unhappy

作者：Fran Lowry  
出處：WebMD醫學新聞

　　April 5, 2010 — 根據線上發表於3月29日臨床腫瘤期刊(Journal of Clinical Oncology)的一篇統合分析，使用標靶藥物sunitinib(商品名Sutent，Pfizer藥廠)和sorafenib(商品名Nexavar，Bayer與Onyx藥廠)治療癌症的病患，與動脈栓塞事件風險顯著增加有關。
　　
　　這篇包括了10,255名各種癌症病患的統合分析發現，和隨機分派使用安慰劑的控制組相比，與sunitinib和sorafenib有關的動脈栓塞事件(ATEs)發生率為1.4% (95%信心區間[CI]為1.2%- 1.6%)，ATEs的相對風險是3.03% (95% CI，1.25- 7.37；P= .015)。
　　
　　第一作者、波士頓達那-法柏/布萊根婦女醫院癌症中心、腎臟癌中心主任Toni K. Choueiri醫師向Medscape Oncology表示，整體發生率其實相當低，不到5%，而相對風險較高且有統計上顯著意義，與控制組相比，sunitinib和sorafenib發生ATEs的相對風險高出3倍。這些是臨床試驗時的案例，一般人口的發生率會不會更高？或許會，但是我們不得而知，不過，我們首要之務在於必須確認的確有發生ATEs。
　　
　　【增加出血也是個風險】
　　2009年10月時，Medscape Oncology報導指出，Choueiri 醫師等人發表的研究顯示，使用sunitinib和sorafenib治療癌症病患會使他們的出血風險加倍。
　　
　　當時，Choueiri醫師指出，年長虛弱的癌症病患與接受化療者的出血風險較高，他也聲明，醫師們對於這些藥物之出血問題的警覺性不足。
　　
　　在目前的研究中，他與其團隊分析了搜尋自PubMed、發表於1966年1月和2009年7月間的10篇第2和第3期試驗，以及在2004-2009年間發表於美國臨床腫瘤協會以及歐洲腫瘤內科協會會議的摘要。
　　
　　其中6篇是腎細胞癌試驗；其他分別是肝細胞癌、胃腸道基質瘤、非小細胞肺癌、神經內分泌瘤之試驗。
　　
　　最常被報導的事件是心臟缺血或梗塞(7篇試驗)，其次是腦缺血(3篇試驗)，2篇試驗報告同時有心臟和腦缺血。
　　
　　Sunitinib和sorafenib的劑量，以及給藥時間，是由美國食品藥物管理局核准，包括sunitinib 50 mg口服每天一次、以4週給藥、2週停藥的療程進行，而sorafenib則是400 mg口服每天兩次。
　　
　　Sunitinib和sorafenib的ATEs發生率相似，sunitinib是1.3% (95% CI，1.0%- 1.6%)、sorafenib是1.7% (95% CI，1.1%- 2.4%)，此一差異未達統計上的顯著意義(P= .35)。
　　
　　Choueiri醫師表示，至於惡性腫瘤類型或者臨床試驗類型，也沒有顯著差異。
　　
　　【VEGF抑制的好處與壞處】
　　Choueiri醫師向Medscape Oncology表示，推測ATEs發生率增加的原因，他相信是因為這些藥物影響了止血平衡。
　　
　　他表示，這些藥物抑制腫瘤的血管新生，獲得許多癌症的主要治療利益，血管內皮生長因子(VEGF)是腫瘤血管新生的重要路徑，但是它在調節內皮細胞上也相當重要，對於維持正常血液黏性和預防異常出血或血栓，內皮細胞在血管止血上很重要，如果這個平衡傾向血栓，就會發生動脈血栓事件，如中風和心肌梗塞，如果傾向另一邊，則是會發生出血。
　　
　　VEGF也會增加一氧化氮的產生，一氧化氮對血管有多種保護效果，例如抗血小板活性以及抑制白血球黏力。
　　
　　如果你用這些藥物抑制VEGF，如同我們研究顯示的，雖不是以一個主要方法，但是是以一個統計上顯著的方法，對這個止血平衡造成破壞，使它傾向血栓或出血。
　　
　　他指出，他相信這是一個典型效應，他不認為有人可以斷言這兩個藥的其中一種優於另一種。
　　
　　【研究進一步了解血管效應】
　　波士頓哈佛醫學院、專責於癌症病患之心臟照護的腫瘤心臟科醫師Ming Hui Chen受邀Medscape Oncology對此研究發表評論時表示，這個研究進一步讓我們了解小分子酪胺酸激酶抑制劑的血管效應。
　　
　　她指出，該研究支持早期試驗的觀察，顯示心臟的ATEs，如心肌梗塞。
　　
　　Chen醫師指出，對這些抗癌藥物的ATE風險有更多警覺，醫師和病患可以合作於早期發現和處置任何血栓事件。
　　
　　【癌症病患需要這些藥物】
　　Choueiri醫師表示，當使用sunitinib和sorafenib時必須進行照護，特別是可能受到影響的病患。
　　
　　他向Medscape Oncology表示，我們不應停止使用這些藥物，絕對不要！ 它們對我們治療這些癌症帶來相當大的差異，不過我們的確必須更加小心，特別是有風險傾向的病患，包括曾經發生中風者、年長者、未控制之高血壓、糖尿病、曾有血栓事件者等等。首先必須知道可能會發生ATEs，接著，最重要的是監測病患，不要只是給他們藥物，然後兩個月後才看他們，應經常對他們密切監測。
　　
　　Choueiri醫師和Chen醫師皆宣告沒有相關財務關係，在報告中，Choueri指出曾和Bayer Pharmaceuticals/Onyx Pharmaceuticals、GlaxoSmithKline、Abbott Laboratories、Genentech、Agennix、Novartis與Pfizer等藥廠有關聯，但是並未從中接受任何補償。
　　
　　J Clin Oncol. 根據線上發表於2010年3月29日。


Significantly Increased Risk for Arterial Thromboembolic Events With Sunitinib and Sorafenib

By Fran Lowry
Medscape Medical News

April 5, 2010 — Treatment of cancer patients with the targeted agents sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer and Onyx) is associated with a significant increase in the risk for arterial thromboembolic events, according to a meta-analysis published online March?29 in the Journal of Clinical Oncology.

