Stricter Active Surveillance Criteria for Prostate Cancer do Not Result in Significantly Better Outcomes: A Comparison of Contemporary Protocols

Author's Accepted Manuscript Stricter active surveillance criteria for prostate cancer do not result in significantly better outcomes: A comparison of contemporary protocols Maria Komisarenko , Narhari Timilshina , Patrick O. Richard , Shabbir M.H. Alibhai , Robert Hamilton , Girish Kulkarni , Alexandre Zlotta , Neil Fleshner , Antonio Finelli

PII: DOI: Reference:

S0022-5347(16)30744-3 10.1016/j.juro.2016.06.083 JURO 13835

To appear in: The Journal of Urology Accepted Date: 17 June 2016 Please cite this article as: Komisarenko M, Timilshina N, Richard PO, Alibhai SMH, Hamilton R, Kulkarni G, Zlotta A, Fleshner N, Finelli A, Stricter active surveillance criteria for prostate cancer do not result in significantly better outcomes: A comparison of contemporary protocols, The Journal of Urology® (2016), doi: 10.1016/j.juro.2016.06.083. 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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Stricter active surveillance criteria for prostate cancer do not result in significantly better outcomes: A comparison of contemporary protocols

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Maria Komisarenko1, Narhari Timilshina1, Patrick O. Richard1, Shabbir M.H. Alibhai2, Robert Hamilton1, Girish Kulkarni1, Alexandre Zlotta1, Neil Fleshner1, Antonio Finelli1 1

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Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto. 2 Department of Medicine, University Health Network and the University of Toronto.

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Please address all correspondence to: Antonio Finelli, MD, FRCSC, MSc, Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, 610 University Ave, Room 3-130, Toronto, Ontario, Canada, M5G 2M9, [email protected]

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Keywords : active surveillance, prostatic neoplasms, criteria Running title: A comparison of contemporary protocols Word count: • Abstract: 250 • Manuscript : 2500

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Total number of tables: 5 Total number of figures: 1 Total number of manuscript pages: 9 Source of funding: The authors have no other competing interests to disclose

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Purpose

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Our aim is to review various, existing active surveillance (AS) criteria and determine the competing trade-offs of the stricter versus more inclusive AS criteria. Methods

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Men enrolled in an AS program at Princess Margaret Cancer Centre (PM) between 1998 and 2014 were identified through a prospectively maintained database. All patients were assessed for entry eligibility into: Prostate Cancer Research International: Active Surveillance(PRIAS), John Hopkins Medical Institute(JH), University of Miami(UM), University of California, San Francisco(UCSF), Memorial SloanKettering Cancer Center(MSK), University of Toronto(UT-Sunnybrook) and Royal Marsden(RM). Twosided t-test, ANOVA, Wilcoxon rank-sum or chi-square tests were used for comparison as appropriate.

Results

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Conclusion

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Of the 1365 men identified, 1085 met the PM inclusion criteria. When JH, PRIAS, and UM criteria were applied 15.2%, 11.5%, and 11.3% of these patients were excluded from AS, respectively. No significant differences noted between men who met the PM criteria and those who were excluded based on more stringent criteria when grade or volume reclassification were compared. No significant differences in PSA velocity, or the number of patients who proceeded to seek treatment noted (p>0.1). Rates of biochemical recurrence among patients who chose to undergo a radical prostatectomy after initial AS was not different between men who met the more inclusive versus more exclusive AS protocols.

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More selective criteria do not significantly improve short-term outcomes when considering relative risk of grade reclassification, or biochemical failure after treatment. In an era of heightened awareness regarding over-diagnosis and overtreatment of PCa, we believe that stricter entry criteria should be reconsidered.

