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。     

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.     

伊马替尼耐药晚期胃肠间质瘤治疗策略分析

目的 分析伊马替尼耐药晚期胃肠间质瘤的治疗策略.方法 回顾性分析本院2013年1月~2013年12月收治的伊马替尼耐药晚期胃肠间质瘤患者30例的临床治疗,观察治疗患者的方法 及疗效,分析治疗策略.结果 30例患者中,采用手术切除治疗7例,采用伊马替尼增量治疗11例,采用舒尼替尼治疗12例.随访可知,手术治疗7例患者OS中位时间(87.5±6.1)周;伊马替尼增量治疗11例OS中位时间(93.2±8.4)周;舒尼替尼治疗12例OS中位时间(90.5±7.7)周.结论 临床治疗伊马替尼耐药晚期胃肠间质瘤患者时可采用的治疗方法 比较多,应依据患者的实际情况选择恰当的治疗方式,提升治疗效果,延长患者生存期.     

吉非替尼治疗晚期非小细胞肺癌的疗效分析

目的 观察吉非替尼二线或二线以上方案治疗晚期非小细胞肺癌(NSCLC)的临床疗效.方法 126例晚期NSCLC患者口服吉非替尼250mg/天,直到疾病进展或不可耐受的毒副反应停药.结果 126例患者,总有效率为30.1%(38/126),疾病控制率为81.7%(103/126).有效患者中位缓解时间为6.6个月,全组中位肿瘤进展时间(TTP)为4.9个月,中位总生存时间为9.8个月,1年生存率为38.2%.腺癌患者有效率、生存时间及TTP均显著高于鳞癌患者,女性患者有效率和生存时间优于男性患者.脑转移患者有效率为50%.主要毒副反应为皮疹和腹泻,皮疹发生率最高(47.6%),但多数较轻并可逆.结论 吉非替尼作为二线及二线以上方案治疗晚期NSCLC安全有效,易为患者接受.     

帕尼单抗与舒尼替尼治疗晚期非小细胞肺癌的临床疗效比较

目的 对帕尼单抗和舒尼替尼在晚期非小细胞肺癌临床治疗中的疗效进行评估,并对二者的疗效进行比较分析。方法　将入选的80 例患者随机分为三组,对照组26 例、帕尼单抗组27 例、舒尼替尼组27 例。对照组采用多西他赛+ 顺铂进行治疗,帕尼单抗组和舒尼替尼组分别给予帕尼单抗、舒尼替尼进行治疗。对三组患者的治疗有效率、不良反应发生率、生存质量、无进展生存期和总体生存期等进行比较分析。结果　帕尼单抗组和舒尼替尼组患者的治疗有效率、病情控制率、生存质量、无进展生存期和总体生存期均显著高于对照组（P<0.05）,且舒尼替尼组患者的治疗有效率、病情控制率、生存质量、无进展生存期和总体生存期均高于帕尼单抗组。不良反应方面,帕尼单抗组患者乏力、腹泻、脱发、恶心呕吐、肝肾功能异常、白细胞减少、血红蛋白降低等毒副反应发生率显著低于对照组（P<0.05）,而舒尼替尼组除脱发外,其余不良反应发生率均显著高于对照组和帕尼单抗组（P<0.05）。结论　帕尼单抗和舒尼替尼用于晚期非小细胞肺癌临床治疗都能够取得一定的疗效,舒尼替尼的疗效更佳,但舒尼替尼易引发较为严重的不良反应。帕尼单抗和舒尼替尼的临床应用仍存在一定的问题,需要在提高疗效、降低毒副反应方面进行改善。     

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.     

