Bortezomib和Sorafenib对甲状腺癌有活性


  November 2, 2006 (凤凰城) — 在上个月,两篇发表于美国甲状腺学会的研究,两种已经被核准用于其它癌症的新的生物治疗方式,显出对传统手术或放射线碘治疗失败之末期弥漫性甲状腺癌有活性;这两篇研究分别是探讨 bortezomib (Velcade, Millennium Pharmaceuticals/Johnson & Johnson Pharmaceutical Research & Development)和 sorafenib (Nexavar, Onyx/Bayer)的效果。
  
  德州大学安德森癌症中心内分泌科主任Steven Sherma 医师指出,对目前没有有效化学治疗方式的末期甲状腺癌病患而言,这无疑是个令人鼓舞的好消息;弥漫性甲状腺肿瘤对放射线碘无效者,一般也对细胞毒素(Cytotoxics)反应不佳,而目前的常规辅助化疗也不建议这样用,所幸,我们进入了一个以新的生物制剂有效治疗甲状腺癌的新领域。
  
  【Bortezomib稳定病情】
  Sherman医师发表的bortezomib结果,是国家癌症研究中心所支持的第二期多中心研究的第一阶段结果,该研究设计分为两个阶段,如果在最初的12位病患没有完整反应或仅有部分反应就会停止。
  
  Bortezomib以三周为一循环,在第1、4、8和11天经静脉注射给予 1.3 mg/m2 剂量;在每两个循环之后,以实体肿瘤治疗反应评价标准(Response Evaluation Criteria in Solid Tumors / RECIST)评估反应。
  
  迄今,在最少四个治疗循环之后,最初的12位病患的结果有7位病患(58%)病情稳定,其中一位在参与试验前已有五年的逐渐恶化病程,但目前病情已经稳定超过一年。
  
  Sherman医师向与会者表示,该药耐受良好,严重的不良反应包括一例肺栓塞和一例运动神经病变,有一位病患因为感到有疲倦感而降低剂量。
  
  本研究持续进行中,Sherman医师认为,目前为止有不错的稳定病情效果,一位原本有恶化疾病的病患目前病情已经稳定超过一年。
  
  【不同的作用机转】
  Bortezomib是蛋白解体抑制剂这一类新药的第一种,作用系藉由预防目标蛋白质分解,蛋白质分解会影响细胞内的多种讯息降解而使细胞死亡;此药在2003年6月获得美国核准用于治疗多发性骨髓瘤,而药厂正进行用于淋巴瘤,非小细胞肺癌(NSCLC)和其它肿瘤的试验。
  
  会议中讨论的另一个药物sorafenib则是有不同机转,这是一个口服的多种激酶抑制剂,可作用于肿瘤细胞的增生和血管新生;在2005年12月核准用于末期肾细胞癌,药厂则进一步研发用于转移性黑色素瘤,恶化的一级肝癌和NSCLC。
  
  宾州大学Abramson癌症中心的Marcia Brose医师所领导的团队发表sorafenib 用于对放射碘无效之甲状腺癌的结果。
  
  目前为止,共有11位病患,平均参与研究3.6个月,以正子断层扫描(PET)在第4周和第8周追踪,且在第8周进行计算机断层摄影(CT)扫描;10位有扫描结果的病患中,有9位的PET在第8周显出在代谢活性上有显著降低,某些病灶位置已经完全消失,第8周的CT扫描显示目标区域之直径减少平均24% 。
  
  有两位病患在治疗后一和两周时移除肿瘤组织、病灶大小和中心坏死区域均减少;第8周治疗后,这些病患之一以CT扫描有部分反应,但其它人显示在颈部和胸部有恶化疾病。
  
  Brose医师认为,我们的研究显示,sorafenib对这些肿瘤有早期抑制效果,这或许可以深入了解此一制剂对甲状腺癌的作用机转。
  
  加州大学洛杉矶分校的Gregory Brent医师,也是美国甲状腺学会的秘书,在被要求对这些发表做评论时向Medscap表示,这些试验中出现的弥漫性甲状腺癌治疗反应是令人鼓舞的,提供给那些没有其它适当治疗方式的病患新希望。
  
  他表示,这些发现也指出促使弥漫性甲状腺癌生长与扩散的因子之潜在机转,在未来可望帮助形成其它的单一或并用治疗;不过,仍需要进一步的研究以定义哪里些人可以从这些制剂获得最大利益,和确定介入治疗的适当时机与治疗期间,最终是要找出弥漫性甲状腺癌的有效制剂。

Bortezomib and Sorafenib Show<

By Zosia Chustecka
Medscape Medical News

November 2, 2006 (Phoenix) — Two new biologic therapies, already approved for use in other cancers, have shown activity in advanced differentiated thyroid cancer that has failed on standard treatment with surgery and radioactive iodine. In separate studies presented at the American Thyroid Association meeting last month, such activity was reported for bortezomib (Velcade, Millennium Pharmaceuticals/Johnson & Johnson Pharmaceutical Research & Development) and sorafenib (Nexavar, Onyx/Bayer).

