From CHART to CHARTWEL in Non-small Cell Lung Cancer: Clinical Radiobiological Modelling of the Expected Change in Outcome

Abstract

CHART (Continuous Hyperfractionated Accelerated Radiotherapy) has been shown to improve the tumour control probability and survival relative to conventional radiotherapy in patients with inoperable non-small cell lung cancer (NSCLC). CHARTWEL (CHART Weekend-less) is a further development of this schedule escalating the physical dose to 60 Gy while maintaining the low dose per fraction of 1.5 Gy. In this schedule, three fractions, with a minimum interval of 6 h between fractions, are delivered 5 days per week. This extends overall treatment time from the 12 days of CHART to 18 days. Radiobiological modelling is used to estimate the expected tumour control and normal tissue morbidity after CHARTWEL relative to CHART. The estimations are based on the outcome of the CHART trial and published values for dose-fractionation and dose-response parameters for human tissues and tumours. Two new estimates of quantitative radiobiological parameters for early normal-tissue morbidity after chest irradiation are reported here. For radiation pneumonitis, the dose recovered per day is estimated at 0.44 Gy/day with 95% confidence limits 0.07 Gy/day and 0.80 Gy/day. For oesophagitis, the normalized dose-response gradient, gamma50, is estimated at 2.1 with 95% confidence limits 1.4 and 3.6. With regard to normal tissue effects, the increase in total dose when going from CHART to CHARTWEL is moderated by the slightly longer overall treatment time in case of early morbidity while the introduction of the weekend gaps may moderate the effect for late-responding normal tissues with a long repair halftime. Tumour control at 3 years is expected to increase by some 7-14 percentage points (from 19% to 26-33%) whereas the incidence of moderate and severe early oesophagitis and pneumonitis is expected to increase by about 2 percentage points. The incidence of late morbidity, lung fibrosis and oesophageal strictures, is expected to increase by 3-4 percentage points. The analyses conclude that CHARTWEL is likely to improve the therapeutic ratio relative to CHART.