The future of radiation therapy for pancreatic and liver malignancies
1College of Medicine, University of Michigan, Michigan, USA
Although pancreatic cancer and hepatocellular cancer (HCC) differ in their natural history, both present significant issues in local control. Only a small minority of patients can undergo resection or, in the case of HCC cancer, transplantation. Thus, a significant fraction of patients with liver cancer die of uncontrolled local disease. Even in the case of pancreatic cancer, which has a strong tendency to metastasize, up to one third of patients were found to have died of local disease at autopsy (Iacobuzio-Donahue CA, et al. J Clin Oncol. 2009;27:1806). Until recently, radiation therapy has played a limited role the treatment of HCC because of the inability to safely deliver high doses to the tumor without producing injury to the uninvolved liver, which is often cirrhotic. Likewise, the location of the pancreas makes it difficult to deliver tumoricidal doses without injuring the intestine. Recent advances in technology, especially stereotactic body radiation therapy, now permit higher doses to be more safely administered, but treatment is still based on the average tumor and normal tissue sensitivities. We are now entering an era of precision radiation medicine, which is beginning to permit the individualization of treatment. We have taken two approaches toward personalized radiation therapy. The first is the use of targeted drugs that selectively abrogate the radiation-induced DNA damage responsive in pancreatic and HCC cells, compared to normal cells, thus leading to cancer-selective cytotoxicity. The second approach is to adapt therapy to the individual patient response. We assess subclinical changes in global liver function after the delivery of 60% of the treatment and use this to predict the effect of the entire course. If the liver would be injured by the current course, we attenuate the latter 40% of treatment and avoid toxicity. In our newest protocol, we are evaluating changes in dynamic contrast-enhanced MRI to determine which parts of the tumor are resistant to therapy, and thus need to receive intensified dose during the latter part of treatment, and which parts of the liver are showing injury, and thus need to be spared. These predictions are improved by assessing changes in other indicators of response such as plasma cytokines and miRNAs. For pancreatic cancer, we are evaluating whether changes in diffusion MRI and in circulating tumor cells during the course of treatment can predict the success of tumor control and reveal resistant regions of the tumor. We hope that by targeting cancer specific pathways and by adapting treatment to the individual patient response, we can help to usher in a new era of precision radiation medicine that will increase cure rates and decrease toxicity in the treatment of pancreatic cancer and HCC as well as other cancers.
Supported by NCI grants P50 CA130810, P30 CA46592, R01 CA138723, and R01 CA132834, a Taubman Scholar Grant, and the Laurie Snow Research Fund