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The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of erectile dysfunction were observed.

3 Background: This trial compared the efficacy of DE-EBRT and LDR-B for National Comprehensive Cancer Network (NCCN) high and intermediate-risk disease. Methods: A planned sample size of 400 patients were randomized to one of two treatment arms and stratified by risk group. Both arms received 12 months of androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist plus a non-steroidal anti-androgen for at least 1 month. After 8 months of neo-adjuvant ADT, both arms received whole pelvis EBRT (46Gy/23#). Patients assigned to DE-EBRT (standard arm) then received a conformal EBRT boost (32Gy/16#). Patients assigned to LDR-B (experimental arm) received an Iodine-125 LDR boost prescribed to a minimum peripheral dose of 115Gy. The primary endpoint was relapse free survival (RFS) defined by biochemical criteria using the nadir+2 ng/mL threshold. Time zero was the date of the first LHRH injection. Results: Between Dec 2002 and Sep 2011, 276 high-risk and 122 intermediate-risk patients were accrued at 6 cancer treatment centers. 200 men were assigned to DE-EBRT and 198 to LDR-B. The treatment arms were well balanced in terms of age and known prognostic factors. Median follow up (FU) is 6.5 years; 65 men have >9 years FU. There were 12 major protocol violations in each arm. By intent-to-treat analysis, the 3-, 5-, 7-, and 9-year Kaplan-Meier RFS estimates are 94% vs 94%, 77% vs 89%, 71% vs 86%, and 63% vs 83% for DE-EBRT and LDR-B respectively (hazard ratio = 0.473; 95% CI 0.292 – 0.765; P = 0.0022). Randomization (p<0.001), percent positive cores (p=0.005), initial PSA (p=0.006) and clinical T-stage (p=0.013) were predictive of RFS in a multivariable Cox model. The median PSA at latest FU for non-relapsing patients assigned to LDR-B is 0.02 vs 0.24 ng/mL for DE-EBRT. Conclusions: In a randomized trial, an Iodine-125 LDR boost was much more effective than an EBRT boost in rendering unfavorable-risk prostate cancer patients biochemically disease free. *ASCENDE-RT- Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy is an NCI registered trial (NCT00175396). Clinical trial information: NCT00175396.

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What ' s known on the subject? and What does the study add? Previous reports, with small numbers of patients, have described the problem of incomplete testosterone suppression ( > 1.1 or 1.7 nmol/L) with LHRH agonists. Various predisposing factors have been suggested: different drug agents and patient factors such as age, pretreatment testosterone levels and weight. Such incomplete testosterone suppression has been shown in one small report to be associated with increased PSA failure rates and in another report in those with metastases, with worse survival.This study used testosterone assays that are more accurate at low levels than those used in most previous reports in a large dataset of 2196 men, and confi rmed incomplete testosterone suppression (breakthrough) rates > 1.7 nmol/L of 3.4% and > 1.1 nmol/L of 6.6%. We showed that younger age was strongly associated with the risk of breakthrough, with a minor effect of increasing body mass index. Repeated breakthroughs were more common (16%) in those who had already had one breakthrough. Interim measures of cancer control (PSA kinetics during LHRH therapy) were inferior in those with a breakthrough, and those with breakthroughs between 1.1 and 1.7 nmol/L had worse long-term biochemical control rates. OBJECTIVES• To describe breakthrough rates above castrate levels of testosterone, in a population-based series of men undergoing adjuvant luteinizing hormone-releasing hormone (LHRH) agonist therapy with curative radiation therapy.• To explore the predisposing factors for such breakthroughs and their impact on subsequent outcomes. PATIENTS AND METHODS• All men treated for prostate cancer between 1998 and 2007 with curative radiation in the province of British Columbia, Canada were potentially eligible ( n = 11 752). Of these, 2196 fulfi lled the eligibility criteria.• Serial testosterone measurements were obtained during continuous LHRH therapy.• Breakthrough rates > 1.1 nmol/L and > 1.7 nmol/L were calculated for each LHRH injection and for each patient course.• Predisposing factors were identifi ed, and early surrogates of oncological outcome (neoadjuvant nadir and post-treatment nadir) were determined. RESULTS• The risk of a breakthrough > 1.1 nmol/L was 6.6%, and > 1.7 nmol/L was 3.4% per patient course and 5.4% and 2.2% per LHRH injection (inclusive ranges).• Repeated breakthroughs occurred in 16% of patients.• Younger men were more liable to breakthroughs ( P < 0.001).• Early PSA kinetic surrogates of cancer control were inferior in those with breakthroughs.• Neither overall biochemical non-evidence of disease (bNED) nor survival were compromised, although subgroup analysis showed inferior 5-year bNED in those with breakthroughs of 1.1 -1.7 nmol/L vs those without (58% vs 73%, respectively; P = 0.048). CONCLUSIONS• Breakthroughs with LHRH agonists occur occasionally per injection, but occur commonly per patient course of treatment, and adversely affect early surrogate measures of outcome.• The monitoring of testosterone levels during therapy is therefore advis...