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Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT)
EURURO-8720; No. of Pages 12 E U R O P E A N U RO L O GY X X X ( 2 019 ) X X X – X X X
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Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) Timothy J. Wilt a,b,*, Tien N. Vo c, Lisa Langsetmo c, Philipp Dahm d,e, Thomas Wheeler f, William J. Aronson g,h, Matthew R. Cooperberg i,j, Brent C. Taylor a,b, Michael K. Brawer k,l a
Minneapolis VA Center for Care Delivery and Outcomes Research, Minneapolis, MN, USA; b Section of General Medicine, University of Minnesota School of
Medicine, Minneapolis MN, USA; c University of Minnesota School of Public Health, University of Minnesota, Minneapolis, MN, USA; d Minneapolis VA Section of Urology, Minneapolis MN, USA; e Department of Urology, University of Minnesota, Minneapolis MN, USA; f Baylor College of Medicine, Houston, TX, USA; g
VA Medical Center, Greater Los Angeles Healthcare System, Los Angeles, CA, USA;
h
Department of Urology, University of California at Los Angeles, Los
Angeles, CA, USA; i Department of Urology, University of California at San Francisco, CA, USA; j Department of Urology and Epidemiology and Biostatistics, University of California at San Francisco, CA, USA; k MDx Health, Irvine, CA, USA; l Nanospectra Biosciences, Houston, TX, USA
Article info
Abstract
Article history: Accepted February 11, 2020
Background: Very long-term mortality in men with early prostate cancer treated with surgery versus observation is uncertain. Objective: To determine long-term effects of surgery versus observation on all-cause mortality for men with early prostate cancer. Design, setting, and participants: This study evaluated long-term follow-up of a randomized trial conducted at the US Department of Veterans Affairs and National Cancer Institute sites. The participants were men (n = 731) 75 yr of age with localized prostate cancer, prostate-specific antigen (PSA) <50 ng/ml, life expectancy 10 yr, and medically fit for surgery. Intervention: Radical prostatectomy versus observation. Outcome measurements and statistical analysis: All-cause mortality was assessed in the entire cohort and patient and tumor subgroups. Intention-to-treat analysis was conducted using Kaplan-Meier methods with log-rank tests and Cox proportional hazard models; cumulative mortality incidence, between-group differences, and relative risks were also assessed at predefined time periods. Results and limitations: During 22.1 yr (median follow-up for survivors = 18.6 yr; interquartile range: 16.6–20.0), 515 men died; 246 of 346 men (68%) were assigned to surgery versus 269 of 367 (73%) assigned to observation (hazard ratio 0.84 [95% confidence interval {CI}: 0.70–1.00]; p = 0.044 [absolute risk reduction = 5.7 percentage points, 95% CI: –0.89 to 12%]; relative risk: 0.92 [95% CI: 0.84–1.01]). The restricted mean survival in the surgical group was 13.6 yr (95% CI: 12.9–14.3) versus 12.6 yr (95% CI: 11.8–13.3) in the observation group; a mean of 1 life-year was gained with surgery. Results did not significantly vary by patient or tumor characteristics, although differences were larger favoring surgery among men aged <65 yr, of white race, and having better health status,
Associate Editor: James Catto Statistical Editor: Andrew Vickers Keywords: Prostate cancer Outcome Prognosis Surgery
* Corresponding author. Minneapolis VA Center for Care Delivery and Outcomes Research, 1 Veterans Drive (111-0), Minneapolis, MN 55417, USA. Tel. +1-612-467-2158; Fax: +1-612-467-2118. E-mail address: [email protected] (T.J. Wilt).
https://doi.org/10.1016/j.eururo.2020.02.009 0302-2838/Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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fewer comorbidities, 34% positive prostate biopsy cores, and intermediate-risk disease. Results were not adjusted for multiple comparisons, and we could not assess outcomes other than all-cause mortality. Conclusions: Surgery was associated with small very long-term reductions in all-cause mortality and increases in years of life gained. Absolute effects did not vary markedly by patient characteristics. Absolute effects and mean survival were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with high-risk disease. Patient summary: In this randomized study, we evaluated death from any cause in men with early prostate cancer treated with either surgery or observation. Overall, surgery may provide small very long-term reductions in death from any cause and increases in years of life gained. Absolute effects were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with highrisk disease. Strategies are needed to identify men needing and benefitting from surgery while reducing ineffective treatment and overtreatment. Published by Elsevier B.V. on behalf of European Association of Urology.
1.
Introduction
We previously reported that radical prostatectomy (RP) did not significantly reduce all-cause or prostate-cancer mortality, but was associated with treatment-related harms compared with observation through 19 yr in men with localized prostate cancer detected in the early prostate-specific antigen (PSA) era [1]. Three other randomized trials compared RP with observation or PSAbased active monitoring [2–4]. One trial showed no difference in overall mortality [2]. Another trial showed relative reductions due to surgery in all-cause and prostate cancer mortality of 26% and 45%, respectively, corresponding to absolute differences of 12.0 and 11.7 percentage points and a mean of 2.9 extra years of life gained with RP at 24 yr [3]. A study of men with PSA screen-detected disease found no difference in all-cause or prostate cancer mortality after 10 yr between radiation, surgery, and PSAbased active monitoring with delayed radical intervention [4]. Prostate cancer mortality was about 1% in all groups. We describe all-cause mortality through 22 yr, compare findings with other trials, and discuss practice implications for men currently diagnosed. 2.
Patients and methods
2.1.
Study design
We previously described our design, methods, baseline, and shorter-term results [1,5]. This study was approved by institutional review boards. Patients provided written informed consent. Randomization was stratified according to site and implemented by means of a central interactive telephone system. The technique used for RP was at the surgeon’s discretion. Additional interventions were determined by each participant and his physician. Men randomly assigned to the observation group were offered palliative therapy or chemotherapy for symptomatic or metastatic progression. After completion of follow-up through January 2010, we assessed extended all-cause and prostate cancer mortality through 2014. We conducted additional analyses of all-cause mortality through January 2017.
2.2.
Patients
Between November 1994 and January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 yr; median PSA value, 7.8 ng/ml) to RP or observation at Department of Veterans Affairs and National Cancer Institute medical centers [1,5]. Patients had to be medically fit for RP and have histologically confirmed stage T1T2NxM0 prostate cancer [6] of any grade diagnosed within the previous 12 mo. Patients had PSA values <50 ng/ml, age 75 yr, bone scan negative for metastatic disease, and life expectancy 10 yr. A central pathologist subsequently reviewed and reclassified biopsy specimens. 2.3.
Follow-up, patient and tumor risk classification, and
clinical outcomes
We assessed all-cause mortality through January 2017, minimum 15 yr, maximum 22.1 yr, or until death [1,7]. We conducted stratified analyses to evaluate baseline tumor characteristics according to age, race, comorbidities, and health status [8]. We evaluated tumor risk using D’Amico tumor risk scores [9]. In post hoc analyses, we explored all-cause mortality based on central pathology readings of prerandomization biopsy specimens using CAPRA criteria [10]. As recorded Gleason scores [11] did not report primary or secondary patterns, we could not determine whether biopsies contained primary or secondary pattern 4 or 5. Therefore, we could not assign tumor histology CAPRA points for Gleason sum = 7. We derived CAPRA scores by assigning 2 points for Gleason biopsy score for Gleason = 7. For men with Gleason 6, we assigned zero Gleason score CAPRA points because it is unlikely these individuals had pattern 4 or 5. For Gleason 8–10, we assigned 3 points because most men with Gleason = 8 have primary pattern 4–5 [12]. We classified CAPRA scores as low, intermediate, and high risks [10]. We conducted additional analyses assigning 1 or 3 points for Gleason = 7 and limited to Gleason 2–6 and 8– 10. We assessed mortality based on <34% versus 34% cores positive, and Gleason = 7 based on <34% versus 34% cores positive.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
EURURO-8720; No. of Pages 12 E U RO P E A N U RO L O GY X X X ( 2 019 ) X X X – X X X
2.4.
Statistical analysis
Our primary outcome was all-cause mortality in the entire cohort according to intention-to-treat analysis using Kaplan-Meier survival curves with log-rank tests and Cox proportional hazard models with 95% confidence intervals (CIs) [13]. We assessed cumulative mortality incidence, between-group differences, and relative risks (RRs) at 5, 10, 15, and 20 yr and at the end of follow-up. The p values were not adjusted for multiple comparisons. We prespecified seven subgroups as previously described [1]. We conducted post hoc analyses for T1c tumors; Gleason 2–6, 7, and 8–10; CAPRA classification based on the percentage of biopsy cores positive (<34% vs 34%); and CAPRA scores (low, intermediate, and high risks). We calculated life-years gained using differences in restricted mean survival time [14]. We used SAS software, version 9.4 (SAS Institute, Cary, NC, USA) and Survival package R 3.5.0 [15]. 3.
