Excess Absolute Risk Research Articles

Dosimetric Evaluation and Second Primary Cancer Risk Prediction after Three-Dimensional Ultrasound-Guided Radiotherapy of Cervical Cancer

To evaluate clinical significance of three-dimensional ultrasound guided radiotherapy on cervical cancer, and then predict the risks of second cancers and radiation dose-volume effects on small bowel. The 65 patients with stage IIb cervical cancer treated with radical radiotherapy were included. A detailed protocol was described in a previously published article [Med Phys, 2016, 43(7):4412-4419]. The centroid displacement and three triaxial changes of all organs were calculated. The lifetime attributed risk (LAR) described by BEIR VII was estimated from the differential DVHs derived from CT and fractional CBCTs of each patient, by employing excess absolute risk (EAR) model and dose-response relationships (RED) mechanistic model. For the ultrasound guidance vs. no-ultrasound guidance, the centroid displacement of targets and bladder, caused by the bladder volume changes [12.14 ± 74.48 ml (5.6% ± 23.74%) vs. -152.92 ± 100.57 ml (-35.50% ± 42.89%)], were 0.91 ± 0.51cm vs. 0.94 ± 0.40 cm and 0.62 ± 0.43cm vs. 1.81 ± 0.76 cm, respectively. Meanwhile, the dose changes of targets were -13.37% ± 9.48% vs. -9.2% ± 8.95% (Dmin) and -0.55% ± 1.60% vs. 1.40% ± 2.39% (Dmax), and the irradiated dose changes of bladders were 0.34% ± 3.60% vs. 4.90% ± 4.40% (Dmean). T-test of two groups showed that there was no significant change in targets (P < 0.05), but significant difference in volume and irradiated dose of bladder (P > 0.05). The relative risk (RR) ratio for bladder, kidneys, rectum, corpus uteri and ovaries was 1.1. The RR was higher among those under age 30 years at exposure (RR = 3.9) than among older women. Late small-bowel toxicity was likely related to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. The high dose pelvic irradiation was associated with increase in cancers of the bladder, kidneys, rectum, corpus uteri and ovaries. However, 3D ultrasound guided radiotherapy for cervical cancer can reduce the incidence of bladder complications and secondary primary cancer.

Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases

SummaryBackgroundThe past few decades have seen substantial improvements in cancer survival, but concerns exist about long-term cardiovascular disease risk in survivors. Evidence is scarce on the risks of specific cardiovascular diseases in survivors of a wide range of cancers to inform prevention and management. In this study, we used large-scale electronic health records data from multiple linked UK databases to address these evidence gaps.MethodsFor this population-based cohort study, we used linked primary care, hospital, and cancer registry data from the UK Clinical Practice Research Datalink to identify cohorts of survivors of the 20 most common cancers who were 18 years or older and alive 12 months after diagnosis and controls without history of cancer, matched for age, sex, and general practice. We compared risks for a range of cardiovascular disease outcomes using crude and adjusted Cox models. We fitted interactions to investigate effect modification, and flexible parametric survival models to estimate absolute excess risks over time.FindingsBetween Jan 1, 1990, and Dec 31, 2015, 126 120 individuals with a diagnosis of a cancer of interest still being followed up at least 1 year later were identified and matched to 630 144 controls. After exclusions, 108 215 cancer survivors and 523 541 controls were included in the main analyses. Venous thromboembolism risk was elevated in survivors of 18 of 20 site-specific cancers compared with that of controls; adjusted hazard ratios (HRs) ranged from 1·72 (95% CI 1·57–1·89) in patients after prostate cancer to 9·72 (5·50–17·18) after pancreatic cancer. HRs decreased over time, but remained elevated more than 5 years after diagnosis. We observed increased risks of heart failure or cardiomyopathy in patients after ten of 20 cancers, including haematological (adjusted HR 1·94, 1·66–2·25, with non-Hodgkin lymphoma; 1·77, 1·50–2·09, with leukaemia; and 3·29, 2·59–4·18, with multiple myeloma), oesophageal (1·96, 1·46–2·64), lung (1·82, 1·52–2·17) kidney (1·73, 1·38–2·17) and ovarian (1·59, 1·19–2·12). Elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were also observed for multiple cancers, including haematological malignancies. HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in patients without previous cardiovascular disease and in younger patients. However, absolute excess risks were generally greater with increasing age. Increased risks of these outcomes seemed most pronounced in patients who had received chemotherapy.InterpretationSurvivors of most site-specific cancers had increased medium-term to long-term risk for one or more cardiovascular diseases compared with that for the general population, with substantial variations between cancer sites.FundingWellcome Trust and Royal Society.

