Roxanne Nelson

June 20, 2013

CHICAGO — Proton therapy is an alternative to conventional radiotherapy for cancer patients, but is much more expensive. As proton therapy centers continue to open in the United States and around the world, the debate continues about whether proton therapy really offers any advantages.

Proton radiotherapy "sells hope," but there is no "clear measurable benefit that we can actually translate and explain to a patient," said Frank H. Saran, MD, from the Royal Marsden NHS Foundation Trust in the United Kingdom.

There are currently no proton facilities in the United Kingdom, but one is expected to open in 2014. In the United States, there are already 11 such facilities, which treat an ever-increasing number of patients.

"I think you've been spending money on something that, at the moment, doesn't deliver. It may deliver in the future, but that will probably be after my retirement," Dr. Saran told his American colleagues during an education session here at the 2013 Annual Meeting of the American Society of Clinical Oncology(ASCO®).

In a debate about the value of proton therapy, Dr. Saran was on the con side.

On the pro side was Anita Mahajan, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, where proton therapy has been used since May 4, 2006.

The Case for Proton Therapy

Dr. Mahajan highlighted the fact that there are fewer toxic effects with proton therapy than with conventional radiotherapy, especially in pediatric cancer patients.

Conventional radiation therapy can lead to long-term toxic effects, especially in growing children, she explained. "There can be effects on all of our developing organs and on sensitive structures, including the heart, the lungs, the gonads, the eyes, the eyes, and the kidneys," she said. "And, of course, there can be the risk of secondary neoplasms."

The risk for thyroid malignancies escalates in children younger than 10 years of age, even at doses of 10 Gy. "Some people suggest that any dose to the thyroid gland increases that risk," Dr. Mahajan said.

One of the ways to reduce the toxicity of treatment is to decrease the irradiated volume. Proton therapy, she argued, is one of the most effective ways of doing that because it delivers the dose to the tumor but limits exposure to surrounding tissue. "There is less dose on the way in and less dose on the way out," she noted.

Dr. Mahajan illustrated her point by describing the "very vulnerable children" treated for retinoblastoma at her institution. Even with the most advanced conventional radiotherapy — intensity-modulated radiation therapy (IMRT) — there is a "splash of radiation everywhere," she explained. With proton therapy, "the radiation is really restricted to the orbit itself."

"If I was to treat a child who has an excess risk of a secondary tumor, I might consider electrons or protons," she explained.

She also described the treatment of genitourinary tumors. "With IMRT, you get the same dose to the tumor but you get more radiation to the rest of the pelvis," she explained. "With protons, the main thing here is that you can reduce the dose to surrounding tissue that could be developing and is at risk for side effects."

Certain areas of the body are more at risk than others, even at low doses of radiation, especially in children. Cataracts can form after exposure to just 1 to 2 Gy, and bone growth can be affected by exposure to 10 to 25 Gy, she noted. The gonads and kidneys are also sensitive to the effects of radiation. Exposure of the testes to 2 to 3 Gy leads to azoospermia and possibly permanent infertility. "So even a very low dose can have significant consequences down the road," Dr. Mahajan explained.

Proton therapy can be beneficial for tumors in the thorax region. She pointed out that IMRT delivers a longer dose to the contralateral lung in adults with lung cancer. "With the proton approach, you can restrict it to the ipsilateral site and you might be able to save some lung function."

Dr. Mahajan described a girl with Hodgkin's lymphoma who had a distribution in the upper mediastinum and the low neck and was treated with proton therapy. "With nice distribution, we were able to spare a lot of her lung. Her thyroid gland did get some radiation but, importantly, her breast tissue got very little," said Dr. Mahajan. "Knowing that these girls are at risk, we can reduce the risk with this therapy," she said.

Candidates for Proton Therapy

Who are the good candidates for proton therapy?

Patients who need a relatively high dose of radiation therapy are, said Dr. Mahajan. "There's no point in this for someone who needs 10 Gy because the benefits will be hard to measure," she said.

Those with tumors that are engulfed in a sensitive organ or tumors that are centric in the body cavity, like iliac tumors in Ewing's sarcoma, are also candidates. In general, children are good candidates, given their vulnerability to late affects and their risk for a secondary malignancy later in life, she noted.

