Proton beam therapy holds ‘great promise’ at a steep cost

Proponents of proton beam therapy contend the technique — designed to allow more precise delivery of radiation to tumors than other forms of external beam radiotherapy, thereby reducing damage to healthy surrounding tissue — may forever alter the nature of cancer treatment.

Others are not so sure.

First, the potential comes at a steep cost. The University of Pennsylvania spent $144 million to open its center in 2010. The Hampton University Proton Therapy Institute in Virginia, which opened a few months later, cost $225 million.

A lack of clinical data that compare the efficacy of proton beam therapy vs. other forms of radiation — particularly in patients with prostate cancer — has further contributed to a debate about whether the oncology community has rushed to conclusions, favoring an unproven treatment over alternatives that cost half as much.

“There’s a group that believes proton therapy is the be-all and end-all of cancer treatment, and there are those who are more skeptical,” Adam P. Dicker, MD, PhD, chairman and professor in the department of radiation oncology, director of the Christine Baxter Research Laboratory for Experimental Cancer Therapeutics, and program leader for radiation research and translational biology at Thomas Jefferson University’s Jefferson Medical College and the Kimmel Cancer Center in Philadelphia, told HemOnc Today. “There is great promise with this technology, but we are still early in the learning curve.”

Cost concerns

Proton beam therapy has been used to treat more than 100,000 patients worldwide since the technology debuted at Berkeley Radiation Laboratory in 1954.

The popularity of the technique has surged in recent years.

Four proton beam therapy centers operated in the United States in 2004. Six others opened by 2010, and up to 20 more are under construction or are in the planning stages, according to a report published in April in BMJ.

Proton beam therapy requires a cyclotron or synchrotron — a 220-ton machine that is similar in size to an SUV yet weighs as much as a Boeing 747 — that uses high-powered magnets to strip protons from hydrogen atoms in water and accelerate them. The high-speed protons are directed into a beamline — an airless tube that is about the length of a football field — and into devices that deliver the desired radiation dose to a tumor.

“It is an expensive technology requiring expensive facilities,” Anita Mahajan, MD, medical director of the Proton Therapy Center at The University of Texas MD Anderson Cancer Center, said in an interview. “Maintenance is also costly. As time goes by, it will get more and more affordable, thanks to newer technology.”

The first generation of cyclotrons required free-standing structures that encompass several thousand square feet, just so proton beams could be directed to three or four concrete vaults where patients undergo treatment.

Newer, smaller machines, a superconducting synchrocyclotron that can be housed in a single large room that is approximately 40 feet high, are expected to cost considerably less — $20 million to $30 million, by some estimates.

Staffing and maintenance also are costly. The facilities — which require 24/7 staffing by engineers and physicists to ensure proper maintenance — usually treat patients in a 16- to 18-hour day.

“These machines require as many as 17 full-time engineers and one physicist to act as air traffic control, and you can only treat one patient at a time,” Dicker said. “Patients have to be lined up and waiting and ready on the table.”

The biggest financial concern, however, may not be the cost of the machine itself but the way health care systems are forced to account for it.

“The unfortunate truth is that many facilities are dealing with a business plan, not necessarily a clinical plan,” Jay  P. Ciezki, MD, staff physician in the radiation oncology department at the Cleveland Clinic, told HemOnc Today. “That’s the rub. Everyone is talking about how to make it cheaper, but we want to see a better machine. If we are getting something that is cheaper that is just a knockdown version of what we have already, who is interested in that?”

Lack of data

The next generation of technology may result in improved outcomes, but there are too few proton beam facilities generating convincing data and conducting meaningful trials, Dicker said.

A 2010 report from the Agency for Healthcare Research and Quality noted only eight randomized controlled trials involving proton beam therapy had been conducted. Most of them evaluated how patients responded to different doses of proton beam therapy rather than comparing patients who received similar doses of photons vs. protons.

Meanwhile, the clinical community has been forced to pursue the use of proton therapy in cancers with high incidence rates to make the machines financially viable.

The lifetime costs associated with proton therapy for prostate cancer approach $73,000, compared with less than $42,000 for intensity-modulated radiation therapy, (IMRT), according to a 2008 report from the Institute for Clinical and Economic Review. Brachytherapy or seed implants would be even less, with similar or possibly superior cure rates.

