No abstract

The mainstay of colorectal cancer chemotherapy has been 5-fluorouracil (5-FU) alone or in combination with other agents. Unfortunately, therapeutic plasma 5-FU levels are achieved in only 20-30% of patients, in response to administration of 5-FU doses calculated from the patient's body surface area. Pharmacokinetic (PK) monitoring of 5-FU has been found to be beneficial for metastatic colorectal cancer patients. However, its utility among Stage II and III patients has not been reported. Purpose: We examined the impact of pharmacokinetic monitoring of 5-FU in colorectal patients with Stage II- Stage IV disease, receiving different 5-FU-based chemotherapy regimens, in terms of therapeutic response and safety. Methods: The study involved 73 colorectal cancer patients. The patients received different 5-FU based regimens; namely, FOLFOX6, mFOLFOX, FOLFIRI, and capecitabine. Thirty-five patients received 5-FU doses based on the traditional body surface area (BSA) method, which takes into account the patient's height and weight. On the other hand, in 38 patients, their 5-FU dose was adjusted based on their plasma 5-FU levels from their previous cycle. 5-FU plasma levels were measured using the commercially available OnDose test (Myriad Genetic Laboratories Inc., Salt Lake City, UT). The 5-FU levels were monitored per cycle and administered doses were adjusted accordingly until a target plasma AUC level of 20-24 mg.h/L was achieved. Results: Pharmacokinetic monitoring among Stage IV patients (n=17) had a trend toward improved survival. Out of the 8 patients that needed at least one dose adjustment, 7 of them involved increasing the 5-FU dose. 5-FU doses were not increased in the patients that did not have their 5-FU levels monitored. The ability to maximize the 5-FU dose administered without risking toxicity with PK monitoring may explain at least in part the trend towards prolonged survival in patients that underwent pharmacokinetic dose adjustment. Among Stage II and III patients, toxicities were markedly reduced by pharmacokinetic dose adjustment of 5-FU. In patients that had their doses adjusted by the BSA method, 38% experienced (7 out of 18 patients) dose-limiting toxicities, that included Grade III diarrhea, fatigue, nausea and vomiting, and cardiotoxicity. In contrast, none of the patients (n=19) that underwent pharmacokinetic monitoring experienced dose-limiting toxicity (Fisher's exact test, p=0.0031). The toxicities observed in the BSA group were not among the patients that received capecitabine. Conclusions: 5-FU dose adjustment in response to pharmacokinetic monitoring results in a trend towards improved survival of Stage IV patients. Moreover, dose-limiting toxicities are reduced in Stage II and III patients. The results presented point to the benefits of pharmacokinetic dose adjustment of 5-FU in clinical practice. Citation Format: Christina Leah B. Kline, Angelique Schiccitano, Jay Zhu, Cheryl Beachler, Hassan Sheikh, Harold Harvey, Heath Mackley, Walter Koltun, Kevin McKenna, Lisa Poritz, Evangelos Messaris, David Stewart, Jeffrey Sivik, Wafik El-Deiry. Pharmacokinetic monitoring of 5-FU appears beneficial in stage II-IV colorectal cancer patients treated with different 5-FU-based chemotherapeutic regimens. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1176. doi:10.1158/1538-7445.AM2013-1176