Subsequent Malignant Neoplasms Research Articles

Abstract 2299: Sarcoma as second cancer in pediatric cancer survivors: Large population analysis

Abstract Introduction: As the prognosis of a pediatric cancer continues to improve, the burden of long term therapy effects, including subsequent malignant neoplasm (SMN), in survivors is an increasing epidemiologic concern. The mortality rate from cancer in the pediatric population decreased from 6.5 per 100,000 in 1970 to 2.3 in 2015, indicating more chance of SMNs. Sarcoma as a SMN in pediatrics has important clinical significance and has been extensively reported globally. We quantified the percentage of sarcoma as second cancer and determined the primary cancer distribution for patients with sarcoma as second cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) database, which includes 28% of the U.S population and data from 18 state cancer registries (SEER-18), was probed for the overall incidence of SMN in pediatric cancer survivors and the incidence of sarcoma as the SMN specifically. Results: Our SEER database analysis found that out of 75,665 cases of primary pediatric malignancies, 1218 (1.61%) developed SMN. The second most common SMN was sarcoma, accounting for 14.37% of them in pediatric population. The breakdown of sarcoma into sub groups showed that osteosarcoma, fibrosarcoma, and rhabdomyosarcoma are the most common second sarcomas seen in pediatric cancer survivors. Finally, we looked at the distribution of primary cancer in pediatric cancer survivors who developed sarcoma as a SMN. We found that retinoblastoma, lymphoid leukemia, and Hodgkin lymphomas were the most common types of primary cancer. Similar results were reported among different racial groups around the world, which show a universal trend of sarcomas as second cancers in pediatric cancer survivors. Conclusion: By analyzing the SEER database, we corroborated previous findings, suggesting that about 14% of SMN after a childhood cancer is encompassed by sarcoma. The exact etiology of cancer, be it primary predisposition or secondary to exposures, is uncertain. Radiation and chemotherapies used in patients with pediatric cancers can be carcinogenic. Our study highlights the need for development of novel non-DNA damaging or alternate antineoplastic therapies to avoid the long-term potential of development of SMN. Citation Format: Monish Ram Makena, Thinh H. Nguyen, Siddhartha Yavvari, Maninder Kaur, Teresia Pham, Eduardo Urias, Narendra Panapitiya, Mohamad M. Al-Rahawan. Sarcoma as second cancer in pediatric cancer survivors: Large population analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2299.

Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study.

Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its impact on long-term toxicity remains unknown. We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population. Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio [95% CI]: 90sSR, 0.2 [0.1 to 0.4]; 90sHR, 0.3 [0.1 to 0.7]), comparable to the US population (standardized mortality ratio [95% CI]: 90sSR, 1.3 [0.8 to 2.0]; 90sHR, 1.7 [0.7 to 3.5]). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio [95% CI], 0.3 [0.1 to 0.6]) that was not different from that of the US population (standardized incidence ratio [95% CI], 1.0 [0.6 to 1.6]). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence [95% CI], 11.0% [9.7% to 12.3%] v 22.5% [19.4% to 25.5%]) and a lower prevalence of impaired memory (prevalence ratio [95% CI], 0.7 [0.6 to 0.9]) and task efficiency (0.5 [0.4 to 0.7]). Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.

Treatment intensity and risk of chronic health conditions and late mortality among long-term survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.

