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The Cancer Treatment and Cardiovascular Toxicity 2016 position paper reviews the different steps in cardiovascular monitoring and decision-making before, during and after anticancer treatment with potential cardiovascular side-effects. Read this highlight by Riccardo Asteggiano, FESC and Victor Aboyans, FESC
The 2016 ESC Position Paper on Cancer Treatment and Cardiovascular Toxicity was published during ESC Congress 2016. This is one of the first attempts inside the ESC to have a summary of indication about the management of the possible cardiovascular effects of chemotherapy (CT) and radiotherapy (RT) in patients with an oncologic pathology.
The possible CVDs that cancer therapy, CT and/or RT, may develop could be grouped into:
More than one pathology may develop and often one may complicate the evolution of another condition. Every single side effect has to be evaluated and fully treated to obtain the best outcome and avoid progression.
Patients developing myocardial dysfunction generally have CVD risk factors and their strict control has to be warranted as first essential issue to avoid any CT or RT side effects.
The Position Paper analyses in detail the drug effects and their management issues. Generally speaking the CT toxicity may be a Type I toxicity that leads to cell necrosis and as a consequence to permanent cardiac damage or may be a Type II toxicity due to a cell dysfunction that generally may evolve into reversible cardiac damage.
Another crucial concept is that of the possible potentiation of toxic effects by un-correct timing of association of type I and II drugs and/or of RT. This issue should be well kept in mind due to the shifting from the concept of years ago to use concentrated high doses of CT in advanced stages of cancer to the concept of a modulated CT with combinations of different agents (type I and II), at lower doses and with prolonged administration.
During therapy with anthracycline some factors associated with risk of cardiotoxicity and of myocardial dysfunction have been well recognized. They are: cumulative dose, female sex, age >65 years or paediatric population (<18 years), renal failure, concomitant or previous radiation therapy involving the heart, concomitant CT with alkylating or anti-microtubule agents and immuno- and targeted therapies, pre-existing conditions like cardiac diseases associated with increased wall stress, arterial hypertension, genetic factors.
To detect and avoid a ventricular dysfunction a precise LVEF assessment before and periodically during CT has to be warranted. The easiest tool is Echocardiography but also other tests may be used (Nuclear cardiac imaging, Cardiac Magnetic Resonance, Cardiac Biomarkers). It is recommended to use the same imaging method with a good quality during all the follow-up management of the same patients to avoid inter-test variability.
In patients with normal ejection fraction (LVEF), a reassessment of LVEF should be done every 4 CT cycles. An ejection fraction (LVEF) under the limit of <50% and a reduction of LVEF > 10% but not under the lower limits is considered expression of toxicity and requires repeated short term assessment during and shortly after CT. A reduction of LVEF > 10% under the lower limit requires ACE-Is (or ARBs) + Beta-Blockers therapy to prevent further LV dysfunction and ACE-Is (or ARBs) + Beta-Blockers are recommended in symptomatic HF or asymptomatic LV dysfunction.
The assessment of CAD based on age, gender, history and eventually diagnostic tests of ischaemia is essential before the beginning of cancer therapy, considering CT as a risk factor for CAD.
Clinic evaluation and diagnostic tests for ischemia detection are indicated to diagnose pre-existing significant CAD and guide the choice of CT drugs potentially eliciting spasm or coronary thrombosis. Pyrimidine analogues are the most dangerous drugs and require close monitoring for ischemia with regular ECGs during administration. Stop of CT is required if ischemia occurs and a drug re-challenge may be considered if no alternatives are possible, eventually with a pre-treatment with TNG and/or Channel blockers.
Long term F-U and ischemia tests are useful for detection of CAD after CT and mainly after RT, also many years after the end of the therapy.
Valvular heart disease(VHD) may be observed in patients with cancer for several reasons.
Radiation-induced VHD has been reported as common, affecting 10% of treated patients, and includes fibrosis and calcification of the aortic root, aortic valve cusps, mitral valve annulus and the base and mid portions of the mitral valve leaflets.
For the diagnostic and therapeutic management Echocardiography is the assessment method of choice, and 3D echocardiography may be particularly useful.
Cardiac surgery is also frequently challenging because of mediastinal fibrosis, impaired wound healing and associated coronary artery, myocardial and pericardial disease. Transcatheter valve implant may be a suitable option in this situation.
A basal 12 leads ECG and QTc are required in all patients at baseline before CT and RT.
Repeated periodical ECGs should be done in patients with history of LQT, organic heart disease, other QT prolonging drugs, bradycardia, thyroid dysfunction and electrolytes abnormalities. Treatment should be discontinued or alternative treatment should be sought if QTc becomes> 500 msec or increases> 60 msec or if arrhythmias develop.
Recommended is careful assessment and avoidance of conditions potentially inducing torsades de pointes, mainly hypokalaemia and extreme bradycardia. It is also mandatory to minimize exposition to other QTc prolonging drugs during CT with potential at-risk drugs.
Every patient should receive careful monitoring of blood pressure before and during CT.
The management of Hypertension should be done according to current GLs. An early and aggressive antihypertensive treatment to prevent is required to avoid CV complications. ACE-Is /ARBs, beta-blockers, dihydropyridine calcium channel blockers should be preferred. Due to possible drug interactions non-dihydropyridine channel blockers should be avoided.
If blood pressure (BP) is not controlled the hypotensive therapy should be reinforced and VEGF inhibitors should be reduced or discontinued. Once BP is controlled VEGF may be re-challenged.
Many clinical factors are associated with an increased risk of cancer-associated venous thromboembolism. Cancer-related factors are: 1) Primary site of cancer (mostly pancreas, brain, stomach, kidney, lung, lymphoma, myeloma), 2) Histology (specially adenocarcinoma), 3) Advanced stage (metastatic), 4) Initial period after cancer diagnosis.
The Patient-related factors are: 1) Demographics: older age, female sex, African ethnicity, 2) Comorbidities (infection, chronic kidney disease, pulmonary disease, atherothrombotic disease, obesity), 3) History of venous thromboembolism, inherited thrombophilia, 4) Low performance status.
Treatment-related factors are: 1) Major surgery, 2) Hospitalization, 3) Type of CT and anti-angiogenic agents, 4) Hormonal therapy, 5) Transfusions, 6) Central venous catheters.
In patients hospitalized for cancer the use of thrombo-prophylaxis is considered, although a recent meta-analysis failed to find evidence of any global benefit or risk of the prevention. LMWH could induce thrombocytopenia that does not occur with VKI.
Severe atherosclerotic and non-atherosclerotic peripheral artery disease (PAD) in the lower extremities can occur in up to 30% in patients treated with nilotinib, ponatinib or BCR-ABL TKIs used for chronic myeloid leukaemia, even in the absence of CVD riskfactors. PAD can occur in the first months of therapy or after several years.
Other toxic effects include Raynaud’s phenomenon and ischaemic stroke. The risk of stroke is increased—at least doubled—after mediastinal, cervical or cranial radiotherapy.
Similar consequences are reported for the aorta and other peripheral arteries, including the subclavian and iliofemoral, with ischaemic limb symptoms.
Acute pericarditis may occur with the use of several CT drugs (predominantly anthracyclines), while it has become uncommon during RT and is usually associated with pericardiac mediastinal tumours.
Acute pericarditis with typical chest pain, fever, ST-T changes and large effusions, even leading to tamponade, may develop 2 – 145 months after thoracic radiotherapy, with an absolute cumulative incidence of 2–5%. Echocardiography is the method of choice for the evaluation of patient, but CT scan can be of help, particularly to identify calcification.
Treatment of pericardial effusion consists primarily of non-steroidal anti-inflammatory drugs and colchicine. Pericardiocentesis may be required for large effusions.
Delayed pericardial disease may develop 6 months to 15 years after radiation treatment.
Pleural effusion Pleural effusion related to the cancer itself, HF, infections or other causes is common in patients with cancer.
Some cancer drugs (e.g. dasatinib and imatinib) may induce fluid retention or a reversible pleural effusion through additional unknown mechanisms.
Radiotherapy damage to the cardiac nervous system may lead to sympathetic–vagal imbalance characterized by inappropriate sinus tachycardia, altered heart rate variability and decreased sensitivity. This may lead to a higher pain threshold or silent ischaemia in cancer survivors with manifest CAD.
