Enrollment Criteria Controversies for Active Surveillance and Triggers for Conversion to Treatment in Prostate Cancer
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Focused 1101 Review Enrollment Criteria Controversies for Active Surveillance and Triggers for Conversion to Treatment in Prostate Cancer David D. Buethe, MD, and Julio Pow-Sang, MD Abstract migration of newly diagnosed prostate cancer3 has In the era of widespread prostate-specific antigen screening, low- occurred, along with the revelation that low-risk tumors risk and very-low-risk prostate cancers are commonly identified, 4–8 many of which will be of clinical insignificance. This has led to are often of clinical insignificance. Despite the fact that overtreatment and undue exposure to treatment-related morbid- these low-risk cancers have a slow growth rate and a low ity in men harboring indolent tumors. Over the past 10 years, ac- probability of metastasis and death within the first 10 years tive surveillance (AS) has been evolving as a management strat- after diagnosis,9 91% of patients with tumors fulfilling egy for these cancers. With continual reevaluation, the intent is Epstein’s criteria for low risk or very low risk still undergo to definitively treat tumors that are clearly progressive before the treatment.10 This occurs amidst recent reporting that, window of opportunity for cure has closed. To date, many of the surveillance parameters are without validation of utility, variably at a median follow-up of 11 years, 37 cancers, spanning used, and without a standardized schedule. However, new instru- all risk categories, must be treated to prevent 1 prostate ments for characterizing prostate cancer offer the potential to bet- cancer–specific mortality.11 In 2011, the United States ter distinguish which men are best managed definitively at the Preventative Services Task Force cautioned that the use outset from those who would be better served with observation. of PSA to screen for prostate cancer in asymptomatic The findings of currently available AS cohorts suggest that initial expectant management of early prostate cancer is reasonable, men leads to overdiagnosis and overtreatment in most 12 showing that only approximately 30% of observed tumors are re- men diagnosed with prostate cancer, supporting AS as a classified to ones of intermediate risk with short-term follow-up. reasonable management option for well-selected patients. Prostate cancer survival for men undergoing AS is close to 100% Critical uncertainties still surround the AS in all available studies, but long-term data remain scarce for those algorithm. Specifically, a need remains to optimize the requiring delayed curative therapy. (JNCCN 2012;10:1101–1110) criteria that qualify a man as either low risk or very low risk, and to establish standardized criteria defining disease progression. Further, there is a paucity of reports on the long-term outcomes of men electing to delay or he year 2012 marks the 10th anniversary of the initial T forgo definitive treatment. reporting of active surveillance (AS) as a management This article reviews the most recent literature 1,2 strategy for low-risk prostate cancer. regarding these clinical questions and provides a Since the widespread use of prostate-specific antigen practical algorithm that may assist practitioners when (PSA) beginning in the early 1990s, a downward risk counseling men undergoing AS. This algorithm may be modified and expanded as new knowledge develops. From H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Submitted April 20, 2012; accepted for publication July 3, 2012. Risk Stratification and Eligibility Criteria The authors have disclosed that they have no financial interests, 13 4 arrangements, or affiliations with the manufacturers of any The D’Amico et al and Epstein et al criteria are the products discussed in this article or their competitors. most commonly used risk stratification systems. Low-risk Correspondence: Julio Pow-Sang, MD, Genitourinary Oncology 14 Program, H. Lee Moffitt Cancer Center and Research Institute, cancers are those presenting with a PSA of less than 10 12902 Magnolia Drive, Tampa, FL 33612-9416. ng/mL and a Gleason sum of 6 or lower, and very-low- E-mail: [email protected] risk tumors4 are those that meet the low-risk criteria and © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 9 | September 2012 1102 Focused Review Buethe and Pow-Sang also show tumor involvement of less than 50% of any ng/mL who were managed with RP and pelvic biopsy core, involve fewer than 3 biopsy cores, are lymph node dissection. Other reports confirm nonpalpable, and are associated with a PSA density this observation.17,23,28 Inspection of whole-mount of 0.15 ng/mL/g or less. Tumors of very low risk have prostatectomy specimens has previously shown a been associated with tumor volume of less than 0.5 significant indirect correlation between percent-free cm3 at prostatectomy. Both sets of criteria require the PSA and prostate cancer volume.29 In 376 patients findings of either a normal prostate or the presence