title: A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy.
abstract: BACKGROUND
  Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting.
  
  
  METHODS
  Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities.
  
  
  RESULTS
  At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg × hour/L), respectively (odds ratio [OR]: 2.20; p = .046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = .03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data (1.9% vs 16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%).
  
  
  CONCLUSIONS
  PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA jai.patel@carolinashealthcare.org.
authors.forename: Jai N
authors.initials: JN
authors.lastname: Patel
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Sherrill
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Oludamilola A
authors.initials: OA
authors.lastname: Olajide
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Prashanti M
authors.initials: PM
authors.lastname: Atluri
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Inzerillo
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Chay
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA; Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, and Biostatistics Core, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Indiana University Simon Cancer Center, Indianapolis, Indiana, USA; Cone Health Cancer Center, Greensboro, North Carolina, USA; Rex Healthcare, Raleigh, North Carolina, USA; Leo W. Jenkins Cancer Center, Greenville, North Carolina, USA; Marion L. Shepard Cancer Center, Washington, North Carolina, USA; Cancer Care of Western North Carolina, Asheville, North Carolina, USA; Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Walko
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001830:Body Surface Area; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine
chemical_list: D005472:Fluorouracil
keywords: Colorectal; Community; Dosing; Fluorouracil; Personalized; Pharmacokinetic