Mortality risk among 5‐year survivors of childhood cancer in Germany—Results from the CVSS study (Cardiac and Vascular late Sequelae in long‐term Survivors of childhood cancer study)

The growing population of long‐term childhood cancer survivors is at increased risk for severe, therapy‐related late effects and premature mortality. The cardiac and vascular late sequelae in long‐term survivors of childhood cancer (CVSS) study is a cohort of patients from Germany diagnosed with a neoplasia prior to 15 years of age in the time period 1980 to 1990. Late mortality was evaluated in a total of 4505 individuals who survived 5 years or more after the initial diagnosis (5‐year survivors). Survivors with a second primary tumor were excluded. Standardized mortality ratios (SMRs) were calculated. By December 2014, 400 patients had died. Available cause of death information from 188 individuals was used to estimate cause‐specific mortality for all deceased persons. Compared to the population of (former) West Germany, we observed an excess overall mortality risk (SMR = 9.53, 95% confidence interval [CI] = 8.62‐10.51). After correcting for missing cause of death information, an increased cancer mortality (SMR = 43.50, 95% CI = 25.79‐73.50) in the 5‐year survivors was detected. Cardiac death was ascertained in 14 individuals, resulting in an SMR of 10.85 (95% CI = 2.80‐32.02) after correcting for missing values. In conclusion, childhood cancer survivors diagnosed in Germany in 1980 to 1990 have a higher mortality risk overall and an elevated risk of dying from cancer and cardiac causes in particular. The results are consistent with those of international cohort studies. However, the reported results are based on few cases and individuals with secondary cancers were excluded.


What's new?
Since the 1970s, significant improvements have been made in the survival of patients diagnosed with childhood malignancies. Long-term survivors of childhood cancer, however, have elevated risks for late-developing therapy-related effects, including premature mortality. The present study examined long-term survival specifically within a cohort of 5-year survivors of childhood cancer in Germany. An excess long-term overall mortality risk was observed among individuals who experienced childhood malignancies. Cancer and cardiac sequelae were the primary causes of death. Cardiac mortality was noticeably elevated in females. The findings emphasize the importance of monitoring and managing long-term health in childhood cancer survivors.

| INTRODUCTION
Advances in diagnosis and treatment of childhood malignancies have improved survival since the 1970s. German patients diagnosed with childhood cancer during the years 1980 to 1990 had a 5-year survival of 69%. 1 Currently, the 5-year survival of patients with childhood cancer in Germany is 86%. 1 Data from the Surveillance, Epidemiology and End Results Study (SEER) database show that 5-year survival in the United States is 83.4%. 2 The 5-year survival is used as a benchmark for cure after diagnosis. However, long-term survivors are at increased risk for severe therapy-related late effects and premature mortality. The US/Canadian Childhood Cancer Survivor Study (CCSS) found that within 30 years from diagnosis, 18% of patients who survived 5 years or more after the initial diagnosis (5-year survivors) had died. 3 Second malignant neoplasms and cardiovascular disease account for a greater proportion of premature deaths and morbidity compared to individuals from the general population. 4 Treatment for pediatric malignancies includes chemotherapy, radiation and surgery. Chemotherapy and radiation therapy account for an increased risk of cardiovascular disease among childhood cancer survivors: anthracyclines have been implicated as a principal cause of irreversible cardiomyopathy, and patients exposed to thoracic radiation can develop systolic or diastolic dysfunction. 4,5 Currently, more than 35 000 long-term childhood cancer survivors have been registered with the German Childhood Cancer Registry (GCCR). 6 The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS) study considered individuals from the GCCR diagnosed with a neoplasia between 1980 and 1990. Outcomes of interest are all-cause mortality, cancer mortality and cardiac mortality of the CVSS cohort in comparison with the general population. The present study is the first to report subsequent mortality among 4505 individuals who survived 5 years or more after their initial diagnosis with cancer.

| Source population and study design
The CVSS study is a retrospective cohort study and based on patients who were registered with the GCCR. 6

| Ascertainment of causes of death
The GCCR performs routine follow-up assessments of the vital status of

| Data protection measures
The GCCR recorded identity data (name, address, date of birth) of each individual with the consent of their legal guardians or, for older patients, with their own consent. For the CVSS study, personal identifiers (ID) were generated for all individuals of the cohort. However, identity data are necessary to conduct a mortality follow-up, where individual requests are sent to the corresponding local health authorities. To be in accordance with data protection laws, the health authorities provided anonymized death certificates labeled with the ID only, while identity data were detached. The (anonymized) cause-of-death information from the death certificates was added to the (anonymized) CVSS study database.

| Statistical analysis
Analyses were performed to investigate all-cause mortality (ICD 10 : A00-Y98) as well as the mortality of three cause-of-death categories: "cancer mortality" (ICD 10 : C00-D48), "all-cardiac   (Table 1). Compared to surviving individuals, the deceased had lower percentages of leukemia, lymphoma, and renal tumors and higher percentages of central nervous system and bone tumors ( Table 2).

| Mortality
The all-cause mortality of survivors of pediatric malignancies was higher than the mortality of the corresponding West German population (SMR = 9.53, 95% CI = 8.62-10.51) (  An increased risk for cardiac mortality among childhood cancer survivors has been described in cohorts with long observation periods.

| Strength and limitations
The present study is the first to describe the mortality risk among Cause of death information was gathered from death certificates.
The validity of medical statements on death certificates is fair to moderate. 12 In addition, death certificates could be obtained for only 188 deceased individuals (47%), which indeed did not affect the results on overall mortality, but may have affected the accuracy of results for specific causes of death. Since missing death certificates were predominantly a matter of the early observational period, results for cancer mortality in particular may be underestimated in our study.
Finally, the CVSS cohort did not include individuals with second primary tumors, which could also lead to an underestimation of all-cause mortality in German 5-year survivors.

ACKNOWLEDGMENTS
The authors would like to thank all patients for their participation, engagement and their willingness to support this scientific project.
We would like to thank Alisha Silvia Mercedes Hall for her thorough review of the manuscript. Open Access funding enabled and organized by Projekt DEAL.

ETHICS STATEMENT
The CVSS study (ClinicalTrials.gov-No.: NCT02181049) was approved by the Scientific Committee of the Society for Pediatric Oncology and Hematology (GPOH). Each patient who agreed to take part in the medical examination gave written consent for the retrieval of therapy data.