OCCULT CANCER AND VTE

MANAGEMENT OF VTE

BREAST, COLON & LUNG CANCERS

These are the most common malignancies associated with thrombosis that is reflecting the

prevalence of these malignancies in the general population, but when adjusted with

disease prevalence, the cancers most strongly associated with thrombotic complications

are those of the pancreas, ovary and brain.

• Idiopathic thrombosis can be the first manifestation of an occult malignancy. However intensive screening for cancer in patients with VTE often does not improve the survival and is not generally warranted.

• Independently of the timing of cancer diagnosis (before or after the VTE), the life expectancy of cancer patients with VTE is relatively short, because of both death from recurrent VTE and the cancer itself.

• A recent randomized trial, the Randomized comparison of the LMWH Vs oralanticoagulant therapy for long term anticoagulation in cancer patients with VTE showed that LMWH may be a better treatment option for this group of patients.

VTE IS A COMMON COMPLICATION OF MALIGNANT DISEASE BUT THE PATHOPHYSIOLOGY REMAINS POORLY UNDERSTOOD.

Patients under going surgery for cancer have a higher risk of post operative DVT thanthose having surgery for nonmalignant diseases.

Autopsy series have reported increased rates of pulmonary embolism in cancer patients compared with patients without cancer.

FINALLY INDIVIDUALS PRESENTING WITH AN

UNPROVOKED EPISODE OF VTE ARE MORE

LIKELY

TO HAVE AN UNDERLYING CANCER THAN THOSE

WITH AN IDENTIFIABLE RISK FACTOR FOR

THROMBOSIS.

ACCORDING TO CLINICAL DATA PROSPECTIVELY COLLECTED ON THE POPULATION OF OLMSTED COUNTY, MINNESOTA SINCE 1966, THE ANNUAL INCIDENCE OF A FIRST EPISODE OF VTE OR PE IN THE GENERAL POPULATION IS 117 OUT OF 100,000. CANCER ALONE WAS ASSOCIATED WITH A 4.1 FOLD RISK OF THROMBOSIS, WHEREAS CHEMOTHERAPY INCREASED THE RISK 6.5 FOLD. COMBINING THESE ESTIMATES YIELDS AN APPROXIMATE ANNUAL INCIDENCE OF VTE OF 1 OF 200 IN A POPULATION OF CANCER PATIENTS.

10% OF WOMEN WITH ADVANCED OVARIAN CANCER RECEIVING CHEMOTHERAPY AND UP TO 28% OF PATIENTS WITH MALIGNANT GLIOMA HAVE BEEN REPORTED TO DEVELOP VTE. CLL HAVE 4% RISK OF CEREBRAL VASCULAR THROMBOSIS DURING THERAPY WITH L-ASPARGINASE WHEREAS 10% OF PATIENTS WITH HODGKIN’S OR NONHODGKIN’S LYMPHOMA DEVELOP VTE.

Age, hormonal treatment and chemotherapy play synergistic roles in thrombosisdevelopment in patients with cancer. The extent of cancer also influences the

risk of thrombosis.

TUMOURS MOST STRONGLY ASSOCIATED WITH THROMBOSIS

Very high rates of VTE have been reported in patients treated with combination therapy including an antiangiogenic agent. For example when thalidomide is combined with cancer chemotherapy, VTE rates of 28% in patients with multiple myeloma and 43% in patients with RCC have been reported. The pathophysiology of thrombosis in these setting has not been elucidate, but endothelial dysfunction, alteration in pro- and anticoagulant protein levels or deregulation of cytokine activity have been proposed as mechanisms.

Cancers of pancreas, lung and stomach and adenocarcinomas of unknown primary are most strongly associated with thrombosis.

In one study by Levitan et al found the highest rates of VTE in cases of ovarian cancer (1.2%), brain tumours (1.2%) and cancer of the pancreas (1.1%)

In summary although patients with mucin-producing adenocarcinomas seems most likely to develop thrombosis, the most frequent types of cancers found in patients with thrombosis are those most prevalent in the population.In every researches there is different numbers of cancers with different varieties and different stages and grades so there is not a unique result just we can find that in every research which cancers are highly associated with VTE.

