Subsequent Malignant Neoplasms Research Articles

Physical late effects of treatment among survivors of childhood cancer in low- and middle-income countries: a systematic review.

Physical late effects of treatment are well-documented among childhood cancer survivors in high-income countries, but whether prevalence and risk factors are comparable in low- and middle-income countries (LMICs) is unclear. We conducted a systematic review to assess physical late effect outcomes among childhood cancer survivors in LMICs. Five health sciences databases were searched from inception to November 2022 in all languages. We included observational studies conducted in LMICs that evaluated physical late effects of treatment in childhood cancer survivors. Mean or median cohort follow-up must have been ≥ 5 years from original cancer diagnosis. Sixteen full articles and five conference abstracts were included. Studies were conducted in lower-middle (n = 12, 57%) or upper-middle income (n = 9, 43%) countries; nearly half (n = 9, 43%) were conducted in India. Five cohorts (24%) were comprised entirely of 5-year survivors. Subsequent malignant neoplasms were reported in 0-11% of survivors (n = 10 studies). Hypothyroidism and metabolic syndrome prevalence ranged from 2-49% (n = 4 studies) and 4-17% (n = 5 studies), respectively. Gonadal dysfunction ranged from 3-47% (n = 4 studies). Cardiac dysfunction ranged from 1-16% (n = 3 studies). Late effects of the musculoskeletal and urinary systems were least investigated. Substantial knowledge gaps exist in LMIC childhood cancer survivorship. No low-income country data were found. In middle-income countries, late effects were defined and assessed variably and limited by selection bias and small sample sizes. Survivors in LMICs can experience physical late effects of treatment, though additionally systematically collected data from survivor cohorts are needed to fill knowledge gaps.

Disability Adjusted Life-Years (DALYs) As a Measure of the Changing Lifetime Disease Burden in Long-Term Survivors of Allogeneic Hematopoietic Cell Transplantation (HCT)

Background: Although HCT is curative for many hematologic diseases, long-term survivors face a high burden of morbidity and premature mortality compared to the general population. Standard risk measures (prevalence, incidence, hazard, and standardized mortality ratios) do not convey a holistic picture of chronic disease burden because they do not account for degradation in quality of life associated with living with health conditions preceding death. DALY is an established risk measure that accounts for quality of life; it is the sum of years of healthy life lost due to disability (YLD) and years of life lost (YLL) to premature death. YLD weighs the years lived with a health condition by its disability weight (range: 0 for full health, 1 for death). Higher DALY, YLL, YLD indicate worse outcomes. We used microsimulation to estimate DALYs in 5-year survivors of HCT done over four decades, taking into consideration the changing practice of transplantation and the evolving burden of morbidity and mortality over time. Methods: The cohort included 1577 patients who underwent HCT at age ≥18 years (y) at City of Hope in 1976-2011, survived 5y, and were followed to December 31, 2016. Vital status and cause of death (COD) were determined using medical records and the National Death Index Plus. CODs were grouped into eleven broad categories used in a Global Burden of Disease (GBD) study ( Chang et al., Lancet Public Health, 2019). All cause and cause-specific mortality risks by attained age and other risk factors were estimated from deceased patients' data. These risks were applied in microsimulation to project age at death and COD for patients known to be alive. The onset age of COD was estimated for each patient using the age-specific disease incidence rates in GBD (https://www.healthdata.org/gbd). Life expectancy (LE) at time of death was determined from the US Life Tables. YLL was calculated as LE minus age at death. YLD was calculated as age at death minus disease onset age, weighted by disability weights of the COD available at Global Health Data Exchange (https://ghdx.healthdata.org). DALY was computed as YLL+YLD. Microsimulation, performed 1000 times, provided mean YLL, YLD, DALY for each patient. Results: Patient and treatment characteristics evolved over 35 years of HCT era ( Table). Patients who underwent HCT in the earliest era (1976-1989) had characteristics consistent with more favorable post-HCT outcomes compared to patients transplanted in later eras. From 1976-1989 to 2005-2011, there was an increase in patients who were older (median, 28y to 49y), had high relapse risk (26% to 42%), had an unrelated donor (0% to 45%), and developed chronic graft vs host disease (54% to 84%). Conversely, fewer patients received total body irradiation over time (88% to 36%). The proportion of patients transplanted for chronic myeloid leukemia declined from 24% to 5%, and there was a relative increase in patients with myelodysplastic syndrome (4% to 17%). Sex and race/ethnicity remained steady. The most common causes of death were relapse (35%), subsequent malignant neoplasms (22%), cardiovascular disease (10%), diabetes, kidney disease (10%), and infection (8%). Despite more patients with higher risk features receiving HCT in recent eras, median DALY was projected to decline from 19.2y to 15.5y from the earliest to latest HCT era (p<0.0001) ( Figure). YLL also declined from a median of 18.0y to 14.2y across eras (p<0.0001). Although YLD constituted a small portion of DALY, patients were projected to lose a median of 1.6y (1976-1989) to 1.2y (2005-2011) of healthy life due to disease-related disability. The projected age at death for the cohort (median, 67.5y to 73.4y across era) adjusted for rising life expectancy (median, 85y to 88y) suggested that survival after HCT increased in more recent HCT eras: age at death / life expectancy ratio median, 0.79 (1976-1989) to 0.84 (2005-2011) (p<0.0001). Conclusion: Outcomes after HCT have improved during the past four decades in spite of the evolving pattern of higher risk disease and patient characteristics with time. There was notable reduction across all measures (DALY, YLL, YLD), suggesting improvements in both the quantity and quality of survival. Our results highlight the importance and utility of DALY when characterizing health outcomes after HCT, as it provides a more comprehensive assessment of the changing pattern of efficacy associated with transplantation.

