Risk Of Subsequent Malignant Neoplasms Research Articles

Abstract 3110: Shorter naïve T cell telomere length is associated with thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study (CCSS)

Abstract Introduction: Reduced blood telomere content has been associated with an increased risk for subsequent malignant neoplasms of the thyroid (thyroid SMN) in survivors of childhood cancer (PMID 24277454). Here, we further investigate this association by examining telomere length (TL) in leukocyte subsets. Methods: Survivors were enrolled to the CCSS, a multicenter, retrospective cohort of 5-year + survivors of childhood cancer. Cases were survivors with thyroid SMN, and matched (1:1) to survivor controls without SMN by primary diagnosis, year of primary diagnosis (decade), chemotherapy (yes/no), radiation field, and follow-up time (exceeding time to SMN for the case). Stem cell transplant recipients were excluded. Absolute TL was determined from viably frozen leukocytes (lymphocytes, naïve T, memory T, B, and NK cells) by telomere flow cytometry fluorescence in situ hybridization (telomere flow FISH, Repeat Diagnostics), and transformed to age-adjusted percentiles based on age at sample collection. For each leukocyte subset, we used McNemar’s test to compare frequency of very low (VL, ≤1st age-adjusted percentile) or low (L, >1st to ≤10th percentile), and a paired t-test to compare age-adjusted TL between cases and controls. Odds ratios were determined by conditional logistic regression. Results: Of the 52 matched pairs identified, 46 pairs (92 survivors) had sufficient cell recovery for flow FISH: primary diagnoses included Hodgkin lymphoma (20 pairs), acute lymphoblastic leukemia (13 pairs), CNS tumors (7 pairs), neuroblastoma (2 pairs), non-Hodgkin lymphoma (3 pairs), and kidney tumor (1 pair). All survivors had age-adjusted TL below the population median. Cases had shorter age-adjusted TL than controls in 4 out of 5 leukocyte subsets: lymphocytes (p=0.04), naïve T cells (p=0.02), B cells (p=0.01), and NK cells (p=0.01). Naïve T cells had an overrepresentation of VL TL (cases with VL TL in 9/46 pairs vs. controls with VL TL in 2/46 pairs, p=0.04). The odds of L or VL naïve T cell TL was significantly higher in cases compared with controls (OR=2.8, 1.11-7.19, p=0.03), an observation that did not change after adjusting for age at diagnosis. Conclusions: Survivors of childhood cancer had shorter age-adjusted leukocyte TL than the general population. This negative deviation was more pronounced among survivors with thyroid SMN than in survivors without SMN, which may reflect a differential risk among survivors for excess premature aging in the hematopoietic compartment. The effect of SMN treatment on TL is unlikely to be a factor, as treatment for thyroid SMN is primarily surgical. In cancer-naïve populations, VL lymphocyte TL is a sensitive and specific indicator of underlying defects in telomere maintenance. In survivors of childhood cancer, VL TL in naïve T cells may reflect an association between SMN risk and defects in T cell-mediated cancer surveillance. Citation Format: Maria M. Gramatges, Geraldine Aubert, Elmira Hariri, Yan Chen, John A. Whitton, Wendy M. Leisenring, Michael A. Arnold, Joseph P. Neglia, Yutaka Yasui, Leslie L. Robison, Gregory T. Armstrong, Smita Bhatia. Shorter naïve T cell telomere length is associated with thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study (CCSS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3110.

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.

Long term morbidity and mortality among survivors of infant neuroblastoma: A report from the Childhood Cancer Survivor Study (CCSS).

