Therapy-Related Solid Neoplasms
Subsequent Neoplasms and Genetic Susceptibility
Drug-metabolizing enzymes and DNA repair polymorphisms
Screening and Follow-up for Subsequent Neoplasms
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 multifactorial in etiology and results from combinations of influences including gene-environment and gene-gene interactions. Outcome after 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.Therapy-Related Leukemia
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.[8-11] Some cases of late recurrence among childhood acute lymphoblastic leukemia have been shown to represent cases of new primary leukemia based on TCR gene rearrangement.[12,13] t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types are recognized by the World Health Organization classification:
- Alkylating agent-related type: Alkylating agents associated with t-MDS/AML include cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, nitrosoureas, chlorambucil, and dacarbazine. The risk of alkylating agent–related t-MDS/AML is dose dependent, with a latency of 3 to 5 years after exposure; it is associated with abnormalities involving chromosomes 5 (-5/del[5q]) and 7 (-7/del[7q]).
- 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 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 SNs represent 80% of all SNs and demonstrate a strong relationship with ionizing radiation. The histological subtypes of solid SNs encompass a neoplastic spectrum ranging from benign and low-grade malignant lesions (e.g., NMSC, meningiomas) to high-grade malignancies (e.g., breast cancers, glioblastomas).[1,11,16-19] SN solid tumors in childhood cancer survivors most commonly involve the breast, thyroid, central nervous system (CNS), bones, and soft tissues.[1,8,11,17,20] With more prolonged follow-up of cohorts of adults surviving childhood cancer, epithelial neoplasms involving the gastrointestinal tract and lung have emerged.[1,8,16] Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors treated with radiation for childhood cancer.[1,17,18]
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. 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. Some of the well-established radiation-related solid SNs include the following:
- Skin cancer: NMSCs represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation. Compared with 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). These data underscore the importance of counseling survivors about sun protection behaviors to reduce ultraviolet radiation exposure that may exacerbate this risk. 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. 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 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. 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.
- 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).[8,25] Excess risk has been reported in female survivors treated with high-dose, extended-volume radiation at age 30 years or younger. 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.[27,28] 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. 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 (131I-mIBG) treatment for neuroblastoma; and after TBI for hematopoietic stem cell transplantation.[1,8,32] 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 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.[34,35] 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.[5,36,37] The risk for subsequent brain tumors also demonstrates a linear relationship with radiation dose.[1,17,37] 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.[39,40]
- 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%. 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.[42,43] 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 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. 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.
- 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%). 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 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 than in 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 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 for GI SNs among their study participants than in 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).
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.
- 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. Highest risk was observed among neuroblastoma survivors (SIR, 85.8; 95% CI, 38.4–175.2) and among those treated with renal-directed radiation therapy of 5 Gy or greater (RR, 3.8; 95% CI, 1.6–9.3) and platinum-based chemotherapy (RR, 3.5; 95% CI, 1.0–11.2).
Literature clearly supports the role of chemotherapy and radiation in the development of SNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome. Previous studies have demonstrated that childhood cancer survivors with either a family history of cancer, but more so, presence of Li-Fraumeni syndrome, carry an increased risk of developing an SN.[51,52] The risk of SNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome). However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes. Table 1 below summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.Table 1. Selected Syndromes of Inherited Cancer Predispositiona
|Syndrome||Major Tumor Types||Affected Gene||Mode of Inheritance|
|Adenomatous polyposis of the colon||Colon, hepatoblastoma, intestinal cancers, stomach, thyroid cancer||APC||Dominant|
|Beckwith-Wiedemann syndrome||Adrenal carcinoma, hepatoblastoma, rhabdomyosarcoma, Wilms tumor||CDKN1C/NSD1||Dominant|
|Bloom syndrome||Leukemia, lymphoma, skin cancer||BLM||Recessive|
|Fanconi anemia||Gynecological tumors, leukemia, squamous cell carcinoma||FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG||Recessive|
|Juvenile polyposis syndrome||Gastrointestinal tumors||SMAD4/DPC4||Dominant|
|Li-Fraumeni syndrome||Adrenocortical carcinoma, brain tumor, breast carcinoma, leukemia, osteosarcoma, soft tissue sarcoma||TP53||Dominant|
|Multiple endocrine neoplasia 1||Pancreatic islet cell tumor, parathyroid adenoma, pituitary adenoma||MEN1||Dominant|
|Multiple endocrine neoplasia 2||Medullary thyroid carcinoma, pheochromocytoma||RET||Dominant|
