Right ventricular function among adult survivors of childhood cancer

doi:10.21203/rs.3.rs-8463341/v1

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Right ventricular function among adult survivors of childhood cancer

https://doi.org/10.21203/rs.3.rs-8463341/v1

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Background: Cardiotoxic effects of childhood cancer treatment on the right ventricle (RV) are sparsely studied among long-term childhood cancer survivors (CCS).

Objectives: We investigated RV function and risk factors for impaired function.

Methods: We invited CCS ≥18 years of age, diagnosed between ages 0–20 years, treated in one of five pediatric oncology centers across Switzerland from 1976–2017, who survived ≥5 years, for an echocardiographic assessment of the RV including tricuspid annular plane systolic excursion (TAPSE, abnormal <17mm) and Doppler tissue imaging (DTI, abnormal <9.5cm/s).

Results: We included 432 CCS with median age at study of 34 years (interquartile range 26–40). Overall prevalence of RV dysfunction was 4% for both methods (mean TAPSE 22.5±3.8mm; mean DTI 13.1±2.2cm/s). Risk factors for decreased RV function were cumulative heart-relevant radiotherapy (RT) dose [Beta coefficient (B)=-0.46;95%CI -0.73– -0.20]; hematopoietic stem cell transplantation (B=-1.88;95%CI -3.35– -0.40); cisplatin (B=-1.29;95%CI -2.38– -0.19); diabetes mellitus (B=-2.57;95%CI -4.99– -0.15); and abdominal obesity (B=-0.79;95%CI -1.58–0.00) when measured by TAPSE. For DTI, we identified cumulative heart-relevant RT dose (B=-0.19; 95%CI -0.37– -0.01); relapse (B=-0.94;95%CI -1.74– -0.15); and abdominal obesity (B=-0.80;95%CI -1.37– -0.24) as risk factors. Cumulative anthracycline dose was not associated with impaired RV function measured by TAPSE (B=-0.23;95%CI -0.49–0.03) or DTI (B=-0.06;95%CI -0.25–0.13).

Conclusions: RV dysfunction is rare in young adult CCS. The risk is increased after heart-relevant RT and by obesity. Given the prognostic value of RV dysfunction for all-cause mortality, we suggest including RV echocardiography to the routine follow-up care of CCS.

Preventive Medicine

Cardiac & Cardiovascular Systems

Oncology

Pediatrics

right ventricular function

childhood cancer survivors

echocardiography

cardiotoxicity

anthracyclines

radiotherapy

Cardiotoxic effects of cancer treatment on the right ventricle have been sparsely studied among long-term survivors of cancer during childhood.¹ While the impact of cardiotoxic treatment on the left ventricle (LV) is well established,²^,³ right ventricle (RV) function has received less attention because it often has been regarded as less important than that of the LV.⁴ The complex anatomy of the RV also poses challenges for transthoracic echocardiography.⁵ Yet RV function, assessed by tricuspid annular plane systolic excursion (TAPSE) and doppler tissue imaging (DTI),⁵ is an important prognostic marker for adverse cardiovascular outcomes in patients with hypertrophic cardiomyopathy, pulmonary hypertension, and asymptomatic aortic stenosis.^6-8 RV dysfunction is a stronger predictor of all-cause mortality and cardiac death than LV dysfunction.⁹

Established cardiotoxic treatments include anthracyclines, mitoxantrone, and heart-relevant radiotherapy (RT).¹⁰ Alkylating agents, vincristine, hematopoietic stem cell transplantation (HSCT), targeted therapies, and immunotherapies also have been suspected of cardiotoxicity in pediatric and adult cancer survivors.^11-15 In addition, modifiable cardiovascular risk factors (such as hypertension, obesity, or diabetes) play an important role and potentiate cardiac dysfunction in CCS.¹⁶