Results
3.1.
Tumor characteristics
Except for PSA levels, tumor characteristics did not differ by prespecified categories of age, race, Charlson score, or performance status (Supplementary Table 1). Among 731 enrollees, information was available on 659 (90%) to evaluate central histopathology data. Most men (366/659, 56%) had six cores submitted, with 26% having more than six cores submitted (Fig. 1). Forty percent had three or more cores positive for cancer, the mean percentage of cores positive was 43% (interquartile range [IQR]: 17–60), and 302/659 (46%) had 34% cores positive (Fig. 2). Among men having central Gleason = 2–6, 105/337 (32%) had 34% cores
3
positive versus 155/260 (60%) with Gleason = 7 and 42/62 (68%) with Gleason = 8–10. Results varied slightly by age and race, being higher in white men and those <65 yr old. Using CAPRA scores assigning 2 points for Gleason 7 tumors, 204 (31%) were considered to be of low, 334 (51%) at intermediate, and 121 (18%) at high CAPRA risk. When limiting calculated CAPRA scores to Gleason sums = 2–6 or 8–10 (n = 399), 204 (51%) were considered to be at low, 153 (38%) at intermediate, and 42 (11%) at high risk. 3.2.
All-cause mortality
Vital status of all participants was available. As of January 27, 2017, 515 of 731 men had died. Median follow-up from randomization to death or end of follow-up was 12.8 yr (IQR: 7.3–17.1). The minimum follow-up for the 216 men surviving was 15.0 yr, with a maximum of 22.1 yr. Median follow-up for participants surviving was 18.6 yr (IQR: 16.6–20.0). The hazard ratio was 0.84 (95% CI: 0.70–1.00; p = 0.044), favoring men assigned to RP (Fig. 3). Hazard and risk ratios corresponded to absolute mortality reductions that increased from 4.0 percentage points at 5 yr to 5.7 percentage points at 22.1 yr, albeit with CIs including null effects at every time point (Supplementary Tables 2 and 3). Cumulative mortality among men assigned to RP was 68% versus 73% in those assigned to observation (RR = 0.92; 95% CI: 0.84–1.01; Table 1). This corresponds to an absolute reduction of 5.7 percentage points (–0.9, 12.3), and a number needed to treat (NNT) to prevent one death = 18 (range: 8 to harm). The restricted mean survival in the surgical group was 13.6 yr (95% CI: 12.9–14.3) and 12.6 yr (95% CI: 11.8–13.3) in the observation group, with a mean of 1 life-year gained with surgery at 22.1 yr (Table 2).
Fig. 1 – Distribution of the numbers of submitted cores. Among 731 enrollees, information was available on 659 (90%) to evaluate central histopathology biopsy data. Most men (366/659, 56%) had six cores submitted, with 26% having more than six cores submitted.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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Fig. 2 – Distribution of the percentage of cores positive for prostate cancer. The mean percentage of cores positive was 43%, while 46% of men had 34% cores positive and thus considered at a higher prostate cancer risk by CAPRA criteria. Among men having central Gleason sum of 2–6, 105/337 (32%) had at least 34% cores positive versus 155/260 (60%) of men with Gleason 7 and 42/62 (68%) of men Gleason 8–10. Among men <65 yr of age, 116/ 228 (51%) had 34% cores positive, while 186/431 (43%) men aged 65 yr had 34% cores positive. For white and black men, 193/404 (48%) and 89/216 (41%), respectively, had 34% cores positive.
3.3.
Subgroup analyses
The effect of surgery on mortality did not differ by prespecified patient characteristics (p for interaction >0.10; Table 1 and Fig. 2), although some variation existed by subgroups. Among men <65 yr old, the absolute allcause mortality difference between surgery and observation was 9.2 percentage points (95% CI: –2.9, 21.3). In men aged 65 yr, the absolute difference was 4.4 percentage points (95% CI: –3.2, 12.1). Differences were numerically greater for white compared with black men and for men with fewer comorbidities and better health status. The effect of surgery on mortality did not differ by prespecified tumor characteristics (p for interaction >0.10 for all comparisons; Fig. 4, Table 1, and Supplementary Table 3). Surgery resulted in little to no reduction in allcause mortality among men with PSA 10 ng/ml, those with D’Amico low-risk cancers, or those with high-risk cancers. Mortality differences were larger for men with PSA > 10 ng/ml, central Gleason <7, and intermediate-risk disease as assessed using local histopathology. Reductions were smaller with CIs including null association for intermediate-risk disease based on central rather than on local Gleason grading. Mortality was numerically higher among men having Gleason scores 8–10 randomized to surgery versus observation, although relatively few met
these criteria. Mean life-years gained and corresponding CIs included no benefit in all patient and tumor subgroups (Table 2), although associations were stronger in men with intermediate-risk disease. In men with D’Amico low-, intermediate-, and high-risk disease, mean lifeyears gained due to surgery were 0.1 yr (95% CI: –1.5, 1.6), 2.1 yr (95% CI: 0.4, 3.7), and 0.9 yr (95% CI: –1.1, 3.0), respectively. Results were similar based on central Gleason scores. Post hoc analyses in men with T1c tumors found little to no mortality reductions due to surgery regardless of PSA or Gleason categories. The effect of surgery on mortality did not differ by CAPRA classification or percentage of positive biopsies (p for interaction = 0.16 and 0.13, respectively; Fig. 4). Results varied little when assigning 1 or 3 points for Gleason 7 tumors (Supplementary Table 3). Based on CAPRA classification, mortality reductions at 22 yr in intermediate CAPRA risk and 34% biopsy cores positive were greater than in low or higher risk scores, or <34% cores positive (Table 1, and Fig. 5A–C, 6A, and B). Absolute differences for low-risk disease either favored observation or were <1 percentage point at all time points. For men with intermediate, but not high, risk disease, differences favored surgery consistently. Relative and absolute differences at 22.1 yr due to surgery were greater in men with 34% cores positive than for men with <34%
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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5
Fig. 3 – Kaplan-Meier plots of all-cause mortality for all enrollees. By the end of the study, 515 men (71%) had died from any cause. The red line shows data from the radical prostatectomy group and the blue line shows data from the observation group (HR = 0.84; 95% CI: 0.70–1.00; p = 0.04). CI = confidence interval; HR = hazard ratio.
cores positive (Supplementary Table 3). Increasing CAPRA scores were associated with increased mortality for both observation and RP, with few large differences between treatment groups (Supplementary Table 4). The mean survival difference for men with CAPRA low risk randomized to surgery compared with observation was –0.7 yr (95% CI: –2.7, 1.2). Among men with intermediate CAPRA scores, the mean survival difference was 1.6 yr (95% CI: 0.2, 3.1), and for men with high CAPRA scores, the mean survival difference was 1.9 yr (95% CI: –0.2, 4.0). Mortality and survival benefits for men with CAPRA high risk were diminished in sensitivity analyses that removed individuals assigned 2 points for Gleason = 7 or those assigned 1 or 3 points (Tables 1 and 2). 4.
Discussion
At a median of 18.6 yr of follow-up, surgery resulted in a relative reduction in all-cause mortality of 8%, which corresponded to an absolute reduction of <6 percentage points compared with observation and an increase in the mean survival of 1 yr [16]. Our results are compatible with estimates ranging from no difference to a moderate difference. The additional follow-up of nearly 3 yr yielded similar all-cause mortality effects due to surgery compared
with earlier findings [1]. While our results suggest that results did not vary by most tumor or patient characteristics, we found numerically greater effects due to surgery in selected subgroups: younger and healthier men, those with intermediate-risk disease based on either D’Amico or CAPRA categorization, and individuals with higher percentage of cancer-positive biopsy cores. NNTs to prevent one death at 22 yr, while including the possibility of increased death, were 18 in the overall cohort and 8 in all subgroups. Among men with low-risk disease, relative and absolute reductions were small, and the mean life-years gained were <5 mo with NNTs = 25–91 and include harm and life-years lost. PIVOT is one of several randomized trials evaluating radical versus conservative treatment strategies for localized prostate cancer and one of only two that included a majority with PSA-detected prostate cancer [4]. Radical treatment adherence in PIVOT was similar to other trials [3,4]. Observation adherence was superior to nonradical adherence in ProtecT [4]. Mortality differences were stable between 10 and 20 yr. More than 70% of men have died. Owing to limited access to medical records, we could not assess prostate cancer mortality. Given our previous results that prostate cancer mortality was 9.4% at 19.5 yr and reductions remained stable after
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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Table 1 – All-cause mortality (N = 515; from randomization up to 22.1 yr) by patient and tumor subgroups. Variable
Overall Age at diagnosis (yr) <65 65 Race White Black Other PSA (ng/ml) 10 >10 Charlson score 0 1 Risk category Locally assessed Low Intermediate High Centrally assessed Low Intermediate High Performance score 0 1–4 Local Gleason score <7 7 Central Gleason score <7 7 Local Gleason score <7 7 8–10 Central Gleason score <7 7 8–10 CAPRA risk score counting 2 points for Gleason score of 7 Low Intermediate High CAPRA risk score counting 1 point for Gleason score of 7 Low Intermediate High
Radical prostatectomy
Observation
Absolute risk difference (95% CI)
Relative risk (95% CI)
No. of events/total no.