The meta-analysis, which consisted of 10,255 patients with a variety of cancers, found that the incidence of arterial thromboembolic events (ATEs) associated with sunitinib and sorafenib was 1.4% (95% confidence interval [CI], 1.2%?- 1.6%), and that the relative risk for ATEs was 3.03% (95% CI, 1.25?- 7.37; P?= .015), compared with control patients randomized to placebo.

"The overall incidence is very low — less than 5%. The relative risk is higher and is statistically significant, suggesting a 3-fold greater risk for developing ATEs with sorafenib or sunitinib, compared with controls," lead investigator Toni K. Choueiri, MD, director of the kidney cancer center at Dana-Farber/Brigham and Women's Cancer Center in Boston, Massachusetts, told Medscape Oncology. "These cases were in clinical trials. Could the incidence be higher in the general population? Probably, but we don't know. However, we have to recognize that ATEs do occur — that's the first thing."

Increased Bleeding Also a Risk

In October 2009, as reported by Medscape Oncology, Dr. Choueiri and colleagues published a study showing that the treatment of cancer patients with sunitinib and sorafenib doubled their risk of bleeding.

At the time, Dr. Choueiri noted that the risk for bleeding might even be higher in older and frailer cancer patients and in those receiving chemotherapy. He also stated that clinicians had scant awareness of the problem of bleeding with these drugs.

In the current study, he and his team analyzed 10 phase?2 and 3 trials published between January 1966 and July 2009 found with a PubMed search, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2004 and 2009.

Six of the trials were on renal cell carcinoma; the others were on hepatocellular cancer, gastrointestinal stromal tumor, nonsmall-lung cancer, and neuroendocrine tumor.

The most reported event was cardiac ischemia or infarction (7 trials), followed by cerebral ischemia (3 trials). Two trials reported both cardiac and cerebral ischemia.

The doses of sunitinib and sorafenib, as well as the dosing schedules, were approved by the US Food and Drug Administration and consisted of sunitinib 50?mg orally once daily on a 4-weeks-on 2-weeks-off schedule, and sorafenib 400?mg orally twice daily.

The incidence of ATEs with sunitinib and sorafenib were similar — 1.3% (95% CI, 1.0%?- 1.6%) for sunitinib and 1.7% (95% CI, 1.1%?- 2.4%) for sorafenib. This difference was not statistically significant (P?= .35).

Nor were there significant differences with regard to the type of malignancy or the type of clinical trial, Dr. Choueiri said.

The Good and the Bad of VEGF Inhibition

Speculating on the reasons for the increased incidence of ATEs, Dr. Choueiri told Medscape Oncology that he believes it is because these drugs disrupt the hemostatic balance.

"These drugs inhibit tumor angiogenesis, which has resulted in a major therapeutic advance for many cancers. The [vascular endothelial growth factor] VEGF pathway is vital for tumor angiogenesis, but it also plays an important part in regulating endothelial cells," he said. "Endothelial cells are important in vascular homeostasis for maintaining normal blood viscosity and preventing abnormal bleeding or abnormal clotting. If the balance is tipped toward clotting, arterial thromboembolic events, such as stroke and myocardial infarction, can occur. If it goes the other way, bleeding can occur."

VEGF also increases the production of nitric oxide, which has several vascular protective effects, such as antiplatelet activity and the inhibition of leukocyte adhesion.

"If you inhibit VEGF with these drugs, you disrupt, not in a major way but in a statistically significant way as we show in our study, this hemostatic balance and you tip it toward thrombosis or bleeding."

He added that he believes that this is a class effect. "I don't think folks can claim that one drug has less of an effect than the other."

Study Furthers Understanding of Vascular Effects

Commenting on this study for Medscape Oncology, Ming Hui Chen, MD, MMSc, an oncocardiologist who specializes in the cardiac care of cancer patients at Harvard Medical School in Boston, said that this study furthers our understanding the vascular effects of the small-molecule tyrosine kinase inhibitors.

She added that the study supports the observation of earlier trials that showed cardiac ATEs such as myocardial infarction.

With greater awareness of the ATE risk of these important anticancer agents, "clinicians and patients alike can partner in the early detection and management of any thrombolic events that occur," Dr. Chen added.

Cancer Patients Need These Drugs

Dr. Choueiri said care should be taken when using sunitinib and sorafenib, especially in patients who might be vulnerable to their effects.

"We should not stop using the drugs. Absolutely not. They have made an enormous difference to the way we treat these cancers. But we do have to exert caution, especially in a predisposed population," he told Medscape Oncology. "These would include people who have had a previous stroke, older people, those with uncontrolled hypertension, diabetes, a history of thrombolic events, and so on. The first thing is to know that ATEs can occur. The next most important thing is to monitor your patients. Don't just give them the drug and then see them 2 months later. Bring them back frequently and monitor closely."

Dr. Choueiri and Dr. Chen have disclosed no relevant financial relationships. In the paper, Dr. Choueri reports having had relationships with Bayer Pharmaceuticals/Onyx Pharmaceuticals, GlaxoSmithKline, Abbott Laboratories, Genentech, Agennix, Novartis, and Pfizer, but adds that he has received no compensation for these relationships.

J Clin Oncol. Published online March?29, 2010.