对于晚期软组织肉瘤的治疗，eon Berard中心的Jean YvesBlay教授近日提出：“近30年来，那些对于标准治疗策略无反应的患者都找不到其他的治疗选择，而Yondelis(trabectedin)的问世对晚期软组织肉瘤来说是一条好消息。
Blay教授的上述评论是对其负责的研讨会上所发表的有关Yondelis治疗软组织肉瘤疗效的介绍所说出的。
Yondelis也称ET-743。它来源于加勒比海和地中海的一种海鞘体内，是一种用于肿瘤化疗的药物，通过与部分DNA结合干扰细胞分裂、DNA修复，从而促进肿瘤细胞凋亡。
研究表明，对未接受过治疗的、不能切除的、局部晚期或转移性软组织肉瘤患者。采用Yondelis治疗能获得良好的应答效果，患者病情无进展生存期也明显提高。
还有报告指出，在平滑肌肉瘤和脂肉瘤的患者中，治疗临床收益、生长调整指数、肿瘤变异度这些参数相对于治疗反应率能更好地评价治疗疗效。该药良好的耐受性也在此报告中被提出，它所引起的副反应有一过性可逆的白细胞数量降低和转氨酶升高，少数患者可以出现脱发，指甲变脆，以及神经和心脏毒性。

Yondelis (trabectedin)以治疗复发性卵巢癌和晚期软组织肉瘤

西班牙Zeltia制药公司日前表示，菲律宾已批准其抗癌药Yondelis的最新适应证，即用于治疗卵巢癌。
至此，Yondelis在菲律宾可以治疗复发性卵巢癌和晚期软组织肉瘤，它在欧洲和阿根廷、委内瑞拉、韩国和俄罗斯等国家也已获准治疗软组织肉瘤。
Zeltia公司希望在今年年底之前，Yondelis也在欧洲和美国获准治疗卵巢癌。近期，美国食品药品管理局将对该药进行审查，以决定是否批准该药用于这种适应证。

【关键词】Yondelis 前列腺癌 肿瘤活性 前列腺特异抗原 药物治疗

【文　摘】每周给非男性激素依赖的晚期前列腺癌患者输注一次三小时的西班牙PharmaMar公司的Yondelis（trabectedin）（Ⅰ）的Ⅱ期研究得出好的结果。这项Ⅱ期临床试验是专为检测有高水平前列腺特异抗原（与肿瘤活性有关的一种生物标识）的激素难治性前列腺癌患者设计的。

Yondelis（trabectedin） 说明书
How does it work?
Yondelis infusion contains the active ingredient trabectedin which is a type of chemotherapy medicine for cancer known as an ‘anti-neoplastic’.
Trabectedin is a naturally occurring compound that is derived from a marine organism, Ecteinascidia turbinate.
Cancers form when cells within the body multiply abnormally and uncontrollably.
These cells spread, destroying nearby tissues. Trabectedin works by stopping the cancer cells from multiplying. It does this by binding to and damaging the DNA in the cancer cells. This stops the cells from growing and multiplying.
In most chemotherapy regimens, doses are administered in courses at various intervals to allow normal cells to recover from the adverse effects of the anticancer medicines between doses. However, during this period, cancer cells will also recover and start to replicate again.
Successful treatment depends on the administration of the next course of therapy before the cancer has regrown to its previous size and the net effect is to decrease the amount of cancer with each successive course.
Trabectedin is used to treat a type of cancer known as soft tissue sarcoma, which affects muscles, fatty tissue and other soft tissue, such as cartilage or blood vessels.
Unfortunately, trabectedin can also affect normal, healthy cells, particularly those that multiply quickly, such as healthy blood cells.
Trabectedin is therefore only used to treat soft tissue sarcoma in people who have enough healthy cells in their blood at the start of treatment.
Regular blood tests are needed to monitor the levels of blood cells.
Trabectedin is given by slow infusion (drip) into a vein (intravenously) over 24 hours. Dexamethasone is always given before treatment with trabectedin to help reduce sickness and protect the liver.

The treatment is repeated every three weeks, for as many courses as your specialist feels is necessary.

What is it used for?
Soft tissue sarcoma.
This medicine is used when other medicines have not been effective or are unsuitable.

