High Risk Prostate Cancer Managed by Active Surveillance

Author's Accepted Manuscript Intermediate-Term Outcomes of Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance Yaw A. Nyame , Nima Almassi , Samuel C. Haywood , Daniel J. Greene , Vishnu Ganesan , Charles Dai , Joseph Zabell , Chad Reichard , Hans Arora , Anna Zampini , Alice Crane , Daniel Hettel , Ahmed Elshafei , Khaled Fareed , Robert J. Stein , Ryan K. Berglund , Michael Gong , J. Stephen Jones , Eric A. Klein , Andrew J. Stephenson

PII: DOI: Reference:

S0022-5347(17)42185-9 10.1016/j.juro.2017.03.123 JURO 14656

To appear in: The Journal of Urology Accepted Date: 18 March 2017 Please cite this article as: Nyame YA, Almassi N, Haywood SC, Greene DJ, Ganesan V, Dai C, Zabell J, Reichard C, Arora H, Zampini A, Crane A, Hettel D, Elshafei A, Fareed K, Stein RJ, Berglund RK, Gong M, Jones JS, Klein EA, Stephenson AJ, Intermediate-Term Outcomes of Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.03.123. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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Title: Intermediate-Term Outcomes of Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance

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Authors: Yaw A. Nyame, Nima Almassi, Samuel C. Haywood, Daniel J. Greene, Vishnu Ganesan, Charles Dai, Joseph Zabell, Chad Reichard, Hans Arora, Anna Zampini, Alice Crane, Daniel Hettel, Ahmed Elshafei, Khaled Fareed, Robert J. Stein, Ryan K. Berglund, Michael Gong, J. Stephen Jones, Eric A. Klein, Andrew J. Stephenson

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Authors' Affiliations: Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio

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Corresponding Author: Dr. Andrew J. Stephenson, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Ave, Q10-100, Cleveland, OH 44113. Phone: +011 216 444 2200; Fax: +011 216 445 2267. E-mail: [email protected]

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Funding: none

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Key words: active surveillance, prostate cancer, outcomes, epidemiology

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Conflict of Interest: The authors have no disclosures to report

Page Count: 14 pages (including title page) Figures and Tables Count: 4 Figure, 3 Tables Word Count: 250 words of abstract, 19 references

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ABSTRACT: Purpose: To compare intermediate-term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer (PCa) managed with active surveillance (AS).

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Materials and Methods: Since 2002, 635 men with localized PCa have been managed with AS at a high-volume U.S. academic hospital with a median follow-up of 50.5 months (IQR 31.180.3). Time to event analysis was performed for our clinical endpoints.

Results: 117 men (18.4% of the cohort) had intermediate/high risk disease. The overall 5- and

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10-year all-cause survival was 98% and 94%, respectively. The cumulative metastasis-free survival at 5- and 10-years was 99% and 98%. To date, no cancer-specific deaths have been observed.

The overall freedom from intervention was 61% and 49%, at 5- and 10-years

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respectively. Overall, the cumulative freedom from failure of AS-—defined as the development of metastasis or biochemical failure after local therapy with curative intent— was 97% and 91% at 5- and 10-years, respectively. Twenty-one (9.9%) men experienced biochemical failure after deferred treatment and the 5-year progression free probability was 92%. Compared to men with favorable risk disease, men with intermediate/high risk cancer experienced no difference in metastases, surveillance failure, or curative intervention.

However, higher risk patients

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experienced significantly higher risk of all-cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and duration of our study period.

Patients with localized prostate cancer on AS demonstrated a low rate of AS

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Conclusions:

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failure, prostate cancer specific mortality, metastases, regardless of baseline risk.

