**2.5.3 Hemopoetic growth factors**

Tumor hypoxia may contribute to the resistance of some tumors to both chemotherapy and radiation therapy (93-94). Many cancer patients are anemic. There are some data from the literature indicating that patients who received transfusions to maintain a higher hematocrit have improved outcomes with radiation therapy for cervical carcinoma. (95)

Studies on inducing and maintaining higher haemoglobin (Hb) levels in patients with malignant disease by administration of recombinant human erythropoietin (rHuEpo), the primary haematopoietic growth factor for erythropoiesis (96), have shown that rHuEpo is effective in increasing Hb levels in the majority of anaemic cancer patients (97-98) and that this increase is associated with an improvement in patient-reported quality of life. Because both fatigue and anemia are common complications of cancer, the use of rHuEpo in patients with cancer has increased significantly (99). Those studies typically have shown that a majority of patients will have an erythropoietic response to doses of rHuEpo between 150 IU/kg and 300 IU/kg given subcutaneously 3 times per week (98, 100).

Pathophysiology and Clinical Aspects of 80 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

drug has been reported at 15-17%. During 5-FU infusion, there is a reduction of protein C

Angiogenesis is a process involving the proliferation of new blood vessels and plays a central role in the growth and metastasis of cancer (85). The angiogenesis is driven mainly by the vascular endothelial growth factor (VEGF). The signaling pathway of VEGF has been a target of many angiogenesis inhibitors including bevacizumab, sorafenib and others (86- 87). Bevacizumab (Avastin, Genentech Inc., South San Francisco California) is a recombinant humanized monoclonal neutralizing antibody against VEGF has shown efficacy in treatment of many solid tumors including colorectal cancer, non-small cell lung cancer and

Shobha R Nalluri et al (88) in their metanalysis of 15 randomized controlled trials (RCTs) demonstrated that bevacizumab is associated with significantly higher risk of VTE (RR, 1.33[95% CI 1.13-1.56]; P<0.001) in patients with a variety of metastatic solid tumors and this

The thrombogenic effect of bevacizumab may be related to (a) its exposure of the subendothelial procoagulant layer and inhibition of the VEGF induced endothelial cell regeneration (89), (b) reduction of production of nitric oxide and prostacyclin by bevacizumab (90), (c) release of procoagulant molecules from the tumor cells into the circulation (91) and (d) increasing the haematocrit and blood viscosity via over production

b. Thalidomide and its derivative Lenalidomide are immunomodulatory agents with antiangiogenic properties through blockade of basic fibroblastic growth factor and VEGF and are associated with increased risk of VTE in cancer patients. This topic has

Tumor hypoxia may contribute to the resistance of some tumors to both chemotherapy and radiation therapy (93-94). Many cancer patients are anemic. There are some data from the literature indicating that patients who received transfusions to maintain a higher hematocrit

Studies on inducing and maintaining higher haemoglobin (Hb) levels in patients with malignant disease by administration of recombinant human erythropoietin (rHuEpo), the primary haematopoietic growth factor for erythropoiesis (96), have shown that rHuEpo is effective in increasing Hb levels in the majority of anaemic cancer patients (97-98) and that this increase is associated with an improvement in patient-reported quality of life. Because both fatigue and anemia are common complications of cancer, the use of rHuEpo in patients with cancer has increased significantly (99). Those studies typically have shown that a majority of patients will have an erythropoietic response to doses of rHuEpo between 150

have improved outcomes with radiation therapy for cervical carcinoma. (95)

IU/kg and 300 IU/kg given subcutaneously 3 times per week (98, 100).

been well covered in chapter 5 of this book by Drs Gonzalez-Porras and Mateos.

and an increase level of fibrinopeptide through the action of thrombin (83-84).

**2.5.2 Angiogenic Inhibitors and immunomodulatory agents** 

a. Angiogenesis Inhibitors Associated with VTE:

renal cell carcinoma.

of erythropoietin (92).

risk is observed for all grades of VTE.

