索拉非尼治疗转移性肾癌的疗效与安全性观察

目的:评估63例转移性肾细胞癌（metastatic renal cell carcinoma,mRCC）患者服用索拉非尼的疗效及安全性。方法:前瞻性观察2010年6月至2018年6月就诊于西安交通大学第一附属医院肿瘤内科及中华慈善总会索拉非尼援助赠药项目mRCC患者共计71例,其中63例可评价疗效及安全性。使用SPSS 18.0 软件进行K-M单因素生存分析,所得阳性因素导入COX回归模型进行多因素分析,明确影响索拉非尼治疗mRCC疗效的因素。结果:63例可评价mRCC患者中,无CR患者,PR 18例,SD 22例,PD 23例,ORR为28.57%（18/63）,DCR为63.49%（40/63）;中位PFS为14月（3~51月）,中位OS为29月（6~69月）;所有不良反应均可控或随剂量减少而降低。索拉非尼作为mRCC一线治疗者39例,二线及以上治疗者24例。一线和二线及以上治疗的ORR及DCR均无统计学差异,且中位PFS分别为24月（4~51月）和13月（3~42月）（P=0.021）。COX回归分析示,索拉菲尼是否为一线治疗是影响PFS的独立危险因素（P=0.030）。结论:索拉非尼治疗mRCC疗效确切,不良反应较少,并且是否为一线治疗是影响患者中位PFS的独立预测因素。     

索拉非尼治疗转移性肾癌的不良反应

目的回顾分析31例使用靶向治疗药物索拉非尼治疗转移性肾癌患者的临床资料,评价索拉非尼治疗晚期转移性肾癌的安全性,探讨其不良反应的特点、预防及治疗方法。方法2006年4月至2008年12月,我们对31例转移性肾癌患者行口服索拉非尼治疗,其中男20例,女11例;有17例患者为一线用药,14例为二线用药。25例行原发肿瘤切除,除1例为肾乳头状细胞癌外,其余均为透明细胞癌(2例含肉瘤成分),6例患者无法行手术切除,但经穿刺活检证实为肾透明细胞癌。治疗方案：索拉非尼400mg,2次/日;2例患者接受索拉非尼增量治疗,每次口服600mg,2次/日;1例同时使用免疫治疗。结果本组31例患者出现的不良反应包括消化系统反应22例(71.0%)、手足综合征17例(54.8%)、疲乏13例(42.0%)、高血压7例(22.6%)、肝功能损害3例(9.7%),其中3级不良反应4例(12.9%),无4级不良反应,给予对症处理、减量或停药后均缓解。结论索拉非尼治疗转移性肾癌有较多的不良反应,但多数较为轻微,经积极适当的处理,绝大多数患者可耐受,安全性较好。     

索拉非尼治疗21例转移性肾细胞癌的临床观察

由于转移性肾细胞癌(renal cell carcinoma,RCC)对放化疗具有抗拒性,故白细胞介素2(IL-2)和于扰素α(INF-α)一直是治疗转移性肾癌的主要药物,但不良反应阻碍了其临床应用.     

索拉非尼治疗21例转移性肾细胞癌的临床观察

由于转移性肾细胞癌(renal cell carcinoma,RCC)对放化疗具有抗拒性,故白细胞介素2(IL-2)和于扰素α(INF-α)一直是治疗转移性肾癌的主要药物,但不良反应阻碍了其临床应用.     

索拉非尼治疗肝细胞癌的疗效评价及不良反应

目的：观察索拉非尼治疗肝细胞癌的临床疗效及不良反应。方法：回顾性分析我院2008年7月至2009年12月间应用索拉非尼400mg每日两次治疗21例肝细胞癌患者的临床疗效与不良反应。结果：2例由于在服药后1月内出现肝功能异常而停药,未进行肿瘤评价。19例接受过1次以上实体瘤治疗反应评价标准（RECIST Response Evaluation Criteria in Solid Tumours 1.0版）的评价,其中无客观缓解者,14例（73.7%）疾病稳定且稳定时间大于3月。5例（26.3%）持续肿瘤进展。药物不良反应最常见的为手足皮肤反应、高血压、腹泻,其次有脱发、乏力、纳差、口腔溃疡、肝功能异常、发热等,不良反应一般在服药后1-2周内出现,其中有2例不能耐受不良反应而减少药物剂量,2例由于肝功能异常而停药。结论：索拉非尼治疗肝细胞癌患者以疾病稳定者多见,应严密监测并及时处理不良反应,以保证持续用药。     

