Cisplatin/etoposide chemotherapy combined with twice daily thoracic radiotherapy for limited small-cell lung cancer: a clinical phase II trial

Abstract

Purpose: To fit the situation of developing countries, where supportive care is not sufficient, a modified combined therapy of cisplatin/etoposide (EP) and hyperfractionated accelerated radiation therapy (HART) was conducted as a Phase II trial for limited-stage small-cell lung cancer (LSCLC) to evaluate the feasibility, toxicity, and tolerance of the combined therapy and to observe its efficacy and patterns of failure.

Methods and materials: Chemotherapy and radiation were sequentially administered in 1 to 3 cycles before and 3 to 5 cycles after HART. Chemotherapy contained cisplatin in doses of 25 to 30 mg/m(2) from Day 1 to Day 3 and etoposide in doses of 50 to 70 mg/m(2) from Day 1 to Day 3. The HART schedule consisted of radiation delivered in 1.4-Gy fractions, twice a day, at intervals longer than 6 h for 5 treatment days a week, to a total dose of 56 Gy in 40 fractions over 4 weeks.

Results: From June 1997 to December 2000, 57 eligible patients were registered for this trial. All were limited stage, and the median age was 60 years (range, 25 to 70 years). Of the 57 patients, 3 were withdrawn because of distant metastases (1 case), Grade (Gr) III thrombocytopenia (1 case), and financial problems (1 case). Fifty-four patients completed the planned combined treatment. A median of 6 cycles of chemotherapy (range, 5-8 cycles) was administered during a median interval of 4.9 weeks (range, 3.0-8.9 weeks), and a radiation dose of 56 Gy in 40 fractions was delivered over 29 days. The most common acute complication was radiation esophagitis, which occurred in 41 cases (72%), 4 with Gr III. Thirty-six patients (64%) had acute pulmonary toxicity, 2 with Gr III. The median survival time was 24 months (95% CI, 21-28 months). The 1-year, 2-year, and 3-year survival rates were 81% (95% CI, 70%-91%), 49% (95% CI, 36%-62%), and 21% (95% CI, 10%-32%), respectively. Of 57 patients, 13 had locoregional progression. Nine patients failed inside radiation fields and 4 patients failed outside. The 1-year, 2-year, and 3-year locoregional progression-free survival rates were 85% (95% CI, 75%-95%), 74% (95% CI, 61%-87%), and 68% (95% CI, 52%-84%), respectively. Forty-four patients suffered distant metastases, 66% of which were in brain. The 1-year, 2-year, and 3-year distant metastasis rates were 31% (95% CI, 19%-43%), 59% (95% CI, 46%-72%), and 79% (95% CI, 68%-91%), respectively.

Conclusions: The study led to the following conclusions: (1) LSCLC patients tolerate HART at 56 Gy in 40 fractions over 4 weeks combined with 6 cycles of EP chemotherapy. (2) Both control of the tumor in the thorax and survival appear superior to conventional fractionated radiation but not as good as that in a study by Turrisi and colleagues. (3) This modified chemoradiation schedule could be recommended to LSCLC patients in developing countries. (4) The lessons learned from our study are (a) higher radiation doses may be needed for better locoregional control, and (b) prophylactic cranial irradiation is necessary for LSCLC patients who show complete response.