CHEMORADIOTHERAPY FOR STAGE III NSCLC

Lancet Oncol. 2015 Jan 15. pii: S1470-2045(14)71207-0. doi: 10.1016/S1470-2045(14)71207-0. [Epub ahead of print]

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

Bradley JD1, Paulus R2, Komaki R3, Masters G4, Blumenschein G3, Schild S5, Bogart J6, Hu C2, Forster K7, Magliocco A7, Kavadi V8, Garces YI9, Narayan S10, Iyengar P11, Robinson C12, Wynn RB13, Koprowski C14, Meng J15, Beitler J16, Gaur R17, Curran W Jr16, Choy H11.

Author information

Abstract

BACKGROUND: 

We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer.

METHODS: 

In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m2 paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m2) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m2 cetuximab was given on day 1 followed by weekly doses of 250 mg/m2, and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949.

FINDINGS: 

Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22·9 months (IQR 27·5-33·3). Median overall survival was 28·7 months (95% CI 24·1-36·9) for patients who received standard-dose radiotherapy and 20·3 months (17·7-25·0) for those who received high-dose radiotherapy (hazard ratio [HR] 1·38, 95% CI 1·09-1·76; p=0·004). Median follow-up for the cetuximab comparison was 21·3 months (IQR 23·5-29·8). Median overall survival in patients who received cetuximab was 25·0 months (95% CI 20·2-30·5) compared with 24·0 months (19·8-28·6) in those who did not (HR 1·07, 95% CI 0·84-1·35; p=0·29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0 16="" 207="" 217="" abstracttext="" and="" between="" cetuximab="" chemoradiotherapy="" common="" comparison:="" deaths="" differences="" eight="" events="" five="" groups.="" groups="" high-dose="" in="" more="" no="" oesophagitis="" of="" p="" patients="" pulmonary="" radiotherapy="" received="" severe="" standard-dose="" ten="" than="" the="" there="" those="" three="" treatment-related="" treatment="" vs="" was="" were="" who="">

INTERPRETATION: 

74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients.