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Purpose Echocardiographic surveillance for asymptomatic left ventricular systolic dysfunction (ALVSD) is advised in child- hood cancer survivors (CCS), because of their risk of heart failure after anthracycline treatment. ALVSD can be assessed with different echocardiographic parameters. We systematically reviewed the prevalence and risk factors of late ALVSD, as defined by contemporary and more traditional echocardiographic parameters. Methods We searched databases from 2001 to 2020 for studies on ≥ 100 asymptomatic 5-year CCS treated with anthracyclines, with or without radiotherapy involving the heart region. Outcomes of interest were prevalence of ALVSD—measured with volumetric methods (ejection fraction; LVEF), myocardial strain, or linear methods (fractional shortening; FS)—and its risk factors from multivariable analyses. Results Eleven included studies represented 3840 CCS. All studies had methodological limitations. An LVEF < 50% was observed in three studies in 1–6% of CCS, and reduced global longitudinal strain (GLS) was reported in three studies in 9– 30% of CCS, both after a median follow-up of 9 to 23 years. GLS was abnormal in 20–28% of subjects with normal LVEF. Abnormal FS was reported in six studies in 0.3–30% of CCS, defined with various cut-off values (< 25 to < 30%), at a median follow-up of 10 to 18 years. Across echocardiographic parameters, reported risk factors were cumulative anthracycline dose and radiotherapy involving the heart region, with no ‘safe’ dose for ALVSD. Conclusions GLS identifies higher prevalence of ALVSD in anthracycline-treated CCS, than LVEF. Implications for Cancer Survivors The diagnostic and prognostic value of GLS should be evaluated within large cohorts. Protocol registration PROSPERO CRD42019126588 . . . . Keywords Cardiotoxicity Systolic dysfunction Echocardiography Anthracyclines Childhood cancer survivors Jan M. Leerink and Esmée C. de Baat contributed equally to this work. * Remy Merkx Department of Haematology, Radboud University Medical Center, Remy.Merkx@radboudumc.nl Nijmegen, The Netherlands Department of Cardiology, Radboud University Medical Center, 1 Nijmegen, The Netherlands Department of Medical Imaging, Medical UltraSound Imaging Centre, Radboud University Medical Center, P.O. Box 9101, Department of Paediatrics, Pediatric Cardiology Unit, Tel Aviv 6500, HB Nijmegen, The Netherlands Sourasky Medical Centre, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands Department of Paediatric Cardiology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands 1 3 J Cancer Surviv (2022) 16:338–352 339 Introduction Study selection With improved childhood cancer survival, cardiotoxicity Two authors independently reviewed titles, abstracts and emerges as the major non-malignant cause of late morbidity full-texts for potentially eligible studies. A third author and mortality. Compared to the general population, childhood solved disagreements. We included original studies eval- cancer survivors (CCS) have a sixfold heart failure specific uating at least 100 asymptomatic CCS , who received mortality . The cumulative incidence of symptomatic heart anthracyclines with or without radiotherapy involving failure reaches 5–12%, 30 to 40 years after cancer diagnosis. the heart region. As childhood cancer types incidentally Major causes are anthracyclines and radiotherapy involving occur at later ages, 90% should be diagnosed before the the heart region [2, 3]. Hence, survivorship care focusses on age of 21 years. Echocardiographic evaluation was re- early detection of left ventricular (LV) dysfunction, and guide- quired at least 5 years after cancer diagnosis. As the lines recommend echocardiographic surveillance of asymp- major screening studies included some symptomatic tomatic CCS at least every 5 years . cases, we accepted a maximum of 2.5%. Knowledge of asymptomatic LV systolic dysfunction Primary outcomes were (1) prevalence of ALVSD, or (2) (ALVSD) in CCS is important to define surveillance recommen- its risk factors derived from multivariable analysis that mini- dations. A systematic review on prevalence of and risk factors for mally included sex, age at diagnosis and either attained age or ALVSD after anthracycline treatment, with or without radiother- follow-up duration since cancer diagnosis. apy, dates from 2002 . Reported systolic dysfunction varied We defined ALVSD according to adult  and pedi- between 0 and 38%, and denoted risk factors were cumulative atric  echocardiography guidelines: (i) a volumetric anthracycline dose and follow-up duration, while age at cancer approach (e.g. reduced biplane or 3D LVEF), (ii) myo- diagnosis and female sex were ambiguous risk factors. The in- cardial strain analysis (e.g. reduced GLS or global cir- cluded studies showed heterogeneity in cardiotoxic exposure cumferential strain (GCS)), by any technique and (iii) a and, importantly, outcome definition, and most studies had meth- linear approach (e.g. reduced FS or Teichholz LVEF) odological limitations. The reported outcome parameters were although currently discouraged in adults. mostly fractional