Excess Absolute Risk Research Articles

Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study.

SummaryBackgroundFew studies have investigated the risks of subsequent primary neoplasms after adolescent and young adult (AYA) cancer. We investigated the risks of specific subsequent primary neoplasms after each of 16 types of AYA cancer.MethodsThe Teenage and Young Adult Cancer Survivor Study is a population-based cohort of 200 945 survivors of cancer diagnosed when aged 15–39 years in England and Wales from Jan 1, 1971, to Dec 31, 2006. The cohort was established using cancer registrations from the Office for National Statistics and the Welsh Cancer registry. Follow-up was from 5-year survival until the first occurrence of death, emigration, or study end date (Dec 31, 2012). In this analysis, we focus on the risk of specific subsequent primary neoplasms after 16 types of AYA cancer: breast; cervical; testicular; Hodgkin lymphoma (female); Hodgkin lymphoma (male); melanoma; CNS (intracranial); colorectal; non-Hodgkin lymphoma; thyroid; soft-tissue sarcoma; ovarian; bladder; other female genital; leukaemia; and head and neck cancer. We report absolute excess risks (AERs; per 10 000 person-years) and cumulative incidence of specific types of subsequent primary neoplasm after each type of AYA cancer.FindingsDuring the 2 631 326 person-years of follow-up (median follow-up 16·8 years, IQR 10·5–25·2), 12 321 subsequent primary neoplasms were diagnosed in 11 565 survivors, most frequently among survivors of breast cancer, cervical cancer, testicular cancer, and Hodgkin lymphoma. AERs of any subsequent primary neoplasms were 19·5 per 10 000 person-years (95% CI 17·4–21·5) in survivors of breast cancer, 10·2 (8·0–12·4) in survivors of cervical cancer, 18·9 (16·6–21·1) in survivors of testicular cancer, 55·7 (50·4–61·1) in female survivors of Hodgkin lymphoma, and 29·9 (26·3–33·6) in male survivors of Hodgkin lymphoma. The cumulative incidence of all subsequent primary neoplasms 35 years after diagnosis was 11·9% (95% CI 11·3–12·6) in survivors of breast cancer, 15·8% (14·8–16·7) in survivors of cervical cancer, 20·2% (18·9–21·5) in survivors of testicular cancer, 26·6% (24·7–28·6) in female survivors of Hodgkin lymphoma, and 16·5% (15·2–18·0) in male survivors of Hodgkin lymphoma. In patients who had survived at least 30 years from diagnosis of cervical cancer, testicular cancer, Hodgkin lymphoma in women, breast cancer, and Hodgkin lymphoma in men, we identified a small number of specific subsequent primary neoplasms that account for 82%, 61%, 58%, 45%, and 41% of the total excess number of neoplasms, respectively. Lung cancer accounted for a notable proportion of the excess number of neoplasms across all AYA groups investigated.InterpretationOur finding that a small number of specific subsequent primary neoplasms account for a large percentage of the total excess number of neoplasms in long-term survivors of cervical, breast, and testicular cancer, and Hodgkin lymphoma provides an evidence base to inform priorities for clinical long-term follow-up. The prominence of lung cancer after each of these AYA cancers indicates the need for further work aimed at preventing and reducing the burden of this cancer in future survivors of AYA cancer.FundingCancer Research UK, National Institute for Health Research, Academy of Medical Sciences, and Children with Cancer UK.

Late mortality and causes of death among 5-year survivors of childhood cancer diagnosed in the period 1960–1999 and registered in the Italian Off-Therapy Registry

IntroductionAdvances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. Materials and methodsCCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). ResultsAmong 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86–88) and at 45 years was 81% (95% CI: 77–84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7–12), corresponding to an AER of 48 (95% CI: 45–51). Mortality decreased by 60% for survivors treated most recently (1990–1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. ConclusionsThis study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

Patterns of Cause-Specific Mortality Among 2053 Survivors of Retinoblastoma, 1914-2016.