10553 Background: Refinement in risk stratification has led to intensification of therapy for Wilms tumor (WT) patients with adverse prognostic factors. Chronic health conditions (CHCs) including cardiac conditions, subsequent malignant neoplasms (SMNs), and late mortality are known risks for WT survivors, however the impact of specific treatment regimens on these outcomes is largely unknown. Methods: Late mortality (all-cause and non-recurrence death > 5 years from diagnosis), SMNs, and severity-graded CHCs (2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal) were assessed in 5-year WT survivors in the Childhood Cancer Survivor Study diagnosed from 1970-99. Survivors were categorized according to therapy received (Table). Cumulative incidence of mortality and standard mortality ratios (SMR) were estimated. Piecewise exponential models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 1507 survivors (median age at follow-up 26 yrs; range 6-55), 35-year cumulative incidence of all-cause mortality was 7.9% (SMR 2.9, CI 2.3-3.6) and 5.1% (SMR 1.9, CI 1.4-2.4) for non-recurrence mortality. RRs for developing any grade 2-5 CHC, grade 3-5 SMN, and grade 2-5 cardiac CHCs were higher for survivors compared to sibling controls (2.0, CI 1.8-2.3; 7.4, CI 5.0-10.8; 2.6, CI 2.2-3.1, respectively). Compared with VA and no RT, RR for non-recurrence late mortality and CHCs among survivors were higher for VAD + any RT, and for ≥ 4 drugs + any RT (Table). Conclusions: Administering increased-intensity therapy for WT is associated with increased late health consequences and non-recurrence late mortality, necessitating strategies to monitor and improve long-term health among survivors. [Table: see text]

Shortened Leukocyte Telomere Length Associates with an Increased Prevalence of Chronic Health Conditions among Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort.

We aimed to analyze and compare leukocyte telomere length (LTL) and age-dependent LTL attrition between childhood cancer survivors and noncancer controls, and to evaluate the associations of LTL with treatment exposures, chronic health conditions (CHC), and health behaviors among survivors. We included 2,427 survivors and 293 noncancer controls of European ancestry, drawn from the participants in St. Jude Lifetime Cohort Study (SJLIFE), a retrospective hospital-based study with prospective follow-up (2007-2016). Common nonneoplastic CHCs (59 types) and subsequent malignant neoplasms (5 types) were clinically assessed. LTL was measured with whole-genome sequencing data. After adjusting for age at DNA sampling, gender, genetic risk score based on 9 SNPs known to be associated with telomere length, and eigenvectors, LTL among survivors was significantly shorter both overall [adjusted mean (AM) = 6.20 kb; SE = 0.03 kb] and across diagnoses than controls (AM = 6.69 kb; SE = 0.07 kb). Among survivors, specific treatment exposures associated with shorter LTL included chest or abdominal irradiation, glucocorticoid, and vincristine chemotherapies. Significant negative associations of LTL with 14 different CHCs, and a positive association with subsequent thyroid cancer occurring out of irradiation field were identified. Health behaviors were significantly associated with LTL among survivors aged 18 to 35 years (P trend = 0.03). LTL is significantly shorter among childhood cancer survivors than noncancer controls, and is associated with CHCs and health behaviors, suggesting LTL as an aging biomarker may be a potential mechanistic target for future intervention studies designed to prevent or delay onset of CHCs in childhood cancer survivors.See related commentary by Walsh, p. 2281.

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma

To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. Diagnosis and mortality from subsequent neoplasm. Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Cumulative burden of subsequent neoplasms, cardiovascular and respiratory morbidity in young people surviving cancer

BackgroundLong-term childhood and young adult cancer survivors are at increased risk of the late effects of multiple chronic conditions. In this study we estimate the cumulative burden of subsequent malignant neoplasms (SMN), cardiovascular and respiratory hospitalisations in long-term survivors of childhood and young adult cancers and associated treatment risks. MethodsFive-year survivors of cancer diagnosed aged 0–29 years between 1992–2009 in Yorkshire, UK were included. The cumulative count of all hospital admissions (including readmissions) for cardiovascular and respiratory conditions and all SMNs diagnosed up to 2015 was calculated, with death as a competing risk. Associations between treatment exposures and cumulative burden were investigated using multiple-failure time survival models. ResultsA total of 3464 5-year survivors were included with a median follow-up of 8.2 years (IQR 4–13 years). Ten-years post diagnosis, the cumulative incidence for a respiratory admission was 6.0 % (95 %CI 5.2–6.9), a cardiovascular admission was 2.0 % (95 %CI 1.5–2.5), and SMN was 1.0 % (95 % CI 0.7–1.4) with an average of 13 events per 100 survivors observed (95 %CI 11–15). The risk of experiencing multiple events was higher for those treated with chemotherapy drugs with known lung toxicity (HR = 1.35, 95 %CI 1.09–1.68). DiscussionSurvivors of childhood and young adult cancer experience a high burden of morbidity due to respiratory, cardiovascular diseases and SMNs up to 20-years post-diagnosis. Statistical methods that capture multiple morbidities and recurrent events are important when quantifying the burden of late effects in young cancer survivors.

