Does oxaliplatin pharmacokinetics (PKs) explain associations between body composition and chemotherapy toxicity risk in older adults with gastrointestinal (GI) cancers?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3095-3095
Author(s):  
Grant Richard Williams ◽  
Mustafa Al-Obaidi ◽  
Joseph Rower ◽  
Christian Harmon ◽  
Chen Dai ◽  
...  
Keyword(s):  
Older Adults ◽  
Body Composition ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Muscle Area ◽  
Wide Variability ◽  
Dosing Strategies ◽  
Gi Cancers ◽  
Grade 3 ◽  
Skeletal Muscle Area

3095 Background: Considerable inter-individual variability in oxaliplatin toxicity exists in older adults with GI cancers. Low lean body mass (LBM), commonly known as sarcopenia, influences toxicity and is not incorporated in standard body surface area-based dosing, which may affect oxaliplatin PK and tolerability, but has not been examined systematically. Methods: We examined oxaliplatin PK in 26 older adults (103 concentrations) with GI cancers (NCT03998202). Using the transverse section at L3, skeletal muscle area (SMA) and total adipose tissue (TAT) were quantified (Slice-O-Matic software) and LBM was calculated (LBM = 0.30 × SMA + 6.06). Noncompartmental methods (WinNonlin 7.0) were used for PK estimates and a one compartment population PK model (PopPK) was developed. Covariates included age, sex, LBM, TAT, weight, BMI, creatinine clearance, BSA, serum albumin, and body composition phenotypes (i.e. low LBM-high TAT, etc.). Results: Median age was 68yrs, 69% male, 88% white, and mostly colorectal (62%) and pancreatic (27%) cancers. There was wide variability in oxaliplatin volume of distribution (Vd: 12.5-259L), peak concentrations (Cmax: 404-3642ng/mL), and clearance (CL: 26.7-270L/hr). Participants with lower LBM had lower Vd (r = 0.51, p< 0.01); those with higher TAT had higher Cmax (r = 0.53, p< 0.01). Higher albumin was associated with lower Cmax (r = -0.49, p= 0.01) and higher CL (r = 0.47, p= 0.01). The phenotype of low LBM + high TAT had the lowest Vd (Relative Risk [RR] 0.32, p= 0.01), lowest CL (RR 0.39, p< 0.01), and highest Cmax (RR 3.3, 95% CI 1.7-6.5, p< 0.01). Eleven patients (44%) had grade 3-5 chemotoxicity. Vd (r = -0.46, p= 0.02) and Cmax (r = 0.44, p= 0.03) were associated with grade 3-5 chemotoxicity. The phenotype of low LBM + high TAT was associated with a 45% higher risk of grade 3-5 chemotoxicity (RR = 1.45, 95% CI 1.1-2.1, p= 0.04), while BSA was not (r = -0.04, p= 0.9). In the popPK model, body composition was associated with PK (TAT with Vd [p = 0.006] and CL [p < 0.001]), as was albumin (Vd p = 0.004; CL p = 0.002), while BSA was not (Vd p = 0.08; CL p = 0.2). Compared to BSA, an additional 11-17% in oxaliplatin PK variability was explained by LBM (11%), TAT (14%), and albumin (17%). Conclusions: Relationships between body composition, oxaliplatin PK, and severe chemotoxicity suggest the need for novel dosing strategies that incorporate body composition to reduce chemotoxicity and improve outcomes. Clinical trial information: NCT03998202.

Abnormal body composition in patients with adrenal adenomas

2021 ◽  
Author(s):  
Danae Delivanis ◽  
Maria Daniela Hurtado Andrade ◽  
Tiffany Cortes ◽  
Shobana Athimulam ◽  
Aakanksha Khanna ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Composition ◽  
Muscle Mass ◽  
Visceral Fat ◽  
Cushing Syndrome ◽  
Cross Sectional Study ◽  
Cortisol Secretion ◽  
Muscle Area ◽  
Cross Sectional ◽  
Skeletal Muscle Area

Objective: Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease Design: Cross-sectional study, 2014-2018 Methods: Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS), and age, sex and body mass index 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal computed tomography imaging. Intraabdominal adipose tissue and muscle mass measurements were performed at the 3rd lumbar spine level. Results: Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS and 131 with NFAT. Median age was 56 years (range, 18-89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR) of 2.2 [95% CI 0.9-6.5], 2.0 [1.3-3.2], and 1.8 [1.2-2.7] and a lower skeletal muscle area (OR of 0.01 [95% CI 0-0.09], 0.31 [0.18-0.49], and 0.3 [1.2-2.7]), respectively. For every 1 mcg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 (P=0.02) and mean total skeletal muscle area decreased by 2.2cm2 (P=0.03). Conclusion: Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.