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INTRODUCTION

The USPTF recommended against routine PSA screening in 2012 with over diagnosis and over treatment of screen-detected cancers forming a large basis for the committee’s recommendations . Since the introduction of widespread PSA screening, AS has represented a seldom-used option

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for screen-detected PCa, even among men with low-risk features and/or limited life expectancy 2. However, based on the results of several recent landmark studies

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, a change in practice has

been observed with a dramatic spike in the use of AS among men with favorable cancer features . However, the majority of men with life expectancy > 10 years and very low-, low-, and

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intermediate-risk features continue to receive curative therapy. 7-10

for disease classification and standardization of pathologic classification

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adjunctive tools

Moreover, it is unclear if

are allowing for more accurate disease characterization among men diagnosed with localized disease. This is especially important given recent evidence from an early AS cohort, initiated in 1995, demonstrating an increased risk of metastatic disease in men with Gleason 7 disease with prolonged follow-up 12.

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We endeavored to summarize the experience of AS in a high-volume U.S. academic setting among select men with very low, low, and intermediate/high risk PCa with a focus on clinical hard endpoints (ACM, PCSM, metastasis), rate of curative intervention (and the success of that therapy), and rate of surveillance failure (defined as clinical progression and/or deferred

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treatment failure).

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METHODS Through review of an institutional review board-approved prospective prostate biopsy database and provider patient lists, we identified 635 patients with localized PCa initially managed

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expectantly from 2002-2015. Enrollment in AS was assessed based on each patient’s individual goals of care, comorbidities, and PCa specific risks, in a shared-decision with each practitioner.

Generally, AS at our institution was restricted to patients with very low and low risk PCa by 13

, although select patients with

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National Comprehensive Cancer Network (NCCN) criteria

intermediate and high risk features and life expectancy < 20 years were enrolled in more recent years.

The surveillance protocol varied by physician, but generally involved interval PSA

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measurement (every 6-12 months), digital rectal examination at each clinic visit, and surveillance prostate biopsy (defined as biopsy performed > 1 year after diagnosis) with a minimum of 12 cores every 1-3 years. Adjunctive diagnostic tests such as prostate multiparametric magnetic resonance (mpMR) imaging, urinary PCA3, and genomic testing on prostate biopsy specimens were also performed at the discretion of the urologists. Patients typically were recommended to undergo a confirmatory biopsy within the first year.

Recently, individual physicians have

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elected to forgo confirmatory biopsy in favor of genomic testing. In recent years, MR-guided prostate biopsy was performed routinely for patients undergoing confirmatory and surveillance prostate biopsy.

Curative intervention was recommended on the basis of disease

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reclassification—i.e, an increase in disease grade or volume—or based on patient preference. Institutional review board approval was obtained for this study.

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Clinical and Demographic Data

The authors manually reviewed each relevant clinical patient encounter, and pertinent clinical and pathologic data was recorded for review, including all pertinent follow-up data. Patients were risk stratified by NCCN risk strata

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. Men selected for surveillance with intermediate or

high risk disease generally had low volume Gleason 7 disease and were over the age of 70; and more recently, genomic testing and/or mpMR have been used to confirm low disease risk in this group. The Memorial Sloan Kettering Cancer Center (MSKCC) preoperative PCa nomogram for predicting disease progression14 was used to calculate the 10-year progression-free probability 4

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(i.e., risk of biochemical failure after prostatectomy) at diagnosis and at last follow-up, and was used as an additional surrogate of disease risk. All pathologic specimens were analyzed by expert genitourinary pathologists at our institution.

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Statistical Analysis

Simple descriptive statistics were performed with Wilcoxon rank-sum test for continuous variables and Χ2 test for categorical variables. Data are presented as medians with interquartile The primary endpoints of this study were ACM, PCSM and

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range (IQR) or proportions.

metastatic progression (MP); and the secondary endpoints were time to curative intervention,

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biochemical failure after deferred treatment, and failure of surveillance (defined as metastasis, biochemical failure after therapy with curative intent, or PCSM). The incidence of each endpoint is reported per 100 person-years. The primary and secondary outcomes were evaluated using Kaplan-Meier analysis and reported as Cox proportion hazards. Entry into all time-to-event analyses occurred at the date of diagnosis. Patients were censored during analysis when they experienced the event of interest, died, or at the end of follow-up. The cumulative survival free

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from each point was additionally calculated at 5- and 10- years for the cohort. All statistical tests were two-sided. Statistical significance was defined as p < 0.05. All analyses were conducted

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using Stata 12.1 (StataCorp 2011, College Station, TX).

