The Role of Thoracic Vertebral Body Dosimetry in Minimizing Acute Hematologic Toxicities of Patients With Non-Small Cell Lung Cancer Receiving Lung Radiation Therapy and Immunotherapy

Abstract

Purpose: Hematologic toxicities (HTs) are among the most common toxicities of combined immunotherapy and radiation therapy (RT). It remains essential to prevent RT-induced HTs because they can cause treatment discontinuation (influencing antitumoral effects) and because lymphopenia might dampen the effects of immunotherapy. To date, there are no studies examining the effect of thoracic vertebral body (TVB) RT dose on HTs in patients with non-small cell lung cancer receiving combined lung RT and programmed cell death (ligand) 1 immunotherapy.

Methods and materials: For standardization, all doses were reported as 2-Gy equivalents (EQD2). Mirroring publications before the immunotherapy era, TVB volumes referred to T1-T10, and specific dosimetric parameters (Dmean_EQD2, V5_EQD2-V60_EQD2) were analyzed. Logistic regression estimated associations between grade ≥3 HTs (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability (NTCP) models were constructed by logistic regression analysis modeling for HT3+. Receiver operating characteristic (ROC) analysis delineated TVB dosimetric thresholds, the stratification of which was able to evaluate post-RT absolute lymphocyte count and immunotherapy responses. Areas under the curve (AUCs) for NTCP models were corroborated by bootstrapping (optimism-corrected) methodology.

Results: In 132 patients, there were 26 (19.7%) instances of HT3+. On multivariate analysis, Dmean_EQD2 and V5_EQD2 to V20_EQD2 were associated with HT3+ (P < .05 for all). The NTCP models illustrated a 50% probability of HT3+ at a Dmean_EQD2 = 39.8 Gy, V5_EQD2 = 87.4%, V10_EQD2 = 77.0%, and V20_EQD2 = 68.4%. ROC analysis delineated optimal thresholds of HT3+ with Dmean_EQD2 ± 30.2 Gy, V5_EQD2 ± 69.1%, V10_EQD2 ± 64.6%, and V20_EQD2 ± 53.5%. Patients treated with values above those cutoffs had over double the risk of HT3+, with significant differences in post-RT absolute lymphocyte count and immunotherapy responses (P < .05 for all). AUCs for each individual parameter ranged from 0.743 to 0.798, and combining all 4 aforementioned cutoffs into a ROC curve resulted in a qualitatively higher AUC (0.836).

Conclusions: This hypothesis-generating work suggests that TVB dosimetry may equate with HT3+ in patients with non-small cell lung cancer undergoing combined lung RT/immunotherapy. Applying TVB dose constraints in this population could reduce HT3+ and avoid dampening of immunotherapy responses, but prospective validation is required.