Whole-process management of cardiotoxicity caused by anti-tumor chemotherapy: stratified screening, regular assessment and myocardial protection

Today, with the rapid development of immune checkpoint inhibitors and targeted drugs, chemotherapy is still one of the cornerstones of anti-tumor systemic therapy.
The continuous updating of chemotherapeutic drugs has significantly improved the survival rate and survival time of cancer patients.

However, this benefit is gradually offset by the cardiotoxicity of chemotherapy drugs.

Chemotherapy drugs represented by anthracyclines may cause progressive and irreversible cardiotoxicity, which may lead to heart failure, dilated cardiomyopathy, myocardial ischemia, coronary artery damage, etc.
, and even death [1-3].

Therefore, it is extremely important to prevent and monitor the cardiotoxicity during the course of anti-tumor chemotherapy in advance [1,3,4].

At the Shanghai Jiahui International Hospital's Oncology and Cardiology Academic Salon on April 25, 2021, many experts discussed the above topics from different angles.

This academic event was organized by Shanghai Jiahui International Hospital Heart Center, Jiahui International Cancer Center, Jiahui Medical Research and Education Group (J-Med), Chinese Society of Clinical Oncology (CSCO) Cancer Cardiology Expert Committee and Chinese Medical Association Heart Center Co-organized by the Oncology and Cardiology Group of the Branch of Vascular Diseases (CSC).

The experts participating in this academic salon on cancer and heart disease are the director of Jiahui International Cancer Center, Professor Andrew X.
Zhu of Harvard Medical School, Professor Wei Meng, director of the Heart Center of Jiahui International Hospital, and the deputy of the First Affiliated Hospital of Dalian Medical University.
Professor Xia Yunlong, Dean and Head of the CSC Oncology Cardiology Group of the Chinese Medical Association, Professor Liu Jiwei, Director of the Oncology Teaching and Research Office of the First Affiliated Hospital of Dalian Medical University, and Chairman of the CSCO Oncology and Cardiology Professional Committee.
Professor Liu Ying of the Vascular Disease Hospital and Director Fang Fengqi of the Oncology Department, Professor Jiang Jingwei of Jiahui International Cancer Center, and Director Shen Hong of the Department of Cardiology, Shanghai Jiao Tong University Sixth People’s Hospital.

We have summarized the highlights of this academic salon here, and we will regularly launch an academic salon on cardiotoxicity management related to anti-tumor targeted therapy, immunotherapy and radiotherapy in the future, so stay tuned.

Cardiotoxicity caused by common chemotherapy drugs.
According to the 2016 guidelines of the European Society of Cardiology (ESC), cardiovascular complications related to tumor treatment can be divided into: cardiac insufficiency and heart failure, coronary artery disease, valvular heart disease, and arrhythmia , Hypertension, thromboembolic disease, peripheral vascular disease, stroke, pulmonary hypertension and other cardiovascular complications.

Anthracycline Antibiotics Anthracyclines (including doxorubicin, epidoxorubicin, pirarubicin, daunorubicin and aclarithromycin, etc.
) cause cardiotoxicity, the main mechanism is iron-mediated reactive oxygen species The production of clusters (ROS) and the promotion of oxidative stress in the myocardium.

Ninety-eight percent of anthracycline cardiotoxicity occurred in the first year of medication, and the resulting 5-year cumulative adverse cardiac events (heart failure, heart failure hospitalization, death due to cardiac events) reached 11%, and the 10-year heart failure rate was as high as 38%; It is currently believed that the incidence is related to the cumulative dose of the drug.
When the cumulative dose reaches 400 mg/m2, the risk of heart failure is 5%; when the dose is increased to 700 mg/m2, the risk of heart failure increases to 25%.

; From the first dose, it can lead to death of myocardial cells and permanent myocardial damage.

The incidence of cardiotoxicity of alkylating agents (cyclophosphamide, ifosfamide) is 7% to 28%.

When the total dose of cyclophosphamide exceeds 1 mg/m2 in a course of treatment, only transient ECG changes and/or asymptomatic changes in enzymes can occur in patients with mild symptoms, and pericarditis and myocardial infarction can occur in patients with severe symptoms.

Heart failure often occurs within 3 weeks of administration and can lead to death.

Cardiotoxicity is related to the type of cancer.
Lymphoma is more likely to develop cardiotoxicity than breast cancer patients.

 Cardiotoxicity caused by fluorouracil is mainly manifested as myocardial ischemia.
The risk of occurrence is higher than that of intravenous bolus (7.
6% vs 2%) during continuous intravenous infusion, and occasionally angina and myocardial infarction.

The incidence of cardiotoxicity after treatment with microtubule inhibitors (taxanes) paclitaxel is about 5%, which can cause arrhythmia, mainly bradycardia, premature contraction, bundle branch block, etc.

These symptoms usually occur a few hours after the beginning, and when combined with cisplatin and anthracyclines, the cardiotoxicity is significantly increased.

