Does concurrent chemotherapy improve local control and survival over radiotherapy alone or induction chemotherapy in stage III non-small cell lung cancer (NSCLC)? Results at 3 years in 140 patients (pts) with a minimum follow-up of 24 months

Purpose/Objective: Recent Phase III trials have demonstrated a significant but limited survival benefit of induction chemotherapy over standard radiotherapy alone in Stage III NSCLC. Induction chemotherapy does not significantly improve local control and substantially prolongs overall treatment time in this poor prognosis population. Concurrent chemotherapy has the potential for improving local control through drug-radiation interactions. This study was designed to determine the overall survival after standard fractionation radiotherapy with concurrent cisplatin or cisplatin-etoposide, as well as the feasibility and toxicity of this approach. Material and Methods: From July 1989 to February 1994, 140 favorable pts according to CALGB criteria with histologically proven medically or technically inoperable stage III NSCLC were treated with radiotherapy and concurrent chemotherapy. Median age was 64 years with a majority of males (93%), WHO status 1 (66.4%), and squamous cell histology (72%). Clinical stage was IIIA (65.7%), IIIB (34.3%), N0-1 (20.8%), N2 (57.8%) or N3 (21.4%). Median tumor size was 6 cm. Using once-daily fractionation, pts received thoracic radiotherapy (TRT) up to a median dose of 60 Gy (n=116), or 45 Gy preceding surgery (n=24). No pts received induction chemotherapy before TRT. During TRT, all pts received two cycles of cisplatin (20 mg/sqm/d over 5 days). In addition to cisplatin, the last 67 pts received etoposide (50 mg/sqm/d over 5 days). After TRT, 48 of these pts received two additional cycles of cisplatin-etoposide. Results: With a minimum follow-up of 24 months (median 58 months), overall survival was 34.3% and 24.9% at 2 and 3 years respectively. Age, sex, performance status, histologic type or grade, tumor size, and T stage, had no significant predictive value for survival. Three-year survival according to clinical stage (IIIA : 26%, IIIB : 22.7%) was not statistically different. Univariate analysis identified 3 significant factors for better survival at 3 years: addition of etoposide (38.5% vs 14.8%, p <.001), negative biopsy at the initial tumor site (36.9% vs 2.1%, p<.0001), and radical surgery following chemoradiotherapy (73.9% vs 14.9%, p<.0001). Pathologic complete response in operated patients was 29.2%. Multivariate analysis demonstrated these three factors to be of independent prognostic value. Local control at 3 years, as determined by CT-scan and fiberoptic bronchoscopy with biopsy at the initial tumor site was 42.4% (cisplatin alone: 28.6%, cisplatin + etoposide: 56.8%, p=.015). A negative biopsy was strongly predictive for actuarial distant failure rate (45.9% vs. 83.8%, p<.0001). Grade 3-4 toxicities were mainly seen in the 2-drug regimen with neutropenia (20.9%) and esophagitis (11.9%). There were no significant late toxicities. Conclusion: In stage III NSCLC, three-year local control and survival appear substantially improved by the addition of concurrent cisplatin and etoposide to standard TRT, as compared to standard TRT alone or preceded by induction chemotherapy. Randomized Phase III trials are underway