Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer

Abstract

PURPOSE Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial’s stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

Immunomodulatory Effects of Radiotherapy

“…Longer survival than SBRT, spares more normal liver cells from radiation damage than treating with conventional RT [39][40][41] Esophageal Proton vs. IMRT Randomized Phase II The mean total toxicity burden was considerably lower with protons than with IMRT [42] Brain (Adult) Proton Trial study unknown Significantly reduced the side effects and better neurocognition over time after treatment [43][44][45][46] Brain (Pediatric) Proton vs. Photon Trial study unknown Spared more surrounding normal tissue; reduced side effects and increased five-year survival rates (72-100%) [32,[47][48][49][50] Safer to deliver high dose of radiation and better neurocognition [44][45][46]51] 2.3.2. Carbon Ion Therapy 12 C ions are the optimal ion for treating deep-seated tumors, because the higher relative biological effectiveness (RBE) resulting from variations in linear energy transfer (LET) along the ion path can be limited to the tumor volume with minimal normal tissue injury along the entrance track.…”

Beam angle comparison for distal esophageal carcinoma patients treated with intensity‐modulated proton therapy

“…Generated IMPT plans are then verified by plan evaluation on maximum exhalation and maximum inhalation respiratory phases, as well as a separate interplay effect calculation. 45 Previous dosimetric studies [56][57][58][59] of esophageal carcinoma treatment compared both proton and photon treatments. Zhang et al reported that proton therapy provided significantly better sparing of the lungs than IMRT.…”

“…34 Most recently, Lin et al reported the result of a phase IIB trial that for locally advanced esophageal cancer, proton beam therapy (PBT) reduced the risk and severity of adverse events (AEs) while maintaining similar progression-free survival (PFS) when compared with IMRT. 59 Specifically for IMPT, different configurations may lead to different outcomes, such as spot sizing and spacing. 38 The selection of beam angles is important as well.…”

Stage III Esophageal Squamous Cell Carcinoma Patients With Three-Dimensional Conformal or Intensity-Modulated Radiotherapy: A Multicenter Retrospective Study

“…Numerous dosimetric studies have illustrated superior cardiopulmonary dose sparing with PBT compared with both 3DCRT and IMRT ( 29 – 32 ). A newly reported randomized phase IIB trial compared total toxicity burden (TTB) and PFS between PBT and IMRT for esophageal cancer ( 33 ). The results suggested that PBT for neoadjuvant or definitive treatment of locally advanced EC produced a lower toxicity profile and fewer postoperative complications, thus leading to a lower TTB, but similar PFS, compared to IMRT.…”