Discussion
To our knowledge this is the first study that examines relationships between the pharmacokinetics of docetaxel and the anthropometric and body composition parameters BSA, LBM and TBW. No correlations were found between clearance or volume of distribution of docetaxel and the anthropometric and body composition parameters BSA, LBM and TBW. Exposure (AUC) was significantly but poorly correlated with BSA and TBW with a Spearman correlation coefficient of 0.452 (p=0.016) and 0.476 (p=0.011), respectively. Besides, we found that docetaxel dosing based on LBM and TBW or fixed dosing appeared not to be superior to BSA after simulated dosing.
Over the last two decades, there has been an increase in the number and homogeneity of studies published who suggested a correlation in body composition parameters other than BSA with chemotherapy pharmacokinetics and toxicity.7,15-23 One example is a study with 1,206 adult cancer patients of whom 162 were obese (body mass index ≥30) in which the absolute clearance of cisplatin, paclitaxel, and troxacitabine was significantly higher in the obese. For docetaxel and doxorubicin, the authors concluded that applying LBM as a dosing scalar seems to be of particular merit.16 Our study included nine obese patients (32.1%), in which we could not find a significant correlation between any of the anthropometric or body composition parameters and docetaxel pharmacokinetics. Another study correlated LBM with epirubicin log-clearance with a Pearson’s correlation of 0.43.17Our study found significant Spearman’s correlations of 0.45 and 0.48 for BSA and TBW with docetaxel AUC, respectively. In contrast to the epirubicin study, we did not apply the variable in a systematic multivariable model.
Several other studies highlighted the difference in drug dosing by LBM. These studies indicated that patients with dose-limiting toxicities (DLTs) had higher doses of gemcitabine, vinorelbine, carboplatin, pemetrexed, oxaliplatin and sunitinib per kg LBM.20-23In our study there was no trend of a higher docetaxel/BSA, docetaxel/LBM or docetaxel/TBW in patients that experienced overall toxicity compared to patients who did not. In our study nine patients experienced severe toxicity, that resulted for seven of them in dose delay, reduction or termination of treatment. Five patients experienced grade 3 or 4 neutropenia, which is lower than in other studies.26
In contrast to most of the other studies, no correlations were found between clearance of docetaxel and the parameters BSA, LBM and TBW. As a consequence, our results do not support the application of any of these parameters for individualisation of docetaxel therapy. This includes BSA, which is widely used in daily practise for this purpose. In our dosing simulation, a fixed dosing method was also executed. Strikingly, a fixed dose of 140 mg had no significant other accuracy or bias compared to dosing based on BSA. A recent ASCO guideline for dosing for obese adult patient with cancer recommend to limit fixed dosing of cytotoxic agents since there is insufficient evidence that fixed-dosing strategies are equivalent to weight- or BSA-based dosing in terms of toxicity and efficacy.32 Therefore, further research is warranted to determine whether fixed dosing is a more appropriate strategy for treatment with docetaxel.
Our study had some limitations. The study population with 28 patients might be too small and too homogeneous to demonstrate the potential influence of BSA, LBM and TBW on pharmacokinetics. Gender and tumour type seems to be an important factor in docetaxel toxicity and exposure.7,33 In addition, there are several methods for assessing body composition available such as anthropometry, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT). In our study we used DEXA scans which have shown strong correlations between body composition parameters obtained by DEXA and those obtained by CT in adults of normal weight. However, obesity can cause changes in body composition that may impact the assessment of fat mass and lean soft tissue mass by DEXA.34 Our study included a relatively high percentage of people with overweight or obesity, for whom a CT may have been a more accurate measurement to determine LBM. Furthermore, the CYP3A4 metabolizing capacity of patients was not examined. In future research it could be interesting to investigate the ability to metabolize exogenous substrates by this enzyme in patients who receive docetaxel.