血小板數值高減少了卵巢癌存活


  【24drs.com】根據發表於2月16日新英格蘭醫學期刊的研究,三分之一的卵巢癌婦女有血小板增多症,也就是血小板數偏高,因此,疾病特定存活率降低的風險增加。
  
  德州大學安德森癌症中心Anil Sood醫師在新聞稿中表示,我們知道卵巢癌病患的血小板數值通常顯著升高,但是我們不清楚何以發生,也不暸解相關性與病程。
  
  Sood醫師等人在美國的4個學院中心、對619名卵巢癌病患進行了前瞻研究,發現192人(31%)患有血小板增多症。
  
  這些血小板增多婦女,存活中位數為2.62年;如果是血小板計數正常者,則是4.65年(P< .001)。納入年紀、疾病分期、腫瘤等級和類型、手術減少腫瘤範圍等因素的多變項分析發現,血小板增多症仍然是存活不佳的獨立預測因子(P< .001)。
  
  Sood醫師表示,血小板的功能可能是腫瘤的能量來源,提供生長因子給腫瘤。「血小板是癌症生長和轉移的關鍵因素」這個觀念是「經年累月累積下來的」,提出實質腫瘤病患的血小板增多症的第一篇臨床觀察可追溯到100年前。
  
  作者們寫道,不過,血小板值這麼高的機轉和生物學重要性還未被充分暸解。
  
  受到這些臨床發現的啟發,研究團隊進行了動物實驗,分析血小板增多症的生物學原因。
  
  老鼠研究中,研究者發現,卵巢癌產生了發炎性的細胞激素、介白素-6(IL)-6,刺激促血小板生成素產生,使得血小板數飆升,並顯著刺激腫瘤生長。
  
  臨床前研究的這些結果,促使研究者結論指出,附腫瘤性血小板增多症在癌症病程中,可能不只是單純的偶然現象,而可能是病程的促成因子。
  
  臨床前研究最後促成了18個病患使用抗IL-6製劑的臨床試驗,也登載於這篇報告。
  
  這個1/2期研究是在英國倫敦大學Barts癌症研究中心進行,發現使用IL-6抗體、siltuximab治療,每2週1次、為期12週,血小板數量顯著且持續降低(P= .009)。
  
  整體的發現使研究者提出「對卵巢癌直接進行抗血小板策略」這個假設。(Siltuximab不符合這種策略。)
  
  他們寫道,附腫瘤性血小板增多症預示著不良的臨床結果,針對此使用直接的抗血小板策略,有可能作為人類的一種有價值的治療方法。
  
  這個方法已經有先例可循,例如,診斷大腸直腸癌之後每天使用阿斯匹靈可降低癌症特定死亡率和整體死亡率。
  
  此外,許多前瞻臨床試驗顯示,低分子量肝素改善了多種癌症病患的存活,而這好處和預防因為抗凝集性引起的血管栓塞併發症無關。
  
  這意味著醫師應使用阿斯匹靈等抗血小板藥物治療卵巢癌病患嗎?未參與這篇研究的專家表示,不是的。
  
  賓州費城美國癌症治療中心的Maurie Markman醫師表示,加入抗血小板治療是有危險的,因為標準化療會引起血小板減少症,抗血小板治療會導致出血併發症;需要仔細地研究設計並進行臨床試驗來探索這個觀念。
  
  不過,研究作者之一認為,這篇研究結果有即時性的臨床應用。
  
  同樣來自安德森癌症中心的Rebecca Stone醫師表示,血小板值可作為卵巢癌和其他癌症的生物標記,如果你發現高血小板缺少性發炎或缺鐵,一定要做癌症篩檢。
  
  這篇研究中,血小板增多症定義為血小板數量超過450,000/mL3,192名血小板增加症婦女中,只有一部份(2%)有缺鐵或非癌症性發炎,這些是血小板值增加的共通原因,因此,血小板增多症顯然與卵巢癌有關。
  
  作者們表示,和血小板值正常者相比,除了存活比較不佳,血小板增多症病患更可能發生末期疾病、血管栓塞併發症、術前的癌症抗原125值較高。血小板增多症婦女疾病惡化期間的中位數也顯著比血小板正常者更短。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6737&x_classno=0&x_chkdelpoint=Y
  

High Platelet Counts Shorten Ovarian Cancer Survival

By Nick Mulcahy
Medscape Medical News

February 16, 2012 — One in 3 women with ovarian cancer have thrombocytosis, or high platelet counts, and are consequently at a significantly increased risk for reduced disease-specific survival, according to research published in the February 16 issue of the New England Journal of Medicine.

"We've long known that ovarian cancer patients often have markedly increased platelet counts, but we haven't known why this happens or understood its relevance, if any, to disease progression," said senior author Anil Sood, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, in a press statement.

In a prospective study of 619 consecutive ovarian cancer patients conducted at 4 academic centers in the United States, Dr. Sood and colleagues found that 192 (31%) had thrombocytosis.

For women with thrombocytosis, median survival was 2.62 years; for those with normal platelet counts, it was 4.65 years (P < .001). In a multivariate analysis that accounted for age, disease stage, tumor grade and type, and the extent of surgical tumor reduction, thrombocytosis remained an independent predictor of poor survival (P < .001).

"Platelets may function as a fuel depot for tumors by providing them with growth factors," Dr. Sood said.

The idea that platelets play key roles in cancer growth and metastasis is "long-standing," say Dr. Sood and his coauthors, who note that the first clinical observation of thrombocytosis in patients with solid tumors was made more than 100 years ago.

However, the mechanisms and biologic significance of this surge in platelets are "not well understood," write the authors.

Inspired by the clinical findings, the team undertook animal studies to analyze the biologic drivers of thrombocytosis.

In mice, they found that ovarian cancers produce the inflammatory cytokine interleukin (IL)-6, which spurs the platelet-production hormone thrombopoietin, causes platelet counts to soar, and apparently stimulates tumor growth.

The insights from their preclinical research led the researchers to conclude that "paraneoplastic thrombocytosis may be not simply an epiphenomenon of cancer progression, but a contributor to the process."

The preclinical studies eventually led to an 18-patient clinical trial of an agent that counters IL-6, which is also reported in the paper.

The phase 1/2 study was conducted at the Barts Cancer Institute, Queen Mary, University of London, United Kingdom, and found that single-agent treatment with siltuximab, an antibody to IL-6, every 2 weeks for 12 weeks "resulted in a significant and sustained reduction" in platelet counts (P = .009), the authors report.

Direct Antiplatelet Therapy for Ovarian Cancer Proposed

The overall findings inspired the researchers to generate a hypothesis about using "direct antiplatelet strategies" for ovarian cancer. (Siltuximab does not qualify as such a strategy.)

They write: "Given that paraneoplastic thrombocytosis portends adverse clinical outcomes, countering it and using direct antiplatelet strategies have the potential to serve as a valuable therapeutic approach in humans."

There are precedents for this approach. For instance, the daily use of aspirin after a diagnosis of colorectal cancer decreases cancer-specific and overall mortality.

Also, several prospective clinical trials have shown that low-molecular-weight heparin improves survival in patients with various cancers, and that the benefit is independent of the prevention of vascular thromboembolic complications due to anticoagulation.

Does this mean that clinicians should treat ovarian cancer patients with antiplatelet drugs, including aspirin?

No, says an expert not involved with the current research.

"It would be dangerous to simply add antiplatelet therapy, considering the fact standard chemotherapy may cause thrombocytopenia and antiplatelet therapy could result in bleeding complications," said Maurie Markman, MD, from the Cancer Treatment Centers of America in Philadelphia, Pennsylvania.

"Exploration of this concept will require carefully designed and conducted clinical trials," he told Medscape Medical News in an email.

However, one of the study authors suggested that the results of this study have an immediate clinical application.

Platelet levels might serve as biomarkers for ovarian and other cancers, said lead author Rebecca Stone, MD, also from the M.D. Anderson Cancer Center. "If you see high platelets absent inflammation or iron deficiency, it would be important to look for cancer," she said in a press statement.

More Study Details

In the study, thrombocytosis was defined as having platelet counts of more than 450,000/mL3. Of the 192 women in the study with thrombocytosis, only a fraction (2%) had an iron deficiency or a noncancerous inflammatory condition, which are common causes of elevated platelet levels, the authors report. Thus, the thrombocytosis appeared to be clearly linked to the ovarian cancer.

In addition to having poorer survival, patients with thrombocytosis were significantly more likely to have advanced-stage disease, vascular thromboembolic complications, and higher preoperative levels of cancer antigen 125 than those with normal platelet counts, the authors write. Women with thrombocytosis also had a significantly shorter median time to disease progression than those with normal platelet counts.

The study was funded by the National Cancer Institute and others. The siltuximab trial was funded by the British Medical Research Council and sponsored and monitored by Queen Mary, University of London. Dr. Stone holds a patent in cancer therapy. The remaining authors have disclosed no relevant financial relationships.

N Engl J Med. 2012;366:610-618.

    
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