As cure rates for childhood cancers have improved, there has been an increasing awareness of the late health consequences of childhood cancer therapies. One outcome associated with significant morbidity and mortality for these survivors is the development of subsequent neoplasms, unique from recurrence of the original childhood malignancy.¹ Survivors with a subsequent neoplasm are more likely to report adverse general and mental health outcomes² and have increased hospitalization rates³ compared with survivors without a subsequent neoplasm. Subsequent malignant neoplasms are the most common nonrelapse cause of late mortality, accounting for approximately one-half of all nonrelapse deaths among 5-year survivors.^1,4

PURPOSE: Therapeutic radiation in childhood cancer has decreased over time with a concomitant increase in chemotherapy. Limited data exist on chemotherapy-associated subsequent malignant neoplasm (SMN) risk. PATIENTS AND METHODS: SMNs occurring > 5 years from diagnosis, excluding nonmelanoma skin cancers, were evaluated in survivors diagnosed when they were < 21 years old, from 1970 to 1999 in the Childhood Cancer Survivor Study (median age at diagnosis, 7.0 years; median age at last follow-up, 31.8 years). Thirty-year SMN cumulative incidence and standardized incidence ratios (SIRs) were estimated by treatment: chemotherapy-only (n = 7,448), chemotherapy plus radiation (n = 10,485), radiation only (n = 2,063), or neither (n = 2,158). Multivariable models were used to assess chemotherapy-associated SMN risk, including dose-response relationships. RESULTS: Of 1,498 SMNs among 1,344 survivors, 229 occurred among 206 survivors treated with chemotherapy only. Thirty-year SMN cumulative incidence was 3.9%, 9.0%, 10.8%, and 3.4% for the chemotherapy-only, chemotherapy plus radiation, radiation-only, or neither-treatment groups, respectively. Chemotherapy-only survivors had a 2.8-fold increased SMN risk compared with the general population (95% CI, 2.5 to 3.2), with SIRs increased for subsequent leukemia/lymphoma (1.9; 95% CI, 1.3 to 2.7), breast cancer (4.6; 95% CI, 3.5 to 6.0), soft-tissue sarcoma (3.4; 95% CI, 1.9 to 5.7), thyroid cancer (3.8; 95% CI, 2.7 to 5.1), and melanoma (2.3; 95% CI, 1.5 to 3.5). SMN rate was associated with > 750 mg/m² platinum (relative rate [RR] 2.7; 95% CI, 1.1 to 6.5), and a dose response was observed between alkylating agents and SMN rate (RR, 1.2/5,000 mg/m²; 95% CI, 1.1 to 1.3). A linear dose response was also demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m²; 95% CI, 1.2 to 1.6). CONCLUSION: Childhood cancer survivors treated with chemotherapy only, particularly higher cumulative doses of platinum and alkylating agents, face increased SMN risk. Linear dose responses were seen between alkylating agents and SMN rates and between anthracyclines and breast cancer rates. Limiting cumulative doses and consideration of alternate chemotherapies may reduce SMN risk.

Purpose: Survivors of childhood cancer have an increased risk for subsequent neoplasms (SNs), but the incidence beyond the age of 40 years and associations with therapeutic exposures have not been well described. Patients and Methods: Among 14,364 survivors of childhood cancer diagnosed between 1970 and 1986, 3,171 had an attained age of 40 years or older at the time of last contact. Cumulative incidence of SNs, standardized incidence ratios (SIRs), excess absolute risk of subsequent malignant neoplasms (SMNs), and relative risks (RRs) for SMNs and nonmelanoma skin cancers were calculated. Results: In total, 679 SNs were diagnosed in patients age 40 years or older. These included 196 SMNs, 419 nonmelanoma skin cancers, 21 nonmalignant meningiomas, and 43 other benign neoplasms. At age 55 years, the cumulative incidence of new SNs and SMNs occurring after age 40 years was 34.6% (95% CI, 28.7 to 40.6) and 16.3% (95% CI, 11.7 to 20.9), respectively. Survivors were four times as likely as the general population to receive a diagnosis of SMN after age 40 years (SIR, 4.4; 95% CI 3.8 to 5.0). Among SMNs, risk was most increased for soft tissue sarcoma (SIR, 12.3; 95% CI, 7.2 to 21.0), breast cancer (SIR, 8.3; 95% CI, 6.9 to 10.0), renal cancer (SIR, 6.1; 95% CI, 3.2 to 11.6), and thyroid cancer (SIR, 5.1; 95% CI, 2.8 to 9.4). Female sex (RR, 1.5; 95% CI, 1.1 to 2.1; P = .008), platinum chemotherapy (RR, 3.4; 95% CI, 1.5 to 7.7; P = .003), epipodophyllotoxins (RR, 2.4; 95% CI, 1.0 to 5.8; P = .05), and therapeutic radiation exposure (RR, 2.0; 95% CI, 1.4 to 3.1; P < .001) were associated with higher risk for SMN in multivariable analysis. Conclusion: Even after age 40 years, survivors of childhood cancer remain at increased risk for treatment-related SNs. These data suggest the need for life-long monitoring and should inform anticipatory guidance provided to survivors of childhood cancer.

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m ^{− 2} : 1.24, 95% confidence interval (CI): 1.18–1.31), with more than twofold increased risk for survivors treated with ≥200 mg m ⁻² cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200–299 mg m ^{− 2} , HR: 2.33 for 300–399 mg m ^{− 2} and HR: 2.78 for ≥400 mg m ^{− 2} ). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59–6.63). For patients treated with or without chest irradiation, HRs per 100 mg m ^{− 2} of doxorubicin were 1.11 (95% CI: 1.02–1.21) and 1.26 (95% CI: 1.17–1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m ^{− 2} cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.