Prospective trials, society guidelines offer new insights into cancer-associated thrombosis

Approximately one in five patients with cancer will develop venous thromboembolism.

However, questions about the ideal strategies to detect, prevent and treat this complication — the second-leading cause of death among patients with cancer — still vex the clinical community.

For example, debate continues about whether all patients with cancer — including those who receive outpatient treatment — should receive VTE prophylaxis.

Additionally, research presented in December at ASH Annual Meeting and Exposition raised new questions about the most appropriate type of anticoagulation for those who develop cancer-associated thrombosis.

Also, there is no consensus for optimal duration of treatment for this population.

“Both the incidence and morbidity associated with VTE are often overlooked and understudied,” Jai N. Patel, PharmD, BCOP, chief of pharmacology research at Levine Cancer Institute at Carolinas HealthCare System and HemOnc Today’s pharmacology section editor, said in an interview. “Consideration of VTE comes secondary to the treatment of cancer, which really is inevitable — both from the patient perspective and provider perspective.”

Source: ©Russell Lee.

Research into cancer-associated VTE has intensified the past few years, raising awareness of the condition among members of the clinical community, according to Alok A. Khorana, MD, professor of medicine at Cleveland Clinic Lerner College of Medicine, vice chair for clinical services at Taussig Cancer Institute and director of the gastrointestinal malignancies program at Cleveland Clinic.

He pointed to new trials designed to examine the safety and efficacy of direct oral anticoagulants for treatment of cancer-associated thrombosis, other large studies that are assessing prevention strategies, and an improved understanding of risk factors.

“There has definitely been an upsurge in the number of investigative teams on this topic,” Khorana told HemOnc Today. “This is a very good sign for the field.”

HemOnc Today spoke with hematologists and oncologists about VTE risk among individuals with cancer, best practices for prevention and treatment, and how results of recently completed trials and new society-issued guidelines may inform decision-making.

Multifactorial risks

Patients with cancer are six times more likely than those in the general population to develop VTE. The reasons for this elevated risk are multifactorial.

One contributor is the malignancy itself.

Tumor cells release microparticles that contain tissue factor, the primary initiator of coagulation. Tumor cells also stimulate platelet activation, thereby increasing VTE risk.

“It is not one mechanism, but a combination of all of these different pathophysiologic mechanisms,” Khorana said. “In addition to the tumor cells driving coagulation, most of the things we do to treat cancer also increase VTE risk.”

Chemotherapy stimulates platelet activation. It also is toxic to the lining of the endothelium, and endothelin injury leads to coagulation. Major surgical procedures also increase VTE risk.

Despite the known risk factors, decisions about who and when to screen remain challenging.

In addition, guidelines have not provided concrete, consistent recommendations about when to recommend VTE prophylaxis and — if it is warranted — which prophylaxis to use.

This is largely due to a lack of definitive data, Patel said.

“As providers, we are not always thinking about VTE risk when primary treatment of the cancer is the focus,” Patel said. “We are not routinely screening patients or even considering patients for clinical trial participation. ...

“All patients with cancer should be made aware of the risk associated with VTE,” he added. “Those defined as high risk should ultimately be monitored more closely for symptoms of VTE, screened by compression ultrasonography, or perhaps referred to a benign hematologic specialist for consideration of thromboprophylaxis.”

Risk assessments

When clinicians try to determine which patients with cancer are at greatest risk for VTE, they must be aware of significant variation based on malignancy.

For example, patients with metastatic pancreatic cancer, gastric cancer or brain tumors are at greatest risk for VTE, whereas those with early-stage breast cancer and prostate cancer are at low risk. However, even patients with cancers that are associated with lower rates of VTE are still at much higher risk than individuals without cancer.

Treatment regimens also can contribute to risk.

“Data on this subject are evolving,” Khorana said. “There are certainly chemotherapy drugs that we know are definitely associated with VTE risk, such as cisplatin.”

Some newer agents — such as bevacizumab (Avastin, Genentech), sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer) — are significantly associated with risk for arterial events, but no clear link to VTE risk has been established, Khorana said.

Anti-EGFR antibodies, but not anti-EGFR small molecules, are associated with risk for VTE.

