domingo, 7 de julio de 2019

Late Effects of Treatment for Childhood Cancer (PDQ®)—Health Professional Version - National Cancer Institute 2/10

Late Effects of Treatment for Childhood Cancer (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

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 according to the following:
  • Host factors (e.g., genetics, immune function, hormone status).
  • Primary cancer therapy.
  • Environmental exposures.
  • Lifestyle factors.
SNs are the leading cause of nonrelapse late mortality (standardized mortality ratio, 15.2; 95% confidence interval [CI], 13.9–16.6).[1] The Childhood Cancer Survivor Study (CCSS) reported the following 30-year cumulative incidence rates:[2]
  • All SNs: 20.5% (95% CI, 19.1%–21.8%).
  • Nonmelanoma skin cancer (NMSC): 9.1% (95% CI, 8.1%–10.1%).
  • SNs with malignant histologies (excluding NMSC): 7.9% (95% CI, 7.2%–8.5%).
  • Meningioma: 3.1% (95% CI, 2.5%–3.8%).
This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population.[2]
The excess risk of SNs has been described in several studies.[3]
Evidence (excess risk of SN after age 40 years):
  1. In a CCSS cohort, at the age of 55 years, the cumulative incidence of any new SN (including malignant neoplasms, NMSCs, benign meningiomas, and other benign neoplasms) occurring after age 40 years was 34.6%. The incidence of malignant SNs was 16.3%. Female sex and therapeutic radiation exposure were associated with an increased risk of developing SNs in multivariate analysis. Moreover, prolonged follow-up has established that multiple SNs are common among aging childhood cancer survivors.[4,5]
  2. The CCSS also reported that individuals treated in more recent treatment eras experienced decreased risk of SNs (including subsequent malignancies, NMSCs, and benign meningiomas) compared with those treated earlier, and this was associated with decreased exposure to therapeutic radiation; however, individuals treated in the 1990s remain at increased risk of SNs compared with the general population.[6]
  3. A follow-up CCSS study evaluated morbidity and mortality associated with meningioma among 4,221 participants treated with cranial radiation therapy.[7]
    • The cumulative incidence of subsequent meningioma by age 40 years was 5.6% in this group of patients, and the incidence was without demonstrable plateau.
    • Risk factors for subsequent meningioma included female sex (hazard ratio [HR], 1.7; 95% CI, 1.2–2.3) and higher cranial radiation dose (HR, 2.6; 95% CI, 1.6–4.2 after 30 Gy or higher).
    • Among survivors reporting meningiomas, the risk of neurologic sequelae occurring 5 or more years after primary cancer diagnosis was increased for seizures (HR, 10.0; 95% CI, 7.0–15.3); auditory-vestibular-visual sensory deficits (HR, 2.3; 95% CI, 1.3–4.0); focal neurologic dysfunction (HR, 4.9; 95% CI, 3.2–7.5); and severe headaches (HR, 3.2; 95% CI, 1.9–5.4).
    • With a median follow-up of 72 months after meningioma diagnosis, 13% of the patients had died, with six deaths attributed to meningioma.
  4. Dutch investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001 (median follow-up, 20.7 years).[8]
    • The 25-year cumulative SN incidence was 3.9% and did not change across decades.
    • Survivors treated with doxorubicin exhibited a dose-dependent increased risk of all solid cancers and breast cancer.
    • Among female survivors who did not receive chest radiation or total-body irradiation (TBI) (n = 31, breast cancer), HRs for doxorubicin dose tertiles were 1.3 (95% CI, 0.3–6.1), 5.6 (95% CI, 1.9–16.2), and 9.9 (95% CI, 4.2–23.8).
    • The doxorubicin–breast cancer dose response was stronger in survivors with Li-Fraumeni syndrome–associated childhood cancers (leukemia, central nervous system [CNS], and sarcomas other than Ewing) than in survivors of other cancers.
    • Study findings also confirmed those of previous SN investigations that have demonstrated a dose-response relationship with cyclophosphamide and subsequent sarcoma, particularly bone sarcoma. The HR for subsequent sarcoma was 3.1 (95% CI, 1.5–6.0) for survivors who received cyclophosphamide at a dose greater than 9,400 mg/m2 and 2.6 (95% CI, 1.3–5.2) for those who received ifosfamide.
  5. St. Jude Lifetime Cohort Study investigators assessed the contribution of pathogenic and likely pathogenic mutations in cancer predisposition genes to SN risk in childhood cancer survivors.[9]
    • Of 3,006 study participants (median age, 35.6 years) evaluated by whole-genome sequencing (30-fold), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 pathogenic or likely pathogenic mutations were identified in 5.8% of survivors; the prevalence of a pathogenic or likely pathogenic mutation among nonirradiated survivors with SNs was much higher at 18%.
    • Mutations were associated with significantly increased rates of breast cancer (relative risk [RR], 13.9) and sarcoma (RR, 10.6) among irradiated survivors and with developing any SN (RR, 4.7), breast cancer (RR, 7.7), nonmelanoma skin cancer (RR, 11), and two or more histologically distinct SNs (RR, 18.6).
    • Mutation carriers did not have an increased rate of meningioma or thyroid cancer.
  6. A study of 4,905 1-year survivors of allogeneic hematopoietic cell transplantation (HCT) who underwent transplant between 1969 and 2014 for malignant or nonmalignant diseases and followed for a median 12.5 years, demonstrated a strong effect of TBI dose and dose fractionation on risk of SNs.[10]
    • There were 581 SNs (excluding squamous and basal cell carcinomas of the skin) that developed in 499 individuals.
    • The cumulative incidence of SN by 30 years after HCT was 22.0%.
    • SN risk was highest in survivors exposed to high-dose unfractionated (600–1,200 cGy) or very high-dose fractionated (1,440–1,750 cGy) TBI.
    • With low-dose TBI (200–450 cGy), the SN risk was comparable to the risk with chemotherapy alone, although still twofold higher than in the general population.
The development of an SN is likely multifactorial in etiology and results from a combination 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.[11]
The incidence and type of SNs depend on the following:
  • Primary cancer diagnosis.
  • Type of therapy received.
  • 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.

