Preventing Cardiac Sequelae in Pediatric Cancer Survivors

NCT ID: NCT01805778

Last Updated: 2019-07-08

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 1128 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2012-12-31
• Study Completion Date: 2018-09-30

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.

Conditions

Anthracycline-induced Cardiotoxicity

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Acute Cohort

Patients newly diagnosed with cancer who will be receiving anthracycline chemotherapy

No interventions assigned to this group

Survivor Cohort

Survivors of childhood cancer who are at least 3 years or more from their last dose of anthracycline therapy.

No interventions assigned to this group

Eligibility Criteria

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

• 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

• 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:

• 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.

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

Ontario Institute for Cancer Research

OTHER

Sponsor Role: collaborator

Pediatric Oncology Group of Ontario

OTHER

Sponsor Role: collaborator

C17 Council

OTHER

Sponsor Role: collaborator

Ottawa Heart Institute Research Corporation

OTHER

Sponsor Role: collaborator

Montreal Heart Institute

OTHER

Sponsor Role: collaborator

McMaster Children's Hospital

OTHER

Sponsor Role: collaborator

Children's Hospital of Eastern Ontario

OTHER

Sponsor Role: collaborator

London Health Sciences Centre

OTHER

Sponsor Role: collaborator

Children's Hospital of Orange County

OTHER

Sponsor Role: collaborator

Princess Margaret Hospital, Canada

OTHER

Sponsor Role: collaborator

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Paul Nathan

Director- Aftercare Program, Staff Oncologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Paul C Nathan, M.D.

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Mark Greenberg, M.D.

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Seema Mital, M.D.

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Luc Mertens, M.D.

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Paul Kantor, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Alberta/Stollery Children's Hospital

Peter Liu, M.D.

Role: PRINCIPAL_INVESTIGATOR

Ottawa Heart Institute

Locations

Children's Hospital of Orange County

Orange, California, United States

McMaster Children's Hospital

Hamilton, Ontario, Canada

London Health Sciences Centre

London, Ontario, Canada

Children's Hospital of Eastern Ontario

Ottawa, Ontario, Canada

SickKids

Toronto, Ontario, Canada

Princess Margaret Hospital

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: DERIVED

PMID: 34396283 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28774277 (View on PubMed)

Other Identifiers

1000032746

Identifier Type: -

Identifier Source: org_study_id