New Take on an Old Problem: Tackling VTE With Biomarkers, Risk Models, and Novel Drugs

Alok Khorana, MD

Despite advances in the oncology field, venous thromboembolism (VTE) remains a significant problem for patients with cancer. VTE, manifesting as deep vein thrombosis and pulmonary embolism (PE), is the second-leading cause of death among patients with cancer, after cancer itself.¹ It can also cause significant delays in treatment, and affect short- and long-term survival.

Although VTE is not a new problem in oncology, it is poised to become a more pressing one. The overall incidence of VTE among US adults is projected to double by 2050, and cancer is among the comorbidities significantly associated with its prevalence.² The reasons that cancer increases the risk of VTE appear to be related to the manner in which a malignancy affects at least 1 of 3 aspects of the Virchow triad for the formation of VTE: stasis (eg, extended bed4 rest; blockage of blood flow caused by the tumor), vessel damage (eg, tumor invasion; introduction of devices such as central catheters), and hypercoagulability. Genetics also plays a role in VTE, as it does in some cancers.³

VTE among patients with cancer was first reported in 1823 by Jean Baptist Bouillaud and again in 1865 by Armand Trousseau. Ironically, Trousseau died in 1867 of VTE, possibly related to gastric cancer.⁵

In recent years, efforts to understand the underlying causes of VTE have focused on identifying biomarkers and creating risk stratification models to help predict which patients may develop VTEs and, thus, which individuals would benefit from prophylaxis. In October 2016, the International Initiative on Thrombosis and Cancer (ITAC) published the latest set of guidelines on VTE that include a detailed analysis of clinical trial evidence regarding novel oral agents.⁶

Defining VTE Risk Factors

New oral anticoagulants have emerged as an attractive potential alternative for patients with cancer who develop VTE and their efficacy and safety are being investigated currently. Some experts, however, believe that clinicians are underusing current tools for managing VTE; therefore, educating patients, families, and providers about the signs and symptoms of VTE is of paramount importance since their awareness can save lives.Patients with cancer and those who have had previous VTE are among the highest risk groups for VTE. And, although all patients with cancer are at some risk of developing VTE, some cancers carry a higher risk (Table).

“Which kind of cancer they have is one of the most important factors. Patients with hematologic malignancies, like lymphoma; lung cancer; gastrointestinal (GI) cancer, especially of the stomach and pancreas; genitourinary cancer (GU) cancer, although not prostate cancer as much as the other GU cancers, kidney cancer; and gynecologic cancers have the highest risk,” said Mary Cushman, MD, a spokesperson for the American Society of Hematology (ASH) in an interview with OncologyLive.^® She is a hematologist who is medical director of the Thrombosis and Hemostasis Program at the University of Vermont Medical Center, and professor at the university’s Larner College of Medicine.^®

The estimated incidence of VTE in oncology is about 15% but, according to Rachel P. Rosovsky, MD, a hematologist at Massachusetts General Hospital and director of the Education Committee for the National Pulmonary Embolism Response Team (PERT) Consortium, it can range anywhere from 4% to 30%. Consistent numbers are difficult to determine because different studies investigating the relationship between cancer and VTE have used different parameters.

In addition to the risk from cancer, once a patient with cancer has had a VTE, he or she is at increased risk of having another, with more serious consequences. “Cancer patients with VTE are 2 to 3 times more likely to have recurrent VTE than noncancer patients with VTE and are 2 to 6 times more likely to have hemorrhagic complications,” Rosovsky explained in an interview.

“In addition to the cancer in and of itself, having advanced or metastatic disease places patients at a higher risk of developing VTE,” Rosovsky said. A large retrospective study in the Netherlands that looked at 66,329 patients found that patients with distant metastases had a 1.9-fold increased risk of VTE compared with patients without metastases. ⁷ “Cancer patients with VTE are also more likely to have shorter survivals,” Rosovsky pointed out. A Danish study showed that patients with cancer who developed VTE had a 1-year survival of 12% compared with 36% in patients with cancer without VTE. ⁸

Hospital admission is another VTE risk factor in this population. Hospitalization itself resulted in a VTE rate of 12.3 per 1000 patients with cancer.⁷ This increased risk for VTE during hospitalization is recognized by the American Society of Clinical Oncology (ASCO) as a critical area for improvement and has generated separate VTE prophylaxis guidelines for hospitalized patients.⁹ Treatment modalities also may play a role in development of VTE. According to the Dutch study, those who had hormonal therapy had a 1.6-fold increased risk of VTE, while chemotherapy led to a 2.2-fold increased risk, compared with patients who did not receive these treatments.

Table. Assesing the Risk Factors for Cancer-Associated VTE The Khorana Calculator

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Cancer-associated venous thromboembolitic disease version I.2016. Updated July 22, 2016. www.nccn.org/professionals/physician_gls/f_guidelines.asp#detection. Accessed February 20, 2017.

A new study published January 2017 in BMC Cancer also suggests that cisplatin-based chemotherapy may increase the incidence of VTE.¹⁰ In this small study of 200 patients, most with metastatic disease, researchers found 31 VTE events in patients with higher mean cumulative dose and no VTE events in those receiving a lower mean cumulative dose. The authors did note that more research is needed to substantiate these findings.