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Introduction:

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With an increasing focus on conservative treatment for prostate cancer (PCa), active surveillance (AS) is of growing interest as an alternative to definitive treatment. While the rationale for AS in patients with low-risk PCa is well established [1-5], there is significant variation among accepted eligibility criteria for AS across different institutions. Low-risk PCa is believed to have reduced metastatic potential [6] and as such, does not necessitate immediate intervention and allows men to undergo AS rather than upfront treatment. However, some men may initially appear to have low-risk disease but in fact are reclassified to higher risk disease. The intention of all AS criteria is to differentiate between men with truly low-risk PCa from those at greater risk.

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AS for carefully selected men with low-risk, localized disease translates into benefits that include, but are not limited to, avoidance of treatment-induced side effects such as erectile dysfunction, urinary incontinence and diminished quality of life. These benefits must be weighed against the risk of cancer progression. Only a limited number of reports have been published that compare real world outcomes of AS protocols and demonstrate the trade-off of stringent versus more inclusive criteria, and risk of future disease progression [7].

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The AS entrance criteria followed at Princess Margaret Cancer Centre (PM) are as follows: PSA ≤10, clinical stage ≤ T2a, Gleason sum ≤ 6, number of positive cores ≤ 3, no single core >50% involved and age ≤ 75 years. The standard follow-up schedule employed at PM is a confirmatory biopsy within 12-18 months of initial biopsy, with re-biopsy every 1-3 years until the patient reaches >75 years of age or declines definitive treatment. PSA is checked quarterly for the initial 24 months, with DRE performed every 6-12 months. This is adjusted to 6-month intervals if the patient is determined to be stable after 24 months.

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The most utilized and cited criteria for AS include: Prostate Cancer Research International: Active Surveillance (PRIAS)[8], John Hopkins Medical Institute (JH)[9, 10], University of Miami (UM)[11], University of California San Francisco (UCSF)[12], Memorial Sloan-Kettering Cancer Center (MSK), Royal Marsden (RM)[13] and University of Toronto (UT-Sunnybrook) [1] (Table 1). The aforementioned can be placed on a spectrum from most restrictive (JH) to the most inclusive (RM). JH having the most stringent AS entrance criteria (as described in its recent publications)[14] is based on the following guidelines: PSA density <0.15ng/ml, < 2 positive cores, < 50% involvement, <3 Gleason pattern, T1c clinical stage. While restrictive criteria may have high specificity for pathologic endpoints, sensitivity of strict criteria is relatively low, therefore yielding poor discriminatory ability when compared to other protocols. Conversely, more sensitive protocols often have low specificity and therefore suboptimal discrimination levels in predicting insignificant PCa. In this work we assess the competing trade-offs between more restrictive and more inclusive AS criteria. The goal is to compare how many patients from our AS cohort fit under each of the other eight protocols, how many are excluded or included into other protocols and whether patients that are excluded from more restrictive protocols do worse with regard to cancer control, time to treatment, and long term biochemical recurrence (BCR).

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Methods:

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This was a single center, retrospective study that received institutional review board approval. Subjects enrolled in an AS program at PM between January 1998 and December 2014 were identified through a prospectively maintained database. Not all men enrolled in AS at PM met the predefined AS inclusion entry criteria; PSA ≤10, clinical stage ≤ T2a, Gleason sum ≤ 6, number of positive cores ≤ 3, no single core >50% involved and age ≤ 75 years. Those who did not meet the criteria, but still chose AS were followed and their outcomes were recorded. Trained data personnel entered a standardized set of data elements for all patients. These include: age, race/ethnicity, family history, serial PSA results, all recorded biopsies with the associated Gleason score, clinical stage, number of positive cores, percentage of any core involved, prostate volume (measured with transrectal ultrasound (TRUS))any cancer-directed treatments, PSA and pathology results. To ensure accuracy of data, all information is verified using the electronic patient record system. AS is discussed with all patients diagnosed with lowvolume, localized disease at our center, as we consider it the preferred management option for these men. All patients who underwent at least 2 biopsies were reviewed and assessed for entry eligibility into the following protocols: PM, PRIAS, UCSF, MSK, UM, JH, RM, UT-Sunnybrook Hospital. The diagnostic biopsy and the first repeat biopsy are referred to as B1 and B2 (or confirmatory), respectively.

