Long-Term Follow-up of PIVOT Argues for Immediate Treatment of Men With Unfavorable-Risk and Possibly High-Volume, Low-Risk Prostate Cancer

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The updated results of the PIVOT1 study—reported in The New England Journal of Medicine by Wilt et al and reviewed in this issue of The ASCO Post (page 20)—did not show a statistically significant difference between treatment and observation for the initial management approach to men with newly diagnosed prostate cancer. But it almost did, missing significance in the P value that evaluated for a potential survival benefit for treatment as compared to observation by only 1/100th of a point. 

Moreover, the results have strengthened greatly in favor of treatment since the initial report in 2012,2 in that the P value assessing the impact on all-cause death with treatment vs observation decreased from .22 to .06, with a percent reduction in all-cause death that also improved from 12% to 16%. This is particularly important because the PIVOT study is the only treatment-vs-observation study with a significant proportion of African American men (approximately one-third of the study cohort), who are an underrepresented group in prostate cancer randomized trials. 

The results are further strengthened by the fact that men in the PIVOT study had a shorter life expectancy compared with men of average health in the United States due to competing risks.3 In particular, both the significantly shorter life expectancy and the fact that the PIVOT study did not reach its accrual goal of approximately 2,000, instead accruing only 731 men, are both factors that should have caused it to be underpowered to measure a significant difference between the two randomized arms. If the study had enrolled healthier men and/or reached its accrual goal, then it is very likely that the P value reporting on the comparison of all-cause death between the two randomized study arms would have reached significance.

Application to Patients Presenting Today

While the absolute differences observed in all-cause and prostate cancer–specific death rates between the two randomized treatment arms appear small—5.5% and 4%, respectively— they are deflated because of the study’s large proportion of men (about 40%) with low-risk prostate cancer, in whom immediate treatment was not shown to prolong survival, compared with observation.1 This is why it is important also to evaluate the endpoint of all-cause death within subgroups of men who had unfavorable-risk prostate cancer (ie, those with intermediate- and high-risk disease). 

If the study had enrolled healthier men and/or reached its accrual goal, then it is very likely that the P value reporting on the comparison of all‑cause death … would have reached ­significance.
— Anthony V. D’Amico, MD, PhD

When doing so, it was observed that for men with intermediate-risk prostate cancer, treatment (vs observation) was associated with a -significant 32% reduction in mortality, whereas in men with high-risk disease, a 22% reduction was observed, which was not significant, likely due to the small sample size. In men with intermediate-risk disease, the incidence of all-cause mortality was 59.7% with treatment and 74.2% with observation (for an absolute difference of 14.5%, which is nearly threefold higher than the 5.5% reported in the overall study cohort). 

Given both the decline in prostate-specific antigen (PSA) screening in the United States in recent years4 and the increasing use of active surveillance for low-risk prostate cancer,5 the benefit of treatment vs observation in men with unfavorable-risk prostate cancer suggested by these subgroup analyses will apply to a greater proportion of men presenting with newly diagnosed prostate cancer today. 

Best Initial Approach to High-Volume, Low-Risk Prostate Cancer

One additional subgroup analysis not performed by the PIVOT investigators—perhaps because of a lack of data on percent-positive biopsies—is in men with low-risk but high-volume prostate cancer as assessed by the percent-positive biopsies. This group is particularly pertinent and deserving of further study, given the known relationship between upgrading and increasing percent-positive biopsies in men with low-risk prostate cancer6 and the very favorable outcomes reported for men on active surveillance with very low-risk prostate cancer,7 a subgroup of men with low-risk prostate cancer but also a low percentage of positive biopsies and PSA density. 

It is possible that men with low-risk prostate cancer but high-volume disease based on percent-positive prostate biopsies (ie, > 50%) may also benefit from immediate treatment, as a high proportion of them have been shown to harbor occult grade IV prostate cancer or intermediate-risk disease.7 Given the significant reduction in mortality observed in the PIVOT study for men with intermediate-risk prostate cancer, this high-volume subgroup of men with low-risk prostate cancer deserves further study. 

Should Metastasis Be a Co-primary Endpoint?

Unfortunately, the impact on metastasis is often overlooked in randomized studies of treatment vs observation. This issue arises because metastasis is not the primary endpoint, and in the case of the updated PIVOT study, the results comparing metastasis between the two randomized arms were published only in the supplemental appendix.1 There, the authors observed a significant 36% reduction in metastasis among men undergoing treatment as compared to observation. This reduction in metastasis is clinically relevant, in light of the pain and suffering often associated with metastatic disease and the side effects of its treatment, including (at a minimum) life-long intermittent androgen-deprivation therapy.8

In conclusion, a significant decrease in metastatic disease and a near-significant overall mortality reduction were observed in the updated PIVOT study,1 despite competing risks. Given these results and the potential for a large and significant benefit seen in men with intermediate-risk prostate cancer, the updated data make a strong case for immediate treatment as compared to observation in men with unfavorable-risk prostate cancer and possibly men with high-volume, low-risk prostate cancer. ■

DISCLOSURE: Dr. D’Amico reported no conflicts of interest.

Dr. D’Amico is Professor of Radiation Oncology, and Chief, Division of Genitourinary Radiation Oncology Institute Physician, Harvard Medical School, Boston.


1. Wilt TJ, Jones KM, Barry MJ, et al: Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med 377:132-142, 2017.

2. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367: 203-213, 2012.

3. Aizer AA, Chen MH, Hattangadi J, et al: Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int 113:43-50, 2014.

4. Fedewa SA, Ward EM, Brawley O, et al: Recent patterns of prostate-specific antigen testing for prostate cancer screening in the United States. JAMA Intern Med 177:1041-1042, 2017.

5. Cooperberg MR, Carroll PR: Trends in management for patients with localized prostate cancer, 1990-2013. JAMA 314:80-82, 2015.

6. Dinh KT, Mahal BA, Ziehr DR, et al: Incidence and predictors of upgrading and upstaging among 10,000 contemporary patients with low-risk prostate cancer. J Urology 194:343-349, 2015

7. Tosoian JJ, Mamawala M, Epstein JI, et al: Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J Clin Oncol 33:3379-3385, 2015.

8. D’Amico AV: Active surveillance versus treatment of prostate cancer: Should metastasis be the primary end point? J Clin Oncol 35:1638-1640, 2017.

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