B P6 C57 Cardio-Oncology: Approach to the Patient

Question 1

One intuitive and practical approach to the cancer patient with CVD can be summarized under the acronym _____.

Answer 1

SCI-FI

CV Subject
Oncology Context
Cardio-Oncology Interaction
Follow-up on Intervention

Question 2

The three CVD groups to be attentive to in particular are _____.

Answer 2

Vascular disease
Arrhythmias
Cardiomyopathy/heart failure (HF)

Question 3

Patients who were diagnosed with cancer and are about to undergo oncological or hematological treatment are referred for a cardiology consultation most commonly out of concern that the _____ could pose a threat to the completion of cancer therapy and the patient

Answer 3

Presence or risk of CVD

Question 4

The key concept is that ______ add to any pre-existing impairment of CV function decreasing the CV reserve to the point of its exhaustion and eventually the clinical appearance of disease states.

Answer 4

Injuries from cancer therapies

Question 5

Moreso, two subtypes had been proposed on the basis of the cardiotoxicity reversibility pattern (_______), and the 2014 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACI) consensus document assigned all (potentially) cardiotoxic medication to one of these two groups.

Answer 5

Irreversible cardiac injury - type 1

Reversible cardiac dysfunction - type 2

Question 6

Alternative classification systems have been proposed, and in the general approach to cancer patients at risk of cardiac dysfunction it might be useful to consider the mechanisms that can account for the decrease in cardiac function:

Answer 6

(1) Directly harmful effects on the myocardium
(2) Indirectly harmful effects on the myocardium, for example, via progression of coronary artery disease (CAD), ischemia, metabolic derangement
(3) Mediated by inflammation

Question 7

Patients with a history of CAD and myocardial infarction (MI) in particular should be informed about the risks and benefits of undergoing chest radiation therapy.

An increased risk of acute coronary events was seen in particular in this subgroup of women who underwent _____ therapy for breast cancer. The risk of these events is not immediate but within the timeline of years.

Answer 7

Radiation therapy - years

Question 8

_____ of dose exposure is the best preventive strategy and several techniques are available.

Answer 8

Reduction of dose exposure

Question 9

Based on pathophysiology, one may propose three main vascular toxicity types:

Answer 9

Acute thrombosis
Acute vasospasm
Accelerated atherosclerosis

Question 10

The risk of venous thrombosis in cancer patients relates not to a single but several factors (patient-, cancer-, and treatment-related). These are captured in risk prediction models such as the most widely used _____ risk score

Answer 10

Khorana risk score

Question 11

Based on data indicating a ___% reduction in VTE and/or VTE-related deaths, practice guidelines of various societies suggest the use of direct oral anticoagulants (DOACs) as primary thromboprophylaxis in ambulatory cancer patients who are about to start chemotherapy and have a Khorana score >/= ___, if there are no drug-drug interactions and no high-risk scenario for bleeding.

Answer 11

60%

> /= 2 score - DOAC

Question 12

_____ remains an option for outpatient thromboprophylaxis in high-risk patients.

Answer 12

Low-molecular-weight heparin (LMWH)

Question 13

For patients with multiple myeloma receiving “IMiD”-based combination therapy, current guidelines recommend _____ mg daily if none or only one individual/myeloma risk factor, otherwise _____

Answer 13

Myeloma risk factor:

0 or 1: Aspirin 81 to 325

> 1: LMWH equivalent to 40 mg enoxaparin daily or full-dose warfarin

Question 14

In hospitalized patients with major surgery or acute medical illness, thromboprophylaxis with _____ is recommended per standard recommendations with consideration for ___ weeks extension in high-risk post- operative patients in the setting of abdominal and pelvic surgery for malignancy.

Answer 14

Heparin or LMWH

High risk post-operative patients in Abdominal or pelvic surgery for malignancy: Extend for 4 weeks

Question 15

Regarding arterial thromboembolic events (ATEs), the highest risk period is within ____ month before and after cancer diagnosis, thereafter declining by persisting for at least 12 months.

Answer 15

1 month

Question 16

_____ pose the highest malignancy-related risk categories for ATEs, similar to VTE

Answer 16

Advanced (stage 3 and 4) Cancers
Gastrointestinal tract Cancer
Lung Cancer

Question 17

A therapy-related risk of ATEs is seen in particular with _____.

