Uncertainty About Proton-Beam Radiotherapy Lingers

Roxanne Nelson

January 30, 2013

Proton-beam radiotherapy (PRT) is much more expensive than conventional radiotherapy, but is it any better? The question is unanswered because few studies have compared the 2 directly.

The main claim is that PRT is safer than conventional radiotherapy.

"Proton therapy gives us a better dose distribution, so there is less harm to healthy tissue," William Hartsell, MD, medical director of ProCure's Proton Therapy Center in Chicago, Illinois, told Medscape Medical News. "This therapy is particularly valuable in children," he explained, because radiotherapy can be quite damaging and have long-term effects in this population.

Because proton treatment is so much less damaging to normal tissue, the course of treatment can be compressed, he added.

It is being used in a variety of adult malignancies, including tumors of the brain, central nervous system, head and neck, lung, and prostate. "The precision of proton therapy has made it possible to reach tumors at the base of skull and along the spinal cord, which are very difficult to treat," said Dr. Hartsell. "We are able to effectively treat more of these patients now."

Increasing Use of Proton Therapy

The first proton accelerator for medicinal use was located at Loma Linda University in California in 1990. There are currently 10 centers in operation in the United States and 9 in various stages of development, according to the National Association for Proton Therapy. By mid-2008, almost 20,000 patients had been treated with PRT in the United States, and more than 30,000 had been treated globally.

There are centers in China, Japan, and in several European countries, although there are still only about 40 worldwide, Dr. Hartsell noted. "But there has been substantial growth over the past decade, and we may be looking at 50 or even 70 centers in the next 10 years."

However, the increasing interest in PRT has been criticized. In an opinion piece published in New York Times last year, Ezekiel Emanuel, MD, an oncologist and former adviser to President Barack Obama, criticized the Mayo Clinic for building 2 proton-beam facilities, at a cost of more than $180 million each. He referred to it as being part of a "medical arms race," and noted that PRT, which costs taxpayers billions of dollars, has not been proven to be better than less expensive options for many patients.

It is "crazy medicine and unsustainable public policy," he wrote.

The higher price would be worth it if PRT cured more people or significantly reduced adverse effects. But to date, the evidence is not there, save for a "handful of rare pediatric cancers," such as brain and spinal cord cancer, he explained.

"For children, the treatment does a better job of limiting damage to normal brain cells and reducing the risk of cognitive impairment and hearing loss," Dr. Emanuel wrote. However, fewer than 3500 children are diagnosed with these cancers each year. It is impossible to keep the "existing proton-beam centers in full use, much less the approximately 20 others in planning or construction, with so few patients."

This is why patients with other types of cancer, most notably that of the prostate, have been targeted, he noted.

Requires Huge Investment

A huge investment is required to establish a PRT center; $25 million to $150 million is needed for equipment and the construction of a suitable housing facility.

In comparison, acquisition costs for intensity-modulated radiation therapy (IMRT) systems are much cheaper (from $1.8 million to $5.4 million), according to a 2009 report by the Institute for Clinical and Economic Review (ICER) on management options for low-risk prostate cancer.

The ICER report found that the average lifetime cost for a 65-year-old man with localized low-risk prostate cancer was $43,122 for IMRT and $59,979 for PRT. Medicare reimbursements range from ~$10,000 for brachytherapy and radical prostatectomy, to $20,000 for IMRT, to $50,000 for PRT.

Misalignment of Incentives?

From a patient's point of view, convenience can be a deciding factor. David S. Aaronson, MD, a urologist at Kaiser Permanente Medical Group in Oakland, California, and colleagues found that men diagnosed with localized prostate cancer were more likely to be treated with PRT if the technology was available nearby (Arch Intern Med. 2012;172:280-283).

That team evaluated the treatment choices of nearly 20,000 men living inside and outside the regional market for Loma Linda University. Nearly 9% of the patients living within the referral region received PRT, compared with less than 2% of patients living outside the region.

"As in most business models, if you have excess capacity...and your overhead is high, you will look for ways of doing more procedures," Dr. Aaronson told Medscape Medical News.

"If we are going to get serious about bending the growth curve of healthcare expenditures in the United States, this type of thing must stop," he explained. "We need to improve reimbursement for active surveillance as a treatment for low-risk prostate cancer so that we can reduce overtreatment of the disease in this country," he explained.

"In the United Kingdom, they are building a proton-beam facility, but with strict rules prohibiting its use in the treatment of prostate cancer," he noted.

Targeting Prostate Cancer

Although the use of PRT is being studied in other cancer types, it is in prostate cancer that the technique appears to be gaining the most popularity and generating the most controversy. Comparative studies have not yet shown the benefit of PRT over other types of radiotherapy used in prostate cancer treatment; in fact, one study suggested that it is more toxic than IMRT (JAMA. 2012;307:1611-1620).