**2.5.3 Hemopoetic growth factors** 

Dusenbery et al (101) in a study of patients receiving rHuEpo along with chemotherapy and radiation therapy for cervical carcinoma, reported that 2 of 20 patients had DVT during therapy, and 2 other patients had DVT 9 days and 10 days after radiation therapy and rHuEpo were discontinued. Although it was a small sample, the rate of 20% in that study is similar to the rate found in by Ted Wun et al (102). The combination of chemotherapy and radiation may lead to a more vigorous inflammatory response that may predispose patients to thrombosis in the background of other predisposing factors.

In a recent Cochrane meta-analysis of 35 trials representing almost 7000 patients, epoetin or darbepoetin treatment was associated with a significantly increased risk for thromboembolic events (103).

Erythropoietin may contribute synergistically to thrombosis in cancer patients through several mechanisms. (a) Increasing red cell mass leading to increasing whole blood viscosity, (b) Erythropoietin therapy results in reticulocytosis, the metabolically active young red blood cells. Elegant studies have demonstrated that metabolically active red blood cells augment platelet reactivity in vitro (104-108) (c) rHuEpo is synergistic with the platelet growth factor, thrombopoietin, for platelet activation in vitro (109-110) at concentrations that can be achieved pharmacologically in vivo. (d) Erythropoietin has been associated with increased platelet reactivity and evidence of endothelial activation when administered to healthy male volunteers (111) (e) In vitro data have demonstrated receptormediated endothelial cell activation in response to rHuEpo and that extracellular matrix produced by the activated endothelial cells enhanced platelet aggregation and recent evidence suggests that platelet-red cell interactions can play a role in venous thrombosis (112).

The role of prophylactic myeloid growth factors: granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) in increasing risk of cancer-associated thrombosis is unclear (113-114).

### **2.5.4 Surgery**

Is a well-known risk factor for development of VTE in patients without cancer. Underlying cancer increases the risk of surgery-related VTE by two-fold. Some studies have demonstrated that longer time in the operating room, longer time under anesthesia, and need for surgical re-exploration is associated with increased risk of VTE in cancer patients (37, 115-116). A study analyzing the effect of surgery in patients with glioma revealed that patients who underwent major neurosurgery or brain biopsy were 70% more likely to develop VTE within 3 months.

#### **2.5.5 Indwelling central venous catheters (CVC)**

The use of CVC has improved the management of patients with cancer as they simplified the administration of chemotherapy, parental nutrition, antibiotics and other supportive intravenous therapy. However, the CVCs are associated with complications including a significant risk of catheter-associated thrombosis (CAT). The risk of VTE associated with hospitalization has increased over the last decade a time associated with increased use of medical thromboprophylaxis. The incidence of symptomatic catheter-related DVT in adult

Venous Thromboembolism in Cancer Patients 83

A completely dissolved right atrial thrombus case without side effects was reported by Adamovich et al in a neonate after 5 days' with infusion of urokinase and heparin (128). Cesaro et al reported on a successful pediatric case that was treated with recombinant tissue plasminogen activator (rt-PA) and heparin for 6 days without significant side effects (129). Korones et al favoured conservative management for small-sized thrombus with no intervention but close follow up for evidence of growth in size is warranted. However, for a moderate-sized thrombus there is a need for anticoagulation rather than surgical thrombectomy (123). If medical treatment fails then surgical thrombectomy should be resolved to. In adults, medical treatment has been tried in only a few reported cases because it is believed that, even though antithrombotic agents may stabilize or regress catheterrelated RA thrombi, anticoagulated patients remain at risk of pulmonary embolism and

The course of action for implantable venous access device (IVAD) after CVT is variable. Medical antithrombotic treatment was widely applied, but most of the devices were still explanted and some were removed before medical treatment is started (5,6) and some were explanted after fibrinolytic, antithrombotic or anticoagulant treatment failed (133-135). The reasons for explantation of IVAD are (a) prevention of thrombosis progression, especially in the case of SVC syndrome, (b) persistent pain, (c) combined with a documented infection and extravasation. However, Lokich et al (136) reported that the vascular occlusion rarely

