Cancer and clots: All cases of venous thromboembolism are not treated the same
ABSTRACTIdiopathic venous thromboembolism (VTE) can be the first sign of cancer, although how extensively one should search for cancer in a patient with idiopathic VTE is not clear. Treating VTE is more complex in cancer patients than in those without cancer. The authors discuss their approach to searching for undiagnosed cancer in patients with idiopathic VTE and to managing VTE in patients with cancer.
KEY POINTS
- We recommend judiciously screening for cancer with age- and sex-specific tests in patients with idiopathic VTE.
- Patients with VTE and cancer have a higher risk of both VTE recurrence and bleeding complications of anticoagulant therapy than do VTE patients without cancer.
- Either unfractionated heparin or a low-molecular-weight heparin (LMWH) should be started as soon as VTE is confirmed or even strongly suspected, while still awaiting confirmation.
- The current (grade 1A) recommendations for treating VTE in cancer patients are to use LMWH monotherapy for at least 3 to 6 months. Anticoagulation is necessary indefinitely when there is ongoing cancer treatment or persistent risk of VTE.
DO LMWHS AFFECT CANCER?
In vitro and animal studies indicate that LMWH may have antimetastatic and antiangiogenic properties.41–44
Altinbas et al45 reported significantly better chemotherapy-induced tumor response rates and survival rates in patients with small cell lung cancer randomized to receive combination chemotherapy plus prophylactic dalteparin 5,000 IU daily compared with combination chemotherapy alone. However, as provocative as these results may be, we need to test the effects of LWMHs on different cancer types in a prospective clinical trial. For now, this area remains controversial.
It has been suggested that anticoagulants may improve survival in patients with nonmetastatic cancer. Supporting this observation, a post hoc analysis of the trial by Lee et al37 found a statistically significantly lower cancer-specific mortality rate in nonmetastatic cancer patients treated with dalteparin vs oral therapy with a coumarin derivative. In patients without metastatic disease, the death rate at 12 months was 36% in patients treated with oral therapy vs 20% in patients treated with dalteparin (P = .03).46
These findings are consistent with those of the Fragmin Advanced Malignancy Outcome Study (FAMOUS),47 the first randomized, placebo-controlled trial of dalteparin 5,000 IU daily in patients with advanced solid tumors and without evidence of underlying thrombosis. Overall, dalteparin prophylaxis did not increase survival. However, in a subgroup of patients with a better prognosis and who were alive 17 months after diagnosis, survival was statistically significantly longer in patients treated with dalteparin.
Another small trial showed similar survival benefits in cancer patients without VTE.48 The results may suggest a long-term favorable effect of LMWH on tumor cell biology, which could translate into a favorable outcome in some patients. It is important to note, however, that not all trials have shown this same clinical benefit.49
In general, the growing body of laboratory and clinical data indicates that LMWHs may suppress tumor growth and metastasis. However, definitive conclusions about these effects are not yet possible because of variations in study design, tumor type, and patient populations. Further investigations into the role of LMWHs in the treatment of VTE and in cancer progression are ongoing.
THE EVIDENCE IN PERSPECTIVE
Illness and the recurrence of VTE in patients with cancer depend on the location and extent of the underlying cancer. Rates of death are higher in VTE patients with cancer than in VTE patients without cancer. Patients with limited or localized disease may not die of the cancer itself but of complications of acute pulmonary embolism. Therefore, it is important to recognize the different options for and the potential side effects of treating VTE.
If patients are hospitalized for an acute thromboembolic event and unfractionated heparin is chosen as the initial anticoagulant, using a weight-based nomogram has been shown to achieve therapeutic levels within 24 hours and reduce the rates of recurrence of thromboembolic events.50
Warfarin treatment may pose a particular challenge for both cancer patients and physicians, since multiple drug interactions, anorexia, and comorbid conditions contribute to an unpredictable response.
The risk of bleeding is higher in cancer patients than in the general population, and the decision to start anticoagulants should be based on an individualized risk-benefit profile. Several trials have shown LMWH to be more effective and safer than warfarin in cancer patients.
These considerations, along with the other advantages of LMWHs (ease of use, less need for laboratory monitoring, and better patient tolerance), make LMWHs a good choice for initial therapy. Extended LMWH therapy is currently favored for initial management in patients with cancer. Trials are under way to further assess the antitumor properties and potential survival benefit in patients with selected solid tumors.
