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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4410-4417 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.125 Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced DiarrheaFrom the Department of Medical Oncology & Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada Address reprint requests to M. Michael, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Victoria, 8006, Australia; e-mail: Michael.Michael{at}petermac.org
PURPOSE: The dose-limiting toxicity of irinotecan (CPT-11; Camptosar) is delayed-onset diarrhea, with an incidence at the grade 3 to 4 level of 20% to 35%. SN38, its active moiety, is responsible by a direct effect on mucosal topoisomerase-I. The aim of this study was to assess whether activated charcoal (AC), possibly by adsorbing free lumenal SN38, can reduce irinotecan-induced diarrhea (CID) and optimize its dose-intensity. PATIENTS AND METHODS: Patients with advanced colorectal cancer receiving irinotecan 125 mg/m2 intravenously once a week for 4 weeks every 6 weeks were studied. In cycle 1, patients received irinotecan plus AC (5 mL aqueous Charcodote [1,000 mg AC] plus 25 mL water) given the evening before the irinotecan dose and then tid for 48 hours after the dose. In cycle 2, no AC was given. National Cancer Institute Common Toxicity Criteria diarrhea grade, irinotecan dose-intensity, and loperamide consumption were recorded prospectively in both cycles. RESULTS: Twenty-eight patients had completed cycle 1 with AC; 24 subsequently completed cycle 2 without AC. Grade 3 to 4 diarrhea was 7.1% v 25%, and grade 0 diarrhea was 46.4% v 20.8% in cycles 1 and 2, respectively. Median percent planned dose delivered was 98% v 70% in cycles 1 and 2, respectively. In cycles 1 and 2, respectively, 25% v 54% patients took more than 10 loperamide tablets. AC was well tolerated with excellent compliance. CONCLUSION: The administration of AC with irinotecan reduced the incidence of grade 3 to 4 diarrhea and antidiarrheal medication consumption and increased irinotecan dose-intensity. Prophylactic AC may have a role in reducing dose-limiting CID and optimizing irinotecan therapy.
Delayed-onset diarrhea represents the dose-limiting toxicity of irinotecan (CPT-11).1 It has a reported overall incidence from 60% to 87%, but with National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 3 and 4 severity seen in 20% to 39% of patients.2-6 Recently, early deaths due to this toxicity have been reported, entailing the interruption of several trials.7 Predisposing factors for irinotecan-induced diarrhea (CID) include increasing age (> 65 years of age), WHO performance status more than 1, and prior abdominopelvic radiotherapy—common features in patients with advanced colorectal cancer.2, 6, 8 CID is thus common, and can be severe and life-threatening especially in combination with neutropenia. It can have a significant impact on quality of life, limiting compliance with therapy and dose-intensity. Irinotecan is converted by hepatic and peripheral carboxylesterase to its active metabolite 7-ethyl-10-hydroxycamptothecin (SN38),9 which is subsequently glucuronidated by hepatic uridine diphosphate glucuronosyl transferase-1A1 (UDP-GT 1A1) to SN38-glucuronide (SN38G).10 The parent drug and its metabolites are actively excreted by the liver to the bowel lumen, via bile. Mass balance studies using carbon-14–labeled irinotecan have demonstrated that the fecal route of excretion is the major route of elimination, accounting for 63.7% of the administered drug.11 SN38G, once in the intestinal lumen, is deconjugated by bacterial ß-glucuronidases to SN38. In feces, SN38 was found to be in excess relative to SN38G, which is suggestive of substantial ß-glucuronidase activity in the human intestinal contents.11 The free intestinal lumenal SN38, either from bile or SN38G deconjugation, is responsible for CID. It induces direct mucosal damage with resultant water and electrolyte malabsorption and mucous hypersecretion.12-15 The distribution and severity of histologic damage within the rat intestine after administration of irinotecan has been correlated to the lumenal ß-glucuronidase activity. This was further supported by the observation that antibiotics given to irinotecan-pretreated rodents ameliorated CID, with reduced cecal damage. This was most likely due to the reduction of gut flora, and hence SN38G deconjugation.12 To date, attempts to develop pharmacokinetic-pharmacodynamic correlations between irinotecan and SN38 area under the concentration-time curve and toxicities have not been consistent.16-20 The biliary index, developed as a surrogate