Jeremy Hamm

Incomplete testosterone suppression with luteinizing hormone-releasing hormone agonists: does it happen and does it matter?

Study Type – Therapy (case series)

Whole prostate D90 and V100: A dose–response analysis of 2000 consecutive 125I monotherapy patients

PURPOSE To examine the relationship between whole prostate dose metrics and disease-free survival (DFS) after (125)I low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALS Data for the first 2000 LDR-PB monotherapy implants were extracted from a database containing patient, tumor, dosimetric, and outcomes information. By National Comprehensive Cancer Network criteria, half (n = 1006) had low-risk disease and half (n = 990) had intermediate-risk disease (four had high-risk disease). Most patients (58.4%) and 75.3% of intermediate-risk patients received 3 months neoadjuvant and 3 months concomitant androgen deprivation therapy (ADT). Univariate and multivariate analyses were conducted using recognized prognostic factors and the whole prostate dose metrics D90 (the minimum dose received by 90% of the postimplant CT-based prostate volume) and V100 (the percent of the postimplant CT-based prostate volume that received at least 100% of the prescription dose). RESULTS The median followup is 5 years (maximum, 12.5 years); the 5-, 7-, and 10-year actuarial DFS estimates are 96.0%, 94.4%, and 93.0%, respectively. Of the recognized prognostic factors, only pretreatment prostate-specific antigen (p = 0.012) and Gleason sum (p = 0.010) were predictive of DFS. When analyzed as continuous variables, dose metrics were not predictive of DFS. However, most nonsignificant trends favored higher doses, and D90 values <130 Gy were predictive of an increased risk of recurrence in the non-ADT subset (N = 833; log rank, p = 0.018). CONCLUSIONS Although D90 values of <130 Gy were predictive of an increased risk of recurrence in the non-ADT subset, neither D90 nor V100, when used as continuous variables, was predictive of DFS when applied to the entire cohort or in the subset analysis. This observation informs us that dose metrics are not equivalent to oncologic end points and must be calibrated against DFS for each physician and each institution offering LDR-PB.

Prostate-Specific Antigen at 4 to 5 Years After Low-Dose-Rate Prostate Brachytherapy Is a Strong Predictor of Disease-Free Survival

PURPOSE To determine (1) the prognostic utility of prostate-specific antigen (PSA) concentration at 45 to 60 months (48mPSA) after low-dose-rate prostate brachytherapy (LDR-PB); (2) the predictors of 48mPSA; and (3) the prognostic utility of directional trends between PSA levels at 24, 36, and 48 months after LDR-PB. METHODS AND MATERIALS Between 1998 and 2008, 2223 patients with low- and intermediate-risk prostate cancer received LDR-PB monotherapy. A cohort of 1434 of these patients was identified with a documented 48mPSA and no evidence of disease relapse prior to the 48mPSA. In addition, a subset of this cohort (n=585) was identified with ≥72 months of follow-up and documented PSA values at both 24 and 36 months after implantation. RESULTS Median follow-up time was 76 months. Eight-year Kaplan-Meier disease-free survival (DFS) rates were 100% vs 73.4% for patients with 48mPSA≤0.2 vs those with >0.2 ng/mL; 99.1% versus 53.8% for a 48mPSA threshold of ≤0.4 versus >0.4 ng/mL, respectively; and 97.3% versus 0% for a threshold of ≤1.0 versus >1.0 ng/mL, respectively. On multivariate analysis, the only factor predictive of DFS was 48mPSA (P<.0001). On subset analysis (n=585), 29 patients had a PSA rise (defined as >0.2 ng/mL) between 24 and 36 months, 24 patients had a rise between 36 and 48 months, and 11 patients had rises over both intervals. Failure rates in these patients were 52%, 79%, and 100%, respectively. On multivariate analysis, initial PSA, androgen deprivation therapy, and dose to 90% of the prostate significantly correlated with 48mPSA but together accounted for only ∼5% of its total variance. CONCLUSIONS The 48mPSA after LDR-PB is highly predictive of long-term DFS. Patients with 48mPSA≤0.4 ng/mL had a <1% risk of disease relapse at 8 years, whereas all patients with 48mPSA>1.0 ng/mL relapsed. Consecutive PSA rises of >0.2 ng/mL from 24 to 36 months and from 36 to 48 months were also highly predictive of subsequent failure.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: A population-based cohort study

BACKGROUND AND PURPOSE To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. MATERIALS AND METHODS Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. RESULTS Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus<the median value (150.5 Gy) or ≥ versus<140 Gy. CONCLUSIONS I-125 brachytherapy with 6 months of ADT demonstrates excellent bNED rates in Gleason 7 disease. We found no evidence of a difference between patients with Gleason 3+4 versus 4+3 disease.

