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Journal of Clinical Oncology, Vol 19, Issue 15 (August), 2001: 3456-3462
© 2001 American Society for Clinical Oncology

Sequence Effect of Irinotecan and Fluorouracil Treatment on Pharmacokinetics and Toxicity in Chemotherapy-Naive Metastatic Colorectal Cancer Patients

By Alfredo Falcone, Antonello Di Paolo, Gianluca Masi, Giacomo Allegrini, Romano Danesi, Monica Lencioni, Elisabetta Pfanner, Silvia Comis, Mario Del Tacca, Pierfranco Conte

From the Division of Medical Oncology, Department of Oncology, Civil Hospital, Livorno; Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, and Division of Medical Oncology, Department of Oncology, S Chiara Hospital, Pisa; and Aventis, Milan, Italy.

Address reprint requests to Alfredo Falcone, MD, Divisione di Oncologia Medica, Presidio Ospedaliero, V.le Alfieri, 36, 57121 Livorno, Italy; email: a.falcone{at}do.med.unipi.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan’s maximum-tolerated dose (MTD).

PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle.

RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P < .05) when irinotecan preceded 5-FU.

CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
FLUOROURACIL (5-FU), since its introduction into clinical oncology almost 40 years ago, remains the most frequently used agent in metastatic colorectal cancer. Although it significantly prolongs survival and improves quality of life in patients with advanced disease, overall results remain unsatisfactory.1,2 Modulation by leucovorin (LV) and administration of 5-FU by continuous infusion have improved its antitumor activity but only marginally improved survival.3,4 More recently, new agents have demonstrated antitumor activity in metastatic colorectal cancer patients, including irinotecan (CPT-11), oxaliplatin, and raltitrexed.5 In particular irinotecan, a topoisomerase I inhibitor, has demonstrated lack of cross-resistance with 5-FU and antitumor activity both in chemotherapy-naive and 5-FU–pretreated patients.6,7 In phase III studies in metastatic colorectal cancer patients not responding to first-line 5-FU or who had progressed after first-line 5-FU, therapy with irinotecan improved survival compared with best supportive care or therapy with 5-FU by continuous infusion.8,9 Because of these findings, the combination of irinotecan and 5-FU has been extensively evaluated in preclinical models and in clinical trials.10 SN-38, the active metabolite of irinotecan, and 5-FU have demonstrated schedule-dependent interactions with respect to cytotoxicity against human tumor cells. Although it is generally agreed that the administration of irinotecan/SN-38 before 5-FU results in additive to synergistic effects in vitro,11-15 the best sequence of treatment in the clinical setting remains to be determined. Various schedules of irinotecan/5-FU/LV were investigated with promising results both in 5-FU–pretreated and in chemotherapy-naive metastatic colorectal cancer patients. Of interest, these clinical studies showed that 5-FU and irinotecan can be administered almost at full doses of each single agent with acceptable toxicities, particularly without an increase in the incidence of irinotecan-induced delayed diarrhea.16,17 A phase I study provided evidence that continuous-infusion 5-FU administered immediately after irinotecan might reduce SN-38 peak plasma concentrations (Cmax) and area under the concentration-versus-time curve (AUC), thus explaining the favorable toxicity profile of the combination.18 On the contrary, other phase I studies in which irinotecan was followed by bolus or infusional 5-FU did not show substantial changes in the distribution of irinotecan and its active metabolite SN-38.19,20

Because of these contrasting findings and the promising results of infusional 5-FU/LV/irinotecan combinations, this study was designed with the main purpose of investigating in metastatic colorectal cancer patients the sequence effect of irinotecan and a protracted 48-hour infusion of 5-FU modulated by LV on (1) the plasma pharmacokinetics of irinotecan and its metabolites, (2) the toxicity profile of this combination, and (3) the maximum-tolerated dose (MTD) or irinotecan.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
The main eligibility criteria included a histologically confirmed diagnosis of colorectal adenocarcinoma with metastatic disease, age <= 70 years, Eastern Cooperative Oncology Group performance status of <= 2, measurable disease, leukocyte count >= 3,500/mm3, platelet count >= 100,000/mm3, serum creatinine <= 1.3 mg/dL, serum bilirubin <= 1.5 mg/dL, and AST and ALT <= 2.5 times normal values. Previous adjuvant 5-FU–based chemotherapy completed at least 6 months earlier was allowed. Exclusion criteria were previous palliative chemotherapy, symptomatic cardiac disease, recent history of myocardial infarction, arrhythmia, active infections, and inflammatory bowel disease. The study was approved by the local ethics committee, and patients were informed of the investigational nature of the study and provided their written informed consent.