If researchers can prove proton therapy is overwhelmingly effective in prostate cancer — which will kill an estimated 28,170 people in the United States this year, according to the NCI — the consensus is the benefit would be worth the cost.

Yet, data are far from conclusive.

In a study published in April in the Journal of the American Medical Association, Sheets and colleagues conducted a propensity score-matched comparison of IMRT to conformal radiation therapy and proton therapy in patients with nonmetastatic prostate cancer.

Patients in the IMRT cohort had a lower gastrointestinal morbidity rate than patients who underwent proton therapy (RR=0.66, 95% CI, 0.55-0.79). The patients who underwent IMRT also experienced fewer hip fractures and required less additional cancer therapy. The patients who underwent proton beam therapy reported higher rates of erectile dysfunction, but the difference was not statistically significant, the researchers wrote.

“This population-based study suggests that IMRT may be associated with improved disease control without compromising morbidity compared with conformal radiation therapy,” the researchers wrote. “Proton therapy does not appear to provide additional benefit.”

The American Society for Radiation Oncology’s emerging technology committee published a review in March that determined proton beam therapy is an effective treatment for prostate cancer but found no evidence that showed it is superior to standard radiation therapy.

“Many business plans require treating men diagnosed with prostate cancer in order to make the proforma financially viable,” said Charles A. Enke, MD, chairman of the radiation oncology department at the University of Nebraska Medical Center.  “If proton therapy is being used to treat prostate cancer because it is the most effective therapy, that is one thing, but if we are using it to treat prostate cancer to make the business plan viable, that is something else.”

Jason A. Efstathiou, MD, DPhil, an assistant professor of radiation oncology at Harvard Medical School and Massachusetts General Hospital, and Justin E. Bekelman, MD, at the University of Pennsylvania, aim to fill in the evidence gap.

Massachusetts General has partnered with the University of Pennsylvania to conduct a multicenter, phase 3, randomized controlled trial of proton therapy vs. IMRT for low- or low/intermediate-risk prostate cancer.

The 5-year study, which will be conducted at a few centers in the United States, is designed to determine whether proton beam therapy leads to a better quality of life and, if so, whether that benefit is worth the additional cost.

“It is very clear that we need better evidence to help guide clinical decision making,” Efstathiou said.

Physics vs. biology

Concerns over proton beam therapy as a treatment for prostate cancer extend beyond a lack of data.

The location of the prostate — next to the rectum, which Ciezki noted “is very intolerant to therapy” — poses a challenge, too.

The key element to proton therapy is the Bragg peak, the range or depth at which the radiation dose is delivered.

The charged particles enter the body and do not penetrate beyond that distance. This reduces the exit dose — the amount of radiation that passes through the tumor and beyond — and limits the potential damage to surrounding healthy tissue.

Because the location of the prostate is not fixed, if a charged particle enters the body and stops at a pre-determined depth, there is a chance the dose could miss the prostate — and the tumor — and be administered to healthy tissue instead.

“You might get 100% of the dose administered in the right place, or you might get 0%,” Enke said.

The issue of organ motion is starting to be addressed by proton centers around the world, Dicker said.

“When we treat a patient with lung cancer, we are able to turn the beam on and off so that the beam only goes on when the tumor is in the right place,” Dicker said. “It is a four-dimensional process, with the fourth dimension being time. The eventual plan is that we can apply this to the prostate.”

Still, the technology currently in use by nearly all proton centers is still first generation, and it is not yet possible to modulate the beam in a sophisticated way, Dicker added. This will complicate any clinical trial designed to compare intensity-modulated photon therapy with non-intensity–modulated proton therapy.

“There is a lot of uncertainty about what goes on with the proton beam,” he said.

Ciezki said the issue is a matter of “high school physics.”

“You have to use something with low energy to treat the prostate because of the location and the surrounding organs,” Ciezki said. “Anything with high energy is a bad thing for the prostate. I would put protons in the category of high energy. Protons, on the scale we are looking at with the prostate, are simply not optimal.”

Another issue of control is how to calculate the dose, Ciezki said.

“With photon radiation, the dose deposition is directly proportional to the density of the material through which the beam is passing,” he said. “With protons, the deposition of dose is directly dependent on the stopping power of the thing through which it is passing. The medical imaging we have at the moment is not good at telling us what the stopping power of that tissue is.”

Despite these difficulties, Dicker remains cautiously optimistic about future opportunities in the field.

