L. L. Robison

Longitudinal patterns of psychological distress in adult survivors of childhood cancer

Background:This study investigated longitudinal patterns of psychological distress in adult survivors of childhood cancer.Methods:Participants included 4569 adult survivors in the Childhood Cancer Survivor Study Cohort (CCSS) who completed the Brief Symptom Inventory-18 on three occasions between 1994 and 2010. Longitudinal latent class analysis was used to identify discrete classes of psychological distress. Predictors of class membership were examined through logistic regression modelling with odds ratios (ORs) and 95% confidence intervals (CIs) reported.Results:Survivors were a median of 39 years of age and 30 years from diagnosis at the most recent follow-up. Most survivors reported few or no symptoms of distress over time, although subsets of survivors reported persistently elevated (depression: 8.9%; anxiety: 4.8%; somatisation: 7.2%) or significant increases in distress symptoms over the follow-up period (depression: 10.2%; anxiety: 11.8%; somatisation: 13.0%). Increasing distress symptoms were predicted by survivor perception of worsening physical health over time (depression: OR=3.3; 95% CI=2.4–4.5; anxiety: OR=3.0; 95% CI=2.2–4.0; somatisation: OR=5.3; 95% CI=3.9–7.4). Persistent distress symptoms were also predicted by survivor perception of worsening physical health over time, as well as by worsening pain and ending analgesic use.Conclusion:Subgroups of adult survivors are at-risk for chronic distress or significant increases in distress decades following their original cancer diagnosis. Routine screening of psychological distress in adult survivors of childhood cancer is warranted, especially for survivors who experience physical health morbidities.

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus

Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio [OR] = 0.81, 95% confidence interval [95% CI] = 0.76–0.86, Pcombined = 3.5 × 10−10), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16.1, 5q31, 6p31.2, 8q24.21 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk

Childhood acute lymphoblastic leukaemia and birthweight: insights from a pooled analysis of case-control data from Germany, the United Kingdom and the United States.

BACKGROUND Heavy birthweight is one of the few established risk factors for childhood acute lymphoblastic leukaemia (ALL). To provide new insight into this relationship, particularly at the extremes (<1500 and > 4500 g), we pooled data from three of the largest childhood cancer case-control studies ever conducted. METHODS Birthweight and gestational age on 4075 children with ALL and 12,065 controls were collected during the course of three studies conducted in the USA, the UK and Germany in the 1990s. Information was obtained from mothers at interview, and the impact of bias was evaluated using the UK study which accessed birth registrations of participants and non-participants. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. RESULTS Children with ALL were, on average, heavier than controls at all gestations, the disparity being driven by a deficit of low-birthweight at all gestations and an excess of high-birthweight at ≥ 40 weeks. Overall, a 1.2 (95% CI 1.1-1.3) increase in ALL risk per kg increase in birthweight was observed; the ORs rising from 0.2 (0.1-0.7) at ≤ 1500 g through to 1.2 (0.9-1.6) at ≥ 4500 g; and 0.8 (0.7-0.9) <10th centile through to 1.3 (1.1-1.4) ≥ 90th centile. CONCLUSION Our findings demonstrate the importance of looking across the full birthweight spectrum when examining associations with disease risk. The new observation of a deficit of very-low-birthweight cases at all gestations has aetiological and study design implications for future work examining not only the in utero origins of ALL, but also other childhood and adult cancers.

Recurrent stroke in childhood cancer survivors

Objective: To estimate the rates and predictors of recurrent stroke among survivors of pediatric cancer who have had a first stroke. Methods: The Childhood Cancer Survivor Study is a retrospective cohort study with longitudinal follow-up that enrolled 14,358 survivors (<21 years old at diagnosis; diagnosed 1970–1986; survived ≥5 years after cancer diagnosis) and followed them prospectively since 1994. We surveyed 443 survivors who reported a first stroke to identify recurrent stroke, and estimated recurrent stroke rates ≥5 years after cancer diagnosis. Results: Among 329 respondents (74% response rate), 271 confirmed a first stroke at a median age of 19 years (range 0–53), and 70 reported a second stroke at a median age of 32 years (range 1–56). In a multivariable Cox proportional hazards model, independent predictors of recurrent stroke included cranial radiation therapy (CRT) dose of ≥50 Gy (vs none, hazard ratio [HR] 4.4; 95% confidence interval [CI] 1.4–13.7), hypertension (HR 1.9; 95% CI 1.0–3.5), and older age at first stroke (HR 6.4; 95% CI 1.8–23; for age ≥40 vs age 0–17 years). The 10-year cumulative incidence of late recurrent stroke was 21% (95% CI 16%–27%) overall, and 33% (95% CI 21%–44%) for those treated with ≥50 Gy of CRT. Conclusion: Survivors of childhood cancer, particularly those previously treated with high-dose cranial radiation, have a high risk of recurrent stroke for decades after a first stroke. Although these strokes are mostly occurring in young adulthood, hypertension, an established atherosclerotic risk factor, independently predicts recurrent stroke in this population.

Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia: an international follow-up study.

A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF–MF) above 0.3 μT, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF–MF exposure categories and by 0.1 μT increases. The HRs by 0.1 μT increases were 1.00 (CI, 0.93–1.07) for event-free survival analysis and 1.04 (CI, 0.97–1.11) for overall survival. ALL cases exposed to >0.3 μT did not have a poorer event-free survival (HR=0.76; CI, 0.44–1.33) or overall survival (HR=0.96; CI, 0.49–1.89). HRs varied little by subtype of ALL. In conclusion, ELF–MF exposure has no impact on the survival probability or risk of relapse in children with ALL.

Cancer Prevention and Screening Practices of Siblings of Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study

Background: To compare the skin and breast/cervical cancer prevention/screening practices of adult siblings of childhood cancer survivors with controls and to identify modifying factors for these practices. Methods: Cross-sectional, self-report data from 2,588 adult siblings of 5+ year survivors of childhood cancer were analyzed to assess cancer prevention/screening practices. Two age, sex, and race/ethnicity-matched samples (N = 5,915 and N = 37,789) of the Behavioral Risk Factor Surveillance System participants served as the comparison populations. Sociodemographic and cancer-related data were explored as modifying factors for sibling cancer prevention/screening practices through multivariable logistic regression. Results: Compared with controls, siblings were more likely to practice skin cancer prevention behaviors: use of protective clothing [OR, 2.85; 95% confidence interval (CI), 2.39–3.39], use of shade (OR, 2.11; 95% CI, 1.88–2.36), use of sunscreen (OR, 1.27; 95% CI, 1.14–1.40), and wearing a hat (OR, 1.77; 95% CI, 1.58–1.98). No differences were noted for breast/cervical cancer screening including mammography and Pap testing. Having less than a high school education and lack of health insurance were associated with diminished cancer prevention/screening behaviors. Survivor diagnosis, treatment intensity, adverse health, chronic health conditions, and second cancers were not associated with sibling cancer prevention/screening behaviors. Conclusions: Siblings of cancer survivors report greater skin cancer prevention practices when compared with controls; however, no differences were noted for breast/cervical cancer screening practices. Access to care and lack of education may be associated with decreased cancer prevention/screening behaviors. Interventions are needed to address these barriers. Impact: Research should be directed at understanding the impact of the cancer experience on sibling health behaviors. Cancer Epidemiol Biomarkers Prev; 21(7); 1078–88. ©2012 AACR.

Risk of rare adult-type carcinomas as a subsequent malignant neoplasm in survivors of childhood cancer: The Childhood Cancer Survivor Study

