The utility of cardiac stress testing for detection of cardiovascular disease in breast cancer survivors: a systematic review

Figures & data

Table 1 Ovid Medline search strategy

1	breast neoplasms/or exp carcinoma, ductal, breast/
2	breast cancer.ti,ab.
3	1 or 2
4	exp cardiac imaging techniques/or ultrasonography/or echocardiography/or echocardiography, doppler/or exp echocardiography, stress/or echocardiography, three-dimensional/or ultrasonography, doppler/or exp echocardiography, doppler/or ultrasonography, doppler, duplex/or ultrasonography, doppler, pulsed/or diagnostic techniques, cardiovascular/or heart function tests/or cardiac output/or cardiography, impedance/or echocardiography, stress/or electrocardiography/or exercise test/or heart auscultation/or heart catheterization/or magnetocardiography/or myocardial perfusion imaging/or oximetry/or radionuclide ventriculography/or plethysmography/or biological assay/or exp ergometry/or exp exercise test/
5	cardiac evaluation.ti,ab.
6	Card* follow-up.ti.
7	echocardio*.ti,ab.
8	exercise echocardiography.ti,ab.
9	exp dobutamine/du [diagnostic use]
10	dobutamine.ti,ab.
11	doppler.ti.
12	radionuclide.ti.
13	or/4–12
14	exp magnetic resonance imaging/
15	13 and 14
16	15 not (screening or mammogra*).ti.
17	13 or 16
18	exp anthracyclines/ae, po, to [adverse effects, poisoning, toxicity]
19	(anthracyclines or anthracycline antibiotics or doxorubicin or adriamycin or epirubicin or idarubicin or daunorubicin or rubidomycin or daunoxome or myocet or caelyx or doxil).ti,ab.
20	fluorouracil.ti,ab.
21	cyclophosphamide.ti,ab.
22	(herceptin or trastuzumab).ti,ab.
23	exp antineoplastic protocols/or exp chemotherapy, adjuvant/or exp radiotherapy, adjuvant/or exp molecular targeted therapy/
24	chemotherapy-induced.ti,ab.
25	exp radiotherapy, adjuvant/ae [adverse effects]
26	radiation.ti,ab.
27	radiation-induced.ti,ab.
28	cancer treatment.ti.
29	cancer therapy.ti.
30	exp antibodies, monoclonal/ae, po, to [adverse effects, poisoning, toxicity]
31	or/18–30
32	exp drug toxicity/
33	toxicity tests/or acute toxicity tests/or cytotoxicity tests, immunologic/or toxicity tests, chronic/
34	heart diseases/or arrhythmias, cardiac/or cardiac output, high/or cardiac output, low/or arrhythmogenic right ventricular dysplasia/or cardiomyopathy, dilated/or cardiomyopathy, hypertrophic/or cardiomyopathy, restrictive/or endomyocardial fibrosis/or myocarditis/or heart failure/or exp myocardial ischemia/or acute coronary syndrome/or angina pectoris/or coronary disease/or myocardial infarction/or pericarditis, constrictive/or exp ventricular dysfunction/
35	heart/de, re, to
36	cardiac dysfunction.ti,ab.
37	cardiomyopath*.ti,ab.
38	cardiotoxic*.ti,ab.
39	cardiac toxic*.ti,ab.
40	heart damage.ti,ab.
41	heart failure/ci
42	cardiovascular injury.ti,ab.
43	(cardiac adj3 injury).ti,ab.
44	or/32–43
45	31 or 44
46	3 and 17 and 45
47	46 not (animal/not human/)
48	48 limit 47 to english language

Abbreviations: ab, abstract; ae, adverse events; de, drug effects; du, diagnostic use; exp, explode; po, poisoning; re, radiation effects; ti, title; to, toxicity; *, truncation that expands a search term to include all forms of a root word.

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of study selection.

