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ABSTRACT & COMMENTARY
The selection of treatment for prostate cancer is determined by clinical stage, which is based on the digital rectal examination combined with the known prognostic factors: prostate-specific antigen (PSA) level and histopathological grading of the tumor. Clinical exam alone understages patients with localized disease because there is clinically undetectable capsular penetration in 40%; however, clinical assessment of extraprostatic extension (i.e. locally advanced disease) is much more accurate and has a specificity of approximately 85-90%. Treatment selection for early-stage prostate cancer has become more complicated with the introduction of newer techniques such as cryosurgery and transperineal implantation of the prostate under ultrasound or CT guidance that go along with the more traditional options of radical prostatectomy, standard external beam radiation therapy, or watchful waiting. For patients with locally advanced disease, the usual recommendation is external beam radiation therapy alone. It is unclear whether a hormonal manipulation should be part of the primary treatment approach because available data were from retrospective reviews or small, randomized studies. Does early use of hormonal therapy improve outcome, or should one wait until first recurrence to begin hormonal therapy?
The recent publication of two large, randomized trials examining the role of adjuvant androgen blockade suggests that the use of combined modality treatment in locally advanced prostate cancer improves local control as well as disease-free and overall survival. We shall highlight one of these studies here.
In an EORTC study, performed by Bolla and associates, standard external beam radiation therapy was compared to the same radiation therapy with the addition of adjuvant goserelin (Zoladex) in patients with locally advanced prostate cancer or with high-grade disease. From 1987-1995, 415 patients were enrolled; 10% had T1/T2 disease with grade III histology, and the remainder had T3/T4 disease, with 80% of cases being clinically stage T3. Lymph node involvement was evaluated by CT scan, lymphangiogram or a lymph node dissection; positive nodes were identified in 3% of cases, and, in 8%, the status of the nodes was unknown. The PSA was less than 10 ng/mL in 50% of the cases, greater than 10 ng/mL in 40% of the cases, and unknown in the remaining 10%. Patients were stratified by institution, clinical stage, results of lymph node biopsy, and radiation technique. The patients were treated initially with a dose of 50 Gy to the whole pelvic field with a cone-down to the prostate and seminal vesicles for an additional 20 Gy with a three- or four-field technique. Approximately 20% of centers used a smaller initial field averaging 12 ´ 12 cm AP/PA and 12 ´ 10 cm right and left lateral fields irradiating the prostate, seminal vesicles, and immediate nodal stations only. Goserelin 3.6 mg was injected subcutaneously every four weeks starting on the first day of pelvic radiation therapy; oral cyproterone acetate 150 mg was given daily for one month starting one week before the first dose of goserelin to inhibit the transient rise of testosterone. The end-points of the study included overall and disease-free survival, as well as biological disease-free survival with an end-point of PSA progression (defined as greater than 1.5 ng/mL or two consecutive measurements being increased). The results were reported after a median follow-up of 45 months.
No patient experienced grade III or IV late toxicity. Sixty-two percent of patients treated with goserelin experienced hot flashes. Grade I to II incontinence was noted in 21% of patients with combined modality therapy vs. only 16% with radiation therapy alone. Nineteen percent of patients had adverse reactions to goserelin, the majority of which consisted of hot flashes. The five-year, overall survival rates were 79% in the combined modality group (95% confidence interval 72-86%) vs. 62% (95% confidence interval 52-72%) for the patients treated with radiation therapy alone (P < 0.001). There were 58 deaths in the radiation therapy alone group and 35 in the combined modality arm, with 26 deaths due to cancer in the radiation alone group vs. only six deaths due to cancer in the combined modality group. The disease-free survival was 85% vs. 48% (P < 0.001), with 78 patients progressing following treatment with radiation therapy alone vs. only 20 treated with adjuvant goserelin. Local control was 97% for patients treated with hormonal therapy vs. 77% treated with radiotherapy alone. The median disease-free interval after therapy was 6.6 years in the combined modality group vs. 4.4 years in the radiation therapy alone group. (Bolla M, et al. N Engl J Med 1997;337:295-300.)
The central question regarding androgen ablation in patients with locally advanced prostate cancer is one of timing. Do patients do better with immediate (so called "adjuvant") androgen blockade, or can equivalent results be obtained by delaying therapy until relapse has occurred? Traditionally, patients were offered external beam radiation therapy with hormonal ablation being reserved until signs and symptoms of recurrent or metastatic disease developed. Although some retrospective studies suggested an improvement in disease-free survival with the addition of androgen ablation at the initiation of treatment, improvements in overall survival could not be demonstrated. Local control could be obtained in approximately 60% of patients treated in this manner.
With the advent of PSA testing for purposes of screening and follow-up, the success of radiation therapy for locally advanced prostate cancer has been questioned. A recent retrospective review of the MD Anderson Cancer Center experience using radiation therapy alone or with adjuvant androgen ablation in patients with unfavorable locoregional prostate cancer (PSA > 20 or a PSA between 10 and 20 and a Gleason score > 7) found that disease outcome was dramatically improved in men receiving combined modality therapy.1 The failure rate at five years was 82% with radiation therapy alone and 15% with combined treatment. However, there was no survival benefit at five years.
The Radiation Therapy Oncology Group also tested adjuvant androgen suppression in patients with unfavorable prognosis carcinoma of the prostate.2 In that study, patients with clinically locally advanced disease, node-positive disease, pathological T3 disease, or pathological seminal vesicle involvement were treated with radiation therapy alone or with adjuvant goserelin given with the radiation therapy and then indefinitely on a monthly basis. The study population was heterogeneous15% of the group underwent surgery and were treated postoperatively with radiation therapy, 25% had lymph node positive disease (pathologically determined in two-thirds of these cases), and one-third had poorly differentiated tumors with Gleason scores of 8-10. With a median follow-up of 4.5 years, statistically significant improvements in local control, freedom from distant metastatic disease, and disease-free survival were found with the use of adjuvant androgen suppression. Overall survival, however, was not different with the 71% of patients treated with radiation therapy alone alive at five years vs. 75% of those treated with combined modality therapy. In a subset analysis, there was a statistically significant difference in five-year survival in patients with tumors showing a Gleason score of 8-1066% in the adjuvant arm vs. 55% in the observation arm. The patients had been stratified for Gleason score, nodal status, and whether they had undergone surgery. Again, the failure of local therapy alone to control unfavorable prostate cancer is indicated by the observation that only 20% of the patients treated with radiation therapy alone had a PSA of less than 1.5 ng/mL five years after therapy vs. 53% of those treated with combined modality therapy.
The results of these studies suggest that the optimum strategy to control local disease and maximize disease-free and overall survival is through the addition of adjuvant androgen suppression at the initiation of radiation therapy rather than at the first sign of relapse. However, many issues still remain. Some studies have suggested increased short-term and long-term morbidity with the use of combined modality therapy perhaps due to a hormone-induced decrease in the volume of the prostate while radiation therapy is being delivered. The side effects of hot flashes, decreased potency, and risk of osteoporosis must also be considered, as well as the considerable cost involved in the use of adjuvant goserelin on a monthly basis. With this latest report suggesting improvement in overall survival, the balance of the risks and benefits of adjuvant treatment appear to favor the use of adjuvant androgen ablation at the initiation of treatment for high-risk disease. One wonders what effect the addition of flutamide or bicalutamide would have on these results.
1. Zagars GK, et al. Cancer 1997;80:764-775.
2. Pilepich MV, et al. J Clin Oncol 1997;15:1013-1021.