Should It Be Prophylaxis for All?

Surgery is another risk factor for VTE among both the general population and those with cancer, and some surgical procedures appear more thrombogenic. For example, according to a study published in 2011, patients who underwent esophageal resection had a VTE rate of 13.2% compared with a VTE rate of 1.8% among patients who underwent prostatectomy. ¹¹ Most patients with cancer undergoing surgery are treated with prophylaxis, and current ASCO guidelines specifically refer to the possible need to extend prophylaxis for longer duration for patients with high-risk features who undergo major abdominal or pelvic surgery.⁹Given the higher risk for VTE among patients with cancer, would prophylaxis for all patients be an appropriate approach in patient management? Not according to the latest guidelines.

According to Alok A. Khorana, MD, director of the Gastrointestinal Malignancies Program at Cleveland Clinic’s Taussig Cancer Institute, researchers have not yet conducted cancer-specific studies and this has resulted in a major knowledge gap in the field.¹

“In more recent years, my collaborators and I developed a risk assessment tool that helps predict which patients are at risk for VTE and that takes into account the type of cancer, but it also takes in other variables, such as obesity, anemia, elevated leukocyte count and elevated platelet count,” Khorana said in an interview.

This is now known as the Khorana Score (Table).¹² “If you score a 3 or higher on that risk score, then you’re at most risk for developing a VTE. The risk score has been validated on 15,000 patients so far and it’s endorsed by the ASCO guidelines, and other guidelines as the best way to assess for VTE risk in cancer patients,” Khorana said.

Rosovsky also pointed out the recent Microtec study, which investigated how circulating tissue-factor bearing microparticles (TFMP) may affect the development of VTE. “We took cancer patients with elevated TFMP and randomized them to either a prophylactic dose of enoxaparin or observation,” she said. “We found that in the patients who had high TFMP and received no blood thinner, the rate of VTE was 27.3%. In the patients who had high TFMP and received enoxaparin, the rate of VTE was only 5.6%,” Rosovsky said. “Using biomarkers such as TFMP may help stratify cancer patients in regard to their risk of VTE and help identify which patients may benefit from prophylactic anticoagulation.”

Following a review of 53 publications, ASCO published recommendations in January 2015, which remained unchanged from their 2013 guidelines.⁹ Patients with active cancer who are hospitalized usually require thromboprophylaxis, but routine prophylaxis for cancer patients outside the hospital is not recommended if they are not at high risk for VTE.

Current Management of VTE

Patients who undergo major surgery should start receiving thromboprophylaxis before the surgery, followed by at least 7 to 10 days postoperatively. For patients undergoing major abdominal or pelvic surgery with high-risk features, up to 4 weeks of continued treatment should be considered. Patients with multiple myeloma who are receiving treatment with antiangiogenesis agents and/or dexamethasone should also receive thromboprophylaxis.There has been much discussion among clinicians and researchers about how best to manage VTE in patients with cancer. Since no studies specifically look at these populations, there are no set rules for anticoagulant use. “The treatment trials that utilize these agents compare the new drugs with warfarin,” Khorana said. “But many of those trials excluded patients with cancer. Globally speaking, there was a small percentage of patients in these large trials who were cancer patients, and then we’re still not sure if they were active cancer patients or if they had a history of cancer.”

“Standard of care for cancer patients with VTE is still LMWH [low molecular weight heparin]; however, novel agents may be an attractive alternative, and their efficacy and safety in cancer patients are being investigated currently,” Rosovsky said. For years, the vitamin K antagonist warfarin was the only oral anticoagulant available to manage VTE.¹³ Hematologists now have direct oral anticoagulants (DOACs) they can use, with 4 agents approved in the United States: dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa).¹³ However, data for these agents in patients with active cancer are lacking.

As a result, the consensus is to use LMWHs, such as dalteparin, enoxaparin, and tinzaparin, over warfarin. There is also concern that some cancer-associated VTE may be resistant to warfarin.¹⁴ However, physicians may experience push-back from some patients and the chance of non-compliance from those who do not want to give themselves regular injections as required with LMWHs, preferring warfarin or a DOAC, which are taken orally.

According to Khorana, the most robust evidence regarding the use of LMWH as the standard of care is demonstrated by the results of the CLOT trial. The study findings showed that 8% of patients who received dalteparin over 6 months developed recurrent VTE compared with 15.8% of those who took warfarin.¹⁵

Another trial, the CATCH trial, evaluated the effectiveness and safety of tinzaparin versus warfarin. It found that fewer patients in the tinzaparin arm, 7.2%, experienced recurrent VTE compared with the warfarin arm at 10.5%, but there were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin). There was, however, a significant difference in clinically relevant nonmajor bleeding, experienced by 11% in the tinzaparin arm compared with 16% in the warfarin arm.^{14, 16}

