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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.

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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 adaptations during corrected by the same reader before calculating the area of each tissue chemotherapy were decided by our multidisciplinary staff and usually (cm2) on the L3 cross section (Figure 1). The calculation of fat-free consisted of dose reductions, change of regimen (FEC recovery after mass (FFM) and fat mass (FM) was performed on the muscle and fat docetaxel toxicities), or chemotherapy disruption. on the L3 cross section using the following formulae (19): FFM (kg)=0.30 × [muscle L3 cross-sectional area] + 6.06 and FM Supportive care. Supportive care during chemotherapy followed the (kg)=0.042 × [fat L3 cross-sectional area] + 11.2 guidelines of daily practice at our Institution. Treatment with Twenty-five of these patients underwent two independent fat granulocyte colony-stimulating factors (G-CSF) was administered as contourings to ensure the reproducibility of the analysis. recommended by the European Organisation for Research and Treatment of Cancer (EORTC) in 2007 (14). Erythropoietin- Follow-up. The duration of follow-up was calculated from the date of stimulating agents (ESA) were initially indicated in cases of diagnosis to the date of the last follow-up visit. symptomatic anaemia (Hb <10 g/dl), as recommended by ASCO in 2007 (15), but the use of ESA gradually stopped, as recommended Statistical analysis. The non-obese patients were randomly chosen by the FDA in 2008 and ASCO in 2010 (16). with the R software (http://www.r-project.org/) using a model of a

5656 Gouérant et al: Dose Intensity of Docetaxel in Obese Patients

Among the obese patients, 71 had a BSA≤2 m2, and 29 had a BSA>2 m2 (15 patients between 2.01 and 2.10 m2, 9 patients between 2.11 and 2.20 m2 and 5 patients between 2.21 and 2.30 m2). There were 57 patients with a BMI between 30 and 34 kg/m2, 35 patients with a BMI between 35 and 39 kg/m2 and eight patients with a BMI>40 kg/m2. None of the non-obese patients had a BSA>2 m2.

Biological characteristics. There was no difference between the two groups in the following biological characteristics: Albumin, renal function and alteration in liver function (data not shown).

Tumor characteristics. The two groups were significantly different regarding tumor grade; grade II was more frequent in the obese population, and grade III was more frequent in the non-obese population. Inflammatory breast cancer (T4d stage) was also more frequent in the obese population. There was no difference between the two groups in regards to other histological criteria (Table I).

Body composition. Among the 200 patients, 89 patients (50 obese and 39 non-obese) had a CT scan at baseline. The characteristics of these sub-groups were not different compared with the total population of obese and non-obese patients included in this study (data not shown). Two independent contourings for 25 patients showed good Figure 1. Body composition analysis with a computed tomographic reproducibility of the body fat evaluation (coefficient of scanning. correlation of 0.99, p<0.001). The body composition analysis confirmed that obese patients had both higher lean body mass and higher fat mass than non-obese patients (Table I). draw without replacement. Comparisons between the different groups Treatment characteristics. The total doses of chemotherapy of patients were performed using the Chi-square test, t-test or Mann- Whitney test. Multivariate analysis of predictive factors was were higher for epirubicin in obese patients (600 vs. 507 mg, performed according to a multiple regression model with the p<0.0001) and for docetaxel (580 vs. 498 mg, p<0.0001). backward method. Statistical analyses were performed using the Obese patients more frequently received neoadjuvant medical software MedCalc® (Ostend, Belgium). chemotherapy (25 vs. 14%, p=0.07) than non-obese patients, but this trend was not significant. This difference may be Results explained by the higher number of obese patients with T4d tumours, which were treated with neoadjuvant chemotherapy. Patients’ characteristics. Between 1 January 2008 and 31 The median number of chemotherapy cycles was six for both December 2010, 469 patients were treated with adjuvant or obese and non-obese patients. Four patients did not receive the neoadjuvant sequential chemotherapy (FEC100 followed by planned number of cycles: three obese patients (two patients docetaxel) for early breast cancer at our Institution. Among received five instead of six cycles, and one patient received them, 100 were obese (21%), and 369 (79%) were non-obese. four instead of six cycles) and one non-obese patient (five From the non-obese patients, 100 were randomly chosen for instead of six cycles). the comparisons performed in this study. Chemotherapy. FEC 100 toxicities: Grade III-IV neutropenia Clinical characteristics. The clinical characteristics were not was significantly more frequent in non-obese patients; it was different between the two populations, except for weight, the only toxicity that was significantly different between the BMI, BSA, and the number of co-morbidities. There was no two groups. However, there was no difference between the two difference between the two populations in age and time-to- groups in febrile neutropenia. No other haematological follow-up (Table I). toxicity was different between obese and non-obese patients

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Table I. Baseline patients’ characteristics.

