Nick Mulcahy

June 21, 2016

CHICAGO — For the first time, there are final results from a randomized controlled trial that compares the much-hyped proton-beam therapy with conventional radiotherapy.

But the data are disappointing.

Overall, the expensive therapy was as effective as conventional therapy for the treatment of lung cancer, but was no less toxic, according to results presented by lead author Zhongxing X. Liao, MD, from the M.D. Anderson Cancer Center in Houston, here at the American Society of Clinical Oncology 2016 Annual Meeting.

Proton therapy should remain experimental in this setting, said Martin Edelman, MD, from the University of Maryland Greenebaum Cancer Center in Baltimore, who discussed the study during a Highlights of the Day session.

"Radiation oncologists have the same obligation as medical oncologists," Dr Edelman pointed out. "A technology, like a drug, should not be adopted until its benefits are demonstrated."

He also criticized the use of proton therapy outside of clinical trials: "Given the costs, are we really choosing wisely with this approach?"

The study was conducted at M.D. Anderson and the Massachusetts General Hospital Cancer Center in Boston, which are two of the 11 proton centers currently operating in North America. However, 13 more centers are in development.

"Proton centers are springing up like mushrooms after a rainstorm. Or, one could say, metastasizing across the country," said Dr Edelman. The centers are "almost unheard of" in other countries around the world, he reported.

Nevertheless, he congratulated the Boston and Houston radiation oncologists for conducting the challenging Bayesian study of 255 patients with locally advanced non-small-cell lung cancer (NSCLC).

The patients were assigned to receive either 3D proton therapy or standard intensity-modulated radiation therapy (IMRT).

Patient characteristics were well balanced in the two groups, but target volumes were larger in the proton therapy group than in the IMRT group (=.071), and more patients in the proton therapy group received higher doses to tumors and had larger lung volumes receiving at least 30 to 80 Gy.

For patients with "larger" tumors, there were more 74 Gy doses delivered in the proton therapy group than in the IMRT group (75.4% vs 63.0%; P < .001).

The primary outcome — treatment failure — was defined as radiation pneumonitis of at least grade 3 or local recurrence within 12 months. There were no significant differences between the groups for these criteria, either alone or in combination.

No differences were found between IMRT and 3D proton therapy.

In fact, "no differences were found between IMRT and 3D proton therapy in treatment failure in this randomized trial," Dr Liao and her colleagues report.

In addition, proton therapy did not outperform IMRT in terms of overall survival.

There has been an ongoing search for a way to increase the radiation dose in locally advanced lung cancer because about 30% of initial relapse in these patients is local/regional, Dr Edelman explained.

The current standard of care for locally advanced NSCLC — "established many years ago" — is concurrent chemoradiotherapy, he pointed out. At the time, data showed that platinum-based chemotherapy plus radiation 60 Gy was the "way to go."

Then, in the landmark RTOG 0617 trial of conventional radiotherapy, it was shown that mortality was worse the high-dose group (74 Gy) than in the low-dose group (60 Gy), and the increase appeared to be related to irradiation of heart, he said.

IMRT allows radiation to be shaped to the irregular edges of tumor. "That's our current modern approach," which is "a vast advantage" over the older approaches, Dr Edelman noted.

"But there is still a great deal of scatter [with IMRT] to the adjacent structures, including the lungs and heart, and therefore there is a greater risk of cardiac damage, as well radiation pneumonitis," he pointed out.

The question of whether doses to primary tumor/regional lymph nodes can be increased without damage to adjacent structures persists.

"The answer to this may be — perhaps — proton therapy," Dr Edelman said.

Although mean doses to the lung and esophagus were equivalent with proton therapy and IMRT, Dr Liao's team reported, there was a significant reduction in mean dose to the heart area with protons.

Still, this randomized clinical trial indicates that proton therapy does not improve treatment failure rates or overall survival.

An Observational Study, Considered and Dismissed

During the same session, results from another study on the treatment of NSCLC — comparing proton therapy with conventional photon therapy — were presented.

Madhusmita Behera, PhD, from the Winship Cancer Institute at Emory University in Atlanta, and her colleagues used the National Cancer Data Base to identify patients with NSCLC (any stage) who were treated from 2004 to 2012. They found about 140,000 patients treated with various forms of photon therapy and 346 patients treated with protons.

"Who got protons? To be very simple, rich white people," Dr Edelman explained.

The researchers found "some advantage" with protons, but, Dr Edelman cautioned, "keep in mind the small numbers."

On multivariate analysis for matched patients, the risk for death was higher with conventional photon therapy than with proton therapy (hazard ratio, 1.24; 95% confidence interval, 1.03 - 1.49; P < .024). However, there was no propensity matching specifically for stage III lung cancer, which is locally advanced disease.

The results are "interesting," said Dr Edelman, but he promptly dismissed them in light of the higher standard of evidence provided by the prospective clinical trial results from Boston and Houston.

Dr Liao has disclosed no relevant financial relationships. Dr Edelman reports financial relationships with multiple pharmaceutical companies, Hospira, and Biomarker Strategies.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstracts 8500 and 8501. Presented June 5, 2016.

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