Previous studies of hereditary retinoblastoma survivors have reported elevated mortality, particularly for sarcomas, compared with the general population. However, cause-specific mortality patterns for long-term hereditary and nonhereditary retinoblastoma survivors are poorly understood. Among 2053 retinoblastoma patients diagnosed during 1914-2006 at two major US treatment centers and followed to 2016, we estimated cumulative mortality, standardized mortality ratios (SMRs), and absolute excess risks (AERs) compared with the US general population. Most deaths occurred in 1129 hereditary retinoblastoma patients (n = 518 deaths, cumulative mortality 70 years after retinoblastoma = 75.8%, 95% CI = 69.0% to 82.6%; SMR = 8.5, 95% CI = 7.7 to 9.2). Of these, 267 were due to subsequent cancers (SMR = 27.4, 95% CI = 24.2 to 30.9; AER = 72.3 deaths/10 000 person-years), for which SMRs were highest 15-29 years after diagnosis (n = 69, SMR = 89.9, 95% CI = 70.0 to 113.8) but remained statistically significantly elevated at 60 and more years (n = 14, SMR = 6.7, 95% CI = 3.6 to 11.2), whereas AERs increased with time (AER<15years = 38.0; AER60+years = 327.5). Increased risk of death due to cancers of pancreas, large intestines, and kidney were noted for the first time. Overall risk of subsequent cancers was greater for those treated with radiotherapy and chemotherapy compared to radiotherapy alone, although patterns varied by organ site. For 924 patients with nonhereditary retinoblastoma, we noted a modestly increased risk of death for subsequent cancers (n = 27, SMR = 1.8, 95% CI = 1.2 to 2.6) possibly due to treatment or misclassification of hereditary status. Risks of noncancer causes of death were not elevated for hereditary or nonhereditary patients. Hereditary retinoblastoma survivors died mainly from an excess risk of subsequent cancers up to six decades later, highlighting the need to develop long-term clinical management guidelines for hereditary retinoblastoma survivors treated in the past.

Trends in the risk and burden of second primary malignancy among survivors of smoking-related cancers in the United States.

While there are a growing number of cancer survivors, this population is at increased risk of developing second primary malignancies (SPMs). We described the incidence, most common tumor sites, and trends in burden of SPM among survivors of the most commonly diagnosed smoking-related cancers. The current study was a population-based study of patients diagnosed with a primary malignancy from the top 10 smoking-related cancer sites between 2000 and 2014 from Surveillance, Epidemiology, and End Results data. SPM risks were quantified using standardized incidence ratios (SIRs) and excess absolute risks (EARs) per 10,000 person-years at risk (PYR). Trends in the burden of SPM were assessed using Joinpoint regression models. A cohort of 1,608,607 patients was identified, 119,980 (7.5%) of whom developed SPM (76% of the SPMs were smoking-related). The overall SIR of developing second primary malignancies was 1.51 (95% CI, 1.50-1.52) and the EAR was 73.3 cases per 10,000 PYR compared to the general population. Survivors of head and neck cancer had the highest risk of developing a SPM (SIR = 2.06) and urinary bladder cancer had the highest excess burden (EAR = 151.4 per 10,000 PYR). The excess burden of SPM for all smoking-related cancers decreased between 2000 and 2003 (annual percentage change [APC] = -13.7%; p = 0.007) but increased slightly between 2003 and 2014 (APC = 1.6%, p = 0.032). We show that 1-in-12 survivors of smoking-related cancers developed an SPM. With the significant increase in the burden of SPM from smoking-related cancers in the last decade, clinicians should be cognizant of long-term smoking-related cancer risks among these patients as part of their survivorship care plans.

The Risk of Radiogenic Second Cancer Based on Differential DVH: Central Nervous System Malignant Tumor in Children.

Objectives:To quantify the risk of radiogenic second cancer in pediatric patients receiving hippocampal-sparing craniospinal irradiation either with intensity-modulated radiation therapy or tomotherapy due to the development of a solid second cancer after radiotherapy using the concept of excess absolute risk.Methods:Computed tomography images of 15 pediatric patients who received craniospinal irradiation treatment were selected for this study. For each case, intensity-modulated radiation therapy and tomotherapy plans were computed. Then, the dosimetry parameters were analyzed. Differential dose–volume histograms were generated, and the excess absolute risks were calculated for each plan of each patient.Results:The tomotherapy group was superior to the intensity-modulated radiation therapy group in target area homogeneity index (P < .001). Tomotherapy offered greater hippocampal sparing than intensity-modulated radiation therapy in terms of D 2% (15.66 vs 23.05 Gy, P < .001) and Dmean (9.79 vs 20.29 Gy, P < .001). Tomotherapy craniospinal irradiation induced a much higher risk than intensity-modulated radiation therapy craniospinal irradiation to the thyroid and lungs (excess absolute risk: thyroid 28.7 vs 26.9 per 10 000 PY, P = .010; lung 20.5 vs 18.9 per 10 000 PY, P = .003). Both techniques conferred a higher risk to the stomach, but there was little difference. In addition, the 2 plans induced less carcinogenic risk to the liver (excess absolute risk 4.2 vs 4.0 per 10 000 PY, P = .020).Conclusions:The tomotherapy plan has obvious advantages in the protection of the hippocampus for children undergoing craniospinal irradiation treatment. Tomotherapy increased the risk of radiogenic second cancer in organ at risk, and therefore, it is imperative to take the risk factor into consideration in the formulation of treatment protocols.