Warning!
Before each treatment with Yondelis you will need to have blood tests to check your blood cells, liver function, kidney function, bilirubin level and CPK level.
These tests should also be carried out weekly during your first two treatments.
This medicine can cause a decrease in the normal amounts of blood cells in the blood. For this reason you should consult your doctor immediately if you experience any of the following symptoms: unexplained bruising or bleeding, purple spots, sore throat, mouth ulcers, high temperature (fever), feeling tired or general illness. Your doctor may want to take a blood test to check your blood cells.
This medicine may have side effects on the muscles. For this reason, you should inform your doctor immediately if you experience muscular symptoms such as pain, tenderness, cramps, or weakness while taking this medicine, particularly if they are accompanied by a fever or feeling generally unwell.

Your doctor may need to check for side effects on the muscles by taking a blood test to measure the level of a compound called creatinine phosphokinase (CPK) in your blood.
This medicine may also have side effects on your liver. Symptoms that may suggest a liver problem include persistent nausea and vomiting, abdominal pain, or the development of jaundice(ayellow colouring to the skin and the whites of the eyes).

Consult your doctor if you experience any of these symptoms.

You should not drink alcohol while having treatment with this medicine because this may increase the chance of side effects on the liver.
This medicine may be harmful to an unborn baby. For this reason, women being treated with this medicine who could get pregnant must use a highly effective method of contraception to prevent pregnancy.
You will be given advice on which forms are suitable for you. Contraception should be started before your treatment begins and continued for at least three months after your treatment is finished. You should tell your doctor immediately if you think you could be pregnant at any point during treatment.
Men being treated with this medicine must use a condom to avoid fathering a child during their treatment and for at least five months after treatment is finished.
There is a risk of irreversible infertility associated with Yondelis. For this reason, men should discuss the possibility of sperm conservation with their doctor before starting treatment.

Use with caution in Decreased kidney function.
Decreased liver function or liver disease.
Not to be used in
Severe or uncontrolled infection.
Breastfeeding.
People with high levels of bilirubin (a pigment produced by the liver).
People with severely decreased kidney function.
People with low numbers of white blood cells (neutropenia), platelets (thrombocytopenia) or haemoglobin in their blood.
People with raised liver enzymes or creatinine phosphokinase (CPK) levels.
This medicine is not recommended for children and adolescents.
This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy.
If you feel you have experienced an allergic reaction, stop using this medicine and informyourdoctororpharmacistimmediately.
Pregnancy and breastfeeding Certain medicines should not be used during pregnancy or breastfeeding.
However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.
This medicine may cause serious birth defects in a developing baby.
It should not be used during pregnancy unless considered essential by your doctor. Effective contraception should be used by women who themselves, or whose male partners, are receiving treatment with this medicine.
Women should continue to use this contraception for at least three months after the medicine is stopped. Consult your doctor immediately if you think you could be pregnant.
Men being treated with this medicine should use condoms to avoid fathering a child, both during treatment and for five months after treatment is finished, if their partner could get pregnant and is not using contraception.
It is not known if this medicine passes into breast milk. Womenshouldnotbreastfeed during treatment with this medicine and for three months after stopping the treatment.
Side effects
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.
Disturbances of the gut, such as nauseaandvomiting,constipation, diarrhoea, indigestion, abdominal pain.
Decrease in the numbers of white blood cells (neutropenia), platelets (thrombocytopenia) or red blood cells (anaemia) in the blood.
Fatigue, weakness or loss of strength (asthenia).
Loss of appetite and weight loss.
Headache.
Elevated levels of liver enzymes.
Injection site reaction.
Dizziness.
Problems with the nerves, for example causing changes in sensation such as pins and needles (paraesthesia) or numbness.
Shortness of breath (dyspnoea).
Pain in muscle or joints (myalgia or arthralgia).
Hair loss (alopecia).
Fever.
Low blood pressure (hypotension).
Swollen ankles (peripheral oedema).
Difficulty sleeping (insomnia).
Inflammation of the lining of the mouth (stomatitis).
Bacterial, viral or fungal infections, sometimes serious.
Muscle breakdown (rhabdomyolysis).
The side effects listed above may not include all of the side effects reported by the drug's manufacturer.
For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.
How can this medicine affect other medicines?
It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while having treatment with this one, to ensure that the combination is safe.
There may be an increased risk of side effects on the liver or blood cells if this medicine is used in combination with other medicines that can have these kinds of side effects, or with medicines that can prevent the breakdown of trabectedin in the body (see below for examples).
There may be an increased risk of side effects on the muscles if Yondelis is used in combination with any of the following medicines:statins for lowering cholesterol, eg simvastatin, atorvastatinfibrates for lowering cholesterol, eg bezafibrate, gemfibrozil ezetimibenicotinic acid (niacin)medicines that can prevent the breakdown of trabectedin in the body (see below for examples).
The following medicines may prevent the breakdown of trabectedin by the body and so may increase the risk of side effects:
azole antifungals,egketoconazole,fluconazoleciclosporinmacrolide antibiotics, eg clarithromycin.
protease inhibitors for HIV infection, eg ritonavir verapamil.
Trabectedin may decrease the blood level of phenytoin used to treat epilepsy, and this could increase the risk of convulsions. The use of phenytoin in combination with Yondelis is not recommended.
The following medicines may decrease the amount of trabectedin in the blood and could therefore make it less effective:
phenobarbitalrifampicinthe herbal remedy St. John's wort.
Vaccines may be less effective in people receiving chemotherapy.

