Clinical Review: Cardiac oncology

Contributed by Dr Daniel Ford, consultant in clinical oncology at the University Hospital Birmingham NHS Foundation Trust and Dr Raj Thakkar, a GP in Wooburn Green, Buckinghamshire, and a former hospital practitioner in echocardiography at Stoke Mandeville Hospital, South Buckinghamshire NHS Trust.

Figure 1. Dilated cardiomyopathy may complicate treatment (Photographs by author)
Figure 1. Dilated cardiomyopathy may complicate treatment (Photographs by author)

Section: 1 Primary tumours
Cancer therapy can have major implications for the cardiovascular system and monitoring is essential. Individual follow-up plans are required, depending on the risk of cardiotoxicity.

General considerations when managing patients with malignancy include anaemia causing breathlessness and high output cardiac failure. Cardiac arrhythmia, pericardial disease, caval obstruction, endocarditis, cardiomyopathy (figure 1) and thromboembolic disease are other causes of breathlessness, which may all complicate malignancy or its treatment.

Atrial myxoma
Figure 2. Atrial myxoma is benign but can be life-threatening

Figure 2. Atrial myxoma is benign but can be life-threatening

Primary tumours of the heart are rare and the incidence varies widely depending on the literature. Atrial myxomas are responsible for up to 75 per cent of these tumours (figure 2). Twice as many women as men develop myxomas, particularly between the ages of 30 and 60. Carney's syndrome is a combination of heart, skin or breast myxomas, cutaneous nodules and endocrine abnormalities.

Atrial myxomas are benign, but can be life-threatening. Three-quarters of cases occur in the left atrium.

In the main, the mobile mass is attached by a pedicle to the fossa ovalis. During diastole, the mass moves forward, prolapsing through the mitral valve orifice and creating a mid-diastolic murmur and 'tumour plop', which may sound like an opening snap. The opening snap of mitral stenosis tends to occur earlier in diastole.

Obstruction of blood flow caused by a large tumour may result in breathlessness or collapse. Emboli from the tumour may occur and the condition may present with stroke. Haemolysis has been documented.

Fever is also a feature of myxoma and endocarditis of a diseased mitral valve is an important differential. The ESR tends to be markedly raised. Echocardiography is required to confirm the diagnosis. Treatment is by surgical removal.

Angiosarcoma
A quarter of all primary cardiac tumours are malignant, with the most common being angiosarcomas.1 Men are affected more than women and the peak incidence is at 20-50 years. Most cases occur in the right atrium.

Clinical features are variable and largely depend on focus of disease and constitutional symptoms. Breathlessness, syncope, superior vena cava obstruction (SVCO), arrhythmias, haemoptysis, fever and weight-loss are all presenting signs.

These tumours are invasive and tend to bleed, so pericardial involvement, including haemopericardium and tamponade, are present. Angiosarcomas tend to be aggressive - most patients have metastatic disease at diagnosis - and survival is poor. Most patients will die within nine months. MRI has superseded CT scanning as the imaging modality of choice. Treatment options vary and include radiotherapy, chemotherapy and surgery.

Section 2: Cardiac complications of other malignancies
All malignancies, particularly when advanced, can affect the cardiac system. Metastatic spread to the pericardium and cardiac tissue can result in morbidity, including pericarditis, effusions and dysrhythmias. Certain malignancies are more likely to affect the cardiovascular system than others.

Carcinoid
Patients with carcinoid syndrome endure chronic intermittent flushing, diarrhoea and wheeze. Eating, ethanol, exertion and excitement can all trigger flushing episodes. Primary disease often occurs in the gut, although ovarian and pulmonary carcinoid tumours may also occur.

The liver usually metabolises 5-HT secreted from neoplastic enterochromaffin cells. Hepatic metastases allow systemic exposure to 5-HT. Right-sided cardiac involvement occurs in about half of these patients, manifesting as endocardial fibrosis. Disease may also affect the vena cava and coronary sinus. Pericarditis has been documented. Pulmonary and tricuspid valves may be stenotic or regurgitant.

In the rare case of bronchial carcinoid, left-sided cardiac lesions are seen. On examination, flushing and wheeze may be present, and checks should be made for telangiectasia, hepatomegaly and valvular disease. Clinical suspicion of carcinoid warrants a 24-hour urine collection for 5-HIAA.

Treatment may require steroids, fluid management, octreotide, interferon-alpha or chemotherapy. Surgery can be used for localised disease.

Lung cancer complications
Cancers affecting the lung can cause a number of cardiac complications, some due to the anatomical proximity, although paraneoplastic effects can also occur.

Pericarditis, AF, SVCO, non-bacterial endocarditis, thrombophlebitis and venous thromboembolism are all seen. Pericarditis and associated effusion may lead to tamponade, and it is essential to carry out a cardiac examination in the unwell cancer patient. The combination of tachycardia, hypotension, pulsus paradoxus and quiet heart sounds is suggestive.

Echocardiography is used to confirm diagnosis because it is more sensitive than chest X-ray, which can only detect effusions of more than 250ml. Diastolic collapse of the right heart free wall is seen early in the disease.

Pericardiocentesis is required to relieve pressure within the pericardial sac. Pericardial involvement may be seen in other malignancies, particularly the latter stages of the condition.

The most common cause of SVCO is carcinoma of the lung. Lymphoma, aneurysms, goitre and mediastinal fibrosis are other causes. It may present with headache, breathlessness, collapse and facial oedema.

Examination reveals dilated veins in the upper body and a plethoric face. SVCO should be referred immediately to secondary care. Once diagnosed, usually by CT, treatment includes diuretics, radiotherapy, chemotherapy or stents.

Electrolyte disturbance stemming from hypercalcaemia and endocrine paraneoplastic syndromes may influence cardiac myocyte function and cause arrhythmias.

Myeloma
Myeloma is responsible for several cardiovascular complications. Anaemia can cause heart failure, hypercalcaemia may lead to electrical disturbance and renal failure causes hyperkalaemia and uraemic pericarditis. AL-type amyloid, a feature of myeloma, can infiltrate sub-endocardial and conduction tissue. Diastolic dysfunction occurs because amyloid stiffens the myocardium. Arrhythmias may also be a feature.

Section 3: Radiotherapy and chemotherapy
Radiotherapy and chemotherapy can cause cardiovascular toxicity. Clinical cases are relatively unusual, however.

The possible toxicity of any treatment should be weighed against the potential benefits and it should be calculated on an individual basis. Remember that although a small number of patients may develop long-term problems from treatment, without it, they may not have survived the initial malignancy.

At-risk groups
The three main groups of patients at risk of cardiac toxicity from radiotherapy are those treated for primary lung cancers, breast malignancies and Hodgkin's lymphoma, because the radiation field will often include part of the heart.

Long-term follow-up of Hodgkin's lymphoma patients shows an increase in cardiac mortality compared with the general population, although other factors besides radiotherapy may also play a part.2

A large meta-analysis of lung cancer patients has shown an increase in mortality for those who received radiotherapy.3 Although the cause was not specified, cardiac toxicity was thought to be a likely significant contributing factor.

Data regarding breast cancer patients are more complete, owing to larger numbers of patients who survive for long-term follow-up.

A meta-analysis of 19,582 patients in 40 randomised trials showed an increased survival in those treated with radiotherapy compared with those who were not, but in the absence of any breast cancer deaths, this trend was reversed.4 The increase in non-breast cancer mortality rates was primarily due to an increase in vascular deaths, although non-vascular deaths were also higher.

The major drawback of these data is that they relate to patients who received radiotherapy up to and in excess of 20 years ago. Modern radio- therapy techniques have changed for all three tumour sites, in terms of volumes treated (reduced) and radiotherapy equipment used (now linear accelerators, as opposed to cobalt machines).

These changes have resulted in a reduction of the total radiation dosage to the heart and vasculature. There is general agreement that cardiac morbidity is related to the volume irradiated and the dosage received.

In keeping with these data, modern treatment techniques gives a conflicting view with regard to the impact of radiotherapy on late cardiovascular morbidity and mortality.5

Anthracyclines
A number of different chemotherapeutic agents can cause cardiovascular toxicity over the short and long term.6 The most established class of drug associated with cardiotoxicity is the anthracycline group.

Late anthracycline cardiotoxicity is cumulative and dose-related and can result in LVF and congestive heart failure. Patients are therefore not usually given cumulative doses of anthracyclines above a threshold level.

Administering anthracyclines in the form of a continuous, as opposed to a rapid, infusion also reduces toxicity, as may newer liposomal forms of these drugs. Cardioprotective drugs, such as dexrazoxane, can be used, although they are generally reserved for patients receiving high cumulative doses.

