Patients With Cancer

Abstract

The Risk

Venous thromboembolism (VTE) is an important and potentially fatal complication in patients with cancer, who have a 7-fold increased risk of VTE compared to patients without malignancy.¹ The results of a record linkage study of 66 329 patients showed an overall cumulative incidence of VTE of 1.23% in the first 6 months after cancer diagnosis with a risk of recurrence within 6 months of the first thrombotic event of 1.84% compared to 0.39% in patients with cancer without a prior thrombotic event.² The risk of VTE varies with the type of malignancy. At 6 months after diagnosis of cancer, the highest rates reported were in patients with tumors of the bone (37.7 per 1000), ovary (32.6 per 1000), brain (32.1 per 1000), and pancreas (22.7 per 1000).² The risk of developing VTE in patients with cancer undergoing surgery is approximately twice that for patients without cancer,^3–5 and pulmonary embolism (PE) has been cited as the most common cause of death among patients undergoing general, urologic, or gynecologic surgery for cancer.⁶ For patients with solid tumors, the risk of VTE is greater in the presence of metastatic disease compared to patients with local disease only.^1,2,7

Studies consistently show a higher risk of VTE during the first 6 months of cancer diagnosis decreasing rapidly thereafter.^1,7,8 This early risk is likely to be related to the use of cancer treatments, especially chemotherapy and hormonal therapy.^1,2,9,10 In a breast cancer prevention trial where women at high risk for the development of cancer were randomized to placebo or the hormone therapy tamoxifen, the rate of deep vein thrombosis (DVT) was 0.84 per 1000 for women receiving placebo compared to 1.34 per 1000 in those receiving tamoxifen (risk ratio [RR] 1.6; 95% confidence interval [CI] 0.91-2.86).¹¹ Corresponding rates for PE were 0.23 per 1000 and 0.69 per 1000 (RR 3.01; 95% CI 1.15-9.27). Increase in disease burden in breast cancer is associated with an increased risk of therapy-associated thrombosis, with rates ranging from 1% in node-negative disease to 17% for advanced disseminated malignancy.^12–17 Rates for other tumor stages or types are summarized in Tables 11.1 and 11.2.

Table 11.1.

Incidence of Thrombosis in Early-Stage Breast Cancer.

Study	Treatment	Number of Patients	Patients With Thrombosis, %
Node-negative
Fisher¹⁴	T	1318	0.9
	Placebo	1326	0.15
	CMFT	768	4.2
	T	771	0.8
Node-positive
Levine¹³	CMFVP	102	8.8
	CMFVP + AT	103	4.9
Pritchard¹⁷	CMF + T	353	9.6
	T	352	1.4
Clahsen¹⁶	Perioperative FAC	1292	2.1
Rivkin⁵⁵	No Rx	1332	0.8
	CMFVP + T	303	3.6
	CMFVP	300	1.3
Fisher¹⁴	T	295	0
	ACT	383	3.1
Weiss¹²	T	367	1.6
	CMFVP	143	6.3
	CMF	144	3.5

Abbreviations: A, adriamycin; C, cyclophosphamide; F, fluorouracil; M, methotrexate; P, prednisone, T, tamoxifen; V, vincristine.

Table 11.2.

Incidence of Venous Thrombosis in Patients With Different Tumors.

Study	Tumor Type	Patients (n)	Cumulative Incidence of VTE (%)	Follow-Up
Alcalay et al⁸	Colorectal	68 142	3.1	2 years
Mandala et al³⁶	Advanced colorectal + chemotherapy	266	10.2	3.3 years
Caruso et al¹⁰	Lymphoma	18 018	5.3	1-3 years
	Non-Hodgkin	997	6.5	1-3 years
	Hodgkin	2505	4.7	1-3 years
Tateo et al⁵⁶	Ovarian	253	16.6 (6.4% during chemotherapy)	12 years
Brandes et al⁵⁷	Malignant glioma	77	26
Weijl et al⁵⁸	Germ cell	179	8.4
Chew et al⁷	Prostate (localized)	33 383	1.0	2 years
	Prostate (regional)	7041	1.3	2 years
	Prostate (remote)	3515	1.2	2 years
	Breast (localized)	27 014	0.8	2 years
	Breast (regional)	13 629	1.3	2 years
	Breast (remote)	2029	2.6	2 years
	Uterus (localized)	6437	1.2	2 years
	Uterus (regional)	1302	2.2	2 years
	Uterus (remote)	598	4.8	2 years
	Lung (localized)	6558	1.3	2 years
	Lung (regional)	8775	2.2	2 years
	Lung (remote)	22 486	2.4	2 years
Jacobson et al⁵⁹	Cervical cancer	436	11.7	7 years
Jacobson et al⁶⁰	Invasive cervical cancer + chemoradiation	48	16.7	≥8 months

Abbreviation: VTE, venous thromboembolism.

