THE "NEW" PROSTATE CANCER INFOLINK

Back in 1997, when mitoxantrone + prednisone became the first form of chemotherapy ever to be approved for the treatment of prostate cancer, the Southwest Oncology Group (SWOG) initiated a trial generally referred to as S9921 — and some of the results of this trial were presented at the annual meetings of the AUA and ASCO over the past couple of weeks.

The abstract of the ASCO presentation is available on line, and a discussion of the AUA presentation is available on the UroToday web site. So what was S9921 designed to do?

The original idea was to investigate whether, in patients with high-risk prostate cancer who had had a radical prostatectomy, 2 years of treatment with combined androgen deprivation therapy (ADT) plus a full course of mitoxantrone and prednisone would improve patient survival compared to 2 years of treatment with combined ADT alone. The form of combined ADT that was used in the trial was goserelin acetate plus bicalutamide.

The research team categorized patients into three risk groups, as follows:

• Risk group 1: Patients with positive surgical margins or extraprostatic extension only with a Gleason score of 7 and patients with a pre-operative PSA level > 15 ng/ml or a pre-operative PSA level > 10 ng/ml and a biopsy Gleason score of 7
• Risk Group 2: Patients with seminal vesicle invasion and patients with a Gleason score of 8 or higher but no positive lymph nodes
• Risk Group 3: Patients with positive lymph nodes

After treatment, patients PSA levels were to be be assessed every 3 months for 5 years and then every 6 months for 10 more years. In other words, the original trial design had planned for 15 years of follow-up post-treatment. However, in 2007 the trial was closed early after 3 cases of acute myelogenous leukemia were identified in patients on the ADT + chemotherapy arm of the trial.

The trial results presented at the AUA and at the ASCO meetings were therefore focused exclusively on the patients who received combined ADT only in this trial:

• The total number of patients enrolled in the trial was 859, of whom 433 received combined ADT with chemotherapy and 426 received only the combined ADT.
• The median follow-up time from patient randomization is 3.8 years.
• Among the total of 426 patients who received only the combined ADT
  • Estimated 5-year PSA relapse-free survival is 92.9 percent
  • Estimated 5-year overall survival is 95.9 percent
• Among 113 patients in Risk Group 1 who received only combined ADT
  • Estimated 5-year PSA relapse-free survival is 97.5 percent
  • Estimated 5-year overall survival is 98.1 percent
• Among 240 patients in Risk Group 2 who received only combined ADT
  • Estimated 5-year PSA relapse-free survival is 92.5 percent
  • Estimated 5-year overall survival is 97.2 percent
• Among 69 patients in Risk Group 3 who received only combined ADT
  • Estimated 5-year PSA relapse-free survival is 88.8 percent
  • Estimated 5-year overall survival is 88.3 percent
• Only 17/426 patients (4.0 percent) have died: 7 from prostate cancer; 4 from other cancers, 1 from cardiovascular disease, and 5 from miscellaneous causes.

In their ASCO abstract the authors state that their data indicate surprisingly low rates of PSA relapse and mortality in patients with prostate cancer at high risk for progression who received just 2 years of combined ADT after a radical prostatectomy. They go on to state that, “This likely is the result of stage migration, patient selection and/or the effects of [combined ADT] itself.”

In a further result of the trial, based on data from 397 patients in both arms of the trial who completed 2 years of combined ADT and who were assessed for time to testosterone recovery:

• The estimated median time to recovery of testosterone levels > 50 ng/ml is 11.7 months from the end of combined ADT.
• The rates of recovery of  testosterone levels > 50 ng/ml were 16 percent at 6 months and 89 percent at 18 months.

What are we to make of the data from this study?

It has to be said that this is a “failed trial” in the sense that we don’t have a lot of data to work from. The actual median follow-up is only 3.8 years as compared to the originally proposed 15 years after randomization, and so we certainly don’t have the data originally planned for — not even close. Only the other hand, the research team was clearly surprised by the high rates of progression-free and overall survival of these high-risk patients.

The clear message here — as from the studies of hormone therapy with and without radiation in high-risk patients — seems to be that adjuvant hormone therapy has some degree of survival benefit in selected patients with high-risk prostate cancer after a radical prostatectomy. What we can’t tell from any of these studies is who are the most appropriate patients to be treating with adjuvant therapy, which ones can be effectively treated with radiation alone, which ones can be effectively treated with hormones alone, and which ones benefit the most from both radiation and hormone therapy. We also still don’t know how long hormone therapy needs to last in such patients, but we do now know that testosterone levels > 50 ng/ml can be recovered in the vast majority of these patients with 18 months after combined ADT is stopped if the period of hormone therapy is 2 years long.

There is little doubt that the role of traditional forms of hormonal therapy in prostate cancer is and will continue to change from where we were 13 years ago when this trial was first designed. It is clear that such therapy should be used more selectively that in the past, in the patients with higher risk disease, and with caution in patients with other significant risks for cardiovascular and metabolic disease. It is also highly likely that intermittent therapy will continue to gain ground, and that the use of first-line hormonal therapy in men with low risk disease should be discouraged. Finally, we suspect that as some of the newer, targeted agents start to come to market or we better understand their potential, we may come to see these agents as appropriate for use well before today’s standard forms of hormone therapy.

“The times they are a’changing” in the management of progressive prostate cancer, and hopefully the consequent outcomes will match up to the opportunities over time.

Filed under: Management, Treatment Tagged: | ADT, androgen deprivation therapy, combined, survival