shortening (FS) and rarely LV ejection fraction Cut-off values for abnormal were adopted as stated. For (LVEF), but also circumferential fibre shortening velocity and strain measurements, these should be specific to the software stress velocity index . used. Studies where outcomes were not reported separately for The introduction of strain measurement by speckle track- the defined population, cohorts with unclear (a)symptomatic ing, especially global longitudinal strain (GLS), has led to status, and studies during pregnancy were excluded. earlier recognition of systolic dysfunction in various cardio- We accepted multivariable risk factor analyses to in- vascular diseases including adult cardio-oncology [6, 7]. The clude CCS not treated with anthracyclines or with prevalence and risk factors for ALVSD in CCS have not been slightly shorter follow-up since diagnosis, since described in a systematic review addressing both strain mea- anthracycline dose and follow-up duration were surements and conventional systolic function measurements. corrected for in the analysis and no analyses were more We systematically reviewed the available literature, continu- specific. From studies reporting identical outcomes in ing from our last systematic review , on (1) the prevalence of overlapping cohorts, a combined or latest report was and (2) risk factors for ALVSD, to add evidence on contempo- selected. rary echocardiographic parameters such as biplane and 3D LVEF and GLS, in long-term survivors of childhood cancer treated with anthracyclines with or without radiotherapy. Data extraction, risk of bias assessment and analysis Abovementioned authors independently extracted data Methods using piloted forms. Up to two written requests were sent to study authors when missing data or eligible sub- Search strategy groups were encountered. Authors reporting continuous values of systolic function were requested to provide the We searched Medline/PubMed, EMBASE and Cochrane prevalence of systolic dysfunction. Risk of bias was CENTRAL with terms for ‘anthracyclines’, ‘children’ and evaluated based on previously published criteria for ob- ‘asymptomatic systolic dysfunction’ (Online Resource 1) servational studies (Online Resource 2)[11, 12]. without language limits, from May 2001, up until April 13, MetaXL 5.3 (EpiGear International) was used to calcu- 2020. We explored reference lists of included articles and late 95% confidence intervals of prevalences with con- narrative reviews and performed automated citation searching tinuity correction. Continuous values are presented as in Web of Science. median [range], unless stated otherwise. 1 3 340 J Cancer Surviv (2022) 16:338–352 Results and children  upon our request . The fourth study reporting GLS was only eligible for its risk factor analysis Identified studies . Two of these studies compared myocardial strain to LVEF [18, 19]. A linear approach was reported in six studies Of the 4004 unique titles and abstracts identified, 163 were (FS n = 1366, Teichholz LVEF n = 557). Two studies reported selected for full-text assessment. Additional data were re- continuous values and provided prevalences according to their ceived from seven studies. To address the prevalence ques- local cut-off values upon request [14, 16, 20–23]. tion, ten studies were included, and for the risk factor question, Median follow-up from cancer diagnosis until echocardio- six were eligible (Fig. 1,Table 1). graphic examination varied between the studies from 9 to 23 Three studies (2174 CCS) used a volumetric approach (bi- years, as did the proportion of survivors who received radio- plane LVEF n = 660, 3D LVEF n = 1514) to quantify ALVSD therapy involving the heart region (5–52%). Median cumula- [13, 15, 18]. Myocardial strain was reported in four studies (n tive anthracycline dose ranged from 166 to 333 mg/m ,but = 2281). One of these studies used vendor specific normative studies used different dose-equivalence ratios. values for GLS and GCS , another study in a pediatric cohort defined abnormal GLS (apical 4-chamber view) as Risk of bias assessment vendor specific z-score < − 2. A third study reported apical 4-chamber GLS and mid-ventricular GCS as continu- Figure 2 depicts the risk of bias assessment. Ninety-one per- ous values, and compared to normative values for adults  cent of the studies did not report original cohort sizes and thus Fig. 1 PRISMA flowchart of study selection. Flowchart describing the systematic literature search and inclusion of studies. *Multiple reasons can be given per study, references in Online Resource 3. **Although directly eligible, 2 of these 6 authors provided additional data upon request 1 3 J Cancer Surviv (2022) 16:338–352 341 1 3 Table 1 Characteristics of included studies assessing prevalence and/or risk factors of asymptomatic left ventricular systolic dysfunction 1st Author, year Design, population Original Prevalence Risk country, period cohort factors (n) Age at Cumulative Current Dexrazoxane Outcome Prevalence Eligible Heart (n) diagnosis, anthracycline RT CHF (n) (n) definition (n (%; 95% Eligible (% Years since dose (mg/m ) (n CI) males) diagnosis, (%)) Attained