Independent association of metabolic tumor response on FDG-PET with pulmonary toxicity following risk-adaptive chemoradiation for unresectable non-small cell lung cancer: Inherent radiosensitivity or immune response?

ABSTRACT

BACKGROUND: In the context of a phase II trial of risk-adaptive chemoradiation, we evaluated whether tumor metabolic response could serve as a correlate of treatment sensitivity and toxicity. METHODS: Forty-five patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the FLARE-RT phase II trial (NCT02773238). [18F]fluorodeoxyglucose (FDG) PET-CT images were acquired prior to treatment and after 24 Gy during week 3. Patients with unfavorable on-treatment tumor response received concomitant boosts to 74 Gy total over 30 fractions rather than standard 60 Gy. Metabolic tumor volume and mean standardized uptake value (SUVmean) were calculated semi-automatically. Risk factors of pulmonary toxicity included concurrent chemotherapy regimen, adjuvant anti-PDL1 immunotherapy, and lung dosimetry. Incidence of CTCAE v4 grade 2+ pneumonitis was analyzed using the Fine-Gray method with competing risks of metastasis or death. Peripheral germline DNA microarray sequencing measured predefined candidate genes from distinct pathways 96 DNA repair, 53 immunology, 38 oncology, 27 lung biology. RESULTS: Twenty-four patients received proton therapy, 23 received ICI, 26 received carboplatin-paclitaxel, and 17 pneumonitis events were observed. Pneumonitis risk was significantly higher for patients with COPD (HR 3.78 [1.48, 9.60], p = 0.005), those treated with immunotherapy (HR 2.82 [1.03, 7.71], p = 0.043) but not with carboplatin-paclitaxel (HR 1.98 [0.71, 5.54], p = 0.19). Pneumonitis rates were similar among selected patients receiving 74 Gy radiation vs 60 Gy (p = 0.33), proton therapy vs photon (p = 0.60), or with higher lung dosimetric V20 (p = 0.30). Patients in the upper quartile decrease in SUVmean (>39.7%) were at greater risk for pneumonitis (HR 4.00 [1.54, 10.44], p = 0.005) and remained significant in multivariable analysis (HR 3.34 [1.23, 9.10], p = 0.018). Germline DNA gene alterations in immunology pathways were most frequently associated with pneumonitis. CONCLUSION: Tumor metabolic response as measured by mean SUV is associated with increased pneumonitis risk in a clinical trial cohort of NSCLC patients independent of treatment factors. This may be partially attributed to patient-specific differences in immunogenicity.