Yet in spite of what we know about cardiotoxicity, only two echocardiographic studies to date have investigated RV function in adult recipients of potentially cardiotoxic treatment for cancer as children. A study showed impaired RV function in 246 long-term survivors of pediatric lymphoma and acute lymphoblastic leukemia (ALL) exposed to cardiotoxic treatments, while RV function was preserved in those not treated with anthracyclines and/or heart-relevant RT.¹⁷ However, neither cumulative treatment exposure nor other risk factors such as modifiable cardiovascular risk factors were investigated. In a smaller study of 90 pediatric ALL survivors, HSCT, obesity, and smoking were associated with reduced RV function.¹⁸ Yet, because all participants had received anthracyclines and only 3% heart-relevant RT, treatment-related factors could not be evaluated.

We therefore 1) evaluated RV function in a large cohort of adult childhood cancer survivors (CCS), and 2) identified treatment-related and modifiable cardiovascular risk factors for impaired RV function.

Study Design and Population

The CardioOnco study investigates cardiovascular health in adult CCS in Switzerland as part of routine follow-up care.¹⁹ CardioOnco was initiated in 2016 as a single-center, cross-sectional study at the University Hospital Inselspital in Bern. In 2021, CadioOnco was extended to a multicenter, longitudinal study including the University Hospitals of Basel and Geneva, and the Cantonal Hospitals in Lucerne and St. Gallen. We invited CCS registered in the Swiss Childhood Cancer Registry (ChCR) who were treated in one of the five centers with any chemotherapy and/or heart-relevant RT, were ≥18-years old, had survived ≥5 years since childhood cancer diagnosis, and were living in Switzerland to a cardio-oncology outpatient clinic at one of the centers. Since 1976, the ChCR has included all persons in Switzerland diagnosed before the age of 20 with any cancer including Langerhans cell histiocytosis. Diagnoses are coded according to the International Classification of Childhood Cancer Third Edition (ICCC-3).²⁰^,²¹ We excluded survivors in the ChCR who were treated only with surgery and/or RT that was not heart-relevant RT with potential for impact upon the heart.

The CardioOnco centers invited eligible survivors by postal mail to visit their cardio-oncology clinic for echocardiography, medical history, and a physical examination. We obtained written informed consent from all participants, and our study was aligned with the principles of the Declaration of Helsinki. Ethical approval was granted by the Ethics Committee of Canton Bern (KEK-BE: 2017-01612).

Explanatory variables

Demographic characteristics, cancer history and treatment

The ChCR provided data on sex, current age, treatment hospital, cancer diagnosis, age at diagnosis, time since diagnosis, relapse history, and whether survivors had received chemotherapy, radiotherapy, or underwent HSCT or intrathoracic surgery. We validated this information with medical records. We asked survivors during clinical visits about second primary malignancies, which we also validated with medical records. We collected information on established cardiotoxic treatments including anthracyclines, mitoxantrone, and heart-relevant RT, and suspected but not established cardiotoxic treatments²²^,²³ that included cyclophosphamide, ifosfamide, cisplatin, vincristine, and steroids. We calculated the doxorubicin isotoxic equivalent dose of daunorubicin, idarubicin, epirubicin, and mitoxantrone according to Children’s Oncology Group (COG) guidelines.¹⁰ We defined heart-relevant RT as RT to the chest, abdomen, spine (thoracic or whole), and total body irradiation.¹⁰ We calculated cyclophosphamide equivalent dose for cyclophosphamide and ifosfamide according to COG guidelines¹⁰, and prednisone equivalent for prednisone and dexamethasone according to Inaba et al.²⁴ We categorized participants into four subgroups based on cardiotoxic exposure: anthracyclines alone (including mitoxantrone), heart-relevant RT alone, anthracyclines (including mitoxantrone) and heart-relevant RT, and no established cardiotoxic therapy.

Self-reported cardiovascular risk factors

During a standardized interview, a trained study nurse asked participants about their cardiovascular risk factors, which included diabetes mellitus, dyslipidemia, history of smoking, hypertension, and medication use.