The impact of sarcopenia on toxicity and pharmacokinetics of 5-fluorouracil (5FU) in colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 633-633 ◽  
Author(s):  
Grant Richard Williams ◽  
Allison Mary Deal ◽  
Shlomit S. Shachar ◽  
Christine Marie Walko ◽  
Jai Narendra Patel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Skeletal Muscle ◽  
Body Composition ◽  
Secondary Analysis ◽  
Cytotoxic Agents ◽  
Composition Analysis ◽  
Muscle Area ◽  
Skeletal Muscle Index ◽  
Grade 3 ◽  
The Impact

633 Background: Great heterogeneity exists in the ability of adults with cancer to tolerate treatment. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The goal of this study was to explore the impact of body composition, in particular sarcopenia, on the pharmacokinetics of 5-fluorouracil (5FU) in a cohort of patients receiving FOLFOX +/- bevacizumab for colorectal cancer. Methods: We performed a secondary analysis of a completed multicenter trial that investigated pharmacokinetic-guided 5FU in patients receiving mFOLFOX6 +/- bevacizumab [Patel et al. The Oncologist 2014]. Computed Tomography (CT) images that were performed as part of routine care were used to for body composition analysis. Skeletal muscle area (SMA) and density (SMD) were analyzed from CT scan L3 lumbar segments using radiological software. SMA and height (m2) were used to calculate skeletal muscle index (SMI = SMA/m2). Skeletal Muscle Gauge (SMG) was created by multiplying SMI x SMD. Differences were compared using two group t-tests and fisher’s exact tests. Results: Of the 70 patients from the original study, 25 had available CT imaging. The mean age was 59, 52% female, 80% Caucasian, and 92% with either stage III or IV disease. Eleven patients (44%) had grade 3/4 toxicity, and 12 patients were identified as sarcopenic (48%) [per Martin et al. JCO 2013]. Sarcopenic patients had numerically higher first cycle 5FU AUCs compared to non-sarcopenic patients (19.3 vs. 17.3 AUC, p= 0.43) and higher grade 3/4 toxicities (50 vs 38.5%, p= 0.70). Patients with low SMG ( < 1475 AU) had higher grade 3/4 toxicities (62 vs 25%, p= 0.11) and higher hematologic toxicities (46 v 8%, p= 0.07). Conclusions: CRC patients with sarcopenia had numerically higher first cycle AUCs of 5FU and a higher incidence of severe toxicities; however, this was not statistically significant, possibly due to limited sample size. SMG, an integrated muscle measure, was more highly correlated with toxicity outcomes than either SMI or SMD alone. Further research exploring the role of body composition in pharmacokinetics is needed with a focus on alternative dosing strategies in sarcopenic patients.

scholarly journals Myosteatosis Differentially Affects the Prognosis of Non-Metastatic Colon and Rectal Cancer Patients: An Exploratory Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Lara Pozzuto ◽  
Marina Nogueira Silveira ◽  
Maria Carolina Santos Mendes ◽  
Lígia Traldi Macedo ◽  
Felipe Osório Costa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Rectal Cancer ◽  
Overall Survival ◽  
Body Composition ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Secondary Outcome ◽  
Muscle Area ◽  
Colon And Rectal Cancer ◽  
Skeletal Muscle Area

Body composition performed by computed tomography (CT) impacts on cancer patients’ prognoses and responses to treatment. Myosteatosis has been related to overall survival (OS) and disease-specific survival in colorectal cancer (CRC); however, the independent impact of the association of myosteatosis with prognosis in colon cancer (CC) and rectal cancer (RC) is still unclear. CT was performed at the L3 level to assess body composition features in 227 patients with CRC. Clinical parameters were collected. Overall survival (OS) was the primary outcome, and the secondary outcome was disease-free survival (DFS). Skeletal muscle attenuation and intramuscular adipose tissue area were associated with DFS (p = 0.003 and p = 0.011, respectively) and OS (p &lt; 0.001 and p &lt; 0.001, respectively) in CC patients but not in RC patients. Only the skeletal muscle area was associated with better prognosis related to OS in RC patients (p = 0.009). When CC and RC were analyzed separately, myosteatosis influenced survival negatively in CC patients, worsening DFS survival (hazard ratio [HR], 2.70; 95% confidence interval [CI], 1.07–6.82; p = 0.035) and OS (HR, 5.76; 95% CI, 1.31–25.40; p = 0.021). By contrast, the presence of myosteatosis did not influence DFS (HR, 1.02; 95% CI, 0.52–2.03; p = 0.944) or OS (HR, 0.76; 95% CI, 0.33–1.77; p = 0.529) in RC patients. Our study revealed the interference of myosteatosis in the therapy and survival of patients with CC but not in those with RC, strengthening the value of grouping the two types of cancer in body composition analyses.

Differences in body composition between patients with early or metastatic breast cancer (BC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21707-e21707
Author(s):  
Shlomit Strulov Shachar ◽  
Allison Mary Deal ◽  
Marc Weinberg ◽  
Grant Richard Williams ◽  
Kirsten A Nyrop ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Composition ◽  
Body Mass ◽  
Metastatic Cancer ◽  
Metastatic Breast ◽  
Linear Regression Models ◽  
Muscle Area ◽  
Age Related ◽  
Skeletal Muscle Area ◽  
The Impact

e21707 Background: There is growing evidence in oncology that skeletal muscle (SM) loss, known as sarcopenia, can be identified from routine computed tomography (CT) imaging and used to predict increased chemotherapy toxicity, mortality, and other adverse clinical outcomes (Shachar-EJC, 2016, Shachar-CCR, 2016). The contributions of age-related and cancer-related loses in SM at diagnosis remains poorly understood. This study compares CT-derived measures of SM at the time of diagnosis in patients with early BC (EBC) versus metastatic BC (MBC) patients to investigate the impact of metastatic cancer on SM. Methods: Body composition measures were compared between patients with EBC receiving adjuvant chemotherapy and MBC initiating first line palliative chemotherapy. Measures were derived from analysis CT scans of L3 lumbar segments using radiological software (ABACS). Measures include: skeletal muscle area (SMA), density (SMD), index (SMI = SMA/height ^2), and integrated density (SMID = SMI x SMD). Sarcopenia was defined as SMI < 41(Martin-JCO, 2013). Lean body mass (LBM) was calculated (kg) = [(L3 Muscle measured by CT (cm2) × 0.3) + 6.06]) (Prado-CCR, 2009). Body surface area (BSA) was calculated using the Mosteller formula. T-tests (continuous) and Chi-squared tests (categorical) compared variables between groups; multivariable linear regression models controlled for age and body mass index (BMI). Results: MBC patients (n = 40) were older than EBC (n = 151) (56 vs 49 years, p < 0.001). Mean BMI and BSA were similar in both groups (29.0 vs 28.8, p = 0.84; 1.87 vs 1.86 m2, p = 0.55). After adjusting for age and BMI, SMI (41.3 vs 44.7 cm2/m2, p = 0.009), SMD (29.8 vs 36.4 Hounsfield Units, p < 0.0001), SMG (1250 vs 1612, p < 0.0001), and LBM (39.3 vs 41.9 kg, p = 0.024) were significantly lower in the MBC group. The MBC group included significantly more sarcopenic patients (58% vs 31%, p = 0.0016). Conclusions: Although BMI and BSA were similar in EBC and MBC patients, SM measures showed significant differences. MBCs had lower LBM, SMI, and SMD. More advanced BC was associated with higher proportions of sarcopenia. Further research is needed to explore interventions in sarcopenic patients in order improve outcomes in women with both EBC and MBC.

