Finally, RCT Results for Proton Therapy in a Cancer

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 (P =.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.

First Proton Therapy Patient Finishes Treatment at New Mayo Facility

The first Mayo Clinic patient to receive proton beam therapy in Minnesota finished her treatments Monday morning.

Twenty-three-year-old Jessica Brenholt was the first person to receive the treatments for her brain tumor at Mayo’s new Proton Center.

Proton beam therapy is a type of radiation doctors recommend for young people and children because it targets hard-to-reach tumors without damaging other, healthy organs in its path.
After six weeks of treatment, Brenholt walked in for her last session on Monday.

“It’s not as scary as you think it might be,” she said.

Her positive and uplifting attitude goes far beyond tumor treatment.

“I never thought I’d be going through this at 23 but I can’t imagine going through this at eight, like with Evie,” she said of one of her new young friends.

Evie can frequently be found at the proton center, too. Like Brenholt, she is also battling a brain tumor.

“It’s a bond I’ve never had between anyone else in my life,” Brenholt said about her relationships with others receiving the treatment.

“It was awesome!” Evie said about participating in Brenholt’s celebration marking the end of her treatment. Evie still has two weeks to go.

“I’m excited to move on and start my life again but I’m really kind of sad,” Brenholt said about saying goodbye to her new friends. “It’s kind of bittersweet.”

From high fives to hugs, everything about this day is something for patients, like Evie, to look forward to experiencing themselves. Especially the final step: ringing the recovery bell. It sits on a wall near the entrance to the exam rooms. You may not notice it unless, of course, you’re a patient. Then, it becomes all you can see in the waiting room.

The bell signifies the end of treatment and Brenholt chose to ring it with another friend from treatment, Ashley. If there was ever a reason to ring noise through those quiet halls, that was it. The two girls rang the bell together three times, and they both walked out with smiles on their faces.

Beam of Hope.



Beth colorfully compares her first proton therapy treatment session to watching a scene from a science fiction movie unfold around her. Although the pristine white walls and state-of-the-art equipment conjure up images from the future, the technology will soon be a reality on the St. Jude Children’s Research Hospital campus. The hospital is currently building the world’s only proton center dedicated solely to the treatment of children.

Part of a $198 million project to enhance the hospital’s clinical and laboratory facilities, the St. Jude Red Frog Events Proton Therapy Center is slated to open in 2015.

The new center will greatly enhance the hospital’s ability to conduct research optimizing the use of proton therapy in children.

“This facility will enable us to complete important trials while providing the support that only St. Jude can provide to patients,” says Larry Kun, MD, chair of St. Jude Radiological Sciences.

What is proton therapy?

Proton therapy offers tremendous advantages compared to X-ray technology because it is more precise and may be used to deliver a potentially higher dose of radiation to the tumor with fewer side effects. By confining radiation exposure to the tumor itself, the pinpointed therapy reduces a person’s risk of experiencing toxic effects on major organs and of developing secondary cancers later in life.

“It’s exciting to hear that St. Jude is building its own proton therapy center,” adds Beth, who participated in a St. Jude protocol that involved traveling to Florida for treatment.

Beth was found to have a rare brain tumor known as craniopharyngioma when she was a college sophomore. After six weeks of daily proton therapy, which lasted from one to two hours each, Beth’s tumor is now smaller.

“St. Jude has given Beth hope, and that was more than any other therapy could offer,” says Beth’s mom.

Precise treatment

Beth’s doctor, Thomas Merchant, DO, PhD, division chief
of St. Jude Radiation Oncology, says proton therapy represents the next logical step for the hospital as it remains a world leader in the research and treatment of brain tumors and radiation therapy. Proton therapy can deliver high radiation doses directly to tumors while sparing normal tissues and reducing the side effects of traditional X-ray therapy. Proton therapy’s chief advantage is the ability to control its depth and intensity in tissue. The more precise the beam, the more targeted the therapy.

“It’s very important that we deliver precise treatment to children, and we’ve designed our facility in such a way that when it opens in 2015, it will have one of the narrowest beams in the United States,” says Merchant, who toured leading proton centers throughout the world in researching the project.

In addition to treating brain tumors, the new technology will also be used to treat Hodgkin lymphoma and other solid tumors such as Ewing sarcoma, neuroblastoma and retinoblastoma. Treatment sessions may range from 20 minutes to an hour.

“It’s been wonderful to be able to offer the treatment to our patients at the facility in Florida, but it’s a huge challenge for the families to have to uproot again,” says St. Jude social worker Melanie Russell. “When we have our own treatment facility here, it will be so much easier for our families.”

The new tower housing the facility will also include expanded surgical suites, an advanced Intensive Care Unit, the new Computational Biology department and a global education and collaboration center.


MRI visualizes proton dose distribution.

“How can proton therapy not be clinically better than intensity-modulated radiation therapy?” That was the question posed by Thomas Bortfeld, PhD, speaking at the recent European Society for Radiotherapy and Oncology (ESTRO) annual meeting in Barcelona, Spain.

The answer lies in uncertainty over the range of the proton beam, surmised the Harvard Medical School professor of medical physics and director of the physics research division of the Massachusetts General Hospital (MGH) Department of Radiation Oncology and its Francis H. Burr Proton Therapy Center in Boston.

This uncertainty can be reduced by measuring the proton range in vivo. Several techniques are being investigated for this purpose, including dosimetry in body cavities; other possibilities are PET and prompt gamma imaging, which detect secondary particles created as the proton beam travels through the patient. But another option is the use of MRI to visualize the proton dose distribution, by imaging radiation-induced tissue changes, Bortfeld told ESTRO attendees.

The idea is to use MRI to image tissue changes that occur on a molecular level following proton irradiation. The technique has already been successfully used to infer the delivered dose in proton therapy of the spine. Here, irradiation causes the blood-producing bone marrow to be replaced by fat, which shows up as areas of increased intensity in post-treatment MR images.

While this MR imaging method works well for treatment of bony structures, can it be used elsewhere? Bortfeld cited an example in which contrast-enhanced MRI was used to observe changes in liver tissue following brachytherapy.

After treatment, a reduction in contrast uptake was seen in the treated areas of the liver. “We expected to see a similar effect for proton therapy, and we did,” he noted.

Bortfeld described a study performed at Massachusetts General Hospital in which MR images were recorded 2.5 months after five fractions of proton therapy. A reduced signal was seen in central parts of the liver. Contours of the area of signal reduction were in good agreement with the high-dose region in the treatment plan.

Bortfeld’s research group is also trying to understand the underlying molecular process, and believes that radiation-induced and cytokine-mediated changes of the irradiated liver cells disable the active contrast media uptake.

The main advantages of MRI range imaging are better spatial resolution and improved signal-to-noise ratio compared with PET. In comparison with prompt gamma imaging, MRI can offer 3D information combined with anatomical information. The main disadvantage at present is the delay between the start of treatment and the observation of changes in the MR image.

The key question now, therefore, is whether similar changes in MR images can be observed after just a few days of treatment. If this is possible, then small misalignments could be detected between proton fractions and compensated for in later treatments. He said that Christian Richter, PhD; Joao Seco, PhD; and colleagues from MGH are currently running a trial to determine the time point in the treatment process at which such changes can be observed.

Source: Radiation Oncology Digital Community.