Questions Linger for Best Use of Proton Beam Therapy

The medical use of protons is an old idea that has generated a new controversy. The inspiration to use protons is usually credited to James Slater, MD, a radiation oncologist at Loma Linda University Medical Center in Loma Linda, Calif., who was seeking a form of radiation treatment that did not inflict collateral damage to healthy tissues. Traditional radiation therapy uses photons or energy from electrons, the negatively charged particles that orbit around the nucleus of an atom. Once their energy is released (say, by smashing them against a metal plate), a beam can be directed through the body, but not stopped. Everything in its path becomes irradiated.

The energy of proton therapy comes from the positively charged particles (the protons) in the nucleus of an atom. Slater realized that proton energy could be controlled, allowing doctors to deliver radiation into a tumor, and presumably no farther, sparing healthy tissues. He first used the therapy, to treat a woman with melanoma in her eye, in 1990.

“We would be having this discussion regardless, but if it were not for the price of the therapy, it would not be so intense,” says Oliver Sartor, MD, a prostate cancer expert at Tulane University Medical Center in New Orleans. With a price tag that can be as much as $225 million, the apparatus that strips protons from atoms of hydrogen is arguably the most expensive medical device ever made. Yet hospitals and private investors are building more proton centers, with 10 already open (an increase from just three in 2001) and seven more under construction. From a financial perspective, it’s considered a worthwhile investment, because the money to build proton centers today will be recouped tomorrow through generous reimbursements by Medicare and insurance companies.

The problem is, while it is theoretically possible for protons to treat with fewer side effects, this has not been confirmed. In a report published in April in the journal Radiotherapy and Oncology, a team of doctors representing the American Society of Radiation Oncology (ASTRO) reviewed the known evidence comparing proton beam to other forms of radiation.

In addition to pediatric brain and spinal tumors, the experts said, protons appear to be better treatment for tumors around the eye and base of the skull. The committee also noted that proton therapy is more difficult to deliver in tumors that move when a person is being treated, such as tumors in the lungs.

Yet the controversy over proton beam treatment is not just about embracing technology before it’s proven itself (a phenomenon that sometimes occurs in medical practice). The controversy is about whether the benefits from protons, particularly for prostate cancer, warrant the cost.

We would be having this discussion regardless, but if it were not for the price of the therapy, it would not be so intense.

So how much will the increasing popularity of proton treatment cost? That’s hard to say. Although proton beam treatment is recommended for a variety of cancers, almost 75 percent of the Medicare beneficiaries at proton centers are there for prostate cancer. Reimbursements for hospital-based proton therapy are nationally set by Medicare, but most men are treated at freestanding facilities where the rates are set region by region by Medicare contractors.

In Indiana last year, a dose of protons was reimbursed at about $500 to $800 a treatment (depending on the case complexity), but in Florida—where the proton caseload increased from 13 patients in 2006 to 286 in 2009—that range is $930 to $1,100.

There’s no set formula to determine how much Medicare pays for care. Once the Food and Drug Administration clears a medical device for use, insurers are the ones who determine whether to pay and how much, says Jason Caron, a health law attorney and reimbursement expert in Washington, D.C. Proton beams get reimbursed at higher rates because the technology itself is more expensive and complicated—requiring a particle accelerator the size of a football field—and therefore needs particular safety precautions and technical expertise.

Also at play is the fact that medical devices have a much lower standard for approval than drugs, says Sean Tunis, MD, founder and director of the Center for Medical Technology Policy in Baltimore. One device does not need to prove it’s better than another. “From an FDA point of view, many devices are considered as tools,” he says. Since the first proton beam facility was built decades ago, most modern centers are considered “substantially equivalent” by government standards and do not have to conduct studies to validate their medical use. From a public health and payer perspective, “The problem ends up being that we pay more for something because it costs more, not necessarily because it’s better,” Tunis says.

No one denies that protons are better at treating certain cancers, but researchers are still trying to determine whether they are superior treatment for prostate cancer, even as new centers open their doors. In 2009, the Department of Health and Human Services’ Agency for Healthcare Research and Quality (AHRQ), which evaluates medical treatments, called proton beam therapy “promising but unproven” after reviewing more than 200 published studies. Other research reports reached similar conclusions. In the ASTRO report, a team of experts asked whether protons were better than intensity-modulated radiation therapy (IMRT), the current state-of-the-art photon radiation. Their conclusion: “Based on current data, proton therapy is an option for prostate cancer, but no clear benefit over the existing therapy of IMRT photons has been demonstrated.”

The largest single study so far to compare treatments was published in The Journal of the American Medical Association in April. To quantify how they stacked up, researchers from the University of North Carolina (UNC) in Chapel Hill analyzed data on 684 men who were treated with proton beams, comparing their Medicare claims against men treated with IMRT to see how many patients sought later medical treatment or were diagnosed with side effects. Not only did proton beam treatment not fare better, but it also came out slightly worse for side effects involving the intestines.

“People think protons go to the tumor and stop right there,” says UNC’s Ronald Chen, MD, one of the study’s main authors. But, he adds, it’s not that simple. “When protons are used for a deep structure like the prostate, the dose actually does not completely stop at the prostate.”

