With more prolonged follow-up of cohorts of adult survivors of childhood cancer, epithelial neoplasms have been observed in the following:[2,5,15]
Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors treated with radiation for childhood cancer.[2,16,17]
In addition to radiation exposure, exposure to certain anticancer agents may result in solid SNs. In recipients of a hematopoietic cell transplant conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), the cumulative incidence of new solid cancers appears to be similar regardless of exposure to radiation. In a registry-based, retrospective, cohort study, Bu-Cy conditioning without total-body irradiation (TBI) was associated with higher risks of solid SNs than in the general population. Chronic graft-versus-host disease increased the risk of SN, especially those involving the oral cavity.
Breast cancer is the most common therapy-related solid SN after HL, largely due to the high-dose chest radiation used to treat HL (SIR of subsequent breast cancer, 25-55).[5,21] The following has been observed in female survivors of childhood HL:
- Excess risk has been reported in female HL survivors treated with high-dose, extended-volume radiation at age 30 years or younger. Emerging data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.
- For female HL patients treated with chest radiation before age 16 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 subsequent 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 than breast cancer in age-matched population controls.
Treatment with higher cumulative doses of alkylating agents and ovarian radiation greater than or equal to 5 Gy (exposures predisposing to premature menopause) have been correlated with reductions in breast cancer risk, underscoring the potential contribution of hormonal stimulation on breast carcinogenesis.[26,27]
Although currently available evidence is insufficient to demonstrate a survival benefit from the initiation of breast cancer surveillance in women treated with chest radiation for childhood cancer, interventions to promote detection of small and early-stage tumors may improve prognosis, particularly for those who may have more limited treatment options because of prior exposure to radiation or anthracyclines.
Thyroid cancer: Thyroid cancer is observed after the following:[2,5,28]
- Neck radiation for HL, ALL, and brain tumors.
- Iodine I 131 metaiodobenzylguanidine (131 I-mIBG) treatment for neuroblastoma.
- TBI for hematopoietic stem cell transplantation.
The risk of thyroid cancer has been reported to be 18-fold that of the general population. Significant modifiers of the radiation-related risk of thyroid cancer include the following:[30,31]
- Female gender.
- Younger age at exposure.
- Longer time since exposure.
- Radiation dose. A linear dose-response relationship between radiation exposure and thyroid cancer is observed up to 29 Gy, with a decline in the odds ratio (OR) at higher doses, especially in children younger than 10 years at treatment, demonstrating evidence for a cell kill effect.[30,32]
CNS tumors: Brain tumors develop after cranial radiation for histologically distinct brain tumors  or for management of disease among ALL or non-Hodgkin lymphoma patients.[6,9,33] SIRs reported for subsequent CNS neoplasms after treatment for childhood cancer range from 8.1 to 52.3 across studies.
The risk of subsequent brain tumors demonstrates a linear relationship with radiation dose.[2,16]
- The risk of meningioma after radiation not only increases with radiation dose but also with increased dose of intrathecal methotrexate.
- Cavernomas have also been reported with considerable frequency after CNS radiation but have been speculated to result from angiogenic processes as opposed to true tumorigenesis.[36,37,38]
Despite the well-established increased risk of subsequent CNS neoplasms among childhood cancer survivors treated with cranial irradiation, the current literature is insufficient to evaluate the potential harms and benefits of routine screening for these lesions.
Bone and soft tissue tumors: The risk of subsequent 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.[40,41] 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 the following data observed by the CCSS and other investigators:
- In a CCSS cohort, an increased risk of subsequent bone or soft tissue sarcoma was associated with radiation therapy, a primary diagnosis of sarcoma, a history of other SNs, and treatment with higher doses of anthracyclines or alkylating agents.
- The 30-year cumulative incidence of subsequent sarcoma in CCSS participants was 1.08% for survivors who received radiation and 0.5% for survivors who did not receive radiation.
- In survivors of bilateral retinoblastoma, the most common SNs seen are sarcomas, specifically osteosarcoma.[43,44,45]
Soft tissue sarcomas can be of various histologic subtypes, including nonrhabdomyosarcoma soft tissue sarcomas, rhabdomyosarcoma, malignant peripheral nerve sheath tumors, Ewing/primitive neuroectodermal tumors, and other rare types. The CCSS reported the following on 105 cases and 422 matched controls in a nested case-control study of 14,372 childhood cancer survivors:
- Soft tissue sarcomas occurred at a median of 11.8 years (range, 5.3-31.3 years) from original diagnoses.
- Any exposure to radiation was associated with increased risk of soft tissue sarcoma (OR, 4.1; 95% CI, 1.8-9.5), which demonstrated a linear dose-response relationship.
- Anthracycline exposure was associated with soft tissue sarcoma risk (OR, 3.5; 95% CI, 1.6-7.7), independent of radiation dose.
Nonmelanoma skin cancers (NMSCs) represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation. The CCSS has observed the following:
The occurrence of a NMSC as the first SN has been reported to identify a population at high risk of a future invasive malignant SN. CCSS investigators observed a cumulative incidence of a malignant neoplasm of 20.3% (95% CI, 13.0%-27.6%) at 15 years among radiation-exposed survivors who developed NMSC as a first SN compared with 10.7% (95% CI, 7.2%-14.2%) whose first SN was an invasive malignancy.
