Elsevier

Clinical Colorectal Cancer

Volume 11, Issue 4, December 2012, Pages 263-267
Clinical Colorectal Cancer

Original study
Individual Fluorouracil Dose Adjustment in FOLFOX Based on Pharmacokinetic Follow-Up Compared With Conventional Body-Area-Surface Dosing: A Phase II, Proof-of-Concept Study

https://doi.org/10.1016/j.clcc.2012.05.004Get rights and content

Abstract

Background

To compare the efficacy and safety of pharmacokinetically (PK) guided fluorouracil (5-FU) dose adjustment vs. standard body-surface-area (BSA) dosing in a FOLFOX (folinic acid, fluorouracil, oxaliplatin) regimen in metastatic colorectal cancer (mCRC).

Patients And Methods

A total of 118 patients with mCRC were administered individually determined PK-adjusted 5-FU in first-line FOLFOX chemotherapy. The comparison arm consisted of 39 patients, and these patients were also treated with FOLFOX with 5-FU by BSA. For the PK-adjusted arm 5-FU was monitored during infusion, and the dose for the next cycle was based on a dose-adjustment chart to achieve a therapeutic area under curve range (5-FUODPM Protocol).

Results

The objective response rate was 69.7% in the PK-adjusted arm, and median overall survival and median progression-free survival were 28 and 16 months, respectively. In the traditional patients who received BSA dosage, objective response rate was 46%, and overall survival and progression-free survival were 22 and 10 months, respectively. Grade 3/4 toxicity was 1.7% for diarrhea, 0.8% for mucositis, and 18% for neutropenia in the dose-monitored group; they were 12%, 15%, and 25%, respectively, in the BSA group.

Conclusions

Efficacy and tolerability of PK-adjusted FOLFOX dosing was much higher than traditional BSA dosing in agreement with previous reports for 5-FU monotherapy PK-adjusted dosing. Analysis of these results suggests that PK-guided 5-FU therapy offers added value to combination therapy for mCRC.

Introduction

Colorectal cancer is one of the most frequent malignancies in humans. It represents a highly treatable and curable disease when localized, but, unfortunately, 50% of patients will experience metastatic progression associated with a poor prognosis. In an adjuvant or metastatic colorectal cancer (mCRC) settings, fluorouracil (5-FU) remains the cornerstone of treatment either as a single agent (10%-20% objective response rate [ORR])1 or in combination therapy, such as FOLFOX (leucovorin, fluorouracil, oxaliplatin). In the past decade, objective response has been reported to increase to as much as 50% in 5-FU–based regimens associated with other cytotoxic agents, such as oxaliplatin and irinotecan,2, 3, 4, 5 and, more recently, with targeted therapies such as bevacizumab6, 7, 8 or cetuximab.9, 10

FOLFOX regimens have become the most commonly used treatment in first-line therapy for patients with mCRC.11, 12, 13 Further modification of FOLFOX with newer agents has enabled a subgroup of patients with hepatic or pulmonary metastases to undergo secondary surgery with the resultant benefit of prolonged disease-free survival and for a few, a real hope of complete response (CR).14, 15, 16 We previously demonstrated a beneficial relationship between systemic plasma levels of 5-FU and treatment efficacy and toxicity, and that both can be improved by means of pharmacokinetically (PK) dose adjustment.17 An increased rate of objective response with a low incidence of toxic adverse effects was shown in a phase III randomized study of PK-guided treatment with 5-FU.18

Our goal in this study was to investigate the value of PK-guided 5-FU dose adjustment in improving efficacy and tolerance in the FOLFOX regimen in patients with mCRC. We performed our evaluation with a prospective study by assessing the prevention of oxaliplatin neurotoxicity with calcium-magnesium infusion by performing post hoc analysis on 2 groups of patients. Of the 157 patients, 118 patients were treated in 8 different institutions with 5-FU PK-guided therapy based on our previously published approach (5-FUODPM Tox and 5-FUODPM Protocol, ODPM, Angers, France),17 and 39 patients were treated in 2 other sister institutions and received 5-FU based on standard BSA dosing. The comparisons between the 2 groups were evaluated quantitatively, and no direct statistical comparisons were performed given that they were not randomized.

Section snippets

Patients

Patients from 10 hospitals with measurable pathologically confirmed metastatic adenocarcinoma of the colon or the rectum who were considered for first-line therapy with a FOLFOX regimen were eligible to participate in this study. To be eligible for inclusion, the patient had to be over 18 years, present with measurable metastatic lesions, and have an estimated life expectancy of at least 3 months. All patients were required to have normal bone marrow and organ function before the administration

Patient Characteristics

A total of 118 patients who fulfilled the inclusion criteria were analyzed in the PK-adjusted group between November 2000 and January 2007. The median follow-up was 1426 days (3.9 years) with a range of 2.2-8.3 years. Clinical characteristics of the population of patients are given in Table 1. Thirty-nine patients were treated in 2 other institutions with the 5-FU dosage based on BSA. Their characteristics are also displayed in Table 1. The characteristics of all the patients were consistent

Discussion

PK-adjusted 5-FU monotherapy with folinic acid has been demonstrated to allow dose intensification and demonstrated to result in improved efficacy and favorable toxicity in patients treated for mCRC.18, 19 Because the standard of practice for the treatment of colorectal cancer has shifted toward combination therapy, the aim of the current proof-of-concept study was to further extend this type of approach in combination chemotherapy with FOLFOX. In this proof-of-concept study, we found an

Conclusion

If our results of tailored FOLFOX therapy are confirmed in a randomized phase III study, either with FOLFOX alone or in combination with newer targeted therapies, the results would provide further justification for generalizing this approach in using an old and effective drug much more optimally when comparing the results of these data with adding newer agents in BSA-based FOLFOX. In line with this statement, and as an example, 2 randomized studies that recently compared first-line 5-FU plus

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgment

We thank the Comité Départemental du Maine et Loire de la Ligue Nationale Contre le Cancer.

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