1. Recognizing Cancer-Associated Thrombosis

2. Faculty/Presenter Disclosure
Faculty: [Speaker’s name]
Relationships with commercial interests:
Grants/Research Support: PharmaCorp ABC
Speakers Bureau/Honoraria: XYZ Biopharmaceuticals Ltd.
Consulting Fees: MedX Group Inc.
Other: Employee of XXY Hospital Group
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3. Disclosure of Commercial Support
This program has received financial support from Pfizer Injectables Inc. in the form of a program sponsorship
This program has received in-kind support from Pfizer Injectables in the form of logistical support
Potential for conflict(s) of interest:
[Speaker/Faculty name] has received [payment/funding, etc.] from [organization supporting this program AND/OR organization whose product(s) are being discussed in this program].
[Supporting organization name] [developed/licenses/distributes/benefits from the sale of, etc.] a product that will be discussed in this program: [insert generic and brand name here].
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4. Mitigating Potential Bias
The content of this program was developed by the planning committee and peer reviewed by Thrombosis Canada. Recommendations involving clinical medicine are based on evidence that is accepted within the profession; and all scientific research referred to, reported, or used in the CME/CPD activity in support or justification of patient care recommendations conforms to the generally accepted standards.
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5. Planning Faculty
Agnes Lee, MD (Program Chair) Vancouver, British Columbia Marc Carrier, MD (Program Chair) Ottawa, Ontario Amine Bouziane, BPharm, MSc Montréal, Québec Maryse Carignan, MSc. Inf., CSIO©, conseillére clinique, DSI Laval, Québec Mary DeCarolis, MD Ayr, Ontario Petr Kavan, MD Reginald Smith, PharmD Victoria, British Columbia

6. Learning Objectives
After attending this program, participants will be better able to:
Understand the incidence and significance of cancer-associated thrombosis (CAT)
Recognize the signs and symptoms associated with CAT
Identify the risks for developing a VTE in patients living with cancer

7. What is Cancer Associated Thrombosis (CAT)?

8. What is Cancer Associated Thrombosis (CAT)?
When a blood clot occurs in patients living with cancer, it’s referred to as cancer-associated thrombosis (CAT)
Can occur at any time during the cancer journey
Most frequently at the beginning, when patient is first diagnosed with cancer
Sometimes, a blood clot occurs a few months before a diagnosis of cancer is made
A common complication that can be prevented and treated effectively, especially if diagnosed early

9. What is Thrombosis? Venous thromboembolism = blood clot
Can develop in the deep veins of the legs (deep vein thrombosis or DVT)
Can occur in the blood vessels of the lungs (pulmonary embolism or PE)
Can occur in the arms, especially if a catheter is in place for giving chemotherapy or taking blood
Can also occur in other organs (kidney, brain or bowels)

10. Is CAT Serious?
Venous thromboembolism (VTE) is the 2nd leading cause of death in patients with cancer
Higher mortality among cancer patients with VTE than without
Can delay treatment or trigger changes in cancer treatment regimen
Can prolong hospitalization
Can compromise outcomes after surgery
1 in 200 cancer patients develop a blood clot, but the risk of developing CAT is not the same for all cancer patients
References:
Carrier M, et al. Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations. Curr Oncol 2015; 22:49-59
Heit Arch Intern Med 2000.
Heit Arch Intern Med 1999.
Sorensen NEJM 2000.
Pradoni N Engl J Med 1992.
Sorensen N Engl J Med 1988.
Chew Arch Intern Med 2006.
Khorana J Thromb Haemost 2007.
Carrier M, et al.. Curr Oncol 2015; 22:49-59; Heit Arch Intern Med Heit Arch Intern Med Sorensen NEJM Pradoni N Engl J Med Sorensen N Engl J Med Chew Arch Intern Med Khorana J Thromb Haemost 2007.

11. The Burden of VTE in Oncology
Cancer
progression
71%
Thromboembolism 9%
Infection
Respiratory
failure 4%
Bleeding 1%
Aspiration
Other 6%
Unknown
70%
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
Speaker Notes:
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?
References:
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;
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;

12. VTE, Cancer and Survival
100 20 40 80 60
VTE + cancer
cancer
VTE
no cancer + no VTE
Number of Days after Admission
Probability of Death, %
100 80 60 40 20
Years after Diagnosis
1-yr survival
Cancer at time of VTE 12%
Cancer without VTE %
ratio = 2.46 (95% CI 2.25 – 2.68)
References:
Levitan et al. Medicine 1999;78:285.
Sorensen et al. NEJM 2000;343:1846.
Levitan et al. Medicine 1999;78:285. Sorensen et al. NEJM 2000;343:1846.