Hyperthyroidism as a late effect in childhood cancer survivors - an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study

Background: Hyperthyroidism is a rare disorder which may negatively affect health and quality of life. Its occurrence in childhood cancer survivors has not previously been investigated in detail.Material and methods: In the hospital registers of the five Nordic countries, 32,944 childhood cancer survivors and 212,675 population comparisons were followed for the diagnosis of hyperthyroidism. Hospitalisation rates, standardised hospitalisation rate ratios and absolute excess risks were calculated with 95% confidence intervals (CI).Results: Hyperthyroidism was diagnosed in 131 childhood cancer survivors, yielding an overall relative risk of 1.6 (95% CI: 1.3–1.9) compared with population comparisons. The risk was greatest 1–5 years after the diagnosis of cancer and in survivors of thyroid cancers, neuroblastomas, acute lymphoblastic leukaemia and Hodgkin lymphoma. Sixty-seven percent of survivors with hyperthyroidism had tumours located in the head, neck or upper body and half of survivors with hyperthyroidism were irradiated with 77% of them in the head and neck area.Conclusion: Childhood cancer survivors are at an increased risk of hyperthyroidism, potentially resulting in non-endocrine morbidity.

Association of Chemotherapy for Solid Tumors With Development of Therapy-Related Myelodysplastic Syndrome or Acute Myeloid Leukemia in the Modern Era

Therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) is a rare, usually fatal complication of chemotherapy, including certain alkylating agents, topoisomerase II inhibitors, and platinum compounds. With the introduction of new chemotherapeutic agents, expanded indications for established agents, and increased neoadjuvant and adjuvant chemotherapy, tMDS/AML risks in the modern age are poorly understood. To quantify tMDS/AML risk after chemotherapy for solid cancer among United States adults since 2000 and correlate tMDS/AML risk patterns with chemotherapy treatment practices. A population-based cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims. Risk analyses included 1619 tMDS/AML cases among 700 612 adults (age, 20-84 years) who were diagnosed with first primary solid cancer during 2000 to 2013 (followed up through 2014), received initial chemotherapy, and survived 1 year or longer, as reported to SEER. Descriptive analyses were conducted of SEER records linked with Medicare claims for chemotherapy in 165 820 older adults (age, 66-84 years) receiving initial chemotherapy for a first primary solid cancer in 2000-2013. Data analysis was conducted from October 2017 to April 2018. Receipt of initial chemotherapy for solid cancer. Second primary tMDS/AML. Based on 1619 tMDS/AML cases in the SEER database (mean [SD] age, 64.3 [12.2] years; 1148 [70.9%] female), tMDS/AML risks were statistically significantly elevated after chemotherapy for 22 of 23 solid cancers (all except colon). Relative risks ranged from 1.5 to greater than 10 and excess absolute risks from 1.4 to greater than 15 cases per 10 000 person-years compared with the general population. Overall survival following tMDS/AML diagnosis was poor (1270 of 1619 patients [78.4%] died; median overall survival, 7 months). For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy. In the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, in initial chemotherapy increased substantially since 2000, most notably for gastrointestinal tract cancers (esophagus, stomach, colon, and rectum; 10% in 2000-2001 to 81% during 2012-2013). Large-scale, United States population-based data demonstrate excess tMDS/AML risks following chemotherapy for nearly all solid tumor types, consistent with expanded use of known leukemogenic agents in the 21st century. Continued efforts to reduce treatment-related adverse events, particularly for solid cancer patients with favorable prognosis, are needed.

Cardiovascular Mortality Among CML Patients in the Pre-TKI and TKI Eras: A SEER Analysis 1992-2004