Patients with myeloma treated with lenalidomide (Revlimid, Celgene)- or thalidomide (Thalomid, Celgene)-based regimens in combination with dexamethasone are at high risk for VTE. However, cancer type may be a more important factor than the treatment regimen.

Khorana and colleagues created the Khorana risk score to predict risk for VTE among patients with cancer. The score — recommended by ASCO and the National Comprehensive Cancer Network — is based on the type of malignancy patients have, as well as factors such as BMI and blood counts.

“I may be biased, but the Khorana risk score remains the only guideline-approved and validated risk score for predicting VTE risk,” Khorana told HemOnc Today. “Multiple modifications to the score have been proposed during the past few years, such as the addition of biomarkers D-dimer and P-selectin, but these modifications have not yet been fully validated.”

Two large, ongoing trials are using the score to predict which patients with cancer are at highest risk for VTE. Researchers will randomly assign high-risk patients to prophylaxis or placebo to “further elucidate risk prediction and the utility of VTE prophylaxis in this setting,” Khorana said.

Although the score helps inform decisions about preventing VTE for patients with cancer, “it is not the gold standard,” Kenneth A. Bauer, MD, professor of medicine at Harvard Medical School, medical oncologist at Beth Israel Deaconess Medical Center and a HemOnc Today Editorial Board Member, said in an interview.

“The reason why this score is not the gold standard is because it is not standard to give prophylaxis across the board to even patients with the highest Khorana risk score,” Bauer said. “The Khorana score may be quite the gold standard when trying to identify patients at highest risk for enrollment in clinical trials, but it applies only to those who have never had a VTE.”

The potential role of biomarkers for VTE risk also remains under investigation. Research has focused predominantly on D-dimer, platelet activation marker, P-selectin and tissue factor. Tissue factor appears to be predictive of primary VTE, particularly among patients with pancreatic cancer.

The randomized CATCH trial — results of which appeared last year in Journal of Clinical Oncology — included 900 patients with cancer who experienced acute, symptomatic VTE. Researchers assigned patients to the antithrombotic drug tinzaparin 175 IU/kg daily or dose-adjusted warfarin for 6 months.

In a prespecified analysis, Khorana and colleagues evaluated the association between recurrent VTE and tissue factor, clinical risk factors and other biomarkers measured at the time of initial VTE.

Seventy-six patients (8.4%) experienced recurrent VTE. Patients in the highest quartile of tissue factor (> 64.6 pg/mL) appeared significantly more likely to experience VTE recurrence (19% vs. 6%; RR = 3.3; 95% CI, 2.1-5.1). Results of a competing risk regression analysis of time to recurrent VTE showed tissue factor remained associated with VTE recurrence (subdistribution HR [SHR] = 3.3; 95% CI, 1.7-6.4), as did venous compression from mass (SHR = 3.1; 95% CI, 1.4-6.5) and hepatobiliary cancer (SHR = 5.5; 95% CI, 2.3-13.6).

However, although tissue factor is commercialized, it is not widely available across hospitals. In addition, D-dimer has appeared promising, but the optimal cutoff has not been established.

“Several groups are looking to see whether biomarkers can predict thrombosis. This includes tissue factor-bearing microparticles, D-dimer and, more recently, soluble VEGF levels,” Jeffrey Zwicker, MD, associate professor of medicine at Harvard Medical School and chief of the section of benign hematology at Beth Israel Deaconess Medical Center, told HemOnc Today.

“Validation externally is required,” he added. “It remains unknown whether any of these existing biomarkers are any better or more specific than simply relying on tumor type for VTE risk. Feasibility remains a significant issue surrounding biomarkers, and the optimal methodology for measuring risk continues to be debated.”

VTE prophylaxis

In the absence of clear biomarkers, debate continues about whether all patients who are undergoing treatment for active cancer should receive VTE prophylaxis.

“Unfortunately, the data from trials that are underway to answer the ongoing question of whether we should administer prophylaxis to patients receiving treatment for active cancer are not yet available,” Gary H. Lyman, MD, MPH, professor in the division of medical oncology at University of Washington and medical oncologist in the breast cancer program at Seattle Cancer Care Alliance, told HemOnc Today. “Many of us are hopeful that we will start to see these results this year.”

