RESPONSE, TOXICITY, FAILURE PATTERNS, AND SURVIVAL IN 5 RADIATION-THERAPY ONCOLOGY GROUP (RTOG) TRIALS OF SEQUENTIAL AND OR CONCURRENT CHEMOTHERAPY AND RADIOTHERAPY FOR LOCALLY ADVANCED NON-SMALL-CELL CARCINOMA OF THE LUNG/

Purpose: The purpose of this study was to assess response, toxicity, f ailure patterns, and survival differences in three chemotherapy (ChT)/ radiation therapy (RT) sequencing strategies for locally advanced non- small cell lung cancer (NSCLC). Methods and Materials: Five completed Radiation Therapy Oncology Group (RTOG) trials for Stage II-IIIA/B ino perable NSCLC patients employed one of the three following strategy gr oupings: 1) sequential ChT followed by standard RT (60 Gy in 6 weeks); 2) combined sequential and concurrent ChT and standard RT (60 Gy in 6 weeks); or 3) concurrent ChT and hyperfractionated RT (69.6 Gy in 6 w eeks). All five trials required KPS greater than or equal to 70; two t rials (314 patients) required <5% weight loss and three trials (147 pa tients) had no minimum weight loss requirement. In all five trials the ChT used cisplatin with either vinblastine or oral etoposide. Combini ng data for the five trials yielded an evaluable group of 461 patients . The three methods of sequencing ChT and RT were evaluated for differ ences in response, acute and late toxicity, patterns of failure, and s urvival. Acute toxicity was defined as that occurring within 90 days f rom the start of RT. Late toxicity was defined as that occurring after 90 days from the start of RT. Acute or late toxicity greater than or equal to grade 3 was defined as severe. Site of first failure was reco rded by date. In-field failure excluded distant metastasis as a failur e and included only tissue in the RT treatment field. Overall progress ion-free survival (PFS) was defined as survival without evidence of in tra- or extrathoracic tumor or death from any cause. Results: Group 1 had a lower overall response rate (63%) compared to either Group 2 (77 %) or Group 3 (79%), p = 0.03 and 0.003, respectively. Overall grade 4 /5 acute toxicities were nearly equal between groups. The severe nonhe matologic acute toxicities were significantly different by strategy gr oup (p < 0.0001). Group 1 and 2 were not statistically different. Grou p 3 had significantly more patients with severe acute nonhematologic t oxicity (55%) than either Group 1 (27%) or 2 (34%) with p < 0.0001 and p = 0.0005, respectively. This was due to a severe acute esophagitis rate of 34% for Group 3 versus 1.3% for Group 1 and 6% for Group 2 (p < 0.0001 for both comparisons). Overall grade 4/5 late toxicities did not differ by group. Severe late nonhematologic toxicities were differ ent by group (p = 0.0098). Group 1 patients had significantly fewer se vere late nonhematologic toxicities (14%) compared to patients in Grou ps 2 (26%) or 3 (28%) (p = 0.046 and 0.038, respectively). Severe late lung toxicity was 10% for Group 1 compared to 21% and 20% for Groups 2 and 3, respectively. Severe late lung toxicities differed by group ( p = 0.033), but not severe late esophagitis (p = 0.077). There were no differences between the three strategy groups for patterns of first f ailure. The in-field failures were higher in Group 2 (71%) compared to Groups 1 (56%) and 3 (55%), p = 0.0478. Pairwise comparisons yielded p-values of 0.068 and 0.015 for Group 2 versus 1 and Group 2 versus 3, respectively. Three-year PFS was better in Group 2 (15%) and 3 (15%) compared to Group 1 (7%), but not statistically significant (p = 0.454 ). Similarly, in-field PFS was better in Group 2 (17%) and 3 (20%) tha n Group 1 (9%), but not significant (p = 0.167). There were improvemen ts in 3-year survival for Group 2 (17%) and Group 3 (25%) compared to Group 1 (15%), but the differences were not statistically significant (p = 0.47). The same results were present for patients with less than 5% weight loss and patients with stage IIIA tumors.Conclusion: Thus, c oncurrent ChT and hyperfractionated RT had a higher incidence of sever e acute esophageal toxicity. Severe late lung toxicity with concurrent ChT/hyperfractionated RT, as well as with induction ChT followed by c oncurrent ChT/standard RT, may be greater compared to sequential ChT/R T. Also, concurrent ChT/hyperfractionated RT, and induction ChT follow ed by concurrent ChT/standard RT, appear to have a benefit in terms of increased tumor response compared to sequential ChT/RT, but not in fa ilure pattern. The latter may reflect the presence of pretherapy micro metastases that are delayed from progression by the combined therapy, but not prevented. (C) 1998 Elsevier Science Inc.