Long-term active surveillance for prostate cancer: answers and questions.

VOLUME NUMBER JANUARY J OURNAL OF C LINICAL O NCOLOGY E D I T O R I A L Long-Term Active Surveillance for Prostate Cancer: Answers and Questions Matthew R. Cooperberg, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA See accompanying article on page 272 In recent years, active surveillance has evolved from an exper- imental protocol to a broadly accepted—in fact, preferred— management strategy for men diagnosed with low-risk prostate cancer. 1 Active surveillance is a crucial aspect of efforts to solve the prostate-specific antigen (PSA) – based early detection conundrum without sacrificing the tremendous gains that have been realized in mortality rates. 2,3 Cohort studies of active surveillance, primarily from academic institutions, have collectively reported short- to intermediate-term outcomes on thousands of men, generally sup- porting the safety and efficacy of the approach over the first years of follow-up. 4 This conservative approach to low-risk disease appears to be making recent inroads even outside of academia, at least in limited settings. 5 The problem has been that the natural history of low-risk prostate cancer is measurable over years and decades, and short-term disease stability does not reliably predict long-term survival. In the article accompanying this editorial, Klotz et al 6 report the longest follow-up to date in one of the largest extant active surveillance cohorts. The median follow-up in the Sunnybrook cohort of 993 men stands at 6.4 years, notably longer than most other centers, but still short in the context of prostate cancer’s typical course. Over 200 of the men had 10 years or more of follow-up, which begins to be sufficient to identify true clinical progression events. Of those with adequate follow-up, more than 75% of the men remained on surveillance at 5 years— higher than in most cohorts—and over half beyond 15 years. 6 In total, 149 men died during active surveillance; 15 of these died of prostate cancer, and another 13 developed metastatic disease. These figures highlight the extent to which competing morbidities are salient for men with low-risk prostate cancer, and it is notable than even among those with metastatic disease four died of other causes rather than of prostate cancer. Klotz et al 6 report an overall rate of metastasis of 2.8%, occurring at a median of 9.6 years after diagnosis. Before this figure is argued by proponents of immediate treatment for low-risk disease to represent the risk of active surveillance, it should be stressed that it is not dissimilar from the risk of lethal disease among men treated immediately for low-risk tumors (ranging from 1.4% to 5.9% at 10 years depending on primary treatment in one large, multicenter series). 7 The last time the Sunnybrook surveillance experience was re- ported, in 2010, the cohort was less than half as large (N ⫽ 450) and median follow-up was similar. At that point, five men had died of prostate cancer, and Klotz et al 8 provided details on their clinical © 2014 by American Society of Clinical Oncology courses. All five had been identified with rapid PSA kinetics and were advised to undergo treatment; two refused, and two had rapidly pro- gressive disease that likely was present at diagnosis. The authors con- cluded that only one man died after treatment delayed by at least 2 years of surveillance. 8 The current article provides only cursory detail on the men pro- gressing to lethal disease: about half were treated with radiation, only two with surgery, and rest with androgen ablation or no treatment. 6 These latter men in point of fact should be considered to have been on watchful waiting, not active surveillance. The article therefore does not yet answer the critical question: not how many men die of prostate cancer in a surveillance cohort, but how many ultimately succumb specifically because they chose surveillance and thereby missed the window of opportunity for cure. Whatever this number truly is, it is greater than zero. These deaths by definition are preventable, and as sins of omission are particularly galling to cancer-focused clinicians. But in the alternative paradigm of immediate intervention for all low-risk tumors, they are vastly outnumbered by men harmed substantially by entirely avoid- able treatments. 9,10 The way forward for active surveillance, then, must be lighted by improved tools for risk stratification at diagnosis and for early identi- fication of progressive disease. The first key question is who should be eligible for active surveillance. Various surveillance cohorts use criteria of varying stringency to select men for surveillance. Klotz et al 6 note that their inclusion criteria were made more restrictive as of 2000, including men with Gleason 3 ⫹ 4 tumors only in the setting of limited life expectancy. Yet over a quarter of the men who devel- oped metastases met the strictest criteria for very low–risk disease, those proposed by Johns Hopkins University. 6,11 While a number of nomograms have been proposed to predict indolent prostate cancer, these actually only have been shown to predict small, low-grade tumors at prostatectomy, and none has proved reliably predictive in the setting of active surveillance. 12 Conversely, the experience at University of California, San Fran- cisco, which has offered active surveillance to a growing number of men with high-volume Gleason 3 ⫹ 3 and low-volume Gleason 3 ⫹ 4 tumors, has shown that such men are no more likely to progress, at least in the short term, than those with lower-risk tumors. 13 Recent articles have argued that Gleason 3 ⫹ 3 cancer does not metastasize no matter what volume of tumor is present, 14 and Gleason 3 ⫹ 4 tumors Journal of Clinical Oncology, Vol 33, No 3 (January 20), 2015: pp 238-240 Information downloaded from jco.ascopubs. org and provided by at UCSF Library on July 12, 2016 from 128.218. 42.124 Copyright © 2015 American Society of Clinical Oncology. 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