Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer

• Published in: British journal of cancer Vol. 106; no. 10; pp. 1591 - 1597
• Main Authors: Jo, J-C, Lee, J-L, Ryu, M-H, Chang, H M, Kim, M, Lee, H J, Kim, H-S, Shin, J-G, Kim, T-W, Kang, Y-K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2012; Nature Publishing Group
• Subjects: 631/92/436/434; 692/699/67/1059/99; 692/699/67/1504/1829; Adult; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Biomedical and Life Sciences; Biomedicine; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cancer Research; Cancer therapies; Cell division; Chemotherapy; Clinical Study; Drug dosages; Drug Resistance; Epidemiology; Female; Gastric cancer; Genotype; Genotype & phenotype; Glucuronosyltransferase - genetics; Hematology; Humans; Male; Medical research; Metastasis; Middle Aged; Molecular Medicine; Neutropenia; Oncology; Patients; Salvage Therapy; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - mortality; Toxicity; irinotecan; gastric cancer; UDP-glucuronosyltransferase; salvage therapy; chemotherapy; genotype
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.143

Background: To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC). Methods: A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m −2 ) was administered every 3 weeks. The dose was increased (425 mg m −2 and 500 mg m −2 ) or decreased (250 mg m −2 ) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood. Results: A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3–4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3–4 neutropenia during the first cycle ( P =0.018). Conclusion: Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation.