Adding Short-Term Androgen Deprivation Therapy to Radiation Therapy in Men With Localized Prostate Cancer: Long-Term Update of the NRG/RTOG 9408 Randomized Clinical Trial.

PURPOSE: For men with localized prostate cancer, NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 demonstrated that adding short-term androgen deprivation therapy (ADT) to radiation therapy (RT) improved the primary endpoint of overall survival (OS) and improved disease-specific mortality (DSM), biochemical failure (BF), local progression, and freedom from distant metastases (DM). This study was performed to determine whether the short-term ADT continued to improve OS, DSM, BF, and freedom from DM with longer follow-up. METHODS AND MATERIALS: From 1994 to 2001, NRG/RTOG 9408 randomized 2028 men from 212 North American institutions with T1b-T2b, N0 prostate adenocarcinoma and prostate-specific antigen (PSA) ≤20ng/mL to RT alone or RT plus short-term ADT. Patients were stratified by PSA, tumor grade, and surgical versus clinical nodal staging. ADT was flutamide with either goserelin or leuprolide for 4 months. Prostate RT (66.6 Gy) was started after 2 months. OS was calculated at the date of death from any cause or at last follow-up. Secondary endpoints were DSM, BF, local progression, and DM. Acute and late toxic effects were assessed using RTOG toxicity scales. RESULTS: Median follow-up in surviving patients was 14.8 years (range, 0.16-21.98). The 10-year and 18-year OS was 56% and 23%, respectively, with RT alone versus 63% and 23% with combined therapy (HR 0.94; 95% confidence interval [CI], 0.85-1.05; P = .94). The hazards were not proportional (P = .003). Estimated restricted mean survival time at 18 years was 11.8 years (95% CI, 11.4-12.1) with combined therapy versus 11.3 years with RT alone (95% CI, 10.9-11.6; P = .05). The 10-year and 18-year DSM was 7% and 14%, respectively, with RT alone versus 3% and 8% with combined therapy (HR 0.56; 95% CI, 0.41-0.75; P < .01). DM and BF favored combined therapy at 18 years. Rates of late grade ≥3 hepatic, gastrointestinal, and genitourinary toxicity were ≤1%, 3%, and 8%, respectively, with combined therapy versus ≤1%, 2%, and 5% with RT alone. CONCLUSIONS: Further follow-up demonstrates that OS converges at approximately 15 years, by which point the administration of 4 months of ADT had conferred an estimated additional 6 months of life.

Oncological outcomes of salvage cryotherapy after primary radiation therapy vs. primary cryotherapy: 10-year experience at a large Canadian referral center.

INTRODUCTION: Salvage cryotherapy is a guideline-recommended treatment of localized prostate cancer recurrence after radiation therapy. There is little published evidence analyzing the outcomes of salvage cryotherapy for recurrent prostate cancer following different primary therapy energy modalities. METHODS: We performed a retrospective analysis of patients who received whole gland salvage cryotherapy from 2007-2017 at a large tertiary referral center after either primary radiation therapy (RT) or primary whole gland cryotherapy. Primary outcome was biochemical failure, defined as per the Phoenix criteria (prostate-specific antigen [PSA] nadir + 2.0 ng/ml). Secondary outcomes included time to biochemical failure and development of metastatic disease. RESULTS: Fifty-eight of 391 patients who received cryotherapy were identified as having received salvage cryotherapy (after RT, n=37; after primary cryotherapy, n=21). Biochemical recurrence occurred in 21 (57%) patients with previous RT and in 17 (81%) patients with previous cryotherapy (p=0.001). Median time to biochemical recurrence was 18 months for patients with previous RT and 13 months for patients with previous cryotherapy (p=0.002). The biochemical-free survival rate for primary radiation therapy patients was 71% at two years compared to 23% at two years for patients who underwent primary cryotherapy (p<0.01). There was no difference in the development of metastatic disease between groups (19% vs. 18%, cryo vs. radiation, p=0.34). CONCLUSIONS: These results suggest that salvage cryotherapy may offer more durable oncological control to patients after radiation compared to primary cryotherapy, with a lower rate and longer duration before biochemical recurrence.

Furthering the prostate cancer screening debate (prostate cancer specific mortality and associated risks).

Screening for prostate cancer remains a contentious issue. As with other cancer screening programs, a key feature of the debate is verification of cancer-specific mortality reductions. Unfortunately the present evidence, two systematic reviews and six randomized controlled trials, have reported conflicting results. Furthermore, half of the studies are poor quality and the evidence is clouded by key weaknesses, including poor adherence to screening in the intervention arm or high rates of screening in the control arm. In high quality studies of prostate cancer screening (particularly prostate-specific antigen), in which actual compliance was anticipated in the study design, there is good evidence that prostate cancer mortality is reduced. The numbers needed to screen are at least as good as those of mammography for breast cancer and fecal occult blood testing for colorectal cancer. However, the risks associated with prostate cancer screening are considerable and must be weighed against the advantage of reduced cancer-specific mortality. Adverse events include 70% rate of false positives, important risks associated with prostate biopsy, and the serious consequences of prostate cancer treatment. The best evidence demonstrates prostate cancer screening will reduce prostate cancer mortality. It is time for the debate to move beyond this issue, and begin a well-informed discussion on the remaining complex issues associated with prostate cancer screening and appropriate management.

Radiotherapy and short-term androgen deprivation for localized prostate cancer.

