Oral Fluoropyrimidine-Based Combination Therapy in Gastrointestinal Cancer

January 2, 2001

Significant emphasis has been placed recently on designing more effective fluorouracil (5-FU)-based combination protocols for gastrointestinal cancer. Promising results were seen with 5-FU/leucovorin in combination with

ABSTRACT: Significant emphasis has been placed recently on designing more effective fluorouracil (5-FU)-based combination protocols for gastrointestinal cancer. Promising results were seen with 5-FU/leucovorin in combination with irinotecan (Camptosar) or oxaliplatin (Eloxatin), especially in colorectal cancer. Clinical trials of UFT, with or without leucovorin, demonstrate the safety of this regimen and an efficacy comparable to that of bolus 5-FU/leucovorin in the treatment of gastrointestinal tumors. Two large randomized phase III trials of capecitabine (Xeloda) showed that capecitabine also offers a convenient alternative to bolus 5-FU/leucovorin with a superior safety profile and at least equivalent antitumor activity. [ONCOLOGY 15(Suppl 2):79-84, 2001]

Introduction

For the past 3 decades, fluorouracil (5-FU)-basedchemotherapy has been the mainstay of therapy for advanced gastrointestinal cancer. Whengiven alone to colorectal cancer patients as a weekly intravenous bolus or for 5consecutive days every 4 to 5 weeks, 5-FU produced response rates ranging from11% to 17% and was associated with a median survival of approximately 1year.[1-3] Although the increased efficacy of 5-FU (in terms of higher responserates) via biomodulation with leucovorin has been well established, ameta-analysis of clinical studies failed to demonstrate a clear survivalbenefit.[4,5]

Moreover, evidence has accumulated that prolonged infusion of5-FU may improve its antitumor effect when compared with 5-FU bolusregimens.[6,7] However, no significant differences in overall survival time werefound when bolus 5-FU, administered according to the North Central CancerTreatment Group (NCCTG)-regimen, was given with one of several 5-FU regimensincluding infusional 5-FU.[8] These data correspond with the recent results of arandomized trial conducted by the European Organization for Research andTreatment of Cancer (EORTC-GICCTG) that compared low-dose leucovorin-modulatedbolus 5-FU with a weekly schedule of high-dose infusional 5-FU/leucovorin inpatients with metastatic colorectal cancer.[9] Thus, significant emphasis hasbeen placed on designing more effective 5-FU-based combination protocols.Promising results were achieved recently with combinations of 5-FU/leucovorinand either irinotecan (CPT-11, Camptosar) or oxaliplatin (Eloxatin). Thesecombinations proved superior to conventional 5-FU/leucovorin schedules,especially in colorectal cancer.[10-16]

5-FU-BasedCombination Protocols

Irinotecan and Fluorouracil

For the combination of irinotecan and 5-FU, three schedules werecarried forward in two large randomized phase III trials: (a) irinotecan at 125mg/m2, leucovorin at 20 mg/m², and 5-FU at 500 mg/m2 on a weekly ´ 4schedule (Saltz regimen),[17] (b) irinotecan at 80 mg/m2 in combination withleucovorin at 500 mg/m2 (2-hour infusion), and 5-FU at 2.6 g/m2 (24-hourinfusion) on a weekly ´ 6 schedule (AIO schedule),[18] or (c) the biweeklyschedule of irinotecan at 180 to 200 mg/m2 in combination withleucovorin-modulated infusional 5-FU administered according to the de Gramontschedule (leucovorin at 200 mg/m2 (2-hour infusion), followed by 400 mg/m2 of5-FU bolus, and then 600 mg/m2 of 5-FU by continuous infusion over 22 hours ondays 1 and 2 every 14 days).[19]

Saltz Regimen

In the first trial, the weekly ´ 4 regimen of irinotecan andbolus 5-FU/leucovorin (Saltz regimen) was compared with conventional low-doseleucovorin/5-FU (Mayo-Clinic protocol).[12] In an intent-to-treat analysis,treatment with the combination of irinotecan and 5-FU/leucovorin resulted in asignificantly higher remission rate (P < .001), significantly longerprogression-free survival time (P = .004), and significantly longer mediansurvival (P = .04) when compared to leucovorin/5-FU alone. National CancerInstitute Common Toxicity Criteria (NCI-CTC) grade 3 and 4 diarrhea was observedin 23% of patients in the combination arm and 13% of patients treated withleucovorin/5-FU alone. On the other hand, there was a significantly higherincidence of grade 4 neutropenia (42%) in patients receiving 5-FU/leucovorinalone compared to those receiving irinotecan/5-FU (24%). Furthermore, it couldbe demonstrated that treatment with the combination ofirinotecan/leucovorin/5-FU had no detrimental effect on overall quality of lifeand global health status compared to 5-FU/leucovorin alone.

AIO Schedule orde 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-hourinfusion of 2.3 g/m2 of 5-FU (AIO schedule) or the biweekly de Gramontregimen.[13] Participating centers had to choose one of the two schedules. Inthe 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 deGramont schedule).