These trials — which will use the Khorana risk score to identify patients receiving chemotherapy who are at high risk for VTE — are designed to determine whether direct oral anticoagulants are as effective and safe as standard subcutaneous low-molecular-weight heparin (LMWH) for VTE prevention.

“Many are encouraged by recent small pilot studies, as well as subgroups of high-risk score patient subgroups within larger trials where randomization to anticoagulation with LMWH has been found to significantly reduce the risk for VTE,” Lyman said.

“The stakes are higher here because, although these patients are high risk, they have not had a previous VTE,” he added. “They are receiving anticoagulation to prevent a thrombosis that has not yet occurred, and may not occur. The onus on demonstrating safety and efficacy is very high in the prevention setting.”

Guidelines from ASCO, NCCN and European Society for Medical Oncology recommend that all patients with cancer who are hospitalized or undergoing major surgery should receive VTE prophylaxis.

“Although I do not think there is dissention about the prophylaxis requirement for patients with cancer at high risk for VTE, I do think there is dissention about whether it is effective, as the dose may be inadequate,” Bauer said.

“Every patient with cancer who is hospitalized is considered a high-risk patient. There is no question [about that],” he added. “The unanswered question is whether patients with cancer who are at high risk for VTE require potentially higher doses of prophylaxis to prevent VTE. This, of course, is a double-edged sword, because these patients also are at high risk for bleeding.”

ASCO plans to update its guidelines for cancer-associated VTE this year.

ASH also is developing VTE guidelines. Lyman — who co-chairs the society’s thrombosis and cancer panel — provided an overview during a special session at the society’s annual meeting in December.

Although the recommendations were not finalized at the time of reporting, the panel is likely to recommend against routine thromboprophylaxis for ambulatory patients with cancer who are receiving chemotherapy.

The panel may recommend LMWH on a conditional basis for those at high risk who are not at elevated risk for bleeds and do not have a contraindication to anticoagulation, such as falls or hepatic dysfunction.

However, Lyman acknowledged these recommendations are hindered due to several limitations of current data.

For example:

• Most randomized controlled trials include patients with multiple cancer types, disease stages and treatments;
• Randomized controlled trial data of LMWH’s efficacy and safety for high-risk patients are limited; and
• VTE risk score results for patients with lung cancer have been inconsistent in prospective observational cohort studies, as well as in individualized patient data meta-analyses of randomized trials presented at ASH in December.

More data are needed to define the role of other VTE risk factors among patients with cancer, such as personal or family history of VTE, thrombogenic mutations, immobility and other biomarkers.

Preventing recurrence

Despite efforts to identify patients with cancer at greatest risk for VTE, a considerable percentage still develop the condition.

In those cases, clinicians must shift their attention toward optimal treatment strategies in hopes of preventing recurrence.

A study by Lee and colleagues, published in 2003 in The New England Journal of Medicine, showed LMWH reduced by half the risk for recurrence among patients with cancer who had a prior documented VTE compared with vitamin K antagonists. Other smaller studies produced similar results.

Consequently, LMWH has been the standard for prevention of VTE recurrence among patients with cancer.

However, results of two prospective studies — the Hokusai VTE-Cancer Study and the SELECT-D trial, both presented in December at ASH — provided the best evidence to date that direct oral anticoagulants may be a viable option.

Direct oral anticoagulants are the preferred option for preventing VTE recurrence among individuals without cancer; however, until recently, they have not been studied extensively in the cancer population.

“Providers have been using these agents for years and, even though there are limited data on their use in patients with cancer, they are more convenient for patients and sometimes less costly than low-molecular-weight heparin,” Patel said.

The Hokusai VTE-Cancer Study included 1,050 patients with acute symptomatic or incidental VTE. All patients received LMWH for a minimum 5 days. Patients then were randomly assigned to daily edoxaban (Savaysa, Daiichi Sankyo) or subcutaneous dalteparin (Fragmin, Pfizer), a LMWH.

Incidence of recurrent VTE or major bleeding during 1-year follow-up — the study’s primary endpoint — was 12.8% among patients assigned edoxaban and 13.5% among those assigned dalteparin. The results met the study’s noninferiority threshold of an HR below 1.5 (HR for edoxaban = 0.97; 95% CI, 0.7-1.36).

In total, 6.5% of patients assigned edoxaban experienced recurrent VTE, compared with 10.3% of patients assigned dalteparin, for a difference in risk of –3.8 percentage points (95% CI, –7.1 to –0.4).