Incidence of second malignancies in prostate cancer patients treated with low-dose-rate brachytherapy and radical prostatectomy.

PURPOSE To compare the second malignancy incidence in prostate cancer patients treated with brachytherapy (BT) relative to radical prostatectomy (RP) and to compare both groups with the cancer incidence in the general population. METHODS AND MATERIALS From 1998 to 2010, 2418 patients were treated with Iodine 125 prostate BT monotherapy at the British Columbia Cancer Agency, and 4015 referred patients were treated with RP. Cancer incidence was compared with the age-matched general population using standardized incidence ratios (SIRs). Pelvic malignancies included invasive and noninvasive bladder cancer and rectal cancer. Cox multivariable analysis was performed with adjustment for covariates to determine whether treatment (RP vs BT) was associated with second malignancy risk. RESULTS The median age at BT was 66 years and at RP 62 years. The SIR comparing BT patients with the general population was 1.06 (95% confidence interval [CI] 0.91-1.22) for second malignancy and was 1.53 (95% CI 1.12-2.04) for pelvic malignancy. The SIR comparing RP patients with the general population was 1.11 (95% CI 0.98-1.25) for second malignancy and was 1.11 (95% CI 0.82-1.48) for pelvic malignancy. On multivariable analysis, older age (hazard ratio [HR] 1.05) and smoking (HR 1.65) were associated with increased second malignancy risk (P<.0001). Radical prostatectomy was not associated with a decreased second malignancy risk relative to BT (HR 0.90, P=.43), even when excluding patients who received postprostatectomy external beam radiation therapy (HR 1.13, P=.25). Older age (HR 1.09, P<.0001) and smoking (HR 2.17, P=.0009) were associated with increased pelvic malignancy risk. Radical prostatectomy was not associated with a decreased pelvic malignancy risk compared with BT (HR 0.57, P=.082), even when excluding postprostatectomy external beam radiation therapy patients (HR 0.87, P=.56). CONCLUSIONS After adjustment for covariates, BT patients did not have an increased second malignancy risk compared with RP patients. Further follow-up of this cohort is needed given the potential latency of radiation-induced malignancies.

Population-based validation of a policy change to use long-term androgen deprivation therapy for cT3–4 prostate cancer: Impact of the EORTC22863 and RTOG 85-31 and 92-02 trials

PURPOSE After publication of EORTC-22863 trial, prolonged androgen deprivation therapy (ADT) combined with radiation therapy (RT) became standard policy for high-risk prostate cancer patients in British Columbia (BC) in 1997. We evaluated whether population-based survival improved after this policy change. PATIENTS AND METHODS Two cohorts comprising all patients with T3-T4 prostate cancer treated with curative-intent RT in BC were reviewed. The Early cohort (n=730) was all patients treated between 1993 and 1995, and the Late cohort (n=584) was all patients treated between 1999 and 2001. The BC Cancer Registry, which collects data on survival, was linked to RT and pharmacy databases. Duration of ADT, age, stage, grade, presenting PSA, and Charlson comorbidity index (CCI; none=0, minor=1, major=2+), were abstracted from charts. RESULTS Usage of ≥6 months and ≥18 months of neoadjuvant and adjuvant ADT increased from 14% and 1% to 97% and 59% (p<0.0001). Baseline characteristics were similar, except for lower Gleason score (G2-6: 45% vs. 20%, G7: 35% vs. 48%, G8-10: 19% vs. 32%; p<0.0001), higher T-stage (T4: 9% vs. 5%, p=0.004) and higher comorbidity (CCI 0: 62% vs. 71%, CCI 1: 26% vs. 20%, CCI 2+: 11% vs. 9%, p=0.002) in the Early cohort. Disease-specific survival adjusted for competing risks from other causes mortality was improved (90% vs. 86%, p=0.042). On multivariate analysis, the Late cohort was independently associated with improved 8-year overall survival (76% vs. 64%, p=0.0002). CONCLUSIONS This population-based study demonstrated improved overall survival following a policy change to use of prolonged ADT with curative RT for patients with T3-T4 prostate cancer.

