Locally advanced prostate cancer treated with concomitant radiation and 5-fluorouracil: Southwest Oncology Group Study 9024.
ABSTRACT Radiation is considered the standard treatment for locally advanced (T3 and T4) prostate cancer but cure with radiation alone is infrequent. Studies have shown that adding androgen ablation improves the results but there is still much room for improvement. We performed a phase II multi-institutional study to explore the feasibility of concomitant chemoradiotherapy.
Eligible patients had prostate cancer with clinical evidence of invasion through the prostatic capsule or into the seminal vesicles without evidence of nodal or distant metastasis. Prior prostatectomy was not allowed and patients could not be candidates for surgical resection due to medical reasons or refusal of surgery. Radiation consisted of 7,020 cGy in 39 fractions. Continuous infusion 5-fluorouracil at a dose of 200 mg/m2 daily was started on day 1 and continued 7 days weekly until the last day of radiation.
All 30 eligible patients were evaluated for toxicity. Diarrhea was the most common toxicity with grade 3 and 4 diarrhea in 2 and 1 patients, respectively. The only other grade 4 toxicity was hemorrhagic cystitis in 1 patient. There was 1 incident each of grade 3 stomatitis, congestive heart failure, edema, proctitis and hematuria. No patient with grade 3 or 4 toxicity required treatment delay. Ten patients (33%) achieved a negative biopsy and 13 (43%) achieved prostate specific antigen less than 1.0 ng/ml. Six patients (20%) achieved a complete response, defined as negative biopsy and prostate specific antigen less than 1.0 (95% CI 8 to 39). Patients without any biopsies or without prostate specific antigen followup were assumed to be nonresponders.
Toxicity was acceptable. The modest response rate indicates that better chemotherapy that improves local and systemic failure is necessary to improve the results. This study confirms the feasibility of a combined chemoradiotherapy approach.
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ABSTRACT: To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2--T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II. As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p = 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p = 0.04), disease-free survival (33% vs. 21%, p = 0.004), biochemical disease-free survival = PSA <1.5 (24% vs. 10%, p < 0.0001), and cause-specific mortality (23% vs. 31%, p = 0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2--6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p = 0.015). In patients with Gleason 7--10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival. In patients with Gleason score 2--6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival.International Journal of Radiation OncologyBiologyPhysics 08/2001; 50(5):1243-52. · 4.52 Impact Factor
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ABSTRACT: In the case of prostate carcinoma, radiation therapy is a locally applied treatment modality in a malignancy known for systemic dissemination. Because significant efforts and resources currently are being consumed to improve local tumor control, failure patterns and potential curative gain deserve appropriate assessment. From 1975-1989, 647 patients with clinically localized prostate carcinoma were definitively irradiated for biopsy-proven adenocarcinoma of the prostate. Failure patterns were examined, and survival advantage based on improvement in either local or distant disease control was calculated. Distant metastatic rate and cause-specific survival analyses were used as parameters by which to compare the outcome for patients in whom local tumor control was achieved with patients who experienced local failure, thereby assessing further the importance of the effectiveness of locally applied therapy. Three hundred ninety-two (61%) patients at the time of this writing were clinically disease free. Sixty-two (10%) patients failed locally only, 133 (20%) distantly only, and 60 (9%) developed local and distant recurrent disease. Both local and distant failure rates were higher in patients with more advanced stage lesions at presentation, and distant failure rates significantly increased in patients with less differentiated tumors. Pretreatment prostate-specific antigen was found to be useful in predicting recurrence patterns. Overall, there appeared to be more potential for improvement in survival secondary to reducing distant metastasis. The distant survival advantage (DSA) of reducing distant metastases, compared with the local survival advantage (LSA) of improving local tumor control, was 26 versus 14%. Although DSA was greater than LSA within each stage category, the potential to improve survival was most significant in the Stage C group, where DSA was 35% and LSA 16%. Although LSA varied little according to tumor grade, DSA was dependent on tumor grade and varied from 13% for well differentiated lesions to 38% for poorly differentiated lesions. Distant failure free survival at 10 years was 63% for patients with local control and 45% for those with local failure (P = 0.01). Similarly, 10-year cause-specific survival was 75% in locally controlled patients compared with 48% for those with local recurrence (P < 0.001). Although better local tumor control should translate into at least modest survival gain for patients with prostate carcinoma, additional advantage may be seen with improved systemic therapy or perhaps earlier diagnosis to reduce further the distant metastasis rate.Cancer 06/1995; 75(9):2373-82. · 5.20 Impact Factor
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ABSTRACT: Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease. From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.New England Journal of Medicine 10/2004; 351(15):1502-12. · 51.66 Impact Factor