Laura Madanat-Harjuoja

Cardiovascular morbidity in long-term survivors of early-onset cancer: A population-based study

Improvements in cancer therapy have resulted in an expanding population of early‐onset cancer survivors. In contrast to childhood and adolescent cancer survivors, there is still a lack of data concerning late morbidities among young adult (YA) cancer survivors. Thus, our aim was to investigate cardiac and vascular morbidity among early‐onset cancer survivors with a special interest in YA cancer survivors. In a population‐based setting, we explored the risk of cardiovascular disease in early‐onset cancer survivors compared to healthy siblings. Patients diagnosed with cancer below 35 years of age since 1975 were identified from the Finnish Cancer Registry, and 5‐year survivors were included in our study (N = 13,860). Information on cardiovascular morbidity was collected from the national hospital discharge registry. Compared to siblings, cancer survivors aged 0–19 and 20–34 at diagnosis had significantly elevated hazard ratios (HRs) for the studied outcomes: HR 13.5 (95% CI 8.9–20.4) and 3.6 (95% CI 2.8–4.6) for cardiomyopathy/cardiac insufficiency; HR 3.4 (95% CI 2.3–5.1) and 1.7 (95% CI 1.4–2.0) for atherosclerosis/brain vascular thrombosis; HR 3.3 (95% CI 1.7–6.5) and 1.8 (95% CI 1.5–2.1) for myocardial infarction/cardiac ischemia and HR 1.7 (95% CI 1.2–2.6) and 1.4 (95% CI 1.2–1.7) for cardiac arrhythmia. In both groups, depending on the outcome, the HR for adverse events was highest among lymphoma, brain tumor, leukemia and testicular malignancy survivors. Our results regarding late effects of childhood cancer survivors confirmed previous findings. Additionally, our study provides novel information concerning the YA cancer survivor population. Hence, our data may help in planning the risk‐based long‐term follow‐up of early‐onset cancer survivors.

Childhood cancer survivor cohorts in Europe

Abstract With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia – PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.

Late mortality among 5-year survivors of early onset cancer: A population-based register study

To date, only few studies have been published documenting late mortality among early onset cancer survivors, especially regarding young adulthood (YA) malignancies. Our nation‐wide population‐based registry study provides information concerning cause‐specific long‐term mortality among 16,769 5‐year survivors of early onset cancer (aged 0–34 years at diagnosis), with follow‐up for death extending from 1971 through 2012. A sibling cohort and population data were used as reference. The overall standardized mortality ratio (SMR) of cancer patients was 4.6‐fold, (95% CI 4.4–4.8). Highest SMRs were found for malignancies (12.8, 95% CI 12.3–13.3), infectious (4.8, 95%CI 2.9–6.7) and cardiovascular diseases (1.9, 95% CI 1.7–2.1). Malignancies and cardiovascular diseases accounted for the largest number of deaths. Childhood and YA cancer survivors with the same primary cancer site had a similarly elevated overall SMR with the exception of markedly higher SMRs after childhood Hodgkin lymphoma. The highest cumulative non‐malignancy‐related mortality was due to cardiovascular disease with a steady rise throughout the follow‐up, but strongly dependent on the primary cancer site and age at diagnosis. In childhood cancer survivors, the cumulative cardiovascular mortality did not reduce over time. However, overall and malignancy‐related mortality showed a declining tendency towards the most recent periods after both, childhood and YA cancer. Our findings on non‐malignancy‐related mortality stress the need to set up long‐term individual follow‐up with a focus on cardiovascular late effects for early onset cancer survivors, especially for YA cancer survivors still lacking those.

The Adult Life After Childhood Cancer in Scandinavia (ALiCCS) Study: Design and Characteristics

During the last five decades, survival of childhood cancer has increased from 25% to 80%. At the same time, however, it has become evident that survivors experience a broad range of therapy‐related late adverse health effects. The aim of the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study is to investigate long‐term health consequences of past and current therapies in order to improve follow‐up care of survivors and to reduce treatment‐related morbidity of future patients.