Platinum animal experiments have shown that cisplatin can change the shape and function of mitochondria, and then cause cardiotoxicity characterized by cardiac insufficiency.
However, clinical trials have shown that cisplatin-based chemotherapy is not treated with anthracyclines at the same time.
Significant symptoms of systolic heart failure rarely occur.

Although central failure is not common in patients treated with cisplatin, it is still necessary to maintain a cautious attitude in clinical practice and further follow-up studies on long-term surviving patients.

Anti-tumor therapy cardiac risk assessment and full-process management baseline cardiac risk assessment In November 2020, the European Society of Cardiology (ESC) Oncology and Cardiology Committee and the American Heart Failure Society (HFSA) Oncology and Cardiology Research Group issued a position statement ——"Baseline Cardiovascular Risk Assessment of Cancer Patients Planning to Receive Cardiotoxic Cancer Treatment"[5].

The statement recommends that cardiovascular specialists in their clinical practice should first risk stratification of cancer patients before they receive anti-tumor treatments with heart failure or other severe cardiotoxicity (Figure 1).

 Figure 1.
The different risk factors that constitute baseline cardiac risk in cancer patients planning to receive cardiotoxic cancer treatment, as well as a list of baseline clinical history and related cardiac function assessments required before initiation of cardiotoxic cancer treatment.
January 2020, Europe The Society of Medical Oncology (ESMO) published a "ESMO Consensus on the Management of Cardiovascular Complications in Anti-tumor Therapy", which proposed the following pathways on how to monitor and manage the potential cardiotoxicity of anti-tumor treatments (Table 1, Figure 2) [6] : Pay attention to the high risk factors of cardiotoxicity.
Cardiotoxicity monitoring flow chart 2.
Anti-tumor therapy potential cardiotoxicity monitoring and management methods [6] View the protection and treatment of myocardial damage during the anti-tumor process according to "Cardiovascular complications in anti-tumor therapy" According to the recommendations of the Management ESMO Consensus (Table 2) [6], when a patient’s left ejection fraction (LVEF) and biomarker abnormalities are monitored, in addition to suspending chemotherapeutics that cause cardiotoxicity, it is necessary to consult a cardiologist and immediately activate the myocardium Protection treatment.

Table 2.
Recommendations for treatment of abnormal screening indicators for patients with myocardial insufficiency during anti-tumor treatment [6] Protection and treatment of myocardial damage Among the many cardiotoxic effects of anti-tumor chemotherapy drugs, the incidence of cardiac insufficiency is high and the prognosis is poor.
It is one of the most common and most vigilant symptoms in clinical practice. For cardiac insufficiency associated with cardiotoxicity of anthracyclines, prophylactic treatment with angiotensin-converting enzyme inhibitors (ACEI) and β-blockers can improve cardiac function.

Cardinale et al.
's study showed that in patients receiving anthracycline chemotherapy, the timely application of ACEI combined with β-blocker therapy after chemotherapy is a key variable for the improvement of cardiac function, and when anthracycline cardiotoxicity occurs, The key to the recovery of cardiac function is to promptly initiate standardized treatment of heart failure [7].

However, the aforementioned preventive medications or treatments cannot completely avoid the progression of anthracyclines' cardiotoxicity.

According to statistics, the incidence of chemotherapy-related cardiomyopathy is ≤10%, and about 2% to 4% of patients will progress to end-stage heart failure.

Studies have shown that patients with end-stage heart failure caused by chemotherapy can benefit from advanced device therapy (including cardiac resynchronization therapy, ventricular assist devices, and heart transplantation), and the benefits are similar to those of other causes of heart failure [7].

Interventions for anti-tumor chemotherapy-related cardiac insufficiency should not be limited to the standardized treatment of heart failure, and preventive measures should be actively taken to improve the prognosis.

 In order to avoid or reduce the occurrence of cardiac insufficiency caused by anthracyclines, if the anthracyclines exceed the recommended lifetime dose, doxorubicin liposome preparations can be used, but the high cost and risk of hand-foot syndrome limit Wide application of the preparation.

In addition, ACEI and β-blockers have a wide range of cardiovascular protective effects, especially in people with high accumulation of anthracyclines.

In the OVERCOME trial, anthracycline chemotherapy was applied to patients with acute leukemia.
After 6 months of follow-up, it was found that the cardiac function of patients with enalapril and carvedilol was relatively stable [7].

PRADA clinical trials have shown that candesartan has a protective effect on early heart insufficiency associated with breast cancer [7].

A recent meta-analysis also showed that β-blockers and ACEI have cardioprotective effects during chemotherapy with anthracyclines [7].

The strategy of multidisciplinary collaboration to reduce the cardiotoxicity of chemotherapy drugs led by anthracyclines, in addition to the aforementioned preventive management, such as optimal management of cardiovascular risk factors before treatment, baseline cardiovascular assessment, and strengthening of cardiac function monitoring during treatment, and timely activation For myocardial protection treatment, the importance and necessity of multidisciplinary cooperation such as oncologists, radiologists and cardiologists should also be emphasized.