A response rate of 41% was achieved with the combinationcompared to 23% with leucovorin/5-FU alone (P < .001). Moreover, the mediantime to disease progression (P < .001) and median survival (P < .028)showed a significant advantage for the combination arm with irinotecan vs thecontrol arm. The incidence of grade 3 and 4 neutropenia was higher in theirinotecan/5-FU arm, but did not translate into a significantly higher incidenceof either neutropenic fever or infection. There was also slightly more grade 3and 4 diarrhea (24% of patients) in the combination arm compared toleucovorin/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 orin accordance with the de Gramont schedule has been compared to the sameleucovorin/5-FU regimen alone in two randomized multicenter phase IIItrials.[15,16] The combination of oxaliplatin with leucovorin/5-FU significantlyimproved overall response rate and median time to disease progression in bothtrials; however, median survival was not significantly prolonged in thesestudies.

UFT Combinations

UFT is an orally administered fixed combination of tegafur anduracil in a 1:4 molar ratio. Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) isabsorbed intact via the gastrointestinal tract and is then converted to 5-FU byhepatic microsomal cytochrome P450 enzymes, as well as through soluble enzymehydrolysis. Uracil is a competitive inhibitor of dihydropyrimidine dehydrogenase(DPD). Preclinical studies demonstrated that the addition of uracil to tegafurin these concentrations significantly increased the tumor-to-serum andtumor-to-normal tissue ratios of 5-FU.[3,20,21] Co-administration of leucovorinto UFT further enhanced the activity of UFT as shown in preclinical and clinicalstudies.[21,22]

The results of clinical trials demonstrate that UFT, with orwithout leucovorin, can be safely administered over weeks and even months. Thecompound is associated with a favorable toxicity profile compared to bolus5-FU/leucovorin, with diarrhea being the main toxicity.[23,24]

UFT, with or without leucovorin, induces overall response ratesin gastrointestinal tumors comparable to those achieved with bolus5-FU/leucovorin.[20,23-29] These experiences prompted further investigation ofUFT 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 fluoropyrimidinecarbamate that is converted to fluorouracil by three enzymes located in theliver and tumor tissue.[30,31] The final step is the conversion of5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-FU by thymidine phosphorylasepreferentially in tumor tissue.

The high thymidine phosphorylase expression in tumor cellsselectively enhances 5-FU concentrations, and may result in higher antitumoractivity and decreased drug levels in nontumor tissue, with a consequentreduction in systemic toxicity.[32] Preclinical studies on human tumorxenografts suggest that the antitumor efficacy of capecitabine is superior tothat of UFT or 5-FU. In these in vivo models, capecitabine was less toxic to theintestinal tract, indicating a higher therapeutic potential.[31] Capecitabine isassociated 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 Clinicprotocol) 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 nosignificant differences in time to disease progression and overall survival wereobserved between capecitabine and bolus 5-FU/leucovorin (time to progression:4.6 months vs 4.7 months, respectively, and overall survival time 12.9 monthsfor both).

Although hand-foot-syndrome occurred more often in patientsreceiving capecitabine than in those receiving bolus 5-FU/leucovorin, itresulted in only two hospitalizations. Furthermore, the treatment-relatedhospitalization rate was significantly reduced in patients treated withcapecitabine. The results of the integrated analysis of both trials demonstratethat capecitabine offers a convenient alternative to bolus 5-FU/leucovorin witha superior safety profile and equivalent antitumor efficacy.

Considering the antitumor activity and safety profile of theoral fluoropyrimidine prodrugs (UFT, capecitabine), different combinations withother cytotoxic agents active in gastrointestinal cancer, such as mitomycin C(Mutamycin), irinotecan, and the platinum analogs are currently under clinicalinvestigation in gastrointestinal cancer.

UFT/LeucovorinCombination Therapy

The combination of irinotecan and UFT, with or withoutleucovorin, is under investigation in different schedules as first- andsecond-line therapy for advanced colorectal cancer.[38,39] Escuder and coworkersconducted a phase I/II trial of a weekly ´ 3 schedule of irinotecan at a doseof 80 mg/m2 to 120 mg/m2 and UFT at a fixed dose of 250 mg/m2, days 1 to 21,repeated every 4 weeks.[38] Of 18 patients entered into the trial, one hadreceived prior chemotherapy for advanced disease. The recommended doses forfurther phase II studies were irinotecan at 110 mg/m2 and UFT at 250 mg/m2.Dose-limiting toxicity consisted of diarrhea. No objective responses wereobserved but 12 of 18 patients (66%) had stable disease and the median time todisease progression was 3.5 months.

