Phase I trial and pharmacokinetics of escalating doses of paclitaxel and concurrent hyperfractionated radiotherapy with or without amifostine in patients with advanced head and neck carcinoma.
BACKGROUND
Amifostine was developed to protect normal tissues from radiation exposure. The current study was undertaken to determine whether amifostine would allow the delivery of greater numbers of weekly paclitaxel treatments with concomitant, hyperfractionated radiotherapy in patients with advanced head and neck carcinoma.


METHODS
Patients received radiation therapy twice daily using 1.6-gray (Gy) fractions up to a total of 70.4 Gy over an elapsed time of 6.5 weeks. All patients received paclitaxel 60 mg/m(2) once weekly starting on Day 1. The number of doses of paclitaxel was escalated from three to a maximum of six in groups of three patients. For the patients who received amifostine, a dose of 400 mg/m(2) was given intravenously over 15 minutes on Days 1-5, 8, 29-33, and 36. Patients underwent surgery for persistent tumor after radiotherapy. The plasma pharmacokinetics of paclitaxel were characterized during treatment with the first weekly dose to determine the effect of concurrently administered amifostine.


RESULTS
Thirty-six patients were evaluable for this study. In the absence of amifostine, a maximum of four doses of paclitaxel were tolerated in combination with the radiotherapy. With amifostine, up to five doses of paclitaxel could be given. Generally, the treatment resulted in Grade 2 and 3 stomatitis. Overall, 69% of patients had a complete remission, and 29% had a partial remission. Both progression-free survival and overall survival were 66% at 30 months. Amifostine had no effect on the pharmacokinetics of paclitaxel.


CONCLUSIONS
The administration of amifostine allowed the authors to give an additional dose of paclitaxel to patients who were undergoing hyperfractionated radiotherapy for head and neck carcinoma. This treatment regimen resulted in a high frequency of complete remissions and an excellent progression-free survival pattern without compromising the plasma kinetics of paclitaxel.
Amrein
Philip C
PC
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. pamrein@partners.org
Clark
John R
JR
Supko
Jeffrey G
JG
Fabian
Richard L
RL
Wang
Chiu C
CC
Colevas
A Dimitrios
AD
Posner
Marshall R
MR
Deschler
Daniel G
DG
Rocco
James W
JW
Finkelstein
Dianne M
DM
McIntyre
James F
JF
D004999:Amifostine / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use; D011336:Probability; D011379:Prognosis; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome
D004999:Amifostine; D017239:Paclitaxel