Introduction
For the past 3 decades, fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy has been the mainstay of therapy for advanced gastrointestinal cancer. When given alone to colorectal cancer patients as a weekly intravenous bolus or for 5 consecutive days every 4 to 5 weeks, 5-FU produced response rates ranging from 11% to 17% and was associated with a median survival of approximately 1 year.[1-3] Although the increased efficacy of 5-FU (in terms of higher response rates) via biomodulation with leucovorin has been well established, a meta-analysis of clinical studies failed to demonstrate a clear survival benefit.[4,5]
Moreover, evidence has accumulated that prolonged infusion of 5-FU may improve its antitumor effect when compared with 5-FU bolus regimens.[6,7] However, no significant differences in overall survival time were found when bolus 5-FU, administered according to the North Central Cancer Treatment Group (NCCTG)-regimen, was given with one of several 5-FU regimens including infusional 5-FU.[8] These data correspond with the recent results of a randomized trial conducted by the European Organization for Research and Treatment of Cancer (EORTC-GICCTG) that compared low-dose leucovorin-modulated bolus 5-FU with a weekly schedule of high-dose infusional 5-FU/leucovorin in patients with metastatic colorectal cancer.[9] Thus, significant emphasis has been placed on designing more effective 5-FU-based combination protocols. Promising results were achieved recently with combinations of 5-FU/leucovorin and either irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) or oxaliplatin(Drug information on oxaliplatin) (Eloxatin). These combinations proved superior to conventional 5-FU/leucovorin schedules, especially in colorectal cancer.[10-16]
5-FU-Based Combination Protocols
Irinotecan and Fluorouracil
For the combination of irinotecan and 5-FU, three schedules were carried forward in two large randomized phase III trials: (a) irinotecan at 125 mg/m2, leucovorin at 20 mg/m², and 5-FU at 500 mg/m2 on a weekly ´ 4 schedule (Saltz regimen),[17] (b) irinotecan at 80 mg/m2 in combination with leucovorin at 500 mg/m2 (2-hour infusion), and 5-FU at 2.6 g/m2 (24-hour infusion) on a weekly ´ 6 schedule (AIO schedule),[18] or (c) the biweekly schedule of irinotecan at 180 to 200 mg/m2 in combination with leucovorin-modulated infusional 5-FU administered according to the de Gramont schedule (leucovorin at 200 mg/m2 (2-hour infusion), followed by 400 mg/m2 of 5-FU bolus, and then 600 mg/m2 of 5-FU by continuous infusion over 22 hours on days 1 and 2 every 14 days).[19]
Saltz Regimen
In the first trial, the weekly ´ 4 regimen of irinotecan and bolus 5-FU/leucovorin (Saltz regimen) was compared with conventional low-dose leucovorin/5-FU (Mayo-Clinic protocol).[12] In an intent-to-treat analysis, treatment with the combination of irinotecan and 5-FU/leucovorin resulted in a significantly higher remission rate (P < .001), significantly longer progression-free survival time (P = .004), and significantly longer median survival (P = .04) when compared to leucovorin/5-FU alone. National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 and 4 diarrhea was observed in 23% of patients in the combination arm and 13% of patients treated with leucovorin/5-FU alone. On the other hand, there was a significantly higher incidence of grade 4 neutropenia (42%) in patients receiving 5-FU/leucovorin alone compared to those receiving irinotecan/5-FU (24%). Furthermore, it could be demonstrated that treatment with the combination of irinotecan/leucovorin/5-FU had no detrimental effect on overall quality of life and global health status compared to 5-FU/leucovorin alone.
AIO Schedule or de Gramont Regimen
The second randomized trial used two forms of 5-FU infusion, either the weekly ´ 6 schedule of high-dose leucovorin followed by a 24-hour infusion of 2.3 g/m2 of 5-FU (AIO schedule) or the biweekly de Gramont regimen.[13] Participating centers had to choose one of the two schedules. In the experimental arm, irinotecan was added to the same 5-FU infusion protocol (80 mg/m2 per week for the AIO schedule or 180 mg/m2 every 2 weeks for the de Gramont schedule).