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RESULTS

Patient demographic information is listed in Table 1. The median follow-up for the 635 men in this study was 50.5 months (IQR 31.1-80.3). The median age of men in the cohort was 65.7

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years (IQR 60.9-70.2), and 10.9% of men in the cohort self-identified as African American. In total, 117 (18.4%) men had intermediate/high risk PCa. Of the 9 patients with high risk disease, none had Gleason score 8-9 disease, 1 had clinical T2c disease, and 8 had PSA > 20 ng/ml. The median 10-year progression free probability by preoperative nomogram at diagnosis and last

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follow-up was 90.7% (IQR 88.8-93.0) and 89.5% (IQR 84.0-93.7), and 77.7% (IQR 70.0-83.5)

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and 81.9% (IQR 60.1-88.0) for very low/low and intermediate/high risk men, respectively.

Primary Endpoint: Mortality and Metastasis

Sixteen (2.5%) men died in the cohort, and there were no PCa related deaths (Table 2). The median time from diagnosis to mortality among these men was 52.8 months (IQR 32.1-76.6), and the median age at the time of death was 72.1 years (range 58.9-88.9). None of the men who

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died in our cohort had developed metastatic PCa, and 6 (37.5%) of these men had received definitive therapy for PCa (3 brachytherapy, 2 external beam radiotherapy, and 1 cryoablation therapy). Four (0.8%) patients developed metastatic disease while on surveillance, of whom 3 and 1 had low- and intermediate-risk features at diagnosis, respectively and 2 developed distant

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metastases despite deferred curative therapy (1 radical prostatectomy and 1 brachytherapy; Table 2). The median time from diagnosis to metastatic disease among the 4 men was 39.5 months

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(IQR 15.1-75.0). The ACM and MP at 5 and 10 years was 2.1% and 0.9% and 6% and 2.3%, respectively.

When stratified by PCa risk, there was no significant difference in cumulative overall (Figure 1) and metastasis-free survival (Figure 2). When compared to men with favorable risk disease, there was a significantly decreased risk of overall survival (HR 0.24, 95% CI 0.09, 0.64), but there was no significant difference in metastasis-free survival (HR 1.50, 95% CI 0.16, 14.5) among men with intermediate/high risk PCa.

The overall and metastases-free survival

probability among men with very low/low risk disease was 98.4 % and 99.2%, respectively, at 56

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years, and 96.5% and 97.4%, respectively, at 10-years (Table 3).

Among men with

intermediate/high risk, the overall and metastasis-free survival probability was 95.6% and

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99.0%, respectively, at 5-years, and 77.0% and 99.0%, respectively at 10-years.

Secondary Endpoint: Treatment and Biochemical Failure Outcomes

Two hundred and twenty-four men (35.2%) received treatment with curative intent, with 107

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(47.8%), 86 (38.4%), 16 (7.1%), and 15 (6.7%) primarily receiving radical prostatectomy, brachytherapy, external-beam radiotherapy, and cryotherapy, respectively. The overall freedom

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from intervention was 61.3 % and 49.4 %, at 5- and 10-years respectively. Of the patients receiving definitive therapy, 145 (64.7%) had either grade or volume progression. 79 (35.3%) underwent therapy without evidence of reclassification, of which, 58 (16.9%) and 21 (23.3%) were very low/low and intermediate/high risk, respectively (p = 0.16). There was no difference in the cumulative rate of treatment over time observed between men with very low/low and

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intermediate/high risk disease (HR 1.01, 95% CI 0.72, 1.43; Figure 3).

213 men who received treatment with curative intent had sufficient follow-up data available to determine biochemical recurrence. Twenty-one (9.9%) men experienced biochemical failure after deferred treatment and the subsequent 5-year freedom from progression was 91.9% (95%

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CI 86.3, 95.3). Of the patients with biochemical failure, 13 (61.9%) had disease reclassification prior to treatment. The NCCN risk classification at the time of deferred therapy was very low,

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low, intermediate, and high-risk in 1 (1.6%), 14 (12.6%), 4 (12.1%), and 2 (40.0%), respectively. When compared to men with very low/low risk, there was an increased risk of biochemical failure (HR 2.71, 95% CI 1.02, 7.20) in patients with intermediate/high risk PCa (Figure 4). Overall, freedom from failure of AS was 97.7% and 90.1% for very low/low risk men and 94.8% and 88.4% for intermediate/high risk men, at 5- and 10-years, respectively.

