Clinical trial NCT01805778: Preventing Cardiac Sequelae in Pediatric Cancer Survivors
Official title: Novel Approaches to the Prediction, Diagnosis and Treatment of Cardiac Late Effects in Survivors of Childhood Cancer: A Multi-centre Observational Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Anthracycline-induced Cardiotoxicity
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Ontario Institute for Cancer Research
name: Pediatric Oncology Group of Ontario
name: C17 Council
name: Ottawa Heart Institute Research Corporation
name: Montreal Heart Institute
name: McMaster Children's Hospital
name: Children's Hospital of Eastern Ontario
name: London Health Sciences Centre
name: Children's Hospital of Orange County
name: Princess Margaret Hospital, Canada
First posted: 2013-03-06
Enrollment: 1128
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients will be recruited from pediatric oncology centres across Ontario, Canada (SickKids in Toronto, McMaster Children's Hospital in Hamilton, Children's Hospital of Eastern Ontario in Ottawa, and London Health Sciences Centre in London) as well as Princess Margaret Cancer Centre (Toronto) and Children's Hospital of Orange County (California, U.S.).

Brief summary: Cancer therapy can place childhood cancer survivors at increased risk for heart disease which can lead to significant illness or early death. Interventions that occur late in the evolution of treatment-related heart disease are usually ineffective at preventing its progression to death or heart transplant. Our team will work in several research cores to test new imaging and biomarker methods that will lead to earlier detection of heart disease before clinical symptoms develop or it become apparent on standard imaging tests. We will evaluate the importance of genetic differences between individuals in determining who is at greatest risk of developing heart disease as a result of exposure to cardiotoxic agents. We will combine this genetic information with the novel imaging and biomarker methods to predict which children are at particular risk. These vulnerable children can then be targeted by modifying their cancer therapy to reduce their exposure to cardiac toxins, or introducing medications that protect the heart from chemotherapy damage. This team brings together the expertise of clinicians and scientists in pediatric oncology, pediatric and adult cardiology, radiation oncology, genetics, and biostatistics. This is a cross-Canada initiative that will leverage the latest knowledge about cardiac toxicity and create a resource for ongoing research into this important cause of morbidity and mortality in childhood cancer survivors.

Detailed description: This is a multi-centre observational cohort study that will be conducted at The Hospital for Sick Children (Toronto), Princess Margaret Hospital (Toronto), McMaster Children's Hospital (Hamilton), London Health Sciences Centre (London), The Children's Hospital of Eastern Ontario (Ottawa) and The Children's Hospital of Orange County (Orange County, California).

The study will address the current limitations in prediction and early diagnosis of anthracycline-induced heart disease. This will be accomplished by the following 3 collaborative cores:

Core 1 (Genomics) will focus on determining which children are most susceptible to treatment-related cardiac toxicity by assessing genes in pathways related to anthracycline absorption, distribution, metabolism, and excretion, as well identifying genes in pathways known to be important in the cardiac response to injury.

Core 2 (Biomarkers) will explore whether existing and novel biomarkers allow for more accurate diagnosis of acute and late treatment-related cardiac toxicity. The core will use a human stem cell platform for discovery of novel biomarkers of anthracycline cardiac damage that will be evaluated in our clinical cohort.

Core 3 (Cardiac imaging) will focus on the evaluation of new echocardiographic and CMR techniques aimed at early identification of cardiac damage after anthracycline exposure.

It will investigate whether changes in cardiac function immediately after anthracycline administration predict which patients will develop progressive cardiac disease over time, and it will explore disease progression through the longitudinal evaluation of innovative echocardiographic parameters of remodeling and dysfunction in CCS exposed to anthracyclines.

Eligibility criteria: ACUTE COHORT:

Inclusion Criteria:

* Aged \<18 years at time of cancer diagnosis
* Diagnosed with a new malignancy (patients with a history of a prior malignancy wlil be eligible if they have not received any anthracycline chemotherapy or chest radiation)
* Cancer treatment plan will require therapy with at least one dose of any anthracycline
* Planned to have all pre-anthracycline echocardiograms (ECHO) at the recruiting site
* Normal cardiac functioning prior to initiation of anthracycline therapy (LV EF \> 55%)
* Patients who are uncooperative during the ECHO without sedation or anesthesia will be included in the study. However, these patients will only undergo clinically indicated echocardiograms, with no echocardiograms added for purely research purposes
* Provision of signed informed consent by the patient and/or patient's legal guardian

Exclusion Criteria:

* Patients who were previously treated with anthracycline chemotherapy or radiation to the chest.
* Significant congenital heart defects, including patients with any other congenital cardiac abnormality, except those with a patent foramen ovale or a small ASD. Patients with familial cardiomyopathies (hypertrophic, dilated and restrictive) will be excluded.

SURVIVOR COHORT:

Inclusion Criteria:

* Aged \< 18 years at time of cancer diagnosis
* Previously diagnosed with cancer and currently in remission
* Patients whose prior treatment plan included therapy with at least one dose of any anthracycline
* Patients who completed their final dose of anthracycline at least 3 years ago
* Routinely followed at the recruiting site approximately ever 12 months

Exclusion Criteria

* Prior allogeneic stem cell transplant
* Significant congenital heart defects, including patients with any other congenital cardiac abnormality, except those with a patent foramen ovale or a small ASD. Patients with familial cardiomyopathies (hypertrophic, dilated and restrictive) will be excluded.

Primary outcomes:
measure: Cardiac Remodeling
timeFrame: one year after last dose of anthracycline therapy in Acute Cohort; anytime during 2 year follow up in Survivor Cohort
Secondary outcomes:
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: SickKids
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Paul C Nathan, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Mark Greenberg, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Seema Mital, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Luc Mertens, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta/Stollery Children's Hospital
name: Paul Kantor, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ottawa Heart Institute
name: Peter Liu, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chaix MA, Parmar N, Kinnear C, Lafreniere-Roula M, Akinrinade O, Yao R, Miron A, Lam E, Meng G, Christie A, Manickaraj AK, Marjerrison S, Dillenburg R, Bassal M, Lougheed J, Zelcer S, Rosenberg H, Hodgson D, Sender L, Kantor P, Manlhiot C, Ellis J, Mertens L, Nathan PC, Mital S. Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors. JACC CardioOncol. 2020 Dec 15;2(5):690-706. doi: 10.1016/j.jaccao.2020.11.004. eCollection 2020 Dec.
citation: Skitch A, Mital S, Mertens L, Liu P, Kantor P, Grosse-Wortmann L, Manlhiot C, Greenberg M, Nathan PC. Novel approaches to the prediction, diagnosis and treatment of cardiac late effects in survivors of childhood cancer: a multi-centre observational study. BMC Cancer. 2017 Aug 3;17(1):519. doi: 10.1186/s12885-017-3505-0.