Background:Since the US Food and Drug Administration (FDA) approved the first BCR-ABL1-targeted tyrosine kinase inhibitor (TKI) imatinib in 2002 as the first line therapy1, chronic phase chronic myeloid leukemia (CML-CP), once a uniformly fatal disease, now has become a disease that is controlled in >90% patients2. Conventional treatment for CML before TKIs included hydroxyurea, interferon alpha with or without cytarabine, busulfan, as well as stem cell transplantation3. Currently, there are five TKIs approved by FDA for chronic-phase CML treatment: imatinib, nilotinib, dasatinib, bosutinib, and ponatinib4.Studies have suggested that CML patients have higher baseline cardiovascular comorbidities than general US population5. Moreover, TKIs, especially later generation, are associated with cardiovascular toxicities including myocardial infarction, ischemic heart disease, cerebrovascular disease, peripheral arterial disease, QT prolongation, hypertension, and venous thrombosis1,4,6-9. As patients may need life-long (or minimum of several years') therapy, the cardiovascular safety profile of TKI treatment warrants utmost attention. Thus, we examined the effect of TKIs on cardiovascular mortality using the SEER database.Methods:Data were extracted from the Surveillance, Epidemiology and End Results (SEER) 18 program 1992-2004. Cardiovascular diseases were defined as diseases of the heart, hypertension, cerebrovascular disease, atherosclerosis, aortic aneurysm and dissection, and other disease of arteries, arterioles, and capillaries. Time of diagnosis between 1992-2002 was defined as pre-TKI era and 2003-2014 as TKI era. Patients had BCR/ABL negative CML or any other cancer before CML were excluded.T-test and chi-square test were used to analyze the baseline characteristics. Multivariable Cox proportional hazards regression was used to calculate the hazard ratio (HR). Sub-distribution hazard ratios (SHRs) for cardiovascular disease (CVD) specific mortality were calculated by using Fine and Gray competing-risks model. All above statistical tests were performed assuming a 2-sided alpha of 0.05 by using SAS 9.4. CVD standard mortality ratio (SMR) and absolute excess risk (AER) were calculated by using SEER*Stat 8.3.5 software MP-SIR Matrix comparing to the total U.S. population (1969-2016 Counties).Results:A total of 10,502 patients were included (Table 1). Table 2 shows that as expected, increased age was associated with higher CVD mortality. Females had a 20% decreased risk of overall CVD mortality compared to males. Notably, those diagnosed in the TKI era had better cardiovascular outcome than the pre-TKI diagnosis, HR=0.78 (95%CI: 0.64-0.94), which was also illustrated in Figure 1. In the adjusted model (Table 3), the significantly decreased mortality in the TKI era was mostly observed at 10-year follow up and among the youngest age group 15-44 years. The 10-year cardiovascular mortality also differed by gender, especially after age 54 (Fig. 2). In the TKI era, males had a 58% increased 10-year CVD mortality (p<0.01) compared to females (Table 4). In comparison to US general population (Fig. 3), CML patients had higher cardiovascular mortality, regardless of year of diagnosis. However, the overall CVD was higher in the pre-TKI era: 1.69 (95% CI: 1.51-1.89) vs. 1.45 (95%CI: 1.24-1.69) in the TKI era. Additionally, the AERs in the TKI era across all age groups were significantly lower compared to the pre-TKI era (Figure 4).Conclusions:Though TKIs appear to be associated with increased cardiovascular toxicity, we herein report an observed decreased cardiovascular mortality among CML patients diagnosed in the TKI era relative to the pre-TKI era. One potential explanation is that TKIs might be less cardiotoxic than conventional chemotherapies such as busulfan, cytarabine, or interferon; additionally these findings could be due to overall decreased CVD mortality since 200010. While CVD mortality among CML patients improved after 2002, it was still higher than the general US population. Besides the cardiovascular toxicities of TKIs, underlying CML associated factors could also be a potential driver for increased CVD mortality11. Our results argue for aggressive management, in general, of CVD risk factors among CML patients, especially elderly and males, and further investigation into specific mechanisms, factors and predictors of risk in TKI-treated CML. [Display omitted] DisclosuresMauro:Takeda: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy.

Risk of Suicide After Cancer Diagnosis in England

A diagnosis of cancer carries a substantial risk of psychological distress. There has not yet been a national population-based study in England of the risk of suicide after cancer diagnosis. To quantify suicide risk in patients with cancers in England and identify risk factors that may assist in needs-based psychological assessment. Population-based study using data from the National Cancer Registration and Analysis Service in England linked to death certification data of 4 722 099 individuals (22 million person-years at risk). Patients (aged 18-99 years) with cancer diagnosed from January 1, 1995, to December 31, 2015, with follow-up until August 31, 2017, were included. Diagnosis of malignant tumors, excluding nonmelanoma skin cancer. All deaths in patients that received a verdict of suicide or an open verdict at the inquest. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) were calculated. Of the 4 722 099 patients with cancer, 50.3% were men and 49.7% were women. A total of 3 509 392 patients in the cohort (74.3%) were aged 60 years or older when the diagnosis was made. A total of 2491 patients (1719 men and 772 women) with cancer died by suicide, representing 0.08% of all deaths during the follow-up period. The overall SMR for suicide was 1.20 (95% CI, 1.16-1.25) and the AER per 10 000 person-years was 0.19 (95% CI, 0.15-0.23). The risk was highest among patients with mesothelioma, with a 4.51-fold risk corresponding to 4.20 extra deaths per 10 000 person-years. This risk was followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach (2.20-fold) cancer. Suicide risk was highest in the first 6 months following cancer diagnosis (SMR, 2.74; 95% CI, 2.52-2.98). Despite low absolute numbers, the elevated risk of suicide in patients with certain cancers is a concern, representing potentially preventable deaths. The increased risk in the first 6 months after diagnosis may indicate an unmet need for psychological support. The findings of this study suggest a need for improved psychological support for all patients with cancer, and attention to modifiable risk factors, such as pain, particularly in specific cancer groups.

Second malignant neoplasms after childhood cancer: A nationwide population-based study in Korea.