10051 Background: Infants with neuroblastoma typically have low-risk disease with excellent survival. Therapy has been de-intensified over time to minimize late effects, however the impact on survivors’ risk of late mortality, subsequent malignant neoplasms (SMN), and chronic health conditions (CHC) is unclear. Methods: We evaluated late mortality, SMNs and CHCs (graded according to CTCAE v4.03), overall and by diagnosis era, among 990 5-year neuroblastoma survivors diagnosed at < 1 year of age between 1970-1999. Cumulative mortality, standardized mortality ratios (SMR), and standardized incidence ratios (SIR) of SMNs were estimated using the National Death Index and SEER rates, respectively. Cox proportional hazards estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC, compared to 5,051 CCSS siblings. Results: Among survivors (48% female; median attained age: 24 years, range 6-46), there was increased treatment with surgery alone across the 1970s, 1980s and 1990s (21.5%, 35.3%, 41.1%, respectively), but decreased treatment with combination surgery + radiation (22.5%, 5.3%, 0.3%, respectively) and surgery + radiation + chemotherapy (28.7%, 14.7%, 9.3%, respectively). The 20-year cumulative mortality was 2.3% (95% CI, 1.4-3.8), primarily due to SMNs (SMRSMN= 10.0, 95% CI, 4.5-22.3). The 20-year cumulative incidence of SMN was 1.2% (95% CI, 0.3-3.2), 2.5% (95% CI, 1.3-4.4), and zero for those diagnosed in the 1970s, 1980s, and 1990s, respectively. SIR was highest for renal SMNs (SIR 12.5, 95% CI, 1.7-89.4). Compared to siblings, survivors were at increased risk for grade 1-5 CHC (HR 2.1, 95% CI, 1.9-2.3) with similar HR across eras (HR1970s= 1.9, 95% CI, 1.6-2.2; HR1980s= 2.2, 95% CI, 1.9-2.6; HR1990s= 2.0, 95% CI, 1.7-2.4). The HR of severe, disabling, life-threatening and fatal CHC (grades 3-5) decreased in more recent eras (HR1970s= 4.7, 95% CI, 3.4-6.6; HR1980s= 4.4, 95% CI, 3.2-6.2; HR1990s= 2.9, 95% CI, 2.0-4.3). Conclusions: Survivors of infant neuroblastoma remain at increased risk for late mortality, SMN, and CHCs many years after diagnosis. However, the risk of grade 3-5 CHCs has declined in more recent eras, likely reflecting de-intensification of therapy.

Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.

Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk. Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.

A Systematic Review and Meta-Analysis of Subsequent Malignant Neoplasm Risk After Radioactive Iodine Treatment of Thyroid Cancer.

Background: The potential risk of subsequent malignant neoplasms (SMNs) after radioactive iodine (RAI) treatment of thyroid cancer (TC) is an important concern. Methods: A systematic review was updated comparing the risk of SMNs in TC patients treated with RAI to TC patients without RAI. Six electronic databases were searched (up to March, 2018), supplemented with a hand search. Two reviewers independently screened citations, reviewed full-text papers, and critically appraised/abstracted data. Random-effects meta-analyses were conducted using crude data and data statistically adjusted for confounders. The outcomes were any SMN and specific SMNs for which sufficient data were available. Results: In total, 3506 unique electronic search citations and 93 full-text papers were examined, including 17 studies (3 systematic reviews and 14 original studies). Published knowledge syntheses were limited by inclusion of small numbers of studies, with two systematic reviews suggesting an increased risk of any SMN and one meta-analysis suggesting a reduced risk of breast SMN after RAI treatment. In a meta-analysis of crude data, the risk ratio of any SMN in RAI-treated TC patients was 0.98 ([confidence interval (CI) 0.76-1.27]; n = 10 studies of 65,539 individuals, heterogeneity Q = 64.26, degrees of freedom [df] = 9, p < 0.001, I2 = 85.99). The pooled risk ratio for any SMN, adjusted for confounders, was 1.16 ([CI 0.97-1.39]; n = 6 studies, data from at least 11,241 TC patients, Q = 10.86, df = 5, p = 0.054, I2 = 53.96). In secondary analyses examining specific SMNs, although relatively rare, the risk of subsequent leukemia was increased, but the risk of multiple myeloma was reduced in RAI-treated TC patients. There was no significant increased relative risk of breast cancer, salivary cancer, or combined hematologic malignancies according to RAI treatment status. Conclusions: The body of evidence on whether 131I treatment of thyroid cancer is associated with the primary outcome of any SMN is highly heterogeneous and complex. More research examining the long-term risk of specific SMNs after 131I treatment is needed.

Subsequent malignancies after long-term follow-up of paediatric hematopoietic stem cell transplantation

IntroductionSurvival after hematopoietic stem cell transplantation has improved dramatically in recent years. Unfortunately, there is an increased risk of subsequent malignant neoplasms (SMN) in this population and this represents a significant cause of late mortality. Patients and methodsIn this study, we analysed the incidence of SMN and the associated risk factors in patients referred at a paediatric age for hematopoietic stem cell transplantation (allogeneic or autologous) in our centre. ResultsWe observed 19 cases of SMN in a cohort of 371 patients, with a cumulative incidence of 6, 12, and 36% at 15, 20, and 30 years of follow-up, respectively. The solid tumours were the most prevalent malignancies. The risk was significantly higher than expected in the general population for each tumour type and in the different age ranges (P<.0001). Radiotherapy and chronic GvHD were the main risk factors for the development of SMN in our series. ConclusionsWe observed a high incidence of SMN among hematopoietic stem cell transplantation survivors highlighting the need for life-long surveillance.

Independent application of an analytical model for secondary neutron equivalent dose produced in a passive-scattering proton therapy treatment unit

The purpose of this study was to independently apply an analytical model for equivalent dose from neutrons produced in a passive-scattering proton therapy treatment unit, H. To accomplish this objective, we applied the previously-published model to treatment plans of two pediatric patients. Their model accounted for neutrons generated by mono-energetic proton beams stopping in a closed aperture. To implement their model to a clinical setting, we adjusted it to account for the area of a collimating aperture, energy modulation, air gap between the treatment unit and patient, and radiation weighting factor. We used the adjusted model to estimate H per prescribed proton absorbed dose, DRx, for the passive-scattering proton therapy beams of two children, a 9-year-old girl and 10-year-old boy, who each received intracranial boost fields as part of their treatment. In organs and tissues at risk for radiation-induced subsequent malignant neoplasms, T, we calculated the mass-averaged H, HT, per DRx. Finally, we compared HT/DRx values to those of previously-published Monte Carlo (MC) simulations of these patients’ fields. HT/DRx values of the adjusted model deviated from the MC result for each organ on average by 20.8 ± 10.0% and 44.2 ± 17.6% for the girl and boy, respectively. The adjusted model underestimated the MC result in all T of each patient, with the exception of the girl’s bladder, for which the adjusted model overestimated HT/DRx by 3.1%. The adjusted model provided a better estimate of HT/DRx than the unadjusted model. That is, between the two models, the adjusted model reduced the deviation from the MC result by approximately 37.0% and 46.7% for the girl and boy, respectively. We found that the previously-published analytical model, combined with adjustment factors to enhance its clinical applicability, predicted HT/DRx in out-of-field organs and tissues at risk for subsequent malignant neoplasms with acceptable accuracy. This independent application demonstrated that the analytical model may be useful broadly for clinicians and researchers to calculate equivalent dose from neutrons produced externally to the patient in passive-scattering proton therapy.

Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy

Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients.To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population.Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

Risk of Solid Cancer After Treatment of Testicular Germ Cell Cancer in the Platinum Era.

Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m2 increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m2 of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.

Risk, Risk Factors, and Surveillance of Subsequent Malignant Neoplasms in Survivors of Childhood Cancer: A Review.

Subsequent malignant neoplasms (SMNs) in childhood cancer survivors cause substantial morbidity and mortality. This review summarizes recent literature on SMN epidemiology, risk factors, surveillance, and interventions. Survivors of childhood cancer experience long-term increased SMN risk compared with the general population, with a greater than twofold increased solid tumor risk extending beyond age 40 years. There is a dose-dependent increased risk for solid tumors after radiotherapy, with the highest risks for tumors occurring in or near the treatment field (eg, greater than fivefold increased risk for breast, brain, thyroid, skin, bone, and soft tissue malignancies). Alkylating and anthracycline chemotherapies increase the risk for development of several solid malignancies in addition to acute leukemia/myelodysplasia, and these risks may be modified by other patient characteristics, such as age at exposure and, potentially, inherited genetic susceptibility. Strategies for identifying survivors at risk and initiating long-term surveillance have improved and interventions are underway to improve knowledge about late-treatment effects among survivors and caregivers. Better understanding of treatment-related risk factors and genetic susceptibility holds promise for refining surveillance strategies and, ultimately, upfront cancer therapies.

