title: Phase I study of pre-operative continuous 5-FU and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma.
abstract: OBJECTIVE
  The standard of care in locally advanced rectal cancer is preoperative treatment with fluoropyrimidine-based chemoradiotherapy. Sorafenib works synergistically with radiation and inhibits Ras/Raf, PDFGR, and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-fluorouracil (5-FU) and radiation in patients with locally advanced rectal cancer.
  
  
  METHODS
  Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level, with an expansion cohort at the maximum tolerated dose. A 3+3 dose escalation design was used. Radiation was given in 28 fractions at 1.8 Gy (50.4 Gy) day 1-5 at all dose levels. Initial dose of sorafenib was 200mg qd and titrated up to 400mg BID to determine the MTD. Standard dose of infusional 5-FU was used (225 mg/m(2)/24h). Patients underwent surgery 6-10 weeks after neoadjuvant therapy.
  
  
  RESULTS
  Between August 2011 and August 2014, 17 patients (median age of 54 years) were enrolled. After toxicities requiring dose interruptions were observed in cohort 1 (2 patients with grade 2 (G2) and grade 3 (G3) hand foot skin reaction and 1 patient with G2 mucositis), the protocol was amended, changing administration of chemotherapy and sorafenib from daily to days 1-5 only. With the amended protocol, the primary G3 toxicity was hypertension in 2 patients at the 200-mg adjusted dose level (day1-5) and 1 patient at the 400-mg twice daily dose level. One patient had G3 ALT elevation at 400mg, and no grade IV toxicities were observed. G1 and G2 toxicities included hand-foot skin reaction, diarrhea, mucositis, nausea, fatigue, and proctitis. No perioperative complications were seen. Two patients refused to undergo surgery. The pathological complete remission (pCR) rate was 33%, and downstaging was observed in 85.7% of patients. Median neoadjuvant rectal cancer score was 8.7.
  
  
  CONCLUSIONS
  With the changed dosing schedule, this regimen was very well tolerated. The tumor pCR and downstaging rates are encouraging and support further clinical investigation of this regimen.
authors: Departments of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA. Electronic address: Richard.Kim@moffitt.org.
authors: Richard
authors: R
authors: Kim
authors: Departments of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Gopi Kesaria
authors: GK
authors: Prithviraj
authors: Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Ravi
authors: R
authors: Shridhar
authors: Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Sarah E
authors: SE
authors: Hoffe
authors: Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Kun
authors: K
authors: Jiang
authors: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Xiuhua
authors: X
authors: Zhao
authors: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Dung-Tsa
authors: DT
authors: Chen
authors: Departments of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Khaldoun
authors: K
authors: Almhanna
authors: Departments of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Jonathan
authors: J
authors: Strosberg
authors: Departments of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: Tiffany
authors: T
authors: Campos
authors: Departments of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors: David
authors: D
authors: Shibata
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D059248:Chemoradiotherapy / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000473:pathology / Q000628:therapy*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D005472:Fluorouracil
keywords: Radiation and rectal cancer; Sorafenib