BackgroundSecond malignant neoplasm is one of the most devastating late effects of childhood cancers. This study aimed to evaluate the incidence and survival outcomes of patients developing second malignant neoplasms (SMNs) after surviving childhood cancer in Korea.MethodsMedical data of childhood cancer patients diagnosed between 1993 and 2012 were obtained from the Korea Central Cancer Registry. The risk of developing SMNs was calculated using standardized incidence ratio (SIR), excess absolute risk (EAR), and cumulative risk. Kaplan-Meier survival curves were estimated, stratified by SMN status.ResultsA total of 28,405 childhood cancer patients were diagnosed in the study period, and 337 (1.2%) developed SMN. The total follow-up period was 197,359 person-years at risk (PYR), with a median follow-up duration of 5.6 years. Overall SIR was 20.0, which was 23.2 in women, and 17.6 in men. The overall EAR was 16.4 per 10,000 PYR. The most common types of SMNs, in order of incidence, were other malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. The cumulative incidence of developing SMNs was 0.7% at 5 years, 1.2% at 10 years, and 2% at 15 years. After primary cancer diagnosis, the 10-year overall survival rate of patients with SMNs was 65.1%, which was lower than the 73.4% in patients without SMN. After SMN diagnosis, the 10-year overall survival rate was 55.8%.ConclusionThrough this registry-based study of 5.6 years of follow up, childhood cancer survivors were found to be at 20-fold higher risk of developing a malignant neoplasm compared to the general population. The majority of malignant neoplasms are malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. Continued surveillance for assessing long-term risks, and guidance for appropriate long-term follow up of childhood cancer survivors, are needed.

Second Primary Malignancies and Cardiovascular Mortality in Hodgkin Disease (HD) Survivors – A SEER Database Study

Over the last few decades there has been significant improvements in survival in patients (pts) with HD. But long-term HD survivors, especially those treated with radiation therapy (RT) have an increased risk of second primary malignancy (SPM) and cardiovascular disease (CVD) related mortality. We conducted this population based study to analyze trends in CVD related mortality and incidence of lung and thyroid cancer (CA) in HD survivors treated with RT. We used the SEER 9 database to calculate the Standardized Incidence Ratio (SIR) and Excess Absolute Risk (EAR) of lung and thyroid CA as SPM in survivors of HD diagnosed between 1973 and 2011, who were treated with RT. Poisson regression models were used to calculate adjusted incidence of lung and thyroid CA. We also divided the pts diagnosed with HD during this period into two groups based on if or not they received RT and calculated the mortality due to CVD for each group, by year of diagnosis (YOD). Poisson regression models were used to calculate adjusted CVD mortality by YOD for each group. In all three cases, trends in incidence or mortality were evaluated by calculating the Estimated Annual Percentage Change (EAPC) from the regression coefficient for YOD. We identified 11,916 HD cases that received RT, who were followed up for a median duration of 160 months (range – 12 to 480 months). 319 pts developed lung CA (SIR of 3.72, 95% CI 3.32 – 4.15; EAR of 13.19 per 10,000 person years at risk (PYAR)) and 86 pts developed thyroid CA (SIR of 3.67, 95% CI 2.94 – 4.53; EAR of 3.54 per 10,000 PYAR). Median ages at diagnosis of secondary lung and thyroid CA were 59 yrs and 42 yrs, with median latency periods of 16 yrs and 17 yrs respectively. 965 pts among 11,916 pts who received RT died from CVD while the number of CVD deaths was 1,182 among the 12,507 pts who were not given RT. Using Poisson regression models, we calculated the adjusted incidence of secondary lung CA and thyroid CA and the adjusted mortality from CVD, by YOD. YOD, age at diagnosis of HD and latency (time since diagnosis of HD) were the independent variables used in the regression model. Between 1973 and 2011, the adjusted incidence of lung CA declined at an EAPC of -2.68 (95% CI -13.06 to -3.92) and that of thyroid CA declined at an EAPC of -3.35 (95% CI -5.73 to -1.00). Over the same period, CVD mortality per 10,000 PYAR for pts who received RT declined at an EAPC of -4.34 (95% CI -4.97 to -3.73) and that of pts who did not receive RT declined at an EAPC of -1.92 (95% CI -2.47 to -1.39). We observed a decline in incidence of lung and thyroid CA and CVD mortality in HD survivors over the study period. The decline in CVD mortality over time in pts who received RT was steeper compared to that of pts who did not receive RT. Though our study was limited by the lack of details regarding RT, chemotherapy and comorbidities, these findings are most likely a reflection of recent trends in use of reduced doses and field of RT.

Somatic late effects in 5-year survivors of neuroblastoma: a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared to background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics.

Cardiovascular and other competing causes of death among patients with cancer from 2006 to 2015: An Australian population-based study.

