Relationship of Serum Bilirubin to Toxicity in Patients With Metastatic Colorectal Cancer Treated With Single-Agent High-Dose Irinotecan

Abstract

TO THE EDITOR: In the April 15th issue of the Journal of Clinical Oncology, Meyerhardt et al 1 published a study showing thatmodest elevations of baseline bilirubin are associated with increased grade 3 to 4 neutropenia in patients treatedwithweeklyirinotecanafterhavingexperienceddisease progression or recurrence from fluorouracil-based chemotherapy. The authors base their conclusions on a secondary analysis of a cohort of 291 patients enrolled onto two clinical trials evaluating monotherapy irinotecan: either taking irinotecan once a week at the dose of 125 mg/m 2 for 4 weeks followed by a 2-week rest period (95 patients), or once every 3 weeks at the dose of 350 mg/m 2 (88 patients) or 300 mg/m 2 (108 patients). We investigated these results in our study of 49 firstline patients treated with single-agent irinotecan every 3 weeks at the dose of 350 mg/m 2 at the first cycle, which could be escalated to 500 mg/m 2 for the second and subsequent cycles, depending on toxicity. 2 One patient was not evaluated for initial bilirubin. Three patients had bilirubin values greater than 1.5 mg/dL but less than 1.7 mg/dL and werenotincludedinthisanalysisinordertobecomparable to the selection criteria of the Meyerhardt study. Thus, 45 patients were used for this analysis. ComparedwiththeMeyerhardtstudy,thedistribution of baseline bilirubin in our analysis was similar: 33%, 58%, and9%inthe0to0.4,0.5to0.9,and1to1.5mg/dLgroups, respectively, in our study, compared with 33%, 55%, and 12% in the Meyerhardt study. Concerning toxicity, 60% of patients experienced grade 3 to 4 neutropenia in our study, compared with 30% in both of the clinical trials analyzed by Meyerhardt et al. Although our study concerns first-line patients, this higher level of maximum toxicity was to be expected since higher doses of irinotecan were given for a longer period of time. Grade 3 to 4 neutropenia was observed for53%,58%,and100%patientsinthe0to0.4,0.5to0.9,and 1 to 1.5 mg/dL groups, respectively, in our study, compared with 29%, 31%, and 45% in both of the Meyerhardt studies. Thesignificantdifferenceswerethusobservedmostlyforthe levels of bilirubin greater than 1 mg/dL. Although not statistically significant in our study (P .22), we noticed neverthelessthatallfourpatientswithbilirubinvaluesgreaterthan1 mg/dLexperiencedgrade3to4neutropeniatoxicity.Ifweadd those four patients to the three patients with bilirubin values greater than 1.5 mg/dL, six (86%) of seven patients experienced grade 3 to 4 neutropenia toxicity. Meyerhardt et al did not provide detailed information on the monitoring of bilirubin during chemotherapy, but we could imagine that more recent values of bilirubin may have a greater impact on toxicity than values at pretreatmentlevels.Inourstudy,wewereabletocorrelatebilirubin levels before each cycle with the maximum neutropenia grade observed during the same cycle. Assuming each cycle to be independent from each other, among the 258 cycles, we observed 58 cycles (22%) overall with grade 3 or 4 neutropenia. Grade 3 to 4 neutropenia was thus observed for17%,22%,17%,and50%ofcyclesforpatientswith0to 0.4, 0.5 to 0.9, 1 to 1.5, and greater than 1.5 mg/dL values for bilirubin at the beginning of each cycle, respectively (P .01). The differences were thus mainly observed for the 11 (50%) of 22 grade 3 to 4 neutropenia patients who attained bilirubin levels greater than 1.5 mg/dL. It thus seems that bilirubin should be monitored before each cycle, since patients with bilirubin values greater than 1.5 mg/dL are at a significantly higher risk of grade 3 to 4 neutropenia, and could justify prophylactic granulocyte colony-stimulating factor treatment.