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Combined Endocrine and Radiation Approach for Locally Advanced Prostate Cancer
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In patients with advanced- or high-risk but local prostate cancer, the addition of local radiotherapy to endocrine treatment was shown to halve the 10-year prostate cancer-specific mortality and substantially reduce overall mortality in a phase III, randomized, multi-center clinical trial conducted in Northern Europe. The impressive findings support this combined modality approach as the standard to which future interventions must be compared.
Source: Widamark A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer: an open randomized phase III trial. Lancet. 2009;373:301-308
For patients with locally advanced prostate cancer, the issue of whether local radiotherapy adds to hormonal treatment alone remains to be established. To address this question, the Scandinavian Prostate Study Group and the Swedish Association for Urological Oncology have recently completed a phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration at the time of progression.
This randomized trial included men from 47 centers in Norway, Sweden, and Denmark. Between February 1996 and December 2002, 875 patients with locally advanced prostate cancer were enrolled. Eligibility criteria were histologically proven prostate cancer in men younger than 76 years, with good performance status, a life expectancy of more than 10 years, and with tumors categorized as clinical T1b-T2, G2-G3, or T3 and WHO Grade 1-3. Participants had a prostate-specific antigen (PSA) of 70 ng/mL or less and no evidence of metastases, as determined by bone scanning and pulmonary radiography. Those with a PSA of 11 ng/mL or more had a pelvic lymph node dissection (fossa obturatoria); patients with nodal disease were not eligible for the trial.
Patients were randomly assigned to either en-docrine alone (n = 439) or endocrine plus radiotherapy (n = 436). After randomization, all patients were given endocrine treatment with total androgen blockade with an LHRH-agonist, leuprorelin (Procren depot; Abbott, 3.75 mg/month or 11.25 mg/every three months), for three months, and were simultaneously treated with 250 mg of an oral antiandrogen, flutamide (Eulexin, Schering-Plough), three times a day. After three months of total androgen blockade, patients continued using flutamide until progression or death. After three months, patients in the endocrine plus radiotherapy group started radiotherapy. For this, a standard 3D conformal radiotherapy technique was applied with a prescribed central dose (of 50 Gy) to the prostate and the seminal vesicles. A sequential boost of at least 20 Gy was added to the prostate, which received a total dose of a minimum of 70 Gy. A margin of 20 mm (15 mm in posterior direction) was added. If optimum immobilization could be achieved, the margins were reduced accordingly.
When antiandrogen treatment side effects were evident, flutamide was stopped and then reinstituted with a stepwise-increased dose to at least 500 mg. If this treatment failed, antiandrogen was changed to bicalutamide (150 mg/once a day). Eighty percent of all patients received breast irradiation to prevent gynecomastia.
The primary endpoint was prostate-cancer-specific survival, and analysis was by intention-to-treat. After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%,;95% CI 4.9-19.1%), for a relative risk of 0.44 (0.30-0.66). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine-alone group and 29.6% in the endocrine plus radiotherapy group (difference 9.8%; 0.8%-18.8%), for a relative risk of 0.68 (0.52-0.89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7% vs. 25.9%, p < 0.0001; HR 0.16; 0.2-0.20). After five years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group.
Thus, in patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate cancer-specific mortality and substantially decreased overall mortality with fully acceptable risk of side effects compared with endocrine treatment alone. Previous studies had shown that the combination of radiotherapy and sustained androgen-deprivation improves outcome compared with radiation therapy alone in high-risk prostate cancer.1,2 However, in studies in which androgen was short-term or of intermediate duration, the survival advantage could only be observed in subgroups of patients.3,4 In the current study, the survival at 10 years increased from 60.6% to 70.4% in favor of the endocrine plus radiotherapy and, thus, accentuate the importance of local radiotherapy treatment in high-risk patients with prostate cancer. It is curious that the combination of surgery and androgen ablation has not shown increased efficacy over surgery alone,5 possibly suggesting a synergy between endocrine factors and radiation-induced biological effects.
1. Granfors T, et al. Long-term follow-up of a randomized study of locally advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus radiotherapy alone. J Urol. 2006;176: 544-547.
2. Bolla M, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;360:103-106.
3. Horwitz EM, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008;26:2497-2504.
4. Pilepich MV, et al. Androgen suppression 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.
5. Aus G, et al. Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial. BJU Int. 2002; 90:561-566.