Given these trials and limited available data regarding patients with cancer, the ASCO guidelines recommend that LWMH continue to be used. They do not recommend the use of DOACs at this point. Guidelines from the American College of Physicians, published in February 2016, concur.¹⁷ Although the ITAC guidelines favor LMWH, the recommendations also say that DOACs may be considered to treat VTE in patients with stable cancer not receiving systemic therapy, or if a vitamin K antagonist is indicated but not available.⁶ Indeed, the ITAC guidelines note that the use of DOACs to treat patients with cancer is growing; in 2015, DOACs were prescribed in 20% of patients with cancer in the United States and worldwide.⁶

DOACs offer the advantage of ease of administration and fixed-dose regimens compared with LMWH therapy. But interactions between DOACs and chemotherapy and antiangiogenic agents pose a risk.⁶ More studies are needed to assess the appropriate dosing, safety, and efficacy of DOACs as a treatment for VTE in patients with cancer, the ITAC guidelines panelists concluded. Although data analyses suggest that DOACs are noninferior to vitamin K antagonists for this population, direct comparisons with LWMH are lacking. More than 35 clinical trials have been launched to compare DOACs with LMWH, the ITAC panel said. When it comes to length of treatment for VTE, opinions also vary; although the consensus is 6 months for curable cancers, this needs to be reevaluated for ongoing risks, Rosovsky said. Spreading the Word Among Oncologists Although the recommendations regarding anticoagulation treatment for patients with cancer are available, there is still a need for better education for oncologists. A study presented at the 2015 ASH Annual Meeting found that many community oncologists were not yet following practice guidelines.¹⁸

“Oncologists are very focused on their treatment of the cancer and that’s a good thing: delivering chemotherapy on time and without delay, and so forth,” Cushman said. “It’s important for providers to consider that when VTE occurs, this often causes treatment delays and other complications such as bleeding. So if we prevent VTE, we can reduce a lot of suffering for patients, getting them to their treatments on time, without added morbidity.”

Educating the Patients

Rosovsky also sees a need for a greater appreciation of the potential for VTE. “I think there can be a lack of awareness among patients and even providers about blood clots, and I think what’s particularly difficult in cancer patients is that many of the symptoms they have from their cancer or treatment can mimic the signs and symptoms of a PE,” Rosovsky said. “For example, if a lung cancer patient is short of breath, they or their providers may think it is due to their underlying cancer, or anemia because they just received chemo, or pneumonia because they’re immunocompromised. PE is on the differential, but there are so many masqueraders of PE that it can be very difficult to tease out and PE can be missed. I think that’s what makes it especially difficult in the cancer population.”When a patient is given a cancer diagnosis, the information he or she receives can be overwhelming and certain issues may not be apparent. “The number one thing is that cancer patients are woefully unaware about the risk of getting blood clots,” Khorana said. “In a couple of surveys that were published in the past few years, as many as half to more than two-thirds of patients don’t even know what the warning signs or symptoms of a blood clot are. “I think the number one issue is education.

Flipping the Story:Idiopathic VTE and Cancer Risk

Oncologists are really good about talking to patients about how to prevent nausea and vomiting, and how you monitor your hemoglobin and white blood cell count, and so on,” Khorana said. “This is another subject that really needs to be discussed, especially in the high-risk population.” Patients also need to be aware that their situation can change, Cushman pointed out. Patients should still be taught the signs and symptoms, even if they have a relatively low risk. “Their risk level could change over time,” she said.Idiopathic, or unprovoked, VTE raises another question about cancer screening and prevention. “There are a lot of data about the risk of cancer in patients who present with idiopathic blood clots,” Rosovsky said. She noted that a hidden cancer will be found in about 15% to 20% of patients who present with an idiopathic VTE when followed for up to 2 years. “This raises a lot of questions about whether or not all patients who present with idiopathic blood clots should be screened extensively for malignancy.” One trial of 201 patients with idiopathic VTE randomized 99 patients to extensive screening (abdominal ultrasound, CT scans, endoscopies, and more) and 102 patients to limited testing (history, physical, lab tests, and chest x-ray). Cancer was found in 13 of the patients in the extensive group and none in the control group; in the 2-year follow-up period, 1 patient in the extensive screening group developed a symptomatic cancer versus 10 in the control group.

“So you think that everybody should have extensive screening,” Rosovsky said, “but when the researchers looked at the mortality, it was 2% in the extensive versus 3.9% in the control, and that was not significant.”

In a recent Canadian study, 845 patients were randomly assigned to limited occult cancer screening (basic blood tests, chest x-ray, and age-specific cancer screening) or limited screening plus an abdominal/pelvic CT.19 The primary outcome was a confirmed cancer that was missed in the screening strategy and detected by the end of 1-year follow-up. “At the beginning of the screening period, there were 3.2% cancers found in the limited screening and 4.5% cancers in the limited plus CT, but that finding was not significant [P = .28],” Rosovsky said. “At the 1-year follow-up, they found 4 occult cancers in the limited group and 5 in the limited plus CT group, but that was also not significant.” Rosovsky suggests, as do current guidelines, that patients who present with idiopathic VTE undergo age-appropriate cancer-related screening (mammogram, colonoscopy, pap smear, prostate-specific antigen), along with pursuing any abnormalities found on history, physical exam, or basic labs.

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