Second malignant neoplasms (SMNs) are defined as histologically distinct malignancies developing at least 2 months after completion of treatment for the primary malignancy. The cumulative incidence of SMNs exceeds 20% at 30 years after diagnosis of the primary cancer; factors that influence the incidence of SMNs include the type of primary cancer, treatment, and genetic predisposition to cancer. This represents a sixfold increased risk of SMNs among cancer survivors, compared with the general population. SMNs are the leading cause of nonrelapse late mortality (standardized mortality ratio = 15.2; 95% confidence interval [CI], 13.9-16.6). The risk of SMNs remains elevated for more than 30 years from diagnosis of the primary cancer. The incidence and type of SMNs 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 SMNs into the following two distinct groups:
Characteristics of t-MDS/AML include a short latency (<3 years from primary cancer diagnosis) and association with alkylating agents and/or topoisomerase II inhibitors. Solid SMNs have a strong and well-defined association with radiation and are characterized by a latency that exceeds 10 years. Furthermore, the risk of solid SMNs continues to climb with increasing follow-up, whereas the risk of t-MDS/AML plateaus after 10 to 15 years.
Treatment Options for Stages I and II
Hepatoblastoma of pure fetal histology: For tumors of pure fetal histology, complete surgical resection followed by watchful waiting or single-agent doxorubicin.In the Children's Oncology Group (COG) study COG-P9645, stage I pure fetal histology hepatoblastomas with two or fewer mitoses per 10 high power fields were not treated with chemotherapy. Completely excised tumor of purely fetal and favorable histology may be carefully followed without...
Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) has been reported after treatment of Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), and sarcomas, with the cumulative incidence approaching 2% at 15 years after therapy.[4,5,6,7] t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types are recognized by the World Health Organization classification:
Topoisomerase II inhibitor-related type: Most of the translocations observed in patients exposed to topoisomerase II inhibitors disrupt a breakpoint cluster region between exons 5 and 11 of the band 11q23 and fuse mixed lineage leukemia (MLL) with a partner gene. Topoisomerase II inhibitor-related t-AML presents as overt leukemia after a latency of 6 months to 3 years and is associated with balanced translocations involving chromosome bands 11q23 or 21q22.
Therapy-Related Solid Second Malignant Neoplasms
Therapy-related solid SMNs demonstrate a strong relationship with ionizing radiation. The risk of solid SMNs is highest when the exposure occurs at a younger age, increases with the total dose of radiation, and with increasing follow-up after radiation. Eighty percent of all SMNs are solid SMNs. Some of the well-established radiation-related solid SMNs include the following:
Breast cancer:Breast cancer is the most common therapy-related solid SMN after HL, largely because of the high-dose chest radiation used to treat HL (standardized incidence ratio [SIR] of second breast cancer = 25 to 55).[4,10] For female HL patients treated with chest radiation before age16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years. The latency period after chest radiation ranges from 8 to 10 years, and the risk of second breast cancer increases in a linear fashion with radiation dose (P for trend <.001). Radiation-induced breast cancer has been reported to have more adverse clinicopathological features compared with breast cancer in age-matched population controls.
Thyroid cancer:Thyroid cancer is observed after neck radiation for HL, ALL, brain tumors, and after total-body irradiation for hematopoietic stem cell transplantation.[1,4] The risk of thyroid cancer has been reported to be 18-fold that of the general population. Radiation therapy at a young age is the major risk factor for the development of second thyroid cancers. A linear dose-response relationship between thyroid cancer and radiation is observed up to 29 Gy, with a decline in the odds ratio at higher doses, especially in children younger than 10 years at treatment, demonstrating evidence for a cell kill effect.[14,15] Female gender, younger age at exposure, and longer time since exposure are significant modifiers of the radiation-related risk of thyroid cancer.
Brain tumors: Brain tumors develop after cranial radiation for histologically distinct brain tumors  or for management of disease among ALL or non-Hodgkin lymphoma patients.[3,17,18] The risk for second brain tumors also demonstrates a linear relationship with radiation dose.[1,16,18] The risk of meningioma after radiation not only increases with radiation dose but also with increased dose of intrathecal methotrexate.
Bone tumors: The risk of second bone tumors has been reported to be 133-fold that of the general population, with an estimated 20-year cumulative risk of 2.8%. Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk. Radiation therapy is associated with a linear dose-response relationship.[21,22] After adjustment for radiation therapy, treatment with alkylating agents has also been linked to bone cancer, with the risk increasing with cumulative drug exposure. These data from earlier studies concur with those observed by the Childhood Cancer Survivor Study (CCSS). In this cohort, an increased risk of secondary sarcoma was associated with radiation therapy (relative risk [RR] = 3.1; 95% CI, 1.5-6.2), a primary diagnosis of sarcoma (RR = 10.1; 95% CI, 4.7-21.8), a history of other secondary neoplasms (RR = 2.2; 95% CI, 1.1-4.5), and treatment with higher doses of anthracyclines (RR = 2.3; 95% CI, 1.2-4.3) or alkylating agents (RR = 2.2; 95% CI, 1.1-4.6). The 30-year cumulative incidence of secondary sarcoma in CCSS participants was 1.08% for survivors who received radiation and 0.5% for survivors who did not receive radiation.
Lung cancer:Lung cancer has been reported after chest irradiation for HL. The risk increases in association with longer elapsed time from diagnosis. Smoking has been linked with the occurrence of lung cancer developing after radiation for HL. The increase in risk of lung cancer with increasing radiation dose is greater among patients who smoke after exposure to radiation than among those who refrain from smoking (P = .04).
Gastrointestinal (GI) cancer: There is emerging evidence that childhood cancer survivors develop GI malignancies more frequently and at a younger age than the general population. The Late Effects Study Group reported a 63.9-fold increased risk of gastric cancers and 36.4-fold increased risk of colorectal cancers in adult survivors of childhood HL. In addition to previous radiation therapy, younger age (0-5 years) at the time of the primary cancer therapy significantly increased risk. In an analysis of a British cohort of survivors of pediatric and adult HL, there was only a borderline association between radiation therapy and GI SMN (SIR = 1.7; 95% CI, 1.0-2.5). However, patients treated with mixed modality therapy including radiation and chemotherapy had a more than threefold increase in risk for GI SMN (SIR = 3.3; 95% CI, 2.1-4.8). The CCSS has also observed a higher risk for developing colorectal carcinoma among its participants treated with chemotherapy compared with those who did not receive chemotherapy. Colorectal carcinoma risk appeared to be higher in survivors exposed to alkylating agents and platinum agents compared with survivors not exposed to those agents.