Heart Failure in Long-Term Survivors of Childhood Cancer: What a Major Research Review Found

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Research Was Conducted
• Key Findings: What the Studies Showed
• Study Quality Assessment
• What These Findings Mean for Patients
• Limitations: What the Study Could Not Prove
• Recommendations for Survivors and Families
• Frequently Asked Questions
• Source Information

Key Points

• A meta-analysis of three population-based studies found a cumulative heart failure incidence of 0.99% in five-year childhood cancer survivors over 5.0 to 72.5 years.
• One Canadian study reported survivors had nearly ten times the risk of heart failure compared with the general population (adjusted hazard ratio 9.7).
• Anthracyclines and chest radiation are major causes of heart damage; higher anthracycline doses increase risk, and no safe dose has been identified.
• Guidelines recommend lifelong cardiac surveillance and management of modifiable risk factors like high blood pressure, diabetes, and high cholesterol.
• Only four population-based studies were included, with substantial variation between them, limiting the strength of conclusions.

Background: Why This Research Matters

Survival after childhood cancer has improved dramatically. More than 80% of children diagnosed with cancer now live at least five years past their diagnosis. This progress comes from better cancer treatments, improved risk assessment, and stronger supportive care.

However, about 40% of childhood cancer survivors still develop serious health problems during long-term follow-up. The most common non-cancer complications involve the heart and blood vessels. These heart problems are called cardiovascular diseases.

One of the most serious heart complications is heart failure (HF). Heart failure is a clinical syndrome. In heart failure, structural or functional abnormalities of the heart cause noticeable symptoms and signs. The consequences are serious. Heart failure reduces quality of life, leads to frequent hospital admissions, and increases the risk of death.

A major cause of heart problems in childhood cancer survivors is a group of chemotherapy drugs called anthracyclines. These drugs have been essential for improving survival rates in children with cancer. However, research has clearly shown that higher total doses of anthracyclines are linked to a higher risk of cardiotoxicity (damage to the heart). No safe dose has yet been identified.

Other treatments can make anthracycline-related heart damage worse. Adding other types of chemotherapy to anthracyclines can increase cardiotoxicity. Combining anthracyclines with radiation therapy to the chest is also a significant risk factor for heart muscle injury.

The cancer itself and its treatment can also affect the biological processes of ageing. This can increase the risk of developing cardiovascular risk factors such as high blood pressure, diabetes, and abnormal cholesterol levels. Identifying and managing these modifiable risk factors is crucial to delay cardiac dysfunction.

In 2023, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) published updated recommendations for heart muscle surveillance in survivors. The European Society of Cardiology (ESC) Guidelines on cardio-oncology (2022) also recommend screening for cardiovascular risk factors. The ESC suggests that regular echocardiographic surveillance should be considered after moderate-risk and high-risk cardiotoxic treatments.

The term population-based refers to studies that include all cases of a particular disease within a specific geographic region. This study design is essential when investigating how common a condition is. Population-based studies reduce the risk of selection bias that can occur when participants are recruited subjectively. They also allow researchers to generalise findings to the broader population.

This systematic review focused exclusively on population-based studies. The primary aim was to identify, critically evaluate, and combine existing population-based studies that reported on the incidence of heart failure in five-year survivors of childhood cancer. The secondary objectives were to identify risk factors for delayed cardiotoxicity and to explore the potential relationship between cancer treatment across different eras and the development of late cardiac insufficiency.

How the Research Was Conducted

The researchers developed a protocol following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-P). They used the PICO model (Participants, Interventions, Comparators, and Outcomes) to formulate their research questions.

The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) in April 2021. The registration number is CRD42021247622. The protocol was published in June 2022.

The researchers searched ten major databases. These databases were Medline, Embase, Scopus, CINAHL, CAB International, AMED, Global Health, PsycINFO, Web of Science, and Google Scholar. They searched from each database's inception date until March 14, 2023. They used all relevant keywords, including MeSH terms, related to cancer, anthracyclines and other treatments, children, heart failure, and epidemiology or survivors. They applied no restrictions based on language or publication status. They also screened the reference lists of retrieved papers.

