多靶点抗肿瘤药物舒尼替尼研究进展

舒尼替尼是目前已知的作用靶点最多的靶向抗肿瘤药物之一,具有广谱的抗肿瘤活性。2006年1月美国食品药品管理局（FDA）批准舒尼替尼用于治疗转移性肾细胞癌和不能耐受或伊马替尼治疗失败的转移性胃肠道间质瘤,2008年5月在我国上市。本文就舒尼替尼的作用机理和临床研究进展作一综述。     

探讨舒尼替尼治疗转移性肾癌的预后因素

目的探究转移性肾癌采用舒尼替尼治疗的临床效果以及影响患者预后的相关因素。方法选取我院54例转移性肾癌患者的临床资料进行回顾性分析,所有患者均采用舒尼替尼治疗,观察治疗后患者生存情况,并采用单因素分析法研究与患者预后相关的主要影响因素。结果本组患者总体生存期为2.5~66.4个月,平均生存期为(22.5±14.8)个月,患者1年存活率为72.2%,2年存活率为63.0%,3年存活率为57.4%。影响患者预后的主要因素有ECOG(体力状况)评分、临床症状、骨转移、舒尼替尼1M-RDI(首月相对剂量密度)等,其中存在临床症状患者生存期短于无症状者(P<0.05),发生骨转移患者生存期短于无骨转移者(P<0.05),舒尼替尼1M-RDI<50%患者生存期短于舒尼替尼1M-RDI≥50%者(P<0.05),各项数据比较均存在明显统计学差异。结论采用舒尼替尼治疗转移性肾癌,影响患者预后的因素较多,临床使用靶向药物时需考虑患者实际病情和首日用药剂量等多方面因素,以提高患者生存率和治疗效果。     

转移性肾癌一线治疗药物舒尼替尼、索拉非尼和培唑帕尼的药物经济学评价文献研究

目的:评估转移性肾癌一线治疗药物舒尼替尼、索拉非尼和培唑帕尼的经济性,为医保目录调整、临床用药决策提供参考依据。方法:以"转移性肾癌""舒尼替尼""索拉非尼""培唑帕尼""成本-效果""成本-效用""成本-效益""经济性分析"等为中文检索词,以"Metastatic renal cell carcinoma""m RCC""Sunitinib""Sorafenib""Pazopanib""Cost-effectiveness""Cost-utility""Cost-benefit""Economic analysis"等为英文检索词,在PubMed、Web of Science、the Cochrane Library、中国知网、万方数据库及维普网等数据库中检索2006年1月1日-2019年7月15日公开发表的相关文献,按照纳入排除标准筛选文献。使用卫生经济学评价报告标准共识(CHEERS)量表对纳入文献进行质量评价,提取相关数据后定性比较舒尼替尼、索拉非尼、培唑帕尼治疗转移性肾癌的有效性和经济性。结果:纳入文献10篇,7篇文献的总符合率均在75.00%以上。其中,对比舒尼替尼与索拉非尼方案的4篇文献研究中,3篇文献研究指出舒尼替尼为绝对优势方案,1篇文献研究指出索拉非尼更有经济性;对比舒尼替尼与培唑帕尼方案的6篇文献研究中,4篇文献研究指出培唑帕尼为绝对优势方案,2篇文献研究指出舒尼替尼更有经济性。结论:大多数情况下,培唑帕尼治疗转移性肾癌的有效性和经济性强于舒尼替尼和索拉非尼,但真实世界数据的研究显示舒尼替尼更有经济性。     

舒尼替尼治疗转移性肾细胞癌的疗效与不良反应及其相关性解析

目的：探讨舒尼替尼治疗转移性肾细胞癌的疗效和不良反应及其相关性。方法：本次医学研究以我院2011年1月～2014年1月收治的100例转移性肾细胞癌患者为观察对象,随机将其分为对照组和实验组,对照组患者接受传统方法治疗,实验组患者接受舒尼替尼治疗,回顾分析两组临床治疗效果。结果：实验组临床治疗总有效率明显高于对照组,不良反应发生率明显低于对照组（P<0.05）。结论：本次医学研究结果证实,转移性肾细胞癌患者接受舒尼替尼治疗,临床治疗效果较为理想,治疗的安全性较高,因而临床推广和应用价值较高。     

