舒尼替尼和索拉非尼一线治疗转移性肾细胞癌的疗效评估和比较

目的：探讨舒尼替尼和索拉非尼一线治疗转移性肾细胞癌的疗效。方法：回顾性分析2009年6月至2017年6月149例经舒尼替尼治疗、112例经索拉非尼治疗的转移性肾细胞癌患者的临床资料。治疗方案：舒尼替尼50 mg,每日1次,口服,治疗4周停2周,6周为1个周期;索拉非尼400 mg,每日2次,口服,1个月为1个周期。每1个周期进行1次安全性评估,每2个周期进行1次疗效评价。索拉非尼治疗患者病情进展而耐受良好时,增加药物剂量。结果：索拉非尼、舒尼替尼治疗后患者的中位无进展生存时间(progression free survival, PFS)分别为15.5、20个月,中位总生存时间(overall survival, OS)分别为31.5、36个月,差异均无统计学意义。随访3~96个月,索拉非尼组疾病控制率为63.4%,舒尼替尼组疾病控制率为83.2%。舒尼替尼疾病控制率优于索拉非尼(P<0.001)。两种药物的不良反应均可控且患者可耐受。结论：舒尼替尼和索拉非尼治疗转移性肾细胞癌疗效均较好,舒尼替尼疾病控制率更优,两种药物的不良反应均可控。     

舒尼替尼治疗晚期肾细胞癌的临床应用

目的评价舒尼替尼治疗晚期肾细胞癌的疗效和安全性。方法晚期肾细胞癌患者19例,男16例,女3例,中位年龄54（35～70）岁,随访时间2008年8月至2010年8月。原发肾脏病灶手术切除17例,穿刺病理证实2例。肾透明细胞癌17例,肾乳头状细胞癌2例。治疗方案：舒尼替尼50mg,每天1次,4/2方案,治疗4周停2周为1个治疗周期;至少每2个周期行影像学检查以确定疗效。结果随访时间3～22个月,可评价疗效18例,1例因患者经济情况停药。11例患者仍在接受舒尼替尼治疗,1例患者因肿瘤进展停药,6例患者因肿瘤进展死亡。中低危患者14例,中位疾病无进展时间（PFS）18个月,尚未测出中位生存时间。高危患者4例,中位PFS6个月,中位生存时间8.5个月。根据实体瘤评价标准（RECIST）进行疗效评价,共16例患者服药超过2个周期,2个周期评价部分缓解（PR）2例（12.5%）;疾病稳定（SD）14例（87.5%）。共10例患者服药超过4个周期,4个周期PR1例（10.0%）;SD6例（60.0%）;疾病进展3例（30.0%）。常见不良反应包括手足皮肤反应、口腔溃疡、高血压、味觉改变、乏力、白细胞降低和血小板下降等,发生的Ⅲ级不良反应为手足反应2例（11.1%）、呕吐1例（5.5%）、白细胞降低1例（5.5%）、血小板降低1例（5.5%）、浮肿1例（5.5%）。通过对症支持及减量,不良反应可以控制并耐受。结论舒尼替尼治疗晚期肾细胞癌的控制率较高,大部分不良反应患者可耐受,部分严重不良反应需要医疗干预。     

舒尼替尼致转移性肾细胞癌患者甲状腺功能异常的临床分析

目的 总结接受舒尼替尼治疗的转移性肾细胞癌患者的甲状腺功能变化规律,评价舒尼替尼对甲状腺功能的影响.方法 前瞻性收集北京大学第一医院泌尿外科2008 年6 月至2010 年4 月37 例转移性肾细胞癌接受舒尼替尼治疗的患者的临床资料,其中22 例患者于基线及每个治疗周期第28 天进行甲状腺功能检测.对甲状腺功能异常发生情况进行分析.结果 22 例患者接受舒尼替尼的中位治疗时间为7 个周期(10.5 个月),共18 例(81.8%)患者出现甲状腺功能减低,其中亚临床甲状腺功能减低14 例(63.6%),临床甲状腺功能减低4 例(18.2%),予左旋甲状腺素片替代治疗;6 例(27.3%)患者出现一过性亚临床甲状腺毒症后转为甲状腺功能减退,无持续甲状腺功能亢进患者.甲状腺功能减低的风险随舒尼替尼用药时间延长而增加,出现甲状腺功能减退的中位时间为3 个周期(1 ～7个周期).治疗3 个周期内,50.0%(11/22 例)的患者出现甲状腺功能减退;4 ～6个周期时,约72.7%(16/22 例)患者出现甲状腺功能减退.结论 舒尼替尼致甲状腺功能减退的发生率较高,程度可较严重,应引起临床重视.舒尼替尼相关性甲状腺功能减退可以用激素替代进行治疗,因此应避免舒尼替尼减量或停药.     

护理干预在晚期肾细胞癌患者不良反应预防中的应用

目的:探讨护理干预在晚期肾细胞癌患者不良反应预防中的应用方法。方法:将40例晚期肾细胞癌患者随机分为研究组和对照组各20例。对照组术后2周开始进行舒尼替尼靶向治疗及常规护理;研究组治疗前1周给予护理干预,其余措施同对照组。比较两组不良反应发生情况。结果:两组治疗第2、3周期的Ⅲ度手足综合征、恶心、呕吐发生情况比较差异有统计学意义(P<0.05)。结论:对晚期肾细胞癌应用舒尼替尼治疗患者给予护理干预,可减少不良反应发生,帮助顺利完成治疗。     

低剂量舒尼替尼辅助治疗高危肾癌术后的疗效观察

肾细胞癌（RCC）是起源于肾实质泌尿小管上皮系统的恶性肿瘤,占肾脏恶性肿瘤的80%~90%,手术能治愈大部分早期患者,但仍有30%的患者术后1~2年出现复发,特别是术前肿瘤已侵犯肾静脉、肾上腺及区域淋巴结转移者,术后复发率更高达35%~65%［1］,舒尼替尼作为靶向治疗药物,治疗转移性肾癌的有效性已被Ⅱ期和Ⅲ期临床实验验证［2,3］,对于高危肾癌,术后尚无标准辅助治疗方案,舒尼替尼辅助治疗预防进展性肾癌术后的复发和转移,其远期疗效及预防剂量尚无参照,2010年8月至2012年10月间本科对45例进展性肾癌术后患者予以舒尼替尼辅助治疗,以此初步探讨舒尼替尼对进展性肾癌治疗的疗效和预防剂量。     

依维莫司在转移性肾细胞癌靶向药物序贯治疗中的应用

肾细胞癌起源于近曲小管上皮,以透明细胞癌为主。血管内皮生长因子（vascular endothelial growth factor,VEGF）和哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）通路的活化导致肿瘤血管生成增加,在肾癌转移中起到关键作用。目前已有多种针对VEGF和mTOR信号通路的靶向药物被批准用于治疗转移性肾细胞癌（metastatic renal cell carcinoma,mRCC）患者,包括血管内皮生长因子受体-酪氨酸激酶抑制剂（VEGFR-TKI）如舒尼替尼、     

晚期肾细胞癌靶向药物治疗后孤立转移灶手术切除的疗效

  目的  探讨靶向药物治疗的转移性肾细胞癌患者远处孤立转移病灶行手术切除的疗效。  方法  回顾性收集2007年12月至2013年12月在北京协和医院接受靶向药物治疗的126例转移性肾细胞癌患者资料, 其中16例对远处孤立转移灶予以手术切除。患者均有明确的肾细胞癌病理诊断, 口服靶向药物索拉非尼、舒尼替尼或依维莫司, 直至孤立转移灶稳定且评估为可切除。对手术治疗的安全性和远期效果进行评价。  结果  接受远处孤立转移灶切除术的16例患者中, 男11例, 女5例, 中位年龄51岁(37~72岁); 其中肾透明细胞癌14例, 肾乳头状细胞癌2例; 肺转移5例, 骨转移2例, 肾上腺转移5例, 脑转移2例, 肝转移1例, 腹壁转移1例。患者围术期均恢复良好, 无严重并发症发生。术后肿瘤相关症状明显缓解, 一般情况有所好转。16例患者1、3、5年生存率分别为75.0%、43.8%和31.3%。无手术相关的死亡。  结论  经靶向药物治疗的晚期肾细胞癌患者有远处孤立转移灶时可从手术治疗中获益, 取得较长时间生存。     