This is because chemotherapy medicines reduce the activity of the immune system and can prevent the body forming adequate antibodies. Live vaccines should be postponed until at least six months after finishing chemotherapy because they may cause serious infections. Live vaccines include: measles, mumps, rubella, MMR, BCG, oral polio, oral typhoid and yellow fever. Other medicines containing the same active ingredient There are currently no other medicines available in the UK that contain
trabectedin as the active ingredient.
Last updated 22.04.2008

Trabectedin治疗复发转移型软组织肉瘤的疗效毒性

【摘要】背景与目的：Yondelis® (trabectedin) ,研制阶段称为ET-743, 为海洋生物Ecteinascidia turbinata的提取物，它直接作用于肿瘤细胞中DNA短支的缺口，影响并抑制蛋白质的合成，从而在基因水平上抑制肿瘤细胞的分裂和成长，总结76例复发或转移的软组织肉瘤的生物治疗经验。方法: 治疗组76 例患者Yondelis® (trabectedin) 1.5mg/m2     24小时静脉滴注，每三周重复，对照组50例常规的化疗方案。结果: 生物治疗组76例患者中完全缓解（Complete Response--CR）8例（10.6 %），部分缓解（Partial Response--PR）4例（5.3 %），稳定（Stable  Disease--SD）34例（44.7 %），恶化（Progressive Disease--PD）30 例。临床受益（CR+PR）12例，受益率为15.9%。对照组临床受益率为2.0%，两组疗效差异有意义（P<0.05）。有关不良反应，生物治疗组骨髓抑制(中性粒细胞减少症) 只有12例（15.8%）,而化疗组42例（84.0%）。

结论: 对于复发或转移的复杂型软组织肉瘤应用Yondelis® (trabectedin)而现治疗优于化疗，而且毒副作用低，有助于保持患者生活质量。

关键词：复发及转移型软组织肉瘤；生物治疗；Yondelis® (trabectedin)

软组织肉瘤是常见肿瘤，发病率为1.2/10万～2.3/10万；主要位于肢体，占所有病例的50%以上。单纯手术治疗，软组织肉瘤患者术后的局部复发转移率很高，导致死亡率也很高. 而非手术综合疗法（包括化疗和生物治疗）对这类肿瘤具有较好的治疗效果，但化疗的毒副作用大，且对多种软组织肉瘤不敏感，这要求软组织肉瘤的治疗需寻求另一条出路。 随着有效的生物抗癌药的出现，目前对这一类恶性肿瘤的治疗水平，尤其是对于复发或有转移的病例和传统化疗效果不明显的病例的二线疗效已有提高，生物抗癌药给患者带来了新的希望。Yondelis® (trabectedin) 现已正式被西班牙药物管理局批准上市发售，用于软组织肉瘤的二线治疗，尤其是对传统治疗如化疗不敏感或不能耐受的患者。

我中心自2005年5月到2007年8月间共收治各种进展型(复发或转移)的软组织肉瘤126例，其中76例使用西班牙Zeltia 公司和美国强生公司联合研制的海洋源性抗肿瘤生物药物(trabectedin)，现将两年来Trabectedin治疗复发或转移型软组织肉瘤的疗效和毒性反应分析报告如下。
1 资料   　　 
1.1 病例一般资料

经西班牙药物管理局( agencia de madicamento de Espanya)批准和筛选的126例患者，入选的患者均为进展型(复发或转移) 软组织肉瘤，病理类型确定，患者在知情的情况下自愿选择化疗或trabectedin治疗。126例病例均来自地中海肿瘤研究中心2005年5月～2007年8月收治的患者，分为两组：生物治疗组76例，男性40例，女性36例；年龄8岁～70 岁，中位年龄40.5岁，对照组50例，男性26例，女性24例；年龄7～65岁，中位年龄40.2岁。两组患者均为术后复发或转移患者，其一般资料之间的差异无统计学意义，具有可比性。