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The different protocol definitions were applied to our cohort to ascertain how this would alter the number of patients eligible for AS and their outcomes. We analyzed PSA velocity, time to treatment and treatment type. Furthermore, pathologic features in patients from the different groups who went on to have definitive treatment were analyzed, using the student t-test or Mann-Whitney U test for continuous variables and the Pearson chi-square test for categorical variables. Specifically, we compared BCR, and positive margins for patients who underwent radical prostatectomy (RP) using Kaplan-Meier curves, and results were compared with the log-rank test. We also compared reclassification and/or discontinuation rates for the groups meeting the various AS criteria. Statistical analysis was conducted using SAS v9.4 software; p < 0.05 was considered statistically significant. All p-values resulted from the use of two-sided statistical tests.

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Results: The eight AS protocols and what proportion of patients from our cohort would be eligible for each are described in Table 1. Table 2 summarizes the characteristics of all the patients reviewed for the purposes of this work. Mean age of those considered for AS was 63.7 years (SD 7.3) and the median PSA at diagnosis was 5.4 (IQR 4.0-7.5). From 1365 men enrolled over the 16-year period in our institution, 1085 met PM inclusion criteria with a median follow-up of 60 months (IQR 34-90). When JH, PRIAS, and UM criteria were applied to this population, 15.2%, 11.5%, and 11.3%, respectively, of men would not have been offered AS based on the criteria used in these institutions. Conversely the RM criteria allowed an additional 15.5% (n=1297) to be included into AS. Thus 30.7% (n=419) of men that would qualify for AS at RM would be excluded and advised to seek definitive treatment at JH. When the PSA threshold is increased to ≤15ng/mL (RM) from ≤10ng/mL (UoT-SB), and no Gleason pattern 4 is accepted, the

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difference in proportion of patients included is 9.7%. When core involvement is not considered (UoT-SB vs. PM) acceptance into an AS program is increased by 5.8%. By restricting number of positive cores to ≤2 (PRIAS) and defining the allowable PSA density as <0.20 approximately 11.5% of patients who otherwise meet the PM AS criteria are excluded. According to the examined cohort for every 100 men who are diagnosed with low risk, localized PCa and who would choose AS, approximately 20 men would be excluded from AS at PM. At JH, PRIAS, and UM the number excluded would be 36, 32 and 32, respectively.

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PSA velocity, the number of patients who proceeded to treatment, treatment types, time to treatment and follow-up time for each subset of the cohort divided according to the set of criteria they meet are described in Table 3. No significant differences in PSA velocity, or the number of patients undergoing treatment (p>0.1) between men who were followed on a more inclusive versus more exclusive AS protocols. Treatment choice was not affected by whether the men met the more exclusive set of criteria. Differences in PSA velocity ranged from 0.42 ng/ml rise per year in patients meeting JH criteria, to 0.53 ng/ml rise per year among patients qualified to enter the RM AS cohort. A comparison of grade or volume re-classification between the various subsets of men is summarized in Table 4. The difference in rate of grade progression in men (at any biopsy including confirmatory) who met the most restrictive criteria (JH) was 3.6% lower than the reference cohort of PM (26.4% vs 22.8%, respectively)(P>0.1). If reclassification at confirmatory biopsy is excluded, this number is reduced to a 1.1% (n=32) difference.

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The difference in the proportion of men who upgraded to Gleason >7 between PM and RM was 3.5% more in the group of men who met the RM criteria (212 more patients met this criteria and not the PM one). The difference between men in the most inclusive (RM) versus those in the most restrictive (JH) groups, experiencing grade progression (at any time after B1) was only 3.5% and 1.8% (if confirmatory biopsy reclassification is excluded). Therefore by restricting the criteria to exclude any T2 disease, anyone with PSA density ≤0.15, 2 or less positive cores; one excludes 15.5% more men from AS and the trade-off is 3.5% fewer men experiencing later upgrade to Gleason 7 or higher disease.