age (years) Slieker, 2019 n = 546 n.m. 467 (54) 3.4 [0.1–13.2] 166 [18–699] 49 (10) 0 17 Biplane LVEF < 50% 2/338 (0.6; 0–1.8) Yes Canada, n.m.,  Cross-sectional, 9.2 [5.0–17.2] (Cardiotoxic GLS Z-score < − 2 (single-view, EchoPac 39/435 (9; 6.4– Last ANT dose 14.1 [5.2–18.8] doxorubicin software) 11.8) + ≥ 3 years. equivalence) Attained age < 18 years No SCT, CHD or familial CMP c d Li, 2019 n = 103 n.m. 103 (55) 8.2 ± 5.0 220 [60–675] 5 (5) 0 n.m. FS < 27% 1/103 (1.0; 0–4.1) No China, n.m.,  Prospective, 15.2 ± 5.8 (Conversion cross-sectional, 25.0 ± 5.8 factor n.m.) ANT, treatment + ≥ 5 years, attained age ≥ 15 years b e Armenian, 2018 n = 221 n.m. 193 (52) 11.4 [< 1–22] 235 [25–642] 30 (16) 1 n.m. Biplane LVEF < 50% 11/193 (5.7; 3– 9) No California, USA, cross-sectional, 15.8 [5.1–44.8] (Haematotoxic 2014–2017  ANT, diagnosis 26.1 [13.0–59.9] doxorubicin + ≥ 2years equivalence) Pourier, 2017 n = 340 n.m. 340 (54) 5.9 [0–17.5] 180 [30–600] 49 (14) 0 n.m. FS < 27% 1/340 (0.3; 0–1.3) No Netherlands, 2006–2010, Retrospective 13.7 [4.9–32.0] (Doxorubicin Teich EF < 50% 1/340 (0.3; 0–1.3)  cross-sectional, 21.3 [6.0–43.0] + daunorubicin) ANT, diagnosis + ≥ 5 years, asymptomatic, no CHD f f f f f f f f Christiansen, 2016 n = 231 n.m. 231 (51) 9.3 ± 5.1 150 [40–485] 52 (23) n.m. n.m. Biplane LVEF < 50% Not eligible Yes f f Norway, 2007–2011  Cross-sectional, 21.9 ± 8.0 (Conversion 40 Gy GLS > controls -1.96SD ALL/lymphoma, 31.1 ± 7.8 factor n.m.) EchoPac software diagnosis + ≥ 5 years, attained age ≥ 18 years Armstrong, 2015 n = 1807 n.m. 1514 (52) n.m. [0–>19] n.m. [up to > 600] 464 (31) 17 n.m. 3D LVEF < 50% n.m./n.m. (5.8; Yes Tennessee, USA, n.m.  Prospective 22.6 [10.4–48.3] (Conversion factor GLS > age/sex norm n.m.) cross-sectional, ANT 31 [18–65] n.m.) GCS > age/sex norm n.m./n.m. (30; or RT, diagnosis (EchoPac software) n.m.) + ≥ 10 years, attained n.m./n.m. (23; age ≥ 18 years n.m.) normal LVEF only n.m. n.m. n.m. n.m. n.m. n.m. GLS > age/sex norm n.m./n.m. (28; n.m.) Mavinkurve- n = 109 n.m. 109 (57) 4.8 [.03–16.9] 180 [50–600] 7 (6.3) 0 n.m. GLS > age/sex norm 22/92 (24; 16 - No Groothuis, 2010 Prospective 13.2 [5.0–29.2] (Doxorubicin GRS < age/sex norm 33) Netherlands, cross-sectional, 20 [5.6–37.4] + daunorubicin) GCS > age/sex norm 4/89 (4.5; 1–10) 2006–2008  ANT, diagnosis (single view, 35/82 (43; 32–54) + ≥ 5 years, no EchoPac software) CHF/CVD/CKD normal LVEF only 49 (57) 5.3 [.03–16.8] 180 [50–450] 4 (8.2) 0 n.m. GLS > age/sex norm 9/45 (20; 9.4–33) 10.8 [5.0–26.2] GRS < age/sex norm 2/43 (4.7; 1–14) 16.8 [5.6–34.4] GCS > age/sex norm 342 J Cancer Surviv (2022) 16:338–352 1 3 Table 1 (continued) 1st Author, year Design, population Original Prevalence Risk country, period cohort factors (n) Eligible Age at Cumulative Heart Current Dexrazoxane Outcome Prevalence (n) diagnosis, anthracycline RT CHF (n) (n) definition (n (%; 95% Eligible (% Years since dose (mg/m ) (n CI) males) diagnosis, (%)) Attained age (years) 10/36 (28; 14– 44) b g van der Pal, 2010 n = 525 n.m. 361 (54) 9.7 [0.1–17.8] 250 [33–720] 58 (16) 0 (7 ) n.m. FS < 30% 107/355 (30; 25 Yes Netherlands, Prospective 13.3 [5.1–28.8] (All –35) 1996–2004,  cross-sectional, 21.7 [18–42.1] anthracyclines ANT/RT/high added up) dose cyclo-/ifosfamide, diagnosis + ≥ 5 years, attained age ≥ 18 years b e Hudson 2007 n = 223 n.m. 217 (51) 5.5 [0–23.6] 202 [25–510] 60 (28) 0 n.m. FS < 28% 32/213 (15; 11 – Yes Tennessee, Prospective 10.2 [5.5–28.0] (Conversion (2 ) 20) USA, n.m.,  cross-sectional, no 16.9 [7.5–38.1] factor n.m.) CHD/CHF/chronic illness/trisomy 21/ anaemia h g Pein, 2004 n = 205 416 205 (58) 5.7 [0–21] 333 [40–600] 106 (52) 0 n.m. FS < 25% 13/205 (6.3; Yes France, n.m,  Cross-sectional, ANT 18 [15+] (Conversion 7.7Gy Teich EF < 50% 3.3–10.1) diagnosis + ≥ 15 years n.m. [n.m.] factor n.m.) 17/205 (8.3; 4.9–12.5) von der Weid, 2001 n = 150 n.m. 140 n.m. [n.m.] n.m. [n.m.] n.m. 0 n.m. FS < 30% 2/140 (1.4; 0–4.3) No Switzerland Prospective, (n.m.) n.m. [5+] 1994–1996,  cross-sectional, n.m. [n.m.] ALL, no BMT diagnosis + ≥ 5 years therapy + ≥ 2 years Numbers are medians [range] unless stated otherwise. Only two studies reported early cancer therapy related cardiotoxicity and two reported median RT dose. None reported mitoxantrone dose or infusion duration. Data shown for symptomatic survivors, ≥ 5 years from diagnosis, treated with anthracyclines b c Authors provided subgroup data; converted continuous values into prevalence data Mean ± SD, follow-up from end of therapy e≥ 90% were diagnosed before age 21 years f g Data presented for entire cohort (n = 231) including non-anthracycline treated CCS, study not included for prevalence estimation Transient CHF during cancer therapy Mean (range) ALL, acute lymphoblastic leukaemia; ANT, anthracyclines; BMT, bone marrow transplant; CHD , congenital heart disease; CHF, congestive heart failure; CKD, chronic kidney disease; CMP, cardiomy- opathy; CVD, cardiovascular disease; GCS, global circumferential strain; GLS, global longitudinal strain; GRS, global radial strain; FS, fractional shortening; Heart RT, radiotherapy involving the heart region, as defined by individual