression and possibly even decrease the morbidity associated
with standard TRUSPB.
Transperineal template biopsy
An alternative method to minimize under-sampling and under-detection of
prostate cancer is to perform a systematic saturation biopsy via the
transperineal route. To aid standardization, a brachytherapy seed type template
is often used. The median number of cores taken using this technique varies
from 18 (168) to over 50(169, 170), with increased number of cores taken in
more contemporary series.
One of the benefits of transperineal template biopsy (TPTB) is improved
sampling of the anterior zone. This has been demonstrated for men undergoing
repeat biopsy using TPTB, with many new cancers found of significant grade and
volume(169). Thus, for men on AS who are suspected of having an anterior
lesion, TPTB is an alternative to mp-MRI. Alternatively, TPTB could be
considered as a standard re-biopsy technique for men on AS. The proportion of
men found to have re-classification using TPTB, depending on the definition of
re-classification used, has been reported as 34-85% (171, 172). A further benefit
of TPTB is a lower rate of infection, as the biopsy is not performed through the
rectum. Thus for men on AS who experienced previous infectious complications
74
from standard TRUSPB, or are deemed to be at high risk of harbouring resistant
organisms, TPTB could provide a safer alternative.
Widespread uptake of TPTB has been slow. This may be over concerns regarding
increased time necessary to perform the procedure compared to TRUSPB, and
requirement of either general or regional anaesthesia. In many places world
wide, TRUSPB is performed as an office based procedure under local
anaesthesia. There is also an increased rate of post-biopsy urinary retention
from peri-urethral oedema. The possibility of increased fibrosis impacting on the
neurovascular bundle and erectile function, and increased technical difficulty at
radical prostatectomy most also be considered. Finally, the important question of
increased detection of insignificant cancers remains to be answered. Taking
more biopsy cores will inevitably lead to more positive cores so the definitions of
AS eligibility, with consideration of allowance of number of positive cores, will
need to be re-evaluated.
Predictive models
Statistical predictive models abound to assist clinicians with the management of
prostate cancer (Chapter 1). Understandably, a predictive model to assist
selection of men with prostate cancer suitable for active surveillance is desirable.
Even better would be a model that predicts risk of pathological progression
whilst on AS that could be used to stratify intensity of follow-up.
The current predictive tools for AS selection published in the literature have
their limitations. The Kattan nomogram (144) was one of the initial predictive
models for insignificant cancer. However, the original dataset the model was
derived from was based on men having sextant biopsies. It is well established
now that schemes taking 12 cores, including laterally directed cores, detect up to
31% more cancers(173). Thus the generalizeability of this model to
contemporary biopsy patterns and patients is questionable. At first glance,
Nakanishi and colleagues’ model has good predictive accuracy (AUC 0.727) and
very good calibration(142). Unfortunately, a good model may not be clinically
75
useful and this model is only applicable to patients having a single positive
cancer involved. Currently, the PRIAS study has the most stringent criteria for
number of positive cores involved, but still allows up to 2 positive cores.
One of the fundamental difficulties in creating an accurate model to predict
indolent disease is that the underlying prevalence of low risk prostate cancer is
already high. Another problem encountered is difficulty in modeling the
sampling error inherently associated with prostate biopsy. With our dataset, we
were unable to develop a predictive model for indolent cancer better than the
PRIAS criteria. It should be also be remembered that few of these models have
been externally validated. Internal validation, for statistical reasons, tends to
over-fit the model, which essentially makes the model look more accurate in its
predictions. Furthermore, there may be differences between the cohort the
model was derived from and the population of patients seen by a particular
clinician. For example, most of the models are derived from white Caucasian
populations and thus may not be as accurate when used in an Asian or African
population.
Thus, current published predictive models for AS are minimally used as they are
at best, marginally more accurate than the eligibility criteria for AS.
Incorporation of additional clinical information such as previous negative biopsy
results and significant family history for prostate cancer would be useful. As
utilization of MRI increases, this should also be considered in models to
minimize the sampling error associated with TRUSPB. Finally, a clinically useful
biomarker to detect presence of more aggressive prostate cancer is desperately
needed.
