Parallel explorations in LA-NSCLC: Chemoradiation dose-response optimisation considering immunotherapy and cardiac toxicity sparing

Background and purpose

Chemoradiotherapy (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC) has undergone advances, including increased overall survival (OS) when combined with immune checkpoint blockade (ICB), and using cardiac-sparing techniques to reduce the radiotoxicity. This research investigated 1) how radiotherapy schedules can be optimised with CRT-ICB schemes, and 2) how cardiac-sparing might change the OS for concurrent CRT (cCRT).

Methods and materials

Survival data and dosimetric indices were sourced from published studies, with 2-year OS standardised and the hazard ratio of mean heart dose (MHD) against radiotoxicity tabulated in purpose. A published CRT dose–response model was selected, then modified with ICB and cardiac-sparing hypotheses. Models were maximum likelihood fitted, then visualised the prediction outcomes after bootstrapping.

Results

The modelled 2-year OS rate of cCRT-ICB reached 71 % (95 % confidence intervals, CI 62 %, 84 %) and 66 % (95 % CI: 53 %, 81 %) for stage IIIA and IIIB/C, respectively, given 60 Gy in 2 Gy-per-fraction. 60 Gy in 30 fractions remained the best schedule for cCRT-ICB, whereas modest dose de-escalation to 55 Gy only reduced the OS in 2 %. Sequential CRT (sCRT)-ICB provided 6 % OS increases versus the best OS rate achieved by sCRT alone. Photon MHD-sparing achieved a 5–10 % increase in modelled 2-year OS, with protons providing a further roughly 5–10 % increase.

Conclusion

Neither dose-escalation nor de-escalation relative to 60 Gy in 30 fractions influenced the survival with cCRT-ICB, while 5 Gy dose de-escalation might benefit patients with heavily irradiated organs at risk. Cardiac-sparing improved OS, and protons provided advantages for tumours anatomically overlapped or lay below the heart.