This document summarizes a journal club discussion on a clinical trial comparing active monitoring, surgery, and radiotherapy for treating clinically localized prostate cancer. The trial included over 2,600 men randomized to one of the three treatment groups or choosing their own treatment. Results found no difference in prostate cancer deaths between groups after 10 years. Exploratory analyses combining randomized and non-randomized cohorts found a lower risk of cancer death with radical treatment versus active monitoring. However, radical treatments were associated with higher rates of urinary incontinence, erectile dysfunction, and bowel issues compared to active monitoring. Limitations included potential for bias in the analyses and unknown long-term outcomes beyond 10 years.

1. Journal Club
Dr Santosh K
Senior Resident
All India Institute of Medical Sciences , Bhubaneshwar

2. Neal, David E.Hamdy, Freddie C. et al.
European Urology, Volume 77, Issue 3, 320 - 330

3. Background
• Clinically localized prostate cancer – detected by prostate specific antigen (PSA) screening
• Huge burden on health care(incidence in the US 164690/year)
• Seemingly localized tumors may be of diverse nature
Low malignant potential - left untreated are unlikely to result in morbidity or reduce life expectancy
Intermediate malignant potential -Curable with a single modality directed exclusively to the gland
itself
High risk cases- destined to recur locally or systemically despite optimal local therapy
• Management remain controversial- Many men do not benefit from treatment
Indolent
Disseminated
• Prostate cancer progresses slowly- Many die of competing causes
• Interventions are associated with adverse effects

4. Data from screening studies - inconsistent
• European Randomized Study of Screening for
Prostate Cancer (ERSPC)- shows clear but
relatively small disease-specific survival
benefit from screening compared with no
active intervention at 8 years and 13 years
follow-up
• US-based Prostate, Lung, Colorectal, and
Ovarian (PLCO) trial reported no benefit from
screening with a similar length of follow-up,
but was limited by substantial contamination
from previous PSA testing in the control
group in more than 50% of the unscreened
men.

5. Lacunae in available literature
• No evidence that PSA-testing, and treatment of localized prostate cancer improved
survival and quality of life
• Increasing burden to health care providers and society
• Uncertainties for patients over best treatment
• Treatment options not compared previously
Most men diagnosed with PSA-detected prostate cancer tend to
undergo radical treatment

7. Intention to treat analysis

8. Present analysis
• Secondary analysis
• According to treatment received
• Includes even those patient did not agree for randomization but
selected their treatment choice

9. Trial design
• A PSA-testing programme and 3-arm randomised + patient
selected treatment option trial to evaluate effectiveness in
prostate cancer:
• Active Monitoring versus surgery versus radiotherapy
• Primary end-point: prostate cancer-specific survival at 10
years
• All-cause deaths
• Cancer progression
• Patient-reported outcomes

10. Study setting
Leeds
Sheffiel
d
Birmingha
m
Cardiff
Brist
ol
Leicester
Cambrid
ge
Edinburgh
Newcastl
e
82,429 men tested
2,965 prostate
cancers

11. Methods
• Recruitment from Primary Care Physicians /GP practices
• Fit men, aged 50-69 years
• Prostate Check Clinics by Research Nurses
– Counseling about prostate cancer
– Obtaining informed consent
– Taking blood for PSA-testing
• Invitation to the hospital for prostate biopsies in men with a raised PSA
• Men with prostate cancer were evaluated by clinicians
• Men suitable for the trial (localized disease) 2664 -1643(62%)
randomized
- 997(38%) Chose
treatment

12. Treatment options
Active Monitoring is a surveillance programme. They were offered radical treatments
if the disease appeared to progress.
• PSA measured 3 monthly in the 1st year and 6–12 monthly thereafter
• An increase of 50% or more in PSA over a 12-mo period triggered a clinical review
Purpose - avoid unnecessary treatment, but to keep them in a ‘window-of-curability’ if
treatment became necessary
Surgery was performed as radical prostatectomy with routine follow-up and additional
treatments
• Men with a PSA level of 10 mg/l or a Gleason score of 7 underwent lymphadenectomy
• Adjuvant RT was considered for positive margins or extracapsular disease
Radiotherapy with regular follow-up, and additional interventions as necessary
• RT protocol included neoadjuvant ADT for 3–6 months before and concomitantly with three-
dimensional conformal RT (74 Gy in 37 fractions)

