Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. OBJECTIVE: To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. INTERVENTIONS: Chemoradiation and consolidation chemotherapy with or without metformin. MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02186847.

Impact of Radiotherapy Dose on Dentition Breakdown in Head and Neck Cancer Patients.

PURPOSE: To evaluate the severity of post-radiation dental lesions and possible correlation with radiation dose to the teeth in patients treated for head and neck cancers. METHODS AND MATERIALS: Data from 93 head and neck radiotherapy patients treated between 1997 and 2008 were analyzed retrospectively. The main effect, radiation dose to the individual teeth, was evaluated with covariates of elapsed time after radiation, xerostomia, topical fluoride use, and oral hygiene status included. Patients' radiotherapy plans were used to calculate cumulative exposure for each tooth. Patients' teeth were evaluated using a validated index and then categorized as having none/slight or moderate/severe post-radiation damage. RESULTS: Patients (31 females, 62 males) ranged in age from 18-82 yrs (mean=57). The number of teeth/patient ranged from 3-30 (mean=20) with a total of 1873 teeth evaluated. Overall, 51% of teeth had moderate/severe damage, with the remaining having little or none. Using odds ratios and 95% confidence intervals, the odds for moderate/severe damage were 2-3x greater for teeth exposed to between 30-60 Gy as compared to no radiation. However, for teeth exposed to ≥60 Gy as compared to no radiation the odds of moderate/severe tooth damage was greater by a magnitude of 10 times. CONCLUSIONS: The results indicate that there is minimal tooth damage below 30 Gy (salivary gland threshold), a greater than 1:1 increased dose-response between 30-60y likely related to salivary gland damage, and a critical threshold of ≥60Gy which may be linked to direct effects of radiation on tooth structure. These findings suggest that care should be taken during the treatment planning process to limit tooth dose, and when clinically possible to limit tooth dose to less than 60 Gy.