Subtypes of atrial fibrillation with concomitant valvular heart disease derived from electronic health records: phenotypes, population prevalence, trends and prognosis.

AimsTo evaluate population-based electronic health record (EHR) definitions of atrial fibrillation (AF) and valvular heart disease (VHD) subtypes, time trends in prevalence and prognosis.Methods and resultsA total of 76 019 individuals with AF were identified in England in 1998–2010 in the CALIBER resource, linking primary and secondary care EHR. An algorithm was created, implemented, and refined to identify 18 VHD subtypes using 406 diagnosis, procedure, and prescription codes. Cox models were used to investigate associations with a composite endpoint of incident stroke (ischaemic, haemorrhagic, and unspecified), systemic embolism (SSE), and all-cause mortality. Among individuals with AF, the prevalence of AF with concomitant VHD increased from 11.4% (527/4613) in 1998 to 17.6% (7014/39 868) in 2010 and also in individuals aged over 65 years. Those with mechanical valves, mitral stenosis (MS), or aortic stenosis had highest risk of clinical events compared to AF patients with no VHD, in relative [hazard ratio (95% confidence interval): 1.13 (1.02–1.24), 1.20 (1.05–1.36), and 1.27 (1.19–1.37), respectively] and absolute (excess risk: 2.04, 4.20, and 6.37 per 100 person-years, respectively) terms. Of the 95.2% of individuals with indication for warfarin (men and women with CHA2DS2-VASc ≥1 and ≥2, respectively), only 21.8% had a prescription 90 days prior to the study.ConclusionPrevalence of VHD among individuals with AF increased from 1998 to 2010. Atrial fibrillation associated with aortic stenosis, MS, or mechanical valves (compared to AF without VHD) was associated with an excess absolute risk of stroke, SSE, and mortality, but anticoagulation was underused in the pre-direct oral anticoagulant (DOAC) era, highlighting need for urgent clarity regarding DOACs in AF and concomitant VHD.

The Potential Role of Intensity-modulated Proton Therapy in the Regional Nodal Irradiation of Breast Cancer: A Treatment Planning Study

AimsTo investigate the role of intensity-modulated proton therapy (IMPT) for regional nodal irradiation in patients with breast carcinoma in comparison with volumetric-modulated arc therapy (VMAT). Materials and methodsA cohort of 20 patients (10 in the breast-conserving surgery group and 10 post-mastectomy patients with tissue expander implants) was investigated. Proton plans were also computed using robust optimisation methods. Plan quality was assessed by means of dose–volume histograms and scored with conventional metrics. Estimates of the risk of secondary cancer induction (excess absolute risk, EAR) were carried out, taking into account fractionation, repopulation and repair. ResultsConcerning target coverage, the data proved a substantial equivalence of VMAT and IMPT: for example, coverage for the 50 Gy target, expressed in terms of V98%, was 47.8 ± 0.4, 47.6 ± 0.4, 47.3 ± 0.8, consistent with the objective of 47.5 Gy, for post-mastectomy patients for the three groups of patients. Also, the conformality of the dose distributions was similar for the two techniques, about 1.1, without statistically significant differences. Organ at risk planning aims were achieved for all structures for both techniques. The mean dose to the ipsilateral lung was 10.8 ± 1.1, 6.2 ± 0.8, 7.2 ± 1.0; for the contralateral lung was 3.2 ± 0.7, 0.3 ± 0.2, 0.4 ± 0.2; for the contralateral breast was: 3.1 ± 0.7, 0.3 ± 0.3 and 0.3 ± 0.3, whereas it was 3.9 ± 0.9, 0.4 ± 0.3 and 0.5 ± 0.5, respectively, for the heart for VMAT, IMPT and robust IMPT plans over the whole group of patients. Robust optimisation affected the near-to-maximum dose values for contralateral lung and breast, the mean dose for the heart and ipsilateral lung, with a deterioration ranging from 20 to 40% of the nominal value of IMPT plans (e.g. from 8.1 ± 6.4 to 11.4 ± 8.8 for the heart compared with 16.2 ± 5.2 for the VMAT plans). The numerical values of EAR per 10 000 patient-years were about one order of magnitude higher for VMAT than for IMPT for contralateral structures: 11.66 ± 2.01, 0.89 ± 0.80, 0.98 ± 0.77 for the contralateral breast and the three groups of plans, respectively; 14.31 ± 2.75, 1.42 ± 0.80, 1.78 ± 0.87 for the contralateral lung; and 34.86 ± 2.64, 18.85 ± 2.15, 20.98 ± 2.35 for the ipsilateral lung. ConclusionIMPT with or without robust optimisation seems to be a potentially promising approach for the radiation treatment of breast cancer when nodal volumes should be irradiated. This was measured in terms of dosimetric advantage and predicted clinical benefit. In fact, the significant reduction in estimated EAR could add further clinical value to the dosimetric sparing of the organs at risk achievable with IMPT.

