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Annals of Oncology 8:1049-1051, 1997
© 1997 European Society for Medical Oncology

other

Severe CPT-11 toxicity in patients with Gilbert's syndrome: Two case reports

E. Wasserman1,, A. Myara2, F. Lokiec3, F. Goldwasser1, F. Trivin2, M. Mahjoubi4, J. L. Misset1 and E. Cvitkovic1

1FSMSIT, Hop Paul Brousse Villejuif, France
2Hop St Joseph Paris, France
3Centre Rene Huguenin Saint Cloud, France
4Rhône-Poulenc Rorer Neuilly, France

Correspondence to: E. Wasserman, MD FSMSIT - Hôpital Paul Brousse 12-14 Avenue Paul Vaillant Couturier 94804 Villejuif Cedex France

BACKGROUND: CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly eliminated through conjugation by hepatic uridine diphosphate glucuronosyl transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation. Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may have an increased risk for related CPT-11 toxicity.

PATIENTS AND METHODS: Two patients with metastatic colon cancer and Gilbert's syndrome were treated with CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC.

RESULTS: Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in every treatment cycle. Biliary index (after Gupta et al) values were well above 4000.

CONCLUSIONS: We present the first clinical evidence linking bilirubin glucuronidation status and CPT-11 related toxicity. The severe toxicity experienced by the two patients with Gilbert's syndrome treated with CPT-11 based chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be predictive parameter of CPT-11 toxicity.

bilirubin, CPT-11, Gilbert's syndrome, glucuronidation, SN-38


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