Published online May 24, 2021. doi: 10.5306/wjco.v12.i5.355
Peer-review started: December 26, 2020
First decision: January 18, 2021
Revised: January 31, 2021
Accepted: March 18, 2021
Article in press: March 18, 2021
Published online: May 24, 2021
People with a low skeletal muscle mass, defined as “sarcopenia”, may have a lower volume of drug distribution and reduced protein binding compared to people with a normal muscle mass thereby resulting in a higher plasma drug concentration and worse treatment toxicity. In cancer patients, sarcopenia is considered a negative prognostic factor for survival and for the development of dose-limiting chemotherapy toxicities.
Pharmacokinetic parameters of a given drug, such as area under the curve and clearance, may differ substantially among patients depending on body composition. The ratio of fat to lean tissue mass could be a better tool than body surface area with which to determine the dose of cytotoxic agents as it affects metabolism, plasma concentration and the toxicity of drugs.
The primary end-point of this study was to assess the association between baseline sarcopenia, evaluated before starting first-line chemotherapy, and overall survival in metastatic colorectal cancer patients. The secondary end-points were to investigate: (1) the potential correlation of baseline sarcopenia with the objective response rate to first-line chemotherapy and with the development of side effects during the first four cycles of treatment; (2) the association between skeletal muscle loss (SML) at first disease reassessment and overall survival (OS); and (3) the relationship between sarcopenia and age, body mass index (BMI), disease stage at the time of first diagnosis and the neutrophil/lymphocyte ratio as an inflammation index.
Computed tomography (CT)-scans were performed before starting chemotherapy and at the first disease reassessment. Sarcopenia was assessed using the skeletal mass index [SMI = muscle area in cm2/(height in m2)] calculated at the L3 vertebra. Sarcopenia was defined by Martin SMI cut-offs that combined both sex-specific and BMI cut-offs: 43 cm2/m2 for men with BMI < 25 kg/m2, 53 cm2/m2 for men with BMI ≥ 25 kg/m2, and 41 cm2/m2 for women regardless of BMI. OS and objective response rate were evaluated. Toxicities were analyzed during the first four cycles of therapy and graded according to Common Terminology Criteria for Adverse Events version 4.0. A loss of skeletal muscle mass ≥ 5% was considered indicative of deterioration in muscle condition.
The prevalence of sarcopenia was 25%: 14 of the 56 patients were sarcopenic at baseline CT and most of them (9/14, 64%) were under the age of 70 years, which indicates that it is not uncommon to find a low skeletal mass in young adults. No patient was underweight, and 8 of the 14 (57%) sarcopenic patients were overweight or obese. Sarcopenia was not correlated to overall survival (P = 0.362), to higher toxicities reported during the first 4 cycles of chemotherapy (P = 1) or to response to treatment (P = 0.221). At the first disease reassessment, a SML ≥ 5% was found in 17 patients (30.3%) 3 of whom were already sarcopenic at baseline CT scan, while 7 became sarcopenic. SML was not correlated to overall survival (P = 0.961).
Although this is a negative study, our results must be interpreted with caution given the limited sample size. Moreover, the body composition of cancer patients should be evaluated before starting chemotherapy to better select the drug (e.g. lipophilic, hydrophilic, immunotherapy or biological) with the shortest regime (for example, shortening induction therapy in favor of a weakened therapy in sarcopenic patients), the most adequate dosage, and ancillary support strategies (e.g. exercise, specific nutrition supplements, drugs, etc.).
There is a need for prospective studies of more homogeneous populations in terms of age, sex, tumor histology, stage of disease, treatment setting, and mono- or polychemotherapy regimens, to investigate the actual role of sarcopenia in prognosis and therapeutic decisions. Greater efforts should be made to diagnose sarcopenia upon cancer diagnosis in order to correct strength and muscle mass as early as possible and thus improve the patient’s treatment tolerability and survival.