HEpatic and CArdiac TOxicity Systems modelling.

Antineoplastic therapy is frequently complicated by the development of
cardiotoxicity. This subject is of rising concern for both cardiologists and
oncologists since many of these adverse effects are likely to have a
significant impact on the overall prognosis and survival of cancer patients.
Moreover, due to the increasing number of patients treated by conventional
chemotherapy and signaling inhibitors (often in combination and at
progressively higher cumulative doses), the incidence of cardiotoxicity is
continuously growing. Therefore, identifying and understanding these effects is
crucial to develop novel diagnostic and prognostic biomarkers, and to obtain
new therapeutics for the successful management of cancer patients with
cardiovascular complications.
Cardiotoxicity can range from asymptomatic subclinical abnormalities, including
electrocardiographic changes and temporary LVEF decline or simply elevated
blood pressure to life-threatening events such as congestive heart failure or
acute coronary syndromes.It may occur during or shortly after treatment (acute;
within days or weeks), or it may become evident a long period (late/chronic;
year(s)) after termination of systemic cancer therapy. The actual magnitude of
the problem is still unclear because only in two trials a prospective
evaluation of cardiac function has been performed. In general, the incidence of
cardiotoxicity is estimated to be 5-10% depending on the chemotherapeutic agent
used. Data from endomyocardial biopsies and troponin I measurements suggest
that conventional chemotherapeutics, such as anthracyclines, can induce
permanent myocardial cell injury*albeit by diverse mechanisms*and by cardiac
remodelling. Signalling inhibitors currently in use, like human epidermal
growth factor receptor 2 (HER2/erbB2) and angiogenesis inhibitors,
predominantly affect cardiac metabolism and contractile proteins, leading to
(transient) contractile dysfunction. Eventually, the increase of myocardial
antineoplastic concentrations can induce myocyte cell death either by apoptosis
or necrosis, a critical factor for long-term cardiovascular prognosis.
Quantitative methods of assessing myocardial injury, such as endomyocardial
biopsies or cardiac biomarkers, can therefore have a prognostic value. To date,
data regarding prognosis and risk factors are contradictory and the
relationship between abnormalities identified by non-invasive cardiac
investigations and survival is not clear. Therefore, further investigation and
evaluation of chemotherapy-related cardiac toxicities are necessary for early
identification, prevention and treatment.
HecaToS is an integrative approach, involving 14 European partners in 6
different countries, to allow prediction of susceptibility to adverse off
treatment effects in the heart of patients receiving chemotherapy for different
clinical indications. The aim is to generate a flexible prediction system, that
can make an in silico prediction of xenobiotic metabolism, toxic liabilities
and threshold doses with regard to heart toxicity. This related to the idea
that leading edge computational chemistry/chemoinformatics and systems biology,
when assembled in properly configured and validated computational systems, can
revolutionize predictive toxicology and human safety assessment. In order to
reach this objective and access relevant data on human heart toxicity, cardiac
biopsies from patients receiving cardiotoxic agents, either anthracyclines or
other possible anti-cancer medications such as signaling inhibitors are
crucial.

Primary Objective: To study known heartfailure biomarkers (proteomics,
microRNAs and metabolomics) for the detection and prognosis of cardiotoxicity
in patients receiving antineoplastic therapy, and to discover predictive
biomarker (values). In the future this will help in the understanding of
mechanisms that may lead to new therapeutics.

The present study is a prospective (partial retrospectieve) cohort study to
investigate the cardiotoxic adverse effects and outcome of patients receiving
antineoplastic treatment. By taking biosamples, we also aim to fulfil an unmet
medical need, for biomarkers to predict, diagnose or prognose cardiotoxicity,
and unravel the mechanisms allowing future development of therapeutics to
prevent/treat cardiotoxicity.
Recruitment will take place in close collaboration with the oncology and
hematology department. Recruitment of patients will be divided into three
groups:
- Acute patients: patients who will be receiving chemotherapy.
- Early chronic patients: patients with toxic cardiomyopathy who received
chemotherapy <12 months ago.
- Late chronic patients: patients who previously received chemotherapy > 12
months ago.

A patient cohort consisting of approximately 500 patients diagnosed with breast
cancer, leukemias or lymphomas and receiving cardio toxic chemotherapeutics
such as: trastuzumab, epirubicin, doxorubicin, rituximab, mitoxantrone,
daunorubicin, idarubicin or taxanes, will be recruited. The latter treatment
regimens are expected to induce cardiotoxicity via direct toxic myocyte
toxicity and through oxidative stress-induced inflammation. The expected number
of positive cases of acute cardiotoxicity will be about 1-3% depending on the
chemotherapeutic agent used. The expended number of positive cases of chronic
cardiotoxicity will be about 5-10%. The period for inclusion of patients is
estimated at 4 years. The follow-up duration is 5 years.
In Maastricht, every year approximately 200-250 patients with newly diagnosed
mamma carcinoma will be curatively operated. Their 10-year survival is
approximately 80%. Within this patient group, ~80 patients/year will receive
adjuvant (in addition to primary breast surgery) or neoadjuvant (prior to
primary breast surgery) chemotherapy. We estimate to include 50% (40 patients)
every year with a total of aproximately 150 patients after a 4 year inclusion
period.
Patients from the early chronic patient group are seen as a consult by the
cardiology department as part of the regular health care. This patient group
will consist of aproximately 50 patients, based on previous years.
We estimate to include 300 patients in the late chronic patient group after a 4
year inclusion period due to a follow-up program of patients from the
haematology department. This patient population will consist of a variable
group of treated malignancies (mainly Hodgkin lymphoma), which received
cardiotoxic chemotherapy mainly more than 5 years ago.