Answer 17

VEGF inhibitors
Platinum drugs

Question 18

____ should be anticipated for patients to be started on 5-fluorouracil (5-FU), capecitabine, paclitaxel, cisplatin, bleomycin, VEGF inhibitors such as sorafenib,a nd Bcr-Abl inhibitors such as dasatinib

Answer 18

Acute vasospasm

Question 19

Accelerated atherosclerosis in cancer patients is most commonly associated with radiation therapy but has received attention with the use of _____ in recent years; it may also be seen with_____.

Answer 19

Bcr-Abl (Nilotinib and ponatinib)
VEGF inhibitors
Cisplatin

Question 20

Main goals of consultation before treatment

Answer 20

Determine and mitigate CV risk with cancer therapy (chemotherapy, radiation, surgery)
* Optimize CV health and disease
* Enable best and safest cancer care
(prevention and surveillance plan)

Question 21

Main goals of consultation after treatment

Answer 21

• Recognize and reduce CV risk, preferably early through surveillance efforts
• Optimize CV health and disease
• Contribute to optimal survivorship
  care

Question 21

Main goals of consultation during treatment

Answer 21

• Define severity (acuity) and treatment
• Determine causality with cancer therapy
  and need for change in cancer therapy
• Co-manage CVD for best outcomes

Question 22

Patients with cancer who have _____ should be assumed to be more susceptible to cancer therapy-induced arrhythmias, as are those undergoing treatment regimens with known cardiotoxicity potential.

Therefore, as a general rule, comorbidities that could represent a possible arrhythmogenic substrate should be identified and treated aggressively before and during cancer therapy

Answer 22

Electrocardiogram (ECG) abnormalities
Impaired exercise capacity
CVD at baseline

Question 23

Early identification and appropriate management of _____ is also likely to be the best strategy to modulate the arrhythmogenic substrate and improve outcomes in patients with cancer therapy-induced arrhythmias

Answer 23

Cardiac ischemia, dysfunction, and remodeling

Question 24

Crizotinib, dasatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib should be administered with caution in patients with _______.

Answer 24

Pre-existing QTc prolongation or QTc-prolongation-related risk factors

Question 25

As illustrated for several tyrosine kinase inhibitors (TKIs), such as vandetanib, electrolytes should be corrected before initiation of cancer therapy (goal value for serum K+ levels >/=____ mEq/L and for magnesium and calcium within normal limits) and monitored along with ECGs, as outlined above (at _____, at _____ weeks, at _____ weeks, and every _____ months thereafter).

Answer 25

4 mEq/L Monitor electrolytes + ECG: Baseline 2-4 weeks 8-12 weeks Every 3 months

Question 26

The common cutoffs for the QTc interval are 450 msec before and 500 msec during therapy (the one exception being nilotinib 480 msec). ______ therapy can be given if the QTc is less than 450 msec, ______ if between 450 and upper limit, _____ if above the upper limit.

Answer 26

TKI - QTC cut-offs: Before: 450 msec During: 500 msec (Except Nilotinib: 480 msec) Dosing: Full dose: < 450 msec Half dose: 450 msec and upper limit No dose: Above upper limit

Question 27

Characteristics of acute vasospasm

Answer 27

Onset: Days to weeks Reversibility: Very likely Examples: 5-fluorouracil, capecitabine, platinum drugs, VEGF inhibitors Treatment: Nitrates, CCB On-site screening: Signs & symptoms Prevention: Vasoreactivity studies, ECG (ST- segment elevation monitoring

Question 28

Characteristics of acute thrombosis

Answer 28

Onset: Weeks to months Reversibility: Likely Examples: Platinum drugs, bleomycin, vinca alkaloids, VEGF inhibitors, ICIs Treatment: Thrombectomy with/without PTCA, stent, DAPT, statin therapy On-site screening: Prevention:

Question 29

Characteristics of accelerated atherosclerosis

Answer 29

Onset: Months to years Reversibility: Very unlikely Examples: Nilotinib, ponatinib, cisplatin, VEGF inhibitors Treatment: Revascularization, aspirin, statin, amlodipine, ACE-inhibitor, exercise On-site screening: Signs & symptoms Prevention: ABI, cardiac stress test, CCTA

Question 30

_____ is commonly used as an umbrella term for any cardiac abnormality encountered with cancer therapy. The first step is therefore to define the abnormality, its causes, and implications.

Answer 30

Cardiotoxicity

Question 31

Of the advocated cardiac surveillance parameters, _____ is most commonly reported and reacted to.

Answer 31

Left ventricular ejection fraction (LVEF)

Question 32

That being said, various consensus documents have forwarded different definitions of cardiotoxicity, and the consensus definition that emerges is a _____ in the ASE/EACI consensus and at 50% in the ESMO consensus.

Answer 32

ASE/EACI: Drop of > 10% to below the lower limit of normal, which is set at 53% ESMO: > 10% to below limit of normal (50%)

Question 33

The cutoff to stop cancer therapy is not universally defined but most would agree with an LVEF of ___% as originally outlined for trastuzumab therapy for cessation of therapy and as outlined in the most recent ESMO document.

Answer 33

40%

Question 34

For global longitudinal strain (GLS), a ___% relative change (confirmed within 2 to 3 weeks upon repeat assessment) is considered to represent subclinical left ventricular dysfunction and is predictive of a more evident future decline in LVEF. At present, however, there is no clear guidance how to react to such changes.

Answer 34

15%

Question 35

Grading of ICI myocarditis (2019 NCCN Clinical Practice Guidelines)

Answer 35

Grade 1 Abnormal cardiac biomarkers or ECG Grade 2 Mild symptoms with abnormal cardiac biomarkers or ECG Grade 3 Moderate symptoms TTE with LVEF <50% or RWMA Cardiac MRI suggestive of myocarditis Grade 4 Life-threatening disease with cardiac study abnormalities in Grades 1–3

Question 36

Recurrence of VTE despite anticoagulation (so-called anticoagulation failure) is seen in 15% of patients on ______ (rate of 2.5% per month). **LMWH** has superior efficacy in this regard at similar major bleeding rates than warfarin.

Answer 36

Warfarin

Question 36

Compared with LMWH, DOACs have similar (e.g. _____) or improved (______) efficacy rates but higher bleeding rates, especially gastrointestinal (GI) bleeding rates.

Answer 36

Similar: Edoxaban Improved: Rivaroxaban, Apixaban

Question 37

The diagnostic criteria for MI in the setting of CABG have been revised and are now based on elevation of cardiac troponin or a myocardial creatine kinase-MB (CK-MB) isoenzyme level more than ________________ in association with new pathologic Q waves, objective evidence of new myocardial dysfunction or graft occlusion based on noninvasive imaging or angiography

Answer 37

10 times the upper limit of normal

Question 38

Cerebrovascular complications posr CABG Injury that is characterized by deterioration in intellectual function and memory.

Answer 38

Type II Injury

Question 39

__________ injury is associated with major neurologic deficits, stupor, and coma

Answer 39

Type I

Question 40

Patients with _____ tumors should receive anticoagulation other than with DOACs

Answer 40

Mucosal tumors (GI/GU malignancy)

Question 41

Treatment with anticoagulants in VTE should continue for as long as the cancer disease process is deemed active, and at a minimum for _____ months.

Answer 41

3-6 months

Question 42

Antiplatelet therapy is a key element and based on current ACC/AHA guidelines, dual antiplatelet therapy (DAPT) should be continued for _____ year in patients with ACS, thereafter guided by risk calcu-ators such as the DAPT score. These, however,do not take malignancy into consideration.Similar toVTE recommendations, one might argue for the continuation of DAPT as long as active cancer is present; however, there are no data for such a recommendation yet.