舒尼替尼治疗伊马替尼耐药晚期胃肠间质瘤的药物经济学评价

目的:比较舒尼替尼和大剂量伊马替尼用于既往伊马替尼治疗耐药的晚期胃肠间质瘤患者的二线治疗的成本-效果。方法:基于Ⅲ期临床试验的研究数据,结合我国相关药物和不良反应治疗成本,利用TreeAge软件建立Markov模型,对两种用药方案进行成本-效果分析。结果:进口药组大剂量伊马替尼和舒尼替尼方案的成本-效果比分别为45 806.19元/质量调整生存月(QALM)和20 330.79元/QALM,计算得到增量成本-效果比超出意愿支付阈值,舒尼替尼为优势药物。国产药组大剂量伊马替尼和舒尼替尼方案的成本-效果比分别为5 855.50元/QALM和15 101.70元/QALM,伊马替尼为优势药物。敏感性分析的结果与成本-效果分析一致。结论:对于伊马替尼耐药的晚期胃肠间质瘤患者,进口药组舒尼替尼治疗比大剂量伊马替尼治疗具有更好的经济性,但在国产药组中大剂量伊马替尼比舒尼替尼治疗具有经济学优势。     

胃肠道间质瘤术后肝转移的临床分析

目的探讨胃肠间质瘤术后肝转移的治疗策略。方法回顾性分析2010年4月至2014年4月收治的16例GIST术后肝转移患者的临床资料、消融治疗及生存情况。结果 9例患者(56.3%)依然存活,其中5例(31.3%)无瘤生存,4例(25.0%)带瘤生存;1年、2年生存率分别为81.3%和56.3%。7例患者进行了微波消融,所有患者均接受伊马替尼400~600 mg/d治疗,耐药改用舒尼替尼治疗。随访期内微波消融组、未消融组中位生存时间分别为25.4、15.7个月。结论对于GIST术后肝转移病例应该首选靶向治疗,靶向治疗联合消融治疗可能是GIST术后肝转移的较佳治疗模式。     

安罗替尼治疗晚期非小细胞肺癌的疗效及安全性

目的评价安罗替尼用于晚期非小细胞肺癌(NSCLC)的疗效及安全性。方法回顾性分析经二线及以上治疗失败的晚期NSCLC患者40例,根据治疗方式不同分为安罗替尼组和对照组,每组20例。安罗替尼组每日口服安罗替尼12 mg,用药2周后停药1周,21 d为1个周期,直至疾病进展或出现无法耐受的不良反应。对照组接受最佳支持治疗。比较2组的疾病控制率(DCR)、无进展生存期(PFS)和总生存期(OS),记录患者不良反应发生情况,并评估多个临床特征与预后的关系。结果安罗替尼组部分缓解3例,疾病稳定11例,疾病进展6例,DCR优于对照组(70%vs.30%,P<0.05)。安罗替尼组中位PFS为2.8个月、中位OS为4.4个月,优于对照组的1.2个月和2个月(P<0.05)。性别、年龄、病理类型、分期、肝及脑转移等与预后无明显相关(P>0.05)。安罗替尼组不良反应包括手足综合征、乏力、纳差、咯血等,予以药物减量后症状可缓解。结论应用安罗替尼作为二线及以上治疗晚期NSCLC有较好的疗效,不良反应可耐受。     

舒尼替尼和索拉非尼序贯治疗转移性肾细胞癌 的成本效果分析

目的：评价舒尼替尼(sunitinib)和索拉非尼(sorafenib)对转移性肾细胞癌的两种不同序贯治疗方案即舒尼替尼一线治疗结合索拉非尼二线治疗(SUSO组)相对于索拉非尼一线治疗结合舒尼替尼二线治疗(SOSU组)的经济性。方法：本研究通过建立Markov模型评价两种方案的成本效果。主要终点指标包括无进展生命年(progression-free survival,PFS),总生命年(overall survival,OS)以及质量调整生命年(quality-adjusted life years,QALYs)。模型周期为6周,基线分析时间跨度设为5年,折现率设为3%。模型稳定性通过概率敏感性分析和单因素敏感性分析来检验。结果：5年模拟结果显示,SUSO组比SOSU组多获得0.3QALYs,0.34 OS以及0.56 PFS,SUSO组显著延长了OS和PFS,但成本高出132,243元。增量成本效果比显示QALY的ICER为437,870元,基本不具备经济性。但敏感性分析表明SUSO组在短期治疗上比SOSU组带来更长的PFS的同时也具备经济性。结论：除非人均GDP约达到13,700美元,舒尼替尼一线治疗结合索拉非尼二线治疗在5年期治疗上相比索拉非尼一线治疗结合舒尼替尼二线治疗不具备经济性。但是,舒尼替尼一线治疗在短期治疗上具备明显优势,从经济型角度出发,应当考虑除索拉非尼以外的其他药物作为二线治疗的药物。     