Hill and coworkers recently reported the results of a phase I/IItrial of irinotecan (dose range: 200 mg/m2 to 300 mg/m2 on day 1) incombination with UFT (dose range: 250 mg/m2 to 350 mg/m2, days 1 to 14) and afixed dose of leucovorin (90 mg per day).[39] The study enrolled 33 patients whoreceived treatment with the recommended dose of irinotecan at 250 mg/m2 and UFTat 250 mg/m2. The dose limiting toxicities were neutropenic fever and diarrhea.So far, 16 patients are response-evaluable including those being entered intothe phase II part of the study. One patient achieved a complete response and 3of 16 patients (18.8%) achieved a partial response.

Gravalos and coworkers reported the results of a phase I studyof UFT/leucovorin in combination with irinotecan administered on aonce-every-3-week schedule.[40] The study enrolled 17 pretreated patients withadvanced colorectal cancer. The maximum tolerated dose was UFT at 300 mg/m2,leucovorin at 45 mg po (fixed dose) on days 1 to 14, and irinotecan at 300mg/m2 on day 1, repeated every 3 weeks. Diarrhea was the dose-limiting toxicityand 4 of 13 patients achieved an objective response.

Oxaliplatin and UFT/ Leucovorin

The combination of oxaliplatin with UFT/leucovorin has beenevaluated in a phase II study as first-line therapy for metastatic colorectalcancer.[41] Oxaliplatin was administered at a dose of 85 mg/m2 on days 1 and14, UFT at a dose of 390 mg/m2 per day for 14 days plus l-leucovorin 250 mg/m2on day 1 followed by l-leucovorin at a dose of 7.5 mg po every 12 hours on days2 to 14. Cycles were repeated every 3 weeks.

High intestinal toxicities in this study (grade 3 and 4 diarrheaand nausea occurred in 56% and 18%, respectively) resulted in a reduction in thedose of UFT to 300 mg/m2 per day after the first 16 patients receivedtreatment. A partial response was achieved by 12 of 34 patients (35%). The finalresults of other phase I studies of UFT/leucovorin in combination with eitheririnotecan or oxaliplatin are not yet published.[42,43]

UFT Plus Raltitrexed

The synergistic cytotoxic interactions between raltitrexed(Tomudex) and 5-FU in preclinical models led to a phase I/II dose-escalationstudy of UFT (dose range: 200 mg/m2 to 350 mg/m2, days 1 to 28) andraltitrexed (dose range: 2.0 mg/m2 to 3.5 mg/m2 IV, days 1 and 21) followed bya 2-week rest.[44] The dose-limiting toxicity was diarrhea. To date, 22 patientshave been enrolled and the maximum tolerated dose has not been reached atdose-level 5 (raltitrexed 3.0 mg/m2; UFT 300 mg/m2) suggesting that both drugscan be combined at the doses recommended for monotherapy.

Based on the results of a phase I trial of UFT and mitomycin(recommended dose for phase II trials: UFT 400 mg/m2, mitomycin 6 mg/m2), 21response-evaluable patients were treated with this combination. The overallresponse rate was 24% (5 of 21 patients) and 38.5% (5 of 13 patients) forpreviously untreated patients.[45]

UFT/LeucovorinCombinations in Esophagealand Stomach Cancer

UFT/leucovorin-based combinations have also been investigated incarcinomas of the esophagus, the esophagogastric junction, and the stomach. Mostof these trials were conducted as small phase I or II trials in Japan. In arandomized trial, Yonemura and coworkers treated 55 patients with advanceddisease with a combination of cisplatin (Platinol) at a dose of 75 mg/m2,mitomycin 10 mg/m2 on day 1, and etoposide (VePesid) (150 mg/m2 IV) and UFT400 mg/day on days 3, 4, and 5 (PMUE).[46] The regimen was administered to 29patients in a neoadjuvant setting and 26 patients, postoperatively. Observedresponse rates were 62% and 35%, respectively.

In another trial, a response rate of 23.5% (4 of 17 responseevaluable patients) was reported for the combination of UFT, cisplatin, andmitomycin. Grade 3 and 4 toxicities were reported in 20% of patients.[47]

Cisplatin and UFT/Leucovorin

The combination of cisplatin (50 mg/m2, continuous infusion[CI] days 1 and 2), 5-FU (500 to 750 mg/m2 CI, days 2 to 7) and UFT (400 mg/d,days 8 to 28) induced a response rate in 2 of 8 patients (25%) with esophagealcancer and in 4 of 13 patients (31%) with gastric cancer.[48] Major side effectsof this regimen were anorexia, nausea/vomiting, and leukocytopenia. When UFT wasadded to a regimen of etoposide, doxorubicin (Adriamycin), and cisplatin(Platinol) (UFT-EAP) in 34 patients with advanced tumors, the response rate was47% and included four complete responses and a median remission duration of 12months.[49] This regimen was felt to be well tolerated; myelosuppression was themain side effect.

A 28-day course of UFT (400 mg/m2) and cisplatin (30 mg/m2,days 1 to 3) resulted in a response rate of 43% (6 of 14 patients) and a mediansurvival time of 11.4 months.[50] With a different schedule of cisplatin (80mg/m2 on day 8) and UFT (400 mg/m2, days 1 to 21), a response rate of 52% anda median survival of 8.3 months were reported by Sato et al.[51] This regimenwas associated with acceptable toxicities.

