Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer:: in vitro evidence and a phase I dose-escalating clinical trial

被引:17
作者
Barone, C.
Landriscina, M.
Quirino, M.
Basso, M.
Pozzo, C.
Schinzari, G.
Di Leonardo, G.
D'Argento, E.
Trigila, N.
Cassano, A.
机构
[1] Univ Cattolica Sacro Cuore, UO Oncol Med, Fac Med & Chirurg, Dept Internal Med,Clin Oncol Unit, I-00168 Rome, Italy
[2] Univ Foggia, Dept Med Sci, Clin Oncol Unit, Foggia, Italy
关键词
5-fluorouracil; irinotecan; SN-38; colon carcinoma cells; phase I trial;
D O I
10.1038/sj.bjc.6603496
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150-300 mg/m(2)) and two of continuous infusion of FU (800-1000 mg/m(2)) in a 3-weekly schedule. The most severe grade III-IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (+/- 20, 95% Cl); seven of 25 patients had stable disease (28%), the overall disease control was 80% (+/- 16, 95% Cl). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity.
引用
收藏
页码:21 / 28
页数:8
相关论文
共 33 条
[1]   CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer [J].
André, T ;
Louvet, C ;
Maindrault-Goebel, F ;
Couteau, C ;
Mabro, M ;
Lotz, JP ;
Gilles-Amar, V ;
Krulik, M ;
Carola, E ;
Izrael, V ;
de Gramont, A .
EUROPEAN JOURNAL OF CANCER, 1999, 35 (09) :1343-1347
[2]   Second-line treatment in advanced colon cancer: are multiple phase II trials informative enough to guide clinical practice? [J].
Atalay, G ;
Cardoso, F ;
Paesmans, M ;
Goldberg, RM ;
Bleiberg, H .
ANTI-CANCER DRUGS, 2003, 14 (09) :703-713
[3]   COMPUTERIZED QUANTITATION OF SYNERGISM AND ANTAGONISM OF TAXOL, TOPOTECAN, AND CISPLATIN AGAINST HUMAN TERATOCARCINOMA CELL-GROWTH - A RATIONAL APPROACH TO CLINICAL PROTOCOL DESIGN [J].
CHOU, TC ;
MOTZER, RJ ;
TONG, YZ ;
BOSL, GJ .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1994, 86 (20) :1517-1524
[4]   QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].
CHOU, TC ;
TALALAY, P .
ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55
[5]   Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial [J].
Douillard, JY ;
Cunningham, D ;
Roth, AD ;
Navarro, M ;
James, RD ;
Karasek, P ;
Jandik, P ;
Iveson, T ;
Carmichael, J ;
Alakl, M ;
Gruia, G ;
Awad, L ;
Rougier, P .
LANCET, 2000, 355 (9209) :1041-1047
[6]   A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients [J].
Garufi, C ;
Bria, E ;
Vanni, B ;
Zappalà, AMR ;
Sperduti, I ;
Terzoli, E .
BRITISH JOURNAL OF CANCER, 2003, 89 (10) :1870-1875
[7]   Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, fluorouracil, and leucovorin in patients with solid tumors [J].
Goetz, MP ;
Erlichman, C ;
Windebank, AJ ;
Reid, JM ;
Sloan, JA ;
Atherton, P ;
Adiei, AA ;
Rubin, J ;
Pitot, H ;
Galanis, E ;
Ames, MM ;
Goldberg, RM .
JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (20) :3761-3769
[8]   Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment [J].
Grothey, A ;
Sargent, D ;
Goldberg, RM ;
Schmoll, HJ .
JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (07) :1209-1214
[9]  
Guichard S, 1997, INT J CANCER, V73, P729, DOI 10.1002/(SICI)1097-0215(19971127)73:5<729::AID-IJC20>3.0.CO
[10]  
2-#