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Proton Therapy for Pediatric Cancer—A Proliferation in the Works?

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000481192.39992.d6
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Proton radiotherapy defines the cutting edge of pediatric cancer treatment. However, it's been 50 years since that “edge” was etched.

“It is the oldest ‘new’ technology,” said Eugen Hug, MD, an expert and pioneer in the use of proton therapy for pediatric tumors and Director of the International Patient Program at ProCure Proton Therapy Center, Somerset, New Jersey. The first cancer patient to receive proton therapy was treated in Upsala, Sweden, in 1953. Since then, it has been a slow ascendance into acceptance and use.

“Proton therapy was largely relegated to a niche existence in research laboratories, with some patient component,” Hug recalled. “The issue really was the adaptation of a new technology, which takes a long time in medicine. New technologies have to establish themselves.”

That crawl to established value may be why, to date, there are little over a dozen cities in the United States with proton centers. However, according to the National Association of Proton Therapy, propagation is starting; the number of planned sites will double the number of active sites in the next two years.

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Evolutionary Medicine

“Part of the reason it has taken so long is because the use of protons must evolve over time,” said Anne F. Reilly, MD, MPH, Medical Director of Oncology and an attending physician with the Cancer Center at The Children's Hospital of Philadelphia (CHOP). “You don't just buy a proton machine and turn it on. At CHOP we have a good sense of how to use protons at baseline, but we are exploring additional indications for use and improved techniques. Our physicists and physicians are constantly figuring out how to use the beam to best advantage in various types of pediatric cancers.”

Still, proton therapy has met with additional challenges beyond that of time and evolution. There has been a lack of understanding about the benefits of proton therapy among some clinicians, and misleading suggestions by hesitant insurers that proton therapy is merely “experimental.” Add to that the significant size and cost requirements of proton centers and it makes for a montage of discouragement.

Nevertheless, proton users, advocates and manufacturers are effectively chipping away at those concerns and painting a convincing canvas for proton therapy deployment. The medium of choice for their medical masterpiece? Improved patient outcomes.

“Ultimately—despite the lack of huge clinical trials—people have come to believe in its potential,” said Hug. “There has been enough mounting evidence to prove that we can deliver protons safely, with great precision, in curative doses directly to the tumor, while minimizing radiation to normal tissue in the neighborhood of the tumor. If you can give a greater dose of radiation to the tumor with less radiation to normal tissue you get better results. That is exactly what we are seeing.”

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Important Implications for Pediatric Patients

While this may be a prescription for remission for many cancer patients, proton therapy has particularly important implications for pediatric patients, well beyond curative treatment of their tumors.

Robert A. Lustig, MD, Chief of Clinical Operations and Processor of Clinical Radiation Oncology at the Hospital of the University of Pennsylvania (HUP), Philadelphia, told OT, “The goal is not to give more dose to the tumor in children; the goal is to protect normal growing tissue.”

He explained, “Growing tissue is more sensitive to radiation than mature tissue. So the side effects—many long-term—are what parents understandably dread: lack of growth, atrophy, lack of development, and the induction of other cancers.”

He said HUP's goal has been to come up with paradigms to use the least radiation possible in treating children.

“In brain tumors, sarcomas, neuroblastomas, even in Hodgkin's Disease, we've been able to use protons to decrease the dose to surrounding tissues and organs,” Lustig noted. This is due in part to the fact that protons, delivered in a narrow beam, enter the body with a lower entrance dose than standard photon radiation and limit dose to surrounding tissue. Protons stop at the tumor; they do not leave an exit trail of radiation.”

Offering an example of side effects that protons may limit, Lustig pointed to those resulting from craniospinal radiation for medulloblastoma. “When you treat the spine with conventional photon therapy, radiation will exit through the heart, the lungs, the thyroid, the breast, the stomach, the intestines, the bladder, and the gonads. We previously moved the ovaries of teenage girls who needed X-ray radiation to avoid sterilizing them. And we saw many of these girls mature and develop breast cancer 15, 20, or 30 years after photon radiation treatment. In contrast, with protons the dose to the ovaries is zero; other parts mentioned receive either zero, or close to zero, dose.”

