TOFFEE Trial
Research type
Research Study
Full title
TOFFEE Trial Toxicity OF Fluoropyrimidines: A comparative study of the cardiotoxicity of capEcitabine and tEysuno
IRAS ID
119796
Contact name
Sally Clive
Eudract number
2012-005282-12
Research summary
Research Summary
Capecitabine is a chemotherapy drug used to treat many types of cancer including bowel and stomach cancer. Capecitabine kills cancer cells and can be used to increase the effectiveness of surgery or radiotherapy in curing some cancers. Unfortunately a side effect of this drug is that it can cause blood vessel or heart problems. Because these side effects can be serious, doctors who treat cancer have to be careful when giving this drug to patients who have underlying heart problems. If heart problems do develop then Capecitabine may have to be stopped before the treatment is finished. A study of cancer doctors in the UK found that 60% felt that the side effects of Capecitabine on the heart were a problem for them in their daily practice. An alternative drug, Teysuno, is used extensively in Asian countries instead of Capecitabine and has recently been licensed for use in Europe. Teysuno has recently been tested in 1,053 patients with stomach and gullet cancer in 24 countries and was found to have equivalent anti-cancer benefit. This study did not look specifically at the effect of Teysuno on the heart, but cardiac toxicity has not been raised as a clinical issue with this drug, despite widespread use over many years. This study will investigate the effect of capecitabine and teysuno on the heart and blood vessels and will be the first of its kind in humans. We aim to recruit 60 patients from the Edinburgh Cancer Centre. Consenting patients will be randomly allocated to get either Capecitabine or Teysuno for their first cycle. During this cycle we will try to determine whether teysuno is a less cardiotoxic alternative to capecitabine and to understand this toxicity better. We will do this by means of heart monitoring (ECG), x-ray tests and special blood tests.
Summary of Results
This trial was conducted at the Edinburgh Cancer Centre, Western General Hospital. The trial sponsor was ACCORD (University of Edinburgh and NHS Lothian Research and Development office). The trial took place between May 2013 and October 2020. Funding to support the study was received from Nordic Pharma and the KIS fund for colorectal cancer research.
The study was designed to provide more information regarding the effects some chemotherapy drugs have on the heart. Capecitabine is a commonly used and important chemotherapy medicine for treating cancer. Unfortunately a side effect of this drug is that it can cause blood vessel or heart problems (cardiotoxicity). This can be serious for the patient and the chemotherapy drug has to be stopped. An alternative chemotherapy medicine, teysuno (S-1), is used for similar cancers to capecitabine. Teysuno (S-1) has not been reported to cause heart problems despite widespread use in Asia, and more recently in Europe, over many years.
The TOFFEE trial investigated the effect of these two oral chemotherapy drugs (capecitabine and teysuno) on the heart. The research was needed to help understand if patients with heart disease were more at risk of chemotherapy induced cardiotoxicity. It was to help understand more about how capecitabine causes heart problems and whether teysuno (S1) also causes heart problems.
Patients with cancer who were due to start capecitabine treatment were recruited into the study. For their first chemotherapy treatment they were randomly allocated to have either capecitabine or teysuno (S-1). This was a tablet treatment, taken twice daily for 14 continuous days. Before starting treatment they had a CT scan of their heart arteries (a CT coronary angiogram, CTCA), a 24 hour electrocardiogram (ECG) and some blood tests. After 3 days of oral chemotherapy treatment they had another 24-hour ECG recording, this time over 3 continuous days. Patients attended weekly for blood tests and assessments. After 3 weeks the study was completed and they continued their planned chemotherapy treatment.
Fifty-nine patients (29 capecitabine and 30 S-1) were enrolled and 56 started treatment. No patients developed chest pain, heart symptoms or unexpected side effects with either medicine.
In 53 patients undergoing CTCA, 30 participants had coronary artery disease, which was moderate or severe in 18 (capecitabine, n=7/26; S-1, n=11/27). The burden of changes seen on the 24-hour ECGs was greater for patients treated with capecitabine compared to S-1. ECG changes were not related to the presence of heart vessel disease seen on CTCA or to risk factors for heart disease in either group. Breakdown products of chemotherapy (fluoro-alanine and fluoroacetate) were seen in greater quantities in those patients treated with capecitabine than teysuno (S-1). This may be associated with cardiotoxicity. No other biomarkers to suggest underlying causes of cardiac damage were seen in either group.
This is the first study to look in a pre-planned way at the ECG changes caused by capecitabine and by teysuno (S-1). It has shown that underlying heart disease does not seem to increase the likelihood of developing ECG changes with capecitabine. It has shown that capecitabine causes more ECG changes than teysuno (S-1) and that this might be because of the different concentrations of their breakdown products. It is still not clear exactly how capecitabine causes cardiotoxicity.
REC name
Scotland B REC
REC reference
12/SS/0229
Date of REC Opinion
8 Jan 2013
REC opinion
Further Information Favourable Opinion