“If you look at radiation oncology, in general, there have been tremendous advances from 3-D to IMRT,” he said. “But we have leveled off in term of the advances. What we are going to see in oncology now is that you can’t improve on biology with only physics. It is just not possible. You have to fight biology with biology. Where radiation oncology is headed is that we are going to combine novel agents with radiotherapy and use physical and biologic agents to individualize care.”

Success in other cancers

Proton beam therapy has been used with consistent success in certain patient populations. These include patients with uveal melanoma, unresectable sarcomas and skull base tumors, which tend to respond well to dose escalation.

“A textbook example of where proton therapy shone was in pediatric malignancies, particularly retinoblastoma,” Ciezki said. “We have found this to be very curable in children.”

Radiation can affect the growth plates of a child’s skull, Ciezki said.

“The result is that children sometimes end up with misshapen heads after radiation therapy,” he said. “If you do protons properly, you minimize exposure to the growth plates in the skull.”

The benefits of limited radiation exposure may extend beyond the physical.

Efstathiou cited findings published by Kuhlthau and colleagues, who conducted a prospective study of quality of life in children with brain tumors who underwent proton radiation.

Their results indicated that higher quality of life was linked to higher IQ scores. Disease type and intensity of treatment also had an effect on health-related quality of life.

“Long-term outcomes among certain populations of cancer patients — especially those with certain base-of-skull, central nervous system and pediatric tumors — treated with protons appear promising, with low rates of long-term toxicities and secondary malignancies,” said Arnab Chakravarti, MD, chair and professor of radiation oncology, Max Morehouse Chair of Cancer Research, and co-director of the brain tumor program at the Ohio State University Comprehensive Cancer Center — Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute. “In children — who are expected to live longer than the average adult lung or prostate cancer patient — this translates into reduced risk for secondary radiation-induced malignancies down the road.”

These benefits could yield significant savings, Mahajan said.

“We may not be seeing the benefits yet, but it is likely that these kids will live a long time, and we will see these benefits in them over the long term,” she said. “If there are fewer cancers among these children down the road, it will be cheaper for all of us. The burden on the system will not be as significant.”

The role of research

The solution lies in ongoing research, Chakravarti said.

“There is a definite need for well-controlled prospective studies on the optimal indications for proton therapy to better personalize care for our patients,” he said. “There is emerging long-term data for certain base-of-skull, ocular, CNS and pediatric tumors suggesting the merits of proton therapy. There is a great need for prospective studies conducted on more common tumors to determine if proton therapy can, indeed, improve the overall therapeutic ratio, which factor in improvements in survival with reductions in long-term toxicity and rates of secondary radiation-induced malignancies.”

From a larger health care perspective, there needs to be more refined cost-benefit analysis of protons for various tumor types, Chakravarti said.

“The obvious solution would be to conduct well-controlled, prospective clinical trials that investigate the comparative effectiveness and overall therapeutic ratios of proton vs. photon radiation, especially for the more common tumor types that drive the business model for protons at many centers,” Chakravarti said.

This may be easier said than done, Chakravarti said.

First, some radiation oncologists believe treating patients with photons inherently exposes them to greater integral dose, or dose to normal tissues. Chakravarti said this may create an ethical dilemma of sorts in passing up a much more conformal proton therapy option, in which less irradiated normal tissue may translate into lower rates of late toxicity and lower rates of secondary malignancies.

“Also complicating matters is that secondary malignancies may appear decades after radiation is administered,” Chakravarti said. “Therefore, definitive results for such comparative effectiveness trials may not be available for the better part of a generation.”

Efstathiou said trial outcomes could lead to improvements in subsequent generations of proton therapy.

“If we can reach a point where an 8-week course of radiation can be reduced to a 2-week course, the costs in the short term and the long term will go down accordingly, as will the burden on the health care system,” he said. “We have an obligation to establish these emerging therapies and find out which ones offer better outcomes.”

Although technical challenges remain, Mahajan said she remains confident that leaders in the clinical and research communities will join forces to meet them.

“Medical technology is always expensive, as are cancer drugs,” she said. “Proton therapy is no exception. Honestly, I don’t know if it is the magic bullet of radiation. It is a very elegant tool; it has great promise and utility. If we can reduce the radiation dose to healthy tissue, we should.” – by Rob Volansky