Major bleeding occurred among 6.3% of patients assigned edoxaban and 3.2% of those assigned dalteparin, for a difference in risk of 3.1 percentage points (95% CI, 0.5-5.7). The risk for major bleeding with edoxaban appeared highest among patients with an underlying gastrointestinal malignancy (P = .02).

The SELECT-D trial, conducted at 58 sites across the United Kingdom, included 406 patients with cancer at risk for recurrent VTE. More than half (53%) had incidental pulmonary embolism, and 47% had symptomatic PE or deep vein thrombosis.

Researchers randomly assigned patients 1:1 to dalteparin or rivaroxaban (Xarelto, Janssen). After 6 months, patients with DVT who were residual vein thrombosis positive as determined by compression ultrasound, as well as those with PE at presentation, could be randomly assigned to rivaroxaban or placebo for an additional 6 months.

At 6 months, rates of VTE recurrence — the study’s primary endpoint — were 11% (95% CI, 7-17) among patients assigned dalteparin and 4% (95% CI, 2-9) among patients assigned rivaroxaban.

Based on these results, Patel said he expects use of direct oral anticoagulants in the cancer population will increase.

“It is very clear that these oral agents are noninferior to — if not better than — low-molecular-weight heparin in terms of reducing VTE recurrence,” Patel said.

Still, potential risks must be considered.

In SELECT-D, incidence of major bleeds appeared comparable between treatment groups; however, the trial excluded patients with gastrointestinal malignancy due to their increased bleeding risk.

A higher percentage of patients assigned rivaroxaban experienced clinically relevant nonmajor bleeds (13% vs. 2%). Three times as many patients assigned rivaroxaban than dalteparin experienced either major bleeds or clinically relevant nonmajor bleeds (17% vs. 5%).

“We need further studies to assess what is really going on with the bleeding rates in terms of the nature of these bleeds and whether they are related to any other risk factors a patient has,” Patel said. “We will obviously need to weigh the risks and benefits of choosing an oral anticoagulant over subcutaneous low-molecular-weight heparin.”

Patient preference likely will play a large role in the decision-making process.

“Even if we do find there is a potential small increased risk for bleeds, these oral agents are at least noninferior to what is typically being used, and some patients are willing to accept this small risk because an oral agent is a lot more convenient,” Patel said.

There also will be a learning curve for members of the clinical community.

“When the time does come for us to start routinely using these oral agents in practice, clinicians who are not familiar with them will need education on their pharmacological factors, and how the agents work, how they are absorbed and how they are metabolized,” Patel said. “We will also need to be cautious about more potential drug interactions that we did not have to think about with low-molecular-weight heparin.”

Guideline panels may want to see more data or develop a nuanced recommendation that discourages a one-size-fits-all approach for use of direct oral anticoagulants by patients with cancer until more safety and efficacy data are available, Lyman said.

“Direct oral anticoagulants are in our future as oncologists and hematologists, but we have to make sure we are not doing more harm than good for the individual patients we care for,” Lyman said. “Although these agents appear to be efficacious ... they may not be appropriate for every patient. There are definite advantages, but bleeding risk clearly will need to be assessed. Clinicians will need to judge the benefit vs. the harms for each individual patient.”

‘Game changer’

Other large, prospective randomized trials designed to compare oral anticoagulants with LMWH are underway.

They include the randomized, open-label ADAM-VTE trial — which will compare apixaban (Eliquis; Bristol-Myers Squibb, Pfizer) with dalteparin for cancer-associated VTE — and the randomized phase 3 CONKO-011 trial, which will compare the efficacy and safety of rivaroxaban with LMWH for the treatment of VTE in patients with cancer.

Additional trials may offer further insight into the prevention and treatment of VTE among patients with cancer.

The double-blind, randomized CASSINI trial is designed to determine whether ambulatory patients with cancer who are initiating systemic therapy and are at high risk for VTE (Khorana score 2) require upfront prophylaxis. Researchers will assign 700 patients to rivaroxaban or placebo for up to 6 months.

Investigators hypothesize that rivaroxaban will reduce the composite of objectively confirmed lower-extremity, proximal DVT; symptomatic, upper-extremity DVT; symptomatic or incidental PE; and VTE-related death. A safety analysis will assess major bleeding events.