Obese patients (n=100) Non-obese patients (n=100) p-Value

Clinical characteristics (n=200) Mean age, years 52.8 CI (51.0-54.6) 52.0 CI (50.1-54.0) 0.58 Median weight, kg 90.0 CI (85.0-93.0) 63.0 CI (60.7-65.0) <0.0001 Median BMI, kg/m2 33.1 CI (32.1-34.7) 23.4 CI (22.8-24.5) <0.0001 Mean BSA, m2 1.94 CI (1.91-1.98) 1.67 CI (1.65-1.70) <0.0001 Median number of co-morbidities 1 CI (0-1) 0 CI (0-0) <0.0001 Median follow-up, months 32.1 CI (27.4-35.3) 28.9 CI (27.0-33.4) 0.65 Tumour characterisitics (n=200) Histological type IDC 91% 92% 1 ILC 9% 8% Grade I 4% 3% 0.02 II 64% 48% III 30% 48% T Stage 1 41% 32% 0.02 2 34% 45% 3 12% 18% 4 a-c 3% 2% 4d 10% 1% N Stage N – 19% 21% 0.83 N + 81% 78% Hormone receptors Negative 28% 37% 0.23 Positive 72% 63% HER2 status Negative 71% 70% 1 Positive 29% 30% Body composition (n=89) Median fat free mass, kg 44.28 CI (42.44-46.28) 39.75 CI (38.43-41.16) 0.0001 Mean fat mass, kg 34.23 CI (32.78-35.67) 22.12 CI (20.46-23.78) 0.0001

BMI: Body mass index, BSA: body surface area, IDC: invasive ductal carcinoma, ILC: invasive lobular carcinoma, CI: confidence interval.

Table II. Chemotherapy toxicities.

FEC 100 Docetaxel

Obese (n=100) Non-obese (n=100) p-Value Obese (n=100) Non-obese (n=100) p-Value

Neutropenia, n 10 25 0.009 11 20 0.12 Febrile neutropenia, n 5 10 0.28 9 17 0.14 Anemia, n 0 0 1 0 0 1 Thrombopenia, n 0 1 1 0 0 1 Cardiac toxicity, n 3 0 0.25 NA NA NA Hospitalisations, n 8 10 0.80 14 22 0.20 Delayed cycles, n 12 17 0.42 4 2 0.68 Dose reductions, n 1 0 1 10 3 0.09 Chemotherapy modifications, n 0 0 1 5 2 0.44 Chemotherapy disruptions, n 0 0 1 3 1 0.61 RDI <1, n 1 0 1 18 5 0.008 Toxic death, n 0 0 1 0 0 1

RDI: Relative dose intensity; NA: not available, FEC100: 5-fluorouracil epirubicin cyclophosphamide.

(Table II). Three obese patients had cardiac toxicity (left receive trastuzumab. No cardiac toxicity was found in the non- ventricular ejection fraction <50%): two patients during obese population. Overall, this difference in cardiac toxicity trastuzumab treatment without clinical symptoms and one was not statistically significant. No toxic deaths occurred patient with late toxicity with clinical symptoms who did not during the cycles of FEC 100.

5658 Gouérant et al: Dose Intensity of Docetaxel in Obese Patients

Table III. Factors predictive of reduction of the docetaxel dose intensity in the entire population (n=200).

RDI <1 (n=23) RDI=1 (n=177) p-Value

Univariate analysis Multivariate analysis

Mean age, years 57.2 CI (53.2-61.2) 51.8 CI (50.4-53.1) 0.009 0.04 Median BMI, kg/m2 32.9 CI (30.6-35.5) 28.4 CI (26.3-30.1) 0.002 0.02 Median BSA, m2 1.84 CI (1.80-2.00) 1.79 CI (1.74-1.80) 0.030 0.10 Median weight, kg 80.0 CI (78.7-93.7) 74.0 CI (69.0-79.0) 0.008 0.08 Median number of co-morbidities 1 CI (0-1) 0 CI (0-0) 0.080 NI Alteration of liver function 21.7% 7.9% 0.080 0.08

BMI: Body mass index, BSA: body surface area, RDI: relative dose intensity, NI: not included in the model, CI: confidence interval.