Therapy-Related Myelodysplastic Syndrome and 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.[12-16]
Characteristics of t-MDS/AML include the following:[12,17,18]
  • A short latency (<10 years from primary cancer diagnosis). The risk of t-MDS/AML plateaus after 10 to 15 years. Although the risk of subsequent leukemia remains significantly elevated beyond 15 years from primary diagnosis (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 1,000 person-years.[18]
  • An association with alkylating agents and/or topoisomerase II inhibitors.
t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types of t-MDS/AML are recognized by the World Health Organization classification:[19]
  • Alkylating agent-related type: Alkylating agents associated with t-MDS/AML include cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, nitrosoureas, chlorambucil, and dacarbazine.[20]
    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)).[20]
  • Topoisomerase II inhibitor–related type: Topoisomerase II inhibitor agents include etoposide, teniposide, and anthracycline-related drugs.
    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.[20] 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.[21]

Therapy-Related Solid Neoplasms

Therapy-related solid SNs represent 80% of all SNs and demonstrate a strong relationship with radiation exposure and are characterized by a latency that exceeds 10 years. The risk of solid SNs continues to increase with longer follow-up. The risk of solid SNs is highest when the following occur:[2,16]
  • Radiation exposure at a younger age.
  • High total dose of radiation.
  • Longer period of follow-up after radiation exposure.
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).[2,14,22-26]
Solid SNs in childhood cancer survivors most commonly involve the following: [2,12,14,16,23,27,28]
With more prolonged follow-up of adult survivors of childhood cancer cohorts, epithelial neoplasms have been observed in the following:[2,12,22,29]
Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors who were treated with radiation therapy for childhood cancer.[2,23,24]
In addition to radiation exposure, exposure to certain anticancer agents may result in solid SNs. In recipients of an HCT 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 TBI was associated with higher risks of solid SNs than in the general population. Chronic graft-versus-host disease increased the risk of SNs, especially those involving the oral cavity.[30]
Some well-established solid SNs are described in the following sections.[31]