For all CVT patients with or without IVAD explantation, antithrombotic treatment is necessary. Removal of the device should be decided by clinical necessity for venous access or by evidence of pulmonary embolism (134), especially in patients with very difficult

Intravenous UFH is the initial treatment of choice for acute CVT. UFH can prevent clot propagation but does not dissolve it and, therefore, recanalization may not develop. UFH can be given by continuous intravenous infusion for 5–10 days, starting with a bolus of 5000 IU followed by 30,000–35,000 IU/day, with activated partial thromboplastin time of 1.5–2.5

In view of the many advantages particularly the subcutaneous route q12 hours dosage, no need for laboratory and home treatment basis of the LMWH over the UFH, many experts

Fibrinolytic agents, such as recombinant tissue plasminogen activator (rt-PA), streptokinase, and urokinase are usually effective for the lysis of fresh thrombi. Resolution of thrombi is

**b. Medical management** 

• **Central Venous Thrombosis a. Surgical management** 

resolve after the explantation. **b. Medical management** 

**c. Unfractionated Heparin** 

**d. Low Molecular Weight Heparin** 

favor its use for management of acute CVT

times the control (137).

**e. Fibrinolytic agents** 

venous access.

need to have surgical thrombectomy eventually (130-132).

cancer patients ranges from 0.3% to 28% while the rate of catheter-related DVT assessed by venography is 27–66% (117).

Some of the factors that may influence the risk of thrombosis of the indwelling central lines are (a) site of the catheter: left subclavian lines are at higher risk than the right (b) synthetic material: polyvinyl chloride or polyethylene lines are more thrombogenic than are polyurethane or siliconized lines (c) number of lumen: triple lumen catheters may be more thrombogenic than double lumen (d) nature of the infusate: infusion of total parenteral nutrition fluids through the line have been found to be more thrombogenic than the infusion of crystalloid fluids (e) the position of the tip of the catheter located in the superior vena cava has almost a three-fold higher risk for thrombosis than that located in the right atrium and (f) insertion attempts of ≥2 carries higher risk for catheter related thrombosis.

Patient with CAT may present with pain, swelling, paresthesia, and prominent veins throughout the arm or shoulder. However, many patients may be asymptomatic.

Contrast venography is the gold standard for evaluation of patients suspected to have the upper extremity thrombosis. However, the non-invasive serial compression ultrasound is the standard test for UEDVT evaluation and if this is negative in a patient with high-pretest probability of UEDVT then the more expensive and invasive ultrasonography is resolved to.

In some centers, Color Doppler duplex ultrasound may be the modality of choice for the diagnosis of symptomatic CVC-R of UEDVT and for screening of suspected asymptomatic thrombosis in specific clinical situations (118)

**Prevention:** Despite the strong association between the CVCs and UEDVT, anticoagulant prophylaxis is not recommended. Studies evaluating the use of 1-mg (low dose) warfarin gave conflicting results **(**119-121).

On the basis of the available data from contemporary trials, it is difficult to recommend routine antithrombotic prophylaxis in cancer patients with central venous catheters. Institutions are encouraged to assess their rates of catheter-associated thrombosis and develop a protocol on how the catheters are inserted and maintained. This will be a useful tool to control the rate of complications associated with CVCs. When symptomatic thrombosis occurs in association with a catheter, it definitely complicates the clinical care of the patient because of the need for anticoagulant therapy and because often the catheter has to be removed.

#### **Management of Catheter Associated Thrombosis**

Treatment: ACCP guidelines recommend treating UEDVT patient with UH or LMWH and warfarin (INR 2-3) for at least 3-months (122).


These thrombi may impede atrial or ventricular inflow and cause sudden death. For a symptomatic patient with a large mobile thrombus, surgical thrombectomy is strongly recommended (123-124) and the catheter should also be explanted (125, 126, 127). Early involvement of the cardiologist, the cardiac surgeon and intensivist is advisable for coordinated optimum management.

