Patients With APECED Have Increased Early Mortality Due to Endocrine Causes, Malignancies and infections

Context Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autoimmune endocrinopathy with severe and unpredictable course. The impact of APECED on mortality has not been determined. Objective To assess overall and cause-specific mortality of patients with APECED. Design and Setting A follow-up study of Finnish patients with APECED from 1971 to 2018. Causes and dates of death were collected from Finnish registries. Patients Ninety-one patients with APECED. Main Outcome Measure Overall and cause-specific standardized mortality ratios (SMRs) determined by comparing the observed numbers of death and those expected on the basis of respective population death rates in Finland. Results The overall disease mortality was significantly increased (29 deaths, SMR 11; 95% confidence interval [CI] 7.2-16; P < 0.001). The relative risk (SMR) was highest in the youngest age groups but the absolute excess risk was similar (about 10 per 10 000 person-years) in all age categories. The highest SMRs were seen for endocrine and metabolic diseases (SMR 570; 95% CI, 270-1000; P < 0.001) and for oral and esophageal malignancies (SMR 170; 95% CI, 68-360; P < 0.001). Mortality was also increased for infections, diseases of digestive system, alcohol-related deaths, and for accidents. Due to the small number of cases we were unable to evaluate whether mortality was affected by disease severity. Conclusions Patients with APECED have significantly increased mortality in all age groups. Highest SMRs are found for causes that are directly related to APECED but also for infections. Increased alcohol- and accident-related deaths may be influenced by psychosocial factors.

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< 1y = 1.2, SMR≥5y = 1.7; AER< 1y = 15.1, AER≥5y = 60.0). Analyses by age, focused on AERs, showed generally similar risks across age groups (cancers excluding lymphoma: AER< 65= 26, AER65-75= 28, AER≥75= 31; non-malignant causes: AER< 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.

Second primary malignancies in anal carcinoma.

534 Background: Survival of cancer patients is increasing. Therefore, there is a need to evaluate long term complications in cancer survivors. There is no data on second primary malignancies in anal cancer. This study was conducted to evaluate second primary malignancies in patients with anal carcinoma. Methods: We selected adult patients diagnosed with anal cancer from National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) 13 database We calculated the risk of second primary malignancies in the anal cancer patients using multiple primary standardized incidence ratio (MP-SIR) session of SEER*stat software. Results: Among 7,661 patients with anal carcinoma, 3,196 were men and 4,465 were women. Median follow up duration was 87 months (range: 7-239 months). Median age at the time of diagnosis of SPM was 69.33 yrs (range: 34-103 yrs). Median latency for SPM was 52 months (range: 6-219 months). A total of 675 patients (9.07%) developed 747 second primary malignancies, with an observed/expected (O/E) ratio of 1.41 (95% confidence interval =1.32-1.52, p<0.001), and an absolute excess risk of 55.36 per 10,000 populations. Significant excess risks were observed for oral cavity and pharyngeal tumor, rectal and anal canal tumor, laryngeal tumor, lung and bronchial cancer, Kaposi sarcoma, hematologic malignancies, ovarian, vaginal, and vulval tumors. Conclusions: The risk of second primary malignancies in adult patients with anal cancer is significantly increased compared to general population.

Second Primary Malignancies In Adult Acute Lymphoblastic Leukemia

Background Pediatric acute lymphoblastic leukemia (ALL) patients have higher rates of second primary malignancies. There is limited data on second primary malignancies (SPM) among adult patients with ALL. This study was conducted to evaluate SPM in adult ALL patients using US Surveillance, Epidemiology and End Results (SEER) cancer registry database. Methods We analyzed the SEER 13 Registries using multiple primary standardized incidence ratio (MP-SIR) session. We analyzed secondary cancer rates among adult ALL patients during the period 1992 - 2010. We used SEER*Stat software provided by national cancer institute for statistical analysis. Results There were 3,259 adult (age ≥20 years) ALL patients reported in SEER database during 1992-2010. Among them, 65 ALL patients developed 75 second primary malignancies. Fifty-nine ALL patients developed 1 SPM each, 3 ALL patients developed 2 SPM each, 2 ALL patients developed 3 SPM each and 1 ALL patient developed 4 SPM. All site cancers were significantly higher among adult ALL patients compared to general population with observed/expected ratio (O/E): 1.47, p value< 0.05, an absolute excess risk of 24.43 per 10,000 populations. Similarly, oral cavity cancer, respiratory system cancer and hematological SPM were significantly higher in ALL patients than expected in general population. (Table) Conclusions Adult patients with ALL have higher rates of second primary malignancies compared to general population. Disclosures: No relevant conflicts of interest to declare.

Second malignant neoplasms (SMN) among 18,627 testicular cancer survivors (TCS) after chemotherapy (CHEM) or surgery (SURG).

1536 Background: Increased risks of SMN after radiotherapy (RT) for testicular cancer (TC) are well established. Few population-based studies, however, have focused on SMN risk among a contemporary group of TCS managed initially with non-RT approaches, including CHEM. Methods: Standardized incidence ratios (SIR) of SMN stratified by site and time since TC diagnosis were calculated for 18,627 TCS reported to the SEER program (1980-2008) who initially had CHEM (n=8,058) or SURG (n=10,569) alone without RT, with each cohort accruing 65,398 and 92,681 person-years (PY) of follow-up respectively. Results: After CHEM, significantly increased risks of solid cancers (n=154; SIR 1.3; 95% CI 1.1-1.5; absolute excess risk (AER) 5.4 per 10,000 PY) and leukemias (n=18, SIR 3.9; 95% CI 2.3-6.1; AER 2.0) were observed. Solid cancer risk remained elevated for > 20 yrs, whereas excess leukemias were concentrated within 10 years after diagnosis. SIRs for solid cancers during the <1, 1-4, 5-9, 10-14, 15-19, and 20+ yr periods were 2.0 (95% CI 1.03-3.5), 1.4 (95% CI 0.97-2.0), 0.8 (95% CI 0.5-1.2), 1.3 (95% CI 0.9-1.8), 1.6 (95% CI 1.05-2.2), and 1.5 (95% CI 0.95-2.2) respectively (P-trend 0.5) whereas SIRs for leukemia were 3.2, 9.9 (P<0.05), 2.6, and 2.3 respectively, with no cases reported in the latter 2 intervals. Median latencies to the development of solid cancers and leukemia were 12.5 yr (0.1-28) and 2.5 yr (0.1-14) respectively. Increased site-specific risks were apparent for cancers of liver (SIR 1.9; 95% CI 0.6-4.4); pancreas (SIR 2.1; 95% CI 0.8-4.6); soft tissue (SIR 4.9; 95% CI 2.1-9.7); bladder (SIR 1.9; 95% CI 1.02-3.3); kidney (SIR 2.6; 95% CI 1.4-4.3); brain/CNS (SIR 1.8; 95% CI 0.7-3.7), and thyroid (SIR 3.9; 95% CI 2.1-6.6). Secondary leukemias included 16 non-lymphocytic and 2 lymphocytic leukemias. In contrast, among TCS managed initially with SURG alone, no excess solid cancers were observed (n=198; SIR 1.0; 95% CI 0.8-1.1), albeit an increased risk of leukemia (n=15; SIR 1.9; 95% CI 1.1-3.2, AER 0.8) was seen. Conclusions: Future analytic studies should further evaluate the site-specific risks of SMN after modern CHEM for TC and the baseline risk among patients managed with non-cytotoxic approaches.

Breast Cancer Risk in Female Survivors of Hodgkin's Lymphoma: Lower Risk After Smaller Radiation Volumes

Purpose We assessed the long-term risk of breast cancer (BC) after treatment for Hodgkin's lymphoma (HL). We focused on the volume of breast tissue exposed to radiation and the influence of gonadotoxic chemotherapy (CT). Patients and Methods We performed a cohort study among 1,122 female 5-year survivors treated for HL before the age of 51 years between 1965 and 1995. We compared the incidence of BC with that in the general population. To assess the risk according to radiation volume and hormone factors, we performed multivariate Cox regression analyses. Results After a median follow-up of 17.8 years, 120 women developed BC (standardized incidence ratio [SIR], 5.6; 95% CI, 4.6 to 6.8), absolute excess risk 57 per 10,000 patients per year. The overall cumulative incidence 30 years after treatment was 19% (95% CI, 16% to 23%); for those treated before age 21 years, it was 26% (95% CI, 19% to 33%). The relative risk remained high after prolonged follow-up (> 30 years after treatment: SIR, 9.5; 95% CI, 4.9 to 16.6). Mantle field irradiation (involving the axillary, mediastinal, and neck nodes) was associated with a 2.7-fold increased risk (95% CI, 1.1 to 6.9) compared with similarly dosed (36 to 44 Gy) mediastinal irradiation alone. Women with ≥ 20 years of intact ovarian function after radiotherapy at young ages (< 31 years) experienced significantly higher risks for BC than those with fewer than 10 years of intact ovarian function. Conclusion Reduction of radiation volume appears to decrease the risk for BC after HL. In addition, shorter duration of intact ovarian function after irradiation is associated with a significant reduction of the risk for BC.

The Risk of Second Primary Malignancies up to Three Decades after the Treatment of Differentiated Thyroid Cancer

