A closer look

Proton Therapy for Cancer: A New Technology Brief

Of the estimated 1.47 million Americans who will be diagnosed with cancer in 2009, 60 to 75 percent will undergo radiation therapy for their disease. In select cities around the country, some of these patients who are hoping to improve their odds for a cure and minimize the long-term adverse effects of radiation therapy will be treated with a relatively new form of it called proton therapy.
The cyclotrons that generate proton beams for treating patients are huge, expensive machines, requiring more than 90,000 feet of space and costing hundreds of millions of dollars. But several companies are working on smaller, less-expensive models that may soon make proton therapy available for many more patients around the country and make it easier to recruit patients for randomized controlled trials that compare effectiveness.

Public interest in proton therapy has grown substantially since the FDA approved it in 2001. However, there is concern among members of the medical and research communities that enthusiasm for this promising therapy may be getting ahead of the research.

“Proton therapy has wonderful potential as a treatment for some cancers,” said Dr. Kevin Camphausen, chief of NCI’s Radiation Oncology Branch, who has referred patients to be evaluated for the treatment when he felt it might work well for their tumor type. “But I don’t think its use should become widespread until we can validate where it’s needed, and where it has the greatest potential benefit for patients.”

The first proton accelerator dedicated to medicine opened at Loma Linda University in California in 1990. Today, a total of seven proton therapy centers in the United States are treating patients and numerous others are under construction or in the planning phase. The treatment is being used most often in children with many cancer types, as well as in adults who have small, well-defined tumors in organs such as the prostate, brain, head, neck, bladder, lungs, or the spine. Proton therapy centers are continuing to test its use for additional cancers.

These images show the difference in tissue exposure with standard radiation therapy (left) and proton therapy (right), using intensity-modulated treatment. Areas of red received higher doses, while those in blue and violet received low doses. The overall area exposed with standard radiation is much larger than that exposed with proton therapy.

Better Precision, but What about Accuracy?

When x-rays are fired at a tumor, because they have no charge, they transfer their energy at an evenly decreasing rate to the healthy tissues between the surface of the body and the target, as well as to the tissues beyond the tumor, until they exit the body.

Proton beams, on the other hand, have a positive charge and deliver most of their energy at a defined depth, within a region called the Bragg Peak, like a depth charge delivered to its calculated destination. When the target is hit, healthy tissues are largely spared side effects from treatment and there is greater damage to the tumor. This may diminish the chance of it coming back or of new tumors in the surrounding tissue arising later on.

“Theoretically, proton beams are much more exact than x-rays,” said Dr. Norman Coleman, associate director of the Radiation Research Program (RRP) at NCI. “On the computer screen, the calculations look great, and the enthusiasm is understandable. But is that what’s really happening in the patient?”

There is no published evidence to indicate that proton therapy is detrimental to patients, Dr. Coleman said, but “when you have something that is so precise with such sharp edges, you need to make sure that it’s also accurate. This requires being certain that the target is hit as planned on the computer, including accounting for the uncertainties in diagnostic imaging, reproducibility in patient setup, and internal organ motion.”

Dr. Bhadrasain Vikram, who is chief of the Clinical Radiation Oncology Branch in RRP, noted that those who administer proton beams to patients are fairly confident of the width of the beam, but as for the final stopping point, “there is some nervousness that what they’re seeing on the computer screen may not be happening in the patient.” So for tumors in front of the spinal cord, for example, they will align the proton beam sideways during treatment to minimize the risk of the beam going too far and damaging the neural tissue, he explained.

Assessing the Value for Patients

Experts at NCI and around the country also point out that there is a lack of published randomized controlled trials (RCT) to show that proton therapy works better than standard radiation therapy at increasing survival or improving quality of life for patients.

Dr. Nancy Mendenhall, medical director at the University of Florida Proton Therapy Institute in Jacksonville, explained that while her institution is committed to learning more about the best uses of proton therapy through clinical research—since the facility opened in 2006, approximately 1,500 patients have been treated there, she said, and 95 percent were enrolled in an observational study—there are numerous practical and ethical barriers to conducting an RCT with proton therapy.

“Proton therapy is a rare resource; less than 1 percent of patients in this country have access to it,” Dr. Mendenhall said. This is because there are so few centers that provide it, and they can only treat a limited number of patients in a day, she explained. The University of Florida Proton Therapy Institute has three proton therapy rooms where between 110 and 120 patients are treated per day.

“It would likely take 800 or more patients to complete enrollment for one arm of an RCT, but with the same number of patients and time interval, 4 pilot studies could be completed that would advance our understanding of the potential of proton therapy for dose escalation, dose intensification, and hypofractionation, which are our basic radiation therapy methods of increasing disease control,” she said. “We believe we have approached these limits with x-ray therapy, but not with proton therapy. We have already completed three pilot studies and feel it is important to continue such studies to learn how to maximize the potential of proton therapy.”

Furthermore, she explained, most of the people who come to Florida for proton therapy would not accept being randomized to the control group in a clinical trial. “These are a very special group of patients who are extraordinarily well informed. They’ve researched the treatment, they understand the technology, and they’ve decided that it’s best for them,” she said, adding that in many cases they have also traveled thousands of miles to get it.

Dr. Mendenhall believes that for now, comparing the outcomes of proton therapy with previously published studies of x-ray therapy should be sufficient, until the treatment capabilities of proton therapy have been explored more, there are more treatment slots available, and there is more confidence in the technology and tools that are used to assess outcomes for the comparison group.

The Ultimate Test: Head-to-Head Comparison

The position of those at NCI is that, while this technology is very promising, the gold standard for research is still an RCT. “We would encourage patients who are looking into proton therapy for their particular disease to seek out an NCI-sponsored clinical trial at one of the facilities that provides the treatment,” said Dr. Vikram.

At the University of Texas M.D. Anderson Cancer Center and Massachusetts General Hospital, more of these trials will soon be available due to a major P01 “Research Project Program” grant from NCI to fund their collaborative RCT studies of proton therapy for lung cancer and pediatric cancers, as well as technology development.

Studies are also under way through the Children’s Oncology Group, noted Dr. James Deye, program director of medical physics in RRP. To ensure that data can be compared across institutions, he added, RRP recently published guidelines for the clinical trials that it sponsors.

In the midst of the national discussion of health care reform, proton therapy may soon start to gather attention for another reason: its suitability for comparative effectiveness research.

“Radiologists and radiation oncologists accumulate electronic data easily; it’s just part of the way that we go about our daily business,” said Dr. Coleman, who explained how the field is particularly ripe for doing comparative effectiveness research with proton therapy, as well as other emerging radiation therapies, such as carbon ion therapy.

“We have the images and the data right in front of us,” he said. “If we add outcomes to that, then we have a lot of good information about whether something new actually works better in the long run than what we were already using.”