Testosterone recovery after androgen deprivation therapy in localised prostate cancer: Long-term data from two randomised trials.

BACKGROUND AND PURPOSE: To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT). MATERIALS AND METHODS: In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly. T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed. RESULTS: Overall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery. CONCLUSIONS: Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.

Optimizing Treatment in Intermediate-Risk Prostate Cancer: Secondary Analysis of a Randomized Phase 3 Trial.

PURPOSE: To identify patients with intermediate-risk prostate cancer (IRPC) benefiting from de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiation therapy (DERT), we performed a secondary analysis of a phase 3 trial by measuring biochemical failure (BF), distant metastases, prostate cancer-specific mortality, overall survival (OS), and distant metastases-free survival (DMFS) rates according to prognostic intermediate risk factors (IRF). METHODS AND MATERIALS: The initial trial randomized 600 patients with IRPC to a 3-arm trial with 200 patients per arm, consisting of 6 months of ADT plus 70 Gy radiation therapy (ADT + RT70) versus ADT plus a DERT of 76 Gy (ADT + DERT76) versus DERT of 76 Gy alone (DERT76). We performed an analysis based on IRF: clinical stage, prostate-specific antigen level, Gleason score, percentage of positive biopsy cores (PBC) ≥50%, and Gleason pattern. Patients were allocated to 2 groups: favorable intermediate risk (FIR), defined as patients with only 1 IRF without Gleason pattern 4 + 3 or PBC ≥50%; and unfavorable intermediate risk (UIR), defined as all other patients. BF, distant metastases, prostate cancer-specific mortality, OS, and DMFS were compared between FIR and UIR. RESULTS: The median follow-up was 11.3 years (interquartile range, 10.9-11.7). In the FIR cohort, BF and OS were not significantly different between arms. UIR patients had significantly worse DMFS (hazard ratio [95% confidence interval], 1.61 [1.20-2.15]; P = .026) and OS (1.51 [1.12-2.04]; P = .0495) and a nonsignificant higher cumulative incidence of BF rate (1.55 [0.98-2.47]; P = .08). In UIR patients, a significant improvement in BF was seen in the arms receiving ADT compared to DERT76 alone. On multivariable analysis, Gleason pattern 4 + 3 and prostate-specific antigen >10 ng/mL independently affected BF and OS, regardless of the treatment arm. CONCLUSIONS: In IRPC, therapeutic optimization appears possible. To avoid ADT side effects, DERT76 alone appears sufficient in patients harboring only 1 risk factor without Gleason pattern 4 + 3 and PBC ≥50% (FIR). All other UIR patients seem to benefit from ADT + DERT76.

The Clinical Significance of Bone Mineral Density Changes Following Long-Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients.

PURPOSE: Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation. MATERIALS AND METHODS: Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored. RESULTS: The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic. CONCLUSIONS: Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.

Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial.

BACKGROUND: The role of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) in intermediate-risk prostate cancer (IRPC) remains controversial, particularly in patients receiving dose-escalated RT (DERT). We compared outcomes between patients with IRPC treated with ADT and two different doses of RT vs. RT alone. METHODS: From December 2000 to September 2010, 600 patients with IRPC were randomised to a three-arm trial consisting of 6 months of ADT plus RT 70 Gy (ADT + RT70) vs. ADT plus a DERT of 76 Gy (ADT + DERT76) vs. DERT of 76 Gy alone (DERT76). Primary end-point was biochemical failure (BF), and secondary end-points were overall survival (OS) and toxicity. RT toxicity was assessed by Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. FINDINGS: With a median follow-up of 11.3 years (interquartile range: 10.9-11.7), patients receiving DERT76 alone, compared with patients receiving ADT + RT70 and ADT + DERT76, had higher rates of BF (32%, 18% and 14%, respectively, p < 0.001), higher rates of prostate cancer progression (12%, 4.5% and 3.3%, respectively, p = 0.001) and more deaths due to prostate cancer (6.5%, 3.0% and 1.5%, respectively, p = 0.03) with no significant difference seen between ADT + RT70 and ADT + DERT76. There was no significant difference in OS between the 3 arms. A higher dose of RT (76 Gy) increased late gastrointestinal (GI) toxicity grade ≥ II compared with lower dose (70 Gy) (16% vs 5.3%, p < 0.001) with no statistical difference for late genitourinary toxicity. INTERPRETATION: In IRPC, the addition of 6 months of ADT to RT70 or DERT76 significantly improves BF and appears to decrease the risk of death from prostate cancer compared with DERT76 alone with no difference in OS. In the setting of IRPC, ADT plus RT 70 Gy yields effective disease control with a better GI toxicity profile. Clinicaltrials.gov#NCT00223145.

Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial.

BACKGROUND: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined. OBJECTIVE: The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT. DESIGN, SETTING AND PARTICIPANTS: From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model. RESULTS AND LIMITATIONS: With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88-95%) and 86% for short arm (83-90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points. CONCLUSIONS: In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC. PATIENT SUMMARY: In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life.