measure of biliary SN38 excretion and hence its glucuronidation, was found to correlate with the severity of CID.20, 21 However, its predictive value has not been confirmed by other studies.16, 22 Patients homozygous or heterozygous to the UDP-GT 1A1 allele ({TA}7TAA) had shown a tendency for reduced conjugation of SN38 with increased toxicity.23, 24 Given the lack of predictability for CID, significant effort has gone into the evaluation of prophylactic and therapeutic measures to reduce its severity. High-dose loperamide has been used widely to treat CID at its onset.2, 25 Trials have assessed the reduction of intestinal bacterial ß-glucuronidase activity by broad-spectrum antibiotics26 and glucuronidase inhibitors.27 Modulation of irinotecan pharmacokinetics, by the addition of phenobarbital and cyclosporine, to reduce SN38 biliary excretion and induce glucuronidation, has also been evaluated.28 Attempts have also been made to pharmacologically upregulate intestinal mucosal UDP-GT 1A1 with the plant flavonoid, chrysin.29 Other therapeutic measures assessed include an encephalinase inhibitor,30 oral alkalinization,31 thalidomide,32 glutamine,33 octreotide,34 budesonide,35 amifostine,36 and Kampo medicine (TJ-14).37 Given that free intestinal luminal SN-38 seems to be the underlying cause of the CID, an alternative approach would be its adsorption to prevent direct gut mucosal damage. Activated charcoal (AC) potentially has the relevant physiochemical properties to achieve this and in this regard has been widely used as an emergency antidote for the treatment of acute poisoning.38, 39 The aim of this exploratory trial was to assess the efficacy of prophylactic AC to reduce the incidence and severity of CID in patients who had been entered onto a phase II trial of irinotecan.
Eligibility Criteria This study was part of an open-label, single-arm, phase II study assessing the palliative benefit of irinotecan in patients with colorectal cancer.40 Patients eligible for the study met following criteria: histologically confirmed adenocarcinoma of the colon or rectum, measurable or assessable locally advanced or metastatic disease that was incurable with surgery or radiotherapy and refractory or resistant to fluorouracil (FU), defined as either progression or relapse during or within 6 months of completing FU-based therapy in the adjuvant or advanced setting. Other eligibility criteria, such as for organ function and patient demographics, were typical for a phase II trial design.40 Informed written consent was obtained according to the institutional and university requirements. The study was approved by the institutional ethics committee.
Pretreatment Evaluation
Treatment Plan Recommended dose modifications during a cycle of therapy and at the start of each subsequent course of therapy were similar to those outlined by Rothenberg et al.4 All toxicities were graded according to the NCI CTC. Dose modifications made during the treatment cycles were based on the worst NCI grade toxicity since the last dose of irinotecan. If multiple toxicities were seen, the dose administered was based on the most severe toxicity experienced. Adjustment of the dose at the beginning of a new course was based on laboratory parameters on the scheduled day of treatment and on maximum toxicity encountered in the previous cycle.
A new cycle of treatment began when the granulocyte count was Supportive care. Treatment of acute cholinergic syndrome included administration of 0.25 to 1 mg of intravenous atropine (unless clinically contraindicated) in patients experiencing diaphoresis, abdominal cramping, or early diarrhea (diarrhea occurring during or within 12 hours after irinotecan administration). For treatment of delayed diarrhea, the high-dose loperamide regimen, as per Abigerges et al,25 was used. Each patient had loperamide readily available, and was advised to commence therapy for delayed diarrhea (diarrhea occurring more than 12 hours following irinotecan administration) at the first episode of poorly formed or loose stool or at the occurrence of one to two more bowel movements than normally expected for the patient. The regimen comprised loperamide 4 mg at the first onset of delayed diarrhea and then 2 mg every 2 hours until the patient was diarrhea free for at least 12 hours. During the night the patient could take 4 mg loperamide every 4 hours. Premedication with loperamide was not allowed. Compliance of with the high-dose loperamide regimen was closely monitored by the research nursing staff by inspection of a provided diary book, in which was recorded the daily loperamide consumption together with diarrhea frequency.
