Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: A phase I-II trial of the Southern Italy Cooperative Oncology Group (SICOG)

被引:7
作者
Caponigro, F
Comella, P
Rivellini, F
Avallone, A
Budillon, A
Di Gennaro, E
Mozzillo, N
Ionna, F
De Rosa, V
Manzione, L
Comella, G
机构
[1] Natl Tumor Inst G Pascale, Div Med Oncol A, I-80131 Naples, Italy
[2] San Carlo Hosp, Potenza, Italy
关键词
cisplatin; 5-fluorouracil; head and neck cancer; levofolinic acid; raltitrexed;
D O I
10.1023/A:1008339428733
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: The combination of cisplatin (CDDP) and 5-fluorouracil (5-FU) can be regarded as a reference regimen in squamous cell carcinoma of the head and neck (SCCHN). Raltitrexed (Tomudex) is a direct and specific thymidilate synthase (TS) inhibitor, which has shown clinical activity against SCCHN in a previous phase I study, when combined with 5-FU and levo-folinic acid (LFA). Preclinical data support the combination of CDDP and raltitrexed. The aim of the present study was to evaluate the combination of cisplatin, raltitrexed, LFA and 5-FU in a phase I-II study. Patients and methods: Patients with locally advanced or metastatic SCCHN were treated with a combination of cisplatin at the starting dose of 40 mg/m(2), followed by raltitrexed at the starting dose of 2.5 mg/m(2) on day 1; levo-folinic acid at fixed dose of 250 mg/m(2), followed by 5-fluorouracil at the starting dose of 750 mg/m(2) on day 2. Doses of the three cytotoxic agents were alternately escalated up to dose-limiting toxicity (DLT). Treatment was recycled every two weeks and given up to a maximum of eight courses; after chemotherapy, patients with locally advanced disease received a locoregional treatment. Results: Forty-five patients were entered into the study. Six dose levels were tested. At CDDP 50 mg/m(2), raltitrexed 3 mg/m(2), 5-FU 900 mg/m(2), four out of six patients showed DLT, which was in all cases grade 4 neutropenia. Therefore, this dose level was defined as maximum tolerated dose (MTD). CDDP 60 mg/m(2), raltitrexed 2.5 mg/m(2), LFA 250 mg/m(2), 5-FU 900 mg/m(2) was the dose level recommended for phase II. CDDP, Raltitrexed and 5-FU mean actually delivered dose intensities at the selected dose level were 26, 1.05, and 378 mg/m(2)/week, respectively. Neutropenia was the main side effect and was observed even at the lowest dose levels. Non-hematologic side effects were mild. Nine complete responses (20%) and twenty-one partial responses (47%) were observed, for an overall response rate of 67% (95% confidence interval (95% CI): 51%-80%), according to intention to treat analysis. Fifteen of fifteen patients (100%) treated at the dose level selected for phase II had an objective response (5 complete responses, 10 partial responses). Conclusions: The results of our dose escalation clearly demonstrate that it is possible to combine CDDP, raltitrexed, and modulated 5-FU at effective doses, without unexpected toxicities. The response data point to an impressive clinical activity, which will be better defined by an ongoing large phase II study.
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收藏
页码:575 / 580
页数:6
相关论文
共 24 条
[1]  
BUDILLON A, 1998, ANN ONCOL S4, V9, pA637
[2]  
Caponigro F, 1999, CANCER, V85, P952
[3]  
Caponigro F, 1999, CLIN CANCER RES, V5, P3948
[4]   Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: Long-term results [J].
Clark, JR ;
Busse, PM ;
Norris, CM ;
Andersen, JW ;
Dreyfuss, AI ;
Rossi, RM ;
Poulin, MD ;
Colevas, AD ;
Tishler, RB ;
Costello, R ;
Lucarini, JW ;
Lucarini, D ;
Thornhill, L ;
Lackey, M ;
Peters, E ;
Posner, MR .
JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (09) :3100-3110
[5]  
CUNNINGHAM M, 1994, ANQ-Q J SHORT ART N, V7, P179
[6]   OVERVIEW OF COMBINED MODALITY THERAPIES FOR HEAD AND NECK-CANCER [J].
DIMERY, IW ;
HONG, WK .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1993, 85 (02) :95-111
[7]  
GEBBIA V, 1993, ONCOLOGY, V50, P490
[8]  
HUININK DT, 1999, P AN M AM SOC CLIN, V18, pA1583
[9]   A PHASE-III RANDOMIZED STUDY COMPARING CISPLATIN AND FLUOROURACIL AS SINGLE AGENTS AND IN COMBINATION FOR ADVANCED SQUAMOUS-CELL CARCINOMA OF THE HEAD AND NECK [J].
JACOBS, C ;
LYMAN, G ;
VELEZGARCIA, E ;
SRIDHAR, KS ;
KNIGHT, W ;
HOCHSTER, H ;
GOODNOUGH, LT ;
MORTIMER, JE ;
EINHORN, LH ;
SCHACTER, L ;
CHERNG, N ;
DALTON, T ;
BURROUGHS, J ;
ROZENCWEIG, M .
JOURNAL OF CLINICAL ONCOLOGY, 1992, 10 (02) :257-263
[10]   RELATIONSHIPS BETWEEN RESISTANCE TO CISPLATIN AND ANTIFOLATES IN SENSITIVE AND RESISTANT TUMOR-CELL LINES [J].
KELLAND, LR ;
KIMBELL, R ;
HARDCASTLE, A ;
AHERNE, GW ;
JACKMAN, AL .
EUROPEAN JOURNAL OF CANCER, 1995, 31A (06) :981-986