Sunitinib

Sunitinib and its active metabolite (SU012662) are selective inhibitors of multiple receptor tyrosine kinases associated with tumour growth and angiogenesis. The clinical efficacy of oral sunitinib has been demonstrated in patients with advanced gastrointestinal stromal tumours (GIST). In a phase III, randomised, double-blind, placebo-controlled, multicentre trial in patients with metastatic and/or unresectable GIST following unsuccessful imatinib therapy, the median time to tumour progression and median progression-free survival time were > or =4-fold longer in patients receiving sunitinib 50 mg/day than in those receiving placebo, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week rest period. Sunitinib also exhibited antitumour activity in patients with advanced renal cell carcinoma (RCC) following unsuccessful cytokine therapy. In two multicentre, single-arm, phase II clinical trials in patients with cytokine-refractory metastatic RCC, partial responses were reported in 40% and 43% of patients receiving sunitinib 50 mg/day for 4 weeks followed by 2 weeks without treatment in 6-week cycles; 27% and 22% of patients achieved stable disease for > or =3 months. Sunitinib was more effective than interferon-alpha as a first-line therapy in patients with metastatic RCC. In a large, well designed, phase III trial in previously untreated patients, progression-free survival was significantly longer in patients receiving sunitinib 50 mg/day in 6-week cycles (4 weeks of treatment followed by a 2-week rest period) compared with those receiving interferon-alpha 9MU three times weekly (47.3 vs 24.9 weeks). In general, sunitinib was well tolerated in patients with GIST and RCC, with adverse events usually being of mild or moderate severity.     

Sunitinib as a second-line therapy for advanced GISTs after failure of imatinib: relationship between efficacy and tumor genotype in Korean patients

Background To assess the efficacy and safety of sunitinib with regards to primary genotypes of tumor in Korean patients with advanced gastrointestinal stromal tumors (GISTs) who failed an initial therapy of imatinib. Methods Clinical data were collected from 88 consecutive patients with metastatic/unresectable GISTs treated with sunitinib at the Asan Medical Center. Results The median time-to-progression (TTP) and overall survival (OS) times were 7.1 months and 17.6 months, respectively. Of the 74 patients tested for KIT (exons 9, 11, 13, 17) and PDGFRA (exons 12 and 18), patients with KIT exon 9 mutant GIST (n = 11, 14.9%) showed numerically better clinical benefit (objective response or stable disease ≥24 weeks) rate (63.6% vs 46.8%, p = 0.504) and TTP (median 13.6 mo vs 6.9 mo, p = 0.631) than those with KIT exon 11 mutant GIST (n = 47, 63.5%). The most common grade 3/4 adverse events included neutropenia (34.1%), thrombocytopenia (33.0%) and hand-foot skin reaction (25.0%). Conclusions Sunitinib is an effective and safe second-line therapy for Korean patients with advanced GIST. The superior efficacy of sunitinib against GISTs with KIT exon 9 mutations appears to be similar in Korean patients to Western experience although statistical significance was not secured.     

The safety of regorafenib for the treatment of gastrointestinal stromal tumors

Introduction: The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose.

Areas covered: Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST – Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression-free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade ≥3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST.

Expert opinion: Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable.     

Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate

Purpose: To establish a recommended sunitinib dosing schedule in Japanese patients with imatinib-resistant/intolerant gastrointestinal stromal tumor (GIST) and to evaluate the efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of sunitinib using this schedule. Patients and methods: In the phase I part of this open-label phase I/II trial, Japanese GIST patients received 25, 50, or 75 mg/day of sunitinib on Schedule 4/2 (4 weeks on treatment; 2 weeks off treatment) following imatinib failure. In phase II, patients received the recommended (maximum tolerated) dose on this schedule; the primary endpoint was clinical benefit rate (CBR; percent objective responses or stable disease [SD] ≥22 weeks). Additional efficacy, safety, pharmacokinetic, and biomarker analyses were performed. Results: In phase I (12 patients), the recommended dose was determined to be 50 mg/day. Sunitinib pharmacokinetics were similar to those observed in studies with Western patients. In the phase II part (36 patients), the CBR was 39% (95% CI: 23–57%; 11% partial responses, 28% SD ≥22 weeks). The most common treatment-related non-hematologic adverse events (AEs) were hand–foot syndrome (86%) and fatigue (67%). A trend towards a correlation between decreases from baseline in plasma soluble KIT levels and improved CB was found. Conclusions: The pharmacokinetics observed and clinical outcomes achieved in Japanese GIST patients on sunitinib (50 mg/day, Schedule 4/2) after imatinib failure appeared similar to those of Western patients in previous sunitinib trials. Although some serious AEs were observed, AEs were generally manageable using dose interruption/modification and/or standard medical treatments.     

A chart review of patients with early stage mycosis fungoides treated with psoralen plus UVA (PUVA)

PUVA has become a common form of treatment for early stage mycosis fungoides (MF). The purpose of this retrospective study was to review the clinical data of 51 MF patients (96% stage IA or IB) treated with PUVA at the Mt. Sinai MF clinic over the past 20 years. We analyzed the efficacy, safety, and remission duration in patients who were treated with a modified PUVA regimen. Forty-four of 51 patients (86%) achieved complete clinical clearing for all stages after initial PUVA therapy. The mean duration of remission with maintenance treatment was more than 27 months (range: 3 weeks to 130 months). The mean duration of disease from start of first PUVA therapy for all patients was 4.8 years (range: 0.7 to 130 months). PUVA for patients with early-stage MF is a safe and effective therapeutic modality with prolonged disease-free remissions, however, PUVA alone was not adequate for more advanced disease.     

Impressive long-term disease stabilization by nilotinib in two pretreated patients with KIT/PDGFRA wild-type metastatic gastrointestinal stromal tumours

KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumours (GISTs) showed a response rate to imatinib ranging from 0 to 25%. Nilotinib is a new-generation tyrosine kinase inhibitor that has demonstrated clinical activity in pretreated GIST patients. At present, no correlation between nilotinib activity and clinical/pathological/molecular features is available. We report on two WT GIST patients resistant to imatinib and sunitinib, and enrolled in the CAMN107A2201 study who achieved an impressive disease control by nilotinib. Both patients have germ-line mutations in the SDHA gene. In April 2004, a 39-year-old woman presented gastric GIST with multiple liver metastases and was treated with imatinib 400 mg/day, followed by imatinib 800 mg/day and then sunitinib. In August 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. In March 2005, a 27-year-old woman started imatinib 600 mg/day and then sunitinib for gastric GIST with multiple liver and lung metastases. In October 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. One patient still showed stable disease after 46 months of treatment according to the Response Evaluation Criteria In Solid Tumors, and a partial response after 9 months according to Choi's criteria. The other patient still showed stable disease after 42 months according to Response Evaluation Criteria In Solid Tumors. At present, they continue to receive nilotinib. We report very long-term disease stabilization under nilotinib treatment in two pretreated WT GIST patients. In-vitro studies and clinical analyses are warranted to evaluate a potential correlation between nilotinib activity and WT genotype or other clinical/pathological features.     

