Purpose: Within a risk-adaptive chemoradiation trial (NCT02773238), we investigated metabolic tumor response as a potential correlate of treatment sensitivity and toxicity.
Methods: Patients with unresectable non-small cell lung cancer (NSCLC) recruited to the clinical trial underwent [¹⁸F]fluorodeoxyglucose (FDG) PET/CT imaging prior to treatment and at 24Gy mid-treatment (week 3) on matching scanners. Based on mid-FDG-PET/CT radiologic interpretation, patients with favorable tumor response received 60Gy in 30 fractions, while those with unfavorable tumor response received 74Gy total in 30 fractions. Consensus metabolic tumor volumes were semi-automatically delineated on FDG-PET and mean standardized uptake values (SUVmean) were calculated. Fine-Gray models of CTCAEv4 grade 2 or higher pneumonitis were generated with competing risks for disease progression or death. Treatment factors included adjuvant immunotherapy, concurrent chemotherapy regimen, proton versus photon radiotherapy, and lung dosimetry (V20). Peripheral germline DNA was sequenced for predefined genes from distinct pathways: 96 DNA-repair, 53 immunology, 38 oncology, 27 lung biology.
Results: Among 45 patients: 24 received proton radiotherapy, 23 received adjuvant immunotherapy, 26 received carboplatin-paclitaxel chemotherapy regimens, and 17 pneumonitis events were observed 62-365 days after consent. Risk of pneumonitis was significantly higher for patients in the upper quartile (>39.7%) decrease in SUVmean (hazard ratio (HR) 4.00 [1.54,10.44], p=0.0046) and those treated with immunotherapy (52% vs 24% cumulative incidence, p=0.043). SUVmean decrease retained significant multivariable association (HR 3.12 [1.01,9.67], p=0.048) with adjustment for immunotherapy. Pneumonitis cumulative incidence was not associated with carboplatin-paclitaxel regimens (47% vs 26%, p=0.19), dose escalation to 74Gy (p=0.33), proton radiotherapy (p=0.60), and higher lung V20 (p=0.30). Germline DNA gene alterations in the immunology pathways were more frequently associated with pneumonitis relative to other pathways.
Conclusion: Metabolic tumor response is associated with increased pneumonitis risk in a clinical trial cohort of NSCLC patients, independent of treatment factors, and may be attributed to germline differences in immunogenicity.
Funding Support, Disclosures, and Conflict of Interest: This work is supported by NIH NCI grants R01CA204301 and R01CA258997