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

During the past five decades, dramatic progress has been made in the development of curative therapies for pediatric malignancies. More than 80% of children with cancer who have access to contemporary therapies are expected to survive into adulthood.[1] The therapies responsible for this survival can also produce adverse, long-term, health-related outcomes, referred to as late effects, which appear months to years after completion of cancer treatment.

Many approaches have been used to study the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have used a spectrum of resources, including data from the following:

High-quality data is needed to establish the occurrence of and risk profiles for late cancer treatment–related toxicity. The highest quality data typically comes from studies that report outcomes in survivors who have undergone medical assessments that provide well-characterized clinical statuses, treatment exposures, and specific late effects. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings.

Prevalence of Late Effects in Childhood Cancer Survivors

Late effects are common in adults who have survived childhood cancer. Their prevalence increases as time from cancer diagnosis elapses. Multi-institutional and population-based studies have shown excess risk of hospital-related morbidity among childhood and young adult cancer survivors compared with age- and sex-matched controls, with some evidence that this risk is disproportionately high among survivors of racial and ethnic minority populations.[3,9-13]

Among adults who were treated for cancer during childhood, late effects contribute to a high burden of morbidity. Research has shown the following:[4,7,14-18]

• 60% to more than 90% of survivors develop one or more chronic health conditions.
• 20% to 80% of survivors experience severe or life-threatening complications during adulthood.
• Morbidity accumulation is accelerated in young adult survivors of childhood cancer, compared with that of siblings and the general population. Accumulation of chronic diseases predicts risk of early mortality.[19]

The St. Jude Life (SJLIFE) cohort study aimed to describe the cumulative burden of cancer therapy using the cumulative burden metric, which incorporates multiple health conditions and recurrent events into a single metric that takes into account competing risks. By age 50 years, survivors in this cohort experienced an average of 17.1 chronic health conditions, 4.7 of which were severe/disabling, life threatening, or fatal.[16] This finding contrasts with the cumulative burden in matched community controls, who experienced 9.2 chronic health conditions, 2.3 of which were severe/disabling, life threatening, or fatal (see Figure 1).[16]

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SJLIFE cohort study investigators compared the cumulative burden of chronic health conditions among 4,612 adolescent and young adult survivors at the ages of 18 years (the time of transition from pediatric to adult health care systems) and 26 years (the time of transition from family to individual health insurance plans) with that of 625 controls.[20]

• Survivors at the age of 18 years experienced an average of 22.3 disabling conditions per 100 individuals versus 3.5 in controls, and 128.7 lower-severity conditions (at risk of progressing to higher-grade disabling conditions) versus 12.4 in controls.
• Survivors at the age of 26 years experienced an average of 40.3 disabling conditions per 100 individuals versus 5.7 in controls, and 240.5 lower-severity conditions versus 51.3 in controls.
• The cumulative burden of disabling, disease-specific conditions at the ages of 18 and 26 years was most notable for survivors of bone tumors (musculoskeletal: 99.9 and 121.70, respectively), soft tissue sarcomas (musculoskeletal: 49.5 and 54.1, respectively), and central nervous system (CNS) tumors (neurological: 24.7 and 36.8, respectively).
• The cumulative burden of lower-severity conditions (potentially amenable to intervention) at the ages of 18 and 26 years was most notable for neurological conditions across most cancer subgroups, with the highest cumulative burden in CNS tumor survivors (95.2 and 162.3, respectively).
• These findings highlight the importance of optimizing access to health care and health insurance as survivors age and can no longer participate in pediatric health care systems.

The variability in prevalence is related to differences in the following:

• Age and follow-up time of the cohorts studied.
• Methods and consistency of assessment (e.g., self-reported vs. risk-based medical evaluations).
• Treatment intensity and treatment era.

Childhood Cancer Survivor Study (CCSS) investigators demonstrated that the elevated risk of morbidity and mortality among aging survivors in the cohort increases beyond the fourth decade of life. By age 50 years, the cumulative incidence of a self-reported severe, disabling, life-threatening, or fatal health condition was 53.6% among survivors, compared with 19.8% among a sibling control group. Among survivors who reached age 35 years without a previous severe, disabling, life-threatening, or fatal health condition, 25.9% experienced a new grade 3 to grade 5 health condition within 10 years, compared with 6.0% of healthy siblings.[4]

The presence of serious, disabling, and life-threatening chronic health conditions adversely affects the health status of aging survivors. The greatest impact is on functional impairment and activity limitations. Predictably, chronic health conditions have been reported to contribute to a higher prevalence of emotional distress symptoms in adult survivors than in population controls.[21] Female survivors demonstrate a steeper trajectory of age-dependent decline in health status than do male survivors.[22] The even-higher prevalence of late effects among cohorts evaluated by clinical assessments is related to the subclinical and undiagnosed conditions detected by screening and surveillance measures.[7]

CCSS investigators also evaluated the impact of race and ethnicity on late outcomes. The study compared late mortality, subsequent neoplasms, and chronic health conditions in Hispanic (n = 750) and non-Hispanic Black (n = 694) participants with those in non-Hispanic White participants (n = 12,397).[23] The following results were observed:

• Cancer treatment did not account for disparities in mortality, chronic health conditions, or subsequent neoplasms observed among the groups.
• Differences in socioeconomic status and cardiovascular risk factors affected risk. All-cause mortality was higher among non-Hispanic Black participants than among other groups, but this difference disappeared after adjustment for socioeconomic status.
• Risk of developing diabetes was elevated among racial and ethnic minority groups even after adjustment for socioeconomic and obesity status.
• Non-Hispanic Black patients had a higher likelihood of reporting cardiac conditions, but this risk diminished after adjusting for cardiovascular risk factors.
• Nonmelanoma skin cancer was not reported by non-Hispanic Black participants, a finding that has been replicated by other studies.[24] Hispanic participants had a lower risk of nonmelanoma skin cancer than non-Hispanic White participants.

