Background Previously, eighteen percent of childhood cancer patients who survived five years died within the subsequent 25 years. In recent decades, cancer treatment regimens have been modified with the goal of reducing risk for life-threatening late effects. Methods Late mortality was evaluated in 34,033 five-year survivors of childhood cancer (diagnosed <21 years of age from 1970-1999, median follow-up 21 years, range 5-38). Demographic and disease factors associated with mortality due to health-related causes, which exclude recurrence/progression of the original cancer but include deaths that reflect late effects of cancer therapy, were evaluated using cumulative incidence and piecewise exponential models estimating relative rates (RRs) and 95% confidence intervals (CI). Results 1,618 (41%) of the 3,958 deaths were attributable to health-related causes, including 746 subsequent neoplasm, 241 cardiac, and 137 pulmonary deaths. Reduction in 15-year mortality was observed for all-cause (12.4% to 6.0%, P for trend <0.001) and health-related mortality (3.5% to 2.1%, P for trend <0.001), attributable to reductions in subsequent neoplasm (P<0.001), cardiac (P<0.001) and pulmonary death (P<0.001). Changes in therapy by decade included reduced rates of: cranial radiotherapy for acute lymphoblastic leukemia (1970s 85%, 1980s 51%, 1990s 19%), abdominal radiotherapy for Wilms’ tumor (78%, 53%, 43%), chest radiotherapy for Hodgkin's lymphoma (87%, 79%, 61%), and anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among lymphoblastic leukemia and Wilms’ tumor survivors. Conclusion The strategy of lowering therapeutic exposure has successfully translated to an observed decline in late mortality among 5-year survivors of childhood cancer.

Background No studies have estimated the population-level burden of morbidity in individuals diagnosed with cancer as children (ages 0-19 years). We updated prevalence estimates of childhood cancer survivors as of 2011 and burden of morbidity in this population reflected by chronic conditions, neurocognitive dysfunction, compromised health-related quality of life and health status (general health, mental health, functional impairment, functional limitations, pain and fear/anxiety). Methods Surveillance Epidemiology and End Results Program data from 1975 to 2011 were used to update the prevalence of survivors of childhood cancers in the US. Childhood Cancer Survivor Study data were used to obtain estimates of morbidity burden indicators which were then extrapolated to SEER data to obtain population-level estimates. Results There were an estimated 388,501 survivors of childhood cancer in the US as of January 1, 2011, of whom 83.5% are ≥5 years post-diagnosis. The prevalence of any chronic condition among ≥5-year survivors ranged from 66% (ages 5-19) to 88% (ages 40-49). Estimates for specific morbidities ranged from 12% (pain) to 35% (neurocognitive dysfunction). Generally, morbidities increased by age. However, mental health and anxiety remained fairly stable and neurocognitive dysfunction exhibited initial decline and then remained stable by time since diagnosis. Conclusions The estimated prevalence of survivors of childhood cancer is increasing, as is the estimated prevalence of morbidity in those ≥5 years post-diagnosis. Impact Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority.

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 compar...

Background: Treatments for childhood cancer have evolved in recent decades, with the goal of maximizing cure rates while minimizing the adverse effects of therapy. We aimed to evaluate incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment. Methods: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with prospective follow-up of 5-year survivors of childhood cancer diagnosed from 1970-1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. Multivariable regression models estimated hazard ratios per diagnosis decade, and addition of treatment variables assessed whether treatment changes attenuated associations between diagnosis decade and chronic disease risk. Findings: Among 23,601 survivors (median age 28, range 5-63 years; 46% female), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI, 32·0%-34·3%) in those diagnosed 1970-1979 to 29·3% (95% CI, 28·4%-30·2%, p<0·0001) in 1980-1989, and 27·5% (95% CI, 26·4%-28·6%, p=0·012 vs. 1980-1989) in 1990-1999. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition among 5,051 siblings was 4·6% (95% CI,3·9%-5·2%). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-1999 compared to 1970-1979 for Hodgkin lymphoma (17·7% vs. 26·4%, p<0·0001), non-Hodgkin lymphoma (16·9% vs. 23·8%, p=0.0053), astrocytoma (30·5% vs. 47·3%, p<0·0001), Wilms tumor (11·9% vs. 17·6%, p=0·034), soft tissue sarcoma (28·3% vs. 36·5%, p=0·021), and osteosarcoma (65·6% vs. 87·5%, p<0·0001). In contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-1999 vs. 1970-1979) for medulloblastoma/PNET (58·9% vs. 42·9%, p=0·00060) and neuroblastoma (25·0% vs. 18·0%, p=0·0045). Results were consistent with changes in treatment as a mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma, Hodgkin lymphoma, and non-Hodgkin lymphoma. Temporal decreases were observed for endocrinopathies, subsequent malignant neoplasms, musculoskeletal conditions, and gastrointestinal conditions, while hearing loss increased. Interpretation: Our results provide novel evidence that more recently treated survivors of childhood cancer have experienced improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximize cure while reducing risk of late effects. Continuing advances in cancer therapy offer promise of further reducing the risk of late effects. However, achieving a cure for childhood cancer continues to come at a cost for many survivors, emphasizing the importance of long-term follow-up care for this population. Funding: National Cancer Institute and t...