study; LVEF, left ventricular ejection fraction; SCT, stem cell transplant; Teich EF, left ventricular ejection fraction according to Teichholz formula; n.m., not mentioned J Cancer Surviv (2022) 16:338–352 343 Fig. 2 Risk of bias summary per study. The risk of bias per study is indicated for each domain. Assessment criteria are shown in Online Resource 2.Green =low risk; yellow = unknown risk; red = high risk; n.a, is not applicable risk of selection bias remained unclear; in 9% the risk was high. Myocardial strain analysis Four studies (36%) reported blinded outcome assessment; the remainder carried a high risk of detection bias. All six studies Three studies assessing myocardial strain reported abnor- assessing risk factors in a multivariable analysis had low risk of mal GLS, according to vendor-, age- and sex-specific confounding. The risk of study group reporting bias was high in cut-off values, in 9–30% (Fig. 3). The lowest preva- 73%. Not all studies reported median cumulative anthracycline lence was again seen in the study with the shortest dose; only three studies summarized radiotherapy doses involv- median follow-up duration (9 years, versus 13 and 23 ing the heart region, and only one reported additional chemother- years). Anthracycline doses varied. Not all studies re- apeutic agents. Follow-up duration was summarized by 91% of ported a median dose. The proportion that received ra- the studies, and all studies provided their outcome definition. diotherapy on the heart region varied from 6 to 31% Risk estimation was not adequate in 17% of the 6 studies [13, 18, 19]. We did again not pool results from these assessing risk factors. The few studies for each outcome heterogeneous cohorts. Two studies reported GLS in prevented formal testing for publication bias. However, as we subjects with normal LVEF, which was abnormal in searched all major databases and most studies were not industry 20–28% (Table 1)[18, 19]. funded, we judge the risk of publication bias ‘low’. Of note, in one study, only 20% of survivors with abnormal LVEF also had abnormal GLS. Two studies reported higher, or lower prevalence of abnormal GCS, com- Prevalence of asymptomatic systolic dysfunction pared to the prevalence of abnormal GLS. Volumetric methods Linear methods Three studies, all defining an abnormal biplane or 3D LVEF < 50%, reported a prevalence of 1–6% (Fig. 3). The prevalence Prevalence of abnormal FS and Teichholz LVEF varied was lowest in the study with the shortest median follow-up between the six studies from 0.3 to 30%, using different duration (9 years, versus 16 and 23 years). Anthracycline definitions of abnormal FS (< 25 to < 30%; Fig. 3). As doses varied. Not all studies reported a median dose. The median follow-up duration (10 to 18 years) and proportion that received radiotherapy on the heart region var- anthracycline dose (180–250 mg/m ) and proportion that ied from 10 to 31%[13, 15, 18]. This observed clinical hetero- received radiotherapy involving the heart region (5– geneity prevented pooling of results. 28%) varied widely, we did not pool results. No direct 1 3 344 J Cancer Surviv (2022) 16:338–352 Fig. 3 Prevalence of asymptomatic left ventricular systolic dysfunction in authors. Symbol size depicts sample size. Continuous values are median childhood cancer survivors. Prevalence is depicted for different [range]. ANT = anthracycline, CI = confidence interval, FS = fractional echocardiographic parameters and cut-off points in the included studies. shortening, GLS = global longitudinal strain, RT = radiotherapy on the *Mean ± SD. Closed symbols depict the original cut-offs from the stud- heart region ies, open symbols were extracted from additional data provided by comparisons between FS and other ALVSD parameters females with abnormal GLS (sex-specific normative values). were found in these studies. The same study analysed traditional cardiovascular risk fac- tors and found hypertension associated with an abnormal LVEF and all components of the metabolic syndrome and Risk factors attained age to be associated with an abnormal GLS . Five out of six studies that reported multivariable risk factor analyses on either dichotomous or continuous outcomes (Table 2) agreed on the incremental risk of ALVSD with Discussion increasing cumulative anthracycline dose [17, 18, 20–22]. For abnormal LVEF and FS, the risk ratios increased with This systematic review shows a high variation in the preva- higher dose categories. However, in the study assessing lence of ALVSD in long-term CCS, also when including con- GLS, the risk ratios showed a more stable elevation through- temporary echocardiographic measurements such as myocar- out dose categories, compared to LVEF . Furthermore, dial strain. The heterogeneity in cardiotoxic exposure and time GLS as a continuous outcome variable was not associated since diagnosis, within and between cohorts, as well as het- with anthracycline dose . Either radiation exposure or erogeneous measurement methods and cut-off values for ab- dose to the heart region were identified as risk factors by three normality, prevented pooling of data. This makes large cohort out of four