PURPOSE Patients undergoing outpatient radiotherapy (RT) or chemoradiation (CRT) frequently require acute care (emergency department evaluation or hospitalization). Machine learning (ML) may guide interventions to reduce this risk. There are limited prospective studies investigating the clinical impact of ML in health care. The objective of this study was to determine whether ML can identify high-risk patients and direct mandatory twice-weekly clinical evaluation to reduce acute care visits during treatment. PATIENTS AND METHODS During this single-institution randomized quality improvement study (ClinicalTrials.gov identifier: NCT04277650 ), 963 outpatient adult courses of RT and CRT started from January 7 to June 30, 2019, were evaluated by an ML algorithm. Among these, 311 courses identified by ML as high risk (> 10% risk of acute care during treatment) were randomized to standard once-weekly clinical evaluation (n = 157) or mandatory twice-weekly evaluation (n = 154). Both arms allowed additional evaluations on the basis of clinician discretion. The primary end point was the rate of acute care visits during RT. Model performance was evaluated using receiver operating characteristic area under the curve (AUC) and decile calibration plots. RESULTS Twice-weekly evaluation reduced rates of acute care during treatment from 22.3% to 12.3% (difference, −10.0%; 95% CI, −18.3 to −1.6; relative risk, 0.556; 95% CI, 0.332 to 0.924; P = .02). Low-risk patients had a 2.7% acute care rate. Model discrimination was good in high- and low-risk patients undergoing standard once-weekly evaluation (AUC, 0.851). CONCLUSION In this prospective randomized study, ML accurately triaged patients undergoing RT and CRT, directing clinical management with reduced acute care rates versus standard of care. This prospective study demonstrates the potential benefit of ML in health care and offers opportunities to enhance care quality and reduce health care costs.

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Background Salvage surgical resection for non-small cell lung cancer (NSCLC) patients initially treated with definitive chemotherapy and radiation can be performed safely, but the long-term benefits are not well characterized. Methods Perioperative complications and long-term survival of all patients with NSCLC who received curative-intent definitive radiation with or without chemotherapy followed by lobectomy from 1995-2012 were evaluated. Results During the study period, 31 patients met inclusion criteria. Clinical stage distribution was: stage I (n=2,6%); stage II (n=5,16%); stage IIIA (n=15,48%);stage IIIB (n=5,16%); stage IV (n=3,10%); and unknown (n=1,3%). The reasons surgery was initially not considered were: patients deemed medically inoperable (5 [16%]); extent of disease considered unresectable (21 [68%]); small cell lung cancer misdiagnosis (1 [3%]); and unknown (4 [13%]). Definitive therapy was radiation alone (n=2, 6%), concurrent chemoradiation (n=28, 90%), and sequential chemoradiotherapy (n=1, 3%). The median radiation dose was 60 Gy. Patients were subsequently referred for resection because of obvious local relapse, medical tolerance of surgery or post-therapy imaging suggested residual disease.Median time from radiation to lobectomy was 17.7 weeks.There were no perioperative deaths, and morbidity occurred in 15 (48%) patients. None of 3 patients with residual pathologic nodal disease survived longer than 37 months, but the 5-year survival of pN0 patients was 36%. Patients who underwent lobectomy for obvious relapse (n=3) also did poorly with median overall survival of 9 months. Conclusion Lobectomy after definitive radiation therapy can be done safely and is associated with reasonable long-term survival, particularly when patients do not have residual nodal disease.

KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRASQ61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRASG12-driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance.

Metastatic lung cancer has long been considered incurable, with the goal of treatment being palliation. However, a clinically meaningful number of these patients with limited metastases (approximately 25%) are living long term after definitive treatment to all sites of active disease. These patients with so-called oligometastatic disease likely represent a distinct clinical group who may possess a more indolent biology compared with their more widely metastatic counterparts. Hellman and Weichselbaum proposed the existence of the oligometastatic state, on the basis of the spectrum theory of cancer spread. The literature suggests that an oligometastatic state exists in patients with non-small-cell lung cancer (NSCLC). This observation in the setting of rapidly evolving systemic therapies, including immune checkpoint inhibitors and an increasing number of targeted therapies, represents a unique clinical opportunity. Metastasis-directed therapies to address sites of disease include surgery (metastasectomy) and/or radiation therapy. Available evidence suggests that treating patients with limited or oligometastases may improve outcomes in a meaningful way; however, the majority of the randomized data includes patients with intracranial metastatic disease, and there are limited robust, randomized data available in the setting of NSCLC with only extracranial sites of metastatic disease. Ongoing randomized trials, including NRG-LU002 and the UK Conventional Care Versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases trial, are aimed at evaluating this question further. One of the current limitations of aggressive treatment of oligometastatic NSCLC is the inability to accurately identify these patients before therapy, yet molecular markers, including microRNA profiles, are being investigated as a promising way to identify these patients.