When articles lacked essential information, the researchers contacted the authors to ask whether missing data could be retrieved.

Eligibility Criteria

The researchers included population-based studies that reported the incidence of heart failure in patients treated for any type of cancer before age 18. Patients had to have survived at least five years after their diagnosis. A study was considered population-based if the patients included were representative of all cases of childhood cancer survivors occurring within a specified geographic area.

Studies that did not meet the criteria for a population-based design were excluded. These excluded study types included randomised controlled trials, case series, and case reports.

A diagnosis of heart failure was considered valid if given by a health care provider and recorded in a medical file, registry, or database. Cases of self-reported heart failure were regarded as credible if diagnosed by a physician or confirmed by medical records.

Study Selection and Data Extraction

Two reviewers independently assessed the titles and abstracts of all retrieved articles. They then performed full-text screening for potentially eligible papers. Any disagreement during screening was resolved by discussion involving a third reviewer. Methodological issues were resolved by a statistician with extensive experience in conducting systematic reviews.

The researchers developed a standardised data extraction form. They tested the form as a pilot and made necessary adjustments before performing full data extraction.

Quality Assessment

Two reviewers used the Effective Public Healthcare Practice Project (EPHPP) tool to score the quality and risk of bias in the studies identified for the review. To receive an EPHPP score, a study is rated across six domains: selection bias, study design, confounders, blinding, data collection methods, and withdrawals and dropouts.

Because several studies lacked a control group and blinding was not feasible, the researchers chose not to evaluate confounders and blinding. Quality was therefore assessed across four domains. Quality was classified as strong if there were no weak ratings in the four domains. Quality was classified as moderate if there was one weak rating. Quality was classified as weak if there were two or more weak ratings.

Analysis and Data Synthesis

The meta-analysis was conducted using Stata statistical software version 15. For studies sufficiently similar in their designs, populations, methods, exposures, outcomes, and assessments, the researchers used a random-effects meta-analysis. They used the method of DerSimonian and Laird to calculate the weights.

The researchers combined results from different studies by merging data on the cumulative incidence of heart failure. They calculated the cumulative incidence for the entire cohort. They reported it at the median follow-up time for studies that provided the total number of heart failure cases at the end of the follow-up period. When data on the total number of heart failure cases were absent, they used the cumulative incidence at the longest follow-up time as a substitute.

When studies with overlapping data were identified, only one was included in the meta-analysis. The I-squared statistic was used to evaluate potential heterogeneity (variation) between studies. The small number and heterogeneity of papers included prevented the researchers from exploring the influence of risk factors and treatment eras on incident heart failure as initially planned.

Key Findings: What the Studies Showed

The literature search identified 4,384 records. After removal of duplicates, 3,883 papers remained. Following title and abstract screening, 3,767 records were excluded. After full-text screening of the remaining 116 papers, 112 reports were found to be ineligible based on the inclusion criteria.

Only four papers were eligible for inclusion. These consisted of three published articles and one research letter.

Characteristics of the Included Studies

One study was conducted in the Netherlands, one in Canada, and one in Switzerland. The remaining study was the PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) cohort. The PanCareSurFup cohort included eight sub-cohorts from seven European countries: France, Hungary, Italy (two sub-cohorts), the Netherlands, Slovenia, Switzerland, and the United Kingdom.

Data from the French sub-cohort and the hospital-based sub-cohort from Italy were not considered population-based. These sub-cohorts were therefore excluded from the systematic review.

In total, the studies assessed in the analysis reported on 45,111 childhood cancer survivors diagnosed between 1940 and 2014. There was notable overlap between the Dutch and Swiss cohorts studied by Feijen and Hau and the PanCareSurFup cohort studied by De Baat and colleagues.

All four studies included in the systematic review were cohort studies. Two studies included a control group. Only one study compared outcomes with matched individuals from the general population. Three studies recruited survivors of all cancer types. The remaining study enrolled only survivors of acute lymphoblastic leukaemia (ALL).

