I am happy to accept the invitation by The ASCO Post to comment on the recent, long-awaited publication of the PIVOT study (Wilt et al: N Engl J Med 367:203-213, 2012) and the accompanying editorial by Thompson and Tangen (N Engl J Med 367:270-271, 2012). The editorial both points out weaknesses of the PIVOT report that limit its applicability to clinical practice and helps to clarify the confusion arising out of the contradictory findings of the PIVOT study and the recently published Scandinavian Prostate Group study 4 (SPG 4).1 The commentators strongly suggest that the PIVOT study is insufficiently powered to support the conclusion that radical prostatectomy does not reduce all-cause or prostate cancer mortality when compared with observation in men with clinically localized prostate cancer
While I fully agree with the critical review of the original and revised power calculations in the editorial, the authors do not point out an underlying clinical factor that is likely to have affected the outcome of the study and that serves to further limit applicability of PIVOT results. The study included a large proportion of T1c Gleason 3+3 cancers, which are likely to be overdiagnosed, with most cases not expected to progress or become life-threatening during the patient’s lifetime. These tumors are part of the low-risk group described in the PIVOT article.
The authors state: “About 50% of the men had stage T1c disease (not palpable, detected by means of [prostate-specific antigen (PSA)] testing) and about 25% had histologic scores of 7 or higher on the Gleason scale.” Although the specific proportion of men with T1c cancers and Gleason scores of 6 or less is not available, these figures imply that somewhere around 75% of the men with T1c cancers had well-differentiated tumors classified as Gleason 6 or less and that somewhere around 37.5% of all patients had these characteristics.
Natural History of Prostate Cancer
Knowledge about the natural history of well-differentiated T1c prostate cancer has developed only in recent years and was not available at the time PIVOT was initiated in 1994. About that time, the first evidence estimating the lead time of locally confined prostate cancer in relation to PSA levels became available.2,3 Estimates of lead time and overdiagnosis produced by PSA-driven screening were first published in 2003.4
An analysis of the effect of prognostic factors on these important predictors of the natural history of prostate cancer is about to be published.5 This analysis shows a rate of overdiagnosis of 30.5% for this lowest risk category. This estimate is in line with an analysis and risk classification of men who had chosen active surveillance in the Rotterdam screening study. The estimated rate of cancers defined as “indolent” in this report is 28.9%.6
Confirmative evidence of these classifications and of estimates that are based on modeling and on biopsy findings comes from the available active surveillance studies, which all have follow-up periods that—at this time—fall short of the lead-time estimates. Still, in a cooperative study in Finnish and Rotterdam European Randomized Study of Screening for Prostate Cancer (ERSPC) centers in 509 patients with a median follow-up of 7.4 years, a prostate cancer–specific survival of 99.1% was observed.7 A prospective study of active surveillance conducted at Johns Hopkins Medical Center included only T1c cases.8 No metastatic disease or prostate cancer deaths were encountered in 769 patients with a median follow-up of 2.7 years (range, 0.1–15.0 years).
Interpreting the Data
What might the inclusion of 37.5% of participants with an almost zero chance of prostate cancer progression or mortality mean for the interpretation, understanding, and clinical application of the PIVOT data? Although I am not a statistician and unable to quantitatively judge the effect of including so many cancers that do not contribute to the endpoint of prostate cancer and all-cause mortality, I would venture to say that as the power of the study decreases further, its outcomes become even less informative.
Subgroup analyses in the PIVOT study show a significant effect of radical prostatectomy in men presenting with PSA ≥ 10 ng/mL (P = .04) and a borderline significance (P = .07) if the low-risk group is compared to cancers with intermediate or high risk. What might the result have been if PIVOT had not included the 50% of T1c cancers? The study would have become very similar to the SPG 4 study and would probably have shown the same result.
Limited Options
How then should we as clinicians understand and use the results of PIVOT? In dealing with prostate cancer, we need to apply current knowledge and either avoid the diagnosis of potentially overdiagnosed cancer altogether or, if such tumors are diagnosed, recommend active surveillance as the first option.
Unfortunately, at present, the options to avoid prostatic biopsy in men who harbor potentially overdiagnosed prostate cancers are limited. The only feasible option is the application of available risk calculators that consider routine clinical findings next to PSA. This has been shown to be effective in a study in the Rotterdam section of the ERSPC.9
In my view, the results of the SPG 4 study apply to prostate cancers that do not fall within the T1c Gleason 6 group. These men remain candidates for potentially curative forms of management such as radical prostatectomy or the different options offered by radiotherapy.
Disclosure: Dr. Schröder reported no potential conflicts of interest.
Fritz H. Schröder, MD
Professor of Urology
Erasmus University Medical Centre
Rotterdam, The Netherlands
References
1. Bill-Axelson A, Holmberg L, Ruutu M, et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 364:1708-1717, 2011.
2. Stenman UH, Hakama M, Knekt P, et al: Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet 344:1594-1598, 1994.
3. Gann PH, Hennekens CH, Stampfer MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 273:289-294, 1995.
4. Draisma G, Boer R, Otto SJ, et al: Lead times and overdetection due to prostate-specific antigen screening: Estimates from the European Randomized study of Screening for Prostate Cancer. J Natl Cancer Inst 95:868-878, 2003.
5. Wever EM, Heijnsdijk EAM, Draisma G, et al: Treatment of PSA-detected prostate cancer: Benefits and harms by prognostic factors. Submitted, 2012.
6. Roemeling S, Roobol MJ, Postma R, et al: Management and survival of screen detected prostate cancer patients who might have been suitable for active surveillance. Eur Urol 50:475-482, 2006.
7. Bul M, van den Bergh RC, Zhu X, et al: Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer. BJU Int. August 29, 2012 (early release online).
8. Tosoian JJ, Trock BJ, Landis P, et al: Active surveillance program for prostate cancer: an update of the Johns Hopkins Experience. J Clin Oncol 29:2185-2190, 2011.
9. Roobol MJ, Steyerberg EW, Kranse R, et al: A risk-based strategy improves prostate-specific antigen-driven detection of prostate cancer. Eur Urol 57:79-85, 2010.
