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Clinical Trial
. 2020 May 10;38(14):1569-1579.
doi: 10.1200/JCO.19.02503. Epub 2020 Mar 11.

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

Steven H Lin  1 , Brian P Hobbs  2 , Vivek Verma  3 , Rebecca S Tidwell  4 , Grace L Smith  1   5 , Xiudong Lei  5 , Erin M Corsini  6 , Isabel Mok  1 , Xiong Wei  1 , Luyang Yao  1 , Xin Wang  7 , Ritsuko U Komaki  1 , Joe Y Chang  1 , Stephen G Chun  1 , Melenda D Jeter  1 , Stephen G Swisher  6 , Jaffer A Ajani  8 , Mariela Blum-Murphy  8 , Ara A Vaporciyan  6 , Reza J Mehran  6 , Albert C Koong  1 , Saumil J Gandhi  1 , Wayne L Hofstetter  6 , Theodore S Hong  9 , Thomas F Delaney  9 , Zhongxing Liao  1 , Radhe Mohan  1
Affiliations
Clinical Trial

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

Steven H Lin et al. J Clin Oncol. .

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.

Trial registration: ClinicalTrials.gov NCT01512589.

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Figures

FIG 1.
FIG 1.
Trial profile. CRT, chemoradiotherapy; IMRT, intensity-modulated radiation therapy; PBT, proton beam therapy.
FIG 2.
FIG 2.
Total toxicity burden in the proton beam therapy and intensity-modulated radiation therapy arms as (A) stratified for surgical status and (B) the severity of individual toxicities in both arms. AE, adverse event; AFIB, atrial fibrillation; AL, anastomotic leak; ARDS, acute respiratory distress syndrome; MI, myocardial infarction; PEF, pericardial effusion; PEM, pulmonary embolism; PLE, pleural effusion; PNA, pneumonia; Post op, postoperative; RI, respiratory insufficiency; RP, radiation pneumonitis; SAFIB, surgical atrial fibrillation; SPNA, surgical pneumonia; ST, stroke.
FIG 3.
FIG 3.
Kaplan-Meier (A) progression-free survival (PFS) and (B) overall survival (OS) curves between the proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) arms.
See this image and copyright information in PMC

Comment in

References

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    1. Chandra A, Guerrero TM, Liu HH, et al. Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planning for distal esophageal cancer. Radiother Oncol. 2005;77:247–253. - PubMed
    1. Lin SH, Wang L, Myles B, et al. Propensity score-based comparison of long-term outcomes with 3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 2012;84:1078–1085. - PMC - PubMed
    1. Lin SH, Zhang N, Godby J, et al. Radiation modality use and cardiopulmonary mortality risk in elderly patients with esophageal cancer. Cancer. 2016;122:917–928. - PMC - PubMed
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