title: A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Crocenzi
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cottam
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA ; The Oregon Clinic, Portland, OR 97213 USA ; Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Pippa
authors.initials: P
authors.lastname: Newell
authors.affiliation: The Oregon Clinic, Portland, OR 97213 USA ; Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Wolf
authors.affiliation: The Oregon Clinic, Portland, OR 97213 USA ; Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Hansen
authors.affiliation: The Oregon Clinic, Portland, OR 97213 USA ; Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Chet
authors.initials: C
authors.lastname: Hammill
authors.affiliation: The Oregon Clinic, Portland, OR 97213 USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Solhjem
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Yue-Yun
authors.initials: YY
authors.lastname: To
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Greathouse
authors.affiliation: Oregon Health and Sciences University, Sam Jackson Parkway, Portland, OR USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Tormoen
authors.affiliation: Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Jutric
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA ; The Oregon Clinic, Portland, OR 97213 USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Young
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gough
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR 97213 USA ; The Oregon Clinic, Portland, OR 97213 USA.
authors.forename: Marka R
authors.initials: MR
authors.lastname: Crittenden
keywords: Chemotherapy; Fractionation; Gemcitabine; Homeostatic repopulation; IL-15; IL-7; Immunotherapy; Lymphocytes; Lymphodepletion; Radiation