From the Journals

In a first, proton therapy bests radiotherapy in an RCT

Less toxicity in esophageal cancer


 

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.

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