ANTICANCER RESEARCH 33: 5655-5662 (2013) A Higher Body Mass Index and Fat Mass Are Factors Predictive of Docetaxel Dose Intensity SOPHIE GOUÉRANT1,2, MARIANNE LEHEURTEUR1, MAHER CHAKER1, ROMAIN MODZELEWSKI1, OLIVIER RIGAL1, CORINNE VEYRET1, GÉRALDINE LAURIDANT3 and FLORIAN CLATOT1,4 1Department of Oncology, Henri Becquerel Center, Rouen, France; 2Department of Oncology, François Baclesse Center, Caen, France; 3Department of Oncology, Oscar Lambret Center, Lille, France; 4Inserm 918 Unit, Rouen, France Abstract. Background: Few data are published on Nevertheless, these regimens are associated with docetaxel toxicity in obese patients. Patients and Methods: haematological and non-haematological toxicities that remain All obese patients (n=100) treated for early breast cancer unpredictable and which may alter the dose intensity of the during three consecutive years at our Institution, were treatment. Doses of chemotherapy are usually based on the retrospectively investigated. The same number of non-obese body surface area (BSA), mostly calculated with the Dubois patients was randomly selected and used as controls. We formula (3), which considers only weight and size. However, assessed the factors predictive of the relative dose intesity several studies have shown that the use of BSA for reducing (RDI) reduction, including body composition. Results: A the inter-individual variability of pharmacokinetic factors total of 18% (n=18) of obese patients and 5% (n=5) of [clearance, area under curve] is efficient only for a small non-obese patients required reduction of docetaxel RDI due number of chemotherapy agents and not for epirubicin or to toxicity (p=0.008). In a multivariate analysis, body mass docetaxel (4). Other factors may impact on the index (BMI) and age were predictive of a reduction in RDI. pharmacokinetics of drugs, including body composition (fat Among the 89 patients with a determination of body mass, lean body mass) (5), which may predict tolerance to composition, patients with a higher fat mass more chemotherapy (6, 7). In the era of personalised medicine, one frequently had a reduction in docetaxel RDI (p=0.002). In of the main issues is the ability to adjust the dose of multivariate analysis, fat mass was the only independent chemotherapy in cases of obesity. factor predictive of a reduction in docetaxel RDI. The rate of obesity, defined by a BMI greater than 30 kg/m2, Conclusion: Obese patients treated for early breast cancer has been increasing in recent years both in developed and more frequently required a reduction in docetaxel RDI. Fat developing countries. With a prevalence of approximately 20% mass seems to be the best factor predictive of a reduction in in the United States, the United Kingdom and Australia, docetaxel RDI. obesity has reached epidemic proportions in Western countries (8). Regarding breast cancer, obesity is both a risk factor in Breast cancer is a common disease: 1.4 million women were post-menopausal women (9) and an indicator of a poor diagnosed worldwide in 2008 (1). Adjuvant chemotherapy prognosis (10). Even if increasing numbers of obese patients based on regimens using anthracyclines (doxorubicin, are treated for breast cancer, few data exist on the adaptation epirubicin) and taxanes (paclitaxel, docetaxel) has significantly of doses of chemotherapy for this sub-population. In daily improved survival for women with early breast cancer (2). practice, some physicians reduce doses for obese patients These regimens are highly codified, and the dose intensity, is because of a fear of excessive toxicity (11), but without actual crucial for efficacy. evidence-based data. Recently, the American Society of Clinical Oncology (ASCO) published guidelines on the adaption of chemotherapy doses for obese patients (12). The recommendation is not to reduce chemotherapy doses for obese Correspondence to: Sophie Gouérant, Avenue General Harris 14000 patients because of the lack of evidence of increased toxicity Caen, France. Tel: +33 620142126, Fax: +33 231455050, e-mail: [email protected] in this population and the risk of reducing the efficacy of the treatment. Nevertheless, among the studies that contributed to Key Words: Early breast cancer, docetaxel, obesity, fat mass, dose these recommendations, none included chemotherapies with intensity, toxicity. taxanes such as docetaxel. 