5-Fluorouracil

BSA dosing results in sub-target 5-FU levels in the majority of patients. PK- guided dosing can move 5-FU levels into the target range. Optimal dosing of 5-FU is associated with increased efficacy and reduced toxicity.
•    Personalize dose to personalize medicine
•    Reduce the risk of under dosing
•    Optimize each individual patient’s dose based on their drug level
•    Potentially improve outcomes with PK-guided dose adjustment.

 

Publications of Interest

Therapeutic drug monitoring of 5-fluorouracil.  
Lee JJ, Beumer JH, Chu E. Cancer Chemother Pharmacol. 2016 78(3):447-464. Review.

This very recent and through review concluded: “Dose adjustment of 5-FU is feasible, and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.”

http://www.ncbi.nlm.nih.gov/pubmed/27217046

 

Prospective, multi-center study of 5-fluorouracil (5-FU) therapeutic drug management (TDM) in metastatic colorectal cancer (mCRC) patients treated in routine clinical practice.
Wilhelm M, Mueller L, Miller MC, et al. Clin Colorectal Cancer. 2016; 15(4):381-388.

Like a number of earlier studies, inter-patient variability of 5-FU level was high and  the majority of the patients were under dosed (64%). PK guided dosing controlled variability of exposure, and adjusted patients into the target AUC range by the fourth cycle (p<0.001). PK-guided dose adjustment according to published algorithms was easy to manage in routine practice.  Physicians followed the dosing recommendations and were able to administer higher doses without an increase in toxicity.

http://www.clinical-colorectal-cancer.com/article/S1533-0028(16)30049-4/abstract

 

Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer.
Gamelin E, Delva R, Jacob J, et al. J Clin Oncol. 2008 May 1;26(13):2099-105.

In this phase III trial studied 208 late stage CRC who were either dosed by BSA or had their doses adjusted based on their 5-FU level. In the Pharmacokinetically (PK) guided arm doses were adjusted to achieve a target exposure (AUC).  The majority of patients required dose adjustment to receive the target level of 5-FU resulting in a higher mean dose and a wider range of doses than in the BSA arm, where adjustments were made only for toxicity. Objective response rate correlated with 5-FU levels.  The patients who had their doses adjusted had higher overall response rate and reduced toxicity.  Though not powered to demonstrate survival, PK guided dosed patients had 6 months longer median survival, which tended toward statistical significance.

http://jco.ascopubs.org/content/26/13/2099.long

 

Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6.
Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL. Oncologist. 2012;17(3):296-302.

This study established a dose adjustment algorithm to achieve optimal 5-FU levels using moderate changes in dose.   

http://theoncologist.alphamedpress.org/content/17/3/296.long

 

A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy.
Patel JN, O’Neil BH, Deal AM, et al. Oncologist. 2014 Sep;19(9):959-65

From five community and one academic center 70 CRC patients received mFOLFOX6 with pharmacokinetically guided dose adjustments after the first cycle.  This study demonstrated that oncologists were successful in adjusting their patient’s doses so that their 5-FU levels were within target range.  In cycle 4 patients had a significantly higher odds ratio of not being under dosed compared to cycle 1: OR: 2.29; p=0.037.  Compared to historical data there was also a reduction in mucositis and diarrhea, though the occurrence of neutropenia was similar. 

http://theoncologist.alphamedpress.org/content/19/9/959.lon

 

Personalized Dosing via Pharmacokinetic Monitoring of 5-Fluorouracil Might Reduce Toxicity in Early- or Late-Stage Colorectal Cancer Patients Treated With Infusional 5-Fluorouracil-Based Chemotherapy Regimens.
Kline CL, Schiccitano A, Zhu J, et al. Clin Colorectal Cancer. 2014 Jun;13(2):119-26.

This was the first study that included patients in the adjuvant setting.  There was a significant difference in disease free survival for those stage II/III patients who had their doses adjusted compared to the patinets in the BSA arm.  PK guided dosing also resulted in longer progression free survival  for stage IV patients, though it did not reach statistical significance.  In addition to improved outcomes toxicity was also reduced in the dose adjustment arms.

http://www.ncbi.nlm.nih.gov/pubmed/24461492

 
 
 
Current Chemo Dosing Practices

Current Chemo Dosing Practices