% (95% CI)
No. of events/total no.
% (95% CI)
Percentage points
246/364
68 (63–72)
269/367
73 (69–78)
5.7 (–0.89 to 12)
0.92 (0.84–1.01)
67/122 179/242
55 (46–64) 74 (68–80)
84/131 185/236
64 (56–72) 78 (73–84)
9.2 (–2.9 to 21) 4.4 (–3.2 to 12)
0.86 (0.70–1.05) 0.94 (0.85–1.04)
163/232 74/111 9/21
70(64–76) 67 (58–75) 43 (22–64)
172/220 82/121 15/26
78 (73–84) 68 (59–76) 58 (39–77)
7.9 (–0.10 to 16) 1.1 (–11 to 13) 15(–14 to 43)
0.90 (0.81–1.00) 0.98 (0.82–1.18) 0.74 (0.41–1.34)
157/238 89/126
66 (60–72) 71 (63–79)
169/241 99/125
70 (64–76) 79 (72–86)
4.2 (–4.2 to 13) 8.6 (–2.1 to 19)
0.94 (0.83–1.06) 0.89 (0.77–1.03)
131/224 115/140
59 (52–65) 82 (76–89)
145/220 124/147
66 (60–72) 84 (79–90)
7.4 (–1.6 to 16) 2.2 (–6.4 to 11)
0.89 (0.77–1.03) 0.97 (0.88–1.08)
89/148 88/129 60/77
60 (52–68) 68 (60–76) 78 (69–87)
96/148 97/120 62/80
65 (57–73) 81 (74–88) 78 (68–87)
4.7 (–6.3 to 16) 13 (1.9 to 23) –0.42(–13 to 13)
0.93 (0.78–1.11) 0.84 (0.73–0.98) 1.01 (0.85–1.19)
63/111 108/155 61/78
57 (48–66) 70 (62–77) 78 (69–87)
79/122 108/139 66/85
65 (56–73) 78 (71–85) 78 (69–87)
8.0 (–4.5 to 21) 8.0 (–2.0 to 18) –0.56 (–13 to 12)
0.88 (0.71–1.08) 0.90 (0.78–1.03) 1.01 (0.86–1.19)
203/312 43/52
65 (60–70) 83 (72–93)
223/310 46/57
72 (67–77) 81 (71–91)
6.9 (–0.41 to 14) –2.0 (–17 to 13)
0.90 (0.81–1.01) 1.02 (0.86–1.22)
158/254 78/98
62 (56–68) 80 (72–88)
189/261 65/86
72 (67–78) 76 (67–85)
10 (2.2 to 18) –4.0 (–16 to 8.1)
0.86 (0.76–0.97) 1.05 (0.90–1.23)
99/168 131/174
59 (52–66) 75 (69–82)
138/196 114/148
70 (64–77) 77 (70–84)
11 (1.7 to 21) 1.7 (–7.6 to 11)
0.84 (0.72–0.98) 0.98 (0.86–1.10)
158/254 53/69 25/29
62 (56–68) 77 (67–87) 86 (74–99)
189/261 49/64 16/22
72 (67–78) 77 (66–87) 73 (54–91)
10 (2.2 to 18) –0.25 (–15 to 14) –13 (–36 to 9.0)
0.86 (0.76–0.97) 1.00 (0.83–1.21) 1.19 (0.88–1.59)
99/168 105/144 26/30
59 (52–66) 73 (66–80) 87 (75–99)
138/196 89/116 25/32
70 (64–77) 77 (69–84) 78 (64–93)
11 (1.7 to 21) 3.8 (–6.8 to 14) –8.5 (–27 to 10)
0.84 (0.72–0.98) 0.95 (0.83–1.09) 1.11 (0.88–1.40)
p value for interaction
0.7
0.7
0.2
0.8
0.4
0.9
0.7
0.3
0.9
0.6
0.7
0.2
57/91 118/177 48/61
63 (53–73) 67 (60–74) 79 (68–89)
72/113 120/157 50/60
64 (55–73) 76 (70–83) 83 (74–93)
1.1 (–12 to 14) 9.8 (0.16 to 19) 4.6 (–9.3 to 19)
0.98 (0.80–1.21) 0.87 (0.76–1.00) 0.94 (0.79–1.12) 0.2
75/120 116/172 32/37
63 (54–71) 67 (60–74) 87 (76–98)
79/124 134/172 29/34
64 (55–72) 78 (72–84) 85 (73–97)
1.2(–11 to 13) 10(1.1 to 20) –1.2(–17 to 15)
0.98 (0.81–1.19) 0.87 (0.76–0.99) 1.01 (0.84–1.22)
CI = confidence interval; PSA = prostate-specific antigen. There were no significant between-group differences in all-cause mortality according to prespecified subgroups, including age, score on the Gleason histological scale (<7 vs 7 on a scale of 2–10, with 10 indicating the most poorly differentiated tumors), self-reported race, self-reported performance status (0 [fully active] vs 1–4, with higher scores indicating poorer functional status), or score on the Charlson comorbidity index, baseline PSA value, and D’Amico tumor risk score (low, intermediate, or high), which was based on tumor stage, histological score, and PSA level (all p values >0.10).
12 yr, it is unlikely that meaningful changes would occur from previously reported results [1,7]. Our results add to CAPRA use to assess surgery versus observation. PIVOT was not powered to detect subgroup differences. Analyses involved multiple comparisons, did not adjust
statistical measures for multiple comparisons, and many were post hoc. We urge caution in interpreting statistical significance measures and encourage readers to focus on effect estimates, 95% CIs, and consistency of results across analytic methods and time points [17–19].
