N. Bi

Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer: A Phase 2 Clinical Trial

Importance Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. Objective To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). Design, Setting, and Participants A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. Intervention Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. Main Outcomes and Measures The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. Results The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45-83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63-86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%-92%) and 62% (95% CI, 43%-77%), respectively. Median overall survival was 25 months (95% CI, 12-32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%-66%) and 30% (95% CI, 16%-45%), respectively. Conclusions and Relevance Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. Trial Registration clinicaltrials.gov Identifier: NCT01190527

Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer.

PURPOSE This study utilizes a survival model and clinical data with various radiation doses from prospective trials to determine radiation dose-response parameters, such as radiosensitivity, and identify single-nucleotide-polymorphism (SNP) biomarkers that can potentially predict the dose response and guide personalized radiotherapy. METHODS The study included 92 consecutive stage-III NSCLC patients with doses varying from 60 to 91Gy. Logistic regression analysis of survival varying with SNP genotype and radiation dose was used to screen candidates for dose-response analysis. The dose-response parameter, represented by D50, was derived by fitting survival data into a model that takes into account both tumor control and treatment mortality. A candidate would be considered as a predictor if the 90% confident intervals (90% CIs) of D50 for the 2 groups stratified by the SNP genotype were separated. RESULTS One SNP-signature (combining ERCC2:rs238406 and ERCC1:rs11615) was found to predict dose-response. D50 values are 63.7 (90% CI: 53.5-66.3) Gy and 76.1 (90% CI: 71.3, 84.6) Gy for the 2 groups stratified by the genotypes. Using this biomarker-based model, a personalized dose prescription may be generated to improve 2-year survival from ∼50% to 85% and ∼3% to 73% for hypothetical sensitive and resistant patients, respectively. CONCLUSIONS We have developed a survival model that may be used to identify genomic markers, such as ERCC1/2 SNPs, to predict radiation dose-response and potentially guide personalized radiotherapy.