Table IV. Factors predictive of reduction of the docetaxel dose intensity in the population with a computed tomographic scanning (n=89).

RDI <1 (n=9) RDI=1 (n=80) p-Value

Univariate analysis Multivariate analysis

Median fat free mass, kg 42.7 CI (40.1-47.9) 41.6 CI (39.9-42.6) 0.180 NI Mean fat mass, kg 36.6 CI (32.2-41.0) 28.1 CI (26.4-29.8) 0.002 0.004 Mean age, years 57.4 CI (49.5-65.4) 52.3 CI (50.3-54.4) 0.120 NI Mean BMI, kg/m2 34.7 CI (31.5-37.9) 28.9 CI (27.5-30.3) 0.007 NI Mean BSA, m2 1.96 CI (1.85-2.07) 1.80 CI (1.75-1.84) 0.010 NI Mean weight, kg 91.8 CI (82.6-101.0) 76.0 CI (72.4-79.7) 0.007 NI Median number of comorbidities 1 (0-1.86) 0 (0-0) NI Alteration of liver function 33.3% 12.5% 0.240 NI

BMI: Body mass index, BSA: body surface area, RDI: relative dose intensity, NI: not included in the model, CI: confidence interval.

FEC 100 dose-intensity: In the present study, 622 cycles of reductions were due to two dose reductions (10 and 25%), two FEC100 were administered to the entire patient population. changes in regimen (FEC 100 recovery in the two cases) and Only one dose reduction (of 25%) was required (at cycle 2 due one chemotherapy disruption. to haematotoxicity), and no change in regimen, cure delay, or The reported causes for reduction of the docetaxel dose chemotherapy disruption was observed. Thus, there was only intensity were mainly mucositis or cutaneous toxicities. In the one patient (who was obese) with a reduction of the epirubicin obese patients, we found 10 cases of cutaneous toxicity dose intensity (epirubicin RDI <1). (associated with mucositis in four cases), three cases of Docetaxel toxicities: No significant difference was observed arthralgia, two cases of rectocolitis, one case of febrile in haematological toxicities (Table II) between the two groups. neutropenia despite G-CSF, one infection and one weight loss. No toxic deaths occurred during docetaxel cycles. In the non-obese patients, we found four cases of cutaneous Docetaxel dose-intensity: In this study, 587 cycles of toxicity, including one case associated with mucositis and one docetaxel were administered. Among the entire population, 23 case of infection. For the obese patients, these toxicities and patients (11.5%) required reduction of the docetaxel dose the related reduction of dose intensity occured at cycle 1 for intensity (docetaxel RDI<1). Reductions of the docetaxel RDI 14 patients and at cycle 2 for four patients. For the non-obese were significantly more frequent in obese patients than in non- patients, they occured at cycle 1 for four patients and at cycle obese patients (18 vs. 5%, p=0.008). Reductions of the 2 for one patient. docetaxel RDI were never related to cure delay but were At our Institution, the doses of chemotherapy are calculated always due to dose reductions, changes in regimen or with a BSA that is capped at 2 m2. In this study, 29 (14.5%) chemotherapy disruptions (Table II). out of the 200 patients had a BSA>2 m2, all of these patients In the obese population, the reduction of the docetaxel dose were obese. Because of capping, we achieved a median intensity was due to 10 dose reductions (10 to 25%), five empirical reduction of 5% (0.5 to 15%) for patients with a changes in regimen (FEC100 recovery in the five cases) and BSA >2 m2. Nevertheless, six additional reductions of the three chemotherapy disruptions. In the non-obese population, docetaxel dose intensity were observed in these 29 patients.

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When comparing the 71 obese patients with a BSA ≤2 m2 and the 29 obese patients with a BSA >2 m2, no differences in rates of reduction of docetaxel dose intensity were observed (20.3 and 26.1%, respectively, p=0.9).