That study found that PRT did not significantly improve outcomes in prostate cancer patients, compared with IMRT and conventional conformal radiation therapy. IMRT also had a lower rate of gastrointestinal (GI) morbidity than PRT (absolute risk, 12.2 vs 17.8 per 100 person-years).

Older conformal radiation therapy was initially used to treat prostate cancer; then came IMRT, a more costly technology. "Today, proton radiation is receiving a lot of attention as a new way to treat prostate cancer," said Ronald Chen, MD, MPH, assistant professor of radiation oncology at the University of North Carolina at Chapel Hill, who presented highlights of a study comparing the 3 approaches at the 2012 Genitourinary Cancers Symposium.

In that study, he and his colleagues concluded that IMRT should be the current standard radiation technique for prostate cancer.

"Currently, there is no clear evidence that proton therapy is better than IMRT. Further comparative-effectiveness research is needed to examine patient outcomes with proton radiation and IMRT," he explained.

Another comparison trial found the opposite effect (Int J Radiation Oncol Biol Phys. 2012;84[3 Suppl 1]:S13). In that study, PRT was associated with better early GI quality of life than 3D conformal IMRT. However, 24 months after treatment, bowel quality-of-life scores were similar.

Nancy Mendenhall, MD, from the University of Florida in Jacksonville, presented those data at the 2012 annual meeting of the American Society of Radiation Oncology (ASTRO), and suggested that PRT is highly effective and has minimal rectal toxicity in patients with early- and intermediate-risk prostate cancer.

"At 3 years, biochemical progression-free survival is 99%, and there have only been 2 grade 3 GI toxicities," she explained. "There was an extremely low toxicity rate and...an extremely high disease-control rate, so the therapeutic ratio for [PRT] is extremely high."

Dr. Mendenhall and colleagues found that disease progression occurred in 1 of 89 low-risk patients and in 1 of 82 intermediate-risk patients.

In another ASTRO presentation, Andrew Lee, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues found that the 1090 prostate cancer patients treated with PRT experienced a high quality of life 1 year after the end of treatment.

"We found no significant difference between those treated with proton therapy and the controls without prostate cancer in terms of urinary and bowel quality of life," said Dr. Lee. He pointed out that there were differences in the sexual domain, primarily driven by men who were older, had received hormonal therapy, and had higher Gleason scores.

"This body of data reconfirms what we know," Dr. Lee explained, "but now we are hearing it from patients who have gone through the treatment."

A third study presented at ASTRO evaluated toxic effects in prostate cancer patients. The researchers found that both genitourinary and GI function appeared to be stable in patients as early as 3 months after treatment. There was no decline seen in the 2 years after treatment, although there appeared to be a slight decline in sexual score in men who did not receive androgen-deprivation therapy.

But No Long-Term Benefits?

The long-term benefits of PRT have not yet been shown in comparative trials. A recent study compared patterns of use, cost, and early toxicity in Medicare beneficiaries with prostate cancer treated with PRT and IMRT (J Natl Cancer Inst. 2013;105:25-32).

In addition to the substantial difference in cost, the researchers, led by James B. Yu, assistant professor of therapeutic radiology at Yale University School of Medicine in New Haven, Connecticut, found "a transient benefit in terms of genitourinary toxicity."

"The events from proton radiation are better, but just transiently so," he told Medscape Medical News.

There was no statistically significant difference in GI or other toxic events 6 or 12 months after treatment, which should be considered in conjunction with the fact that per patient Medicare reimbursement for PRT is 1.7 times that of IMRT, note Dr. Yu and colleagues. The median reimbursement was $32,428 for PRT and $18,575 for IMRT.

"For prostate cancer, I'm not sure we know" whether proton therapy is worth the cost, Dr. Yu said. "For other cancers, particularly pediatric cancers, proton therapy is very valuable, and I do believe it is worth the cost."

Dr. Yu and colleagues note that the "relative reimbursement of new medical technologies needs to be considered carefully so that physicians and hospitals do not have a financial incentive to adopt a technology before supporting evidence is available."

Currently, most patients are treated with standard therapies, but Dr. Hartsell believes that during the next 5 to 10 years, the cost of PRT is going to decrease. "We don't think it's the solution for everything or for everyone...but in certain circumstances, it is the best therapy, and we want to do what is best for patients," said Dr. Hartsell.

At the Proton Therapy Center where Dr. Hartsell works, 6 clinical trials, including 1 evaluating PRT in children with specific brain cancers and 3 evaluating it in men with prostate cancer, are now underway.

But at least 1 major medical center is bucking the trend. The Oregon Health and Science University in Portland has decided that it will not to build a proton-beam therapy center. After careful consideration, the plan to develop one was nixed, as previously reported by Medscape Medical News.