Alternating radiotherapy and chemotherapy for inoperable stage III non–small-cell lung cancer: long-term results of two phase II GOTHA trials

Abstract

Purpose/Objective: To report on two consecutive Phase II cooperative trials in which we evaluated the combination of alternating hyperfractionated accelerated radiotherapy and cisplatin-based chemotherapy in inoperable Stage III non-small cell lung cancer (NSCLC).

Patients & Methods: Between February 1986 and September 1989, 65 patients were entered in the first trial (GOTHA I), and between December 1989 and October 1992 67 were enrolled in the second trial (GOTHA II). In both protocols, radiotherapy (RT) was administered twice daily, at 6 h intervals, 5 days a week, to a total dose of 63 Gy in 42 fractions of 1.5 Gy. RT was given during weeks 2, 3, 6, and 7, over an elapsed time of 6 weeks. In GOTHA I, three cycles of cisplatin, 60 mg/m² day 1, mitomycin, 8 mg/m² day 1, and vindesin 3 mg/m² day 1 and the first day of the following week, were given during weeks 1, 5, and 9; in GOTHA II, cisplatin 70 mg/m² day 1 and vinblastin 5 mg/m² day 1 and the first day of the following week were given during weeks 1, 5, 9, 13, 17, and 21.

Results: With a minimum follow-up of 3 years, the 1-, 2-, 5-, and 8-year overall survival probability was 56% (95% CI 47–64%), 27% (20–35%), 12% (7–18%) and 9% (3–16%), respectively, with a median survival of 13.6 months (11.4–16.8). Median follow-up for survivors was 6 years (3.3–9.9). There were no survival differences between Stages IIIA and IIIB (p = 0.84), performance status 0, 1, 2 (p = 0.87), sex (p = 0.45) or between the two treatment protocols. At this time, 14 patients are alive, and 118 have died: 102 from NSCLC, 4 from acute toxicity, 2 from secondary surgery, 4 from other medical causes, and 6 from unknown causes. Correlation between response and long-term survival was poor, since of the 24 patients who survived 3 years or more, only 6 (25%) were classified as having a complete response; the remainder having either a partial response (11, 46%), no change (6, 25%), or “progressive disease” (1, 4%). First site of relapse was local in 31% of these cases, distant in 43%, local and distant in 15%, and unknown in 11%. Main grade 3–4 acute toxicities were nausea-vomiting (17%), mucositis (15%), leukopenia (41%), and thrombocytopenia (11%). Eight patients presented with grade 3–4 symptomatic lung radiation pneumopathy.

Conclusion: Based on this experience with 132 patients, this combination of alternated RT and chemotherapy (CT) for inoperable Stage III NSCLC is feasible with acceptable toxicity, and long-term results suggest a gain in survival when compared to those obtained with conventional RT alone. However, the still high local and distant failure rates indicate that both local and systemic therapies need to be improved.

Introduction

Locally advanced Stage IIIA and IIIB disease represents about 40% of all currently diagnosed cases of non-small cell lung cancer (NSCLC). Although treatment philosophy toward this disease at this stage varies considerably from country to country (1), conventionally fractionated, moderate- to high-dose radiotherapy (RT) was considered by many as the treatment of choice, since it was shown to have a small but definitive curative potential, with a median survival of 9–12 months 2, 3. With radiotherapy alone, both local and distant failures rates were high; therefore, many studies were conducted in which chemotherapy was added to standard radiotherapy, aiming at improving local and distant control 4, 5, 6. From several randomized Phase III trials, it appeared that only platin-based combinations of chemotherapy (CT) and radiotherapy had an impact on survival 7, 8, 9, 10, 11, 12. In the EORTC trial, daily, low-dose cisplatin with RT demonstrated a significant improvement in local control and survival (12), whereas in the French study, the addition of vindesin, cyclophosphamide, cisplatin, and lomustin, before and after radiotherapy, led to a decrease of distant metastases with an improved survival when compared to RT alone 9, 10. A large number of drug associations and RT-CT combinations have been tested. The majority of published Phase II or III trials deal with sequential CT-RT regimes or concomitant CT-RT regimes; only very few have tried truly alternated RT-CT in NSCLC (13). Our group elected to study the latter type of combination, based on theoretical and practical considerations. According to the Goldie and Coldman mathematical model (14), and experimental animal data (15), a rapid alternance of chemotherapy and radiotherapy may prove efficient by decreasing the emergence of resistant tumor cells to either modality. In addition, rapidly alternating schedules, like concomitant schedules, allow the delivery of RT and CT in a shorter period of time when compared to sequential schemes, while trying to avoid the synchronous additive toxic effect of CT and RT produced by their simultaneous application.

We present here the results of two consecutive Phase II trials, GOTHA I and GOTHA II, in which a total of 132 patients with Stages IIIA and IIIB NSCLC were entered from 1986 to 1992.