Low skeletal muscle is associated with toxicity in patients included in phase I trials Sophie Cousin, A. Hollebecque, S. Koscielny, O. Mir, A. Varga, V. E. Baracos, J. C. Soria & S. Antoun Investigational New Drugs The Journal of New Anticancer Agents ISSN 0167-6997 Invest New Drugs DOI 10.1007/s10637-013-0053-6
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Author's personal copy Invest New Drugs DOI 10.1007/s10637-013-0053-6
SHORT REPORT
Low skeletal muscle is associated with toxicity in patients included in phase I trials Sophie Cousin & A. Hollebecque & S. Koscielny & O. Mir & A. Varga & V. E. Baracos & J. C. Soria & S. Antoun
Received: 7 October 2013 / Accepted: 26 November 2013 # Springer Science+Business Media New York 2013
Summary Background Low muscle mass has been associated with chemotherapy toxicity. We conducted this prospective study to evaluate the effects of body composition on the occurrence of toxicity in phase I trials. Patients and Methods Patients were consecutively enrolled irrespective of the type of tumor or the type of drug. The Skeletal Muscle Index (SMIndex) and visceral and subcutaneous adipose tissue were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues (cm2/m2). Dose-limiting toxicity (DLT) corresponded to toxicities occurring during the 1st cycle that necessitated dose reduction, postponement or interruption of drug administration and severe toxicity events (STE) corresponded to DLT or permanent treatment withdrawal due to toxicity. Results 93 patients were evaluated. Ten percent of patients experienced DLT and had a lower SMIndex: 40.8±4.6 vs. 48.1±9.6 cm2/m2 (p =0.01). STE occurred in 14 % of the patients. The only factor associated with STE was a low SMIndex: 42.4±5.8 vs. 48.4±9.7 cm2/m2 (p =0.02). STE were observed in 25.5 % of the patients when the SMIndex was below the median value compared to 6.5 % of patients with a high SMIndex (p =0.02). Conclusion S. Cousin : A. Hollebecque : O. Mir : A. Varga : J. C. Soria Phase I Department, Gustave Roussy, Villejuif, France S. Koscielny Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France V. E. Baracos Department of Oncology, Cross Cancer Institute, Edmonton, Canada S. Antoun Department of Ambulatory Care, Gustave Roussy, Villejuif, France S. Cousin (*) Department of Medical Oncology, Centre Oscar Lambret, 3, rue Frédéric Combemale, 59000 Lille, France e-mail:
[email protected]
Muscle mass is a critical predictor of severe toxicity events in phase I patients, suggesting that sarcopenia may be considered in assessing patients for eligibility of phase-1 studies. Keywords Skeletal muscle . Sarcopenia . Drug interruption . Severe toxicity . Phase I studies
Introduction Phase I clinical trials are dose- and toxicity-finding studies. As potential phase I patients are in a vulnerable position with an advanced and progressive malignancy, proper selection of these patients remains challenging. Conventional eligibility criteria in phase I trials therefore include a good performance status and adequate organ function, with an expected life expectancy exceeding 3 months. These criteria are prognostic factors for survival [1–3]. However, these criteria are suboptimal for predicting toxicity among phase I patients [4]. A better determination of predictive toxicity criteria could improve the selection of phase I trial candidates. Results suggesting a link between a low body mass index (BMI) and drug toxicities are few and far between [5, 6]. Cancer patients have heterogeneous body composition (BC) characteristics which could potentially engender variations in drug concentration and metabolism; thus BC parameters should be considered. BC assessment is currently possible through the analysis of Computed Tomography (CT) images, which has been demonstrated to be accurate and reproducible [7, 8]. Sarcopenia refers to a state where muscle mass is abnormally low, and was found to be linked to poor overall survival (OS) [9, 10]. Recently, sarcopenia was shown to be associated with toxicity among cancer patients treated with cytotoxic drugs [11, 12] or targeted therapy [13–16]. We hypothesized that enrolling patients with a high risk of experiencing toxicity in phase I trials could bias the evaluation
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of drugs. We therefore conducted a prospective study among consecutively treated phase I patients in order to evaluate the relationship between the BMI, BC and the incidence of toxicity events.
distribution for each parameter by patient gender was (arbitrarily) chosen as the cutoff. The cut point between a low and high skeletal muscle index (SMIndex) was equal to the median for patients of the same gender: 54.1 cm2/m2 for males and 40.8 cm2/m2 for females.
Patients and methods
Statistical analysis
Patients
Descriptive statistics were used: number of cases, percentages, mean and standard deviation, median and extreme values. The surface areas of BC parameters in patients with and without toxicity were compared with Wilcoxon tests. BC parameters and the BMI were entered as continuous covariates in univariate logistic regression models. A multivariate logistic regression analysis including all the variables with a p -value
