Cardiovascular testing in patient with cancer

KEY POINTS

New imaging modalities play a central role in identifying cardiovascular complications. Cardiotoxicity can manifest in a number of ways, depending on the agent, and can include disease states such as heart failure and cardiomyopathy, coronary artery disease, coronary vasospasm, myocarditis, pericardial constriction, and pulmonary hypertension. In light of the many potential cardiovascular diseases (CVD), a broad range of cardiovascular imaging modalities is needed to best serve the needs in the cancer population ( Table 22.1 ).

TABLE 22.1

Overview of Cardiac Imaging Recommendations

(From Biersmith MA, Tong MS, Guha A, et al. Multimodality cardiac imaging in the era of emerging cancer therapies. J Am Heart Assoc. 2020;9(2):e013755. https://doi.org/10.1161/JAHA.119.013755 . Used with the permission of John Wiley & Sons.])

CANCER THERAPY	MONITORING RECOMMENDATION	REFERENCE
Anthracyclines	Echo
	Recommended for those with symptoms of heart failure	ASCO [1]
	Recommended for surveillance of those undergoing treatment; frequency based on clinical discretion	ASCO [1]
	Recommended to perform in asymptomatic patients 6–12 months after completion of therapy in those felt to be at a higher risk for CTRCD	ASCO [1]
	LVEF measurement at baseline and during treatment (frequency not defined) (2D/3D) and GLS with treatment or risk factor modification at LVEF ≥60%, 50%–59%, 40%–49%, and <40%	Liu et al. [2]
	LVEF at baseline and at end of treatment. Regular LVEF monitoring if cumulative dose exceeds 240 mg/m ² . Recommendation based on use of 2D echocardiogram and GLS	SEOM [3] ESC [4]
	Measurement of LVEF at baseline, every 3 months during chemotherapy, at the end of treatment (within 1 month), every 3 months during the first year after chemotherapy, every 6 months during the following 4 years, and yearly afterward	Cardinale et al. [5]
	CMR
	Recommended instead of echo only if echo unavailable or not technically feasible	ASCO [1]
	Recommendation is to perform in asymptomatic patients 6–12 months after completion of therapy in those felts to be at a higher risk for CTRCD and not a good candidate for echocardiogram	ASCO [1]
	Utility of CMR over LVEF monitoring in terms of myocardial fibrosis and inflammation quantification	Jordan et al. [6]
	Multigated acquisition scan (MUGA)
	Recommended instead of echo only if echo unavailable or not technically feasible and CMR unavailable	ASCO [1]
	Recommended to perform in asymptomatic patients 6–12 months after completion of therapy in those felt to be at a higher risk for CTRCD and not a good candidate for echocardiogram and CMR unavailable	ASCO [1]
	LVEF >50% at baseline 1. Measurement at 250–300 mg/m ² 2. Measurement at 450 mg/m ² 3. Measurement before each dose above 450 mg/m ² 4. Discontinue therapy if LVEF decreases by ≥10% from baseline and <50%	ASNC [7]
	LVEF <50% at baseline 1. Do not treat if LVEF is <30% 2. Serial measurement before each dose 3. Discontinue therapy is LVEF decreases by ≥10% from baseline or LVEF ≤30%	ASNC [7]
Trastuzumab	Echo
	Recommended for surveillance of patients with metastatic breast cancer receiving trastuzumab	ASCO [1]
	Recommended: 1. Baseline evaluation of LVEF 2. Repeat measurement of LVEF every 3 months while on treatment 3. Repeat echo at 4 week intervals if therapy is withheld for significant LVEF decline. The caveat to this recommendation is that ASCO does not endorse holding treatment unless deemed clinically necessary by oncologist (E, evidence quality: insufficient) 4. Every 6 months for the immediate 2-year period after completing the regimen	SEOM [3] ASCO [1] Manufacturer [8,9]
	Transthoracic echocardiograms that includes comprehensive 2D, 3D, and strain imaging in patients with LVEF 40%–49% and no HF signs or symptoms 1. Baseline 2. After starting HER2 targeted therapy every 6 weeks for 2 assessments 3. Every 3 months during the study 4. Asymptomatic absolute decline in LVEF of ≥10% points from baseline or to ≤35%, HER2 targeted therapy held with a confirmatory echocardiogram at 2–4 weeks 5. Repeat echo at the end of treatment and 6 months after end of treatment	SAFE’ HEaRt study [10,11]
Immune checkpoint inhibitors	1. Echo recommended with signs/symptoms of myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis 2. Additional testing guided by cardiology may include stress testing, cardiac MRI, and cardiac catheterization	ASCO [12]
Tyrosine kinase inhibitors	Echo
Tyrosine kinase inhibitors	1. Recommended baseline echo with follow up at 1 months and every 3 months while on therapy with VEGF or VEGF receptor inhibitors (the authors recognize lack of sufficient data) 2. Recommended stress echo in risk stratifying patients with intermediate or high pretest probability of CAD who are to undergo tyrosine kinase inhibitor therapy, particularly sorafenib and sunitinib	ASE/EACVI [13]
Radiation therapy	Echo
	Baseline and repeated echo after radiation therapy involving the heart are recommended for the diagnosis and follow up of valvular heart disease 1. Annual echocardiogram if symptomatic valvular disease 2. Screening echocardiogram 10 years after radiation therapy and every 5 years thereafter in asymptomatic patients	ASE/EACVI [14]
	Cardiac MRI
	Recommended in those with suboptimal echocardiography or discrepant results	ESC [4]
	Coronary CT angiography/calcium artery calcium score
	Reasonable to perform ≥5 years after radiotherapy, and further workup (e.g., coronary angiography, functional testing) is indicated for risk stratification if there is concern for severe ischemic heart disease	SCAI [15]
	SPECT	ASE [14]
	1. Reasonable to screen for CAD with a functional noninvasive stress test 5–10 years after radiation exposure in asymptomatic individuals deemed a high risk for radiation-induced heart disease 2. Repeat stress testing can be planned every 5 years if the first examination does not show inducible ischemia
Prior exposure (not currently on therapy)	Echo
	Recommended for those with symptoms of heart failure	ASCO [1]
	CMR
	Recommended instead of echo only if echo unavailable or not technically feasible	ASCO [1]
Potentially cardiotoxic therapy	Echo
Potentially cardiotoxic therapy	LVEF measurement at baseline and during ^$ treatment (2D/3D) and GLS with treatment or risk factor modification at LVEF ≥60%, 50%–59%, 40%–49%, and <40%	Liu et al. [2]