Recognition of late effects, concurrent with advances in cancer biology, radiological sciences, and supportive care, has resulted in a change in the prevalence and spectrum of treatment effects. In an effort to reduce and prevent late effects, contemporary therapy for most pediatric malignancies has evolved to a risk-adapted approach that is assigned on the basis of a variety of clinical, biological, and sometimes genetic factors.

The CCSS reported that with decreased cumulative dose and frequency of therapeutic radiation from 1970 to 1999, survivors have experienced a significant decrease in risk of subsequent neoplasms.[25]

• With the exception of survivors requiring intensive multimodality therapy for refractory/relapsed malignancies, life-threatening treatment effects are relatively uncommon after contemporary therapy in early follow-up (up to 10 years after diagnosis).
• However, survivors still frequently experience life-altering morbidity related to effects of cancer treatment on endocrine, reproductive, musculoskeletal, and neurological function.

A CCSS investigation examined temporal patterns in the cumulative incidence of severe to fatal chronic health conditions among survivors treated from 1970 to 1999.[26]

• The 20-year cumulative incidence of at least one grade 3 to 5 chronic condition decreased significantly, from 33.2% for survivors diagnosed between 1970 and 1979, to 29.3% for those diagnosed between 1980 and 1989, to 27.5% for those diagnosed between 1990 and 1999, compared with a 4.6% incidence in a sibling cohort.
• The overall decrease in incidence of chronic conditions across the three treatment decades was, in part, because of a substantial reduction of endocrinopathies, subsequent malignant neoplasms (SMNs), musculoskeletal conditions, and gastrointestinal conditions, whereas the cumulative incidence of hearing loss increased during this time.
• Declines in morbidity were not uniform across the diagnosis groups or condition types because of differences in treatment and survival patterns over time. For more information, see Figure 2.
• Despite declines in chronic health conditions over time, self-reported health status has not improved in more recent treatment eras. This finding may be because of the survival of children with higher-risk disease who would have previously died of cancer, or an enhanced awareness of and surveillance for late effects among more recently treated survivors.[27]

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Monitoring for Late Effects

Recognition of both acute and late modality–specific toxicity has motivated investigations evaluating the pathophysiology and prognostic factors for cancer treatment–related effects. Consequently, the results of late effects research have played an important role in the following areas:

• Changing pediatric cancer therapeutic approaches to reduce treatment-related mortality among survivors treated in more recent eras.[46]
• The development of risk counseling and health screening recommendations for long-term survivors by identifying the clinical and treatment characteristics of those at highest risk of therapy-related complications.[47]

The common late effects of pediatric cancer encompass several broad domains, including the following:

• Growth and development.
• Organ function.
• Reproductive capacity and health of offspring.
• Secondary carcinogenesis.
• Psychosocial sequelae related to the primary cancer, its treatment, or maladjustment associated with the cancer experience.

Late sequelae of therapy for childhood cancer can be anticipated based on therapeutic exposures, but the magnitude of risk and the manifestations in an individual patient are influenced by numerous factors. Multiple factors should be considered in the risk assessment for a given late effect (see Figure 3).[48]

Cancer-related factors:

• Organs or tissues affected by the cancer.
• Direct tissue effects.
• Cancer-induced organ dysfunction or other tissue effects.

Treatment-related factors:

• Radiation therapy: Total dose, fraction size, organ or tissue volume exposed.
• Chemotherapy: Agent type, dose-intensity, cumulative dose, schedule.
• Surgery: Technique, site, consequential organ dysfunction.
• HSCT.
• Combined-modality effects (therapeutic interactions).
• Blood product transfusion.
• Chronic graft-versus-host disease.

Host-related factors:

• Sex.
• Genetic predisposition.
• Premorbid, comorbid, posttreatment health states and exposures.
• Developmental status (age).
• Time from diagnosis/therapy.
• Inherent tissue sensitivities and capacity for normal tissue repair.
• Hormonal milieu.
• Socioeconomic status.
• Health habits.

