Considering that cancer patients who develop venous thromboembolism (VTE) are at double the risk of mortality compared with cancer patients without VTE, and that VTE is a leading cause of death in hospitalized patients with cancer second only to death from cancer alone, it is surprising that more cancer patients do not receive prophylaxis.
“Compliance with prophylaxis is far from where it needs to be,” said Gary H. Lyman, MD, lead author of the American Society of Clinical Oncology's updated guidelines for prophylaxis and treatment of VTE (JCO 2013;31:2189-2204). “Although compliance has improved, there is a need for more awareness that VTE is not only something that occurs with frequency, but has mortality.”
The substantial morbidity and mortality rates seen in clinical trials are probably higher in the real world, as malignancy is associated with blood stasis, anatomical barriers to blood flow, and disturbance in coagulation itself, he added.
As with the original 2007 ASCO guidelines on venous thromboembolism prophylaxis and treatment in patients with cancer (JCO 2007;25:5490-5505), an expert panel was convened to develop these practice guideline recommendations based on a review of evidence provided by a systematic review of the medical literature.
VTE doesn't receive as much attention as do such problems as nausea and vomiting, febrile neutropenia, and infections, noted Lyman, Professor of Medicine and Director of the Comparative Effectiveness and Outcomes Research Program at Duke University School of Medicine. “But cancer patients are often bedridden and frequently have comorbid conditions, a perfect setup for VTE.”
He said some hospitals have instituted alerts in electronic records systems asking admitting physicians to consider whether the patient is a candidate at risk for thrombosis or bleeding, and whether anticoagulation is appropriate. “But cancer patients have so many other issues going on—treatment, febrile neutropenia, infections, nausea and vomiting, bleeding—that oncologists are always hard-pressed for time,” Lyman said.
“Most clinicians who take care of patients in the hospital are aware of the risks of thrombosis, but if you look at the hectic setting of admitting a patient and treating the patient acutely for whatever brought them into the hospital, thrombosis is not at the top of their list. The answer is, we need to be relentless in our education efforts, but we also need to build in automatic prompts. Just to get the admitting physicians to think about VTE in the admission process is shown to have a real impact on prophylaxis rates in the in-patient setting.”
Routine Use Not Recommended in Ambulatory Patients
As in the 2007 ASCO guidelines, the updated guidelines recommend against the routine use of thromboprophylaxis for most ambulatory patients with cancer. But the new document does add a recommendation that oncologists now risk-stratify cancer patients going through treatment, identify those at higher risk, and consider them for thromboprophylaxis at the time of chemotherapy initiation and periodically afterwards.
“The issue is to better identify cancer patients outside the hospital who are at higher risk, and therefore the risk-benefit ratio for giving prophylaxis is far more favorable,” Lyman said.
The updated guidelines also call for increased communication with the patient about VTE, telling cancer patients when they are at increased risk for VTE, and making sure patients have a basic recognition of warning signs such as swelling in legs or shortness of breath.
“We want to tell them ‘don't wait, call the physician immediately,’” Lyman said.
In the past, that discussion would be rare (other than in multiple myeloma—the updated guidelines reiterate that the risk of VTE in multiple myeloma patients is 15 to 40 percent)—“but we are encouraging that discussion now,” Lyman said.
Asymptomatic VTE Requires Treatment
As patients are undergoing much more sophisticated imaging today, asymptomatic venous thromboembolism is being picked up more frequently, he noted.
“In the past, when we did postmortems in patients we found that up to 50 percent of cancer patients had unknown, underlying blood clots, particularly pulmonary emboli that could have caused the death or contributed to the circumstances. Unsuspected thrombi have real potential for embolism and should be treated the same way as symptomatic.”
Symptoms of pulmonary embolism such as shortness of breath might easily be attributed to cancer while they are actually due to blood clots.
Bleeding vs. VTE: Weighing the Risks
The ASCO guidelines acknowledge that the risk of thrombosis must be weighed against the risk of bleeding, which is always higher in cancer patients.
Lyman said clinicians would understandably have an inherent apprehension about giving a blood thinner to a cancer patient that might block their platelets: “There is an anxiety among some oncologists about the bleeding risks, but there are randomized trials with both outpatients and inpatients that suggest the bleeding risk is not as much as one might fear. It is a bit higher than in the general population, but the bleeding risk of a cancer patient on anticoagulation is probably no more than two percent of major bleeding, so if the thrombosis risk is sufficiently high, that overshadows the bleeding risk.”
Anticoagulation Not Recommended as Cancer Treatment
A controversial research topic is whether anticoagulation therapy has a direct antitumor effect, which might lead to a potential survival benefit in patients with cancer who do not have VTE. The hypothetical mechanism, based on experimental models, is that interruption of coagulation pathways might block cell-adhesion molecules, inhibit extracellular-matrix protease heparanase, and inhibit angiogenesis.
The guidelines panel, though, considered this but found no evidence to recommend using anticoagulants to increase survival in patients with cancer without VTE. The guidelines do recommend, however, that patients with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.
“Cancer itself seems to be affected by the coagulation system, and there clearly are coagulation factors that may facilitate tumor growth, invasion, or metastasis,” Lyman said. “This is a very hot area of research, but it is very controversial, and while there is new data, we didn't feel we could make any explicit recommendations about using anticoagulation as a part of cancer therapy other than preventing blood clots in higher-risk settings.”
ASCO's Top 10 Recommendations for VTE Prophylaxis and Treatment in Patients with Cancer
- Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization.
- Thromboprophylaxis is not routinely recommended for outpatients with cancer. It may be considered for very select high-risk patients.
- Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low molecular weight heparin (LMWH) or low-dose aspirin to prevent VTE.
- Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least seven to 10 days.
- Extending prophylaxis up to four weeks should be considered in those with high-risk features.
- Low molecular weight heparin is recommended for the initial five to 10 days of treatment for patients with established deep vein thrombosis and pulmonary embolism as well as for long-term (six months) secondary prophylaxis.
- Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE.
- Anticoagulation should not be used to extend survival in patients with cancer in the absence of other indications.
- Patients with cancer should be periodically assessed for VTE risk.
- Oncology professionals should provide patient education about the signs and symptoms of VTE.
The full text of the ASCO guidelines with a data supplement including evidence tables, clinical tools, patient information sheets, dosing tables, slide sets, and other resources, can be found at bit.ly/ASCO-VTE.