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ONC: Nutrition Status and Outcomes in Adult Oncology Patients (2013)

Citation:

Prado CM, Baracos VE, McCargar JL, Mourtzakis M, Mulder KE, Reiman T, Butter CA, Scarfe AG, Sawyer MB. Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity. Clin Cancer Res. 2007 Jun 1; 13(11): 3,264-3,268.

PubMed ID: 17545532
 
Study Design:
Prospective Cohort Study
Class:
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To determine if the highest doses of 5-fluorouracil (5-FU) per kilogram (kg) lean body mass (LBM) were associated with dose-limiting toxicity in stage II or III colon cancer patients treated with 5-Fu and leucovorin.

Inclusion Criteria:
  • Histologically proven high-risk stage II or III colon cancer:
    • Stage II defined as T3 or T4, N0, M0; high-risk features including perforation, obstruction, lymphovascular or perineural invasion, high grade aneuploidy, and signet ring cell
    • Stage III defined as Tany, N1-2, M0
  • Complete resection of the primary
  • World Health Organization (WHO) performance status less than two
  • No prior chemotherapy
  • Adequate bone marrow reserve, defined as neutrophils 1.5 x 109 or more cells per L and platelets 100 x 109 or more cells per L.
Exclusion Criteria:

Known dihydropyrimidine dehydrogenase deficiency.

Description of Study Protocol:

Recruitment

Subjects were obtained from a prospective study designed to determine if thymidylate synthase gense polymorphisms are associated with 5-FU/leucocorin efficacy and toxicity conducted at the Cross Cancer Institute, Edmonton, Alberta, Canada.

Design

Toxicity after initial cycle of 5-FU/leucovorin was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was evaluated by computerized tomography (CT) and extrapolated to the LBM compartment of the whole body.   

Intervention

Patients were set to receive six 28-day cycles of daily 5-FU/leucovorin based on body surface area (BSA) calculated using the Mosteller formula. Initial doses were planned as 5-FU (425mg per m2) and leucovorin (20mg per m2), administered by intravenous bolus for five days.

Statistical Analysis

  • Data expressed as mean ± standard deviation
  • Fisher's exact tests were used to determine significance of the association between two variables
  • Student's T-tests were used to determine significance between unpaired variables
  • Associations between 5-FU dose and toxicities with 5-FU dose expressed as amount of 5-FU per estimated LBM (mg 5-FU per kg LBM)
  • Significance level set as P<0.05
  • SPSS for Windows, version 14.0, SPSS. 
Data Collection Summary:

Timing of Measurements

  • Toxicity assessments were obtained from a patient diary provided before each cycle of chemotherapy, though only cycle one was used as some patients required dose modifications after cycle one
  • Neutropenia was assessed from blood samples obtained during cycle one and before cycle two
  • Weight, measured with a medical balance beam scale, and height, measured with a stadiometer were recorded during visits and BMI was calculated from these measurements
  • Computerized tomography (CT) images were obtained for diagnostic purposes on average 37 days before or after initiation of chemotherapy cycle one.

Dependent Variables

  • Regional adipose tissue (visceral and subcutaneous) was measured by CT
  • Muscle tissue was measured by CT
  • A cross-sectional area of muscle and adipose tissue was measured using a landmark of the third lumbar vertebrae (L3) was chosen with four consecutive slices extending from L3 to the iliac crests. The average value of four images was computed per patient and analyzed using Slice-O-matic software version 4.3 (Tomovision).
    • Pre-established thresholds of Hounsfield units were used to identify and quantify specific tissues
    • Cross-sectional areas (cm2) of tissues were computed for each image and abdominal muscle area was extrapolated to whole-body LBM using a specified formula.

Independent Variables

  • Patients were set to receive six 28-day cycles of daily 5-FU/leucovorin based on body surface area (BSA) calculated using the Mosteller formula: m2=([height in centimeters x weight in kilograms]/3600)1/2
  • Initial doses were planned as 5-FU (425mg per m2) and leucovorin (20mg per m2), administered by intravenous bolus for five days. 
Description of Actual Data Sample:
  • Initial N: 95 patients completed the original study
  • Attrition: 62 patients (32 male, 30 female) had useful CT scans and were selected for analysis
  • Age: 60.3±9.9 years.

Anthropometrics

Patient Characteristics
Characteristic Female Male Total P
Weight (kg) 68.8±17.1 86.5±19.7 77.9±20.4 <0.001
Height (m) 1.6±0.1 1.7±0.1 1.7±0.1 <0.001
BMI (kg/m2) 26.7±6.4 28.5±5.4 27.6±5.9 0.212
BSA (m2) 1.7±0.2 2.0±0.3 1.9±0.3 <0.001
Whole-body LBM (kg) 38.2±7.6 55.7±9.3 47.2±12.2 <0.001

Location

Alberta, Canada.

 

Summary of Results:

Key Findings

  • Mean 5-FU per kg LBM values of the population varied with regards to presence or absence of toxicity (P=0.036)
  • A cut-point of 20mg 5-FU per kg LBM was identified as a threshold and predictor for developing toxicity (P=0.005) [odds ratio (OR), 16.5; P=0.013], specifically among women (OR, 16.73; P=0.021)
  • Age was a significant predictor of toxicity (OR ,1.06; P=0.047).
Author Conclusion:

Low LBM is a significant predictor of toxicity among female patients administered 5-FU using the convention of dosing per unit of BSA, and variation in toxicity between males and females may be partially explained by this feature in body composition.

Funding Source:
Not-for-profit
Alberta Cancer Foundation/Alberta Cancer Board; Canadian Institutes for Health Research; Alberta Cancer Board Provincial Clinical Research Program grant 10; American Society of Clinical Oncology; Alberta Heritage Foundation
Reviewer Comments:

Odds ratios did not provide a 95% confidence interval.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) No
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? No
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? No
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes