Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

Background:

Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients.

Patients and methods:

Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy.

Results:

In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6–78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11–0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13–0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand–foot skin reaction were correlated with drug exposure.

Conclusions:

Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.     

The impact of kidney function on the outcome of metastatic renal cell carcinoma patients treated with vascular endothelial growth factor-targeted therapy

BACKGROUND:

A study was undertaken to investigate the effect of baseline renal function on treatment outcome in patients treated with vascular endothelial growth factor (VEGF)‐targeted therapy for metastatic renal cell carcinoma (mRCC).

METHODS:

Retrospective data from 6 North American cancer centers (3 US and 3 Canadian) were pooled to identify patients with mRCC treated with VEGF‐targeted therapy. Patient characteristics, response rate, time to treatment failure, and overall survival were collected. The Modification of Diet in Renal Disease formula was used at therapy initiation for calculation of glomerular filtration rate (GFR).

RESULTS:

Five hundred twenty‐nine patients with mRCC who received sunitinib (n = 323), sorafenib (n = 165), or bevacizumab (n = 41) were included in this analysis. Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1 mL/min/1.73 m² (range, 6.5‐174.2). On univariate analysis, patients with a GFR <60 (n = 262) were more likely to have had a previous nephrectomy (P < .0001) and to be older (P < .0001), but were less likely to have poor prognostic features such as anemia (P = .041), hypercalcemia (P = .008), neutrophilia (P = .039), thrombocytosis (P < .0001), short diagnosis to treatment interval (P = .007), and low Karnofsky performance status (P = .051). GFR <60, when adjusted for poor risk factors, did not have an impact on type of objective response (odds ratio, 1.31; 95% confidence interval [CI], 0.74‐2.32; P = .359), time to treatment failure (hazard ratio [HR], 0.97; 95% CI, 0.79‐1.19; P = .772), or overall survival (HR, 0.90; 95% CI, 0.69‐1.17; P = .439).

CONCLUSIONS:

Renal function at therapy initiation does not adversely affect the efficacy of VEGF‐targeted therapy in mRCC. Clinicians should not avoid treating patients with impaired baseline renal function. Cancer 2011;. © 2011 American Cancer Society.     

索拉非尼治疗中晚期肝细胞癌的不良反应及其处理

背景与目的：SHARP（sorafenib hcc assessment randomized protocol）和ORIENTAL（sorafenib in patients in asia-pacific region with hepatocellular carcinoma）两个Ⅲ期临床试验证实,多激酶抑制剂索拉非尼在一定程度上能延长晚期肝癌患者的总生存期（overall survival,OS）,并显著改善无进展生存期（progress free survival,PFS）和延长疾病进展时间（time to progression,TTP）,但治疗过程中出现的各种不良反应在一定程度上会影响其临床治疗。本研究使用索拉非尼治疗25例中晚期肝细胞癌患者,并对其不良反应情况及临床处理进行总结。方法：选取2008年1月-2009年10月期间符合原发性肝癌临床诊断标准的晚期肝癌患者25例,给予索拉非尼治疗所有患者均满足以下标准：⑴化疗栓塞术后病情进展;⑵广泛门脉癌栓无法栓塞;⑶肝门部、腹膜后淋巴结或肺、骨等多发转移者;⑷弥漫乏血供肿瘤;⑸签署知情同意书。在开始服用索拉非尼治疗后的前12周,观察患者不同级别不良反应发生情况,并给予相应临床处理。结果：共25例患者接受索拉非尼治疗,其中男性17例,女性8例,年龄范围30～72岁,平均51.44岁。期间9例患者死亡,其中3例在服药开始的12周内死亡。3例患者中断索拉非尼治疗,其中2例为治疗不满12周停药,1例为服药5个月后停药。共20例患者符合观察标准。不良反应发生情况如下：手足皮肤反应（hand-foot-skin reaction,HFSR）4例（4/20）,腹泻4例（4/20）,脱发5例（5/20）,皮疹4例（4/20）,乏力8例（8/20）,白细胞和血小板减少4例（4/20）,高血压1例（1/20）,腹痛1例（1/20）。这些不良反应经临床处理后,20例患者均能继续接受索拉非尼治疗。结论：索拉非尼治疗中晚期肝细胞癌具有良好的安全性和良好的耐受性。     

