Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: A population‐based cohort study of 32,308 one‐year survivors

The lifetime risk for cardiovascular disease in a large cohort of childhood cancer survivors has not been fully assessed. In a retrospective population‐based cohort study predicated on comprehensive national health registers, we identified a cohort of 32,308 one‐year survivors of cancer diagnosed before the age of 20 in the five Nordic countries between the start of cancer registration in the 1940s and 1950s to 2008; 211,489 population comparison subjects were selected from national population registers. Study subjects were linked to national hospital registers, and the observed numbers of first hospital admission for cardiovascular disease among survivors were compared with the expected numbers derived from the population comparison cohort. Cardiovascular disease was diagnosed in 2,632 childhood cancer survivors (8.1%), yielding a standardized hospitalization rate ratio (RR) of 2.1 (95% CI 2.0–2.2) and an overall absolute excess risk (AER) of 324 per 100,000 person‐years. At the end of follow‐up 12% of the survivors were ≥ 50 years of age and 4.5% ≥ 60 years of age. Risk estimates were significantly increased throughout life, with an AER of ～500–600 per 100,000 person‐years at age ≥ 40. The highest relative risks were seen for heart failure (RR, 5.2; 95% CI 4.5–5.9), valvular dysfunction (4.6; 3.8–5.5) and cerebrovascular diseases (3.7; 3.4–4.1). Survivors of hepatic tumor, Hodgkin lymphoma and leukemia had the highest overall risks for cardiovascular disease, although each main type of childhood cancer had increased risk with different risk profiles. Nordic childhood cancer survivors are at markedly increased risk for cardiovascular disorders throughout life. These findings indicate the need for preventive interventions and continuous follow‐up for this rapidly growing population.     

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

BackgroundChildhood 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.MethodsWe 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.ResultsWe 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.ConclusionSurvivors 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.     

Gastrointestinal and liver disease in Adult Life After Childhood Cancer in Scandinavia: A population‐based cohort study

Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer‐directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population‐based cohort study included all 1‐year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver diseases, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RRs) and absolute excess rates comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow‐up in the hospital registries were 10 years (range: 0–42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases [RR: 1.6, 95% confidence interval (CI): 1.6–1.7], which corresponds to an absolute excess of 360 (95% CI: 330–390) hospitalizations per 100,000 person‐years. Survivors of hepatic tumors, neuroblastoma and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2–20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0–4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects.     

Second malignant neoplasms after childhood non-central nervous system embryonal tumours in North America: A population-based study

BackgroundFew studies in North America have quantified the risks of second malignant neoplasms (SMNs) among survivors of childhood non-central nervous system (non-CNS) embryonal tumours due to their rarity. We aimed to investigate these risks by combining population-based data from the United States of America and Canada.MethodsWe evaluated patients with childhood non-CNS embryonal tumours reported to the Surveillance Epidemiology and End Results program and eight Canadian cancer registries from 1969 to 2010. Standardised incidence ratio (SIR) and cumulative incidence of SMNs were calculated. Subgroup analyses were conducted by the type of first primary cancer, age at first primary diagnosis and follow-up duration.FindingsOf the 13,107 survivors, 190 SMNs were reported over 134,548 person-years of follow-up. The SIR for all SMNs combined was 6.4 (95% confidence interval [CI]: 5.5–7.4). Most site-specific SIRs were significantly increased, ranging from 36 (95% CI: 26–49) for bone and joint cancer to 3.1 (95% CI: 1.5–5.2) for brain tumour. The risk for second malignancies declined as the time elapsed from the first primary diagnosis and was less prominent for patients first diagnosed at age 1–4 years. Notably, rhabdomyosarcoma survivors had a higher risk for SMNs than those with other first primaries. The overall cumulative incidence of SMNs was 1.0% at 10 years, increasing to 2.2% at 20 years and 4.1% at 30 years.InterpretationSurvivors with childhood non-CNS embryonal tumours faced an increased risk for SMNs compared to the general population. The risk variations observed in different patient categories may help target prevention strategies in high-risk subgroups.     

Increased risk of cancer among siblings of long-term childhood cancer survivors: a report from the childhood cancer survivor study.