Impact of body composition on outcomes from anti-programmed death-1 (PD-1) treatment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9516-9516 ◽  
Author(s):  
Arissa Young ◽  
Henry T. Quach ◽  
Elizabeth J. Davis ◽  
Javid Moslehi ◽  
Grant R. Williams ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Composition ◽  
Adipose Tissue ◽  
Favorable Effect ◽  
High Fat ◽  
Muscle Area ◽  
Skeletal Muscle Index ◽  
Pre Treatment ◽  
Skeletal Muscle Area ◽  
The Impact

9516 Background: Obesity is associated with improved outcomes in melanoma patients (pts) treated with PD-1, whereas low muscle mass, known as sarcopenia, has been associated with poor outcomes in many cancers. We sought to assess the impact of body composition on PD-1 outcomes. Methods: We analyzed pre-treatment CT scans at the L3 slice using Slice-o-matic software (Tomovision V. 5.0) to determine skeletal muscle, visceral adipose, and subcutaneous adipose tissue parameters for 104 pts with metastatic melanoma who received PD-1 monotherapy. We assessed sarcopenia using skeletal muscle index (SMI=skeletal muscle area/m2). We also quantified total adipose tissue index (TATI), and skeletal muscle gauge (SMG = SMI x skeletal muscle density [SMD]). We stratified pts into high/low groups using previously published cutoffs and assessed toxicity (tox), progression-free and overall survival (PFS/OS), and response rate (RR) by group. Results: Sarcopenia (low SMI) was negatively associated with any tox (39% vs. 60%, p=0.04) but not OS, PFS, or RR. Adiposity (TATI) was not associated with outcomes. By contrast, SMG was significantly associated with OS (median 35.5 vs. 16.0m, p=0.01 for high vs. low SMG). Interestingly, when incorporating TATI with SMG, we found that high SMG/high TATI pts (high muscle/high fat) have superior clinical outcomes (Table). Notably, low SMG/high TATI pts (low muscle/high fat) had seemingly the worst outcomes. Conclusions: We found that high SMG, a measure incorporating muscle area and density, was associated with improved OS in PD1 treated pts. Further, pts with high adiposity and high SMG had superior outcomes, potentially identifying the population responsible for the favorable effect of obesity in these pts. Validation and combination treated cohorts will be presented. [Table: see text]

scholarly journals The product of trunk muscle area and density on the CT image is a good indicator of energy expenditure in patients with or at risk for COPD

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Toru Shirahata ◽  
Hideaki Sato ◽  
Sanehiro Yogi ◽  
Kaiji Inoue ◽  
Mamoru Niitsu ◽  
...  
Keyword(s):  
At Risk ◽  
Body Composition ◽  
Energy Expenditure ◽  
Trunk Muscle ◽  
Rectus Abdominis ◽  
Activity Level ◽  
Erector Spinae ◽  
Trunk Muscles ◽  
Muscle Area ◽  
The Relationship

Abstract Background Physical inactivity due to cachexia and muscle wasting is well recognized as a sign of poor prognosis in chronic obstructive pulmonary disease (COPD). However, there have been no reports on the relationship between trunk muscle measurements and energy expenditure parameters, such as the total energy expenditure (TEE) and physical activity level (PAL), in COPD. In this study, we investigated the associations of computed tomography (CT)-derived muscle area and density measurements with clinical parameters, including TEE and PAL, in patients with or at risk for COPD, and examined whether these muscle measurements serve as an indicator of TEE and PAL. Methods The study population consisted of 36 male patients with (n = 28, stage 1–4) and at risk for (n = 8) COPD aged over 50 years. TEE was measured by the doubly labeled water method, and PAL was calculated as the TEE/basal metabolic rate estimated by the indirect method. The cross-sectional areas and densities of the pectoralis muscles, rectus abdominis muscles, and erector spinae muscles were measured. We evaluated the relationship between these muscle measurements and clinical outcomes, including body composition, lung function, muscle strength, TEE, and PAL. Results All the muscle areas were significantly associated with TEE, severity of emphysema, and body composition indices such as body mass index, fat-free mass, and trunk muscle mass. All trunk muscle densities were correlated with PAL. The product of the rectus abdominis muscle area and density showed the highest association with TEE (r = 0.732) and PAL (r = 0.578). Several trunk muscle measurements showed significant correlations with maximal inspiratory and expiratory pressures, indicating their roles in respiration. Conclusions CT-derived measurements for trunk muscles are helpful in evaluating physical status and function in patients with or at risk for COPD. Particularly, trunk muscle evaluation may be a useful marker reflecting TEE and PAL.

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