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THE ASSOCIATION BETWEEN VTE AND OCCULT

CANCER A diagnosis of cancer is more likely to arise in patients without identified risk factors for thrombosis who present with apparently spontaneous DVT than in those in whom secondary DVT occurs postoperatively or in another high risk situation or patients with signs and symptoms of DVT in whom thrombosis is subsequently excluded.

On the basis of results from cohort studies and clinical trials 10% of persons presenting with idiopathic VTE are subsequently diagnosed with cancer over 5-10 years and the diagnosis is stablished within the first year of presentation of DVT in more than 75% of cases.

In the study by Sorensen et al, 40% of patients diagnosed with cancer within 1 year after VTE had distant metastasis by the time of cancer diagnosis.

Given the association between idiopathic VTE and occult cancer, it has been suggested that patients with unprovoked thrombosis routinely undergo investigation for underlying malignancy. However, there is little evidence to date that routine cancer screening would be worthwhile or cost-effective in this situation.

The preliminary results of a small randomized trial evaluating extensive screening versus no screening in patients presenting with idiopathic VTE were reported recently.

Extensive screening means USS, CT scan of head, chest, abdomen and pelvis, stool guaiac examination, gastroscopy, colonoscopy, sputum cytology, mammography, manual pelvic or prostate examination and measurement of tumour markers such as PSA, CEA, AFP, ...

30 OF 99 PATIENTS ALLOCATED TO THE EXTENSIVE SCREENING GROUP COMPARED WITH 0 OF 102 PATIENTS IN THE CONTROL GROUP WERE INITIALLY FOUND TO HAVE CANCER BY THESE MEANS. DURING THE 2 YEAR FOLLOWUP PERIOD, A DIAGNOSIS OF CANCER WAS ESTABLISHED IN 10 PATIENTS IN THE CONTROL GROUP AND 1 IN THE SCREENED GROUP. THERE WAS NO SIGNIFICANT DIFFERENCE IN CANCER RELATED MORTALITY BETWEEN THE 2 GROUPS (3.9% VERSUS 2%, RESPECTIVELY).

AS CONCLUSION EARLY DIAGNOSIS OF CANCER POST VTE DOESN’T TRANSLATE INTO IMPROVED PROGNOSIS AND SURVIVAL.

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IN PATIENTS WITH IDIOPATHIC VTE SUPPLEMENTATION OF A COMPREHENSIVE MEDICAL HISTORY AND A PHYSICAL EXAMINATION WITH BASIC BLOOD WORK, AND A CHEST XRAY IN SMOKERS, CAN BE EXPECTED TO DETECT 90% OF OCCULT CANCERS.

In summary acute VTE can be the first manifestation of an occult malignancy, and patients presenting with idiopathic VTE are more likely to have underlying cancer than those in whom a secondary cause of thrombosis is apparent. Extensive screening for cancer in patients with idiopathic VTE is not routinely warranted. However further large-scale studies of the role of such screening in idiopathic VTE are necessary.

WHAT IS THE TREATMENT OF VTE IN PATIENTS WITH CANCER?

LMWH is superior to heparin plus warfarin

Long-term anticoagulation using vitamin K antagonists is associated with high rates of recurrent VTE and bleeding in patients with cancer. This therapy is also difficult to supervise in this group of patients, as it requires frequent blood testing to maintain dosage levels within the therapeutic range.

ANTICOAGULATION THERAPY AND CANCER

PROGRESSION

The potential for anticoagulant therapy to retard tumour progression and improve survival was first examined in a large clinical trial in 1984.

The first study designed to specifically examine the influence of LMWH on overall survival in cancer patients with advanced solid tumours was reported recently.

In this randomized placebo controlled study, Kakkar et all found no difference in survival at 1,2 and 3 years between 185 patients treated with dalteparin and 181 patients who received placebo.

Patients with cancer who develop VTE have reduced life expectancy. On the basis of long term follow-up data on patients with thrombosis, those with cancer have a 4-8 fold higher risk of dying after an acute thrombotic event than patients without cancer.

Furthermore, patients with cancer and thrombosis have a lower survival rate than those with cancer without thrombosis.

