[NEJM] No difference in survival between intermittent androgen deprivation therapy and continuous therapy for prostate cancer patients with rising PSA

Image: CC/EAS. Human PSA. 

Primer: Androgen deprivation therapy is the cornerstone for metastatic prostate disease. Intermittent therapy, essentially cycles of androgen deprivation followed by exposure to testosterone, has been shown to lengthen the time to hormonal resistance. In lengthening this time, some men may be able to avoid castration through intermittent therapy. Published today, Crook and colleagues sought to investigate survival in intermittent versus continuous androgen deprivation.

This [randomized] study: A phase 3 trial, by the NCIC Clinical Trials Group, comparing intermittent vs. non-stop androgen deprivation after radiotherapy and no evidence of metastatic disease in men with rising PSA levels. Primary endpoint was survival, follow up was ~7years. 1386 patients with a PSA of 3 ng/ml more than 1 year after primary or salvage radiotherapy were included. Subjects were randomized to intermittent vs. non-stop (690 and 696, respectively). Continuous androgen-deprivation therapy consisted of a luteinizing hormone–releasing hormone agonist (LHRHa) or orchiectomy. Intermittent androgen-deprivation therapy was defined as an 8-month treatment cycles with LHRHa injections.

While 37.8% of subjects died in the follow-up period, only 14.2% of these deaths were from prostate-related disease. The key finding is that there was no difference in median overall survival (8.8 years in the intermittent group and 9.1 years in the non-stop group).  This persisted after adjustment for age, performance status, time since radiation therapy, treatment with neoadjuvant hormonal therapy, and baseline PSA values. As expected, patients in the intermittent-therapy group were found to have fewer hot flashes, higher sexual desire and less urinary symptoms.

In sum: This is the most rigorous study to date comparing survival in intermittent androgen deprivation vs. non-stop deprivation, and reports no significant difference in survival. Some improvement in quality of life was expected, and demonstrated, in intermittent therapy. However, note that results cannot be extrapolated to other treatment schedules. The study also does not define a set PSA level for initiating treatment – a current major issue in prostate cancer (the set level of 3ng/ml was for recruitment purposes) treatment. While only a small number of men in the recruits might be able to expect a consequence from rising PSA – which asymptomatic ones actually truly benefitted from treatment? These questions will require further research. Lastly, the intermittent therapy group costs about 1/3 of that of the non-stop group, however they also require closer follow-up – issues which may play into clinical decision making.

Click to read in the New England Journal of Medicine [NEJM]

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