EAL

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

Citation:

Prado CM, Lima IS, Baracos VE, Bies RR, McCargar LJ, Reiman T, Mackey JR, Kuzma M, Damaraju VL, Sawyer MB. An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity. Cancer Chemother Pharmacol. 2011; 67(1): 93-101.

PubMed ID: 20204364

Study Design:

Cross-Sectional Study

Class:

D - Click here for explanation of classification scheme.

Quality Rating:

NEUTRAL: See Quality Criteria Checklist below.

Research Purpose:

To relate epirubicin pharmacokinetics (PK) and toxicity to specific features of body composition of patients with breast cancer, focusing on lean body mass and functional liver volume.

Inclusion Criteria:

Women with stage II or III breast cancer treated with adjuvant FE100_C, epirubicin 100mg per m², cyclophosphamide 500mg per m² chemotherapy were eligible
Patients provided written informed consent
Age 18 years or older
No pre-existing liver disease
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) three or less times the upper limit of normal (ULN)
A total bilirubin less than or equal to the ULN
Normal cardiac and renal function.

Exclusion Criteria:

Patients with metastatic disease.

Description of Study Protocol:

Recruitment

Patients were part of a prospective study carried out at the Cross Cancer Institute in Edmonton, Canada from January 2002 to December 2004. The study looked at pharmacogenetic predictors of toxicity to epirubicin chemotherapy in patients with stage II or III breast cancer.

Design

Exploratory analysis and cross-sectional study.

Statistical Analysis

Exploratory data analyses were performed to better understand the characteristics and patterns of the participants and variables as well as to find trends in the dataset
The Students T-test for continuous variables was used to examine the bivariate analyses of associations between outcome variables, explanatory variables and potential confounders
All P values were two-sided and levels of significance were P≤0.05, although clinically important variables were included in the model if their contribution was important and the P value was close to P=0.05.
Explanatory variables significant at the bivariate analysis, potential confounders and clinically important variables (age, BSA, BMI, LBM, albumin, urea, liver volume, liver attenuation, bilirubin, tumor stage and AST) were analyzed by applying a systematic multi-variable model building
Statistical analysis was completed using SPSS version 16.0, Chicago IL USA and STATA.

Data Collection Summary:

Timing of Measurements

Patient toxicity assessments were obtained by a diary provided prior to each cycle of chemotherapy and this was reviewed in person by a research nurse after each cycle. Toxicity profiles were obtained for all cycles but only first-cycle toxicities were analyzed for this study because patients who had severe toxicities had dose reductions for subsequent cycles.
Weight and height were recording according to standard methods. Weight was measured with a medical balance beam scale and height was measured with a stadiometer. Body mass index was calculated weight (kg)/height (m²)
HPLC UV fluorescence detection method with modifications was used to measure epirubicin concentrations. The limit of quantification is 10ng per ml, the range of the standard curve was 10 to 100ng per /ml
Pharmacokinetic data were analyzed using NONMEM and epirubicin clearance values calculated for each patient.

Dependent Variables

Lean body mass (LBM) and functional liver volume: Regional muscle tissue was measured by CT from electronically stored images that had been performed previously for diagnostic purposes. Images taken within 30 days prior to or after initiation of cycle one were selected. The third lumbar vertebrae (L3) was chosen as a landmark and two consecutive slices extending from L3 to the iliac crest were assessed to measure cross-sectional area of muscle. Average value from two images was computed for each patient.
Liver volume was also measured by CT and the organ tissue surface was analyzed. Liver surface area on each image were then used by the Slice-o-matic db volumes function to calculate volume. Liver mean attenuation was also used to estimate liver fat content (the lower the attenuation, the higher the fat content).

Description of Actual Data Sample:

Initial N: 132 patients enrolled
Attrition (final N): 24 (all women) included in the final analysis (N=5 stage II; N=19 stage III)
Age: Median age 52.5 years, range (28.1 to 67.1)
Other relevant demographics: Mean estimated lean total body mass (kg) 42.8 (32.9 to 67.3)
Anthropometrics: Median body mass index kg/m² was 27.6, range (19.4 to 44.4)
Location: Alberta, Canada.

Summary of Results:

Key Findings

Estimated lean body mass was variable ranging from 32.9 to 67.3kg
Lean body mass was associated with neutrophil nadir (R=0.5, P=0.023) and mean lean body mass was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2kg, P=0.002)
33% of the variance in clearance was explained by LBM and aspartate aminotransferase (AST)
Liver mass was not realted to epirubicin clearance likely due to larger livers presenting with larger fat content but liver attenuation and AST were associated with AUC.

Author Conclusion:

Lean body mass predicts epirubicin clearance and may be a better measure with which to individualize treatment than the current convention of normalizing the dose to BSA. This warrants validation in prospective trials testing lean body mass based epirubicin dosing.

Funding Source:

Other:

Roche Translational Research Cancer Foundation

Reviewer Comments:

Limitations to this study include the small sample size

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?		No
	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?	No
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)	N/A
	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.)	N/A
	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.)	Yes
	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?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	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?	Yes
	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?	Yes
	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)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	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?	No
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