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

2. 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

3. Interactions Between Tumor Cells and the Hemostatic System
Lyman GH et al: J Clin Oncol 27:
Falanga A: Cancer Invest 2009; 27:

4. 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:

5. 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
% 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

6. 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
% 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

7. 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:
Sandler DA, et al. J R Soc Med. 1989;82:
Nicolaides AN, et al. Int Angiology. 2006;25:
Khorana AA et al: J Throm Haemost 2007; 5:
Lyman GH et al: J Clin Oncol 2009; 27:
Lyman GH: Cancer 2011; 117;

8. 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:

9. 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 /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:

10. 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:

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

12. 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: Leizorovicz A, et al. Circulation. 2004;110:874-9.
3Cohen AT, et al. BMJ 2006; 332:
* Alikhan R et al, Blood Coag Fibrinolysis, :

13. 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?

14. 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

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

16. 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.