The toxic effects of androgen deprivation have been well described, with numerous potential adverse effects on quality of life, including sexual dysfunction, hot flashes, fatigue, anemia, decreased bone density and muscle mass, an altered blood lipid profile, depression, cognitive dysfunction, and worsening of the metabolic syndrome, with effects on glucose metabolism and cardiovascular morbidity.21-27
All adverse events associated with per-protocol treatment are shown in Table S3 in the Supplementary Appendix
. The early diagnosis of failure of definitive treatment, as determined according to the PSA level, subjects otherwise asymptomatic men to many years of androgen deprivation, adversely affecting their quality of life.
Compelling laboratory evidence from animal models has suggested that reexposure to androgens after a period of androgen ablation helps preserve hormonal responsiveness, and a number of phase 2 and 3 clinical studies with different inclusion criteria and treatment schedules have shown that the cyclic approach to androgen deprivation is feasible and is associated with a reduction in toxic effects (Tables S4
and S5 in the Supplementary Appendix
). However, assessment of the effect on overall survival requires a randomized trial with sufficient power and duration of follow-up.
For these reasons, the NCIC Clinical Trials Group undertook this phase 3 study in 1999, enrolling 1386 patients over a period of 6 years in an international cooperative effort. On the basis of the planned interim analysis, which showed that the prespecified noninferiority threshold for intermittent therapy had been met, the data and safety monitoring committee recommended early reporting of results. The longer-than-expected median survival of 9 years for all patients with biochemical evidence of disease progression supports the need for a reduction in the toxicity of treatment. However, the finding that overall survival was not reduced by using the study-defined intermittent androgen-deprivation approach should not be extrapolated to other treatment schedules. In addition, this trial did not address the question of when, or at what PSA level, treatment should be initiated; the PSA level of 3 ng per milliliter used as an eligibility criterion for this study was chosen to facilitate accrual.
Although intermittent androgen-deprivation therapy appears to provide an overall quality-of-life benefit, as compared with continuous androgen-deprivation therapy, the difference is not as profound as one might expect. Part of the explanation for this lies in the timing of the qualityof-life assessments, which were performed at regular intervals in both treatment groups without regard to the treatment phase (on or off treatment). For the first 8 months, the two study groups received identical treatment. Within a few months after the start of the first off-treatment period (median duration, 20 months), we observed a benefit in the intermittent-therapy group. Later in the off-treatment period, the effect diminished because of dilution by patients entering the next treatment cycle. The longer the time from randomization, the more likely that patients in the intermittent-therapy group were distributed between treatment and nontreatment phases. Quality-of-life benefits for an individual patient may depend on the treatment cycle, status with respect to testosterone recovery, and age.
The role of predictive factors such as age, Gleason score, and PSA kinetics in the selection of patients for intermittent therapy remains to be defined. The time that it took for the PSA level to double before study entry was not available, but stratification was planned on the basis of the interval since the completion of radiotherapy (1 to 3 years vs. >3 years) as a surrogate for the doubling time. Men who had been treated with radiotherapy more than 3 years before being enrolled in the study had better disease-specific survival (), with no significant difference according to the treatment they received (P = 0.65). Furthermore, there was no significant difference in treatment effect according to the Gleason score, but this was an unplanned subgroup analysis and the trial was not powered to detect a difference of this magnitude. Whether the Gleason score should be used in the selection of patients for intermittent androgen-deprivation therapy remains a matter of clinical judgment (Fig. S3 in the Supplementary Appendix
This trial raises provocative questions. The non-significant increase in deaths from other causes among patients in the continuous-therapy group cannot be attributed to any specific type of toxic effect. Although the cost savings from the reduction in drug use in the intermittent-therapy group (approximately one third of that in the continuous-therapy group) may be partially offset by the closer follow-up required, this follow-up may have undefined health benefits.
An intermittent approach to androgen deprivation for men with a rising PSA level after definitive radiotherapy does not result in inferior survival, as compared with continuous androgen deprivation. 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.