Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis

Abstract

Purpose: In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation.

Material and methods: We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy.

Results: In non-small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non-lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities.

Conclusion: Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

Fig 1.

Flowchart of the trial selection and contribution to analyses. NSCLC, non–small-cell lung cancer; RCTs, randomized controlled trials; SCLC, small-cell lung cancer.

Fig 2.

Effect of modified radiotherapy (RT) versus conventional RT on overall survival, by RT types in non–small-cell lung cancer trials. Each trial is represented by a blue square, the center of which denotes the hazard ratio (HR) for that trial comparison, with the horizontal lines showing the 95% CIs. The size of the square is directly proportional to the amount of information contributed by the trial. The gold diamonds represent pooled HRs for the trial groups and the blue diamond the overall HRs, with the center denoting the HR and the extremities the 95% CI. The fixed effect model was used. CHART, Continuous Hyperfractionated Accelerated Radiation Therapy; CHARTWEL, CHART Week-End Less; CT, chemotherapy; Conv., conventional; ECOG, Eastern Cooperative Oncology Group; Exp., experimental; NCCTG, North Central Cancer Treatment Group; O-E, observed-expected; PCMI, Peter MacCallum Institute; RTOG, Radiation Therapy Oncology Group.

Fig 3.

Survival curves for the non–small-cell lung cancer trials: (A) overall and progression-free survival; (B) locoregional failure; (C) distant failure; (D) lung and non–lung cancer mortality. RT, radiotherapy.

Fig 4.

Effect of modified radiotherapy (RT) versus conventional RT on overall survival by patient characteristics. Conv., conventional; Exp., experimental; O-E, observed-expected.