A recently reported National Cancer Institute of Canada (NCIC) Clinical Trials Group study, reported by Crook and colleagues in The New England Journal of Medicine, showed that intermittent androgen suppression was associated with noninferior overall survival when compared with continuous suppression in patients with prostate cancer and rising prostate-specific antigen (PSA) levels after radiotherapy. Intermittent therapy is of interest because it may improve quality of life (QOL) and delay hormone resistance. Experimental models have shown that successive castration and reexposure to androgens resulted in multiple apoptotic regressions and increased time to androgen independence, and early-phase trials have provided proof of principle of an intermittent suppression approach in humans.
Study Design
In the NCIC study, 1386 patients with PSA level > 3 ng/mL more than 1 year after definitive primary or salvage radiotherapy for localized prostate cancer were randomly assigned to intermittent (n = 690) or continuous (n = 696) androgen-deprivation therapy. Prior androgen suppression for up to 12 months in association with definitive treatment was permitted if it had been completed ≥ 12 months before enrollment. Patients had to have a serum testosterone level > 5 nmol/L and life expectancy of > 5 years. The primary endpoint was median overall survival.
Continuous androgen suppression consisted of a luteinizing hormone-releasing hormone agonist (LHRHa) plus a nonsteroidal antiandrogen or orchiectomy. Intermittent androgen suppression consisted of 8-month treatment cycles with a LHRHa plus a nonsteroidal antiandrogen followed by a nontreatment period if there was no evidence of clinical progression and PSA level was < 4 ng/mL and ≤ 1 ng/mL above the prior value obtained in monitoring during the treatment cycle. The nontreatment period continued, in the absence of clinical progression, until PSA level reached 10 ng/mL, with PSA levels being measured every 2 months. Castration-resistant disease was defined as three increases in PSA level at least 1 month apart or evidence of new clinical disease while patients were receiving androgen-deprivation therapy and testosterone was at castrate levels.
At baseline, the intermittent group and continuous group were well matched for median age (74 vs 74 years), ECOG performance status (0 in 79% vs 82%), baseline PSA (> 15 ng/mL in 23% vs 23%), prior radical prostatectomy (11% vs 11%), time since radiotherapy (> 3 years in 79% vs 78%), and proportion without prior hormone therapy (61% vs 61%).
Median follow-up was 6.9 years (range, 2.8–11.2 years). Patients in the intermittent group completed 1 to 9 treatment cycles; 95% entered the first nontreatment interval, 58% a second, and 32% a third, with median durations of the nontreatment intervals progressively decreasing from 20.1 months to 13.2 months and 9.1 months over the first three intervals, and to 4 to 5 months in intervals 4 to 7. The median cumulative nontreatment period for patients in the intermittent group was 37.6 months. Patients in the continuous group had a median of 43.9 months of LHRHa treatment compared with 15.4 months of LHRHa treatment in patients in the intermittent group.
Noninferior Overall Survival
On intent-to-treat analysis, median overall survival was 8.8 years in the intermittent group vs 9.1 years in the continuous group, a nonsignificant difference (hazard ratio [HR] = 1.02, 95% confidence interval [CI] = 0.86–1.21). The P value for noninferiority (HR > 1.25) was .009, supporting the hypothesis that intermittent androgen-deprivation therapy was not inferior to continuous treatment.
A per-protocol analysis yielded similar results. Multivariate analysis including age, ECOG performance status, time since completion of radiotherapy, baseline PSA level, and neoadjuvant androgen suppression also yielded similar results (HR = 1.03, 95% CI = 0.86–1.22). No differential treatment effect was observed in analysis by Gleason score categories of ≤ 6, 7, and 8 to 10.
In total, 59% of deaths were not related to prostate cancer. Thus, an unplanned retrospective analysis was performed to determine disease-specific survival. Risk of prostate cancer–related death was comparable with intermittent androgen-deprivation therapy (HR = 1.18, P = .24), with a similar finding after adjustment for stratification and confounding factors (HR = 1.23, P = .13).
Estimated 7-year cumulative disease-related death rates were 18% in the intermittent group and 15% in the continuous group. Factors that were significantly associated with increased risk of prostate cancer–related death in the entire population on this analysis were age ≥ 75 vs < 75 years (HR = 1.58, P = .001), baseline PSA > 15 vs 3 to 15 ng/mL (HR = 1.98, P < .001), and prior hormone therapy (HR = 1.66, P < .001). Time since radiotherapy of > 3 vs 1 to 3 years was associated with a significantly decreased risk (HR = 0.41, P < .001).
Castration-resistant Disease
Castration-resistant disease developed in 202 patients in the intermittent group and 243 in the continuous group, yielding a significant 20% reduction in risk in the intermittent group (HR = 0.80, P = .02), with the reduction remaining significant after adjustment for prognostic factors (HR = 0.81, P = .03). A 4-month survival gain after diagnosis of castration-resistant disease observed in the intermittent group likely reflected the inherent delay in identification of such disease in this group (ie, treatment had to be restarted in these patients, who then had to satisfy testosterone and PSA criteria for diagnosis).
A return to pretreatment testosterone levels occurred in 35% of intermittent group patients within 2 years of completing the first treatment period, and 79% had a level of ≥ 5 nmol/L (the required entry level). Return to pretreatment levels was significantly less likely in patients aged 75 years or older compared with younger patients (P = .001). Recovery of potency occurred in 29% of patients who were potent at baseline.
Some QOL Improvement
Quality of life was assessed at fixed time points, irrespective of treatment phase, using the EORTC QLQ-C30. Assessment occurred at baseline, every 4 months for 2 years, and then every 8 months until diagnosis of castration-resistant disease and annually thereafter. For functional domains (physical, role, and general health), the intermittent group had scores that were slightly but nonsignificantly better than those in the continuous group. For symptom items, the intermittent group had significantly better scores for hot flashes (P < .001), desire for sexual activity (P < .001), and urinary symptoms (P = .006), with a trend toward improvement in fatigue (P = .07). A safety analysis showed no significant between-group differences in adverse events.
The investigators noted that the improvements in QOL were not as marked as might be expected in the intermittent group and suggested that this finding likely reflects the fact that, over time, intermittent group patients were increasingly distributed between treatment and nontreatment intervals at the times of QOL assessment. The observed difference in QOL between the two groups was greatest during the first nontreatment interval, entered at the same time point by the majority of intermittent group patients, and diminished thereafter. For an individual patient receiving intermittent androgen-deprivation therapy, differences in QOL might be more striking between treatment and nontreatment phases, with benefits also expected to be affected by such factors as testosterone recovery and age.
The authors concluded: “An intermittent approach to androgen deprivation for men with a rising PSA level after definitive radiotherapy does not result in inferior survival…. Although testosterone recovery was not universal, benefits in some aspects of quality of life were observed. These results cannot be extrapolated to other intermittent-treatment schedules or disease characteristics.” ■
Reference
1. Crook JM, O’Callaghan CJ, Duncan G, et al: Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 367:895-903, 2012.