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DISCUSSION

The aim of this study was to assess intermediate follow-up in patients on AS to determine the risk of this management strategy. Ultimately, we sought to understand the number of patients

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who failed AS, which we defined as death from PCa, metastatic disease, or biochemical failure after undergoing therapy with curative intent. In total, 635 men were identified at our institution that elected AS since 2002 with median follow-up of 50.5 months contributing to 3010.8 personyears. During that time, 403 men who entered a surveillance protocol avoided any form of

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treatment for their disease, and the cumulative freedom from intervention was 61.3% and 49.4%, at 5- and 10-years, respectively. Moreover, during our follow-up there have been no PCa

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specific deaths reported to-date. The cumulative risk of metastatic disease was 0.9% and 2.4%, at 5- and 10-years, respectively. Lastly, the rate of surveillance failure was 2.8% and 9.4% at 5and 10-years, respectively. In an era in which PCa screening is under scrutiny, these results affirm the clinical utility of AS for very low, low, and select intermediate and high risk men diagnosed with PCa.

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Approximately 19% of patients in our cohort were classified as intermediate or high risk at initial diagnosis by NCCN criteria.

There are no current institutional guidelines for selecting

intermediate/high risk patients for AS, and ultimately, a shared-decision is made with our patients based on the patient’s comorbidities and treatment expectations. In our cohort, men with

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intermediate/high risk disease who elected AS were significantly older, had higher PSA, had a higher percent of positive cores, were more likely to self-identify as African-American, and had

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lower MSKCC preoperative nomogram scores at diagnosis. Despite these differences in clinical and demographic characteristics, there were no significant differences in the risk of PCSM, metastases, or treatment with curative intent. Of note, Cooperberg and colleagues similarly demonstrated no difference in the rate of progression-free survival or the rate of treatment at 4 years 15. There was a higher risk of ACM among men with intermediate/high risk PCa surveilled in our cohort, likely representing the higher rates of comorbid conditions and older age in these patients. And it could be argued that these men were appropriately assessed and counseled away from definitive treatment at diagnosis given their health status.

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It is important to note, that recent data from two prospective cohorts have shown results demonstrating concern for surveilling men with intermediate risk disease. First, the Sunnybrook Hospital (Toronto, Canada) group recently demonstrated an increased risk of metastatic disease in men with Gleason 7 PCa with longer-term follow-up; however, the overall rate of metastasis

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(3.1%) was low in their cohort with median follow-up of 6.4 years 12. Secondly, the Goteborg screening study reported an increased risk of AS failure and treatment in men with intermediate risk disease; however, it must be noted that only 6 men died from PCa in this cohort during the study period with a 10-year PCa specific survival rate of 98% for intermediate risk men 16. Our

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cohort did not demonstrate any significant difference in outcomes when stratified by Gleason 6 vs. 7 disease (data not shown), and the rate of surveillance failure at 10- years were similar

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between very low/low and intermediate/high risk men (90.1% vs 88.4%). The differences in results between our cohort and those described above likely reflect variation in patient selection and length of follow-up. Specifically, our institution has experienced an increase in surveillance patients in the last 5 years, especially among intermediate/high risk men. In fact, men with Gleason 7 disease have significantly shorter follow-up compared to men with Gleason 6 disease in this cohort (39.1 [IQR 23.5-71.5] vs. 51.3 [IQR 32.3-82.3] months, p < 0.01), despite no

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difference in follow-up between the NCCN risk groups studied. Additionally, our patients differ from early surveillance cohorts, in that their overall disease risk is often adjusted based on PCA3, mpMR 9, and more recently, tumor genomics

7,8,10

. This likely reflects findings such as

lower rates of confirmatory biopsy among intermediate/high risk men observed in our cohort.