Normal tissue complication probability models in plan evaluation of children with brain tumors referred to proton therapy

Background: Children with brain tumors undergoing radiotherapy are at particular risk of radiation-induced morbidity and are therefore routinely considered for proton therapy (PT) to reduce the dose to healthy tissues. The aim of this study was to apply pediatric constraints and normal tissue complication probability (NTCP) models when evaluating the differences between PT and contemporary photon-based radiotherapy, volumetric modulated arc therapy (VMAT).Methods: Forty patients (aged 1–17 years) referred from Norwegian institutions to cranial PT abroad during 2014–2016 were selected for VMAT re-planning using the original CT sets and target volumes. The VMAT and delivered PT plans were compared by dose/volume metrics and NTCP models related to growth hormone deficiency, auditory toxicity, visual impairment, xerostomia, neurocognitive outcome and secondary brain and parotid gland cancers.Results: The supratentorial brain, temporal lobes, hippocampi, hypothalamus, pituitary glands, cochleas, salivary glands, optic nerves and chiasm received lower mean doses from PT. Reductions in population median NTCP were significant for auditory toxicity (VMAT: 3.8%; PT: 0.3%), neurocognitive outcome (VMAT: 3.0 IQ points decline at 5 years post RT; PT: 2.5 IQ points), xerostomia (VMAT: 2.0%; PT: 0.6%), excess absolute risk of secondary cancer of the brain (VMAT: 9.2%; PT: 6.7%) and salivary glands (VMAT: 2.8%; PT:0.5%). Across all patients, 23/38 PT plans had better or comparable estimated risks for all endpoints (within ±10% of the risk relative to VMAT), whereas for 1/38 patients all estimates were better or comparable with VMAT.Conclusions: PT reduced the volumes of normal tissues exposed to radiation, particularly low-to-intermediate dose levels, and this was reflected in lower NTCP. Of the included endpoints, substantial reductions in population medians were seen from the delivered PT plans for auditory complications, xerostomia, and risk of secondary cancers of the brain and salivary glands.

Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958-2009.

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0-9, 10-19 and 20-29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: -0.02, 95% CI: -0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

Second primary malignancies in patients with non-melanoma skin cancer: Results from a cancer registry–based study in Emilia Romagna, north-east Italy

Backgroundprevious research on the risk of subsequent, primary non-cutaneous malignancies among patients with non-melanoma skin cancers (NMSCs) led to conflicting results. We aimed to investigate a possible link between NMSC and second primary malignancies by using the population-based data available in cancer registries. Methodsthis observational study retrospectively assessed the risk of occurrence of both synchronous and methachronous second primary tumours in a cohort of cancer patients whose first diagnosis was NMSC. The cohort came from the network of general cancer registries of the Emilia-Romagna Region, northeast Italy, in the period between 1978 and 2012, and was compared with the general population living in the same area. Two main indexes were used: i) Standardized Incidence Ratio (SIR), calculated as the ratio between the observed and the expected number of second cancers and ii) Excess Absolute Risk (EAR), expressing the absolute excess or deficit of second cancer incidence. Resultsin the period analysed (1978–2012, 72,503,157 person/years, PYs), 89,912 primary NMSC were found in 76,414 patients. Among them, 14,195 developed a second primary cancer in the subsequent 501,763 follow-up PYs. NMSC patients showed an overall SIR of 1.22 (CI 95% 1.20-1,24) and an EAR of 5.11 cases/1000 PYs (CI 95% 4.48–5.74). Conclusionsthe study results showed that NMSC patients had an increase in relative risk and, at least for some tumours, in absolute risk of developing a second cancer when compared with the general population. Genetic, environmental and personal risk factors may influence this finding.