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

Background:Hodgkin lymphoma (HL) patients are at an increased risk of late adverse treatment effects. While published studies focussed on the risk of either subsequent malignant neoplasms (SMNs) or cardiovascular disease (CVD), we examined the combined burden from SMN and CVD.Methods:In 2908 5-year HL survivors treated between 1965 and 2000, the burden from SMN and/or CVD was assessed using cumulative incidences (CIs) and the mean cumulative count (MCC).Results:We identified 888 SMNs and 1153 CVDs in 1247 patients (median follow-up 22 years). At 40 years, the CI for developing either SMN or CVD was 68% and the CI for developing both SMN and CVD was 17%, and an average of 1.2 events per patient (MCC) was observed. HL patients who developed a solid malignancy had similar 15-year risks to develop another subsequent malignancy or CVD (15%), whereas patients who developed a CVD after HL had a higher 15-year risk to develop another CVD compared with a subsequent malignancy (46 vs 15%). Radiotherapy was the strongest risk factor for developing both SMN and CVD in multivariable Cox regression models.Conclusions:Treating physicians should be aware of the increased risk of both SMN and CVD in patients treated for HL until 2000.

Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy.

Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( Ptrend < .001) and breast cancer ( Ptrend < .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( Pdifference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( Ptrend = .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.

Increased late mortality in underweight survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

110 Background: Approximately one-in-ten adult survivors of childhood cancer are underweight. While the consequences of being overweight or obese have been well-described, outcomes among underweight childhood cancer survivors are unknown. Methods: Underweight was defined as a body mass index (BMI)&lt; 18.5 kg/m2, calculated from self-reported height and weight on either the baseline or the first follow-up questionnaire from the Childhood Cancer Survivor Study (CCSS). National Death Index provided death data and self-reported subsequent malignant neoplasm were validated by pathology report. Chi-square test was used to examine the association between underweight status (&lt; 8.5 kg/m2 vs ≥ 18.5 kg/m2) and baseline demographic characteristics. Marginal models with generalized estimating equations were used to evaluate the associations between BMI and outcomes. Results: Of 9454 survivors (median age 35 years old, range 17-58, with an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline and had at least two years of additional follow-up. 29 of 184 deaths were among underweight survivors. In univariate analysis, underweight status was more common among females (9.1% vs 4.5 %, p&lt;0.01) and participants with younger age (8.2% for &lt;5 yrs vs. 6.1% for &gt;=5yr, p&lt;.01), lower household income (8.9% for &lt;$20,000 vs. 6.0% for &gt;=$20,000, p&lt;0.01), and a history of a grade 3 to 4 chronic condition (p = 0.05). After adjustment for these factors, in addition to race/ethnicity, prior smoking, and a history of radiation therapy, the odds of all-cause mortality within two years of BMI report was 2.82 (95% CI: 1.64-2.2; p&lt;0.01) for underweight survivors, compared to normal weight survivors. The risk of subsequent malignant neoplasms within two years of BMI report among underweight survivors compared to normal weight survivors was not significantly increased (OR 1.31; 95% CI: 0.60-2.85; p = 0.49). Conclusions: Childhood cancer survivors who are underweight are at significant risk for late mortality that is unrelated to smoking status, chronic illness, or second malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.

