Elsevier

Clinical Colorectal Cancer

Volume 15, Issue 4, December 2016, Pages 381-388
Clinical Colorectal Cancer

Current Trial Report
Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice

Presented at the American Society of Clinical Oncology 2015 Annual Meeting (abstract no. 3542).
https://doi.org/10.1016/j.clcc.2016.04.001Get rights and content

Abstract

Background

Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice.

Patients and Methods

A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data.

Results

The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU–related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses.

Conclusion

Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU–related toxicities.

Introduction

The fluoropyrimidine, 5-fluorouracil (5-FU), has been used in the treatment of cancer for > 50 years and is currently the most widely used chemotherapy agent in the world. It continues to be the cornerstone of treatment regimens for many different cancers, including colorectal (CRC), head and neck, and pancreatic cancers.1, 2 As with many other chemotherapy agents, the standard of care in dosing 5-FU has been based on the body surface area (BSA). This dosing method was first developed in 1916 using a limited number of patients as a method of converting the drug doses used in animals to doses that could be used in humans.3 BSA-based dosing was applied to chemotherapy drugs starting in the 1950s without rigorous scientific evaluation4 and has been the standard of care for chemotherapeutic drug dosing ever since. Numerous studies of 5-FU have demonstrated that BSA-based dosing leads to a wide range of pharmacokinetic (PK) variability, resulting in significant differences in individual exposure and a significant proportion of patients receiving suboptimal exposure.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19

Clinical studies, including 1 randomized trial,6, 7, 9, 14, 15, 16, 19, 20 have demonstrated that 5-FU therapeutic drug management (TDM) reduces toxicity and improves efficacy. In a recent trial comparing conventionally dosed 5-FU to TDM of 5-FU in patients receiving a FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin) regimen,14 5-FU TDM improved the objective response rate from 46% to 70%, increased the median overall survival from 22 to 28 months, and reduced the incidence of grade 3 and 4 toxicities. In the TDM arm of the study, 80% of the patients had dose adjustments, with 50% having their dose increased and 30% having their dose decreased. In another report, Kline et al13 compared a cohort of patients with stage II/III and stage IV CRC for whom where 5-FU TDM was implemented with a similar group of patients dosed using the BSA. Their study showed that TDM resulted in a significant improvement (P = .0429) in disease-free survival in the adjuvant setting (stage II/III) and a significant reduction in adverse events.

Without TDM, patients will often have their dose decreased when toxicity is observed, but rarely will they have their dose increased when toxicity is not observed. Although TDM is commonly used in other areas of medicine (ie, infectious diseases, cardiology, psychology), it has not gained wide acceptance in oncology. The reasons include that oncologists are not trained to rely on TDM to adjust chemotherapeutic drug doses, studies identifying the optimal target ranges for drug exposure are limited, and routine laboratory tests to measure the plasma levels of cytotoxic drugs have not been widely available.11, 12

A guideline for adjusting initial 5-FU dosing based on the dihydropyrimidine dehydrogenase (DPD) genotype has been suggested.10 Although DPD polymorphisms are relevant and can often cause dramatic changes in 5-FU exposure, the genotype alone is not sufficient to control or fine tune the exposure during the entire treatment course.10, 21, 22 Other factors play a role in 5-FU exposure, and determining the area under the curve (AUC) of 5-FU directly reflects the phenotype of the drug on an individual basis. Several algorithms for adjusting 5-FU doses according to the AUC have been reported6, 8, 9, 10, 16, 17, 23 and an optimal exposure target identified. The purpose of the present study was to assess 5-FU exposure variability in patients with metastatic CRC (mCRC) receiving the most commonly used regimens in the German population and demonstrate the feasibility of TDM to achieve target exposure in routine clinical practice.

Section snippets

Patients

The eligibility criteria included male or female patients aged ≥ 18 years, ≤ 1 previous line of therapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, life expectancy of > 3 months, normal bone marrow and organ function, and hemoglobin levels of ≥ 9 g/dL. Patients who were pregnant or had symptomatic brain metastasis, known DPD deficiency, or unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 1

Patients

A total of 77 patients with mCRC were enrolled from July 2012 to July 2014, 75 (97%) of whom were treated. Of the 75 patients, 16 (21%), 26 (35%), and 33 (44%) were treated with the AIO, FOLFOX6, and FUFOX regimens, respectively. The demographic data, baseline characteristics, and study treatment details are listed in Table 2. In the 75 patients who received ≥ 1 cycles of infusional 5-FU treatment, a total of 404 infusions were given (average of 5 infusions per patient). Most patients (81%)

Discussion

Numerous and consistent reports during the past 25 years have demonstrated 5-FU PK variability and the relationship of exposure to both toxicity and outcomes.5, 8, 17, 18, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 Studies with the more commonly used 5-FU regimens for CRC have demonstrated that not only does exposure vary significantly, but that most patients are also receiving suboptimal exposure.5, 13, 14, 17, 18, 19 This has led investigators to conclude that dosing 5-FU using the

Conclusion

The use of TDM in 5-FU treatment is an important step in individualizing treatment on a patient-by-patient basis. It is easy to implement and results in higher dose intensity with lower toxicity. The results of the present study were consistent with previous reports, providing further support for the use of TDM in routine clinical practice.

Disclosure

The authors declare that they have no competing interests.

Acknowledgments

This study was sponsored by CESAR Central European Society for Anticancer Germany. Financial support for the study was provided by Saladax Biomedical, Inc.

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