In a large population-based study, Sorensen and colleagues examined the survival of patients with cancer and VTE compared with those without VTE matched for type of cancer, sex, age, and the year of diagnosis.

The 1 year survival rate for patients with thrombosis was 12% compared with 36% in control patients (P<0.001). The mortality ratio associated with VTE was 2.2 for the 1-year follow-up period. This high mortality probably reflects death due to both thromboembolism and a more aggressive course of malignancies associated with VTE.

CIRCULATION, AHA (AMERICAN HEART ASSOCIATION)

TREATMENT OF VTEDrugs:

UFH: such as heparin

LMWH: enoxaparin, dalteparin, nadroparin, tinzaparin, certoparin, reviparin, ardeparin, parnaparin and bemiparin

Indirect factor Xa inhibitor: Fondaparinux

Direct factor Xa inhibitor: rivaroxaban, apixaban, edoxaban

Direct thrombin inhibitor: dabigatran

Currently available anticoagulations have well-known limitations. LMWH requires subcutaneous administration. Vitamin K antagonists are orally active but requires laboratory monitoring for dose initiation and adjustment, have a narrow therapeutic window, and are subject to drug and food interactions. An orally active, safe, and effective anticoagulant that requires no monitoring for dose adjustment would have the potential to radically simplify the management of thromboembolic disorders (selective inhibitor of factor Xa).

Selective factor Xa inhibitor can be effective for the prevention and treatment of VTE, as shown by clinical experience with subcutaneous fondaparinux (an indirect factor Xa inhibitor).

Rivaroxaban is an orally active, selective direct factor Xa inhibitor and also inhibits prothrombinaseactivity and clot-associated factor Xa activity.

Rivaroxaban has predictable pharmacokinetics and pharmacodynamics in healthy subjects and those undergoing orthopedic surgery. Its relative bioavailability is high (80%) and has dual mode of excretion.

WHAT IS VTE RISK FACTORS?- Pregnancy

- Obesity

- Smoking

- Heart failure

- Previous DVT or PE

- Increased age

- Cancer

- Nephrotic syndrome

- Drugs such as OCP, thalidomide, HRT, tamoxifen and erythropoietin

- Surgery and immobility

- Acquired thrombophilia: PCV, essential thrombocytemia

- Antiphospholipid Ab, lupus anticoagulant and anti cardiolipin Ab

- Herediatry thrombophilia: anti thrombin, protein C and S deficiency and factor V leiden

The treatment of DVT and pulmonary embolism (PE) are similar. In DVT, the main goal of treatment is to prevent a PE. Other goals of treatment include preventing the clot from becoming larger, preventing new blood clots from forming, and preventing long-term complications of PE or DVT.

The primary treatment for venous thrombosis is anticoagulation. Other available treatments, which may be used in specific situations, include thrombolytic therapy or placing a filter in a major blood vessel (the inferior vena cava).

●Low molecular weight heparin, which is given as an injection under the skin – Options include enoxaparin (brand name: Lovenox), dalteparin (brand name: Fragmin), and tinzaparin(brand name: Innohep).

●Fondaparinux (brand name: Arixtra), also given by injection

●Unfractionated heparin, which is given into a vein (intravenously) – This may be the preferred choice in certain circumstances, such as if the patient has severe kidney failure or unstable blood pressure.

●Direct oral anticoagulants – These are available in pill form; they include rivaroxaban (brand name: Xarelto) and apixaban(brand name: Eliquis).

Initial anticoagulation is continued for 5 to 10 days. After that, long-term anticoagulation is continued for 3 to 12 months. In most cases, the direct oral anticoagulants are the preferred choice for long-term anticoagulation; these pills include rivaroxaban (brand name: Xarelto), apixaban (brand name: Eliquis), dabigatran (brand name: Pradaxa), and edoxaban (brand name: Savaysa). In some situations, another oral medication called warfarin (sample brand name: Coumadin) is given instead. For patients taking warfarin, the clotting factors in the blood need to be measured on a regular basis with a blood test called the International Normalized Ratio (INR), whereas this is not needed for patients on direct oral anticoagulations. Less commonly, the patient does not take warfarin or any of the direct oral anticoagulants but takes a daily injection of low molecular weight heparin or fondaparinux for the entire treatment period.

