Pharmacogenetic Tailoring of Irinotecan-based First-line Chemotherapy in Metastatic Colorectal Cancer: Results of a Pilot Study

Background: Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5- fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer. Patients and Methods: Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety. Results: Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI. Conclusion: The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification. In most Western societies, colorectal cancer (CRC) is the second most common cause of cancer-related death. Approximately 35% of patients have stage IV disease at presentation, and 20% to 50% of patients with stage II or III disease will progress to stage IV. With the introduction of new therapies and the improvement of surgical techniques, the death rate continues to decline at a rate of approximately 1.8% per year. Until recently, the 5-fluorouracil-leucovorin regimen (5-FU/LV) was the standard treatment used, producing median survival times of approximately 12 months as first-line therapy for advanced CRC (1, 2). Starting in the mid-1990s, new efficient cytotoxic chemotherapeutic agents became available (3, 4).