SC Oncologia Medica ASST Fatebenefratelli Sacco
MILANO
Nicla La Verde
Napoli, 17 novembre 2017
BODY COMPOSITION
BODY COMPOSITION MEASUREMENT
CHEMOTHERAPY DOSE CALCULATION
Body Surface Area (BSA)
In 1916 used for 8 patients, by DuBois and DuBois to adjust for basal metabolic rates in estimating the human starting dose from animal doses.
This formula was used by Freireich in the1960s to achieve uniformity in dosing patients who were being treated with phase I cytotoxics.
Beumer, JCO, 2012
CHEMOTHERAPY DOSE CALCULATION
• However, there is no scientific basis for such use of BSA
• BSA dosing is associated with high pharmacokinetic variability and is a poor indicator of optimal drug exposure
• The variability in clearance of the most commonly used cytotoxics to be between 25% and 70%, with most drugs showing variability above 35%.
• Obese patients are particularly involved in the proper use of BSA calculation: capped dose vs full dose administration and ideal weight calculation
Beumer, JCO, 2012
CHEMOTHERAPY IN OBESE PATIENTS
Griggs J, JCO, 2012
Griggs J, JCO, 2012
CHEMOTHERAPY IN OBESE PATIENTS
ASCO guidelines CAVEAT
• This evidence is derived from old studies, conducted with non-taxane based chemotherapy
• More recent retrospective studies show that in overweight and obese patients, there is an increased toxicity rate that causes dose reductions, especially with taxanes
R Raman, SL Mott, MC Schroeder et al. Effect of Body Mass Index and Actual Weight-Base Neoadjuvant Chemotherapy Doses on Pathologic Complete Response in Operable Breast Cancer. Clinical Breast Cancer December 2016
H Lote , A Sharp, S Redana et al. Febrile Neutropenia Rates According to Body Mass Index and Dose Capping in Women Receiving Chemotherapy for Early Breast Cancer.Clin Oncol (R Coll Radiol.Sep;
28(9):597-603, 2016
CONSIDERATIONS FROM ASCO GUIDELINES
The pharmacokinetics of some drugs maybe altered in obese patients, but there is no single valid method to relate drug clearance to degree of obesity, so changes in drug dosing are not currently recommended.
3 observations regarding drug clearance and obesity:
1. Obese individuals exhibit higher absolute drug clearance than non-obese
2. Clearance does not increase linearly with total body weight
3. Clearance and lean body weight are correlated
Griggs, JCO, 2012
BODY COMPOSITION PHENOTYPES
Prado C, 2016
SARCOPENIA muscle mass greater than two
standard deviations below that of healthy adults Roubenoff R, 2003
SARCOPENIC OBESITY AND CANCER
250 pts
38 (15%) sarcopenic
Prado C, Lancet 2008
“Assuming that FFM (fat free mass) represents the volume of distribution of many cytotoxic chemotherapy drugs, we estimated that individual variation in FFM could account for up to three-times variation in effective volume of distribution for chemotherapy administered per unit body-surface area, in this population”
SARCOPENIC OBESITY AND CANCER
BODY COMPOSITION AND ANTICANCER DRUGS
BODY COMPOSITION AND ANTICANCER DRUGS
1504 articles 24 original articles selected
3 domains of interest:
• impact of body composition on pharmacokinetics
• relationship between body composition and chemotoxicity
• effect of anti-cancer chemotherapy on body composition
Results
• The selected studies suggested that pharmacokinetic was influenced by lean mass, that lower lean mass could be correlated with toxicity, and that sarcopenic patients experienced more toxicities that non-sarcopenic patients
• Regarding fat mass, results were less conclusive
Gerard S, J Nutr Health Aging, 2016
BODY COMPOSITION AND ANTICANCER DRUGS
• The changes in body composition (cancer patients, elders) could have an important impact on the pharmacokinetics for a large number of drugs depending on their lipo- or hydro- solubility
• They result in increased volume of distribution, longer half-life for liposoluble drugs (i.e., risk of accumulation then re-release), decreased volume of distribution for hydrosoluble drugs (i.e., risk of overdose), and increase in the free fraction of protein bound drugs in the case of hypoalbuminemia
• Weight monitoring is however a poor instrument to follow the changes in body composition that can occur despite stable weight.
