Chemohormonal therapy + EBRT for treatment of locally advanced prostate cancer

Several years ago, Bolla et al. planned and carried out the major European trial showing that external beam radiation therapy with 3 years of androgen deprivation therapy (ADT, using goserelin acetate)  extended the prostate cancer-specific and the overall survival of patients with high-risk localized prostate cancer as compared to radiation alone. It appears that they want to be able to replicate their prior success.

In a report on a recent Phase II trial, Bolla et al. now discuss the feasibility of combining three-dimensional conformal radiotherapy (3D-CRT) with ADT and docetaxel chemotherapy in patients with high-risk forms of localized or locally advanced prostate cancer. The trial structure was as follows:

  • 50 patients were enrolled — with high-risk localized (n = 16), locally advanced (n = 28), or very high-risk (n = 6) prostate cancer.
  • All patients were treated with
    • 70 Gy of 3D-CRT delivered to the prostate and the seminal vesicles in 35 fractions
    • Concurrent weekly docetaxel (at 20 mg/m2)
    • Three cycles of docetaxel (at 60 mg/m2) starting 3 weeks after the completion of 3D-CRT, and given every 3 weeks
    • 3 years of LHRH agonist therapy (presumably starting prior to radiation and chemotherapy)

The results of the trial to date show that:

  • 46/50 patients completed the full-dose chemohormonal/radiation regimen.
  • 413 cycles of docetaxel chemotherapy were delivered to the patients
  • 4/50 patients stopped chemotherapy as a consequence of acute Grade 3/4 toxicity.
  • For the patients who completed the treatment regimen
    • The average (median) follow-up was 54 months.
    • The 5-year progression-free survival was 66.7 percent.
    • The 5-year overall survival was 92.2 percent.
    • 5 patients experienced Grade 3 toxicity.
    • 15 patients experienced Grade 2 toxicity.

The authors conclude that 3D-CRT with androgen deprivation and concurrent weekly docetaxel, followed by three cycles of adjuvant docetaxel, is a feasible regimen for the treatment of patients with high-risk prostate cancer. They suggest that this regimen should be evaluated in a phase III, randomized clinical trial.

Now before we all decide that this is a wonderful idea, we might want to consider some facts about the original trial:

  • It took 7 years (from 1987 to 1995) to enroll 415 patients into this trial.
  • It took another 7 years (until 2002) to see publication of the 5-year survival data (which were, certainly, highly significant).
  • The 5-year prostate cancer-specific survival data from the radiation + LHRH arm of this study was 94 percent (which doesn’t leave much room for improvement).
  • The necessity for 3 years 0f hormone therapy has been widely questioned.
  • To demonstrate a statistically significant clinical result in the proposed new trial might require more like 1,500 patients than 500 (assuming that the patients are randomized to chemotherapy vs. a saline placebo — or perhaps just to no chemotherapy, but in the latter case the trial won’t be double-blinded).

Since 1987, as a consequence of stage migration,  there has been a significant reduction in the number of patients who are initially diagnosed with high-risk, localized prostate cancer, and many such patients do not wish to receive external beam radiation as their first-line therapy in any case.

The “New” Prostate Cancer InfoLink suggests that before we rush into a Phase III trial of the type outlined above, it might be better to carry out a randomized Phase II trial of external beam radiation + hormone therapy + docetaxel chemotherapy vs. external beam radiation + LHRH therapy + abiraterone acetate in men with progressive disease after initial surgery for intermediate or high-risk prostate cancer. Such a trial might only require 200 or so patients (instead of more like 1,500). We might discover that abiraterone acetate was a better first-line option for such men than chemotherapy! Then we could consider a Phase III trial.

Note: As an interesting aside, the 10-year survival data from  the original 415-patient EORTC trial of radiation + ADT vs. radiation alone have just been published in The Lancet Oncology. According to that report:

  • 10-year progression-free survival was 22·7 percent in the radiotherapy-alone group
  • 10-year progression-free survival was 47·7 percent in the combined treatment group.
  • 10-year overall survival was 39·8 percent in the radiotherapy-alone group.
  • 10-year overall survival was 58·1 percent in the combined treatment group.
  • 10-year prostate cancer-specific mortality was 30·4 percent in the radiotherapy-alone group.
  • 10-year prostate cancer-specific mortality was 10.3 percent in the combined treatment group.

Clearly the combination of radiation and hormonal therapy in this group has a very real long-term survival benefit compared to radiation alone. However, in an accompanying editorial comment Dr. Anthony D’Amico again questions just how many patients really need such long-term hormonal therapy (3 years on treatment) in addition to radiation. Other data now suggest that a briefer period of ADT may be sufficient.

2 Responses

  1. What about hormone therapy alone? Maybe it and not the radiation is the main factor.

  2. Dear John:

    There were data from a major, European, randomized, multi-center study published a couple of years ago showing that hormone therapy alone is not as effective as hormone therapy + radiation therapy in this group of patients. Quality of life data have also been reported from that trial.

    Until that study was published I had always been dubious about the fact that in the US studies radiation had been assumed to be necessary, and I was actually quite surprised at the fact that radiation clearly added significantly to the oncologic outcome.

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