AC The initial dose was derived empirically. The manufacturer's recommendation is to administer AC at a dose of up to 5x to 10x the dose of the toxin ingested. The average patient with a body-surface area of 1.6 m2 in cycle 1 received 1.6 x 125 mg/m2/wk or 200 mg of irinotecan per week of active therapy. Approximately 20% of the total irinotecan exposure in plasma is in the form of SN38 and SN38G,41, 42 and the majority of fecal excretion is completed within 24 hours.42 Administration of at least 1,000 mg AC per dose, before and for at least 48 hours after the irinotecan dose, was considered well in excess of the expected SN38 gastrointestinal exposure. To optimize patient tolerance, the aqueous charcoal solution was diluted to 1:6 with purified water and was dispensed in this form. The AC was administered orally. Patients were advised not to mix the preparation with another liquid or food before ingesting. Given that it may bind to other drugs given concurrently, patients were advised to take other drugs at least 1 hour before or 4 to 6 hours after taking AC, to avoid impeding their absorption. In cycle 1, AC treatment was commenced the night prior to the administration of each dose of irinotecan and given tid for 48 hours after (Ir + AC). Patients did not receive AC in the subsequent cycle 2 (Ir – AC) and any additional cycles, to allow for a comparison with course 1. Hence patients served as their own controls. Three dose levels were planned. Dose level 1 comprised 30 mL diluted solution (5 mL aqueous Charcodote [1,000 mg AC] plus 25 mL water) tid; dose level 2 comprised 60 mL diluted solution (10 mL aqueous Charcodote [2,000 mg AC] plus 50 mL water) tid, and dose level 3 comprised 90 mL diluted solution (15 mL aqueous Charcodote [3,000 mg AC] plus 75 mL water) tid. No intrapatient dose escalation was allowed.
Treatment Evaluation Gastrointestinal toxicity. The patient recorded diarrhea by worst NCI grade in the provided diary book daily in cycles 1 and 2 of therapy. AC consumption was recorded daily by the patient in the provided diary book during this period. Dose-intensity. Dose (milligrams per square meter) of irinotecan delivered weeks 1 to 4 (of a 6-week cycle) in cycles 1 and 2 were recorded. This was expressed as dose-intensity: the ratio of actual total dose delivered over a 6-week cycle relative to the planned dose to be delivered (ie, 4 x 125 mg/m2/wk or 500 mg/m2 per 6-week cycle). There was no correction for dose level reduction at the commencement of cycle 2 as a result of toxicities experienced in cycle 1. Loperamide consumption. Loperamide consumption was recorded on a daily basis in the provided diary book. Patient outcomes. Response or duration of therapy was not a designated end point of the study. Patients entered onto this study did not receive AC beyond the initial cycle of therapy. Charts and radiologic studies were reviewed once all patients were no longer receiving treatment to collect information on duration of therapy and best response. Given that patients were a subset of another study of irinotecan, radiologic evaluations were conducted routinely.40 Response was assessed using standard criteria.
Criteria for Removal From Study
Statistical Analysis The grade of diarrhea for cycle 1 (Ir + AC) was compared to the worst grade in cycle 2 (Ir – AC). The irinotecan dose-intensity and loperamide consumption were also compared between cycles 1 and 2. Because this was an exploratory trial with small patient numbers, the results were not analyzed by descriptive statistics.
Patients The response criteria described above were met at the first dose level of AC (aqueous Charcodote [1,000 mg AC] tid), and hence this cohort was expanded to 34 patients in total. All 34 patients were accrued as a substudy to a concurrent phase II study.40 Patient demographics were typical of patients with FU-resistant or FU-refractory advanced colorectal cancer, and are summarized in the phase II report.40 Of the 34 patients entered at the first dose level, six patients were ineligible for evaluation: one patient with grade 3 diarrhea and fistula at baseline; one patient with a starting dose of irinotecan 75 mg/m2; and four patients with failure to complete cycle 1 because of severe chemotherapy-induced nausea and vomiting (three patients), and cessation of chemotherapy by febrile neutropenia (one patient). Twenty-eight patients completed cycle 1 (Ir + AC) of therapy and 24 of these completed cycle 2 on the protocol (Ir – AC). Four patients failed to complete cycle 2 as planned: one patient received AC in both cycles and three patients experienced disease progression.