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The rate of volume progression (according to the AS criteria used at PM; an increase above 3 positive cores, or any one core with >50% tumor involvement) in men who met the JH criteria was slightly lower than the reference cohort of PM, with 5.9% (23.3% vs 29.3%) more experiencing volume progression at any time. The difference between PM and RM was in 4.3% more of men included as per RM criteria demonstrating volume progression. The difference between the inclusive (RM) and most stringent (JH) criteria proportion was 10.3%. Table 5 demonstrates the rate of BCR among patients who chose to undergo a RP after initial AS. This group was also subdivided into men who were eligible for the different AS protocols and those who would have been excluded with the more selective criteria. The rate of BCR was not different among the men. AS discontinuation rates that include re-classification/ progression and definitive treatment is shown in Figure 1. There were no significant differences between the groups who met the various AS criteria. At 5

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years, an estimated 28%, 27%, 27% of men who met RM, UoT, and UCSF (respectively) criteria discontinued AS, whereas rates at MSK, PM, PRIAS and JH would have been 22%, 22%, 21% and 20%, respectively. The variance between the most inclusive criteria and the most stringent one is approximately 8% for discontinuation of AS for any reason.

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Discussion

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One of the major goals of AS is to identify patients who have been diagnosed with PCa and truly harbor low-risk disease. The various AS criteria being utilized by different institutions were developed in an attempt to predict potentially insignificant disease - maximizing the number of patients who can avoid treatment while minimizing the number of aggressive PCa cases missed. The difficulty lies in finding the optimal balance of including all patients that would do well on AS and identifying those that may have been initially diagnosed with insignificant disease but actually harbor high-risk PCa and would benefit from definitive treatment. Because long-term outcomes of the various contemporary AS protocols still require some time to mature, it is difficult to discern whether having stricter or more inclusive criteria is better for the greatest number of patients and which variables are most important in evaluating patient prognosis. The result is a degree of variation among the most prominent protocols with respect to sensitivity and specificity of eligibility criteria. Finding the optimal trade-off of risk of progression and benefit from deferring definitive treatment is key. JH and PRIAS protocols are the most stringent among the widely used approaches, and exclude a large portion of men who would otherwise be eligible for AS under other protocols. Excluded patients were likely being offered definitive treatment.

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Reports have characterized tumors in patients who would potentially be eligible for certain AS protocols [3, 15-19]. Iremashvili et al [1] went further and compared the ability of contemporary AS criteria (looking at JH, MSK, PRIAS, UCSF, and UM) to identify patients with certain pathologic tumour features based on the results of an extended transrectal prostate biopsy. They concluded that while significant variations exist in the ability of contemporary AS criteria to predict pathologically insignificant PCa at RP, of the studied protocols, PRIAS and UM demonstrated the highest ability to identify patients with insignificant PCa. However, only a limited body of work has considered the differences in AS criteria protocols against a real AS cohort with an intermediate follow-up (median 64 months). Iremashvili et al. [1] studied RP patients who had PCa with Gleason scores <6 on transrectal biopsy with >10 cores, but who were never actually on AS. Hawken et al [7] considered men with newly diagnosed PCa entered into the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry from March 2012 to June 2014, and thus only evaluated the initial entry into AS and follow-up of these patients was not described. Because only a small portion of patients from the PM cohort underwent RP (n=139), it is difficult to address which of the AS criteria better selects pathologically insignificant PCa in our population of men on AS. However, based on BCR rates and adverse pathology from the men who did undergo RP there were no statistically significant differences among the sub-cohorts. Interestingly the rates of reported positive margins were higher for men who qualified for AS under JH, PRIAS and UM criteria, but not significant. The proportion of BCR among the men meeting the different criteria ranged from 6-6.9%.