13. Follow up
• Follow-up was standardized according to treatment-specific pathways
• In all groups, ADT was offered when serum PSA reached a concentration of 20 ng/ml (or
less if clinically indicated)
• Skeletal imaging was carried out if PSA was 10 ng/mll

14. Outcomes measures
• Cause of death - was determine by a committee.
• Metastatic disease - Bony, visceral, or lymph node metastases
PSA levels above 100 mg/l
Progression - Metastases
Clinical T3 or T4disease
ureteric obstruction, rectal fistula, or need for urinary catheter due local tumour growth
Initiation of ADT - objective marker of disease progression
• Cancer grades were classified into the following Gleason grade groups: (1) 3 + 3 = 6; (2) 3 + 4 = 7;
(3) 4 + 3 = 7; (4) 4 + 4 = 8, 3 + 5 = 8, 5 + 3 = 8; and (5) 9.
• D’ Amico score was used for risk stratification
• Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using
patient-reported outcome measures (PROMs) ( at randomization and then yearly)
-Expanded Prostate Index Composite (EPIC )
-International Continence Society Male Short Form (ICSmaleSF).

15. Statistical analysis
• Secondary analysis of the randomized cohort as well as treatment choice cohort based
on treatment received
• “Overall test” of event rates across the three groups done initially
• Pairwise tests of RP versus AM and RT versus AM was done if overall test showed
significant difference
• Propensity score approach because it was straightforward generalization for comparisons
between three groups and could use the same method for the randomized and
treatment choice cohorts

16. • Propensity scores were generated using multinomial logistic
regression, with treatment received as the three-category outcome
variable, and the following covariates: cT stage (1 or 2), Gleason grade
group (1, 2, 3, and >3 [4 and 5 combined]), log-transformed PSA, age
in years, and study center.
• Data from the two cohorts were combined, and survival curves for
prostate cancer mortality and metastasis drawn
• For PROMs data from the cohorts were combined, and all data
after treatment were compared between treatment groups

17. Study accrual(Consort Diagram)
391 received surgery
within 9 months
95 Monitoring*
33 Radiotherapy*
11 Other
1643 participants were randomlyassigned
553 to Radical
Prostatectomy
545 to Active Monitoring
545 to Radical
Radiotherapy
405 began allocated
protocol within 9 months
75 Monitoring*
41 Surgery*
11 Other
482 began allocated
protocol within 9 months
37 Surgery*
17 Radiotherapy*
2 Brachytherapy
2664 eligible participants with localiseddisease
997 patients chose treatment
507 to Active
Monitoring
262 to Radical
Prostatectomy
189 to Radical
Radiotherapy

18. Results
• Baseline characteristics were
similar across the randomization
cohort and the treatment choice
cohort
• Only difference was in the
occupation of the participants
with more managerial
occupation in the treatment
choice cohort

19. Men at risk switch over to radical treatment
Blue – randomization cohort
Red- treatment selection cohort

20. Clinical outcomes

22. Active monitoring (red)
Surgery (Blue)
Radiotherapy (yellow)

23. Fig. 2
European Urology 2020 77, 320-330DOI: (10.1016/j.eururo.2019.10.030)
Active monitoring (yellow)
Surgery (red)
Radiotherapy (blue)

24. • Most progression
• development of a high stage (T3 orT4)
• starting of ADT
• Higher in the AM group (60% [85/142] in the randomized cohort and
57% [45/79] in the treatment choice cohort).
• The presence of stage T3 or T4 did not prevent subsequent radical
treatment in some men, with 20% (22/112) undergoing RP and 35%
(39/112) undergoing RT.

25. Exploratory ancillary analyses
• Combined surgery group + RT group - compared with AM
• Reduction in prostate cancer-specific mortality with radical treatment compared with AM
• Randomised cohort (hazard ratio = 0.34; 95% [CI] 0.13, 0.94)
• Treatment choice cohort (hazard ratio = 0.27; 95% CI 0.08, 0.91)
• Pooling of these two estimates - marked decrease in prostate cancer mortality with
radical treatment (hazard ratio = 0.31; 95% CI 0.14, 0.67; p = 0.003)
• Small number of prostate cancer deaths means that the absolute reduction is modest!!

