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Subsequent Neoplasms

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    The risk of solid SNs is highest when the exposure occurs at a younger age, increases with the total dose of radiation, and with increasing follow-up after radiation.[1] 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 compared with the general population. Chronic graft-versus-host disease increased the risk of SN, especially those involving the oral cavity.[20] Some of the well-established radiation-related solid SNs include the following:[5]

    • Skin cancer: NMSCs represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation. Compared to participants who did not receive radiation, CCSS participants treated with radiation had a 6.3-fold increase in risk (95% CI, 3.5–11.3) of reporting a NMSC. Ninety percent of tumors occurred within the radiation field. A CCSS case-control study of the same cohort reported on subsequent basal cell carcinoma. Children who received 35 Gy or more to the skin site had an almost 40-fold excess risk of developing basal cell cancer (odds ratio [OR], 39.8; 95% CI, 8.6–185), compared with those who did not receive radiation; results were consistent with a linear dose-response relationship, with an excess OR per Gy of 1.09 (95% CI, 0.49–2.64).[21] These data underscore the importance of counseling survivors about sun protection behaviors to reduce ultraviolet radiation exposure that may exacerbate this risk.[18] The occurrence of a NMSC as the first SN has been reported to identify a population at high risk for a future invasive malignant SN.[3] 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 to 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 included radiation therapy or the combination of alkylating agents and antimitotic drugs. Melanomas most frequently developed in survivors of Hodgkin lymphoma, 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.[22]

    • Breast cancer: Breast cancer is the most common therapy-related solid SN after HL, largely because of the high-dose chest radiation used to treat HL (SIR of subsequent breast cancer = 25 to 55).[8,23] Excess risk has been reported in female survivors treated with high-dose, extended-volume radiation at age 30 years or younger.[24] 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.[25,26] Emerging data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[27] For female HL patients treated with chest radiation before age 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years.[8] 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).[28] Radiation-induced breast cancer has been reported to have more adverse clinicopathological features compared with breast cancer in age-matched population controls.[29] 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 neck radiation for HL, ALL, and brain tumors; after iodine I 131 metaiodobenzylguanidine (131 I-mIBG) treatment for neuroblastoma; and after TBI for hematopoietic stem cell transplantation.[1,8,30] The risk of thyroid cancer has been reported to be 18-fold that of the general population.[31] Radiation therapy at a young age is the major risk factor for the development of subsequent thyroid cancers. A linear dose-response relationship between thyroid cancer and radiation is observed up to 29 Gy, with a decline in the OR at higher doses, especially in children younger than 10 years at treatment, demonstrating evidence for a cell kill effect.[32,33] Female gender, younger age at exposure, and longer time since exposure are significant modifiers of the radiation-related risk of thyroid cancer.[33]
    • Brain tumors: Brain tumors develop after cranial radiation for histologically distinct brain tumors [17] or for management of disease among ALL or non-Hodgkin lymphoma patients.[5,34,35] The risk for subsequent brain tumors also demonstrates a linear relationship with radiation dose.[1,17,35] The risk of meningioma after radiation not only increases with radiation dose but also with increased dose of intrathecal methotrexate.[36] 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.[37,38]
    • Bone 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%.[39] Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk.[40] 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.[40] These data from earlier studies concur with those observed by the CCSS. In this cohort, an increased risk of subsequent 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.[42] 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.
    • Sarcomas: Subsequent sarcomas are uncommon SNs and 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 on 105 cases and 422 matched controls in a nested case-control study of 14,372 childhood cancer survivors. 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 (OR, 4.1; 95% CI, 1.8–9.5), which demonstrated a linear dose-response relationship. Anthracycline exposure was associated with sarcoma risk (OR, 3.5; 95% CI, 1.6–7.7), independent of radiation dose.[43]
    • 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%).[1] 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).[44]
    • 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.[8] 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 a SN in the digestive organs varied with therapy. The SNs most often involved the colon/rectum (42%), liver (24%), and stomach (19%). The risk was 9.7-fold higher compared with population controls and exhibited 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 survivors who had not received radiation. 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).[45]

      CCSS investigators reported a 4.6-fold higher risk for GI SNs among their study participants compared with the general population (95% CI, 3.4–6.1). The most prevalent GI SN histology was adenocarcinoma (56%). The SNs most often involved the colon (39%), rectum/anus (16%), liver (18%), and stomach (13%). The highest risk for 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 for GI SNs. The SIR for colorectal cancer was 4.2 (CI, 2.8–6.3).[46]

      St. Jude Children's Research Hospital investigators observed that the 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. The SIR for subsequent colorectal carcinoma was 10.9 (95% CI, 6.6–17.0) compared with U.S. population controls. 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.[47]

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