索拉非尼治疗肝细胞癌的疗效评价及不良反应

目的:观察索拉非尼治疗肝细胞癌的临床疗效及不良反应。方法:回顾性分析我院2008年7月至2009年12月间应用索拉非尼400mg每日两次治疗21例肝细胞癌患者的临床疗效与不良反应。结果:2例由于在服药后1月内出现肝功能异常而停药,未进行肿瘤评价。19例接受过1次以上实体瘤治疗反应评价标准(RECIST Response Evaluation Criteria in Solid Tumours 1.0版)的评价,其中无客观缓解者,14例(73.7%)疾病稳定且稳定时间大于3月。5例(26.3%)持续肿瘤进展。药物不良反应最常见的为手足皮肤反应、高血压、腹泻,其次有脱发、乏力、纳差、口腔溃疡、肝功能异常、发热等,不良反应一般在服药后1-2周内出现,其中有2例不能耐受不良反应而减少药物剂量,2例由于肝功能异常而停药。结论:索拉非尼治疗肝细胞癌患者以疾病稳定者多见,应严密监测并及时处理不良反应,以保证持续用药。     

索拉非尼治疗肾癌肾移植术后肺转移一例报告

1病例报告 患者男,60岁.于2003-07出现肉眼血尿,肾脏CT示右肾占位,于2003-07-10在中国人民解放军总医院行右肾根治性切除术.术后病理:肾上极透明细胞癌,少部分为颗粒细胞癌.术后应用干扰素治疗3个月,此后发现肾功能异常,于2008-10-10因左肾功能衰竭在我院行肾移植术,术后肾功能恢复正常,并开始口服泼尼松、骁希、环孢素A等免疫抑制剂治疗.于2010-01-26肾脏CT发现左肾上腺占位,大小约6.2 cm×6.1cm,左肾萎缩.拟诊为右肾癌术后左肾上腺转移,在我院行左肾上腺及左侧萎缩肾切除术,术后病理示左肾及左肾上腺转移性透明细胞癌,结合病史,考虑来自右肾.于2010 04-22胸部CT发现双肺多发转移.     

以索拉非尼为基础治疗晚期肝细胞癌的疗效和不良反应临床观察

背景与目的:多激酶抑制剂索拉非尼因SHARP(Sorafenib HCC Assessment RandomizedProtocol)和ORIENTAL(Sorafenib in Patients in Asia-pacific Region with Hepatocellular Carcinoma)2项Ⅲ期临床试验证实能显著改善无进展生存期(progress free survival,PFS)和延长疾病进展时间(time toprogression,TTP)和总生存期(overall survival,OS),2008年被批准为晚期肝细胞癌的治疗。本研究观察索拉非尼单用或联合TACE治疗30例晚期肝细胞癌的疗效和不良反应。方法:选择2009年3月—2011年1月,符合晚期原发性肝癌临床或病理诊断的患者30例,每次口服索拉非尼400 mg,每日2次,至少口服2个月以上,其中20例联合1～9次TACE,10例单用索拉非尼治疗。按RESIST标准,每2个月评价疗效,随访TTP和OS。结果:30例患者部分缓解(PR)3例,疾病稳定(SD)16例,疾病进展(PD)11例,临床获益率(clinical benefit rate,CBR)为63.3%。其中10例单用索拉非尼组PR 1例,SD 5例,PD 4例,CBR为60.0%;20例联合治疗组PR 2例,SD 11例,PD 7例,CBR为65.0%。27例患者生存3个月,24例6个月,21例9个月,9例1年以上,全组TTP为7个月,OS为9个月。联合组患者TTP为7个月,OS为14个月,单用索拉非尼组患者TTP为6个月,OS为9个月,差异无统计学意义(P>0.05)。患者用药1～2周开始出现不良反应,手足皮肤反应23例,腹泻24例,高血压14例,乏力24例,脱发9例,出现3度不良反应10例,给予对症治疗后,均能完成治疗。结论:索拉非尼联合TACE治疗较单用索拉非尼治疗可延长患者的TTP和OS,但两组差异无统计学意义(P>0.05)。两组患者不良反应可耐受,不良反应发生率差异无统计学意义(P>0.05)。     