“We still do not have a good grasp on whether we can prevent VTE in the outpatient setting,” Patel said. “This trial hopefully will provide us with the answers we need, but it also may provide us with more questions as to the best screening method to use.”

Although the Khorana score is being used to identify patients at high risk, some studies have shown the score may not always correctly identify high-risk patients depending on their tumor type or treatment, Patel said.

“An area that may need more study is whether we need to include other lab correlates, such as inflammatory markers, D-dimer or soluble P-selectin, in addition to Khorana risk score factors, to widen the margin of benefit,” Patel said. “The results of this study will most likely come out in the fall and likely will be a game changer for how we screen patients, whether we need to screen patients and if prophylaxis is required upfront in the ambulatory setting.”

The Cancer Associated Thrombosis and Isoquercetin (CAT IQ) trial is designed to investigate isoquercetin, a common oral flavonoid present in fruits and vegetables, for the prevention of VTE in patients with cancer.

“Protein disulfide isomerase is now known to play a key role in mediating platelet aggregation and fibrin generation,” said Zwicker, principal investigator on the trial. “We are almost finished with the phase 2 version of the study, where we are taking high-risk patients with cancer and administering this flavonoid to try to prevent thrombosis.”

Despite the increased research, the experts with whom HemOnc Today spoke suggested efforts to increase clinician and patient awareness must remain a priority.

“As oncologists, we feel very good about discussing a lot of the known toxicities of chemotherapy, including hair loss, nausea and vomiting,” Khorana said. “We are not as good at discussing the warning signs and symptoms of VTE.”

Cleveland Clinic introduced an early detection system through which patients with cancer who are at increased risk for VTE undergo lower-extremity ultrasounds. Early indications are the combination of early education and early surveillance can lead to early diagnosis of VTE and potentially avoid hospitalizations, Khorana said.

“Many patients with cancer do not know they are at increased risk for VTE,” he said. “We really need to do a better job teaching patients about the warning signs of this deadly complication and ensure we have the discussion before they start treatment.” – by Jennifer Southall

Click here to read the , “Should anticoagulation for cancer-associated thrombosis extend beyond 6 months?”

References:

Ay C, et al. Blood. 2010;doi:10.1182/blood-2010-02-270116.

Khorana AA, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.67.4564.

Khorana AA, et al. Thromb Haemost. 2017;doi:10.1160/TH17-03-0171.

Lee AY, et al. N Engl J Med. 2003;349:146-153.

Lyman GH, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.59.7351.

McBane II R, et al. Thromb Haemost. 2017;doi:10.1160/TH17-03-0193.

Raskob GE, et al. LBA-6. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

U.S. National Library of Medicine. Cancer associated thrombosis and isoquercetin (CAT IQ). Available at: www.clinicaltrials.gov/ct2/show/NCT02195232. Accessed on Feb. 4, 2018.

U.S. National Library of Medicine. Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients. Available at: https://clinicaltrials.gov/ct2/show/NCT02583191. Accessed on Feb. 4, 2018.

Young A, et al. Abstract 625. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

For more information:

Kenneth A. Bauer, MD, can be reached at Beth Israel Deaconess Medical Center, Hematology-Oncology, 330 Brookline Ave., Boston, MA 02215; email: kbauer@bidmc.harvard.edu.

Alok A. Khorana, MD, can be reached at Cleveland Clinic, 10201 Carnegie Ave./CA60, Cleveland, OH 44195; email: khorana@ccf.org.

Gary H. Lyman, MD, MPH, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., M3-B232, P.O. Box 19024, Seattle, WA 98109-1024.

Jai N. Patel, PharmD, BCOP, can be reached at Carolinas HealthCare System, Levine Cancer Institute, Department of Cancer Pharmacology, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: jai.patel@carolinashealthcare.org.

Jeffrey Zwicker, MD, can be reached at Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215; email: jzwicker@bidmc.harvard.edu.

Disclosures: Khorana reports consulting honoraria from Bayer, Janssen, Pfizer and Sanofi. Zwicker reports research funding from Incyte and Quercegen Pharma and an advisory board role with Daiichi Sankyo. Bauer, Lyman and Patel report no relevant financial disclosure.