Chapter 9: Vascular Complications of Cancer and Cancer Treatment Gary H Lyman Anna Catino Bonnie Ky Cardio-Oncology Eds: Kimmick, Lenihan, Sawyer, Mayer, Hershman

Introduction Pathogenesis: Virchow’s Triad Rudolph Virchow Stasis Bed rest and immobility Extrinsic compression of vessel Blood Components [Hypercoagulability] Tumors and macrophages produce procoagulants, inflammatory cytokines Vessel Damage Direct tumor invasion Chemotherapy, indwelling catheters Antiangiogenic agents, ESAs

Interactions Between Tumor Cells and the Hemostatic System Lyman GH et al: J Clin Oncol 27: 4821-4826 Falanga A: Cancer Invest 2009; 27: 105-115

Hemostatic Tumor System Cells Growth Invasion Metastases Angiogenesis Procoagulant Activity Cytokines Growth Factors Fibrinolytic Activity Tumor cells 1. release procoagulants activating coagulation system and blood cells; 2. stimulate release of cytokines and growth factors activating angiogenesis; 3. inhibit fibrinolytic system Hemostatic system: TF/FVIIa, FXa. Thrombin stimulate tumor growth, invasiveness, metastases, angiogenesis Kuderer NM et al J Clin Oncol 2009; 29: 4902-4911

Cancer and Venous Thromboembolism (VTE) Armand Trousseau Association recognized since Trousseau’s observation >140 years ago Approximately 20% of cases of VTE occur in patients with cancer VTE has been reported in 4-20% of cancer patients 60 - 70% of fatal PE at autopsy were not suspected or diagnosed Cancer-associated VTE has important clinical and economic consequences * “I am lost; the phlebitis that has appeared tonight leaves me no doubt about the nature of my illness” Patients with cancer: 20% All deep venous thrombosis and pulmonary embolism

Magnitude of the Problem Venous thromboembolism (VTE) is one of the most frequent causes of preventable mortality and morbidity in hospitalized patients About 25% of all cases of VTE are related to hospitalization 50 - 75% of cases of VTE in hospitalized patients are on the medical service Pulmonary embolism is associated with 5% to 10% of deaths in patients in hospitals

What is the true burden of VTE in oncology? Cancer progression 71% Thromboembolism 9% Infection Respiratory failure 4% Bleeding 1% Aspiration Other 6% Unknown 70% One possible interpretation is that we could assess our patients for the development of VTE and then treat the patient when a DVT or PE occurs. However, the problem with such an approach is that VTE diagnosis may be difficult and often goes undetected until it is too late. At least 70% of the time, a fatal PE is not detected until post-mortem. Studies have also shown that at autopsy, approximately 63% of DVT cases were clinically undiagnosed. The 2001 ACCP Consensus Conference publication states that it is inappropriate to wait for the symptoms and then rely on the diagnosis and treatment of established VTE. So what available evidence do we have to clue us into, or point to, the types of patients who are at risk for VTE that enter our hospitals? Fatal PE is the leading cause of sudden death among hospitalized patients and contributes to up to 10% of in-hospital deaths VTE accounts for approximately 10% of deaths in ambulatory cancer patients receiving chemotherapy Stein PD, et al. Chest. 1995;110:978-981 Sandler DA, et al. J R Soc Med. 1989;82:203-205 Nicolaides AN, et al. Int Angiology. 2006;25:101-106 Khorana AA et al: J Throm Haemost 2007; 5: 632-635 Lyman GH et al: J Clin Oncol 2009; 27: 4821-4826 Lyman GH: Cancer 2011; 117; 1334-1349

Risk factors for VTE in patients with malignant disease Patient-related factors Older age Race (higher in AA; lower in Asian-Pacific Islanders) Comorbidities (obesity, infection, renal, lung, ATE) History of VTE Heritable prothrombotic mutations Cancer-related factors Site of cancer (GI, brain, lung, gyn, renal, heme) Advanced stage Treatment-related factors Major surgery Hospitalization Chemotherapy Hormonal therapy Antiangiogenic therapy (thalidomide, lenalidomide, bevacizumab?) Erythropoiesis-stimulating agents Central venous catheters Lyman GH et al. J Clin Oncol. 2007;25:5490-505

Risk Score for Predicting Outpatient VTE in Cancer Patients Patient Characteristics Risk Score Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, bladder, testicular)   2 1 Prechemotherapy platelet count 350000/mm3 or more Hemoglobin level less than 10g/dL or use of red cell growth factors Prechemotherapy leukocyte count more than 11000/mm3 Body mass index 35kg/m2 or more   High-risk score ≥ 3 Intermediate risk score =1-2 Low-risk score =0 Khorana AA et al. Blood. 2008; 111: 4902-4907

ASCO VTE Guidelines (2006 – 2015): Clinical Questions (1) Should hospitalized patients with cancer receive anti-coagulation for VTE prophylaxis? (2) Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? (3) Should patients with cancer undergoing surgery receive periop VTE prophylaxis? (4) What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? (5) Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? (6) What is known about risk factors and risk prediction of VTE among patients with cancer? Lyman GH et al. J Clin Oncol 2015; 33: 654-656

Cumulative risk for VTE in patients with cancer undergoing chemotherapy. Abbreviation: VTE, venous thromboembolism Lyman, GH et al: The Oncologist 2013; 18: 1321-1329

Thromboprophylaxis of Hospitalized Medically Ill Patients 3 large, placebo-controlled, double-blind RCTs in high-risk medical patients MEDENOX (enoxaparin) PREVENT (dalteparin) ARTEMIS (fondaparinux) Screening for asymptomatic DVT with venography or US Subgroup analysis in cancer pts* Post-hoc analysis: MEDENOX Cancer patients: 12.4% VTE with 40mg enoxaparin vs placebo RR = 0.50 (95% CI, 0.14 – 1.72; NS) 1Samama MM, et al. N Engl J Med. 1999;341:793-800. 2 Leizorovicz A, et al. Circulation. 2004;110:874-9. 3Cohen AT, et al. BMJ 2006; 332: 325-329. * Alikhan R et al, Blood Coag Fibrinolysis, 2003 14: 341-346

2.1 Routine pharmacologic thromboprophylaxis is NOT RECOMMENDED in ambulatory cancer outpatients. 2.2 Based on limited RCT data, clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy. Additional Questions What is the true burden of VTE in ambulatory patients receiving cancer chemotherapy? Can we identify patients at higher risk who might be candidates for thromboprophylaxis?

Thrombosis and Cancer: Conclusions The association of VTE with cancer has been recognized for over 100 years and is a major cause of morbidity and mortality. Despite limited cancer-specific data, current guidelines recommend routine thromboprophylaxis of most hospitalized cancer patients While thromboprophylaxis in ambulatory patients receiving cancer therapy appears to be effective, results from RCTs suggest a relatively low risk for VTE among unselected controls

Proposed mechanisms for the “off-target” vascular toxicities from VEGF Signaling Pathway inhibitors

Coronary angiogram of a 60 year old male with metastatic renal cell cancer treated with multiple angiogenic inhibitors over a 9 year period. Panel A shows pre-percutaneous coronary intervention with occlusion of the left circumflex. Panel B shows post-percutaneous coronary intervention with restoration of flow in the left circumflex.