ASCO, American Society of Clinical Oncology; ASE, American Society of Echocardiography; ASNC, American Society of Nuclear Cardiology; CAD, coronary artery disease; CMR, cardiac magnetic resonance imaging; CTRCD, cancer therapeutics-related cardiac dysfunction; EACVI, European Association of Cardiovascular Imaging; ESC, European Society of Cardiology; GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; SCAI, Society for Cardiovascular Angiography and Interventions; MRI, magnetic resonance imaging; SEOM, Spanish Society of Medical Oncology; SPECT, single-photon emission computed tomography; VEGF, vascular endothelial growth factor.

REFERENCES

[1] Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2017;35(8):893–911.

[2] Liu J, Banchs J, Mousavi N, et al. Contemporary role of echocardiography for clinical decision making in patients during and after cancer therapy. JACC Cardiovasc Imaging. 2018;11(8):1122–1131.

[3] Virizuela JA, García AM, de Las Peñas R, et al. SEOM clinical guidelines on cardiovascular toxicity (2018). Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. 2019;21(1):94–105.

[4] Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–2801.

[5] Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981–1988.

[6] Jordan JH, Todd RM, Vasu S, Hundley WG, et al. Cardiovascular magnetic resonance in the oncology patient. JACC Cardiovasc Imaging. 2018;11(8):1150–1172.

[7] Russell RR, Alexander J, Jain D, et al. The role and clinical effectiveness of multimodality imaging in the management of cardiac complications of cancer and cancer therapy. J Nucl Cardiol. 2016;23(4):856–884.

[8] Herceptin Hylecta. Genentech-Manufacturer Information. https://www.gene.com/download/pdf/herceptin_hylecta_prescribing.pdf . Accessed September 19, 2021.

