Jop C. Teepen

Background: The growing population of childhood cancer survivors faces an elevated risk of developing subsequent malignant neoplasms (SMNs). Over the past decades, childhood cancer treatments have evolved. Although reductions in radiation dose have been shown to lower SMN risk, the impact of changes in chemotherapy remains unclear. We evaluated whether treatment changes have affected SMN risk over time and examined treatment-related risk factors. Methods: We included 10 612 5-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (1963-2014). Multivariable Cox proportional hazard regression was used to estimate SMN risks, and to evaluate effects of treatment changes over time. Results: After a median follow-up of 20.4 years, 493 survivors developed an SMN. Overall, the risk for SMN declined over the periods of diagnosis (P-trend = .04). The decline in SMN risk was primarily associated with a decreased use of radiotherapy (P-trend after radiotherapy adjustment = .51). Chemotherapy seemed to have the opposite effect, mainly due to the use of anthracyclines and/or epipodophyllotoxins (P-trend after chemotherapy adjustment = <.001). Survivors treated with anthracyclines (HR = 1.3, 95% CI = 1.0 to 1.6), epipodophyllotoxins (HR = 1.3, 95% CI = 1.0 to 1.7), or radiotherapy (HR = 2.3, 95% CI = 1.9 to 2.8) had significantly increased risks of SMN. Conclusions: While reductions in radiotherapy have lowered SMN risk throughout the periods of diagnosis, the increased use of chemotherapy, especially anthracyclines and epipodophyllotoxins, increased SMN risk. Furthermore, survivors treated with radiotherapy, anthracyclines, or epipodophyllotoxins have an elevated risk of any SMN. This highlights the importance of continued optimization of treatment protocols, for example through chemotherapy dose reduction, to balance treatment efficacy with long-term health risks and to better identify survivors at risk.

Survivors of childhood cancer are at risk of subsequent primary melanoma (SPM), but the magnitude of the risk after different childhood cancer types and beyond age 50 remains inadequately characterised. We quantified risks in the largest cohort of childhood cancer survivors worldwide. The PanCareSurFup cohort includes 68,002 five-year childhood cancer survivors across Europe (diagnosed 1940 to 2008). SPM risks were quantified using standardised incidence ratios (SIRs), absolute excess risks (AERs), cumulative incidence and relative risks (RRs). Over 1,239,675 person-years, 197 SPMs were ascertained whereas 84.9 were expected (SIR = 2.3, 95%CI = 2.0 to 2.7). Although the SIR decreased with attained age (P_trend<0.001), it remained increased at 2.1-fold (95%CI = 1.5 to 3.1) age 50+. By age 65, cumulative incidence was 1.2% (0.8% expected). Of all cancer types, heritable retinoblastoma survivors had the greatest risk (SIR = 16.5, 95% CI = 10.8 to 25.3; AER = 94.4, 95% CI = 59.9 to 148.9), with cumulative incidence of 3.3% at age 50 and 5.5% at age 60. Survivors treated with radiotherapy had a 70% greater risk than those treated without (RR = 1.7, 95% CI = 1.1 to 2.7) increasing to 4-fold age 50 + (RR = 3.9, 95%CI = 1.1 to 13.9). For chemotherapy, no significant association was found (RR=0.9, 95%CI = 0.5 to 1.6). Childhood cancer survivors, particularly those with heritable retinoblastoma and those treated with radiotherapy, remain at increased risk of melanoma beyond age 50. Current survivorship guidelines focus principally on treatment history; however, our findings suggest that long-term follow-up guidelines should additionally include childhood cancer type and attained age as risk-stratifying factors, particularly where individual treatment records are unavailable.