Biomarkers
Exploration for a biomarker in prostate cancer better than the current standard
(e.g. PSA) has been difficult. A clinical priority is to develop a prognostic
biomarker to separate prostate cancer that is indolent and at low risk of
76
progression, from more aggressive disease. One of the difficulties at present with
AS, is inability to differentiate between re-classification (sampling error) and
true disease progression when adverse histology is found at re-biopsy
Urinary PCA3, a prostate cancer-specific non-coding mRNA, has been
demonstrated to improve the diagnostic accuracy of externally validated
nomograms among men with an elevated PSA undergoing biopsy (174). There
are preliminary results that suggest urinary PCA3, when combined with urine
TMPRSS2:ERG fusion transcript, can predict higher volume and higher grade
disease in an active surveillance cohort (175, 176). The TMPRSS2-ERG gene
fusion was one of the initial well-characterized chromosomal re-arrangements
for prostate cancer. The rearrangement causes androgen, via the androgenresponsive promoter elements of the TMPRSS2 gene, to drive expression of the
ERG transcription factors and cause tumor proliferation. The frequency of this
fusion gene has been described present in 40-78% of radical prostatectomy
series (177) but the timing of its pathogenesis in the course of prostate cancer
remains unclear. Urinary PCA3 alone, does not appear to be useful to identify
men with progression on prostate biopsy(178).
Genomics may be able to help predict aggressiveness of individual prostate
cancer by measuring activity of multiple key genes and biological pathways. The
Oncotype DX Genomic Prostate Score, is an assay and algorithm of 17 genes
which can be performed on a small amount of tissue obtained by needle biopsy,
even if formalin-fixed paraffin-embedded. It had been validated in a study of
biopsies from patients suitable for AS and found to be able to predict high grade
and/or pT3 disease(179). Further validation is required to justify the cost
associated with this test.
Secondary chemoprevention
Active surveillance, by monitoring men with low risk disease for change to more
aggressive disease, also presents opportunities for secondary chemoprevention.
77
Primary prevention of prostate cancer, using 5 alpha -reductase inhibitors
(5ARI) has been investigated in 2 large randomized control trials. In the Prostate
Cancer Prevention Trial (PCPT, n=18 882) (180) and the Reduction by
Dutasteride of Prostate Cancer Events Trial (REDUCE, n=6729)(181), 5ARIs
were shown to significantly reduce the relative risk of prostate cancer detected
on biopsy by ~25% (22.8% and 24.8% respectively) over 4 and 7 year follow-up
respectively. However, despite these impressive results there has been a
reluctance to use 5ARIs in this setting because of the findings of increased highgrade prostate cancer (Gleason 7-10) in the 5ARI group in PCPT. The absolute
increase in risk however was noted to be small (PCPT, 6.4% vs 5.1%, p=0.005)
and not present in REDUCE. REDUCE further sub-classified high-grade cancer to
Gleason 8-10, and described 12 of these patients in the 5ARI arm compared to 1
in the placebo arm. The issue of high grade prostate cancer and 5ARI remains
controversial and unresolved despite attempts by several post randomization
analyses to attribute this association to sampling or detection bias resulting from
decreased prostate volume whilst on 5ARI(182-184).
Secondary prevention of prostate cancer, to prevent progression or worsening of
disease already diagnosed, using 5ARI has also been investigated. The reduction
by dutasteride of clinical progression events in expectant management
(REDEEM) trial, was a randomized control trial comparing Dutasteride to
placebo for men on AS (n=302) (185). A composite end point of both
pathological (worsening biopsy findings) and therapeutic (proceeded to
treatment) progression was used. By 3 years fewer men in the Dutasteride arm
had reached this composite end point (38% versus 48%, HR 0.62, 95% C.I. 0.430.89, p=0.009). Unfortunately, the study was not powered to examine
pathological progression, and investigators and patients were not blinded to PSA
results. A previous retrospective analysis from the PMCC AS database also
examined the effect of 5ARI on pathological progression(186). This found that
lack of 5ARI use to be associated with pathological progression (HR 2.91, 95%
C.I. 1.5-5.6). When a time-dependent covariate analysis was used to re-examine
the data, the results still held to be true (187).
