A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma

TLDR

Preclinical studies show synergy between radiation and immunotherapy, yet most preclinical work uses hypofractionated doses while clinical practice relies on standard fractionated regimens. The study aimed to determine the optimal radiation dose and schedule for combining chemotherapy and immunotherapy by comparing standard fractionated versus hypofractionated chemoradiation in patients with locally advanced or borderline resectable pancreatic adenocarcinoma. Hypofractionated chemoradiation prevented the extensive lymphocyte depletion seen with standard fractionation and reduced systemic T‑cell loss. ClinicalTrials.gov identifiers: NCT01342224 and NCT01903083.

Abstract

Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy.To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma.We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation.Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.