Outpatient clinic data

A study nurse performed anthropometric measurements to obtain survivor body mass index (BMI) and waist-hip ratio. We measured hip circumference at the widest circumference over the buttocks and waist circumference at the midpoint between the lower margin of the lowest rib and the top of the iliac crest while participants stood with both feet tight together.¹⁹ We applied the World Health Organization cut-off points to classify BMI as underweight (<18.5kg/m2), normal weight (18.5–24.9kg/m2), overweight (25.0–29.9kg/m2), and obesity (≥ 30kg/m2)²⁵; we also classified abdominal obesity (waist-to-hip ratio of ≥0.90 in men and ≥0.85 in women).²⁶ A nurse also measured blood pressure according to guidelines and recorded the average of the last two blood pressure readings.²⁷ Hypertension was defined as a mean systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg and/or if survivors were taking antihypertensive medications.²⁷

Outcome variables

Experienced cardiologists at participating study centers, who were blinded with respect to participant cancer treatment, performed the echocardiography using Vivid E9, E90, E95, or S70 scanner from GE (Horten, Norway), or EPIQ CVx, 7C, or 7 scanners from Philips (Bothell, USA) following the latest guidelines for standard practice.²⁸ For this study, we analyzed TAPSE and DTI. As suggested by Lang et al., we defined RV systolic dysfunction as TAPSE values <17 mm or DTI <9.5 cm/s.²⁹

Statistical Analysis

First, we tested normality in the distribution of TAPSE and DTI measurements. Both distributions were normal.³⁰ For TAPSE, the skewness was 0.23 and kurtosis 3.31, and for DTI, the skewness was 0.48 and kurtosis 3.80. We compared TAPSE and DTI values between exposure groups using Student’s t-test and analysis of variance. We calculated the prevalence of RV systolic dysfunction dichotomized as TAPSE <17 mm and DTI <9.5 cm/soverall and stratified by cardiotoxic exposure group, comparing groups with a chi-squared test. We fitted univariable linear regression models to study associations between explanatory variables and lower TAPSE or DTI measurements. We assessed factors associated with the two outcomes using two multivariable linear regression models—one for TAPSE and one for DTI. We included variables known from literature to be associated with systolic function—sex, age at study, cumulative anthracycline dose, and heart-relevant RT dose³^,³¹—and those associated with a change in RV function in unadjusted analyses at p <0.1 (see Supplemental Tables 1 and 2). To avoid overfitting of the multivariable analysis, we performed a backward selection of variables from the univariable models using corrected Akaike’s information criterion.³² All p-values are two-sided; we considered p <0.05 as statistically significant. If information on self-reported cardiovascular risk factors was missing, we assumed the condition was absent, as done previously.³³ We performed all analyses using Stata software, version 16.1 (StataCorp, College Station, TX).

Characteristics of study population

Between January 2017 and June 2023, we invited 1293 eligible CCS to the CardioOnco study (Supplemental Figure 1). We performed TAPSE and/or DTI measurement in 432 CCS (33%)—TAPSE in 413 (32%) and DTI in 306 (24%). Median age of participants was 6 years (IQR 3–12) at cancer diagnosis and 34 years [interquartile range (IQR) 26–40] at study (Table 1). Most frequent cancer diagnoses were leukemia (38%) and lymphoma (21%). Fifty-four (13%) participants had experienced a relapse of their malignancy. Of all participants, 299 (69%) had received anthracyclines and/or mitoxantrone, 122 (28%) heart-relevant RT, and 101 (23%) had been treated without anthracyclines (including mitoxantrone) or heart-relevant RT. Thirty-two (7%) participants had undergone autologous or allogeneic HSCT. Abdominal obesity was present in 141 (32%) CCS, 90 participants (21%) had hypertension.

