151751-Najiba-Chargi

260 CHAPTER 14 MATERIALS AND METHODS ETHICAL CONSIDERATIONS The Medical Research Ethics Committee (METC) of the University Medical Center Utrecht has reviewed the study in accordance with the Dutch Medical Research Involving Human Subjects Act (WMO) and other applicable Dutch and European regulations and has approved this study in June 2018 (METC 18-225/D). The study was conducted in compliance with Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent prior to inclusion in the study. STUDY POPULATION, STUDY DESIGN AND SAMPLE SIZE This study was designed as a monocenter prospective observational cohort study in HNSCC patients receiving three-weekly high-dose (100 mg/m 2 ) primary or adjuvant CRT. To estimate the sample size a clinical trial simulation (n = 200) was performed based on a previously pub - lished PK model on ultrafilterable cisplatin. 14 An allometric relationship between SMM and cisplatin clearance was assumed. Patient characteristics (SMM and body surface area (BSA)) were simulated in accordance with clinical practice. It was estimated that data from 45 pa - tients was sufficient to find a significant relationship between cisplatin clearance and SMM with a power of >80%. As PK models with SMM and BSA are non-hierarchical, the difference between the two models cannot be statistically tested. However, in approximately 70% of the trials, this relationship showed better goodness-of-fit than a BSA-based relationship. Finally, the allometric exponent could be estimated with acceptable precision (approximately 28% relative standard error) with a sample size of 45 patients. SKELETAL MUSCLE MASS MEASUREMENT Segmentation of SMMwas manually performed using the SliceOmatic software (Tomovision, Canada). Skeletal muscle area (SMA) was measured on pre-treatment computed tomography (CT) imaging at the level of the third lumbar vertebrae (L3) by a validated method. 15 If no pre-treatment imaging was available at the level of L3, SMA was measured at the level of the third cervical vertebrae (C3) and then converted to SMA at the level of L3 by use of an earlier defined formula. 15 To correct for height, SMA was divided by squared height to yield the skel- etal muscle mass index (SMI). Low SMM was defined as a lumbar SMI (LSMI) ≤ 43.2 cm 2 /m 2 . 16 For PK analysis, the absolute volume of the muscle compartment was used by converting SMA to SMM with use of the following equations 17,18 : (1) (2) (3) (4) (5) (1) (1) (2) (3) (4) (5) (2) For simulation purposes, the threshold value of low LSMI was converted to a threshold value for SMM in kilograms. Using the median height in our patient population, the threshold for low SMMwas defined to be ≤ 25.8 kg. SMMwas compared with the calculated fat-free mass (FFM), which is another way to estimate body composition. For calculation of FFM the equations of Janmahasatian et al. were used 19 :