studies that assessed radiotherapy, and across all studies and pooling of individual patient data the most appro- systolic function parameters [17, 18, 20]. Younger age at di- priate ways to study the epidemiology of ALVSD in long- agnosis and shorter follow-up duration were associated with term CCS. The prevalence of abnormal GLS is higher com- abnormal FS in one of the three studies that analysed these pared to abnormal LVEF, and both are increased in studies variables . Only one study found a sex association with, with longer periods of follow-up. The reviewed studies add discrepantly, more males with an LVEF < 50%, but more data to the conclusions from our previous review on the 1 3 J Cancer Surviv (2022) 16:338–352 345 1 3 Table 2 Reported risk factors for asymptomatic left ventricular systolic dysfunction 1st Author, year Population Outcome definition; (% abnormal) Tested risk factors Tested categories (effect size; 95% confidence interval) Model (reference category) comments Slieker, 2019  n = 546 GLS Z-score (continuous) Attained age, years β −0.086; −0.140– −0.031 Includes 14% Last Age at diagnosis, years n.m. survivors anthracycline Female sex n.m. 3-5 years dose + ≥ 3 Body surfaceareaper 0.1 β −0.065; −0.118– −0.013 since years. m increment diagnosis Attained age < Years since last n.m. 18 years anthracycline dose No stem cell Heart RT exposure n.m. transplant, Anthracycline dose per 50 n.m. congenital mg/m increment heart disease Dexrazoxane therapy n.m. or familial cardiomyop- athy Christiansen, 2016  n = 231 GLS Age at diagnosis OR 0.96; 0.90–1.03 23% had no Acute > − 18.3% (female) Attained age OR 1.02; 0.98–1.06 anthracycline lymphoblas- > − 17.2% (male) Heart RT exposure OR 5.2; 2.2–12 exposure tic (32%) Anthracycline dose (< >300 (OR 4.8; 1.7–14) leukaemia/- 300 mg/m ) lymphoma, diagnosis + ≥ 5years, attained age ≥ 18 years Armstrong, 2015  n = 1807 3D LVEF < 50% Ethnicity (non-Hispanic Other (RR 1.53; 0.93–2.52) 17% had no any cancer, (5.8%) white) anthracycline anthracycline Female sex RR 0.54; 0.36–0.83 exposure or Heart RT, Age at diagnosis (≥ 15 0–4(RR0.66;0.35–1.27), 5–9(RR0.67;0.36–1.25), 10–14 (RR 1.02; diagnosis + ≥ years) 0.59–1.76) 10 years, Attained age (18–30 31–40 (RR 1.38; 0.81– −2.35), > 40 (RR 0.98; 0.52–1.84) attained age years) ≥ 18 years Heart RT dose (0 Gy) 1-19 (RR 1.24; 0.70–2.22), 20–29 (RR 1.86; 1.00–3.45), ≥ 30 (RR 7.99; 3.88–16.48) Anthracycline dose (0 1–100 (RR 1.74; 0.66–4.61), 101-200 (RR 2.80; 1.24–6.31), 201-300 mg/m ) (RR 3.80; 1.59–9.10), 301-400 (RR 4.76; 2.16 – 10.50), > 400 (RR 7.71; 3.04 – 19.57) Metabolic syndrome (≥ 3 RR 1.07; 0.74–1.53 of the following) Waist circumference > RR 1.34; 0.99-1.82 102 (male) > 88 cm (female) Triglycerides > 150 mg/dl RR 1.01; 0.70–1.44 HDL < 40 (male) < 50 RR 1.01; 0.74–1.38 mg/dl (female) Blood pressure ≥ 130/ RR 1.44; 1.22–1.70 and/or /85 mmHg or treated RR 1.02; 0.75–1.39 346 J Cancer Surviv (2022) 16:338–352 1 3 Table 2 (continued) 1st Author, year Population Outcome definition; (% abnormal) Tested risk factors Tested categories (effect size; 95% confidence interval) Model (reference category) comments Fasting glucose > 100 mg/dl or diabetes treat- ment GLS > age/sex norm Ethnicity (non-Hispanic Other (RR 1.22; 1.03–1.46) (31.8%) white) Female sex RR 1.55; 1.34–1.79 Age at diagnosis (≥ 15 0–4 (RR 1.02; 0.82–1.27), 5–9 (RR 0.92; 0.74 – 1.15), 10–14 (RR 1.02; years) 0.83–1.24) Attained age (18–30 31–40 (RR 1.25; 1.05–1.48), > 40 (RR 1.49; 1.20–1.85) years) Heart RT dose (0 Gy) 1–19 (RR 1.38; 1.14–1.66), 20–29 (RR 1.65; 1.31– 2.08), ≥ 30 (RR 2.39; 1.79–3.18) Anthracycline dose (0 1–100 (RR 1.38; 1.05–1.82),101–200 (RR 1.16; 0.89–1.50), 201–300 mg/m ) (RR 1.06; 0.78–1.45), 301–400 (RR 1.72; 1.31–2.26), > 400 (RR 1.73; 1.19–2.50) Metabolic syndrome (≥ 3 RR 1.94; 1.66–2.28 of the following) Waist circumference > RR 1.73; 1.48–2.01 102 (male) > 88 cm (female) Triglycerides > 150 mg/dl RR 1.65; 1.40–1.95 HDL < 40 (male) < 50 RR 1.40; 1.23–1.59 mg/dl (female) Blood pressure ≥ RR 1.48; 1.33–1.65 130/and/or /85 mmHg or treated Fasting glucose > 100 RR 1.37; 1.19–1.59 mg/dl or diabetes treat- ment GCS > age/sex norm Ethnicity (non-Hispanic Other (RR 0.84; 0.64–1.09) (23.1%) white) Female sex RR 1.01; 0.84–1.21 Age at diagnosis (≥ 15 0–4(RR1.24;0.92–1.67), 5–9(RR1.01;0.74–1.38), 10–14 (RR 1.11; years) 0.84–1.48) Attained age (18–30 31–40 (RR 0.85; 0.69–1.06), > 40 (RR 0.98; 0.73–1.33) years) Heart RT dose (0 Gy) 1–19 (RR 0.86; 0.66–1.11), 20–29 (RR 1.14; 0.83–1.57), ≥ 30 (RR 1.64; 1.05–2.56) Anthracycline dose (0 1–100 (RR 0.99; 0.66–1.48), 101–200 (RR 1.24; 0.86–1.79), 201–300 mg/m ) (RR 1.36; 0.90 – 2.04), 301–400 (RR 1.61; 1.08–2.40), > 400 (RR 1.34; 0.78–2.31) Metabolic syndrome (≥ 3 RR 1.02; 0.84–1.24 of the following) Waist circumference > RR 1.10; 0.92–1.32 102 (male) > 88 cm (female) Triglycerides > 150 mg/dl RR 1.01; 0.82–1.13 HDL < 40 (male) < 50 RR 0.92; 0.78–1.08 mg/dl (female) J Cancer Surviv (2022) 16:338–352 347 1 3 Table 2 (continued) 1st Author, year Population Outcome definition; (% abnormal) Tested risk factors Tested categories (effect size; 95% confidence interval) Model (reference category) comments