When treating the brain, proton therapy can focus on just the tumor and leave unharmed the surrounding parts of the brain a child needs growing up. “An area of particular interest is in very young children who previously never received radiation to the brain because the side effects were just too devastating. Now we are able to treat very young children, less than 3 years old, with highly focused radiation,” said Lustig.

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Cutting Edges on the Cutting Edge

That “highly focused radiation” is possible thanks to “pencil beam” delivery of protons—just one of the newer developments of proton radiotherapy.

Medical physicist Stanley “Skip” Rosenthal, PhD, Vice President of Clinical Systems at Mevion Medical Systems, explained these slender beams can paint the dose of radiation onto a tumor in dots—likening it to an Impressionistic Seurat painting.

Not only can clinicians better define the edges of the field (Rosenthal compared protons to lasers, photons to flashlights), and take advantage of many more ports through which beams can be directed, they can deliver the dose spot-by-spot. Each spot can be delivered to a certain depth.

“Think about it,” said Rosenthal. “If the target we want to avoid is right in the middle of the tumor, we can deliver the bullets of treatment, spot-by-spot, all around it and never touch the tissue we want to save.”

Other advances in proton therapy are being made in speed of dose delivery, minimizing negative effects wrought by patient movement during treatment. “Right now, if we want to spot-by-spot ‘paint’ a tumor about a liter in size, it might take three minutes with technology that is still being rolled out,” said Rosenthal. “But the industry is moving toward hyperspeed scans that will complete that liter scan in five seconds. It's a very different experience for patients to hold their breath for five seconds instead of three minutes. It matters.”

Image guidance in proton technology is also being improved, with the inclusion of in-room CT scans with diagnostic quality imaging in proton centers. “This means treating clinicians will be able to adapt therapy on a weekly or even daily basis. If the scan shows a change in tumor size (they tend to shrink when hit by protons), or patient size (due to weight loss), therapy can be appropriately recalculated, on the spot.”

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Size Matters

Finally, Rosenthal points to another driver in the emergence of proton therapy. “We are making huge strides in reducing the footprint of proton centers, making the technology smaller, cheaper, and more localized.”

He recalled when the University of Pennsylvania built its groundbreaking Roberts Proton Therapy Center, the cost was about $140 million and required a dedicated facility. “Today we have centers going up for about $25 million—a 10-fold reduction. Our dream has been to make a proton machine that fits into a conventional vault—and we've done that. We've managed to reach the goal of housing a proton machine on the hall of an oncology clinic,” Rosenthal noted.

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Reimbursement Challenges

While Medicare approves proton therapy for most cancers, many private insurers do not.

“Some insurers say there's no proof that it's a better therapy. That means they don't understand protons,” exclaimed Lustig. “Look, no one will ever run a study and give half of the children photons and half of them protons—it would be unethical and no parent would agree for their children to participate. So ‘proof’ is a challenge. But what we already know is that children treated with protons will be protected from collateral damage; they will be less likely to develop cancers caused by radiation later in life; they will have a better quality of life both during treatment and throughout their lifetimes.

“Oncologists need to wake up to the fact that insurers have spread a myth that protons are ‘experimental.’ Whenever a denial for payment comes in, it is couched in the suggestion that the denial is ‘protecting’ the patient from an ‘investigational’ therapy. Sadly, too many clinicians accept that as fact. And that means too many patients are never even told about the proton option,” lamented Lustig.

Hug said that when we speak of proton therapy as an “emerging technology,” the real truth is that it is merely the attitude of acceptance that is still emerging. “We need to educate medical professionals, and demystify protons. We need to get new data out and get it into the hands of physicians and public alike. Protons are not the miracle weapon for everything, but for certain patients—many of them children—they are the next evolutionary step of radiation oncology.”

Lustig added, “You just have to know one basic principle: Radiation is never beneficial for normal tissue. Period. End of discussion.”

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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