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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Table 2 – Mean years of life gaineda in the entire cohort at 22 yr by patient and tumor characteristics. Patient characteristics
Restricted mean survival time for the radical prostatectomy group
Restricted mean survival time for the observation group
Years of life gained (95% CI)
Overall Age (yr) <65 65 Race White Black Other Charlson score 0 1 Performance status 0 1–4 Central Gleason scoreb <7 7 Local Gleason scoreb <7 7 PSAb 10 >10 Risk (local)b Low Intermediate High Risk (central)b Low Intermediate High CAPRA risk scorec Low Intermediate High CAPRA risk score—removing 2 points for Gleason score of 7 Low Intermediate High
13.6 (12.9, 14.3)
12.6 (11.8, 13.3)
1.0 (0.0, 2.0)
14.9 (13.6, 16.0) 12.5 (11.7, 13.3)
13.9 (12.8, 15.0) 11.4 (10.6, 12.3)
0.9 (–0.7, 2.6) 1.1 (–0.1, 2.3)
13.1 (12.3, 13.9) 13.3 (12.1, 14.6) 15.8 (13.0, 18.6)
12.0 (11.1, 12.8) 12.7 (11.5, 14.0) 13.3 (10.4, 16.2)
1.1 (–0.1, 2.3) 0.6 (–1.2, 2.3) 2.5 (–1.5, 6.5)
14.6 (13.8, 15.5) 11.3 (10.3, 12.3)
13.7 (12.8, 14.6) 10.3 (9.2, 11.3)
0.9 (–0.3, 2.1) 1.0 (–0.4, 2.4)
13.7 (13.0, 14.4) 10.9 (9.2, 12.6)
12.8 (12.1, 13.5) 9.8 (8.1, 11.6)
0.9 (–0.1, 2.0) 1.1 (–1.3, 3.5)
14.3 (13.3, 15.3) 12.4 (11.5, 13.4)
13.3 (12.3, 14.2) 11.3 (10.2, 12.4)
1.0 (–0.4, 2.4) 1.1 (–0.3, 2.6)
13.9 (13.0, 14.7) 12.1 (10.8, 13.4)
12.6 (11.7, 13.4) 11.9 (10.4, 13.3)
1.3 (0.1, 2.5) 0.2 (–1.7, 2.2)
13.5 (12.6, 14.4) 13.1 (11.9, 14.3)
13.1 (12.2, 14.0) 11.2 (10.0, 12.3)
0.4 (–0.8, 1.7) 1.9 (0.2, 3.6)
14.0 (12.9, 15.1) 13.6 (12.4, 14.7) 11.5 (10.0, 13.0)
14.0 (12.9, 15.0) 11.5 (10.4, 12.7) 10.6 (9.1, 12.0)
0.1 (–1.5, 1.6) 2.1 (0.4, 3.7) 0.9 (–1.1, 3.0)
14.3 (13.0, 15.6) 13.4 (12.4, 14.4) 11.6 (10.2, 13.1)
13.9 (12.7, 15.2) 12.0 (11.0, 13.1) 10.6 (9.3, 12.0)
0.4 (–1.4, 2.1) 1.4 (–0.1, 2.9) 1.0 (–1.0, 3.0)
13.7 (12.3, 15.2) 14.0 (13.0, 14.9) 11.5 (10.0, 13.0)
14.5 (13.2, 15.7) 12.3 (11.3, 13.4) 9.6 (8.1, 11.0)
–0.7 (–2.7, 1.2) 1.6 (0.2, 3.1) 1.9 (–0.2, 4.0)
13.7 (12.3, 15.2) 15.1 (13.5, 16.6) 8.9 (6.3, 11.4)
14.5 (13.2, 15.7) 12.0 (10.5, 13.5) 10.1 (7.8, 12.3)
–0.7 (–2.7, 1.2) 3.1 (0.9, 5.2) –1.2 (–4.6, 2.2)
CI = confidence interval; PSA = prostate-specific antigen. Calculated using the difference between the restricted mean survival times. Complete data were available for 661 men. c Complete biopsy data were available for 659 men a
b
Relative reductions in all-cause mortality from PIVOT are generally consistent with SPCG-4 [3] and ProtecT [4]. However, PIVOT findings reflect men diagnosed, and using treatments available, during the early PSA era, a midpoint between the pre-PSA (SPCG-4) and later PSA era (ProtecT). Furthermore, ProtecT used 10 biopsy cores for prostate cancer evaluation versus and average six cores in PIVOT. The lead time resulting from PSA screening and histological grading modifications make it unlikely that current patients will experience absolute mortality benefits achieved in these two trials [3,4,20]; the NNT to achieve mortality reduction will be higher and will take longer, and the risk of overdiagnosis and overtreatment will be greater. Notably, SPCG-4 enrolled men with clinically detected prostate
cancer; 12% had T1c, PSA-detected disease (mean PSA =14 ng/ml). Through 23 yr, 32% men died of prostate cancer; absolute reductions in prostate cancer and all-cause mortality due to surgery were 12 percentage points (NNT = 8). Mean survival was increased by 2.9 yr. PIVOT enrolled men from 1994 to 2002 (mean PSA =10 ng/ml). Approximately 50% had T1c prostate cancers. Less than 10% of PIVOT participants died from prostate cancer through nearly 20 yr; absolute reductions due to surgery were 4 percentage points (NNT = 25). After >22 yr, all-cause mortality reductions associated with surgery were <6 percentage points; the mean survival increase was 1 yr. ProtecT enrolled men with PSA screen-detected prostate cancer (mean PSA = 6), and found that 10-yr all-cause
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Fig. 4 – Forest plot of all-cause mortality by patient and tumor subgroups. There were no significant between-group differences in all-cause mortality according to prespecified or post hoc subgroups, including age, score on the Gleason histological scale (<7, 7, or 7 on a scale of 2–10, with 10 indicating the most poorly differentiated tumors), self-reported race, self-reported performance status (0 [fully active] vs 1–4, with higher scores indicating poorer functional status), Charlson comorbidity index (0 vs 1–4 Charlson-defined comorbidities), baseline PSA categories (10 vs >10 ng/ml), D’Amico tumor risk score (low, intermediate, or high; this score was based on tumor stage, histological score, and PSA level), CAPRA risk scores (low, intermediate, or high), and percentage biopsy cores positive for cancer (<34% vs 34%; all p > 0.10). The bars indicate 95% confidence intervals. CI = confidence interval; PSA = prostate-specific antigen.
mortality with active monitoring, surgery, or radiotherapy was 10.8%, 9.9%, and 10.1%, respectively. Prostate cancer mortality was 1% in all groups. Our results, together with SPCG-4, ProtecT, and two earlier trials that found no mortality benefits of surgery [2] or radiation [21] versus observation, indicate that observation, PSA-based monitoring, and possibly biopsy-based active surveillance can inform guideline recommendations and expand indications for observation, PSA-based monitoring, or active surveillance regardless of cancer risk status. Convincing evidence exists that observation and PSA-based monitoring result in similar long-term mortality with less harm compared with surgery or radiation for men with PSAdetected low-risk prostate cancer and many with intermediate- or high-risk disease [1–4,22]. Early intervention results in morbidity and negatively impacts urinary, sexual, and erectile function, as well as physical comfort and activities of daily living [1,23–26]. Clinical decisions should incorporate information that surgery and radiation reduce
and androgren deprivation therapy progression [1,3,4]. However, most progression is asymptomatic, and reductions due to surgery or radiation are small. Active surveillance programs could safely reduce biopsy frequency and increase thresholds triggering interventions. Surgery may have important mortality benefits in men with long-life expectancies having clinically detected, intermediate-risk, and possibly high-risk prostate cancer, especially if conducted at higher-volume centers with experienced surgeons [27]. We do not have information on physician experience or surgical volume, measures associated with surgical quality. However, center selection for study participation was based, in part, on demonstrated higher surgical volume. All surgery was conducted by, or under the direct supervision of, staff urologists. We previously reported that more direct measures of surgical quality such as perioperative morbidity, mortality, surgical margin positivity, and time to initiate additional therapy for disease progression were similar to those reported by others
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9
Fig. 5 – Kaplan-Meir plots of mortality by CAPRA risk scores. All-cause mortality according to CAPRA risk scores: (A) low risk (score: 0–2; n = 204; HR = 1.08; 95% CI: 0.76–1.52); (B) intermediate risk (score: 3–5; n = 334; HR = 0.74; 95% CI: 0.57–0.96); and (C) high risk (score 6–10; n = 121; HR = 0.70; 95% CI: 0.47–1.05). Data from the prostatectomy group are shown in the red line and data from the observation group in the blue line. CI = confidence interval; HR = hazard ratio.
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Fig. 6 – Kaplan-Meir plots of mortality by percentage of biopsy cores positive. All-cause mortality according to CAPRA risk scores: (A) <34% cores positive (HR = 0.96; 95% CI: 0.75–1.24; n = 357) and (B) 34% cores positive (HR = 0.73; 95% CI: 0.56–0.95; n = 302). The red line shows data from the prostatectomy group and the blue line shoes data from the observation group. CI = confidence interval; HR = hazard ratio.
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[22]. While men with high Gleason sums and D’Amico highrisk disease have poorer prognosis, surgery did not reduce mortality at extended follow-up and resulted in 1 yr of life gained, with CIs including life-years lost. We previously found that surgery did not reduce prostate cancer mortality or treatment for regional or systemic progression in D’Amico high-risk disease [1]. Mortality differences and life-years gained were greater in CAPRA high-risk disease. Treatment decisions should incorporate findings demonstrating mortality benefits of new drug therapies among men developing advanced disease [28–30]. Randomized trials of biopsy-based active surveillance are needed in intermediate- and high-risk disease and to assess riskstratified treatment decisions, including multimodality treatment, based on multiparametric magnetic resonance imaging or tissue-based molecular markers [31]. 5.
Conclusions
In conclusion, at a median 18 yr of follow-up, surgery was associated with small but lower all-cause mortality compared with observation in men with clinically localized prostate cancer. The relative reduction was 8%, corresponding to an absolute reduction of 5.7 percentage points and mean survival increase of 1 yr. Our results are compatible with estimates ranging from no difference to a moderate difference. Absolute effects did not vary markedly by patient characteristics. Absolute effects and mean survival were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with high-risk disease. Strategies are needed to effectively communicate the results of these findings, and to enhance identification of individuals needing and benefitting from early intervention while reducing harms of ineffective treatments and/or overtreatment.
11
Funding/Support and role of the sponsor: This study was funded by the Department of Veterans Affairs Cooperative Studies Program, the National Cancer Institute, and the Agency for Health Care Research and Quality (PIVOT ClinicalTrials.gov number, NCT00007644). Researchers were independent from the funders. Authors had access to study data. The contents do not represent the views of the U.S. Department of Veterans Affairs or the US government.
