Dataset Information

Clinical pharmacokinetics and drug exposure-toxicity correlation study of docetaxel based chemotherapy in Chinese head and neck cancer patients.

ABSTRACT: Background:Area under time-concentration curve (AUC) of docetaxel is related with its toxicity and efficacy. The aim of this study is to investigate the target range of docetaxel AUC in Chinese head and neck cancer (HNC) patients. Methods:Eligible HNC patients were enrolled and received at least 2 cycles of docetaxel-based chemotherapy. A simplified pharmacokinetic (PK) strategy (2 monitored samples) was developed to simulate docetaxel AUC using the nonlinear mixed-effect modelling program. Preliminary target range of AUC was pre-set as 2.5-3.7 µg·hr/mL according to pooled analysis from 8 previous studies. Fisher exact test was used to analyze the relationship between AUC with neutropenia and efficacy, and to verify the target range. Results:Thirty-nine eligible patients were enrolled. Grade 3-4 and grade 4 neutropenia rate in 1st cycle was 64% and 36%, respectively. AUC simulation by simplified PK strategy was acceptable compared to full sampling method from the analysis of archived 300 patients' data, with -5.67% of mean prediction error (MPE). Median AUC of all patients was 2.58 µg·hr/mL (range from 1.28 to 9.39). A significant correlation (P=0.007) was detected between AUC and body surface area (BSA)-dosage, but BSA contributed only 18.3% of AUC inter-individual variability. Docetaxel AUC was significantly related with the severity (grade 3-4) of neutropenia (correlation of coefficient was 0.452, P=0.004). Fourteen patients (36%) were within the target AUC range. Patients with AUC above the target experienced more severe neutropenia (grade 3-4 rate 100% vs. 56%, P=0.036; grade 4 rate 86% vs. 25%, P=0.005). No significant difference of response rate was found between patients within the target or not. Conclusions:A simplified samples PK strategy was developed for docetaxel AUC simulation. The target range of docetaxel AUC in Chinese HNC patients was suggested at 2.5-3.7 µg·hr/mL for reduced toxicity without compromising efficacy of docetaxel treatment.

SUBMITTER: Ma Y

PROVIDER: S-EPMC7154422 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Clinical pharmacokinetics and drug exposure-toxicity correlation study of docetaxel based chemotherapy in Chinese head and neck cancer patients.

Ma Yuxiang Y Lin Qingguang Q Yang Yunpeng Y Liang Weiting W Salamone S J SJ Li Yunying Y Lin Yuehao Y Zhao Hongyun H Zhao Yuanyuan Y Fang Wenfeng W Huang Yan Y Zhang Li L

Annals of translational medicine 20200301 5

<h4>Background</h4>Area under time-concentration curve (AUC) of docetaxel is related with its toxicity and efficacy. The aim of this study is to investigate the target range of docetaxel AUC in Chinese head and neck cancer (HNC) patients.<h4>Methods</h4>Eligible HNC patients were enrolled and received at least 2 cycles of docetaxel-based chemotherapy. A simplified pharmacokinetic (PK) strategy (2 monitored samples) was developed to simulate docetaxel AUC using the nonlinear mixed-effect modellin ...[more]

PMID: 32309383

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Project description:This review focuses on the molecular biology of head and neck squamous cell carcinomas and presents current and emerging biomarkers of the response of patients to induction chemotherapy. The usefulness of genes, proteins, and parameters from diagnostic clinical imaging as well as other clinicopathological parameters is thoroughly discussed. The role of induction chemotherapy before radiotherapy or before chemo-radiotherapy is still debated, as the data on its efficacy are somehow confusing. Despite the constant improvement of treatment protocols and the introduction of new cytostatics, there is still no consensus regarding the use of induction chemotherapy in the treatment of head and neck cancer, with the possible exception of larynx preservation. Such difficulties indicate that potential future treatment strategies should be personalized. Personalized medicine, in which individual tumor genetics drive the selection of targeted therapies and treatment plans for each patient, has recently emerged as the next generation of cancer therapy. Early prediction of treatment outcome or its toxicity may be highly beneficial for those who are at risk of the development of severe toxicities or treatment failure-a different treatment strategy may be applied to these patients, sparing them unnecessary pain. The literature search was carried out in the PubMed and ScienceDirect databases as well as in the selected conference proceedings repositories. Of the 265 articles and abstracts found, only 30 met the following inclusion criteria: human studies, analyzing prediction of induction chemotherapy outcome or toxicity based on the pretreatment (or after the first cycle, if more cycles of induction were administered) data, published after the year 2015. The studies regarding metastatic and recurrent cancers as well as the prognosis of overall survival or the outcome of consecutive treatment were not taken into consideration. As revealed from the systematic inspection of the papers, there are over 100 independent parameters analyzed for their suitability as prognostic markers in HNSCC patients undergoing induction chemotherapy. Some of them are promising, but usually they lack important features such as high specificity and sensitivity, low cost, high positive predictive value, clinical relevance, short turnaround time, etc. Subsequent studies are necessary to confirm the usability of the biomarkers for personal medicine.

Project description:BackgroundThe rate of toxic deaths related to induction chemotherapy in the treatment of locally advanced head and neck cancers is unacceptable and calls into question this therapeutic strategy, which is however highly effective in terms of rate and speed of response. The purpose of the study was to investigate predictive factors of toxicity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced head and neck cancers (LAHNC).MethodsBetween June 2009 and December 2017, 113 patients treated consecutively with TPF were included retrospectively. Patients were receiving induction chemotherapy for either an inoperable cancer or laryngeal preservation. For inoperable cancer, induction chemotherapy was proposed to patients presenting either a large tumor with strong symptoms (dyspnea, dysphagia, pain) or a tumor with rapid progression. Risk factors were chosen among the initial patient and tumour characteristics and chemotherapy modalities.ResultsEighty-nine patients (79%) were male; the median age was 58 years [32-71]. Sixty-nine (61%) patients were treated for inoperable cancer and 44 (39%) for laryngeal preservation. 45% had stage IVa cancer, 28% stage III and 25% stage IVb. Sixty percent of patients had a partial response after TPF, 22% had a complete response, 12% were stable, 5% were progressing, and 1% had a discordant response. Thirty-four patients (30%) received enteral feeding during induction chemotherapy with TPF. The possibility of oral feeding without a tube was predictive of a better response (p = 0.003). Seven (6%) patients died during TPF. There was an increased risk of death with preexisting liver dysfunction (liver dysmorphia on imaging or decrease prothrombin rate) (p = 0.032). There was an increased risk of grade ≥ 3 infection if an enteral feeding occurred during the period of induction chemotherapy (p = 0.03).ConclusionsTPF induction chemotherapy had an 82% objective response rate with 6% toxic deaths. Nutritional status and the presence of hepatic dysfunction are significant risk factors to be taken into account in therapeutic decisions.

Project description:(1) Background: Head and neck cancer treatment, including advanced techniques like Volumetric Modulated Arc Therapy (VMAT), presents challenges for maintaining patient quality of life (QoL). Thus, thoroughly investigating how radiation therapy (RT) affects patients has been proved essential. Derived by that, this study aims to understand the complex interactions between not only RT and QoL but also symptom severity, and treatment-related toxicities in three distinct time points of patient's treatment; (2) Methods: To achieve that, EORTC-QLQ-C30 and EORTC QLQ-H&N35 questionnaires were used in combination with EORTC_RTOG scoring criteria and Spearman's rho statistical analysis for 74 patients with cancer undergoing VMAT radiation therapy; (3) Results: The results revealed a significant improvement in the Overall Health Index post-treatment, indicating a temporary decline during therapy followed by subsequent recovery, often surpassing pre-treatment QoL levels. Concurrently a reduction in symptomatology was observed, notably in pain, swallowing difficulties, and dry mouth, aligning with prior research indicating decreased symptom burden post-treatment. However, Spearman's correlation coefficient analysis at two distinct time points during therapy uncovered varying degrees of correlation between dosimetric data at Organs at Risk (OARs) and reported symptoms, highlighting potential limitations in using QoL questionnaires as sole indicators of treatment efficacy. Our investigation into the correlation between dosimetric data, toxicity, and symptoms focused on the relationship between radiation doses and oral mucositis levels, a common toxicity in head and neck cancer patients. Significant associations were identified between toxicity levels and dosimetric parameters, particularly with OARs such as the parotid glands, oral cavity, and swallowing muscles, underlining the utility of the EORTC method as a reliable toxicity assessment tool; (4) Conclusions: To summarize, current research attempts to underscore the importance of refining QoL assessments for enhanced patient care. The integration of dosimetric data, symptom severity, and treatment-related toxicities in the QoL outcomes of head and neck cancer patients undergoing VMAT radiation therapy, can lead towards the optimization of treatment strategies and the improvement of patient outcomes in future patient-centered radiation therapy practices.

Dataset Information

Clinical pharmacokinetics and drug exposure-toxicity correlation study of docetaxel based chemotherapy in Chinese head and neck cancer patients.

Publications

Clinical pharmacokinetics and drug exposure-toxicity correlation study of docetaxel based chemotherapy in Chinese head and neck cancer patients.

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