舒尼替尼治疗转移性肾细胞癌患者的药物经济学评价

目的:评价舒尼替尼、索拉非尼、干扰素α(IFN-α)在卫生资源使用、治疗费用及健康产出等方面的差异,从而分析哪种药物具有更好的成本-效果,为政府报销和临床用药提供决策依据。方法:使用基于Microsoft Excel建立的Markov模型来模拟5年的疾病进展、成本及健康产出,运用成本-效果分析对转移性肾细胞癌一线治疗药物舒尼替尼、索拉非尼、IFN-α进行经济学评价。结果:模拟5年的成本结果显示,舒尼替尼组的人均成本高于IFN-α组,低于索拉非尼组;5年的健康结果显示,舒尼替尼组患者获得的生命年及质量调整生命年均大于索拉非尼组和IFN-α组。结论:舒尼替尼与IFN-α相比不具有成本-效果优势,但与索拉非尼相比则为成本节约方案。     

舒尼替尼对转移性肾肿瘤的安全性及护理观察

目的 观察舒尼替尼对转移性肾癌治疗的安全性和护理措施.方法 2008年1月至2009年12月,22例转移性肾癌患者纳入研究,口服舒尼替尼50 mg/d.主要终点为治疗反应,次要终点为生存时间和药物的不良反应,根据个体化需要提供护理措施.结果 患者治疗的平均时间为17.4月(5.7~23.1月),11例患者治疗反应良好,1例完全缓解,10例患者部分缓解.毒副反应主要为乏力、发热、注射部位的皮下结节、皮疹及皮肤脱屑、肾功损伤、血糖升高、血压升高等.毒副反应大多为用药后1周内出现,对症治疗及相应护理后缓解.结论 舒尼替尼对转移性肾肿瘤治疗有效,采取必要的护理可提高患者的药物耐受性.     

多靶点酪氨酸激酶抑制剂舒尼替尼临床评价

苹果酸舒尼替尼是一种选择性多受体酪氨酸激酶抑制剂,具有抗肿瘤生长和抗血管生成作用.多中心随机双盲安慰剂对照研究显示,转移性和(或)不能切除的胃肠道间质瘤(GIST)在伊马替尼治疗失败后改用舒尼替尼(一日50mg,服用4周,间隔2周,一个治疗周期共为6周),结果与安慰剂组相比,至疾病进展时间和中位无进展生存期均延长,约为安慰剂组的4倍以上.初步评价显示,舒尼替尼作为晚期肾细胞癌(RCC)一线治疗用药比干扰素α更有效.     

舒尼替尼对转移性肾肿瘤的安全性和效果观察

目的观察舒尼替尼对转移性肾癌治疗的安全性和效果。方法 2008年1月至2009年12月,22例转移性肾癌患者纳入研究,舒尼替尼口服,剂量为50 mg/d。主要终点为治疗反应,次要终点为生存时间和药物的不良反应。结果患者治疗的平均时间为17.4个月(5.7～23.1个月),11例患者治疗反应良好,1例完全缓解,10例患者部分缓解。中位无进展生存时间为13.4个月(95%CI,21.8～34.4个月),总生存期为28.1个月。患者对治疗耐受良好。结论舒尼替尼对转移性肾肿瘤治疗有效,耐受性良好。     

1例舒尼替尼致肾脏血栓性微血管病变及肾病综合征报道

舒尼替尼是一种口服多靶点酪氨酸激酶抑制剂,具有抗肿瘤、抗血管增生的作用。该药对肾脏的损伤多表现为非肾病范围蛋白尿,导致肾病综合征相对少见,国内尚无舒尼替尼引起肾脏血栓性微血管病变报道。本文报道1例胃间质瘤术后接受舒尼替尼治疗患者,出现肾病综合征伴肾功能减退,肾活检证实为血栓性微血管病变,同时结合相关文献,对舒尼替尼所致肾脏损伤的临床表现、发病机制及治疗方法进行讨论,以提高对此类药物肾脏损伤的认识与重视。     