Breast cancer

Breast cancer is the most common therapy-related solid SN after HL, largely due to the high dose of chest radiation used to treat HL (SIR of subsequent breast cancer, 25–55).[12,32] The following has been observed in female survivors of childhood HL:
  • Excess risk of breast cancer has been reported in female HL survivors treated with high-dose, extended-volume radiation at age 30 years or younger.[33] Emerging data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[34]
  • Patients with HL who received supradiaphragmatic radiation therapy (excluding the axillae) had a significantly lower risk of subsequent breast cancers than did patients who received mantle-field radiation therapy.[35]
  • For female HL patients treated with radiation therapy to the chest before age 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years.[12]
  • The latency period after chest irradiation 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).[36]
Radiation-induced breast cancer has been reported in one population-based study to have more adverse clinicopathological features, as evidenced by a twofold increased risk of estrogen receptor–negative, progesterone receptor–negative breast cancer observed among 15-year HL survivors, compared with women who had sporadic breast cancer.[37] Several studies that have investigated the clinical characteristics of subsequent breast cancers arising in women treated with radiation for childhood cancer have observed a higher proportion of more histologically aggressive subtypes (e.g., triple-negative breast cancer) than age-matched sporadic invasive cancers.[38,39] These findings are in contrast to other smaller hospital-based, case-control studies of breast cancer among HL survivors that have not identified a significant variation in hormone receptor status when compared with primary breast cancer controls. Previous studies have also not demonstrated significant difference in overall risk of high-grade versus low-grade tumors.[40-42]
Treatment of childhood HL with higher cumulative doses of alkylating agents and ovarian radiation of 5 Gy or higher (exposures predisposing to premature menopause) have been correlated with reductions in breast cancer risk, underscoring the potential contribution of hormonal stimulation on breast carcinogenesis.[35,43,44]
Most data describing the risk of radiation-associated breast cancer are based on patients treated for HL, with doses ranging from 15 Gy to 50 Gy. However, the risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer metastatic to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue:
  1. In 116 children in the CCSS cohort treated with 2 Gy to 20 Gy to the lungs (median, 14 Gy), the SIR for breast cancer was 43.6 (95% CI, 27.1–70.1).[45]
  2. A report of 2,492 female participants in the National Wilms Tumor Studies 1 through 4 (1969–1995) addressed the excess risk of breast cancer.[46]
    • Sixteen of 369 women who received chest irradiation for metastatic Wilms tumor developed invasive breast cancer (cumulative risk at age 40 years, 14.8% [95% CI, 8.7–24.5]). The SIR of 27.6 (95% CI, 16.1–44.2) was based on 5,010 person-years of follow-up.
    • Of the 369 patients, radiation doses to the chest were less than 12 Gy in 4%, 12 Gy in 64%, 13 Gy to 15 Gy in 19%, and more than 15 Gy in 13% of patients.
    • For all patients who developed breast cancer (with or without chest irradiation), the median age at first breast cancer diagnosis was 34.3 years (range, 15.5–48.4) and the median time from Wilms tumor diagnosis was 27.1 years (range, 7.9–35.7).
Although currently available evidence is insufficient to demonstrate a survival benefit from the initiation of breast cancer surveillance in women treated with radiation therapy to the chest 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 previous exposure to radiation or anthracyclines.
  1. Childhood sarcoma or leukemia survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.[47]
    • CCSS investigators observed a fourfold excess risk (SIR, 4.0; 95% CI, 3.0–5.3) of breast cancer compared with rates in the general population among 3,768 female participants who did not receive chest radiation.
    • Breast cancer risk was highest among sarcoma (SIR, 5.3; 95% CI, 3.6–7.8) and leukemia (SIR, 4.1; 95% CI, 2.4–6.9) survivors, for whom the cumulative incidence of breast cancer was estimated to be 5.8% and 6.3%, respectively, by age 45 years.
    • Treatment with alkylating agents and anthracyclines increased the risk of breast cancer in a dose-dependent manner.
  2. Dutch investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[8]
    • Survivors treated with doxorubicin exhibited a dose-dependent increased risk of breast cancer (HR, 3.1; 95% CI, 1.4–6.5 among survivors treated with anthracycline doses of 250 mg/m2 or higher).
    • The doxorubicin–breast cancer dose response was stronger for survivors of Li-Fraumeni–associated cancers (leukemia, CNS, and sarcomas other than Ewing) than for survivors of other cancers.