Study Design and Treatment
Eligible patients were randomized to receive irinotecan immediately before (day 1) or after (day 3) a 48-hour continuous infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle in the same patient, and following cycles were administered every 21 days according to the best tolerated schedule until disease progression, unacceptable toxicity, or patient refusal. 5-FU was administered as a 48-hour continuous infusion through an implantable central venous catheter and an external volumetric programmable pump (Deltec CADD-PLUS; Deltec Inc, St Paul, MN) at the fixed dose of 3,500 mg/m2. The L-isomer form of LV was infused at the dose of 250 mg/m2 over a 2-hour period in 250 mL of NaCL 0.9% before 5-FU. Irinotecan was infused over a 60-minute period in 250 mL of NaCl 0.9% at the starting dose of 150 mg/m2 in the first three patients; it was immediately followed by 5-FU when given on day 1 or it immediately followed 5-FU when given on day 3 (Fig 1). The MTD was defined, similarly to other phase I studies with irinotecan combinations,16 as the dose level associated with dose-limiting toxicity (DLT) in at least two out of three or three out of six patients. DLT was defined as any World Health Organization grade 3 to 4 nonhematologic toxicity, except for alopecia and vomiting, any grade 4 neutropenia lasting more than 3 days or associated with fever >= 38°C, and any grade 4 thrombocytopenia. In patients in whom DLT was observed after the first cycle, the second cycle was administered at the same irinotecan dose but with the reverse sequence, unless life-threatening toxicity occurred. If the MTD was reached only for one of the two irinotecan and 5-FU/LV sequences at the same dose level, the patients who followed were entered at the higher irinotecan dose level but without any randomisation, because all patients received the best tolerated schedule for which the MTD had not yet been reached.



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  		Fig 1. Treatment schedule.

 
To prevent nausea and vomiting, ondansetron 8 mg intravenously (IV) and dexamethasone 16 mg IV were administered before irinotecan. Atropine 0.25 mg was given subcutaneously in case of cholinergic syndrome and given prophylactically in the following cycles. Loperamide 2 mg orally every 2 hours and oral rehydration were prescribed in cases of delayed diarrhea. No prophylactic treatment with cytokines was used. Granulocyte colony-stimulating factor in combination with antibiotics was used in cases of grade 4 neutropenia and fever >= 38°C.

Pharmacokinetics
Pharmacokinetic analysis of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38glu), was performed in all patients receiving irinotecan at doses ranging from 150 to 300 mg/m2 at the first and second cycles of chemotherapy (total of 23 patients). Blood was drawn using a peripheral catheter placed in a forearm vein at baseline, 30 minutes after the start of infusion, at the end of irinotecan infusion, and then at 5, 15, 30, 45, and 60 minutes and 2, 4, 6, and 24 hours after the end of infusion. Blood samples were immediately centrifuged and plasma was stored at -20°C until the assay for concentrations of drugs and catabolites according to the high-performance liquid chromatographic methods previously reported for irinotecan21,22 with minor modifications. Briefly, plasma concentrations of total irinotecan and SN-38 were evaluated after extraction of plasma with methanol containing 0.1% HCl 10 N; the samples were then centrifuged and the clear supernatant was evaporated to dryness under nitrogen flow in a thermostated bath at 45°C. The resulting pellet was reconstituted in methanol acidified with 0.1% HCl 10 N and eluted through a µBondapack C18 stationary phase column (300 x 3.9 mm, 10 µm; Waters, Milford, MA, USA) by KH2PO4 0.1 M/acetonitrile (65:35, v/v; pH 4.0) containing sodium heptansulfonate 3 mmol/L. The chromatographic system was the LC Module I Plus (Waters) equipped with a Model 474 scanning fluorescence detector with excitation and emission wavelengths set at 375 and 525 nm, respectively. Data analysis was performed using Millennium 2.1 software (Waters). To measure the SN-38glu concentration, plasma samples were incubated with beta-glucuronidase at 37°C for 2 hours before extraction, and the difference between peak height corresponding to SN-38 from beta-glucuronidase–treated versus untreated samples corresponded to the plasma levels of SN-38glu.