[9] Perjeta. Genentech-Manufacturer Information. https://www.gene.com/download/pdf/perjeta_prescribing.pdf . Accessed September 19, 2021.

[10] Lynce F, Barac A, Tan MT, et al. SAFE-HEaRt: rationale and design of a pilot study investigating cardiac safety of HER2 targeted therapy in patients with HER2-positive breast cancer and reduced left ventricular function. Oncologist. 2017;22(5):518–525.

[11] Lynce F, Barac A, Geng X, et al. Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study. Breast Cancer Res Treat. 2019;175(3):595–603.

[12] Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714–1768.

[13] Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2014;15(10):1063–1693.

[14] Lancellotti P, Nkomo VT, Badano LP, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2013;14(8):721–740.

[15] Iliescu C, Grines CL, Herrmann J, et al. SCAI expert consensus statement: evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologıa Intervencionista). Catheter Cardiovasc Interv. 2016;87(5):895–899.

When choosing an imaging technique, a nonradiating cardiovascular imaging method is preferred if comparable in terms of accuracy, cost, and convenience ( Table 22.2 ).

TABLE 22.2

Strengths and Limitations of Different Imaging Modalities for Diagnosis and Monitoring of Cardiotoxicity

From Seraphim A, Westwood M, Bhuva AN, et al. Advanced imaging modalities to monitor for cardiotoxicity. Curr Treat Options Oncol. 2019;20(9):73.

IMAGING MODALITY	VOLUME/FUNCTION ASSESSMENT	TISSUE/MASS CHARACTERIZATION	MYOCARDITIS/INFLAMMATION	VALVE DISEASE	PERICARDIAL DISEASE	CORONARY DISEASE/ ISCHEMIA	RADIATION EXPOSURE	REPRODUCIBILITY/ACCURACY	COST	AVAILABILITY
2D echo	+	+	0	+++	++	0	None	+	+	+++
3D echo	++	++	0	+++	+	0	None	++	+	++
Stress echo	++	0	0	++	+	+++	None	++	++	++
CMR	+++ ^a	+++ ^b	+++	++	+++	+++	None	+++	+++	++
PET	++	++	+++	0	++	+++	+++	+++	+++	+
Nuclear ^b	++	+	+	0	++	++	+++	++	+	++
CTCA	+	+	0	+	++	+++ ^c	+/++	+++	++	++

+++, Excellent diagnostic accuracy or features/ high cost; ++, intermediate diagnostic accuracy or features/intermediate cost; +, reasonable diagnostic accuracy or features/low cost; 0, unable to diagnose; 2D echo, 2-dimensional echocardiography; 3D echo, 3-dimensional echocardiography; CMR, cardiac magnetic resonance; CTCA, computed tomography coronary angiogram; PET, positron emission tomography; Stress echo, stress echocardiography.

a Established gold standard.

b Includes SPECT, MUGA.

c CTCA is the only noninvasive test that provides anatomic information with regard to presence of coronary disease. All other modalities rely on functional assessment.

Given its great accessibility and low cost, echocardiography is the recommended method for serial evaluation of left ventricular ejection fraction (LVEF), ideally with three-dimensional (3D) quantitation. The use of global longitudinal strain (GLS) is also strongly encouraged.
One of the most studied deformation parameters, GLS holds utility in detecting preclinical changes during cancer therapy. It is predictive of subsequent declines in LVEF. However, high image quality and consistent acquisition and analyses platforms are critical for comparisons over time. Moreover, ongoing research is aimed at determining the incremental utility of GLS over conventional parameters.
Cardiac magnetic resonance (CMR), which is the gold standard for the evaluation of LVEF, allows also for the detailed assessment of cardiac morphology, including measures of myocardial injury, which may be particularly relevant to cancer therapy cardiotoxicity. Cost, access, and technical requirements limit its widespread use.
The use of one modality for serial assessment of LVEF throughout cancer therapy evaluation is recommended to limit variability.

Echocardiography

Given multiple advantages, including accessibility, relatively low cost, lack of ionizing radiation, and portability, echocardiography is an essential tool and the cornerstone for the assessment of cancer therapy complications. Although at times limited owing to poor acoustic windows, echocardiography is versatile and can provide comprehensive information on both cardiac structure and function. These include parameters related to left and right ventricular size, systolic function (left ventricular ejection fraction [LVEF] and right ventricular fractional area change), and measures of cardiac mechanics such as global longitudinal strain (GLS), diastolic function, valve disease, and pericardial disease. Echocardiography can also be used to gain insight into cardiac hemodynamics, as well as in the diagnosis of ischemia. In the following section, we focus primarily on the echocardiographic assessment of left ventricular systolic function and left ventricular cardiac mechanics and briefly discuss the role of echocardiography in diagnosing pericardial, valvular, and coronary artery disease as well as its use in hemodynamic assessment.

Evaluation of cardiac systolic function and mechanics

Prior to starting cancer therapy, baseline LVEF evaluation by echocardiography should be assessed with the best technique available. The American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) recommend the modified biplane Simpson’s method. However, it is difficult to diagnose small, nearly subclinical changes in LV function by using two-dimensional (2D) measurements. Previous studies comparing different transthoracic echocardiogram techniques demonstrated that 2D echocardiography LVEF quantitation by Simpson’s method can only distinguish changes in LVEF on the order of approximately 10%. ^, Compared with 2D methods, which has a temporal variability (as defined by the standard error) of 0.049 (95% CI, 0.045–0.054), for serial evaluation of LVEF in patients with cancer over one year, noncontrast three-dimensional (3D) echocardiography has a variability of 0.028 (95% CI, 0.025–0.031). ^, 3D-derived left ventricular volumes are more precise, accurate, and reproducible and do not rely on geometric assumptions. ^, However, to obtain accurate 3D volumes, there is still a need for high-quality images and advanced training and time for image post-processing.

Echocardiography can be limited owing to poor acoustic windows, which may be worsened in patients with cancer following radiation or surgery (mastectomy). If the quality of the image is suboptimal as defined as two or more nonvisualized contiguous segments, microbubble contrast (Optison, Definity, or Lumason) should be used, as recommended by the ASE guidelines to help in improving endocardial border detection. Echocardiographic contrast can also be used to improve the diagnostic yield of associated complications of cardiomyopathy and of cancer, such as intracardiac thrombus.

Limitations of LVEF assessment also include its inability to identify small changes in cardiac function or robustly identify patients at increased risk for the development of cancer therapeutics-related cardiac dysfunction (CTRCD). However, a growing body of literature supports the use of myocardial mechanics and deformation, and in particular, strain assessment to detect subclinical changes in cardiac function. Global longitudinal strain, one of the most studied deformation parameters, has been shown to be predictive of subsequent declines in LVEF. ^, GLS is typically derived from the apical two-, three-, and four-chamber images. In a prospective study of 81 women with breast cancer receiving trastuzumab, an 11% (95% CI, 8.3%–14.6%) reduction in GLS derived from the apical two- and four-chamber views predicted future cardiotoxicity with a sensitivity of 65% and a specificity of 94%. Based largely on this study and others, the ASE and the EACVI recommended that a change of more than 15% in GLS during cancer therapy is significant and should be interpreted as abnormal. Of note, the use of the same vendor and analysis software for the follow up of serial GLS are also of importance, and several factors that can influence strain values need to be recognized ( Fig. 22.1 ). GLS is highly dependent on image quality. Furthermore, GLS is load dependent (like LVEF) and a function of chamber size and hypertrophy. There is an important need to demonstrate appropriate quality control prior to the use of strain. The SUCCOUR (Strain sUrveillance of Chemotherapy for improving Cardiovascular Outcomes) trial did not meet its primary endpoint at 1 year and the clinical management implications of GLS remain to be defined.

FIG. 22.1, Strain values are significantly influenced by loading conditions, chamber geometry, conduction delays, and tissue characteristics.

Circumferential motion contributes substantially more to LVEF than longitudinal motion and may also be highly relevant to cardio-oncology. In a prospective study of 135 patients with breast cancer receiving doxorubicin and/or trastuzumab, every 1% worsening in the circumferential strain, patient had an increased odds of developing CTRCD by 17% to 23% ( P < .001). In comparison, for every 1% worsening in the longitudinal strain, there was a 3% to 25% increased odds of developing CTRCD ( P = .037). The role of circumferential strain in the cardio-oncology population is an area of active investigation.

3D measurement of cardiac mechanics is also an interesting and promising area of study. In a study of 142 patients with breast cancer receiving anthracyclines, with or without trastuzumab, a decrease in 3D measures of LVEF, GLS, and global circumferential strain was more marked than changes in analogous 2D-derived parameters during anthracycline chemotherapy; it was associated with subsequent declines in LVEF. 3D-derived LV strain is a new technique that incorporates data from all the layers of the myocardium. Its role in detecting subclinical cardiotoxicity is an area of active research. However, widespread feasibility of 3D echocardiography remains a limitation.

Cardiac structure and hemodynamic assessment

Echocardiography can also be used to diagnose pericardial disease, including effusions, which can be a consequence of metastatic disease, drug exposure, infection, or a consequence of radiation with subsequent pericardial constriction. Echocardiography is also important in assessing valvular function. Indeed, radiation may result in abnormal valve morphology and cause valvular regurgitation or stenosis. Patients with cancer are also at risk of developing valvular endocarditis, either secondary to bacteremia or marantic disease. Echocardiography plays a central role in assessing for vegetations. In cases of poor acoustic windows, transesophageal echocardiography is used to better assess valvular dysfunction, and identify valvular endocarditis, either of the infective or marantic subtype.

Assessment of right ventricular function and pulmonary pressures is also important, because some newer cancer therapies, including tyrosine kinase inhibitors and proteasome inhibitors, have been associated with the development of pulmonary hypertension. ^, Serial pulmonary arterial systolic pressure measurement is recommended whenever using medications such as dasatinib.

Echocardiography can also be readily used to assess diastolic function. E/e′, the ratio between early mitral inflow velocity (E) and mitral annular early diastolic velocity (e′), can be used to estimate LV filling pressures and LV compliance. A recent systematic review and meta-analysis reported that four diastolic function variables were associated with a long-term risk of cardiotoxicity in patients treated with doxorubicin. Changes in mitral E (odds ratio [OR], 3.4; 95% CI, 1.5–7.8; P = .003), mitral E/A, the ratio of early mitral inflow velocity (E) and late diastolic transmitral flow velocity (A), (OR, 4.3; 95% CI, 2.1–8.9; P < .0001), lateral E′ (OR, 3.7; 95% CI, 1.5–-9.4; P < .005) and lateral S′, the peak tissue Doppler imaging systolic velocity, (OR, 2.7; 95% CI, 1.2–5.8; P = .01) were all significantly associated with a subsequent decrease in systolic function. It is of critical importance not only to understand the potential changes in diastolic function with cardiotoxic cancer therapy, but also to determine if changes in diastolic function are associated with an increased risk of heart failure with reduced or preserved ejection fraction, as they are in the general population. This is an area of active research. Assessment of diastolic function should be performed when evaluating patients with cancer as per the ASE guidelines.

Stress echocardiography

Stress echocardiography with exercise or pharmacologic stress (e.g., dobutamine) is an excellent tool to diagnose ischemia. It can also be used to assess for contractile reserve and severity of valvular disease with low-flow, low-gradient severe aortic stenosis. ^, In a small study of 49 cases of breast cancer with patients undergoing high-dose chemotherapy, a decrease in contractile reserve, as defined by difference between peak and rest LVEF in absolute units by five or more units, was a predictor of a subsequent decline in LVEF. The sensitivity and specificity of stress echocardiography is 88% and 83%, respectively for obstructive coronary artery disease.

In conclusion, echocardiography is an affordable, accessible, and safe imaging technique to assess baseline and serial LVEF during cancer therapy. GLS should be used whenever possible to identify preclinical changes in ventricular function, especially in patients receiving cardiotoxic cancer therapy who are at increased risk for CTRCD. Echocardiography can also be used to gain important insight into pericardial disease, valvular disease, cardiac hemodynamics, and ischemia.

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Echocardiography

Evaluation of cardiac systolic function and mechanics

Cardiac structure and hemodynamic assessment

Stress echocardiography

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