Factors predictive of reduction in docetaxel dose intensity. Predictive factors in the entire population (n=200): In the univariate analysis, there were four factors predictive of a docetaxel RDI less than 1: Advanced age, higher BMI, higher BSA and higher body weight. The number of co-morbidities and alteration of hepatic function tests were not predictive of a docetaxel RDI less than 1 (Table III). In the multivariate analysis, two factors were predictive of diminution of the docetaxel RDI: Age (p=0.04) and BMI (p=0.02). Patients with a CT scan (n=89): We performed an analysis Figure 2. Docetaxel relative dose intensity according to fat mass. of the subgroup of patients for whom a CT scan was available (50 obese and 39 non-obese). In the univariate analysis, there were five factors predictive of a docetaxel RDI less than 1: higher fat mass, higher BMI, higher BSA, higher number of in obese patients vs. 0.9% in non-obese patients, p=0.03) in the comorbidities and higher body weight. Age, FFM and treatment of early breast cancer. Overall, only one patient (1%) alteration of hepatic function were not predictive of a had an epirubicin RDI less than 1 in the obese population, docetaxel RDI less than 1 (Table IV). which suggests that the tolerance to FEC100 in obese patients In the multivariate analysis, the FM was the only factor allows for maintenance of the dose intensity of this protocol. predictive of a docetaxel RDI less than 1 (p=0.004), whereas These findings are consistent with the ASCO recommendations BMI was not retained by the model. The docetaxel RDI of 2012 (12). ASCO recommends the use of full doses of according to the FM is represented in Figure 2. chemotherapy and the use of actual body weight to calculate chemotherapy doses for obese patients (as is performed for Discussion non-obese patients) because there is no evidence of increased toxicity in the short-term or long-term in this population. In the present study, we performed a retrospective comparison In contrast, docetaxel was less tolerated in obese patients, of the dose intensity of chemotherapy in 100 obese and 100 18 obese patients had a docetaxel RDI of less than 1, compared non-obese patients receiving a sequential treatment of an to five non-obese patients (p=0.008). Furthermore, this epirubicin regimen (FEC) followed by docetaxel for the difference in tolerance may have been underestimated due to treatment of early breast cancer. We showed that the tolerance capping of doses for the 29 obese patients with a BSA >2 m2 to chemotherapy and the dose intensity of chemotherapy with and also because this was a retrospective study. The reasons for an epirubicin-based regimen or with docetaxel in obese and lowering the dose intensity (for obese or non-obese patients) non-obese patients were different. were often cutaneous toxicities and mucositis. This finding of After the FEC100 regimen, the rate of grade III-IV increased toxicity of docetaxel in obese patients, which led to neutropenia was more common in the non-obese population a decrease of the dose intensity, was in opposition to the ASCO (25% vs. 10%, p=0.009), but the rate of febrile neutropenia did recommendations, previously mentioned (12). Indeed, the not differ between the two groups. These data are consistent recommendations are not to reduce the dose of chemotherapy with the studies of Jenkins et al. (20) and Rosner et al. (21), in obese patients. However, these recommendations are based which showed that haematological toxicities were not higher on studies that examined first-generation chemotherapy in obese patients treated with FEC60 or CAF regimens such as CMF (23, 24) or anthracyclines (20, 21) but (cyclophosphamide, adriamycin and 5-fluorouracil), not taxanes. Moreover, most of these studies were limited to respectively. In our study, cardiac toxicity occurred in three haematological toxicities, but other side- effects can also affect patients (1.5%), all of whom were obese, but the difference the dose intensity of chemotherapy, as shown in our study. We between obese and non-obese patients was not significant, found only one study with data on docetaxel dose intensity in perhaps due to the small number of patients. These results are obese patients treated for early breast cancer. De Azambuja et also consistent with data from the retrospective study of al. (25) studied retrospective data from the BIG 02-98 trial Fumoleau et al. (22), which showed that BMI was a factor (26). This study included 365 obese patients who received predictive of cardiac toxicity associated with epirubicin (1.8% docetaxel (75 or 100 mg/m2). No significant difference was