Acknowledgments: We wish to thank Karen M. Jones, MS, and the Perry Point VA Cooperative Studies Program Coordinating Center for many years of support, data coordination, and analyses on prior manuscripts, and assistance in data transfer under a Data Use Agreement to the Minneapolis VA Center for Care Delivery and Outcomes Research.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. eururo.2020.02.009.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Prostatic Disease Editorial by XXX on pp. x–y of this issue
Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) Timothy J. Wilt a,b,*, Tien N. Vo c, Lisa Langsetmo c, Philipp Dahm d,e, Thomas Wheeler f, William J. Aronson g,h, Matthew R. Cooperberg i,j, Brent C. Taylor a,b, Michael K. Brawer k,l a
Minneapolis VA Center for Care Delivery and Outcomes Research, Minneapolis, MN, USA; b Section of General Medicine, University of Minnesota School of
Medicine, Minneapolis MN, USA; c University of Minnesota School of Public Health, University of Minnesota, Minneapolis, MN, USA; d Minneapolis VA Section of Urology, Minneapolis MN, USA; e Department of Urology, University of Minnesota, Minneapolis MN, USA; f Baylor College of Medicine, Houston, TX, USA; g
VA Medical Center, Greater Los Angeles Healthcare System, Los Angeles, CA, USA;
h
Department of Urology, University of California at Los Angeles, Los
Angeles, CA, USA; i Department of Urology, University of California at San Francisco, CA, USA; j Department of Urology and Epidemiology and Biostatistics, University of California at San Francisco, CA, USA; k MDx Health, Irvine, CA, USA; l Nanospectra Biosciences, Houston, TX, USA
Article info
Abstract
Article history: Accepted February 11, 2020
Background: Very long-term mortality in men with early prostate cancer treated with surgery versus observation is uncertain. Objective: To determine long-term effects of surgery versus observation on all-cause mortality for men with early prostate cancer. Design, setting, and participants: This study evaluated long-term follow-up of a randomized trial conducted at the US Department of Veterans Affairs and National Cancer Institute sites. The participants were men (n = 731) 75 yr of age with localized prostate cancer, prostate-specific antigen (PSA) <50 ng/ml, life expectancy 10 yr, and medically fit for surgery. Intervention: Radical prostatectomy versus observation. Outcome measurements and statistical analysis: All-cause mortality was assessed in the entire cohort and patient and tumor subgroups. Intention-to-treat analysis was conducted using Kaplan-Meier methods with log-rank tests and Cox proportional hazard models; cumulative mortality incidence, between-group differences, and relative risks were also assessed at predefined time periods. Results and limitations: During 22.1 yr (median follow-up for survivors = 18.6 yr; interquartile range: 16.6–20.0), 515 men died; 246 of 346 men (68%) were assigned to surgery versus 269 of 367 (73%) assigned to observation (hazard ratio 0.84 [95% confidence interval {CI}: 0.70–1.00]; p = 0.044 [absolute risk reduction = 5.7 percentage points, 95% CI: –0.89 to 12%]; relative risk: 0.92 [95% CI: 0.84–1.01]). The restricted mean survival in the surgical group was 13.6 yr (95% CI: 12.9–14.3) versus 12.6 yr (95% CI: 11.8–13.3) in the observation group; a mean of 1 life-year was gained with surgery. Results did not significantly vary by patient or tumor characteristics, although differences were larger favoring surgery among men aged <65 yr, of white race, and having better health status,
Associate Editor: James Catto Statistical Editor: Andrew Vickers Keywords: Prostate cancer Outcome Prognosis Surgery
* Corresponding author. Minneapolis VA Center for Care Delivery and Outcomes Research, 1 Veterans Drive (111-0), Minneapolis, MN 55417, USA. Tel. +1-612-467-2158; Fax: +1-612-467-2118. E-mail address: [email protected] (T.J. Wilt).
https://doi.org/10.1016/j.eururo.2020.02.009 0302-2838/Published by Elsevier B.V. on behalf of European Association of Urology.
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fewer comorbidities, 34% positive prostate biopsy cores, and intermediate-risk disease. Results were not adjusted for multiple comparisons, and we could not assess outcomes other than all-cause mortality. Conclusions: Surgery was associated with small very long-term reductions in all-cause mortality and increases in years of life gained. Absolute effects did not vary markedly by patient characteristics. Absolute effects and mean survival were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with high-risk disease. Patient summary: In this randomized study, we evaluated death from any cause in men with early prostate cancer treated with either surgery or observation. Overall, surgery may provide small very long-term reductions in death from any cause and increases in years of life gained. Absolute effects were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with highrisk disease. Strategies are needed to identify men needing and benefitting from surgery while reducing ineffective treatment and overtreatment. Published by Elsevier B.V. on behalf of European Association of Urology.
1.
Introduction
We previously reported that radical prostatectomy (RP) did not significantly reduce all-cause or prostate-cancer mortality, but was associated with treatment-related harms compared with observation through 19 yr in men with localized prostate cancer detected in the early prostate-specific antigen (PSA) era [1]. Three other randomized trials compared RP with observation or PSAbased active monitoring [2–4]. One trial showed no difference in overall mortality [2]. Another trial showed relative reductions due to surgery in all-cause and prostate cancer mortality of 26% and 45%, respectively, corresponding to absolute differences of 12.0 and 11.7 percentage points and a mean of 2.9 extra years of life gained with RP at 24 yr [3]. A study of men with PSA screen-detected disease found no difference in all-cause or prostate cancer mortality after 10 yr between radiation, surgery, and PSAbased active monitoring with delayed radical intervention [4]. Prostate cancer mortality was about 1% in all groups. We describe all-cause mortality through 22 yr, compare findings with other trials, and discuss practice implications for men currently diagnosed. 2.
Patients and methods
2.1.
Study design
We previously described our design, methods, baseline, and shorter-term results [1,5]. This study was approved by institutional review boards. Patients provided written informed consent. Randomization was stratified according to site and implemented by means of a central interactive telephone system. The technique used for RP was at the surgeon’s discretion. Additional interventions were determined by each participant and his physician. Men randomly assigned to the observation group were offered palliative therapy or chemotherapy for symptomatic or metastatic progression. After completion of follow-up through January 2010, we assessed extended all-cause and prostate cancer mortality through 2014. We conducted additional analyses of all-cause mortality through January 2017.
2.2.
Patients
Between November 1994 and January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 yr; median PSA value, 7.8 ng/ml) to RP or observation at Department of Veterans Affairs and National Cancer Institute medical centers [1,5]. Patients had to be medically fit for RP and have histologically confirmed stage T1T2NxM0 prostate cancer [6] of any grade diagnosed within the previous 12 mo. Patients had PSA values <50 ng/ml, age 75 yr, bone scan negative for metastatic disease, and life expectancy 10 yr. A central pathologist subsequently reviewed and reclassified biopsy specimens. 2.3.
Follow-up, patient and tumor risk classification, and
clinical outcomes
We assessed all-cause mortality through January 2017, minimum 15 yr, maximum 22.1 yr, or until death [1,7]. We conducted stratified analyses to evaluate baseline tumor characteristics according to age, race, comorbidities, and health status [8]. We evaluated tumor risk using D’Amico tumor risk scores [9]. In post hoc analyses, we explored all-cause mortality based on central pathology readings of prerandomization biopsy specimens using CAPRA criteria [10]. As recorded Gleason scores [11] did not report primary or secondary patterns, we could not determine whether biopsies contained primary or secondary pattern 4 or 5. Therefore, we could not assign tumor histology CAPRA points for Gleason sum = 7. We derived CAPRA scores by assigning 2 points for Gleason biopsy score for Gleason = 7. For men with Gleason 6, we assigned zero Gleason score CAPRA points because it is unlikely these individuals had pattern 4 or 5. For Gleason 8–10, we assigned 3 points because most men with Gleason = 8 have primary pattern 4–5 [12]. We classified CAPRA scores as low, intermediate, and high risks [10]. We conducted additional analyses assigning 1 or 3 points for Gleason = 7 and limited to Gleason 2–6 and 8– 10. We assessed mortality based on <34% versus 34% cores positive, and Gleason = 7 based on <34% versus 34% cores positive.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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2.4.
Statistical analysis
Our primary outcome was all-cause mortality in the entire cohort according to intention-to-treat analysis using Kaplan-Meier survival curves with log-rank tests and Cox proportional hazard models with 95% confidence intervals (CIs) [13]. We assessed cumulative mortality incidence, between-group differences, and relative risks (RRs) at 5, 10, 15, and 20 yr and at the end of follow-up. The p values were not adjusted for multiple comparisons. We prespecified seven subgroups as previously described [1]. We conducted post hoc analyses for T1c tumors; Gleason 2–6, 7, and 8–10; CAPRA classification based on the percentage of biopsy cores positive (<34% vs 34%); and CAPRA scores (low, intermediate, and high risks). We calculated life-years gained using differences in restricted mean survival time [14]. We used SAS software, version 9.4 (SAS Institute, Cary, NC, USA) and Survival package R 3.5.0 [15]. 3.