舒尼替尼致不良反应的文献分析

目的:为舒尼替尼临床安全使用提供参考。方法:以"舒尼替尼""不良反应"等为检索词,检索2006年1月-2017年3月Pub Med、维普、中国知网和万方数据库关于舒尼替尼致不良反应(ADR)文献的个案报道和病例系列报道,筛选后采用回顾性研究的方法,对患者基本情况、疾病信息、ADR累及器官/系统及临床表现、ADR关联性评价及转归进行统计分析。结果:共纳入文献57篇,涉及66个病例,其中新的不良反应15例;患者中男性34例(51.52%)、女性32例(48.48%),男女比例为1.06∶1,平均年龄(63.4±10.5)岁。舒尼替尼主要用于治疗肾透明细胞癌,占65.15%;其次是胃肠间质瘤,占21.21%。用药8～14 d和22～28 d时ADR发生率最高(27.27%、22.73%)。ADR累及器官/系统以内分泌系统为主(25.76%),主要临床表现为甲状腺功能减退;其次为皮肤及其附件(21.21%)和血液淋巴系统(16.67%),主要临床表现为手足综合征和血小板减少症(以4度骨髓抑制为主)。因果关系评价为肯定9例,很可能57例。舒尼替尼致ADR停药后自然好转的有14例(21.21%);停药并经药物治疗后好转的有27例(40.91%);需经手术治疗,严重延长病程或治疗后仍有后遗症的有17例(25.76%);死亡的有8例(12.12%)。结论:舒尼替尼所致的不良反应涉及全身多个器官/系统,不乏严重致死病例;在临床用药过程中应加强观察监测,及时处理ADR,保障患者安全。     

Response to Sorafenib After Sunitinib-Induced Acute Heart Failure in a Patient with Metastatic Renal Cell Carcinoma: Case Report and Review of the Literature

Cardiotoxicity is an emerging concern with a new class of drugs known as targeted agents, which include trastuzumab and sunitinib. Sunitinib is a small molecule that inhibits multiple tyrosine kinase receptors. This drug was approved by the United States Food and Drug Administration in 2006 for the treatment of clear cell metastatic renal cell carcinoma and advanced gastrointestinal stromal tumors. We describe a 65-year-old woman who was treated with sunitinib for metastatic clear cell renal cell carcinoma. After 5 months of therapy, she developed acute heart failure requiring hospitalization; sunitinib was immediately discontinued. The patient had classic symptoms of heart failure, including pleural effusion. An echocardiogram revealed a left ventricular ejection fraction of 30%. She received standard treatment for heart failure, including a β-blocker, an angiotensin-converting enzyme inhibitor, and diuretics. Within 1 month, the patient's symptoms resolved, and subsequent cardiac evaluation showed that her left ventricular ejection fraction returned to normal. According to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute, her cardiac event associated with sunitinib was defined as grade III toxicity. One month later, sorafenib, another tyrosine kinase inhibitor, was started with the aim of continuing her previous response to sunitinib. After 7 months of sorafenib therapy, the patient had no evidence of heart failure, and her condition was responding to treatment. Clinicians should be aware that sunitinib-induced heart failure occurs occultly and that many—but not all—cases resolve with discontinuation of the drug. Use of sorafenib after sunitinib-induced heart failure appears to be safe and effective, which suggests that cardiotoxicity is not a general class effect of the tyrosine kinase inhibitors.     

The emerging role of sunitinib in the treatment of advanced epithelial thyroid cancer: our experience and review of literature

Tyrosine kinase receptors have been shown to play an important role in epithelial thyroid tumor growth and angiogenesis. Thyroid cancers commonly present oncogene mutations involved in MAPK kinase pathway like BRAF and RET; they are also frequently dependent on VEGF stimuli. Preliminary clinical experiences suggest a promising role of sunitinib (a tyrosine kinase inhibitor) for the treatment of advanced thyroid cancers. This review deals with the available data on the effect of sunitinib in the treatment of metastatic, radioiodine refractory thyroid cancers. We also report our experience with the off-label use of sunitinib in such patients.     

