Table 1. Selected Factors Relevant to Pancreas Cancer and Thrombosis

Molecular Associations
Tissue factor^36,42
Thrombomodulin³⁴
Thrombin³⁵
Thrombin-antithrombin III complex³⁶
Plasminogen activator inhibitor-1³⁷
Platelet factor 4³⁸
Fibrin⁴⁰
Tissue factor pathway inhibitor⁴¹
Clinical and Treatment Variables
Hospitalization/sedentary status
Surgery
Venous access/catheterization
Weight extremes^14,21
Blood type group A²²
Leukocytosis^13,14
Anemia^13,14
Thrombocytosis^13,14
Medications (erythropoietin-stimulating agents,^13,14 chemotherapy,^31–33 megestrol⁸⁶)
Comorbidities (heart, liver, and kidney disease; diabetes)

Molecular Associations

Tissue factor^36,42

Thrombomodulin³⁴

Thrombin³⁵

Thrombin-antithrombin III complex³⁶

Plasminogen activator inhibitor-1³⁷

Platelet factor 4³⁸

Fibrin⁴⁰

Tissue factor pathway inhibitor⁴¹

Clinical and Treatment Variables

Hospitalization/sedentary status

Surgery

Venous access/catheterization

Weight extremes^14,21

Blood type group A²²

Leukocytosis^13,14

Anemia^13,14

Thrombocytosis^13,14

Medications (erythropoietin-stimulating agents,^13,14 chemotherapy,^31–33 megestrol⁸⁶)

Comorbidities (heart, liver, and kidney disease; diabetes)

Table 2. Incidence of Thrombosis in Pancreas Cancer–Specific Cohorts

Reference	N	Study Type	%^a	Notes
Cubilla and Fitzgerald,² 1978	380	Retrospective	14	Histologically confirmed patients at MSKCC^b from 1949–1972
Pinzon et al.,⁵ 1986	130	Retrospective	6.9	Consecutive patients at MDACC; mucin production and body/tail location associated with thrombosis
Mandala et al.,³ 2007	227	Retrospective	26	Patients with unresectable pancreas cancer in 3 clinical trials
Mitry et al.,⁶ 2007	90	Retrospective	27	No survival differences between patients with and without thrombosis
Oh et al.,⁴ 2008	75	Retrospective	5	Korean authors suggest possible ethnobiologic factors in relatively low incidence
Epstein et al.,⁷⁵ 2011	1915	Retrospective	36	Patients with pancreas cancer at MSKCC receiving chemotherapy
Mikal et al.,⁷⁰ 1950	100	Autopsy series	67	18% in head of pancreas, 49% in body/tail
Thompson et al.,⁷¹ 1952	157	Autopsy series	31	25 single thromboses, 23 patients with multiple thromboses
Soederstroem and Bjersing,⁷² 1963	50	Autopsy series	52	Included anatomy: inferior vena cava, pelvic and thigh veins
Lowe and Palmer,⁷⁴ 1967	100	Autopsy series	29	8% clinical, 21% autopsy
Mao et al.,⁷³ 1995	154	Autopsy series	19.4	Consecutive autopsies at 3 affiliated Ohio teaching hospitals
Blom et al.,¹ 2006	202	Prospective	108.3^b	Increased risk with body/tail tumors, chemotherapy, surgery, and metastatic disease

Abbreviations: MDACC, MD Anderson Cancer Center; MSKCC, Memorial Sloan-Kettering Cancer Center.
^aPercentage incidence figures are relative to the individual specific study periods.
^bIn 1000 patient years