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References

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31. Byrne J, Schmidtmann I, Rashid H, et al.: Impact of era of diagnosis on cause-specific late mortality among 77 423 five-year European survivors of childhood and adolescent cancer: The PanCareSurFup consortium. Int J Cancer 150 (3): 406-419, 2022. [PUBMED Abstract]
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33. Dixon SB, Liu Q, Chow EJ, et al.: Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet 401 (10386): 1447-1457, 2023. [PUBMED Abstract]
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47. 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]
48. Dixon SB, Bjornard KL, Alberts NM, et al.: Factors influencing risk-based care of the childhood cancer survivor in the 21st century. CA Cancer J Clin 68 (2): 133-152, 2018. [PUBMED Abstract]
49. Kirchhoff AC, Leisenring W, Krull KR, et al.: Unemployment among adult survivors of childhood cancer: a report from the childhood cancer survivor study. Med Care 48 (11): 1015-25, 2010. [PUBMED Abstract]
50. Mitby PA, Robison LL, Whitton JA, et al.: Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 97 (4): 1115-26, 2003. [PUBMED Abstract]
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57. Mueller EL, Park ER, Kirchhoff AC, et al.: Insurance, chronic health conditions, and utilization of primary and specialty outpatient services: a Childhood Cancer Survivor Study report. J Cancer Surviv 12 (5): 639-646, 2018. [PUBMED Abstract]
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59. Casillas J, Oeffinger KC, Hudson MM, et al.: Identifying Predictors of Longitudinal Decline in the Level of Medical Care Received by Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Health Serv Res 50 (4): 1021-42, 2015. [PUBMED Abstract]
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61. Casillas J, Castellino SM, Hudson MM, et al.: Impact of insurance type on survivor-focused and general preventive health care utilization in adult survivors of childhood cancer: the Childhood Cancer Survivor Study (CCSS). Cancer 117 (9): 1966-75, 2011. [PUBMED Abstract]
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Subsequent neoplasms (SNs) are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. SNs may be benign or malignant. Childhood cancer survivors have increased risks of developing SNs that are multifactorial in etiology and vary according to the following:

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]

This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population.[2]

Several studies have described the excess risk of SNs.[3,4]

Evidence (excess risk of SNs):

The incidence and type of SNs depend on the following:

Unique associations with specific therapeutic exposures have resulted in the classification of SNs into the following two distinct groups:

Therapy-Related Solid SNs

Therapy-related solid SNs represent 80% of all SNs, 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:[4,13]

• Younger age at time of radiation exposure.
• 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) (see Figure 4).[4,13,22,23]

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Solid SNs in childhood cancer survivors most commonly involve the following:[4,13,22,24-27]

• Breast.
• Thyroid.
• CNS.
• Bone and soft tissue.
• Skin.

With longer follow-up of adult survivors of childhood cancer cohorts, epithelial neoplasms have been observed in the following:[13,28]

• Lung.
• Gastrointestinal tract.
• Oral cavity.
• Genitourinary system.
• Kidney.

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.[4,10,29]

Subsequent neoplasms after hematopoietic stem cell transplant (HSCT)

Recipients of HSCT are treated with high-dose chemotherapy and, often, TBI, which makes their risk of SNs unique from that of the general oncology population.

• Among 4,318 first-time allogeneic HSCT recipients treated for AML and chronic myeloid leukemia between 1986 and 2005, and conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), 66 solid cancers were reported at a median of 6 years post-HSCT.[30]
  • The cumulative incidence of new solid cancers was 0.9% at 5 years and 2.4% at 10 years and appears to be similar, regardless of exposure to radiation.
  • 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.
• A study of 4,905 1-year survivors of allogeneic HSCT who underwent transplant between 1969 and 2014 for malignant or nonmalignant diseases, and were followed for a median 12.5 years, demonstrated a strong effect of TBI dose and dose fractionation on risk of SNs.[31]
  • The 20-year cumulative incidence of SN after HSCT for individuals treated at younger than 20 years was 8.1%.
  • SN risk was highest in survivors exposed to high-dose, single-fraction TBI (6–12 Gy) or very high-dose fractionated TBI (14.4–17.5 Gy).
  • With low-dose TBI (2–4.5 Gy), the SN risk was comparable to the risk with chemotherapy alone, although it was still twofold higher than in the general population.
  • Among individuals treated at younger than 20 years, the number of SNs was 12.5-fold higher than expected in the general population, and the excess absolute risk was 10.6 per 1,000 person-years. Survivors treated with HSCT at this young age were more likely to develop SNs than were survivors who were treated after age 50 years (HR, 2.3).

Some well-established solid SNs are described in the following sections.

Breast cancer

Female survivors of childhood, adolescent, and young adult cancer treated with radiation therapy to fields including the chest are at increased risk of developing breast cancer.

• The cumulative breast cancer incidence ranges from 8% to 20% by age 40 to 45 years among childhood cancer survivors and is as high as 35% by age 50 years in Hodgkin lymphoma survivors, comparable to that observed among BRCA gene variant carriers.[17,32-35]
• Radiation dose and volume of breast exposed are important factors affecting risk. Specific chemotherapeutic agents, particularly alkylating agents and anthracyclines, may affect risk as well.[32,34,36]

Evidence (excess risk of breast cancer):

1. Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[17,33] The following has been observed in female survivors of childhood Hodgkin lymphoma:
   • Excess risk of breast cancer has been reported in survivors treated with high-dose, extended-volume radiation at age 30 years or younger.[37]
   • Data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[38]
   • Patients who received limited volume supradiaphragmatic radiation therapy (excluding the axillae) had a significantly lower risk of subsequent breast cancers than patients who received full mantle-field radiation therapy.[36]
   • For patients treated with radiation therapy to the chest before age 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years.[17]
   • 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).[39]
   • Treatment 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.[36,40,41]
   • The observed number of invasive breast cancer cases among young (aged <30 years) survivors, compared with what is expected in the general population, has decreased over recent treatment eras (1970s SIR, 55.0 vs. 1990s SIR, 14.3).[35]
2. The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized 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).[34]
   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.[42]
      • 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).
3. An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[43]
   • Doxorubicin was associated with a dose-dependent increase of subsequent breast cancer risk (HR per 100 mg/m2, 1.24; 95% CI, 1.18–1.31).
   • There was a more-than-twofold increased risk for survivors treated with 200 mg/m2 or higher cumulative doxorubicin dose, compared with no doxorubicin (HR, 2.50 for 200–299 mg/m2; HR, 2.33 for 300–399 mg/m2; HR, 2.78 for ≥400 mg/m2).
   • The associations were not statistically significant for daunorubicin, whereas epirubicin was associated with increased subsequent breast cancer risk (exposure yes vs. no: HR, 3.25; 95% CI, 1.59–6.63).
   • The HRs per 100 mg/m2 of doxorubicin were 1.11 (95% CI, 1.02–1.21) for patients treated with chest radiation therapy and 1.26 (95% CI, 1.17–1.36) for patients who did not receive chest radiation therapy.
4. The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[32]
   • For the study group, the median age of first cancer diagnosis was 15 years and the median age at breast cancer diagnosis was 39 years.
   • The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5–6.5) and was similar for estrogen receptor–positive and estrogen receptor–negative cancers.
   • The OR per 10 Gy to the breast was higher for women who received ovarian doses less than 1 Gy (OR, 6.8; 95% CI, 3.9–12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0–6.4).
   • The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09–1.39; P < .01 for trend).
   • There was an additive interaction between radiation therapy and anthracycline treatment. The OR was 19.1 (95% CI, 7.6–48.0) for the combined association of anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) versus 9.6 (95% CI, 4.4–20.7) without anthracycline therapy.
5. Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.
   1. The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[24]
      • In women who received neither chest radiation nor anthracyclines, the cumulative incidence of breast cancer was 2% at age 35 years and 15% at age 50 years. For women who were treated with 250 mg/m2 or higher of anthracyclines, the rates were 7% at age 35 years and 46% at age 50 years.
      • Anthracycline doses of 250 mg/m2 or higher remained significantly associated with increased risk of breast cancer in models, excluding survivors with cancer predisposition gene variants, chest radiation of 10 Gy or higher, or both.
      • Breast cancers detected by imaging and/or prophylactic mastectomy were more likely to be in situ carcinomas, be smaller masses, have no lymph node involvement, and be treated without chemotherapy, compared with breast cancers detected by physical findings.
      • Dual imaging with mammography and breast magnetic resonance imaging (MRI) in this cohort was a sensitive and specific approach to identify breast cancers that require less aggressive therapy than breast cancers detected by physical findings.
   2. A CCSS investigation examined the breast cancer risk of 3,768 female participants who did not receive chest radiation.[44]
      • A fourfold excess risk (SIR, 4.0; 95% CI, 3.0–5.3) of breast cancer was observed compared with rates in the general population.
      • Breast cancer risk was highest among survivors of sarcoma (SIR, 5.3; 95% CI, 3.6–7.8) and leukemia (SIR, 4.1; 95% CI, 2.4–6.9), 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.
   3. CCSS investigators also examined SN risk among 7,448 participants who were treated with chemotherapy only.[12]
      • Breast cancer incidence was 4.6-fold greater than what would be expected in the general population (SIR, 4.6; 95% CI, 3.5–6.0).
      • A linear dose response was demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95% CI, 1.2–1.6).
   4. DCOG-LATER investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[13]
      • 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.
6. A SEER Program–based study evaluated trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer among women who were treated with radiation therapy for Hodgkin lymphoma before age 30 years and diagnosed with a subsequent breast cancer between 1990 and 2016.[45]
   • Overall, 263 (89.2%) women presented with unilateral breast cancer, 50 of whom (19.0%) underwent breast-conserving surgery and 213 of whom (81.0%) underwent mastectomy (40.5% bilateral).
   • The 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% (95% CI, 5.6%–15.4%), increasing to 20.2% (95% CI, 13.7%–29.2%) at 10 years and 29.9% (95% CI, 20.8%–41.9%) at 15 years. This finding underscores the importance of ongoing breast cancer surveillance and consideration of prophylactic mastectomy.

Breast cancer risk varies among childhood cancer survivors who are treated with chest radiation therapy, and the risk is based on multiple clinical factors. The first personalized breast cancer risk prediction model was developed and validated using multinational cohorts of female 5-year cancer survivors who were diagnosed at younger than 21 years and treated with chest irradiation (n = 2,147). The model includes current age, chest radiation field, whether chest radiation was delivered within 1 year of menarche, anthracycline exposure, age of menopause, and history of a first-degree relative with breast cancer. The model is available as an online risk calculator.[46]

Subsequent versus de novo breast cancer

Several studies have investigated the clinical characteristics of subsequent breast cancers arising in women treated with radiation therapy for childhood cancer.[47-51]

• In one population-based study, radiation-induced breast cancer was noted 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 Hodgkin lymphoma survivors, compared with women who had sporadic breast cancer.[47]
• Other studies have observed a higher proportion of more histologically aggressive subtypes (e.g., triple-negative breast cancer) than age-matched sporadic invasive cancers.[48,49]
• These findings are in contrast to other smaller, hospital-based, case-control studies of breast cancer among Hodgkin lymphoma 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 a significant difference in overall risk of high-grade versus low-grade tumors.[50,51]
• A study using SEER Program data evaluated the clinicopathological features of 321 breast cancers diagnosed in 257 women (median age, 22 years; range, 18–26 years at Hodgkin lymphoma diagnosis) who were previously treated with radiation for Hodgkin lymphoma.[52]
  • Women who developed breast cancer after radiation for Hodgkin lymphoma were younger than women diagnosed with breast cancer without a prior malignancy (43 vs. 60 years) and were less likely to present with ductal carcinoma in situ (0.4% vs. 14.9%).
  • Radiation was not associated with poorer biological features, compared with breast cancers diagnosed in similarly aged women with no prior malignancy. However, higher proportions of upper outer quadrant and smaller tumors (≤2 cm) were found.
  • Most tumors in survivors of Hodgkin lymphoma were hormone sensitive (nearly two-thirds were estrogen receptor–positive/HER2-negative). This finding suggests that endocrine prevention may be an option for this high-risk population.