肾嫌色细胞癌的临床特点及微创外科手术治疗

目的研究肾嫌色细胞癌的临床表现、诊断要点、治疗方法及疗效。方法回顾性分析2008～2010年期间经后腹腔镜微创手术治疗,病理确诊肾嫌色细胞(ChRCC)的11例患者,对其临床症状、影像学特点、病理及免疫学表现进行总结,对其预后进行随访跟踪评估。结果 11例患者的影像学均无明显特征性的表现,依靠病理确诊,具有相对特异的免疫组化指标,11例患者全部按时随访,随访时间6～30个月,平均13个月。1例T2N0M1患者术后1周立即开始给予舒尼替尼进行靶向药物治疗,9月后复查腰椎MRI病灶评估SD。余10例患者未见肿瘤局部复发或转移灶。预后良好。结论微创手术是早期肾嫌色细胞癌的首选治疗方式,靶向药物治疗对中晚期患者具有确切疗效。     

索拉非尼治疗晚期肾透明细胞癌的临床观察

目的观察索拉非尼治疗晚期肾癌的疗效和安全性。方法 22例晚期转移性肾透明细胞癌患者给予单药口服索拉非尼治疗9～23个月,每8周评定疗效,并登记、处理不良反应。结果部分缓解(PR)1例、疾病稳定(SD)15例、疾病进展(PD)4例、死亡2例,无完全缓解(CR)病例。主要不良反应有手足综合征、胃肠道反应及血压升高等。结论索拉非尼能够稳定病情,延长晚期RCC患者无进展生存时间,且毒副反应轻,耐受性好。     

阿西替尼治疗转移性肾细胞癌的不良反应及护理

目的总结阿西替尼治疗转移性肾细胞癌患者所致不良反应的观察要点及相应的护理措施。方法对我院16例转移性肾细胞癌患者给予口服阿西替尼治疗,针对可能出现的不良反应给予预防性的健康指导,密切观察患者用药过程,针对出现的不良反应及时给予对症治疗及护理。结果 16例患者口服药物后,不良反应主要表现为谷丙转氨酶升高及促甲状腺激素升高、皮肤毒性、高血压、蛋白尿、腹泻等,其中轻、中度不良反应较多,经给予患者合理的护理措施,无1例患者由于不良反应退出治疗。结论阿西替尼治疗转移性肾细胞癌不良反应较多,但通过及时有效的治疗及护理,药物毒性可得到有效控制,患者耐受性良好。     

A cost‐effectiveness analysis of sunitinib in patients with metastatic renal cell carcinoma intolerant to or experiencing disease progression on immunotherapy: perspective of the Spanish National Health System

Aim: To investigate the cost‐effectiveness of sunitinib (50 mg/day, schedule 4/2) vs. best supportive care (BSC) in patients with cytokine‐refractory metastatic renal cell carcinoma (mRCC), from the perspective of the Spanish National Health Service. Material and Methods: A Markov model compared the cost‐effectiveness (taking into account drugs; medical visits; laboratory tests; X‐rays; terminal care; adverse event management) of sunitinib and BSC across three disease states: no progression, survival with progression and death from mRCC or other causes. Results: The monthly incremental cost‐effectiveness ratio (ICER) values for sunitinib treatment were €6073/progression‐free survival month, €25 199/life years and €34 196/quality‐adjusted life years (QALY) gained. In 95% of cases, the ICER/QALY values were below the accepted €45 000/QALY threshold. Efficacy and cost of sunitinib had the greatest impact on cost‐effectiveness. Conclusion: Sunitinib has a good cost‐effectiveness profile in mRCC. The cost per life year and QALY gained is affordable according to current effectiveness thresholds in developed countries.     

Sunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors

BACKGROUND: Sunitinib was approved by the US Food and Drug Administration (FDA) on January 26, 2006, for the treatment of metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST) in patients who have failed to respond to imatinib or were unable to tolerate it. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of sunitinib; potential drug interactions; and the results of clinical trials evaluating its efficacy and tolerability. METHODS: Pertinent literature was identified by searches of MEDLINE (1966-January 31, 2007), the American Society of Clinical Oncology abstracts database (2000-2007 annual meetings/symposia and previous meetings), and the FDA Web site (October 2006). Search terms included, but were not limited to, sunitinib, SUl1248, renal cell carcinoma, gastrointestinal stromal tumor, pharmacology, pharmacokinetic, adverse events, and clinical trial. Additional publications were found by scanning the reference lists of the identified articles. RESULTS: Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors. Its Tmax is reached within 6 to 12 hours, and food does not appear to affect its bioavailability. Sunitinib is metabolized by cytochrome P450 (CYP) 3A4 to an active metabolite, SU12662, which is further metabolized by CYP3A4 to an inactive moiety. The parent compound and active metabolite have similar biochemical activity and potency and reach similar plasma concentrations. Sunitinib and SU12662 have a tl/2 of 40 to 60 hours and 80 to 110 hours, respectively. Steady-state concentrations of both active entities are reached after 10 to 14 days of therapy. In a Phase III trial comparing sunitinib with interferon-alfa (IFN-00 as first-line therapy for mRCC, sunitinib was associated with a median progression-free survival of 11 months, compared with 5 months with IFN-cz (P < 0.001). A randomized, double-blind, placebo-controlled trial evaluating sunitinib as second-line therapy for GIST found a median time to progression of 28.9 weeks in the sunitinib arm, compared with 7 weeks in the placebo arm (hazard ratio = 0.28; P < 0.001). In Phase II trials, sunitinib also had anti-tumor activity in patients with breast cancer, neuroendocrine tumors, and non-small cell lung cancer. Further evaluation in these tumors, as well as in patients with acute myelogenous leukemia, may lead to expanded indications. The approved dose of sunitinib is 50 mg/d PO for 4 weeks, followed by a 2-week rest; this pattern is repeated until tumor progression or the occurrence of intolerable adverse effects. The most common clinical toxicities attributable to sunitinib include diarrhea, mucositis/stomatitis, hypertension, rash, skin discoloration, and altered taste, whereas commonly occurring laboratory abnormalities have been seen in association with gastrointestinal toxicity, renal toxicity, and hematologic toxicity. Of grade 3/4 toxicities occurring with sunitinib (which are relatively uncommon [<10%]), those that are clinically important include hypertension, diarrhea, fatigue, and hand-foot syndrome. CONCLUSIONS: Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of mRCC and GIST. Evidence for long-term clinical benefit in renal cell cancer and other tumors awaits the results of ongoing trials.     

Drug monitoring of sunitinib in patients with advanced solid tumors: a monocentric observational French study

Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3–4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients treated with sunitinib were prospectively monitored between days 21 and 28 of the first cycle, then monthly until disease progression. At each consultation, the composite AUC_?,ss (sunitinib + active metabolite SU12662) was assayed. The decisions taken during each consultation were matched with AUC_?,ss and compared to the decisional algorithm based on TDM. A total of 105 cancer patients and 288 consultations were matched with the closest AUC_?,ss measurement. The majority (60%) of the patients had metastatic renal clear‐cell carcinoma (mRCC). Fifty‐five (52%) patients experienced grade 3–4 toxicity. Multivariate analysis identified composite AUC_?,ss as a parameter independently associated with grade 3–4 toxicity (P < 0.0001). Using the ROC curve, the threshold value of composite AUC_?,ss predicting grade ≥3 toxicity was 2150 ng/mL/h (CI 95%, 0.6–0.79%; P < 0.0001). At disease progression in patients with mRCC, AUC_?,ss tended to be lower than the one assayed during the first cycle (1678 vs. 2004 ng/mL/h, respectively, P = 0.072). TDM could have changed the medical decision for sunitinib dosing in 30% of patients at the first cycle of treatment, and in 46% of the patients over the whole treatment course. TDM is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure at the time of disease progression.     