0250-7005/2013 $2.00+.40 5655 ANTICANCER RESEARCH 33: 5655-5662 (2013) In our daily practice, docetaxel appears to be less well- To prevent docetaxel-related hypersensitivity or fluid retention, the tolerated in obese patients, but to date, no study has evaluated patients received pre-medication with six doses of corticosteroids the safety of this drug in obese patients. The aim of this (equivalent to 50 mg of prednisolone) starting at 12 h before and ending at 24 h after docetaxel infusion. retrospective study was to assess the toxicities of adjuvant During epirubicin and docetaxel infusion, the patients wore a chemotherapy for early breast cancer in obese patients. We frozen helmet to reduce the risk of alopecia, and during docetaxel also analyzed the potential for using body composition in the infusion, the patients wore frozen gloves to reduce the risk of ungual prediction of chemotherapy toxicity. toxicity. Patients and Methods Toxicity evaluation. At baseline and at the end of the chemotherapy, a complete biological assessment was carried out, including evaluation of liver function, renal function and albumin level. 2 Study population. Every obese patient (BMI ≥30 mg/m ) who The tolerance to chemotherapy was evaluated before each cycle. received adjuvant or neoadjuvant sequential chemotherapy for early A clinical examination and a complete blood count were performed breast cancer between 1 January 2008 and 31 December 2010 at the before each cycle. The haematological toxicities were evaluated from Henri Becquerel Center (France) was included. For comparison, the the complete blood count performed systematically the day before 2 same number of non-obese patients (BMI <30 kg/m ) treated chemotherapy or in the case of fever, and were graded according to identically was randomly chosen from among all non-obese patients the national cancer institute common terminology criteria for adverse treated over the same period. The data on co-morbidities were events (NCI CTCAE) version 4.0 (17). The cardiac toxicity was collected (arterial hypertension, diabetes, cardiac diseases, respiratory monitored by radioisotopic methods or by echocardiogram at baseline insufficiency, and venous thromboembolism). and every two cycles of FEC 100. This retrospective study was approved by our Institutional Non-haematological toxicities were not systematically determined Scientific and Ethic Committees, in accordance with the Declaration because of the risk of bias in the evaluation of such toxicities when of Helsinki. assessed retrospectively. Nevertheless, the type of toxicity that led to a reduced dose intensity of chemotherapy was determined. Tumour evaluation. The tumors were staged according to the Information on unplanned hospitalisations was also collected. Seventh TNM classification (2009) (13). A diagnosis of breast cancer was histologically-verified for each patient after breast Dose intensity evaluation. All events modifying the dose intensity biopsy or surgical excision. The tumours were considered hormone- were collected, i.e. dose reductions, delayed chemotherapy, changes in dependent if hormone receptors were present in more than 10% of regimen or chemotherapy disruptions. the tumor cells. The tumours were considered human epidermal The dose intensity was evaluated by calculating the relative dose growth factor receptor 2 (HER2) positive if the immunochemistry intensity (RDI) (18). RDI=Received dose intensity (mg/m2/week) / score was +++ or if HER2 was amplified by chromogenic in situ planned dose intensity (mg/m2/week) for each drug. These data were hybridization (CISH). collected from our centralized database. The reason for reductions of the dose intensity were also recorded. Chemotherapy. All patients were planned to receive a sequential chemotherapy of three cycles of FEC 100 (5-fluorouracil at 500 Body composition evaluation. Since mid-2009, computed mg/m2, epirubicin at 100 mg/m2, and cyclophosphamide at 500 tomographic (CT) scanning is routinely performed at our Institution mg/m2) followed by three cycles of docetaxel (100 mg/m2) when after a diagnosis of invasive breast carcinoma. When available, the treated with adjuvant chemotherapy and three to four cycles of FEC analysis of body composition was performed with this initial staging 100 followed by three to four cycles of docetaxel when treated with CT scan and was performed on a cross-section centered on the third neoadjuvant chemotherapy. The chemotherapy was administered lumbar vertebra (L3) using dedicated LITIS EA 4108 software intravenously every 21 days. developed in our laboratory. This software was developed to allow for The chemotherapy doses were calculated based on BSA, using the automatic contouring of muscles and fat (sub-cutaneous and visceral) Dubois formula with the actual body weight: BSA (m2)=0.007184 × based on specific Hounsfield units (HU) for each tissue: −29 to 150 height (cm)0.725 × weight (kg)0.425. The BSA was limited to 2 m2, as HU for muscle, −190 to −30 HU for sub cutaneous fat and −150 to is standard at our Institution. −50 HU for visceral fat (19). This automatic contouring was manually In cases of excessive toxicity, treatment