How I Treat In Brief: Treating Cancer-Associated Venous Thromboembolism

Recently, Noémie Kraaijpoel, MD, and Marc Carrier, MD, MSc, FRCPC, discussed the management of venous thromboembolism in patients with cancer. Below, we summarize their approach.

This material was repurposed from “How I treat cancer-associated venous thromboembolism” published in the January 24, 2019, edition of Blood.

  • Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication of cancer and is associated with significant morbidity and mortality.
  • Several factors need to be considered when tailoring anticoagulation management in a patient with cancer-associated thrombosis, including patient preference, drug-drug interactions, and bleeding risk.
  • Low molecular-weight heparins (LMWHs) have been the firstline treatment of cancer-associated thrombosis. Direct oral anticoagulants (DOACs) have been well established as first-choice treatment of DVT and PE in patients without cancer, but there is limited evidence on their efficacy and safety in patients with cancer.
  • Patients diagnosed with cancer and incidental PE should be treated with a similar approach as patients with symptomatic PE.
  • In managing catheter-related thrombosis, keep the catheter in place if it is functional and there is an ongoing need for the catheter to deliver medication.
  • Future directions of research include risk-stratifying patients for bleeding complications with DOACs and determining the safety of extended anticoagulant treatment beyond 6 months.

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication of cancer, with an incidence of up to 15% per year. Several cancer-associated risk factors for VTE have been identified, including patient-, treatment-, and tumor-related factors (TABLE).

When VTE is diagnosed, anticoagulant therapy is indicated in almost all cases. In patients with cancer, though, the risks of recurrent VTE despite anticoagulant therapy and bleeding complications are particularly challenging – and higher than in those without cancer.

For many years, low-molecular-weight heparins (LMWHs) have been the firstline treatment in this setting. Compared with vitamin K antagonists (VKAs) such as warfarin, LMWHs have been associated with a lower risk of recurrent VTE without an associated increased risk of major bleeding complications. Direct oral anticoagulants (DOACs) have been well established as first-choice treatment of DVT and PE in patients without cancer, but there is limited evidence of their efficacy and safety in the cancer population.

This review will discuss three common cancer-associated VTE patient scenarios.

Case 1: Deep Vein Thrombosis

A 61-year-old man with a recent diagnosis of stage IIA prostate carcinoma presents to the emergency room with a three-day history of acute pain, swelling, and erythema of the right lower limb. Compression ultrasonography demonstrates a filling defect consistent with a diagnosis of a proximal lower-limb DVT. He is not receiving any cancer-specific therapies, has denied previous bleeding episodes, and indicated that he would prefer oral over parenteral therapy. What would be the appropriate anticoagulant treatment regimen for this patient?

Table: Risk Factors for Cancer-Associated VTE

Commentary on Case 1

Several factors need to be considered when tailoring anticoagulation management in a patient with cancer-associated thrombosis.

Patient preference: Qualitative research including patients with cancer-associated VTE suggests that the most important consideration of anticoagulant therapy from the patient’s perspective is related to potential delays or drug-drug interactions with cancer-related therapies. Route of administration is another important concern; most patients find tablets more convenient, but LMWH can be used in the context of cancer and its treatment.

Drug-drug interactions: Systemic cancer-related therapies may interfere with DOACs. Potent inhibitors or inducers of P-glycoprotein and cytochrome p450 CYP3A4 are known to influence the metabolization of DOACs and thereby potentially alter their efficacy and/or safety profiles. The extent to which these agents influence DOAC plasma concentrations is unknown, so LMWH might be a preferred anticoagulant in this situation.

Bleeding risk assessment: The rates of major bleeding and clinically relevant nonmajor bleeding events seem to be higher in patients with cancer-associated thrombosis using DOACs. Unfortunately, no tool can predict the risk of bleeding episodes in this specific patient population, although patients with gastrointestinal cancer appear to have a higher risk. Until we can stratify these patients according to their underlying risk of bleeding complications, the use of DOACs should be carefully considered by balancing patients’ preference and the risk of bleeding, as well as age, previous bleeding episodes, anemia, thrombocytopenia, and renal function.

The Scientific and Standardization Committee on Haemostasis and Malignancy of the International Society on Thrombosis and Haemostasis (SSC-ISTH) suggests:

  • specific DOACs (edoxaban or rivaroxaban) for cancer patients with an acute diagnosis of VTE, a low bleeding risk, and no drug-drug interactions
  • LMWH for those with a high risk of bleeding, including those with thrombocytopenia
  • VKAs reserved for patients for whom LMWHs/DOACs are contraindicated, unaffordable, or unavailable or in those patients already treated with and stable on this agent

Case 1: Follow-Up

The patient was treated with five days of therapeutic LMWH (enoxaparin 1 mg/kg subcutaneously, twice daily), followed by edoxaban 60 mg once daily for a planned minimal duration of six months. At outpatient follow-up, he denied any recurrent VTE or bleeding episodes and remained on anticoagulant treatment. However, recent laboratory investigations demonstrated that his cancer had progressed; androgen-deprivation therapy and docetaxel were initiated. Is extended anticoagulant therapy indicated for this patient with advanced-stage cancer?

Commentary: Most clinical practice guidelines recommend a minimum of three to six months of anticoagulant therapy and suggest extending treatment duration in patients with active cancer because they are considered at high risk of recurrent VTE. These recommendations are based largely on expert opinion; most high-quality controlled studies have evaluated anticoagulant therapy for a duration of six months.

The decision to stop or continue anticoagulation therapy after an initial treatment period of three to six months should be based on the balance between the risk of recurrent VTE and bleeding complications in combination with patient preference, life expectancy, and treatment costs.

