Subsequent neoplasms (SNs), which may be benign or malignant, are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. Childhood cancer survivors have an increased risk of developing SNs that varies by host factors (e.g., genetics, immune function, hormone status), primary cancer therapy, environmental exposures, and lifestyle factors. The Childhood Cancer Survivor Study (CCSS) reported a 30-year cumulative incidence of 20.5% (95% confidence interval [CI], 19.1%–21.8%) for all SNs, 7.9% (95% CI, 7.2%–8.5%) for SNs with malignant histologies (excluding nonmelanoma skin cancer [NMSC]), 9.1% (95% CI, 8.1%–10.1%) for NMSC, and 3.1% (95% CI, 2.5%–3.8%) for meningioma. This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population. SNs are the leading cause of nonrelapse late mortality (standardized mortality ratio = 15.2; 95% CI, 13.9–16.6). The risk of SNs remains elevated for more than 30 years from diagnosis of the primary cancer. Moreover, prolonged follow-up has established that multiple SNs are common among aging childhood cancer survivors.
The development of an SN is likely multi-factorial in etiology and results from combinations of influences including gene-environment and gene-gene interactions. Outcome following the diagnosis of an SN is variable as treatment for some histological subtypes may be compromised if childhood cancer therapy included cumulative doses of agents and modalities at the threshold of tissue tolerance. The incidence and type of SNs differ with the primary cancer diagnosis, type of therapy received, and presence of genetic conditions. Unique associations with specific therapeutic exposures have resulted in the classification of SNs into the following two distinct groups:
- Chemotherapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML).
- Radiation-related solid SNs.
Characteristics of t-MDS/AML include a short latency (<10 years from primary cancer diagnosis) and association with alkylating agents and/or topoisomerase II inhibitors.[5,6] Although the long-term risk of subsequent leukemia more than 15 years from primary diagnosis remains significantly elevated (standardized incidence ratio [SIR] = 3.5; 95% CI, 1.9–6.0), these events are relatively rare with an absolute excess risk of 0.02 cases per 1000 person-years. Solid SNs have a strong and well-defined association with radiation and are characterized by a latency that exceeds 10 years. Furthermore, the risk of solid SNs continues to climb with increasing follow-up, whereas the risk of t-MDS/AML plateaus after 10 to 15 years.