Body Composition and Dose-limiting Toxicity in Colorectal Cancer Chemotherapy Treatment; a Systematic Review of the Literature. Could Muscle Mass be the New Body Surface Area in Chemotherapy Dosing?

Chemotherapy dosing is traditionally based on body surface area calculations; however, these calculations ignore separate tissue compartments, such as the lean body mass (LBM), which is considered a big pool of drug distribution. In our era, colorectal cancer patients undergo a plethora of computed tomography scans as part of their diagnosis, staging and monitoring, which could easily be used for body composition analysis and LBM calculation, allowing for personalised chemotherapy dosing. This systematic review aims to evaluate the effect of muscle mass on dose-limiting toxicity (DLT), among different chemotherapy regimens used in colorectal cancer patients. This review was carried out according to the PRISMA guidelines. MEDLINE and EMBASE databases were searched from 1946 to August 2019. The primary search terms were 'sarcopenia', 'myopenia', 'chemotherapy toxicity', 'chemotherapy dosing', 'dose limiting toxicity', 'colorectal cancer', 'primary colorectal cancer' and 'metastatic colorectal cancer'. Outcomes of interest were - DLT and chemotoxicity related to body composition, and chemotherapy dosing on LBM. In total, 363 studies were identified, with 10 studies fulfilling the selection criteria. Seven studies were retrospective and three were prospective. Most studies used the same body composition analysis software but the chemotherapy regimens used varied. Due to marked study heterogeneity, quantitative data synthesis was not possible. Two studies described a toxicity cut-off value for 5-fluorouracil and one for oxaliplatin based on LBM. The rest of the studies showed an association between different body composition metrics and DLTs. Prospective studies are required with a larger colorectal cancer cohort, longitudinal monitoring of body composition changes during treatment, similar body composition analysis techniques, agreed cut-off values and standardised chemotherapy regimens. Incorporation of body composition analysis in the clinical setting will allow early identification of sarcopenic patients, personalised dosing based on their LBM and early optimisation of these patients undergoing chemotherapy.

Lysophosphatidic acid cooperates with 1alpha,25(OH)2D3 in stimulating human MG63 osteoblast maturation.

Osteoblast maturation is partly controlled by the interaction of 1alpha,25(OH)(2)D(3) (D3), an active metabolite of Vitamin D, with other growth factors. The first reports describing the in vitro effect of D3 on human osteoblast differentiation performed experiments in the presence of serum. One potentially exciting candidate that might help explain the D3 responses observed for osteoblasts cultured with serum is lysophosphatidic acid (LPA). Drawn to the possibility that D3 and serum borne LPA might interact to induce osteoblast maturation we co-treated human cells with D3 and serum in the presence of Ki16425, an LPA receptor antagonist. Ki16425 inhibited osteoblast maturation as determined by markedly reduced alkaline phosphatase (ALP) expression. We subsequently found that LPA and D3 acted synergistically in generating mature osteoblasts and that this differentiation response could be inhibited using pertussis toxin, implying an important role of Galphai signal transduction. Furthermore, we found evidence for a dependency on both mitogen activated protein kinase kinase (MEK) and Rho associated coiled kinase (ROCK) for LPA and D3 stimulated maturation.