Answer 42

1 year

Question 43

In this context thrombocytopenia is an important factor to consider and the Society for Cardiovascular Angi- ography and Interventions (SCAI) recommendations for platelet cut- offs are as following: Surgical PCI CAG

Answer 43

50K 30K 10K

Question 44

In case of 5-FU, the presentation can be so typical that treatment with vasodilator therapy is both diagnostic and thera- peutic. For patients experiencing acute vasospasm, vasodilators such as ____ amd _____ are mainstay therapy and have been used even in combination

Answer 44

Nitrates and calcium channel blockers (CCBs)

Question 45

QTc prolongation noted on surveillance ECGs should prompt the adjustment of therapy. For most drugs, therapy should be held if the QTc interval exceeds 500 msec and resumed at a reduced dose upon resolution of QTc prolongation.

Question 46

With nilotinib, any QTc greater than 480 msec requires cessation of therapy until the QTc is 450 to 480 msec (then resume therapy at half dose) or less than 450 msec (then resume therapy at full dose).

Question 47

Ventricular arrhyth- mias should be managed as usual according to clinical guidelines.26 Important to address in cancer patients on multiple other medications are drug-drug interactions and electrolyte abnormalities (goal value for serum K+ levels 4 mEq/L and for calcium and magnesium within normal limits).

Question 48

The principles and goals of the management of AF in patients with cancer are generally the same as those in the general population, albeit with some important nuances. The first is a more lenient heart rate goal (_____) with the use of beta-blockers, CCBs, and digoxin. The second is the potential for drug-drug interactions, especially with antiarrhythmic drugs, which are indicated if patients remain symptomatic.An illustrating example is ibrutinib as outlined in the extended online content.

Answer 48

<115 beats/min [bpm] Ibrutinib - bawal Carvedilol; use Atenolol or Metoprolol

Question 49

Anticoagulation in patients with cancer can be problematic in gen- eral and especially in patients receiving ibrutinib because of a pre- disposition to bleeding. _______ has a unique antiplatelet effect, inhibiting mainly von Willebrand factor (vWF) and collagen-mediated platelet activation (in addition to fibrinogen-activated platelet activa- tion).

Answer 49

Ibrutinib

Question 50

Patients after exposure to cardiotoxic therapy are considered to be in Stage A HF just like patients with hypertension, diabetes, and other well-known risk pre- disposition

Question 51

How to best follow these patients and when to act and in which format is not well defined.Serial echocardiographic studies over the first 3 years after cancer therapy indicate that the main neg- ative deflection in LVEF is occurring in the first year after start of can- certherapy

Question 52

Following radiation therapy, an increase in HF rates is seen after 15 years in breast cancer patients and an exponential increase in CV events follow the same timeline in lymphoma patients after chest radiation

Question 53

While anthracycline therapy in adults leads to a _____ and HF with reduced LVEF, radiation therapy classically leads to a _____ and HF with preserved LVEF. As HF can be the final common pathway of the various elements in the spectrum of radiation-induced heart disease, all contributing factors need to be evaluated, including ischemic and structural heart disease.

Answer 53

Anthracycline - DCMP; HFrEF Radiation - Restrictive CMP; HpEF

Question 54

Cancer patients have a sixfold higher risk of VTE recurrence with an annual rate as high as ____ in the absence of anticoagulation and as high as 20% even within the initial 6 months on anticoagulation therapy.

Answer 54

30% risk of VTE in the absence of anticoag

Question 55

The original and modified Ottawa prediction scores were developed to risk stratify for recurrent VTE; among the variables included in the score, female gender and lung cancer increase the risk, whereas breast cancer and stage I (/II) decrease the risk

Question 56

In terms of VTE, most cancer therapies do not pose a long-term risk though exceptions need to be recognized such as

Answer 56

The first is cisplatin, and its circulating levels can remain detectable for decades after completion of cancer therapy. The second is Bcr-Abl TKIs, especially nilotinib and ponatinib, though ischemic events may not relate to thrombosis (alone) The same holds true for radiation therapy.

Question 57

For many years after completion of therapy, cancer patients can experience an altered vasoreactivity profile, which can present as typical and atypical angina,microvascular angina,cardiac syndrome X, and Raynaud’s. ______ are usually first-line therapy for patients with Raynaud’s, especially slow-release/long-acting dihydropyridine CCB such as nifedipine XL. They may also be more effective than nitrates in cases of microcirculatory involvement (microvascular angina).

