Chemotherapy induced right ventricular cardiomyopathy; a systematic review and meta-analysis

Background Left ventricular dysfunction and cardiomyopathy are well documented adverse effects associated with chemotherapy agents. Limited information exists regarding the impact of chemotherapeutic agents on the integrity and function of the right ventricle (RV). Objectives The current metanalysis compared pre- chemotherapy versus post- chemotherapy RV parameters measured on 2D echocardiography in patients receiving anthracycline and/or trastuzumab across all breast cancer patients. Methods A systematic search across PubMed, EMBASE and Cochrane databases were performed from inception of the databases until November 2021 for relevant studies. We used the inverse variance method with a random effect model and DerSimonian and Laird method of Tau2 generation to calculate mean difference [MD] with 95% confidence interval [CI]. The analysis was carried out using RevMan Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Results Fifteen studies, constituting total of 644 patients, met the inclusion criteria, with most studies having a follow up period of less than 12 months from initiation of chemotherapy. Anthracycline and/or Trastuzumab chemotherapy resulted in a statistically significant reduction in right ventricular ejection fraction (RVEF) at follow-up [MD: 2.70, 95% CI: 0.27 to 5.13, P-value- 0.03, I2- 71%, χ2 P-value < 0.05]. Treatment with Anthracycline and/or Trastuzumab chemotherapy resulted in a significant reduction in RV fractional area change (RVFAC) at follow-up [MD: 3.74, 95% CI: 1.33 to 6.15, P-value < 0.01, I2- 68%, χ2 P-value < 0.05]. RV free wall longitudinal strain (RVFWLS) was lower at baseline, while LVEF was significantly reduced at follow-up [MD: -1.00, 95% CI: -1.86 to -0.15, P-value < 0.05, I2- 0%, χ2 P-value-0.40], [MD: 4.04, 95% CI: 2.08 to 6.01, P-value < 0.01, I2- 91%, χ2 P-value < 0.05], respectively. However, treatment with Anthracycline and/or Trastuzumab chemotherapy had no statistically significant effect on Tricuspid annular plane systolic excursion (TAPSE) at follow-up [MD: 0.53, 95% CI: -0.11 to 1.17, P-value-0.11, I2- 98%, χ2 P-value < 0.05]. Conclusions Chemotherapy with anthracyclines and trastuzumab negatively affects right ventricular function leading to decline in RVEF, RVFAC, RVFWLS and LVEF.

[1]  Arjun K. Ghosh,et al.  BSE and BCOS Guideline for Transthoracic Echocardiographic Assessment of Adult Cancer Patients Receiving Anthracyclines and/or Trastuzumab , 2021, JACC. CardioOncology.

[2]  N. Chattipakorn,et al.  Effects of doxorubicin on the heart: From molecular mechanisms to intervention strategies. , 2019, European journal of pharmacology.

[3]  P. Nihoyannopoulos,et al.  Longitudinal changes of right ventricular deformation mechanics during trastuzumab therapy in breast cancer patients , 2019, European journal of heart failure.

[4]  Gabriel A. Hernandez,et al.  Cancer Therapy-Related Cardiac Dysfunction: An Overview for the Clinician , 2019, Clinical Medicine Insights. Cardiology.

[5]  S. Cha,et al.  Two-dimensional speckle tracking echocardiography predicts early subclinical cardiotoxicity associated with anthracycline-trastuzumab chemotherapy in patients with breast cancer , 2018, BMC Cancer.

[6]  J. Coviello Cardiovascular and Cancer Risk: The Role of Cardio-oncology , 2018, Journal of the advanced practitioner in oncology.

[7]  W. Hundley,et al.  Cardio-oncology: an evolving hybrid subspecialty. , 2018, Future cardiology.

[8]  T. Powell-Wiley,et al.  Methodological Standards for Meta-Analyses and Qualitative Systematic Reviews of Cardiac Prevention and Treatment Studies: A Scientific Statement From the American Heart Association. , 2017, Circulation.

[9]  D. Hering,et al.  The influence of chemotherapy on the right ventricle: did we forget something? , 2017, Clinical cardiology.

[10]  Kelvin K. W. Chan,et al.  Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study , 2017, Journal of Cardiovascular Magnetic Resonance.

[11]  D. Rodríguez-Sanz,et al.  Footwear used by older people and a history of hyperkeratotic lesions on the foot , 2017, Medicine.

[12]  G. Lip,et al.  2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines:  The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). , 2016, European heart journal.

[13]  F. Mokarian,et al.  Alterations in the echocardiographic variables of the right ventricle in asymptomatic patients with breast cancer during anthracycline chemotherapy , 2016, Postgraduate Medical Journal.

[14]  Jhi-Joung Wang,et al.  The Early Predictive Value of Right Ventricular Strain in Epirubicin-Induced Cardiotoxicity in Patients with Breast Cancer. , 2016, Acta Cardiologica Sinica.

[15]  M. Turek,et al.  Right heart function deteriorates in breast cancer patients undergoing anthracycline-based chemotherapy , 2016, Echo research and practice.

[16]  T. Naqvi,et al.  Temporal Trends of Cardiac Chambers Function with Trastuzumab in Human Epidermal Growth Factor Receptor II–Positive Breast Cancer Patients , 2016, Echocardiography.