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Nonetheless, we note the importance of longer term follow-up in our cohort given the low rate of oncologic events among men with localized PCa and the results of the aforementioned studies.

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Overall, numerous institutions have previously reported outcomes in men electing AS 15,17-20. In 2015, two large series with longer-term follow-up demonstrated that the cumulative risk of prostate-cancer specific mortality among men on AS is low, ranging from 0.1 to 2.0 %, at 10years 3,4. In addition, the risk of progression to metastatic disease in men from these cohorts was also low at 2-3%; and the cumulative risk of intervention ranged from 36.5% to 50.0%, at 10 years 3,4,16. Additionally, The incidence of disease reclassification was 8.5 per 100 person-years in the cohort are similar to the reclassification rates reported by Tosoian and colleagues 4.

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Despite heterogeneous management strategies among 11 clinicians at our institution, to-date our outcomes are markedly similar to those from the two aforementioned cohorts.

There are a few limitations of our study that deserve brief discussion. Firstly, the retrospective

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nature of our data collection and the lack of uniform selection, selection of higher risk based on age and favorable disease features, and follow-up criteria contribute to selection bias in the cohort that we report. Secondly, our median follow-up time of 50.5 months limits the accuracy of our estimated longer- term survival analyses, although 256 (40.3%) men had greater than 5 years

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of follow-up. Additionally, longer follow-up is needed to observe the infrequent PCa related deaths and metastatic events among men on surveillance, as demonstrated in prior studies

3,4

.

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Lastly, the lack of uniform criteria for inclusion in AS made it difficult to use previously utilized definitions and outcomes, such as volume progression (i.e., > 33% of total cores positive), to describe our cohort.

Overall, despite a heterogeneous definition in patient population and

clinician practices, our clinical outcomes among men undergoing surveillance are consistent with the results in the recent literature. However, continued study of men with intermediate/high risk, and prospective validation of mpMR/genomic tools, is needed to ensure the continued safety of

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surveillance in the longer term.

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CONCLUSION

Patients with localized PCa on AS demonstrated a low rate of surveillance failure, PCSM, and metastases, regardless of baseline risk in our experience. AS should be part of a shared treatment

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conditions given the current risk of localized therapy.

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decision in carefully selected men with PCa based on low volume of disease, age, and comorbid

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REFERENCES 1. Moyer VA, U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120-134. 2. Lu-Yao GL, Albertsen PC, Moore DF, et al. Outcomes of localized prostate cancer following

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conservative management. JAMA. 2009;302:1202-1209.

3. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol. 2015;33:272-277.

4. Tosoian JJ, Mamawala M, Epstein JI, et al. Intermediate and Longer-Term Outcomes From a

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Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer. J Clin Oncol. 2015;33:3379-3385.

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

6. Cooperberg MR, Carroll PR. Trends in Management for Patients With Localized Prostate Cancer, 1990-2013. JAMA. 2015;314:80-82.

7. Blume-Jensen P, Berman DM, Rimm DL, et al. Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. Clin Cancer Res.

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2015;21:2591-2600.

8. Boström PJ, Bjartell AS, Catto JW, et al. Genomic Predictors of Outcome in Prostate Cancer. Eur Urol. 2015;68:1033-1044.

9. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided

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biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015;313:390-

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10. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014;66:550-560. 11. Epstein JI, Allsbrook WC, Amin MB, Egevad LL, ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228-1242. 12. Yamamoto T, Musunuru B, Vesprini D, et al. Metastatic Prostate Cancer in Men Initially Treated with Active Surveillance. J Urol. 2016;195:1409-1414.

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13. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer, Version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30. 14. Stephenson AJ, Scardino PT, Eastham JA, et al. Preoperative nomogram predicting the 10-

2006;98:715-717.

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year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst.

15. Cooperberg MR, Cowan JE, Hilton JF, et al. Outcomes of active surveillance for men with intermediate-risk prostate cancer. J Clin Oncol. 2011;29:228-234.

16. Godtman RA, Holmberg E, Khatami A, Pihl C-G, Stranne J, Hugosson J. Long-term Results

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of Active Surveillance in the Göteborg Randomized, Population-based Prostate Cancer Screening Trial. Eur Urol. 2016.

