Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study.
OBJECTIVE
To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level.


METHODS
Twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. Tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured.


RESULTS
Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy-assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2).


CONCLUSIONS
A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio.
Eisbruch
A
A
Departments of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA. eisbruch@umich.edu
Shewach
D S
DS
Bradford
C R
CR
Littles
J F
JF
Teknos
T N
TN
Chepeha
D B
DB
Marentette
L J
LJ
Terrell
J E
JE
Hogikyan
N D
ND
Dawson
L A
LA
Urba
S
S
Wolf
G T
GT
Lawrence
T S
TS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001706:Biopsy; D003131:Combined Modality Therapy; D003597:Cytosine Nucleotides / Q000378:metabolism; D003841:Deoxycytidine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011878:Radiotherapy / Q000009:adverse effects; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003597:Cytosine Nucleotides; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine