Androgen-deprivation Therapy plus Radiation Proven as Standard of Care for High-risk Prostate Cancer

Use of radium-223 in this setting also addressed at ‘Innovation in Care’ session.


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A combined-modality approach of androgen-deprivation therapy plus radiation therapy achieves a substantial survival benefit over androgen-deprivation therapy alone in patients with locally advanced prostate cancer according to final analysis of an intergroup randomized phase III study conducted by the National Cancer Institute of Canada, Southwest Oncology Group, and UK Medical Research Council. At a median follow-up of 8 years, both overall survival and disease-specific survival were significantly improved by combined-modality therapy, and the combined therapy was well tolerated, as reported at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO).1

Level 1 Evidence

“Combined-modality therapy with androgen deprivation plus radiation should be considered the standard of care for locally advanced prostate cancer. The benefits of this therapy should be discussed with all patients,” said presenting author Padraig Warde, MD, Princess Margaret Hospital, Toronto, Canada. He said that combined-modality therapy is the only guideline-recommended primary therapy with level 1 evidence, and that the optimal duration of androgen-deprivation therapy remains to be defined.

The study randomly assigned 1,205 men with a median age of 69.7 years in a 1:1 ratio to androgen-deprivation therapy alone or androgen deprivation plus radiation. About 90% had T3/T4 disease and about 10% had T2 or lower-stage disease. About 81% had Gleason score ≤ 7. Continuous androgen-deprivation therapy was either bilateral orchiectomy or a luteinizing hormone–releasing hormone agonist. Radiation was delivered to the prostate, plus or minus seminal vesicles with or without pelvic node irradiation. An antiandrogen was given for 2 weeks, with an option to continue; 72% in the combination therapy group had pelvic nodes irradiated.

Ten-year overall survival was significantly improved, from 49% in the androgen-deprivation therapy–alone group to 55% in the combined-modality group, representing a survival improvement that was statistically significant (P = .0003). Androgen-deprivation therapy plus radiotherapy significantly improved disease-specific survival as well, with 134 deaths due to prostate cancer and/or its treatment on androgen-deprivation therapy alone and 65 deaths on the combined-modality therapy arm, representing a 54% improvement with combined-modality therapy (P < .0001).

Adding radiation to androgen-deprivation therapy resulted in a small detrimental effect on late gastrointestinal toxicity, specifically greater than grade 2 proctitis (0.3% on androgen-deprivation therapy alone vs 1% for combined-modality therapy), but the difference was not statistically significant.

Radium-223

In another study presented at the “Clinical Trials and Innovation in Care” session, an updated analysis of the ALSYMPCA trial upheld the overall survival benefit of radium-223 vs placebo as well as delayed time to first skeletal-related event in patients with symptomatic castration-resistant prostate cancer with bone metastases.2 Skeletal-related events included spinal cord compression, pathologic fracture, and first use of external-beam radiation therapy for pain. The safety profile of radium-223 was similar between treatment groups, with fewer adverse events reported in the active-treatment group.

“In symptomatic men with castration-resistant prostate cancer and bone metastases, radium-223 prolonged overall survival and median time to first skeletal-related event, and was well tolerated. This may be a new standard of care if it is approved by FDA,” said lead author Howard M. Sandler, MD, Cedars-Sinai Medical Center, Los Angeles.

Updated analysis of overall survival found an absolute difference of 3.6 months favoring radium-223, representing a 31% improvement in survival that was statistically significant (P = .0001). Subgroup analysis showed a benefit for radium-223 in all prespecified subgroups, including prior docetaxel treatment.

Time to first skeletal-related event was significantly delayed in the radium-223 group (median of 13.6 months vs 8.4 months for placebo, P = .0005). Radium-223 delayed the time to first use of external-beam radiotherapy for pain: a median of 17 months vs 10.9 months, respectively (P = .004). Radium-223 halved the rate of spinal cord compression from 6% with placebo to 3%.

“No difference in hematologic toxicity was reported between the two arms, suggesting that radium-223 spares the bone marrow,” Dr. Sandler told listeners.

As part of the development program, a phase I trial is evaluating radium-223 plus docetaxel, and radium-223 is also being studied in patients with breast cancer and bone metastases. ■

Disclosure:Dr. Warde reported no potential conflicts of interest. Dr. Sandler has consulted for Bayer and Algeta in regard to radium-223, but has no related leadership positions, employment, or ownership.

References

1. Gospodarowicz MK, Mason M, Parulekar W, et al: Final analysis of intergroup randomized phase III study of androgen deprivation therapy (ADT) ±radiation therapy in locally advanced prostate cancer (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633). 54th ASTRO Annual Meeting. Abstract 8. Presented October 28, 2012.

2. Sandler HM, Nilsson S, Parker C, et al: Radium-223 chloride safety and use of external beam radiation therapy (EBRT) in the phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. 54th ASTRO Annual Meeting. Abstract 7. Presented October 28, 2012.


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