The Spanish Oncopaz Cooperative Group evaluated UFT (390 mg/m2,days 1 to 14) plus leucovorin (500 mg/m2 IV on day 1, then 15 mg every 12 hoursorally on days 2 to 14) in combination with etoposide (100 mg/m2 IV, day 1 and200 mg/m2 orally on days 2 and 3).[52] Responses among 46 patients included 5(11%) complete and 12 (26%) partial responses, and a median survival of 9months. Grade 3 and 4 diarrhea (according to WHO) was observed in 17% of allpatients; 1 patient died of neutropenia and sepsis.

Epirubicin, Cisplatin, and UFT/Leucovorin Combinations

Based on the positive results reported with epirubicin,cisplatin, and 5-FU (ECF) administered as continuous infusion over 21 weeks,three groups replaced 5-FU in the ECF regimen with UFT/leucovorin.[53-55] Kimand coworkers administered epirubicin (50 mg/m2) and cisplatin (60 mg/m2) onday 1 and UFT (360 mg/m2) plus a fixed dose of leucovorin (40 mg po) for 21days.[53] Cycles were repeated every 4 weeks. Of 46 patients with advancedgastric cancer entered into the trial, 3 achieved a complete response and 22achieved a partial response resulting in an overall response rate of 54.3% and amedian survival of 10 months. Treatment-related grade 3 and 4 toxicities wereleukopenia (36%), mucositis (6%), and diarrhea (6%). The authors considered thisregimen significantly active and tolerable.

In a phase I/II study, 30 previously untreated patients withadvanced upper gastrointestinal cancer were treated with the same doses ofepirubicin and cisplatin administered every 3 weeks and a continuousadministration of UFT (150 mg/m2 to 325 mg/m2) plus a fixed dose of oralleucovorin (45 mg on days 1, 8, and 15).[54] The dose of UFT recommended forfurther study was 200 mg/m2 per day. Among 15 patients with gastroesophagealcancer, 9 objective responses including 2 complete responses were reported.Severe side effects were infrequent with this combination. Both studies indicatethat UFT/leucovorin in combination with cisplatin and epirubicin may becomparable in efficacy to the original ECF regimen. These results need to beconfirmed further in randomized studies.

The preliminary toxicity analysis of another ongoing trialindicates that a regimen of epirubicin/cisplatin/UFT (ECU) is less toxic andmore convenient compared to the ECF regimen.[55]

Gallardo et al reported the results of a combination ofepirubicin, cisplatin, and oral tegafur (ECT) in patients with advanced gastriccancer.[56] In this study, 20 patients received epirubicin at 60 mg/m2 andcisplatin at 70 mg/m2 IV on day 1, oral tegafur at 700 mg/m2 for 14 days incombination with a fixed dose of oral l-leucovorin (25 mg). The overall responserate was 50% (7 of 14 response evaluable patients) and six patients had stabledisease. Major toxicities included grade 3 and 4 neutropenia and grade 3thrombocytopenia.

In addition, combination chemotherapy of UFT, with or withoutleucovorin, was also evaluated in cancer of the pancreatico-biliary tract. Feliuet al investigated the combination of gemcitabine (Gemzar) at a dose of 1,000mg/m2 on a once-weekly ´ 3 schedule in combination with UFT (390 mg/m2, days1 to 14) plus leucovorin (l-form 250 mg/m2 IV on day 1 followed by 7.5 mg every12 hours on days 2 to 14).[57] Cycles were repeated every 4 weeks and 42patients with measurable pancreatic cancer were entered into the study.

Among 38 response evaluable patients, six (16%) achieved apartial response and 15 (39%) had stable disease. An improvement in performancestatus and symptoms was reported in 29% and 45% of patients, respectively, with18 patients (47%) achieving a response. The regimen was well tolerated andappeared to be a meaningful palliative treatment for this tumor entity.

CapecitabineCombination Therapy

The modest toxicity of capecitabine, particularly its lowincidence of neutropenia, makes it a suitable candidate for fluoropyrimidinecombination therapies involving other cytotoxic agents (eg, irinotecan andoxaliplatin) that are active in gastrointestinal cancer. Moreover, most of thefluoropyrimidine combinations either with oxaliplatin or irinotecan are based oninfusional 5-FU regimens (AIO- or de Gramont schedule) associated with theinconvenience of central catheters and portable pumps.[13,15,16] Thus,capecitabine combinations with irinotecan or oxaliplatin are currently underclinical investigation for colorectal cancer.[58-60]

Capecitabine and Irinotecan

An extended phase I study evaluated the combination ofcapecitabine with a weekly schedule of irinotecan.[58] Capecitabine wasadministered on days 1 to 14 and 22 to 35 every 7 weeks at doses of 1,000 mg/m2or 1,250 mg/m2 twice daily. Irinotecan was administered on a weekly ´ 6schedule at doses of 70 mg/m2 and 80 mg/m2. All patients had metastaticcolorectal cancer, measurable disease, and had received no prior chemotherapyfor metastatic disease. Preliminary data from 37 patients demonstratedsignificant antitumoral activity, with neutropenia and diarrhea beingdose-limiting. Notably, only a few patients experienced hand-foot syndrome. Thedose of 1,000 mg/m2 of capecitabine twice daily for days 1 to 14 and 22 to 35 incombination with weekly irinotecan at a dose of 70 mg/m2 has been considered therecommended dose for further phase II studies.