Within the Swiss sub-cohort reported by De Baat and colleagues, it is possible that a few individuals were older than the specified age limit of 18 years. This is because the study included cancer patients up to 20 years old.

Detailed Results from Each Study

Feijen and colleagues (Netherlands): This study identified 116 cases of heart failure among 5,845 childhood cancer survivors during a median follow-up of 19.9 years. The cumulative incidence of heart failure was 1.98% (95% CI 1.66–2.37). The study collected data using questionnaires and physician diagnosis, with heart failure graded according to the Common Terminology Criteria for Adverse Events (CTCAE).

Khanna and colleagues (Canada): This study examined 7,289 childhood cancer survivors. The cumulative incidence of heart failure was 1.1% after 15 years and 1.8% after 20 years from the survivor's last paediatric cancer diagnosis. The corresponding rates for the cancer-free general population were 0.1% and 0.2%. This resulted in an adjusted hazard ratio of 9.7 (95% CI 6.8–14.0). This means that childhood cancer survivors had nearly ten times the risk of heart failure compared with the general population, after accounting for other factors.

De Baat and colleagues (PanCareSurFup, seven European countries): This study calculated the overall cumulative incidence of heart failure across multiple European sub-cohorts. The total study population was followed for a median of 23 years. However, specific follow-up times for individual sub-cohorts were not provided. The study identified potential heart failure cases by linking information from population-based databases and administering patient-based questionnaires. Heart failure was diagnosed if the clinical state aligned with grade 3–5 based on CTCAE criteria.

Hau and colleagues (Switzerland): Among five-year survivors of acute lymphoblastic leukaemia, this study identified 12 cases of heart failure (2.35%). Only one case occurred among their siblings (0.08%). This resulted in a weighted odds ratio of 13.9 (95% CI 1.8–107.4). This means that survivors of ALL had significantly higher odds of heart failure compared with their siblings.

Meta-Analysis Results

The meta-analysis of three comparable studies yielded a cumulative incidence of heart failure of 0.99% (95% CI 0.57–1.42). This analysis covered an extended period of 5.0 to 72.5 years. The I-squared value was 94.4% (p < 0.001). This high I-squared value indicates substantial variation between the studies. In plain language, this means the studies produced quite different results from one another, likely because of differences in how they were designed and conducted.

Study Quality Assessment

The overall quality of the four studies was evaluated as strong in two studies and moderate in the remaining two studies.

The quality assessment of the study by De Baat and colleagues considered the ratings of all six sub-cohorts from the participating European countries.

Two studies were rated as strong overall. These were the studies by Feijen and colleagues and by De Baat and colleagues. Two studies were rated as moderate overall. These were the studies by Khanna and colleagues and by Hau and colleagues.

The quality assessment examined four domains: selection bias, study design, data collection methods, and withdrawals and dropouts.

• Feijen et al.: Strong in selection bias, moderate in study design, strong in data collection methods, and strong in withdrawals and dropouts. Overall quality: strong.
• Khanna et al.: Moderate in selection bias, moderate in study design, strong in data collection methods, and weak in withdrawals and dropouts. Overall quality: moderate.
• De Baat et al.: Strong in selection bias, moderate in study design, moderate in data collection methods, and moderate in withdrawals and dropouts. Overall quality: strong.
• Hau et al.: Moderate in selection bias, moderate in study design, weak in data collection methods, and moderate in withdrawals and dropouts. Overall quality: moderate.

Data collection and validation of heart failure varied between studies. Two studies collected information on the diagnosis of heart failure by questionnaire. In one of these studies, the diagnosis was validated against medical records. Overt heart failure was considered present if it was graded 3–5 according to the Common Terminology Criteria for Adverse Events (CTCAE).

One study identified heart failure cases using algorithms derived from hospital admission and physician billing codes. Another study identified potential cases by linking information from population-based databases and administering patient-based questionnaires. Heart failure was diagnosed if the clinical state aligned with grade 3–5 based on CTCAE.