Table 2 Summary of articles using cardiac stress testing in breast cancer survivors

Study	Na	Treatments	Timing relative to treatment	Stress technique	Stress parameters	Stress findings	Rest technique	Rest parameters	Rest findings	Utility of stress
Cassidy et al 1998^Citation26	12	Vincristine (4.2 mg/m^2) and mitozantrone (77 mg/m^2)	2–7 months post	Cold pressor ventriculography	LVEF	9 LVEFstress < LVEFrest by >5%	Ventriculography	LVEF	1 LVEF <40%	Benefit: stress scintigraphy identified abnormal LVEF response in 9 with normal resting LVEF.
Civelli et al 2006^Citation16	8	Docetaxel (85 mg/m^2), epirubicin (200 mg/m^2) and cyclophosphamide (4 g/m^2), 3×, 4 weeks apart	Before each cycle, 2, 4, 7, and 12–18 months post	Dobutamine echo	Peak LVEF, LVCR, regional ventricular contractility	↓ peak LVEF and LVCR before 3rd CT cycle, 1, 4, 7 months post-CT in group Ab	Echo	LVEF, LVEDV, LVESV, LVEDD, LVESD, PWTd, PWTs, IVSd, IVSs, peak E, peak A, E/A ratio, DT, IVRT, regional ventricular contractility	↑ LVEDV in group Ab at 4, 7 and 12–18 months; no difference in LVEF until final follow-up; ↓ E wave and E/A in both groups	Benefit: stress echo identified ↓ peak LVEF and LVCR as early as 3rd CT cycle in those who had abnormal LVEF at 12–18 months post-CT (group Ab), whereas resting LVEF did not change significantly.
Cowen et al 1998^Citation17	17	L-Radiation (50–60 Gy, 2 Gy/day)	Mean follow-up of 57.8 months	Exercise scintigraphy Exercise ECG	Perfusion defects Abnormalities	None 1 ST-segment depression considered false-positive	Post-stress scintigraphy ECG	Perfusion defects Abnormalities	None None	No benefit: no abnormalities identified by stress scintigraphy or ECG.
Galluci et al 2010^Citation18	30	Anthracyclines (360–540 mg/m^2) and L-radiation (50–60 Gy, 2 Gy/day), trastuzumab (2), hormonal (11)	Median follow-up of 33.8 months	Exercise gated SPECT	Perfusion defects, LVEF	7 RPD	Post-stress gated SPECT Echo ECG	Perfusion defects LVEF, diastolic or valvular dysfunction, septal hypertrophy Abnormalities	1 IPD 2 LVEF ≤50%, 29 diastolic dysfunction, 1 mitral stenosis, 3 septal hypertrophy 1 atrial fibrillation; 1 ST elevation; 1 pathologic Q-wave; numerous negative T-waves;	Possible benefit: 7 perfusion defects identified by stress SPECT that were not identified by SPECT at rest, but resting echo and ECG identified several abnormalities as well and overlap is not known.
Gustavsson et al 1999^Citation29	34	L-radiation (38–45 Gy, 1.9–2.25 Gy/day) (34); controls: R-radiation (33) and cyclophosphamide only (23)	Median follow-up of 13 years	Exercise scintigraphy	Perfusion defects	None	Scintigraphy Echo ECG	Perfusion defects FS, LV mass, LV and LA dimensions, E/A ratio, DT, valvular dysfunction, pericardial effusion Abnormalities	L-radiation: 4 IPD; R-radiation: 2 IPD; L-radiation: 1 abnormal relaxation & 1 abnormal restrictive filling; R-radiation: 2 abnormal relaxation; CT only: 1 abnormal relaxation & 1 abnormal restrictive filling; L-radiation: 11 abnormalities; R-radiation: 6 abnormalities; CT only: 1 abnormality	No benefit: stress scintigraphy did not identify any perfusion defects, but resting scintigraphy, echo and ECG identified several abnormalities.
Gyenes et al 1994^Citation19	20	L-radiation (45 Gy, 1.8 Gy/day)	Mean follow-up of 18.4 years	Exercise scintigraphy Exercise ECG	Perfusion defects ST segment depression and other abnormalities	3 RPD 7 ST segment depression, 3 other abnormalities	Scintigraphy Echo	Perfusion defects Cardiac dimensions, LVEF, IVRT, DT, E/A ratio, valvular dysfunction, pericardial effusion	2 IPD or MPD 1 LVEF <50% and enlarged LV and LA diameters; 6 LV hypertrophy; 7 abnormal diastolic relaxation;c 2 abnormal diastolic filling;d 3 significant valvular dysfunction;e 1 pericardial effusion	Possible benefit: 3 perfusion defects identified by stress scintigraphy not identified by scinitgraphy at rest; 10 abnormalities identified by stress ECG, but resting echo identified numerous abnormalities as well and overlap is not known.
