151751-Najiba-Chargi

181 Systemic therapy: skeletal muscle mass and chemoradiotherapy INTRODUCTION Head and neck cancer accounts worldwide for more than 500.000 cases annually. 1 Local- ly advanced head and neck cancer (LA-HNC) is the most frequent clinical manifestation of head and neck cancer. Platinum-based chemoradiotherapy is the main treatment option for (technical or functional) irresectable LA-HNC and is also offered in a postoperative setting for resected LA-HNC in which the tumor is resected irradically or in the presence of extracapsular lymph-nodal extension. Malnutrition is a common problem in LA-HNC in part due to dysphagia caused by the tumor or its treatment. 2 Malnutrition is also a major contributor in the development of low skele- tal muscle mass (SMM). Image-based analysis of SMM has shown critical new insights of low SMM as an important predictor and prognosticator in patients with cancer . 3–5 Cisplatin is the preferred platinum agent used in platinum-based chemoradiotherapy in LA-HNC. Cisplatin is dosed based on body surface area. This approach was initially advocated on the assumption that dosing based on body surface area leads to an acceptable degree of toxicities without reducing the therapeutic effect. 6 Cisplatin is highly emetogenic, neurotoxic, nephrotoxic and ototoxic. 7 Clinically, there is a wide interindividual heterogeneity in the ability of LA-HNC pa - tients to tolerate cisplatin-based chemoradiotherapy. Over the last years, emerging evidence suggests a significant negative relationship between low SMM and adverse effects of cytotoxic drugs leading to dose-limiting toxicities (DLTs). 8–11 As such, SMMmay (partly) explain the het - erogeneity of patient’s tolerance for chemotherapy. Cisplatin DLTs lead to frequent hospital readmissions, decreased survival and reduced quality of life. Themechanismunderlying the relationship between lowSMMand DLTs of chemotherapeutical drugs is not fully understood. Several hypotheses have been proposed in literature. 12,13 It has been hypothesized that altered fat-to-lean body mass (LBM) influences the pharmacokinetics of anti-cancer drugs and/or may be associatedwith increased chronic low-grade inflammation, which results in a higher risk of adverse events. The most commonly supported hypothesis is based on the influence of low SMM on the volume of distribution of anti-cancer drugs. 13 Cisplatin is a hydrophilic agent; due to its hydrophilicity it favors distribution to the LBM of which SMM is the largest component. However, SMM is currently not (directly) taken into ac - count in cisplatin dosing. Body surface area is calculated by use of several formulas such as the formula of Du Bois. 6 These formulas incorporate body weight and height. Lower SMM can, however, occurs independently of adiposity, therefore in overweight or obese patients, the loss of SMMmay bemasked. Hence, dosing according to body surface area leads to substantial variation in drug doses per kilogramof LBM. 8 Higher dose per kilogram LBM has shown to have a significant correlation with higher rates of toxicities in other cancer types. 9 A loss of SMM in patients with head and neck cancer may, consequently, induce drug overdose when dose calculation is based on the conventional body surface area method. 10