Gerard S, J Nutr Health Aging, 2016
Prado C, Clin Cancer Res 2009
BODY COMPOSITION AND TOXICITY
55 women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included
Toxicity and TTP
Results: Approximately 25% of patients were classified as sarcopenic
BODY COMPOSITION AND TOXICITY
Prado C, Clin Cancer Res 2009
BODY COMPOSITION AND TOXICITY
Prado C, Appl. Physiol. Nutr. Metab, 2014
Background
Pegylated liposomal doxorubicin (PLD) has a greater distribution in adipose tissue compared with muscle tissue. Hence, leaner individuals would present with reduced tissue distribution and increased plasma exposure of the drug (Zamboni et al. 2009).
Trabectedin is extensively distributed in peripheral tissues and is highly hydrophobic.
Results
• 74 pts
• In overweight and obese patients (body mass index (BMI) ≥ 25 kg/m2, n = 48) toxicity was more prevalent in those with lower BMI (p = 0.028) and a lower FM (n
= 43, p = 0.034). Although LBM alone was not predictive of toxicity, a lower FM/LBM ratio was the most powerful variable associated with toxicity (p = 0.006).
• A clear association between both FM and LBM (primarily driven by FM) in explaining PLD plus trabectedin toxicity emerged, but only in individuals with excess body weight, with a lower ratio predicting higher exposure and risk for toxicity.
Prado C, Appl. Physiol. Nutr. Metab, 2014
BODY COMPOSITION AND TOXICITY
DOSE LIMITING TOXICITY IN SARCOPENIA
BODY COMPOSITIONS AND DRUG EFFICACY
Cespedes, Cancer 2017
BODY COMPOSITIONS AND DRUG EFFICACY
Cespedes, Cancer 2017
Patients
From 2006 through 2011, 533 pts who underwent to FOLFOX as initial adjuvant chemotherapy, were enrolled. Patients’ muscle mass was quantified using clinically acquired computed tomography scans.
Results
Compared with the highest sex-specific tertile of muscle mass, patients in the lowest tertile were more likely to experience toxicities and had twice the risk of adverse outcomes while receiving FOLFOX; for early discontinuation, the odds ratio (OR) was 2.34, whereas the ORs were 2.24 for treatment delay and 2.28 for dose reduction.
BODY COMPOSITIONS AND DRUG EFFICACY
Cespedes, Cancer 2017
BODY COMPOSITIONS AND DRUG EFFICACY
Cespedes, Cancer 2017
BODY COMPOSITIONS AND DRUG EFFICACY
Del Fabbro, The Oncologist, 2012
Objectives
To compare pathological complete response (pCR) cases with controls and evaluate associations among a pCR, survival outcome, and sarcopenia as well as the combination of both sarcopenia and a BMI
>25 kg/m
2Results
129 pts 14% sarcopenic - 34% normal weight - 26% overweight
- 40% obese
BODY COMPOSITIONS AND DRUG EFFICACY
Del Fabbro, The Oncologist, 2012
Conclusions
Overweight patients treated with NC had a lower pCR rate and shorter PFS time.
Among patients with a normal BMI, the pCR rate was better in sarcopenic patients.
Comment on toxicity
A potential consequence of a low LBM in relation to a person’s height and weight could be a low volume of distribution of cytotoxic chemotherapy drugs in proportion to the BSA, resulting in greater treatment toxicity.
Del Fabbro, The Oncologist, 2012
BODY COMPOSITIONS AND DRUG EFFICACY
CONCLUSIONS
• BSA chemotherapy dosage is inaccurate and does not reflect the real drug pharmacokinetic, especially for obese patients
• Body composition influences drug distribution and its efficacy/toxicity (chemo and biological agents)
• Lipophilic drug and hydrophilic have a different behavior according to lean vs fat mass
• Toxicity is body composition related, especially in overweight and obese patients
• Sarcopenic obesity is a unfavorable prognostic factor and is predictive of higher toxicity
• Further studies are warranted …
CALL FOR COLLABORATION!!!!
ONCOLOGIA MEDICA FATEBENEFRATELLI
