Concomitant b.i.d. radiotherapy and chemotherapy with cisplatin and 5-fluorouracil in unresectable squamous-cell carcinoma of the pharynx: clinical and pharmacological data of a French multicenter phase II study.
OBJECTIVE
The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed.


METHODS
Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care.


RESULTS
Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival.


CONCLUSIONS
This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.
Bensadoun
R J
RJ
Department of Radiation Oncology, Centre Antoine-Lacassagne, Nice, France. r-bensadoun@aol.com
Etienne
M C
MC
Dassonville
O
O
Chauvel
P
P
Pivot
X
X
Marcy
P Y
PY
Prevost
B
B
Coche-Dequeant
B
B
Bourdin
S
S
Vallicioni
J
J
Poissonnet
G
G
Courdi
A
A
Teissier
E
E
Lagrange
J L
JL
Thyss
A
A
Santini
J
J
Demard
F
F
Schneider
M
M
Milano
G
G
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
D002945:Cisplatin; D005472:Fluorouracil