Mortality after subsequent breast cancer

In a study of female participants in the CCSS who were subsequently diagnosed with breast cancer (n = 274) and matched to a control group of women (n = 1,095) with de novo breast cancer, the following was observed:[53]

• Survivors of childhood cancer were found to have elevated mortality rates (HR, 2.2; 95% CI, 1.7–3.0), even after adjusting for breast cancer treatment.
• Survivors were five times more likely to die from other health-related causes, including other SMNs and cardiovascular or pulmonary disease (HR, 5.5; 95% CI, 3.4–9.0).
• The cumulative incidence of a second asynchronous breast cancer was elevated significantly compared with controls (at 5 years, 8.0% among childhood cancer survivors vs. 2.7% among controls; P < .001).

Although current evidence does not show 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. Those with more limited treatment options because of previous exposure to radiation or anthracyclines may especially benefit.

In support of surveillance, SJLIFE investigators observed that breast cancers detected by imaging and/or prophylactic mastectomy were more likely to be in situ carcinomas, be smaller masses (3.3 cm mean tumor size detected by physical examination vs. 1.1 cm detected by imaging), have no lymph node involvement, and be treated without chemotherapy, compared with breast cancers detected by physical findings.[24]

Investigators used data from the CCSS and two Cancer Intervention and Surveillance Modeling Network breast cancer simulation models to estimate the clinical benefits, harms, and cost-effectiveness of breast cancer screening among childhood cancer survivors who were previously treated with chest radiation.[54]

• Screening with mammography and MRI, as recommended in COG Long-Term Follow-Up guidelines, is projected to avert half of the expected breast cancer deaths among high-risk survivors.
• On an annual schedule, a survivor will have an average of 4 to 5 false-positive screening results and 1 to 2 benign biopsy results over the course of their lifetime.
• Because of the large survival benefits, the harm-benefit tradeoffs for survivors were found to be appropriate, resulting in more favorable harm-benefit ratios.

Another CCSS investigation quantified the association between temporal changes in cancer treatment over three decades and subsequent breast cancer risk.[35]

• The cumulative incidence of breast cancer was 8.1% (95% CI, 7.3%–9.0%) by age 45 years among 11,550 female survivors (median age, 34.2 years), representing a more than sixfold excess risk (SIR, 6.6; 95% CI, 6.1–7.2), compared with age-, sex-, and calendar year–matched controls.
• Concurrent with changes in therapy by decade, including reduced rates of chest and pelvic radiation therapy and increased rates of anthracycline chemotherapy exposure, and adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% for every 5 years of primary cancer diagnosis era (rate ratio, 0.82; 95% CI, 0.74–0.90). This finding was largely associated with the reduced rate of chest radiation therapy.

Thyroid cancer

Thyroid cancer is observed after the following:[12,23,55,56]

• Neck radiation therapy for Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and brain tumors.
• Iodine I 131-metaiodobenzylguanidine (131I-MIBG) treatment for neuroblastoma.
• TBI for HSCT.
• Chemotherapy only, without therapeutic radiation.

The 25-year cumulative incidence of thyroid cancer among survivors of childhood cancer is 0.5%.[13] The risk of thyroid cancer among childhood cancer survivors is more than tenfold higher than that of the general population (SIR, 10.5; 95% CI, 9.1–12).[4] Significant modifiers of the radiation-related risk of thyroid cancer include the following:[27,57]

• 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 10 Gy, with a leveling off between 10 Gy and 30 Gy, and a decline in the OR at higher doses, especially in children younger than 10 years at treatment, suggesting a cell killing effect of the target cells at higher doses.[23,27,58]

In a Dutch case-control study, childhood cancer survivors with subsequent thyroid cancer were more likely to present with smaller tumors and bilateral tumors than the general population. Treatment outcomes were similar between subsequent and sporadic thyroid cancers.[59]

For information about detecting thyroid nodules and thyroid cancer, see the Thyroid nodules section.

CNS tumors

Subsequent CNS tumors represent a spectrum of histological subtypes, from high-grade gliomas to benign meningiomas. The CCSS has reported briefer latency for gliomas than for meningiomas.[60] Accurate assessment of the prevalence of low-grade and benign lesions is challenging because of the variable opinions and practices related to neuroimaging versus symptom surveillance in long-term survivors treated with cranial irradiation. Therefore, the prevalence of these tumors is likely higher than proven.