Thyroid cancer

Thyroid cancer is observed after the following:[2,12,48]
  • Neck radiation therapy for HL, ALL, and brain tumors.
  • Iodine I 131-metaiodobenzylguanidine (131I-MIBG) treatment for neuroblastoma.
  • TBI for hematopoietic stem cell transplantation.
The risk of thyroid cancer among survivors of Hodgkin disease has been reported to be 18-fold that of the general population.[49] Significant modifiers of the radiation-related risk of thyroid cancer include the following:[50,51]
  • Female sex.
  • 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.[50,52]
(Refer to the Thyroid nodules section of this summary for information on detecting thyroid nodules and thyroid cancer.)

CNS tumors

Brain tumors develop after cranial irradiation for histologically distinct brain tumors [23] or for management of disease among ALL or non-Hodgkin lymphoma patients.[13,53] SIRs reported for subsequent CNS neoplasms after treatment for childhood cancer range from 8.1 to 52.3 across studies.[54]
The risk of subsequent brain tumors demonstrates a linear relationship with radiation dose.[2,23]
  • The risk of meningioma after radiation not only increases with radiation dose but also with increased dose of intrathecal methotrexate.[55]
  • Cavernomas have also been reported with considerable frequency after CNS irradiation but have been speculated to result from angiogenic processes as opposed to true tumorigenesis.[56-58]
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.[54]

Bone and soft tissue tumors

Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk of developing subsequent bone and soft tissue tumors.[59-63]
A population-based study of 69,460 5-year survivors of cancer diagnosed before age 20 years observed the following:
  • The risk of subsequent primary bone cancer was 22-fold greater than that of the general population, with an estimated 45-year cumulative incidence of 0.6%, compared with an expected rate of 0.03% in the general population.[61] The observed excess numbers of subsequent primary bone cancer declined with both age and years from diagnosis.
  • In the same cohort, the risk of subsequent soft tissue sarcoma was almost 16-fold higher than the general population, with an estimated 45-year cumulative incidence of 1.4%, compared with an expected rate of 0.1%.[62] The median time from diagnosis to occurrence of a soft tissue sarcoma was 19 years.
    • The most commonly observed soft tissue sarcomas were leiomyosarcoma, fibromatous neoplasms, and malignant peripheral nerve sheath tumors. The SIR for subsequent fibromatous primary sarcomas decreased with increasing years from diagnosis and attained age, whereas the SIR for leiomyosarcoma and malignant peripheral nerve sheath tumors remained consistently high across all years from diagnosis and at all attained ages.
    • Notably, absolute excess risks of all sarcoma subtypes were generally low, except for leiomyosarcoma that followed a retinoblastoma diagnosis (absolute excess risks, 52.7 per 10,000 person-years among survivors 45 years or more from diagnosis). The risk of developing a leiomyosarcoma was 30-fold higher among survivors of childhood cancer, compared with an excess risk of 0.7 for the general population. Retinoblastoma survivors were at the highest risk (SIR, 342.9), followed by Wilms tumor survivors (SIR, 74.2). Ninety percent of leiomyosarcomas observed after a Wilms tumor diagnosis developed within the irradiated tissue.
Radiation therapy is associated with a linear dose-response relationship.[59,64] After adjustment for radiation therapy, treatment with alkylating agents has also been linked to bone cancer, with the risk increasing with cumulative drug exposure.[59] These data from earlier studies concur with the following data observed by the CCSS and other investigators:
  1. 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.[65] The 30-year cumulative incidence of subsequent sarcoma in CCSS participants was 1.08% for survivors who received radiation therapy and 0.5% for survivors who did not receive radiation therapy.[65]
  2. Dose-risk modeling was used to study the risk of bone sarcoma in a retrospective cohort of 4,171 survivors of a childhood solid cancer treated between 1942 and 1986 (median follow-up, 26 years).[64]
    • Dose-risk modeling demonstrated that the risk of bone sarcoma increased slightly up to a cumulative organ-absorbed radiation dose of 15 Gy (HR, 8.2; 95% CI, 1.6–42.9) and then rapidly increased for higher radiation doses (HR for 30 Gy or more, 117.9; 95% CI, 36.5–380.6), compared with patients not treated with radiation therapy.
    • The excess RR per Gy in this model was 1.77 (95% CI, 0.62–5.94).
  3. In survivors of bilateral retinoblastoma, the most common SNs seen are sarcomas, specifically osteosarcoma.[66-69] The contribution of chemotherapy to solid malignancy carcinogenesis was highlighted in a long-term follow-up study of 906 5-year hereditary retinoblastoma survivors who were diagnosed between 1914 and 1996 and observed through 2009.[60]
    • Treatment with alkylating agents significantly increased risk of subsequent bone tumors (HR, 1.60; 95% CI, 1.03–2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22–5.85) among members of the cohort.
    • Leiomyosarcoma occurrence was more common after treatment with alkylating agent chemotherapy and radiation therapy compared with radiation therapy alone (5.8% vs. 1.6% at age 40 years; P = .01).
  4. Dutch investigators studied the risk of sarcoma in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[8]
    • The use of cyclophosphamide, an alkylating agent, was found to increase sarcoma risk, particularly bone sarcoma, in a dose-dependent manner (HR, 3.1; 95% CI, 1.5–6.0 among survivors treated with cyclophosphamide doses of 9,400 mg/m2 or higher).
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:[70]
  • 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.