Gyenes et al 1997^Citation20	12	L-radiation (46–50 Gy, 2 Gy/day); previous CT	Pre, post 1 year	Exercise scintigraphy Exercise ECG	Perfusion defects Changes	None None	Scintigraphy Echo	Perfusion defects LVEF, presence of LV hypertrophy, valvular disease or pericardial effusion	6 IPD None	No benefit: all perfusion defects were identified by scintigraphy.
Haykowsky et al 2009^Citation21	17	Trastuzumab (6–8 mg/kg every 3 weeks) and mixed CT	Pre, 4 months later	Dobutamine cardiac MRI	LV volumes, mass, LVEF	↑ peak LVEDV and LVESV, ↓ peak LVEF	Cardiac MRI	LV volumes, mass, LVEF	↑ LV mass, ↑ LVEDV and LVESV, ↓ LVEF	No benefit: identical changes for stress and rest cardiac MRI.
Højris et al 2000^Citation22	16	L-radiation (50 Gy, 2 Gy/day) and CMF (600/40/600 mg/m^2) (9); CMF alone (7)	Median follow-up of 7.9 years	DipyridamoleSPECT Dipyridamole ECG	Perfusion defects ST depression and pathologic Q waves	L-radiation and CMF: 2 RPDCMF alone: 1 RPD L-radiation and CMF: 1 ST depression CMF alone: 2 ST segment depression	SPECT ECG	Perfusion defects( ST depression and pathologic Q waves	L-radiation and CMF: 1 IPD, 1 MPD; CMF alone: 2 IPD, 1 MPD L-radiation and CMF: 1 Q-wave; 1 partial right bundle block; CMF alone: 2 Q-waves, 1 ST depression	Benefit: L-radiation and CMF: stress SPECT identified 2 cases of perfusion defects not identified at rest; CMF alone: stress SPECT and ECG identified the same 1 case that was not identified at rest.
Khouri et al 2011^Citation23	38	Doxorubicin (dosage NR) (38); healthy controls (11)	Mean follow-up of 35 months	Exercise echo	SV, LVEF, GLS, exercise-rest % change in GLS	↓ LVEF, ↑ GLS, ↓ exercise-rest percentage change in GLS than controls	Resting echo	SV, LVEF, GLS, GRS	No differences	Benefit: stress echo identified a statistical difference in LVEF and GLS in survivors compared to healthy controls, whereas no differences were identified at rest.
Kirthi et al 2011^Citation28	12	Trastuzumab (all), anthracyclines (6), taxanes (3) – dosages NR	Post (timing NR)	Stress (type NR) scintigraphy	Perfusion defects	2 RPD	Scintigraphy Cardiac MRI	Perfusion defects LVEF, LGE, STIR	1 IPD 4↓ LVEF by 10%	Possible benefit: stress scintigraphy identified 2 perfusion defects, but with unknown overlap with defects and abnormalities identified by resting scintigraphy or MRI.
Lindahl et al 1983^Citation27	157	Radiation (L- or R 42 Gy)	Pre, 6 months post	Exercise ECG	Numerous abnormalities	At 6 months post, +4 ectopic beats, +1 Q-wave, +3 ST depression, +30 T-wave items than baseline	ECG	Numerous abnormalities	At 6 months post, +2 ectopic beats, +7 arrthymias, +1 AV conduction, +39 T-wave items than baseline	Possible benefit: exercise ECG identified more cases of ST depression, ectopic beats and Q-waves, while resting ECG identified more arrthymias, AV conduction and T-wave items, but with unknown overlap between cases.
Seddon et al 2002^Citation24	24	L-radiation (50 Gy, 2 Gy/day) (24); controls: R-radiation (12); prior CT	Follow-up ≥5 years	Adenosine SPECT combined with submaximal exercise	SSS, SRDS, perfusion defects	↓ SSS than controls; 7 RPD	Gated SPECT ECG	SRS, perfusion defects, LVEF, regional wall motion abnormalities Abnormalities	↓ SRS than controls; 10 IPD or MPD; 8 wall motion abnormalities 3 abnormalities	Possible benefit: 7 perfusion defects identified by stress SPECT not identified by SPECT at rest, but gated SPECT at rest identified 8 cases of regional wall abnormalities and 3 with ECG abnormalities with unknown overlap.
Sioka et al 2011^Citation25	28	L-radiation (60 Gy, 2 Gy/day) (28); controls: R-radiation (18); prior CT in 29; healthy controls (85)	Mean follow-up of 40 months	Exercise, dipyridamole or dobutamine SPECT	SSS, ASSS myocardial ischemia gradingf (based on SSS), S-RSS	↑ SSS compared to healthy controls but not R-radiation controls; 12 (43%) mild and 3 (11%) moderate myocardial ischemia, whereas 6 (33%) R-radiation controls had mild and 2 (11%) had moderate myocardial ischemia, and 28 (33%) healthy controls had mild myocardial ischemia	Rest SPECT	SRS	No differences between groups	Benefit: exercise, dipyridamole, or dobutamine T-SPECT differentiated between L-radiation and healthy controls, whereas rest T-SPECT did not.