Late psychiatric morbidity in survivors of cancer at a young age: A nationwide registry-based study

Childhood cancer survivors have been shown to be prone to psychosocial adverse outcomes. Data on young adults and their psychiatric late effects are still scarce. In a nationwide, registry‐based study, we explored the risk (HR) of new psychiatric diagnoses in 5‐year survivors of childhood and young adulthood (YA) cancer (n = 13,860) compared with a sibling cohort (n = 43,392). Hazard ratios (HRs) were calculated using Cox regression models. Patients and siblings were identified from the Finnish Cancer Registry and Central Population Registry, respectively. Outcome diagnoses were retrieved from the national hospital discharge register. The risk of organic memory/brain disorders was significantly increased in both childhood (HR 4.9; 95%CI 2.7–8.9) and YA (HR 2.1; 95%CI 1.4–3.1) cancer survivors compared with siblings. Mood disorders were also more common in childhood (HR 1.3; 95%CI 1.1–1.7) and YA survivors (1.3; 95%CI 1.1–1.5) than in siblings. Radiotherapy did not explain the differences. Female childhood cancer survivors had significantly increased HRs for mood disorders, psychotic disorders, neurotic/anxiety disorders, somatization/eating disorders and personality disorders. In survivors of YA cancers, females had significantly increased HR for neurotic/anxiety disorders, and the difference between female survivors and siblings was significantly (p < 0.05) higher than that between male survivors and male siblings. The effect of treatment era was also analyzed, and the risk of organic memory and brain disorders in childhood cancer survivors did not diminish over time. Despite the trend of decreased use of cranial irradiation in children, the risk of organic memory/brain disorders was elevated, even during the most recent era. Thus, additional research on chemotherapy‐only protocols and their impact on mental health, is warranted.

Long-term inpatient disease burden in the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study: A cohort study of 21,297 childhood cancer survivors

Background Survivors of childhood cancer are at increased risk for a wide range of late effects. However, no large population-based studies have included the whole range of somatic diagnoses including subgroup diagnoses and all main types of childhood cancers. Therefore, we aimed to provide the most detailed overview of the long-term risk of hospitalisation in survivors of childhood cancer. Methods and findings From the national cancer registers of Denmark, Finland, Iceland, and Sweden, we identified 21,297 5-year survivors of childhood cancer diagnosed with cancer before the age of 20 years in the periods 1943–2008 in Denmark, 1971–2008 in Finland, 1955–2008 in Iceland, and 1958–2008 in Sweden. We randomly selected 152,231 population comparison individuals matched by age, sex, year, and country (or municipality in Sweden) from the national population registers. Using a cohort design, study participants were followed in the national hospital registers in Denmark, 1977–2010; Finland, 1975–2012; Iceland, 1999–2008; and Sweden, 1968–2009. Disease-specific hospitalisation rates in survivors and comparison individuals were used to calculate survivors’ standardised hospitalisation rate ratios (RRs), absolute excess risks (AERs), and standardised bed day ratios (SBDRs) based on length of stay in hospital. We adjusted for sex, age, and year by indirect standardisation. During 336,554 person-years of follow-up (mean: 16 years; range: 0–42 years), childhood cancer survivors experienced 21,325 first hospitalisations for diseases in one or more of 120 disease categories (cancer recurrence not included), when 10,999 were expected, yielding an overall RR of 1.94 (95% confidence interval [95% CI] 1.91–1.97). The AER was 3,068 (2,980–3,156) per 100,000 person-years, meaning that for each additional year of follow-up, an average of 3 of 100 survivors were hospitalised for a new excess disease beyond the background rates. Approximately 50% of the excess hospitalisations were for diseases of the nervous system (19.1% of all excess hospitalisations), endocrine system (11.1%), digestive organs (10.5%), and respiratory system (10.0%). Survivors of all types of childhood cancer were at increased, persistent risk for subsequent hospitalisation, the highest risks being those of survivors of neuroblastoma (RR: 2.6 [2.4–2.8]; n = 876), hepatic tumours (RR: 2.5 [2.0–3.1]; n = 92), central nervous system tumours (RR: 2.4 [2.3–2.5]; n = 6,175), and Hodgkin lymphoma (RR: 2.4 [2.3–2.5]; n = 2,027). Survivors spent on average five times as many days in hospital as comparison individuals (SBDR: 4.96 [4.94–4.98]; n = 422,218). The analyses of bed days in hospital included new primary cancers and recurrences. Of the total 422,218 days survivors spent in hospital, 47% (197,596 bed days) were for new primary cancers and recurrences. Our study is likely to underestimate the absolute overall disease burden experienced by survivors, as less severe late effects are missed if they are treated sufficiently in the outpatient setting or in the primary health care system. Conclusions Childhood cancer survivors were at increased long-term risk for diseases requiring inpatient treatment even decades after their initial cancer. Health care providers who do not work in the area of late effects, especially those in primary health care, should be aware of this highly challenged group of patients in order to avoid or postpone hospitalisations by prevention, early detection, and appropriate treatments.