Severity of Diarrhea Between Cycles 1 (Ir + AC) and 2 (Ir – AC)
Consumption of Loperamide Tablets in the Treatment of CID Loperamide was self-administered by patients only at the onset of CID as described above.25 Patients were stringently counseled regarding the use of loperamide and monitored closely to ensure compliance, as reflected by its use in relation to diarrhea grade in both cycles 1 and 2. For cycle 1, the mean consumption during the 6 weeks per diarrhea grade was as follows: grade 1, 11.8 tablets; grade 2, 15.5 tablets; and grade 3, 98.5 tablets. For cycle 2, the mean consumption over the 6 weeks per diarrhea grade was grade 1, 15.8 tablets; grade 2, 42.5 tablets; grade 3, 37.5 tablets; and grade 4, 50 tablets. The frequency distribution of loperamide use is listed in Table 2. The loperamide consumption in cycle 1 (Ir + AC) relative to cycle 2 (Ir – AC) was reduced overall. The mean number of tablets consumed in cycles 1 and 2 was 13.1 (range, 0 to 100) versus 23.4 tablets (range, 0 to 87), respectively. No loperamide was consumed by 50% of patients in cycle 1 relative to 37% of patients in cycle 2, with 75% of patients requiring 10 or fewer tablets versus 46%, respectively.
These results suggest that prophylactic treatment with AC may have reduced the risk of developing CID and potentially reduced its severity once established.
Dose-Intensity of Irinotecan
In those patients who had completed both cycles 1 and 2 (n = 24), the ratio of the mean dose delivered in cycle 1 relative to cycle 2 was 1.33. The ratio was less than 1 in two patients, equal to 1 in four patients, and in excess of 1 in 18 patients. The dose modifications during and at the start of each subsequent cycle of therapy were as described by Rothenberg et al.4 In cycle 1 (Ir + AC), 12 of 24 patients received full-dose therapy (ie, 500 mg/m2 during 6 weeks). The remaining 12 patients had dose reductions because of the following maximum toxicities encountered: neutropenia, grade 2 (two patients) and grade 3 (five patients, two also with grade 2 diarrhea); diarrhea, grade 3 (two patients); and other nonhematologic toxicities, grade 3 (three patients, two with concurrent grade 2 diarrhea). In cycle 2, nine of 24 patients had a dose level reduction at the start of the cycle based on the maximum toxicities of cycle 1. Five patients had full-dose therapy. The reasons for dose reductions in terms of maximum toxicity encountered were neutropenia, grade 2 (one patient) and grade 3 (three patients); diarrhea, grade 2 (six patients), grade 3 (four patients), and grade 4 (two patients); other nonhematologic toxicities, grade 2 (one patient) and grade 3 (one patient); and unknown, one patient.
