Venous thromboembolism (VTE) is the second cause of death in people with cancer, after cancer itself.

Cancer and VTE are deeply intertwined since cancer creates hypercoagulation, which activates blood clotting. The mechanisms behind the pathogenesis of cancer-associated thrombosis (CAT) are multifactorial and depend on the tumor and its DNA, the host, and the administered treatments.

Treatment and prevention of CAT are tricky because cancer patients have a high risk of bleeding and drug–drug interactions.

In this article, we summarize the recent European Society for Medical Oncology (ESMO) recommendation about VTE in cancer patients, including the levels of evidence and grade of recommendation [1].

The levels of evidence describe the quality of existing evidence (trials, cohort studies, case–control studies, expert opinion) that address a specific clinical question.

The grade of recommendation is a composite parameter, incorporating both the quality of evidence and the clinical significance/magnitude of benefit or harm given by a novel therapy.

VTE diagnosis

The most prevalent clinical phenotypes observed in malignancy-associated hypercoagulation are deep vein thrombosis (DVT) and pulmonary embolism (PE). Diagnosis of DVT and PE requires a careful assessment by an experienced clinician and precise empirical evaluation based on objective testing, like imaging, which is necessary to confirm the diagnosis [2].

• The ESMO guidelines recommend clinicians not to use clinical prediction rules or D-dimer testing to refer patients for imaging testing methods. In cancer patients, suspected DVT should be diagnosed by compression ultrasonography, and suspected PE should be diagnosed by computed tomography pulmonary angiography [I, A]. [1]

Primary prevention of VTE

Thromboprophylaxis in the surgical setting

The risk of thrombosis and bleeding should be assessed before any surgical procedure, considering patient risk factors, intervention type, and pharmacological prophylaxis contraindications.

• The ESMO guidelines recommend using low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) for the pharmacological prophylaxis of VTE in cancer patients undergoing major surgery (unless contraindicated for high-risk bleeding) [I, A] [1].
• Fondaparinux may be an alternative to LMWH and UFH, but conflicting evidence is available for this weak recommendation [II, C] [1].
• If pharmacological VTE prophylaxis is not possible or contraindicated, the EMSO guidelines suggest using mechanical methods, such as intermittent pneumatic or graduated compression stockings. These methods may be combined with pharmacological VTE prophylaxis if the VTE risk is very high [II, C] [1].
• Based on heparin type and dosage, LMWH or UFH should be administered 2–12 hours before the surgical procedure ad pharmacological thromboprophylaxis [II, B] [1].
• In addition, if more than one heparin prophylactic dosage is approved, it is recommended to use the highest dose of LMWH or 5000 IU UFH three times a day [II, A] [1].
• In patients undergoing major cancer surgery, pharmacological prophylaxis should be administered for 10 days after surgery [I, A]. A 4-week treatment with LMWH after surgery is recommended for patients undergoing open abdominal or pelvic surgery or laparoscopic colorectal cancer surgery [I, A] [1].

Prevention of VTE in non-surgical patients with cancer

The risk of VTE varies for each patient, depending on patient-related, cancer-related, and treatment-related factors.

• Risk assessment for VTE should be based on validated risk assessment models, such as KRS, COMPASS-CAT, or Vienna-CATS nomogram score [III, C]. The threshold for thromboprophylaxis discussion is set at an estimated VTE risk higher than 8–10% at 6 months [II, C] [1].
• In ambulatory pancreatic cancer patients under first-line systemic anticancer treatment, LMWH may be considered for a maximum of 3 months at 150/IU/kg for dalteparin and 1 mg/kg for enoxaparin [II, C] [1].
• Apixaban, rivaroxaban, or LMWH may be considered for a maximum of 6 months for primary thromboprophylaxis in ambulatory cancer patients with a high risk of thrombosis and starting systemic anticancer treatment [I, B] [1].
• Instead, LMWH, UFH [I, B], or fondaparinux [II, B] are recommended for prophylaxis in hospitalized cancer patients confined to bed with an acute medical complication [1].

Patients with multiple myeloma

The risk of VTE in patients with multiple myeloma (MM) is higher than in the general population; it is multifactorial and related to myeloma-specific therapy, disease-related physiologic changes, iatrogenic procedures, and patient comorbidities [3].