MP11-18 ORIGIN OF A SECOND MALIGNANCY HARBORING ISOCHROMOSOME 12P IN PATIENTS WITH HISTORY OF TESTICULAR GERM CELL TUMOR (TGCT)

INTRODUCTION AND OBJECTIVE:The cumulative incidence of subsequent solid malignant neoplasm (SMN) after treatment of TGCT is about 10% over a 25-year period. Isochromosome 12p has been used to defin...

Origin of a second malignancy harboring isochromosome 12p [i(12p)] in patients with history of testicular germ cell tumor (TGCT).

412 Background: The cumulative incidence of subsequent solid malignant neoplasm (SMN) after treatment of TGCT is about 10% over a 25-year period. i(12p) has been used to define tumor of germ cell origin. We evaluated the prevalence of i(12p) on various subsequent SMN in patients with a history of TGCT. Methods: From the Tumor Registry database at MD Anderson, we identified 655 TGCT patients who developed a second (third or fourth) malignancy between January 1990 and September 2018. Of those 114 SMN from the GI tract, GU system, chest, brain, sarcomas or melanomas between 2011 and 2017, 43 had tumor tissue available at our institution and of sufficient quality for fluorescence in situ hybridization (FISH) of i(12p). Results: Our cohort comprised 43 patients, excluding 2 cases (#6 and 7) whose SMN tested positive and their non-tumor controls negative for i(12p). Diagnosis of primary TGCT and SMN: age, mean 41 yrs (range 20-68 yrs) and 59 yrs (range 34-86 yrs), respectively, and interval of 18 yrs (range 0-57 yrs). Of those 43 cases (5 did not hybridize), 5 (11%) harbored i(12p), while 16 (37%) had additional copies of chromosome 12 without apparent gain of 12p. Conclusions: Prevalence of i(12p) on subsequent SMN in our patient cohort with a history of TGCT was 11%. Detection of i(12p) in those patients with TGCT in general and with nonseminomas in particular suggests somatic transformation, emphasizes importance of a complete surgical resection of residual teratomatous tumor after chemotherapy, and implicates a stem-cell origin and nature (e.g., plasticity, heterogeneity, dormancy) of cancer. *deceased; Rx – initial treatments; S – seminoma; NS – nonseminoma; BEP – bleomycin, etoposide, cisplatin; CEB – carboplatin, etoposide, bleomycin; XRT – radiation therapy. Groot HJ, Lubberts S, de Wit R, et al. Risk of solid cancer after treatment of testicular germ cell cancer in the platinum era. J Clin Oncol 2018;36:2504-13.

Ultrasound is superior to palpation for thyroid cancer detection in high-risk childhood cancer and BMT survivors

Thyroid cancer is a common subsequent malignant neoplasm in childhood cancer survivors (CCS). Patients who received radiotherapy (RT) to the head, neck, upper thorax, or total body irradiation (TBI) are considered to be at risk for subsequent thyroid cancer. Current Children's Oncology Group screening guidelines recommend annual neck palpation. Our objective was to determine if ultrasound (US) is more sensitive and specific than palpation to detect thyroid cancer in high-risk CCS and bone marrow transplant (BMT) survivors. Electronic medical records of patients followed in a longitudinal survivorship clinic from January 1, 2010 to December 31, 2017 were reviewed. Inclusion criteria included history of RT to the head, neck, upper thorax, or TBI for primary therapy or preparation for BMT prior to the age of 20years. Two hundred and twenty-five patients had documented palpation and 144 (64%) also had US evaluation. Mean radiation dose was 28.6Gy. Sixteen of 225 patients (7.1%) developed a subsequent thyroid cancer at a mean of 9.7years from the completion of RT. Sensitivity of US was 100% compared with 12.5% for palpation. US demonstrated higher accuracy, with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.87 versus 0.56 for palpation (P < 0.0001). Routine screening with US was more sensitive than palpation for detection of subsequent thyroid cancer after high-risk RT in CCS and BMT survivors. Screening US may lead to earlier detection of thyroid cancer in this population. Earlier diagnosis has the potential to decrease operative complexity, and earlier definitive therapy reduces the likelihood of metastatic disease.

Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study.

Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes. We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets. The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004). Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.

Genetic basis of subsequent malignant neoplasms

Subsequent malignant neoplasms (SMNs) are one of the most serious late complications in pediatric patients with cancer, with more than 10% of long-term cancer survivors developing SMNs. Germline mutations in cancer predisposition genes have been recently highlighted as a risk factor. For example, germline mutations in the TP53 gene were reported to be a risk factor for SMNs. A comprehensive genomic analysis for a large cohort of long-term survivors of childhood cancer showed that variants in cancer predisposition genes were correlated with the higher cumulative incidence of SMNs. As another genetic risk, previous reports suggested that polymorphisms in genes regulating thiopurine pathway such as TPMT gene might contribute to SMN development after acute lymphoblastic leukemia treatment. Considering improved survival probability, attention should be paid for late complications. Thus, therapeutic strategy should be optimized based on a risk for SMNs of each individual.

Risk of subsequent malignant neoplasms after an index potentially-human papillomavirus (HPV)-associated cancers

BackgroundSince the number of cancer survivors is increasing, it is imperative that we better understand the long-term consequences of these survivors. We assessed the risk of developing a second primary malignant neoplasm (SPMN) after an index potentially-HPV-associated cancers (P-HPV-AC). MethodsWe constructed a population-based cohort of patients with P-HPV-AC using Surveillance, Epidemiology, and End Results registry data (2000–2015). We limited patients to those with invasive P-HPV-AC [cervical, vagina, vulva, penile, anal, and oropharynx] based on the International Classification of Diseases for Oncology, 3rd edition. Excess SPMN risks were calculated based on standardized incidence ratios (SIRs) and excess absolute risks (EARs) per 10,000 person-years at risk (PYR). ResultsA total of 105,644 patients with an index P-HPV-AC were identified, and 7.8 % developed a SPMN. In all P-HPV-AC patients, the overall SIR was 1.73 (95 % CI: 1.69–1.77) and EAR of 70.72 per 10,000 PYR. All index P-HPV-AC sites showed statistically significant increases in the risk of SPMN, except for anal cancer among men, compared with the general population. The greatest increase in risk of SPMN was observed among patients diagnosed with an index P-HPV-oropharyngeal cancer (SIR = 1.83; 95 % CI, 1.70–1.82 and SIR = 2.29; 95 % CI, 2.12–2.47 for men and women, respectively). Men developed SPMN mostly in aero-digestive tract whiles women developed SPMN both in aero-digestive tract and other HPV-associated cancer sites. ConclusionsP-HPV-AC survivors experienced excess risk of SPMN. These findings have the potential to affect future surveillance practices and improve preventive healthcare for survivors of P-HPV-ACs.

Large Population Analysis of Secondary Cancers in Pediatric Leukemia Survivors.

