Combined Androgen Suppression/Radiotherapy Improves Progression-Free Survival

ABSTRACT: Over the past 10 years, the Radiation Therapy Oncology Group has evaluated, by Phase III trials, the value of using a combination regimen, including androgen suppression (goserelin [Zoladex] and flutamide [Eulexin]) and radiation therapy, in locally advanced prostate cancer. Androgen suppression prior to or during radiation has not been shown to increase overall survival, but it has been shown to increase progression-free survival and freedom from distant metastases. In addition, a subset of men with poorly differentiated tumors who received goserelin following external beam radiation have had a significant overall survival benefit at 5 years’ follow-up. [Oncol News Int 6(Suppl 3):19-20, 1997]

Introduction

Clinical trials conducted by the Radiation Therapy Oncology Group have shown that androgen suppression prior to or during radiation therapy increases progression-free survival and freedom from distant metastases in patients with localized prostate cancer, although an effect on overall survival has yet to be seen. A subset of men with poorly differentiated tumors who received goserelin following external beam radiation have, however, had a significant overall survival benefit at 5 years’ follow-up.

These and other results of RTOG clinical trials of combined androgen suppression and radiation in treating localized prostate cancer were presented at the First Sonoma Conference on Prostate Cancer by William U. Shipley, MD, Chairman of the RTOG Genitourinary Committee.

The RTOG trials build on experimental data using rodent models that show androgen suppression prior to irradiation enhances tumor eradication. Clinical studies have also “suggested,” according to Dr. Shipley “that there was a major impact on probability of local control by shrinking the tumor, maximally, before radiation.”

 Improvement in Disease-Free Survival

A randomized RTOG protocol evaluated the efficacy and safety of administering the combination of goserelin (Zoladex) (3.6 mg every 4 weeks) and flutamide (Eulexin) (250 mg tid) prior to and during radiation therapy in patients with bulky locally advanced prostate cancer (T2c, T3, and T4). Androgen suppression began 8 weeks before radiation and continued through radiation for a total of 16 weeks.

At a median follow-up of 4.5 years, the estimated cumulative incidence of local failure at 5 years was 71% for the control patients and 46% for those on androgen suppression, and the PSA relapse-free survival was 15% among the controls, but 36% for those in the experimental group. But even with these differences in disease-free survival, overall survival was identical at 5 years.

Reviewing an update of the data at 61-months’ median follow-up, Dr. Shipley said: “We’re still seeing increased progression-free survival, freedom from distant metastases, but as yet, no overall separation of the survival curve at 5 years.”

 p53 As Independent Prognostic Factor

“In a report of RTOG translational research, in a subset on whom we could do p53 testing, an abnormal p53 is now a prognostic factor independent of stage and grade,” Dr. Shipley told the conference participants. “Using a clinical definition of local progression, which was all we had for this trial, whether or not you had an abnormal p53, which we did in 19% of the patients, didn’t seem to matter as far as local progression was concerned, but it did, very much so, for distant metastases, progression-free survival, and overall survival—an impressive effect,” he stated, adding: “This was a relatively small subset of the entire population.”

Follow-Up Trial Accruing Patients

“RTOG is now doing a randomized trial testing the efficacy of the same neoadjuvant hormone therapy with radiation vs radiation alone in men with earlier, more favorable tumors--those with stage T1 or T2 tumors and an initial PSA of less than 20 ng/mL,” Dr. Shipley reported to Oncology News International.

Dr. Shipley declared the accrual is above 900 patients. “We’re accruing about 35 patients a month, and we have just extended the number of patients that we will accrue to this trial to 1,980 patients,” Dr. Shipley said at the conference, “because of the confounding problem of comorbidity that we’ve learned from our other data—that 2 out of every 3, if not 3 out of every 4 men with these early tumors will die of something other than prostate cancer.”

“Because we are anxious to document the therapeutic survival benefit, we need those numbers. And we’re very respectful that the National Cancer Institute supported that increase in case number, so it will be adequately powered. We will be looking at a reduction in tumor-related death. And, of course, we’re looking at all other surrogate end points.”

Androgen Suppression After Radiation

RTOG is also using goserelin in a trial among patients with unfavorable prognosis treated with definitive external beam radiation. “They could even have had a radical prostatectomy, with positive margins, or they could have positive nodes, or they could have non-bulky T3 disease,” Dr. Shipley said.

Patients were randomized to receive adjuvant goserelin following radiation or on progression of disease. Five-year actuarial projections showed significant differences in the two arms of the study:

• Absence of local recurrence was 84% in the adjuvant goserelin arm, and 71% in the goserelin on progression arm.
• Freedom from distant metastases was 83% in the adjuvant goserelin arm, and 70% in the goserelin on progression arm.
• PSA failure-free survival was 53% in the adjuvant goserelin arm, and 20% in the goserelin on progression arm.

The 5-year overall survival rate, however, was similar: 75% in the adjuvant goserelin arm, and 71% in the goserelin on progression arm. The trial “has a median follow-up of 54 months,” Dr. Shipley reported “...But when we looked at all 970 patients, there is no overall survival benefit; it’s running about 71% at 5 years.”

Survival Benefit in Subset of Men

“But we did see, in a subset of men with poorly differentiated tumors, a significant survival benefit,” Dr. Shipley said. Men in this subset have Gleason scores of 8 to 10 by RTOG pathology review. The 5-year actuarial survival was 66% for the adjuvant goserelin vs 55% for the goserelin on progression arm. Dr. Shipley reported “differences between 10% and 15% in cancer deaths, 12% overall, and about 15% in comorbid deaths.”

More information on adjuvant goserelin therapy will come from analysis of a recently completed RTOG protocol 92-02 in which 1,550 men were randomized to receive or not to receive 2 or more years of adjuvant goserelin therapy following neoadjuvant maximum androgen blockade for 4 months and conventional external beam radiation.

 “There is quite an interest evolving, in our country, as everybody senses, about trying to evaluate the use of adjuvant therapy, of hormones after local treatment,” Dr. Shipley remarked. And with subsequent evaluation of RTOG 92-02 data, he added “I think we’ll have a well-powered Phase III trial to answer this question at least for men with moderate to locally advanced prostate cancer.”