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Open Access 20-11-2023 | Chemotherapy | Cardiac

Long-term cardiotoxicity in germ cell cancer survivors after platinum-based chemotherapy: cardiac MR shows impaired systolic function and tissue alterations

Authors: Antonia Beitzen-Heineke, Christina Charlotte Rolling, Christoph Seidel, Jennifer Erley, Isabel Molwitz, Kai Muellerleile, Dennis Saering, Juliana Senftinger, Niklas Börschel, Nils Wolfgang Engel, Carsten Bokemeyer, Gerhard Adam, Enver Tahir, Hang Chen

Published in: European Radiology

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Abstract

Objectives

Long-term toxicities of germ cell cancer (GCC) treatment are of particular importance in young men with a life expectancy of several decades after curative treatment. This study aimed to investigate the long-term effects of platinum-based chemotherapy on cardiac function and myocardial tissue in GCC survivors by cardiac magnetic resonance (CMR) imaging.

Methods

Asymptomatic GCC survivors ≥ 3 years after platinum-based chemotherapy and age-matched healthy controls underwent CMR assessment, including left ventricular (LV) and right ventricular (RV) ejection fraction (EF), strain analysis, late gadolinium enhancement (LGE) imaging, and T1/T2 mapping.

Results

Forty-four survivors (age 44 [interquartile range, IQR 37–52] years; follow-up time 10 [IQR 5–15] years after chemotherapy) and 21 controls were evaluated. LV- and RVEF were lower in GCC survivors compared to controls (LVEF 56 ± 5% vs. 59 ± 5%, p = 0.017; RVEF 50 ± 7% vs. 55 ± 7%, p = 0.008). Seven percent (3/44) of survivors showed reduced LVEF (< 50%), and 41% (18/44) showed borderline LVEF (50–54%). The strain analysis revealed significantly reduced deformation compared to controls (LV global longitudinal strain [GLS] -13 ± 2% vs. -15 ± 1%, p < 0.001; RV GLS -15 ± 4% vs. -19 ± 4%, p = 0.005). Tissue characterization revealed focal myocardial fibrosis in 9 survivors (20%) and lower myocardial native T1 times in survivors compared to controls (1202 ± 25 ms vs. 1226 ± 37 ms, p = 0.016). Attenuated LVEF was observed after two cycles of platinum-based chemotherapy (54 ± 5% vs. 62 ± 5%, p < 0.001).

Conclusion

Based on CMR evaluation, combination chemotherapy with cumulative cisplatin ≥ 200 mg/m2 is associated with attenuated biventricular systolic function and myocardial tissue alterations in asymptomatic long-term GCC survivors.

Clinical relevance statement

Platinum-based chemotherapy is associated with decreased systolic function, non-ischemic focal myocardial scar, and decreased T1 times in asymptomatic long-term germ cell cancer survivors. Clinicians should be particularly aware of the risk of cardiac toxicity after platinum-based chemotherapy.

Key Points

Platinum-based chemotherapy is associated with attenuation of biventricular systolic function, lower myocardial T1 relaxation times, and non-ischemic late gadolinium enhancement.
Decreased systolic function and non-ischemic late gadolinium enhancement are associated with a cumulative cisplatin dose of  ≥ 200 mg/m2.
Cardiac MRI can help to identify chemotherapy-associated changes in cardiac function and tissue in asymptomatic long-term germ cell cancer survivors.