Patient Outcomes
Compliance With AC Solution
In this study we evaluated the usefulness of AC to reduce the severity of CID—a toxicity that is dose limiting and is associated with significant morbidity and reduction of drug delivery. Thus far, there are no approved prophylactic measures to prevent CID; however, at its onset, high-dose loperamide has been found to be active.4, 25 The first dose level of AC was efficacious in the first cohort of 14 patients as prospectively defined above, and hence the sample was expanded to 34 patients in total. It must be emphasized that the sample size was small, and any statistical comparison in the efficacy parameters defined in the trial would be associated with large CIs. The results, however, are hypothesis generating and require additional confirmation in larger studies. The results of this trial demonstrated that the use of AC in patients receiving irinotecan in cycle 1 resulted in a markedly reduced incidence of grade 3 and 4 diarrhea compared with those patients treated in cycle 2 without AC. The reduced severity of CID by AC translated into a parallel change in loperamide consumption and ultimately an increased irinotecan dose-intensity in cycle 1, with fewer dose reductions due to diarrhea, relative to cycle 2. However, the reduced dose-intensity in cycle 2 may be a consequence of two factors: AC did not prevent diarrhea in all patients in cycle 1, and the reduced dose of irinotecan at the start of cycle 2 because of toxicities in the previous cycle. The fact that the patients had worse diarrhea in cycle 2 (without AC), despite a lower intensity of irinotecan delivered, supports the utility of AC. As discussed, there are limitations to the conclusions of this trial because of the small sample size, patients acting as their own controls, and the complexities of irinotecan dose reductions and supportive care. The efficacy of AC in the treatment of CID can only be addressed in a randomized phase III trial: the control arm would be irinotecan alone and the experimental arm would be irinotecan plus AC. This would entail a much larger study, in a similar patient cohort, but would account for the pharmacodynamic variation among patients. An alternative design has also been tested in CID, although with inherent difficulties. This alternative is to treat patients with irinotecan alone in the first course, and those patients who had developed grade 2 or higher diarrhea despite loperamide therapy would then receive AC in the second course with full-dose irinotecan. This approach had been used to assess the efficacy of neomycin in reducing CID.26 Of the 20 patients who were treated with the 3-weekly regimen of irinotecan in cycle 1, seven patients developed grade 2 diarrhea, but no patients had grade 3 diarrhea. These seven patients subsequently went on to receive neomycin in cycle 2 together with irinotecan.26 This approach has merit; however, it requires a large cohort to be treated in cycle 1 and there may be a reluctance by clinicians not to reduce the dose of irinotecan for severe diarrhea in cycle 1. Another potential confounding factor was allowing all patients to use loperamide at the onset of the CID. It would be unethical to exclude loperamide from the supportive care of these patients enrolled onto the trial; however, this would make the trial results cleaner. The pivotal phase II studies in the United States demonstrated that the addition of high-dose loperamide at the first onset of the diarrhea reduced grade 3 or 4 diarrhea from 17.5% to 9.8%.2 Initial reports also demonstrated that the use of high-dose loperamide also reduced the incidence of cycle 2 diarrhea to approximately 12% to 14%.2, 43 This had not been our multicenter experience, where despite the use of high-dose loperamide and rigorous staff and patient education, grade 3 or 4 diarrhea was observed in 26% of a 65-patient cohort.40 Similarly, in this trial, despite intensive clinical review and the use of a high-dose loperamide regimen, the compliance with which was measured by a daily diary card, six of 24 patients (25%) in cycle 2 suffered grade 3 and 4 diarrhea. There is significant room for improvement in the reduction of CID, even with the use of loperamide. In this study, the use of AC met the defined efficacy end point: it was associated with a decreased requirement for supportive loperamide that had translated into greater irinotecan delivery. As expected, there was no significant correlation between diarrhea grade and loperamide consumption within both cycles, given the large interpatient variation in the sensitivity to loperamide and irinotecan and the small number of patients suffering specific grades of diarrhea. However, the consumption of loperamide in cycle 1 (Ir + AC) relative to cycle 2 was reduced overall, and none was consumed by 50% of patients in cycle 1 relative to 37% in cycle 2. This suggests that prophylactic treatment with AC may have reduced the risk of developing CID and potentially reduced its severity once established. The calculation of dose-intensity in this population is far from straightforward, given that there are prospectively defined dose reductions for hematologic and nonhematologic toxicities, that toxicities can occur concurrently, and because the carry-over of dose reductions into cycle 2 was based on the toxicities in the previous cycle. In this trial, this calculation was prospectively defined and rigid because it was expressed as the ratio of actual total dose delivered over a 6-week cycle relative to the planned full dose to be delivered (ie, 4 x 125 mg/m2/wk or 500 mg/m2 per 