Hematopoietic Stem Cell Transplantation for Fanconi Anemia: Outcome and Prognostic Factors for Survival and Subsequent Neoplasms

Introduction Fanconi anemia (FA) is an inherited disorder of impaired DNA repair, associated with progressive bone marrow failure (BMF), leukemia, and cancer predisposition. Hematopoietic cell transplantation (HCT) may be curative for FA associated BMF, and changes in HCT practice over the past decades may have impacted outcomes in FA patients. Methods We used CIBMTR database to perform a retrospective cohort study of children and adults undergoing first allogeneic HCT for FA BMF (patients with MDS/AML excluded) from 2000-2018. We hypothesized that contemporary HCT approaches, including decreases in radiation and increase in use of serotherapy and ex-vivo graft manipulation, would associate with improved outcomes in FA patients receiving HCT. The primary endpoints were overall survival (OS) and early subsequent malignant neoplasm (SMN; by 5 yr post-HCT). Secondary endpoints included event free survival (EFS; death, SMN or graft failure), treatment related mortality (TRM), graft failure, and acute (grade II-IV) and cGVHD. Univariate and multivariate Cox regression models were created to evaluate the impact of conditioning, donor and graft source, treatment era, and patient characteristics on outcomes, adjusting for other significant covariates. Due to confounding factors, we were not able to create a single multivariate model that included radiation, ex-vivo graft manipulation, and donor and graft source; therefore, we performed subgroup univariate analysis for patients receiving unrelated donor bone marrow (BM) or peripheral blood stem cell (PBSC) HCT. Results We analyzed 652 HCTs from 2000-07 (n=353) and 2008-18 (n=293). 223 (35%) patients had a matched related donor (MRD) with any graft type, 244 (38%) had an unrelated donor BM or PBSC grafts, 123 (19%) had an unrelated cord blood graft, and 44 (7%) had a related haploidentical donor with any graft type. Between the two treatment eras, 5-yr OS has dramatically improved (78.8% 2008-18 v 62.5% 2000-07, p<0.01; figure 1) driven by lower 5-yr TRM (15.2% v 25.5%, p=0.004) and lower rates of primary (7.9% v 12.9% at 42 days, p=0.038) and secondary (4.1% v 8.9% at 1 year, p=0.014) graft failure. No statistically significant change was observed for aGVHD, cGVHD, or early SMN. Assessing the entire cohort, use of total body irradiation (TBI) >300cGy was associated with lower OS (HR=1.75, 95% CI 1.24-2.47) and increased TRM (HR=3.36, 95% CI 1.54-7.34; figure 2) on multivariable analysis. For patients that received unrelated BM or PBSC HCT, use of TBI was associated with inferior OS survival (HR=1.93, 95% CI 1.18-3.17), EFS (HR=1.78, 95% CI 1.13-2.80), and TRM (HR=2.31, 95% CI 1.20-4.46) on univariate analysis. Among all patients, CD34 selection or T-cell depletion ( ex vivo depletion) were not associated with better OS (95% HR=1.014, 95% CI 0.84-1.56), EFS (HR=1.163, 95% CI 0.86-1.58), or TRM (HR=0.79, 95% CI 0.52-1.19) but was associated with less aGVHD (HR=0.35 95% CI 0.22-0.57) and lower but not-statistically significant cGVHD (HR=0.54, 95% CI 0.29-1.01) on multivariable analysis. Within the unrelated donor setting, univariate analysis showed reduced aGVHD (HR=0.39 95% CI 0.23-0.68) and cGVHD (HR=0.47 95% CI 0.28-0.79) but did not have a significant effect on OS, EFS, or TRM. Early SMN occurred in 3.2% of participants by 5-years post-HCT and was associated with cGVHD occurrence (HR=2.14, 95% CI 1.06-4.33) and older age (>18 v <9 years, HR=6.35, 95% CI 2.66-15.14), but not ex-vivo depletion or use of ATG or alemtuzumab. Early SMN risk was not impacted by the use of TBI (HR=1.60, 95% CI 0.77-3.34), but secondary analysis demonstrated a trend towards a relationship with doses >300 cGy (HR=2.24, 95% CI 0.99-5.08). Conclusions Outcomes for patients with FA BMF have improved significantly in more recent HCT eras, driven by reductions in TRM and graft failure risk. Although radiation doses >300cGy were associated with greater toxicity, doses of 100-300cGy were not associated with inferior outcomes in our cohort. Use of CD34 selection or T-cell depletion may reduce the risk of GVHD in transplant FA patients, but does not appear to impact 5-yr OS. Risk for early SMN development in FA patients receiving HCT associates with older age and cGVHD.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort

Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. Canadian Institutes of Health Research, US National Cancer Institute.