Introduction: Survivors of childhood cancer have an increased risk of developing a subsequent secondary malignant neoplasm (SMN). Among five-year survivors of primary cancer, SMNs account for nearly half of non-relapse deaths, which make them the most frequent cause of non-relapse mortality. Leukemia is the most common childhood cancer and the five-year survival rate of leukemia has drastically improved over the past two decades. Therefore, the chances of developing SMNs are higher in pediatric (0–19 years) leukemia survivors. Methods: The US based Surveillance, Epidemiology, and End Results (SEER-18) database (1973–2014) was probed for SMNs in the pediatric population (age ≤ 19). Variables Sequence-number central, primary site and ICCC3WHO were used to identify the first and second cancers among patients who developed SMN. Results: Our SEER database analysis found 99,380 cases of pediatric primary malignancies (0–19 years), of which 1803 (1.81%) patients developed SMN. The breakdown of SMNs in pediatric leukemia survivors (n = 251) showed thyroid carcinoma (18.33% of cases) as the most common second cancer, followed by sarcoma (15.14%), astrocytoma (10.36%), lymphoma (9.56%), salivary gland carcinoma (7.17%), melanoma (4.38%), and breast cancer (3.98%). Interestingly, we found that over 76% of SMNs that were developed by leukemia patients occurred within 20 years after initial leukemia diagnosis. However, some SMNs occur during later age, for example, the mean age for breast cancer occurrence in leukemia survivors is 26.20 ± 8.53 years after initial leukemia diagnosis. Conclusions: Our study presented comprehensive rates of SMNs among pediatric cancers survivors, and the potential SMNs for pediatric leukemia survivors. This information could we used by oncologists, patients, patient families, and cancer researchers to understand the long-term risks that are associated with the development of SMNs in pediatric leukemia survivors.

NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children

Background: Secondary or subsequent malignant neoplasms (SMNs) are one of the most serious late complications in children and adolescents after treatment for acute lymphoblastic leukemia (ALL). Several studies have reported that excess dosing of 6-mercaptopurine (6-MP) therapy and polymorphisms of 6-MP metabolizing enzyme coding gene might influence the risk of SMNs. Recently, nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants have been identified as a cause of high sensitivity to 6-MP, which reflects a high sensitivity to 6MP in East Asians. Therefore, we investigated an association between NUDT15 genotype and incidence of SMNs in pediatric ALL. Methods: Germline samples including bone marrow samples, peripheral blood samples and buccal swab samples during remission were obtained from 13 cases who suffered from SMN after childhood ALL. The prevalence of major NUDT15 non-functional alleles (*2 and *3), which is categorized intermediate or poor metabolizer of 6-MP in Clinical Pharmacogenetics Implementation Consortium Guideline (Relling M et al. Clin Pharmacol Ther 2019), was evaluated by using Sanger sequencing and/or whole exome sequencing. The NUDT15 variants prevalence in SMN patients with primary ALL was compared to those without SMN, who were registered in the TCCSG L04-16 study, which was conducted by the Tokyo Children's Cancer Study Group (TCCSG). Results: Patients' profiles and NUDT15 genotypes were summarized in table 1. Median ages at diagnoses of ALL and SMNs were 4 (1-15) and 13 (5-44) years, respectively. Median duration between ALL and SMNs was 8 (1-30) years. SMNs included acute myeloblastic leukemia (AML) / myelodysplastic syndrome (MDS) (n = 8), brain tumor (n = 1), basal cell carcinoma (n = 1), bladder cancer (n = 1), Ewing sarcoma (n = 1) and osteosarcoma (n = 1). Among the 13 SMN cases, six patients (46.2%) possessed NUDT15 non-functional alleles. The SMNs of these cases included AML / MDS (n = 4), bladder cancer (n = 1) and osteosarcoma (n = 1). Among them, 3 patients, whose SMNs were AML, bladder cancer and osteosarcoma, were treated with radiation therapy against primary ALL. All NUDT15 genotypes were heterozygous variants (3 were *1/*2 and 3 were *1/*3) and seemed to be intermediate metabolizers. In patients without known SMNs in TCCSG ALL L04-16 cohort study, 73 of 437 (16.7%) possessed NUDT15 non-functional alleles. Three of them had bi-allelic variants (2 cases were *3/*3, 1 case was *2/*3), and the others were all heterozygous. The prevalence of NUDT15 non-functional alleles was significantly higher in SMNs compared to that of non-SMN cases (P = 0.012). Conclusion: Our study indicated the NUDT15 hypomorphic variant alleles could be a risk of SMNs after ALL treatment with 6-MP. NUDT15 heterozygotic variants carriers are generally tolerable of 6-MP, and are usually treated with normal or slightly low-dose of 6-MP. However, our results suggested that standard adjustment of 6-MP in maintenance therapy might cause potential overdose of 6-MP for cases with NUDT15 variants, leading to increased risk of SMNs. To certify it, a higher number of study samples and somatic samples analysis of 6-MP induced SMNs are required. To obtain the best long-term event-free survival probability, it might be necessary to reduce the risk of SMNs development without compromising therapeutic effect by further optimal adjustment of 6-MP dose (or alternative agents). Disclosures No relevant conflicts of interest to declare.

