Greg Trottier

Growth Kinetics of Renal Masses: Analysis of a Prospective Cohort of Patients Undergoing Active Surveillance

BACKGROUND Active surveillance (AS) represents a treatment option for renal masses in patients who are not surgical candidates either because of existing comorbidities or patient choice. Among renal masses undergoing AS, some grow rapidly and require treatment or progress to metastatic disease. Patient and tumour characteristics related to this more aggressive behaviour have been poorly studied. OBJECTIVE To report the analysis of a multi-institutional cohort of patients undergoing AS for small renal masses. DESIGN, SETTING, AND PARTICIPANTS This prospective study included 82 patients with 84 renal masses who underwent AS in three Canadian institutions between July 2001 and June 2009. INTERVENTION All patients underwent AS for renal masses presumed to be renal cell carcinoma (RCC) as based on diagnostic imaging. MEASUREMENTS Age, sex, symptoms at presentation, maximum diameter at diagnosis (cm), tumour location (central/peripheral), degree of endophytic component (1-100%), and tumour consistency (solid/cystic) were used to develop a predictive model of the tumour growth rate using binary recursive partitioning analysis with a repeated measures outcome. RESULTS AND LIMITATIONS With a median follow-up of 36 mo (range: 6-96), the mean annual renal mass growth rate for the entire cohort was 0.25 cm/yr (standard deviation [SD]: 0.49 cm/yr). Only one patient (1.2%) developed metastatic RCC. Amongst all variables, maximum diameter at diagnosis was the only predictor of tumour growth rate, and two distinct growth rates were identified. Masses that are ≥2.45 cm in largest diameter at diagnosis grow faster than smaller masses. This series was limited by its moderate sample size, although it is the largest published prospective series to date. CONCLUSIONS We confirm that most renal masses grow slowly and carry a low metastatic potential. Tumour size is a predictor of tumour growth rate, with renal masses <2.45 cm growing more slowly than masses >2.45 cm.

PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade.

Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2–ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2–ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous=42 and homozygous=14). TMPRSS2–ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (P<0.001). Although TMPRSS2–ERG fusions showed a strong relationship with PTEN deletions (P=0.007), TMPRSS2–ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2–ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2–ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.

Comparison of risk calculators from the Prostate Cancer Prevention Trial and the European Randomized Study of Screening for Prostate Cancer in a contemporary Canadian cohort

Study Type – Prognosis (inception cohort)

Impact of 5α-reductase inhibitors on men followed by active surveillance for prostate cancer.

BACKGROUND In two large randomized controlled trials, 5α-reductase inhibitors (5-ARIs) were shown to prevent prostate cancer. No prior work had shown the effect of 5-ARIs on those already diagnosed with low-risk prostate cancer. OBJECTIVE Our aim was to determine the effect of 5-ARIs on pathologic progression in men on active surveillance. DESIGN, SETTING, AND PARTICIPANTS We conducted a single-institution retrospective cohort study comparing men taking a 5-ARI versus no 5-ARI while on active surveillance for prostate cancer. MEASUREMENTS Pathologic progression was evaluated and defined as Gleason score >6, maximum core involvement >50%, or more than three cores positive on a follow-up prostate biopsy. Kaplan-Meier analyses were conducted along with multivariable Cox proportional hazard regression modeling for predictors of pathologic progression. RESULTS AND LIMITATIONS A total of 288 men on active surveillance met the inclusion criteria. The median follow-up was 38.5 mo (interquartile range: 23.6-59.4) with 93 men (32%) experiencing pathologic progression and 96 men (33%) abandoning active surveillance. Men taking a 5-ARI experienced a lower rate of pathologic progression (18.6% vs 36.7%; p=0.004) and were less likely to abandon active surveillance (20% vs 37.6%; p=0.006). On multivariable Cox proportional hazards analysis, lack of 5-ARI use was most strongly associated with pathologic progression (hazard ratio: 2.91; 95% confidence interval, 1.5-5.6). The main study limitation was the retrospective design and variable duration of 5-ARI therapy. CONCLUSIONS The 5-ARIs were associated with a significantly lower rate of pathologic progression and abandonment of active surveillance.

Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment

Study Type – Therapy (cohort) Level of Evidence 2b

A Negative Confirmatory Biopsy Among Men on Active Surveillance for Prostate Cancer Does Not Protect Them from Histologic Grade Progression

BACKGROUND Many men (21-52%) are reported to have no cancer on the second, also known as the confirmatory, biopsy (B2) for prostate cancer active surveillance (AS). If these men had a reduced risk of pathologic progression, particularly grade related, the intensity of their follow-up could be decreased. OBJECTIVE To investigate if men with no cancer on B2 are less likely to undergo subsequent pathologic progression. DESIGN, SETTING, AND PARTICIPANTS Men were identified from our tertiary care center AS prostate cancer database (1995-2012). Eligibility criteria were prostate-specific antigen (PSA) ≤ 10, cT2 or lower, no Gleason grade 4 or 5, three or fewer positive cores, and no core >50% involved. Only patients with three or more biopsies were selected and then dichotomized on cancer status (yes or no) at B2. INTERVENTION AS OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Pathologic progression was defined as grade (advancement in Gleason score) and/or volume (more than three positive cores, >50% core involved). Progression-free survival was compared. Predictors of progression were investigated using a Cox proportional hazards model. RESULTS AND LIMITATIONS Of the 286 patients remaining on AS after B2, 149 (52%) had no cancer and 137 (48%) had cancer. The median follow-up after B2 was 41 mo (interquartile range [IQR]: 26.5-61.9). Progression-free survival at 5 yr was 85.2% versus 67.3% for negative B2 versus cancer on B2, respectively (p = 0.002). Men with no cancer at B2 had a 53% reduction in risk of subsequent progression (hazard ratio [HR]: 0.47; 95% confidence interval [CI], 0.29-0.77; p = 0.003). Subanalysis showed prognostic indicators of volume-related progression were absence of cancer (HR: 0.36; 95% CI, 0.20-0.62; p = 0.0006) and PSA density (HR: 1.79; 95% CI, 1.12-2.89; p = 0.01). The only predictor of grade-related progression was age (HR: 1.05; 95% CI, 1.00-1.10; p = 0.04). Retrospective analysis was the major limitation of the study. CONCLUSIONS Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression. This must be considered when counseling men on AS.

Measurement of peri‐prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer

Study Type – Prognosis (cohort)

Sex differences in bladder cancer outcomes among smokers with advanced bladder cancer

Study Type – Aetiology (individual cohort)

An analysis of world media reporting of two recent large randomized prospective trials investigating screening for prostate cancer

What’s known on the subject? and What does the study add?

Should Follow-up Biopsies for Men on Active Surveillance for Prostate Cancer Be Restricted to Limited Templates?

OBJECTIVE To investigate if prostate biopsy templates with fewer cores can be used during active surveillance (AS) for prostate cancer. METHODS At present, we use an AS protocol template (ASPT) consisting of 13-17 cores. We hypothesize in the setting of known cancer, sextant (6 cores) or standard extended (10-12 cores) templates, could be used with similar effect. We identified patients in our referral institution database (1997-2009) with entry prostate-specific antigen <10 ng/mL, stage ≤cT2, Gleason sum ≤6, ≤3 cores positive for cancer, <50% of single core involved, and age ≤75 years (N = 272). Patients fulfilling standard criteria for pathologic reclassification (N = 94) at any follow-up biopsy were selected for evaluation. By mapping tumor location on the pathologic reclassification determining biopsy, hypothetical scenarios of sextant or standard extended templates (SET) were compared with our ASPT and examined for frequency of cancer detection and pathologic reclassification. RESULTS For the 94 patients analyzed, the median number of cores taken was 9.7 (6-22) at baseline and 15 (14-17) for the reclassification biopsy. The median time between baseline and the pathologic reclassification determining biopsy was 15.4 months. Analysis of subgroupings showed that sextant template would identify 84% of cancers and 47.9% of the reclassification events, whereas SET detected 99% of cancers and 81.9% of patients who pathologically reclassified. When only considering Gleason sum ≥7 related progression events, SET found 16.2% less (n = 57) compared with ASPT (n = 68). CONCLUSION When monitoring patients on AS, a 13-17 core template detects more pathologic reclassification than standard sextant (18.1%) or extended (52.1%) biopsy templates.