Clotting – What's New in GU?

Babak B. Navi, MD, MS
Stroke Center Director
Assistant Professor of Neurology
Weill Cornell Medicine | NewYork-Presbyterian

Over the past decade, there has been tremendous progress in cancer therapeutics. This includes targeted agents that act on specific receptors in cancer cells, immunotherapy which harnesses the body’s immune system to attack cancer cells, and personalized medicine whereby oncologists use different combinations of cancer drugs to optimize the chance of success based on the molecular profile of the tumor. These amazing scientific advances have led to prolonged survival for people with several cancer types, and it is possible that in the not-too-distant future, cancer will become more of a chronic disease with periodic flare-ups similar to what has occurred with diabetes and HIV. However, with this paradigm shift, long-term quality of life and well-being has become more important, and preventing diseases and complications that can affect these factors is paramount.

Stroke is the leading cause of disability in the United States. In addition, in many parts of the world, including Asia, it is the leading cause of death. In the United States alone, 800,000 people each year suffer stroke and this number is expected to rise as average life expectancy increases. Many factors can increase a person’s risk for stroke including age, hypertension, diabetes, high cholesterol, obesity, and smoking. Besides these traditional stroke risk factors, we now know that cancer and its treatments also increase the risk of stroke. In particular, patients with certain types of cancer, such as lung, pancreatic, and bladder cancers, as well as patients with metastatic disease, tend to have the highest risk. For instance, elderly patients with newly-diagnosed lung cancer face roughly an 8% risk of stroke in the first year after being diagnosed with cancer. In addition, cancer patients’ stroke risk varies with time and is highest in the first 3 months after diagnosis, when some cancer patients face up to a 3-fold higher risk of stroke than usual. It also turns out that certain necessary and potentially life-saving cancer treatments, including some forms of chemotherapy and radiation, can increase stroke risk.

At the moment, the exact reasons why cancer patients face a heightened risk of stroke are unclear. It is well known that circulating cancer cells can alter individuals’ clotting systems to promote clot formation but exactly how they do this is uncertain. Furthermore, doctors know that certain chemotherapy and radiotherapy treatments can damage blood vessels, but once again, the exact mechanisms underlying these processes are poorly understood.

At Weill Cornell Medicine and NewYork-Presbyterian, my team is actively working to determine what the exact risks of stroke are in people with newly diagnosed cancer, what clinical factors and biomarkers in blood can help doctors identify high-risk patients, and what the optimal strategies are to prevent and treat stroke in cancer patients. One particular study that we are currently enrolling into is entitled MOST-Cancer. This study uses cutting-edge ultrasound and blood tests to evaluate the predictors and mechanisms of stroke in people with cancer. If you or a loved one has cancer and are interested in learning more about these studies, please email our team at stroketrials@med.cornell.edu or call 212-746-6757.

May is National Stroke Awareness Month. The main intent of this campaign is to raise awareness about the symptoms and signs of stroke and to educate the public to call 911 if they suspect stroke. The most popular campaign is FAST, which stands for Face, Arm, Speech, and Time – Time to call 911.

If you or a companion develops unexplained facial asymmetry, arm weakness, or speech changes, you should call 911 immediately so that an ambulance is activated to provide rapid delivery to the closest stroke center. This is imperative as there are medicines and surgical procedures that have been proven to improve outcomes after stroke but these are only effective in the first few hours after stroke onset. Therefore, if stroke is suspected, do not hesitate, call 911, as it could be life saving!

Furthermore, I recommend that cancer patients have a frank discussion with their doctors about their individual risks for stroke and other cardiovascular diseases, as well as potential strategies to reduce their risks through medicines and lifestyle modifications.

We’ve made great strides in oncological care so that patients routinely get cured or live many years with their disease. Therefore, it is now time that we turn our attention to long-term quality of life, and in particular, to preventing stroke and the other secondary complications of cancer.

Stroke_BE FAST SIGN NEW

: Image Credit: National Cancer Institute (NCI)

What We Already Know

In the body, there is a tight relationship between cancer development and growth, treatment, and the clotting system. Cancer cells produce substances that “thicken” the blood, so men and women with cancer have a significantly higher risk of developing blood clots. On average, people with cancer are 4-7 times more likely to have blood clots than similar people without cancer. Additionally, patients with cancer being treated for blood clots with traditional anticoagulants have a higher risk of bleeding than patients without cancer.