The antimetabolite 5-fluorouracil (5-FU) is associated with acute ischaemia. This is more likely in those with known IHD and can result in acute MI. Usually, the ischaemia is reversed on cessation of treatment. Rechallenging the patient often causes a recurrence of symptoms and signs, resulting in the curtailing of treatment.

Other agents
The oral antimetabolite capecitabine is often used in place of 5-FU and is thought to have fewer acute cardiotoxic effects. Documented toxicity, however, includes cardiac ischaemia, arrhythmias, ECG changes and cardiomyopathy.

Alkylating agents, such as cisplatin, are used in a wide range of tumour types and can cause both acute palpitations and ischaemia, as well as long-term cardiovascular complications, such as left ventricular hypertrophy and ischaemia.

Cyclophosphamide can cause cardiac toxicity, particularly at high doses in preparation for bone marrow transplantation. Toxicity includes ischaemia and congestive cardiac failure.

Other chemotherapy agents, including the commonly used agents paclitaxel and ifosfamide, have been associated with acute cardiac toxicity, such as arrhythmias and ischaemia, and long-term effects, such as congestive cardiac failure.

Non-cytotoxic drugs can also have an effect on the cardiovascular system, particularly those used in the treatment of breast cancer.

Tamoxifen has been well documented to increase the risk of venous thrombosis in patients and the new aromatase inhibitors, such as anastrozole, have been associated with acute coronary syndrome and dyslipidaemia.

Section 4: Newer agents and patient monitoring
Developments in cancer therapy have resulted in new monoclonal antibodies that are often used in combination with standard chemotherapy agents. Infusion of these agents can result in initial hypotension owing to cytokine release, as well as specific individual toxicity.

Trastuzumab
Trastuzumab is used in adjuvant and metastatic breast cancer. Cardiac dysfunction has been observed in 27 per cent of patients receiving this drug, particularly when given with an anthracycline and cyclophosphamide in patients with metastases. Dysfunction was less when given in combination with paclitaxel (13 per cent), or as a single agent (1 per cent).7

In view of this, NICE recommends regular cardiac monitoring of patients given trastuzumab and it is not usually given in combination with anthracyclines.8

In the adjuvant setting, women with a left ventricular ejection fraction (LVEF) less than 55 per cent, or one of a number of defined cardiac conditions, should not be offered trastuzumab. All patients undergoing treatment should have a baseline cardiac assessment, repeated every three months.

If the patient's LVEF drops by 10 per cent or below 50 per cent, treatment should cease.9 Other new treatments, such as cetuximab used in metastatic bowel cancer and rituximab used in non-Hodgkin's lymphoma, are associated with hypotension, whereas bevacizumab used in metastatic bowel cancer is associated with hypertension.

Patient monitoring
Generally, an ECG is performed before treatment and in some cases, a test of cardiac function, such as an echocardiogram, is undertaken. A clinical decision is then made, taking into account clinical history and the potential for treatment-related cardiovascular toxicity.

There is no agreed protocol for assessing cardiac function after treatment in adults. Early treatment of changes with standard medication can result in good outcomes, although patients may be asymptomatic at this stage. Individualised follow-up is needed, depending on the risk of cardiovascular toxicity and patient factors.

References
1. Sultan A, Amour A, Khan S. Cardiac angiosarcoma presenting with death due to cardiac perforation. Br J Cardiol 2006; 13: 213-5.

2. Hancock SL, Hoppe RT. Long-term complications of treatment and causes of mortality after Hodgkin's disease. Semin Radiat Oncol 1996; 6: 225-42.

3. Postoperative radiotherapy in non-small-cell lung cancer. PORT Meta-analysis Trialists Group. Lancet 1998; 352: 257-63.

4. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists Collaborative Group. Lancet 2000; 355: 1757-70.

5. Prosnitz RG, Chen YH, Marks LB. Cardiac toxicity following thoracic radiation. Semin Oncol 2005; 32(2 Suppl 3): S71-80.

6. Yeh ET, Tong AT, Lenihan DJ et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 2004; 109: 3122-31.

7. Seidman A, Hudis C, Pierri MK et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215-21.

8. NICE. Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Technology Appraisal 34. London, NICE, 2002.

9. NICE. Trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer. Technology Appraisal 107. London, NICE, 2006.

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