The Blood Neutrophil-to-lymphocyte Ratio Predicts Survival in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib

Background and Aim: Increasing evidence correlates the presence of systemic inflammation with poorsurvival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate theprognostic significance of the blood neutrophil-to-lymphocyte ratio (NLR) in patients with advanced HCC whoreceived sorafenib monotherapy. Methods: A total of sixty-five patients with advanced HCC, not eligible forlocoregional therapy, treated with sorafenib were enrolled. Potential prognostic factors such as age, gender,tumoral characteristics, performance status and NLR were analyzed. Results: Median OS and TTP for the entirecohort were 10.0 months (95%CI, 7.6-12.3 months) and 4.5 months (95% CI, 4.0-4.9 months). The mean NLRat baseline was 2.89. The median OS of patients with a high NLR (>4) was 6.5 months (95%CI, 5.2-7.7 months)compared with 12.5 months (95%CI, 9.9-15.0) for patients with a normal NLR (≤4) (P=0.01). Age ≤65, NLR>4, extrahepatic metastases and vascular invasion were all predictors of poorer overall survival. Multivariateanalysis showed that NLR > 4, vascular invasion and extrahepatic metastases were independent predictors ofpoorer overall survival. The median TTP of patients with a high NLR was 2.5 months (95%CI, 1.4-3.6 months)compared with 4.5 months (95%CI, 3.9-5.1 months) for patients with a normal NLR (P=0.012). Conclusions: Highbaseline NLR was associated with worse OS and TTP for patients with advanced HCC treated with sorafenib.     

Efficiency and Side Effects of Sorafenib Therapy for Advanced Hepatocellular Carcinoma: A Retrospective Study by the Anatolian Society of Medical Oncology

Background: Inoperable and metastatic hepatocellular carcinoma (HCC) is associated with a poor prognosisand low chemotherapeutic efficiency. Sorafenib is an oral multi-kinase inhibitor exerting its effects via the RAF/MEK/ERK pathway, vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factorreceptor beta (PDGFR-β) tyrosine kinases. Randomized studies have shown a significant contribution of sorafenibto life expectancy and quality of life of cancer patients. The aim of the present study is to evaluate the efficacy andside effects of sorafenib therapy in Turkey. Materials and Methods: Data for 103 patients (82 males, 21 females)receiving sorafenib therapy in 13 centers from February 2008 to December 2012 were evaluated. Median agewas 61 years and median ECOG performance status was 1 (range: 0-2). 60 patients (58%) had hepatitis B, 15patients (15%) had hepatitis C infection and 12 patients (12%) had a history of alcohol consumption. All of thepatients had Child scores meeting the utilization permit of the drug in our country (Child A). Results: A totalof 571 cycles of sorafenib therapy were administered with a median of four per patient. Among the evaluablecases, there was partial response in 15 (15%), stable disease in 52 (50%), and progressive disease in 36 (35%).Median progression-free survival was 18 weeks and median overall survival was 48 weeks. The dose was reducedonly in 6 patients and discontinued in 2 patients due to grade 3-4 toxicity, 18 patients (17%) suffering hand-footsyndrome, 7 (7%) diarrhea, and 2 (2%) vomiting. Conclusions: This retrospective study demonstrated betterefficacy of sorafenib therapy in patients with advanced HCC compared to the literature while progression-freesurvival and overall survival findings were comparable. The side effect rates indicate that the drug was toleratedwell. In conclusion, among the available treatment options, sorafenib is an efficient and tolerable agent in patientswith inoperable or metastatic HCC.     