Skin cancer

Nonmelanoma skin cancers (NMSCs) represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation therapy.[71] The CCSS has observed the following:
  • Compared with participants who did not receive radiation therapy, CCSS participants treated with radiation therapy had a 6.3-fold increase in risk of NMSC (95% CI, 3.5–11.3).[72]
  • Ninety percent of tumors occurred within the radiation field.[72]
  • A CCSS case-control study of the same cohort reported on subsequent basal cell carcinomas (BCCs). Children who received 35 Gy or more to the skin site had an almost 40-fold excess risk of developing BCCs (OR, 39.8; 95% CI, 8.6–185), compared with those who did not receive radiation therapy; results were consistent with a linear dose-response relationship, with an excess OR per Gy of 1.09 (95% CI, 0.49–2.64).[72]
    These data underscore the importance of counseling survivors about sun protection behaviors to reduce ultraviolet radiation exposure that may exacerbate this risk.[24]
In 5,843 childhood cancer survivors in the Dutch Childhood Oncology Group (DCOG)-LATER cohort, investigators found that childhood cancer survivors had a 30-fold increased risk of developing BCCs. After a first BCC diagnosis, 46.7% of patients had more BCCs later. This risk was associated with any radiation therapy to the original radiation field (HR,14.32) and with estimated percentage of in-field skin surface area (26%–75%: HR, 1.99; 76%–100%: HR, 2.16 vs. 1%–25% exposed; Ptrend among exposed = .002). BCC risk was not associated with prescribed radiation dose and likelihood of sun-exposed skin area. Of all chemotherapy groups examined, only vinca alkaloids increased the BCC risk (HR, 1.54).[73]
The occurrence of an NMSC as the first SN has been reported to identify a population at high risk of a future invasive malignant SN.[4] 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 an 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.[74]
Risk factors for malignant melanoma identified among these studies include the following:[74]
  • 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.[74]
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.[75]

