The NRG Oncology and the American College of Radiology Network (ACRIN) multicenter, phase II trial, NRG-RTOG 1106/ACRIN 6697 is the first randomized trial to demonstrate the feasibility and safety of performing adaptive radiotherapy escalation in patients with locally advanced non-small cell lung cancer (NSCLC). The improvement of in-field tumor control appeared similar to the level (1% improvement with 1Gy dose escalation) of the Single Institutional Study of adaptive radiotherapy performed at University of Michigan, and different from that of RTOG617 with non-adaptive high dose radiation in stage III NSCLC. The results were presented at the virtual edition of the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer, Singapore.
The NRG Oncology randomized phase III trial NRG-RTOG 0617 offered the insight that a higher dose of radiotherapy delivered with chemoradiotherapy actually worsened tumor control and survival for this patient population. NRG-RTOG 1106/ACRIN 6697 was designed to bridge this treatment gap by testing adaptive radiotherapy dose escalation with chemotherapy to see if this treatment could enhance 2-year local-regional tumor control compared to the 60 Gy standard dose of radiotherapy this patient population typically receives. The use of fluorodeoxyglucose-positron emission tomography (FDG-PET/CT) imaging would help identify resistant aggressive tumor identified mid-treatment and adapt personalized treatment plans per each individual's tolerance.
Patients with Stage III NSCLC were randomly assigned in a 2:1 ratio to receive either the standard radiotherapy at 60 Gy (Standard Arm) or the adaptive radiotherapy treatment that resulted in a median dose escalation of 11 Gy (Adaptive Arm). Patients on both treatment arms received FDG-PET/CT imaging at mid-treatment for radiation. The Standard Arm included 43 eligible patients whereas the Adaptive Arm included 84 eligible patients. The Standard Arm had a median follow up of 3.7 years for surviving patients with acceptable overall radiotherapy compliance rates (92.9% and 50% per protocol). The 2-year overall local-regional progression free rate was 59.5% (95% CI: 37.9, 75.7). Median local-regional progression free time was 27.5 months (95% CI: 14.3, not reached) in the Standard Arm. The Adaptive Arm had a median follow up of 3.4 years for surviving patients with acceptable overall radiotherapy compliance rates (95.8% for the initial course of treatment and 32.4% for adaptive course per protocol) and 2-year overall local-regional progression free rates were 54.6% (95% CI: 39.9, 67.0). Median local-regional progression free time was 28.4 months (95% CI: 19.1, not reached) in the Adaptive Arm. There were no significant differences in grade 3 or worse toxicity of lung, esophagus, and heart or overall survival, progression-free survival, and lung cancer specific survival between treatment arms. Adaptive radiotherapy did increase in-field local-regional tumor control by 11% and in-field primary tumor control by 17% during the trial.
"Not all patients respond the radiation dose escalation in the same way. We have already learned from a genotypic study of RTOG617 (which was recently presented in ASTRO 2020) that only one third of stage III patients with radiation resistant genotype on DNA repair pathway genes will benefit from dose escalation. Future trial designs should be focused on individualizing radiotherapy dose prescriptions according to patient's intrinsic sensitivity in order to improve survival. Additionally, further research should investigate if adaptive radiotherapy could increase normal tissue sparing factor (Sp) to improve survival on top of dose optimization in each individual," stated Feng-Ming (Spring) Kong, MD, PhD, FACR, FASTRO of the Clinical Oncology Center, the University of Hong Kong - Shenzhen Hospital; and Li Ka Shing Faculty of Medicine, The University of Hong Kong; Department of Radiation Oncology, Case Western Reserve University, and the lead author of the NRG-RTOG 1106/ACRIN 6697 abstract.
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This project was supported in parts by National Cancer Institute (NCI) National Institutes of Health (NIH) grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Biospecimen Bank), R01CA142840 (Kong), Shenzhen KQTD20180411185028798 (Kong), and NRG NCORP grant.
Citations
Kong FM, Hu C, Machtay M, Haken RT, Xiao Y, Matuszak M, Hirsh V, Pryma D, Siegel BA, Gelblum D, Hayman J, Robinson C, Loo, Jr. BW, Videtic GMM, Faria SL, Ferguson C, Dunlap N, Kundapu V, Paulus R, Bradley J. Results of RTOG1106/ACRIN9969: A Randomized Phase II Trial of Individualized Adaptive Radiotherapy Using Mid-Treatment FDG-PET/CT and Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (NSCLC). Paper presented at the annual meeting of the International Association for the Study of Lung Cancer. Virtual meeting platform.
Kong FMS, Jin JY, Hu C, Wang W, Bogart J, Garces YI, Narayan S, Robinson CG, Kavadi VS, Rothman J, Koprowski CD, Gore E, Welsh J, Gaur R, MacRae RM, Cannon G, Machtay M, Bradley JD, Lu B. (2020, October). RTOG0617 to externally validate blood cell ERCC1/2 genotypic signature as a radiosensitivity biomarker for both tumor and normal tissue for individualized dose prescription.
International Journal of Radiation Oncology*Biology*Physics, Volume 108, Issue 3, Supplement, 2020, Page S2, ISSN 0360-3016, https://doi.org/10.1016/j.ijrobp.2020.07.2070. (http://www.sciencedirect.com/science/article/pii/S0360301620334891)
Kong FM, Ten Haken RK, Schipper M, Frey KA, Hayman J, Gross M, Ramnath N, Hassan KA, Matuszak M, Ritter T, Bi N, Wang W, Orringer M, Cease KB, Lawrence TS, Kalemkerian GP. 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. JAMA Oncol. 2017 Oct 1;3(10):1358-1365. doi: 10.1001/jamaoncol.2017.0982. PMID: 28570742; PMCID: PMC5674997.
About NRG Oncology
NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology's extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI's National Clinical Trials Network.