• The ESMO guidelines state that patients with MM scheduled to receive or receiving immunomodulatory imide drug treatment should be assessed for VTE risk with the International Myeloma Working Group/National Comprehensive Cancer Network score [III, B] [1].
• Ambulatory patients with MM receiving immunomodulatory imide drugs and without additional risk factors should be administered 100 mg/day aspirin combined with low-dose dexamethasone [III, B] [1].
• In ambulatory patients with MM classified as high risk for VTE, pharmacological thromboprophylaxis with LMWH for 3–6 months is recommended [II, B], and extension of thromboprophylaxis should be considered on a case-by-case basis [IV, B] [1].
• For patients with CrCl >30 ml/min and presenting contraindications or intolerance to LMWH, the use of apixaban 2.5 mg twice a day or rivaroxaban 10 mg once a day might be considered [IV, C] [1].

Treatment of CAT

The treatment of CAT can be divided into three phases: the first 5–10 days after diagnosis represent the acute phase, the first 3–6 months belong to the long-term phase, and beyond 6 months is the extended phase.

Acute phase

Evidence about CAT treatment in the acute phase is indirect and based on randomized control trials conducted in non-cancer patients.

• LMWH, UFH, fondaparinux, apixaban, or rivaroxaban are recommended for acute-phase CAT treatments [I, A]. LMWH is preferred over UFH or fondaparinux [V, A]. UFH may be considered in patients with CAT and severe renal impairment (defined as CrCl <30 ml/min) [IV, C] [1].

Long-term phase

For 20 years, LMWH has been the treatment of choice for CAT in the long-term phase, but oral factors Xa have recently been highlighted as an acceptable alternative.

• For long-term anticoagulation (for at least 6 months), LMWH, apixaban, edoxaban, or rivaroxaban should be preferred over vitamin K antagonists [I, A] [1].
• LMWH is preferred in patients with luminal gastrointestinal cancer [II, B], urothelial cancer [II, B], at high risk for gastrointestinal bleeding, and receiving strong inhibitors or inducers of P-glycoprotein and CYP3A [IV, B] [1].

Extended phase

The optimal duration of treatment for CAT is still under debate.

• Extended anticoagulation beyond the initial 6 months with LMWH, apixaban, edoxaban, rivaroxaban, or VKAs should be considered for patients with active cancer with a higher risk of recurrent thrombosis than of bleeding [III, B]. The risk–benefit profile of anticoagulant therapy should be regularly assessed to ensure a favorable balance [IV, C] [1].

Incidental CAT

50% of VTE diagnoses in patients with cancer are incidental and happen during routine imaging scans requested for other reasons [4].

• The ESMO guidelines recommend treating incidentally detected VTE as symptomatic [II, A] [1].
• Anticoagulant therapy is suggested for most patients with subsegmental PE [II, A] [1].
• A watchful approach or a shorter course of anticoagulation may be considered in patients with a high risk of bleeding or single incidental subsegmental PE without concomitant DVT if an adequate cardiopulmonary reserve is present [V, C] [1].

Prevention and management of catheter-related venous thrombosis in adults with cancer

Patients receiving systemic anticancer medications or supportive care are often provided with central venous catheters, which often leads to the development of catheter-related thrombosis (CRT). The overall rate for CRT is 14–18%, of which approximately 5% is symptomatic [1].

• The ESMO guidelines do not recommend routine pharmacological prophylaxis of CRT [II, D] [1].
• It is recommended to treat CRT in patients with cancer with anticoagulants for a minimum of 3 months [III, A]. LMWH is the suggested treatment, but because of the lack of direct anticoagulant comparisons, VKA or DOAC may be considered alternative options [IV, C] [1].
• The catheter should be removed if not needed or infected, or if anticoagulant treatment is contraindicated or in case of thrombus extension despite treatment [III, B] [1].
• Finally, extending the anticoagulant treatment after 3 months is suggested until catheter removal in patients with CRT and low bleeding risk [IV, C] [1].

References

1. Falanga A, Ay C, Di Nisio M, Gerotziafas G, Langer F, Lecumberri R, Mandala M, Maraveyas A, Pabinger I, Jara-Palomares L, Sinn M, Syrigos K, Young A, Jordan K, on behalf of the ESMO Guidelines Committee. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol 2023 doi: https://doi.org/10.1016/j.annonc.2022.12.014 (Epub ahead of print).
2. Metharom P, Falasca M, Berndt MC. The history of Armand Trousseau and cancer-associated thrombosis. Cancers (Basel). 2019;11(2):158. doi:10.3390/cancers11020158.
3. Swan D, Rocci A, Bradbury C, Thachil J. Venous thromboembolism in multiple myeloma – choice of prophylaxis, role of direct oral anticoagulants and special considerations. Br J Haematol. 2018;183(4):538-556.
4. Di Nisio M, Carrier M. Incidental venous thromboembolism: is anticoagulation indicated? Hematology Am Soc Hematol Educ Program. 2017;2017(1):121-127. doi:10.1182/asheducation-2017.1.121