Subsequent Malignant Neoplasms Among Children and Adolescents with Hodgkin Lymphoma Treated with Response-Adapted Therapy: A Report from the Children's Oncology Group Study AHOD0031

▪Background:Survivors of childhood Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMN). Response-adapted treatment for HL may decrease the SMN risk by reducing therapy in patients who have a good initial response to treatment. The Children's Oncology Group Study AHOD0031, which enrolled patients from 2002 - 2009, evaluated the role of early treatment response in directing therapy for children and adolescents with intermediate-risk Hodgkin lymphoma. We report the incidence and risk factors for SMN among 1,711 eligible patients enrolled on AHOD0031.Methods:Eligible patients had clinical stage I-IIA with bulk, I-IIAE, I-II B, IIIA-IVA with or without bulk. Patients initially received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), followed by a response evaluation of rapid early (RER) versus slow early responder (SER) status. All SER patients were randomized to an additional two cycles of ABVE-PC +/- 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA). All SER patients received 21 Gy involved field radiotherapy (IFRT) following completion of chemotherapy. RER patients received 2 additional cycles of ABVE-PC. RER with complete responder (CR) status (RER/CR) patients were randomized to involved field radiotherapy (IFRT) or no further therapy. RER/non-CR patients were non-randomly assigned to IFRT. At a median follow-up of 6.2 years, an analysis of SMN was undertaken. The cumulative incidence of SMNs as a first event was calculated from the time of diagnosis adjusted for competing events due to relapse or death. Comparisons of the cumulative incidence among treatment groups were made using the K-sample test. A multivariable analysis using the Cox proportional hazard model assessed risk conferred by age, gender, race, disease stage, B symptoms, bulk disease, and IFRT.Results:Among 1,711 patients with a median follow up of 6.2 years, excluding non-melanoma skin cancer, 16 SMNs occurred, 13 as a first event. SMNs included seven hematologic malignancies and nine solid tumors. No subsequent breast cancer has been reported to date. Patients who experienced a SMN did not differ from those who did not with respect to age, gender, race, disease stage, B symptoms, or bulk disease. The median time to SMN as a first event was 4.1 years (range 1.1-9.5 years). The 5-year cumulative incidence of SMN as a first event was 0.53% (95% CI 0.16 to 0.90) (Figure 1A). A comparison of the cumulative incidence of SMN in patients who received IFRT and those who did not demonstrated an increased incidence of SMN in the IFRT group (p = 0.03) (Figure 1B). In fact, to date, all SMNs have occurred in patients who received IFRT. Therefore, a multivariate analysis was conducted among patients who received IFRT, which included age, gender, race, disease stage, B symptoms, and bulk disease. The presence of B symptoms was independently associated with increased risk for SMN with a hazard ratio of 15.24 (95% CI 1.73-134.04, p=0.01). Among the 13 patients with a SMN as first event, there were 4 deaths.Conclusions:With a median follow up of 6.2 years, the 5-year cumulative incidence of SMN in patients treated with response-adapted treatment on AHOD0031 is very low. It is likely that we have captured the cases of secondary leukemia related to etoposide exposure, as these generally occur within five years of treatment. Longer follow-up will be needed to assess the risk of solid tumors, which are generally known to have longer latencies without plateau in incidence over time. Evaluation of the location of secondary solid tumors relative to the IFRT fields is in progress. As AHOD0031 demonstrated no benefit in event-free or overall survival for RER/CR patients treated with IFRT, future intermediate risk patients treated according to this treatment strategy will be less likely to receive IFRT and can be expected to be at lower risk of SMN. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk of Subsequent Neoplasms During the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort.