13. VTE in Hospitalized Cancer Patients
Patients on chemotherapy were selected by presence of the code for chemotherapy, or chemotherapy adverse event, or neutropenia.
Overall 272,409 of 2,130,790 (12.8%) we classified as on chemotherapy.
References:
Lyman GH et al ASCO 2015
Lyman GH et al ASCO 2015

14. Surgical Cancer Patients
Thrombosis in Cancer
Surgical Cancer Patients
@RISTOS
Prospective cohort
N=2373
Symptomatic VTE 2.1%
Overall mortality 1.7%
Incidence of VTE, No.
46% due to
fatal PE
References:
Agnelli et al. Ann Surg 2006.
>30
Days post surgery
BCCA Webcast Jun 2011 14

15. Million Women Study 947,454 middle aged women in UK 1996-2001
Thrombosis in Cancer
Million Women Study
947,454 middle aged women in UK
Prospectively followed for PE, DVT or death from VTE using national hospital admission databases
In first 12 weeks after surgery, risk of symptomatic VTE:
1 in 45 for hip or knee replacement
1 in 85 for cancer surgery
1 in 115 for vascular surgery
1 in 140 for any surgery
References:
Sweetland et al. BMJ 2009
Sweetland et al. BMJ 2009
BCCA Webcast Jun 2011 15

16. Million Women Study 91-fold 53-fold 34-fold Peak incidence at 3 weeks
Thrombosis in Cancer
Million Women Study
91-fold
Peak incidence at 3 weeks
53-fold
References:
Sweetland et al. BMJ 2009
34-fold
Risk of PE higher than DVT
Sweetland et al. BMJ 2009
BCCA Webcast Jun 2011 16

17. What causes CAT?

18. What causes CAT?
Coagulation system is highly activated in patients with cancer for multiple reasons
Common mechanisms are:
Venous stasis
Damage to the endothelium
Expression of procoagulant proteins on tumour cell surface
Activation of inflammatory responses

19. Risk factors are cumulative
Virchow’s Triad
Risk factors are cumulative
Vascular injury
Surgery
Chemotherapy
Trauma
Catheterization
Venous stasis
Obesity
Immobility
Chronic heart disease
References:
Anderson and Spencer, Circulation 2003
Hypercoagulability
Malignancy
Hereditary risk factors
Age >40

20. Cancer and Thrombosis Host inflammatory responses Extrinsic factors
Thrombosis in Cancer
Cancer and Thrombosis
Host inflammatory responses
Angiogenesis
Metastasis
Extrinsic factors
Patient
Coagulation
Tumour
Tumour procoagulants (tissue factor)
ASH Education Session 2010

21. Who is at risk for CAT?

22. Audience Interactivity
Which factors increase the risk of VTE in patients living with Cancer
Age
Stage of cancer
Type of Chemotherapy
Race
All of the above

23. Risk Factors for VTE in Cancer
Thrombosis in Cancer
Risk Factors for VTE in Cancer
Risk varies from 1 – 30% depending on:
Patient-related
Older age
Race
Prior VTE
Platelet count
Comorbid conditions
Cancer-related
Primary site
Histology
Stage
Grade
Time interval since diagnosis
Treatment-related
Surgery
Chemotherapy
Hormonal therapy
Antiangiogenic therapy
Erythropoietin Stimulating Agents (ESA)
Hospitalization
Catheters
References:
Lyman J Clin Oncol 2007.
Heit Arch Intern Med 2000.
Blom JAMA 2005.
Lyman J Clin Oncol Heit Arch Intern Med Blom JAMA 2005.
ASH Education Session 2010

24. Risk of VTE with Age References:
Silverstein et al Arch Intern Med 1998
Silverstein et al Arch Intern Med 1998

25. Tumour Type and VTE RR of VTE Range from 1.02 to 4.34 References:
Thrombosis in Cancer
Tumour Type and VTE
RR of VTE Range from 1.02 to 4.34
References:
Stein PD et al. Am J Med 2006
Stein PD et al. Am J Med 2006
ASH Education Session 2010 25 25