Plan Quality and Secondary Cancer Risk Assessment in Patients with Benign Intracranial Lesions after Radiosurgery using the CyberKnife M6 Robotic Radiosurgery System

This study was performed to examine the quality of planning and treatment modality using a CyberKnife (CK) robotic radiosurgery system with multileaf collimator (MLC)-based plans and IRIS (variable aperture collimator system)-based plans in relation to the dose–response of secondary cancer risk (SCR) in patients with benign intracranial tumors. The study population consisted of 15 patients with benign intracranial lesions after curative treatment using a CyberKnife M6 robotic radiosurgery system. Each patient had a single tumor with a median volume of 6.43 cm3 (range, 0.33–29.72 cm3). The IRIS-based plan quality and MLC-based plan quality were evaluated by comparing the dosimetric indices, taking into account the planning target volume (PTV) coverage, the conformity index (CI), and the dose gradient (R10% and R50%). The dose–response SCR with sarcoma/carcinoma induction was calculated using the concept of the organ equivalent dose (OED). Analyses of sarcoma/carcinoma induction were performed using excess absolute risk (EAR) and various OED models of dose–response type/lifetime attributable risk (LAR). Moreover, analyses were performed using the BEIR VII model. PTV coverage using both IRIS-based plans and MLC-based plans was identical, although the CI values obtained using the MLC-based plans showed greater statistical significance. In comparison with the IRIS-based plans, the MLC-based plans showed better dose falloff for R10% and R50% evaluation. The estimated difference between Schneider’s model and BEIR VII in linear-no-threshold (Lnt) cumulative EAR was about twofold. The average values of LAR/EAR for carcinoma, for the IRIS-based plans, were 25% higher than those for the MLC-based plans using four SCR models; for sarcoma, they were 15% better in Schneider’s SCR models. MLC-based plans showed slightly better conformity, dose gradients, and SCR reduction. There was a slight increase in SCR with IRIS-based plans in comparison with MLC-based plans. EAR analyses did not show any significant difference between PTV and brainstem analyses, regardless of the tumor volume. Nevertheless, an increase in target volume led to an increase in the probability of SCR. EAR showed statistically significant differences in the soft tissue according to tumor volume (1–10 cc and ≥10 cc).

Estimation of radiotherapy modalities for patients with stage I-II nasal natural killer T-Cell lymphoma.

PurposeThe objective of this study is to estimate radiotherapy (RT) modalities for patients with stage I-II nasal natural killer T-Cell lymphoma (NNKTCL), including plan quality, radiation delivery efficiency, cost of RT and excess absolute risk (EAR).Materials and methodsTwenty-four representative patients with stage I-II NNKTCL treated with fix-field intensity-modulated radiotherapy (FF-IMRT) were re-planned for volumetric modulated arc therapy (VMAT), TomoDirect (TD) and TomoHelical (TH) on the TomoHDA system, respectively. Plan characteristics, cost of RT and EAR were compared.ResultsCompared with IMRT, TD and TH showed significant improvement in terms of D98%, D2%, cold spot volume and homogeneity index (HI) of planning target volume (PTV), while achieving worse Dmean and conformity index (CI). The mean dose of oropharynx, thyroid and left salivary, and the maximum dose of right salivary by TD (249.20%, p=0.000; 52.94%, p=0.000; 160.23%, p=0.022; 122.67%, p=0.027), VMAT (15.76%, p=0.000; 23.53%, p=0.000; 34.09%, p=0.000; 31.33%, p=0.000) and TH (250.32%, p=0.000; 58.82%, p=0.000; 120.45%, p=0.020; 117.33%, p=0.032) increased significantly compared to IMRT. VMAT reduced treatment time (p=0.000; 0.000; 0.000) and monitor units (MUs) (p=0.000; 0.000; 0.000) obviously compared with IMRT, TD and TH. The cost of RT for TD and TH increased 150% compared with IMRT and VMAT. IMRT obtained the lowest EAR to oropharynx, thyroid, left and right salivary gland in the four treatment modalities.ConclusionThe results show that both TD and TH can achieve higher conformal target quality while getting worse organs at risk (OARs) sparing and EAR to some organs than IMRT for patients with stage I-II NNKTCL. IMRT delivers the lowest dose to most OARs, VMAT requires the lower cost of RT and shortest delivery time, and TH obtained the optimal target coverage. The results could provide direction for selecting proper RT modalities for different cases.

