Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy.
The kinetics of local drug uptake and metabolism of the anticancer drug 5-fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy. All of the patients underwent an accelerated hyperfractionated, concomitant-boost radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra were obtained during and after the administration of 5-FU in a 15-T scanner with the use of a 5-cm diameter surface coil positioned on a cervical lymph node metastasis. Examinations were performed at day 1 of therapy and, in 13 patients, also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle. Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the second compared with the first examination, whereas the level of DHFU did not change. This effect could indicate an increased delivery of 5-FU into the interstitial space of the tumor in the course of the combined treatment, which would result in an enhanced exposure of the tumor cells to the drug. A potential mechanism for synergy between radio- and chemotherapy is discussed, but alternative mechanisms are also being considered. The findings indicate that a method is available to rationally address the design of dosing schedules in concurrent therapy regimens.
Schlemmer
H P
HP
Research Program Radiological Diagnostics and Therapy, German Cancer Research Center (Deutsches Krebsforschungszentrum), University of Heidelberg. h.schlemmer@dkfz-heidelberg.de
Becker
M
M
Bachert
P
P
Dietz
A
A
Rudat
V
V
Vanselow
B
B
Wollensack
P
P
Zuna
I
I
Knopp
M V
MV
Weidauer
H
H
Wannenmacher
M
M
van Kaick
G
G
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001711:Biotransformation; D016190:Carboplatin / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005461:Fluorine; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000032:analysis / Q000493:pharmacokinetics*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D007554:Isotopes; D008207:Lymphatic Metastasis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000032:analysis
D000964:Antimetabolites, Antineoplastic; D007554:Isotopes; D015091:beta-Alanine; D005461:Fluorine; C032348:alpha-fluoro-beta-alanine; C019389:5-fluorodihydrouracil; D016190:Carboplatin; D005472:Fluorouracil