Objective HIV-infected people have greatly elevated risk of non-Hodgkin lymphoma (NHL), particularly the AIDS-defining NHL subtypes: diffuse large B-cell lymphoma, Burkitt lymphoma and primary lymphomas arising in the central nervous system. The goals of this analysis were to comprehensively describe risks of NHL subtypes, especially those not well studied, among HIV/AIDS patients; examine risks specifically in the HAART era; and distinguish risks in HIV-infected individuals prior to diagnosis with AIDS. Design Population-based registry linkage study. Methods We used data from the US HIV/AIDS Cancer Match Study from 1996 to 2010 (N = 273 705) to calculate standardized incidence ratios (SIRs) comparing subtype specific NHL risks in HIV-infected people to those in the general population, and used Poisson regression to test for differences in SIRs between the HIV-only and AIDS periods. Results NHL risk was elevated 11-fold compared to the general population, but varied substantially by subtype. AIDS-defining NHL subtypes comprised the majority, and risks were high (SIRs ≥ 17), but risks were also increased for some T-cell lymphomas (SIRs = 3.6–14.2), marginal zone lymphoma (SIR = 2.4), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (SIR = 3.6), and acute lymphoblastic leuke mia/lymphoma (SIR = 2.4). Conclusion HIV-infected people in the HAART era continue to have elevated risk of AIDS-defining NHL subtypes, highlighting the contribution of moderate and severe immunosuppression to their cause. Whereas non-AIDS-defining subtypes are much less common, immunosuppression or other dysregulated immune states likely play a role in the cause of some T-cell lymphomas, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, and acute lymphoblastic leukemia/lym phoma.

Background:Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.Methods:We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.Results:The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.Conclusion:Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.

PURPOSE The impacts of radiotherapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk for late-onset cardiac disease in survivors of childhood cancer remain unresolved. PATIENTS AND METHODS We determined the rates of severe to fatal cardiac disease in 24,214 5-year survivors in the Childhood Cancer Survivor Study diagnosed between 1970 and 1999 at a median age of 7.0 years (range, 0 to 20.9 years), with a median attained age of 27.5 years (range, 5.6 to 58.9 years). Using piecewise exponential models, we evaluated the association between cardiac disease rates and demographic and treatment characteristics. RESULTS The cumulative incidence of cardiac disease 30 years from diagnosis was 4.8% (95% CI, 4.3 to 5.2). Low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (≥ 50% of heart) were associated with an increased rate of cardiac disease (relative rate, 1.6; 95% CI, 1.1 to 2.3) compared with survivors without cardiac radiotherapy exposure. Similarly, high doses (≥ 20 Gy) to small cardiac volumes (0.1% to 29.9%) were associated with an elevated rate (relative rate, 2.4; 95% CI, 1.4 to 4.2). A dose-response relationship was observed between anthracycline chemotherapy and heart failure with younger children (age ≤ 13 years) at the greatest risk for heart failure after comparable dosing. CONCLUSION These observations support advances in radiation field design and delivery technology to reduce cardiac dose/volume and should guide future treatment protocols. They also inform clinical practice guidelines for post-therapy surveillance and risk-reducing strategies.

ObjectiveTo investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer.DesignRetrospective cohort study.Setting27 institutions participating in the Childhood Cancer Survivor Study.Participants23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included.Main outcome measuresCumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments.ResultsThe 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10).ConclusionsHistorical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes.Trial registrationClinicalTrials.gov NCT01120353.