Pharmacokinetically Determined Docetaxel Exposure As A Predictor Of Neoadjuvant Chemotherapy In 56 Patients With Locally Advanced Breast Cancer

Back ground:Breast cancer has became one of the most common malignant tumors which threatening the physical and mental health of women.Although the incidence rate of it is rising year by year and remains high,the mortality rate is on decline which mainly because of the standardization and improvement of the diagnosis and treatment.The improvement is obvious from the radical mastectomy a century years ago to today’s comprehensive treatment.It has been proved that breast cancer is a systemic disease and simple surgery is not enough to earn a better outcome.New treatments are needed deadly.Chemotherapy has played an critical role in treating breast cancer,now neoadjuvant chemotherapy(NACT)is becoming an essential and standard part in treating inflammatory breast cancer(IBC)and locally advanced breast cancer(LABC).Because of the implemention of NACT is earlier than the surgery so it can increase the rate of operation for LABC patients and at the same time enhance the possibility of breast conserving surgery.Furthermore,NACT can significantly improve the overall survival(OR)and disease-free survival(DFS)of those NACT patients who achieved the pathological complete response(pCR).And we can keep a close eye on the sensitivity of tumor to chemotherapy drugs and could make plan for patients’further treatment.According to the latest CSCO basic strategy for NACT should contains both anthracyclines and taxanes,for example,AT or TAC or AC-T.Docetaxel,a more potent semisynthetic derivative of paclitaxel,derived from extracts of the leaves of the European yew tree(Taxus baccata),was discovered in the1980s and act by inducing microtubular stability and disrupting the dynamics of the microtubular network.The drug has shown a broad spectrum of antitumor activity in non-small cell lung cancer,gastric cancer,head and neck cancer,ovary cancer,esophageal cancer,uterus body cancer and prostate cancer.Docetaxel(Taxotere)was first approved for use by the US Food and Drug Administration in 1996 for locally advanced or metastatic breast cancer after failure of prior chemotherapy with a dose of 60 to 100 mg/m~2 administered intravenously over 1 hour every 3 weeks.Thereafter,additional indications were approved at a dose of 75 mg/m~2.In contrast,a clinical trial of Japan recommended a dose of 60 mg/m~2,every 3 weeks.There still no clinical trials about docetaxel in China,the recommended dose of docetaxel was 75mg/m~2according to CSCO.Docetaxel is one of the most important chemotherapeutic drugs especially for NACT patients with breast cancer and several clinical studies have been conducted to extend its clinical applications.However,there are still enough clinical experiment of docetaxel in China so we still don’t know the best treatment window of docetaxel in breast cancer patients of China especially for the goal of achieving pCR in NACT breast cancer patients.Undoubtedly,the determination of the best treatment window of docetaxel is very important for Chinese patients and even Asia patients.This present article focuses on reviewing pharmacokinetic(PK)/pharmacodynamic(PD)and toxicological profiles of docetaxel and discussing the relationship of PK/PD of docetaxel and the efficiency of NACT of breast cancer patients.We also discuss with the optimal dosage of docetaxel of Chinese patients.Objective:This study was to investigate the relationship between pharmacokinetically determined docetaxel exposures and the treatment efficacy of NACT patients with breast cancer and infer whether pharmacokinetic index of docetaxel could be a predictor of the efficacy of NACT of breast cancer.Materials and Methods:Collect 56 cases,in patients with advanced breast cancer at the First Affiliated Hospital of Zhengzhou University,2015 October-2017 October,both for initial treatment of women.All patients accepted Bilateral breast and axillary lymph nodes ultrasound and measured the size of tumor and the number of axillary lymph nodes.After that,they received the excision biopsy of mass or Bard puncture needle biopsy under local anesthesia and was proved to be breast cancer according to Intraoperative rapid frozen pathology.With the result of Intraoperative rapid frozen pathology,Bard port was implanted into patient’s jugular vein for the administration of chemotherapy.All patients were administrated with epirubicin combined with cyclophosphamide sequential docetaxel.Patients was injected with docetaxel(75mg/m~2)at the 5th course after 4 courses of EC,every 3 weeks and the infusion time was more than 1h.At the first cycle of docetaxel,a patient’s docetaxel exposure was determined as an area under the curve(AUC)using plasma concentrations of decetaxel measured at two different time points(at the end of the infusion and 30-60 minutes after the end of the infusion).After the last cycle of chemotherapy,every patient accepted breast ultrasound again to measure the size of tumor.Breast cancer radical operation therapy was administrated in 1~2 weeks after NACT and administrated pathological examination again for the resection part of the tumor to see whether there was any tumor cells remain.The clinical efficacy of neoadjuvant chemotherapy was assessed using RECIST Response Evaluation Criteria in solid tumors.Pathological Miler and Payne(MP)treatment response evaluation method was used on the determination of the efficacy of pathological response in NACT breast cancer patients.Analyze the relationship of the efficacy of NACT and the AUC of docetaxel statistically.Results:The mean AUC((?)±s)of all patients is about(2.77±0.95)mg·h/L,and the range of it is(1.0-5.8)mg·h/L.19(33.9%)patients achieved cCR and the AUC of them is(3.1±0.9)mg·h/L.There is a significant difference in the mean docetaxel AUC by the clinical response.15(26.8%)patients achieved pCR and the AUC of them is(3.3±0.1)mg·h/L.There is a significant difference in the mean docetaxel AUC by the clinical response.Conclusion:1.Individual exposure to docetaxel was highly variable and the efficiency of NACT was related to the AUC of docetaxel.2.AUC of docetaxel could be a predictor to the efficiency of NACT of breast cancer patients.3.Further studies are needed to determine the optimal AUC of docetaxel which could improve the efficiency and minimize the toxicity.