What These Findings Mean for Patients

The findings confirm that heart failure is a real concern for long-term childhood cancer survivors. The meta-analysis found that approximately 1 in 100 survivors (0.99%) developed heart failure over follow-up periods ranging from 5.0 to 72.5 years.

However, individual study results varied considerably. The cumulative incidence ranged from 0.99% in the pooled analysis to 1.98% in the Dutch study. The Canadian study found that survivors had nearly ten times the risk of heart failure compared with the general population (adjusted hazard ratio 9.7). The Swiss study found that survivors of acute lymphoblastic leukaemia had 13.9 times the odds of heart failure compared with their siblings.

These findings highlight the importance of lifelong cardiac monitoring for childhood cancer survivors. The risk of heart failure does not disappear after five years of survival. It persists for decades.

The study also underscores the role of anthracyclines and chest radiation in causing heart damage. Higher cumulative doses of anthracyclines are associated with increased risk, and no safe dose has been identified. Combining anthracyclines with chest radiation significantly increases the risk of heart muscle injury.

Identifying and managing modifiable risk factors such as high blood pressure, diabetes, and abnormal cholesterol levels is crucial. These conditions can accelerate cardiac dysfunction in survivors who are already at increased risk.

Limitations: What the Study Could Not Prove

The most important limitation is the small number of eligible studies. Only four population-based studies met the inclusion criteria. This limited the researchers' ability to draw firm conclusions.

The studies were also heterogeneous (varied). The I-squared value of 94.4% indicates substantial differences between studies. These differences likely reflect variations in study design, populations, methods, and how heart failure was defined and measured.

There was notable overlap between some cohorts. The Dutch and Swiss cohorts studied by Feijen and Hau overlapped with the PanCareSurFup cohort studied by De Baat and colleagues. This overlap could affect the combined results.

The small number and heterogeneity of papers prevented the researchers from exploring the influence of risk factors and treatment eras on incident heart failure as initially planned. This means the study could not determine how much specific treatments or treatment eras contributed to heart failure risk.

Data collection methods varied across studies. Some used questionnaires, some used medical records, some used billing codes, and some used combinations of these methods. This variation could lead to differences in how many heart failure cases were identified.

Only one study compared heart failure outcomes with matched individuals from the general population. Without such comparisons in all studies, it is difficult to determine the exact excess risk attributable to childhood cancer treatment.

Within the Swiss sub-cohort, it is possible that a few individuals were older than the specified age limit of 18 years, because the study included cancer patients up to 20 years old.

Recommendations for Survivors and Families

Based on this research and existing guidelines, childhood cancer survivors should be aware of their increased risk for heart failure. The following recommendations are supported by the study findings and the guidelines referenced in the article:

1. Continue lifelong cardiac surveillance. The risk of heart failure persists for decades after cancer treatment. Regular follow-up with a cardiologist or a long-term follow-up clinic is important.
2. Know your treatment history. Ask your healthcare provider about the specific chemotherapy drugs and radiation treatments you received. Anthracyclines and chest radiation are particularly important to document.
3. Manage modifiable risk factors. Keep blood pressure, blood sugar, and cholesterol levels under control. These conditions can worsen heart function in survivors who are already at risk.
4. Follow screening recommendations. The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) and the European Society of Cardiology (ESC) recommend regular echocardiographic surveillance after moderate-risk and high-risk cardiotoxic treatments.
5. Report symptoms promptly. If you experience shortness of breath, fatigue, swelling in the legs or ankles, or other symptoms that could indicate heart problems, seek medical attention promptly.
6. Maintain a healthy lifestyle. Regular physical activity, a balanced diet, and avoiding smoking can help protect your heart health.

The researchers emphasise that future population-based studies comparing heart failure incidence in childhood cancer survivors with the general population would be of significant value. Such studies would help clarify the exact risk and guide screening recommendations.

Frequently Asked Questions

How common is heart failure in long-term childhood cancer survivors?

