Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3?h prior to the start of a 4?h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7?L and 30.0?μg·h/mL, respectively. A dose reduction of L-OHP by 30%?50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.     

Hepatic Artery Infusion Chemotherapy Using Fluorouracil,Leucovorin, and Oxaliplatin versus Transarterial Chemoembolization as Initial Treatment for Locally Advanced Hepatocellular Carcinoma: A Propensity Score–Matching Analysis

PurposeTo compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC).MethodsThis retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score–matching methodology was used to reduce the influence of confounding factors on the outcomes.ResultsThe study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237–0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization.ConclusionsCompared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.     

Oxaliplatin-induced neuropathic pain involves HOXA6 via a TET1-dependent demethylation of the SOX10 promoter

Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole-genome expression microarray and gene ontology analysis to identify the upregulation of a sequence-specific DNA-binding protein, HOXA6, in the spinal dorsal horn on Day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV-SOX10-EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1-mediated promoter demethylation of SOX10 may contribute to oxaliplatin-induced neuropathic pain.     

Gemcitabine,paclitaxel, and oxaliplatin (GEMPOX) in the treatment of relapsed/refractory intracranial nongerminomatous germ cell tumors

Intracranial germ cell tumors (GCT) account for less than 5% of all central nervous system tumors in children in Western countries. Approximately 40% are nongerminomatous GCT (NGGCT). Despite correct treatment, 16% to 47% of the patients will relapse. There are no standard approaches in case of recurrence, and treatment in this situation remains a challenge. We report three patients diagnosed with relapsed intracranial NGGCT treated with gemcitabine, paclitaxel, and oxaliplatin, in whom the tumor showed a remarkable response with normalization of tumor markers.     

Suitability of the AUC Ratio as an Indicator of the Pharmacokinetic Advantage in HIPEC

The purpose of this study was to evaluate the area under the concentration-time curve (AUC) ratio as an optimal indicator of the pharmacokinetic advantage during hyperthermic intraperitoneal perioperative chemotherapy. The impact on the AUC ratio on the variables related to the calculation of systemic drug exposure, instillation time, and peripheral drug distribution was evaluated through simulations as well as through a retrospective analysis of studies published in the literature. Both model simulations and the retrospective analysis showed that the 3 variables evaluated had an impact on the AUC ratio value if the complete systemic exposure was not fully considered. However, when that complete systemic exposure was considered, none of these variables affected the AUC ratio value. AUC ratio is not a characteristic parameter of a drug if the calculated systemic drug exposure is not complete. Thus, AUC ratio is not valid for comparing the pharmacokinetic advantage of 2 drugs, and it should not be employed to prove whether a drug can be used in hyperthermic intraperitoneal perioperative chemotherapy safely with regard to toxicity. As an alternative, the study of the absorption rate constant and the bioavailability are proposed as the true and independent parameters that reflect the amount of drug absorbed.     

奥沙利铂注射剂质量分析及探索性研究

目的：评价国内不同企业生产的奥沙利铂注射剂的质量。为奥沙利铂注射剂的标准提高和质量控制提供合理化建议。方法：将法定检验与探索性研究相结合,对抽验样品进行检验和研究,对结果进行统计分析。结果：共抽取样品51批次,按法定检验合格率100%。但现行注射液法定标准无法完全检出奥沙利铂已知和未知杂质,本研究建立了专属性更高的杂质检查方法,并通过杂质谱的比较,发现注射液剂型杂质检出量明显高于注射用无菌粉末。进一步研究表明注射液剂型的终端灭菌方式、贮藏时间、贮藏温度、金属离子含量等影响了奥沙利铂稳定性。结论：目前国内注射用奥沙利铂总体质量较好,奥沙利铂注射液（小水针和大输液）总体质量一般。注射液剂型现行标准有待进一步提高。建议小水针和大输液企业加强药品生产全过程风险管控,对各影响因素进行有效控制。     

黄芪桂枝五物汤熏洗联合艾灸治疗奥沙利铂所致恶性肿瘤患者周围神经毒性的临床疗效

[目的]探讨黄芪桂枝五物汤熏洗联合艾灸治疗奥沙利铂所致恶性肿瘤患者周围神经毒性的临床疗效。[方法]将100例符合纳入标准的患者随机分为A组、B组、C组和D组,每组各25例,A组采用甲钴胺治疗,B组在A组基础上联合艾灸治疗,C组在A组基础上联合黄芪桂枝五物汤熏洗治疗,D组为A组基础上联合艾灸及黄芪桂枝五物汤熏洗治疗。4个疗程结束后合格病例计100例,采用奥沙利铂Levi专用感觉神经毒性分级标准、欧洲癌症研究和治疗组织癌症患者生存质量测定量表评估疗效。[结果]与治疗前比较,四组患者治疗后神经毒性反应降低,差异均有统计学意义(P0.05);A组、B组、C组、D组总有效率分别为56.0%、72.0%、76.0%、92.0%,D组有效率均优于其他三组,B组、C组优于A组,差异均有统计学意义(P0.05);与其他三组比较,D组患者总体健康状况、躯体功能和情绪功能评分显著高于其他三组,差异具有统计学意义(P0.05),A组、B组、C组间比较各有优劣,但差异无统计学意义(P0.05)。本研究过程中无任何明显不良事件的报告。[结论]在甲钴胺治疗的基础上,采用黄芪桂枝五物汤熏洗联合艾灸可以有效改善奥沙利铂所致周围神经毒性患者的躯体功能、情绪功能和社会功能,并能有效缓解疼痛,且较单独使用黄芪桂枝五物汤或艾灸或甲钴胺治疗效果更佳。     

奥沙利铂致外周神经毒性症状特性及变化趋势的纵向研究

目的探讨肠癌患者使用奥沙利铂期间外周神经毒性症状特性、变化趋势及非药物影响因素。方法对113例使用奥沙利铂肠癌患者,采用神经毒性患者自述问卷（PNQ）于累积剂量达200mg/m2、540mg/m2、850mg/m2时进行随访调查,评估外周神经毒性症状的严重度;Podo触觉测量笔及温度觉测量笔分别检测患者触觉及温度觉有无异常。结果首次使用奥沙利铂后88.5%患者出现肢体感觉异常,首发表现以手部麻木为主,其次为刺痛。不同累积剂量时外周神经毒性严重度比较,差异有统计学意义（均P〈0.01）;当累积剂量达200mg/m2、540mg/m2时,不同给药方式的患者外周神经毒性严重度比较,差异有统计学意义（P〈0.05,P〈0.01）。4例患者触觉减弱。结论肠癌患者使用奥沙利铂期间感觉神经损伤发生率高于运动神经损伤,且程度较重;随着剂量的累积,外周神经毒性症状越严重。健康教育时应提供针对性指导,鼓励患者使用中心静脉导管给药,可有效避免化疗前期肢体感觉异常,延缓外周神经毒性症状加重。