"This is encouraging news for advanced thyroid cancer patients, given that there is currently no effective chemotherapy treatment," says Steven Sherma, MD, chair of endocrinology at the University of Texas MD Anderson Cancer Center, in Houston. Differentiated thyroid carcinoma resistant to radioiodine generally responds poorly to cytotoxics, and at present routine adjuvant use of chemotherapy is not recommended. "Hopefully, we are entering a new era of effective chemotherapy with new biologic agents in thyroid cancer," he said in a statement.

Bortezomib Stabilizes Disease

Dr. Sherman was presenting results for bortezomib, from the first stage of a multicenter phase 2 study sponsored by the National Cancer Institute. A 2-stage design was used, with an early stopping rule if no complete or partial responses were seen in the first 12 patients.

Bortezomib was administered intravenously at 1.3 mg/m2 on days 1, 4, 8, and 11 in 3 weekly cycles. Responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria after every 2 cycles.

So far, the results from these initial 12 participants show stable disease in 7 patients (58%), after a minimum of 4 treatment cycles. One of these patients had steadily progressive disease for 5 years before entering the study but has now been stable for more than a year.

The drug appears to be well tolerated, Dr. Sherman told the meeting. Serious adverse events included 1 case each of pulmonary embolism and motor neuropathy, and 1 patient had a dose reduction because of fatigue.

The study is continuing. "Although the best responses to date have been stable disease, at least 1 patient with previously progressive disease has stabilized for 1 year," Dr. Sherman commented.

Different Mechanism of Action

Bortezomib is a proteasome inhibitor — the first in this new class of drugs — and acts by preventing targeted proteolysis that can affect multiple signaling cascades within the cell, leading to cell death. The drug was approved in the United States in June 2003 for the treatment of multiple myeloma, and the manufacturer is conducting trials in lymphomas, non–small-cell lung cancer (NSCLC), and other tumors.

The other drug discussed at the meeting, sorafenib, which has a different mechanism of action, is an oral multiple kinase inhibitor that targets both tumor-cell proliferation and angiogenesis. Approved in December 2005 for advanced renal cell carcinoma, it is being further developed by the manufacturer for metastatic melanoma, advanced primary liver cancer, and NSCLC.

Results for sorafenib in thyroid cancer unresponsive to radioiodine were presented by a team headed by Marcia Brose, MD, PhD, from the Abramson Cancer Center at the University of Pennsylvania, in Philadelphia.

To date, 11 patients have been enrolled, averaging 3.6 months in the study, and have been followed with positron emission tomography (PET) scans at 4 and 8 weeks and computed tomography (CT) scans at 8 weeks. For 9 of the 10 patients for whom scans are available, PET scans at 8 weeks showed a marked decrease in metabolic activity, with complete disappearance of some lesions, while CT scans at 8 weeks showed an average decrease of 24% in the dimensions of the target lesions.

In 2 patients, tumor tissue was removed at 1 and 2 weeks after treatment, and both lesions had shrunk in size and were necrotic at the center. One of these patients had a partial response on CT scans, but the other showed progressive disease in the neck and chest after 8 weeks of therapy.

"Our studies show that sorafenib has early inhibitory effects on these tumors, and this may lead to insights into the mechanism of action of this agent in thyroid cancer," Dr. Brose commented.

Asked to comment on these presentations, Gregory Brent, MD, from the University of California, Los Angeles and secretary of the American Thyroid Association, told Medscape: "The response of differentiated thyroid cancer to chemotherapy in these trials is very encouraging and offers hope to patients for whom there were previously no other legitimate treatments.

"These findings also point to the potential mechanism of factors that promote differentiated thyroid cancer growth and spread and may lead to other single or combination therapies in the future," he said. Further study is needed to define the individuals who will receive the greatest benefit from these agents and the appropriate time of intervention and duration of therapy, he commented, but "ultimately there will be efficacious chemotherapeutic agents for differentiated thyroid cancer."

    
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