瘤内注射重组溶瘤病毒联合FOLFOX-4方案治疗晚期肝癌

目的观察和评价超声引导下瘤体内注射重组溶瘤病毒（H101）联合FOLFOX-4方案治疗晚期肝癌的疗效及安全性。方法：22例晚期原发性肝癌患者,采用超声引导下肝内瘤体内注射重组溶瘤病毒（H101）联合FOLFOX4方案进行治疗,分别以RECIST标准和NCICTC标准观察和评价其疗效和毒性。结果：共22例患者,有20例可以评价客观疗效,其中获得PR5例,SD7例,PD8例;患者的肿瘤进展时间（TTP）为1．2-6．1个月,中位,TTP 3．1个月。22例中,11例临床症状和KPS评分有明显改善,AFP阳性的17例患者中,有11例下降,5例明显下降（AFP下降超过原始基线的1／2）。22例患者均可评价毒性,主要不良反应为轻、中度的发热（45．6％）,白细胞减少（44．5％）和腹泻（33．7％）。结论：本试验证实,瘤体内注射重组溶瘤病毒（H101）联合FOLFOX4方案治疗国人晚期原发性肝癌,疗效确切;较单纯全身化疗有更高的有效率;安全性高,不良反应较轻,患者易于耐受,值得进一步研究试用。     

抗血管生成药物治疗晚期肾癌疗效的Meta分析

目的系统评价干扰素和靶向血管内皮生长因子（VEGF）抗血管生成药物（索拉非尼、舒尼替尼和贝伐单抗）治疗晚期肾癌的疗效。方法计算机检索MEDLINE、EMbase、中国生物医学期刊文献数据库、中文科技期刊数据库,收集1979～2009年国内外公开发表的抗血管生成药物与干扰素比较的随机对照试验。按Cochrane系统评价方法评价纳入研究质量和提取有效数据,并用RevMan4.2软件进行Meta分析。结果最终纳入4个随机对照试验,共2320例。Meta分析结果显示：①与干扰素相比,血管生成抑制剂单用能有效抑制晚期肾癌进展[OR=0.38,95%CI（0.29,0.51）,P〈0.01]和控制晚期肾癌[OR=2.53,95%CI（1.87,3.43）,P〈0.01],但两者对治疗肾癌的总有效率差异无统计学意义[OR=1.97,95%CI（0.20,19.57）,P=0.56];②与单用干扰素相比,血管生成抑制剂联合干扰素能有效抑制晚期肾癌进展[OR=0.67,95%CI（0.53,0.84）,P=0.0005]和控制晚期肾癌[OR=2.14,95%CI（1.65,2.78）,P〈0.01],显著提高晚期肾癌治疗的总有效率[OR=2.65,95%CI（1.94,3.61）,P〈0.01];③血管生成抑制剂与干扰素各自单用治疗发生严重不良事件的可能性相当[OR=1.98,95%CI（0.90,4.34）,P=0.09],但二者联用更易发生严重不良事件[OR=2.63,95%CI（2.09,3.31）,P〈0.01]。结论与干扰素相比,血管生成抑制剂单用能更有效抑制肿瘤进展,控制晚期肾癌;血管生成抑制剂与干扰素联用能显著提高肿瘤治疗总有效率,但也伴随着更多药物相关严重不良事件的发生。     

Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

Background

New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had progressed on sunitinib and/or sorafenib. The only targeted therapy for mRCC currently reimbursed in Serbia is sunitinib.

Objective

The aim of this study was to estimate the cost-effectiveness and the budget impact of the introduction of everolimus in Serbia in comparison to best supportive care, for mRCC patients refractory to sunitinib.