索拉非尼不良反应３６例的分析与处理

目的：回顾性分析肾癌和肝胆癌患者在服用索拉非尼治疗过程中不良反应的出现频率、治疗及护理方法等,总结经验,指导临床。方法：对使用索拉非尼出现不良反应的３６例晚期肝癌和肾癌患者进行常规护理及心理护理,观察服药期间出现的各种症状并及时处理,对各种可能与索拉非尼有关的不良反应进行分级、记录与统计分析。结果：３６例患者中除１例患者因心肌梗死死亡,１例患者因Ⅲ度皮肤不良反应而停药外,其余３４例均能够继续接受索拉非尼。其中皮疹、疼痛及腹泻为常见不良反应,且分级多为Ⅰ度和Ⅱ度,Ⅲ度不良反应的发生率为１９.４％。结论：索拉非尼合并皮疹及腹泻等轻中度不良反应的发生率较高,亦有心肌梗死的严重不良反应发生。常规护理、心理护理和积极治疗将有助于减轻不良反应。     

局部放疗联合索拉非尼治疗转移性肾癌1例分析

1 病案摘要 患者,女,53岁。2003年因左肾占位于我院行肾癌根治术,术后病理示：“左肾透明细胞癌”。术后曾分别行5-Fu单药化疗1周期及α-干扰素生物治疗1天,因恶心呕吐、全身乏力、疼痛等毒副作用难以耐受未继续治疗。2007年4月因左侧髋部疼痛行ECT全身骨扫描及骨盆X线片检查发现左侧髂骨溶骨性破坏,胸部CT检查发现左肺尖及左肺门处两个转移结节,直径均小于1．5cm。     

舒尼替尼与索拉非尼交替应用治疗肾癌1例并文献复习

目的:探讨舒尼替尼与索拉非尼交替应用治疗转移性肾癌的疗效。方法:报道舒尼替尼与索拉非尼交替应用治疗转移性肾癌1例并结合文献讨论。结果:该患者一线舒尼替尼治疗疾病进展时间（TTP）为6个月。二线索拉非尼治疗TTP为5个月。二线治疗失败后改变舒尼替尼给药方式（37.5mg 每日1次,连续口服）继续治疗,三线TTP为8个月。结论:患者一线应用舒尼替尼和二线应用索拉非尼的治疗疗效与文献报道相符。二线治疗失败后改变舒尼替尼给药方式继续治疗仍获得较好的疗效。     

Nutlin‐3 enhances sorafenib efficacy in renal cell carcinoma

The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi‐specific tyrosine kinase inhibitor sorafenib has improved the progression‐free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin‐3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin‐3 synergistically inhibited the cell survival and enhanced caspase‐3 cleavage leading to apoptosis in RCC. Nutlin‐3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin‐3 decreased the phosphorylation of vascular endothelial growth factor receptor‐2 (VEGFR‐2) and ERK along with inducing p53 activity. The sorafenib and nutlin‐3 co‐treatment lead to enhanced levels of p53, p‐p53, and increase in the levels of p53 pro‐apoptotic effector PUMA, Bax, and decrease in the anti‐apoptotic Bcl‐2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co‐treatment of nutlin‐3 with sorafenib leads to increased half‐life of p53, which in turn can be activated by sorafenib, to induce downstream pro‐apoptotic and anti‐proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin‐3 while providing a strong clinical‐translational rationale for further testing of sorafenib and nutlin‐3 combinatorial regimen in human RCC. © 2011 Wiley Periodicals, Inc.     

Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib.

BACKGROUND: Sorafenib is an orally bioavailable vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity in metastatic renal cell carcinoma (RCC). Sunitinib, also a VEGFR inhibitor, induces biochemical hypothyroidism in 85% of metastatic RCC patients, the majority of whom have signs or symptoms of hypothyroidism. Hence, the incidence of thyroid function test (TFT) abnormalities in patients with metastatic RCC receiving sorafenib was investigated. PATIENTS AND METHODS: Sixty-eight patients with metastatic RCC were treated with sorafenib at the Cleveland Clinic Taussig Cancer Center, and 39 patients had TFTs available. RESULTS: Eight patients (21%) had thyroid dysfunction possibly caused by sorafenib [seven hypothyroidism (18%) and one hyperthyroidism (3%)] and eight additional patients (21%) had findings compatible with nonthyroidal illness. Only two patients had clinical signs and symptoms secondary to thyroid dysfunction and received thyroid hormone replacement. CONCLUSIONS: In summary, clinically significant TFT abnormalities were not common in patients treated with sorafenib, and replacement therapy was rarely indicated. TFTs should be measured before sorafenib therapy in RCC patients and subsequently only if clinically indicated.     