Sunitinib: new drug. For some gastrointestinal stromal tumours

(1) Sunitinib, a tyrosine kinase inhibitor, is marketed for the treatment of advanced-stage and metastatic renal carcinoma, and for second-line treatment of gastrointestinal stromal tumours. Sorafenib arrived on the market almost simultaneously for second-line treatment of kidney cancer. (2) In second-line treatment of kidney cancer, two non comparative trials showed an unusually high rate of at least partial tumour regression with sunitinib (25%, compared to only 2% with sorafenib). Head-to-head trials of the two drugs are lacking. Although indirect comparisons are notoriously unreliable, sunitinib appears to provide longer progression-free survival than sorafenib (about 9 months versus 5.5 months), although overall survival times are similar. (3) Preliminary results of a trial comparing sunitinib with interferon alfa as first-line treatments in 750 patients with kidney cancer show a 6-month event-free survival advantage in the sunitinib arm. The precise overall survival time has not yet been calculated. (4) In 312 patients with gastrointestinal stromal tumours in whom imatinib has failed, a double-blind placebo-controlled trial showed that sunitinib prolonged overall survival time, but potential biases undermine these results. (5) The adverse effect profile of sunitinib appears to be similar to those of imatinib and sorafenib, apart from more thyroid disorders. The principal adverse effects are cutaneous, gastrointestinal, cardiovascular and haematological disorders. Arterial hypertension, sometimes severe, occurred in 16% of patients treated with sunitinib. Other serious adverse events included tumour haemorrhage and pulmonary embolism. A risk of cardiac toxicity leading to heart failure cannot currently be ruled out. (6) Sunitinib is metabolised by cytochrome P450 isoenzyme CYP 3A4, increasing the likelihood of drug interactions. (7) These results support the use of sunitinib as second-line therapy for patients with gastrointestinal stromal tumours. Additional clinical evaluation is needed, however. In first-line treatment of kidney cancer, it is preferable to wait for detailed results of the ongoing trial, especially effects on survival time, before judging the possible advantages and disadvantages of sunitinib compared to interferon alfa. In second-line treatment, sorafenib is better-assessed than sunitinib and should therefore be preferred, pending a direct comparison of the two drugs.     

Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma

The limited therapeutic options available for patients with metastatic papillary thyroid carcinomas (PTC) and follicular thyroid carcinomas (FTC) necessitates the development of novel therapies. Identification of somatic rearrangements of the tyrosine kinase domain of the RET gene in PTC have improved our understanding of thyroid tumorigenesis. Sunitinib is active against the RET kinase and has both antineoplastic and antiangiogenic properties. Its role in the treatment of patients with thyroid carcinoma has yet to be evaluated in clinical trials. Two patients with progressive metastatic thyroid carcinoma (case 1: PTC, and case 2: FTC) were enroled in a phase I clinical trial to evaluate positron emission tomography (PET) in the monitoring of response to sunitinib. Tumour biopsies and PET were performed at baseline and 4 weeks after the commencement of sunitinib. Activation of the RET kinase pathway was evaluated using immunohistochemistry (IHC) and western blot analysis of total phosphorylated tyrosine and downstream signalling targets of the RET pathway. Both patients demonstrated sustained clinical responses to sunitinib over a duration of 4 years. In case 1, (PTC) PET confirmed evidence of a partial metabolic response, and IHC and western blot analysis demonstrated inhibition of the RET kinase pathway posttreatment. In case 2, (FTC) PET confirmed stable disease after sunitinib. IHC staining of the tumour showed low total phosphorylated tyrosine staining at baseline which did not change after treatment. These case studies highlight potential activity of sunitinib in patients with metastatic thyroid carcinoma. Sunitinib seems to be a promising agent in the treatment of thyroid cancers and this requires validation in future clinical trials.     

甲状腺手术中甲状旁腺损伤的治疗体会

目的 探讨由于甲状腺手术而导致的甲状旁腺损伤的治疗体会.方法 选取该院收治的行甲状腺手术后并发甲状旁腺损伤的11例患者 病症较轻患者给予口服钙尔奇D片,病症较重患者静脉滴注葡萄糖酸钙溶液,结果 全部11例甲状旁腺损伤患者均没有造成永久性的甲状旁腺功能的异常,并且在接受治疗后其症状能基本消失并且随访未发现有复发征象 结论 在进行甲状腺手术中一定要小心操作,避免导致甲状旁腺损伤.但发现甲状旁腺损伤后应该及时合理使用钙剂和维生素D,并且积极开展治疗.     

Preclinical evaluation of sunitinib as single agent or in combination with chemotherapy in nasopharyngeal carcinoma

Purpose: Sunitinib is a multi-target receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors (PDGFR), c-kit and RET. Several of these RTKs are known to be involved in the progression of nasopharyngeal carcinoma (NPC). Here, we evaluated the preclinical activities of sunitinib in NPC. Method: We determined the basal level of total and phosphorylated PDGFR, c-kit and RET by immunoblotting in a panel of five NPC cell lines. The effect of sunitinib on NPC cell proliferation was evaluated by MTT assay. We further studied the effect of sunitinib on NPC cell cycle progression and apoptosis. We investigated the in vitro and in vivo activities of sunitinib as single agent and in combination with cisplatin or docetaxel in NPC cell lines and tumor xenografts. Results: Sunitinib exhibited dose-dependent growth inhibition in all NPC cell lines tested with IC₅₀ between 2–7.5 μM and maximum inhibition of over 97%. Sunitinib induced apoptosis and cell cycle arrest at G₀/G₁ phase. In vitro, sunitinib moderately enhanced the growth inhibition of cisplatin or docetaxel. Single agent sunitinib demonstrated significant growth inhibition, reduced microvessel density and caused extensive tumor necrosis in a NPC xenograft model. However, concurrent administration of sunitinib and docetaxel induced severe toxicity in mice without enhanced antitumor effect. Conclusions: Single agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. When combined with chemotherapy, sequential instead of concurrent administration schedule should be further explored.     

