| | 肾癌专题 >> TORISEL® (temsirolimus) 用于TKI无效肾癌 |
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| TORISEL® (temsirolimus) 用于TKI无效肾癌 | |
| 德国维克特（Weikert）报告，29例转移性肾细胞癌患者在至少一种酪氨酸激酶抑制剂（TKI）治疗失败后，接受temsirolimus治疗，无进展生存（PFS）期和总生存（OS）期分别达5.1个月和18.0个月，疾病控制率为55%，毒性反应可接受。 Temsirolimus On this page •Temsirolimus •How temsirolimus works •How it is given •Possible side effects •Less common side effects •Additional information •References This information is about a drug called temsirolimus (Torisel®). It may be used to treat certain people with kidney cancer| (also known as renal cancer) which has spread. This is known as advanced cancer. If you have any further questions you can ask your doctor or nurse at the hospital where you’re having your treatment or speak to one of our cancer support specialists|. Temsirolimus Back to topAlthough temsirolimus is licensed and can be prescribed in the UK, the National Institute for Health and Clinical Excellence (NICE) has recommended that it shouldn’t be used on the grounds that it is not cost effective (value for money) enough. NICE gives advice about which new drugs or treatments should be available on the NHS in England and Wales. The Scottish Medicines Consortium (SMC) gives similar advice in Scotland. NICE and the SMC are going to issue further guidance so this situation may change in England and Scotland. On the guidance of the Welsh Assembly, temsirolimus is available in Wales if two specialists request funding for it. As a result, temsirolimus may not be widely available on the NHS, although you may be given it as part of a clinical trial|. How temsirolimus works Back to topTemsirolimus is a type of drug called a kinase inhibitor. Kinases work as chemical messengers in the body. Temsirolimus blocks a kinase called mTOR. The mTOR kinase sends signals to the cancer cell that tell it to grow. Temsirolimus blocks these signals by interfering with the cancer’s ability to grow. Temsirolimus also works by stopping the cancer from making new blood vessels. Cancer cells need to make new blood vessels to grow and spread. People with kidney cancer produce high levels of a substance called vascular endothelial growth factor (VEGF) which stimulates the production of blood vessels. Temsirolimus blocks this growth factor and stops new blood vessels being produced. How it is given Back to topTemsirolimus (a clear fluid) is given by injection into a vein (intravenously) through a fine tube (cannula). It is usually given once a week and takes between 30–60 minutes. Possible side effects Back to topEach person reacts to temsirolimus differently. Some people have few side effects, while others experience more. As it is still a new drug it is too early to know everything about the possible side effects. If you notice any effects which you think may be due to the medicine, but we haven’t mentioned here, please discuss them with your doctor. Tiredness and feeling weak You may feel tired| during and after your treatment. It’s important to allow yourself plenty of time to rest. Skin changes A rash, redness or itching is quite common. These effects are usually mild. Speak to your doctor or nurse if you have any of these symptoms. They can advise you about creams or lotions