1.2、肿瘤的病理类型及发病部位  滑膜肉瘤22例，横纹肌肉瘤22例，脂肪肉瘤16例，恶性纤维组织细胞肉瘤16例，纤维肉瘤16例，皮肤隆突性纤维瘤9例，软组织尤文氏肉瘤7例，恶性神经鞘瘤5例，血管肉瘤5例，恶性巨细胞瘤5例，软组织透明细胞肉瘤1例。其中，肿瘤位于四肢86例，包括上肢39例，下肢47例；位于躯干部40例。

1.3 药物来源 

Yondelis® (trabectedin)是西班牙Zeltia 公司和美国强生公司联合研制的首个海洋源性抗肿瘤生物药物，Zeltia 公司是专门从事从海洋生物提取生物制剂的高科技公司，有多种生物制剂药物在市场销售另有多种药物处在研制临床试验阶段。Yondelis®欧盟批号为EU/1/07/417/001, trabectedin为海洋生物Ecteinascidia turbinata的提取物，作为一种全新概念的抗肿瘤生物制剂，它直接作用于肿瘤细胞中DNA短支的缺口，影响并抑制蛋白质的合成，从而抑制肿瘤细胞的分裂和成长，达到抑制恶性肿瘤的作用，也认为是一种全新的细胞毒性药物，尤其用于治疗进展型软组织肉瘤的二线治疗。

1.4 治疗方法

1.4.1  生物治疗组: 

生物治疗组：trabectedin 1.5mg/m2，持续24h静脉滴注，d1；G-CSF（粒细胞集落刺激因子）

1.4.2  对照组:   VCD方案:IE方案：每3周重复

以上两组治疗患者，重复3个疗程，评价疗效和副作用。

2.结果 

2.1治疗疗效生物治疗组: 
 
共收治患者76例，均完成3疗程的治疗， 其中完全缓解病例（CR）4例（5.3%），部分缓解病例（PR）2例（2.6%），稳定的（SD）有34例（44.7%），恶化（PD）的为30例（39.5%）。临床受益（CR+PR）6例，占7.9% 。对照组: 共收治50例患者，均完成3周期的治疗，50例患者中完全缓解（CR）的有0例（0 %），部分缓解（PR）的有1例（2%），稳定（SD）的为15例（30%），恶化 （PD）的为34例（68%）。临床受益率（CR+PR）1例.

2.2不良反应 

生物治疗组: 在生物治疗组76 例患者的治疗中，主要不良主要为骨髓抑制，Ⅰ+Ⅱ级白细胞下降为34.2%( 26/ 76), Ⅲ～Ⅳ级为11.8%（9/76），血小板下降占14.5%( 11/ 76), 恶心呕吐率Ⅲ+Ⅳ级5.3%( 4/76) ，Ⅲ+Ⅳ级的脱发症状仅占4.0% ( 3/ 76)，静脉炎占6.6% (5/ 76) , 肝功能异常ALT升高12例次（15.8%），疲劳乏力Ⅲ+Ⅳ级13．2% (10/76)，心电图及肾功均未见异常，未出现出血性膀胱炎。经观察，不良反应无累积。对照组: 在对照组50 例患者的治疗中，主要不良主要为骨髓抑制，Ⅰ+Ⅱ级白细胞下降为20.0%, Ⅲ～Ⅳ级为64.0%，血小板下降占24%, 恶心呕吐率Ⅲ+Ⅳ级80.0%，脱发也为主要反应，50例患者均出现不同程度脱发，Ⅲ+Ⅳ级占66.0%（33/50），静脉炎占40.0%，肝功能异常ALT升高38例次（76.0%）, 疲劳乏力Ⅲ+Ⅳ级35例占70.0% 。不良反应有累积.

