title: Kinetically guided neoadjuvant chemoradiotherapy based on 5-Fluorouracil in patients with locally advanced rectal cancer.
abstract: OBJECTIVE
  This study estimated patients' early response following neoadjuvant chemoradiotherapy (CHRT) of locally advanced rectal cancer based on 5-fluorouracil (5-FU). The target was to achieve pathological complete response (pCR; residual disease-free stage) and toxicities of grade ≤2, using individual dosing predicted according to the steady-state plasma concentration (C ss) and pharmacokinetic parameters of 5-FU: the area under the time-concentration curve at steady state (AUC) and clearance (CL).
  
  
  METHODS
  This open-label prospective study enrolled 33 adult patients treated with 5-FU administered as a continuous intravenous infusion over 4-5 weeks, as follows: in Group 1a (N = 6), the patients received a standard dose of 300 mg/m(2)/24 h. In Group 1b (N = 7), the patients were treated with an escalated dose of 400-1,000 mg/m(2)/24 h. In Group 2 (N = 20), the patients were given dosing kinetically guided in order to reach the target range of 5-FU C ss 50-100 µg/L. Tolerability was tested according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Radiotherapy was delivered with 10-15 MV photon beams at 1.8 Gy/fraction up to 50.4 Gy in 28 daily fractions for 5 days a week. Surgery followed 4-6 weeks after the completion of CHRT and clinical restaging. The pCR and residual tumour stage were evaluated using preoperative tumour downstaging in magnetic resonance, postoperative histopathological staging and tumour regression rate (residual disease).
  
  
  CONCLUSIONS
  The cumulative AUC of 5-FU (total exposure to the drug) correlated with cumulative 5-FU dose (r = 0.61; p < 0.001) and residual disease (r s = -0.53; p < 0.005). A higher target pCR rate was reached in patients individually treated (Group 2) who finished the whole 5-week CHRT. The individual daily dose needed to reach the target C ss should be >350 mg/m(2) (up to 600 mg/m(2)) provided that 5-FU metabolic ratio is within the range of 2.5-6 and the cumulative AUC5wks is within 50-100 mg·h/L.
authors.affiliation: Department of Oncology and Radiotherapy, University Hospital, Sokolská Street, 500 05, Hradec Králové, Czech Republic, grimj@lfhk.cuni.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Grim
authors.forename: Miloš
authors.initials: M
authors.lastname: Hroch
authors.forename: Hroch
authors.initials: H
authors.lastname: Miloš
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chládek
authors.forename: Chládek
authors.initials: C
authors.lastname: Jaroslav
authors.forename: Jiří
authors.initials: J
authors.lastname: Petera
authors.forename: Petera
authors.initials: P
authors.lastname: Jiří
authors.forename: Jiřina
authors.initials: J
authors.lastname: Martínková
authors.forename: Martínková
authors.initials: M
authors.lastname: Jiřina
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging / Q000379:methods; D011446:Prospective Studies; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil