HIGH PLATELET COUNT AS ADVERSE PROGNOSTIC FACTOR IN OVARIAN CANCER

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. Abstract