We determined risk of cancer among first-degree relatives of 5-year survivors of childhood leukemia, lymphoma, central nervous system tumors, sarcomas, Wilms' tumor, and neuroblastoma. Subjects were 13,703 participants in the Childhood Cancer Survivor Study. Family history was collected on 56,759 first-degree relatives using a self-reported questionnaire. Incidence was compared with age- and sex-specific rates using the U.S. Surveillance, Epidemiology and End Results program. Siblings of the survivors had an increased risk of cancer [standardized incidence ratio (SIR), 1.5; 95% confidence interval (95% CI), 1.35-1.7]. Risk was elevated for siblings of probands of leukemia (SIR, 1.3; 95% CI, 1.0-1.6), Hodgkin's disease (SIR, 1.5; 95% CI, 1.2-1.9), non-Hodgkin's lymphoma (SIR, 1.8; 95% CI, 1.3-2.5), Wilms' tumor (SIR, 1.9; 95% CI, 1.2-3.2), soft tissue sarcoma (SIR, 1.5; 95% CI, 1.0-2.2), and bone tumors (SIR, 1.6; 95% CI, 1.2-2.2). Cancer risk was elevated in siblings (SIR, 2.4; 95% CI, 1.5-3.7) and offspring (SIR, 15.0; 95% CI, 5.3-42.9) of probands with second malignant neoplasms (SMN) compared with relatives of probands without SMNs. Siblings of probands with leukemia, Hodgkin's disease, neuroblastoma, and Wilms' tumor had elevated risks for the same malignancies. Parents had no increased risk (fathers' SIR, 0.7; 95% CI, 0.7-0.8; mothers' SIR, 0.9; 95% CI, 0.9-1.0). Seventy percent of siblings' cancers developed in adulthood. These findings suggest that familial cancer syndromes may be revealed as this cohort and family members age and with accrual of more offspring and subjects with SMNs.     

Male infertility in long-term survivors of pediatric cancer: a report from the childhood cancer survivor study

Purpose

The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors.

Methods

Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided.

Results

Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR?=?2.64, 95 % CI 1.88–3.70, p?<?0.001). Of survivors who met the definition for infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR?=?2.13, 95 % CI 1.69–2.68 for AAD ≥3 versus AAD <3), surgical excision of any organ of the genital tract (RR?=?1.63, 95 % CI 1.20–2.21), testicular radiation ≥4 Gy (RR?=?1.99, 95 % CI 1.52–2.61), and exposure to bleomycin (RR?=?1.55, 95 % CI 1.20–2.01).

Conclusion

Many survivors who experience infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation.

Implications for Cancer Survivors

Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.     

The risk of preterm birth and growth restriction in pregnancy after cancer

It is unclear whether cancer and its treatments increase the risk of adverse pregnancy outcomes. Our aim was to examine whether cancer survivors have higher risks of poor outcomes in pregnancies conceived after diagnosis than women without cancer, and whether these risks differ by cancer type and race. Diagnoses from cancer registries were linked to pregnancy outcomes from birth certificates in three U.S. states. Analyses were limited to the first, live singleton birth conceived after diagnosis. Births to women without a previous cancer diagnosis in the registry were matched to cancer survivors on age at delivery, parity, race/ethnicity and education. Log‐binomial regression was used to estimate risk ratios. Cervical cancer survivors had higher risks of preterm birth (Risk ratio = 2.8, 95% Confidence interval: 2.1, 3.7), as did survivors of invasive breast cancer (RR = 1.3, 95% CI: 1.1, 1.7) and leukemia (RR = 2.1, 95% CI: 1.3, 3.5). We observed a higher risk of small for gestational age (SGA) infants (<10% of weight for age based on a national distribution) in survivors of brain cancer (RR = 1.7, 95% CI: 1.1, 2.8) and extranodal non‐Hodgkin lymphoma (RR = 2.3, 95% CI: 1.5, 3.6). We did not see an increased risk of infants born preterm, low birth weight, or SGA in pregnancies conceived after ductal carcinoma in situ, thyroid cancer, melanoma, or Hodgkin lymphoma. While our results are reassuring for survivors of many cancers, some will need closer monitoring during pregnancy.     

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.     

