title: A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients.
  
  
  METHODS
  Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood.
  
  
  RESULTS
  The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05).
  
  
  CONCLUSIONS
  This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: tshong1@partners.org.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Hong
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Shweta
authors.initials: S
authors.lastname: Shinagare
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Wo
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Wadlow
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jill N
authors.initials: JN
authors.lastname: Allen
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Mamon
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Judith
authors.initials: J
authors.lastname: Adams
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Barbara
authors.initials: B
authors.lastname: Winrich
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Tarin
authors.initials: T
authors.lastname: Grillo
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: DeLaney
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-del Castillo
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D018395:CA-19-9 Antigen / Q000097:blood; D000069287:Capecitabine; D002272:Carcinoembryonic Antigen / Q000097:blood; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods* / Q000401:mortality; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011905:Genes, ras / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016577:Pancreaticoduodenectomy; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000032:analysis; D016283:Proto-Oncogene Proteins p21(ras); D061766:Proton Therapy / Q000379:methods*; D054387:Receptors, CXCR / Q000032:analysis; D018631:ras Proteins / Q000032:analysis
chemical_list: C501896:ACKR3 protein, human; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D002272:Carcinoembryonic Antigen; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D054387:Receptors, CXCR; D003841:Deoxycytidine; D017228:Hepatocyte Growth Factor; D000069287:Capecitabine; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D005472:Fluorouracil