Pancreatic cancer is the fourth leading cause of cancer-related deaths in Western and Western-style societies. The American Cancer Society (ACS) estimates that nearly 42,000 Americans will die from the disease in 2016. While chemoradiation therapies can help extend the lives of borderline surgery patients, those eligible for surgical resection, and those with advanced pancreatic cancer, these treatments are not yet curative.
Research to better understand the genetic, biochemical and molecular levels of pancreatic cancer carcinogenesis is leading to the development of novel, molecularly targeted agents. Clinical trials are underway to test therapies directed against vascular endothelial growth factors, epidermal growth factor receptor signaling, K-Ras mutations, cancer stem cells, and more. These are discussed in an article summarizing recent advances and describing future potential of multimodality treatments published in Seminars in Radiation Oncology.1
But what are the current and near future roles of radiation therapy? It depends on whether a patient has potentially resectable cancer, is borderline resectable, or has locally advanced unresectable cancer. Co-author Sunil Krishnan, MD, a professor in the Department of Experimental Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston, and director of its Center for Radiation Oncology Research, told Applied Radiation Oncology that with few exceptions, most patients with nonmetastatic pancreatic cancer receive radiation therapy during their course of treatment at MD Anderson. It is used both for curative intent and palliation.
Potentially resectable patients often get chemoradiation therapy prior to surgery. Clinical trials of the past 10 to 15 years show conflicting results about the value of radiation therapy treatment following surgery. A phase III clinical trial (RTOG 0848) launched in 2014 is one study evaluating the role of adjuvant radiation therapy for resectable patients. Several hundred U.S. cancer centers are still recruiting patients for this study, whose future findings may help optimize adjuvant treatments for this minority subgroup.
A much larger subgroup consists of those with threatened retroperitoneal margins, classified as having borderline resectable pancreatic cancer (BRPC). Benefits of neoadjuvant chemoradiotherapy include early treatment of micrometastatic and subclinical disease, enhanced delivery of treatment prior to surgical modification of vasculature, better tolerance and lower toxicities, and lower rates of postoperative complications. The value to oncologists is that they can better identify patients with good or poor surgical prognoses during this treatment time frame.
Lead author Awalpreet S. Chadha, MD, of the Department of Radiation Oncology at MD Anderson Cancer Center, and co-authors, reference multiple published reports from single treatment centers that neoadjuvant chemoradiotherapy is beneficial for these borderline resectable patients. A multi-institutional clinical trial (Alliance A021501) is still recruiting patients to receive a specific chemotherapy treatment with or without radiation therapy. Its findings should better help determine if radiation therapy provides additional value to the patient.
The authors state that there has been increased interest in the use of chemoradiotherapy after a period of tumor control with induction chemotherapy. Induction chemotherapy is believed to identify patients who will benefit from supplemental chemoradiotherapy treatment. Clinical trial findings have shown mixed results. Preliminary data from a multi-institutional European clinical trial (LAP-07) comparing the effectiveness of treating patients with either chemotherapy or chemoradiotherapy reported in 2013 that after a median of three years following treatment, there was no difference in overall survival among treatments compared. These results question the utility of radiation therapy for the treatment of advanced disease.
The results of a recent study conducted by MD Anderson researchers suggests that patients with advanced pancreatic cancer may benefit from focal radiation therapy dose escalation. The study compared the outcomes of patients treated with chemotherapy and dose intensity modulated radiation therapy (IMRT) after induction chemotherapy and the outcomes of patients who were treated with standard fractionation radiation therapy. The patients who received IMRT with a dose > 70 Gy had an estimated two-year survival rate of 36% compared with 19% who received a median radiation dose of 50.4 Gy. A total of 31% of these patients were alive three years after treatment, compared to 9% receiving conventional treatment. Among the variables compared, the only predictor of improved overall survival was the higher radiation dose. Dr. Krishnan advised that after completing the study, the preferred dosing schedule is 67.5 Gy delivered in 15 fractions as long as normal tissue dose constraints can be met and the patient’s tumor is located more than 1 cm from the closest luminal organ.2
The Swedish Radiosurgery Center of Swedish Cancer Institute in Seattle treats unresectable pancreatic cancer patients with stereotactic body radiation therapy (SBRT). SBRT delivers a conformal high dose of radiation over 1-5 fractions with minimal dose to surrounding critical tissue. Radiation oncologist Sandra S. Vermuelen, MD, said the use of SBRT at the center is slowly increasing. She said that studies from multiple treatment centers are showing excellent local control rates > 88% at one year, and that patients are experiencing minimum toxicities of > grade 3. However, SBRT is not recommended at this time for patients who have had prior radiation to the abdomen.
“I believe the use of SBRT for unresectable pancreatic tumors will continue to increase,” Dr. Vermuelen told Applied Radiation Oncology. “SBRT is becoming an alternative focused local therapy to conventional radiation for the treatment of unresectable pancreatic cancer. Combining SBRT with neoadjuvant chemotherapy has the hope of converting initially presenting unresectable patients to resectable candidates.”
MD Anderson uses a hyperfractionated radiation regime to treat patients with recurring tumors confined to the tumor bed after prior radiation therapy. However, most patients with recurrent tumors do not receive repeat irradiation often because recurrences are more systemic than local.
“If there is dominant local recurrence in the setting of synchronous metastatic disease, we typically start with chemotherapy, and if the local disease remains the site of maximum disease burden and or symptom burden, we use a hyperfractionated radiation regimen,” he said. “The two disease scenarios assume that radiation was part of the initial treatment.”
Dr. Krishnan’s clinical effort is directed toward developing novel therapies for patients with gastrointestinal tumors and finding molecular and imaging biomarkers of response to chemoradiation therapy. Dr. Krishnan, principal investigator of several clinical trials on radiation sensitization strategies for pancreatic cancer, discussed with Applied Radiation Oncology two trials accruing patients:
The evolving role of radiation therapy treatment for pancreatic cancer. Appl Rad Oncol.