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17. Bul M, Zhu X, Valdagni R, et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol. 2013;63:597-603.

18. van den Bergh RCN, Vasarainen H, van der Poel HG, et al. Short-term outcomes of the prospective multicentre 'Prostate Cancer Research International: Active Surveillance' study. BJU Int. 2010;105:956-962.

19. Soloway MS, Soloway CT, Eldefrawy A, Acosta K, Kava B, Manoharan M. Careful

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selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. Eur Urol. 2010;58:831-835. 20. Berglund RK, Masterson TA, Vora KC, Eggener SE, Eastham JA, Guillonneau BD. Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for

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active surveillance. J Urol. 2008;180:1964-7; discussion 1967-8.

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Figure Caption Figure 1: Kaplan-Meier plot of overall survival stratified by very low/low risk and intermediate/high risk prostate cancer

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Figure 2: Kaplan-Meier plot of freedom from metastasis stratified by very low/low risk and intermediate/high risk prostate cancer

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Figure 3: Kaplan-Meier plot of freedom from intervention stratified by very low/low risk and intermediate/high risk prostate cancer

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Figure 4: Kaplan-Meier plot of freedom from biochemical progression following definitive therapy stratified by very low/low risk and intermediate/high risk prostate cancer

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Table 1: Baseline demographic and clinical characteristics of patients undergoing active surveillance stratified by risk (N = 635). IR/HR (N = 117)

p-value

65.1 (60.2-69.1) 28.4 (25.9-31.2) 2010 (2008-2012) 51.2 (30.6-81.9) 4.8 (3.5-6.3) 0.11 (0.08-0.16) 39.0 (30.0-54.0) 8.3 (8.3-16.7) 12.0 (12.0-13.0) 1 (1-2) 0 (0-1) 90.7 (88.8-93.0) 89.5 (84.0-93.7)

68.6 (63.7-73.8) 27.9 (25.6-30.7) 2011 (2008-2013) 44.2 (31.7-72.3) 8.0 (5.0-11.8) 0.15 (0.11-0.27) 43.0 (30.0-70.0) 14.3 (8.3-25.0) 12.0 (12.0-14.0) 1 (1-2) 0 (0-1) 77.7 (70.0-83.5) 81.9 (60.1-88.0)

< 0.001* 0.34 0.12 0.20 < 0.001* < 0.001* 0.04* 0.002* 0.38 < 0.001* 0.003* <0.001* <0.001*

165 (32.1)

50 (42.7)

0.03*

5 (1.0) 120 (23.3) 275 (53.5) 114 (22.2) 379 (73.7)

1 (0.8) 11 (9.4) 60 (51.3) 45 (38.5) 74 (63.3)

< 0.001*

45 (8.8) 444 (86.4) 25 (4.9)

23 (19.7) 89 (76.1) 5 (4.3)

0.007*

514 (100) ---

39 (33.3) 67 (57.3) 11 (9.4)

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Categorical, n (%) 5-ARI use, yes Age at diagnosis, years ≤ 50.0 50.1- 60.0 60.1-70.0 > 70 Confirmatory biopsy, yes (N = 631) Race/Ethnicity African American European American Other/Declined Gleason score at initial biopsy G3+3 G3+4 G4+3

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Continuous, median (IQR) Age at diagnosis, years Body-mass-index, kg/m2 (n = 623) Year of diagnosis Follow-up, months PSA at diagnosis, ng/ml (n = 634) PSA density, ng/ml/cm3 (n = 534) Prostate volume, cm3 (n = 535) Positive cores, initial, % of total cores Total no. of cores at biopsy, initial No. of biopsies, after diagnosis No. of biopsies, surveillance Nomograma score, at diagnosis, % Nomograma score, at last follow-up, %

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VLR/LR (N = 514)

Characteristic

1

0.02*

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Serum PSA Level (ng/ml) ≤ 10.0 514 (100) 67 (57.3) 10.1- 20.0 -42 (35.9) > 20.0 -8 (6.8) NCCN Risk Strata Very low 213 (41.4) -Low 301 (58.6) -Intermediate -108 (92.3) High 9 (7.7) a Memorial Sloan Kettering prostate cancer preoperative 10-year event-free survival; Abbreviation: 5-ARI = 5-alpha reductase inhibitor, GS = Gleason score, HR = high risk, IR = intermediate risk, LR = low risk, NCCN = National Comprehensive Cancer Network, PSA = prostate specific antigen, VLR = very low risk

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Table 2: Clinical event rates per 100 person-years among men on active surveillance from 2002 to 2015

Incidence (95 % CI)

No.

