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% CI, 13.9–16.6). The Childhood Cancer Survivor Study (CCSS) reported the following 30-year cumulative incidence rates:
- All SNs—20.5% (95% confidence interval [CI], 19.1%–21.8%).
- SNs with malignant histologies (excluding nonmelanoma skin cancer [NMSC])—7.9% (95% CI, 7.2%–8.5%).
- NMSC—9.1% (95% CI, 8.1%–10.1%).
- 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.
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.[3,4]
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.
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.[6-9]
- 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.
- 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:
- 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: 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. 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 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:
- Radiation exposure at a younger age.
- High total dose of radiation.
- Longer period of follow-up after 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).[2,8,15-18]
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.
Some of the well-established solid SNs include the following:
- Breast cancer: 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).[6,22] 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 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. This finding is 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.[27-29]
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.[30,31]
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. Lower radiation doses used to treat cancer metastatic to the lungs (e.g., Wilms tumor, sarcoma) that expose the breast tissues also appear to increase the risk of breast cancer. 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).
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 previous exposure to radiation or anthracyclines.
- Thyroid cancer: Thyroid cancer is observed after the following:[2,6,33]
- Neck radiation for HL, ALL, and brain tumors.
- Iodine I 131 metaiodobenzylguanidine (131I-mIBG) treatment for neuroblastoma.
- TBI for hematopoietic stem cell transplantation.
- 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.[35,37]
- 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.[7,38] SIRs reported for subsequent CNS neoplasms after treatment for childhood cancer range from 8.1 to 52.3 across studies.
- 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.[41-43]
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.[45,46] 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.[48-50]
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.
- Skin cancer:
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:
- 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 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 (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 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.
- 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.[61,62]
Underlying genetic predisposition may also play a role because rare cases of renal carcinoma have been observed in children with tuberous sclerosis.
Subsequent Neoplasms and Genetic Susceptibility
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.[63,64]
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.
|Syndrome||Major Tumor Types||Affected Gene||Mode of Inheritance|
|AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation.|
|aAdapted from Strahm et al.|
|bDominant in a fraction of patients, spontaneous mutations can occur.|
|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|
|Diamond-Blackfan anemia||Colon cancer, osteogenic sarcoma, AML/MDS||RPS19 and other RP genes||Dominant, spontaneousb|
|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|
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.
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 childhood cancer survivors 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.
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], Dutch Children's Oncology Group) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors.
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.[67,68]
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.
- 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. 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 radiation.
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; therefore, the American Cancer Society recommends including adjunct screening with 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.[72-74] 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 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 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 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 (whichever occurs later).
- 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:
- Mertens AC, Liu Q, Neglia JP, et al.: Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 100 (19): 1368-79, 2008. [PUBMED Abstract]
- Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract]
- Armstrong GT, Liu W, Leisenring W, et al.: Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 29 (22): 3056-64, 2011. [PUBMED Abstract]
- van Eggermond AM, Schaapveld M, Lugtenburg PJ, et al.: Risk of multiple primary malignancies following treatment of Hodgkin lymphoma. Blood 124 (3): 319-27; quiz 466, 2014. [PUBMED Abstract]
- Milano MT, Li H, Gail MH, et al.: Long-term survival among patients with Hodgkin's lymphoma who developed breast cancer: a population-based study. J Clin Oncol 28 (34): 5088-96, 2010. [PUBMED Abstract]
- Bhatia S, Yasui Y, Robison LL, et al.: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol 21 (23): 4386-94, 2003. [PUBMED Abstract]
- Bhatia S, Sather HN, Pabustan OB, et al.: Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 99 (12): 4257-64, 2002. [PUBMED Abstract]
- Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007. [PUBMED Abstract]
- Bhatia S, Krailo MD, Chen Z, et al.: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 109 (1): 46-51, 2007. [PUBMED Abstract]
- Berger C, Trombert-Paviot B, Casagranda L, et al.: Second malignant neoplasms following childhood cancer: a study of a recent cohort (1987-2004) from the childhood cancer registry of the Rhône-Alpes region (ARCERRA) in France. Pediatr Hematol Oncol 28 (5): 364-79, 2011. [PUBMED Abstract]
- Nottage K, Lanctot J, Li Z, et al.: Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study. Blood 117 (23): 6315-8, 2011. [PUBMED Abstract]
- Tefferi A, Vardiman JW: Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22 (1): 14-22, 2008. [PUBMED Abstract]
- Thirman MJ, Larson RA: Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 10 (2): 293-320, 1996. [PUBMED Abstract]
- Pedersen-Bjergaard J, Philip P: Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II. Blood 78 (4): 1147-8, 1991. [PUBMED Abstract]
- Bassal M, Mertens AC, Taylor L, et al.: Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 24 (3): 476-83, 2006. [PUBMED Abstract]
- Neglia JP, Robison LL, Stovall M, et al.: New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 98 (21): 1528-37, 2006. [PUBMED Abstract]
- Perkins JL, Liu Y, Mitby PA, et al.: Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol 23 (16): 3733-41, 2005. [PUBMED Abstract]
- Boukheris H, Stovall M, Gilbert ES, et al.: Risk of salivary gland cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 85 (3): 776-83, 2013. [PUBMED Abstract]
- Ronckers CM, Sigurdson AJ, Stovall M, et al.: Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat Res 166 (4): 618-28, 2006. [PUBMED Abstract]
- Majhail NS, Brazauskas R, Rizzo JD, et al.: Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood 117 (1): 316-22, 2011. [PUBMED Abstract]
- Bhatia S, Sklar C: Second cancers in survivors of childhood cancer. Nat Rev Cancer 2 (2): 124-32, 2002. [PUBMED Abstract]
- Kenney LB, Yasui Y, Inskip PD, et al.: Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med 141 (8): 590-7, 2004. [PUBMED Abstract]
- Travis LB, Hill D, Dores GM, et al.: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 97 (19): 1428-37, 2005. [PUBMED Abstract]
- O'Brien MM, Donaldson SS, Balise RR, et al.: Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol 28 (7): 1232-9, 2010. [PUBMED Abstract]
- Inskip PD, Robison LL, Stovall M, et al.: Radiation dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol 27 (24): 3901-7, 2009. [PUBMED Abstract]
- Dores GM, Anderson WF, Beane Freeman LE, et al.: Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy. Br J Cancer 103 (7): 1081-4, 2010. [PUBMED Abstract]
- Castiglioni F, Terenziani M, Carcangiu ML, et al.: Radiation effects on development of HER2-positive breast carcinomas. Clin Cancer Res 13 (1): 46-51, 2007. [PUBMED Abstract]
- Gaffney DK, Hemmersmeier J, Holden J, et al.: Breast cancer after mantle irradiation for Hodgkin's disease: correlation of clinical, pathologic, and molecular features including loss of heterozygosity at BRCA1 and BRCA2. Int J Radiat Oncol Biol Phys 49 (2): 539-46, 2001. [PUBMED Abstract]
- Janov AJ, Tulecke M, O'Neill A, et al.: Clinical and pathologic features of breast cancers in women treated for Hodgkin's disease: a case-control study. Breast J 7 (1): 46-52, 2001 Jan-Feb. [PUBMED Abstract]
- Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003. [PUBMED Abstract]
- van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95 (13): 971-80, 2003. [PUBMED Abstract]
- Moskowitz CS, Chou JF, Wolden SL, et al.: Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol 32 (21): 2217-23, 2014. [PUBMED Abstract]
- van Santen HM, Tytgat GA, van de Wetering MD, et al.: Differentiated thyroid carcinoma after 131I-MIBG treatment for neuroblastoma during childhood: description of the first two cases. Thyroid 22 (6): 643-6, 2012. [PUBMED Abstract]
- Sklar C, Whitton J, Mertens A, et al.: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85 (9): 3227-32, 2000. [PUBMED Abstract]
- Bhatti P, Veiga LH, Ronckers CM, et al.: Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 174 (6): 741-52, 2010. [PUBMED Abstract]
- Michaelson EM, Chen YH, Silver B, et al.: Thyroid malignancies in survivors of Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 88 (3): 636-41, 2014. [PUBMED Abstract]
- Sigurdson AJ, Ronckers CM, Mertens AC, et al.: Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365 (9476): 2014-23, 2005 Jun 11-17. [PUBMED Abstract]
- Neglia JP, Friedman DL, Yasui Y, et al.: Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 93 (8): 618-29, 2001. [PUBMED Abstract]
- Bowers DC, Nathan PC, Constine L, et al.: Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol 14 (8): e321-8, 2013. [PUBMED Abstract]
- Taylor AJ, Little MP, Winter DL, et al.: Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol 28 (36): 5287-93, 2010. [PUBMED Abstract]
