L. Bazhenova

Frameless Image-Guided Stereotactic Body Radiation Therapy for Lung Tumors with 4-Dimensional Computed Tomography or 4-Dimensional Positron Emission Tomography/ Computed Tomography

BACKGROUND/PURPOSE To augment the accuracy of stereotactic body radiation therapy (SBRT), a variety of image guidance systems are used for patient positioning and target localization. Clinical outcomes evaluating these systems, especially frameless image-guided systems, are still limited. This article aims to describe and evaluate our frameless image-guided SBRT technique for lung tumors. METHODS Between 2007 and 2009, 85 pulmonary tumors (50 primaries and 35 metastases) were treated with SBRT using daily image guidance for patient positioning and target localization in lieu of a body frame. Four-dimensional computed tomography (4DCT) or an in-house protocol for integrated 4D positron emission computed tomography (4DPET/CT) was used for planning simulation. RESULTS Median follow-up was 17 months (range, 4-42). Median overall survival (OS) was 31 months (95% CI, 26-34), and median local failure-free survival was 30 months (95% CI, 18-32). At last follow-up, 9 of 83 evaluable lesions failed locally. Actuarial local control at 24 months was 87% (95% CI, 75-98) and was significantly worse for metastatic lesions (95% vs. 74%; P = .045; log-rank test). No acute or late toxicities (grade ≥ 4) were observed. CONCLUSIONS Frameless image-guided SBRT is a feasible, safe, and effective treatment for lung tumors.

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors. Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials. Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA. Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.

Definitive Radiation Therapy for Stage I Non-Small-Cell Lung Carcinoma: Institutional Experience With Contemporary Conformal Planning

PURPOSE Surgical resection for stage I non-small-cell lung cancer (NSCLC) is not always feasible because of the high likelihood of medical comorbidity in this patient population. We report our experience using conventional and hypofractionated radiation therapy schedules with a conformal approach. PATIENTS AND METHODS Between 1991 and 2006, 102 patients with medically or otherwise inoperable stage T1/T2 N0 NSCLC were treated with curative radiation therapy alone at our institution. Patients received a median total dose of 6600 cGy, with median daily dose fractions of 250 cGy. The following outcomes were analyzed: local failure-free survival (LFFS; time to local failure or death from any cause), time to local or distal failure or death as first event, and overall survival (OS). Local failure was defined as an increase in size on imaging studies. Toxicities were evaluated using Common Terminology Criteria for Adverse Events, version 3.0. RESULTS Median follow-up was 20.9 months (range, 4.0-138.9 months). Median LFFS was 21.2 months (95% CI, 17.3-27.2 months), and median OS was 21.3 months (95% CI, 17.9-28.8 months). Analysis of competing risks showed that at 5 years, the probability of local failure as the first detected event was 15.1% (95% CI, 8.5%-23.4%), the probability of distal failure as the first detected event was 18% (95% CI, 10.9%-26.5%), and the probability of death without recording a failure was 51.6% (95% CI, 40.6%-61.5%). No patients experienced grade >or= 4 toxicity, and only 4 patients experienced grade 3 toxicity. CONCLUSION Conformal radiation therapy is an effective and safe alternative to surgery for selected patients with stage I NSCLC.

Conformal Radiation Therapy as Definitive Treatment of Stage I Non—Small-Cell Lung Cancer: University of California San Diego Experience

Abstract Purpose Surgical resection remains the treatment of choice for patients with stage I non—small-cell lung cancer (NSCLC). However, there is high likelihood of medical comorbidity in this patient population, requiring management by nonsurgical approaches. We report our experience using conventional and hypofractionated radiation therapy schedules with conformal approach. Patients and Methods Between 1991 and 2006, 108 patients with medically or otherwise inoperable stage T1/T2 N0 NSCLC were treated with curative radiation therapy alone at our institution. Patient characteristics were as follows: median age, 73 years (range, 37–86 years); male, 88/108 (81.5%); stage T2, 46/108 (42.6%), and histology/cytology, 91/108 (84.3%). Patients received a median total dose of 6500 cGy using median daily dose fractions of 250 cGy. The majority of patients were treated using hypofractionated schedules: daily dose fractions > 200 cGy, 79/108 (73.1%). The following outcomes were analyzed: local failure-free survival (LFFS; time to local failure or death from any cause), time to local or distal failure as first event, and overall survival (OS). Local failure was defined as an increase in size on imaging studies. Toxicities were evaluated using Common Terminology Criteria for Adverse Events v3.0. Results Median follow-up was 19.9 months (range, 4–138.9 months). Median LFFS was 20.8 months (95% CI, 15.1–24.3 months), and median OS was 20.9 months (95% CI, 17.1–27.2 months). Analysis of competing risks showed that, at 5 years, the probability of local failure as the first detected event was 17.1% (95% CI, 10.3–25.3%), the probability of distal failure as the first detected event was 17.9% (95% CI, 11–26.1%), and the probability of death without recording a failure was 50.7% (95% CI, 40.1–60.3%). Patients aged ≥ 70 years had higher probability of death without recording a failure within 5 years (55.5%; 95% CI, 41.7% −67.3%) than patients aged Conclusion Conformal radiation therapy is an effective and safe alternative to surgery for patients with stage I NSCLC. The results are limited because this is a single-institution observational study. Nevertheless, a large majority of patients remained free of local recurrence and without significant clinical toxicity.