A second pilot study investigated two different doses andschedules of capecitabine and irinotecan in advanced colorectal cancer: (a)irinotecan at 300 mg/m2 on day 1 every 3 weeks; or (b) irinotecan at a dose of150 mg/m2 on days 1 and 8 every 3 weeks. Capecitabine was administered with bothschedules of irinotecan at 1,250 mg/m2 twice daily for 14 days followed by a1-week rest period. This study entered 19 patients, 5 of whom had received priorchemotherapy for metastatic disease.[59] For both schedules, the most commonrelated toxicities were diarrhea, neutropenia, and hand-foot-syndrome. Partialresponses were reported for 13 of 17 response-evaluable patients (76%, 95%confidence interval: 50%-93%).

Oxaliplatin and Capecitabine

Oxaliplatin has significant efficacy in colorectal cancer.[10]Moreover, preclinical data suggest that the synergistic antitumor activity ofthe fluoropyrimidines and oxaliplatin may partially overcome resistance to thefluoropyrimidines. Thus, the combination of capecitabine with oxaliplatin hasbeen investigated.[60] In a phase I study of advanced solid tumors, the dose ofcapecitabine was escalated from 500 mg/m2 (starting dose) to 1,250mg/m2 twicedaily on days 1 to 14 followed by a 1-week rest period. Oxaliplatin wasadministered at a fixed dose of 130 mg/m2 on day 1 of each 21-day cycle.Twenty-three patients who had progressed with prior chemotherapy have beenenrolled. Dose-limiting toxicities were diarrhea, thrombocytopenia, and neutropenia. The doses recommended for further phase II studies were suggested asfollows: capecitabine at 1,000 mg/m2 twice daily for 14 days combined withoxaliplatin at 130 mg/m2 on day 1 every 21 days. Five of nine patients (56%)with advanced colorectal cancer achieved a response.

The results of this phase I trial demonstrate that thecombination of capecitabine and oxaliplatin was well tolerated and had promisingantitumor activity in colorectal cancer. The combination of capecitabine andoxaliplatin is currently under clinical evaluation as first-line therapy forpatients with metastatic colorectal cancer.

Conclusions

Oral fluoropyrimidine prodrugs could become an importantcomponent of our therapeutic armamentarium in the treatment of gastrointestinalcancer. Two large randomized phase III trials in metastatic colorectal cancerdemonstrated that capecitabine offers a convenient alternative to bolus5-FU/leucovorin with a superior safety profile and equivalent antitumoractivity.[35,36] Similar results have been achieved with UFT/leucovorin in tworandomized trials.[23,24] S-1, a fixed combination of5-chloro-2,4-dihydroxypyrimidine (CDHP), ftorafur, and oxonic acid is also underinvestigation in gastrointestinal cancer and may constitute another promisingapproach in the treatment of gastrointestinal cancer.[61]

Based on these results, fluoropyrimidine prodrug-basedcombination therapy (eg, combinations with either irinotecan, oxaliplatin,anti-EGF- or VEGF-receptor mAb, or tyrosine kinase inhibitors) forgastrointestinal cancer deserves further clinical investigation in themetastatic or adjuvant setting.

Questions and Answers

Dr Haller: Just a question in terms of choosing the weeklyirinotecan regimen vs a less frequent regimen as you approach myelosuppression.It’s hard to use growth factors with weekly regimens. Could you contemplatedoing the same schedule of capecitabine with thrice weekly irinotecan, therebyallowing for use of growth factors?

Dr. Vanhoefer: With the weekly schedule of irinotecan incombination with capecitabine, we have not observed significantmyelosuppression, so we did not have to use growth factors.

Dr. Haller: Part of your dose limiting toxicity (DLT) wasneutropenia though. Is this correct.

Dr. Vanhoefer: Yes, neutropenia was reported in 2 of 17patients.

Dr. Saltz: I have two thoughts about that. One is that we havebeen able in those rare patients where neutropenia alone is the DLT, to useG-CSF with weekly irinotecan and I think it seems to get them through it. Myconcern is that we already have to stretch a little bit to go for the rationaleof the oral fluorinated pyrimidine with the parenteral other agent, be itoxaliplatin or irinotecan, and I don’t know that we know yet if that’s theright thing to do.

Dr. Vanhoefer: There’s a difference between Europe and theUnited States. In Europe, combination regimens are based on infusional schedulesof fluorouracil such as the biweekly deGramont or weekly AIO schedule. Theseregimens are associated with portable pumps. In addition, drug intake andtoxicity may be better managed by a weekly schedule. Therefore, it might be avery interesting approach to substitute capecitabine for the infusional 5-FU.