Although data on extended therapy with DOACs are lacking, one can assume that there is no need to change the choice of anticoagulant after the initial three to six months of anticoagulation therapy. We recommend continuing anticoagulant treatment for this patient, as there are no significant drug-drug interactions with his cancer medications and his bleeding risk is low.

Case 2: Incidental Pulmonary Embolism

A 72-year-old woman diagnosed with stage IIIA distal esophageal carcinoma is started on neoadjuvant radiation therapy and chemotherapy with carboplatin and paclitaxel. Two months later, a CT scan for treatment response detected a filling defect in a segmental pulmonary artery of the right lower lobe. The patient reported no dyspnea, chest pain, or hemoptysis. She had an active lifestyle and denied exertional dyspnea. Should this patient with incidentally detected PE receive anticoagulant treatment?

Commentary: Up to 50% of all PEs in patients with cancer are incidentally detected, and the prevalence of incidental PE diagnosis has been reported to be between 1% and 15% in this patient population. Given that the signs and symptoms of PE are not specific, they are often attributed by both the clinician and the patient to the cancer itself or its underlying treatment – not immediately leading to suspicion of PE.

In clinical practice, most clinicians would anticoagulate patients with cancer and isolated symptomatic subsegmental PE. However, the decision to start anticoagulant treatment in patients with an isolated incidental single subsegmental PE is more nuanced as it could unnecessarily expose patients to a risk of bleeding.

Therefore, the SSC-ISTH recommends the following diagnostic workup: Review imaging results with an experienced thoracic radiologist, then perform bilateral compression ultrasonography of the lower extremities to detect possible incidental DVT. In patients with concomitant proximal DVT, standard-of-care anticoagulant therapy should be initiated. In patients with no DVT, the decision to prescribe anticoagulation should be individualized according to the risk of recurrent VTE and bleeding and the patient’s performance status and preference. If anticoagulation is withheld, clinical monitoring can include serial ultrasonography in those with distal DVT to assess thrombus extension.

For this patient with a segmental incidental PE in the context of esophageal carcinoma, bleeding risk was considered high. After discussion, the patient was started on therapeutic doses of LMWH (dalteparin 200 IU/kg once-daily followed by 150 IU/kg once daily after the first month) and a follow-up appointment was scheduled to monitor for bleeding complications.

Case 3: Catheter-Related Thrombosis

A 58-year-old man with stage IIB non–small cell lung cancer presents with a four-day history of pain, swelling, and redness in his left arm. One week after initiating chemotherapy through a peripherally inserted central catheter (PICC) line, the patient started having progressive symptoms but denied worsening of dyspnea or chest pain. Examination reveals redness and edema of the entire left arm. Ultrasonography identified obstructive nonfilling defects in the axillary and brachial veins, and Doppler showed no flow within the subclavian vein. How should this patient with catheter-related proximal upper-extremity DVT be treated?

Commentary: Central venous catheters (CVCs; implanted port, centrally inserted catheter, or PICC) are often used for long-term chemotherapy or parenteral nutrition in patients with cancer and may be complicated by catheter-related thrombosis, mostly in the upper extremities. Risk factors for catheter-related DVT may include intrinsic factors such as CVC size and type, tip location, side of placement, and extrinsic factors including inherited thrombophilia, previous VTE, and metastasized cancer.

Figure 1A: Suggested treatment algorithms for symptomatic and incidental DVT or PE in patients with cancer.
Figure 1B: Suggested treatment algorithm for catheter-related thrombosis in patients with cancer.

Recent guidelines from the American College of Chest Physicians recommend that the catheter should remain in situ as long as it is functional and there is an ongoing need for it. Anticoagulant therapy is recommended for three to six months, regardless of whether the catheter is removed, and continued treatment is recommended for as long as the catheter remains.

However, if the catheter is not functional or is improperly positioned, or in most cases of infection, removal of the catheter is recommended and a short duration of anticoagulation (3-5 days) is suggested prior to removal (if possible). Again, anticoagulant therapy is recommended for a minimum of three months and for as long as the catheter remains.

Based on data supporting LMWHs for the management of lower-extremity DVT and PE in patients with cancer, most guidance documents and expert consensus suggest LMWHs over VKAs for managing cancer-associated, catheter-related, upper-extremity DVT. Evidence on the efficacy and safety of DOACs in this patient population is emerging, with a prospective pilot study of rivaroxaban demonstrating recurrence and bleeding event incidence rates of 1.43 percent and 12.85 percent, respectively.

For this patient, the catheter remained in place as it was functional, and he needed ongoing chemotherapy. He was started on therapeutic LMWH (enoxaparin 1.5 mg/kg once-daily dose) for at least three months.

Future Directions

VTE is a common complication of cancer, and different manifestations require specific treatment approaches. LMWHs are the recommended firstline anticoagulant treatment, but ongoing studies are evaluating the safety and efficacy of DOACs in patients with cancer-associated thrombosis. Future trials should focus on stratifying patients at low and high risk of major bleeding complications with DOACs to provide clinicians with guidance on how to better tailor individual treatment regimens.

Furthermore, the efficacy and safety of extended anticoagulant treatment beyond six months has not yet been determined. Although evidence on the clinical outcomes of patients with cancer with incidental VTE is emerging, future studies need to include assessment of the safety of withholding anticoagulant therapy in those with single subsegmental PE without proximal DVT, as the risks of anticoagulant treatment may outweigh the benefits in these patients.

Finally, there are limited data to guide treatment decisions on catheter-related thrombosis in patients with cancer. Management studies randomizing patients with cancer to LMWHs or DOACs for this indication are needed to compare the safety of both regimens.