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In addition to its retrospective nature, there are other limitations to this work. The outcomes were assessed based on a population treated in a single center, and the majority of the studied men met the PM criteria. Thus, the results should be interpreted with consideration that men who would potentially be offered AS at the RM or at UCSF, are not well represented in our cohort. As such, the results are mostly applicable to differences in medium to highly restrictive criteria, but can be extrapolated to the more inclusive criteria (such as RM, UoT and UCSF) as some patients that may have been on the cusp of meeting the PM criteria were not included in our AS program, but met the more sensitive AS cut-offs and therefore, were part of our analysis. The outcomes used were intermediate outcome measures and the optimal AS criteria should be based on longer based data and with greater number of patients (to add power). In addition, some detection bias may exist as centers that have less frequent biopsies within their follow-up protocol likely have slightly lower discontinuation rates that those centers that biopsy more frequently. Lastly, the role of MRI remains to be determined and this may level the playing field on inclusion criteria. The recent National Comprehensive Cancer Network (NCCN)[20] change to add low volume intermediate risk prostate cancer for consideration of active surveillance is supported by this work. As here we report that more stringent criteria does not necessarily translate to increased benefit for the patient. Conclusion:

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In conclusion it seems that while there are differences in inclusion criteria for AS, the results presented here demonstrate that more stringent criteria do not significantly improve patient outcomes when considering relative risk of Gleason Score upgrading, or BCR after treatment. In an era of heightened awareness regarding over-diagnosis and overtreatment of prostate cancer, we believe that these stricter entry criteria should be reconsidered.

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References

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Iremashvili V, Pelaez L, Manoharan M, Jorda M, Rosenberg DL, Soloway MS: Pathologic prostate cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of contemporary protocols. Eur Urol 2012, 62(3):462-468. Mufarrij P, Sankin A, Godoy G, Lepor H: Pathologic outcomes of candidates for active surveillance undergoing radical prostatectomy. Urology 2010, 76(3):689-692. Kane CJ, Im R, Amling CL, Presti JC, Aronson WJ, Terris MK, Freedland SJ, Group SDS: Outcomes after radical prostatectomy among men who are candidates for active surveillance: results from the SEARCH database. Urology 2010, 76(3):695-700. van den Bergh RC, Roemeling S, Roobol MJ, Aus G, Hugosson J, Rannikko AS, Tammela TL, Bangma CH, Schroder FH: Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly. Eur Urol 2009, 55(1):1-8. Wilt TJ, Brawer MK, Barry MJ, Jones KM, Kwon Y, Gingrich JR, Aronson WJ, Nsouli I, Iyer P, Cartagena R et al: The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials 2009, 30(1):81-87. Ross HM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI: Do adenocarcinomas of the prostate with Gleason score (GS)
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Louie-Johnsun M, Neill M, Treurnicht K, Jarmulowicz M, Eden C: Final outcomes of patients with low-risk prostate cancer suitable for active surveillance but treated surgically. BJU Int 2009, 104(10):1501-1504. Suardi N, Briganti A, Gallina A, Salonia A, Karakiewicz PI, Capitanio U, Freschi M, Cestari A, Guazzoni G, Rigatti P et al: Testing the most stringent criteria for selection of candidates for active surveillance in patients with low-risk prostate cancer. BJU Int 2010, 105(11):1548-1552. Lee MC, Dong F, Stephenson AJ, Jones JS, Magi-Galluzzi C, Klein EA: The Epstein criteria predict for organ-confined but not insignificant disease and a high likelihood of cure at radical prostatectomy. Eur Urol 2010, 58(1):90-95. Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A: Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010, 28(1):126131. Carroll PR, Parsons JK, Andriole G, Bahnson RR, Castle EP, Catalona WJ, Dahl DM, Davis JW, Epstein JI, Etzioni RB et al: NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016. J Natl Compr Canc Netw 2016, 14(5):509-519.

