Radiotherapy and Short-term Androgen Deprivation for Localized Prostate Cancer

Abstract & Commentary

By Samir P. Kanani, MD, Associate Clinical Professor of Neurosurgery and Radiation Oncology, George Washington University; Radiation Oncology, Inova Fairfax Hospital. Dr. Kanani reports no relationships to this field of study.

Synopsis: In a large multi-institutional prospective trial conducted from 1994-2001, 1979 eligible patients (median age 70 years) with PSA < 20 were randomized to radiation therapy alone or radiotherapy plus 4 months of total androgen suppression starting 2 months before radiotherapy. The 10-year rate of overall survival and disease-specific survival was improved among patients receiving short-term androgen suppression. When stratified according to widely used risk groups, the benefit was limited to intermediate-risk patients. Toxicity was minimal. There still remains a question as to the benefit of short-term androgen suppression in the current setting of highly precise radiation therapy to higher doses.

Source: Jones U, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 2011;365:107-118.

Luteinizing hormone-releasing hormone analogues and oral antiandrogen agents have been shown to induce apoptotic cell death in androgen-responsive prostate cancers.1 Long-term (> 2 years) androgen deprivation therapy (ADT) combined with external beam radiotherapy in patients with locally advanced prostate cancer has been shown to improve overall survival but is associated with some toxicity including cardiac complications and erectile dysfunction. Short-term ADT could potentially mitigate the toxicity while maintaining the therapeutic benefit seen in long-term ADT. A previous Radiation Therapy Oncology Group (RTOG) trial conducted in the 1980s demonstrated a benefit to short-tem ADT for 4 months for patients with advanced prostate cancer, but this was in a pre-PSA era.2 The current report reflects the results of the RTOG multicenter randomized Phase 3 trial (RTOG 94-08), opened in 1994 for the purpose of elucidating the role of short-term ADT combined with radiotherapy in patients with non-bulky localized prostate cancer with PSA levels of 20 ng/mL or less.

This Phase 3 trial was conducted in Canada and the United States between 1994 and 2001. A total of 1979 patients were randomized to 4 months ADT concurrent with radiotherapy to a dose of 66.6 Gy or radiotherapy alone. ADT consisted of flutamide 250 mg PO tid and either goserelin SQ 3.6 mg or luprolide IM 7.5 mg. Radiotherapy commenced after 2 months of ADT.

The majority of the patients had a NCCN intermediate risk disease (Gleason score of 7 or a Gleason score of 6 with PSA 10-20 or a clinical stage T2b). The median patient age was 71 years. With a median follow-up of 9.1 years, the 10-year overall survival was 57% in the radiotherapy-alone group and 62% in the combined-therapy group (P < 0.03). The 10-year disease specific mortality was 8% in the radiotherapy-alone and 4% in the combined-therapy group (P < 0.001). The 10-year biochemical failure rate was 41% in radiotherapy-alone group and 26% in the group receiving short-term ADT (P < 0.001). There was no difference in erectile dysfunction between the two groups in a survey completed 1 year after treatment. The incidence of grade 3 or higher hormone-related toxicity was less than 5%. A secondary analysis of the data based on NCCN risk categories showed an improvement in overall survival and disease-specific survival with the addition of short-term ADT primarily among intermediate-risk patients, with no significant improvement among low-risk patients. In all three risk subgroups, short-term ADT was associated with a reduction in biochemical failure.

Commentary

The current treatment of prostate cancer has evolved to a risk-based management protocol. Although the RTOG 94-08 trial was not designed specifically to evaluate the value of ADT therapy in the specific risk groups, the subgroup analysis provides valuable information for management of this common cancer. The use of ADT in patients with high-risk prostate cancer — defined as one or more of the following: PSA > 20 ng/mL, Gleason score 8-10, and stage T2c — is well-established from three prospective Phase 3 trials, EORTC 22863,3 SPCG-7,4 and TROG 9601.5 The current trial demonstrated a benefit in this population, but it was not statistically significant. The lack of statistical benefit is likely because 4 months of ADT is not enough and a minimum of 6 months of ADT is needed in this high-risk population.5 For patients in the low-risk group, this study along with others has consistently demonstrated no significant benefit in the use of ADT. However, this trial did demonstrate a benefit in biochemical failure, begging the question that with longer follow-up perhaps a benefit in survival would have been seen. In addition, there may be a benefit in certain low-risk patients with adverse features such as > 50% of cores positive, perineural invasion, or ominous PSA kinetics such > 2 ng/mL rise per year. This must be weighed against the mounting evidence that ADT does result in muscle loss, fat accumulation, decreased insulin sensitivity, and increased cholesterol levels leading to a small but real increase risk of developing diabetes, heart disease, stroke, and sudden death.6,7 This report of the RTOG 94-08 trial confirms a published report from D'amico et al that found patients with intermediate-risk disease demonstrated a 23-point advantage in survival (56% vs. 79%).8 In this RTOG study, there was a 7-point advantage to the addition of ADT (54% vs. 61%). The difference in the magnitude of benefit could be explained by the fact that the D'amico trial used higher doses of radiation. Another explanation could be because the duration of ADT was 6 months in the D'amico trial vs 4 months in the RTOG trial.

The current study is important and underscores the value of cooperative group trials and funding for long-term follow-up. Prostate cancer trials with survival endpoints provide the best evidence for managing this often indolent disease. Advances in radiotherapy delivery over the last decade, such as intensity-modulated radiation therapy and image-guided radiotherapy, have allowed higher doses of radiotherapy to be delivered safely, improving the efficacy of treatment bringing into question once again the value of ADT. The RTOG has opened a successor trial to elucidate the value of ADT on prostate cancer treated in the contemporary era with modern radiotherapy techniques and risk-based management.

References

1. Griffiths K, et al. Hormonal treatment of advanced disease: Some newer aspects. Semin Oncol 1994;21:672-687.

2. Pilepich MV, et al. Androgen supression adjuvant to definitive radiotherapy in prostate carcinoma—long-term results of Phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61: 1285-1290.

3. Bolla M, et al. External irradiation with or without long-term androgen supression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11:1066-1073.

4. Widmark A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG/SFUO-3): An open randomised Phase III trial. Lancet 2009;373: 301-308.

5. Denham JW, et al. Short-term neoadjuvant androgen devripation and radiotherapy for locally advanced prostate cancer: 10-year data from TROG 96.01 randomised trial. Lancet Oncol 2011;12:451-459.

6. Nanda A, et al. Hormonal therapy use for prostate cancer mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA 2009;302:866-873.

7. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2009;181: 1998-2008.

8. D'Amico AV, Chen M, Renshaw AA, et al. Androgen suppression and radiation vs radiation alone for prostate cancer: A randomized trial. JAMA 2008;299:289-295.