Survivors of childhood cancer have an increased risk for subsequent neoplasms (SNs), but the incidence beyond the age of 40 years and associations with therapeutic exposures have not been well described. Among 14,364 survivors of childhood cancer diagnosed between 1970 and 1986, 3,171 had an attained age of 40 years or older at the time of last contact. Cumulative incidence of SNs, standardized incidence ratios (SIRs), excess absolute risk of subsequent malignant neoplasms (SMNs), and relative risks (RRs) for SMNs and nonmelanoma skin cancers were calculated. In total, 679 SNs were diagnosed in patients age 40 years or older. These included 196 SMNs, 419 nonmelanoma skin cancers, 21 nonmalignant meningiomas, and 43 other benign neoplasms. At age 55 years, the cumulative incidence of new SNs and SMNs occurring after age 40 years was 34.6% (95% CI, 28.7 to 40.6) and 16.3% (95% CI, 11.7 to 20.9), respectively. Survivors were twice as likely as the general population to receive a diagnosis of SMN after age 40 years (SIR, 2.2; 95% CI, 1.9 to 2.5). Among SMNs, risk was increased for breast cancer (SIR, 5.5; 95% CI, 4.5 to 6.7), renal cancer (SIR, 3.9; 95% CI, 2.0 to 7.5), soft tissue sarcoma (SIR, 2.6; 95% CI, 1.5 to 4.4), and thyroid cancer (SIR, 1.9; 95% CI, 1.0 to 3.5). Female sex (RR, 1.9; 95% CI, 1.3 to 2.6; P < .001) and therapeutic radiation exposure (RR, 2.2; 95% CI, 1.4 to 3.3; P < .001) were associated with an increased for risk for SMN in multivariable analysis. Even after age 40 years, survivors of childhood cancer remain at increased risk for treatment-related SNs. These data suggest the need for life-long monitoring and should inform anticipatory guidance provided to survivors of childhood cancer.

Subsequent Malignant Neoplasms in Pediatric Patients Initially Diagnosed With Neuroblastoma

Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.

Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors.

Subsequent malignant neoplasms (SMNs) are associated with significant morbidity and are a major cause of premature mortality among cancer survivors. Several large studies have demonstrated a strong association between the radiation and/or chemotherapy used to treat primary cancer and the risk of developing SMNs. However, for any given therapeutic exposure, the risk of developing an SMN varies between individuals. Genomic variation can potentially modify the association between therapeutic exposures and SMN risk and may explain the observed interindividual variability. In this review, the author provides a brief overview of the current knowledge regarding the role of genomic variation in the development of therapy-related SMNs and discusses the methodological challenges in undertaking an endeavor to develop a deeper understanding of the molecular underpinnings of therapy-related SMNs, such as an appropriate study design, the identification of an adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, clinical validation of the phenotype, and the selection of an appropriate approach or platform for genotyping. Understanding the factors that can modify the risk of treatment-related SMNs is critical to developing targeted intervention strategies and optimizing risk-based health care for cancer survivors.

Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy.

Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks. In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale. Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01). This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.

Risk of subsequent malignant neoplasms in long-term retinoblastoma survivors following chemotherapy and radiotherapy.

10079 Background: Hereditary retinoblastoma (Rb) survivors have increased risk for developing subsequent malignant neoplasms (SMN). Previous studies report elevated SMN risks related to radiotherap...

Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report.

Multi-modality therapy has resulted in improved survival for childhood malignancies. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers provide practitioners with exposure- and risk-based recommendations for the surveillance and management of asymptomatic survivors who are at least 2years from completion of therapy. This review outlines the pathophysiology and risks for oral and dental late effects in pediatric cancer survivors and the rationale for oral and dental screening recommended by the Children's Oncology Group. An English literature search for oral and dental complications of childhood cancer treatment was undertaken via MEDLINE and encompassed January 1975 to January 2013. Proposed guideline content based on the literature review was approved by a multi-disciplinary panel of survivorship experts and scored according to a modified version of the National Comprehensive Cancer Network "Categories of Consensus" system. The Children's Oncology Group oral-dental panel selected 85 relevant citations. Childhood cancer therapy may impact tooth development, salivary function, craniofacial development, and temporomandibular joint function placing some childhood cancer survivors at an increased risk for poor oral and dental health. Additionally, head and neck radiation and hematopoietic stem cell transplantation increase the risk of subsequent malignant neoplasms in the oral cavity. Survivors require routine dental care to evaluate for potential side effects and initiate early treatment. Certain childhood cancer survivors are at an increased risk for poor oral and dental health. Early identification of oral and dental morbidity and early interventions can optimize health and quality of life.