3、讨论

软组织肉瘤都是起源于非造血系统间叶组织，部分起源于外胚层神经组织的周围神经恶性肿瘤也为软组织肉瘤，软组织肉瘤占成人恶性肿瘤的1%，软组织肉瘤多发于肢体，手术仍是骨与软组织肉瘤主要的治疗手段，但软组织肉瘤的一个重要生物特征是局部复发和血道转移，早期软组织肿瘤以手术为主，手术是治疗四肢软组织肉瘤和骨肉瘤的主要方法，但是单纯手术治疗,患者术后的局部复发率很高。即使局部肿瘤得到控制，仍然有50﹪以上的软组织肉瘤患者，在术后2年内因发生复发或转移。术后一旦出现复发和转移，对化疗不再敏感，几乎不能治愈，中位生存期大多为1年左右。随着综合治疗的逐步应用，对软组织肉瘤治疗取得了一些进展，一定程度上降低了局部复发率并提高了生存率，对于不能再手术、局部复发或已发生转移的晚期软组织肉瘤患者，以前只能考虑以化疗为唯一的治疗疗法，但其疗效一般，而且毒副作用很影响患者的治疗。

应用Zeltia和美国强生公司联合研制生产的全新肿瘤生物制剂Yondelis® (Trabectedin) 对于复发或转移的复杂型软组织肉瘤的生物治疗，目的是为了保肢和提高患者生活质量及延长患者的生存期，这是我们研究中心参与Yondelis® (Trabectedin)的临床研究的主要方向。Trabectedin为海洋生物Ecteinascidia turbinata的提取物，它直接作用于肿瘤细胞中DNA短支的缺口，影响并抑制蛋白质的合成，从而在基因水平上抑制肿瘤细胞的分裂和成长，这正是与常规化疗的不同之处。Trabectedin是海洋生物碱，直接损伤肿瘤细胞的DNA，也属于细胞毒性药物,它的研制和生产厂家Zeltia是一家专门从事海洋生物制剂研发的企业,这是首支海洋源性的生物制剂，主要用于复发转移型软组织肉瘤的二线治疗，改善患者的生活质量，降低了对患者的毒副作用,提高中位生存期。 欧盟把这首个海洋源性的制剂定位为生物药物,在2007年夏天的欧盟医药管理部门已批准其市。

上述126例病例均来自我中心2005年5月～2007年8月收治的软组织肉瘤的复发或转移患者，接受Trabectedin生物治疗和化疗的目的有如下几点：

a) 部分患者的术前综合治疗，目的是尽可能的减小肿瘤体积，保肢等。

b) 全身转移的患者，无法手术，化疗或生物治疗为唯一方法。

c) 预测手术无法广泛切除者。

d) 晚期患者，已接受化疗数次但无效者。

2007年九月在巴塞罗那召开的第十四届 欧洲肿瘤会议(la Conferencia Europea sobre el Cancer - ECCO 14) 来自法国里昂的Jean Yves Blay医生 ，和来自英国伦敦的Royal Marsden Hospital 的Ian Judson医生，和同样来自法国的Institut Gustave Roussy en Villejuif的Axel Le Cesne医生，他们度报告了Trabectedin对于进展型软组织肉瘤患者较好的疗效，但同时他们也提到了Trabectedin的一些毒副作用,如白细胞减少，和一些患者转氨酶的升高。

关于Trabectedin治疗中的毒副作用,在不同的国家也见过相应的报道， 如美国的医生在2007年报道过在Trabectedin的使用中出现了心电图改变和心动过速及肠梗阻和肺部感染 及腹泻； 英国的医生在2007年报道过 中性细胞减少症和急性肾衰； 波兰的医生在2007年报道过Trabectedin引起的轻度贫血,咽痛和口疮和恶心呕吐等。在研究中发现， Trabectedin也会影响到正常健康的细胞，特别是那些快速增值的的健康细胞，像健康的血细胞，所以在使用Trabectedin之前，对那些血象正常的软组织肉瘤患者才能使用，并且需要经常的血象和肝功能的检测。

Trabectedin作为世界首个海洋源性生物抗癌药物，仍有尚未解答的问题，这也是今后要继续研究的方向，我们认为应该在以下几点展开进一步的研究： 1，有关他的毒副作用,既避免毒副作用的方法。 2，由于上市时间不长，他与其他药物的联合用药及配伍疗效有待研究。目前Trabectedin主要用于对化疗不敏感或无效的患者，即为软组织肉瘤的二线药物，作为一线药物的治疗研究正在继续，需要一段时间。4，考虑到Trabectedin治疗肿瘤的原理的特异性， 现在利用Trabectedin对卵巢癌及其他种类肿瘤的临床研究也正在进行。5，Trabectedin对怀孕的妇女的影响。6， Trabectedin对其他药物的影响，如一些广谱抗菌素。7，Trabectedin对一些常用疫苗的影响。