With improved cancer survivorship, cardiovascular disease (CVD) and other noncancer events compete with cancer as the underlying cause of death, but the risks of mortality in competing-risk settings have not been well characterized. The authors identified 21,637 individuals who had a first cancer registered between 2006 and 2013, with follow-up to 2015, in the Australian population-based Tasmanian Cancer Registry. The cumulative incidence of deaths from specific competing events was assessed in competing-risk analyses. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) for deaths from noncancer causes were calculated for comparison with the general population. Overall, 8844 deaths were observed, with 1946 (22%) from competing events. The cumulative incidence of deaths from CVD increased significantly with age at first cancer diagnosis and exceeded other competing events at age ≥65 years. The risk of death from CVD was more common than expected in the first year of follow-up (SMR, 1.44 [95% confidence interval, 1.26-1.64]; AER, 36.8 per 10,000 person-years). The SMR and AER for CVD deaths varied by first cancer site, indicating increased risks after a first diagnosis of lung cancer, hematologic malignancy, and urinary tract cancer. For other noncancer events, the SMRs increased significantly for deaths from infectious disease and respiratory disease and were highest in the first year of follow-up. CVD was the leading cause of competing mortality among Tasmanian patients with cancer who were diagnosed from 2006 to 2013. The higher than expected occurrence of death from CVD and other noncancer events during the first year after a cancer diagnosis highlights the importance of early preventive interventions.

Risk of Suicide After a Cancer Diagnosis in England: A Population-Based Study

Background: Previous research has identified an increased risk of suicide among cancer patients, however this has not been investigated at a population level in England. Those subgroups of patients most at risk need to be identified to ensure appropriate access to psychological support. Aim: To examine the variation in suicide risk among individuals diagnosed with cancer in England. Methods: We identified 4,453,547 individuals (21 million person-years at risk) aged 18 to 99 years at diagnosis of cancer during 1995 to 2015 from the national cancer registry, and followed them up until 31 August 2017. The outcomes of interest were both suicide and open verdicts (ICD-10 X60-X84, Y87.0, Y10-Y34 [excluding Y33.9, Y87.2]). Population-based expected deaths were as published by ONS [2]. We calculated standardized mortality ratios (SMRs) and absolute excess risks (AERs), and explored variation in suicide risk by cancer type, age at death, sex, deprivation, ethnicity, and years since cancer diagnosis. Results: 2352 cancer patients died by suicide. This was 0.08% of all deaths. The overall SMR for suicide was 1.19 (95% CI 1.14-1.24) and AER per 10,000 person-years was 0.18 (0.13-0.22). The risk was highest among individuals diagnosed with mesothelioma, with a 4.34-fold risk corresponding to 4.00 extra deaths per 10,000 person-years. This was followed by pancreatic (3.94-fold), esophageal (2.53-fold), lung (2.52-fold), and stomach (2.14-fold) cancer (all significantly elevated). Suicide risk was highest in the first 6 months following cancer diagnosis (SMR: 2.64 [2.42-2.89]), but a significantly increased risk persisted for 2 years (SMR: 1.21 [1.08-1.35]). Conclusion: Despite low numbers, the elevated risk of suicide in patients with certain cancers is a concern, representing potentially preventable deaths. The increased risk in the first 6 months after diagnosis, which is consistent with previous studies, highlights unmet needs for psychological support delivered alongside cancer diagnosis and treatment. Our findings suggest a need for improved risk stratification across cancer services, followed by targeted psychological support.

De Novo Myelodysplastic Syndrome and Subsequent Diagnosis of Primary Solid Tumors: Evidence from the National Cancer Institute 2001-2011.

To our knowledge there are no population-level studies on the association between non-treatment-related myelodysplastic syndrome (MDS) and subsequent primary solid tumors. Adult patients diagnosed with non-treatment-related MDS were selected from the SEER 18 database and the risk of subsequent primary solid tumor was calculated. A total of 40,780 patients with a diagnosis of MDS were reported in the SEER 18 registry during 2001 to 2011. In these patients, 2,111 subsequent primary solid tumors were diagnosed with an observed/expected (O/E) ratio of 1.16 and an absolute excess risk of 26.86 per 10,000. Diagnosis of subsequent solid tumor was most likely immediately after diagnosis of MDS or within 1 year of diagnosis. The risk of diagnosis of primary solid tumor malignancy in adult patients with de novo MDS is significantly higher compared to the general population. It is unclear whether this is due to detection bias or underlying pathophysiology.

Quantifying Decreased Radiation Exposure From Modern CT Scan Technology and Surveillance Programs of Germ Cell Tumors.