#### **b. Medical management**

Pathophysiology and Clinical Aspects of 82 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

cancer patients ranges from 0.3% to 28% while the rate of catheter-related DVT assessed by

Some of the factors that may influence the risk of thrombosis of the indwelling central lines are (a) site of the catheter: left subclavian lines are at higher risk than the right (b) synthetic material: polyvinyl chloride or polyethylene lines are more thrombogenic than are polyurethane or siliconized lines (c) number of lumen: triple lumen catheters may be more thrombogenic than double lumen (d) nature of the infusate: infusion of total parenteral nutrition fluids through the line have been found to be more thrombogenic than the infusion of crystalloid fluids (e) the position of the tip of the catheter located in the superior vena cava has almost a three-fold higher risk for thrombosis than that located in the right atrium

Patient with CAT may present with pain, swelling, paresthesia, and prominent veins

Contrast venography is the gold standard for evaluation of patients suspected to have the upper extremity thrombosis. However, the non-invasive serial compression ultrasound is the standard test for UEDVT evaluation and if this is negative in a patient with high-pretest probability of UEDVT then the more expensive and invasive ultrasonography is resolved to. In some centers, Color Doppler duplex ultrasound may be the modality of choice for the diagnosis of symptomatic CVC-R of UEDVT and for screening of suspected asymptomatic

**Prevention:** Despite the strong association between the CVCs and UEDVT, anticoagulant prophylaxis is not recommended. Studies evaluating the use of 1-mg (low dose) warfarin

On the basis of the available data from contemporary trials, it is difficult to recommend routine antithrombotic prophylaxis in cancer patients with central venous catheters. Institutions are encouraged to assess their rates of catheter-associated thrombosis and develop a protocol on how the catheters are inserted and maintained. This will be a useful tool to control the rate of complications associated with CVCs. When symptomatic thrombosis occurs in association with a catheter, it definitely complicates the clinical care of the patient because of the need for anticoagulant therapy and because often the catheter has

Treatment: ACCP guidelines recommend treating UEDVT patient with UH or LMWH and

These thrombi may impede atrial or ventricular inflow and cause sudden death. For a symptomatic patient with a large mobile thrombus, surgical thrombectomy is strongly recommended (123-124) and the catheter should also be explanted (125, 126, 127). Early involvement of the cardiologist, the cardiac surgeon and intensivist is advisable for

and (f) insertion attempts of ≥2 carries higher risk for catheter related thrombosis.

throughout the arm or shoulder. However, many patients may be asymptomatic.

venography is 27–66% (117).

thrombosis in specific clinical situations (118)

**Management of Catheter Associated Thrombosis** 

warfarin (INR 2-3) for at least 3-months (122).

• **Right Atrial Thrombus a. Surgical management** 

coordinated optimum management.

gave conflicting results **(**119-121).

to be removed.

A completely dissolved right atrial thrombus case without side effects was reported by Adamovich et al in a neonate after 5 days' with infusion of urokinase and heparin (128). Cesaro et al reported on a successful pediatric case that was treated with recombinant tissue plasminogen activator (rt-PA) and heparin for 6 days without significant side effects (129). Korones et al favoured conservative management for small-sized thrombus with no intervention but close follow up for evidence of growth in size is warranted. However, for a moderate-sized thrombus there is a need for anticoagulation rather than surgical thrombectomy (123). If medical treatment fails then surgical thrombectomy should be resolved to. In adults, medical treatment has been tried in only a few reported cases because it is believed that, even though antithrombotic agents may stabilize or regress catheterrelated RA thrombi, anticoagulated patients remain at risk of pulmonary embolism and need to have surgical thrombectomy eventually (130-132).

• **Central Venous Thrombosis** 

#### **a. Surgical management**

The course of action for implantable venous access device (IVAD) after CVT is variable. Medical antithrombotic treatment was widely applied, but most of the devices were still explanted and some were removed before medical treatment is started (5,6) and some were explanted after fibrinolytic, antithrombotic or anticoagulant treatment failed (133-135). The reasons for explantation of IVAD are (a) prevention of thrombosis progression, especially in the case of SVC syndrome, (b) persistent pain, (c) combined with a documented infection and extravasation. However, Lokich et al (136) reported that the vascular occlusion rarely resolve after the explantation.