The advantage of the new data is that the study was large. Yet even Chen points out the drawbacks. Almost all of the proton patients came from just a few centers, so the men most likely had the income and stamina to travel for care. “If they have more resources, they may seek medical attention more readily,” Chen says.

To collect more information, some proton centers are actively encouraging patients to become part of a registry that will follow their progress. The best data, however, may come from a clinical trial just now getting off the ground, which will be the first direct comparison of protons to IMRT. Researchers from the Massachusetts General Hospital and the University of Pennsylvania are starting a randomized phase 3 clinical trial—considered the gold standard of medical research.

“The current economic climate is a huge factor in driving this question,” Vapiwala says. “Why wasn’t this research done years ago? It’s only coming up now because of the financial implications.” The study is not asking whether protons are superior treatment for prostate cancer; in early, low-risk disease, prostate cancer is highly curable with modern radiation, regardless of the type. The main question will be about side effects.

In the new trial, men will be randomly assigned to receive either proton treatment or IMRT and then followed to see how they do. One of the challenges will be finding men who will participate, chancing that they might not get protons when Internet searches and word of mouth has already convinced them that protons are the way to go.

“We are in an era where people go to the Internet and other media and come in with preconceived ideas,” Vapiwala says. She hopes to get participation by appealing to a patient’s sense of altruism. “This study will try to obtain information that could guide the decisions of patients in the future. It’s for the greater good.”

Almost no one expects the proton building boom to wait for science to catch up. An analysis published in January by the AHRQ found that, although fewer than 1 percent of men with prostate cancer are treated with proton therapy, that number is expected to rise as new centers bring the treatment to more backyards. In an analysis called “Proton Beam Therapy and Treatment for Localized Prostate Cancer: If You Build It, They Will Come,” researchers from California found that the closer men lived to a proton center, the more likely they were to choose protons.

If it is superior, is it really that much more superior, and for whom?

Since then, proton therapy has been tried in a variety of cancers and now appears promising for many types of tumors, such as certain neurological tumors. It’s particularly useful in pediatric cancers, in part because radiation to healthy tissue in adults could have far fewer medical consequences than radiation to children. One of the biggest fears with radiation is that it could induce malignancy in normal tissue. But this process could take decades to appear. A man in his 80s receiving treatment for prostate cancer may be destined to develop a secondary cancer from radiation, but he’s not likely to live long enough for the cancer to cause any health problems. For a 5-year-old child, the risk may be more significant.

Because a child’s tissue is still growing, especially in the brain, it’s “much more sensitive to the effects of radiation than adult tissue,” says Neha Vapiwala, MD, chief of genitourinary service at the University of Pennsylvania’s Radiation Oncology. “With prostate cancer, an incremental benefit may not be as dramatic.”

But it is among men with prostate cancer that protons are gaining popularity, landing proton therapy in one of the most heated controversies to grip radiation oncology. The claim that proton therapy may be more effective or have fewer side effects compared with conventional external radiation has not yet been established through the gold standard of randomized clinical trials.

However, given the high number of patients at these crossroads, in part due to the rapid adoption of prostate-specific antigen (PSA) screening, the stakes are much higher. Despite the lack of evidence, Medicare and insurance companies started reimbursing for prostate cancer treatment with protons at a much higher rate than standard treatment, creating a cottage industry of proton centers.

Although payment varies across the country, a dose of the most advanced form of traditional radiation receives about a third of the reimbursement of a dose of protons. And because prostate cancer generally requires six to eight weeks of treatments, a man with prostate cancer will bring more revenue to a proton center than a patient with a cancer requiring fewer sessions. All of which means that proton therapy in prostate cancer, fairly or not, has become another example of the excesses of U.S. medicine.

If studies do find that proton beam treatment is better for certain kinds of tumors, a still more uncomfortable question awaits: How much better justifies the price?

“If it is superior, is it really that much more superior, and for whom?” asks Joseph Herman, MD, a radiation oncologist at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

Because so much of the debate is over money, proton treatment has forced many doctors and patients into uncomfortable territory, Herman says. All doctors and patients want the best, but when the differences between treatments are not dramatic, the price of therapy is a legitimate consideration, he says.

The irony is that, although most doctors agree that protons probably offer an advantage for children, parents and doctors of pediatric patients can sometimes find their insurance coverage battles to be much greater than adults, says Susan Ralston of Virginia Beach, Va., founder and executive director of the Pediatric Proton Foundation. Five years ago, Ralston’s then 2-year-old son developed Ewing’s sarcoma on his spine, making him unable to stand. After fighting to obtain proton treatment for him—ultimately threatening to take the insurer to court—she formed the foundation to help other parents.

Proton therapy, Ralston says, “has turned into a prostate debate.” Yet she acknowledges that it is the revenue from men with prostate cancer that makes treatment available to less profitable patients, like children.

“I worry that if the prostate cancer battle isn’t won quickly with scientific evidence, business will slow down and our children won’t get treated.”