Impact of estimated dose of radiation to immune cells (EDRIC) in locally advanced Non-Small-Cell lung Cancer: A secondary analysis of the multicenter randomized PET-Plan trial

Abstract

Purpose: A higher estimated dose of radiation to immune cells (EDRIC) has been proposed as an explanation for failed attempts at thoracic radiation intensification as a part of concurrent chemoradiotherapy (cCRT) for locally advanced non-small-cell lung cancer (NSCLC), as lymphopenia in particular is a negative prognostic factor in this context. We studied the impact of EDRIC on survival in this secondary analysis of the prospective PET-Plan trial (ARO-2009-09; NCT00697333). Considering the immune system as an organ at risk for radiotherapy is of major importance in the current era of consolidation immunotherapy.

Methods: Eligible patients had previously received chemoradiotherapy up to 60-74 Gy with radiation treatment planning based on an ¹⁸F-FDG PET/CT targeting all CT positive lymph nodes plus 50 Gy elective nodal irradiation (arm A) versus targeting only PET-positive nodes (arm B). EDRIC was calculated with the original model by Jin et al. in addition to a modified score with cohort-specific weight parameters.

Results: Sufficient data were available in 153 patients with a median follow-up time (95 % confidence interval [CI]) of 41.6 (34.6 - 53.7) months. Using the original model, the mean EDRIC (range) was 5.70 (3.23 - 8.44) Gy and showed a strong inverse correlation with PFS (hazard ratio [HR] = 1.77; 95 % CI 1.23-2.54; p = 0.002) and OS (HR = 1.72; 95 % CI 1.12-2.65; p = 0.01). The mean modified EDRIC (range) was 5.30 (3.01 - 8.38) Gy, again with a strong inverse correlation with PFS (HR = 1.66; 95 % CI 1.16-2.38; p = 0.006) but not OS (HR = 1.40; 95 % CI 0.91-2.15; p = 0.122). Neither radiation treatment allocation (arm A vs. B) nor technique (3D-CRT vs. IMRT) influenced EDRIC (p = 0.889 and p = 0.958, respectively) and EDRIC did not influence the rate of early or delayed hematological toxicity. On multivariate analysis, mean body dose (MBD) was the main contributing factor of the EDRIC equation to PFS and OS.

Conclusion: Higher doses of radiation to the immune system were associated with worse PFS in this secondary analysis of the PET-Plan trial. The omission of elective nodal irradiation did not influence EDRIC. MBD could potentially suffice as a surrogate for EDRIC, as it is more readily available and requires fewer calculations. Future trials should aim to refine existing models and investigate ways to reduce EDRIC to limit its effects in patients undergoing cCRT for locally advanced NSCLC.

Keywords: Concurrent chemoradiotherapy; EDRIC; Estimated dose of radiation to immune cells; Locally advanced non-small-cell lung cancer.