Suicide, other externally caused injuries and cardiovascular death following a cancer diagnosis: study protocol for a nationwide population-based study in Japan (J-SUPPORT 1902)

IntroductionA growing body of literature has demonstrated that cancer patients have a higher risk of suicide and cardiovascular mortality compared with the general population, especially immediately after a cancer diagnosis....

Risk of subsequent primary leukaemias among 69,460 five-year survivors of childhood cancer diagnosed from 1940 to 2008 in Europe: A cohort study within PanCareSurFup

BackgroundSurvivors of childhood cancers are at risk of developing subsequent primary leukaemias (SPLs), but the long-term risks beyond 20 years of treatment are still unclear. We investigated the risk of SPLs in five-year childhood cancer survivors using a large-scale pan-European (PanCareSurFup) cohort and evaluated variations in the risk by cancer and demographic factors. MethodsThis largest-ever assembled cohort comprises 69,460 five-year childhood cancer survivors from 12 European countries. Standardised incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. ResultsOne hundred fifteen survivors developed an SPL including 86 myeloid leukaemias (subsequent primary myeloid leukaemias [SPMLs]), 17 lymphoid leukaemias and 12 other types of leukaemias; of these SPLs, 31 (27%) occurred beyond 20 years from the first childhood cancer diagnosis. Compared with the general population, childhood cancer survivors had a fourfold increased risk (SIR = 3.7, 95% confidence interval [CI]: 3.1 to 4.5) of developing leukaemia, and eight leukaemias per 100,000 person-years (AER = 7.5, 95% CI: 6.0 to 9.2) occurred in excess of that expected. The risks remained significantly elevated beyond 20 years from the first primary malignancy (SIR = 2.4, 95% CI: 1.6 to 3.4). Overall, the risk ratio for SPML (SIR = 5.8, 95% CI: 4.6 to 7.1) was higher than that for other SPLs. ConclusionsWe demonstrate that beyond 20 years after childhood cancer diagnosis, survivors experience an increased risk for SPLs compared with that expected from the general population. Our findings highlight the need for awareness by survivors and their healthcare providers for potential risk related to SPL.

Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation

AbstractWe examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMNs) in the era of reduced-intensity and nonmyeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4905 1-year survivors of allogeneic HCT for hematologic malignancies (N = 4500) or nonmalignant disorders (N = 405) who received transplants between 1969 and 2014, we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMNs by 30 years after HCT was 22.0%. Compared with age-, sex-, and calendar year–matched Surveillance, Epidemiology, and End Results (SEER) population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR, 28.8), oral cavity (SIR, 13.8), skin (SIR, 7.3), central nervous system (SIR, 6.0), and endocrine organs (SIR, 4.9). The highest excess absolute risks (EARs) were seen with breast cancer (EAR, 2.2) and cancers of the oral cavity (EAR, 1.5) and skin (EAR, 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1000 cGy) or high-dose fractionated (1440-1750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still twofold higher than in the general population. These data demonstrate a strong effect of TBI dose, dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMNs increases with follow-up time; thus, HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs.

Cause-specific mortality in survivors of lymphoplasmacytic lymphoma (LPL) and waldenstrom macroglobulinemia (WM).

