Cancer-Associated Thrombosis
Treatment Options
LMWH
More effective (52% reduction, 9% vs 17%) and as safe (similar bleeding and mortality risk) than warfarin for the treatment of CAT, as shown in the CLOT trial (NEJM 2003) which specifically looked at dalteparin. This trial established LMWH as the "gold standard" for the treatment of CAT. Since then, a few trials have examined this same question with other LMWH:
| Trial | LMWH | Comparator | Notes |
|---|---|---|---|
| Meyer et al. 2002 | Enoxaparin | Warfarin | Trend towards more effective, less mortality. |
| ONCENOX | Enoxaparin | Warfarin | Trend towards more effective |
| LITE | Tinzaparin | Warfarin | Significantly more effective |
| CATCH | Tinzaparin | Warfarin | Trend towards more effective |
CATCH had a healthier population which is why it might have been negative compared to LITE which showed a statistically significant advantage. However ONCENOX patients were quite sick as well with a high proportion of metastatic disease. Thus, although LMWH was established as the gold standard for treatment after publication of the CLOT study, the results of individual randomized clinical trials have not consistently shown an efficacy benefit over warfarin.
DOACs
Based on the results of 4 clinical trials, DOACs are the preferred options for treatment of CAT in some patients due to similar efficacy (VTE recurrence and mortality), more patient-friendly format. However, they may slightly increase bleeding risk, particularly for those with GI malignancies or prone to GU bleeding.
Patients with cancer for whom DOAC is the preferred initial therapy for VTE - Ambulatory patients with cancer with an intact upper gastrointestinal tract that can take oral medications - Hospitalized patients with cancer for whom surgical intervention is not planned
DOACs not recommended for patients with - Creatinine clearance <25-30 mL/min. - Rivaroxaban should not be used in patients with creatinine clearance (CrCl) <30 cc/minute or end‐stage renal disease (ESRD). The apixaban trials excluded patients with serum creatinine >2.5 mg/dL or CrCl <25 cc/minute. Edoxaban dose should be reduced to 30 mg daily for patients with CrCl 30 to 50 cc/minute, or a body weight of ≤60 kg. Edoxaban should be avoided in patients with CrCl <30 cc/minute or ESRD. - Luminal gastrointestinal or gastrointestinal lesion. - GI and GU cancers have shown increased risk of major bleeding with DOACs. DOACs should either not be used (especially in those with intact intraluminal tumors) or be used with caution in patients with these cancers. About 75% of the major bleeding events occur in patients with unresected tumors. Fatal or life‐threatening bleeding occurs with similar frequency to LMWH, and most major bleeds with the DOACs can be managed with transfusion and standard measures. The patient's willingness and ability to comply with LMWH injections, and their treatment preference, should also be considered. - Recent (<3 months) history of peptic ulcer disease or other bleeding lesion - Anticancer therapies that significantly affect P‐glycoprotein, CYP3A4, or CYP2J2 pathways - Severe hepatic impairment with coagulopathy. DOACs are not recommended for patients with Child‐Turcotte‐Pugh class B or C cirrhosis. - Surgery or invasive procedure imminent - Patients with recent (<1 month) brain surgery (major surgery) or metastatic brain lesions with melanoma, renal cell carcinoma, or thyroid cancer should not receive DOACs. Data are limited for all anticoagulants in the setting of brain metastases.
| Trial | DOAC | Comparator | VTE recurrence risk | Major bleeding | Mortality | Note |
|---|---|---|---|---|---|---|
| HOKUSAI-VTE (2013) | Edoxaban | Dalteparin | 7.9 vs 11.3% | 6.9 vs 4.5% | 39.5 vs 36.6% | More major bleeding in those with GI malignancy. |
| SELECT-D (2018) | Rivaroxaban | Dalteparin | 3.9 vs 8.9% | 5.4 vs 3.0% | 23.6 vs 27.6% | UGI cancer more likely to experience major bleeding with rivaroxaban. Nonmajor GI or GU bleeding more frequent with rivaroxaban as well, about 13%. |
| ADAM VTE (2019) | Apixaban | Dalteparin | 0.7 vs 6.3% | 0 vs 1.4% | 16 vs 11% | |
| Caravaggio (2020) | Apixaban | Dalteparin | 5.6 vs 7.9% | 3.8 vs 4.0% | 23.4 vs 26.4% | Major bleeding events similar for all-comers, GI subgroup not presented and intracranial mets excluded. Patients < 65 may benefit more from apixaban. |
Duration of Therapy
- Patients with cancer and VTE should be treated with anticoagulation for a minimum of 6 months. This differs slightly from the recent NCCN guidelines, which recommend a minimum duration of 3 months, because all of the clinical trials of LMWH or DOACs evaluated treatment for 6 months.
- Patients with cancer and VTE should continue anticoagulation beyond 6 months if the malignancy is still present, unless there are contraindications to anticoagulation (i.e., there is some detectable solid tumor or hematologic malignancy is not in remission).
- Patients with cancer who have been diagnosed with VTE and treated with anticoagulation for 6 months may discontinue anticoagulation if they have no evidence of disease or are in complete remission.
References
- O’Connell C, Escalante CP, Goldhaber SZ, McBane R, Connors JM, Raskob GE. Treatment of Cancer‐Associated Venous Thromboembolism with Low‐Molecular‐Weight Heparin or Direct Oral Anticoagulants: Patient Selection, Controversies, and Caveats. The Oncologist. 2021;26(1):e8-e16. doi:10.1002/onco.13584
- Xiong W. Current status of treatment of cancer-associated venous thromboembolism. Thrombosis Journal. 2021;19(1):21. doi:10.1186/s12959-021-00274-x
- Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Advances. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442