Timing of salvage hormone therapy when radiotherapy has failed

The question of when one should initiate hormone therapy in a man who has a rising PSA after radiation therapy has long been a topic of controversy. And a reanalysis of data from RTOG 85-31 has not helped to give us a definitive answer.

Radiation Therapy Oncology Group (RTOG) 85-31 was a randomized clinical trial in which  radiotherapy (RT) alone was compared to RT plus adjuvant androgen deprivation therapy (ADT) for life in patients with prostate cancer with a relatively poor prognosis. The data collected in this trial have also allowed Souhami et al. to compare what happened to patients who were randomized to the RT-only arm of the trial when their disease progressed at the time of failure of the RT — depending on whether the patients received early initiation of salvage ADT  (before the patient’s PSA reached 10 ng/ml) or whether ADT was delayed (until their PSA was 10 ng/ml or higher).

Outcomes assessed by the investigators were overall survival (OS), prostate cancer-specific mortality (PCSM), and local failure (LF), i.e., local progression of the patient’s disease.

The results of this secondary analysis of data from RTOG 85-31 showed the following:

  • Median follow-up for surviving patients in the early and late salvage ADT groups were about 11 and 13 years, respectively.
  • The late salvage ADT group had a significantly higher number of patients who had received an initial radical prostatectomy (before RT) and patients with high Gleason scores.
  • OS was significantly longer in the early salvage ADT group (hazard ratio [HR] = 1.5).
  • There were no statistically significant differences in LF or PCSM between the early and late ADT groups.

The basic conclusion of the investigators is that we need to carry out a new, randomized clinical trial to define the optimal timing of salvage ADT in patients who have a rising PSA after RT but who have never previously received ADT. This is a logical idea — but The “New” Prostate Cancer InfoLink is concerned that the availability of new treatments over the past 25 years (since the initial design of RTOG 85-31) may make such a new trial very difficult to conduct in a meaningful way.

The only really viable endpoints for such a trial are overall survival and prostate cancer-specific survival. However, we are very soon going to be presented with questions about the appropriate treatment of all patients failing even first-line radiation treatment because of all the new options on the table. Assuming that sipuleucel-T (Provenge) is approved this year, should selected (or all) patients failing first-line RT receive this form of treatment? If abiraterone acetate is shown to extend survival in patients who have hormone-refractory disease but no visible metastasis, do we need to consider a direct, head-to-head trial of ADT + abiraterone acetate vs. ADT followed by abiraterone acetate in men with rapidly progressive advanced prostate cancer? Even if we can carry out the planned trial, will the later use of treatments like sipuleucel-T and abiraterone acetate so alter the long-term survival of patients that any difference that might be observed between the use of early or delayed ADT be “swamped” (and therefore rendered irrelevant) by the later treatments?

We are entering a period of time when some of the old questions about management of progressive prostate cancer may be becoming irrelevant compared to newer and more important questions. It is not going to be easy to make really good decisions about some types of clinical trial under these circumstances. Prioritization of the most clinically important questions will become imperative if we are to make progress in the most appropriate and timely manner.

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