乌鸦传媒

CHICAGO -- Adding a short course of androgen deprivation therapy (ADT) to dose-escalated radiotherapy (RT) led to a mixed bag of outcomes in intermediate-risk prostate cancer, according to a large randomized trial.

The addition of 6 months of ADT did not improve overall survival (OS) compared with RT alone, but the hormonal therapy was associated with a lower rate of biochemical failure, fewer distant metastases, and better cancer-specific survival. Additionally, ADT modestly increased acute adverse events and temporarily reduced some aspects of quality of life.

Subgroup analysis of the 1,500-patient trial did not identify any patient groups who derived more benefit from ADT than others, reported Daniel J. Krauss, MD, of Beaumont Health in Royal Oak, Michigan, at the American Society for Radiation Oncology meeting.

"At a median follow-up of 6.3 years, the addition of short-term androgen deprivation did not improve overall survival rates for men with intermediate-risk prostate cancer who are treated with dose-escalated radiation," he said. "Androgen deprivation did result in reductions in biochemical failure, distant metastases, initiation of salvage therapy, and prostate cancer-specific mortality (PCSM). Benefits in PSA failure and distant metastasis rates persisted irrespective of the number of risk factors, baseline ACE (Adult Comorbidity Evaluation)-27 score, and primary Gleason pattern three plus four versus four plus three."

"These advantages of short-term androgen deprivation, together with dose-escalated radiation, for these patients will need to be weighed against a modest increased risk in acute adverse events and the results of the accompanying patient-reported quality-of-life study," he added.

The trial began in 2008, when the benefits of ADT in prostate cancer had already been established for high-risk localized and locally advanced disease, said Rahul Tendulkar, MD, of the Cleveland Clinic, during a genitourinary highlights session. However, a number of questions remained unanswered regarding ADT's use in intermediate-risk prostate cancer and with modern dose-escalated RT protocols.

"The goal of the trial was to better study the mechanism of short-term androgen deprivation therapy in the dose-escalation era to try to elicit more information about whether the synergy of the two treatments was about treating micrometastatic disease or radiosensitizing disease in the prostate or both," said Tendulkar. "We also wanted to better quantify how much ADT may impact outcomes and to better define exactly which patients may benefit from a dose-escalation approach such as this."

Improvement in secondary endpoints in the absence of an OS benefit was consistent with several previous trials evaluating RT with or without ADT, Tendulkar continued. Noting that the survival curves in NRG/RTOG 0815 appeared to separate after 5 years of follow-up, he said, "I'll be really curious to see where things go long term."

Investigators in NRG/RTOG 0815 enrolled patients with intermediate-risk prostate cancer as defined by Gleason score 7, pretreatment PSA >10 but ≤20 ng/mL, and clinical stage T2b-T2c. The trial had statistical power to detect an improvement in 5-year OS from 90% with RT alone to 93% with ADT.

Patients could receive one of three types of RT: dose-escalated external-beam RT (EBRT) to a maximum dose of 79.2 Gy, EBRT plus low-dose brachytherapy, or EBRT plus high-dose brachytherapy. Krauss said 11% of patients received brachytherapy. Patients assigned to ADT received combined androgen blockade with an LHRH agonist plus an antiandrogen.

The primary analysis showed no improvement in 5-year OS, but continued follow-up offered a suggestion of benefit. The 8-year OS was 79% for patients treated with RT alone and 84% for those who received ADT, although the difference still did not achieve statistical significance (P=0.22). In contrast, addition of ADT resulted in significant improvements in key secondary endpoints at 5 and 8 years compared with RT alone:

• PSA failure: 8% vs 14% at 5 years and 10% vs 21% at 8 years (P<0.001)
• Distant metastasis: 0.6% vs 3.1% and 1.0% vs 4.3% (P<0.001)
• Salvage therapy: 4.2% vs 6.1% and 5.3% vs 9.8% (P=0.025)
• PCSM: 0% vs 0.9% and <1% vs 1.6% (P=0.007)

Subgroup analysis of the primary and secondary endpoints did not identify groups of patients to target with ADT.

The addition of short-term ADT significantly increased the incidence of acute adverse events (69.5% vs 20.7%, P<0.001). Endocrine, sexual/reproductive function, and metabolic/laboratory AEs accounted for most of the disparity, said Krauss. Patient age, number of risk factors, type of RT, ACE-27 grade, or race did not significantly affect the likelihood of adverse events.

A companion quality-of-life study showed a significant adverse impact of ADT on sexual and endocrine function, which resolved without complication after about a year.

Comment