The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy

PURPOSE The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort. METHODS AND MATERIALS Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) >0.4ng/mL at ≥48 months postimplant. Actuarial estimates were calculated by the Kaplan-Meier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model. RESULTS There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6-96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8-96.2) for patients treated with RS according to Phoenix definition (p=0.846). Using the PSA >0.4ng/mL definition, estimated rates were 91.3% (95% CI, 88.0-94.6) and 91.9% (95% CI, 89.7-94.1) for loose and stranded seeds, respectively (p=0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED. CONCLUSION This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA >0.4ng/mL definitions of biochemical failure.

Long-Term Prostate Specific Antigen Stability and Predictive Factors of Failure after Permanent Seed Prostate Brachytherapy

Purpose Defining biochemical failure as nadir + 2 may overestimate cure after radiotherapy. We assessed long‐term prostate specific antigen stability after low dose rate prostate brachytherapy and predictors of biochemical failure when prostate specific antigen was slowly rising below the nadir + 2 ng/ml threshold. Materials and Methods A total of 2,339 patients with low or intermediate risk prostate cancer received 125iodine brachytherapy from 1998 to 2010 with a minimum 3‐year followup. In addition, 49.7% of the patients received 6 months of androgen deprivation. Clinical, dosimetric and prostate specific antigen data were retrieved from a prospective database. Biochemical results were classified as stable or rising prostate specific antigen (0.2 ng/ml or greater and increased 0.1 ng/ml or greater during the preceding 2 years), or biochemical failure (defined as nadir + 2). Multivariate analysis was done to identify predictors of failure used to create logistic regression models. Results At a median followup of 89 months (range 37 to 199) prostate specific antigen was stable (nadir 0.03 ng/ml and at 60 months 0.04 ng/ml) in 2,004 patients (86%) and rising (nadir 0.16 ng/ml and at 60 months 0.29 ng/ml) in 145 (6%) while biochemical failure (nadir 0.51 ng/ml, p <0.001) was noted in 190 (8%). When there was no prior androgen deprivation therapy, the prostate specific antigen nadir and prostate specific antigen at 60 months were the strongest predictors of failure (OR 20.6 and 18.3, respectively, each p <0.0001). The logistic regression model had 85% sensitivity and 98% specificity, and predicted failure in 8 of 82 men (9.8%). A second model was created for the group with androgen deprivation therapy and rising prostate specific antigen using the predictive factors prostate specific antigen at 60 months (OR 53.9, p <0.0001) and T stage (OR 0.25, p = 0.0008). This model predicted biochemical failure in 30 of 56 men (54%) with 85% sensitivity and 93% specificity. The 2 predictive models yield an anticipated 90% cure rate in the entire cohort. Conclusions Brachytherapy is highly curative with stable prostate specific antigen at a surgical ablation level in 86% of patients. Rising prostate specific antigen is rare at a 6% incidence and often innocuous.

The impact of comorbidities on the benefits of prolonged androgen ablation in patients with T3-4 prostate cancer treated with external beam radiation therapy☆

PURPOSE To determine whether the survival benefit associated with prolonged androgen deprivation therapy (ADT) and radiotherapy (EBRT) varies with baseline estimates of overall survival in cT3-4 prostate cancer patients (PCa). METHODS AND MATERIALS In 1997, the BC Cancer Agency adopted as standard a policy of prolonged ADT (>18months) with EBRT for locally advanced PCa. Two cohorts of cT3-T4 PCa treated with EBRT were selected: 1993-1995 (early: N=725) and 1999-2001 (late: N=584). Duration of ADT and baseline prognostic factors (age, clinical stage, grade, presenting PSA, and Charlson index (CCI)) were abstracted from charts. Estimates of 10-year (E10) survival using an age-adjusted CCI were calculated and patients were grouped into low (<60%), medium (60-90%) and high (>90%) E10. In each E10 group, actual overall survivals were compared by era using log rank test. RESULTS There were 318 low, 544 medium, and 447 high E10 patients with median follow-up of 11.1years. Gleason grade and T stage were not statistically different between E10 groups. As expected, median age and baseline CCI were higher in lower E10 groups (p<0.0001). Overall survival was higher in the late era, but varied with E10 group: low (43% vs. 49%, p=0.54), medium (55% vs. 64%, p=0.02) and high (66% vs. 77%, p=0.01). CONCLUSION The policy of prolonged ADT with EBRT provides a survival benefit that varies with baseline risk of death from other causes. Absolute benefit from ADT is largest in those with medium or high E10.