Burden of Long-Term Morbidity Borne By Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: BMT is now an integral part of consolidation and/or salvage for patients with AML. With the growing population survivors, there is a need to understand the quality of survival. This would allow for appropriate resource allocation and implementation of risk-based screening for early detection of chronic health conditions over time. Yet, a comprehensive evaluation of the long-term burden of morbidity borne by AML patients treated with BMT remains unknown. We addressed this gap by evaluating long-term severe/life-threatening/fatal chronic health conditions (CHCs) in AML patients treated with BMT using the BMTSS. Methods: Patients were eligible if they had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for ≥2y after BMT, and were ≥21y of age at BMT. Of the 1,113 eligible subjects, 711 (64%) participated. BMT survivors identified a nearest-age sibling to constitute an unaffected comparison group (N=1,136). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHC diagnosis by their healthcare provider, including age at onset of CHC. Scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0) to determine the severity of CHCs. Using multivariable logistic regression, we determined the risk of any severe (CTCAE grade 3) or life-threatening (CTCAE grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information regarding therapeutic exposures (pre-BMT and transplant-related) was abstracted from medical records. Cumulative incidence of CHCs (including fatal [CTCAE grade 5] CHCs) were calculated for BMT survivors, treating relapse-related death as a competing risk. Results: Mean age at BMT was 48.6±13.8y and at survey was 58.2±11.5y. Mean interval between BMT and study participation was 9.7±6.8y; 53% were females, and 78% were non-Hispanic white; 86% received allogeneic BMT (48% from an unrelated donor). Conditioning was Fludarabine/Melphalan-based in 53% and TBI-based in 35%; stem cell source was peripheral blood (70.3%), bone marrow (19.3%), and cord (10.4%). For the siblings, the mean age at survey was 56.9+13.4y; 61% were females, and 88% were non-Hispanic white. BMT survivors vs. sibs: 53.3% of the BMT survivors and 30.4% of the sibs reported grades 3-4 CHCs, placing the survivors at a 3.0-fold higher odds of grades 3-4 CHC (95%CI, 2.4-3.7, p&amp;lt;0.0001). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings: subsequent malignant neoplasms (SMNs: odds ratio [OR]=10.0, 95% CI, 5.5-17.9, p&amp;lt;0.0001), diabetes (OR=5.3, 95% CI, 3.0-9.3, p&amp;lt;0.0001), venous thromboembolism (OR=3.8, 95%CI, 2.5-5.8 p&amp;lt;0.0001), cataracts (OR=3.7; 95%CI, 2.7-5.0, p&amp;lt;0.0001), and major joint replacement (OR=1.5, 95% CI, 1.1-2.1, p=0.02). Among BMT survivors: The 10- and 20y cumulative incidence of a grade 3-5 CHC was 52.0%±1.4% and 66.2%±1.6%, respectively (Figure 1). 75 survivors had developed SMNs: skin (melanoma/ squamous cell [56%]), breast (13%), colon (7%), prostate (7%), and other cancers (24%). The 10- and 20y-cumulative incidence of the most common CHCs were as follows (Figure 2): SMN (10y: 17.9%±1.7%, 20y: 32.1%±2.9%), cataract (10y: 21.5%±1.9%, 20y: 31.5%±3.0%), major joint replacement (10y: 12.5%±0.9%, 20y: 17.5%±3.4%), venous thromboembolism (10y: 8.6%±1.1%, 20y: 13.2%±2.1%), and diabetes (10y: 6.0%±1.9%, 20y: 8.0%±1.5%). Conclusion: The burden of severe/life-threatening CHCs is substantially higher in BMT survivors when compared with an unaffected comparison group. The incidence of severe/ life-threatening/ fatal chronic health condition following BMT for AML exceeds 50% at 10y, and continues to increase with time, approaching 70% at 20y post-BMT. Subsequent malignant neoplasms, diabetes, thrombo-embolic events, cataracts, and major joint replacement constitute the largest burden of morbidity. These findings suggest the need for increased awareness of the long-term burden of morbidity, to ensure close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

Interventions to improve adherence to surveillance guidelines in survivors of childhood cancer: a systematic review.

