The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance study that is currently enrolling participants at Stanford University, University of California at San Francisco, University of British Columbia, University of Washington, and University of Texas Health Science Center at San Antonio. The study is supported by both the Canary Foundation and the Early Detection Research Network (EDRN) of the National Cancer Institute. The primary objective is to discover and confirm biomarkers that predict aggressive disease as defined by pre-specified histological, PSA, and clinical criteria, or outcomes based on those variables. Secondary objectives are to determine the proportion of patients on active surveillance who progress based on defined criteria, and to determine the clinical predictors of disease progression. The study is recruiting patients with previously untreated, early stage prostate cancer, regardless of date of diagnosis, who have elected active surveillance as a preferred management plan for prostate cancer. The eligibility criteria are given in . These criteria are deliberately broad and are designed to allow most men who choose active surveillance without confounding conditions to enroll. The broad scope of disease characteristics will likely provide greater insight into the natural history of prostate cancer and be the basis for a rich biospecimen resource.
Summary of PASS Entry and Progression Criteria
Participants will be evaluated by serial DRE, serum PSA, and prostate biopsies according to the timeline outlined in . Serum PSA measurements are performed every three months from the time of entry, and physical examinations are performed at study entry and every 6 months from enrollment. Patients who are diagnosed within one year prior to study entry will undergo repeat biopsy at the baseline visit if a biopsy with at least 10 cores is not available, at 6–12 months from the baseline visit, at 2 years, then every 2 years. Patients who are diagnosed greater than one year prior to the baseline visit will undergo repeat biopsy with the following schedule: at baseline visit if only one prior biopsy or if the most recent biopsy was greater than 2 years prior to the baseline visit, and then every 2 years from the most recent biopsy. The rationale for this schema is to ensure that initial diagnostic biopsy adequately samples the prostate, to avoid false negative diagnosis of high grade cancer, and to capture early histologic progression. Patients are free to choose treatment at any time. Progression in PASS will be defined when patients fulfill one or more of the criteria summarized in . Biochemical Progression is defined as a PSA doubling time less than 3 years, based on at least 5 separate consecutive measurements over a minimum of 12 months and maximum of 24 months. PSA values from the time of diagnosis will be used in calculations. Histologic/Grade Progression is any increase in tumor grade. Grade progression will be calculated from the highest existing Gleason grade. Clinical Progression can either be local, defined as a stepwise increase in tumor stage by DRE or identification of regional or distant metastasis, as defined by radiology, cytology, or histology at sites remote from prostate. Progression events will be noted by local investigators, programmed in the study database, and adjudicated by the PASS Endpoints Committee. These definitions of disease progression are sensitive but not necessarily specific for disease progression. Therefore, while active treatment will be offered to a participant should any of these elements be met, the participant may opt to remain on active surveillance. If this occurs, a new PSA/stage/grade status will be assigned and further progression events will be determined using the new baseline criteria.
A paramount objective of PASS is the formation of a bio-specimen repository with associated clinical data that will serve as a rich resource for biomarker and prediction studies. Blood and urine are collected at baseline, every subsequent six months, and, if applicable, at the time of intervention; blood is also collected at baseline for isolation of both DNA and white blood cells for future immortalization (). Frozen cores from needle core biopsies are collected, and, if a participant undergoes a radical prostatectomy, both formalin-fixed paraffin embedded and fresh frozen tissue are collected. Specimens are collected and processed according to uniform standard operating procedures at all institutions. Close adherence to standard operating procedures is maintained by in-person staff training for specimen processing and data collection prior to initiation of the study as well as regular site visits and inspection of specimens. Data collected at baseline and every subsequent 6 months include demographics (e.g. age, race and ethnicity, height and weight, cigarette and alcohol use, family history of prostate cancer), medication use, and clinical data (e.g. PSA, prostate biopsy, and cancer history) while on the study and from the 5 years prior to enrollment. In addition, diet and supplement use are collected at baseline using validated instruments, and changes in supplement use are followed on a yearly basis. Study coordination and data management are conducted by the Data Management and Coordinating Center (DMCC) of the EDRN. De-identified data are stored in the Validation Studies Information Management System (VSIMS),34
a secure database managed by the DMCC, and location and attributes of all specimens are tracked in VSIMS. Specimens will be stored in a PASS Central Biorepository. Proposals from the scientific community to use PASS specimens to interrogate biomarkers will be reviewed by the PASS Biomarker Review Committee.
The primary objective for developing the PASS repository is to discover and/or confirm biomarkers that are predictive of progressive and/or aggressive prostate cancer, with an emphasis on confirmation. The sample size and power are therefore based on confirmation of a biomarker after its initial discovery. A desirable biomarker should have high specificity in order to identify the subset of patients at high risk for progression while minimizing the proportion of men for whom aggressive treatment is undertaken. Therefore the sensitivity of a biomarker is evaluated at 95% specificity. The threshold of a biomarker corresponding to 95% specificity does not have to be pre-fixed prior to the confirmation study, and it can be estimated from PASS study data within the confirmation study. The proportion of disease progression at 3 and 5 years from diagnosis is estimated at 25% and 33%. At 95% specificity, a power of 90% is desired to confirm a sensitivity greater than 10% (which is unacceptable) if the true sensitivity is 30% or better. Point estimates of sensitivity, specificity, and threshold and their 95% confidence intervals will be calculated. The samples size also depends on the slope of Receiver Operating Characteristic (ROC) curve at 95% specificity, usually quite steep when specificity is near 100%. For PASS power analysis a slope parameter of 4 was used.35
Based on these assumptions, for a cohort with at least 5 years follow up, this study requires 125 men with progression and 250 men without progression, for a total of 375 participants, or a total of 1,875 total person years of follow up. The intent of PASS is to enroll at least 400 participants.