- Faraci M, Morana G, Bagnasco F, et al.: Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: a cross sectional, single center study. Pediatr Blood Cancer 57 (2): 240-6, 2011. [PUBMED Abstract]
- Vinchon M, Leblond P, Caron S, et al.: Radiation-induced tumors in children irradiated for brain tumor: a longitudinal study. Childs Nerv Syst 27 (3): 445-53, 2011. [PUBMED Abstract]
- Koike T, Yanagimachi N, Ishiguro H, et al.: High incidence of radiation-induced cavernous hemangioma in long-term survivors who underwent hematopoietic stem cell transplantation with radiation therapy during childhood or adolescence. Biol Blood Marrow Transplant 18 (7): 1090-8, 2012. [PUBMED Abstract]
- Tucker MA, D'Angio GJ, Boice JD Jr, et al.: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317 (10): 588-93, 1987. [PUBMED Abstract]
- Hawkins MM, Wilson LM, Burton HS, et al.: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88 (5): 270-8, 1996. [PUBMED Abstract]
- Le Vu B, de Vathaire F, Shamsaldin A, et al.: Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int J Cancer 77 (3): 370-7, 1998. [PUBMED Abstract]
- Henderson TO, Whitton J, Stovall M, et al.: Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 99 (4): 300-8, 2007. [PUBMED Abstract]
- Shinohara ET, DeWees T, Perkins SM: Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 61 (1): 116-9, 2014. [PUBMED Abstract]
- MacCarthy A, Bayne AM, Brownbill PA, et al.: Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 108 (12): 2455-63, 2013. [PUBMED Abstract]
- Yu CL, Tucker MA, Abramson DH, et al.: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst 101 (8): 581-91, 2009. [PUBMED Abstract]
- Henderson TO, Rajaraman P, Stovall M, et al.: Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys 84 (1): 224-30, 2012. [PUBMED Abstract]
- Watt TC, Inskip PD, Stratton K, et al.: Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 104 (16): 1240-50, 2012. [PUBMED Abstract]
- Braam KI, Overbeek A, Kaspers GJ, et al.: Malignant melanoma as second malignant neoplasm in long-term childhood cancer survivors: a systematic review. Pediatr Blood Cancer 58 (5): 665-74, 2012. [PUBMED Abstract]
- Pappo AS, Armstrong GT, Liu W, et al.: Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Pediatr Blood Cancer 60 (3): 461-6, 2013. [PUBMED Abstract]
- van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 87 (20): 1530-7, 1995. [PUBMED Abstract]
- Tukenova M, Diallo I, Anderson H, et al.: Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study. Int J Radiat Oncol Biol Phys 82 (3): e383-90, 2012. [PUBMED Abstract]
- Henderson TO, Oeffinger KC, Whitton J, et al.: Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med 156 (11): 757-66, W-260, 2012. [PUBMED Abstract]
- Nottage K, McFarlane J, Krasin MJ, et al.: Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 30 (20): 2552-8, 2012. [PUBMED Abstract]
- Wilson CL, Ness KK, Neglia JP, et al.: Renal carcinoma after childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 105 (7): 504-8, 2013. [PUBMED Abstract]
- Fleitz JM, Wootton-Gorges SL, Wyatt-Ashmead J, et al.: Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood. Pediatr Radiol 33 (8): 540-5, 2003. [PUBMED Abstract]
- Hedgepeth RC, Zhou M, Ross J: Rapid development of metastatic Xp11 translocation renal cell carcinoma in a girl treated for neuroblastoma. J Pediatr Hematol Oncol 31 (8): 602-4, 2009. [PUBMED Abstract]
- Argani P, Laé M, Ballard ET, et al.: Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 24 (10): 1529-34, 2006. [PUBMED Abstract]
- Andersson A, Enblad G, Tavelin B, et al.: Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma. Br J Cancer 98 (5): 1001-5, 2008. [PUBMED Abstract]
- Hisada M, Garber JE, Fung CY, et al.: Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 90 (8): 606-11, 1998. [PUBMED Abstract]
- Strahm B, Malkin D: Hereditary cancer predisposition in children: genetic basis and clinical implications. Int J Cancer 119 (9): 2001-6, 2006. [PUBMED Abstract]
- Collins A, Harrington V: Repair of oxidative DNA damage: assessing its contribution to cancer prevention. Mutagenesis 17 (6): 489-93, 2002. [PUBMED Abstract]
- Landier W, Bhatia S, Eshelman DA, et al.: Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22 (24): 4979-90, 2004. [PUBMED Abstract]
- Kremer LC, Mulder RL, Oeffinger KC, et al.: A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatr Blood Cancer 60 (4): 543-9, 2013. [PUBMED Abstract]
- Diller L, Medeiros Nancarrow C, Shaffer K, et al.: Breast cancer screening in women previously treated for Hodgkin's disease: a prospective cohort study. J Clin Oncol 20 (8): 2085-91, 2002. [PUBMED Abstract]
- Mulder RL, Kremer LC, Hudson MM, et al.: Recommendations for breast cancer surveillance for female survivors of childhood, adolescent, and young adult cancer given chest radiation: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 14 (13): e621-9, 2013. [PUBMED Abstract]
- Saslow D, Boetes C, Burke W, et al.: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57 (2): 75-89, 2007 Mar-Apr. [PUBMED Abstract]
- Berrington de Gonzalez A, Berg CD, Visvanathan K, et al.: Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers. J Natl Cancer Inst 101 (3): 205-9, 2009. [PUBMED Abstract]
- Young KC, Burch A, Oduko JM: Radiation doses received in the UK Breast Screening Programme in 2001 and 2002. Br J Radiol 78 (927): 207-18, 2005. [PUBMED Abstract]
- Spelic DC: Updated Trends in Mammography Dose and Image Quality. Silver Spring, Md: U.S. Food and Drug Administration, 2006. Available online. Last accessed October 27, 2014.