Local or distant metastases (N = 533)

4

0.17 (0.06, 0.45)

3

Overall mortality

16

0.53 (0.33, 0.87)

9

PCa specific mortalitya

0

--

0

Treatment, curative intent

224

9.96 (8.73, 11.3)

Reclassification Grade reclassification Any reclassification

184 199

Biochemical recurrence (N = 213b)

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No.

Incidence (95 % CI)

0.15 (0.05, 0.48)

1

0.24 (0.03,1.69)

0.37 (0.19, 0.70)

7

1.38 (0.66, 2.88)

--

0

--

182

9.93 (8.59,11.5)

40

10.3 (7.53, 14.0)

7.72 (6.68, 8.92) 8.50 (7.40, 9.76)

163 170

9.48 (7.27, 9.90) 8.95 (7.70, 10.4)

19 27

4.32 (2.76, 6.78) 6.44 (4.41, 9.40)

2.09 (1.36,3.20)

15

1.77 (1.07, 2.93)

6

4.03 (1.81, 8.97)

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No cases of prostate-specific mortality to-date; bPatients were excluded if they did not have postintervention PSA available (i.e., recent treatment or loss of follow-up); Abbreviation: ADT = Androgen deprivation therapy, HR = high risk, IR = intermediate risk, LR = low risk, VLR = very low risk

AC C

a

IR/HR

Incidence (95 % CI)

SC

No.

TE D

Event

VLR/LR

RI PT

Overall

ACCEPTED MANUSCRIPT

Table 3: Cumulative freedom from metastases, mortality, curative intervention, or biochemical recurrence in men on active surveillance 5- years Cumulative Incidence of Survival 10- years % (95% CI) % (95% CI)

99.1 (97.2, 99.7) 99.2 (96.6, 99.8) 99.0 (93.2, 99.9)

97.7 (91.6, 99.4) 97.4 (89.6, 99.4) 99.0 (93.2, 99.9)

All-Cause Survival Overall VLR/LR IR/HR

97.9 (95.9, 98.9) 98.4 (96.2, 99.3) 95.6 (86.9, 98.6)

94.0 (87.9, 97.1) 96.5 (92.9, 98.3) 77.0 (34.4, 93.8)

Freedom from Surveillance Failure Overall VLR/LR IR/HR

97.2 (95.1, 98.4) 97.7 (82.8,95.3) 94.8 (87.8, 97.8)

90.6 (83.6,94.7) 90.1 (82.8, 95.3) 88.4 (67.4, 96.3)

61.3 (56.8, 65.6) 62.0 (57.0, 66.6) 58.8 (46.4, 68.7)

49.4 (42.8,5 5.6) 48.7 (41.1, 55.8) 52.3 (38.9, 64.1)

91.9 (86.3, 95.3) 93.6 (87.3, 96.8) 85.0 (67.3, 93.6)

75.7 (60.2, 85.8) 77.9 (61.1, 88.1) --

a

TE D

Freedmon from Biochemical Progressiona Overall VLR/LR IR/HR

M AN U

Freedom from Intervetnion Overall VLR/LR IR/HR

SC

RI PT

Freedom from Metastases Overall VLR/LR IR/HR

AC C

EP

213 patients who were treated had sufficient follow-up to calculate biochemical recurrence risk; Abbreviation: HR = high risk, IR = intermediate risk, LR = low risk, VLR = very low risk

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

ACM: all-cause mortality CSM: cancer-specific mortality HR: hazard ratio MSKCC: Memorial Sloan Kettering Cancer Center NCCN: National Comprehensive Cancer Network

RI PT

Abbreviations