肝细胞癌根治术后辅助疗法在预防复发转移中的应用

随着医学技术和医疗器械的不断进步和完善,使得肝脏的手术已没有了“禁区”。许多肝细胞癌患者均能得到较为妥善和规范的手术治疗。但是,肝细胞癌术后复发和转移问题一直未能取得突破性进展,成为影响手术效果和术后不能长期存活的原因。因此,抗根治术后复发转移成为了外科医生面临的一大挑战。本文就肝细胞癌根治术后的多种辅助疗法进行综述,希望对肝细胞癌术后的临床防治提供参考。     

白头翁皂苷D联合索拉非尼对人肝癌细胞侵袭与转移的影响

[摘要]目的 探讨白头翁皂苷D联合索拉非尼对人肝癌细胞株侵袭与转移的影响。 方法 将人肝癌细胞BEL-7402分为白头翁皂苷D单药处理组、索拉非尼单药处理组及两药联合处理组,观察比较三种处理方式对肝癌细胞侵袭和转移的影响。结果 检测分析各组黏附抑制率,作用3h,索拉非尼组显著高于白头翁皂苷D组（P＜0.05或＜0.01）,联合用药组显著高于索拉非尼组和白头翁皂苷D组（P＜0.01）;作用5h,白头翁皂苷D组黏附抑制率显著高于索拉非尼组（P＜0.01）,并且高于白头翁皂苷D组作用3h（P＜0.01）,说明两药联合对肝癌细胞的黏附抑制率具有协同作用（Q=2.33＞1.15）;检测分析各组迁移抑制率,索拉非尼单药组和两药联合组对肝癌细胞的迁移抑制率均显著高于白头翁皂苷D单药组（P＜0.01）,并且两药联合组的抑制率显著高于索拉非尼单药组（P＜0.01）,说明两药联合对肝癌细胞的迁移抑制作用具有协同作用（Q=1.39＞1.15）;检测分析侵袭抑制率,索拉非尼单药组和两药联合组均显著高于白头翁皂苷D组（P＜0.01）,说明两药联合对肝癌细胞的侵袭抑制作用具有拮抗作用（Q=0.68＜0.85）。各组的VEGF-C、MMP-9表达情况：白头翁皂苷D单药组的MMP-9表达水平显著下降,索拉非尼组和两药联合组的VEGF-C、MMP-9及表达水平均显著下降（P＜0.05）;与白头翁皂苷D单药组比较,两药联合组的VEGF-C表达水平显著下降;两药联合组较白头翁皂苷D单药组VEGF-C水平显著下降（P＜0.05）。结论 白头翁皂苷D、索拉非尼单药以及两药联合对肝癌细胞BEL-7402细胞株的黏附、迁移、侵袭具有一定的抑制作用,且二者对肝癌细胞的黏附、迁移的抑制具有协同作用。     

索拉非尼固体脂质纳米粒冻干粉制备及体外释药特性研究

 目的 制备索拉非尼固体脂质纳米粒,并考察其理化性质及体外释药特性。方法 采用乳化蒸发-低温固化法制备索拉非尼固体脂质纳米粒,透射电镜观察形态,激光粒度仪测定粒径和Zeta电位,葡聚糖凝胶法和HPLC测定其包封率,透析法考察其体外释药特性,冷冻干燥法制备索拉非尼固体脂质纳米粒冻干粉,差示扫描量热分析其物相状态。结果 制得索拉非尼固体脂质纳米粒为类球形实体,粒径分布比较均匀,平均粒径为(108.2±7.0) nm,多分散指数为（0.250±0.022）,Zeta电位为(-16.4±0.7) mV;测得3批样品的平均包封率为(73.49±1.87)%;体外释放符合Weibull模型;等体积15%甘露醇作冻干保护剂效果较好;DSC分析证明纳米粒已形成。结论 乳化蒸发-低温固化法适用于索拉非尼固体脂质纳米粒的制备,所制纳米粒各项物理指标稳定,具有明显缓释作用。