Lung cancer

Lung cancer: Among 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%).[2] The following has been observed in adult survivors of childhood HL:[76]
  • 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 therapy 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 substantial evidence that childhood cancer survivors develop GI malignancies more frequently and at a younger age than the general population.[12,77-80]
The following has been observed in adult survivors of childhood cancer:
  1. 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.[12]
  2. 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:[77]
    • 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).
  3. 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:[78]
    • 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 irradiation (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 (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.
  4. 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:[79]
    • 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.
  5. A multi-institutional prospective study observed that potentially precancerous neoplastic polyps were found in 27.8% of childhood cancer survivors who received radiation to the abdomen/pelvis at least 10 years earlier and who had colonoscopic screening between age 35 and 49 years.[81]
    • This polyp prevalence is at least as high as that previously reported for the average-risk population older than 50 years and is similar to the 24% incidence rate for patients with hereditary non-polyposis colon cancer; polyp prevalence rates in the general population for people aged 35 to 49 years are unclear.
  6. A DCOG-LATER record linkage study evaluated the risk of histologically confirmed colorectal adenomas among 5,843 5-year childhood cancer survivors followed for a median of 24.9 years.[82]
    • The cumulative incidence of colorectal adenoma by age 45 years was 3.6% among survivors who received abdominal pelvic radiation versus 2.0% for survivors who did not receive abdominal pelvic radiation, versus 1.0% among siblings.
    • Factors associated with adenoma risk were abdominal pelvic radiation (HR, 2.1), TBI (HR, 10.6), cisplatin (HR, 2.1 for <480 mg/m2; HR, 3.8 for ≥480 mg/m2), diagnosis of hepatoblastoma (HR, 27.1), and family history of early-onset colorectal cancer (HR, 20.5).
    • Procarbazine exposure was also associated with an increased risk among survivors not exposed to abdominal pelvic radiation or TBI (HR, 2.7).
  7. In a large series from two institutions, 2,053 patients with retinoblastoma (diagnosed between 1914 and 2016) were identified.[83]
    • Most deaths occurred in hereditary retinoblastoma patients more than 70 years from diagnosis (518 of 1,129), and 267 of these deaths were caused by secondary cancers.
    • Increased risk of death resulting from cancers of the pancreas, large intestines, and kidney were reported.
    • Overall risk of subsequent cancer was higher for patients who were treated with radiation therapy and chemotherapy than for patients treated with radiation therapy alone, although patterns varied by organ site.
    • Based on a new cohort of 143 retinoblastoma survivors diagnosed between 1997 and 2006, continued improvements in mortality were observed.
    • For patients with nonhereditary retinoblastoma, only 27 deaths in 924 patients were attributed to second malignancies.
Collectively, these studies support the need for initiation of colorectal carcinoma surveillance at a young age among survivors receiving high-risk exposures.[12,77-79,84]

Renal carcinoma

Consistent with reports among survivors of adult-onset cancer, an increased risk of renal carcinoma has been observed in survivors of childhood cancer.[29,85,86]
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.[85] 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).[85] Radiation has been hypothesized to predispose children with high-risk neuroblastoma to renal carcinoma.[87]
  • Those treated with renal-directed radiation therapy of 5 Gy or higher (RR, 3.8; 95% CI, 1.6–9.3).[85]
  • Those treated with platinum-based chemotherapy (RR, 3.5; 95% CI, 1.0–11.2).[85] 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.[88,89]
Underlying genetic predisposition may also play a role because rare cases of renal carcinoma have been observed in children with tuberous sclerosis.[85]

Subsequent Neoplasms and Genetic Susceptibility

Literature clearly supports the role of chemotherapy and radiation therapy 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.[90,91] Previous studies have demonstrated that childhood cancer survivors with a family history of Li-Fraumeni syndrome in particular, or a family history of cancer, carry an increased risk of developing an SN.[92,93]
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).[93] However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes.
Table 1 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
SyndromeMajor Tumor TypesAffected GeneMode of Inheritance
AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation.
aAdapted from Strahm et al.[94]
bDominant in a fraction of patients, spontaneous mutations can occur.
Adenomatous polyposis of the colonColon, hepatoblastoma, intestinal cancers, stomach, thyroid cancerAPCDominant
Ataxia-telangiectasiaLeukemia, lymphomaATMRecessive
Beckwith-Wiedemann syndromeAdrenal carcinoma, hepatoblastoma, rhabdomyosarcoma, Wilms tumorCDKN1C/NSD1Dominant
Bloom syndromeLeukemia, lymphoma, skin cancerBLMRecessive
Diamond-Blackfan anemiaColon cancer, osteogenic sarcoma, AML/MDSRPS19 and other RPgenesDominant, spontaneousb
Fanconi anemiaGynecological tumors, leukemia, squamous cell carcinomaFANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCGRecessive
Juvenile polyposis syndromeGastrointestinal tumorsSMAD4/DPC4Dominant
Li-Fraumeni syndromeAdrenocortical carcinoma, brain tumor, breast carcinoma, leukemia, osteosarcoma, soft tissue sarcomaTP53Dominant
Multiple endocrine neoplasia 1Pancreatic islet cell tumor, parathyroid adenoma, pituitary adenomaMEN1Dominant
Multiple endocrine neoplasia 2Medullary thyroid carcinoma, pheochromocytomaRETDominant
Neurofibromatosis type 1Neurofibroma, optic pathway glioma, peripheral nerve sheath tumorNF1Dominant
Neurofibromatosis type 2Vestibular schwannomaNF2Dominant
Nevoid basal cell carcinoma syndromeBasal cell carcinoma, medulloblastomaPTCHDominant
Peutz-Jeghers syndromeIntestinal cancers, ovarian carcinoma, pancreatic carcinomaSTK11Dominant
RetinoblastomaOsteosarcoma, retinoblastomaRB1Dominant
Tuberous sclerosisHamartoma, renal angiomyolipoma, renal cell carcinomaTSC1/TSC2Dominant
von Hippel-Lindau syndromeHemangioblastoma, pheochromocytoma, renal cell carcinoma, retinal and central nervous system tumorsVHLDominant
WAGR syndromeGonadoblastoma, Wilms tumorWT1Dominant
Wilms tumor syndromeWilms tumorWT1Dominant
Xeroderma pigmentosumLeukemia, melanomaXPA, XPB, XPC, XPD, XPE, XPF, XPG, POLHRecessive