A meta-analysis of three population-based studies found a cumulative incidence of heart failure of 0.99% (95% CI 0.57–1.42) over follow-up periods ranging from 5.0 to 72.5 years. That means about 1 in 100 survivors developed heart failure. However, individual study results varied, with one Dutch study reporting 1.98% and a Canadian study reporting 1.1% after 15 years.

What does a cumulative incidence of 0.99% mean for me?

Cumulative incidence is the proportion of people who develop a condition over a certain period. In this analysis, 0.99% means that among 100 childhood cancer survivors followed for 5 to 72.5 years, about one developed heart failure. This is an average across three studies, and individual risks may differ based on treatment and other factors.

Why is heart failure a concern for childhood cancer survivors?

Survivors have a higher risk of heart failure compared with the general population. One Canadian study found survivors had nearly ten times the risk (adjusted hazard ratio 9.7). A Swiss study of acute lymphoblastic leukaemia survivors found 13.9 times the odds compared with siblings. Treatments like anthracyclines and chest radiation can damage the heart, and risk persists for decades.

What treatments increase the risk of heart failure?

A group of chemotherapy drugs called anthracyclines is a major cause. Higher total doses are linked to higher risk, and no safe dose has been identified. Adding other chemotherapy to anthracyclines or combining them with radiation therapy to the chest also increases the risk of heart muscle injury. These treatments were essential for improving survival.

What can survivors do to lower their risk?

Survivors should continue lifelong cardiac surveillance, know their treatment history (especially anthracyclines and chest radiation), manage modifiable risk factors like high blood pressure, diabetes, and high cholesterol, follow screening recommendations, report symptoms promptly, and maintain a healthy lifestyle. Guidelines recommend regular echocardiographic surveillance after moderate-risk and high-risk cardiotoxic treatments.

How reliable are these findings?

The review included only four population-based studies, and the meta-analysis combined three. The I-squared value was 94.4%, indicating substantial variation between studies. Two studies were rated strong quality and two moderate. The small number and differences in design, populations, and heart failure definitions limit how firmly conclusions can be drawn.

What are the limitations of this research?

Only four population-based studies met the inclusion criteria, and they were heterogeneous. There was overlap between some cohorts, and data collection methods varied. Only one study compared outcomes with the general population. The small number of studies prevented researchers from exploring how specific treatments or treatment eras contributed to heart failure risk.

I survived childhood cancer and my doctor says I need lifelong heart monitoring — when should I get a second opinion on my heart failure risk and surveillance plan?

A second opinion can be useful when the surveillance plan does not clearly reflect your treatment history. Anthracyclines and chest radiation raise heart failure risk, no safe anthracycline dose has been identified, and risk persists for decades, so survivors need lifelong cardiac follow-up. Guidelines recommend echocardiographic surveillance after moderate-risk and high-risk cardiotoxic treatments. A second opinion can review whether your imaging schedule, risk-factor management, and symptom follow-up match that history. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Heart failure in long-term survivors of childhood cancer - a systematic review and meta-analysis of population-based studies.

Authors: Tove Berg, Jens Böhmer, Bright I. Nwaru, Kristjan Karason, and Marianne Jarfelt

Author affiliations: Department of Pediatric Medicine, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Pediatrics, Frankfurt Hoechst Clinic, Frankfurt am Main, Germany; Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; The Long-Term Follow Up Clinic for Childhood Cancer Survivors, Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Journal: Acta Oncologica, 2025, Volume 64, pages 917–926

DOI: https://doi.org/10.2340/1651-226X.2025.43654

Article history: Received 17 April 2025; Accepted 27 June 2025; Published 23 July 2025

Study registration: PROSPERO registration number CRD42021247622 (registered April 2021, published June 2022)

Funding and conflicts of interest: The original article is published as an Open Access article under the Creative Commons Attribution 4.0 International License. Supplemental data for the article can be accessed online at the DOI link above.

This patient-friendly article is based on peer-reviewed research.