Impact of Unfavorable Factors on Outcomes Among Inoperable Stage II-IV Non–Small Cell Lung Cancer Patients Treated with Proton Therapy

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Clinical trials evaluating proton therapy (PT) for locally advanced non–small cell lung cancer (LA-NSCLC) have been slow to accrue despite the many patients on registry PT studies. We investigated patients with LA-NSCLC treated at a single proton center to better understand who is being treated with PT and describe their outcomes. From May 2008 through September 2016, 101 patients with unresectable stage II-IV (oligometastatic) NSCLC were treated on an IRB-approved outcomes tracking protocol and/or clinical trials with PT. Unfavorable factors including age ≥80 yrs, stage IV, weight loss >5% in 1 month, Performance Status (PS) ≥2, FEV1 <1.0 or O2 dependency, prior lung cancer, prior lung surgery, prior second cancer in the past 3 years, prior chest irradiation, and other severe comorbidities listed as clinical trial ineligibility criteria were evaluated. Ninety-one patients received standard fractionation of 1.8-2 Gy(RBE) (median dose, 70 Gy[RBE]), while 10 others were treated with hypofractionation (≥ 2.5 Gy[RBE]/fraction). Overall survival (OS) and progress-free survival (PFS) were calculated with the Kaplan-Meier method. The impact of unfavorable factors was analyzed in univariate and multivariate Cox regression models. Median follow-up for living patients was 27.7 months. Of the 101 patients, 27% were favorable-risk (0 factors), 40% had 1 unfavorable factor, 20% had 2 factors, and 13% had ≥3 factors; 59% (n=16) of favorable-risk and 9% (n=7) of unfavorable-risk patients were enrolled in clinical trials (P <.001). Seventy-seven percent of patients were ≥age 65 years qualifying for Medicare, only 19% of whom were favorable-risk (P =.003). More favorable- than unfavorable-risk patients received concurrent chemotherapy (96% vs 75.7%; P=.02). Restricted to 91 patients treated with standard fractionation, the 2- and 5-year OS rates were 52% and 13% for favorable-risk patients compared to 43% and 25% for unfavorable-risk patients (P=.84). There was a trend toward a better 2-year PFS rate for unfavorable-risk patients (44% vs 21%; P=.053). None of the unfavorable factors had a significant impact on OS. In a subset analysis for only stage III-IV patients, PS≥2 adversely impacted OS (P=.002). Of the favorable-risk patients, 19% (n=4) developed grade 3 or higher toxicities including 3 GI-related and 1 pulmonary. For unfavorable-risk patients, 11.4% (n=8) had grade 3 or higher toxicities including 4 GI-related and 7 pulmonary. Most patients treated with PT for LA-NSCLC have unfavorable risk factors. These patients had similar outcomes to favorable-risk patients. Enrollment in future clinical trials may improve if eligibility is less restrictive.