Individual plasma concentrations of irinotecan, SN-38, and SN-38glu were normalized to the dose level of 250 mg/m2 and fitted according to a two-compartment open model using nonlinear least-squares regression analysis by means of ADAPT II software (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). The calculation of pharmacokinetic parameters included AUC, elimination half-life, volume of distribution, and total body clearance. Cmax and time to reach Cmax were obtained from visual inspection of the plasma profiles. Finally, the biliary index of irinotecan/SN-38 was calculated for the two treatment sequences, as previously described.22

Assessability, Toxicity, and Response Criteria
The pretreatment evaluation included history and physical examination, performance status assessment, complete blood cell with differential and platelet counts, complete blood profile, carcinoembryonic antigen, urine analysis, ECG, chest-x-ray or computed tomography scan, abdominal computed tomography scan and/or sonogram, and any other appropriate diagnostic procedure to evaluate metastatic sites. During treatment, a physical examination was performed every 3 weeks, a complete blood cell count, every week, and blood profile and urine analysis, every 3 weeks. Sites of metastatic disease were radiologically re-evaluated every 8 weeks. A chest x-ray and/or an abdominal sonogram was repeated at least every 6 months if there was no evidence of lung or abdominal disease, respectively. Toxicities and responses were scored according to standard World Health Organization criteria.23 Responses were confirmed by an external monitor, and their duration was calculated from the first day of treatment to the date of first observation of progressive disease or last examination.

Statistical Analysis
Pharmacokinetic parameters were examined by analysis of variance followed by the Student-Newman-Keuls test to evaluate statistical significance of differences among dose levels. Student’s t test was used to assess significant differences in pharmacokinetics of normalized plasma concentrations of irinotecan and its metabolites.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 33 patients with metastatic colorectal carcinoma entered the study. Patients characteristics are listed in Table 1. Irinotecan was given at doses of 150, 200, 250, 300, 350, 400, and 450 mg/m2, and the number of patients treated at each dose level is reported in Table 2. The first 23 patients received irinotecan/5-FU/LV with irinotecan doses ranging from 150 to 300 mg/m2 and with both irinotecan/5-FU sequences. On the basis of improved tolerability of the sequence irinotecan->5-FU, the next 10 patients received irinotecan/5-FU/LV with irinotecan at doses of 350, 400, and 450 mg/m2 only with the sequence irinotecan->5-FU, and not for the opposite sequence. In fact, the MTD for the sequence of 5-FU followed by irinotecan was reached at 300 mg/m2, and for this reason the dose of irinotecan was not escalated further with this sequence. A total of 253 cycles were administered (median, seven cycles per patient), and overall toxicities included mainly nausea and vomiting (grade 3, 12% of patients), diarrhea (grade 3, 18%; grade 4, 4%), stomatitis (grade 3, 6%), and neutropenia (grade 4, 27%). In particular, in the first 23 patients who received irinotecan/5-FU/LV with both sequences, a decreased toxicity was observed for irinotecan given before 5-FU versus the reverse sequence in terms of grade 3/4 diarrhea (4% v 17%), grade 3/4 neutropenia (22% v 39%), and febrile neutropenia (4% v 17%) (Table 3). The reduced toxicity observed when irinotecan was administered immediately before infusional 5-FU (day 1) resulted in a minor number of DLT events in comparison to irinotecan given after 5-FU (day 3), ie, two (9%) versus eight (35%) events (Table 2). Of interest, in seven patients, DLT (mainly diarrhea and febrile neutropenia) was observed only with 5-FU followed by irinotecan, and not for the reverse sequence administered at the same doses, thus confirming the better tolerance of irinotecan followed by infusional 5-FU. The last 10 patients received irinotecan/5-FU/LV with irinotecan given only on day 1 before 5-FU. With this sequence, the dose of irinotecan could be escalated up to 450 mg/m2, a dose level at which the MTD of irinotecan was reached. With respect to the evaluation of antitumor activity of treatment, 31 patients were assessable for response (one was not assessable because a liver biopsy did not confirm the presence of metastatic disease, and one was not assessable because the patient underwent surgery for a pelvic abscess 25 days after treatment start and chemotherapy was interrupted). Two patients (6.5%) with liver and lymph node metastases obtained a complete response and 10 (32.5%) achieved a partial response for an objective response rate of 39% (95% confidence interval, 22% to 58%). Responses lasted a median of 7.5 months (range, 2 to 14 months). In the remaining 19 patients, three minor responses (10%) (minor response was defined as 25% to 50% reduction in disease), 11 disease stabilizations (35%), and five progressions (16%) were observed. The median progression-free and overall survival times were 8.1 and 16.3 months, respectively.