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Tables 1: Proportion of patients selection by various criteria Lead Investigator

Eligibility criteria

Total Sample N=1365 Included 95%CI Excluded

Difference Follow-up regimen Intervention (%) criteria

Royal Marsden

Parker

GS ≤7 (3+4, if ≥65yo), PSA levels <15ng/mL, cT1c-T2a, ≤50% of any cores involved

1297 (95.0)

(1217-1248) 68 (5.0)

15.5


University of Toronto Sunnybrook

Klotz

1164 (85.3)

(971-1015)

UCSF

Carroll

GS≤6, PSA≤10ng/mL, cT1c, <3 cores positive, < 50% of any cores involved (or if >70years, GS≤3+4, PSA<15ng/mL) GS≤6, PSA<10ng/mL, cT1c-T2a, <33% of total cores

1103 (80.8)

(868-925)

Princess Margaret Cancer Centre

Finelli

GS≤6, PSA<10ng/mL,
1085 (79.5)

MSK

Eastham

GS≤6, PSA<10ng/mL, cT1-T2a, ≤3 cores positive, ≤50% of any cores involved

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Institution

5.8


262 (19.2)

1.3


(840-896)

280 (20.5)

Reference

(840-896)

280 (20.5)

0

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201 (14.7)

1085 (79.5)



PSA q3months for 1st year, q4months for 2nd year, then q6months Confirmatory biopsy within 18-24 months, then q2years PSA q3months for 2 years, then q6months Confirmatory biopsy within 6-12months, then q3-4 years until 80years PSA q3months TRUS q6-12months Biopsies repeated q1224months PSA q3months for 2 years, then q6months Confirmatory biopsy before being considered on AS, DRE q6-12months (q12-18 months) Re-biopsy q1-3years PSA q6months Confirmatory biopsy before being considered on AS, 3rd biopsy within 18months and then, q1-3years ±MRI q1-3 years

GS >3+4 >50% of any cores involved PSAV>1ng/mL/ye ar

PSA DT < 3 years (until 2008) GS>6 Stage >cT2a

GS >6 PSAV >0.75ng/mL/year GS>6

Not standardized

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Schroder

GS≤6, PSA≤10ng/mL, cT1c-T2a, PSAD<0.2ng/mL/g, ≤2 cores involved

929 (68.0)

(609-655)

436 (32.0)

University of Miami

Soloway

GS≤6, PSA≤10ng/mL, cT1c-T2a, ≤20% of any cores involved, ≤2 cores involved

934 (68.4)

(616-662)

431 (31.6)

John Hopkins Medical Institute

Carter

GS≤6, PSA<10ng/mL, cT1c, ≤50% of any cores and ≤3 cores involved, PSAD˂0.15ng/mL/g

878 (64.3)

(542-587)

SC 487 (35.7)

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11.5 

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PRIAS

11.3 

15.2 

PSA q3months for 2 years, then q6months Biopsies repeated at 1,4 and 7 years (or yearly if PSA DT <10years) PSA q3-4months for 2 years, then q6months Confirmatory biopsy within 9-12months (starting after 2000) and annually thereafter PSA and free to total PSA ratio q6months Biopsies repeated annually

GS>6, >T2, PSA DT <3years, >2 cores involved

GS>6, >2 cores involved, >20% of any cores involved

GS >6, >2 cores involved, >50% of any core involved

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(N=1365)

Yes No

Follow up time (months)

Median (IQR)

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TRUS nodule present (n,%)

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63.7 (40-81) 226 (16.6) 462 (33.9) 677 (49.6) 5.4 (4.0-7.5) 45 (35-62) 0.11 (0.08-0.16) 264 (19.3) 1101 (80.7) 3 (2-3) 5 (2-10) 149 (10.9) 1216 (89.1) 202 (14.8) 1163 (85.2) 61 (4.5) 1304 (95.5) 271 (19.9) 1094 (80.2)

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Table 2: Summary of patients used for selection criteria N Age (year) Median Range Family History (n,%) Yes No Unknown PSA at diagnosis Median (IQR) Prostate Volume Median (IQR) PSA density, Median (IQR) Total number of cores taken <10 ≥10 Number of Biopsies Median(IQR) Max. % core, Median (IQR) 5ARI use (N,%) Yes No Presence of HGPIN Yes No (n,%) Presence of ASAP (n,%) Yes No Previous neg Bx prior Yes No toAS(n,%)