Dr. Saltz: The interesting question that I’ve been concernedabout and thinking about in combining all of these agents with irinotecan, is towhat effect the rise in bilirubin that we see on occasion will influenceirinotecan metabolism. Any idea?

Dr. Vanhoefer: For those patients, who have been treated withcapecitabine, we have had no problems.

Dr. Saltz: In this trial, have you seen people with rise in thebilirubin?

Dr. Vanhoefer: No. We also have no problems with the phase I andII trials.

References:

1. Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med330:1136-1142, 1994.

2. Machover D: A comprehensive review of 5-fluorouracil andleucovorin in patients with metastatic colorectal carcinoma. Cancer80:1179-1187, 1997.

3. Rustum YM, Harstrick A, Cao S, et al: Thymidylate synthaseinhibitors in cancer therapy: Direct and indirect inhibitors. J Clin Oncol15:389-400, 1997.

4. Valone FH, Friedman MA, Wittlinger PS, et al: Treatment ofpatients with advanced colorectal carcinoma with fluorouracil alone, high-doseleucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, andleucovorin: A randomized trial of the Northern California Oncology Group. J ClinOncol 7:1427-1436, 1989.

5. Advanced Colorectal Cancer Meta-Analysis Project: Modulationof fluorouracil by leucovorin in patients with advanced colorectal cancer:Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.

6. De Gramont A, Bosset JF, Milan C, et al: Randomized trialcomparing monthly low-dose leucovorin and fluorouracil bolus with bimonthlyhigh-dose leucovorin and fluorouracil bolus plus continuous infusion foradvanced colorectal cancer: A French Intergroup Study. J Clin Oncol 15:808-815,1997.

7. Meta-analysis Group in Cancer: Efficacy of intravenouscontinuous infusion of fluorouracil compared with bolus administration inadvanced colorectal cancer. J Clin Oncol 16:301-308, 1998.

8. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study offluorouracil and its modulation in advanced colorectal cancer: A SouthwestOncology Group Study. J Clin Oncol 13:1303-1311, 1995.

9. Schmoll HJ, Köhne CH, Lorenz M, et al: Weekly 24-h infusionof high-dose 5-fluorouracil, with or without folinic acid, vs bolus 5-FU/folinicacid (NCCTG/Mayo) in advanced colorectal cancer: A randomized phase III study ofthe EORTC GITCCG and the AIO (abstract 935). Proc Am Soc Clin Oncol 19:241a,2000.

10. Cvitkovic E, Bekradda M: Oxaliplatin: A new therapeuticoption in colorectal cancer. Semin Oncol 26:647-662, 1999.

11. Vanhoefer U, Harstrick A, Achterrath W, et al: Irinotecan inthe treatment of colorectal cancer: A clinical overview. J Clin Oncol, 2001 (inpress).

12. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plusfluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan StudyGroup. N Engl J Med 343(13):905-914, 2000.

13. Douillard JY, Cunningham D, Roth AD, et al: Irinotecancombined with fluorouracil compared with fluorouracil alone as first-linetreatment for metastatic colorectal cancer: A multicentre randomised trial.Lancet 355:1041-1047, 2000.

14. Knight RD, Miller LL, Pirotta N, et al: First-lineirinotecan (C) fluorouracil (F), leucovorin (L) especially improves survival(DS) in metastatic colorectal cancer (MCRC) patients (PT) with favorableprognostic indicators (abstract 991). Proc Am Soc Clin Oncol 19:255a, 2000.

15. Giacchetti S, Perpoint B, Zidani R, et al: Phase IIImulticenter randomized trial of oxaliplatin added to chronomodulatedfluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.J Clin Oncol 18:136-147, 2000.

16. De Gramont A, Figer A, Seymour M, et al: Leucovorin andfluorouracil with or without oxaliplatin as first-line treatment in advancedcolorectal cancer. J Clin Oncol 18: 2938-2947, 2000.

17. Saltz LB, Kanowitz J, Kemeny NE, et al: Phase I clinical andpharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patientswith advanced solid tumors. J Clin Oncol 14:2959-2967, 1996.

18. Vanhoefer U, Harstrick A, Köhne CH, et al: Phase I study ofa weekly schedule of irinotecan, high-dose leucovorin, and infusionalfluorouracil as first-line chemotherapy in patients with advanced colorectalcancer. J Clin Oncol 17:907-913, 1999.

19. Ducreux M, Ychou M, Seitz JF, et al: Irinotecan combinedwith bolus fluorouracil, continuous-infusion fluorouracil, and high-doseleucovorin every 2 weeks (LV5FU2 regimen): A clinical dose-finding andpharmacokinetic study in patients with pretreated metastatic colorectal cancer.J Clin Oncol 17:2901-2908, 1999.