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.
  1. 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.
  2. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST) enzymes, NAD(P)H:quinone oxidoreductase-1 (NQO1) enzyme, 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.[95] A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity.[95] 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 childhood cancer survivors at risk.[96] 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.
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], DCOG) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors.[97]
All pediatric cancer survivor health screening 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.[96,97]
The COG Guidelines for malignant SNs indicate that certain high-risk populations of childhood cancer survivors merit heightened surveillance because of predisposing host, behavioral, or therapeutic factors.[96]
  • Screening for leukemia: t-MDS/AML usually manifests within 10 years after exposure. Recommendations include monitoring with history and physical examination for signs and symptoms of pancytopenia for 10 years after exposure to alkylating agents or topoisomerase II inhibitors.
  • Screening after radiation exposure: Most other SNs are associated with radiation exposure and usually manifest more than 10 years after 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 are as follows:
    • Screening for early-onset skin cancer: Annual dermatological exam focusing on skin lesions and pigmented nevi in the radiation field is recommended. Survivors are counseled about the following:
      • Increased risk of skin cancer.
      • Potential exacerbation of risk through tanning.
      • Benefits of adhering to behaviors to protect the skin from excessive ultraviolet radiation exposure.
    • Screening for early-onset breast cancer: Because outcome after breast cancer is directly linked to stage at diagnosis, close surveillance resulting in early diagnosis may confer survival advantage.[98] Several pediatric cancer groups have endorsed the recommendation for early (before population breast cancer screening) initiation of breast cancer surveillance using mammography, breast magnetic resonance imaging (MRI), or both imaging modalities in young women who were treated with chest irradiation.[99]
      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. On the basis of research among young women with inherited susceptibility to breast cancer, dual-imaging modalities may enhance early detection related to the higher sensitivity of MRI in detecting lesions in premenopausal dense breasts and the superiority of mammography in identifying ductal carcinoma in situ;[100-102] therefore, the American Cancer Society recommends including adjunct screening with MRI.[103] The high sensitivity and specificity in detecting early-stage lesions with dual-imaging surveillance is offset by a substantial rate of additional investigations attributable to false-positive results.[102]
      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.[104-106] 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 recommends the following for females who received a radiation dose of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields:
      • Monthly breast self-examination beginning at puberty.
      • Annual clinical breast examinations beginning at puberty until age 25 years.
      • A clinical breast examination every 6 months, with annual mammograms and MRIs beginning 8 years after radiation therapy or at age 25 years (whichever occurs later).
      The risk of breast cancer in patients who received less than 20 Gy of radiation with potential impact to the breast is of a lower magnitude compared with those who received more than 20 Gy. Monitoring of patients treated with less than 20 Gy of radiation with potential impact to the breast is determined on an individual basis after a discussion with the provider regarding the benefits and risk/harms of screening. If a decision is made to screen, the recommendations for women exposed to more than 20 Gy are used.
    • 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) includes colonoscopy every 5 years beginning at age 35 years or 10 years after radiation therapy (whichever occurs later).[81]
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