Malignant melanoma has also been reported as a SN in childhood cancer survivor cohorts, although at a much lower incidence than NMSCs. A systematic review including data from 19 original studies (total N = 151,575 survivors; median follow-up of 13 years) observed an incidence of 10.8 cases of malignant melanoma per 100,000 childhood cancer survivors per year.
Risk factors for malignant melanoma identified among these studies include the following:
- Radiation therapy.
- Combination of alkylating agents and antimitotic drugs.
Melanomas most frequently developed in survivors of HL, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors, but the relatively small number of survivors represented in the relevant studies preclude assessment of melanoma risk among other types of childhood cancer.
CCSS investigators observed an approximate 2.5-fold increased risk (SIR, 2.42; 95% CI, 1.77-3.23) of melanoma among members of their cohort (median time to development, 21.0 years). The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% (95% CI, 0.37-0.73), and absolute excess risk was 0.10 per 1,000 person-years (95% CI, 0.05-0.15). Family history of cancer, demographic, or treatment-related factors did not predict risk of melanoma.
Lung cancer: Among pediatric childhood cancer survivor cohorts, lung cancer represents a relatively uncommon SN; the 30-year cumulative incidence of lung cancer among CCSS participants was 0.1% (95% CI, 0.0%-0.2%). The following has been observed in adult survivors of childhood HL:
- 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 that develops 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 a French and British cohort-nested, case-control study of childhood solid cancer survivors diagnosed before age 17 years, the risk of developing an SN in the digestive organs varied with therapy. The following was also observed:
- The risk of GI cancer was 9.7-fold higher than in population controls.
- The SNs most often involved the colon/rectum (42%), liver (24%), and stomach (19%).
- A strong radiation dose-response relationship, with an OR of 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 Gy and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses of 30 Gy and above, compared with the dose response in survivors who had not received radiation therapy.
- Chemotherapy alone and combined-modality therapy were associated with a significantly increased risk of developing a GI SN (SIR, 9.1; 95% CI, 2.3-23.6; SIR 29.0; 95% CI, 20.5-39.8).
CCSS investigators reported a 4.6-fold higher risk of GI SNs among their study participants than in the general population (95% CI, 3.4-6.1). They also reported the following:
- The SNs most often involved the colon (39%), rectum/anus (16%), liver (18%), and stomach (13%).
- The SIR for colorectal cancer was 4.2 (CI, 2.8-6.3).
- The most prevalent GI SN histology was adenocarcinoma (56%).
- The highest risk of GI SNs was associated with abdominal radiation (SIR, 11.2; CI, 7.6-16.4), but survivors not exposed to radiation also had a significantly increased risk (SIR, 2.4; CI, 1.4-3.9).
- High-dose procarbazine (relative risk [RR], 3.2; CI 1.1-9.4) and platinum drugs (RR, 7.6; CI, 2.3-25.5) independently increased the risk of GI SNs.
St. Jude Children's Research Hospital investigators observed that the SIR for subsequent colorectal carcinoma was 10.9 (95% CI, 6.6-17.0) compared with U.S. population controls. Investigators also observed the following:
- Incidence of a subsequent colorectal carcinoma increased steeply with advancing age, with a 40-year cumulative incidence of 1.4% ± 0.53% among the entire cohort (N = 13,048) and 2.3% ± 0.83% for 5-year survivors.
- Colorectal carcinoma risk increased by 70% with each 10 Gy increase in radiation dose, and increasing radiation volume also increased risk.
- Treatment with alkylating agent chemotherapy was also associated with an 8.8-fold excess risk of subsequent colorectal carcinoma.
Collectively, these studies support the need for initiation of colorectal carcinoma surveillance at a young age among survivors receiving high-risk exposures.[5,51,52,53]
Renal carcinoma: Consistent with reports among survivors of adult-onset cancer, CCSS investigators reported a significant excess of subsequent renal carcinoma among 14,358 5-year survivors in the cohort (SIR, 8.0; 95% CI, 5.2-11.7) compared with the general population. The reported overall absolute excess risk of 8.4 per 105 person-years indicates that these cases are relatively rare. Highest risk was observed among the following:
- Neuroblastoma survivors (SIR, 85.8; 95% CI, 38.4-175.2). Radiation has been hypothesized to predispose children with high-risk neuroblastoma to renal carcinoma.
- Those treated with renal-directed radiation therapy of 5 Gy or greater (RR, 3.8; 95% CI, 1.6-9.3).
- Those treated with platinum-based chemotherapy (RR, 3.5; 95% CI, 1.0-11.2). Cases of secondary renal carcinoma associated with Xp11.2 translocations and TFE3 gene fusions have also been reported and suggest that cytotoxic chemotherapy may contribute to renal carcinogenesis.[56,57]
Underlying genetic predisposition may also play a role because rare cases of renal carcinoma have been observed in children with tuberous sclerosis.