8530 Background: Subsequent malignant neoplasms (SMNs) are a leading cause of late mortality in survivors of childhood cancer. Using the Childhood Cancer Survivor Study (CCSS) cohort, we determined the risk of carcinomas occurring as SMNs excepting breast, thyroid and skin cancers. METHODS A retrospective cohort of 14,352 five-year survivors of childhood cancers treated at 25 US and Canadian institutions was assembled. SMNs were ascertained through self-administered questionnaires and confirmed with pathology reports. Cumulative incidence, age- and gender-matched standardized incidence ratios (SIRs) were calculated. RESULTS In 71 individuals, 71 carcinomas of interest were found at a median age of 27 years (range 10-44 years) and a median elapsed time of 15 years (range 6-28 years) from first malignancy. Twenty-five (35%) SMNs occurred in the genitourinary system, 23 (32%) in the head and neck area, 16 (23%) in the digestive tract, 4 (6%) in the thorax and the remainder (4%) in other sites. Fifty-nine subjects (83%) had received radiation therapy, 49 (69%) had a history of alkylator therapy, and 8 (11%) had a history of epipodophyllotoxin therapy. Forty-two carcinomas (59%) arose in a radiation field. An excess of carcinomas was found following all childhood diagnoses, and was highest for neuroblastoma (SIR = 24.2 [95% confidence interval [CI] = 12.6-46.5]), soft tissue sarcomas (SIR = 6.2, [95% CI = 3.5-11]) and Wilms tumor (SIR = 4.8 [95% CI = 1.5-14.8]). There was a significant excess of carcinomas in most of the morphology types examined and was greatest for mucoepidermoid neoplasms (SIR=34.0 [95%CI= 19.3-59.9]) and renal cell carcinomas (SIR = 13.3 [95%CI = 6.7-26.7]). The 20-year cumulative incidence for all SMNs in this report is 0.45%. CONCLUSIONS Childhood cancer survivors are at increased risk of developing subsequent adult-type carcinomas, but the cumulative incidence is low. Further analyses of the contribution of patient and treatment factors to the increased risk of carcinomas in this population are in progress. No significant financial relationships to disclose.

Predictors of Colorectal Cancer Surveillance among Radiation-treated Survivors of Childhood Cancer

Purpose: To identify predictors of adherence to colorectal cancer (CRC) surveillance guidelines among survivors of childhood cancer who received ≥30 Gy radiotherapy to the abdomen, pelvis, or spine, and were 36 years or older at the time of last contact. Methods: We sought to identify predictors of self-reported CRC surveillance participation among 5-year survivors who completed the Childhood Cancer Survivor Study (CCSS) 2007 Follow-Up Questionnaire and met the criteria above. Univariate and multivariable generalized linear models with a log link and Poisson distribution were used to calculate relative risks (RR) with 95% confidence intervals (95% CI) for adherence to CRC surveillance guidelines (i.e., home stool blood testing and/or colonoscopy/sigmoidoscopy). Results: The mean age of 711 childhood cancer survivors eligible for the study was 44 years (SD = 5.2 years). Among them, 231 (32.5%) reported ever performing home stool blood testing and 276 (38.8%) reported ever having colonoscopy or sigmoidoscopy. Of the 711 participants, 60 (8.4%) reported home stool blood testing in the past year (meeting screening guidelines for the general adult population) and 207 (29.1%) reported having a colonoscopy or sigmoidoscopy in the past 5 years (meeting surveillance recommendations for survivors of childhood cancer treated with radiation). In the multivariable analyses, factors associated with CRC surveillance were age 50 years or older (RR = 2.4, 95% CI = 1.9–2.9); having routine cancer follow-up visit within one year prior to questionnaire completion (RR = 1.7, 95% CI = 1.2–2.5); having a physical impairment requiring the assistance of others for routine activities of daily living (RR = 1.7, 95% CI = 1.2–2.2); and having discussed future cancer risk with a physician at their most recent follow-up visit (RR = 1.3, 95% CI = 1.1–1.6). Conclusions: More than 70% of survivors at risk for CRC were not screened as recommended. Indeed, unless a physician discussed their future cancer risk, most survivors were not screened until they reached age 50, the time at which CRC screening is recommended for individuals at average CRC risk. These findings underscore the need for education of survivors and their physicians regarding the heightened CRC risk following radiation.Purpose: To identify predictors of adherence to colorectal cancer (CRC) surveillance guidelines among survivors of childhood cancer who received ≥30 Gy radiotherapy to the abdomen, pelvis, or spine, and were 36 years or older at the time of last contact. Methods: We sought to identify predictors of self-reported CRC surveillance participation among 5-year survivors who completed the Childhood Cancer Survivor Study (CCSS) 2007 Follow-Up Questionnaire and met the criteria above. Univariate and multivariable generalized linear models with a log link and Poisson distribution were used to calculate relative risks (RR) with 95% confidence intervals (95% CI) for adherence to CRC surveillance guidelines (i.e., home stool blood testing and/or colonoscopy/sigmoidoscopy). Results: The mean age of 711 childhood cancer survivors eligible for the study was 44 years (SD = 5.2 years). Among them, 231 (32.5%) reported ever performing home stool blood testing and 276 (38.8%) reported ever having colonoscopy or sigmoidoscopy. Of the 711 participants, 60 (8.4%) reported home stool blood testing in the past year (meeting screening guidelines for the general adult population) and 207 (29.1%) reported having a colonoscopy or sigmoidoscopy in the past 5 years (meeting surveillance recommendations for survivors of childhood cancer treated with radiation). In the multivariable analyses, factors associated with CRC surveillance were age 50 years or older (RR = 2.4, 95% CI = 1.9–2.9); having routine cancer follow-up visit within one year prior to questionnaire completion (RR = 1.7, 95% CI = 1.2–2.5); having a physical impairment requiring the assistance of others for routine activities of daily living (RR = 1.7, 95% CI = 1.2–2.2); and having discussed future cancer risk with a physician at their most recent follow-up visit (RR = 1.3, 95% CI = 1.1–1.6). Conclusions: More than 70% of survivors at risk for CRC were not screened as recommended. Indeed, unless a physician discussed their future cancer risk, most survivors were not screened until they reached age 50, the time at which CRC screening is recommended for individuals at average CRC risk. These findings underscore the need for education of survivors and their physicians regarding the heightened CRC risk following radiation. The following are the 18 highest scoring abstracts of those submitted for presentation at the 37th Annual ASPO meeting held March 10–12, 2013, in Memphis, TN.