Blood pressure ≥ 130/ RR 1.04; 0.92–1.18 and/or /85 mmHg or treated Fasting glucose > 100 RR 1.06; 0.89–1.25 mg/dl or diabetes treat- ment van der Pal, 2010  n = 525 FS Male sex β 0.77 (−0.27–1.80) 31% had no any cancer, (continuous) Age at diagnosis (>15 0–5(β −3.55; −5.80– −1.30) > 5–10 (β −1.95; −4.03–0.12), > 10–15 anthracycline anthracyclin- years) (β −1.32; −3.21–0.58) exposure e/RT/high Time since diagnosis 10–15 (β 0.41; −1.25–2.08), 15–20 (β 1.71; −0.07–3.50), 20–25 (β dose (5-10 years) 2.07; −0.08–4.22), > 25 years (β 4.86; 2.28–7.43) cyclo-/- Vincristine exposure β −1.30; −2.88–0.27 ifosfamide, Anthracycline dose 151–300 (β −1.93; −3.71−−0.15), 301–450 (β −4.24; -6.32−−2.16), > diagnosis + (0–150 mg/m ) 450 ≥5years, (β −5.38; −7.98−−2.79) attained age Cyclophosphamide (≤ 10 No (β 0.38; -1.13–1.90), >10 (β -0.85; -2.91–1.22) ≥ 18 years g/m ) Ifosfamide (≤ 10 g/m)No(β 0.54; −2.89–3.96), > 10 (β 0.66; −3.06–4.39) RT exposure (none) Thorax (β − 3.67; − 5.54 − − 1.79), Abdomen (β − 3.54; -5.87−− 1.20), Spine (β −− 0.79; − 2.92–1.24), total body (β − 0.53; − 4.01–2.94) FS < 30% Male sex OR 0.73; 0.47–1.13 (27%) Age at diagnosis (> 15 0–5(OR 2.94;1.08–8.02), > 5–10 (OR 1.64; 0.67– 4.01), > 10–15 (OR years) 1.45; 0.64–3.28) Time since diagnosis 10–15 (OR 0.80; 0.41–1.54), 15–20 (OR 0.40; 0.18–0.86), 20–25 (OR (5–10 years) 0.48; 0.19–1.23), > 25 (OR 0.11; 0.03–0.42) Vincristine exposure OR 1.47; 0.71–3.05 Anthracycline dose 151–300 (OR 3.98; 1.58–10.01), 301–450 (OR 7.77; 2.85–21.22), > 2 b (0–150 mg/m ) 450 (OR 10.58; 3.35–33.40) Cyclophosphamide (≤ 10 No (OR 1.01; 0.52–1.99), > 10 (OR 1.01; 0.45–2.26) g/m ) Ifosfamide (≤ 10 g/m)No(OR1.25;0.23–6.67), > 10 (OR 1.50; 0.26–8.82) RT exposure (none) Thorax (OR 3.49; 1.60–7.61), Abdomen (OR 2.66; 1.00–7.05), Spine (OR 0.64; 0.23–1.74), total body (OR 0.53; 0.10–2.87) Hudson, 2007  n = 278 disease/congestive heart FS Age at diagnosis < 5 years (mean various cancers, failure/chronic illness/trisomy21/- (continuous) 35%), ≥ 5 no congenital anaemia years (mean heart 32%) 22% had no Diagnosis group Leukaemia anthracycline exposure (mean 36%), Sarcoma (mean 32%), Lymphoma (mean 33%), Embryonal (mean 34%) QTc time Normal (mean 34%), 348 J Cancer Surviv (2022) 16:338–352 1 3 Table 2 (continued) 1st Author, year Population Outcome definition; (% abnormal) Tested risk factors Tested categories (effect size; 95% confidence interval) Model (reference category) comments prolonged (mean 29%) Years off therapy per 5-year increment β −.004 Anthracycline dose per 50 β −.008 mg/m increment FS < 28% Age at diagnosis (< 5 years) ≥ 5 (OR 2.41; (14%) 0.91–6.40) Diagnosis group (leukaemia) Sarcoma (OR 5.09; 1.30–19.89), Lymphoma (OR 2.04; 0.47–8.94), Embryonal (OR 1.70; 0.36–8.04) Years off therapy per 5-year increment OR 1.08; 0.52–2.27 Anthracycline dose per OR 1.19; 50 mg/m increment 1.01–1.39 Pein, 2004  n = 205 FS Anthracycline dose ≤ 150 mg/m (mean 35%), 151–250 (mean 34%), 251–400 (mean any cancer, (continuous) 33%), > 400 anthracyclin- (mean 30%) e, Teich LVEF Anthracycline dose ≤ 150 mg/m (mean 64%), 151–250 (mean 62%), 251–400 (mean diagnosis + ≥ (continuous) 61%), > 400 15 years (mean 57%) Bolded values indicate statistical significance in multivariable analysis that at least included sex, age at diagnosis and either attained age or follow-up time since cancer diagnosis. Included, but no effect size reported for multivariable model; significant trend FS, fractional shortening; GCS, global circumferential strain; GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; OR, odds ratio; Heart RT, radiotherapy involving the heart region; RR, risk ratio; n.m., not mentioned J Cancer Surviv (2022) 16:338–352 349 increased risk of ALVSD with higher doses of cardiotoxic associated with abnormal GLS and hypertension associated exposures . However, for additional risk factors that could with abnormal LVEF . This substantiates the evidence aid further risk stratification, the studies show little agreement. provided by large cohort studies that assess risk factors for clinical heart failure in CCS [28, 29], indicating especially Prevalence of ALVSD hypertension as clinically actionable risk factor. Within two studied cohorts, GLS-based ALVSD was more Comparison of different echocardiographic prevalent than LVEF-based ALVSD (9% versus 1%, and parameters 30% versus 6%, respectively), at a median of one to two decades after diagnosis [13, 18]. Although the CCS studied Abnormal GLS is regarded as an early and sensitive indicator by Christiansen et al. did not all receive anthracyclines, they of systolic dysfunction in adults with cardiovascular disease, found prevalences of abnormal GLS (32%) and either abnor- including adult cardio-oncology patients [6, 7, 30]. As expect- mal LVEF or FS (11%), at a mean of 22 years since diagnosis, ed, abnormal GLS was more prevalent than abnormal LVEF that were in accordance with the included studies . within our included cohorts. However, GLS measurement Strikingly, for CCS at median ages of 20 to 31 years, these should not replace LVEF, since not only longitudinal shorten- four to five times greater prevalences of GLS-based ALVSD ing