Notes:

a N reflects number of study participants evaluable with stress imaging technique, rather than total in study, and does not include controls

b group A (n=8): study participants whose 12–18-month post-CT resting LVEF decreased to <50% and ≥10% drop from baseline; group B (n=39): study participants with follow-up rest LVEF ≥50%

c abnormal relaxation defined as two out of three of: E/A ratio ≤0.9, DT >230 m/s, IVRT ≥100 m/s

d abnormal filling defined as two out of three of: E/A ratio >1.30, DT <190 m/s, IVRT <80 m/s

e significant valvular dysfunction defined as: the regurgitation extended up to the most proximal area of the atrium or the distal third of the LV

f grading of myocardial ischemia: mild: SSS of 4–8, moderate: SSS of 9–13, severe: SSS >13.

Abbreviations: echo, echocardiography; LVEF, left ventricular ejection fraction; LVCR, left ventricular contractile reserve; peak LVEF, calculated as peak LVEF – resting LVEF; CT, chemotherapy; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; pre, before treatment; post, after treatment; PWTd, posterior wall thickness in diastole; PWTs, posterior wall thickness in systole; IVSd, intraventricular septum at diastole; IVSs, intraventricular septum at systole; E, early (passive) diastolic filling velocity; A, late (active) diastolic filling velocity; DT, mitral deceleration time; IVRT, isovolumetric relaxation time; L-radiation, radiation to left breast; Gy, gray, unit of absorbed radiation; SPECT, single-photon emission computed tomography; ECG, electrocardiography; RPD, reversible perfusion defect; IPD, irreversible perfusion defect; R-radiation, radiation to right breast; MPD, mixed perfusion defect; LV, left ventricle; MRI, magnetic resonance imaging; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; GLS, global longitudinal strain; GRS, global radial strain; LGE, late gadolinium enhancement; STIR, short T1 inversion recovery sequence; TID, transient ischemic dilatation index (ventricular dilatation at exercise); SRDS, summed redistribution score; T-SPECT, translatory single-photon emission computed tomography; SRS, summed rest score; SSS, summed stress score; S-RSS, difference between summed stress score and summed rest score; NR, not reported; SV, stroke volume; ASSS, anterior wall summed stress score; AV, atrioventricular; LA, left atrium; FS, fractional shortening.

Figure 2 Distribution of utility (ie, “benefit”, “possible benefit”, or “no benefit”) of stress.

Notes: (A) Distribution of utility among different techniques. (B) Timing of imaging and types of treatment among studies utilizing myocardial perfusion imaging techniques. (C) Distribution of utility among different breast cancer treatments. (D) Utility of type of stress. Note that one study used exercise, dobutamine, or dipryidamole, and is counted in each category.²⁵

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