Duration of treatment — Anticoagulation is recommended for a MINIMUM of three months in a patient with DVT.

●In patients who had a reversible risk factor contributing to their DVT, such as trauma, surgery, or being confined to bed for a prolonged period, the person is often treated with anticoagulation for three months or until the risk factor is resolved.

●Expert groups suggest that people who develop a venous thrombosis and who do not have a known risk factor for thrombosis may need treatment with an anticoagulant for an indefinite period of time. However, this decision should be discussed with the person's healthcare provider after three months of treatment, and then reassessed on a regular basis. Some people prefer to continue the anticoagulant, which may carry an increased risk of bleeding, while others prefer to stop the anticoagulant at some point, which may carry an increased risk for repeat thrombosis.

●Most experts recommend continuing anticoagulation indefinitely for people with two or more episodes of venous thrombosis or if a permanent risk factor for clotting is present (eg, antiphospholipid syndrome, cancer).

Walking during DVT treatment — Once an anticoagulant has been started and symptoms (eg, pain, swelling) are under control, the person is strongly encouraged to get up and walk around. Studies show that there is no increased risk of complications (eg, pulmonary embolus) in people who get up and walk, and walking may in fact help the person feel better faster.

Thrombolytic therapy — In some cases, a healthcare provider will recommend an intravenous medicine to dissolve blood clots. This is called thrombolytic therapy. This therapy is reserved for patients who have serious complications related to PE or DVT, and who have a low risk of serious bleeding as a side effect of the therapy. The response to thrombolytic therapy is best when there is a short time between the diagnosis of DVT/PE and the start of thrombolytic therapy.

Inferior vena cava filter — An inferior vena cava (IVC) filter is a device that blocks the circulation of clots in the bloodstream. It is placed in the inferior vena cava.The IVC filter typically is inserted through a small incision in a leg vein with the use of a local anesthetic and takes 20 to 30 minutes to perform. An IVC filter is often recommended in patients with venous thromboembolism who cannot use anticoagulants because of a very high bleeding risk. However, in the long term, IVC filters can increase the risk of developing blood clots.

Low molecular weight heparin (LMWH) is the parenteral treatment of choice for most patients, although fondaparinux and unfractionated heparin (UFH) are also options. Although effective, heparins and fondaparinux require administration by injection, and UFH can also be administered intravenously. Self-injection is an option with LMWHand fondaparinux but may be unsuitable for patients who lack dexterity, such as the elderly, or for those with self-injection anxiety. Heparin induced thrombocytopenia (HIT) is an adverse event that should be considered when using UFH, and to a lesser extent LMWHand fondaparinux. Patients with a history of HIT should receive an alternative anticoagulant, such as argatroban, lepirudin or danaparoid. Limited evidence suggests that fondaparinux may be another alternative treatment for patients with a history of HIT. Osteoporosis is another potential adverse effect when heparin is administered for longer than 1 month.

The novel OACs apixaban, edoxaban, rivaroxaban, (direct Factor Xa inhibitors) and dabigatran (direct thrombin inhibitor), are approved in Europe and North America for the treatment of DVT, PE and prevention of recurrent DVT and PE in adult patients. As with VKAs, dabigatran and edoxaban are administered as part of a dual-drug approach, following acute-phase parenteral anticoagulation. Rivaroxaban and apixaban can be administered from the start of treatment in a ‘single-drug approach’, thus overcoming the complications of overlapping parenteral anticoagulant with VKA.

Recently, the updated ESC guidelines have recommended rivaroxaban, dabigatran, apixaban and edoxaban as alternatives to parenteral/VKAanticoagulation for acute-phase treatment and secondary prevention of patients at an intermediate or low risk of early mortality from PE. Rivaroxaban, dabigatran and apixaban are also recommended as alternatives to conventional therapy for patients who require extended anticoagulation (>3 months).