Risk of second malignant neoplasms after childhood central nervous system malignant tumours: an international study

PurposeThe aim of this study was to assess the risk of second malignant neoplasms (SMNs) other than central nervous system (CNS) neoplasms after childhood CNS cancer in an international multicentre study.MethodsIndividual data on cases of CNS cancer in children (0–14 years) and on subsequent SMNs were obtained from 13 population-based cancer registries contributing data for different time periods in 1943–2000. Standardised incidence ratios (SIRs) with 95% confidence intervals (CI), absolute excess risk and cumulative incidence of SMNs were computed.ResultsWe observed 43 SMNs in 8431 CNS cancer survivors. The SIR was 10.6 (4.85–20.1) for thyroid cancer (nine cases), 2.75 (1.01–5.99) for leukaemia (six cases) and 2.47 (0.90–5.37) for lymphoma (six cases). The SIRs were highest in the first 10 years after CNS cancer diagnosis. The cumulative incidence of non-CNS SMNs was 3.30% (0.95–5.65%) within 45 years after a CNS cancer diagnosis. Within 15 years, the cumulative incidence was highest for cases diagnosed after 1980 (0.56%, 95% CI: 0.29–0.82%).ConclusionThis population-based study indicates that about one every 180 survivors of a childhood CNS cancer will develop a non-CNS SMN within the following 15 years. The excess is higher after glioma and embryonal malignant tumour than after another CNS tumour.     

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.     

Association between physical activity and mortality among breast cancer and colorectal cancer survivors: a systematic review and meta-analysis

BackgroundPhysical activity improves physical function during and after cancer treatment, but whether physical activity imparts survival benefit remains uncertain.DesignUsing prospective studies published through June 2013, we conducted a systematic review and random-effects meta-analysis of pre- and post-diagnosis physical activity in relation to total and cancer mortality among breast or colorectal cancer survivors.ResultsSixteen studies of breast cancer survivors and seven studies of colorectal cancer survivors yielded 49095 total cancer survivors, including 8129 total mortality cases and 4826 cancer mortality cases. Comparing the highest versus lowest levels of pre-diagnosis physical activity among breast cancer survivors, the summary relative risks (RRs) of total and breast cancer mortality were 0.77 [95% confidence interval (CI) = 0.69–0.88] and 0.77 (95% CI = 0.66–0.90, respectively. For post-diagnosis physical activity, the summary RRs of total and breast cancer mortality were 0.52 (95% CI = 0.42–0.64) and 0.72 (95% CI = 0.60–0.85), respectively. For pre-diagnosis physical activity among colorectal cancer survivors, the summary RRs of total and colorectal cancer mortality were 0.74 (95% CI = 0.63–0.86) and 0.75 (95% CI = 0.62–0.91), respectively. For post-diagnosis physical activity, the summary RRs of total and colorectal cancer mortality were 0.58 (95% CI = 0.48–0.70) and 0.61 (95% CI = 0.40–0.92), respectively. Each 10 metabolic equivalent task-hour/week increase in post-diagnosis physical activity (equivalent to current recommendations of 150 min/week of at least moderate intensity activity) was associated with 24% (95% CI = 11–36%) decreased total mortality risk among breast cancer survivors and 28% (95% CI = 20–35%) decreased total mortality risk among colorectal cancer survivors. Breast or colorectal cancer survivors who increased their physical activity by any level from pre- to post-diagnosis showed decreased total mortality risk (RR = 0.61; 95% CI = 0.46–0.80) compared with those who did not change their physical activity level or were inactive/insufficiently active before diagnosis.ConclusionPhysical activity performed before or after cancer diagnosis is related to reduced mortality risk among breast and colorectal cancer survivors.     

Risk for congenital anomalies in offspring of childhood,adolescent and young adult cancer survivors