to use, or prescribe medicines to relieve itching. Anaemia (low number of red blood cells) While having treatment with temsirolimus you may become anaemic. This may make you feel tired and breathless|. Let your doctor or nurse know if you develop these symptoms. Sore mouth Your mouth may become sore|, or you may notice small ulcers, during this treatment. Drinking plenty of fluids and cleaning your teeth regularly can help. Tell your nurse or doctor if you have mouth problems. They may prescribe mouthwashes and medicines to prevent or clear any infection. Loss of appetite A dietitian or specialist nurse at your hospital can give advice about how to boost your appetite, cope with eating difficulties| and maintain your weight. Nausea (feeling sick) Mild nausea| is quite common but it is usually easy to control. Your doctor can prescribe anti-sickness drugs to prevent or greatly reduce this. Fluid retention You may experience mild swelling in your ankle caused by fluid retention. This is not harmful but can be uncomfortable. Less common side effects Back to topAllergic reactions Signs of a reaction include skin rashes and itching, a feeling of swelling in the tongue or throat, irritation of the nasal passages, wheezing, a cough and breathlessness. You will be monitored closely during your treatment, but tell your nurse or doctor if you have any of these symptoms. To reduce the chance of developing an allergic reaction, certain drugs (antihistamines) can be given before the infusion (injection). Your drip can also be slowed down or stopped until the reaction is over. Lowered resistance to infection Temsirolimus can reduce the production of white blood cells by the bone marrow, making you more prone to infection|. Contact your doctor or the hospital straight away if your temperature goes above 38°C (100.4°F) or if you suddenly feel unwell (even with a normal temperature). Changes to your blood cholesterol Samples of your blood may be taken from time to time to monitor this. The levels of sugar in your blood may change temporarily While you are having temsirolimus, your blood-sugar levels may be checked by blood tests. People with diabetes should be more careful than usual about checking their blood-sugar levels and should contact their doctor if there is any problem with controlling their diabetes. Tell your doctor if you get very thirsty or if you are passing more urine than usual. Bleeding problems Temsirolimus may increase your chance of bleeding. This is a less common side effect and can affect people in different ways. For example, your gums may bleed, or you may bruise more easily or notice blood in your urine or stools. If you notice any unusual bleeding contact your doctor immediately. Breathlessness Some people may become breathless. This is more likely if you already have lung problems. Let your doctor know if you get more breathless. Muscle and joint pain You may notice that you have muscle or joint pain. Let your doctor know if you get these side effects as they can prescribe painkillers. Diarrhoea This can usually be controlled with medicine, but let your doctor know if it is severe or if it continues. It’s important to drink plenty of fluids if you have diarrhoea|. Constipation