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study

Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. American Lebanese Syrian Associated Charities and US National Institutes of Health.

Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report.

Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.

Hospitalisations and Cost of Inpatient Care for Physical Diseases in Survivors of Childhood Cancer in Western Australia: a Longitudinal Matched Cohort Study.

The long-term effects of childhood cancer are unclear in the Australian context. We examined hospitalisation trends for physical diseases and estimated the associated inpatient care costs in all 5-year childhood cancer survivors (CCS) diagnosed in Western Australia (WA) from 1982-2014. Hospitalisation records for 2,938 CCS and 24,792 comparisons were extracted from 1987- 2019 (median follow-up=12 years, min=1, max=32). The adjusted hazard ratio (aHR) of hospitalisation with 95% confidence intervals (CI) was estimated using the Andersen-Gill model for recurrent events. The cumulative burden of hospitalisations over time was assessed using the mean cumulative count method. The adjusted mean cost of hospitalisation was estimated using the generalised linear models. We identified a higher risk of hospitalisation for all-cause (aHR=2.0, 95%CI= 1.8-2.2) physical disease in CCS than comparisons, with the highest risk for subsequent malignant neoplasms (aHR=15.0, 95%CI 11.3-19.8) and blood diseases (aHR=6.9, 95%CI 2.6-18.2). Characteristics associated with higher hospitalisation rates included female gender, diagnosis with bone tumours, cancer diagnosis age between 5-9 years, multiple childhood cancer diagnoses, multiple comorbidities, higher deprivation, increased remoteness, and Indigenous status. The difference in the mean total hospitalisation costs for any disease was significantly higher in survivors than comparisons (publicly funded $11,483 United States Dollar, p<0.05). The CCS population face a significantly higher risk of physical morbidity and higher cost of hospital-based care than the comparisons. Our study highlights the need for long-term follow-up healthcare services to prevent disease progression and mitigate the burden of physical morbidity on patients and hospital services.

Acute monocytic leukemia with KMT2A::LASP1 developed 9months after diagnosis of acute megakaryoblastic leukemia in a 2-year-old boy.

Acute myeloid leukemia (AML) is known as one of the subsequent malignant neoplasms that can develop after cancer treatment, but it is difficult to distinguish from relapse when the preceding cancer is leukemia. We report a 2-year-old boy who developed acute megakaryoblastic leukemia (AMKL, French-American-British classification [FAB]: M7) at 18months of age and achieved complete remission with multi-agent chemotherapy without hematopoietic stem cell transplantation. Nine months after diagnosis and 4months after completing treatment for AMKL, he developed acute monocytic leukemia (AMoL) with the KMT2A::LASP1 chimeric gene (FAB: M5b). The second complete remission was achieved using multi-agent chemotherapy and he underwent cord blood transplantation 4months after AMoL was diagnosed. He is currently alive and disease free at 39 and 48months since his AMoL and AMKL diagnoses, respectively. Retrospective analysis revealed that the KMT2A::LASP1 chimeric gene was detected 4months after diagnosis of AMKL. Common somatic mutations were not detected in AMKL or AMoL and no germline pathogenic variants were detected. Since the patient's AMoL was different from his primary leukemia of AMKL in terms of morphological, genomic, and molecular analysis, we concluded that he developed a subsequent leukemia rather than a relapse of his primary leukemia.

Mortality and the burden of subsequent malignant neoplasms in survivors of childhood cancer beyond age 50: A report from the Childhood Cancer Survivor Study (CCSS).