26. Venous Thromboembolism in Cancer Patients Receiving Chemotherapy: A Real-world Analysis of VTE Risk
VTE at 3.5 Months (%)
Speaker Notes:
The IMPACT claims database is a fully de-identified, United States Health Insurance Portability and Accountability Actcompliant
national database that includes the complete medical history for 100 million individuals with managed care health plans. The IMPACT database was used to identify patients retrospectively who had cancer of the lung, pancreas, stomach, colon/rectum, bladder, or ovary who initiated chemotherapy between January 1, 2005,andDecember31, Because the claims data used were fully de-identified, approval from a local human investigations committee was not required.
References:
Lyman, GH et al: The Oncologist 2013; 18:
Lyman, GH et al: The Oncologist 2013; 18: 26

27. VTE and Site of Cancer: Risk of VTE in Cancer Patients Receiving Chemotherapy
Speaker Notes:
Patients with ≥12 months of coverage prior to the index date and without prior VTE, major bleeding, or recent anticoagulant treatment were included.
Definition A, was an ‘all inclusive’ analysis comprising all individuals with an ICD-9-CM code relating to VTE who met the inclusion and exclusion criteria for the study (ie, study period, tumor type). This definition considered a VTE case as a patient who had at least 1 VTE claim. Definition B considered a VTE case as only patients who had 2 or more outpatient claims at least 30 days apart, or one inpatient claim, or a single outpatient claim in which an anticoagulation drug was disbursed within 90 days, and excluded the ICD-9-CM code (peripheral vascular complications not elsewhere classified). The most stringent definition C further excluded from (B) any VTE events within 90 days of any major or invasive surgery. Codes relating to esophageal, kidney, and uterine cancer were not included.
References:
Lyman, GH et al: The Oncologist 2013; 18:
Lyman, GH et al: The Oncologist 2013; 18:

28. Thrombosis in Cancer
Tumour Stage and VTE
Patients with metastatic disease have 20-fold risk of VTE compared with those without
Cancer
Distant Mets
Adjusted OR
(95% CI) No
1.0
Yes
3.9
(2.5 – 6.0)
58.0
(9.7 – 346.7)
19.8
(2.6 – 149.1)
References:
Blom JAMA 2005.
Blom JAMA 2005.
ASH Education Session 2010 28

29. Surgical Cancer Patients
Thrombosis in Cancer
Surgical Cancer Patients
@RISTOS
Risk Factors for VTE
Odds Ratio (95% CI)
Previous history of VTE
6.0 (2.1 – 16.8)
Anesthesia lasting > 2 hours
4.5 (1.1 – 19.0)
Bed rest post-op > 4 days
4.4 (2.5 – 7.8)
Advanced tumour
2.7 (1.4 – 5.2)
Age > 60
2.6 (1.2 – 5.7)
References:
Agnelli et al. Ann Surg 2006.
Agnelli et al. Ann Surg 2006.
BCCA Webcast Jun 2011 29

30. Highest Risk Factors for VTE in Patients Living With Cancer
Older patients
Pancreatic, brain, upper GI, lung, ovarian, lymphoma
Metastatic disease
First 3 months after cancer diagnosis
First month after surgery
During systemic chemotherapy
Cisplatin
Anthracyclines
Thal/lenalidomide
Bevacizumab

31. How do we recognize CAT?

32. How to Recognize VTE
DVT: When clots form in deep veins, there is reduced drainage of blood, which increases the pressure in the venous system below the clot = swelling, pain, discoloration and warmth in the affected leg or arm
PE: When clots travel to the lungs = worsening fatigue, chest pain, unexplained shortness of breath and a rapid heartbeat
Learning to recognize the key signs and symptoms of VTE can help health care providers (HCPs) to make a timely diagnosis
Up to 50% of the time there are no symptoms, and clots are incidentally discovered when diagnostic scans are done for other reasons

33. Signs and Symptoms of PE
Signs and symptoms might mimic other conditions, so special tests are required to confirm a diagnosis

34. Signs and Symptoms of DVT
Aching in the shoulder or neck
Veins in back of hands pop out
Catheter might not work properly
Difficult to draw blood
Difficult to inject fluids/drugs