Health conditions associated with metabolic syndrome after cancer at a young age: A nationwide register-based study

PURPOSE Childhood cancer survivors are at risk for developing metabolic syndrome (MetS), which subsequently leads to cardiovascular morbidity and excess mortality. Our aim was to investigate the purchases of medications associated with MetS among 7551 early onset cancer patients compared to siblings. METHODS Our nationwide Finnish population-based registry study analyzed the drug purchase of medication among early onset cancer patients diagnosed with cancer below the age of 35 years between 1994 and 2004 compared to siblings by linkage to the drug purchase registry, allowing for a maximal follow-up of 18 years. RESULTS The hazard ratios (HRs) for purchasing antihypertensives and diabetes drugs were higher after both childhood (HR 4.6, 95%CI 3.1-7.0; HR 3.0, 95%1.5-6.1) and young adulthood (YA) cancer (HR 1.5, 95%CI 1.3-1.8; HR 1.6, 95%CI 1.1-2.2) compared to siblings. The HRs for purchasing lipid-lowering drugs were elevated both after childhood (HR 4.3,95%CI 0.9-19.5) and YA cancer (HR 1.6, 95%CI 1.04-2.5), but only reached significance in YA cancer patients. Among specific cancer diagnosis groups, highest HR values for antihypertensives were found in childhood acute lymphoblastic leukemia (ALL) (HR 6.1, 95%CI 3.7-10.3) and bone tumor (HR 4.3, 95%CI 1.9-9.4), and YA ALL (HR 4.8, 95%CI 3.1-7.0) and acute myeloid leukemia (AML) (HR 3.4, 95%CI 2.5-5.1) patients. Moreover, childhood ALL (HR 6.3, 95%CI 2.7-14.8), AML (HR 7.6, 95%CI 1.9-24.5) and central nervous system (CNS)-tumor (HR 3.5, 95%CI 1.3-9.2) and YA ALL (HR 3.7, 95%CI 1.2-9.5) patients showed the strongest likelihood of purchasing diabetes drugs compared to siblings. CONCLUSION The purchase of medications associated with MetS was increased after early onset cancer and highly dependent on the age at cancer diagnosis and the cancer diagnosis. Prevention strategies are imperative for reducing potentially life-threatening cardiovascular complications after early onset cancer.

Long-term risk of renal and urinary tract diseases in childhood cancer survivors: A population-based cohort study

BACKGROUND Childhood cancer has been associated with long-term risk of urinary tract diseases, but risk patterns remain to be comprehensively investigated. We analysed the lifetime risk of urinary tract diseases in survivors of childhood cancer in the Nordic countries. METHODS We identified 32,519 one-year survivors of childhood cancer diagnosed since the 1940s and 1950s in the five Nordic cancer registries and selected 211,156 population comparisons of a corresponding age, sex, and country of residence from the national population registries. To obtain information on all first-time hospitalizations for a urinary tract disease, we linked all study subjects to the national hospital registry of each country. Relative risks (RRs) and absolute excess risks (AERs) and associated 95% confidence intervals (CIs) for urinary tract diseases among cancer survivors were calculated with the appropriate morbidity rates among comparisons as reference. RESULTS We observed 1645 childhood cancer survivors ever hospitalized for urinary tract disease yielding an RR of 2.5 (95% CI 2.4-2.7) and an AER of 229 (95% CI 210-248) per 100,000 person-years. The cumulative risk at age 60 was 22% in cancer survivors and 10% in comparisons. Infections of the urinary system and chronic kidney disease showed the highest excess risks, whereas survivors of neuroblastoma, hepatic and renal tumours experienced the highest RRs. CONCLUSION Survivors of childhood cancer had an excess risk of urinary tract diseases and for most diseases the risk remained elevated throughout life. The highest risks occurred following therapy of childhood abdominal tumours.