Methods

A Markov model was designed corresponding with Serbian treatment protocols. A health care payer perspective was taken, including direct costs only. Treated and untreated cohorts were followed up over 18 cycles, each cycle lasting 8 weeks, which covered the lifetime horizon of mRCC patients refractory to the first-line treatment. Annual discounted rates of 1.5% for effectiveness and 3% for costs were applied. Transitions between health states were modeled by time-dependent probabilities extracted from published Kaplan-Meier curves of PFS and overall survival (OS). Utility values were obtained from the appraisals of other mRCC treatments. One-way and probabilistic sensitivity analyses were done to test the robustness and uncertainty of the base–case estimate. Lastly, the potential impacts of everolimus on the overall health care expenditures on annual and 4-year bases were estimated in the budget-impact analysis.

Results

The incremental cost-effectiveness ratio for everolimus was estimated at €86,978 per quality-adjusted life-year. Sensitivity analysis identified the hazard multiplier, a statistical approximator of OS gain, as the main driver of everolimus cost-effectiveness. Furthermore, probabilistic sensitivity analyses revealed a wide 95% CI around the base–case incremental cost-effectiveness ratio estimate (€32,594–€425,258 per quality-adjusted life-year). Finally, an average annual budgetary impact of everolimus in first 4 years after its potential reimbursement would be around €270,000, contributing to <1% of the total budget in Serbian oncology.

Conclusions

Everolimus as a second-line treatment of mRCC is not likely to be a cost-effective option under the present conditions in Serbia, with a relatively limited impact on its budget in oncology. A major constraint on the estimation of the cost-effectiveness of everolimus relates to the uncertainty around the everolimus effect on extending OS. However, prior to a final decision on the acceptance/rejection of everolimus, reassessment of the whole therapeutic group might be needed to construct an economically rational treatment strategy within the mRCC field.     

肾透明细胞癌组织中B7-H3的表达及意义

目的评价B7-H3在肾透明细胞癌组织中的表达及其与预后的关系。方法采用免疫组化方法检测154例肾透明细胞癌患者肿瘤标本中B7-H3的表达,分析其与患者临床病理因素以及术后生存时间之间的关系。结果 154例患者中,B7-H3阳性28例（18.18%）,其中无瘤生存6例,复发7例,死亡15例,至最后随访日期,总生存期（OS）为（19.71±20.32）个月;B7-H3阴性126例（81.82%）,其中无瘤生存119例,复发3例,死亡4例,OS为（33.47±18.32）个月,两者比较差异有统计学意义（P〈0.05）。单因素分析表明,B7-H3阳性表达患者在肿瘤大小、原发肿瘤分期、区域淋巴结转移、远处转移、临床分期等方面较阴性表达患者有明显差异,B7-H3阳性表达患者术后生存时间较阴性表达患者明显缩短。结论 B7-H3的表达可能与肾透明细胞癌的转移和进展有关,可以作为肾透明细胞癌的一个独立预后因素。     

Laparoscopic cytoreductive nephrectomy with cytokine therapy for metastatic renal cell carcinomas compared with open nephrectomy

Introduction: We retrospectively reviewed and compared the operation records and long‐term results of patients with metastatic renal cell carcinoma (mRCC) who underwent laparoscopic cytoreductive nephrectomy and those who underwent open procedure. Methods: A total of 75 patients with mRCC who underwent cytoreductive nephrectomy between 1997 and 2007 were studied: 23 patients in the laparoscopy group (LCN group) and 52 in the open group (OCN group). Most patients received interferon‐based cytokine therapy after surgery. Patients with tumor thrombus in the inferior vena cava were excluded from this study. Results: Operating time in the LCN group was significantly longer than in the OCN group (320.3 min vs 269.6 min, P=0.049). Blood loss was less in the LCN group (527.8 ml) than in the OCN group (1372.3 ml, P=0.072). Convalescence was shorter in the LCN group (18.1 d) than in the OCN group (32.9 d, P<0.0001). Median follow‐up periods were 15 months (range 2–110 months) and 17 months (range 1–103 months) in the LCN group and OCN group, respectively. There was no statistically significant difference between the two groups with regard to disease‐specific patient survival and progression‐free survival. Conclusions: Laparoscopic cytoreductive nephrectomy is a feasible alternative for patients with mRCC because its benefits include less blood loss and shorter convalescence. In addition, the long‐term oncological results of laparoscopic cytoreductive nephrectomy are comparable to those of the open procedure.