10052 Background: The first generation of survivors of childhood cancer is now older than 50 years (y) of age. There is a paucity of information on the risk for late mortality and the evolving burden of subsequent malignant neoplasms (SMNs) in these aging survivors. Methods: We assessed cause-specific mortality (National Death Index) and self-reported SMNs (excluding nonmelanoma skin cancers) among CCSS participants diagnosed between 1970-1999, conditional on having survived to 50y by 12/31/2017. There were 4,772 survivors alive at 50y eligible for mortality analyses. Of the 3,355 who completed a baseline CCSS questionnaire, 2,273 also completed a follow-up questionnaire at ≥50y and were included in the SMN analyses. Cumulative mortality, standardized mortality ratios (SMRs), and, for SMNs, cumulative burden, standardized incidence ratios (SIRs), and relative rate (RR) with 95% confidence intervals (CIs) were calculated, compared with the general US population and by survivor subgroups. Piecewise-exponential multivariable regression was used to identify risk factors associated with the development of SMNs after 50y. Results: Mean age at diagnosis was 14y (standard deviation 4.2y). Mortality: Among survivors who attained 50y of age, the subsequent 5y, 10y, and 15y incidences of all-cause mortality were 9%, 19%, and 35%, respectively, (overall SMR 3.7 [95% CI 3.4-4.1]). SMRs were highest for SMN (SMR 5.1 [95% CI 4.4-5.9]), pulmonary (SMR 4.7 [95% CI 3.3-6.5]) and cardiovascular (SMR 3.9 [95% CI 3.2-4.8]) causes of death. The highest SMR (SMR 9.2 [95% CI 7.7-10.8]) was seen in female survivors of Hodgkin lymphoma. SMN: By age 50y, 14% of CCSS participants reported &gt;1 SMN. History of SMN &lt;50y was independently associated with the rate of developing another SMN at &gt;50y (RR 1.6 [95% CI 1.1-2.3]). The most frequent SMNs ≥50y were breast (41%) in females and prostate (21%) in males, followed by gastrointestinal cancers in both (14% [females], 19% [males]). The cumulative burden of SMNs in survivors treated with radiation therapy (RT) increased sharply with age and exceeded 50 per 100 survivors by 65y (SIR 3.3 95%CI 2.0-5.2]). Survivors who did not receive RT had a SMN rate comparable to the general population (Table). Conclusions: This sentinel population of survivors of childhood cancer is at high risk for poor outcomes as they enter older adulthood. RT exposure and history of SMN &lt;50y are associated with increased risk for developing SMNs after 50y. The evolving burden of late morbidity attributed to SMNs may be lower for contemporary survivors projected to have less RT exposure. [Table: see text]

Congenital anomalies and health outcomes among survivors of childhood cancer: A report from the childhood cancer survivor study.

e22021 Background: Although congenital anomalies are established risk factors for developing childhood cancer, less is known about health outcomes among survivors of childhood cancer with known congenital anomalies. Therefore, we estimated the risk of chronic health conditions (CHCs) and subsequent malignant neoplasms (SMNs) among survivors of childhood cancer by congenital anomaly status in the Childhood Cancer Survivor Study (CCSS). Methods: Overall, 22,247 five-year survivors self-reported congenital anomalies. We included 16 conditions present at birth, excluding self-reported genetic conditions. Patient-reported CHCs were graded using the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03). Self-reported SMNs were confirmed through pathology report review. Hazard ratios (HR) of CHCs comparing survivors with vs. without congenital anomalies and their 95% confidence intervals (CI) were estimated using Cox regression with age as the time scale, adjusted for race/ethnicity, education, household income, health insurance, and original cancer treatment. Results: Among survivors (median age at cancer diagnosis 6 years (range 3-12), age at follow-up 31 years (range 25-39)), 16.9% (n = 3880) reported a congenital anomaly. The most common anomalies included: large/multiple birth marks (n = 1540, 40.4%); congenital heart defects (n = 693, 18.4%); and kidney, bladder, or genital abnormalities (n = 607, 14.6%). Relative to survivors without anomalies, those with anomalies more commonly had astrocytoma, Wilms tumor, and neuroblastoma primary cancers (p &lt; 0.001), treated with radiation (p = 0.011), cyclophosphamide (p &lt; 0.001), anthracyclines (p &lt; 0.001), and epipodophyllotoxins (p = 0.044), and younger age at cancer diagnosis (11.3% vs. 5.7% diagnosed prior to one year of age, p &lt; 0.001). Survivors with anomalies were more likely to develop any CHC (CTCAE grades 1-5 HR: 1.31, 95% CI: 1.23, 1.39); severe, disabling, life-threatening or fatal CHCs (grades 3-5 HR: 1.42 (95% CI: 1.28, 1.58); and multiple CHCs (≥2 conditions HR: 1.36, 95% CI: 1.27, 1.46; ≥3 conditions HR: 1.49, 95% CI: 1.37, 1.63). Survivors with anomalies had increased risk for adverse outcomes across multiple systems (all p &lt; 0.001), including: hearing/vision/speech (HR: 1.37); urinary (HR: 1.42); hormonal/endocrine (HR: 1.24); heart/circulatory (HR: 1.35); digestive (HR: 1.49); and brain systems (HR: 1.42). We observed no differences in the risk of any SMN by congenital anomaly status (HR: 1.12, 95% CI: 0.90, 1.38). Conclusions: In our assessment, survivors of childhood cancer with self-reported congenital anomalies had an increased risk of developing CHCs compared to survivors without reported anomalies, but no increased risk of SMNs. Evaluating congenital anomalies allows identification of a population of childhood cancer survivors at high risk for poor long-term health outcomes.

A multicenter cooperative group study of late effects after high-risk neuroblastoma: COG ALTE15N2—LEAHRN study.