Adverse Obstetric Outcomes Among Early-Onset Cancer Survivors in Finland.

OBJECTIVE: To evaluate risk of adverse obstetric outcomes and operative deliveries in female cancer survivors (diagnosed younger than 35 years of age) compared with female siblings of survivors. METHODS: Nationwide cancer and birth registries were merged to identify 1,800 first postdiagnosis deliveries of female cancer survivors and 7,137 first deliveries of female siblings between January 1987 and December 2013. Multiple unconditional logistic regression models were used to estimate the risk for adverse obstetric outcomes and operative deliveries adjusting for maternal age, year of delivery, gestational age, and smoking. RESULTS: We found a significantly elevated risk for induction of labor, 19.1% in survivors and 15.6% in siblings (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.02–1.35) and cesarean delivery, 23.6% in survivors and 18.6% in siblings (OR 1.15, 95% CI 1.01–1.31) among cancer survivors compared with female siblings. The risks of instrumental vaginal delivery, malpresentation, placental pathologies, and postpartum hemorrhage were not, however, elevated among cancer survivors. The highest risks of adverse obstetric outcomes were seen among women treated in their childhood (aged 0–14 years). CONCLUSION: Cancer survivors have a small but statistically increased risk for induction of labor and cesarean delivery compared with siblings without a history of cancer. Our findings indicate that pregnancies in cancer survivors are typically uncomplicated and cancer survivors should not be discouraged to have children after their cancer is cured. LEVEL OF EVIDENCE: II

Cardiovascular medication after cancer at a young age in Finland: A nationwide registry linkage study

Despite improved survival rates, childhood and young adult (YA) cancer survivors face elevated risks for life‐threatening morbidities, especially cardiovascular complications. Our nationwide Finnish registry study investigated the purchases of cardiovascular medication from 1993 to 2011 in patients diagnosed with cancer aged below 35 years (N = 8,197) between 1993 and 2004 compared to siblings (N = 29,974) via linkage to the drug purchase registry. The cumulative incidence for purchasing cardiovascular medications was higher in childhood and YA cancer patients compared to siblings with a rising trend over time. After childhood cancer, the highest hazard ratio (HR) was found for purchasing anticoagulants (HR 19.8, 95% CI 8.5–45.9). The HRs for any cardiovascular medication (HR 7.2, 95% CI 5.1–10.1) and cardiac medication (HR 4.8, 95% CI 3.3–6.9) were markedly elevated after childhood cancer as well. Regarding YA cancer patients, the respective HRs were 2.5 (95% CI 2.0–3.2) for anticoagulants, HR 1.7 (95% CI 1.5–1.9) for any cardiovascular medication and HR 1.5 (95% CI 1.3–1.7) for cardiac medication. Among cancer patients, highest HRs for cardiovascular medication were observed after childhood acute lymphoblastic leukemia (ALL) and bone tumors (HR 10.2, 95% CI 6.8–15.5 and HR 7.4, 95% CI 4.0–13.7) and YA ALL and acute myeloid leukemia (HR 5.1, 95% CI 3.5–7.1 and HR 2.8, 95% CI 1.8–4.0). Our study demonstrated increased HRs for purchasing cardiovascular medication after early‐onset cancer compared to siblings reflecting elevated cardiovascular morbidity. Thus, the implementation of long‐term cardiovascular disease screening is imperative to prevent, detect and adequately treat cardiovascular late effects after cancer at a young age.