Table 3. Randomized Trials of Primary Thromboprophylaxis in Pancreas Cancer

Reference	N	Drug	Chemotherapy	Median Survival	Notes
Maraveyas et al.,⁷⁷ 2009	123	Dalteparin	Gemcitabine	Lethal thrombosis and sudden death, 0% in dalteparin arm vs. 9% in control (P = .028); but “early death burden,” 7% vs. 11% (P = .62). No overall survival difference	Reduction in primary end point of thrombosis (25% to 3.5% over first 100 d; 31% to 12% overall)
Riess et al.,⁷⁹ 2010	312	Enoxaparin	Gemcitabine-based (+/– 5FU/cisplatin depending on performance status)	8 mo without enoxaparin, 8.3 mo with enoxaparin (P = .501); median follow-up time of 45 mo	Closed early because of significant symptomatic thromboembolism reduction 9.9% vs. 1.3% at 3 mo (primary end point); at 12 mo: 15.1% vs. 5.0%
NCT00031837^a	400	Dalteparin	Systemic gemcitabine	Pending (secondary end point)	Pending results, primary end point is quality of life
NCT00662688^a	136	Dalteparin	Gemcitabine +/–capecitabine	Pending (secondary end point)	Pending results, primary end point is thromboembolic event rate
NCT00966277^a	87	Dalteparin	Investigator choice	Pending (secondary end point)	Pending results, primary end point is thromboembolic event rate

^aClinicalTrials.gov identifier.

Table 4. Key Points in Pancreas Cancer Thrombosis and Anticoagulation

Numerous clinical and molecular factors contribute to thrombogenicity in pancreas cancer. The relatively high incidence of thrombosis and its contribution to morbidity and mortality in pancreas cancer calls for vigilance in diagnosis and treatment of these events. Superficial vein thrombosis with proximity to the deep venous system should be treated with at least 4 weeks of anticoagulation (category 2B⁸⁷) unless the thrombosis is catheter-associated and the catheter is removed. Deep vein thrombosis, including pulmonary embolism, should be anticoagulated.^b Primary prophylactic anticoagulation of hospitalized patients with pancreas cancer is recommended. Primary prophylactic anticoagulation of outpatients with pancreas cancer should be performed only in the context of a clinical trial.

Numerous clinical and molecular factors contribute to thrombogenicity in pancreas cancer.
The relatively high incidence of thrombosis and its contribution to morbidity and mortality in pancreas cancer calls for vigilance in diagnosis and treatment of these events.
Superficial vein thrombosis with proximity to the deep venous system should be treated with at least 4 weeks of anticoagulation (category 2B⁸⁷) unless the thrombosis is catheter-associated and the catheter is removed.
Deep vein thrombosis, including pulmonary embolism, should be anticoagulated.^b
Primary prophylactic anticoagulation of hospitalized patients with pancreas cancer is recommended.
Primary prophylactic anticoagulation of outpatients with pancreas cancer should be performed only in the context of a clinical trial.

^aRisk of bleeding must always be considered in the decision to initiate anticoagulation.
^bDuration of anticoagulation treatment for deep vein thrombosis is indefinite for as long as pancreas cancer is active, and low-molecular-weight heparin is recommended over warfarin.

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Author(s)

Andrew S. Epstein, MD

Memorial Sloan-Kettering Cancer Center, New York, New York

Disclosures

Disclosure: Andrew S. Epstein, MD, has disclosed no relevant financial relationships.

Eileen M. O'Reilly, MD

Memorial Sloan-Kettering Cancer Center, New York, New York

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Disclosure: Eileen M. O'Reilly, MD, has disclosed no relevant financial relationships.

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Kerrin M. Green, MA

Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

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Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME Author

Charles P. Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine

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Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

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Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

CME

Exocrine Pancreas Cancer and Thromboembolic Events: A Systematic Literature Review

Authors: Andrew S. Epstein, MD; Eileen M. O'Reilly, MD
CME Released: 7/7/2012
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 7/7/2013, 11:59 PM EST

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Target Audience and Goal Statement

This activity is intended for primary care physicians, oncologists, gastrointestinal specialists, surgeons, and other physicians who care for patients with pancreatic cancer.

The goal of this activity is to evaluate the risks for thromboembolism among patients with pancreatic cancer as well as appropriate management of thromboembolism among these patients.

Upon completion of this activity, participants will be able to:

Distinguish risk factors for thromboembolism among patients with pancreatic cancer
Analyze recommendations for primary prophylaxis against thromboembolism among patients with pancreatic cancer
Assess the best treatment for thromboembolism among patients with pancreatic cancer
Evaluate outcomes improved with treatment of thromboembolism among patients with pancreatic cancer

Disclosures

Author(s)

Andrew S. Epstein, MD

Memorial Sloan-Kettering Cancer Center, New York, New York

Disclosures

Disclosure: Andrew S. Epstein, MD, has disclosed no relevant financial relationships.