Graphical Abstract

Appendix
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Literature
1.
go back to reference Hanna N, Einhorn LH (2014) Testicular cancer: a reflection on 50 years of discovery. J Clin Oncol 32:3085–3092 CrossRefPubMed Hanna N, Einhorn LH (2014) Testicular cancer: a reflection on 50 years of discovery. J Clin Oncol 32:3085–3092 CrossRefPubMed
2.
go back to reference Beyer J, Collette L, Sauvé N et al (2021) Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium. J Clin Oncol 39:1553–1562 CrossRefPubMedPubMedCentral Beyer J, Collette L, Sauvé N et al (2021) Survival and new prognosticators in metastatic seminoma: results from the IGCCCG-update consortium. J Clin Oncol 39:1553–1562 CrossRefPubMedPubMedCentral
3.
go back to reference Gillessen S, Sauvé N, Collette L et al (2021) Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium. J Clin Oncol 39:1563–1574 CrossRefPubMedPubMedCentral Gillessen S, Sauvé N, Collette L et al (2021) Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium. J Clin Oncol 39:1563–1574 CrossRefPubMedPubMedCentral
4.
go back to reference Chovanec M, Lauritsen J, Bandak M et al (2021) Late adverse effects and quality of life in survivors of testicular germ cell tumour. Nat Rev Urol 18:227–245 CrossRefPubMed Chovanec M, Lauritsen J, Bandak M et al (2021) Late adverse effects and quality of life in survivors of testicular germ cell tumour. Nat Rev Urol 18:227–245 CrossRefPubMed
5.
go back to reference Belt-Dusebout AWvd, Nuver J, Wit Rd et al (2006) Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24:467–475 CrossRefPubMed Belt-Dusebout AWvd, Nuver J, Wit Rd et al (2006) Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24:467–475 CrossRefPubMed
6.
go back to reference Haugnes HS, Wethal T, Aass N et al (2010) Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 28:4649–4657 CrossRefPubMed Haugnes HS, Wethal T, Aass N et al (2010) Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 28:4649–4657 CrossRefPubMed
7.
go back to reference Huddart RA, Norman A, Shahidi M et al (2003) Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513–1523 CrossRefPubMed Huddart RA, Norman A, Shahidi M et al (2003) Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513–1523 CrossRefPubMed
8.
go back to reference Lauritsen J, Hansen MK, Bandak M et al (2020) Cardiovascular risk factors and disease after male germ cell cancer. J Clin Oncol 38:584–592 CrossRefPubMed Lauritsen J, Hansen MK, Bandak M et al (2020) Cardiovascular risk factors and disease after male germ cell cancer. J Clin Oncol 38:584–592 CrossRefPubMed
9.
go back to reference Bjerring AW, Fosså SD, Haugnes HS et al (2021) The cardiac impact of cisplatin-based chemotherapy in survivors of testicular cancer: a 30-year follow-up. Eur Heart J Cardiovasc Imaging 22:443–450 CrossRefPubMed Bjerring AW, Fosså SD, Haugnes HS et al (2021) The cardiac impact of cisplatin-based chemotherapy in survivors of testicular cancer: a 30-year follow-up. Eur Heart J Cardiovasc Imaging 22:443–450 CrossRefPubMed
10.
go back to reference Altena R, Hummel YM, Nuver J et al (2011) Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer. Ann Oncol 22:2286–2293 CrossRefPubMed Altena R, Hummel YM, Nuver J et al (2011) Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer. Ann Oncol 22:2286–2293 CrossRefPubMed
11.
go back to reference Nuver J, Smit AJ, Sleijfer DT et al (2005) Left ventricular and cardiac autonomic function in survivors of testicular cancer. Eur J Clin Invest 35:99–103 CrossRefPubMed Nuver J, Smit AJ, Sleijfer DT et al (2005) Left ventricular and cardiac autonomic function in survivors of testicular cancer. Eur J Clin Invest 35:99–103 CrossRefPubMed
12.
go back to reference Altena R, de Haas EC, Nuver J et al (2009) Evaluation of sub-acute changes in cardiac function after cisplatin-based combination chemotherapy for testicular cancer. Br J Cancer 100:1861–1866 CrossRefPubMedPubMedCentral Altena R, de Haas EC, Nuver J et al (2009) Evaluation of sub-acute changes in cardiac function after cisplatin-based combination chemotherapy for testicular cancer. Br J Cancer 100:1861–1866 CrossRefPubMedPubMedCentral