Answer 57

CCBs

Question 58

______ is the leading entity in terms of vas- cular risk after completion of cancer therapy. The risk is particu- larly high in patients who received Bcr-Abl inhibitors or radiation therapy,and also after allogenic bone marrow transplantation

Answer 58

Accelerated atherosclerosis

Question 59

Following chest radiation therapy, consensus guidelines rec- ommend a _____ in patients with defined high-risk features

Answer 59

Cardiac stress test every 5 years

Question 60

Arrhythmias in cancer survivors are most commonly expected after radiation therapy to the chest and therapies that exerted a lasting negative effect on cardiac function

Question 61

This is by far the most common rhythm abnormality in cancer patients, even as a reflection of autonomic dysfunction, after radiation as well as after anthracycline therapy.

Answer 61

Sinus tachycardia

Question 62

The 2017 American Society of Clinical Oncology (ASCO) practice guide- lines focus on _____ as the main cancer therapies with direct cardiotoxicity concern, placing patients at risk of cardiac dysfunction along with chest radiation.

Answer 62

Anthracyclines and trastuzumab

Question 63

For anthracyclines, modes of prevention of cardiotoxicity have included the use of ______ instead of doxorubicin, ______ of doxorubicin, ______ of doxorubicin, addition of ______, and the use of _____, which might or might not have equivalent anti-cancer efficacy.

Answer 63

Epirubicin Liposomal formulations Prolongation of the infusion rate Dexrazoxane Non-anthracycline-based therapies

Question 64

Adjunctive car- diovascular medications, which have been shown to have a preventive effect against anthracycline-related cardiomyopathy include the second- generation and third-generation beta-blockers carvedilol and nebivolol, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs),spironolactone,and statins.2,4

Question 65

The American Society of Echocardiography (ASE)/European Associ- ation of Cardiovascular Imaging (EACI) consensus statement recommends reassessment of left ventricular ejection fraction (LVEF), global longitudinal strain (GLS),and cardiac troponin (cTn) at ________ anthracycline-based therapy, unless the cumulative dose is greater than 240 mg/m2 doxorubicin equivalents,in which case repeated measurements of LVEF,GLS,and cTn should be performed even during cancer therapy, before each additional _____

Answer 65

Anthracycline - LVEF, GLS, Trop after completion and at 6 months During tx: if > 240mg/m2 dose, repeat LVEF, GLs and Trop before each additional 50mg/m2 dose

Question 66

For cardiotoxicity related to any other non-anthracycline therapy, the ASE/EACI consensus recommendation is for 3-monthly follow-up of LVEF, GLS, and cTn during therapy, albeit with two exceptions: (1) patients receiving tyrosine kinase inhibitors (TKIs) or vascular endothelial growth factor (VEGF) inhibitors, who should have an additional early follow-up at 1 month, and (2) patients with previous anth- racycline exposure,who should have an additional evaluation at 6 months.

Question 67

ASCO and National Comprehensive Cancer Network (NCCN) practice guidelines focus on anthracyclines and recommend cardiac function assessment 6 to 12 months after completion of therapy.1

Question 68

The 2020 European Society of Medicine Oncology (ESMO) guidelines include natriuretic peptides (NPs) in addition to cTn in the recommendation for periodic (every 3 to 6 weeks or before each cycle) anthracycline cardiotoxicity surveillance (see eTable 57.1).11 Reassessment of cardiac function is to be done after a cumulative dose of 250 mg/m2 doxorubicin, each additional 100 mg/m2 thereafter, at the end of therapy,6 to 12 months and 2 years thereafter.11

Answer 68

Question 69

These include high-dose statins even in the absence of hyperlipidemia and ACE inhibitors or amlodipine if hypertensive (with an ideal BP goal of <130/80 mm Hg, and a definite BP goal of <140/90 mm Hg for all)

Question 70

Patients should adhere to the physical exercise recommendation and 150 minutes of moderate- intensity exercise like brisk walking for 30 minutes five times a week

Question 71

ABIs, carotid intima-media thickness (IMT), and stress tests may be used to serially follow the patients and to detect disease before signs and symptoms develop.The cost of these tests should be taken into consideration, but a reasonable schedule might consist of ABIs every 6 to 12 months, carotid intima-media thickness every 2 years,and a cardiac stress test every 5 years.