A response rate of 41% was achieved with the combination compared to 23% with leucovorin/5-FU alone (P < .001). Moreover, the median time to disease progression (P < .001) and median survival (P < .028) showed a significant advantage for the combination arm with irinotecan vs the control arm. The incidence of grade 3 and 4 neutropenia was higher in the irinotecan/5-FU arm, but did not translate into a significantly higher incidence of either neutropenic fever or infection. There was also slightly more grade 3 and 4 diarrhea (24% of patients) in the combination arm compared to leucovorin/5-FU alone (11% of patients).
Oxaliplatin Combinations
Oxaliplatin, a trans-l-1-diaminocyclohexan-oxalato [DACH]-platinum analog, has also shown efficacy in colorectal cancer.[10] Oxaliplatin in combination with leucovorin/5-FU given either chronomodulated or in accordance with the de Gramont schedule has been compared to the same leucovorin/5-FU regimen alone in two randomized multicenter phase III trials.[15,16] The combination of oxaliplatin with leucovorin/5-FU significantly improved overall response rate and median time to disease progression in both trials; however, median survival was not significantly prolonged in these studies.
UFT Combinations
UFT is an orally administered fixed combination of tegafur(Drug information on tegafur) and uracil in a 1:4 molar ratio. Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) is absorbed intact via the gastrointestinal tract and is then converted to 5-FU by hepatic microsomal cytochrome P450 enzymes, as well as through soluble enzyme hydrolysis. Uracil is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD). Preclinical studies demonstrated that the addition of uracil to tegafur in these concentrations significantly increased the tumor-to-serum and tumor-to-normal tissue ratios of 5-FU.[3,20,21] Co-administration of leucovorin to UFT further enhanced the activity of UFT as shown in preclinical and clinical studies.[21,22]
The results of clinical trials demonstrate that UFT, with or without leucovorin, can be safely administered over weeks and even months. The compound is associated with a favorable toxicity profile compared to bolus 5-FU/leucovorin, with diarrhea being the main toxicity.[23,24]
UFT, with or without leucovorin, induces overall response rates in gastrointestinal tumors comparable to those achieved with bolus 5-FU/leucovorin.[20,23-29] These experiences prompted further investigation of UFT as part of combination chemotherapies in esophageal, gastric, pancratico-biliary tract, and colorectal cancers.
Capecitabine
Capecitabine (Xeloda) (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate that is converted to fluorouracil by three enzymes located in the liver and tumor tissue.[30,31] The final step is the conversion of 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-FU by thymidine phosphorylase preferentially in tumor tissue.
The high thymidine phosphorylase expression in tumor cells selectively enhances 5-FU concentrations, and may result in higher antitumor activity and decreased drug levels in nontumor tissue, with a consequent reduction in systemic toxicity.[32] Preclinical studies on human tumor xenografts suggest that the antitumor efficacy of capecitabine(Drug information on capecitabine) is superior to that of UFT or 5-FU. In these in vivo models, capecitabine was less toxic to the intestinal tract, indicating a higher therapeutic potential.[31] Capecitabine is associated with significant antitumor efficacy in various malignancies, including colorectal cancer and breast cancer.[33-36]
In two large randomized trials in metastatic colorectal cancer, capecitabine was significantly superior to bolus 5-FU/leucovorin (Mayo Clinic protocol) in terms of response rate (25.7% vs 16.7% confirmed responses; P < .0002 [integrated results of 1,207 patients]).[37] However, in both trials no significant differences in time to disease progression and overall survival were observed between capecitabine and bolus 5-FU/leucovorin (time to progression: 4.6 months vs 4.7 months, respectively, and overall survival time 12.9 months for both).
Although hand-foot-syndrome occurred more often in patients receiving capecitabine than in those receiving bolus 5-FU/leucovorin, it resulted in only two hospitalizations. Furthermore, the treatment-related hospitalization rate was significantly reduced in patients treated with capecitabine. The results of the integrated analysis of both trials demonstrate that capecitabine offers a convenient alternative to bolus 5-FU/leucovorin with a superior safety profile and equivalent antitumor efficacy.
Considering the antitumor activity and safety profile of the oral fluoropyrimidine prodrugs (UFT, capecitabine), different combinations with other cytotoxic agents active in gastrointestinal cancer, such as mitomycin(Drug information on mitomycin) C (Mutamycin), irinotecan, and the platinum analogs are currently under clinical investigation in gastrointestinal cancer.
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