Pulmonary hypertension is a rare but serious complication of some cancer agents and stem cell bone marrow transplantation. Dasatinib can induce severe precapillary pulmonary hypertension. Unlike other forms of PAH, this is often reversible after drug discontinuation or replacement with another TKI, such as nilotinib. Recently, cyclophosphamide and other alkylating agents were suggested as contributing to the development of pulmonary veno-occlusive disease, the most severe form of pulmonary hypertension lacking effective pharmacological treatment.
Baseline echocardiographic assessment, including the search for signs of right ventricular overload, should be considered in individuals requiring treatment with cancer drugs that can cause pulmonary hypertension (e.g. dasatinib). Patients with echocardiographic signs suggesting increased baseline pulmonary arterial pressure require cardiology assessment to determine its aetiology, as it may affect the strategy of cancer treatment, particularly when due to LV dysfunction or chronic thromboembolic pulmonary hypertension.
A steadily growing number of childhood cancer survivors have to face lifelong side effects of cancer therapies, some of them affecting the cardiovascular system, with an eight-fold increased risk for severe CVD.
Anthracyclines and radiotherapy are the most commonly implicated cardiotoxic agents in childhood cancer. Compared with a control group, the risk for any CVD varied considerably, with an almost 20-fold increase in young patients compared with merely 1.3 for survivors at 60 years of age due to a sharp increase in the incidence of common CVD.
A lifelong follow-up for survivors of childhood cancer treated with either high-dose anthracyclines, RT to the chest or both is recommended.
Elderly patients treated with cancer therapy are the second subpopulation most commonly affected by cardiotoxicity, due largely to the common prevalence of classic CVD risk factors and co-morbidities. A history of HF, cardiac dysfunction, arterial hypertension, diabetes or CAD all make the cardiovascular system more vulnerable to the additional burden of CT or RT.
There is very little evidence regarding maternal risk of cardiotoxicity. It can be expected that cardiotoxicity can be influenced by pharmacokinetic and pharmacodynamic changes occurring during pregnancy.
Little data is available from the literature, however, a strategy of monitoring, including clinical cardiac assessment and echocardiographic functional evaluation before starting CT and re-evaluation before every dose should be considered.
A long-term case observation does not show significant long-term cardiotoxic effects in children born from mothers treated with cancer therapy during pregnancy.
It is imperative to raise awareness of possible cardiac disease among cancer survivors as well as to provide appropriate follow-up of such patients in clinical practice.
Patients should be informed of their increased risk of CVD at the outset of their CT / RT and should be advised and supported to make appropriate lifestyle modifications.
They should also be instructed to promptly report early signs and symptoms of CVD.
Even in asymptomatic patients, LV dysfunction and HF can potentially occur. Periodic screening with cardiac imaging and biomarkers, such as BNP, should be considered in survivors, particularly those treated with high cumulative doses or who demonstrated reversible LV dysfunction during cancer treatment.
Any symptom suggestive of HF should be investigated.
Early discontinuation of cardioprotective HF therapy is not recommended and it should be continued indefinitely unless normal systolic LV function remains stable and no further cancer therapy is planned.
Evaluation for CAD, ischaemia and vascular disease is recommended in patients with a history of mediastinal radiation, even if asymptomatic, starting 5 years post-treatment and then at least every 5 years thereafter.
Due to risk of stroke in patients with previous neck irradiation, ultrasound scanning of carotid arteries is indicated to rule out the presence of subclinical atherosclerosis.
Radiation-induced VHD incidence is increasing and occurs late after mediastinal radiotherapy. A minority of patients have completely normal functioning aortic valves at the 20-year follow-up. At the time of VHD diagnosis, the diagnosis of cancer or history of radiation therapy is often not mentioned in the patients’ current medical records.
For asymptomatic patients, the EACVI/ASE recommends a screening echocardiogram at 10 years post-radiation and serial exams every 5 years thereafter.
Riccardo Asteggiano MD FESC – Chairperson of the Council of Cardiology Practice – Chief Out of Hospital Cardiology Service – ASL To 3, Turin Italy
Victor Aboyans, MD, PhD, FESC, FAHA - Professor, Head of Dept. of Cardiology - Dupuytren University Hospital, Limoges, France
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