The novel OACs have been tested against conventional therapy in large studies for the treatment of VTE: EINSTEIN DVT and EINSTEIN PE for rivaroxaban, RE-COVER and RE-COVER II for dabigatran, AMPLIFY for apixaban and Hokusai-VTE for edoxaban Across these studies, novel OACs (administered following initial heparin therapy in the case of dabigatran and edoxaban) were shown to be at least as effective as VKAs for preventing recurrent VTE and VTE-related death for all studies (primary efficacy endpoint events), and demonstrated a similar or reduced incidence of the major, major-plus or minor clinically relevant bleeding, compared with conventional treatment. The efficacy and safety of novel OAC use for the extended secondary prevention of VTE following an initial DVT/PE in patients who have received 6–12 months anticoagulation therapy has been evaluated in placebo-controlled studies: EINSTEIN EXT for rivaroxaban, RE-SONATE for dabigatran and AMPLIFY-EXT for apixaban. All three novel OACs demonstrated superior efficacy compared with placebo for preventing recurrent VTE and VTE-related death, with small but non-significant differences in the incidence of major bleeding. Dabigatran was also compared with warfarin for extended VTE treatment in the RE-MEDY study, and was associated with non-inferior efficacy and similar rates of major bleeding. These studies are difficult to compare directly owing to variations in study design; therefore, in the absence of head-to-head comparison trials, there is no direct evidence to support the use of one novel OAC over another.

2012 American College of Chest Physicians (ACCP) guidelines for the treatment of DVT and PE with anticoagulants:

Acute DVT or PE: LMWH or fundaparinux following with VKA or rivaroxaban

For long-term therapy of DVT or PE in patients without cancer: VKA>LMWH and LMWH>dabigatran or rivaroxaban

In DVT or PE in patients with cancer: LMWH>VKA and VKA>dabigatranor rivaroxabanDURATION OF ANTICOAGULATION THERAPY:

Proximal DVT or PE: 3 month

First proximal DVT or PE provoked by surgery or nonsurgical transient factor: 3 month

Unprovoked DVT or PE: extended therapy if risk of bleeding is low to moderate, if risk of bleeding is high: 3 month

DVT or PE associated with active cancer: over 3 month therapy

2014 updated European Society of Cardiology (ESC) guideline recommendations for novel OACs for low- to intermediate-risk PE patients:

Novel OACs are recommended as alternatives to VKA/parenteral anticoagulation such as: rivaroxaban (15 mg BID for 3 weeks, followed by 20 mg QD)

for patients ≥80 years of age or those under concomitant verapamil treatment following acute-phase parenteral anticoagulation, then Dabigatran (150 mg bid, or 110 mg bid)

Edoxaban following acute-phase parenteral anticoagulation

Thrombolytic therapy (for patients who do not have high risk of bleeding)

All of the above mentioned doesn’t have superiority over each other.

In case of extended anticoagulation therapy for more than 3 month:

Novel OACs should be considered as alternatives to VKA anticoagulation if extended anticoagulation treatment is necessary.

Rivaroxaban: 20 mg od

Dabigatran: 150 mg bid (or 110 mg bid for patients >80 years old /those taking verapamil)

Apixaban: 2.5 mg bid

Approved anticoagulants for treatment of DVT and PE:

- UFH: Factor Xa and thrombin inhibitor (indirect via AntiThrombin)- LMWH: Factor Xa and thrombin inhibitor (indirect via AntiThrombin)

- Fondaparinux: Factor Xa inhibitor (indirect via AntiThrombin)

- VKA: Vitamin K (inhibits synthesis of Factors II, VII, IX and X)

- Rivaroxaban: Factor Xa inhibitor(direct)

- Apaxiban: Factor Xa inhibitor (direct)

- Dabigatran: Thrombin inhibitor (direct)

- Edoxaban: Factor Xa inhibitor (direct)

IN PATIENTS WITH ATRIAL FIBRILLATION IF THERE IS MECHANICAL

VALVULOPATHY VKA SHOULD BE ADMINISTERED AND IN NON-

MECHANICAL CASES DABIGATRAN AS IN CASES OF MECHANICAL VALVULOPATHY

DABIGATRAN INCREASE THE RISK OF INTRA-ARTERIAL THROMBOSIS.

DABIGATRAN IS NOT PROVED BY FDA

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