Brain tumors develop after cranial irradiation for histologically distinct brain tumors or for management of disease among ALL or non-Hodgkin lymphoma patients.[61] SIRs reported for subsequent CNS neoplasms after treatment for childhood cancer range from 8.1 to 52.3 across studies.[23]

The risk of subsequent brain tumors demonstrates a linear relationship with radiation dose.[25,60,62]

• The risk of meningioma after radiation increases with radiation dose,[9,62] and in some studies is further potentiated with increased exposure to intrathecal methotrexate.[25] However, this finding has not been consistently replicated.[10]
• 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.[63-65]

The Dutch Long-Term Effects after Childhood Cancer (LATER) investigators have described the clinical characteristics of childhood cancer survivors who developed histologically confirmed meningiomas.[11]

• In 6,015 childhood cancer survivors from the LATER cohort, 1,551 of whom had prior cranial radiation therapy, 93 survivors developed meningiomas.
• Of these patients, 89 (95.7%) were treated with prior cranial radiation therapy. The median age at diagnosis was 31.8 years (range, 13.2–50.5 years).
• Thirty of the survivors presented with synchronous meningiomas, and 84 survivors presented with symptoms. Only 16% of the meningiomas were detected in late effects clinics.
• All survivors underwent surgery, and one-third (n = 31) of them also received radiation therapy. Twelve survivors had three or more surgeries for growth of residual tumor, recurrences, and new meningiomas. Although the extent of surgical resection was not described, the indications for radiation therapy during follow-up after surgical resection included residual tumor, recurrences, location, or new meningioma. During follow-up, 38 survivors (40.9%) developed new meningiomas, 22 (23.7%) had recurrences, and at least 4 died because of the meningioma.

Neurological sequelae associated with meningiomas can include seizures, auditory-vestibular-visual deficits, focal neurological dysfunction, and severe headaches.[9] Despite the well-established increased risk of subsequent CNS neoplasms among childhood cancer survivors treated with cranial irradiation and the growing recognition of associated morbidity, the current literature is insufficient to evaluate the potential harms and benefits of routine screening for these lesions.[66] The decision to initiate surveillance should be shared by the cancer survivor and health care provider after carefully considering the potential harms and benefits of surveillance for CNS neoplasms, such as meningioma.

Proton radiation therapy for pediatric medulloblastoma is associated with low rates of brain stem injury and secondary malignancies. The long-term effects were reported in 178 pediatric patients with medulloblastoma who were treated with surgery, proton radiation therapy, and chemotherapy between 2002 and 2016 (median follow-up, 9.3 years).[67]

• At 10 years, eight patients (4.5%) developed a secondary tumor (benign or malignant), with median follow up of 9.1 years. Three patients (1.7%) developed a secondary malignancy.
• In-field second malignancies were glioblastoma (n = 2), meningioma (n = 2), and high-grade glioma (n = 1). The other malignancies were one each of ovarian fibroma, plexiform fibromyxoma of the esophagus, and papillary thyroid carcinoma.
• Four patients developed brain stem injury at a median of 4.2 years. The 5-year cumulative incidence of brain stem injury was 1.1%, and the 10-year cumulative incidence was 1.9%.

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.[68-72]

• Radiation therapy is associated with a linear dose-response relationship.[73,74]
• After adjustment for radiation therapy, treatment with alkylating agents [13,62] and anthracyclines [75] have both been linked to sarcoma, with the risk increasing with cumulative drug exposure.[75]
• Soft tissue sarcomas can be of various histological subtypes, including nonrhabdomyosarcoma soft tissue sarcomas, rhabdomyosarcoma, malignant peripheral nerve sheath tumors, Ewing/primitive neuroectodermal tumors, and other rare tumor types.

Evidence (excess risk of bone and soft tissue tumors):

1. A nested case-control study included 228 cases and 228 matched controls within a cohort of 69,460 5-year survivors of childhood cancer. The study investigated the risks of subsequent primary bone cancer by different levels of cumulative radiation exposure and dose-response relationships according to different specific types of chemotherapy.[76]
   • Compared with unexposed bone tissue, the OR associated with bone tissue exposed to 1 to 4 Gy was 4.8-fold (95% CI, 1.2–19.6). The OR associated with bone tissue exposed to 5 to 9 Gy was 9.6-fold (95% CI, 2.4–37.4). The OR increased linearly with increasing doses of radiation (P_trend < .001), up to 78-fold (95% CI, 9.2–669.9) for doses of 40 Gy or higher.
   • For cumulative alkylating agent doses of 10,000 to 19,999 mg/m2 and 20,000 mg/m2 or higher, the radiation-adjusted ORs were 7.1 (95% CI, 2.2–22.8) and 8.3 (95% CI, 2.8–24.4), respectively. There were independent contributions from exposure to procarbazine, ifosfamide, or cyclophosphamide.
2. A population-based study of 69,460 5-year survivors of cancer diagnosed before age 20 years observed the following:[69,70]
   • 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.[69]
   • The observed excess numbers of subsequent primary bone cancer declined with both age and years from diagnosis.[69]
   • 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%.[70]
   • The median time from diagnosis to occurrence of a soft tissue sarcoma was 19 years.[70]
   • The most commonly observed soft tissue sarcomas were leiomyosarcoma, fibromatous neoplasms, and malignant peripheral nerve sheath tumors.[70]
   • 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.[70]
   • The 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).[70]
   • 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.[70]
     • Retinoblastoma survivors were at the highest risk (SIR, 342.9), followed by Wilms tumor survivors (SIR, 74.2).
     • 90% of leiomyosarcomas observed after a Wilms tumor diagnosis developed within the irradiated tissue.
3. 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.[26]
   • 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.
4. 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).[73]
   • Results 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).
5. In survivors of bilateral retinoblastoma, the most commonly observed malignant SN is sarcoma, specifically osteosarcoma.[77-79] 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.[68]
   • 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).
6. The CCSS reported the following on 105 cases and 422 matched controls in a nested case-control study of 14,372 childhood cancer survivors:[75]
   • 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.
7. In a cohort of 952 irradiated survivors of hereditary retinoblastoma diagnosed between 1914 and 2006, CCSS investigators observed that elevated bone and soft tissue sarcoma risks differed by age, location, and sex.[79]
   • Head and neck bone and soft tissue sarcomas were diagnosed beginning in early childhood and continued well into adulthood (60-year cumulative incidence of 6.8% and 9.3%, respectively).
   • Body and extremity bone sarcoma incidence flattened after adolescence (60-year cumulative incidence, 3.5%).
   • Body and extremity soft tissue sarcoma incidence was rare until age 30 years, when incidence rose steeply (60-year cumulative incidence, 6.6%) particularly for females (60-year cumulative incidence, 9.4%).
8. In a retrospective study of 160 patients with hereditary retinoblastoma who received radiation therapy, no correlation was identified between age (before or after 12 months) at which external-beam radiation therapy was given and development of subsequent malignancy.[71]
   • Patients with and without subsequent malignancies did not differ by RB1 variant type. Also, there was no association with variant type and location of SMN, or SMN type and age at diagnosis.
   • The study showed that patients who have a low penetrance variant and receive external-beam radiation therapy remain at risk of SMNs and should be cautiously monitored.