The Stockholm surgical studies evaluated potential benefits from preoperative radiotherapy to reduce local recurrence in patients with rectal cancer undergoing operative intervention. Patients who received radiotherapy had a higher frequency of VTE within 3 months of therapy and surgery compared to those who did not (7.5% vs 3.5%).¹⁸ In a more recent cohort study of 66 329 patients, individuals who underwent chemotherapy as initial treatment were at increased risk of VTE versus those who did not receive this therapy, whereas there was no such increased risk among patients undergoing radiotherapy (RR 0.7; 95% CI 0.6-0.9) or surgery (RR 1.0; 95% CI 0.8-1.2).²

Despite the use of venous thromboprophylaxis, patients with a malignancy remain at risk of a thrombotic event. In a post hoc analysis of a randomized study in 23 078 patients undergoing surgery lasting more than 30 minutes who received heparin thromboprophylaxis, autopsy data showed that fatal PE was more common among patients with cancer compared to noncancer patients (0.33% vs 0.09%; P = .0001) at 14 days post prophylaxis.¹⁹

There is a well-validated VTE risk assessment model for ambulatory patients with cancerrequiring chemotherapy that has been validated in multiple outpatient cancer groups.²⁰ Five predictive variables were identified in a multivariate model namely site of cancer (2 points for very high-risk site, 1 point for high-risk site), platelet count of 350 × 10⁹/L or more, hemoglobin less than 100 g/L (10 g/dL), use of erythropoiesis-stimulating agents, leukocyte count more than 11 × 10⁹/L, and body mass index of 35 kg/m² or more (1 point each). Rates of VTE in the derivation and validation cohorts, respectively, were 0.8% and 0.3% in low-risk (score = 0), 1.8% and 2% in intermediate-risk (score = 1-2), and 7.1% and 6.7% in high-risk (score ≥ 3) category over a median of 2.5 months (C-statistic = 0.7 for both cohorts). This model can identify patients with a nearly 7% short-term risk of symptomatic VTE and may be used to select cancer outpatients who would benefit from thromboprophylaxis.

Prophylactic Methods and Recommendations

General Considerations

Surgical patients

In surgical patients with malignancy, low-dose unfractionated heparin (LDUH) reduces the risk of DVT and fatal PE ^15,21–24 and low-molecular-weight heparin (LMWH) is at least as effective as LDUH.^25–29 The intensity of perioperative antithrombotic therapy in patients with cancerhas been assessed by several studies. In gynecologic oncology patients, LDUH twice a day demonstrated no benefit when compared to no prophylaxis,³⁰ whereas administration three times a day was effective (RR 0.47; 95% CI 0.22-0.98).²⁴ In a study of 2070 patients, 65% of whom underwent laparotomy for malignant disease, 2 different doses of the LMWH (dalteparin sodium) were assessed.³¹ The frequency of VTE was reduced from 14.9% in patients receiving 2500 anti-Xa U to 8.5% in patients receiving 5000 units once daily (RR 0.52; 95% CI 0.37-0.74) without any significant increase in perioperative bleeding complications.

Continuation of LMWH for 4 weeks after discharge home reduces the risk of asymptomatic DVT as demonstrated by venography from 13.8% to 5.5% (RR 0.36; 95% CI 0.16-0.79).³² A systematic review comparing the relative efficacy and safety of 4 weeks’ therapy versus limited duration LMWH thromboprophylaxis confirmed this finding in patients with cancer undergoing major abdominal or pelvic surgery (RR 0.21; 95% CI 0.05-0.94). However, extended thrombophylaxis was associated with increased bleeding at 4 weeks (RR 2.94; 95% CI 0.12-71.85) and failed to demonstrate a reduction in death at 3 months (RR 0.49; 95% CI 0.12-1.94).³³

In a randomized, double-blind study (CANBESURE), 625 patients admitted for abdominal or pelvic surgery for cancer received bemiparin once daily for 8 days followed by either bemiparin or placebo for 20 days.³⁴ Although extended thromboprophylaxis with bemiparin did not result in an improvement in the primary efficacy endpoint of venographically detected DVT, nonfatal PE, and all-cause mortality (10.1% in bemiparin group vs 13.3% in the placebo group; RR reduction [RRR]: 24.4%; 95% CI 23.7-53.8%; P = .26), the incidence of major VTE (proximal DVT, nonfatal PE, and VTE-related deaths) was decreased (0.8% vs 4.6%; RRR 82.4%; 95% CI 21.5-96.1%; P = .010) without any increase in major bleeding complications.

Patients with medical cancer

The LMWH is effective for preventing thromboembolic disease associated with acute medical illness (see Medical Patients section).