The development prospect of oncology cardiology is an emerging cross-discipline.
Although the development of oncology cardiology has made great progress in recent years, experts at the conference pointed out that there are still many problems and challenges in this discipline, mainly as follows: 1.
Medical treatment at all levels Institutions have different understanding of tumor-related cardiotoxicity, and insufficient attention has been paid to pre-treatment screening and full-process evaluation.

2.
It is necessary to further explore the mechanism of cardiotoxicity in the process of anti-tumor therapy.

3.
It is necessary to optimize the process, frequency and item category of screening and regular evaluation of high-risk patients during the anti-tumor treatment process.

4.
Most of the randomized controlled clinical trials related to the treatment of cardiovascular diseases clearly excluded tumor patients at the time of enrollment.
As a result, there is a lack of strong evidence on the efficacy and safety of these drugs on the cardiotoxicity of tumor patients.
Further exploration of tumors is needed.
Medical treatment of patients with cardiovascular complications.

5.
In some medical institutions, especially cancer hospitals, there is insufficient support from a team of cardiovascular experts.
Therefore, it is imperative to build a medical unit or a multidisciplinary team to prevent and treat cardiotoxicity against tumors. References [1] Chinese Society of Clinical Oncology, Hematology Branch of Chinese Medical Association.
Guidelines for the Prevention and Treatment of Cardiotoxicity of Anthracyclines (2013 Edition).
Journal of Clinical Oncology.
2013;18:925-934.
[2] European Society of Cardiology ography and Cardiovascular Magnetic Resonance; American Society of Nuclear Cardiology.
Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Eur Heart J Cardiovasc Imaging 2013 ;14:721–740[3]Herrmann J, Lerman A, Sandhu N, et al.
Evaluation and management of patients with heart disease and cancer: cardio-oncology.
Mayo Clin Proc 2014;89:1287–1306[4]Curigliano G, Lenihan D, Fradley M, et al.
Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.
Ann Oncol,2020;31: 171-189.
[5]Alexander RL, Susan D, Susannah S,et al.
Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio- Oncology Society.
Eur J Heart Fail.
2020;22:1945-1960.
[6]Curigliano G, Lenihan D, Fradley M, et al.
Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.
Ann Oncol.
2020 ;31:171-190.
[7] Lin Hui, Zuo Song, Liu Nian, et al.
Clinical prevention and progress of chemotherapy-related cardiotoxicity.
Chinese Journal of Cardiovascular Diseases.
2017;45:1004.
Copyright information, this article is provided by Jiahui Translation, writing or commissioning of the "NEJM Frontiers in Medicine" jointly created by the Medical Research and Education Group (J-Med) and the New England Journal of Medicine (NEJM).
a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.
Eur J Heart Fail.
2020;22:1945-1960.
[ 6]Curigliano G, Lenihan D, Fradley M, et al.
Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.
Ann Oncol.
2020;31:171-190.
[7]Lin Hui, Zuo Song, Liu Nian, et al.
Clinical prevention and progress of chemotherapy-related cardiotoxicity.
Chinese Journal of Cardiovascular Diseases.
2017;45:1004.
Copyright information.
This article is sponsored by Jiahui Medical Research and Education Group (J-Med) and "New England Journal of Medicine.
" (NEJM) The "NEJM Medical Frontiers" jointly created by translation, writing or commissioning.
a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.
Eur J Heart Fail.
2020;22:1945-1960.
[ 6]Curigliano G, Lenihan D, Fradley M, et al.
Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.
Ann Oncol.
2020;31:171-190.
[7]Lin Hui, Zuo Song, Liu Nian, et al.
Clinical prevention and progress of chemotherapy-related cardiotoxicity.
Chinese Journal of Cardiovascular Diseases.
2017;45:1004.
Copyright information.
This article is sponsored by Jiahui Medical Research and Education Group (J-Med) and "New England Journal of Medicine.
" (NEJM) The "NEJM Medical Frontiers" jointly created by translation, writing or commissioning.
Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.
Ann Oncol.
2020;31:171-190.
[7]Lin Hui, Zuo Song, Liu Nian, et al.
Clinical prevention and progress of chemotherapy-related cardiotoxicity Chinese Journal of Cardiovascular Diseases.
2017;45:1004.
Copyright information.
This article was translated and written by "NEJM Frontiers in Medicine" jointly created by Jiahui Medical Research and Education Group (J-Med) and "New England Journal of Medicine" (NEJM) Or commissioned.
Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.
Ann Oncol.
2020;31:171-190.
[7]Lin Hui, Zuo Song, Liu Nian, et al.
Clinical prevention and progress of chemotherapy-related cardiotoxicity Chinese Journal of Cardiovascular Diseases.
2017;45:1004.
Copyright information.
This article was translated and written by "NEJM Frontiers in Medicine" jointly created by Jiahui Medical Research and Education Group (J-Med) and "New England Journal of Medicine" (NEJM) Or commissioned. The Chinese translation of the full text and the included diagrams are exclusively authorized by the NEJM Group.

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