20. Sulkes A, Benner E, Canetta RM: Uracil-ftorafur: An oralfluoropyrimidine active in colorectal cancer. J Clin Oncol 16:3461-3475, 1998.

21. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: Areview of its clinical development and therapeutic potential in the oraltreatment of cancer. Anticancer Drugs 9:479-490, 1998.

22. Taguchi T: Clinical application of biochemical modulation incancer chemotherapy: Biochemical modulation of 5-FU. Oncology 54:12-18, 1997.

23. Pazdur R, Douillard JY, Skillings JR, et al: Multicenterphase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin(LV) in patients with metastatic colorectal cancer (abstract). Proc Am Soc ClinOncol 18:263a, 1999.

24. Carmichael J, Popiela T, Radstone D, et al: randomizedcomparative study of Orzel (oral uracil-tegafur (UFT) plus leucovorin (LV) vsparenteral 5-fluorouracil (5-FU) plus LV in patients with metastatic colorectalcancer (abstract). Proc Am Soc Clin Oncol 18:264a, 1999.

25. Kim YH, Shin SW, Kim BS, et al: A phase II trial of oral UFTand leucovorin in patients with advanced gastric cancer. Oncology 11(suppl10):119-123, 1997.

26. Takiuchi H, Ajani JA: Uracil-tegafur in gastric carcinoma: Acomprehensive review. J Clin Oncol 16 (8):2877-2885, 1998.

27. Ravaud A, Borner M, Schellens JH, et al: UFT and oralcalcium folinate as first-line chemotherapy for metastatic gastric cancer.Oncology 13(suppl 3):61-63, 1999.

28. Mani S, Kugler JW, Sciortino DF, et al: Phase II trial ofuracil/tegafur (UFT) plus leucovorin in patients with advanced pancreaticcarcinoma: A University of Chicago phase II consortium study. Ann Oncol9:1035-1037, 1998.

29. Mani S, Sciortino DF, Samuels B, et al: Phase II trial ofuracil/tegafur (UFT) plus leucovorin in patients with advanced biliarycarcinoma. Invest New Drugs 17(1):97-101, 1999.

30. Ishikawa T, Utoh M, Sawada N, et al: Tumor selectivedelivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidinecarbamate, in human cancer xenografts. Biochem Pharmacol 55:1091-1107, 1998.

31. Ishikawa T, Fukase Y, Yamamoto T, et al: Antitumoractivities of a novel fluoropyrimidine,N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (capecitabine). Biol Pharm Bull21:713-717, 1998.

32. Miwa M, Ura M, Nishida M, et al: Design of a novel oralfluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracilselectively in tumours by enzymes concentrated in human liver and cancer tissue.Eur J Cancer 34:1274-1281, 1998.

33. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase IIstudy of capecitabine in paclitaxel-refractory metastatic breast cancer. J ClinOncol 17:485-493, 1999.

34. Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine,an oral fluoropyrimidine carbamate with substantial activity in advancedcolorectal cancer: Results of a randomized phase II study. J Clin Oncol18:1337-1345, 2000.

35. Twelves C, Harper P, Van Cutsem E, et al: A phase III trial(SO 14796) of Xeloda ( capecitabine) in previously untreated advanced metastaticcolorectal cancer (abstract). Proc Am Soc Clin Oncol 18:263a, 2000.

36. Cox JV, Pazdur R, Thibault A, et al: A phase III trial of(Xeloda) capecitabine in previously untreated advanced metastatic colorectalcancer (abstract). Proc Am Soc Clin Oncol 18:265a, 2000.

37. Hoff P: Capecitabine as first-line treatment for colorectalcancer (CRC): Integrated results of 1207 patients (pts) from two randomized,phase III studies. On behalf of the Capecitabine CRC Study Group. Ann Oncol11(suppl 4):263PD, 2000.

38. Escudero P, Vicente A, Herrero A, et al: Phase I/II trial ofirinotecan (CPT-11) over a short IV weekly infusion combined with a fixed doseof UFT in second-line advanced colorectal carcinoma (ACRC) (abstract 1136). ProcAm Soc Clin Oncol 19:290a, 2000.

39. Hill M, Mackay H, Cunningham D, et al: Phase I/II study withoral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advancedcolorectal cancer. Ann Oncol 11(suppl 4):193p, 2000.

40. Gravalos C, Garcia-Alfonso, P, Castellanos D, et al: Phase Itrial of escalating doses of irinotecan (CPT-11) in combination with UFT/folinicacid (FA) in patients with advanced colorectal cancer (CRC). Ann Oncol 11(suppl2):199P, 2000.

41. Dorta FJ, Feliú J, Vicent J, et al: Phase II clinical trialwith the combination of oxaliplatin-UFT-l,-leucovorin (OXA-UFT-l,LV) for thefirst line treatment of advanced colorectal cancer (ACC). Preliminary results(Oncopaz Cooperative Group - Spain). Ann Oncol 11(suppl 4):220P, 2000.

42. Schilling G, Lipp R, Hegewisch-Becker S: UFT/leucovorin plusweekly irinotecan in advanced or metastatic colorectal cancer. Oncology 14(10suppl 9):38-40, 2000.

43. Stevenson JP, Redlinger M, Sun W, et al: Irinotecan andUFT/leucovorin in patients with advanced cancers. Oncology 14(suppl 9):91-92,2000.

44. Mel JR, Vieitez JM, Garcia Alfonso P, et al: Raltitrexed(Tomudex) combined with UFT: A phase I/II dose-escalation study in metastaticCRC (abstract 1108). Proc Am Soc Clin Oncol 19:283a, 2000.

45. Ikeda E, Kodaira S, Teramoto T, et al: Optimal dosage of UFT—MMCcombination chemotherapy for advanced colorectal cancer—phase I/II study ofcombination chemotherapy of MMC with 2-week intervals and intermittent UFTadministration—Study Group of UFTM therapy for advanced colorectal cancer. GanTo Kagaku Ryoho 23:1291-1298, 1996.

46. Yonemura Y, Sawa T, Kinoshita K, et al: Neoadjuvantchemotherapy for high-grade gastric cancer. World J Surg 17:261-262, 1993.

47. Iwazaki R, Yasutake K, Fukuyama Y, et al: UFTPM (UFT + CDDP+ MMC) therapy for progressive stomach cancer. Research Association ofProgressive Stomach Cancer. Gan To Kagaku Ryoho 20:1179-1185, 1993.

48. Hashimoto T, Omura K, Ishida F, et al: Clinical efficacy ofcis-diamminedichloro-platinum (II) and 5-fluorouracil (UFT) in advanced cancerof the alimentary tract. Gan To Kagaku Ryoho 20:1333-1338, 1993.

49. Hayakawa M, Morise K, Chin K, et al: Combinationchemotherapy with tegafur/uracil (UFT), etoposide, Adriamycin, and cisplatinum(UFT-EAP) for advanced gastric cancer. Jpn J Clin Oncol 24:282-288, 1994.

50. Sato A, Hasegawa K, Kurihara M, et al: Combinationchemotherapy with tegafur-uracil (UFT) and cisplatin (CDDP) for advanced gastriccancer. UFTP Study Group. Gan To Kagaku Ryoho 22:1355-1362, 1995.

51. Sato A, Kurihara M, Koizumi W, et al: A phase II study ofUFT plus cisplatin (UFTP) therapy in patients with advanced gastric cancer(abstract 1087). Proc Am Soc Clin Oncol 19:279a, 2000.

52. Gonzales Baron M, Espinosa E, Feliu J, et al: TheUFT/leucovorin/etoposide regimen for the treatment of advanced gastric cancer.Oncopaz Cooperative Group. Oncology 11(suppl 10):109-112, 1997.

53. Kim YH, Shin SW, Kim BS, et al: Phase II trial of epirubicin(E), cisplatin (P), oral UFT and leucovorin (L) in advanced gastric carcinoma(AGC) patients. Ann Oncol 11(suppl 4):2740, 2000.

54. Seymour MT, Dent JT, Papamichael D, et al: Epirubicin,cisplatin and oral UFT with leucovorin (ECU): A phase I-II study in patientswith advanced upper gastrointestinal tract cancer. Ann Oncol 10:1329-1333, 1999.

55. Bernabe R, Reina J, Salvador J, et al: Epirubicin,cisplatin, and UFT (ECU): A less toxic regimen in the treatment of advancedgastric cancer (abstract 1207). Proc Am Soc Clin Oncol 19:306a, 2000.

56. Gallardo E, Arcusa A, Saigi E, et al: Epirubicin, cisplatinand oral tegafur with levofolinate (ECT) in patients with advanced gastriccancer (AGC): A pilot study. Ann Oncol 11(suppl 4):285P, 2000.

57. Feliu J, Lopez Alvarez MP, Jaraiz MA, et al: Phase II trialof gemcitabine and UFT modulated by leucovorin in patients with advancedpancreatic carcinoma. Cancer 89:1706-1713, 2000.

58. Vanhoefer U, Mayer S, Achterrath W, et al: Phase I study ofcapecitabine in combination with a weekly schedule of irinotecan as first-linechemotherapy in metastatic colorectal cancer. Ann Oncol 11(suppl 4):212P, 2000.

59. Cassata A, Alù M, Beretta E, et al: Capecitabine incombination with two schedules of irinotecan (CPT-11) in advanced colorectalcancer: A pilot experience. Ann Oncol 11(suppl 4):192P, 2000.

60. Evans J, Tabernero J, Cassidy J, et al: Safety profile andpreliminary efficacy of capecitabine (Xeloda) in combination with oxaliplatin inpatients with advanced or metastatic solid tumors: Results from a phase I study.Ann Oncol 11(suppl 4):222P, 2000.

61. Vermorken J, Schöffski P, Schellens J, et al: S-1 incolorectal cancer (CRC): Interim results of an early phase II study. Ann Oncol11(suppl 4):262PD, 2000.