Comparing the efficacy of sunitinib with sorafenib in xenograft models of human hepatocellular carcinoma: mechanistic explanation

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.     

A combination of liposomal sunitinib plus liposomal irinotecan and liposome co-loaded with two drugs enhanced antitumor activity in PC12-bearing mouse

Pheochromocytomas are highly angiogenic neuroendocrine tumors. The side effects of treatment with cytotoxic agents frequently outweigh the benefits. Neuroendocrine tumors are highly angiogenic, dependent on vascular endothelial growth factor and receptor (VEGFR) activation. Sunitinib has antitumor and antiangiogenic activities that target VEGFRs. We investigated the antitumor activity of liposomal sunitinib and irinotecan alone and in combination. Liposomal sunitinib and irinotecan, and liposomes co-loaded with both drugs were prepared, and antitumor activity and biodistribution were examined in nude mice bearing PC12 tumors. Liposomal sunitinib increased in life span (ILS, 14.3%) compared with free sunitinib (?17.1% ILS) with moderate tumor growth suppression, whereas liposomal irinotecan suppressed tumor growth significantly without a survival benefit compared with free irinotecan (?21.7 and ?13.3% ILSs, respectively). The combination of liposomal sunitinib plus liposomal irinotecan, and liposomes co-loaded with both drugs, induced significant inhibition of tumor growth and increased life-span more than the combination of free drugs. Accumulation of irinotecan in tumors by the combination of the two liposomal drugs and liposomes co-loaded with both drugs was significantly increased compared with the combination of free drugs. This study provides novel formulations of sunitinib and irinotecan in combination for the treatment of pheochromocytoma.     

Targeting RET for thyroid cancer therapy

The limited efficacy of conventional treatments in progressive thyroid carcinomas indicates the need for new therapeutic options. Activating mutations of the receptor tyrosine kinase-encoding RET gene have been identified as driving oncogenic events in subsets of papillary (PTC) and medullary (MTC) thyroid carcinomas suggesting the interest of targeted therapy. The role of RET oncogenes and the encoded constitutively active oncoproteins as potential targets has been investigated by different strategies including gene therapy and pharmacological approaches, but targeted treatment for RET-driven cancers is not clinically available in current therapy. Small molecule tyrosine kinase inhibitors, including sorafenib, sunitinib, motesanib and vandetanib, which have already shown efficacy against other neoplastic diseases, are being evaluated in clinical trials for treatment of thyroid carcinomas. Most of them, also described as Ret inhibitors, are multi-kinase inhibitors with antiangiogenic activity related to inhibition of receptor tyrosine kinases, such as the vascular endothelial growth factor receptors. Preclinical evidence supports the relevance of Ret oncoproteins as therapeutic targets for a subset of thyroid neoplastic diseases and, although targeting the original causal genetic change may not be sufficient to control the disease efficiently, the available knowledge outlines therapeutic opportunities for exploiting Ret inhibition.     

长效糖皮质激素局部注射治疗儿童甲状腺功能亢进症疗效观察

目的；观察长效糖皮质激素甲状腺局部注射治疗儿童甲状腺功能亢进症的临床疗效。方法：16例甲亢患儿在抗甲状腺药物治疗的同时，加用醋酸去炎舒松-A甲状腺局部注射，比较治疗前后症状体征及甲状腺功能变化。结果：在治疗过程中，16例患儿症状体征改善，甲状腺缩小，甲状腺功能恢复正常，并趋于稳定，无反复现象，治疗结束后2年，随访到11例患儿其中10例甲亢症状持续缓解，甲状腺继续缩小，甲状腺功能保持正常。结论：长效糖皮质激素甲状腺局部注射，能有效控制儿童甲亢患者的症状体征及功能，且疗效持久，能作为抗甲状腺药物治疗的辅助治疗。