radiotherapy after mastectomy
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Recent studies of radiation toxicity in the treatment of breast cancer show that the effects on normal tissues can constitute a significant clinical problem and increased cardiac mortality may offset any potential survival benefit (Cuzick et al 1994; Host et al 1986; Rutqvist & Johansson 1990; Rutqvist et al 1992; Trott 1991; Gagliardi et al 1996; Haybittle et al 1989). There are no data on lesser degrees of late cardiac damage, but it seems likely that non-fatal ischaemic heart disease must also be induced. An excess of cardiac deaths begins at about 7 years post radiotherapy and increases each year thereafter (Rutqvist et al 1992). Thus, reported values depend on length of follow up. The maximum heart distance is the distance from the posterior field border of the tangential fields to the most anterior border of the heart on the simulator film and correlates well with the volume of myocardium included in the target volume (Canney, unpublished data). There has been no prospective assessment of potential cardiac morbidity in patients having cardiotoxic treatments as adjuvant therapy for breast cancer. In particular combinations of cardiotoxic agents may introduce additional risks of late morbidity or mortality. B type natriuretic peptideB type Natriuretic Peptide (BNP) is synthesized in the myocardium and increased levels are found in serum in patients with left ventricular dysfunction. B type natriuretic peptide (BNP) has a high negative predictive value for the diagnosis of left ventricular systolic dysfunction (McDonagh et al, 1998).
Aim: to assess the role of B type natriuretic peptide in identifying left ventricular dysfunction (LVD) in patients undergoing adjuvant radiotherapy and/or chemotherapy Schedule of investigations: ECG and blood for B type Natriuretic Peptide to be obtained: Plan of investigation: Consenting patients will have a baseline history (including personal and family history or personal history of cardiac disease cardiac symptomatology), clinical examination, serum cholesterol, electrocardiogram and assessment of left ventricular function by echocardiography (or radio-isotope ventriculography where this is routinely used). For patients in centres where isotope ventriculography is the standard investigation for patients undergoing anthracycline containing chemotherapy, an echocardiogram will also be carried out at baseline. Echocardiography and not isotope ventriculography will be the follow up investigation at all subsequent time points. Baseline and follow up clinical data at the same time points as the schedule of investigations (see above) will be recorded on a standard proforma kept in the patients notes. The proforma based on the cardiovascular data fields –body mass index, history of hypertension, alcohol history, smoking history, diabetes, family history of cardiac disease, peripheral vascular disease, exercise history, cholesterol profile. A copy will be sent to the trial office. Data collection for the various time points of the cardiac sub study including blood pressure, cardiac symptoms of chest pain, breathlessness, ankle swelling and palpitations will be collected by a research nurse in each UK centre. ECGs will be reported by the local department and a copy of the report sent to the trial office. Plasma BNP, ECG and clinical assessment will be done at each follow up visit. Blood from patients will be collected in chilled EDTA tubes and plasma separated by local biochemistry labs before storing at-80 C (or -20 C if not available). A whole blood sample will be send immediately to a central llabratory for analysis of BNP levels. Centres will be notified of abnormal results in writing with a copy sent to the trial office.. If there is any significant rise in serum BNP during the study period, the patient will be recalled for clinical and cardiac assessment by the investigator and referred, if necessary, to a cardiologist. The local investigator will request echocardiography in the participating centre to assess cardiac function. It is recommended that patients with new and increasing cardiac symptomatology, abnormal ECG and/ or a raised serum BNP levels are referred to a cardiologist for assessment and appropriate treatment. Advice on the management of individual patients will be available from the Chief Investigator (Peter Canney) and the trial cardiologists (Dr Martin Denvir, Dr Theresa McDonagh and Dr David Northridge). In order to assess whether BNP has a similar threshold for detecting LVD in this clinical setting to that observed in other studies, the first 100 patients enrolled in designated centres taking part in the cardiac study will undergo echocardiography and ECG at each time point thereafter. Patients enrolled into the cardiac sub study after this will not be required to undergo these serial echocardiograms. It is recognized that radio-isotope ventriculography would be the most reproducible method to assess changes in left ventricular systolic function but lack of availability in all centres and expense preclude this. In patients randomised to chest wall irradiation, the maximum heart distance at simulation will be measured on beam’s eye view. Statistical considerations:Assuming a 0.5% per annum rate of heart failure in non-exposed patients, if anthracycline containing regimes increase this to 1.5% p.a., and 70% of patients receive such treatment, then with 1000 patients recruited and 25% attrition, there will be 90% power to obtain a statistically significant result at the 5% level at 5 years.
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