Patients should meet all of the inclusion criteria and none of the exclusion
criteria. All patients will be seen by an oncologist/hematologist and
cardiologist at a specialized out-patient clinic for chemotherapy-induced heart
disease, originated in the Maastricht University Medical Centre.

Group related:
The study population includes patients post- or during chemotherapy with
different forms of cancer, especially breast cancer and haematological cancers.
In almost all of these patients chemotherapeutics are given, which are known to
be cardiotoxic. Different subgroups are made, based on the moment in time when
cardio toxicity occurs after chemotherapy (acute -, early chronic - and late
chronic cardiac toxicity).

Risk benefit:

Endomyocardial Biopsies:
Endomyocardial biopsy (EMB) will only be performed upon routine clinical
indication, when exclusion of other causes of cardiomyopathies, such as immune
dysregulation, virus-mediated or storage diseases, need to be excluded (i.e. in
patients with decreased LVEF <50% without evidence of coronary artery disease
or primary valvular disease). EMB is the most sensitive and specific test to
assess cardiotoxicity, virus presence, auto-immunity, storage diseases and
metabolic disorders (such as M. Fabry).18-20 These EMBs are performed on the
cardiac catheterization laboratory, in a procedure similar to cardiac
catheterization. Through a sheath, a catheter called a pulmonary artery
catheter that is guided into the right side of the heart, a biotome is guided
into the heart where seven tissue samples approximately 2.0 to 3.0 millimeters
in size will be obtained. The collected samples will be analyzed according to a
standardized protocol. The obtained data will be used for both routine
diagnostics and this study. The degree of myocardial injury will be assessed
using electron microscopy on endomyocardial biopsies, which is considered to be
the most sensitive and specific means of evaluating cardiotoxicity and permits
direct assessment of the presence and extent of disease.21 Characteristic
electron microscopy findings such as depletion of myofibrillary bundles,
myofibrillar lysis, distortion and disruption of the Z-lines, mitochondrial
disruption, and intramyocyte vacuolization will be examined.22 In addition, the
cardiac biopsy samples will be analyzed for the detection of viral genomic
nucleic acid sequences by PCR, inflammation by immunostainings (CD45 and CD3),
and storage disease (Congo-red) providing a highly sensitive and specific
method to diagnose or exclude different causes of cardiomyopathies. The
procedure to obtain EMB is a very safe one, with a very low risk (<0,5 %) of
peri-procedure complications21. This low risk is in concordance with the number
of complications in our centre during the last three years. Most of the
complications from transmural biopsies occur at the time of venous access, i.e.
incidental arterial puncture or bleeding. The major complication is pericardial
bleeding (literature up to 2 %, in our center 0.5 %), caused by incidental
perforation of the right ventricle, requiring direct pericardial drainage only
in 50 %. All complications, except perforation, are transient and have no
long-term consequences.

Cardiac Magnetic Resonance:
CMR can only be made in CMR-proof patients this excludes patients who are
claustrophobic, pregnant or when they have metal(implants). A previous study
saw predictive differences in T1 values, which resulted in a higher chance for
symptoms later on, a closer follow-up can be advised here. There are no
mentionable risks of CMR and the estimated burden is low. CMR*s will only be
made upon indication as mentioned below the tables.

Cardiac echography:
A Cardiac echography will be performed on different time points as shown in the
table per subgroup. Each echocardiography will take place during a combined
visit with physical examination.

Blood samples:
If possible the amount of blood taken for clinical investigation will be used
for research purpose. If additional blood is needed, this will be drawn
simultaneously with clinical blood samples to avoid extra burden to the
patient. Later on in the research project, an additional sting may be needed if
it is not possible to combine with regularly check-ups. There are no
mentionable risks to this venous blood drawing. It*s in the benefit of the
patient to find early markers of heart-failure so it can be diagnosed in an
early stage.

Urine samples:
Urine collection has no risks. Patients collect urine samples in a cup provided
by us. The estimated burden of this will be none. The benefit of the patient is
still unsure. Hypothetically there might be proteins in urine which might have
a predictive value in cardio-toxicity/ heart-failure.

Visit number and physical examination:
The number of visits is shown in the table and depends on the subgroup they*re
divided in. If possible the research visits will be combined with the regularly
visits.
Physical examination will be held during the visits (blood pressure
measurement, auscultations of heart en lungs). There are no risks attached and
the estimated burden will be low. It*s in the benefit of the patient to find
early symptoms of heart-failure so it can be treated.

Questionnaire:
One questionnaire has to be filled in during different visits. It*s a short
list, which may help detect asymptomatic patients with only subtle changes in
the daily life. The burden is estimated low, because it does not take a lot of
time. It*s in the benefit of the patient to find early symptoms of
heart-failure so it can be treated