| 作者：Allison Gandey |
| 出處：WebMD醫學新聞 |
May 30, 2006 — 紅血球生成素（Epo）─常被用於癌症病患之貧血─可降低輸血需求，但也可能增加血栓性栓塞風險，而無法改善存活率；這些發現刊登於5月17日出版的美國國家癌症研究院期刊期刊中的一篇後設分析(meta-analysis)。
研究團隊指出，儘管稍早時美國FDA 提出有關安全性之勸告，許多醫師和研究者仍持續忽略潛在危害；來自德國科隆大學的主要研究者Julia Bohlius醫師向Medscape表示，Epo增加了血栓性栓塞風險，可能醫師和臨床研究者對此潛在併發症仍未有足夠注意。
Bohlius醫師和她的團隊提出警告，當癌症病患使用紅血球生成素和血栓形成作用化學治療劑時，會造成高風險。
美國癌症學會的醫學編輯、Herman Kattlove醫師表示，對此發現我並不感到驚訝，這只是把之前曾喧騰一時的論點加以確定；Kattlove 醫師認為紅血球生成素製造商在行銷上的努力鼓吹了醫師們提高其對改善病患血紅蛋白之目標值；他認為爭議處在於，並不需要有正常的血紅蛋白值才表示是正常的。
2004年時，美國FDA諮詢委員會提出使用紅血球生成素和血栓性栓塞風險的關聯是否存在之疑問；來自FDA藥品評估及研究中心的主要作者Harvey Luksenburg醫師，在所準備的簡短摘要中提到，該團隊認為應考慮起因，而他們認為血紅蛋白快速增加會導致血壓升高、血管栓塞、缺血和梗塞。
這位FDA 的評論者指出，關於臨床實務，醫師們應該依照血紅蛋白增加速率調整劑量，而不是照著包裝裡面的說明書。
【分析超過十年的數據】
目前的這篇後設分析中，Bohlius醫師和她的團隊分析了一些隨機控制研究，比較紅血球生成素併輸血或僅有輸血於進行或未進行化療之癌症病患預防或治療貧血。
研究團隊共回顧57篇試驗、共計超過9350位癌症病患，他們發現那些以epoetin (Epogen, Amgen; Procrit, Ortho Biotech) 或darbepoetin (Aranesp, Amgen)治療者，比控制組較低風險(相對危險比、0.64；95% 信心區間[CI]、0.60 - 0.68)；他們也發現接受這些製劑的病患較容易使血紅蛋白增加2 g/dL (相對危險比、3.43；95% CI、 3.07 - 3.84)。
但是，這樣的治療和增加血栓性栓塞風險有關(相對危險比、1.67；95% CI：1.35 - 2.06；35篇試驗、包含6769 位病患)，Bohlius醫師和她的團隊提出質疑，認為此藥是否會降低存活率，他們指出，統計上的不具顯著意義之危險比(1.08；95% CI，0.99 - 1.18) ，意指以epoetin或 darbepoetin治療，存活率並未因治療改善，且存活率可能因而降低的可能性也增加。
團隊中有個別成員提到接受Amgen and Ortho Biotech之贊助；這些最新發現和作者們稍早的後設分析所認為的紅血球生成素可以增加存活率有所衝突。
Bohlius醫師向Medscape表示，在2001年前後出版的文獻之存活率差異，在於研究的世代不同，此點是惹人注目的；然而，這些改變或許因利益導向、偏見等因素影響了研究設計之後而有所不同。
【貧血之潛在危害】
較新的研究包含了無貧血的病患、增加血紅蛋白值超過產品標籤之建議值，但是作者們指出他們並無個別病患與此相關之數據。
研究團隊指出，高血紅蛋白值和血栓性栓塞風險之間或許有著因果關係，而重組之紅血球生成素也可能會致栓塞，機轉則和血紅蛋白值無關；他們的結論認為，以epoetin 或darbepoetin調控癌症病患的血紅蛋白值達超過12 g/dL時，會有潛在傷害。 |
Evidence Mounting That Erythropoietins Boost Thromboembolism Risk
By Allison Gandey
Medscape Medical News
May 30, 2006 — Erythropoietins — frequently used in cancer patients to correct anemia — can reduce the need for blood transfusions but may also increase the risk of thromboembolism and may not improve survival. These are the findings of a meta-analysis reported in the May 17 issue of the Journal of the National Cancer Institute.
The researchers say that despite an early US Food and Drug Administration (FDA) advisory alerting of safety concerns, many clinicians and investigators continue to overlook the potential harm. "Epo increases the risk for thromboembolic events," lead author Julia Bohlius, MD, from the University of Cologne in Germany, told Medscape. "Maybe both physicians and clinical researchers have not paid close enough attention to this potential complication."
Dr. Bohlius and her team caution against using erythropoietins with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for events.
"I'm not surprised by this finding," Herman Kattlove, MD, a medical editor at the American Cancer Society in Atlanta, Georgia, said during an interview. "This confirmed the concerns that had been floating around for awhile." Kattlove says that marketing efforts by the manufacturers of erythropoietins have largely encouraged clinicians to aim too high when correcting hemoglobin levels. "You don't need to have a normal hemoglobin to feel normal," he argues.
In 2004, a US Food and Drug Administration advisory committee questioned whether a link existed between the use of erythropoietins and thromboembolic events. In a briefing document prepared by lead author Harvey Luksenburg, MD, from the FDA's Center for Drug Evaluation and Research, Rockville, Maryland, the group said there is cause to be concerned, and they pointed to an association between a rapid rise in hemoglobin and an increased incidence of hypertension, vascular thrombosis, ischemia, and infarction.
"With regard to clinical practice," the FDA reviewers write, "clinicians should adhere to the dose adjustments governing the rate of rise of hemoglobin that have been incorporated into the package inserts.”
Analyzing More Than a Decade of Data
In the current meta-analysis, Dr. Bohlius and her team include randomized controlled trials that compared erythropoietins plus red-blood-cell transfusion with red-blood-cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy.
The researchers looked at 57 trials and included over 9350 cancer patients. They found that those treated with epoetin (Epogen, Amgen; Procrit, Ortho Biotech) or darbepoetin (Aranesp, Amgen) had a lower risk of transfusion than control subjects (relative risk, 0.64; 95% confidence interval [CI], 0.60 - 0.68). They also found that patients receiving the products were more likely to achieve a hemoglobin increase of 2 g/dL (relative risk, 3.43; 95% CI, 3.07 - 3.84).
But therapy was linked to an increased risk of thromboembolic events (relative risk, 1.67; 95% CI, 1.35 - 2.06; 35 trials including 6769 patients). Dr. Bohlius and colleagues also question whether the drugs may actually decrease survival. They write, "The [statistically nonsignificant] pooled hazard ratio (1.08; 95% CI, 0.99 - 1.18) indicates that survival was not improved by treatment and raises the possibility that survival may be decreased among patients treated with epoetin or darbepoetin."
Individual members of the research team report that they received funding from Amgen and Ortho Biotech. These latest findings conflict with the authors' earlier meta-analysis, which suggested that erythropoietins increase survival.
"The difference in survival between the study cohorts published before and after 2001 is striking," Dr. Bohlius told Medscape. "However, this change in direction from beneficial to detrimental might be caused by bias, confounding, or chance or may truly reflect the changes in the design of the trials."
Targeting Beyond Anemia Potentially Harmful
Newer trials included nonanemic patients or aimed to increase hemoglobin to levels higher than those recommended by product labels, but the authors point out that they did not have the individual patient data needed to clarify these possible associations.
The researchers note that while a causal relationship may exist between higher hemoglobin levels and the risk of thromboembolism, it is also possible that recombinant erythropoietins are thrombogenic by mechanisms that are independent of hemoglobin levels. They conclude that treatment with epoetin or darbepoetin to target hemoglobin levels beyond that of anemia (>12 g/dL) in cancer patients is potentially harmful and should be considered only in an experimental setting.
J Natl Cancer Inst. 2006;98:708-714 |