13.
go back to reference van Schinkel LD, Willemse PM, van der Meer RW et al (2013) Chemotherapy for testicular cancer induces acute alterations in diastolic heart function. Br J Cancer 109:891–896 CrossRefPubMedPubMedCentral van Schinkel LD, Willemse PM, van der Meer RW et al (2013) Chemotherapy for testicular cancer induces acute alterations in diastolic heart function. Br J Cancer 109:891–896 CrossRefPubMedPubMedCentral
14.
go back to reference Negishi K, Negishi T, Haluska BA, Hare JL, Plana JC, Marwick TH (2014) Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection. Eur Heart J Cardiovasc Imaging 15:324–331 CrossRefPubMed Negishi K, Negishi T, Haluska BA, Hare JL, Plana JC, Marwick TH (2014) Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection. Eur Heart J Cardiovasc Imaging 15:324–331 CrossRefPubMed
15.
go back to reference Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH (2014) Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 63:2751–2768 CrossRefPubMed Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH (2014) Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 63:2751–2768 CrossRefPubMed
18.
go back to reference Narayan HK, French B, Khan AM et al (2016) Noninvasive measures of ventricular-arterial coupling and circumferential strain predict cancer therapeutics-related cardiac dysfunction. JACC Cardiovasc Imaging 9:1131–1141 CrossRefPubMedPubMedCentral Narayan HK, French B, Khan AM et al (2016) Noninvasive measures of ventricular-arterial coupling and circumferential strain predict cancer therapeutics-related cardiac dysfunction. JACC Cardiovasc Imaging 9:1131–1141 CrossRefPubMedPubMedCentral
19.
go back to reference Jeong D, Gladish G, Chitiboi T, Fradley MG, Gage KL, Schiebler ML (2019) MRI in cardio-oncology: a review of cardiac complications in oncologic care. J Magn Reson Imaging 50:1349–1366 CrossRefPubMed Jeong D, Gladish G, Chitiboi T, Fradley MG, Gage KL, Schiebler ML (2019) MRI in cardio-oncology: a review of cardiac complications in oncologic care. J Magn Reson Imaging 50:1349–1366 CrossRefPubMed
20.
go back to reference Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200 CrossRefPubMed Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200 CrossRefPubMed
21.
go back to reference Tahir E, Azar M, Shihada S et al (2022) Myocardial injury detected by T1 and T2 mapping on CMR predicts subsequent cancer therapy-related cardiac dysfunction in patients with breast cancer treated by epirubicin-based chemotherapy or left-sided RT. Eur Radiol 32:1853–1865 CrossRefPubMed Tahir E, Azar M, Shihada S et al (2022) Myocardial injury detected by T1 and T2 mapping on CMR predicts subsequent cancer therapy-related cardiac dysfunction in patients with breast cancer treated by epirubicin-based chemotherapy or left-sided RT. Eur Radiol 32:1853–1865 CrossRefPubMed
22.
go back to reference Schulz-Menger J, Bluemke DA, Bremerich J et al (2013) Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson 15:35 CrossRefPubMedPubMedCentral Schulz-Menger J, Bluemke DA, Bremerich J et al (2013) Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson 15:35 CrossRefPubMedPubMedCentral
23.
go back to reference Kellman P, Wilson JR, Xue H, Ugander M, Arai AE (2012) Extracellular volume fraction mapping in the myocardium, part 1: evaluation of an automated method. J Cardiovasc Magn Reson 14:63 CrossRefPubMedPubMedCentral Kellman P, Wilson JR, Xue H, Ugander M, Arai AE (2012) Extracellular volume fraction mapping in the myocardium, part 1: evaluation of an automated method. J Cardiovasc Magn Reson 14:63 CrossRefPubMedPubMedCentral
24.