Results
3.1.
Tumor characteristics
Except for PSA levels, tumor characteristics did not differ by prespecified categories of age, race, Charlson score, or performance status (Supplementary Table 1). Among 731 enrollees, information was available on 659 (90%) to evaluate central histopathology data. Most men (366/659, 56%) had six cores submitted, with 26% having more than six cores submitted (Fig. 1). Forty percent had three or more cores positive for cancer, the mean percentage of cores positive was 43% (interquartile range [IQR]: 17–60), and 302/659 (46%) had 34% cores positive (Fig. 2). Among men having central Gleason = 2–6, 105/337 (32%) had 34% cores
3
positive versus 155/260 (60%) with Gleason = 7 and 42/62 (68%) with Gleason = 8–10. Results varied slightly by age and race, being higher in white men and those <65 yr old. Using CAPRA scores assigning 2 points for Gleason 7 tumors, 204 (31%) were considered to be of low, 334 (51%) at intermediate, and 121 (18%) at high CAPRA risk. When limiting calculated CAPRA scores to Gleason sums = 2–6 or 8–10 (n = 399), 204 (51%) were considered to be at low, 153 (38%) at intermediate, and 42 (11%) at high risk. 3.2.
All-cause mortality
Vital status of all participants was available. As of January 27, 2017, 515 of 731 men had died. Median follow-up from randomization to death or end of follow-up was 12.8 yr (IQR: 7.3–17.1). The minimum follow-up for the 216 men surviving was 15.0 yr, with a maximum of 22.1 yr. Median follow-up for participants surviving was 18.6 yr (IQR: 16.6–20.0). The hazard ratio was 0.84 (95% CI: 0.70–1.00; p = 0.044), favoring men assigned to RP (Fig. 3). Hazard and risk ratios corresponded to absolute mortality reductions that increased from 4.0 percentage points at 5 yr to 5.7 percentage points at 22.1 yr, albeit with CIs including null effects at every time point (Supplementary Tables 2 and 3). Cumulative mortality among men assigned to RP was 68% versus 73% in those assigned to observation (RR = 0.92; 95% CI: 0.84–1.01; Table 1). This corresponds to an absolute reduction of 5.7 percentage points (–0.9, 12.3), and a number needed to treat (NNT) to prevent one death = 18 (range: 8 to harm). The restricted mean survival in the surgical group was 13.6 yr (95% CI: 12.9–14.3) and 12.6 yr (95% CI: 11.8–13.3) in the observation group, with a mean of 1 life-year gained with surgery at 22.1 yr (Table 2).
Fig. 1 – Distribution of the numbers of submitted cores. Among 731 enrollees, information was available on 659 (90%) to evaluate central histopathology biopsy data. Most men (366/659, 56%) had six cores submitted, with 26% having more than six cores submitted.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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Fig. 2 – Distribution of the percentage of cores positive for prostate cancer. The mean percentage of cores positive was 43%, while 46% of men had 34% cores positive and thus considered at a higher prostate cancer risk by CAPRA criteria. Among men having central Gleason sum of 2–6, 105/337 (32%) had at least 34% cores positive versus 155/260 (60%) of men with Gleason 7 and 42/62 (68%) of men Gleason 8–10. Among men <65 yr of age, 116/ 228 (51%) had 34% cores positive, while 186/431 (43%) men aged 65 yr had 34% cores positive. For white and black men, 193/404 (48%) and 89/216 (41%), respectively, had 34% cores positive.
3.3.
Subgroup analyses
The effect of surgery on mortality did not differ by prespecified patient characteristics (p for interaction >0.10; Table 1 and Fig. 2), although some variation existed by subgroups. Among men <65 yr old, the absolute allcause mortality difference between surgery and observation was 9.2 percentage points (95% CI: –2.9, 21.3). In men aged 65 yr, the absolute difference was 4.4 percentage points (95% CI: –3.2, 12.1). Differences were numerically greater for white compared with black men and for men with fewer comorbidities and better health status. The effect of surgery on mortality did not differ by prespecified tumor characteristics (p for interaction >0.10 for all comparisons; Fig. 4, Table 1, and Supplementary Table 3). Surgery resulted in little to no reduction in allcause mortality among men with PSA 10 ng/ml, those with D’Amico low-risk cancers, or those with high-risk cancers. Mortality differences were larger for men with PSA > 10 ng/ml, central Gleason <7, and intermediate-risk disease as assessed using local histopathology. Reductions were smaller with CIs including null association for intermediate-risk disease based on central rather than on local Gleason grading. Mortality was numerically higher among men having Gleason scores 8–10 randomized to surgery versus observation, although relatively few met
these criteria. Mean life-years gained and corresponding CIs included no benefit in all patient and tumor subgroups (Table 2), although associations were stronger in men with intermediate-risk disease. In men with D’Amico low-, intermediate-, and high-risk disease, mean lifeyears gained due to surgery were 0.1 yr (95% CI: –1.5, 1.6), 2.1 yr (95% CI: 0.4, 3.7), and 0.9 yr (95% CI: –1.1, 3.0), respectively. Results were similar based on central Gleason scores. Post hoc analyses in men with T1c tumors found little to no mortality reductions due to surgery regardless of PSA or Gleason categories. The effect of surgery on mortality did not differ by CAPRA classification or percentage of positive biopsies (p for interaction = 0.16 and 0.13, respectively; Fig. 4). Results varied little when assigning 1 or 3 points for Gleason 7 tumors (Supplementary Table 3). Based on CAPRA classification, mortality reductions at 22 yr in intermediate CAPRA risk and 34% biopsy cores positive were greater than in low or higher risk scores, or <34% cores positive (Table 1, and Fig. 5A–C, 6A, and B). Absolute differences for low-risk disease either favored observation or were <1 percentage point at all time points. For men with intermediate, but not high, risk disease, differences favored surgery consistently. Relative and absolute differences at 22.1 yr due to surgery were greater in men with 34% cores positive than for men with <34%
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Fig. 3 – Kaplan-Meier plots of all-cause mortality for all enrollees. By the end of the study, 515 men (71%) had died from any cause. The red line shows data from the radical prostatectomy group and the blue line shows data from the observation group (HR = 0.84; 95% CI: 0.70–1.00; p = 0.04). CI = confidence interval; HR = hazard ratio.
cores positive (Supplementary Table 3). Increasing CAPRA scores were associated with increased mortality for both observation and RP, with few large differences between treatment groups (Supplementary Table 4). The mean survival difference for men with CAPRA low risk randomized to surgery compared with observation was –0.7 yr (95% CI: –2.7, 1.2). Among men with intermediate CAPRA scores, the mean survival difference was 1.6 yr (95% CI: 0.2, 3.1), and for men with high CAPRA scores, the mean survival difference was 1.9 yr (95% CI: –0.2, 4.0). Mortality and survival benefits for men with CAPRA high risk were diminished in sensitivity analyses that removed individuals assigned 2 points for Gleason = 7 or those assigned 1 or 3 points (Tables 1 and 2). 4.
Discussion
At a median of 18.6 yr of follow-up, surgery resulted in a relative reduction in all-cause mortality of 8%, which corresponded to an absolute reduction of <6 percentage points compared with observation and an increase in the mean survival of 1 yr [16]. Our results are compatible with estimates ranging from no difference to a moderate difference. The additional follow-up of nearly 3 yr yielded similar all-cause mortality effects due to surgery compared
with earlier findings [1]. While our results suggest that results did not vary by most tumor or patient characteristics, we found numerically greater effects due to surgery in selected subgroups: younger and healthier men, those with intermediate-risk disease based on either D’Amico or CAPRA categorization, and individuals with higher percentage of cancer-positive biopsy cores. NNTs to prevent one death at 22 yr, while including the possibility of increased death, were 18 in the overall cohort and 8 in all subgroups. Among men with low-risk disease, relative and absolute reductions were small, and the mean life-years gained were <5 mo with NNTs = 25–91 and include harm and life-years lost. PIVOT is one of several randomized trials evaluating radical versus conservative treatment strategies for localized prostate cancer and one of only two that included a majority with PSA-detected prostate cancer [4]. Radical treatment adherence in PIVOT was similar to other trials [3,4]. Observation adherence was superior to nonradical adherence in ProtecT [4]. Mortality differences were stable between 10 and 20 yr. More than 70% of men have died. Owing to limited access to medical records, we could not assess prostate cancer mortality. Given our previous results that prostate cancer mortality was 9.4% at 19.5 yr and reductions remained stable after
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Table 1 – All-cause mortality (N = 515; from randomization up to 22.1 yr) by patient and tumor subgroups. Variable
Overall Age at diagnosis (yr) <65 65 Race White Black Other PSA (ng/ml) 10 >10 Charlson score 0 1 Risk category Locally assessed Low Intermediate High Centrally assessed Low Intermediate High Performance score 0 1–4 Local Gleason score <7 7 Central Gleason score <7 7 Local Gleason score <7 7 8–10 Central Gleason score <7 7 8–10 CAPRA risk score counting 2 points for Gleason score of 7 Low Intermediate High CAPRA risk score counting 1 point for Gleason score of 7 Low Intermediate High
Radical prostatectomy
Observation
Absolute risk difference (95% CI)
Relative risk (95% CI)
No. of events/total no.