10002 Background: Aggressive therapies for high-risk neuroblastoma (HRNBL) have resulted in increased survival, but late effects have not been well-characterized. Methods: Comprehensive cross-sectional evaluation of health outcomes in HRNBL survivors enrolled on the COG Neuroblastoma Biology Study after 1/1/2000 and ≥ 5 years from primary diagnosis, using medical record abstraction and in-person clinical assessments. Descriptive and multivariable analyses identified extent of and risk factors for late toxicity. Results: There were 375 participants from 88 COG centers, 205 (55%) male; 92 (26%) non-white; 45 (13%) Hispanic. Median age at neuroblastoma diagnosis was 2.5 years (range: 0.2-15.8), at enrollment was 12.0 years (range: 5.0-24.0). All had received chemotherapy; 94% received cisplatin (median dose: 398 mg/m2). Other exposures included: radiation (95%), isotretinoin (91%), anti-GD2 antibody therapy (64%), MIBG (7%), single (79%) or tandem autologous transplantation (ASCT; 20%). ASCT conditioning included: Busulfan/Melphalan (BuMel) (18%), Carboplatin/Etoposide/Melphalan (CEM) (73%), Thiotepa/Cytoxan (19%), and total body irradiation (5%). Severe ototoxicity (requiring hearing aids) was observed in 58% of participants. Physician-reported late effects included hypothyroidism (17%), pulmonary hypertension (1%), congestive heart failure (2%), and hypertension (6%). Pulmonary Function Studies revealed restrictive lung disease [RLD - Total Lung Capacity &lt; 70% predicted] in 8% of subjects. Laboratory study showed elevated creatinine in 7% and Hemoglobin A1c in 7%. Growth failure (height Z-score &lt; -1.7) was observed in 34%. Subsequent malignant neoplasms (SMN) developed in 15 participants (4%; 4 sarcomas, 3 MDS/t-AML, single instance of 8 other malignancies). Adjusting for sex, follow-up time, age, and race, there were no differences in risk of SMN, severe ototoxicity, growth failure, or RLD for participants who received BuMel vs. CEM-based condtioning, or among those who received anti-GD2 antibody therapy vs. those who did not. Use of carboplatin during ASCT was not assocoiated with increased ototoxicity risk for any category of cisplatin induction dose. Comparing subjects who received CEM as a component of tandem ASCT (vs. single CEM), there was increased risk of growth failure [OR (95%CI) = 4.2(2.1, 8.4); p &lt; 0.0001], but not RLD. Exposure to isotretinoin was not associated with increased risk of growth failure. Further multivariable analyses will be presented, exploring risks for late toxicity associated with conditioning regimens, radiation therapy, surgical approaches, and acute and chronic complications of therapy. Conclusions: The burden of late toxicity in HRNBL survivors is substantial. Anti-GD2 immunotherapy and isotretinoin do not appear to be associated with SMN, ototoxicity, growth failure, or RLD.

Long-Term Risk of Subsequent Malignant Neoplasms Among Childhood and Adolescent Lymphoma Survivors (1975-2013): A Population-Based Predictive Nomogram.

Studies are needed to assess risk factors pertinent to the incidence of secondary malignancies among childhood and adolescent lymphoma survivors. We aimed to identify risk factors pertinent to the incidence of secondary malignancies and subsequently establish a clinically practical predictive nomogram. A total of 5561 patients who were diagnosed with primary lymphoma below the age of 20 years between 1975 and 2013 and survived for at least 5 years were identified. Standardized incidence ratio (SIR) and excess risk (ER) analysis were performed by sex, age, and year when primary lymphoma was diagnosed, sites and types of primary lymphoma, and therapy strategies. Univariable and multivariable logistic regression were used to identify independent risk factors for adolescent and childhood lymphoma-related secondary malignancies. Based on 5 factors (age, time from lymphoma diagnosis, gender, lymphoma type, and therapy), a nomogram for predicting the risk of a secondary malignancy for patients with childhood and adolescent primary lymphoma was established. Among 5561 lymphoma survivors, 424 developed a secondary malignancy. Females (SIR = 5.34, 95% CI, 4.73-5.99; ER = 50.58) exhibited a higher SIR and ER than males (SIR = 3.28, 95% CI, 2.76-3.87; ER = 15.53). Blacks were at a higher risk than Caucasians or others. Nodular lymphocyte-predominant Hodgkin lymphoma survivors exhibited typically high SIR (13.13, 95% CI, 6-24.92) and ER (54.79) among all lymphoma classifications. Lymphoma survivors who underwent radiotherapy, whether they received chemotherapy or not, had typically higher SIR and ER. Among all types of secondary malignancies, "bone and joint neoplasms" (SIR = 11.07, 95% CI, 5.52-19.81) and "soft tissue neoplasms" (SIR = 12.27, 95% CI, 7.59-18.76) presented significantly high SIR whereas "breast cancer" and "endocrine cancer" associated with higher ER. The median diagnosis age of secondary malignancies was 36 years old, and the median time interval between the diagnosis of two malignancies was 23 years. A nomogram was constructed to predict the risk of secondary malignancies in patients diagnosed with primary lymphoma before 20 years of age. After internal validation, the AUC and C-index of the nomogram are 0.804 and 0.804, respectively. The established nomogram provides a convenient and reliable tool for predicting the risk of a secondary malignancy among childhood and adolescent lymphoma survivors, concluding significant concern for lymphoma survivors with high-risk estimates.

