Severe toxicity of capecitabine in a patient with DPD deficiency after a safe FEC-100 experience: why we should test DPD deficiency in all patients before high-dose fluoropyrimidines.

We report the case of a 44-year-old patient who experienced severe toxicity while being treated with capecitabine at standard dose for metastatic breast cancer. As the patient had already received 5-FU within the FEC protocol (5-FU 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) 10 years ago without experiencing any severe adverse event, no DPD deficiency testing was performed before capecitabine treatment. Nevertheless, she experienced severe diarrhea and grade 2 hand-foot syndrome from the first cycle, forcing her to stop the treatment. Phenotypic and genotypic investigation of DPD activity revealed that the patient had a partial deficiency and had therefore been exposed to a higher risk of developing severe toxicities on fluoropyrimidines. This case proves that tolerance to low-dose fluoropyrimidines does not preclude DPD deficiency and the occurrence of severe toxicities if higher doses of fluoropyrimidines are used as a second-line treatment. It emphasizes the role of DPD phenotyping testing based on uracilemia in patients scheduled for fluoropyrimidine drugs, even if previous courses with low-dose 5-FU were safely administered.

Population pharmacokinetics of peritoneal, plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia.

PURPOSE: First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity. METHODS: IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m(2)) at 360 (n = 58) or 460 mg/m(2) (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma. RESULTS: IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis-Menten equation. The mean (±SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean (±SD) ratio AUC(IP)/AUC(UF) was 5.3 (±2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC(UF) accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUCUF, partly dependent on the extent and rate of oxaliplatin absorption. CONCLUSIONS: Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.