Duration of hormone therapy in combination with radiation for locally advanced prostate cancer

An important article by Bolla et al. has been published in the New England Journal of Medicine today, together with editorial comment by Albertsen. We advise readers to study this article in conjunction with a second article published today under the heading “Hormone therapy and radiation treatment: a topical update.”

In 2008 Horwitz et al. published 10-year data from the RTOG 92-02 trial showing that radiation + adjuvant long-term hormone therapy (28 months in total) improved multiple endpoints by comparison to radiation + adjuvant short-term hormone therapy (4 months in total) in men with locally advanced prostate cancer. However, in their study, only men with Gleason scores of > 7 showed a statistically significant overall survival benefit.

This new study by Bolla and his colleagues has some close similarities to the Horwitz study. The trial, EORTC 22961, enrolled patients with prostate cancer that met one of the following sets of 1992 IUCC staging criteria:

  • Clinical stages T1N1-2Mo
  • Clinical stages T2a,bN1-2M0
  • Clinical stages T2c,N0-2M0
  • Clinical stages T3-4,N0-2,M0

Patients could have a PSA level of up to 40 times the “upper limit of the normal range.” We take this to mean that a PSA of 160 ng/ml (40 x 4 ng/ml) was acceptable.

Treatment was structured as follows:

  • All patients were scheduled to receive radiation therapy once a day, 5 days a week for 7 weeks at a relatively conservative dose.
  • Patients were also randomized to receive 6 months of complete androgen blockade with an LHRH agonist and antiandrogen followed by 30 months of LHRH agonist only (long-term) or just the initial 6 months of complete androgen blockade (short-term).

The authors report the following results:

  • 1,113 patients entered the trial, of whom 970 were actually randomized  to short-term (n = 483) or long-term (n = 487) hormone therapy and were evaluable in the “intent-to-treat” analysis.
  • As of September 4, 2007, 132/483 patients (27.3 percent) receiving short-term androgen blockade had died as compared to 98/487 patients (20.1 percent) receiving long-term hormones.
  • Also as as September 4, 2007, the numbers of prostate cancer-specific deaths in the two groups were 47/483 (9.7 percent) and 28/487 (5.7  percent) respectively.
  • The 5-year overall mortality rates were 15.2 percent for the long-term hormone group as compared to 19.0 percent for the short-term hormone group.

Clearly, therefore, there were statistically significant overall and disease-specific survival benefits associated with long-term hormone therapy.

The next question one has to try to address is whether the long-term hormone therapy had a high enough impact on quality of life over 3 years compared to the short-term hormone therapy for 6 months to be able to discount the survival benefit compared to the quality of life detriment.

This appears not to have been the case. Despite the fact that mean scores on quality of life scales were worse for patients receiving long-term hormone therapy with regard to insomnia, hot flashes, reduced sexual interest and reduced sexual activity, when patients were asked to assess their overall quality of life, there was no significant difference between those receiving short-term as opposed to long-term hormone therapy. In addition, there was no significant difference between the numbers of patients in each group who died of cardiac events.

Various reports are now suggesting that this paper has “proved” that long-term hormone therapy is better than  short-term hormone therapy in patients being treated with the combination of radiation and hormone therapy for locally advanced prostate cancer. However, The “New” Prostate Cancer InfoLink has still to be convinced that this is the case. Why? Because other data have suggested that the patient’s PSA level in resp0nse to neoadjuvant hormone therapy and therefore his PSA at the time radiation therapy is initiated may be the single most critical factor in overall response to radiation.

For more information on this issue, we refer the reader to the other commentary published today, but as far as we are aware no trial of radiation therapy + hormone therapy for locally advanced disease has ever incorporated pre-radiation neoadjuvant hormones.

In an editorial commentary on this paper in the New England Journal of Medicine, Albertsen  focuses on the fact that, by comparison with the period in which this trial was developed, significantly fewer patients are now diagnosed with locally advanced disease of this type, whereas significantly more would be likely to receive radiation + hormone therapy as second line therapy after failure of some form of primary treatment. This points to the questions of who should get hormone therapy + radiation in such a setting; should they get neoadjuvant hormones prior to the radiation; and are  there some patients for whom either the radiation or the hormones (or even both) should not be given because their disease progression is so slow?

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