contributes to LVEF but also circumferential shortening, versus LVEF-based ALVSD, approximate those in a> 80 wall thickness and end-diastolic volume . This may also years old subgroup of a United States community-based explain why some subjects with abnormal LVEF exhibited cohort. normal GLS [17, 19]. Combined measurements may add Ageing is an important risk factor for cardiovascular dis- prognostic value to single measurements. ease in the general population. The highest prevalence of A systematic review found that GCS abnormalities were ALVSD indeed was reported in cohorts with the longest more consistently present than GLS abnormalities in CCS at follow-up since diagnosis, but not all included risk factor anal- longer follow-up after anthracycline therapy. It also showed, yses support this finding. with some heterogeneity, that GLS abnormalities were more frequent in the first year posttreatment . In our review, Risk factors for ALVSD only one of two studies showed a higher prevalence of abnor- mal GCS than of abnormal GLS . Since the reproducibil- Cumulative anthracycline dose and radiotherapy involving the ity of GCS measurements is questionable, GCS may be less heart region are evident risk factors for ALVSD, across echo- useful as a sensitive marker for ALVSD [18, 24]. cardiographic parameters. Even the lowest anthracycline dose Different contraction and remodelling patterns, which categories carry a risk of ALVSD . Interestingly, in the might be caused by different cardiotoxic exposures, affect largest included study, the risk ratios for abnormal GLS were different parameters of systolic function. Furthermore, preva- only slightly elevated in the higher dose categories (up to lence of abnormality is affected by the definition of abnormal- 1.73), compared to the straightforward increasing risk for ab- ity, including measurement method and cut-off value. In the normal LVEF up to 7.71 . This may reflect a higher prev- present review, the prevalence of abnormal FS, when defined alence of abnormal GLS among CCS with no anthracycline with a liberal cut-off value of < 30%, approximates that of an exposure. These CCS were, in this study, exposed to radio- abnormal GLS, albeit in different cohorts [18, 20, 21]. therapy involving the heart region. Reporting systolic function However, GLS was shown to better correlate with parameters as continuous outcomes might allow to find the LVEF than with FS . Ideally, the relationships of lowest cardiotoxic doses and takes the degree of abnormality systolic function parameters and cut-off values should into account in risk factor analyses. be studied within large cohorts that include a control There was no agreement on the role of sex, age at cancer group, to put the abnormality in perspective. diagnosis or attained age as risk factors for ALVSD. Interestingly, Armstrong et al. found more abnormal LVEF in males but more abnormal GLS in females . Since males Which systolic function parameter to use? are known to have lower LVEF values , this perceived discrepancy might dissolve after application of sex-specific Different LV function parameters may serve different pur- LVEF cut-off values, as was already done for GLS. Studies poses, such as selecting CCS that would benefit from therapy, on clinical heart failure incidence also remain ambiguous on or identification of CCS with very low risk of future heart the roleoffemalesex asa riskfactor[2, 27]. failure. Prognostic evidence for echocardiographic parameters The largest included study investigated the association of was only recently presented with retrospective data on longi- ALVSD with modifiable cardiovascular risk factors. The au- tudinal changes of LVEF and FS , and the 10-year pre- thors found all components of the metabolic syndrome dictive value of LVEF measurement, when added to 1 3 350 J Cancer Surviv (2022) 16:338–352 anthracycline dose and radiotherapy, for developing an LVEF confounders. Our attempts to contact study authors made <40% . new data available, to construct a complete as possible review. Regarding GLS, the recently published results on GLS- Narrowing down the inclusion criteria to specific cut-off guided cardioprotection in adults on active cancer treatment values for ALVSD would result in missing information. We do not justify early initiation of heart failure treatment . highlight that the prevalence of ALVSD is related to the def- However, the evidence on the added sensitivity and prognos- inition used, underscoring the need to harmonize ALVSD tic value of GLS over LVEF in predicting severe endpoints is definitions in CCS. accumulating in cardiology and adult cardio-oncology [6, 7]. The lack of evidence in CCS should not be confused with lack of prognostic value. Knowing this, research may focus on Conclusions strict cardiovascular risk management in CCS with abnormal GLS, and surveillance reduction for those with normal GLS. ALVSD detected with echocardiography is common in long- The current cardiomyopathy surveillance guideline de- term CCS treated with anthracyclines. GLS identifies a higher scribes LVEF, FS and wall stress as ‘most frequently used prevalence of ALVSD, compared to