An older trial designed to evaluate the benefits of adjuvant therapy following radical prostatectomy in patients with high-risk prostate cancer showed no difference in overall or disease-free survival between 2 years of androgen-deprivation therapy and 2 years of androgen-deprivation therapy plus chemotherapy with mitoxantrone and prednisone.1
“There was no evidence for improvement in survival with the type of chemotherapy used in the study. However, survival was greater than anticipated in both arms,” said lead investigator L. Michael Glodé, MD, FACP, Professor Emeritus of Medical Oncology at the University of Colorado Cancer Center, Denver.
According to Dr. Glodé, the take-home points from this study are that adjuvant trials are feasible, and in the modern era, with newer tools and better therapies, accrual may be easier. The trial was initiated in 1999, when mitoxantrone was the de facto chemotherapy in this setting. Since then, a mini-explosion of new therapies for prostate cancer has increased the available armamentarium.
“We initiated the trial in the Jurassic age,” Dr. Glodé quipped.
Study Details
The phase III intergroup trial (SWOG S9921) enrolled just under 1,000 patients with high-risk localized prostate cancer. The addition of chemotherapy to androgen-deprivation therapy did not significantly improve overall survival. The 10-year disease-free survival rate was 72% in both arms, and 10-year overall survival was 87% for androgen-deprivation therapy alone compared with 86% for androgen-deprivation therapy plus chemotherapy. Among patients who died, 40% had no recurrence of prostate cancer.
There was no evidence for improvement in survival with the type of chemotherapy used in the study. However, survival was greater than anticipated in both arms.— L. Michael Glodé, MD, FACP
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Patient accrual took 9.5 years, and the study never met its initial target accrual. The data safety and monitoring committee stopped the trial at 983 patients because of 3 cases of leukemia in the chemotherapy arm; subsequently, an additional 3 leukemia cases occurred.
High-risk patients—as defined in 1999 when the trial was started—included features such as prostate-specific antigen (PSA) level > 15 ng/mL, Gleason score of 8 or higher, extracapsular extension of tumor, seminal vesical involvement, and nodal metastasis.
“This was a high-risk group, with a 50% or higher chance of biochemical relapse at 5 years,” he said. “At the time the trial was initiated, we assumed that 2 years of adjuvant androgen-deprivation therapy would improve overall survival, and we hoped that chemotherapy would provide an additional advantage.”
Patients with one or more high-risk features as defined above were randomized in a 1:1 ratio to androgen-deprivation therapy with bicalutamide plus goserelin (Zoladex) for 24 months vs androgen-deprivation therapy for 24 months plus mitoxantrone and prednisone for 6 cycles. The primary endpoint was a drop in PSA to undetectable levels (< 0.2 ng/mL).
Key Data
Results were presented for 963 evaluable patients followed for a median of 11.2 years. At baseline, the median age was 60 years, median PSA levels were 7.9 ng/mL in the androgen-deprivation therapy arm and 7.4 ng/mL in the androgen deprivation plus chemotherapy arm. About 50% of both groups had Gleason scores of 8 or higher; 16% had positive nodes, and 63% had positive margins.
Adjuvant Therapy in Prostate Cancer
- In a study designed in 1999, the addition of mitoxantrone plus prednisone to 2 years of androgen-deprivation therapy post radical prostatectomy did not improve survival over androgen-deprivation therapy alone in high-risk localized prostate cancer.
- Although mitoxantrone is an older chemotherapy, a number of newer agents can be studied as adjuvant therapy.
- The optimal way to study the benefits of adjuvant therapy is in trials enriched for a high-risk population. Tools such as genomic assays and new grading systems provide improved methods of identifying patients at high risk.
Grade 3 or higher adverse events were reported in 30% of the androgen-deprivation therapy arm and 56% of the androgen-deprivation therapy plus chemotherapy arm (P = .0001). The key difference in adverse events was significantly more leukopenia in the chemotherapy-containing arm. In addition to leukemia, other cancers were twice as common in the chemotherapy arm, and the difference was statistically significant (P = .01).
By 18 months, 90% of patients in both arms had begun to recover testosterone.
There were 85 deaths in the androgen-deprivation therapy arm and 91 in the androgen-deprivation therapy plus chemotherapy arm. The rate of prostate cancer–specific deaths was 18% and 22%, respectively. Noncancer deaths were due to variable causes, including heart disease and Alzheimer’s disease.
“Given the time necessary to obtain this sort of data,” Dr. Glodé told The ASCO Post, “it is a significant challenge to try and design trials with the newer agents now available, particularly given their high costs and, in some cases, limited time for patent protection.” ■
Disclosure: Dr. Glodé has a leadership role as well as stock and other ownership interests in association with Gonex and ProTechSure Scientific, a consulting/advisory role with and travel expenses paid by Janssen, and patents held by the University of Colorado in his name relating to gonadotropin-releasing hormone and epidermal growth factor toxin conjugates and silibinin. The study was sponsored by the National Cancer Institute.
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