PURPOSE: With new evidence emerging about breast cancer risk following anthracycline chemotherapy, the International Late Effects of Childhood Cancer Guideline Harmonization Group updated the evidence and breast cancer surveillance recommendations for female childhood, adolescent, and young adult (CAYA) cancer survivors. METHODS: The Grading of Recommendations Assessment, Development, and Evaluation methodology was used to incorporate new knowledge and refine breast cancer surveillance recommendations. The guideline panel updated the systematic literature review and revised recommendations based on new evidence, clinical judgment, and assessments of benefits and harms of surveillance, ensuring adaptability across various health care systems. RESULTS: The literature update revealed new findings on the effects of anthracyclines on breast cancer risk in female CAYA cancer survivors. Moderate-quality evidence shows no significant association between doxorubicin doses 2 and breast cancer risk. High-quality evidence indicates a statistically significant but weak association between breast cancer risk and 100-199 mg/m ² doxorubicin (relative risk, 2 in the absence of radiotherapy exposing breast tissue (chest radiation). Routine breast cancer surveillance after ≥200 mg/m ² doxorubicin in the absence of chest radiation is reasonable from age 30 years onward or ≥8 years from exposure (whichever occurs last). Due to inconclusive evidence, no recommendation could be formulated for routine breast cancer surveillance after daunorubicin, epirubicin, or idarubicin, in the absence of chest radiation. CONCLUSION: The newly identified evidence on breast cancer risk after anthracyclines supports changes in the 2019 recommendations regarding breast cancer surveillance for survivors treated with ≥200 mg/m ² doxorubicin without chest radiation.

Purpose: Primary hypothyroidism is common in childhood cancer survivors (CCS). Exposure to radiation and hematopoietic stem cell transplantation (HSCT) are known risk factors; however, the impact of chemotherapy and the role of thyroid peroxidase antibodies (anti‐TPO) remain unclear. The prevalence of primary hypothyroidism, anti‐TPO, and treatment‐related risk factors in a cohort of CCS was assessed. Methods: In total, 1774 five‐year CCS were included. The prevalence of primary hypothyroidism according to treatment strategy was evaluated: radiotherapy involving the thyroid gland (±chemotherapy), chemotherapy only, HSCT, and controls. Multivariable logistic regression was performed to identify risk factors for hypothyroidism. Results: After a median follow‐up time of 25.3 years (range, 14.8–54.7), primary hypothyroidism was present in 8.2%. When evaluating subgroups specifically, the prevalence of primary hypothyroidism increased to 28% in CCS treated with radiotherapy and 30.6% after HSCT. In multivariable analyses, survivors treated with chemotherapy only were not at increased risk of hypothyroidism (odds ratio [OR], 0.74; 95% CI, 0.28–2.00), whereas survivors treated with radiotherapy had an almost 14‐fold increased risk (OR, 13.91; 95% CI, 5.34–36.22). In irradiated CCS, the use of platinating agents was associated with an increased risk of hypothyroidism (OR, 3.25; 95% CI, 1.39–7.59). The prevalence of anti‐TPO did not differ between the treatment groups ( p = .42). Conclusions: Primary hypothyroidism is prevalent after radiation exposure and HSCT. Chemotherapy only does not increase the risk for primary hypothyroidism. The use of platinating agents combined with radiotherapy may increase its risk. Treatment for childhood cancer does not increase the risk of anti‐TPO.

