The PET-boost trial: isotoxic homogeneous or FDG-directed dose escalation in stage II-III NSCLC

Abstract

Purpose or Objective The randomized phase II PET-boost trial(NCT01024829) aimed to improve freedom from local failure(FFLF) by boosting either the whole primary tumor(PT) or the high FDG uptake region inside the PT(> 50%SUVmax) in non-small cell lung cancer (NSCLC) patients. Here we report on the primary endpoint FFLF at 1 year, and secondary endpoint overall survival(OS). Material and Methods Eligible patients had stage II-III NSCLC with a primary tumor ≥4 cm, SUVmax ≥5.0 and WHO PS ≤ 2. For each patient, before randomization, a treatment plan (24x2.75Gy) was made for both arms with a simultaneously integrated boost to the whole PT (armA) or to the PT 50%SUVmax area (armB). The boost dose (up to 5.4 Gy per fraction) was maximized by normal tissue constraints while the mean lung dose of the two plans was normalized. In case dose escalation of ≥3 Gy per fraction was not possible, patients were not randomized. Response was assessed with (PET/)CT at 3, 6, 12 and 18 months. All CT-scans were centrally reviewed by a dedicated radiologist. Local failure was defined as 20% growth from nadir (akin to RECIST). The trial was powered(one sided α=0.05;β=0.80) to detect an increase of FFLF at 1 year from 70% (historical rate) to 85%, requiring 82 randomized patients in each arm. Results Between Apr 2010 and Sep 2017, 150 patients were included in 7 institutions. The trial was closed after randomization of 107 patients (initial target 164): 54 to armA and 53 to armB. Patient characteristics are summarized in Table1. Median FU for FFLF was 12.6 months (IQR 5.2-24.6). Median escalated prescribed dose to the PTVwhole tumor (armA) was 3.25 Gy per fraction (IQR 3.13-3.40), and median total dose was 78.0 Gy (IQR 75.0-81.6). Median prescribed dose to the PTV50%SUVmax (armB) was 3.50 Gy per fraction (IQR 3.35-3.90), and median total dose was 84.0 Gy (IQR 80.4-93.6). 72% of patients received concurrent chemo-radiotherapy. Central review showed that the PT was non-measurable in 27% of CT-scans (96/352), mainly due to inflammation, fibrosis and/or atelectasis. If lesions remained stable over time, this was scored as no local failure. In the first year, 22 patients died without known local failure, 16 were lost to CT follow-up and 8 were not-evaluable. The 1-year FFLF rate in evaluable patients was 97% (95% CI 91-100) in armA, and 91% (95% CI 82-100) in armB. The 1- and 3-year OS rates were 77% and 37% in armA, and 62% and 33% in armB, respectively. Conclusion In this randomized phase II trial, dose escalation to the primary tumor as a whole or 50%SUVmax in NSCLC patients led to respectively 97% and 91% FFLF at 1 year in central CT review. Many scans were not evaluable (27%), likely due to the effect of high dose radiation. Predefined FFLF increase from 70% to 85% was achieved in both arms, however the trial did not reach predefined sample size. In locally advanced non-resectable NSCLC a homogeneous boost, sparing central structures as much as possible, should be considered in future research.