Summary Background Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been ...studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. Methods The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18–39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. Findings 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk RR 1·48 95% CI 1·23–1·78; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 95% CI 1·18–7·20, p=0·020, in participants ≤24 years; 1·61 1·05–2·48, p=0·029, in those aged 25–29 years; and 1·37 1·11–1·69, p=0·0035, in those aged 30–40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 95% CI 0·46–0·70, p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. Interpretation A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. Funding National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Epidemiologic studies that include patients who underwent radiation therapy for the treatment of cancer aim to quantify the relationship between radiotherapy and the risk of subsequent late effects. ...Because of the long follow-up period required to observe late effects, these studies are conducted retrospectively. The studies routinely include patients treated across numerous institutions using a wide range of technologies and represent treatments over several decades. As a result, determining the dose throughout the patient's body is uniquely challenging. Therefore, estimating doses throughout the patient's body for epidemiologic studies requires special methodologies that are generally applied to a wide range of radiotherapy techniques. Over ten years ago, the MD Anderson Late Effects Group described various dose reconstruction methods for therapeutic and diagnostic radiation exposure for epidemiologic studies. Here we provide an update to the most widely used dose reconstruction methodology for epidemiologic studies, analytical model calculations combined with a 3D age-specific computational phantom. In particular, we describe the various adaptations (and enhancements) of that methodology, as well as how they have been used in radiation epidemiology studies and may be used in future studies.
IMPORTANCE: Cancer treatments are associated with subsequent neoplasms in survivors of childhood cancer. It is unknown whether temporal changes in therapy are associated with changes in subsequent ...neoplasm risk. OBJECTIVE: To quantify the association between temporal changes in treatment dosing and subsequent neoplasm risk. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, multicenter cohort study of 5-year cancer survivors diagnosed before age 21 years from pediatric tertiary hospitals in the United States and Canada between 1970-1999, with follow-up through December 2015. EXPOSURES: Radiation and chemotherapy dose changes over time. MAIN OUTCOMES AND MEASURES: Subsequent neoplasm 15-year cumulative incidence, cumulative burden, and standardized incidence ratios for subsequent malignancies, compared by treatment decade. Multivariable models assessed relative rates (RRs) of subsequent neoplasms by 5-year increments, adjusting for demographic and clinical characteristics. Mediation analyses assessed whether changes in rates of subsequent neoplasms over time were mediated by treatment variable modifications. RESULTS: Among 23 603 survivors of childhood cancer (mean age at diagnosis, 7.7 years; 46% female) the most common initial diagnoses were acute lymphoblastic leukemia, Hodgkin lymphoma, and astrocytoma. During a mean follow-up of 20.5 years (374 638 person-years at risk), 1639 survivors experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 nonmelanoma skin cancers. The most common subsequent malignancies were breast and thyroid cancers. Proportions of individuals receiving radiation decreased (77% for 1970s vs 33% for 1990s), as did median dose (30 Gy interquartile range, 24-44 for 1970s vs 26 Gy interquartile range, 18-45 for 1990s). Fifteen-year cumulative incidence of subsequent malignancies decreased by decade of diagnosis (2.1% 95% CI, 1.7%-2.4% for 1970s, 1.7% 95% CI, 1.5%-2.0% for 1980s, 1.3% 95% CI, 1.1%-1.5% for 1990s). Reference absolute rates per 1000 person-years were 1.12 (95% CI, 0.84-1.57) for subsequent malignancies, 0.16 (95% CI, 0.06-0.41) for meningiomas, and 1.71 (95% CI, 0.88-3.33) for nonmelanoma skin cancers for survivors with reference characteristics (no chemotherapy, splenectomy, or radiation therapy; male; attained age 28 years). Standardized incidence ratios declined for subsequent malignancies over treatment decades, with advancing attained age. Relative rates declined with each 5-year increment for subsequent malignancies (RR, 0.87 95% CI, 0.82-0.93; P < .001), meningiomas (RR, 0.85 95% CI, 0.75-0.97; P = .03), and nonmelanoma skin cancers (RR, 0.75 95% CI, 0.67-0.84; P < .001). Radiation dose changes were associated with reduced risk for subsequent malignancies, meningiomas, and nonmelanoma skin cancers. CONCLUSIONS AND RELEVANCE: Among survivors of childhood cancer, the risk of subsequent malignancies at 15 years after initial cancer diagnosis remained increased for those diagnosed in the 1990s, although the risk was lower compared with those diagnosed in the 1970s. This lower risk was associated with reduction in therapeutic radiation dose.
Summary Background The reproductive implications of mutagenic treatments given to children with cancer are not clear. By studying the risk of untoward pregnancy outcomes, we indirectly assessed the ...risk of transmission of germline damage to the offspring of survivors of childhood cancer who were given radiotherapy and chemotherapy. Methods We did a retrospective cohort analysis, within the Childhood Cancer Survivor Study (CCSS), of the risk of stillbirth and neonatal death among the offspring of men and women who had survived childhood cancer. Patients in CCSS were younger than 21 years at initial diagnosis of an eligible cancer, were treated at 25 US institutions and one Canadian institution, and had survived for at least 5 years after diagnosis. We quantified the chemotherapy given to patients, and the preconception radiation doses to the testes, ovaries, uterus, and pituitary gland, and related these to the risk of stillbirth or neonatal death using Poisson regression analysis. Findings Among 1148 men and 1657 women who had survived childhood cancer, there were 4946 pregnancies. Irradiation of the testes (16 1% of 1270; adjusted relative risk 0·8 95% CI 0·4–1·6; mean dose 0·53 Gy SD 1·40) and pituitary gland (17 3% of 510, 1·1 0·5–2·4 for more than 20·00 Gy; mean dose 10·20 Gy 13·0 for women), and chemotherapy with alkylating drugs (26 2% of 1195 women, 0·9 0·5–1·5; ten 1% of 732 men, 1·2 0·5–2·5) were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased risk of stillbirth and neonatal death at doses greater than 10·00 Gy (five 18% of 28, 9·1 3·4–24·6). For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1·00–2·49 Gy significantly increased the risk of stillbirth or neonatal death (three 4% of 69, 4·7 1·2–19·0). Interpretation Our findings do not support concern about heritable genetic changes affecting the risk of stillbirth and neonatal death in the offspring of men exposed to gonadal irradiation. However, uterine and ovarian irradiation had serious adverse effects on the offspring that were probably related to uterine damage. Careful management is warranted of pregnancies in women given high doses of pelvic irradiation before puberty. Funding Westlakes Research Institute, National Cancer Institute, and Children's Cancer Research Fund.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the ...stroke risk in cancer survivors.
The Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors.
During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval CI 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6).
Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
The development of endocrinopathies in survivors of childhood cancer as they age remains understudied. We characterized endocrine outcomes in aging survivors from the Childhood Cancer Survivor Study ...on the basis of therapeutic exposures.
We analyzed self-reported conditions in 14,290 5-year survivors from the Childhood Cancer Survivor Study, with a median age 6 years (range, < 1 to 20 years) at diagnosis and 32 years (range, 5 to 58 years) at last follow-up. Identification of high-risk therapeutic exposures was adopted from the Children's Oncology Group Long-Term Follow-Up Guidelines. Cumulative incidence curves and prevalence estimates quantified and regression models compared risks of primary hypothyroidism, hyperthyroidism, thyroid neoplasms, hypopituitarism, obesity, diabetes mellitus, or gonadal dysfunction between survivors and siblings.
The cumulative incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors (P < .01 for all). Risk was significantly higher in survivors exposed to high-risk therapies compared with survivors not so exposed for primary hypothyroidism (hazard ratio HR, 6.6; 95% CI, 5.6 to 7.8), hyperthyroidism (HR, 1.8; 95% CI, 1.2 to 2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2 to 7.5), thyroid cancer (HR, 9.2; 95% CI, 6.2 to 13.7), growth hormone deficiency (HR, 5.3; 95% CI, 4.3 to 6.4), obesity (relative risk, 1.8; 95% CI, 1.7 to 2.0), and diabetes mellitus (relative risk, 1.9; 95% CI, 1.6 to 2.4). Women exposed to high-risk therapies had six-fold increased risk for premature ovarian insufficiency (P < .001), and men demonstrated higher prevalence of testosterone replacement (P < .001) after cyclophosphamide equivalent dose of 20 g/m(2) or greater or testicular irradiation with 20 Gy or greater. Survivors demonstrated an increased risk for all thyroid disorders and diabetes mellitus regardless of treatment exposures compared with siblings (P < .001 for all).
Endocrinopathies in survivors increased substantially over time, underscoring the need for lifelong subspecialty follow-up of those at risk.
•Radiation-related late cardiac disease risk is updated for the Childhood Cancer Survivor Study using enhanced dosimetry.•Consistent with previous findings, late cardiac disease risk increases with ...Dm ≥ 10 Gy, V20 ≥ 0.1%, and V5,V20=0% ≥ 50%.•Risks are significantly (P < 0.05) higher than previously estimated for survivors with Dm in the range of 20–29.9 Gy.•Risks are significantly (P < 0.05) higher than previously estimated for survivors with V20 in the range of 30–79.9%.
We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort.
We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20 = 0 (V5,V20=0%) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3–5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and V5,V20=0% (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable.
Consistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10 Gy, V20 ≥ 0.1%, and V5,V20=0% ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for Dm in the category of 20 to 29.9 Gy and V20 in the category of 30% to 79.9%. When changes in the linear dose–response relationship for Dm were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy.
These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date ...because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses.
Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression.
One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio OR = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors.
Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.
To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood ...cancer.
Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models.
Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%).
Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions.
Purpose We aimed to predict individual risk of ischemic heart disease and stroke in 5-year survivors of childhood cancer. Patients and Methods Participants in the Childhood Cancer Survivor Study ...(CCSS; n = 13,060) were observed through age 50 years for the development of ischemic heart disease and stroke. Siblings (n = 4,023) established the baseline population risk. Piecewise exponential models with backward selection estimated the relationships between potential predictors and each outcome. The St Jude Lifetime Cohort Study (n = 1,842) and the Emma Children's Hospital cohort (n = 1,362) were used to validate the CCSS models. Results Ischemic heart disease and stroke occurred in 265 and 295 CCSS participants, respectively. Risk scores based on a standard prediction model that included sex, chemotherapy, and radiotherapy (cranial, neck, and chest) exposures achieved an area under the curve and concordance statistic of 0.70 and 0.70 for ischemic heart disease and 0.63 and 0.66 for stroke, respectively. Validation cohort area under the curve and concordance statistics ranged from 0.66 to 0.67 for ischemic heart disease and 0.68 to 0.72 for stroke. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were < 5%, compared with approximately 20% for high-risk groups ( P < .001); cumulative incidence was only 1% for siblings ( P < .001 v low-risk survivors). Conclusion Information available to clinicians soon after completion of childhood cancer therapy can predict individual risk for subsequent ischemic heart disease and stroke with reasonable accuracy and discrimination through age 50 years. These models provide a framework on which to base future screening strategies and interventions.
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