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  		Table 1.  Patient Characteristics
 

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  		Table 2.  Dose-Limiting Toxicities Versus Irinotecan Dose and Schedule
 

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  		Table 3.  Overall Worst Toxicity: Irinotecan Day 1 Versus Day 3 (23 assessable patients)
 
Pharmacokinetics
In order to elucidate a possible influence of drug disposition on schedule-dependent tolerability, plasma pharmacokinetic analysis was performed after the first and second cycles in all patients who received both sequences of irinotecan/5-FU/LV (total of 23 patients). The pharmacokinetics of irinotecan administered on day 1 or on day 3 at 150, 200, 250, and 300 mg/m2 was linear, as demonstrated by the dose-proportional increase in AUC values and no significant changes in clearance (Table 4). After normalization of individual plasma concentrations to the dose level of 250 mg/m2, mean AUC and Cmax values of irinotecan on day 1 and 3 did not differ significantly (Table 5). At variance with irinotecan, however, the AUC of SN-38 when irinotecan was administered on day 1 was significantly lower (-40.1%) than that on day 3 (0.202 ± 0.031 v 0.340 ± 0.058 h · µg/mL, respectively, P < .05), whereas the Cmax values did not differ significantly (Table 5, Fig 2). Therefore, the different tolerability profile of irinotecan given on day 1 with respect to the reverse schedule may be dependent, at least in part, on the significant decrease in SN-38 exposure when irinotecan was followed by 5-FU. The analysis of SN-38glu plasma profiles revealed increased concentrations on day 3, although a statistically significant schedule-dependent pharmacokinetics was not apparent (P = .181). Finally, the increase in biliary index calculated for the sequence 5-FU->irinotecan (77.4% ± 29.9%) was also not significant.


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  		Table 4.  Linearity of Irinotecan Pharmacokinetics as Demonstrated by Dose-Proportional Increase Parameters of Irinotecan in Patients
 

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  		Table 5.  Mean AUC and Cmax of Irinotecan and Metabolites After Normalization
 


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  		Fig 2. Mean plasma concentrations versus time profiles of SN-38 normalized to the 250-mg/m2 dose level in patients treated with irinotecan before (day 1) or after (day 3) infusional 5-FU.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Irinotecan and fluorouracil are active agents in advanced colorectal cancer, have different mechanisms of action, and have synergistic or additive cytotoxicity in experimental models and incomplete overlapping toxicities. Therefore, their association has been evaluated extensively in clinical trials in the last few years. Two recent well-controlled phase III trials have clearly demonstrated that the combination irinotecan/5-FU/LV has improved activity and efficacy in the first-line treatment of metastatic colorectal cancer in comparison to 5-FU/LV alone,24,25 and this combination represents the new first-line reference treatment in metastatic colorectal cancer. However, preclinical and clinical studies have not clarified which is the best modality to combine these two agents. Experimental studies have been contradictory in terms of establishing the most cytotoxic sequence of drug combination, even though the sequence irinotecan->5-FU displays improved activity as compared with either drug alone or the reverse schedule.11-15 Indeed, more recent preclinical data in human colorectal cancer cell lines confirm that the sequence irinotecan->5-FU is synergistic.11,14 Clinical studies have been contradictory in defining the occurrence, if any, of pharmacokinetic and/or pharmacodynamic interactions between these two agents. Initial phase I/II studies showed a favorable toxicity profile of irinotecan/5-FU combinations, which allowed their association at doses near the MTD of each single agent. In a phase I study, Sasaki et al18 suggested that the tolerable toxicity of irinotecan followed by continuous-infusion 5-FU could be related to the inhibition by 5-FU of carboxylesterase and a reduced conversion of irinotecan into SN-38.18 A following study suggested that irinotecan itself might modulate SN-38 metabolisms, thus affecting the pharmacokinetics of the active metabolite.26 More recently, differences in SN-38 pharmacokinetics between the two arms of treatment, in which irinotecan and 5-FU were administered in two opposite sequences as 90-minute and brief IV infusions, respectively, were observed, as well as, in particular, a reduction of the AUC and Cmax values of SN-38 by 8.2% with respect to irinotecan alone.19 However, the clinical relevance of this observation was unclear. Therefore, the authors concluded that their results did not suggest an interaction of 5-FU on the metabolism of irinotecan to SN-38. However, in these studies, 5-FU was administered as a short IV infusion or 24 hours after irinotecan, two conditions that are unlikely to affect irinotecan pharmacokinetics and metabolism to SN-38, considering the short half-life of 5-FU and the time interval between the administration of the two drugs. In the present study, however, conditions for drug interactions were indeed present since the half-life of irinotecan is long and the conversion to SN-38 is a sustained process. Thus, the 48-hour infusion of 5-FU adopted in the present study could interfere to a greater extent than short IV infusion on the disposition of irinotecan and its metabolite SN-38.

