Abstract
Fluoropyrimidines, including 5-fluorouracil (5-FU) and its oral prodrugs capecitabine and tegafur, are among the most commonly prescribed anticancer drugs for the adjuvant and palliative treatment of various types of solid malignancies, including colorectal cancer, gastric cancer and breast cancer. The major lines of research described in this thesis focus on
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the treatment optimization of fluoropyrimidine therapy, in terms of both safety and efficacy. The studies include clinical pharmacogenetic, pharmacokinetic, and phase I-II trials with fluoropyrimidines. In 568 patients with advanced colorectal cancer treated with capecitabine-based chemotherapy the effect of genetic polymorphism within the primary fluoropyrimidine inactivating enzyme dihydropyrimidine dehydrogenase was investigated. Five polymorphism were predictive for development of grade ? 3 diarrhea, of which the clinically most relevant polymorphism was DPYD*2A. All patients polymorphic for DPYD*2A experienced any type of severe toxicity of treatment, which was lethal in one patient. In a prospective study, patients intended to undergo treatment with capecitabine or 5-FU were prospectively screened for presence of the DPYD*2A polymorphism prior to start of therapy. Polymorphic patients were treated with an initially ? 50% reduced fluoropyrimidine dose during the first two cycles, which was further dose-titrated based on clinical tolerability. Toxicity by genotype-guided dosing was compared to toxicity in historical DPYD*2A controls having received full dose treatment (n=40 variant allele carriers obtained from 9 cohort studies including a total of 3391 patients). A total number of 1600 patients was prospectively genotyped prior to start of therapy, of which 17 were heterozygously polymorphic for DPYD*2A. With a median fluoropyrimidine dose intensity of 48% (range 24-91%) per cycle, the DPYD*2A patients could be safely treated. Thereby, the risk of grade ? 3 toxicity reduced from 70% in historical controls to 15% by genotype-guided dosing. Drug-induced death reduced from 10% to 0%. In addition, upfront genotyping proved to be cost-effective. In another study the effect of gastric surgery on the systemic exposure to capecitabine was investigated in patients with gastric cancer. A total and partial gastrectomy resulted in a faster absorption, a higher maximum concentration, and a higher total systemic exposure of capecitabine compared to patients with an intact stomach. Three phase I-II trials were conducted: one investigated the combination of docetaxel, oxaliplatin and capecitabine in 33 patients with advanced gastric cancer. The overall response rate was 46% including two complete responses. Median progression-free and overall survival were 6.9 and 11.6 months. Febrile neutropenia occurred in 14% of the patients. A second phase I-II trial was performed in 18 patients with anal cancer treated with simultaneous-integrated boost radiation therapy (33x1.8/1.5 Gy 3x1.8 Gy boost) with concomitant capecitabine and mitomycin-C on day 1. Predominant grade ? 3 toxicities included dermatitis within the radiation area (61%), fatigue (22%) and pain (6%). 72% of the patients achieved a complete response. A third phase I-II trial investigated the combination of everolimus with capecitabine in patients with advanced solid malignancies. 18 patients were recruited, the recommended dose was everolimus 10 mg/day continuously plus capecitabine 1000 mg/m2 bid for 14 days in three-weekly cycles. Toxicities remained mostly grade ? 2.
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