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Protons Can Markedly Reduce Toxicity in Breast Cancer Radiotherapy

Goodwin, Peter M.

doi: 10.1097/01.COT.0000558226.52108.3d
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breast cancer; radiotherapy
breast cancer; radiotherapy:
breast cancer; radiotherapy

VIENNA—The promise of greatly reducing off-target toxicity from radiation therapy for breast cancer was discussed at the 2019 St. Gallen International Breast Cancer Conference by radiation oncologist John H. Maduro, MD, PhD, from the University of Groningen, The Netherlands, who reported on the potential role of proton irradiation as an alternative to using conventional X-ray photon radiotherapy to treat early breast cancer.

John H. Maduro, MD, PhD
John H. Maduro, MD, PhD:
John H. Maduro, MD, PhD

“We feel that patients can benefit from proton irradiation compared to photon—especially when we're talking about long-term toxicity like heart and lung toxicity, or induction of tumors,” he told Oncology Times.

Maduro said the different physical properties of protons offered a way to reduce exposure to surrounding organs such as the heart. Unlike photons, protons have mass and are electrically charged. They are not easily scattered by body tissues and don't penetrate into tissues beyond distances that can be calculated precisely to avoid reaching organs behind the target.

“Given the physical properties of protons and the location of the target in breast cancer, [by] using protons you can avoid all the organs at risk which are behind the target—like heart, lung, and even the esophagus,” Maduro explained. The goal of opting for proton irradiation to treat a subgroup of selected patients was to reduce long-term toxicity, he said.

“By using protons, we can reduce [dose intensity] and make sure that some parts don't get radiation.” Rates of myocardial infarction after radiotherapy had already been reduced by cardiac intervention. But new approaches to radiotherapy could improve this further, and recent study findings illustrated the potential of proton therapy, Maduro stated.


Lifetime risk for ischemic heart disease was found to be 7.4 percent per gray (Gy) of radiation in a case-control study from Sweden and Denmark (N Engl J Med 2013;368:987-998). In theory, this was the level of risk that could potentially be avoided by reducing radiation exposure to the heart.

“On paper we can show that by using protons we actually reduce the dose to organs at risk,” said Maduro.

A systematic review and meta-analysis of the risk for “second non-breast cancer” in 762,468 patients found tumors were 12 percent more common overall 5 or more years after breast cancer diagnosis (Radiother Oncol 2015;114(1):56-65).

For lung tumors, the study found an increased cancer risk of 39 percent in patients who had radiotherapy. Esophagus malignancies were reported in 53 percent more patients and the increase of sarcomas was 153 percent. The risk also increased with longer follow-up. More than 15 years after breast cancer diagnosis, the increased risk for second tumors was 66 percent for lung tumors and 117 percent for esophagus cancer.

Maduro quoted findings from a case-control study in which there was a 2.5-fold greater risk for contralateral breast cancer in women younger than 40 who received a dose of more than 1.0 Gy to the contralateral breast compared to unexposed women. The excess risk was dose-dependent and inversely related to age at exposure (Int J Radiat Oncol Biol Phys 2008;72(4):1021-1030).

Large dose reductions to off-target organs could be achieved by using proton therapy as compared with photons, according to Maduro. For heart irradiation, he reported a reduction of dose from 6.53 Gy to only 0.02 Gy with protons. Ipsilateral lung exposure dose was reduced by a factor of nearly 10 (8.12 Gy to 0.87 Gy), while contralateral lung dose went down from 1.07 Gy (with X-rays) to 0 with protons.

Some patients were more at risk from radiotherapy toxicity than others, he noted. So it was important to select patients carefully for protons. His group had been using a model to calculate toxicity risk, and they had defined risk levels at which protons could be expected to produce clinically relevant benefits.

“We can show that whenever you lower the dose to the same organ the probability of having a toxicity will be less,” Maduro said. “And if we can show that the toxicity [using photons] exceeds a certain value, patients are eligible for protons.”

He admitted that the long-term evidence base for the clinical benefit of proton therapy was still lacking. But when he was asked about the clinical message coming out of this research, he said that proton therapy had become a practical option.

“If you feel that the heart dose is exceeding certain thresholds for individual patients, [you can] consider referring them for protons,” he said. In Europe this policy had been helped by cooperation across borders. “If a patient in one of the European countries needs access to a certain therapy that's not given in their country, they can get it in one of the other European partners.”

Maduro acknowledged the value of recent improvements in conventional photon radiotherapy methods—including the potential for defining patient risk groups in which radiation could be avoided altogether. But he said there was a role for protons. “Some patients can benefit from protons.”

Peter M. Goodwin is a contributing writer.

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