PURPOSE: Among childhood cancer survivors, we evaluated not previously explored relationships between colorectal subsequent malignant neoplasm (SMN) incidence and colorectum-specific radiation dose metrics currently used in radiation therapy (RT) planning and expanded upon previously reported chemotherapy associations. METHODS: The Childhood Cancer Survivor Study (CCSS) includes 5-year survivors of childhood cancer diagnosed between 1970 and 1999. RT was assessed as mean colorectal dose (MCD) and the percent volume (V _{X Gy} ) receiving ≥5, 10, 20, 30, and 40 Gy. Chemotherapy was assessed as cumulative doses for procarbazine and platinum agents, cyclophosphamide-equivalent doses for alkylating agents, and doxorubicin-equivalent doses for anthracyclines. Piecewise-exponential models and excess rate ratio (ERR) models evaluated dose-response relationships for the incidence of colorectal SMNs. Reference groups were those not receiving the assessed treatment(s). RESULTS: Among 25,723 survivors (median follow-up = 28.5 years; range = 5.0-48.9), 104 colorectal SMNs were identified. A dose-response relationship was observed between MCD and colorectal SMN rates; incidence rate ratios (IRRs) for 10 to 20 Gy IRRs were 3.8 (95% CI, 1.9 to 7.6), 4.9 (95% CI, 2.0 to 12.0), and 8.7 (95% CI, 3.5 to 21.6) for irradiated volumes of 20% to 2 , 3.7 (95% CI, 2.2 to 6.4) for cyclophosphamide-equivalent dose ≥6,000 mg/m ² , and 4.5 (95% CI, 2.0 to 10.1) for platinum dose ≥450 mg/m ² . For procarbazine dose, the IRR was 6.3 (95% CI, 3.0 to 13.2) for 4,200 to 2 and 9.0 (95% CI, 4.3 to 18.9) for ≥7,036 mg/m ² . In the absence of RT, colorectal SMN rates increased with exposure to any platinum-based agent (IRR, 3.8 [95% CI, 1.1 to 12.7]), alkylator (IRR, 4.8 [95% CI, 1.6 to 14.4]), or procarbazine (IRR, 16.9 [95% CI, 5.9 to 48.8]). Colorectal SMN rates increased linearly with procarbazine dose (ERR per 1,000 mg/m ² = 73.0 [95% CI, 26.4% to 119.6%]) and MCD (ERR per 1 Gy = 20.8 [95% CI, 9.0% to 32.5%]). Quadratic ERR models did not improve data fit compared with linear ERR models. CONCLUSION: These RT and chemotherapy dose-response relationships can better inform contemporary RT planning for pediatric patients and surveillance guidelines for high-risk survivors.

Background: Survivors of childhood cancer face excess risk of developing basal cell carcinoma. Age-specific basal cell carcinoma risk prediction models for survivors may support targeted screening recommendations. Methods: We developed models predicting basal cell carcinoma risk by ages 40 and 50 years featuring detailed cancer treatment predictors, utilizing statistical and machine-learning algorithms and data from 23 166 five-year survivors in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study. Selected models were externally validated in 5314 survivors in the St Jude Lifetime Cohort. Model discrimination and precision were evaluated using the area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC) and benchmarked against the current Children’s Oncology Group Long-Term Follow-Up Guidelines (COG LTFU, v6.0) for skin cancer screening. Results: By ages 40 and 50 years, basal cell carcinoma cumulative incidence was 5% and 15% in the Childhood Cancer Survivor Study and 7% and 21% in the St Jude Lifetime Cohort, respectively. The XGBoost algorithm-based models with treatment dose-specific predictors performed best, showing good external discrimination (age 40 years: AUROC = 0.75; age 50 years: AUROC = 0.76) and precision (age 40 years: AUPRC = 0.20; age 50 years: AUPRC = 0.52), outperforming COG LTFU Guideline-directed risk stratification (age 40 years: AUROC = 0.65; age 50 years: AUROC = 0.62; age 40 years: AUPRC = 0.09; age 50 years: AUPRC = 0.26; P < .01). These novel models reclassified 37% of survivors with COG-recommended skin cancer screening as low risk by age 40 years and 29% of survivors without COG-recommended screening as moderate or high risk by age 50 years, suggesting these recommendations overestimate risk in younger survivors and miss relevant predictors (eg, attained age, chemotherapy). Conclusions: In this study, we present validated basal cell carcinoma risk prediction models for childhood cancer survivors that outperform current practice guidelines. The associated online risk calculator can inform risk- and age-based screening recommendations.

PURPOSE: Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors. METHODS: We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors. RESULTS: In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine ( ^131I MIBG) treatment. Survivors treated with ^131I MIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without ^131I MIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6). CONCLUSION: Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs. ^131I MIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care.