Authors: Dillman RO, Herndon J, Seagren SL, et al.
Source: JNCI. 88(17):1210, 1996.
When this trial was originally published, radiation alone was the standard of care for unresectable non-small cell lung, but survival rates remained poor. This study was the first to demonstrate in a randomized trial the benefit of adding chemotherapy to radiation.
The study randomized 155 patients to receive chemotherapy followd by radiation or radiation alone in the curative treatment of locally advanced non-small cell lung cancer. To be eligible, patients had to have either stage T3 or stage N2 tumors with radiographically visible disease after biopsy. Patients were excluded if they had scalene lymph node involvement, pleural effusion, or distant metastasis. They were also excluded for ECOG performance status greater than 1, weight loss greater than 5% over 3 months, or substantially abnormal blood counts or liver function tests. Staging included a chest x-ray, a bone scan, and a CT scan of the chest and upper abdomen. The trial accrued patients from 1984 through 1987.
Radiation was delivered in 2 Gy fractions to a total dose of 60 Gy. The initial fields delivered 40 Gy to the primary tumor plus a 1.5 cm margin, the ipsilateral hilum plus a 1.5 cm margin, and the mediastinum plus 1 cm lateral margins. The mediastinal radiation extended at least 2 cm inferior to the tumor and at least 4 cm inferior to the carina. The ipsilateral supraclavicular fossa was included in every case. The contralateral supraclavicular fossa was included when the primary tumor was located in the left lower lobe. Following the initial 40 Gy, an additional 20 Gy was delivered to the pre-therapy primary tumor volume plus a 1.5 cm margin. The ipsilateral supraclavicular fossa was only included in these conedown fields if the primary tumor was located at apex of the lung. Chemotherapy consisted of vinblastine 5 mg per square meter weekly for 5 weeks and cisplatin 100 mg per square meter on days 1 and 29. Quality was assured by central radiation review and by site visits to all CALGB institutions every 3 years.
Twenty-five patients (14%) were excluded from the analysis. Of the patients excluded following randomization, 7 were assigned to the chemoradiation arm and 4 were assigned to the radiation only arm. Reasons for exclusion included metastases, poor performance status, and lack of radiographically visible disease following biopsy. Half of the study patients underwent mediastinoscopy or thoracotomy as part of their staging workup. The two treatment arms were well balanced for sex, age, histologic subtype, and performance status. Follow-up was excellent, with only 5 patients censored in the first 4 years of follow-up.
The addition of chemotherapy prior to radiation improved median survival from 10 months to 14 months (P = 0.01). Furthermore, it improved 5 year overall survival from 7% to 17%. These benefits came at the cost of moderately increased toxicity. The addition of chemotherapy increased infections requiring hospitalization from 6% to 14%, severe weight loss from 6% to 14%, and vomiting requiring hospitalization from 0% to 5%. Severe esophagitis and severe pneumonitis were each experienced by 1% of patients in each treatment arm. There were no treatment-related deaths. Among those patients assigned to the chemotherapy arm, 86% received both doses of cisplatin, 37% received all 5 doses of vinblastine, and 72% received at least 4 doses of vinblastine. There was no difference in the sites of recurrence between the two treatment arms.
This trial clearly demonstrated the survival benefit provided by the addition of chemotherapy to radiation in locally advanced, inoperable non-small cell lung cancer. Toxicity was increased but remained acceptable. The relatively strict eligibility criteria would exclude approximately 75% of stage III non-small cell lung cancer patients, which illustrates the importance of patient selection in generalizing this or any more aggressive treatment approach to patients seen in everyday practice. Subsequent trials went on to address the optimal timing of chemotherapy relative to radiation therapy.