Background: The 10-yr survival rate of patients with differentiated thyroid cancer exceeds 90%. These patients may be at elevated risk for secondary cancers. Methods: The risk of nonthyroid second primary malignancies after differentiated thyroid cancer was determined in 30,278 patients diagnosed between 1973 and 2002 from centers participating in the National Cancer Institute’s Surveillance, Epidemiology, and End Results program. Median follow-up was 103 months (range, 2–359 months). Risk was further assessed for the addition of radioisotope therapy, gender, latency to development of secondary cancer, and age at thyroid cancer diagnosis. Results: There were 2158 patients who developed a total of 2338 nonthyroid second primary malignancies, significantly more than that expected in the general population [observed/expected (O/E) = 1.09; 95% confidence interval (CI), 1.05–1.14; P &lt; 0.05; absolute excess risk per 10,000 person-years (AER) = 6.39]. A significantly greater risk of second primary malignancies over that expected in the general population was for patients treated with radioisotopes (O/E = 1.20; 95% CI, 1.07–1.33; AER = 11.8) as well as for unirradiated patients (O/E = 1.05; 95% CI, 1.00–1.10; AER = 3.53). However, the increased risk was greater for the irradiated vs. the unirradiated cohort (relative risk = 1.16; 95% CI, 1.05–1.27; P &lt; 0.05). Gender did not affect risk. The greatest risk of second primary cancers occurred within 5 yr of diagnosis and was elevated for younger patients. Conclusions: The overall risk of second primary malignancies is increased for thyroid cancer survivors and varies by radioisotope therapy, latency, and age at diagnosis.

Overall and cause specific long term mortality following childhood cancer: The role of cancer treatment

9520 Background: A multi-centre French cohort study was performed to evaluate the role of treatment in the long-term overall and cause-specific mortality among childhood cancer survivors. Methods: This study cohort included 3,057 patients treated for a solid tumours before the age of 17 between 1942–1986, in 5 French centres and who survived at least 5 years from diagnosis. Detailed clinical and therapeutic data were extracted for each patients from medical records. For 2,081of the 2,178 patients who received radiotherapy, radiation doses were estimated at 188 anatomical sites, including heart (7 sites) and lungs (10 sites). 98% of patients were identified in French National Registry of Physical Persons (RNIPP) and we obtained the death causes of 95% of dead patients. Overall and cause-specific mortality standardized ratios (SMR), absolute excess risk (AER) of death were studied using Poisson regression. Results: 50% of patients were treated by chemotherapy (CT) plus radiotherapy (RT), 22% by CT alone and 21% by RT alone. During an average follow-up of 25 years, 465 patients dead. The overall SMR was 7.3 (95% CI: 6.7–8.0) and AER was 6 deaths per 1,000 person-years. SMR for death due to cancer other than the 1st cancer (SC) was 16.1 (95%, CI 13.5–18.9). SMRs were significantly elevated for non-cancer overall mortality, infectious and parasitic diseases, diseases of the circulatory, nervous and respiratory system, congenital anomalies, symptoms, signs and ill- defined conditions’ (SMRs of 2.6, 15.7, 6.4, 8.5, 4.6, 3.2, respectively). RT was associated an increase in the risk for overall and SC related deaths (RR = 2.0; 95% CI: 1.5–2.7; RR = 1.8; 95% CI: 1.1–2.9; respectively). CT was associated with an increased risk for overall, SC and non- cancer related deaths (RR = 1.6; 95% CI: 1.3–2.0; RR = 1.9; 95% CI: 1.2–3.0; RR = 1.8; 95% CI: 1.1–2.9 respectively). We were not able to find any evidence for an interaction between CT and RT, whatever the end point considered. Among the 26 circulatory deaths, 24 received RT, the mean radiation dose of the heart (P=0.0006) and treatment with spindle inhibitors (P=0.009) were significantly associated to death by cardiac disease. Conclusions: In the future, death due to cardiac pathologies could be an important issue for long term survivors of childhood cancer. No significant financial relationships to disclose.

Stroke Rates and Risk Factors in Patients Treated With Radiation Therapy for Early-Stage Breast Cancer

Purpose To examine whether stroke risk is elevated in American breast cancer patients treated with modern techniques, as well as whether supraclavicular radiation therapy (RT) is associated with increased risk. Methods Observed rates of stroke in 820 eligible early-stage breast cancer patients treated at the University of Michigan Hospital (Ann Arbor, MI) were compared with expected rates. Relationships between potential risk factors and actuarial rate of first stroke were analyzed. Results Median follow-up was 6.8 years. Twenty patients had at least one cerebrovascular accident (CVA) in follow-up; 35 patients had at least one CVA or transient ischemic attack (CVA/TIA). The standardized incidence ratios were 1.74 (0.94 to 2.37) for CVA and 1.68 (1.003 to 2.06) for CVA/TIA. The absolute excess risk per 1,000 patients per year was 1.67 for CVA and 2.76 for CVA/TIA. On bivariate analysis, factors significantly associated with actuarial rate of first CVA included hypertension (P = .002), age (P < .0001), coronary artery disease (P = .001), atrial fibrillation (P = .009), and supraclavicular RT (P = .021). Factors associated with CVA/TIA were hypertension (P < .001), coronary artery disease (P = .002), and age (P < .0001). Tamoxifen use alone was not significant (P = .19), but tamoxifen combined with baseline hypertension led to increased risk of CVA/TIA (log-rank P < .0001). On multivariate analysis, only age (P < .001) and hypertension (P = .003) remained significant predictors of CVA/TIA. Age was the only significant predictor of CVA alone (P < .001). Conclusion American breast cancer survivors may have an elevated risk of stroke compared with the general population, but the absolute excess risk is low. This study found no significant association between supraclavicular RT and stroke after controlling for other factors.