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Journal of Clinical Oncology, Vol 23, No 3 (January 20), 2005: pp. 650 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.163
Relationship of Serum Bilirubin to Toxicity in Patients With Metastatic Colorectal Cancer Treated With Single-Agent High-Dose IrinotecanCRLC Val d’Aurelle, Parc Euromédecine, Montpellier, France To the Editor: In the April 15th issue of the Journal of Clinical Oncology, Meyerhardt et al1 published a study showing that modest elevations of baseline bilirubin are associated with increased grade 3 to 4 neutropenia in patients treated with weekly irinotecan after having experienced disease 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/m2 for 4 weeks followed by a 2-week rest period (95 patients), or once every 3 weeks at the dose of 350 mg/m2 (88 patients) or 300 mg/m2 (108 patients). We investigated these results in our study of 49 first-line patients treated with single-agent irinotecan every 3 weeks at the dose of 350 mg/m2 at the first cycle, which could be escalated to 500 mg/m2 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 were not included in this analysis in order to be comparable to the selection criteria of the Meyerhardt study. Thus, 45 patients were used for this analysis. Compared with the Meyerhardt study, the distribution of baseline bilirubin in our analysis was similar: 33%, 58%, and 9% in the 0 to 0.4, 0.5 to 0.9, and 1 to 1.5 mg/dL groups, 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 for 53%, 58%, and 100% patients in the 0 to 0.4, 0.5 to 0.9, and 1 to 1.5 mg/dL groups, respectively, in our study, compared with 29%, 31%, and 45% in both of the Meyerhardt studies. The significant differences were thus observed mostly for the levels of bilirubin greater than 1 mg/dL. Although not statistically significant in our study (P = .22), we noticed nevertheless that all four patients with bilirubin values greater than 1 mg/dL experienced grade 3 to 4 neutropenia toxicity. If we add 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 pretreatment levels. In our study, we were able to correlate bilirubin 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 for 17%, 22%, 17%, and 50% of cycles for patients with 0 to 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. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Meyerhardt JA, Kwok A, Ratain MJ, et al: Relationship of baseline serum bilirubin to efficacy and toxicity of single-agent irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 22:1439-1446, 2004 2. Ychou M, Raoul JL, Desseigne F, et al: High-dose, single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer. Cancer Chemother Pharmacol 50:383-391, 2002[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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