Radiosensitizers in pancreatic cancer--preclinical and clinical exploits with molecularly targeted agents.

There has been an explosion in the number of molecularly targeted agents engineered to inhibit specific molecular pathways driving the tumorigenic phenotype in cancer cells. Some of these molecularly targeted agents have demonstrated robust clinical effects, but few result in meaningful durable responses. Therapeutic radiation is used to treat a majority of cancer patients with recent technologic and pharmacologic enhancements, leading to improvements in the therapeutic ratio for cancer care. Radiotherapy has a very specific role in select cases of postoperative and locally advanced pancreatic cancer patients, but control of metastatic disease still appears to be the major limiting factor behind improvements in cure. Recent rapid autopsy pathologic findings suggest a sub-group of advanced pancreatic cancer patients where death is caused from local disease progression and who would thus benefit from improved local control. One promising approach is to combine molecularly targeted agents with radiotherapy to improve tumor response rates and likelihood of durable local control. We review suggested recommendations on the investigation of molecularly targeted agents as radiosensitizers from preclinical studies to implementation in phase I–II clinical trials. We then discuss a select set of molecularly targeted therapies that we believe show promise as radiosensitizers in the treatment of pancreatic cancer.