71fue darme cuenta de como todos los ulmenes, creian verdad lo que yo traia pero que los

Leonard P. Bokhorst, Arnout R. Alberts, Antti Rannikko, Riccardo Valdagni, Tom Pickles, Yoshiyuki Kakehi, Chris H. Bangma, Monique J. Roobol, for the PRIAS study group.

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AbSTRACT

Background: Men with prostate cancer on active surveillance are advised to follow strict

follow-up schedules and switch to definitive treatment if risk reclassification occurs. How- ever, some men might not adhere to these strict protocols.

Objective: To determine the number of non-compliers and disease reclassification rates in

men not complying with the follow-up protocol of the Prostate cancer Research Interna- tional: Active Surveillance (PRIAS) study.

Design, setting, and participants: 4547 men with low-risk prostate cancer were included

and prospectively followed on active surveillance. Men were regularly examined using PSA, DRE, and repeat biopsies and advised to switch to definitive treatment if disease reclassification occurred (>cT2c, Gleason score >3+3, >2 cores positive, or PSA-doubling time (PSA-DT) 0-3 year).

Outcome measurements and statistical analysis: Rates of men not complying with the

follow-up visits or recommendation to discontinue active surveillance were reported. Biopsy outcome (Gleason score >=7 or > 2 cores positive) between compliers and non- compliers was compared using cox proportional hazard analysis.

Results and limitations: The compliance rate with PSA visits was 91%. In contrast compli-

ance rates with standard repeat biopsies decreased over time (81%, 60%, 53%, and 33% for 1, 4, 7, and 10 years after diagnosis respectively). Yearly repeat biopsies in men with faster rising PSA (PSA-DT 3-10 year) was low at less than 30%, although these men had higher upgrading rates at repeat biopsy (25-30% versus 16%). A PSA-DT of 0-3 year was the most common recommendation to discontinue, nevertheless 71% continued active surveillance. Men with PSADT 0-3 year were at higher risk of upgrading on repeat biopsy (HR 2.02; 95% CI 1.36-3.00) as compared to men without fast rising PSA.

Conclusion: Some men and their physician do not comply with an active surveillance

follow-up protocol. Especially yearly repeat biopsies in men with fast rising PSA, are often ignored, as is the recommendation to discontinue active surveillance due to a very fast rising PSA. Although these men are at increased risk of having higher Gleason scores on repeat biopsy, the majority still presents favorable tumor characteristics. A fast rising PSA should therefore not be a recommendation to advice active treatment, but should rather serve as a criterion for stricter follow-up. In addition, we should aim to find ways of safely reducing the amount of biopsies to increase adherence to active surveillance protocols.

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Patient summary: In this report we looked at the compliance with a large active surveil-

lance protocol for low risk prostate cancer. We observed reluctance with yearly biopsies due to a fast rising PSA, despite a higher risk of disease progression. Further research should aim to safely reduce the amount of repeat biopsies in men on active surveillance, to increase protocol adherence.

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InTROdUCTIOn

Active surveillance for prostate cancer is a treatment option aimed at reducing the nega- tive side effects of radical treatment, while at the same time preserving the option for cura- tive treatment. It does so by strictly following men and only offering curative treatment to those that show signs of disease progression / reclassification. However, optimal criteria for follow-up, inclusion and exclusion are currently still being investigated. Most common protocols include criteria based on a combination of PSA tests, digital rectal examinations (DRE), and repeated prostate biopsies to both include patients and define disease reclas- sification (1-6). Some men and their physicians might however choose to deviate from these strict protocols, ignoring either the follow-up schedule or the advice to switch to curative treatment.

The aim of the current analysis is to determine the number of men who do not comply with the protocol of the Prostate cancer Research International: Active Surveillance (PRIAS) study. The PRIAS study is currently the largest prospective study on active surveillance, including over 100 centers in 17 countries aimed to represent a real world situation (1). Furthermore, follow-up of men not complying with the approved protocol allows us to evaluate the protocol by investigating their intermediate term outcomes (i.e. Gleason score upgrading at repeat biopsy).

PATIEnTS And METHOdS

In the PRIAS study men with low risk prostate cancer are prospectively followed on active surveillance (7). All centers enter data on inclusion and follow-up trough an online tool (www.prias-project.org), which automatically provides all recommendations for follow-up based on the protocol (7). Criteria for inclusion are: Gleason score <=3+3, <=cT2c, PSA <=10ng/ml, <= two cores positive for prostate cancer, PSA density <=0.2ng/ml/ml, and fitness for curative treatment. A minimum number of biopsy cores taken is advised based on prostate volume (prostate volume <40cm3: 8 cores, 40-60cm3: 10 cores, >60cm3: 12 cores), but is not a strict inclusion criterion. As of 2012 men with minimal Gleason score 3+4 disease (<=10% core involvement) can be included if aged >=70 year (n=24)(for follow-up all regular criteria apply except for Gleason score, which can be 3+4 on repeat biopsy).

Men are followed using PSA testing every 3 months the first 2 years and every 6 months thereafter. Digital rectal examination is advised every 6 months the first 2 years and every year thereafter. Repeat biopsies are done 1,4,7,10, and subsequent every 5 years after di- agnosis. Yearly repeat biopsies are only advised if PSA doubling time (PSA-DT) is between 3 and 10 years. PSA-DT is calculated using all available PSA values since diagnosis by plot-

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