Summaries for patients. Increased risk for gastrointestinal cancer in childhood cancer survivors.

and P.C. Nathan. What is the problem and what is known about it so far? Patients who survived cancer as a child, adolescent, or young adult have been noted to develop second cases of cancer at a rate higher than that of the general population. In particular, cancer of the gastrointestinal tract (such as colon cancer) occurs more often. However, whether specific factors related to the childhood cancer or its treatment are related to the increased incidence of second cancer is not well-defined.

Secondary leukemia 15 years or more after treatment for childhood cancer: A report from the Childhood Cancer Survivor Study.

9577 Background: Previous evaluations of survivors of childhood cancer suggest that the cumulative incidence of secondary leukemia plateaus at ~2% 10-15 years after primary cancer therapy. Risk beyond 15 years has not been comprehensively assessed, in part because of the lack of comprehensive long-term follow-up of previous cohorts beyond this time period. METHODS The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study of 5-year survivors of childhood cancer treated between 1970 and 1986. Self-reported secondary leukemias >5 years from primary diagnosis were confirmed by pathology report or medical records. Diagnostic bone marrow samples were acquired and centrally reviewed. The standardized incidence ratio (SIR) was derived using age, gender, and calendar year specific rates from surveillance epidemiology and end results data. RESULTS Of 14,358 5-year survivors, 43 developed subsequent leukemia >5 years from primary diagnosis with 13 cases of leukemia occurring ≥ 15 years from diagnosis. Five were AML (2 with confirmed preceding MDS), 4 ALL (2 pre-B lineage, 1 T-cell, 1 unknown), 2 were APL with t(15;17). Two AML cases had 7q- deletion. One ALL had a complex karyotype including t(9;22) and another a p53 mutation. The mean age at diagnosis of leukemia was 31.6 years (range 18 to51), and occurred after a latency of 21.6 years from diagnosis. Sarcomas (n=5) and Hodgkin lymphoma (n=4) were the most common primary diagnoses. Six of the 13 patients received radiation therapy, while only 5 received alkylating agents, and none received epipodophyllotoxins. The SIR for leukemias occurring ≥ 15 years from diagnosis was 3.5 (95% CI 1.9 - 6.0). Eight of 13 are deceased with a median survival of 2 years after diagnosis of leukemia. CONCLUSIONS This is the first description of increased risk of secondary leukemia ≥ 15 years from primary malignancy, demonstrating a 3.5-fold increased risk above that of the general population. Radiation was the most common treatment exposure. These findings indicate a high level of suspicion should be maintained for subjects who received radiation or alkylators and develop pancytopenia to facilitate early detection and intervention.