Upgrading computerized tomography (CT) scanners to iterative reconstruction techniques (IRT) decreases radiation dose. This reduction, combined with changes in surveillance protocols in clinical stage I testicular cancer (CS1TC) measurably decrease the lifetime attributable risk (LAR) of dying of radiation-associated cancer. This IRB-approved study enrolled 24 CS1TC patients who had CT scans on the same Toshiba Aquilion 64 CT before and after IRT software installation. Dose-length product and CT dose index volume were recorded. A physicist calculated effective doses. Radiation doses were compared using the Wilcoxon signed rank test. Median effective dose per scan was multiplied by scan number based on 16 versus 7 scans in 5-year AS protocols to calculate estimated cumulative dose (ECD). LAR of dying of radiation-associated solid tumor was estimated using ECD for a single exposure at age 35 with the excess absolute risk transport model from the BEIR VII analysis of long-term atomic bomb survivors. Median preupgrade and postupgrade effective doses were 12.5 and 7.7 mSv, respectively (P<0.0001). A linear regression model with a constrained zero intercept fit to the data found that IRT dose was estimated as 61% of filtered back projection dose (95% confidence interval, 0.56-0.66). The IRT upgrade reduced the LAR of the 16-scan protocol 35%. Combination of IRT upgrade and 7-scan protocol reduced surveillance LAR 72%. Modern CT technology combined with reduced scanning strategies can markedly decrease lifetime radiation exposure, further lowering the already small potential mortality of imaging-associated cancers.

Trends in Risks for Second Primary Cancers Associated With Index Human Papillomavirus–Associated Cancers

In the last 4 decades, survival among patients with human papillomavirus (HPV)-associated cancers has improved, while the incidence of these cancers has increased among younger cohorts. Among survivors of HPV-associated cancers, persistent HPV infection may remain a risk factor for preventable HPV-associated second primary cancers (HPV-SPCs). To investigate the risk of HPV-SPCs among survivors of HPV-associated index cancers and to test the hypothesis that the HPV-SPC risk among these persons has increased over the last 4 decades. A retrospective cohort study of 9 cancer registries of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to identify patients with HPV-associated (cervical, vaginal, vulvar, oropharyngeal, anal, and penile) cancers diagnosed from January 1, 1973, through December 31, 2014. The dates of analysis were July 1, 2017, to January 31, 2018. The HPV-SPC risk was quantified by calculating standard incidence ratios (SIRs) and excess absolute risks (EARs) per 10 000 person-years at risk (PYR). The HPV-SPC risk by time was estimated using Poisson regression. From 113 272 (73 085 female and 40 187 male) survivors of HPV-associated cancers, 1397 women and 1098 men developed HPV-SPCs. The SIRs for HPV-SPCs were 6.2 (95% CI, 5.9-6.6) among women and 15.8 (95% CI, 14.9-16.8) among men. The EARs were 18.2 per 10 000 PYR for women and 53.5 per 10 000 PYR for men. Among both women and men, those who had index oropharyngeal cancers had the highest HPV-SPC risk (SIR, 19.8 [95% CI, 18.4-21.4] and EAR, 80.6 per 10 000 PYR among women; SIR, 18.0 [95% CI, 16.9-19.1] and EAR, 61.5 per 10 000 PYR among men). Women who had index cervical cancers and men who had index anal cancers had the lowest HPV-SPC risk (SIR, 2.4 [95% CI, 2.2-2.7] and EAR, 4.5 per 10 000 PYR among women; SIR, 6.5 [95% CI, 4.7-8.8] and EAR, 18.5 per 10 000 PYR among men). Both women and men who had index HPV-associated cancers of any kind had a significantly higher risk of oropharyngeal HPV-SPCs. Over the last 4 decades, the risk of developing most types of HPV-SPCs after index cervical, vaginal, and vulvar cancers increased. According to this study, the HPV-SPC risk among survivors of HPV-associated cancers is significant, implying that persistent HPV infection at multiple sites may be associated with HPV-SPCs. These findings have the potential to inform surveillance recommendations for survivors of HPV-associated cancers.

Second cancer risk after radiation therapy of ependymoma using the flattening filter free irradiation mode of a linear accelerator.

Pediatric patients suffering from ependymoma are usually treated with cranial or craniospinal three‐dimensional (3D) conformal radiotherapy (3DCRT). Intensity‐modulated techniques spare dose to the surrounding tissue, but the risk for second malignancies may be increased due to the increase in low‐dose volume. The aim of this study is to investigate if the flattening filter free (FFF) mode allows reducing the risk for second malignancies compared to the mode with flattening filter (FF) for intensity‐modulated techniques and to 3DCRT. A reduction of the risk would be advantageous for treating pediatric ependymoma. 3DCRT was compared to intensity‐modulated radiation therapy (IMRT) and volumetric‐modulated arc therapy (VMAT) with and without flattening filter. Dose–volume histograms (DVHs) were compared to evaluate the plan quality and used to calculate the excess absolute risk (EAR) to develop second cancer in the brain. Dose verification was performed with a two‐dimensional (2D) ionization chamber array and the out‐of‐field dose was measured with an ionization chamber to determine the EAR in peripheral organs. Delivery times were measured. Both VMAT and IMRT achieved similar plan quality in terms of dose sparing in the OAR and higher PTV coverage as compared to 3DCRT. Peripheral dose in low‐dose region, which is proportional to the EAR in organs located in this region, for example, gonads, bladder, or bowel, could be significantly reduced using FFF. The lowest peripheral EAR and lowest delivery times were hereby achieved with VMATFFF. The EAR calculated based on DVH in the brain could not be reduced using FFF mode. VMATFFF improved the target coverage and homogeneity and kept the dose in the OAR similar compared to 3DCRT. In addition, delivery times were significantly reduced using VMATFFF. Therefore, for radiotherapy of ependymoma patients, VMATFFF may be considered advantageous for the combination of Elekta Synergy linac and Oncentra External Beam planning system used in this study.