e19056 Background: LPL and WM are rare, indolent mature B-cell lymphomas. While recent studies reveal improving survival after LPL/WM, cause-specific mortality has not been comprehensively studied. Methods: We identified 6659 adults with first primary LPL (n = 2866) or WM (n = 3793) within 17 US population-based cancer registries from 2000 to 2015. Patients were followed for vital status (mean follow-up = 5.07 years), and causes of death were determined from death certificates. Standardized mortality ratios (SMRs) estimated relative risk of death compared to the general population. We estimated cumulative mortality and absolute excess risk (AER) per 10,000 person-years. Results: We observed 2826 deaths overall, of which 43%, 13%, and 42% were due to lymphoma, cancers excluding lymphoma, and non-malignant causes, respectively. There was a 20% higher risk of death due to non-malignant causes compared to the general population (n = 1194, SMR = 1.2, 95% confidence interval [CI] = 1.1 to 1.2). The most common non-malignant causes included infectious (n = 162, SMR = 1.8, 95% CI = 1.5 to 2.1, AER = 21.0), respiratory (n = 131, SMR = 1.2, 95% CI = 1.0 to 1.5, AER = 7.4), and digestive (n = 76, SMR = 1.9, 95% CI = 1.5 to 2.4, AER = 10.7) diseases. Cause-specific mortality varied by time since and age at LPL/WM diagnosis. Risks were highest in the first year after LPL/WM for non-malignant causes (SMR = 1.4, AER = 34.3), particularly infections (SMR = 2.4, AER = 34.4) and non-neoplastic hematologic diseases (SMR = 17.3, AER = 20.7). In contrast, risk of death due to cancers excluding lymphoma increased with time since diagnosis (SMR&lt; 1y = 1.2, SMR≥5y = 1.7; AER&lt; 1y = 15.1, AER≥5y = 60.0). Analyses by age, focused on AERs, showed generally similar risks across age groups (cancers excluding lymphoma: AER&lt; 65= 26, AER65-75= 28, AER≥75= 31; non-malignant causes: AER&lt; 65= 52, AER65-75= 66, AER≥75= 23). Cumulative mortality from non-malignant causes (23.7%) exceeded that from lymphoma (22.9%) beginning 9 years after LPL/WM diagnosis. Conclusions: Using population data, we identified areas to improve survivorship care of LPL/WM patients, particularly for non-malignant causes of death.

The risk of second primary malignancy in patients with localized thymoma: A U.S. population-based study.

8568 Background: Thymoma is a rare neoplasm of anterior mediastinum. Patients often have an indolent disease. The prognosis of limited stage disease is excellent with a 10-year survival rate of 70 to 80%. Data regarding the risk of second primary malignancy in thymoma survivors are limited in recent years. In this study, we aimed to determine the risk of second primary malignancies (SPMs) among patients with limited stage thymoma. Methods: We utilized the Surveillance, Epidemiology and End Results (SEER)-13 registry to identify adult patients (≥ 18 years) with limited stage thymoma. We calculated the risk of SPM, developing ≥ 6 months after an index thymoma diagnosis, using Multiple Primary Standardized Incidence Ratio and an Absolute Excess Risk (AER) between 2004 and 2010. Statistical significance was defined as p &lt; 0.05. Results: The database identified a cohort of 1,544 patients with limited stage thymoma with a median follow-up duration of 107 months (11-281 months). A total of 176 (11.39%) patients developed SPMs with a median latency of 62.5 months (range 6-272 months). Median age at diagnosis of SPM was 69 years (range 25- 96 years). Overall, SPM occurred at an observed to expected (O/E) ratio of 1.53 (95% CI 1.32-1.76), p &lt; 0.001 with an AER of 60.52 per 10,000 patient-years at risk. A significantly increased risk was noted for cancer of lung and bronchus (O/E 1.77, 95% CI 1.21-2.52, p = 0.004; AER 12.17/10,000), skin excluding basal and squamous (O/E 2.09, 95% CI 1.04-3.75, p = 0.03; AER 5.17/10,000), urinary bladder (O/E 2.14, 95% CI 1.17-3.6, p = 0.014; AER 6.72/10,000), thyroid (O/E 3.48, 95% CI 1.4-7.17,p = 0.009; AER 4.49/10,000), and leukemia (O/E 3.26, 95% CI 1.63-5.83, p = 0.001; AER 6.86/10,000), including acute lymphocytic leukemia (O/E 16.09, CI: 1.95-58.11; AER 1.69/10,000), acute myeloid leukemia (O/E 3.83, CI: 1.04-9.8; AER 2.66/10,000) and other acute leukemia (O/E 29.45, CI: 3.57-106.39; AER 1.74/10,000). The risk was not significant for lymphoma (Hodgkin and non-Hodgkin), chronic leukemia, oropharyngeal, digestive tract and hepatobiliary cancer as SPM. Conclusions: The risk for SPMs is significantly increased in patient with thymoma compared to general population. Given the long-term risk of SPM, patient should be followed closely with judicious use of age-appropriate cancer screening.