RV echocardiographic findings

Mean TAPSE in our cohort was 22.5 mm [standard deviation (SD) ± 3.8 mm], 22.8 mm (SD ± 3.8 mm) after exposure to anthracyclines alone, 20.6 mm (SD ± 3.7 mm) after heart-relevant RT alone, 21.5 mm (SD ± 3.5 mm) after anthracyclines and heart-relevant RT, and 23.6 mm (SD ± 3.6 mm) in those without exposure to established cardiotoxic therapy. Difference in mean TAPSE values among the cardiotoxic exposure groups was statistically significant using analysis of variance (p < 0.001). Using Student’s t-test, mean TAPSE after heart-relevant RT only, and after combination of anthracyclines and heart-relevant RT was significantly lower than in those without exposure to established cardiotoxic therapy.

In the overall cohort, mean DTI was 13.1 cm/s (SD ± 2.2 cm/s); 13.3 cm/s (SD ± 2.2 cm/s) in survivors treated with anthracyclines only, 12.6 cm/s (SD ± 2.4 cm/s) after heart-relevant RT only, 12.4 cm/s (SD ± 2.2 cm/s) after anthracyclines and heart-relevant RT exposure, and 13.4 cm/s (SD ± 2.1 cm/s) in those with no established cardiotoxic therapy. Difference in mean DTI values among the cardiotoxic exposure groups was statistically significant using analysis of variance (p = 0.027). Using Student’s t-test, mean DTI after combination of anthracyclines and heart-relevant RT was significantly lower than in those without exposure to established cardiotoxic therapy.

Prevalence of RV dysfunction

Using TAPSE, the overall prevalence of RV dysfunction was 4% [95% confidence interval (CI) 2.0%–5.7%] (Table 2). Abnormal TAPSE was most common in CCS who had received heart-relevant RT only (13%; 95% CI 1.0%–23.6%), followed by CCS treated with anthracyclines combined with heart-relevant RT (6%; 95% CI 0.9%–10.6%).

Using DTI, the overall prevalence of RV dysfunction was also 4% (95% CI 1.7%–6.1%). We saw a similar pattern for abnormal DTI as for TAPSE, with 9% (95% CI 0%–21.1%) in CCS who had received only heart-relevant RT, and 7% (95% CI 1.1%–13.4%) in CCS who had received anthracyclines combined with heart-relevant RT. A subset of 6 participants (2%; 95% CI 0.4%–3.7%) was identified as having RV dysfunction by both TAPSE and DTI.

Risk factors for RV dysfunction

Factors associated with impaired TAPSE measurement in multivariable linear regression were cumulative heart-relevant RT dose [unstandardized coefficient (B) = -0.46; 95% CI -0.73– -0.20]; HSCT (B = -1.88; 95% CI -3.35– -0.40); cisplatin (B = -1.29; 95% CI -2.38– -0.19); diabetes mellitus (B = -2.57; 95% CI -4.99– -0.15); and abdominal obesity (B = -0.79; 95% CI -1.58–0.00; Table 3). Factors associated with DTI measurement were cumulative heart-relevant RT dose (B = -0.19; 95% CI -0.37– -0.01); relapse (B = -0.94; 95% CI -1.74– -0.15); and abdominal obesity (B = -0.80; 95% CI -1.37– -0.24; Table 4). Cumulative anthracycline dose was not associated with impaired RV function measured by TAPSE (B = -0.23; 95%CI -0.49–0.03) or DTI (B = -0.06; 95%CI -0.25–0.13). Apart from cisplatin, we found no association between other potentially cardiotoxic agents and a lower TAPSE or DTI. Unadjusted results are shown in Supplemental Tables 1 and 2.

The overall prevalence of RV dysfunction in 432 long-term survivors of childhood cancer was low, at 4%, but it increased to 13% among those treated with heart-relevant RT. Risk factors for RV dysfunction included both treatment-related and lifestyle factors: cumulative heart-relevant RT, HSCT, cisplatin, diabetes mellitus, and abdominal obesity by TAPSE; and cumulative heart-relevant RT, relapse, and abdominal obesity by DTI (Central Illustration).