347 (25.4) 1018 (74.6) 60 (34-90)

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Table 3: Pathologic progression of patient’s selection by various criteria

Princess Margaret Cancer Centre 171 MSK PRIAS University of Miami John Hopkins Medical Institute

(15.8) 129 (13.9) 134 (14.4) 117 (13.3)

0.1  Ref.

0 1.9  1.4  2.5 

Diff. (%) 3.5


Volume 436 (33.6)

Diff. Total (%) 4.3
585 (45.1)

Diff. (%) 5.2


0.6


397 (34.1)

4.8
512 (44.0)

4.1


207 (18.8) 199 (18.3)

0.5
284 (25.6) Ref. 276 (25.4)

0.2
290 (26.3) Ref. 286 (26.4)

0.1

339 (30.8)

1.5
454 (41.2)

1.3


Ref.

318 (29.3)

Ref.

433 (39.9)

Ref

199 (18.3) 145 (15.6)

0

276 (25.4) 2.7 206 (22.2)

0

0

318 (29.3)

0

433 (39.9)

0

1.9

247 (26.6)

2.7 343 (37.0)

2.9 

135 (14.5) 115 (13.0)

3.8 201 (21.5) 5.3 175 (19.9)

3.9 227 (24.3) 5.5 200 (22.8)

2.1

229 (24.5)

4.8 333 (35.7)

4.2 

3.6

204 (23.3)

6.0 296 (33.8)

6.1

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Diff. Grade (%) 2.7
386 (29.9) 2.4
314 (27.0)

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173 (15.7) 171 (15.8)

0.8


270 (20.8) 245 (21.0)

Diff. Total (%) 2.5
365 (28.1) 2.7
324 (27.8)

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University of Toronto Sunnybrook UCSF

227 (17.5) 193 (16.6)

Volume

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Royal Marsden

Diff. (%) 1.7


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Grade

Over all Progression (any biopsy including confirmatory)

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Pathological Progression on confirmatory biopsy

286 (26.4) 3.2 227 (24.5)

Diff. = Difference Note: proportion difference based on Princess Margaret Cancer Centre criteria

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Table 4: PSA velocity and treatment modality of patients in the various institutions. PI PSAV

Diff. (%)

Treatment N (%)

Diff. (%)

Treatment type

Treatment time Median (IRQ) *

Follow up Time Median (IQR) *

RP

RT

Other

Parker

0.53

0.02


3 (2-3)

391 (30.2)

1.3


170 (13.1)

172 (13.3)

49 (3.8)

29 (18-50)

60 (34-91)

University of Toronto Sunnybrook UCSF

Klotz

0.51

0 

3 (2-3)

350 (30.7)

0.8


152 (13.1)

157 (13.5)

41 (3.5)

29 (17-50)

60 (34-91)

Carroll

0.49

-0.2 

3 (2-3)

316 (28.7)

Princess Margaret Cancer Centre

Finelli

0.51

Ref.

3 (2-3)

314 (28.9)

MSK

Eastham

0.51

PRIAS

Shroder

0.48

0  -0.3 

3 (2-3) 3 (2-4)

University of Miami

Soloway 0.52

0.1


John Hopkins Medical Institute

Carter

-0.9 

M AN U -0.2 

142 (12.9)

139 (12.6)

35 (3.2)

30 (17-51)

60 (33-91)

Ref.