Constipation| can usually be helped by drinking plenty of fluids, eating a high-fibre diet and taking gentle exercise. Sometimes you may need to take medicines called laxatives to stimulate your bowels. These can be prescribed by your doctor. Additional information Back to topOther medicines Some medicines can interact with temsirolimus and may make it less effective. Let your doctor know about any medicines you are taking, including non-prescribed drugs such as complementary therapies and herbal drugs. Avoid taking St John’s wort, eating grapefruits or drinking grapefruit juice while you are having temsirolimus. Contraception It is not advisable to become pregnant or father a child while taking temsirolimus, as the medicine may harm a developing foetus. It’s important to use effective contraception while taking temsirolimus, and for at least a few months afterwards. If you or your partner think you may be pregnant, you must let your doctor know immediately. Breastfeeding must be avoided while taking temsirolimus, as it is not known if it can be passed in breast milk. Fertility It’s not yet known how temsirolimus may affect fertility|. If you have concerns about this, you can discuss them with your specialist. Live vaccinations Avoid close contact with anyone who’s just had a live vaccine while you’re taking temsirolimus. References Back to topThis section has been compiled using information from a number of reliable sources including: •Martindale: The Complete Drug Reference (35th edition), Eds. Sweetman et al, Pharmaceutical Press, 2006. •British National Formulary (57th edition), British Medical Association and Royal Pharmaceutical Society of Great Britain, March 2009. •Hudes G et al. RJ Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma, The New England Journal of Medicine, Vol 256 (22), 31 May 2007, p.2271–2281. •Gore ME, Symposium article, Temsirolimus in the treatment of advanced renal cell carcinoma, Annals of Oncology, 18 (Supplement 9), 2007. 新型的治疗肾癌的靶向制剂Temsirolimus 简介：Temsirolimus Temsirolimus（TEM, CCI-779）是mTOR（调节细胞生长和血管形成的信号蛋白）的特异性抑制剂。用法为25 mg加入250 mL生理盐水，30～60分钟静脉滴注，每周重复，直至进展。治疗预后差的晚期肾癌患。 Temsirolimus（TEM, CCI-779）是mTOR（调节细胞生长和血管形成的信号蛋白）的特异性抑制剂。用法为25 mg加入250 mL生理盐水，30～60分钟静脉滴注，每周重复，直至进展。治疗预后差的晚期肾癌患者（Hudes G，Carducci M，Tomczak P，et al. 2007），有效率9%，疾病控制率49%，与IFN-α组比能显著延长OS（10.9月vs.7.3月）。主要不良反应为乏力、胃肠道反应、外周水肿、贫血、血糖升高、高脂血症。具备以下3个或以上特征为预后较差的患者：①LDH>1.5倍正常值高限；②HGB<正常值低限；③校准血钙>10 mg/dL（2.5 mmol/L）；④初始诊断与开始全身治疗的时间小于1年；⑤KPS评分≤70；⑥转移灶≥2个。 Wood等（Wood L，Bukowski RM，Dreicer R，et al. 2008）总结了应用TEM治疗抗VEGF靶向治疗失败后转移性肾癌的安全性和疗效。TEM中位剂量强度21 mg/周，3例患者由于不良反应中断治疗。SD 47%、PD 47%，1例不能评价疗效，中位PFS 5个月。主要的不良反应为贫血（89%）、疲乏（79%）、高甘油三酸酯血症（74%）、高血糖（74%）、血肌酐升高（58%）、皮疹（53%）、血小板减少（53%）、高胆固醇血症（42%）、搔痒（37%）、食欲减退（32%）、粘膜炎（21%）。32%的患者有3级不良反应（疲乏、高血钾、中性白细胞减少、血肌酐升高、高甘油三酸酯血症）。 Souza等（Souza P L， Radulovic S，Beck J，et al. 2008）总结了应用TEM或IFN-α治疗肾癌而引起的高血糖（hyperglycemia，HG）、高胆固醇血症（hypercholesterolemia，HC）、高脂血症（hyperlipid-emia，HL）的特点。与IFN-α治疗相比，TEM治疗易发生＞2级的HG和HC，需要药物治疗，未发现HG或HC与患者的OS或PFS相关。 美国临床肿瘤学学会第42届年度会议（2006年6月在美国亚特兰大召开）上公布的数据表明，靶向mTOR激酶抑制剂Temsirolimus单独给药是一种有效的治疗进展期肾癌的一线疗法。在多个国家进行的Ⅲ期临床研究中期分析显示， Temsirolimus单独治疗可将进展期肾癌患者总生存期显著地延长50%（对照组为标准治疗药物干扰素α）。接受Temsirolimus联合干扰素α治疗的患者与单独使用干扰素α的患者相比，总生存期延长了15%。 