Skin cancer

Nonmelanoma skin cancers (NMSCs) are one of the most common SNs among childhood cancer survivors and show a strong association with radiation therapy.[4,80] Adherence to sun protection behaviors can reduce exposure to UV radiation that may exacerbate risk.

The CCSS performed a randomized, controlled, comparative effectiveness trial to test methods to improve early detection of skin cancer among survivors of childhood cancer at high risk after radiation therapy exposure. Participants were randomly assigned to the experimental arm, which included print materials in combination with mHealth strategies (text messages and use of the Advancing Survivors’ Knowledge website), or the control arm. Screening rates improved by 1.5-fold in the experimental arm. Rates of physician skin examination increased from baseline to 12 months, and rates of self-examination increased from baseline to 18 months in all three intervention groups. However, the increase in rates did not differ between the intervention groups.[81]

Evidence (excess risk of NMSCs):

1. Compared with participants who did not receive radiation therapy, CCSS participants treated with radiation therapy had a 6.3-fold increased risk of NMSCs (95% CI, 3.5–11.3).[82]
   • 90% of tumors occurred within the radiation field.
   • 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).
2. In 5,843 childhood cancer survivors in the DCOG-LATER cohort, investigators found that childhood cancer survivors had a 30-fold increased risk of developing BCCs.[29]
   • After a first BCC diagnosis, 46.7% of patients developed additional BCCs.
   • BCC risk was associated with any radiation therapy to the relevant radiation field (site of BCC) (HR, 14.32) and with estimated percentage of exposed skin surface area (26%–75%: HR, 1.99; 76%–100%: HR, 2.16 vs. 1%–25% exposed; P_trend 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).
3. 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.[7]
   • 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 an NMSC as a first SN, compared with 10.7% (95% CI, 7.2%–14.2%) among survivors 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.

Risk factors for malignant melanoma identified among these studies include the following:[83]

• Radiation therapy.
• Combination of alkylating agents and antimitotic drugs.

Evidence (excess risk of melanoma):

1. A systematic review that included 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.[83]
   • Melanomas most frequently developed in survivors of Hodgkin lymphoma, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors. However, the relatively small number of survivors represented in the relevant studies preclude assessment of melanoma risk among other types of childhood cancer.
2. 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 years).[84]
   • The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% (95% CI, 0.37%–0.73%), and the absolute excess risk was 0.10 per 1,000 person-years (95% CI, 0.05–0.15).
   • Family history of cancer, demographic characteristics, or treatment-related factors did not predict risk of melanoma.

Skin cancer risk after retinoblastoma

The incidence of melanoma and NMSC was evaluated in a cohort of 1,851 long-term, White survivors of retinoblastoma (1,020 hereditary and 831 nonhereditary) who were diagnosed from 1914 to 2006 and monitored through 2016.[85]

• Of all patients, 33 hereditary and 7 nonhereditary survivors developed melanoma, and 26 hereditary and 9 nonhereditary survivors developed NMSC. The median age of skin cancer development was about 20 years younger for hereditary survivors than nonhereditary survivors.
• Most NMSCs were on the head/neck, whereas melanomas were more broadly distributed, with patterns similar to melanoma-prone families.
• At 50 years after retinoblastoma diagnosis, in hereditary survivors, the cumulative incidence of melanoma was 4.5% and the cumulative incidence of NMSC was 3.7%. In nonhereditary survivors, the cumulative incidence of melanoma was 0.7% and the cumulative incidence of NMSC was 1.5%.