Eileen M. O'Reilly, MD

Memorial Sloan-Kettering Cancer Center, New York, New York

Disclosures

Disclosure: Eileen M. O'Reilly, MD, has disclosed no relevant financial relationships.

Editor

Kerrin M. Green, MA

Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosures

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME Author

Charles P. Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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From JNCCN - Journal of the National Comprehensive Cancer Network

CME

Exocrine Pancreas Cancer and Thromboembolic Events: A Systematic Literature Review

Authors: Andrew S. Epstein, MD; Eileen M. O'Reilly, MDFaculty and Disclosures

THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME Released: 7/7/2012

Valid for credit through: 7/7/2013, 11:59 PM EST

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Abstract and Introduction

Abstract

Exocrine pancreas cancer continues to represent a significant therapeutic challenge, with high rates of mortality and morbidity, including from thromboembolic events, which have long been described as a frequent complication of the disease. This article provides a systematic and comprehensive review of the literature to address the clinical and pathologic features recognized in pancreas cancer pertaining to thrombosis, and to discuss ongoing investigations of prophylactic anticoagulation in the hopes of improving disease-related outcomes. (JNCCN 2012;10:835–846)

Introduction

Malignancy is a well-established risk factor for the development of venous thromboembolic events, both in hospitalized and ambulatory patients. Venous thromboembolic events are a major contributor to cancer- and treatment-related morbidity and mortality. Exocrine pancreas cancer is one of the most common malignancies associated with thrombosis, with most modern studies reporting incidence ranging from 5% to 27%.^[1–6] Various patient-, treatment-, and increasingly recognized pancreas tumor–related factors contribute to thrombosis ( Table 1 ). Additionally, venous thromboembolic events have been found to portend a poorer prognosis in patients with pancreas cancer,^[3] and have been implicated in early deaths after diagnosis.^[7] Patients with various cancers diagnosed within 1 year of a thrombosis often have more extensive malignancy and worse outcome.^[8] This association between thrombosis and shorter survival has been validated in a prospective case-control study by Mandala et al.^[9] Anticoagulants may have treatment effects on the malignancy.^[10,11]

Pancreas cancer is notoriously difficult to treat, and current chemotherapy regimens offer only modest disease control. Therefore, new therapies are clearly needed in hopes of impacting survival and treatment- and disease-related morbidity, including that from thrombosis. Although both superficial thrombophlebitis and arterial thromboses, such as myocardial infarction and stroke, have been well described in pancreas cancer, this article focuses on deep venous thromboses (hereafter referred to as thrombosis), because these predominate. The clinical and molecular underpinnings of thrombosis in patients with cancer are first discussed, highlighting key studies performed not only in pancreas cancer but also in other tumor types.

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Methods

CME Information

References

References

Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

Published by Harborside Press

Table 1. Selected Factors Relevant to Pancreas Cancer and Thrombosis

Table 2. Incidence of Thrombosis in Pancreas Cancer–Specific Cohorts

Table 3. Randomized Trials of Primary Thromboprophylaxis in Pancreas Cancer

Table 4. Key Points in Pancreas Cancer Thrombosis and Anticoagulation

References

Faculty and Disclosures

Author(s)

Andrew S. Epstein, MD

Eileen M. O'Reilly, MD

Editor

Kerrin M. Green, MA

CME Author

Charles P. Vega, MD

CME Reviewer

Nafeez Zawahir, MD

CME

Exocrine Pancreas Cancer and Thromboembolic Events: A Systematic Literature Review

Target Audience and Goal Statement

Disclosures

Author(s)

Andrew S. Epstein, MD

Eileen M. O'Reilly, MD

Editor

Kerrin M. Green, MA

CME Author

Charles P. Vega, MD

CME Reviewer

Nafeez Zawahir, MD

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Exocrine Pancreas Cancer and Thromboembolic Events: A Systematic Literature Review

Abstract and Introduction

Abstract

Introduction

Table of Contents