Our results demonstrate that the sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of treatment. In particular, the schedule of irinotecan followed by 5-FU infusion was clearly less toxic, resulting in a different irinotecan MTD for the two sequences: 300 mg/m2 for 5-FU->irinotecan and 450 mg/m2 for irinotecan->5-FU. The different degrees of toxicity between the two schedules were evident in seven out of 23 patients treated with both sequences at irinotecan doses ranging between 200 and 300 mg/m2. In fact, in these seven patients, DLT (mainly neutropenia and diarrhea) was observed when irinotecan was administered after 5-FU, whereas the opposite sequence (irinotecan->5-FU) at identical irinotecan and 5-FU doses was well tolerated. The plasma pharmacokinetic analysis suggested that the reduced toxicity observed when irinotecan was followed by 5-FU might be explained, at least in part, by a reduced formation and AUC of SN-38, because the analysis of data after normalization at the 250-mg/m2 dose level demonstrated a significant decrease in the SN-38 AUC value on day 1 with respect to day 3 (-40.1%). Indeed, it is also possible that when irinotecan is given after 5-FU there might be an increased conversion of irinotecan into SN-38, thus explaining an increased toxicity of 5-FU followed by irinotecan. This aspect cannot be evaluated in the present study because there was no irinotecan-only arm. However, this arm was not planned because we considered it very unlikely that 5-FU, which has a half-life of only few minutes, could affect irinotecan/SN-38 pharmacokinetics when given before irinotecan. In addition, previous clinical studies had suggested a possible pharmacokinetic interaction only for irinotecan followed by 5-FU (with a particularly good toxicity profile for this treatment confirmed also in phase III studies), and not for 5-FU followed by irinotecan. This last sequence was studied by Saltz et al,19 and the SN-38 AUC was identical for irinotecan preceded by 5-FU and for irinotecan alone (166 v 167 ng · h/mL) and slightly, but significantly, reduced for irinotecan followed by 5-FU (146 ng · h/mL, P < .002). The lack of significance in terms of pharmacokinetic parameters of irinotecan or SN-38glu may be dependent on the large interpatient variability of drug and metabolite disposition, as observed by others,16 as well as on the small number of patients per dose level, since the present study was designed as a phase I dose-escalation protocol. Therefore, the mechanism by which drug administration sequences interfere with irinotecan and SN-38 disposition should be investigated further. Results in terms of antitumor activity and efficacy confirm the promising results already reported in other studies which have combined irinotecan and 5-FU; however, it is not possible from our study to have information regarding the effects of the schedule on the activity because the same patients received both schedules.

Up to now, the sequence of irinotecan followed by infusional 5-FU has been the most frequently used in metastatic colorectal cancer patients. Our findings might explain the good toxicity profiles of these combinations when irinotecan and 5-FU doses near their MTDs as single agents have been used. The schedule-dependent tolerability profile of this new combination, which also results in differences in SN-38 AUC between groups, calls for the need to use well-defined 5-FU/irinotecan regimens in terms of doses and scheduling because apparently minor modifications, such as the sequence of administration or the interval between use of the two agents, might potentially affect treatment tolerance and activity. Finally, our findings should promote further studies of 5-FU combined with irinotecan according to different schedules in the attempt to better define its importance in affecting not only treatment tolerance but also treatment activity and efficacy. A randomized phase III study will be indicated if phase II studies suggest that the scheduling might affect not only pharmacokinetics and toxicities but also antitumor activity.


   ACKNOWLEDGMENTS
 
Supported in part by grants from the University of Pisa and Ministry of the University of Scientific and Technology Research, Rome, Italy, titled "Molecular Basis for the Pharmaceutical Control of Neoplastic Diseases."

We thank Cinzia Orlandini for data analysis and technical assistance.


   NOTES
 
Aventis, Milan, Italy, provided free drugs and funding on a per-patient basis for this study.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Cohen AM, Minsky BD, Schilssky RL: Cancer of the colon, in De Vita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997, pp 1144-1197

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18. Sasaki Y, Ohtsu A, Shimada Y, et al: Simultaneous administration of CPT-11 and fluorouracil: Alteration of the pharmacokinetics of CPT-11 and SN-38 in patients with advanced colorectal cancer. J Natl Cancer Inst 86: 1096-1098, 1994[Free Full Text]

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22. Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhoea. Cancer Res 54: 3723-3725, 1994[Abstract/Free Full Text]

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25. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343: 905-914, 2000[Abstract/Free Full Text]

26. Rothemberg ML, Eckert JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14: 1128-1135, 1996[Abstract/Free Full Text]

Submitted December 1, 2000; accepted April 18, 2001.




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