Many survivors of childhood cancer are at high risk of late effects of their cancer therapy, including cardiac toxicity and subsequent malignant neoplasms (SMN). Current North American guidelines recommend periodic surveillance for these late effects. We conducted a systematic review of the literature to estimate rates of adherence to recommended surveillance and summarize studies evaluating interventions intended to increase adherence. We searched MEDLINE, Embase, Web of Science, and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) for articles published between January 2000 and September 2018 that reported adherence to surveillance for cardiac toxicity and SMN (breast and colorectal cancer) and interventions implemented to improve completion of recommended testing. Risk of bias was assessed using relevant Cochrane checklists. Due to heterogeneity and overlapping study populations, we used narrative synthesis to summarize the findings. This review was registered in PROSPERO: CRD42018098878. Thirteen studies met our inclusion criteria for assessing adherence to surveillance, while five assessed interventions to improve rates of surveillance. No studies met criteria for low risk of bias. Completion of recommended surveillance was lowest for colorectal cancer screening (11.5-30.0%) followed by cardiomyopathy (22.3-48.1%) and breast cancer (37.0-56.5%). Factors such as patient-provider communication, engagement with the health care system, and receipt of information were consistently reported to be associated with higher rates of surveillance. Of five randomized controlled trials aimed at improving surveillance, only two significantly increase completion of recommended testing-one for echocardiography and one for mammography. Both involved telephone outreach to encourage and facilitate these tests. The majority of childhood cancer survivors at high risk of cardiac toxicity or SMN do not receive evidence-based surveillance. There is paucity of rigorous studies evaluating interventions to increase surveillance in this population. Robust trials are needed to assess whether tailored interventions, designed based on unique characteristics and needs of each survivor population, could improve adherence.

Late-onset anorectal disease and psychosocial impact in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known. A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1years; age at survey, 30.2years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). By 45years after the diagnosis, 394 survivors (fistula, n=291; stricture, n=116; anorectal SMN, n=26) and 84 siblings (fistula, n=73; stricture, n=23; anorectal neoplasm, n=1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30Gy within 5years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains. Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.

Clinical characteristics and survival patterns of subsequent sarcoma, breast cancer, and melanoma after childhood cancer in the DCOG-LATER cohort

PurposeChildhood cancer survivors are at increased risk of developing subsequent malignant neoplasms (SMNs). We compared survival and clinical characteristics of survivors with SMNs (sarcoma, breast cancer, or melanoma) and a population-based sample of similar first malignant neoplasm (FMN) patients.MethodsWe assembled three case series of solid SMNs observed in a cohort of 5-year Dutch childhood cancer survivors diagnosed 1963–2001 and followed until 2014: sarcoma (n = 45), female breast cancer (n = 41), and melanoma (n = 17). Each SMN patient was sex-, age-, and calendar year-matched to 10 FMN patients in the population-based Netherlands Cancer Registry. We compared clinical and histopathological characteristics by Fisher’s exact tests and survival by multivariable Cox regression and competing risk regression analyses.ResultsAmong sarcoma-SMN patients, overall survival [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.23–2.87] and sarcoma-specific mortality (HR 1.91, 95% CI 1.16–3.13) were significantly worse compared to sarcoma-FMN patients (foremost for soft-tissue sarcoma), with 15-year survival rates of 30.8% and 61.6%, respectively. Overall survival did not significantly differ for breast-SMN versus breast-FMN patients (HR 1.14, 95% CI 0.54–2.37), nor for melanoma-SMN versus melanoma-FMN patients (HR 0.71, 95% CI 0.10–5.00). No significant differences in tumor characteristics were observed between breast-SMN and breast-FMN patients. Breast-SMN patients were treated more often with mastectomy without radiotherapy/chemotherapy compared to breast-FMN patients (17.1% vs. 5.6%).ConclusionsSurvival of sarcoma-SMN patients is worse than sarcoma-FMN patients. Although survival and tumor characteristics appear similar for breast-SMN and breast-FMN patients, treatment differs; breast-SMN patients less often receive breast-conserving therapy. Larger studies are necessary to substantiate these exploratory findings.