Offspring of cancer survivors (CS) may be at risk for congenital anomalies due to the mutagenic therapies received by their parents. Our population‐based cohort study aimed to investigate the risk for congenital anomalies in offspring of CS compared to offspring of their siblings. Using the Finnish Cancer Registry, Central Population Register, and Hospital Discharge Register, we identified hospital contacts due to congenital anomalies in 6,862 offspring of CS (early‐onset cancer between 1953 and 2004) and 35,690 offspring of siblings. Associations between congenital anomalies and cancer were evaluated using generalized linear regression modelling. The ratio of congenital anomalies in offspring of CS (3.2%) was slightly, but non‐significantly, elevated compared to that in offspring of siblings (2.7%) [prevalence ratio (PR) 1.07, 95% confidence interval (CI) 0.91–1.25]. When offspring of childhood and adolescent survivors (0–19 years at cancer diagnosis) were compared to siblings' offspring, the risk for congenital anomalies was non‐significantly increased (PR 1.17, 95% CI 0.92–1.49). No such increase existed for offspring of young adult survivors (20–34 years at cancer diagnosis) (PR 1.01, 95% CI 0.83–1.23). The risks for congenital anomalies were elevated among offspring of CS diagnosed with cancer in the earlier decades (1955–1964: PR 2.77, 95% C I 1.26–6.11; and 1965–1974: PR 1.55, 95% C I 0.94–2.56). In our study, we did not detect an overall elevated risk for congenital anomalies in offspring of survivors diagnosed in young adulthood. An association between cancer exposure of the parent and congenital anomalies in the offspring appeared only for those CS who were diagnosed in the earlier decades.     

Loss of a parent and the risk of cancer in early life: a nationwide cohort study

Background

While early-life exposure to stress has been associated with subsequent psychiatric and cardiovascular morbidity, little is known regarding its potential role in cancer development. We hypothesized that severe emotional stress, such as the loss of a parent through death during childhood, may increase the risk of cancer in early life.

Method

Based on the Swedish Multi-Generation Register, we identified a cohort of 4,219,691 individuals who had both parents identifiable in the same register and followed the cohort from birth to the age of 40 years between 1961 and 2006. Through information retrieved from the Swedish Causes of Death and Cancer Registers, we ascertained death among the parents and cancer diagnosis among the cohort individuals. We used Poisson regression to calculate the relative risks (RRs) and 95 % confidence intervals (CIs).

Results

Parental death was not associated with total cancer risk. However, parental death during childhood was associated with a higher risk of human papillomavirus (HPV) infection-related cancers (RR 1.4; 95 % CI 1.2–1.7), and loss during early adulthood (>18 years) entailed a higher risk of cancers of the stomach (RR 1.8; 95 % CI 1.3–2.6), lung (RR 1.7; 95 % CI 1.1–2.4), rectum (RR 1.4; 95 % CI 1.0–2.0), and breast (RR 1.1; 95 % CI 1.0–1.3). A significant association was observed for pancreatic cancer for both loss during childhood (RR 2.6; 95 % CI 1.6–4.2) and afterward (RR 2.8; 95 % CI 1.9–4.3).

Conclusion

Our results suggest that severe psychological stress in early life may be associated with premature development of certain malignancies, particularly cancers related to smoking and HPV infection.     

Leukemia after therapy with alkylating agents for childhood cancer

The risk of leukemia was evaluated in 9,170 2-or-more-year survivors of childhood cancer in the 13 institutions of the Late Effects Study Group. Secondary leukemia occurred in 22 nonreferred individuals compared to 1.52 expected, based on general population rates [relative risk (RR) = 14; 95% confidence interval (CI), 9-22]. The influence of therapy for the first cancer on subsequent leukemia risk was determined by a case-control study conducted on 25 cases and 90 matched controls. Treatment with alkylating agents was associated with a significantly elevated risk of leukemia (RR = 4.8; 95% CI, 1.2-18.9). A strong dose-response relationship was also observed between leukemia risk and total dose of alkylating agents, estimated by an alkylator score. The RR of leukemia reached 23 in the highest dose category. Radiation therapy, however, did not increase risk. Although doxorubicin was also identified as a possible risk factor, the excess risk of leukemia following treatment for childhood cancer appears almost entirely due to alkylating agents.     

Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study.