Colorectal Cancer Risk and Recommendations for Colorectal Cancer Surveillance in Adult Survivors of Childhood Cancer.

While many organizations have published guidance on the approach to colorectal cancer (CRC) screening in average-risk and certain high-risk groups, adult survivors of childhood cancer (ASCC) who have a heightened risk of CRC are rarely included as a target group for enhanced CRC surveillance. The population of ASCC continues to grow due to increasingly effective cancer therapies and improved survival. With this increased survival comes an increased risk for subsequent malignant neoplasms, including CRC. Since there is little published guidance for CRC surveillance in ASCC and limited awareness of increased CRC risk among both physicians and patients, the objectives of our paper are to review the incidence of and risk factors for colorectal neoplasia in ASCC, describe the clinical phenotypes of colorectal neoplasia in ASCC, review published surveillance strategies based on consensus-based survivorship guidelines, and outline areas for future research to optimize surveillance strategies.

Risk Factors and Trends for HPV-Associated Subsequent Malignant Neoplasms among Adolescent and Young Adult Cancer Survivors.

Subsequent malignant neoplasms (SMN; new cancers that arise after an original diagnosis) contribute to premature mortality among adolescent and young adult (AYA) cancer survivors. Because of the high population prevalence of human papillomavirus (HPV) infection, we identify demographic and clinical risk factors for HPV-associated SMNs (HPV-SMN) among AYA cancer survivors in the SEER-9 registries diagnosed from 1976 to 2015. Outcomes included any HPV-SMN, oropharyngeal-SMN, and cervical-SMN. Follow-up started 2 months after their original diagnosis. Standardized incidence ratios (SIR) compared risk between AYA survivors and general population. Age-period-cohort (APC) models examined trends over time. Fine and Gray's models identified therapy effects controlling for cancer and demographic confounders. Of 374,408 survivors, 1,369 had an HPV-SMN, occurring on average 5 years after first cancer. Compared with the general population, AYA survivors had 70% increased risk for any HPV-SMN [95% confidence interval (CI), 1.61-1.79] and 117% for oropharyngeal-SMN (95% CI, 2.00-2.35); cervical-SMN risk was generally lower in survivors (SIR, 0.85; 95% CI, 0.76-0.95), but Hispanic AYA survivors had a 8.4 significant increase in cervical-SMN (SIR, 1.46; 95% CI, 1.01-2.06). AYAs first diagnosed with Kaposi sarcoma, leukemia, Hodgkin, and non-Hodgkin lymphoma had increased HPV-SMN risks compared with the general population. Oropharyngeal-SMN incidence declined over time in APC models. Chemotherapy and radiation were associated with any HPV-SMN among survivors with first HPV-related cancers, but not associated among survivors whose first cancers were not HPV-related. HPV-SMN in AYA survivors are driven by oropharyngeal cancers despite temporal declines in oropharyngeal-SMN. Hispanic survivors are at risk for cervical-SMN relative to the general population. Encouraging HPV vaccination and cervical and oral cancer screenings may reduce HPV-SMN burden among AYA survivors.

Treatment patterns and outcomes in adolescents and young adults with nodular lymphocyte-predominant Hodgkin lymphoma: an IMPACT cohort study.

We leveraged population-based clinical and healthcare data to identify treatment patterns and long-term outcomes among adolescents and young adults (AYA) with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). All Ontario, Canada, AYA aged 15-21 years at diagnosis with NLPHL between 1992 and 2012 were identified, and their detailed clinical data were collected. Linkage to healthcare databases identified additional events (subsequent malignant neoplasms [SMN], relapses and deaths). Event-free survival (EFS) and overall survival (OS) were compared by locus of care (adult vs. paediatric) and predictors of outcomes determined. Of 1014 AYA with Hodgkin lymphoma, 54 (5.3%) had NLPHL; 15 (27.8%) were treated at a paediatric centre. No paediatric centre patient received radiation only versus 16 (41.0%) of adult centre patients. Excision only was more common in paediatric centres (p < 0.001). The 20-year EFS and OS rates were 82.9% ± 5.2% and 100% respectively. Advanced stage (hazard ratio: 4.9, 95% CI: 1.3-18.4; p=0.02) was associated with inferior EFS. Although the 25-year cumulative incidence of SMN was 19.3% ± 9.6% for the entire cohort, there were no SMN among the patients treated with excision only. AYA with NLPHL have outstanding long-term survival. Resection alone was rare outside of paediatric institutions but associated with excellent outcomes. Given substantial SMN risks, chemotherapy-sparing and radiation-sparing strategies for appropriate subsets of patients are warranted.

