650 - Pharmacokinetic and pharmacodynamic analysis of fluorouracil in Chinese colorectal cancer patients

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Pharmacology
Colon Cancer
Rectal Cancer
Presenter Zhiqiang Wang
Authors Z. Wang1, L. Zhao2, F. Wang1, Y. Lin1, Y. Huang1, F. Xu1, C. Xue1, H. Zhao1, Z. Li1
  • 1Department Of Medical Oncology, Cancer Center of Sun Yat-Sen University, 510060 - Guangzhou/CN
  • 2Medical Oncology Dept., Cancer Center of Sun Yat-Sen University, 510060 - Guangzhou/CN

Abstract

Background

Pharmacokinetic (PK) variability of 5-FU (fluorouracil) has been demonstrated for +30 years and a significant link between 5-FU exposure and therapeutic response has been identified. A maximum tolerated exposure (MTE) using area under curve (AUC) has been characterized for various regimens and therapeutic drug management (TDM) has been used to achieve effective dosing. In China the regimen most used to treat colorectal (CRC) cancer are FOLFOX or FOLFIRI. The objective of this study was to characterize the PK variability of 5-FU in this population and examine the relationship between AUC and toxicity.

Methods

Seventy-five treatment naïve colorectal cancer patients were treated with mFOLFOX6(Oxaliplatin 100 mg/m2,d1; LV 400 mg/m2,d1;5-FU 3g/m2,IV 46h,biweekly) or mFOLFIRI (Irrinotecan 180 mg/m2, d1;LV 400 mg/m2,d1;5-FU 3g/m2, IV 46h,biweekly). Blood samples were collected at steady state 18 hrs after the start of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay and AUC was calculated. We examined the relationship between 5-FU AUC and 5-FU-related toxicities.

Results

The patient AUC values varied widely, ranging from 6 to 57 mg • h/L. 44% of the patients were in the 20-30 mg• h/L target range of 29% were below and 27% were above. Toxicity was recorded for 75 patients. Severe mucositis or myelosuppression occurred in 9 of 20 patients with AUCs greater than the target range and in 3 of 55 patients in or below the target range (p = 0.00018). ROC analysis for 5-FU AUC and severe mucositis identified a cut-point of 39 mg• h/L, Area under the ROC curve = 0.870, efficiency = 88.0% (p < 0.001).

Conclusions

Results of this observational study demonstrate wide PK-variability of 5-FU exposure and a significant relationship between severe toxicity and AUC in colorectal cancer patients. The lower percentage of patients below the target range compared to European population suggests lower clearance of 5-FU in Asian population. The study confirms that the MTE in this population is similar to a European CRC population treated with mFOLFOX6 or FOLFIRI. TDM using the target range of 20-30 mg• h/L may have benefit in lowering toxicity in colorectal cancer patients.

Disclosure

All authors have declared no conflicts of interest.