A PROspective, explorative cohort study to correlate CARdiac BIomarkers with late cardiac toxicity induced by radiotherapy alone or combined with anthracycline chemotherapy for hodgkin lymphoma (PROCARBI)

1.1 * Cardiac morbidity in long-term Hodgkin Disease survivors

With improvement in chemotherapy and radiotherapy regimens, Hodgkin Lymphoma
(HL) has become a highly curable disease with an overall relative survival at
10 years of >80%. Long-term survivors are however exposed to several severe
late side effects from the therapy. This includes cardiovascular diseases,
which negatively impacts the overall survival.. Both anthracycline-containing
chemotherapy and radiotherapy (RT) to the mediastinum cause cardiovascular
diseases (CVD), even 35 years after initial treatment.

Radiation-induced CVD include (a) coronary heart disease (CHD), (b) valvular
heart disease (VHD), (c) myocardial dysfunction, (d) electrical conduction
abnormalities and (e) pericardial disease. Follow-up studies of HL survivors
show a 2 to 7 folds increased risk in cardiac death, mainly due to myocardial
infarction (MI). This is significantly correlated with patients* age; the
younger the patient at time of RT the larger is the risk. The risk of MI is
also strongly correlated with the RT techniques, depending how much of dose is
received by the heart, and follow-up time. Eventually, 3 to 6 folds higher
Standardized Incidence Ratios (SIRs) of CHD, VHD and heart failure (HF) are
observed in patients treated for HL compared to the general population.

Similarly, depending on the cumulative dose, anthracycline also leads to acute
cardiomyopathy, chronic cardiac complications (especially HF) and increased
cardiac mortality.

1.2 * A national BETER clinic

Because of the increased risk of adverse effects after HL treatment a
nationwide BETER consortium (Better Care after HL, Evaluation of long-term
Treatment Effects and screening Recommendations) was established in 2007. The
goal was to improve the life expectancy and quality of life of Hodgkin Lymphoma
and selected Non Hodgkin lymphoma (NHL) patients by reducing morbidity through
the careful assessment and interventions on delayed side effects.

National follow-up guidelines for lymphomas survivors have been developed
recommending this follow-up. As a result, patients previously treated at
Erasmus MC were identified and since November 1st, 2015, a BETER-clinic was
started at Erasmus MC to follow-up lymphoma survivors. The national
cardiovascular screening guideline currently includes tests focusing on early
detection of heart failure, including a physical examination, ECG, blood test
to measure NT-proBNP and other risk factors of CHD, and a cardiac ultrasound
every 5 years.

1.3 * Prognostic markers of congestive heart failure

The diagnosis of heart failure is often only possible when symptoms have become
manifest. A panel of cardiac biomarkers (such as NT-proBNP, ST2, GDF15,
Galectin 3, hsTn) could have the potential to monitor subtle changes in the
heart that reflect and possibly predict adverse changes before they become
clinically apparent. NT-proBNP has been established as a good marker of
chemotherapy-induced damages, however for the radiotherapy it has not been
formally demonstrated if a specific or a panel of markers could help early
diagnosis or prognosis of heart failure.

The other markers proposed in this study, namely ST2, GDF15, Galectin 3, and
hsTn, are not part of the current guideline, however they are focusing on the
mechanisms of cardiac injury of the 7 physiopathological pathway of cardiac
insufficiency described by Braunwald (myocardial stretch, collagene matrix
remodelling, myocyte injury), excepted those involved in the renal consequences
of cardiac insufficiency (oxidative stress, inflammation, neurohumoral
activation, renal dysfunction) since those may only occur at a late stage (ref

Hypothesis:
We hypothesize that the combination of biomarkers (e.g. NT-proBNP, ST2, GDF15,
Galectin 3, hsTn) is an early predictor of cardiac toxicity from radiotherapy
and chemotherapy in a population at risk of developing late cardiac toxicity
after previous radiotherapy alone or combined with chemotherapy. We also
hypothesize that imaging tests including functional US and cardiac MRI can
objectively confirm those early signs of cardiac toxicities, and that the
clinical impact can be assessed using PROMs.

Objectives
* Primary Objective

The primary objective is to evaluate in terms of sensitivity, specificity and
predictive value a panel of cardiac biomarkers for the early detection of an
increase in cardiac symptoms for HL and (selected) NHL long-term survivors. The
panel of biomarkers will be compared to an evaluation including clinical
assessment, ECG, heart US and PROMs.

* Secondary Objectives

* To describe the early symptoms of long-term cardiac toxicity induced by
radiotherapy with or without chemotherapy for HL and NHL patients.
* Develop a screening tool for the early detection of cardiac toxicity
including biomarkers, imaging tests and PROMs.
* Difference in score of Kansas City Cardiomyopathy Questionnaire (KCCQ-12) and
the Seattle Angina Questionnaire (SAQ-7).
* To evaluate the value of cardiac MRI as an objective diagnostic tool for
mediastinal radiotherapy and/or chemotherapy induced cardiac toxicities.
* To evaluate the dose effect relationship between the detected increase in
cardiac symptoms and various late severe cardiac toxicities.
- Evaluation of the radiation with/without anthracycline dose effect
relationship, and the impact of other factors of risk (age at treatment,
gender, body mass index (BMI), hypertension, diabetes, dyslipidaemia, and
tobacco use).

This study is a prospective explorative cohort study for patients in long-term
follow-up after radiotherapy alone or combined with chemotherapy for Hodgkin
and selected non-Hodgkin lymphoma to assess the correlation between a panel of
blood biomarkers, cardiac US and MRI imaging, and PROMs.

This is a non-interventional prospective follow-up cohort. The burden and the
risks associated with participation for the patient include those associated
with blood sampling (temporary bruising and pain), imaging (time commitment and
anxiety associated with going to the Hospital) and questionnaires (time and
possible anxiety). With MRI contrast dye is given intravenously. This can
result in hematoma and in a rare case to an allergic reaction.
Patients will be blinded to the results since the diagnostic value of the
combined cardiac biomarkers, imaging test or PROMs assessment performed in this
trial has not been validated. The results will be used for research purposes
only. However, if the study is positive it is possible that some patients may
benefit from an earlier detection of cardiovascular disease. Those patients
will then be called back and proposed standard intervention for early stage of
cardiovascular disease.