In a First, Proton Therapy Bests Radiotherapy in an RCT

Less Toxicity in Esophageal Cancer

Nick Mulcahy

July 28, 2020

In a first, proton beam therapy has demonstrated significantly reduced toxicity when compared with conventional radiotherapy in a randomized controlled trial (RCT) in patients with esophageal cancer.

The results, from 107 evaluable patients, were published online July 25 in the Journal of Clinical Oncology.

Proton therapy significantly reduced the total toxicity burden (TTB), a coprimary endpoint, report the study authors, led by Steven Lin, MD, of the University of Texas MD Anderson Cancer Center in Houston.

However, the investigators of the single-center trial acknowledge that the better toxicity outcome is accompanied by a caveat: TTB, which combines 11 adverse effects, was not a previously validated endpoint.

Efficacy was similar. Proton therapy and intensity-modulated radiotherapy (IMRT) had nearly identical 3-year rates of progression-free survival (50.8% vs 51.2%), the other coprimary endpoint, as well as overall survival (44.5% vs 44.5%). Median follow-up was 44.1 months.

Quality of life outcomes were also not significantly different in the phase 2B trial, which was underpowered due to protocol anomalies, including 22 patients who were randomized to proton therapy but then denied insurance coverage, and thus participation in the trial.

Lack of validation of TTB "dampens the enthusiasm of a positive primary endpoint," writes Charles Simone, MD, of the New York Proton Center and Memorial Sloan Kettering Cancer Center, New York City, in an accompanying editorial.

TTB encompasses seven postoperative complications measured up to 30 days after surgery (such as reintubation) and six toxicities measured up to 12 months from randomization (such as pleural effusion and radiation pneumonitis); two of the adverse events — atrial fibrillation and pneumonia — were included in both categories, depending on the timing of the event.

The posterior mean TTB, which is a synthesis of the cumulative severity of adverse events, was 2.3 times higher for IMRT (39.9) than for proton therapy (17.4), the investigators report. 

Simone believes the TTB measure — and associated significant reduction in events with protons compared to IMRT in the current study —  has value, especially in "high-stakes malignancies" such as esophageal and lung cancers.

"They are two of only a few cancers where there is an expected mortality rate from treatment," he told Medscape Medical News. "For proton therapy to reduce those toxicities [measured by TTB in esophageal patients] may be a real benefit."

Asked for independent comment, Mark Langer, MD, IU Health Simon Cancer Center, Indiana, Indianapolis, said "the novel TTB was well put together and is a credit to the investigators."

He explained that the esophagus is typically the focus of complications, but that events like atrial fibrillation are important because the esophagus runs down to the stomach and passes by the lungs and heart. "The investigators call attention to morbidities that we may not have previously recognized," said Langer, a radiation oncologist who does not use protons, as Indiana does not have a unit.

Reduced toxicity is the main claim for superiority for proton therapy over conventional radiotherapy, but to date there has been little clinical evidence.

For example, a randomized trial in inoperable lung cancer published 2 years ago showed that proton therapy was not superior in reducing serious lung toxicity compared with IMRT.

"That trial really disillusioned a lot of people," Simone commented.

But he points out that protons have been found to be superior compared with photon radiation in terms of toxicity in a variety of observational studies, including multicenter retrospective comparative analyses.

Trial Closed Early

The RCT conducted by Lin and colleagues, which began in 2012, randomly assigned 145 patients with newly diagnosed locally advanced esophageal cancer to one of the two modalities (72 IMRT and 73 proton therapy). The investigators allowed a wide variety of patients, including those with ECOG performance status 2, differing tumor locations, squamous cell and adenocarcinoma histologies, and unresectable and potentially resectable cases. However, only 107 patients were evaluable (61 IMRT and 46 proton therapy), as the trial did not report on those afore-mentioned patients denied insurance coverage for proton therapy after randomization and those patients in the IMRT group who refused that treatment and wanted proton therapy.

Patients received 50.4 Gy (CGE) with concurrent chemotherapy and 51 patients underwent surgery, generally 8-10 weeks following chemoradiation.

The full list of adverse events for the TTB measure for toxicities was atrial fibrillation, myocardial infarction, pericardial effusion, pleural effusion, pneumonia, and radiation pneumonitis. For post-op complications, the list was acute respiratory distress syndrome, anastomotic leak, atrial fibrillation, pulmonary embolism, reintubation, stroke, and pneumonia.

The most common toxicity was pleural effusion (in 24 patients on IMRT and 13 on proton therapy). The most common post-op complication was atrial fibrillation (in seven patients on IMRT and two on proton therapy).

Simone points out that combining these adverse events in the TTB measure allowed a relatively small number of participants and events to show statistically significant results "without statistically apparent differences for [some] individual events."

The investigators highlight the fact that 80% of patients in the proton group received passive scattering proton therapy, an older technology that increases normal tissue exposure relative to more modern intensity-modulated proton therapy.

The trial closed early because of the start of the phase 3 NRG-GI006 trial. The stoppage was just before the preplanned third and final interim analysis, which would have exceeded the trial's stopping boundary (due to a positive result for TTB).

"The now-activated NRG-GI006 phase 3 randomized trial should prove to be the gold standard comparison of protons versus IMRT for esophageal cancer," writes Simone in his editorial.

The trial was supported by National Cancer Institute. Multiple study authors have financial ties to industry, including radiation therapy manufacturers. Simone has reported financial ties to Varian Medical Systems. Langer has reported no relevant financial relationships.

J Clin Oncol. Published online July 25, 2020. Study, Editorial

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday, and had bylines in the, MSNBC, and Yahoo. Reach him by email and follow him on Twitter.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.