Colon cancer as a subsequent malignant neoplasm in young adults.

The incidence of colon cancer (CC) is rising in younger adults and can occur de novo or in patients previously treated for another cancer. To the authors' knowledge, the impact on survival of CC occurring as a subsequent malignant neoplasm (SMN) has not been described for younger patients, which the authors anticipate to be lower with SMNs than that of primary CC. Patients aged <50years with CC in the 2004 through 2014 National Cancer Data Base were identified. Patients were stratified by primary or subsequent occurrence. The impact of SMN status on overall survival (OS) was evaluated. Of 41,915 patients, 2852 (6.8%) had colon SMNs. More patients with colon SMNs were aged 40 to 49years compared with patients with primary CC (83% vs 77%; P<.001). Patients with colon SMNs presented with earlier clinical and pathological T, N, and M classifications (all P<.001). Colon SMNs more commonly occurred in the right colon, whereas primary CC was found to have a higher prevalence in the sigmoid colon (P<.001). Patients with colon SMNs more frequently underwent total colectomy (17% vs 5%; P<.001), but received less chemotherapy (53% vs 65%; P<.001). When adjusted for demographic, tumor, and treatment characteristics, SMN status was associated with a 23% decreased OS compared with primary CC (95% CI, 1.14-1.31; P<.001). Chemotherapy offered a 33% improvement in OS (95% CI, 0.56-0.8; P<.001). Colon SMNs in younger patients present at an earlier stage and are treated more aggressively surgically compared with primary CCs. Patients with SMNs of the colon have decreased survival, although chemotherapy offers a survival advantage. Further investigation is warranted to determine whether these disparities are due to the effects of cancer treatment or differences in tumor biology.

Adjuvant carboplatin therapy in patients with clinical stage 1 testicular seminoma: is long-term morbidity increased?

Clinical stage (CS) 1 testicular seminoma is cured in almost 100% of cases following either retroperitoneal radiotherapy, carboplatin monotherapy, or surveillance strategies. Little is known about potential long-term effects of carboplatin. We, therefore, examined late sequelae of this drug in seminoma patients. We retrospectively identified 451 patients with CS1 testicular seminoma treated between 1994 and 2014, of whom 243 underwent carboplatin therapy [median follow-up (F/U) 96months], 81 received radiotherapy (median F/U 142months), and 127 underwent surveillance (median F/U 40months). Satisfaction regarding management, as well as the following events during F/U, were analysed by questionnaire: subsequent malignant neoplasms (SMNs), cardiovascular events, arterial hypertension, peptic ulcer, tinnitus, peripheral neuropathy, hypogonadism, and infertility. The relative frequencies of the events were analysed using descriptive statistics. The frequency of observed SMNs was compared with the expected number. Patients receiving carboplatin tolerated the treatment less well (71.2%) than those under surveillance (81.9%). After carboplatin, 12 SMNs (5.0%) were noted vis-a-vis 5.0 expected. There were three cases of prostatic cancer and 3 melanomas among the SMNs. Half of these SMNs occurred early after treatment. Among the other health events, only reported hypogonadism (13.2%) appeared to be marginally increased in frequency. This study found a 2.4-fold higher than expected rate of SMN-and a slightly increased rate of hypogonadism-in the long-term period following carboplatin treatment. Although further studies are needed to confirm these preliminary findings, these results are probably informative for clinicians caring for seminoma patients.