ABSTRACT
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer in the United States. Using clinically-
acquired computed tomography (CT) scans to measure muscle cross-sectional area (CSA), the prevalence of
low muscle in nonmetastatic CRC patients is estimated to be 42%. Low CT CSA has been associated with a
more than 2-fold increased risk of chemotoxicity, a 26% increased risk of surgical complication and a 46%
increased risk of CRC-specific death. However, the use of CT to estimate muscle mass is constrained because
CT is not the standard of care in all cancers, is often limited to one anatomic region and cannot distinguish
between contractile muscle protein and other tissue in muscle fascia. Alternatives include dual energy x-ray
absorptiometry (DXA), which measures all lean body mass (LBM), including fibrotic and connective tissue,
water, and organs. However, neither DXA nor CT directly quantifies total body muscle mass and both methods
expose patients to radiation. Safe and non-invasive methods to assess muscle mass will contribute to our
understanding of the mechanisms by which muscle loss may affect morbidity and mortality after cancer and
enhance interventions such as physical activity that target muscle mass in cancer patients. To this end, for the
first time in cancer patients, the proposed study will evaluate the associations of a direct and non-invasive
method to assess total body muscle mass with outcomes. Deuterated creatine dilution (d3-creatine) estimates
total creatine pool size, and thus muscle mass, using an oral dose of d3-creatine and measuring d3-creatinine
enrichment in a single, spot-urine sample a few days later. Since creatine is located within the contractile
components of the sarcomere, d3-creatine dilution provides a measure of functional muscle mass. This study
will measure d3-creatine muscle mass in 90 colon cancer patients participating in a randomized controlled trial
of resistance training during chemotherapy in which CT CSA and DXA LBM are already being collected. We
will test whether d3-creatine muscle mass changes in response to resistance training and examine whether d3-
creatine muscle mass is associated functional, metabolic, inflammatory and chemotherapy outcomes. In
addition, we will compare the strength of the associations with outcomes found with d3-creatine muscle mass
to those with CT CSA and/or DXA LBM. If d3-creatine muscle mass in cancer patients is predictive of strength,
function, chemotoxicity and cancer-related biomarkers, then d3-creatine dilution will be a useful tool for
research on the role of muscle mass and physical activity interventions in cancer patients. In the future,
informed by the evidence generated in this study, the simple d3-creatine dilution test might someday be used
clinically to identify cancer patients with low muscle mass for interventions to mitigate chemotoxicity,
cardiometabolic risk, functional impairment and mortality.