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]
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. 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. 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]
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), (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), 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).
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). 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. 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, a trans-l-1-diaminocyclohexan-oxalato[DACH]-platinum analog, has also shown efficacy in colorectal cancer.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 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 (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. 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. 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]). 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.
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. 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). 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. 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. 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. 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.
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). 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.
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. 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. 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. 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. 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). 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. 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). 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.
Gallardo et al reported the results of a combination ofepirubicin, cisplatin, and oral tegafur (ECT) in patients with advanced gastriccancer. 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). 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.
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. 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. 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.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. 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.
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.
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.
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.
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