6-week cycle). In cycle 1 (Ir + AC) the median dose-intensity was 0.975 v 0.700 in cycle 2 (Ir – AC). The reduced dose-intensity in cycle 2 (Ir –AC), as seen above, is a direct function of the larger number of dose reductions caused by diarrhea as the major toxicity (ie, diarrhea grade 2, six patients; grade 3, four patients; and grade 4, two patients) relative to cycle 1 (diarrhea grade 2, zero patients; and grade 3, two patients). The reduced dose-intensity of cycle 2 was influenced by the reduced starting dose based on the maximum toxicities of cycle 1; however, these were for the most part because of nondiarrheal toxicities. AC is postulated to act by the enhanced intestinal elimination of adsorbed substrates.39 Drug characteristics associated with enhanced clearance by multiple-dose AC include low intrinsic clearance, prolonged distributive phase, nonrestrictive protein binding, and small volume of distribution.39, 44, 45 The influence of oral AC on the pharmacokinetics of intravenous phenobarbital,46 luxabendazole,47 propranolol,48 and other drugs44 has been evaluated. AC acts by enhancing clearance via enterocapillary exsorption (diffusion of drugs from the intestinal wall to the lumen) or interruption of enterohepatic circulation.39 The effect of oral AC on the pharmacokinetics of irinotecan and its metabolites was not assessed in this study, nor has it been explored in preclinical models. The hypothesis generated from this study is that the reduction of CID observed is a direct consequence of AC enhancing the intestinal or systemic clearance of SN38, by a combination of its direct adsorption and interruption of its enterohepatic recirculation. To prove this would require a full pharmacokinetic profile of irinotecan and its metabolites performed in patients receiving both cycles 1 and 2, together with the estimation of the fecal content of free (unabsorbed) SN38. The values would be compared between the cycles within the same patient and also to historically reported data for the identical irinotecan schedule. The effects of AC on irinotecan and metabolite pharmacokinetics therefore need to be addressed in a prospective trial. A significant reduction in systemic drug exposure would not be desirable. In this cohort of 28 patients who completed the study, the best response was partial response in two patients (7%), with 75% of patients overall being free of progression for 3 months or greater. In the larger phase II trial with the same entry criteria (for which this study was a substudy), the overall response rate was 11% (complete and partial responses; n = 46), with 23 patients achieving stable disease.40 Given the small sample size, an effect of AC on drug efficacy can not be excluded with certainty. However, it seems that SN38 may have the relevant features which make AC therapy viable. From carbon-14–irinotecan disposition studies in cancer patients, fecal excretion accounted for 63.7% of the administered dose, with SN38 and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin being the major metabolites in feces. SN38 was found in excess in feces relative to SN38G, indicating significant activity of ß-glucuronidases in the bowel lumen.11 However, SN38 is at least 98% protein bound (although in a nonrestrictive manner), mainly to albumin, neutrophils, and erythrocytes. Given that SN38 has extensive protein binding, its volume of distribution would be expected to be large.49 The plasma disposition of irinotecan and its metabolites have been re-examined by extended sampling out to 500 hours in cancer patients receiving the agent at a dose level of 300 mg/m2. The half-life of SN38 was found to be 47 ± 7.9 hours, at least two-fold greater than prior estimates, which may be due to extensive formation of SN38 from irinotecan and 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin by plasma carboxylesterase and to enterohepatic recirculation.50 Patient compliance was excellent in this trial. Three of the four patients who were ineligible had not completed cycle 1 because of significant nausea and vomiting. It was unclear whether this was related to their disease, their treatment with irinotecan, or to the AC solution. One patient who was diarrhea free in cycle 1 had refused to receive cycle 2 without AC, thus rendering him ineligible. The lack of toxicity of AC, apart from the black discoloration of stools, also contributed to the excellent patient compliance. In conclusion, AC has been shown to reduce the severity of CID with a parallel reduction in the use of antidiarrheal medication and provision for greater dose-intensity. Prophylactic AC may have a role in reducing the potential and severity of dose-limiting CID and optimizing irinotecan therapy. A phase III randomized trial is required to validate this finding, in addition to direct comparisons with other agents that have similar antidiarrheal activity.
The authors indicated no potential conflicts of interest.
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology Annual Meeting, San Francisco, CA, May 12-15, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 x 109/L, platelet count was 100 x 109/L, and treatment-related diarrhea had fully resolved. If toxicities had not resolved, treatment was withheld, and the patient was evaluated weekly. Treatment continued if clinically appropriate once toxicity had resolved, but with dose modification. If treatment was withheld for 1 week, the irinotecan dose was reduced by one dose level (ie, by 25 mg/m2); if treatment was withheld for 2 weeks or more, irinotecan dose was reduced by two dose levels (ie, by 50 mg/m2). 