|Neurofibromatosis type 1||Neurofibroma, optic pathway glioma, peripheral nerve sheath tumor||NF1||Dominant|
|Neurofibromatosis type 2||Vestibular schwannoma||NF2||Dominant|
|Nevoid basal cell carcinoma syndrome||Basal cell carcinoma, medulloblastoma||PTCH||Dominant|
|Peutz-Jeghers syndrome||Intestinal cancers, ovarian carcinoma, pancreatic carcinoma||STK11||Dominant|
|Tuberous sclerosis||Hamartoma, renal angiomyolipoma, renal cell carcinoma||TSC1/TSC2||Dominant|
|von Hippel-Lindau syndrome||Hemangioblastoma, pheochromocytoma, renal cell carcinoma, retinal and central nervous tumors||VHL||Dominant|
|WAGR syndrome||Gonadoblastoma, Wilms tumor||WT1||Dominant|
|Wilms tumor syndrome||Wilms tumor||WT1||Dominant|
|Xeroderma pigmentosum||Leukemia, melanoma||XPA, XPB, XPC, XPD, XPE, XPF, XPG, POLH||Recessive|
|WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation.|
|aAdapted from Strahm et al.|
Drug-metabolizing enzymes and DNA repair polymorphisms
The interindividual variability in risk of SNs is more likely related to common polymorphisms in low-penetrance genes that regulate the availability of active drug metabolites or are responsible for DNA repair. Gene-environment interactions may magnify subtle functional differences resulting from genetic variations.Drug-metabolizing enzymes
Metabolism of genotoxic agents occurs in two phases. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase-1 (NQO1), and others. The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.DNA repair polymorphisms
DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and oncogenes that can lead to cancer initiation and progression. An individual’s DNA repair capacity appears to be genetically determined. A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity. Evaluation of the contribution of polymorphisms influencing DNA repair to the risk of SN represents an active area of research.Screening and Follow-up for Subsequent Neoplasms
Vigilant screening is important for those at risk. Because of the relatively small size of the pediatric cancer survivor population and the prevalence and time to onset of therapy-related complications, undertaking clinical studies to assess the impact of screening recommendations on the morbidity and mortality associated with the late effect is not feasible. However, well-conducted studies on large populations of childhood cancer survivors have provided compelling evidence linking specific therapeutic exposures and late effects. This evidence has been used by several national and international cooperative groups (Scottish Collegiate Guidelines Network, Children’s Cancer and Leukaemia Group, Children's Oncology Group [COG]) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors. The COG Guidelines employ a hybrid approach that is both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with the intensity of the screening recommendations). The screening recommendations in these guidelines represent a statement of consensus from a panel of experts in the late effects of pediatric cancer treatment.
In regard to screening for malignant SNs recommended by the COG Guidelines, certain high-risk populations of childhood cancer survivors merit heightened surveillance due to predisposing host, behavioral, or therapeutic factors.
- Screening for leukemia: t-MDS/AML usually manifests within 10 years after exposure. Recommendations include monitoring with annual complete blood count for 10 years after exposure to alkylating agents or topoisomerase II inhibitors.
- Screening after radiation exposure: Most other SNs are associated with radiation exposure. Screening recommendations include careful annual physical examination of the skin and underlying tissues in the radiation field. Specific comments about screening for more common radiation-associated SNs follow:
- Screening for early-onset skin cancer: Annual dermatological exam should focus on skin lesions and pigmented nevi in the radiation field. Survivors should be counseled about their increased risk of skin cancer, the potential exacerbation of risk through tanning, and the benefits of adhering to behaviors to protect the skin from excessive ultraviolet radiation exposure.
- Screening for early-onset breast cancer: Since outcome after breast cancer is directly linked to stage at diagnosis, close surveillance resulting in early diagnosis should confer survival advantage. Mammography, the most widely accepted screening tool for breast cancer in the general population, may not be the ideal screening tool by itself for radiation-related breast cancers occurring in relatively young women with dense breasts; hence, the American Cancer Society recommends including adjunct screening with magnetic resonance imaging (MRI). Many clinicians are concerned about potential harms related to radiation exposure associated with annual mammography in these young women. In this regard, it is important to consider that the estimated mean breast dose with contemporary standard two-view screening mammograms is about 3.85 mGy to 4.5 mGy.[58-60] Thus, 15 additional surveillance mammograms from age 25 to 39 years would increase the total radiation exposure in a woman treated with 20 Gy of chest radiation to 20.05775 Gy. The benefits of detection of early breast cancer lesions in high-risk women must be balanced by the risk predisposed by a 0.3% additional radiation exposure. To keep young women engaged in breast health surveillance, the COG Guideline recommendations for females who received radiation with potential impact to the breast (i.e., radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields) include monthly breast self-examination beginning at puberty; annual clinical breast examinations beginning at puberty until age 25 years; and a clinical breast examination every 6 months, with annual mammograms and MRIs beginning 8 years after radiation or at age 25 years (whichever occurs later).
- Screening for early-onset colorectal cancer: Screening of those at risk of early-onset colorectal cancer (i.e., radiation doses of 30 Gy or higher to the abdomen, pelvis, or spine) should include colonoscopy every 5 years beginning at age 35 years or 10 years after radiation (whichever occurs later).
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