The impetus for doing the study was to see if the improved dose distribution achievable with protons as compared with photons would translate into a reduced rate for second cancers. Previous math modeling studies showed that protons decreased the risk of second tumors; however, there was no clinical data to date. Additionally, critics of proton therapy have speculated that passive scattering — currently the most common technique used to deliver protons — was generating an unacceptable amount of neutrons, which may negate any perceived benefit and possibly even increase the second tumor risk.

“We wanted to look at this issue and settle it,” said Torunn I. Yock, M.D., chief of Pediatric Radiation Oncology at Massachusetts General Hospital, associate professor at Harvard Medical School, and one of the study authors. “That’s why we embarked on this study.”

 

Study specifics

The study, titled “Incidence of Second Malignancies Among Patients Treated With Proton Versus Photon Radiation,” compared the frequency of second cancers in 558 patients treated with proton radiation using the passive scattering technique to 558 patients treated with photon radiation from the population-based Surveillance, Epidemiology, and End Results (SEER) registry. Patients were matched by age at radiation treatment, sex, year of treatment, histology (or type of cancer), and cancer site.

Funded by the National Cancer Institute, SEER is a coordinated system of cancer registries strategically located across the United States. Proton patients cited in the study were treated from 1973 to 2001 at the Harvard Cyclotron in Cambridge, Massachusetts. Harvard offers the largest proton patient database in the world with long-term follow-up. During the study period, nearly all patients treated at the Harvard Cyclotron received some photon radiation (typically 20 percent of their treatment) in addition to proton radiation.

Medium length of follow-up was 6.7 years and 6.0 years in the proton and photon groups, respectively. Median age at treatment was 59 years in each group. Second malignancies occurred in 29 proton patients (5.2 percent) and 42 photon patients (7.5 percent).

After adjusting for sex, age at treatment, primary cancer site and year of diagnosis, proton therapy appeared to be associated with a decreased risk of developing a second tumor.

“When you use the passive scattering technique, you end up generating neutrons, and we don’t know what neutrons do,” said Dr. Yock. “But in the radiation world, we assign them a high quality factor for safety reasons. We err on the side of overestimating the detrimental effects of radiation in order to keep exposure limits to workers within limits that are believed to be safe.”

In many cases, the quality factor assigned to neutrons is 20 times that of photons (the more typical x-ray radiation). The same quality factors were used to estimate for carcinogenesis risk (the risk of developing cancer), although there is a near complete lack of data that inform doctors of what that risk is. In short, the study suggests that the carcinogenesis risk from the tiny amount of neutrons generated in passively scattered proton techniques does not completely negate the second tumor benefits of protons compared with photons.

 

Passive scattering vs. pencil beam scanning

Passive scattering entails placing a solid brass disk, with an aperture matching the shape of the tumor cut into it, near to the patient to help the proton beam find its target. The proton beam is directed through the aperture at the tumor. Some of the protons hit the brass, which then releases a small amount of neutrons that can be absorbed by the patient. In addition, there is neutron production from protons interacting with tissues that are also absorbed by the body, but this amount of neutron radiation is even smaller.

Pencil beam scanning, a more advanced technology that is available at some proton therapy centers, eliminates the need for brass apertures because the proton beam is so narrow in diameter. Therefore, it dramatically reduces the production of external neutron dose.

“We are still working on refining the technology for pencil beam scanning,” said Dr. Yock. “Once that happens, I think it will be better in many circumstances than passively scattered beams. We’re just not there yet.” With a beam spot of 3 millimeters — about the diameter of a headphone jack — “most pencil beams are still too large to do the finest of tumor targeting,” she said.

Dr. Yock said a major takeaway from the study was that fears that protons might increase the rates of secondary cancers due to neutron scatter were not realized and that, in fact, the clinical data seem to support that protons do indeed reduce the risk of a second tumor. “I think that’s very reassuring,” she said.

 

 

Torunn I. Yock, M.D., is chief of Pediatric Radiation Oncology at Massachusetts General Hospital and  associate professor at Harvard Medical School in Boston, Massachusetts.