26. Urinary incontinence
AM RP RT
n/N (%) n/N (%) n/N (%) p-value
Baseline 0/563 (0) 3/354 (0.84) 0/312 (0)
6 months 2/717 (0.28) 272/492 (55) 6/448 (1.3)
12 months 4/740 (0.54) 164/508 (32) 7/460 (1.5)
24 months 23/828 (2.8) 134/562 (24) 12/504 (2.4)
36 months 29/901 (3.2) 143/609 (23) 10/544 (1.8)
48 months 45/942 (4.8) 122/618 (20) 12/567 (2.1)
60 months 48/970 (4.9) 123/619 (20) 13/589 (2.2)
72 months 66/948 (7.0) 127/619 (21) 13/567 (2.3) <0.001
EPIC item: One or more pads per day in the past 4 weeks

27. Nocturia
AM RP RT
n/N (%) n/N (%) n/N (%) p-value
Baseline 201/985 (20) 146/650 (22) 114/581 (20)
6 months 236/971 (24) 225/646 (35) 388/598 (65)
12 months 223/981 (23) 168/645 (26) 217/596 (36)
24 months 275/978 (28) 150/645 (23) 193/606 (32)
36 months 304/995 (31) 158/644 (25) 190/586 (32)
48 months 320/984 (33) 160/648 (25) 193/589 (33)
60 months 347/982 (35) 147/637 (23) 214/595 (36)
72 months 363/968 (38) 156/635 (25) 198/576 (34) <0.001
Supplementary Table 4: ICSmaleSF nocturia item: twice or more per night

28. Erection firmness
AM RP RT
n/N (%) n/N (%) n/N (%) p-value
Baseline 370/548 (68) 229/345 (66) 196/312 (63)
6 months 415/698 (59) 25/490 (5.1) 81/439 (18)
12 months 433/716 (60) 28/502 (5.6) 154/450 (34)
24 months 437/807 (54) 73/552 (13) 159/491 (32)
36 months 436/882 (49) 86/600 (14) 179/533 (34)
48 months 397/918 (43) 93/624 (15) 173/555 (31)
60 months 374/943 (40) 99/625 (16) 166/584 (28)
72 months 325/938 (35) 93/624 (15) 162/566 (29) <0.001
Supplementary Table 5: EPIC item: Erections firm enough for intercourse

29. Bloody stools
AM RP RT
n/N (%) n/N (%) n/N (%) p-value
Baseline 7/559 (1.3) 3/356 (0.84) 4/314 (1.3)
6 months 9/722 (1.2) 3/495 (0.61) 16/451 (3.5)
12 months 8/738 (1.1) 2/511 (0.39) 17/462 (3.7)
24 months 4/834 (0.48) 4/570 (0.70) 36/505 (7.1)
36 months 8/906 (0.88) 7/612 (1.1) 44/546 (8.1)
48 months 12/953 (1.3) 6/630 (1.0) 43/569 (7.6)
60 months 16/980 (1.6) 6/639 (0.94) 46/595 (7.7)
72 months 11/968 (1.1) 10/644 (1.6) 34/574 (5.9) <0.001
Supplementary Table 6: EPIC item: Bloody stools about half the time or more frequently

30. Discussion
• Comparison of groups (treatment received) -no difference in prostate cancer death
between the three treatments –at 10 yr follow-up
• In accordance with the primary ITT analysis
• Exploratory analysis also in accordance with primary ITT analysis
• When the two cohorts were pooled and analysed according to treatment received-
significantly lower risk of cancer death following Radical treatment compared to AM,
although absolute reduction is modest
• Similar advantage was noticed with respect to metastasis free survival
• Results of PROMs concur with the ITT analysis
• Higher rates of urinary incontinence and erectile dysfunction following surgery, nocturia
erectile dysfunction and bloody stools following RT
• AM patients avoided these side effects , but gradually started showing there which can
be attributed to aging and increased crossover to radical treatments

31. Limitation
• Potential for bias- inherent to the method of analysis
• Evolution of new diagnostic modalities that target biopsies detection
only in significant tumours
• Young and non white population?? Prognosis not known
• Caution while counselling patients- prognosis beyond 10 years not
known.