索拉菲尼治疗肝癌常见不良反应及处理的研究进展

索拉菲尼是一种口服多激酶抑制剂。通过作用于Raf激酶直接抑制肿瘤细胞增殖,还可作用于血管内皮生长因子受体1,2,3（VEGFR-1, -2, -3）,以及血小板源生长因子受体-β（PDGFR-β）、受体酪氨酸激酶、抑制肿瘤新生血管生成。索拉菲尼通过抑制肿瘤细胞增殖和抗血管生成的双重作用,从而达到抗肿瘤的目的。已被多个国家批准作为首个系统治疗肝细胞肝癌的分子靶向药物。其常见不良反应包括皮肤反应、恶心、腹泻、体质量减轻、高血压等,影响了患者的长期使用依从性,进而影响治疗效果。正确地认识和管理索拉非尼的不良反应则有助于发挥索拉非尼的治疗作用,提高临床效果。本文从索拉菲尼靶向治疗的常见不良反应、发生机制及处理方法等方面进行综述。      

Adverse events of sorafenib in hepatocellular carcinoma treatment

Sorafenib is an oral multikinase inhibitor approved by the US Food and Drug Administration for treatment of the patients with surgically unresectable hepatocellular carcinoma (HCC). Sorafenib mitigates angiogenesis by targeting vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes. Moreover, it suppresses cell proliferation via blockage of B-RAF and RAF1 of the mitogen-activated protein kinase pathway in tumor cells. Sorafenib has been the standard molecular targeted medication in the treatment of advanced-stage HCC patients ineligible for potentially curative interventional (radiofrequency or microwave ablation) or palliative trans-arterial chemoembolization (TACE) therapies for over a decade. However, it only increases overall survival by less than 3 months, and systemic exposure to sorafenib causes clinically significant toxicities (about 50% of patients). Given the high frequency and severity of these toxicities, sorafenib dose must be often reduced or discontinued altogether. In this review, we discussed the mechanism of sorafenib-associated adverse events and their management during HCC treatment.     

Efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma

Objective: To determine the safety and efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma.

Material and methods: We conducted an observational study in 156 patients with advanced renal cell carcinoma unsuitable for surgical treatment. Participants received cryoablation?+?sorafenib (n?=?67) or sorafenib only (n?=?89). Objective response rate (ORR), disease control rate (DCR), progression-free survival time (PFS), overall survival (OS), change in immune function after treatment, rate of adverse events, and quality of life were compared between the two groups.

Results: In the cryoablation?+?sorafenib group, ORR and DCR were significantly higher and PFS and OS were significantly longer than in the sorafenib only group (both p?<?.05). Immune function-related indicators were significantly improved after treatment in the cryoablation?+?sorafenib group (p?<?.05), but no significant difference was found between before and after treatment in the sorafenib only group (p?>?.05). The incidence of targeted drug-related side effects was not significantly different between the groups (p?>?.05), and cryoablation did not increase the risk of side effects of targeted drugs.

Conclusion: Cryoablation combined with sorafenib had superior clinical efficacy compared with sorafenib-only for the treatment of advanced renal cell carcinoma unsuitable for surgical treatment. Moreover, this combined therapy may enhance the body’s anti-tumor immunity and effectively prolong PFS and OS without compromising patient quality of life, thus representing a new treatment strategy for advanced renal cell carcinoma.     

A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma

There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand–foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.     

Management of sunitinib adverse events in renal cell carcinoma patients: the Asian experience

Sunitinib is the gold standard of care for patients with metastatic renal cell carcinoma, demonstrating an overall survival benefit of over 2 years in a pivotal phase 3 trial of 750 patients. While sunitinib is generally well tolerated with most adverse events, manifesting as mild to moderate in severity and manageability, it has a distinctive adverse event profile that benefits from careful monitoring during treatment. As sunitinib gains widespread use across the globe, best practices are being developed for specific patient groups. This review will focus on the current clinical trial data in Asian populations and on the mechanism, incidence and management of selected sunitinib-related adverse events, including hand-foot syndrome, hypertension, proteinuria, cardiac toxicities, myelosupression, fatigue/asthenia, hypothyroidism, diarrhea and hepatotoxicity. Taken together, the developing body of literature reviewed here demonstrates that sunitinib is well tolerated in Asian patients and provides efficacy that is similar, if not superior, to other patient groups. Asian patients, like all patients, should begin treatment of sunitinib at 50 mg on Schedule 4/2 (4 weeks on treatment/2 weeks off). Prophylactic measures, good communication between patient and health-care providers, and early, aggressive intervention at the development of adverse events can limit the dose reductions required and maximize both patients' response to treatment and their quality of life.     

Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial

Background:

Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC).

Methods:

In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability.

Results:

After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone (P=0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand–foot syndrome, hypertension, and diarrhoea. Grade 3–4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively.

Conclusion:

The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.