5660 Gouérant et al: Dose Intensity of Docetaxel in Obese Patients found in docetaxel dose intensity between obese and non-obese phase III clinical trials of adjuvant chemotherapy in early patients (95 vs. 96%, p=0.72). However, docetaxel toxicity was breast cancer, the BMI of the patients was not always different with a dose of 75 mg/m2 from that with a dose of reported, but the patients included in clinical trials have 100 mg/m2, as seen in our study. Unfortunately, the number of fewer co-morbidities and may have lower BMIs than patients patients treated with the more toxic docetaxel dose of in daily practice. 100 mg/m2 (27) is not known. Furthermore, the characteristics of the patients included in this type of trial are often different Conclusion from those of patients in daily practice, particularly in terms of co-morbidities, which are more frequent in daily practice. This study confirms that the FEC 100 regimen is well- Therefore, we question whether BSA is an accurate tool for tolerated in obese patients doses of FEC should not be reduced calculating the docetaxel dose for obese patients and why in this population. However, this study also shows that obese patients tolerate docetaxel less than non-obese patients. docetaxel is less tolerated in obese patients and is associated Chemotherapy is used at a ‘threshold dose’ to achieve with a significant decrease in dose intensity. Using the BSA optimal efficacy while maintaining acceptable tolerance. Renal is not a suitable method for calculating the dose of docetaxel clearance and AUC are two parameters correlated with required. In contrast, we have shown that the evaluation of FM efficacy of docetaxel and tolerance to docetaxel (28). by CT scan may be a promising tool for predicting tolerance Adjusting the dose of docetaxel by using the BSA should to docetaxel. Additional studies examining obese patients are reduce the inter-individual variability of docetaxel needed to evaluate tolerance to docetaxel and the efficacy of pharmacokinetics. However, this method is not able to reduce docetaxel in this population, and to identify a better method inter-individual variability of clearance (4) and AUC (29) of for dose calculation of docetaxel by exploring the pharmaco- docetaxel. In addition, Sparreboom et al. examined 162 obese kinetics of this drug. patients for whom the body weight was used to calculate the BSA, and this increased the AUC of docetaxel by 33% Conflicts of Ιnterest (p=0.004) compared with non-obese patients (5). Overall, using the BSA is not the optimal method for calculating the None declared. dose of docetaxel required for obese patients. This retrospective study was approved by the Committee of Clinical An alternative method for calculating the dose of Research Centre Henri Bacquerel on January 15, 2013, with the docetaxel would take into account body composition. Indeed, registration number No. 150113. a few studies have shown that body composition was an independent determinant of chemotherapy tolerance (6, 7). References In the present study, a high FM, evaluated by CT scan, appears to be an independent factor for predicting docetaxel 1 Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM and toxicity. Several hypotheses could explain this result. The Baade PD: The descriptive epidemiology of female breast cancer: volume of drug distribution (Vd) is a pharmacokinetic an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol 36: 237-248, 2012. parameter that is more often altered in obese patients (30, 2 Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter 31). FM increases more than lean mass in these patients (32). D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, The increase of the ratio between FM and lean body mass Albain K, Swain S, Piccart M and Pritchard K: Comparisons leads to an increase in the Vd of lipophilic drugs such as between different polychemotherapy regimens for early breast docetaxel. Sparreboom et al. (5) showed that the Vd of cancer: meta-analyses of long-term outcome among 100,000 docetaxel in obese patients was two-fold higher than the Vd women in 123 randomised trials. Lancet 379: 432-444, 2012. of docetaxel in non-obese patients. An increase in the Vd 3 Du Bois D and Du Bois EF: A formula to estimate the approximate surface area if height and weight be known. Nutrition may lead to docetaxel accumulation in the fat, with the risk 5: 303-311; discussion 312-303, 1989. of its late release. In fact, increased Vd results in an 4 Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens increased half-life and thus increases the toxic effects of JH, Grochow LB and Sparreboom A: Role of body surface area docetaxel. Conversely, at a constant dose, an increase in Vd in dosing of investigational anticancer agents in adults, 1991-2001. is responsible for a decrease in plasma concentration and J Natl Cancer Inst 94: 1883-1888, 2002. may reduce docetaxel efficacy. In summary, an increase of 5 Sparreboom A, Wolff AC, Mathijssen RH, Chatelut E, Rowinsky FM could increase the risk of toxicity but also reduce the EK, Verweij J and Baker SD: Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J efficacy of docetaxel. 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