Abstract 5763: Risk factors, trends, and disparities in HPV-associated subsequent malignant neoplasms among adolescent and young adult cancer survivors

Abstract Background: Subsequent malignant neoplasms (SMN) are a leading cause of premature mortality among adolescent and young adult (AYA) cancer survivors, who have unique health needs. Human Papillomavirus-related second cancers (HPV-SMN) are generally preventable through screenings and vaccination. We identified disparities in HPV-SMN among AYA survivors by demographics and first cancer therapy, and examined temporal trends in incidence of HPV-SMN. Methods: We identified diagnoses of any HPV-SMN, oropharyngeal-SMN, and cervical-SMN among AYA survivors in the SEER 9 1976-2015 registries starting two months after the first cancer. Standardized incidence ratios (SIR) compared risk between AYA survivors and general population. We used Fine and Gray competing risk models to estimate hazard ratios (HR) of therapy on risk for HPV-SMN while controlling for cancer site and demographic confounders. Age-period-cohort (APC) models identified temporal trends in HPV-SMN incidence. Results: Of 374,408 survivors diagnosed with a first primary cancer ages 15-44, a total of 1,369 had an HPV-SMN occurring on average five years after the first cancer. Compared to the general population, AYA survivors had increased risks of 70% for any HPV-SMN (95%CI=1.61-1.79) and 117% for oropharyngeal-SMN (95%CI=2.00-2.35). Cervical-SMN risk was generally lower in survivors (SIR=0.85, 95%=CI 0.76-0.95). Hispanic AYA survivors had a significant increase in cervical-SMN relative to the general population (SIR=1.46, 95%CI=1.01-2.06). AYAs who were uninsured or on Medicaid at diagnosis had significant increases in HPV-SMN risk relative to the general populations (Uninsured SIR=5.23, 95%CI=2.26-10.31; Medicaid SIR=5.95, 95%CI=4.07-8.40). AYAs first diagnosed with Kaposi sarcoma, leukemia, Hodgkin, and Non-Hodgkin lymphoma had increased risk for HPV-SMN relative to the general population. Among survivors with HPV-related first primary cancers, radiation was associated with increased risk for HPV-SMN (HR=1.35, 95%CI-1.03-1.77). Among survivors whose first primary cancer was not HPV-related, chemotherapy was associated with increased risk for HPV-SMN (HR=1.20, 95%CI=1.00-1.44) but the general effect of treatment was not significant (p=0.16). In APC models, incidence of oropharyngeal-SMN significantly declined over time. Conclusion and Impact: While the overall risk is low, AYA survivors are at higher risk for HPV-SMNs than the general population, largely driven by oropharyngeal-SMN. Hispanic survivors are the only group at higher risk for cervical-SMN than the general population suggesting a need to improve their cervical cancer screening. Uninsured/Medicaid AYA survivors also face higher HPV-SMN risks. Improving access to screening and HPV vaccination is needed to reduce the burden of HPV-SMN in AYA survivors. Citation Format: Judy Y. Ou, Natalie Bennion, Kellee Parker, Douglas Fair, Heidi A. Hanson, Deanna Kepka, Echo L. Warner, Joemy M. Ramsay, Heydon K. Kaddas, Anne C. Kirchhoff. Risk factors, trends, and disparities in HPV-associated subsequent malignant neoplasms among adolescent and young adult cancer survivors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5763.

Unmet Needs, Barriers, and Facilitators for Conducting Adolescent and Young Adult Cancer Survivorship Research in Southern California: A Delphi Survey.

Introduction: An adolescent and young adult cancer (AYAC) patient is an individual who has received a cancer diagnosis between 15 and 39 years of age. They require significant survivorship care due to a combination of practical, physical, and mental health problems, but research in these areas is sparse. This study aimed to identify the unmet needs, barriers, and facilitators for conducting AYAC survivorship research in Southern California (SoCal) from the providers' and researchers' perspectives. Methods: A two-round, electronically administered Delphi survey study was conducted, involving a panel of 12 health care professionals and/or researchers with substantial work experience in AYAC. A 10-point Likert scale was used to evaluate 24 areas of unmet needs in AYAC survivors, 39 barriers, and 25 facilitators. Results: The top unmet needs in AYAC survivorship requiring research were in mental health issues, improving school/occupational performance, neurocognitive disorders, subsequent malignant neoplasms, and reproductive health. The top barriers identified were as follows: (1) institutions are too short-staffed to administer survivorship studies; (2) oncologists do not have the time/resources; and (3) lack of available funding. The top facilitators identified were as follows: (1) development of a mechanism/program to fund AYAC survivorship research studies; (2) in-person or virtual investigator engagement between children's hospitals and adult cancer centers to discuss research studies; and (3) developing personalized survivorship goals with AYAC patients and survivors to facilitate enrollment into survivorship studies. Conclusion: Experts identified the lack of time, manpower, funding, and resources as major barriers in AYAC survivorship research. Enhancing communication and collaboration with different stakeholders may facilitate AYAC survivorship research efforts within the SoCal region.