35. Diagnosis and Examination for DVT
Initial diagnostic investigations=general medical history, physical examination
If DVT is suspected, use the two-level DVT Wells Score to estimate clinical probability
If suspected and likely, offer patients in whom DVT is suspected and with a likely two-level DVT Wells score either:
a proximal leg vein ultrasound scan carried out within 4 hours of being requested and, if the result is negative, a D-dimer test or
a D-dimer test and an interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.
Repeat the proximal leg vein ultrasound scan 6–8 days later for all patients with a positive D-dimer test and a negative proximal leg vein ultrasound scan.
Diagnose DVT and treat patients with a positive proximal leg vein ultrasound scan
References:
Diagnosing venous thromboembolism in primary, secondary and tertiary care - NICE Pathways [Internet]. [cited 2017 Apr 12]. Available from:
Diagnosing venous thromboembolism in primary, secondary and tertiary care - NICE Pathways [Internet]. [cited 2017 Apr 12]. Available from:

36. Two-level DVT Wells score
Clinical feature
Points
Active cancer (treatment ongoing, within 6 months, or palliative) 1
Paralysis, paresis or recent plaster immobilisation of the lower extremities
Recently bedridden for 3 days or more, or major surgery within 12 weeks requiring general or regional anaesthesia
Localised tenderness along the distribution of the deep venous system
Entire leg swollen
Calf swelling 3 cm larger than asymptomatic side
Pitting oedema confined to the symptomatic leg
Collateral superficial veins (non-varicose)
Previously documented DVT
An alternative diagnosis is at least as likely as DVT −2
Clinical probability simplified score
DVT likely
2 points or more
DVT unlikely
1 point or less
1Adapted with permission from Wells PS et al. (2003) Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis.

37. Diagnosis and Examination for PE
Initial diagnostic investigations: general medical history, physical examination and chest x-ray
If PE is suspected, use the two-level PE Wells Score to estimate clinical probability
If suspected and likely, offer patients either:
an immediate computed tomography pulmonary angiogram (CTPA) or
immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately.
Consider a proximal leg vein ultrasound scan if the CTPA is negative and DVT is suspected.
Diagnose PE and treat patients with a positive CTPA or in whom PE is identified with a V/Q SPECT or planar scan
If suspected and likely, offer patients either:
an immediate CTPA or
immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately.
Consider a proximal leg vein ultrasound scan if the CTPA is negative and DVT is suspected.
For patients who have an allergy to contrast media, or who have renal impairment, or whose risk from irradiation is high:
Assess the suitability of a V/Q SPECT scan or, if a V/Q SPECT scan is not available, a V/Q planar scan, as an alternative to CTPA.
If offering a V/Q SPECT or planar scan that will not be available immediately, offer immediate interim parenteral anticoagulant therapy.
Diagnose PE and treat patients with a positive CTPA or in whom PE is identified with a V/Q SPECT or planar scan
References:
Diagnosing venous thromboembolism in primary, secondary and tertiary care - NICE Pathways [Internet]. [cited 2017 Apr 12]. Available from:
Diagnosing venous thromboembolism in primary, secondary and tertiary care - NICE Pathways [Internet]. [cited 2017 Apr 12]. Available from:

38. Two-level PE Wells score
Clinical feature
Points
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins) 3
An alternative diagnosis is less likely than PE
Heart rate > 100 beats per minute
1.5
Immobilisation for more than 3 days or surgery in the previous 4 weeks
Previous DVT/PE
Haemoptysis 1
Malignancy (on treatment, treated in the last 6 months, or palliative)
Clinical probability simplified score
PE likely
More than 4 points
PE unlikely
4 points or less
Adapted with permission from Wells PS et al. (2000) Derivation of a simple clinical model to categorize patients' probability of pulmonary embolism: increasing the model's utility with the SimpliRED D-dimer.

39. How do we evaluate individual risk?

40. Khorana Model for Outpatients
Thrombosis in Cancer
Khorana Model for Outpatients
Patient Characteristic
Score
Site of Cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2 1
Pre-chemotherapy platelet count > 350,000/mm3
Hb < 10g/dL or use of ESA
Prechemotherapy leukocyte count > 11,000/mm3
BMI > 35 kg/m2
References:
Khorana et al. Blood 2008.
Khorana et al. Blood 2008.
BCCA Webcast Jun 2011 40 40