Chronic health conditions (CHC) and late mortality in survivors of acute lymphoblastic leukemia (ALL) in the Childhood Cancer Survivor Study.

10016 Background: The impact of evolving risk-stratified therapy on long-term morbidity and mortality in survivors of childhood ALL remains largely unknown. Methods: All-cause and health-related late mortality (HRM; captures death from late-effects occurring &gt; 5 yrs from diagnosis), subsequent (malignant) neoplasm [S(M)N], CTCAE graded CHC and neurocognitive outcomes were assessed in 5-yr survivors of ALL diagnosed &lt; 21 yrs of age from 1970-99. Therapy combinations defined 6 groups: 1970s-like ( 70s), standard and high risk 1980s- and 1990s-like ( 80sSR, 80sHR, 90sSR, 90sHR), relapse/transplant ( R/BMT). Cumulative incidence and standardized mortality ratios (SMR) were calculated. Piecewise exponential and log-binomial models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 6148 survivors (median age 31.5 yrs), 15-yr cumulative incidence of all-cause mortality was 5.8% (CI 5.3-6.2) and HRM was 1.5% (1.2-1.7). Compared to 70s, HRM was lower for 90sSR and 90sHR (RR 0.1, CI 0.0-0.3; 0.2, 0.1-0.7), similar to that in the US population (SMR; CI: 90sSR 1.1; 0.6-1.9, 90sHR 1.9; 0.8-3.7). 20-yr cumulative incidence of SN was 3.5% (CI 3.1-3.9). Compared to 70s, 90sSR had lower risk of benign meningioma (RR 0.1, CI 0.0-0.3) and SMN (0.3, 0.1-0.6) with no absolute excess risk compared to the US population. 90sSR was associated with a lower risk of CHCs (Table). Conclusions: More recent risk-stratified therapy has succeeded in reducing risk of late mortality and CHCs among long-term survivors of ALL. [Table: see text]

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.

Risk of Mortality and Hospitalization After Post-Pancreatitis Diabetes Mellitus vs Type 2 Diabetes Mellitus: A Population-Based Matched Cohort Study

To investigate the risk of mortality and hospitalization in individuals with post-pancreatitis diabetes mellitus (PPDM) compared with those with type 2 diabetes mellitus (T2DM). Using nationwide hospital discharge data on pancreatitis and diabetes in New Zealand (n = 231,943), a total of 959 individuals with PPDM were identified. For each individual with PPDM, 10 age- and sex-matched individuals with T2DM were randomly selected. Multivariable Cox regression analysis was conducted, and the risk was expressed as hazard ratio (HR) and 95% confidence interval (CI). A total of 3,867 deaths occurred among 10,549 study individuals. Individuals with PPDM had all-cause mortality rate at 80.5 (95% CI, 70.3-90.6) per 1,000 person-years, which was higher compared with T2DM individuals (adjusted HR, 1.13 (95% CI, 1.00-1.29); absolute excess risk, 14.8 (95% CI, 4.5-25.2) per 1,000 person-years). Compared with T2DM, PPDM was associated with higher risks of mortality from cancer (adjusted HR, 1.44; 95% CI, 1.13-1.83), infectious disease (adjusted HR, 2.52; 95% CI, 1.69-3.77), and gastrointestinal disease (adjusted HR, 2.56; 95% CI, 1.64-4.01). Individuals with PPDM vs T2DM were also at significantly higher risks of hospitalization for chronic pulmonary disease, moderate to severe renal disease, and infectious disease. Individuals with PPDM have higher risk of mortality and hospitalization compared with individuals with T2DM. Guidelines for management of PPDM need to be developed with a view to preventing excess deaths and hospitalizations in individuals with PPDM.

Disease-specific Hospitalizations Among 5-Year Survivors of Hepatoblastoma: A Nordic Population-based Cohort Study.