go back to reference Morais P, Marchi A, Bogaert JA et al (2017) Cardiovascular magnetic resonance myocardial feature tracking using a non-rigid, elastic image registration algorithm: assessment of variability in a real-life clinical setting. J Cardiovasc Magn Reson 19:24 CrossRefPubMedPubMedCentral Morais P, Marchi A, Bogaert JA et al (2017) Cardiovascular magnetic resonance myocardial feature tracking using a non-rigid, elastic image registration algorithm: assessment of variability in a real-life clinical setting. J Cardiovasc Magn Reson 19:24 CrossRefPubMedPubMedCentral
25.
go back to reference Ma H, Jones KR, Guo R, Xu P, Shen Y, Ren J (2010) Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. Clin Exp Pharmacol Physiol 37:460–465 CrossRefPubMed Ma H, Jones KR, Guo R, Xu P, Shen Y, Ren J (2010) Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. Clin Exp Pharmacol Physiol 37:460–465 CrossRefPubMed
26.
go back to reference Hellesnes R, Myklebust TÅ, Fosså SD et al (2021) Testicular cancer in the cisplatin era: causes of death and mortality rates in a population-based cohort. J Clin Oncol 39:3561–3573 CrossRefPubMed Hellesnes R, Myklebust TÅ, Fosså SD et al (2021) Testicular cancer in the cisplatin era: causes of death and mortality rates in a population-based cohort. J Clin Oncol 39:3561–3573 CrossRefPubMed
27.
go back to reference Heidenreich PA, Bozkurt B, Aguilar D et al (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e876–e894 PubMed Heidenreich PA, Bozkurt B, Aguilar D et al (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e876–e894 PubMed
28.
go back to reference Modi K, Joppa S, Chen KA et al (2021) Myocardial damage assessed by late gadolinium enhancement on cardiovascular magnetic resonance imaging in cancer patients treated with anthracyclines and/or trastuzumab. Eur Heart J Cardiovasc Imaging 22:427–434 CrossRefPubMed Modi K, Joppa S, Chen KA et al (2021) Myocardial damage assessed by late gadolinium enhancement on cardiovascular magnetic resonance imaging in cancer patients treated with anthracyclines and/or trastuzumab. Eur Heart J Cardiovasc Imaging 22:427–434 CrossRefPubMed
29.
go back to reference Domenech-Ximenos B, Sanz-de la Garza M, Prat-González S et al (2020) Prevalence and pattern of cardiovascular magnetic resonance late gadolinium enhancement in highly trained endurance athletes. J Cardiovasc Magn Reson 22:62 CrossRefPubMedPubMedCentral Domenech-Ximenos B, Sanz-de la Garza M, Prat-González S et al (2020) Prevalence and pattern of cardiovascular magnetic resonance late gadolinium enhancement in highly trained endurance athletes. J Cardiovasc Magn Reson 22:62 CrossRefPubMedPubMedCentral
31.
go back to reference LotaAmrit S, Tsao A, Owen R et al (2021) Prognostic significance of nonischemic myocardial fibrosis in patients with normal LV volumes and ejection-fraction. JACC Cardiovasc Imaging 14:2353–2365 CrossRef LotaAmrit S, Tsao A, Owen R et al (2021) Prognostic significance of nonischemic myocardial fibrosis in patients with normal LV volumes and ejection-fraction. JACC Cardiovasc Imaging 14:2353–2365 CrossRef
32.
go back to reference Muehlberg F, Funk S, Zange L et al (2018) Native myocardial T1 time can predict development of subsequent anthracycline-induced cardiomyopathy. ESC Heart Fail 5:620–629 CrossRefPubMedPubMedCentral Muehlberg F, Funk S, Zange L et al (2018) Native myocardial T1 time can predict development of subsequent anthracycline-induced cardiomyopathy. ESC Heart Fail 5:620–629 CrossRefPubMedPubMedCentral
Metadata
Title
Long-term cardiotoxicity in germ cell cancer survivors after platinum-based chemotherapy: cardiac MR shows impaired systolic function and tissue alterations
Authors
Antonia Beitzen-Heineke
Christina Charlotte Rolling
Christoph Seidel
Jennifer Erley
Isabel Molwitz
Kai Muellerleile
Dennis Saering
Juliana Senftinger
Niklas Börschel
Nils Wolfgang Engel
Carsten Bokemeyer
Gerhard Adam
Enver Tahir
Hang Chen
Publication date
20-11-2023
Publisher
Springer Berlin Heidelberg
Published in
European Radiology
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-023-10420-w