Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis

Abstract

Background: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT.

Materials and methods: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival.

Results: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy.

Conclusion: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

Keywords: chemotherapy compliance; individual participant data meta-analysis; radiotherapy timing; randomized clinical trials; small-cell lung cancer; thoracic radiotherapy.

Figure 1.

Effect of ‘earlier or shorter’ radiotherapy versus ‘later or longer’ radiotherapy on overall survival according to CT compliance. Each trial is represented by a square, the centre of which denotes the HR of death 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 clear diamonds represent pooled HRs for the trial groups and the black diamond the overall HR, with the centre denoting the HR and the extremities the 95% CI. The fixed-effect model was used. Trials were chronologically ordered within each category of trials. Of note, data on CT compliance were not available for the CCCWFU62286 trial, which is thus not included in this analysis. CI, confidence interval; CT, chemotherapy; HR, hazard ratio; O-E, observed-expected; RT, radiotherapy.

Figure 2.

Survival curves for overall survival according to chemotherapy compliance. CI, confidence interval; CT, chemotherapy; HR, hazard ratio; PY, person-year; RT, radiotherapy.

Figure 3.

Effect of ‘earlier or shorter’ radiotherapy versus ‘later or longer’ radiotherapy on progression-free survival according to chemotherapy compliance. Each trial is represented by a square, the centre of which denotes the HR of death or tumour progression 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 clear diamonds represent pooled HRs for the trial groups and the black diamond the overall HRs, with the centre denoting the HR and the extremities the 95% CI. The fixed-effect model was used. CI, confidence interval; CT, chemotherapy; HR, hazard ratio; O-E, observed-expected; RT, radiotherapy.