PURPOSE: The objectives of this report are to examine the incidence of and risk factors for stroke among childhood Hodgkin's disease (HD) survivors. PATIENTS AND METHODS: The Childhood Cancer Survivor Study is a multi-institutional cohort study of more than 5-year cancer survivors diagnosed between 1970 and 1986 and a sibling comparison group. Incidence rates of stroke among HD survivors (n = 1,926) and siblings (n = 3,846) were calculated and compared. Cox proportional hazards models were used to estimate the hazard ratios, reported as relative risks (RR), of developing stroke between HD survivors and siblings. RESULTS: Nine siblings reported a stroke, for an incidence of 8.00 per 100,000 person-years (95% CI, 3.85 to 14.43 per 100,000 person-years). Twenty-four HD survivors reported a stroke. The incidence of late-occurring stroke among HD survivors was 83.6 per 100,000 person-years (95% CI, 54.5 to 121.7 per 100,000 person-years). The RR of stroke among HD survivors was 4.32 (95% CI, 2.01 to 9.29; P = .0002). All 24 survivors received mantle radiation exposure (median dose, 40 Gy). The incidence of late-occurring stroke among HD survivors treated with mantle radiation was 109.8 per 100,000 person-years (95% CI, 70.8 to 161.1 per 100,000 person-years). The RR of late-occurring stroke among HD survivors treated with mantle radiation was 5.62 (95% CI, 2.59 to 12.25; P < .0001). CONCLUSION: Survivors of childhood HD are at increased risk of stroke. Mantle radiation exposure is strongly associated with subsequent stroke. Potential mechanisms may include carotid artery disease or cardiac valvular disease.     

Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study

BACKGROUND: Survivors of childhood brain tumors (CBTs) are at high risk for a variety of late adverse effects. Most research on long-term effects of CBTs has been comprised of single-institution case series without comparison groups. Research on CBT late effects often is focused on neurologic and sensory outcomes, with less emphasis on other potential targets such as the endocrine and circulatory systems. The current study was conducted to contrast the incidence of endocrine and cardiovascular conditions among CBT survivors as a function of treatment and to determine the risk of occurrence of these conditions relative to a sibling comparison group. METHODS: As part of the Childhood Cancer Survivor Study (CCSS), treatment data were collected from medical records and self-reported late effects were ascertained from a survey questionnaire of 1,607 CBT patients who survived their disease for 5 or more years. For comparison purposes, questionnaire data were also collected from 3418 randomly selected siblings of participants in CCSS. RESULTS: One or more endocrine conditions were reported by 43% of CBT survivors. Compared with siblings, CBT survivors had a significantly increased risk of late-onset (>/= 5 years postdiagnosis) hypothyroidism (relative risk [RR] = 14.3; 95% confidence interval [95% CI] 9.7-21.0), growth hormone deficiency (RR = 277.8; 95% CI 111.1-694.9), the need for medications to induce puberty (RR = 86.1; 95% CI 31.1-238.2), and osteoporosis (RR = 24.7; 95% CI 9.9-61.4). One or more cardiovascular conditions were reported by 18% of CBT survivors, with an elevated late-onset risk for stroke (RR = 42.8; 95% CI 16.7-109.8), blood clots (RR = 5.7; 95% CI 3.2-10.0), and angina-like symptoms (RR = 2.0; 95% CI 1.5-2.7). Very few late effects were evident among those treated with surgery only, but risks were consistently elevated for those treated with radiation and surgery, and higher still for those who also received adjuvant chemotherapy. CONCLUSIONS: Childhood brain tumor survivors are at a significantly increased risk for several adverse endocrine and cardiovascular late effects, particularly if they were treated with radiation and chemotherapy. Lifetime medical surveillance and follow-up for potential toxicities are necessary because treatment-related complications may occur many years after therapy.     

Leukemia following breast cancer: an international population-based study of 376,825 women

Purpose To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year. Patients and methods We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943–2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model. Results A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5–10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3–2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2–1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9–6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively. Conclusions Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.     

Prospective study of breast cancer in relation to coffee,tea and caffeine in Sweden

