Adjuvant mitoxantrone + prednisone + ADT in treatment of high-risk prostate cancer

About 25 years ago the addition of the combination of mitoxantrone + prednisone to androgen deprivation therapy (ADT) was the first form of chemotherapy ever approved for the treatment of metastatic, castration-resistant prostate cancer. It had no effect on patient survival, but it did help to alleviate metastasis-related bone pain.

About 22 years ago, the South West Oncology Group (SWOG) decided to investigate whether adding mitoxantrone + prednisone to ADT would help to improve the survival of patients diagnosed with high-risk forms prostate cancer as adjuvant therapy after first-line surgery. It took nearly 20 years to get the results of this trial (the SWOG 9921 trial), but they have now been published by Hussain et al. in the Journal of Clinical Oncology.

The trial enrolled patients who  had initially been diagnosed with localized prostate cancer (cT1N0Mo through cT3N0Mo); who had responded will to surgery (i.e., they had a PSA level of < 0.2 ng/ml); and who had at least one of a spectrum of factors indicative of high-risk prostate cancer after completion of initial surgery:

  • A Gleason score of ≥ 8
  • pT3b, pT4, or pN+ disease
  • A Gleason score of 7 and any one of
    • Positive surgical margins
    • A pre-surgical PSA level of > 15 ng/ml
    • A pre-surgical Gleaon score of > 7  (i.e., at biopsy)b
    • A PSA > 10 ng/ml and biopsy Gleason score of ≥ 7.

Patients could be enrolled whether or not they were going to be given early adjuvant radiation therapy, and they were randomized to treatment with

  • Either ADT (with bicalutamide and goserelin) for 2 years
  • Or ADT plus six cycles of mitoxantrone + prednisone

The primary end point pf ther study was overall survival (OS) and median OS was projected to be 10 years for the men in the ADT arm.

Now it is important to remember that this trial was being planned in the 1990s. The D’Amico risk categories hadn’t been created. No one knew that docetaxel could be used effectively to treat metastatic prostate cancer. And so for that time this was a distinctly sophisticated clinical trial. There was only one “fly” in the ointment. It would have been a much better trial if there had been a third arm to the trial in which patients received no further treatment with the exception of adjuvant radiation therapy as considered appropriate by the treating physicians and the patients.

However, here are the study results as presented by Hussain et al.:

  • The trial enrolled 961 eligible and evaluable patients between October 1999 and January 2007.
  • Enrollment into the trial was stopped by the data monitoring committee in January 2007 when it became evident that patients in the ADT + mitoxantrone + prednisone arm were at higher risk for leukemia than those in the ADT alone arm.
  • Average (median) follow-up was 11.2 years.
  • Estimated rates of OS at 10 years of follow-up are:
    • 87 percent with ADT alone (as compared to the projected 50 percent)
    • 86 percent with ADT + mitoxantrone + prednisone
    • With a hazard ratio (HR) of 1.06
  • Estimated rates of disease-free survival (DFS; i.e., biochemical progression-free survival) are 72 percent in both arms of the trial.
  • Prostate cancer-specific mortality rates are
    • 18 percent in the ADT alone arm
    • 22 percent in the ADT + mitoxantrone + prednisone arem
  • Twice as many patients died of other forms of cancer in the ADT + mitoxantrone + prednisone arm (36 percent) than in the ADT alone arm (18 percent).
  • Hussain et al. conclude that:

    [Mitoxantrone + prednisone] did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

    The good news from this trial, however, is just how good we now are at treating men with high-risk prostate cancer. Roughly 80 percent of all men with high-risk prostate cancer will live for another 10 years and roughly 80 percent of the men who did die in this trial did not die of their prostate cancer.

    As the authors are careful to point out, however, we still have no idea whether adding a 2-year course of adjuvant ADT immediately after surgery can improve the survival of men with high-risk prostate cancer compared to no adjuvant ADT. And given the median overall survival of men diagnosed with high-risk prostate cancer today, which is probably well over 15 years, there is really no way to do that trial now — even if it was to be done with biochemical progression-free and metastasis-free survival as the key endpoints. Even then, it might take 15 years to complete the trial.

    Your sitemaster wasn’t in the room when this trial was designed and he has no idea why this trial did not include a third arm of no adjuvant treatment (other than the optional adjuvant radiation therapy). Cost and time to enroll patients would certainly have been factors, because it would have needed at least another 500 or so patients. However another issue may have been the simple fact that ADT, in 1998, was the only known effective therapy for the treatment of advanced prostate cancer. Maybe the current patient representative to the SWOG prostate cancer trials group can enlighten us?

3 Responses

  1. In colon cancer the standard of care is surgery followed by chemo. The trial presented here shows that immediate ADT after primary therapy can provide excellent results for high-risk prostate cancer patients. Therefore I think this treatment should be used more often.

    The trial has started almost 20 years ago and there will be no randomized trial comparing immediate ADT, deferred ADT and no ADT after primary therapy. So you cannot wait for that.

  2. As that current patient representative at SWOG, I don’t have much to add on S9921 other than the obvious already stated. When the trial kicked off in 1999 I was not even a patient yet for prostate cancer and I didn’t join SWOG until 2012. But the obvious issues are that if this trial added a placebo arm, which would have been required, the accrual may have been challenging and much larger. Plus the fact that you really can’t keep it “blind” in the control arm that would not have had the patients on ADT. The side effects are very obvious thus a patient may “jump ship” once they figured out that their arm was the do nothing arm. The mindset of the primary investigators was to clearly have two actionable arms to enhance accrual.

    I am leaving Friday morning for San Francisco for the 2018 SWOG Spring meeting which begins today. The GU committee working group is Friday afternoon, then dinner, then the public session on Saturday. I am certain that I can tag the Dr. Hussain or the “et al’s” on why the trial was released as it was. In fact, Cathy Tangen will probably have the best reasons being the bio-statistition.

  3. The control arm could be: surgery, waiting for biochemical progression followed by salvage radiation, then ADT at second biochemical progression. I guess one could generate this data retrospectively and then compare it to the results in this trial.

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