Comparison of RV function between exposure groups

Our findings on RV function in cardiotoxic exposure groups are similar to what was found in previous studies. Christiansen et al., including 246 adult survivors of childhood lymphoma or ALL with a mean age of 31 years, showed that mean TAPSE after heart-relevant RT (19.2 mm; SD ± 4.9 mm) or a combination of heart-relevant RT with anthracyclines (21.3 mm; SD ± 3.1 mm) was lower compared to survivors not exposed to established cardiotoxic treatment (23.6 mm; SD ± 3.3 mm).¹⁷ CCS treated with anthracyclines alone did not have a lower TAPSE compared to CCS with “no cardiotoxic treatment”—a finding in line with our study. The mean TAPSE measurements within the cardiotoxic exposure groups reported by Christiansen et al. are comparable to ours. For DTI, we found that CCS treated with heart-relevant RT and anthracyclines had a significantly decreased RV function compared to those without cardiotoxic treatment whereas Christiansen et al. found no significant difference.¹⁷ When comparing our results with Heredia et al., we see similar TAPSE (22.8; SD ± 3.8mm versus 23.3; SD ± 4.0mm) and DTI (13.3; SD ± 2.2mm versus 13.8; SD ± 2.4mm) measurements in the group with only anthracycline exposure, as in this study all 90 adult survivors of childhood ALL were treated with anthracyclines (and only 3% additionally exposed to heart-relevant RT).¹⁸

RV dysfunction prevalence

Prevalence of RV dysfunction as a dichotomous outcome in our cohort is comparable to previous studies. Heredia et al. found, that 4.4% of survivors had RV dysfunction by TAPSE, and between 2.2–4.4% by DTI, using same cut-off values as in our study.¹⁸^,²⁹ However, participants were younger (mean age 24.6; SD ± 9.7years) than in our study (median age 34 years, IQR 26‒40), therefore RV function might further decrease while survivors age. Christiansen et al. defined the cut-off for abnormal RV function as mean value of their control group –1.96 SD, thus <20 mm for TAPSE (<17 mm in our study) and < 9.4 cm/s for DTI (<9.5cm/s in our study).¹⁷ Using these cut-off values, they reported a RV dysfunction prevalence of 22% by TAPSE and 8% by DTI.¹⁷ When applying their cut-off values to our data, prevalence of RV dysfunction in our cohort was 23% by TAPSE and 4% by DTI, i.e. comparable to their findings.

Risk factors

We found several risk factors for impaired RV function. Cumulative heart-relevant RT was associated with impaired RV function, which is consistent with the literature and plausibly linked to the RV’s anterior location and proximity to the radiation field,³⁴^,³⁵ leading to pericardial disease, restrictive cardiomyopathy, valvular abnormalities, premature coronary disease, and arrhythmias.²² HSCT and relapse, both intensive treatments with multiple toxicities, were also predictive of RV dysfunction in our study and another.¹⁸ The association of cisplatin with impaired RV function may relate to its vascular toxicity.²² Though rarely reported and needing further study, impaired RV function was observed in adult survivors of malignant ovarian germ cell tumors treated with high-dose cisplatin.³⁶ Decreased RV ejection fraction evaluated by MRI, and a reduced RV deformation by RV global longitudinal strain was observed in long-term germ cell cancer survivors treated with cisplatin-based chemotherapy.³⁷ The association of diabetes mellitus with RV and LV dysfunction is well known and explained by pathologic remodeling of the heart as a result of diabetes mellitus.^38-40 The negative effect of obesity on RV function has been observed in long-term survivors of childhood ALL¹⁸ and others.⁴¹^,⁴² Notably, cumulative anthracycline dose was not associated with RV impairment in our study, in contrast to its established role in LV cardiotoxicity. Differences across echocardiographic measures may explain this finding, as previous studies have shown declines in other RV measures, but not TAPSE, after anthracycline therapy.⁴³