78
Despite evidence of benefit in 3 randomized clinical trials, utilization of 5ARI, in
either primary or secondary chemoprevention settings for prostate cancer, has
not been widely accepted. The main concern has been possible increased risk of
high-grade cancer. Whilst it may also improve lower urinary tract symptoms,
5ARI use is not without potential side effects. Presence of sexual side effects in
particular, defeat one of the main aims of AS.
Multiple exogenous factors have been unsuccessfully investigated for causative
associations with prostate cancer (Chapter 1). These factors represent adjustable
factors that could be targeted for primary and secondary chemoprevention of
prostate cancer. Current areas of interest for secondary chemoprevention
include exploration of the roles of folate (188), statins(189), anti-inflammatories
(190) and metformin(191).
Quality of life
A principle premise of AS is preservation of quality of life (QoL) by avoiding the
side effects associated with radical treatment. When investigating changes in
QoL during AS, the interaction between physiological symptoms from the cancer,
emotional distress over living with cancer and the inexorable burden of age is
challenging to differentiate.
It has been hypothesized that living with cancer that remains untreated could
adversely affect a patient’s psyche and thus impact on their QoL. Using various
different validated scores to assess depression, anxiety and decisional conflict,
van den Bergh and colleagues found men in the PRIAS study to report mainly
favourable levels of anxiety and distress(192). However, disparities in term
mental health may become more apparent with longer follow-up as suggested in
a randomized control trial comparing radical prostatectomy and watchful
waiting (WW)(58).
Erectile function and lower urinary tract function are also important domains of
QoL that should be monitored during AS. From the same trial comparing WW to
radical prostatectomy, men undergoing radical prostatectomy had more erectile
79
dysfunction (80% vs 45%) and more urinary leakage (49% vs 21%) but less
urinary obstruction (28% vs 44%). However, the population of men on AS
compared WW is very different and hence more prospective study is needed.
Conclusion:
In this thesis on active surveillance for prostate cancer, the selection process for
inclusion was examined.
Summary of clinical implications:
Selection of men for AS:

More stringent AS criteria were shown to decrease the amount of
upgrading and upstaging found at radical prostatectomy but also
decreased the number of men deemed suitable for AS.

For institutions choosing which eligibility criteria for AS to use,
consideration of local population factors, such as the background
prevalence of PSA testing, should be taken.

Predictive models may help with selection of men for AS but care must
be taken when applying models developed from a different
population. Efforts should be made to generate predictive models
from local data.

Future investigation into selection of men for AS should include
advances in imaging and biomarkers where possible.
80
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Appendix A: List of variables
5ARI
AS
AUC
B1
B2
CAPRA-S
CI
cT
DRE
EPE
FHx
GS
HR
MRI
OR
PCore
PRIAS
PSA
PSAD
PSA-DT
PSM
pT
PZ
ROC
SET
SVI
TRUS
TZ
5 alpha reductase inhibitor
active surveillance
area under curve
baseline, or diagnostic prostate biopsy
confirmatory, or 1st prostate re-biopsy after B1
the Cancer of the Prostate Risk Assessment PostSurgical - SCORE
confidence interval
clinical stage of prostate cancer, from DRE.
digital rectal examination
extra-prostatic extension
family history
Gleason score
hazard ratio
magnetic resonance imaging
odds ratio
positive cores (from prostate biopsy)
European Prostate Cancer Research International:
Active Surveillance Study
prostate specific antigen
prostate specific antigen density
prostate specific antigen doubling time
positive surgical margin (from radical prostatectomy)
pathological stage of prostate cancer, from pathology
review of specimen.
peripheral zone (of prostate)
receiver-operating curve
standard extended template (prostate biopsy)
seminal vesicle invasion
trans rectal ultrasound
transition zone (of prostate)
94
Appendix B: Published manuscripts from thesis
95
96
97
98
99
100
101
102
103
104
105