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。
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。
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.