% (95% CI)
No. of events/total no.
% (95% CI)
Percentage points
246/364
68 (63–72)
269/367
73 (69–78)
5.7 (–0.89 to 12)
0.92 (0.84–1.01)
67/122 179/242
55 (46–64) 74 (68–80)
84/131 185/236
64 (56–72) 78 (73–84)
9.2 (–2.9 to 21) 4.4 (–3.2 to 12)
0.86 (0.70–1.05) 0.94 (0.85–1.04)
163/232 74/111 9/21
70(64–76) 67 (58–75) 43 (22–64)
172/220 82/121 15/26
78 (73–84) 68 (59–76) 58 (39–77)
7.9 (–0.10 to 16) 1.1 (–11 to 13) 15(–14 to 43)
0.90 (0.81–1.00) 0.98 (0.82–1.18) 0.74 (0.41–1.34)
157/238 89/126
66 (60–72) 71 (63–79)
169/241 99/125
70 (64–76) 79 (72–86)
4.2 (–4.2 to 13) 8.6 (–2.1 to 19)
0.94 (0.83–1.06) 0.89 (0.77–1.03)
131/224 115/140
59 (52–65) 82 (76–89)
145/220 124/147
66 (60–72) 84 (79–90)
7.4 (–1.6 to 16) 2.2 (–6.4 to 11)
0.89 (0.77–1.03) 0.97 (0.88–1.08)
89/148 88/129 60/77
60 (52–68) 68 (60–76) 78 (69–87)
96/148 97/120 62/80
65 (57–73) 81 (74–88) 78 (68–87)
4.7 (–6.3 to 16) 13 (1.9 to 23) –0.42(–13 to 13)
0.93 (0.78–1.11) 0.84 (0.73–0.98) 1.01 (0.85–1.19)
63/111 108/155 61/78
57 (48–66) 70 (62–77) 78 (69–87)
79/122 108/139 66/85
65 (56–73) 78 (71–85) 78 (69–87)
8.0 (–4.5 to 21) 8.0 (–2.0 to 18) –0.56 (–13 to 12)
0.88 (0.71–1.08) 0.90 (0.78–1.03) 1.01 (0.86–1.19)
203/312 43/52
65 (60–70) 83 (72–93)
223/310 46/57
72 (67–77) 81 (71–91)
6.9 (–0.41 to 14) –2.0 (–17 to 13)
0.90 (0.81–1.01) 1.02 (0.86–1.22)
158/254 78/98
62 (56–68) 80 (72–88)
189/261 65/86
72 (67–78) 76 (67–85)
10 (2.2 to 18) –4.0 (–16 to 8.1)
0.86 (0.76–0.97) 1.05 (0.90–1.23)
99/168 131/174
59 (52–66) 75 (69–82)
138/196 114/148
70 (64–77) 77 (70–84)
11 (1.7 to 21) 1.7 (–7.6 to 11)
0.84 (0.72–0.98) 0.98 (0.86–1.10)
158/254 53/69 25/29
62 (56–68) 77 (67–87) 86 (74–99)
189/261 49/64 16/22
72 (67–78) 77 (66–87) 73 (54–91)
10 (2.2 to 18) –0.25 (–15 to 14) –13 (–36 to 9.0)
0.86 (0.76–0.97) 1.00 (0.83–1.21) 1.19 (0.88–1.59)
99/168 105/144 26/30
59 (52–66) 73 (66–80) 87 (75–99)
138/196 89/116 25/32
70 (64–77) 77 (69–84) 78 (64–93)
11 (1.7 to 21) 3.8 (–6.8 to 14) –8.5 (–27 to 10)
0.84 (0.72–0.98) 0.95 (0.83–1.09) 1.11 (0.88–1.40)
p value for interaction
0.7
0.7
0.2
0.8
0.4
0.9
0.7
0.3
0.9
0.6
0.7
0.2
57/91 118/177 48/61
63 (53–73) 67 (60–74) 79 (68–89)
72/113 120/157 50/60
64 (55–73) 76 (70–83) 83 (74–93)
1.1 (–12 to 14) 9.8 (0.16 to 19) 4.6 (–9.3 to 19)
0.98 (0.80–1.21) 0.87 (0.76–1.00) 0.94 (0.79–1.12) 0.2
75/120 116/172 32/37
63 (54–71) 67 (60–74) 87 (76–98)
79/124 134/172 29/34
64 (55–72) 78 (72–84) 85 (73–97)
1.2(–11 to 13) 10(1.1 to 20) –1.2(–17 to 15)
0.98 (0.81–1.19) 0.87 (0.76–0.99) 1.01 (0.84–1.22)
CI = confidence interval; PSA = prostate-specific antigen. There were no significant between-group differences in all-cause mortality according to prespecified subgroups, including age, score on the Gleason histological scale (<7 vs 7 on a scale of 2–10, with 10 indicating the most poorly differentiated tumors), self-reported race, self-reported performance status (0 [fully active] vs 1–4, with higher scores indicating poorer functional status), or score on the Charlson comorbidity index, baseline PSA value, and D’Amico tumor risk score (low, intermediate, or high), which was based on tumor stage, histological score, and PSA level (all p values >0.10).
12 yr, it is unlikely that meaningful changes would occur from previously reported results [1,7]. Our results add to CAPRA use to assess surgery versus observation. PIVOT was not powered to detect subgroup differences. Analyses involved multiple comparisons, did not adjust
statistical measures for multiple comparisons, and many were post hoc. We urge caution in interpreting statistical significance measures and encourage readers to focus on effect estimates, 95% CIs, and consistency of results across analytic methods and time points [17–19].
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Table 2 – Mean years of life gaineda in the entire cohort at 22 yr by patient and tumor characteristics. Patient characteristics
Restricted mean survival time for the radical prostatectomy group
Restricted mean survival time for the observation group
Years of life gained (95% CI)
Overall Age (yr) <65 65 Race White Black Other Charlson score 0 1 Performance status 0 1–4 Central Gleason scoreb <7 7 Local Gleason scoreb <7 7 PSAb 10 >10 Risk (local)b Low Intermediate High Risk (central)b Low Intermediate High CAPRA risk scorec Low Intermediate High CAPRA risk score—removing 2 points for Gleason score of 7 Low Intermediate High
13.6 (12.9, 14.3)
12.6 (11.8, 13.3)
1.0 (0.0, 2.0)
14.9 (13.6, 16.0) 12.5 (11.7, 13.3)
13.9 (12.8, 15.0) 11.4 (10.6, 12.3)
0.9 (–0.7, 2.6) 1.1 (–0.1, 2.3)
13.1 (12.3, 13.9) 13.3 (12.1, 14.6) 15.8 (13.0, 18.6)
12.0 (11.1, 12.8) 12.7 (11.5, 14.0) 13.3 (10.4, 16.2)
1.1 (–0.1, 2.3) 0.6 (–1.2, 2.3) 2.5 (–1.5, 6.5)
14.6 (13.8, 15.5) 11.3 (10.3, 12.3)
13.7 (12.8, 14.6) 10.3 (9.2, 11.3)
0.9 (–0.3, 2.1) 1.0 (–0.4, 2.4)
13.7 (13.0, 14.4) 10.9 (9.2, 12.6)
12.8 (12.1, 13.5) 9.8 (8.1, 11.6)
0.9 (–0.1, 2.0) 1.1 (–1.3, 3.5)
14.3 (13.3, 15.3) 12.4 (11.5, 13.4)
13.3 (12.3, 14.2) 11.3 (10.2, 12.4)
1.0 (–0.4, 2.4) 1.1 (–0.3, 2.6)
13.9 (13.0, 14.7) 12.1 (10.8, 13.4)
12.6 (11.7, 13.4) 11.9 (10.4, 13.3)
1.3 (0.1, 2.5) 0.2 (–1.7, 2.2)
13.5 (12.6, 14.4) 13.1 (11.9, 14.3)
13.1 (12.2, 14.0) 11.2 (10.0, 12.3)
0.4 (–0.8, 1.7) 1.9 (0.2, 3.6)
14.0 (12.9, 15.1) 13.6 (12.4, 14.7) 11.5 (10.0, 13.0)
14.0 (12.9, 15.0) 11.5 (10.4, 12.7) 10.6 (9.1, 12.0)
0.1 (–1.5, 1.6) 2.1 (0.4, 3.7) 0.9 (–1.1, 3.0)
14.3 (13.0, 15.6) 13.4 (12.4, 14.4) 11.6 (10.2, 13.1)
13.9 (12.7, 15.2) 12.0 (11.0, 13.1) 10.6 (9.3, 12.0)
0.4 (–1.4, 2.1) 1.4 (–0.1, 2.9) 1.0 (–1.0, 3.0)
13.7 (12.3, 15.2) 14.0 (13.0, 14.9) 11.5 (10.0, 13.0)
14.5 (13.2, 15.7) 12.3 (11.3, 13.4) 9.6 (8.1, 11.0)
–0.7 (–2.7, 1.2) 1.6 (0.2, 3.1) 1.9 (–0.2, 4.0)
13.7 (12.3, 15.2) 15.1 (13.5, 16.6) 8.9 (6.3, 11.4)
14.5 (13.2, 15.7) 12.0 (10.5, 13.5) 10.1 (7.8, 12.3)
–0.7 (–2.7, 1.2) 3.1 (0.9, 5.2) –1.2 (–4.6, 2.2)
CI = confidence interval; PSA = prostate-specific antigen. Calculated using the difference between the restricted mean survival times. Complete data were available for 661 men. c Complete biopsy data were available for 659 men a
b
Relative reductions in all-cause mortality from PIVOT are generally consistent with SPCG-4 [3] and ProtecT [4]. However, PIVOT findings reflect men diagnosed, and using treatments available, during the early PSA era, a midpoint between the pre-PSA (SPCG-4) and later PSA era (ProtecT). Furthermore, ProtecT used 10 biopsy cores for prostate cancer evaluation versus and average six cores in PIVOT. The lead time resulting from PSA screening and histological grading modifications make it unlikely that current patients will experience absolute mortality benefits achieved in these two trials [3,4,20]; the NNT to achieve mortality reduction will be higher and will take longer, and the risk of overdiagnosis and overtreatment will be greater. Notably, SPCG-4 enrolled men with clinically detected prostate
cancer; 12% had T1c, PSA-detected disease (mean PSA =14 ng/ml). Through 23 yr, 32% men died of prostate cancer; absolute reductions in prostate cancer and all-cause mortality due to surgery were 12 percentage points (NNT = 8). Mean survival was increased by 2.9 yr. PIVOT enrolled men from 1994 to 2002 (mean PSA =10 ng/ml). Approximately 50% had T1c prostate cancers. Less than 10% of PIVOT participants died from prostate cancer through nearly 20 yr; absolute reductions due to surgery were 4 percentage points (NNT = 25). After >22 yr, all-cause mortality reductions associated with surgery were <6 percentage points; the mean survival increase was 1 yr. ProtecT enrolled men with PSA screen-detected prostate cancer (mean PSA = 6), and found that 10-yr all-cause