Is there something other than imatinib mesilate in therapeutic options for GIST?

INTRODUCTION: In the last decade, the introduction of imatinib mesilate into the clinical practice has resulted in a dramatic improvement in the treatment of gastrointestinal stromal tumor (GIST). Nowadays, the median overall survival in patients with advanced disease has increased to 5 years, while recent Phase III trials demonstrated that imatinib mesilate can be successfully employed as adjuvant therapy in patients at significant risk of recurrence. Despite these good results, the emergence of secondary resistance represents the main cause of treatment failure. In recent years, many efforts have been made in search of drugs to overcome imatinib mesilate resistance; some of these have been employed as second-line treatment or salvage therapy. AREAS COVERED: Summarized and investigated in this paper are the results obtained by imatinib mesilate in advanced and adjuvant setting, the role of sunitinib malate as second-line therapy in imatinib mesilate-resistant patients and the clinical results concerning new drugs, mainly tyrosine-kinase inhibitors. EXPERT OPINION: Current research on novel therapeutic agents, as third-line treatments in GIST, is ongoing. However, despite the promising results obtained with the new molecules, imatinib mesilate remains the cornerstone in the medical treatment of GIST and to date no other drugs can replace it.     

Experience in the use of sunitinib given as a single agent in metastatic chemoresistant and castration-resistant prostate cancer patients

Objective: Vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) correlate with poor prognosis in castration-resistant prostate cancer (CRPC). Sunitinib has shown activity in CRPC and at the time of this analysis there was no standard therapy for docetaxel-refractory CRPC.

Methods: We present a case series data collection of 19 patients with a median age of 73 years, CRPC and rising prostate-specific antigen (PSA). Patients received sunitinib 37.5 mg continuous daily dose. One cycle comprised a 4-week period. Patients were evaluated by CT scan every 8 weeks and PSA was monitored every 4 weeks.

Results: Median Eastern Cooperative Oncology Group (ECOG) performance status score was 2. Patients received a median of two previous treatment lines for the hormone-refractory setting. Baseline median PSA was 280 ng/ml. Patients received a median of 16 weeks of therapy (4 – 48+). One patient achieved a partial response (5%) and 12 (66.7%) achieved stable disease for at least 3 months according to RECIST criteria. Median progression-free survival was 4 months. PSA declined > 50% in 5/19 (26.3%) and stabilized in 7/19 (37%) patients. Frequent adverse events were grade 3 asthenia (21%), grade 3 diarrhea (10%) and grade 3 hand-foot syndrome (15.7%).

Conclusions: Activity with sunitinib was observed in highly pretreated docetaxel-refractory CRPC with acceptable tolerability. Additional studies should confirm the role of antiangiogenic agents in this setting.     

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-na?ve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P < 0.001). Median overall survival was 26.4 versus 21.8 months, respectively (P = 0.0510). In preclinical and phase I/II studies, sunitinib inhibits tyrosine kinase inhibitors in a dose-dependent manner, suggesting a correlation between increasing exposure and greater response. A pharmacokinetics/pharmacodynamics meta-analysis investigating the relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.     

A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma

Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promising activity in some tumors. In this trial, 10 patients with metastatic renal cell carcinoma refractory to previous therapy with sunitinib or sorafenib (median age 61 years, 80% performance status 0, 60% intermediate MSKCC risk classification) received tandutinib 500 mg bid daily with RECIST-defined response as the primary endpoint and progression-free survival (PFS) and overall survival (OS) as secondary endpoints. No patient had more than 2 cycles of therapy and 50% of patients only received 1 cycle with 70% of patients discontinuing for progressive disease and 30% for toxicity. Tandutinib was not well tolerated with dose reduction in 60% of patients due to adverse events. The most common grade 3 toxicity was fatigue (30%). Tandutinib had no clinical activity and due to the excessive toxicity should not be developed further in patients with sunitinib or sorafenib-refractory metastatic renal cell carcinoma.