Retrospective Evaluation of 5-FU Exposure Optimization in CRC Patients

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate whether the management of colorectal cancer (CRC) patients with 5-fluorouracil (5-FU) exposure optimization testing reduces 5-FU related toxicities and improves outcomes compared to the current standard of care. A secondary objective is to characterize the variability of 5-FU levels among CRC patients managed with 5-FU exposure optimization testing and the impact of such management on 5-FU plasma levels and drug doses during the course of chemotherapy.

Detailed Description
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This is a multi-center retrospective matched cohort study of early and late stage CRC patients who received 5-FU doses determined using body surface area (BSA) and in patients who underwent pharmacokinetically (PK)-guided 5-FU dose monitoring and adjustment. A retrospective chart / electronic medical record review of colorectal cancer patients treated with infusional 5-FU regimens between May 1, 2009 and December 31, 2013, satisfying the inclusion/exclusion criteria, will be performed. In this multi-center study, patients who underwent PK-testing during at least two different 5-FU administrations will be matched to patients who received doses based on their BSA, treated at the same institution. Matching for selection of the BSA cohort at each site will be done using the following criteria (based on factors that may influence 5-FU metabolism): age, gender, disease stage, prior chemotherapy treatment, and 5-FU containing treatment regimen being used. Each patient will be assigned a random five-digit Study ID number to protect patient confidentiality. Minimal medical history/demographics data will be collected from the patient's medical records / clinic chart using paper case report forms (CRFs). The data to be collected from each patient's records will include: patient demographics (i.e. gender, age, height, and race), colorectal cancer diagnosis (i.e. date of primary diagnosis, tumor stage, grade, histology and phenotype, and date of metastatic diagnosis and sites of metastases if applicable), use of prior therapies for treatment of CRC, 5-FU containing regimen details throughout the 5-FU treatment (i.e. weight, BSA, ECOG status, doses of each drug used in the regimen, and 5-FU infusion start/stop dates and times), 5-FU PK testing results (if applicable), concomitant procedures and medications, CBC and chemistry testing results, adverse events experienced during 5-FU therapy regimen, and tumor response and follow-up information. Patients will not be contacted for the purposes of this study and a waiver of HIPAA authorization will be requested from the appropriate IRB. Once data has been collected and monitored, all records tying the random Study ID number to a specific patient at the sites will be destroyed, rendering all information de-identified.

Official Title
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Retrospective Data Comparison of Toxicity and Efficacy in Colorectal Cancer (CRC) Patients Managed With and Without 5-FU Exposure Optimization Testing

Conditions
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Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, 5-FU Containing Therapy Regimens

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients 18 years of age or older. Patients with histologically confirmed colorectal cancer who were treated with an infusional 5-FU regimen between May 1, 2009 and December 31, 2013. PK-Guided Cohort: Patients monitored with 5-FU PK-testing at a minimum of two administrations of 5-FU throughout the course of a single infusional 5-FU containing treatment regimen. BSA Cohort: Patients who received infusional 5-FU doses calculated based on their BSA. Exclusion Criteria: Patients less than 18 years of age. Patients with concurrent treatment of other active malignancies. Patients that underwent radiation therapy concurrently with chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PK-Guided Cohort<br>CRC patients who were treated with 5-FU containing therapy regimen where 5-FU dosing was monitored and optimized using PK-guided dose adjustment. | |
| BSA Cohort<br>CRC patients who were treated with 5-FU containing therapy regimen where 5-FU dosing was done according to body surface area (BSA) and no PK monitoring was performed. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability of 5-FU plasma levels (exposure) | At each treatment cycle (i.e. Cycle 1, Cycle 2, Cycle 3, etc.), we will plot the 5-FU exposure (i.e. AUC value) and determine the average, median, standard deviation, and percent coefficient of variation (%CV). These statistics will also be determined for all 5-FU exposure values combined. | At each cycle after initiation of 5-FU containing therapy, or approximately every 1 - 2 weeks, depending on the 5-FU infusion schedule, for up to  12 cycles ( 24 weeks) total. | 
| Hematological and non-hematological toxicity rates | Incidence of 5-FU related toxicities, such as diarrhea, oral mucositis, neutropenia, anemia, febrile neutropenia, thrombocytopenia, nausea, etc., will be recorded throughout the duration of the 5-FU containing therapy regimen. | From initiation of the 5-FU containing therapy until up to 30 days after its discontinuation, or for up to  28 weeks total | 
| Tumor response | Tumor response rates as determined by imaging [classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]. | At each follow-up disease assessment following initiation of 5-FU containing thearpy, expected to occur an average of every 8 - 12 weeks, until discontinuation of therapy, or up to  24 weeks total. | 
| Progression-free survival (PFS) |  | up to 3.5 years after initiation of 5-FU containing therapy regimen | 
| Overall survival |  | up to 3.5 years after initiation of 5-FU containing therapy regimen | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal, OnDose, MyCare, 5-FU, pharmacokinetics, exposure, optimization, dose adjustment