BACKGROUND: It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma. METHODS: From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. RESULTS: The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients. CONCLUSIONS: Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).

Associations between comorbidity, and overall survival and bladder cancer specific survival after radical cystectomy: results from the Alberta Urology Institute Radical Cystectomy database.

PURPOSE: We determined the associations between comorbidity, and overall survival and bladder cancer specific survival after radical cystectomy. MATERIALS AND METHODS: The Alberta Urology Institute Radical Cystectomy database is an ongoing multi-institutional computerized database containing data on all adult patients with a diagnosis of primary bladder cancer treated with radical cystectomy in Edmonton, Canada from April 1994 forward. The current study is an analysis of consecutive database patients treated between April 1994 and September 2007. Comorbidity information was obtained through a medical record review using the Adult Comorbidity Evaluation 27 instrument. The outcome measures were overall survival and bladder cancer specific survival. Cox proportional regression analysis was used to determine the associations between comorbidity, and overall survival and bladder cancer specific survival. RESULTS: Of the database patients 160 (34%), 225 (48%) and 83 (18%) had no/mild comorbidity, moderate comorbidity and severe comorbidity, respectively. Compared to patients with no or mild comorbidity, multivariate Cox proportional regression analyses that included age, adjuvant chemotherapy, surgeon procedure volume, pathological T stage, pathological lymph node status, total number of lymph nodes removed, surgical margin status and lymphovascular invasion showed that increased comorbidity was independently associated with overall survival (moderate HR 1.59, 95% CI 1.16-2.18, p = 0.004; severe HR 1.83, 95% CI 1.22-2.72, p = 0.003) and bladder cancer specific survival (moderate HR 1.50, 95% CI 1.04-2.15, p = 0.028; severe HR 1.65, 95% CI 1.04-2.62, p = 0.034). CONCLUSIONS: Increased comorbidity was independently associated with an increased risk of overall mortality and bladder cancer specific mortality after radical cystectomy.

Return to continence after radical retropubic prostatectomy: a randomized trial of verbal and written instructions versus therapist-directed pelvic floor muscle therapy.

OBJECTIVES: To test the effectiveness of weekly postoperative pelvic floor muscle training (PFMT) versus supportive telephone contact by a urology nurse for men at 4 weeks after radical prostatectomy. METHODS: This was a randomized controlled trial in three Canadian centers. At 4 weeks after surgery, standardized verbal and written instruction about PFMT was provided to all subjects. Randomization occurred after initial instruction. Continence was defined as 8 g or less of urine loss on a 24-hour pad test. Primary outcome was grams of urine loss on pad test; secondary outcomes were International Prostate Symptom Score (IPSS), Incontinence Impact Questionnaire (IIQ-7) score, cost, and perception of urine loss as a problem. Data were obtained at baseline (preoperatively) and at weeks 4, 8, 12, 16, and 28 and 1 year after surgery. RESULTS: A total of 216 men were enrolled; 11 were dry or withdrew at 4 weeks. Ninety-nine were randomized to the control group and 106 to the treatment group. There were no group differences at baseline for prostate-specific antigen level (mean [standard deviation] 8.4 [10.4] ng/mL; 7.6 [4.6] ng/mL), Gleason score (6.3 [0.86]), IPSS, IIQ-7 score, pad test, or voiding diary. At 8 weeks 23% of the control group and 20% of the treatment group were continent; at 12 weeks, 28% and 32%; 16 weeks, 40% and 44%; 28 weeks, 50% and 47%; and at 52 weeks, 64% and 60%, respectively. There were no significant differences between groups at any time point for the outcome variables. CONCLUSIONS: Verbal instruction and written information with telephone support seemed to be as effective as intensive PFMT. Less-intense therapy may be more cost-effective.

Guidelines for the surveillance of localized renal cell carcinoma based on the patterns of relapse after nephrectomy.

PURPOSE: We characterized relapse patterns in patients with sporadic renal cell carcinoma (RCC) following radical and partial nephrectomy, and developed surveillance guidelines. MATERIALS AND METHODS: Between 1989 and 2000, 495 patients underwent nephrectomy for RCC at 1 of 5 Canadian referral centers. Median followup was 42 months. RESULTS: The rate of relapse, time to relapse and site of relapse were associated with pathological stage. Five-year progression-free probability was 93% for pT1, 81% for pT2, 67% for pT3A and 57% for pT3B (p <0.001). Compared to patients with pT1-2 those with pT3A-B lesions had earlier relapse after nephrectomy (median 12 vs 26 months, p = 0.001) and were at higher risk for relapse at abdominal sites (14% vs 1.8%, p < 0.001). Abdominal relapse was detected in the absence of symptoms, abnormal biochemical profile or thoracic metastases detectable by chest x-ray in 7 patients (1.4%) overall, including 3 (0.9%) with pT1, 3 (4%) with pT3A and 1 (3%) with pT3B. CONCLUSIONS: The risk and the pattern of relapse of RCC after nephrectomy are associated with pathological stage. For the surveillance of recurrent disease after nephrectomy we recommend annual clinical assessment and chest x-ray in pT1-2 cases. Patients with pT3A-B should be followed every 6 months for the first 3 years with clinical assessment and chest x-ray, and annual followup thereafter. The higher risk of abdominal relapse in patients with pT3A-B indicates that they should receive surveillance abdominal imaging. We recommend abdominal computerized tomography 6, 12, 24 and 36 months postoperatively.