139 (12.9)

139 (12.8)

35 (3.2)

30 (18-52)

61 (34-92)

0  -1.2 

139 (12.9) 111 (12.0)

139 (12.8) 117 (12.6)

35 (3.2) 29 (3.1)

30 (18-52) 32 (19-54)

61 (34-92) 62 (36-92)

258 (27.6)

-1.3 

110 (11.8)

118 (12.6)

26 (3.2)

31 (19-54)

63 (36-93)

223 (25.4)

-3.5 

100 (11.4)

100 (11.4)

33 (2.6)

32 (19-51)

62 (36-93)

TE D

AC C

0.42

3 (2-4)

3 (2-4)

*Follow up (months); PSAV= PSA velocity (per year)

SC

Royal Marsden

EP

PSAV

# of Biopsy Median (IQR)

RI PT

Institution

314 (28.9) 257 (27.7)

ACCEPTED MANUSCRIPT

Table 5: Positive margin and biomedical recurrence among the patients with radical prostatectomy (RP)

PI

Margin N (%)

Diff. (%)

Bio-chemical recurrence N (%)

Diff. (%)

6

7

111 (61.3)

Parker

38 (21.0)

0.9 

11 (6.1)

0.8 

41 (22.7)

University of Toronto Sunnybrook UCSF

Klotz

33 (20.8)

1.1 

10 (6.3)

0.6 

38 (23.9)

Carroll

33 (22.2)

0.3


10 (6.7)

Finelli

32 (21.9)

Ref.

10 (6.9)

0  1.1
2.2
2.3 

10 (6.9) 8 (6.8) 7 (6.0) 7 (6.5)

#

pT-stage at RP, n (%) pT2 pT3 #

5 (2.8)

24 (13.3)

114 43 24 (62.9) (23.8) (13.3)

M AN U

97 (61.0)

5 (3.1)

19 (11.9)

99 41 19 (62.2) (25.8) (11.9)

0.2 

33 (22.2)

93 (62.4)

5 (3.4)

18 (12.1)

93 38 18 (62.4) (25.5) (12.1)

Ref.

32 (21.9)

92 (63.0)

5 (3.4)

17 (11.6)

92 37 17 (63.0) (25.3) (11.6)

0  0.1  0.9  0.4 

32 (21.9) 30 (25.4) 28 (24.1) 28 (26.2)

92 (63.0) 67 (56.8) 67 (57.8) 58 (54.2)

5 (3.4) 5 (4.2) 5 (4.3) 5 (4.7)

17 (11.6) 16 (13.6) 16 (13.8) 16 (14.9)

92 (63.0) 75 (63.6) 75 (64.7) 72 (67.3)

TE D

University of Miami John Hopkins Medical Institute

32 (21.9) Shroder 27 (23.0) Soloway 28 (24.1) Carter 21 (19.6)

EP

PRIAS

Eastham

AC C

Princess Margaret Cancer Centre MSK

SC

Royal Marsden

GS at RP, n (%) 8+

RI PT

Institution

37 (25.3) 26 (22.0) 26 (22.4) 18 (16.8)

17 (11.6) 17 (14.4) 15 (12.9) 17 (15.9)

ACCEPTED MANUSCRIPT

RI PT

Figure 1. Discontinuation rates (either due to re-classification/progression or proceeding to treatment).

SC

0.3

M AN U

0.25

0.2

0.05

0 0 Months

12 Months

EP

0.1

24 Months

36 Months

Follow-up Time

RM (Parker et al.) UoT (Klotz et al.) PRIAS (Scroder et al.) UCSF (Carroll et al.) MSK (Eastham et al.)

TE D

0.15

AC C

Cumulative Incidence (0-1)

0.35

UM (Soloway et al.) JH (Carter et al.) PM (Finelli et al.)

48 Months

60 Months

ACCEPTED MANUSCRIPT

List of Abbreviations 5-ARI= 5 alpha-reductase inhibitor ANOVA= Analysis of variance

RI PT

AS= Active Surveillance ASAP= Atypical small acinar proliferation B1= Diagnostic biopsy (1st biopsy)

SC

B2= Confirmatory biopsy (2nd biopsy) IQR= Interquartile range

PCa= Prostate Cancer Pcore= positive core PSA= Prostate-Specific Antigen

SD= Standard deviation

TE D

SAS= Statistical Analysis System

M AN U

MRI= Magnetic resonance imaging

AC C

EP

TRUSBP= Transrectal ultrasound-guided prostate biopsies