Dr. Mahajan acknowledged that there are practical issues that need to be addressed. Many countries do not have the resources to support a center, which limits the availability of proton therapy. To equip and construct a suitable proton center can cost $25 to $150 million.

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

In addition, proton therapy is far more expensive than any of the other radiation therapies. Some data show that the median Medicare reimbursement for prostate cancer treatment was $32,428 for proton therapy and $18,575 for IMRT.

In the United States, medical insurance does not always cover it, and treatment can take a lot longer and can involve more complex planning. "IMRT is a very good solution in certain situations," she said.

Dr. Mahajan pointed out that the cost of technology tends to decline over time. For instance, in 1983, cell phones cost $4000; now a smartphone can be purchased for under $500. "As technology develops, it will get become less expensive," she predicted. "Industry is interested in what we are doing, and they will make it more practical and more affordable as time goes by."

The Case Against Proton Therapy

Whereas Dr. Mahajan talked about the future, "I am going to talk about what is happening today," Dr. Saran told the audience.

In a talk that was infused with more than a bit of dry humor and wit, Dr. Saran pointed out that Dr. Mahajan used very select and well chosen cases to make her point. But in practical terms, pediatric cancers constitute about 1% of all cancers diagnosed each year; of those, 35% are pediatric patients with noncentral nervous system (CNS) malignancies.

Dr. Saran acknowledged that there is some evidence to suggest that proton therapy has an advantage over conventional radiotherapy for pediatric CNS tumors. In fact, the United Kingdom has been sending some of these patients across the Atlantic to be treated at proton facilities in the United States.

However, he pointed out that if the main advantage of photon therapy is in pediatric patients with CNS tumors, then only about 1400 patients per year in the United States would be candidates, about enough to fill the volume of 1 facility.

"On paper, proton therapy looks very elegant and is tissue-sparing and highly precise, but there are always a few things that people tend to drop from the discussions," he said. "There are still some medical uncertainties."

Dr. Saran believes that there are really "no clinical data to suggest that protons are superior to photons for pediatric indications."

"Over the past decade, there has been a steady increase in evidence bases and publications relating to proton therapy," he said. However, that is "just dwarfed" by the data that exist for conventional radiotherapy, he said.

Although the radiation dose delivered by proton therapy is lower, the benefit of that is unclear. He noted that some problems unique to proton therapy are not problematic with conventional radiotherapy, such as if a patient's body weight changes during the course of treatment. With proton therapy, this can lead to a complete change in the treatment plan. In addition, there are simpler methods to avoid excess radiation to neighboring tissue, such as the use of a spacer to move the gut away from a tumor prior to treatment.

But the primary drawback to proton therapy is cost, and the economics of proton therapy play a significant role in its use, Dr. Saran said.

Dr. Saran took a swipe at the American healthcare system by explaining that "in the United Kingdom, we spend about 8% of our GDP [gross domestic product] on healthcare for a nation of 60 million. In the United States, you spend almost 18% of the GDP on healthcare, but from what I understand, not all of you benefit from that."

If this same degree of spending was applied to poorer countries, Honduras, for instance, would have to spend 2.4 times its GDP on healthcare to be equivalent, and Malawi would have to spend nearly 30 times its GDP.

"At some point, all the money we spend on healthcare should translate into a meaningful benefit to the patient at an affordable cost," he said.

He used the risk for secondary malignancy in the treatment of medulloblastoma to illustrate his point. Even if proton therapy can halve the risk, that amounts to a decrease from a baseline rate of 10% 30 years after treatment. To prevent 1 secondary malignancy, 20 patients would have to undergo treatment, at a cost of at least $150,000 more per patient than conventional radiotherapy.

"How many millions have you spent over the course of 30 years to prevent that 1 child from having a second malignancy?" he asked.

"If we have to balance what we spend in our current climate, photon radiotherapy is not a cost-effective way to achieve good outcomes," Dr. Saran said. "There are some areas where proton therapy could benefit patients if it is available, but across the board, for non-CNS malignancies, I don't think it is mandatory."

In addition to the 11 centers in operation in the United States and the few that are in various stages of development, there are centers in China, Japan, and several European countries. However, there are still only about 40 worldwide.

2013 Annual Meeting of the American Society of Clinical Oncology. Presented June 2, 2013.


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