41. Khorana Model Validation
Thrombosis in Cancer
Khorana Model Validation
Prospective follow-up of 819 patients
Median observation time/follow-up: 656 days
Log-rank test P<0.001)
6-mo cumulative VTE rates:
Patients
Events n %
Score ≥3 93
17.7%
Score 2
221
9.6%
Score 1
229
3.8%
Score 0
276
1.5%
References:
Ay et al Blood 2010.
Ay et al Blood 2010.
BCCA Webcast Jun 2011 41 41

42. Ay Model for Outpatients
Thrombosis in Cancer
Ay Model for Outpatients
Addition of D-dimer and soluble P-selectin to Khorana model:
6-mo cumulative VTE rates:
Patients, n
Events, %
Score ≥5 30
35%
Score 4 51
20.3%
Score 3
130
10.3%
Score 2
218
3.5%
Score 1
190
4.4%
Score 0
200
1.0%
References:
Ay et al Blood 2010.
Ay et al Blood 2010.
BCCA Webcast Jun 2011 42 42

43. What should I remember about CAT?

44. Conclusions CAT is a common, costly and potentially fatal complication
Patients at highest risk are those with metastatic disease receiving systemic chemotherapy and have other additional risk factors
Use a risk assessment model to estimate an individual’s risk of symptomatic thrombosis
It is important to consider CAT when patient complains of non-specific symptoms
Early recognition is important because highly effective therapies are available

45. How can we inform our patients about CAT?

46. Our Research VTE is not top of mind for physicians or patients
HCPs are not consistently discussing the risk of VTE at the time of cancer diagnosis
Patients are often surprised and discouraged upon diagnosis of VTE

47. 6.4 69.1 45% 55% 9% Who We Interviewed TYPE OF CANCER*
YEARS SINCE FIRST CANCER DIAGNOSIS :
AGE:
Colon/Colorectal 5
Prostate 4
Ovarian 3
Lymphoma
Bladder 1
Cervical
Head and Neck 2
Lung
Chondrosarcoma
Kidney
Breast
Uterine
Vulvar
6.4
69.1
Avg.
Avg.
EDUCATION:
GENDER:
45%
55%
BLOOD CLOT 9%
TOTAL 22 PEOPLE INTERVIEWED
Since Cancer Diagnosis
Total type of cancer will exceed 22, as one patient had 3 types of cancer, and two patients had 2. Lymphoma includes Lymphoma, Non-Hodgkin’s and Waldenstrom’s
*Cancers with a high risk of blood clots were prioritized in recruiting

48. Patient Interviews
List of questions asked during the patient interviews
Please prioritize the following 12 questions from 1 (the highest priority) to 12 (the lowest priority) using this column – Enter a number from 1 to 12 (use each number once)
Please indicate if this question should not be part of the Q&A list – For each question, enter either the word: delete or keep
How urgently should I be seen once I suspect I have a clot?
Where do I seek help- the oncology clinic, my family doctor, emergency or walk-in clinic? Or How soon should I seek medical attention? 1
Keep
How do I know whether the symptoms I am experiencing aren't just age or something else? 2
If treatment can cause blood clots, should I not take the chemotherapy or radiation treatment? What is the impact on my treatment plan? 3
How long are you at risk of getting a clot? Is it something that can vary with time? 4
What is the risk of getting a blood clot (%) ? 5
How are clots diagnosed? 6
How long after surgery could I get a clot? Could it happen that you have blood clots even before surgery? If that is the case, should surgery be postponed? 7
Could you be asymptomatic and still have a blood clot? 8
If I am already on a "blood thinner“ could I still develop a clot? Or What if I'm other medication to prevent a clot, will that protect me or can I still form a clot? 9
What causes blood clots and who is at risk? 10

49. ELEVATE Materials - Handouts
Waiting Room Poster
Exam Room Poster
Symptom Checklist
Patient Slide Kit

50. What can our team do to raise awareness around CAT?

51. Participant Workshop 25 minutes
Organize the participants into cross-disciplinary teams as best as possible (based on # of participants)
Nurse
Family physician
GPO
Oncologist
Support staff
Handout the package to each group
Ask each cross-functional team/group to review the patient resources and complete the worksheet
Ask each group to share their answers
Handout Package (one per group)
Worksheet
Patient resources
Waiting room poster
Exam room poster
Symptom checklist
Patient educational slide kit

52. Participant Worksheet
Team Member
Message to Patient
Material to be Used
Timing of Conversation
Pharmacist
Nurse
Family physician
GPO
Oncologist
Support staff

53. Questions?