The long-term risk of somatic disease in hepatoblastoma survivors has not been thoroughly evaluated in previous studies. In this population-based study of 86 five-year HB survivors, we used inpatient registers to evaluate the risk for a range of somatic diseases. In total, 86 five-year survivors of hepatoblastoma were identified in the Nordic cancer registries from 1964 to 2008 and 152,231 population comparisons were selected. Study subjects were followed in national hospital registries for somatic disease classified into 12 main diagnostic groups. Standardized hospitalization rate ratios (RRs) and absolute excess risks were calculated. After a median follow-up of 11 years, 35 of the 86 five-year hepatoblastoma survivors had been hospitalized with a total of 69 hospitalizations, resulting in an RR of 2.7 (95% confidence interval [CI], 2.2-3.5) and an overall absolute excess risk of 4.2 per 100 person-years. Highest risk was seen for benign neoplasms (RR=16) with 6 hospitalizations for benign neoplasms in the colon and one in rectum. The pattern of hospitalizations found in this first comprehensive follow-up of hepatoblastoma survivors seems reassuring. Less than 50% of the 5-year survivors had been hospitalized and often for diseases that were not severe or life-threatening.

Incidence of second malignancies in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) have near-normal life expectancies. With this comes the possibility of developing second cancers; we aimed to evaluate the incidence of second malignancies in patients with CML using Surveillance, Epidemiology, and End Results Program data. We identified 13,276 patients with CML newly diagnosed in 2001-2014. Patients who had prior history of cancer, a concurrent diagnosis of other malignancies in the same diagnostic year, or a second leukemia after CML diagnosis were excluded. Second malignancies were observed in 597 patients (4%) with a median follow-up of 69months. The 5- and 10-year cumulative incidences of death for all patients were 30.5% and 41.8%. The 5- and 10-year cumulative incidences of second malignancies were 4.4% and 7.2%, respectively. The overall standardized incidence ratio (SIR) was 1.204. Increased SIRs compared to the general population were observed for the male genital system, 1.593; digestive system, 1.291; skin, 1.588; and urinary system, 1.366. Overall excess absolute risk was 1.714 per 1000 person-years at risk. Our results suggest that relative incidence of overall second malignancies in CML is slightly higher than that of the general population, with minimal increase in the excess absolute risk.

Long-Term Risk of Skin Cancer Among Childhood Cancer Survivors: A DCOG-LATER Cohort Study.

Skin cancer is common after radiotherapy among childhood cancer survivors (CCSs). We studied risks and risk factors for subsequent skin cancers, with emphasis on radiation dose, exposed skin surface area, and chemotherapeutic agents. The DCOG-LATER cohort study includes 5-year Dutch CCSs diagnosed 1963-2001. Subsequent skin cancers were identified from record linkages with the Netherlands Cancer Registry and Dutch Pathology Registry. Incidence rates were compared with general population rates. Multivariable Cox regression models were used, applying a novel method of case-control sampling enabling use of tumor location in cohort analyses. All statistical tests were two-sided. Among 5843 CCSs, 259 developed 1061 basal cell carcinomas (BCCs) (standardized incidence ratio [SIR] = 29.8, 95% confidence interval [CI] = 26.3 to 33.6; excess absolute risk per 10 000 person-years (EAR) = 24.6), 20 had melanoma (SIR = 2.3, 95% CI = 1.4 to 3.5; EAR = 1.1), and 10 had squamous cell carcinoma (SIR = 7.5, 95% CI = 3.6 to 13.8; EAR = 0.8). Cumulative incidence of BCC 40 years after childhood cancer was 19.1% (95% CI = 16.6 to 21.8%) after radiotherapy vs 0.6% expected based on general population rates. After a first BCC, 46.7% had more BCCs later. BCC risk was associated with any radiotherapy to the skin compartment of interest (hazard ratio [HR] = 14.32, 95% CI = 10.10 to 20.29) and with estimated percentage in-field skin surface area (26-75%: HR = 1.99, 95% CI = 1.24 to 3.20; 76-100%: HR = 2.16, 95% CI = 1.33 to 3.53, vs 1-25% exposed; Ptrend among exposed = .002), but not with prescribed radiation dose and likelihood of sun-exposed skin-area. Of all chemotherapy groups examined, only vinca alkaloids increased BCC risk (HR = 1.54, 95% CI = 1.04 to 2.27). CCSs have a strongly, 30-fold increased BCC risk. BCC risk appears to increase with increasing skin surface area exposed. This knowledge underscores the need for awareness by survivors and their health care providers.