Implications for Practice

Current guidelines for cardiomyopathy surveillance in CCS recommend only echocardiography of the LV.¹⁰^,⁴⁴ Yet RV dysfunction was shown to be more common in CCS than in healthy controls (22% vs. 1% using TAPSE and 8% vs. 1% using DTI).¹⁷ Given the fact that RV systolic dysfunction has a stronger prognostic value for all-cause mortality than LV ejection fraction in other patients,⁹ we consider RV echocardiographic assessment to be an important component of routine follow-up care in CCS after cardiotoxic therapy. If echocardiography is not feasible, cardiac magnetic resonance might be reasonable instead.⁴⁴

Study limitations

As is the case in other long-term cohorts, so too in our group of CCS there is a risk of survival bias. The CardioOnco study excludes CCS treated with only surgery, thus are survivors of low-grade CNS tumors, retinoblastomas, or germ cell tumors without systemic treatment possibly underrepresented. However, neither intrathoracic surgery nor curative surgery elsewhere in the body has been associated with alteration of RV function. We also did not include free-wall strain measurement. However, this is a method with very limited use in current clinical practice.⁵ Even though the echocardiographic findings were not independently reviewed, all echocardiography adhered to standard measurement practices. Finally, because of the observational design of our investigation we could not compare the prevalence of RV dysfunction with that of a healthy control group. We cannot formally link causality with the identified risk factors.

Using echocardiography, we identified adult survivors of childhood cancer at increased risk of RV dysfunction—particularly those treated with heart-relevant RT, HSCT, and cisplatin, as well as survivors with relapses and those with diabetes mellitus or obesity. Given the prognostic significance of RV systolic dysfunction, we suggest that assessment of RV function be incorporated into routine echocardiographic follow-up care of adult CCS.

Perspectives

Competency in Medical Knowledge

TAPSE and DTI are widely used techniques of echocardiography for the assessment of RV function. We suggest performing a comprehensive echocardiogram including TAPSE and DTI in all CCS who received heart-relevant RT alone or in combination with anthracyclines.

Translational Outlook

Future studies should investigate the effect of anthracyclines and the effect of other potentially cardiotoxic substances (e.g., cisplatin) on RV function. The different sensitivities of echocardiographic techniques used to examine RV dysfunction among CCS with different history of cardiotoxic exposure also need to be better understood to inform standardization of methodological choices for this examination.

CCS – childhood cancer survivors

ChCR – Childhood Cancer Registry

DTI – Doppler tissue imaging

HSCT – hematopoietic stem cell transplantation

IQR – interquartile range

LV – left ventricle / left ventricular

RT – radiotherapy

RV – right ventricle / right ventricular

SD – standard deviation

TAPSE – tricuspid annular plane systolic excursion

Disclosures: Authors have no relevant financial or non-financial interests to disclose.

Funding: We received funding for our study from the Swiss Cancer Research foundation (KFS-5027-02-2020 and KFS-6096-02-2024, Bern, Switzerland), Stiftung für krebskranke Kinder‒Regio Basiliensis (Basel, Switzerland), University of Basel Research Fund for Excellent Junior Researchers (Basel, Switzerland), Kinderkrebshilfe Schweiz (Olten, Switzerland), and Kinderkrebs Schweiz (Basel, Switzerland).

Acknowledgements: We thank all survivors for participating in our study, the study team of the Childhood Cancer Research Group, the data managers of the Swiss Pediatric Oncology Group, and the team of the Swiss Childhood Cancer Registry. We thank Christopher Ritter for his editorial work on our manuscript.

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Tables 1 to 4 are available in the supplementary files section

The authors declare no competing interests.

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Right ventricular function among adult survivors of childhood cancer

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Abstract

Figures

INTRODUCTION

METHODS

Study Design and Population

Explanatory variables

Outcome variables

Statistical Analysis

RESULTS

Characteristics of study population

RV echocardiographic findings

Prevalence of RV dysfunction

Risk factors for RV dysfunction

DISCUSSION

Comparison of RV function between exposure groups

RV dysfunction prevalence

Risk factors

Implications for Practice

Study limitations

CONCLUSIONS

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

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