LVEF, but should not and readily reproducible variables of LV systolic function’. replace LVEF measurement. Even CCS treated with the low- It should be noted that linear measurements of global LV est anthracycline doses may show ALVSD. Hypertension function, such as FS, are discouraged in adult guidelines for might be an important modifiable risk factor for ALVSD. echocardiography . Linear measurements may also be in- The diagnostic and prognostic value of GLS, as well as the ferior to volumetric methods in children . They ig- relations between different echocardiographic measurements, nore regional wall motion abnormalities and abnormal should be evaluated within large cohorts. ventricular geometry, which may not be uncommon in CCS since cardiotoxicity can include valvular and isch- aemic heart disease . Also, 3D LVEF measurement is more reproducible than Supplementary Information The online version contains supplementary biplane LVEF , which is useful in detecting subtle chang- material available at https://doi.org/10.1007/s11764-021-01028-4. es during follow-up. It is also more comparable to magnetic resonance imaging as gold standard . Multi-view GLS Acknowledgements Librarian Alice Tillema assisted with the search. measurements are considered more reproducible than mea- Doctors Pourier, Mavinkurve-Groothuis, Slieker, Hudson, van der Pal, surements in a single apical view . Li, and Armenian provided additional information on their studies. Echocardiography labs incorporating GLS measurement in Author contribution Concept/design: R Merkx, EAM Feijen, WEM their clinical routine will facilitate future studies. GLS mea- Kok, AMC Mavinkurve, J Loonen, HJH van der Pal, L Bellersen, CL surement has been standardized by recommendations of a de Korte, LCM Kremer, EC van Dalen and L Kapusta. Data analysis: R dedicated task force . Practical cut-off values were pro- Merkx, JM Leerink, EC de Baat and EAM Feijen. Data interpretation: all posed in adult cardio-oncology patients with an LVEF of 50– listed authors. Draft: R Merkx and L Kapusta. Critical revision and ap- proval: all listed authors. 59%, with − 16% as most specific cut-off for abnormal with- out losing sensitivity. Values between − 16 and − 18% Funding Dutch Heart Foundation grant CVON2015-21. constitute a ‘grey zone’, which can be acceptable in elderly subjects with hypertension but abnormal in Data availability All data relevant to the study are included in the article healthy young adults [6, 41]. These cut-off values are or uploaded as supplementary information. not yet validated in pediatric subjects. Declarations Strengths and limitations Ethics approval This is a literature review for which ethical approval is not applicable. Studies carried an unknown risk of selection bias and a sub- stantial risk of detection bias and reporting bias, the latter Consent to participate Informed consent was not applicable for this hampering detailed comparison of heterogeneous cohorts. literature review. Large within-study variation in important study characteristics always prevents pooling of results. We chose rather stringent Conflict of interest The authors declare no competing interests. inclusion criteria, as small studies would be underpowered to estimate prevalences . Prevalence estimation was not the Open Access This article is licensed under a Creative Commons primary goal of many potentially eligible studies. No multi- Attribution 4.0 International License, which permits use, sharing, adap- variable risk factor analysis exactly matched our inclusion tation, distribution and reproduction in any medium or format, as long as criteria, but all adequately adjusted for the most important you give appropriate credit to the original author(s) and the source, 1 3 J Cancer Surviv (2022) 16:338–352 351 provide a link to the Creative Commons licence, and indicate if changes 12. Laupacis A, Wells G, Richardson WS, Tugwell P. Users’ guides to were made. The images or other third party material in this article are the medical literature. V. How to use an article about prognosis. included in the article's Creative Commons licence, unless indicated oth- Evidence-Based Medicine Working Group. JAMA. 1994;272(3): erwise in a credit line to the material. If material is not included in the 234–7. article's Creative Commons licence and your intended use is not permitted 13. Slieker MG, Fackoury C, Slorach C, Hui W, Friedberg MK, Fan by statutory regulation or exceeds the permitted use, you will need to CPS, et al. Echocardiographic assessment of cardiac function in obtain permission directly from the copyright holder. To view a copy of pediatric survivors of anthracycline-treated childhood cancer. this licence, visit http://creativecommons.org/licenses/by/4.0/. Circulation: Cardiovascular Imaging. 2019;12(12):e008869. 14. Li VWY, Liu APY, Wong WHS, Ho KKH, Yau JPW, Cheuk DKL, et al. 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Journal of Cancer Survivorship – Springer Journals
Published: Apr 1, 2022
Keywords: Cardiotoxicity; Systolic dysfunction; Echocardiography; Anthracyclines; Childhood cancer survivors
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