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Fig. 4 – Forest plot of all-cause mortality by patient and tumor subgroups. There were no significant between-group differences in all-cause mortality according to prespecified or post hoc subgroups, including age, score on the Gleason histological scale (<7, 7, or 7 on a scale of 2–10, with 10 indicating the most poorly differentiated tumors), self-reported race, self-reported performance status (0 [fully active] vs 1–4, with higher scores indicating poorer functional status), Charlson comorbidity index (0 vs 1–4 Charlson-defined comorbidities), baseline PSA categories (10 vs >10 ng/ml), D’Amico tumor risk score (low, intermediate, or high; this score was based on tumor stage, histological score, and PSA level), CAPRA risk scores (low, intermediate, or high), and percentage biopsy cores positive for cancer (<34% vs 34%; all p > 0.10). The bars indicate 95% confidence intervals. CI = confidence interval; PSA = prostate-specific antigen.
mortality with active monitoring, surgery, or radiotherapy was 10.8%, 9.9%, and 10.1%, respectively. Prostate cancer mortality was 1% in all groups. Our results, together with SPCG-4, ProtecT, and two earlier trials that found no mortality benefits of surgery [2] or radiation [21] versus observation, indicate that observation, PSA-based monitoring, and possibly biopsy-based active surveillance can inform guideline recommendations and expand indications for observation, PSA-based monitoring, or active surveillance regardless of cancer risk status. Convincing evidence exists that observation and PSA-based monitoring result in similar long-term mortality with less harm compared with surgery or radiation for men with PSAdetected low-risk prostate cancer and many with intermediate- or high-risk disease [1–4,22]. Early intervention results in morbidity and negatively impacts urinary, sexual, and erectile function, as well as physical comfort and activities of daily living [1,23–26]. Clinical decisions should incorporate information that surgery and radiation reduce
and androgren deprivation therapy progression [1,3,4]. However, most progression is asymptomatic, and reductions due to surgery or radiation are small. Active surveillance programs could safely reduce biopsy frequency and increase thresholds triggering interventions. Surgery may have important mortality benefits in men with long-life expectancies having clinically detected, intermediate-risk, and possibly high-risk prostate cancer, especially if conducted at higher-volume centers with experienced surgeons [27]. We do not have information on physician experience or surgical volume, measures associated with surgical quality. However, center selection for study participation was based, in part, on demonstrated higher surgical volume. All surgery was conducted by, or under the direct supervision of, staff urologists. We previously reported that more direct measures of surgical quality such as perioperative morbidity, mortality, surgical margin positivity, and time to initiate additional therapy for disease progression were similar to those reported by others
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Fig. 5 – Kaplan-Meir plots of mortality by CAPRA risk scores. All-cause mortality according to CAPRA risk scores: (A) low risk (score: 0–2; n = 204; HR = 1.08; 95% CI: 0.76–1.52); (B) intermediate risk (score: 3–5; n = 334; HR = 0.74; 95% CI: 0.57–0.96); and (C) high risk (score 6–10; n = 121; HR = 0.70; 95% CI: 0.47–1.05). Data from the prostatectomy group are shown in the red line and data from the observation group in the blue line. CI = confidence interval; HR = hazard ratio.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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Fig. 6 – Kaplan-Meir plots of mortality by percentage of biopsy cores positive. All-cause mortality according to CAPRA risk scores: (A) <34% cores positive (HR = 0.96; 95% CI: 0.75–1.24; n = 357) and (B) 34% cores positive (HR = 0.73; 95% CI: 0.56–0.95; n = 302). The red line shows data from the prostatectomy group and the blue line shoes data from the observation group. CI = confidence interval; HR = hazard ratio.
Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009
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[22]. While men with high Gleason sums and D’Amico highrisk disease have poorer prognosis, surgery did not reduce mortality at extended follow-up and resulted in 1 yr of life gained, with CIs including life-years lost. We previously found that surgery did not reduce prostate cancer mortality or treatment for regional or systemic progression in D’Amico high-risk disease [1]. Mortality differences and life-years gained were greater in CAPRA high-risk disease. Treatment decisions should incorporate findings demonstrating mortality benefits of new drug therapies among men developing advanced disease [28–30]. Randomized trials of biopsy-based active surveillance are needed in intermediate- and high-risk disease and to assess riskstratified treatment decisions, including multimodality treatment, based on multiparametric magnetic resonance imaging or tissue-based molecular markers [31]. 5.
Conclusions
In conclusion, at a median 18 yr of follow-up, surgery was associated with small but lower all-cause mortality compared with observation in men with clinically localized prostate cancer. The relative reduction was 8%, corresponding to an absolute reduction of 5.7 percentage points and mean survival increase of 1 yr. Our results are compatible with estimates ranging from no difference to a moderate difference. Absolute effects did not vary markedly by patient characteristics. Absolute effects and mean survival were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with high-risk disease. Strategies are needed to effectively communicate the results of these findings, and to enhance identification of individuals needing and benefitting from early intervention while reducing harms of ineffective treatments and/or overtreatment.
11
Funding/Support and role of the sponsor: This study was funded by the Department of Veterans Affairs Cooperative Studies Program, the National Cancer Institute, and the Agency for Health Care Research and Quality (PIVOT ClinicalTrials.gov number, NCT00007644). Researchers were independent from the funders. Authors had access to study data. The contents do not represent the views of the U.S. Department of Veterans Affairs or the US government.
Acknowledgments: We wish to thank Karen M. Jones, MS, and the Perry Point VA Cooperative Studies Program Coordinating Center for many years of support, data coordination, and analyses on prior manuscripts, and assistance in data transfer under a Data Use Agreement to the Minneapolis VA Center for Care Delivery and Outcomes Research.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. eururo.2020.02.009.
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Please cite this article in press as: Wilt TJ, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol (2020), https://doi.org/ 10.1016/j.eururo.2020.02.009