#### **b. Medical management**

For all CVT patients with or without IVAD explantation, antithrombotic treatment is necessary. Removal of the device should be decided by clinical necessity for venous access or by evidence of pulmonary embolism (134), especially in patients with very difficult venous access.

#### **c. Unfractionated Heparin**

Intravenous UFH is the initial treatment of choice for acute CVT. UFH can prevent clot propagation but does not dissolve it and, therefore, recanalization may not develop. UFH can be given by continuous intravenous infusion for 5–10 days, starting with a bolus of 5000 IU followed by 30,000–35,000 IU/day, with activated partial thromboplastin time of 1.5–2.5 times the control (137).

#### **d. Low Molecular Weight Heparin**

In view of the many advantages particularly the subcutaneous route q12 hours dosage, no need for laboratory and home treatment basis of the LMWH over the UFH, many experts favor its use for management of acute CVT

#### **e. Fibrinolytic agents**

Fibrinolytic agents, such as recombinant tissue plasminogen activator (rt-PA), streptokinase, and urokinase are usually effective for the lysis of fresh thrombi. Resolution of thrombi is

Venous Thromboembolism in Cancer Patients 85

of streptokinase, AstraZeneca, released an Important Safety Information letter on streptokinase in December 1999 and warned that there is a risk of significant allergic reactions and that streptokinase is not indicated for restoration of IVAD patency (144).

There are limited data on the effect of isolated radiation modality on risk of cancer-associated thrombosis. However, the combination of chemotherapy and radiation could lead to a more vigorous inflammatory response that may predispose patients to thrombosis in the setting of other predisposing factors. In a study of patients receiving rHuEpo along with chemotherapy and radiation therapy for cervical carcinoma, Dusenbery et al (101) reported that 2 of 20 patients had DVT during therapy, and 2 other patients had DVT 9 days and 10 days after radiation therapy and rHuEpo were discontinued. Although it was a small sample, the rate of 20% in that study is remarkably close to the rate found by other investigators. Large, randomized studies of combined chemotherapy and radiation therapy in patients with

Tamoxifen was discovered by pharmaceutical company Imperial Chemical Industries (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. However, the drug, even before its patent expiration, was and still widely referred to by its generic

Tamoxifen binds to estrogen receptors but produces both estrogenic and antiestrogenic effects. It reduces circulating insulin-like growth factor-1, inhibits angiogenesis, and induces

Tamoxifen is highly beneficial as adjuvant therapy for breast cancer, and more recently, its effectiveness has been demonstrated for prevention of breast cancer in high-risk women.

The most frequent side effect in patients treated with tamoxifen versus placebo was a doubling of the rate of DVT and PE: 118 versus 62 cases and a similar increase in superficial phlebitis (68 versus 30 cases) (152) A systematic review of adjuvant hormonal therapy for breast cancer estimated that women treated with 5 years of tamoxifen have a 1.5-7.1 fold increased risk of VTE compared to women treated with placebo or on observation only.

As to the evaluation of women who are about to initiate tamoxifen to prevent the development of breast cancer, the question raised is cost: benefit ratio of tamoxifen therapy if the patient have risk factors for DVT or PE. On the basis of the solid data favoring tamoxifen, the prevention of breast cancer should take priority over the risk of venous thromboembolism. If the risk of developing DVT is high, it is reasonable to go for concomitant anticoagulation with Coumadin (INR 2-3) for the planned treatment period

However VTE risk may become less problematic in breast cancer patients as the thirdgeneration oral aromatase inhibitors, such as the irreversible steroidal inactivator

carcinoma of the cervix did not report on the rate of venous thrombosis (145-148).

**2.5.7 Hormonal therapy: Tamoxifen and exemestane** 

**2.5.6 Radiation** 

name "tamoxifen."

apoptosis (149)

(150-151)

(153)

with tamoxifen.

more significant in acute occlusions than in CVT, which is always detected after a period of time i.e. chronic organized thrombosis. Although some studies mentioned their usage, antithrombotic agents are still the first choice (134,138).