In a prospective study of 311 ambulant patients with cancer with metastatic breast cancer receiving chemotherapy, patients were randomized to low-dose warfarin (international normalized ratio [INR] between 1.3 and 1.9) or placebo.³⁵ The frequency of symptomatic VTE was reduced from 4.5% with placebo to 0.8% with warfarin (Fisher exact test 0.038; RR 0.14; 95% CI 0.02-1.18).

In a randomized, double-blind study in ambulatory patients with metastatic or locally advanced cancer, 1150 patients received either the LMWH nadroparin (3800 IU anti-Xa once daily, subcutaneously) or placebo.³⁶ The rate of symptomatic venous or arterial events was halved in the LMWH group (2.0% for nadroparin vs 3.9% for placebo; single-sided P = .02) with similar reductions in events reported for VTE (1.4% vs 2.9%, respectively). The rate of major bleeding events did not differ between treatment groups (0.7% vs 0%, respectively; 2-sided P = .18).

A recent large study compared subcutaneous semuloparin 20 mg once daily with placebo for ambulatory patients receiving chemotherapy for cancer.³⁷ The median treatment duration was 3.5 months. The VTE occurred in 20 (1.2%) of 1608 patients receiving semuloparin, when compared to 55 (3.4%) of 1604 receiving placebo (RR 0.36; 95% CI 0.21-0.60), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of VTE. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (RR 1.40; 95% CI, 0.89-2.21). Major bleeding occurred in 19 (1.2%) of 1589 patients receiving semuloparin and 18 (1.1%) of 1583 receiving placebo (RR 1.05; 95% CI, 0.55-1.99).

In a meta-analysis of 3 randomized trials of patients with lung cancer, concomitant treatment with warfarin was associated with an increased risk of bleeding (odds ratio 1.7; 95% CI 1.2-2.6), whereas no such association was apparent for LMWH.³⁸

For bedridden hospitalized patients with cancer, no specific studies have evaluated the potential benefits of thromboprophylaxis. Therefore, data derived from contemporary trials assessing the value of LMWH in the prevention of thromboembolic disease in acutely ill medical patients need to be extrapolated to the cancer population.

Prophylactic anticoagulation with warfarin significantly reduced the risk of DVT in patients treated with thalidomide for a variety of indications (5.5% vs 23.7%, P = .010).⁹ The role of warfarin among patients with cancer receiving thalidomide requires further investigation. The potential role of LMWH in prolonging survival among patients with cancer is currently under investigation.³⁹

Prevention of thromboembolic disease in patients with central venous catheters

Historical data suggest that patients with cancer with central venous catheters have a high frequency for development of VTE. More recent research suggests a low incidence of symptomatic catheter-related thrombosis of 5% or less,^40–43 but reported rates of venographically detected upper limb DVT in the absence of thromboprophylaxis, while highly variable, remain high (18%).^41,44

The use of LMWH (dalteparin sodium 2500 U once daily) in patients with cancer with central venous catheters has been shown in one study to be effective in reducing venographic thrombosis from 62% to 6% (RR 0.04; 95% CI 0.01-0.42).⁴⁵ Warfarin (1 mg/d) has been shown to be effective in reducing the risk of all venographic thromboses, from 37% to 9.5% (RR 0.17; 95% CI 0.05-0.59).⁴⁶ However, more recent clinical trials evaluating low-dose warfarin, fixed-dose warfarin, or LMWH^{40–42,47–51} as well as several meta-analyses^44,52–54 have shown no benefit of routine thromboprophylaxis in this situation. This may be due to changes in the way the newer generations of catheters are inserted or maintained and improvements in catheter biocompatibility. Further adequately powered studies are needed to determine the benefits and harms of new anticoagulant drugs in patients with cancer with indwelling central venous catheters and in specific subgroups of patients.

Recommendations

In surgical patients with cancer, LDUH (5000 IU commenced 8 hours prior to operation; level of evidence: high) or LMWH (initiated and dosed according to manufacturer’s recommendations; level of evidence: high) should be used. In the postdischarge period, prolonged thromboprophylaxis with LMWH (enoxaparin, dalteparin or bemivarin) for up to 4 weeks after operation should be considered (level of evidence: moderate).

In ambulant nonsurgical patients with advanced breast cancer receiving chemotherapy, the use of vitamin K antagonist to maintain an INR of between 1.3 and 1.9 may be considered (level of evidence: moderate). Semuloparin is an alternative (level of evidence: high).

For patients with cancer hospitalized with acute medical illness, thromboprophylaxis should be based on the risk of VTE determined by the acute medical comorbidity. The LMWH (initiated and dosed according to manufacturer’s recommendations) or LDUH should be used (5000 IU 8 hours; level of evidence: high).

For patients with cancer with central venous catheters, routine use of thromboprophylaxis to prevent central venous catheter-associated thrombosis is not recommended (level of evidence: moderate).

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