Malignant Neoplasms of the Gastrointestinal Tract After Blood or Marrow Transplant

Survivors of blood or marrow transplant (BMT) are at increased risk of subsequent malignant neoplasms (SMNs). Cancers of the gastrointestinal (GI) system are of special interest because their clinical behavior is often aggressive, necessitating early detection by increasing awareness of high-risk populations. To describe the risk of SMNs in the GI tract after BMT. A cohort study of 6710 individuals who lived at least 2 years after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. End of follow-up was March 23, 2020. Data analysis was performed between September 1, 2022, and September 30, 2022. Demographic and clinical factors; therapeutic exposures before or as part of BMT. Development of SMNs in the GI tract after BMT. Participants self-reported SMNs in the GI tract; these were confirmed with pathology reports, medical records, or both. For deceased patients, death records were used. Standardized incidence ratios determined excess risk of SMNs in the GI tract compared with that of the general population. Fine-Gray proportional subdistribution hazard models assessed the association between risk factors and SMNs in the GI tract. The cohort of 6710 individuals included 3444 (51.3%) autologous and 3266 (48.7%) allogeneic BMT recipients. A total of 3917 individuals (58.4%) were male, and the median age at BMT was 46 years (range, 0-78 years). After 62 479 person-years of follow-up, 148 patients developed SMNs in the GI tract. The standardized incidence ratios for developing specific SMNs ranged from 2.1 for colorectal cancer (95% CI, 1.6-2.8; P < .001) to 7.8 for esophageal cancer (95% CI, 5.0-11.6; P < .001). Exposure to cytarabine for conditioning (subdistribution hazard ratio [SHR], 3.1; 95% CI, 1.5-6.6) was associated with subsequent colorectal cancer. Compared with autologous BMT recipients, allogeneic BMT recipients with chronic graft-vs-host disease were at increased risk for esophageal cancer (SHR, 9.9; 95% CI, 3.2-30.5). Conditioning with etoposide (SHR, 2.0; 95% CI, 1.1-3.5) and pre-BMT anthracycline exposure (SHR, 5.4; 95% CI, 1.3-23.4) were associated with an increased risk of liver cancer compared with no exposure to the respective agents. The findings of this cohort study are relevant for oncologists and nononcologists who care for the growing number of survivors of transplant. Awareness of subgroups of survivors of BMT at high risk for specific types of SMNs in the GI tract may influence recommendations regarding modifiable risk factors, as well as individualized screening.

Компьютерная томография как фактор риска злокачественных новообразований среди населения города атомной промышленности Озёрск

Exposure to ionizing radiation resulted from computed tomography (CT) examinations concerns a risk associated with potential radiation-induced cancers. Widespread use of this diagnostic method during the last decades has led to significant increase of collective dose of the world’s population. Minor dose restrictions for diagnostic X-ray procedures involve considerable “beneficial” exposure burden among CT-examined patients. Assessment of possible consequences became necessary in order to manage potential risks in terms of “benefit-harm” control. Retrospective epidemiological study has been performed using the cohort of individuals exposed to diagnostic radiation from CT. The source of information was the “CT Register” database which contains medical and dosimetric data on the population of nuclear city of Ozyorsk, including data on several potential risk factors such as gender, age at exposure, cancer anamnesis and contact with occupational radiation. Risk calculation was performed using conditional logistic regression. A hypothesis on increasing chances of developing of malignant neoplasm depending on the number of recurrent CT during the lifetime, taking into account potential confounders and the impact of reverse causation was tested. The relation between recurrent CT examinations and the subsequent malignant neoplasm (OR 1.01-1.10) can be confirmed at (1-alpha) 90%, which indicates the probable radiogenic component of carcinogenic risk. Further investigation with expanded follow-up period will facilitate accounting possible unrealized cancer cases with long latency period and improve the results of the study.

Stem Cell Theory of Cancer: Origin of Metastasis and Sub-clonality.

Metastasis may be the secret weapon cancer uses to dominate and subjugate, to persist and prevail. However, it is no longer a secret when we realize that a stem cell has the same ways and means to fulfill its own omnipotence and accomplish its own omnipresence… and when we realize that a cancer cell has its own version of stem-ness origin and stem-like nature. In this perspective, we discuss whether stem-ness enables metastasis or mutations drive metastasis. We ponder about low-grade versus high-grade tumors and about primary versus metastatic tumors. We wonder about stochasticity and hierarchy in the genesis and evolution of cancer and of metastasis. We postulate that metastasis may hold the elusive code that makes or breaks a stem-cell versus a genetic theory of cancer. We speculate that the vaunted model of multistep carcinogenesis may be in error and needs some belated remodeling and a major overhaul. We propose that subsequent malignant neoplasms from germ cell tumors and donor-derived malignancies in organ transplants are quintessential experiments of nature and by man that may eventually empower us to elucidate a stem-cell origin of cancer and metastasis. Unfortunately, even the best experiments of cancer and of metastasis will be left unfinished, overlooked, or forgotten, when we do not formulate a proper cancer theory derived from pertinent and illuminating clinical observations. Ultimately, there should be no consternations when we realize that metastasis has a stem-cell rather than a genetic origin, and no reservations when we recognize that metastasis has been providing us some of the most enduring tests and endearing proofs to demonstrate that cancer is indeed a stem-cell rather than a genetic disease after all.