The importance of this connection is highlighted by a dedicated conference, the International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC). The ICTHIC meeting features educational and scientific presentations on epidemiology, biology, prevention, and treatment of clotting and bleeding related to cancer.

The 8th meeting just took place in Bergamo, Italy. World-renowned clinicians and laboratory scientists once again met and updated colleagues. Highlights included multiple presentations and discussions about risk factors for and treatment of cancer-associated venous thrombosis, blood test-based biomarkers assessing the risk of the development or recurrence of clots, lab studies investigating the mechanisms of the tight relationship between the development, progression, and treatment of cancer and thrombosis, and clinical data regarding the treatment or prevention of blood clots in patients with cancer. Special lectures included Dr. Wolfram Ruf delivering the 4th Simon Karpatkin memorial lecture on “Targeting clotting proteins in cancer therapy” where he described years of research on tissue factors involved in cancer growth and spread (metastasis). Dr. Frederick Rickles described the history of the ICTHIC from its inception in 2001 and how the field has progressed since then with an improvement in both the science in the lab and in the treatment methods and diagnostics used in the patient clinic setting.

What’s New?

Much of this year’s conference focused on venous thromboembolism (VTE), which is most commonly manifested by deep vein thrombosis (DVT = blood clots usually in legs/pelvis) and pulmonary embolism (PE = blood clots in lungs). However, it is now clear that patients with cancer also suffer from a higher rate of arterial thrombosis, meaning that they experience a higher rate of heart attacks and stroke.

In the initial Plenary session on Epidemiology, Dr. Babak Navi, Assistant Professor of Neurology at Weill Cornell Medicine (WCM), presented data on the risk of heart attacks and stroke in women with breast cancer. In collaboration with colleagues at Memorial Sloan Kettering Cancer Center, he used data from a large database of patients with Medicare. This dataset showed that women diagnosed with breast cancer have a higher risk of a heart attack or stroke in the first year after diagnosis compared to similar women without breast cancer.

What We’ve Discovered

This year at ICTHIC, we presented data that followed up on a small pilot study presented at the 7th ICTHIC Meeting in 2014 in which Drs. Choe, Tagawa, and others from WCM’s Meyer Cancer Center and the Englander Institute for Precision Medicine utilized genomic data from men with different types of prostate cancer. Patients with advanced prostate cancer had higher expression of genes involved in coagulation and thrombosis compared to patients with early stage (localized) prostate cancer. Interestingly, patients with NEPC had different gene expression compared to patients with metastatic castration-resistant prostate cancer.

Historically, multiple studies showed that patients with cancer and blood clots had more recurrent clots compared to similar patients without cancer. This led to a change in practice starting in 2003 and now many patients use injectable medications (low molecular weight heparin) as opposed to the traditional oral medications (such as warfarin/Coumadin).

Shortly after this change in best practice, we launched a collaborative study with the University of Southern California, testing one of these injectable low molecular weight heparins (tinzaparin) for the treatment of patients with cancer and blood clots. Part of the study included regular and ongoing blood draws in order to examine the biology of the blood in these patients. In the Plenary session on the treatment of cancer-related blood clots, Dr. Tagawa from WCM and Drs. Piatek, Liebman and others from USC presented the results of this study to a global audience.

The results showed that Tinzaparin performed well when examining recurrent blood clot and bleeding rates. In addition, a blood test at the initial diagnosis of the clot called D-dimer was associated with the chance of a recurrent blood clot 6 months later. The team continues to investigate a number of additional blood test biomarkers from patients with and without blood clots in this study. We hope to be able to identify patients who are most likely to develop a blood clot and for those that do, who is most likely to have recurrence of their blood clot. In the future, this may lead to individualization of the type and/or length of treatment.

What We’re Still Trying to Find Out

WCM and other investigators continue to delve into the problem of neuroendocrine prostate cancer (NEPC), an increasingly common lethal form of the disease. Clinicians dealing with this disease believe that men with this variant of prostate cancer suffer from more blood clots than those with the more common types. However, we still don’t know whether this is related to bulkier tumors, the propensity of treating physicians to use platinum-chemotherapy (which is associated with clots), or underlying disease biology.

In addition to gaining additional insight for individual patients using biomarkers, we are also continuing to develop new drugs for the treatment of clots in patients with cancer. Several new oral agents work in patients without cancer with preliminary data in cancer patients, as well. WCM physicians are joining a global study comparing one of these new oral drugs with the standard injectable medication.