on AS, a multivariate analysis accounting for age, of only a small nodule (cT1, cT2a) on digital rectal PSA, PSA density, and number of cores positive for examination (DRE) and have been incorporated prostate cancer found that a percent-free PSA of 15 or into the NCCN Clinical Practice Guidelines in less was predictive of future tumor reclassification.25 Oncology (NCCN Guidelines) for Prostate Cancer Nevertheless, this parameter is not widely accepted (to view the most recent version of these guidelines, as a predictor of cancer extent.30–33 visit NCCN.org). Current NCCN Guidelines define Number of Cores and Volume of Involvement low-risk tumors as clinical T1 through T2a tumors All but one of the evaluated AS studies lists the with a Gleason sum of 6 or lower and are associated number of positive cores and the extent to which with a PSA of less than 10 ng/mL. Very-low-risk each core is involved as part of the enrollment tumors are clinically T1 tumors, have a Gleason sum criteria. Reports are consistent in showing the of 6 or lower, involve fewer than 3 cores and 50% or predictive value of the number of positive cores,34,35 less of any individual core, and are associated with but limited data support optimal cutoff points,35,36 15 a PSA density of less than 0.15 ng/mL/g. Patients and this finding remains controversial regarding with these characteristics have been found to harbor outcomes in AS cohorts.17,23 clinically insignificant tumors with a tumor volume Cheng et al34 investigated the significance 3 of less than 0.5 cm , have a Gleason sum of 6 or lower, of the extent to which a single biopsy core was have no extraprostatic extension, and have negative involved. They found a significant correlation with margins, seminal vesicles, and lymph nodes at the prostate cancer volume in univariable analysis, and 4 time of radical prostatectomy (RP). These men also provided a graphical representation showing that the have a very low prostate cancer–specific mortality probability of finding only low-volume disease at RP 16 even at long-term follow-up. in patients with greater than 30% of any one core 17–24 A review of reported AS series reveals was less than 5%. significant lack of standardization with respect to Accounting for both the number of positive inclusion criteria (Table 1). Although PSA, Gleason cores and the extent to which each core was involved grade, and clinical stage are generally accepted by tumor, Ploussard et al37 prospectively found that selection criteria, the additional parameters of PSA obtaining 21 cores, compared with 12, provided a density, percent-free PSA, and extent to which biopsy more accurate prediction of those with truly indolent cores are involved by tumor are variably considered. prostate cancer based on RP specimens. However, PSA Density Eggener et al19 found that the total number of A PSA density of 0.08 ng/mL/g or greater25 is positive cores after 2 standard biopsies (but not the identified as a significant predictor of future disease total number of cores) identified before assignment progression in those with low-risk prostate cancer to AS correlated with progression-free interval. initially managed expectantly.26 However, this is not a consistent finding,17,23 because other clinicians use a level of 0.15 ng/mL/g as a threshold.4 Surveillance Protocols Percent Free/Total PSA Frequency of PSA/DRE Shariat et al27 indentified percent-free PSA to be No standardized protocol exists for the frequency a significant predictor of organ-confined disease, of PSA or DRE. Current guidelines vary, with seminal vesicle invasion, lymphovascular invasion, recommendations to obtain a PSA every 3 to 6 and Gleason sum on multivariate analysis of 402 months and perform a DRE every 3 to 6 months, patients presenting with a PSA of less than 10 or 12 months in men with a life expectancy of 10 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 9 | September 2012 Focused Review 1103 Prostate Cancer: What About Surveillance? Table 1 Inclusion Criteria Inclusion Critera Gleason Study (Author) n PSA Parametersa Clinical Stage Grade Volume Cores Royal Marsden 326 PSA ≤ 15 cT1–2a,N0–x, ≤ 3 + 4 – ≤ 50% of (van As et al17) M0–x cores involved UCSF 321 PSA ≤ 10 cT1–2a ≤ 3 + 3 – ≤ 33% of (Dall’Era et al18) cores involved Multi- 262 PSA ≤ 10 cT1–2a ≤ 3 + 3 – ≤ 3 cores institutional positive (Eggener et al19) PASS 233 – CT1–2,N0–x, – – – (Newcomb et al20) M0–x Toronto 450 If age ≤ 70 y; ≤ 10 cT1 If age ≤ 70 – – (Klotz et al21) y; ≤ 3 + 3 If age > 70 y; ≤ 15 If age > 70 y; ≤ 3 + 4 Miami 230 PSA ≤ 10 cT1a–2 ≤ 3 + 3 ≤ 20% of each ≤ 2 cores (Soloway et al22) involved core positive Johns Hopkins 769 PSA ≤ 10 cT1c ≤ 3 + 3 ≤ 50% of each ≤ 2 cores (Tosoian et al23) PSAd < 0.15 involved core positive PRIAS > 2000 PSA ≤ 10 cT1c–T2 ≤ 3 + 3 – ≤ 2 cores (Bangma et al24) PSAd < 0.2 positive Abbreviations: PASS, Prostate Active Surveillance Study; PRIAS, Prostate Cancer Research International: Active Surveillance study; PSA, prostate-specific antigen; PSAd, prostate-specific antigen density; UCSF, University of California San Francisco.