初诊时即有25%-35%的肾癌患者已属于进展期，包括局部侵袭和远处转移。晚期患者5年生存率不超过20%，而高风险的危重患者总生存期不到半年。肾癌的标准疗法通常为采用干扰素α或白细胞介素2的免疫疗法。 不多的治疗药物 Gary Hudes博士评论说：“进展期肾细胞癌是一种特别难治的癌症，目前尽管有些进展，但是可供病人选择的疗法很少。” Gary Hudes博士来自美国宾夕法尼亚州费城的Fox Chase癌症中心。 另文： Temsirolimus是一种新型的治疗肾癌的靶向制剂，特异性抑制mTOR（哺乳类动物的雷帕霉素靶蛋白）激酶。mTOR激酶是影响细胞内信号传导途径的重要成分，与调节细胞生长和生存有关。Ⅱ期临床研究显示，Temsirolimus单药疗法治疗患有细胞因子耐受性转移性肾癌，无疾病进展存活期和总生存期的数据结果令人鼓舞。通过对高危病人的基础数据进行回顾性亚组分析表明，接受Temsirolimus治疗的患者与以干扰素α作为一线治疗的患者相比，前者的总生存期比后者延长了17%。Ⅰ期临床研究显示，Temsirolimus联合干扰素α具有临床抗瘤功效，这之前的临床前研究已经证实了上述两种药物具有协同作用。 在多个国家进行的Ⅲ期临床研究中期分析结果公布于美国临床肿瘤学大会，该项研究对单独使用干扰素α与单独使用Temsirolimus或Temsirolimus联合干扰素α治疗危重肾癌患者进行了对比。 这项研究的准入标准为以前未曾接受过系统治疗的Ⅳ期或复发性肾癌患者。此外，还包括卡诺斯基评分(karnofsky performance score)超过60%，以及符合6项危险因子的3项或3项以上（5项Motzer标准和至少一个转移病灶）的患者。 26个国家209个研究中心的626名患者被随机分组，接受标签公开的开放式治疗，其中209名患者静脉注射Temsirolimus 15mg，每周一次；210名患者静脉注射Temsirolimus 15mg，每周1次，外加皮下注射干扰素α 6MU，每周3次；其他患者皮下注射干扰素α 18MU，每周3次。 患者中位年龄59岁，69%为男性。83%的患者卡诺斯基评分基础值不超过70%，67%的患者以前做过肾脏切除手术，81%的患者为透明细胞型肾癌，82%的患者从确诊到随机分组的时间间隔不到一年。32%的患者符合3项危险因子，而62%的患者符合3项以上。另外，82%的患者出现2个或以上转移病灶。 这项研究的主要疗效指标为总生存期，次要疗效指标包括无疾病进展存活期、至治疗失败时间、总应答率和临床获益率。 可延长总生存期 在对病人跟踪治疗13个月（中间值）后进行中期分析，治疗结果为：442人死亡，Temsirolimus治疗组死亡率为67.5%，Temsirolimus联合干扰素α治疗组死亡率为72.4%，干扰素α治疗组死亡率为72.0%。 与单独给药干扰素α相比， Temsirolimus单药治疗可显著延长总生存期，可将总生存期的中位值延长49%（风险比为0.73）。 接受Temsirolimus联合干扰素α治疗的患者，其总生存期中位值比单独接受干扰素α治疗的患者延长了15%(风险比为0.95)；但组间差异无统计学意义。 接受Temsirolimus单药治疗的患者与接受Temsirolimus联合干扰素α治疗的患者，总生存期的中位值分别为10.9个月和8.4个月，而单独接受干扰素α治疗的患者仅为7.3个月（见表1）。 表1.疗效结果 干扰素α Temsirolimus 干扰素α+ Temsirolimus (n=207) (n=209) (n=210) 总生存期（月） 中位值 7.3 10.9 8.4 无疾病进展存活期（月） 中位值 1.9 3.7 3.7 至治疗失败时间（月） 中位值 2.1 4.0 3.5 应答率（患者的%） 客观反应率 7 9 11 临床获益率 29 46 41 对无疾病进展存活期的影响 Temsirolimus治疗组中无疾病进展存活期明显延长。接受Temsirolimus单药治疗的患者与接受Temsirolimus联合干扰素α治疗的患者，中间无疾病进展存活期均为3.7个月，而单独接受干扰素α治疗的患者仅为1.9个月（见前面表1）。 Temsirolimus治疗组中至治疗失败时间也同样明显延长，接受Temsirolimus单药治疗的患者与接受Temsirolimus联合干扰素α治疗的患者至治疗失败时间中间值分别为4.0个月和3.5个月，而单独接受干扰素α治疗的患者仅为2.1个月。 Temsirolimus治疗组、Temsirolimus联合干扰素α治疗组以及干扰素α治疗组的客观反应率分别为9%、11%和7%。相应的临床获益率分别为46%、41%和29%。 耐受性更好 Temsirolimus单药治疗组中3-4度不良事件发生率为69%，而Temsirolimus联合干扰素α治疗组以及干扰素α治疗组分别为87%和85%（见表2）。Temsirolimus单药治疗组中3-4度不良事件发生率比干扰素α治疗组显著降低了16%，因此研究人员报道：“患者对Temsirolimus单一制剂的耐受性比干扰素α更好。” 3个治疗组中，报道最多的3-4度不良事件依次为虚弱、贫血、呼吸困难和恶心（见表2和表3）；与其他2组服用干扰素α的患者相比，接受Temsirolimus单药治疗的患者较少发生虚弱和恶心（见表2）。 表2.不良事件发生率 干扰素α Temsirolimus 干扰素α+ Temsirolimus (n=203) (n=209) (n=209) 3-4度不良事件发生率(患者的%) ≥1个不良事件 85 69 87 虚弱 27 12 30 恶心 5 4 2 皮疹 0 1 2 呼吸困难 8 9 11 腹泻 2 1 5 外周水肿 0 0 2 呕吐 3 3 2 口腔炎 0 1 5 另外，Temsirolimus单药治疗组中因不良事件而中断治疗的发生率较低（仅为7%），Temsirolimus联合干扰素α治疗组为22%,干扰素α治疗组为14%。 Temsirolimus会引起一些不良反应，如皮疹和高血糖，这些不良反应在干扰素α治疗中较少报道，不过这些不良反应并不严重，很容易得到控制。据报道，接受Temsirolimus单药治疗的患者中发生皮疹的比率为37%，单独接受干扰素α的为5%，接受Temsirolimus联合干扰素α治疗的为16%（见表2）。相应地发生高血糖的比率分别为26%、11%和16%（见表3）。 表3.血液化验异常发生率 干扰素α Temsirolimus 干扰素α+ Temsirolimus 3-4度血液化验异常发生率(患者的%) 贫血 24 21 39 高脂血症 1 7 2 高血糖 1 10 4 肌酸酐增多 1 4 2 血小板减少 0 1 9 中性白细胞减少 8 3 14 第一个提高总生存期的新型药物 Hudes博士说：“前几年还没有治疗肾癌的理想药物。FDA目前已经批准了2个新药，还有几个前景不错的药物正在进行临床试验，Temsirolimus是这些新型药物中第一个可提高肾癌患者总生存期的药物。而且，这是首次针对于进展期肾癌患者进行的一项研究，这些患者无法达到其他临床试验的要求。”Hudes博士认为，这些治疗肾癌的新型靶向药物可使患者获得最大利益，下一步的目标是确定这些药物的最佳给药方案。 标准的一线治疗药物 研究人员表示：“这项全球性的Ⅲ期临床试验结果证实，mTOR是肾细胞癌的一个重要的治疗靶点。每周静脉注射Temsirolimus25mg可以作为治疗转移性肾癌和高危肾癌的标准一线疗法。” 发布时间：2010年05月08日 |
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