Studies of coffee and tea consumption and caffeine intake as risk factors for breast cancer are inconclusive. We assessed coffee and tea consumption, caffeine intake, and possible confounding factors among 42,099 women from the Swedish Women's Lifestyle and Health study, the participants of which were aged 30–49 years at enrollment in 1991–1992. Complete follow‐up for breast cancer incidence was performed through 2012 via linkage to national registries. Poisson regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer. During follow‐up 1,395 breast cancers were diagnosed. The RR was 0.97 (95% CI 0.94–0.99) for a 1‐unit increase in cups of coffee/day, 1.14 (95% CI 1.05–1.24) for a 1‐unit increase in cups of tea/day, and 0.97 (95% CI 0.95–1.00) for a 100 mg/day increase in caffeine intake. Although the RR for no consumption (RR = 0.86, 95% CI 0.69–1.08), a group with a relatively small number of women, was not statistically significant, women with higher consumption had a decreased breast cancer risk (3–4 cups/day: RR = 0.87, 95% CI 0.76–1.00; ≥5 cups/day: RR = 0.81, 95% CI 0.70–0.94) compared to women consuming 1–2 cups of coffee/day. Compared to no consumption, women consuming >1 cups tea/day showed an increased breast cancer risk (RR = 1.19, 95% CI 1.00–1.42). Similar patterns of estimates were observed for breast cancer risk overall, during pre‐ and postmenopausal years, and for ER+ or PR+ breast cancer, but not for ER? and PR? breast cancer. Our findings suggest that coffee consumption and caffeine intake is negatively associated with the risk of overall and ER+/PR? breast cancer, and tea consumption is positively associated with the risk of overall and ER+/PR+ breast cancer.     

Probability of parenthood after early onset cancer: a population-based study

We evaluated in a population-based setting the postdiagnosis parenthood among survivors compared with the fertility patterns of siblings. Cancer patients aged 0-34 years at diagnosis were identified from the Finnish Cancer Registry (N = 25,784), and their siblings (N = 44,611) by registry linkage. Further linkage identified the offspring of the patient and sibling cohorts. The relative probabilities of parenthood for first and second births separately were estimated for male and female survivors in different diagnostic age-groups and subsites using a Cox proportional hazards model, with age as the time variable and adjusting for the birth cohort of parents. In addition, estimates were calculated for 5 diagnostic eras in all subsites combined. Compared to siblings, both female and male cancer survivors were less likely to parent at least 1 child (RR 0.46, 95% CI 0.44-0.48 and RR 0.57, 95% CI 0.54-0.60, respectively). The relative probability of parenthood was especially low in male childhood cancer survivors and female young adult cancer survivors. However, cancer patients were only slightly less likely than siblings to parent a second child, with RR 0.91, 95% CI 0.86-0.97 and RR 0.95, 95% CI 0.89-1.01 for females and males, respectively. The relative probability of parenthood increased over calendar time among young adult cancer patients. The relative probability of parenthood following early onset cancer was overall significantly reduced by approximately 50%. Parenting a second child, however, was not reduced among pediatric and adolescent survivors, and only slightly reduced among early adulthood cancer survivors compared to siblings.     

Reproductive factors and risk of premenopausal breast cancer by age at diagnosis: Are there differences before and after age 40?

We examined the relationship between reproductive factors and risk of premenopausal breast cancer among women less than age 40 compared with older premenopausal women. We documented 374 incident cases of breast cancer diagnosed before age 40, and 2,533 cases diagnosed at age 40 and older among premenopausal women in the Nurses’ Health Study cohorts. Biennial questionnaires were used to determine age at menarche, age at first birth, parity, breastfeeding, and other reproductive factors. Multivariate relative risks (RR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models within age at diagnosis groups. Tumors in younger women were significantly more likely to be higher grade, larger size, and hormone receptor negative than were tumors in older premenopausal women (p < 0.0001). There was no significant heterogeneity according to age in associations between reproductive factors and risk of premenopausal breast cancer. First birth at age 30 or older increased breast cancer risk in both age groups (age <40: RR 1.10, 95 % CI 0.80–1.50; age ≥40: RR 1.16, 95 % CI 1.02–1.32; p-heterogeneity = 0.44). Risk of premenopausal breast cancer decreased with each additional year of age at menarche in both age groups (age <40: RR 0.93, 95 % CI 0.87–0.99; p trend = 0.02; age ≥40: RR 0.94, 95 % CI 0.91–0.97; p trend = <0.0001). Among premenopausal parous women, breastfeeding was protective regardless of age at diagnosis (age <40: RR 0.84, 95 % CI 0.57–1.22; age ≥40: RR 0.85, 95 % CI 0.72–0.99; p-heterogeneity = 0.79). In the largest prospective examination of reproductive risk factors and risk of breast cancer before and after age 40, we found that younger women were more likely to develop tumors with less favorable prognostic characteristics. However, associations between reproductive factors and risk of breast cancer were similar regardless of age at diagnosis of premenopausal breast cancer.