Acute Pericarditis and Cancer Risk: A Matched Cohort Study Using Linked UK Primary and Secondary Care Data.

BackgroundWe aimed to examine whether acute pericarditis is an indicator of undetected cancer and identify patient‐level factors associated with high cancer risk among patients presenting with pericarditis.Methods and ResultsA population‐based matched cohort study was conducted using primary care data from the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients with acute pericarditis (n=6530) were matched to a comparison cohort (n=26 111) on age, sex, calendar time, and general practice. We estimated cumulative cancer incidences, and calculated hazard ratios using Cox regression. Effect modification by patients' characteristics and lifestyle factors was examined, and we fitted a parsimonious model to evaluate absolute excess risk of later cancer among pericarditis patients by key patient‐level factors. We identified 728 and 1379 incidents of cancer among pericarditis patients and the comparison cohort (median follow‐up, 2.8 and 3.5 years). Pericarditis was associated with an elevated subsequent risk of any cancer (hazard ratio=3.03; 95% confidence interval, 2.74–3.36). The association was particularly pronounced 0 to 3 months after pericarditis (hazard ratio=23.56; 95% confidence interval, 18.00–30.83), but a more‐modest association remained thereafter (hazard ratio=1.95; 95% confidence interval, 1.48–2.57 after 3–12 months, and hazard ratio=1.40; 95% confidence interval, 1.21–1.62 after >12 month). Older individuals hospitalized with pericarditis and with combinations of obesity and smoking were at the highest excess risk of having a cancer diagnosis 3 to 12 months later, reaching 4.8%.ConclusionsOccult cancers may be going undiagnosed during the acute episode of pericarditis. Patients presenting with pericarditis and combinations of older age, obesity, smoking, and a need for hospitalization might warrant targeted investigations for cancer.

P137] Joint estimation of radiation-induced late toxicity and cancer recurrence risks for bilateral breast cancer after photon versus spot-scanning proton therapy

Purpose Joint estimation of risks of radiation-induced secondary lung cancer (SLC) and ischemic heart disease (IHD) modeled with consideration of patient-level risk factors and risk of cancer recurrence caused by compromising target coverage. Methods Five patients with bilateral breast cancer were treated with postoperative radiotherapy in 2013–2016: two patients received chest wall and comprehensive nodal irradiation (2 Gy x 25), two patients received whole breast irradiation (2.67 Gy x 15) and one patient received whole breast and left-sided lymph node irradiation (2 Gy x 25). Two patients were treated with 3D-CRT, three patients with VMAT. All patients were re-planned with intensity modulated spot-scanning proton therapy. One or three fields were used (anterior, left anterior oblique and right anterior oblique) with multi-field optimization. Models estimating risks of SLC and IHD were developed from published dose-response data and a model for risk of recurrence was derived based on hazard ratios from published randomized trials. Results The average mean heart dose was 7.6 (range, 1.5–12.7) Gy for the photon plans while mean heart dose was below 0.4 Gy (RBE) for proton plans in all patients using protons (RBE, relative biological effectiveness, assuming RBE = 1.1). The average values of the mean lung dose and V20Gy were 12.2 (range, 5.2–16.3) Gy and 20.7% (range, 10.1%-27.4%) for photon plans, and 5.0 (range, 0.8–9.2) Gy (RBE) and 9.6% (range, 0.8%-19.1%) for proton plans. Median excess absolute risk (EAR) of SLC by age 80 for non-smokers/smokers was 2.6% (range, 0.6%-2.8%)/5.3% (range, 1.1%-5.7%) with photon therapy and 1.2% (range, 0.1%-1.6%)/2.4% (range, 0.2%-3.2%) with proton therapy. For the photon plans median EAR of IHD by age 80 was 2.8% (range, 0.2%-3.2%)/4.5% (range, 0.5%-5.6%) without/with cardiac risk factors whereas risks were below 0.2% for both scenarios using protons. Median EAR of recurrence or death by ten years was 0.9% (range, 0.1%-1.9%) with photons and 0.1% (range, 0.1%-0.3%) with protons. Conclusions Proton therapy did reduce the predicted risk of SLC and IHD by up to 3.3% and 5.5%, respectively, and the risk of recurrence by up to 1.6% in individual patients.