The current standard of care for many gastrointestinal (GI) cancers is chemoradiation followed by surgical resection. This approach is associated with improved outcomes but also with an increased risk of toxicity in the cells of critical organs. Cellular damage increases with the radiation dose — the amount of energy ionizing radiation deposits in a given volume of tissue. For select patients with certain GI tumors, proton beam therapy may be a superior alternative to the broader and more damaging radiation emitted by X-rays (photons).
In proton beam therapy, the majority of energy is deposited as a localized Bragg peak in targeted cells; there is no exit dose, and the entrance dose is greatly reduced relative to the peak. Intensity-modulated proton beam therapy with pencil scanning — available at Mayo Clinic campuses in Minnesota and Arizona — goes a step further, dividing a proton beam into smaller beams of varying intensity that paint radiation within the tumor. Conforming the beam more precisely to the tumor's size and shape causes even less collateral damage.
"Pencil beam scanning is the next generation of proton beam radiation therapy," says Robert L. Foote, M.D., chair of Radiation Oncology at Mayo Clinic's campus in Rochester, Minnesota, and director of the Proton Beam Therapy Program there. "It should yield better survival with fewer long- and short-term side effects."
The most promising results to date are in patients with esophageal cancer, where conventional chemoradiation is associated with high rates of acute and chronic toxicity of the lungs and heart. Lung and heart dose, especially, are major risk factors for toxicity because efforts to spare the spinal cord can increase the dose received by these organs.
"A 2012 study in The New England Journal of Medicine demonstrated that the best cure rate for esophageal cancer is obtained with induction chemoradiation followed by surgical resection when compared to surgery alone," Dr. Foote says. "But with conventional radiotherapy, this protocol leads to more wound-healing complications, prolonged hospital stays, and more perioperative deaths from heart and pulmonary failure. These complications are reduced when proton beam therapy is used."
He points to a retrospective pooled analysis of nearly 600 patients with esophageal cancer treated at MD Anderson Cancer Center, the University of Maryland or Mayo Clinic from 2007 to 2013. The analysis found that patients receiving proton beam therapy had higher survival rates, fewer wound, heart and lung complications, and shorter hospital stays than patients treated with conventional radiation therapy. The results were presented at the 2015 annual meeting of the Particle Therapy Co-Operative Oncology Group.
A 2013 study published in the International Journal of Radiation Oncology, Biology, Physics had similar findings. Of 444 patients treated with 3-D conformal radiation therapy, intensity-modulated radiation therapy or proton beam therapy, postoperative pulmonary and GI complications were lowest among those receiving proton beam therapy.
Proton beam therapy also appears effective for hepatocellular carcinomas, especially those that are too large, too numerous or located too close to vascular structures to be operable. A systematic review and meta-analysis of 70 observational studies involving more than 5,000 patients found that survival rates were significantly higher and toxicity lower in liver cancer patients treated with proton beam therapy compared with photon chemoradiotherapy or stereotactic body radiotherapy. The review was published in Radiotherapy and Oncology in 2015.
An interim analysis of a phase II clinical trial comparing outcomes in patients with hepatocellular carcinoma treated with proton beam therapy or transarterial chemoembolization reported trends toward improved tumor control, progression-free survival and reduced length of hospitalization with the use of proton beam therapy. The analysis was published in the International Journal of Radiation Oncology, Biology, Physics in 2016.
Radiotherapy is commonly offered to patients with pancreatic cancer, but its ultimate utility is controversial because the pancreas is surrounded by highly radiosensitive organs, including the duodenum, stomach, liver, spinal cord and kidneys. Research hasn't been definitive, with some studies showing benefit and others not. But a large study published in 2016 in the International Journal of Radiation Oncology, Biology, Physics demonstrated a significant advantage.
In that study, researchers looked at the records of more than 450 patients who underwent pancreatic cancer surgery at Mayo Clinic between 1987 and 2011. Of these, 378 received postoperative chemoradiation and 80 received chemotherapy only. Eighty percent of those treated with chemotherapy and radiation had no recurrence in the irradiated area at five years postsurgery compared with 68 percent of those in the chemotherapy-only group.
Patients in the study did not receive proton beam therapy, but other research suggests it may reduce GI complications and lower the dose to the spinal cord and kidneys in pancreatic cancer cases. "Proton beam therapy is also being investigated for improving outcomes of pancreatic cancer," Dr. Foote says. "There is minimal nausea, vomiting or diarrhea, and after just five days of treatment, the tumor is evaluated for resectability."
At Mayo Clinic's Minnesota campus, proton beam therapy has been used to treat a small number of patients with colon, rectal or anal cancer.
"In these cancers, there is a lower dose to the small bowel and bladder so there should be less nausea, vomiting and diarrhea during treatment and less cystitis," Dr. Foote says. "We are still learning about proton beam therapy for these cancers, but with regard to esophageal cancer, there is clear clinical evidence emerging that it is safe and effective and better than other forms of radiotherapy."
Not for everyone
Sameer R. Keole, M.D., a radiation oncologist at Mayo Clinic's campus in Arizona, points out that many cancer patients needing radiotherapy aren't candidates for proton beam therapy. It offers no benefit in metastatic cancers, for instance. Still, he says, "Having the ability to use proton beam therapy will allow Mayo Clinic to match each cancer patient to the radiation treatment that best fits the individual. We now offer our patients all forms of radiation therapy — one of the few cancer centers worldwide to do so."
For more information
Van Hagen P, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. The New England Journal of Medicine. 2012;366:2074.
Wang J, et al. Predictors of postoperative complications after trimodality therapy for esophageal cancer. International Journal of Radiation Oncology, Biology, Physics. 2013;86:885.
Wei XQ, et al. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: A systematic review and meta-analysis. Radiotherapy and Oncology. 2015;114:289.
Bush DA, et al. A randomized clinical trial comparing proton beam radiotherapy to transarterial chemoembolization for hepatocellular carcinoma - Results of an interim analysis. International Journal of Radiation Oncology, Biology, Physics. In press.
Merrell KW, et al. Predictors of locoregional failure and impact on overall survival in patients with resected exocrine pancreatic cancer. International Journal of Radiation Oncology, Biology, Physics. 2016;94:561.