[17]  M. Iacoviello,et al.  Right Ventricular Longitudinal Strain Measures Independently Predict Chronic Heart Failure Mortality , 2016, Echocardiography.

[18]  W. Finch,et al.  Radiation Toxicity to the Cardiovascular System , 2016, Current Oncology Reports.

[19]  Christian Haarmark,et al.  Pre-chemotherapy values for left and right ventricular volumes and ejection fraction by gated tomographic radionuclide angiography using a cadmium-zinc-telluride detector gamma camera , 2016, Journal of Nuclear Cardiology.

[20]  B. Popescu,et al.  Right ventricular remodeling, its correlates, and its clinical impact in hypertrophic cardiomyopathy. , 2015, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[21]  H. Rakowski,et al.  Right Ventricular Dysfunction in Patients Experiencing Cardiotoxicity during Breast Cancer Therapy , 2015, Journal of oncology.

[22]  M. Cerqueira,et al.  Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. , 2014, European heart journal cardiovascular Imaging.

[23]  Scott D Flamm,et al.  Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. , 2014, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[24]  M. Capogrossi,et al.  Doxorubicin and trastuzumab regimen induces biventricular failure in mice. , 2014, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[25]  H. Dursun,et al.  Echocardiographic signs of right ventricle changes after Trastuzumab treatment in breast cancer patients with erb-2 overexpression , 2014, Anatolian journal of cardiology.

[26]  R. Starling,et al.  Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support). , 2014, Journal of the American College of Cardiology.

[27]  D. Leong,et al.  Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: a prospective study using novel cardiac imaging and biochemical markers. , 2013, International journal of cardiology.

[28]  A. Praestgaard,et al.  Right Ventricular Structure Is Associated With the Risk of Heart Failure and Cardiovascular Death: The Multi-Ethnic Study of Atherosclerosis (MESA)-Right Ventricle Study , 2012, Circulation.

[29]  A. Praestgaard,et al.  Surface Electrocardiogram Criteria For Right Ventricular Hypertrophy: The Multi-Ethnic Study Of Atherosclerosis (MESA): Right Ventricle Study , 2012, ATS 2012.

[30]  Jens Jung,et al.  Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy , 2012, Clinical Research in Cardiology.

[31]  U. Demirci,et al.  Assessment of right ventricular functions during cancer chemotherapy. , 2011, European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

[32]  F. Sam,et al.  Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer. , 2010, Oxidative medicine and cellular longevity.

[33]  M. Fiuza Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer , 2009, Advances in therapy.

[34]  J. Ioannidis,et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration , 2009, BMJ : British Medical Journal.

[35]  M. Somerfield,et al.  American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  V. Valero,et al.  Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  S. Lippman,et al.  Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  I. Hozo,et al.  Estimating the mean and variance from the median, range, and the size of a sample , 2005, BMC medical research methodology.

[39]  R. Benjamin,et al.  A mathematical model for doxorubicin cardiotoxicity: Added evidence for the concept of sequential stress , 2004 .

[40]  E. Perez,et al.  Clinical cardiac tolerability of trastuzumab. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[42]  D. Keefe,et al.  Trastuzumab‐associated cardiotoxicity , 2002, Cancer.

[43]  D J Pennell,et al.  Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? , 2000, European heart journal.

[44]  R H Hruban,et al.  Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. , 2000, The New England journal of medicine.

[45]  P. Singal,et al.  Doxorubicin-induced cardiomyopathy. , 1998, The New England journal of medicine.

[46]  Y. Cottin,et al.  Diastolic or systolic left and right ventricular impairment at moderate doses of anthracycline? , 1996, European Journal of Nuclear Medicine.

[47]  G A Diamond,et al.  Correspondence of left ventricular ejection fraction determinations from two-dimensional echocardiography, radionuclide angiography and contrast cineangiography. , 1995, Journal of the American College of Cardiology.

[48]  J. Mason,et al.  Invasive and noninvasive methods of assessing adriamycin cardiotoxic effects in man: superiority of histopathologic assessment using endomyocardial biopsy. , 1978, Cancer treatment reports.

[49]  T. Kasai,et al.  Cardiac magnetic resonance imaging-based myocardial strain study for evaluation of cardiotoxicity in breast cancer patients treated with trastuzumab: A pilot study to evaluate the feasibility of the method. , 2016, Cardiology journal.

[50]  S. Solomon,et al.  GUIDELINES AND STANDARDS , 2010 .

[51]  J. Melin,et al.  Assessment of left ventricular diastolic function in patients receiving anthracycline therapy , 2007, European Journal of Nuclear Medicine.

[52]  P. Dombernowsky,et al.  Prospective evaluation of chronic cardiotoxicity due to high-dose epirubicin or combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil , 2004, Cancer Chemotherapy and Pharmacology.

[53]  R. Benjamin,et al.  A mathematical model for doxorubicin cardiotoxicity: Added evidence for the concept of sequential stress. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  D. Karnofsky,et al.  Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia , 1967, Cancer.

[55]  Douglas G. Altman,et al.  Explanation and Elaboration , 2022 .

[56]  P. Freedson,et al.  Scientific Statement From the American Heart Association Guide to the Assessment of Physical Activity: Clinical and Research Applications: A , 2015 .