COMPOSIZIONE CORPOREA: QUALE IMPORTANZA HA NELLA PRESCRIZIONE DELLA CT?

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SC Oncologia Medica ASST Fatebenefratelli Sacco

Nicla La Verde

Milano, 11.5.2017

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BODY COMPOSITION

ONCOLOGIA MEDICA FATEBENEFRATELLI

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BODY COMPOSITION MEASUREMENT

ONCOLOGIA MEDICA

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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

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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

ONCOLOGIA MEDICA

Beumer, JCO, 2012

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CHEMOTHERAPY IN OBESE PATIENTS

Griggs J, JCO, 2012

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ONCOLOGIA MEDICA

Griggs J, JCO, 2012

CHEMOTHERAPY IN OBESE PATIENTS

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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

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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

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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

ONCOLOGIA MEDICA

Griggs, JCO, 2012

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BODY COMPOSITION PHENOTYPES

Prado C, 2016

SARCOPENIA muscle mass greater than two standard deviations below that of healthy adults

Roubenoff R, 2003

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SARCOPENIC OBESITY AND CANCER

250 pts; 38 (15%) sarcopenic

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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

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BODY COMPOSITION AND ANTICANCER DRUGS

ONCOLOGIA MEDICA

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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

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ONCOLOGIA MEDICA

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

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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

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ONCOLOGIA MEDICA

BODY COMPOSITION AND TOXICITY

Prado C, Clin Cancer Res 2009

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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.

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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.

ONCOLOGIA MEDICA

Prado C, Appl. Physiol. Nutr. Metab, 2014

BODY COMPOSITION AND TOXICITY

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DOSE LIMITING TOXICITY IN SARCOPENIA

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BODY COMPOSITIONS AND DRUG EFFICACY

ONCOLOGIA MEDICA

Del Fabbro, The Oncologist, 2012

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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

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Results

129 pts  14% sarcopenic 34% normal weight 26% overweight

40% obese

BODY COMPOSITIONS AND DRUG EFFICACY

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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.

ONCOLOGIA MEDICA

BODY COMPOSITIONS AND DRUG EFFICACY

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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!!!!