Lung cancer

Among childhood cancer survivor cohorts, lung cancer represents a relatively uncommon SN. There is a long latent period between the childhood cancer diagnosis and the development of a lung SN.[13,86]

Evidence (excess risk of lung cancer):

1. The 30-year cumulative incidence of lung cancer among CCSS participants was 0.16% (95% CI, 0.09%–0.23%), representing a SIR of 4.0 (95% CI, 2.9–5.4).[86]
   • Lung cancer risk demonstrated a dose-related association with chest radiation dose: 10 to 30 Gy (HR, 3.4; 95% CI, 1.05–11.0), more than 30 to 40 Gy (HR, 4.6; 95% CI, 1.5–14.3), and more than 40 Gy (HR, 9.1; 95% CI, 3.1–27.0).
   • Cumulative incidence of lung SMNs was higher among current or past smokers, compared with those who had never smoked.
   • The SIR for lung cancer was highest among survivors of Hodgkin lymphoma (SIR, 9.3; 95% CI, 6.2–13.4) and bone cancer (SIR, 4.4; 95% CI, 1.8–9.1).
2. The 25-year cumulative incidence of lung cancer among the DCOG-LATER cohort was 0.1% (95% CI, 0.0%–0.3%).[13]
   • Incidence was approximately fourfold higher than what would be expected in the general population (SIR, 4.3; 95% CI, 1.9–8.5).
3. Lung cancer has been reported after chest irradiation for Hodgkin lymphoma.[87]
   • The risk increases in association with longer elapsed time from diagnosis.
4. Smoking has been linked with the occurrence of lung cancer that develops after radiation therapy for Hodgkin lymphoma.[87]
   • 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. This evidence supports the need for early initiation of colorectal carcinoma surveillance.[88-90]

Evidence (excess risk of GI cancer):

1. In a French and British cohort-nested, case-control study of childhood solid tumor survivors diagnosed before age 17 years, the risk of developing a digestive organ SN varied with therapy.[91]
   • 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 was observed, with an OR of 5.2 (95% CI, 1.7–16.0) for local radiation doses between 10 Gy to 29 Gy and 9.6 (95% CI, 2.6–35.2) for doses of 30 Gy and above, compared with survivors who had not received radiation 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, respectively).
2. The PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) consortium quantified the absolute risks by radiation therapy treatment characteristics in a cohort of 69,450 5-year childhood cancer survivors in Europe. ORs were calculated from a case-control study comprising 143 subsequent colorectal cancers within the cohort of childhood cancer survivors.[90]
   • Survivors treated with any abdominopelvic radiation therapy were three times more likely to develop a subsequent colorectal cancer than those who did not receive radiation therapy (OR, 3.1; 95% CI, 1.4–6.6).
   • By age 40 years, survivors who were treated with abdominopelvic radiation therapy already have a similar risk of colorectal cancer as individuals aged 50 years in the general population when population-based colorectal cancer screening begins.
   • The risk of colorectal cancer increases with abdominopelvic radiation therapy dose. Survivors treated with spinal or whole-abdomen radiation therapy are at higher risk than those treated with radiation to other abdominopelvic fields.
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).[88]
   • 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:[89]
   • Incidence of a subsequent colorectal carcinoma increased steeply with advancing attained 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. Increasing radiation volume also increased the 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.[92]
   • 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 nonpolyposis 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.[93]
   • 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. The PanCareSurFup consortium reported on digestive cancers in a cohort of 69,460 5-year childhood cancer survivors in Europe.[94]
   • Survivors of Wilms tumor (SIR, 12.1; 95% CI, 9.6–15.1) and Hodgkin lymphoma (SIR, 7.3; 95% CI, 5.9–9.0) were at the highest risk for GI SMNs.
   • By age 55 years, 2.3% of survivors of Wilms tumor and Hodgkin lymphoma developed a secondary colorectal cancer, a rate that is comparable to that of the general population with two or more first-degree relatives affected by GI cancer.
8. A nested case-control study examined the rate of colorectal cancer according to large bowel radiation therapy dose and procarbazine dose among 5-year Hodgkin lymphoma survivors who were diagnosed between age 15 and 50 years (only 27% of cases were 15 to 24 years old) at five hospital centers in the Netherlands (diagnosed between 1964 to 2000; median follow-up, 26 years).[95]
   • The median interval between Hodgkin lymphoma diagnosis and subsequent colorectal cancer was 25.7 years (range, 18.2–31.6 years).
   • Treatment with subdiaphragmatic radiation therapy (RR, 2.4; 95% CI, 1.4–4.1) and more than 8.4 g/m2 of procarbazine (RR, 2.5; 95% CI, 1.3–5.0) were associated with increased rates of colorectal cancer on univariable analysis.
   • Colorectal cancer rate increased linearly with mean radiation therapy dose to the whole large bowel and dose to the affected bowel segment. The dose response became steeper with higher doses of procarbazine and increased 1.2-fold (95% CI, 1.1–1.3) for each 1 g/m2 increase in procarbazine.

Oral cancers

The PanCareSurFup consortium reported on risks of oral second primary neoplasms (validated through pathology reports) in a cohort of 69,460 5-year childhood cancer survivors in Europe.[96]

• Oral second primary neoplasms (n = 145; 64 salivary gland, 38 tongue, 20 pharynx, 2 lip, and 21 other) developed in 143 survivors at a median age of 32 years. This represents a fivefold excess risk compared with that expected in the general population.
• Childhood cancer diagnostic groups at greatest risk for an oral second primary neoplasm included leukemia (SIR, 19.2; 95% CI, 14.6–25.2), bone sarcoma (SIR, 6.4; 95% CI, 3.7–11.0), Hodgkin lymphoma (SIR, 6.2; 95% CI, 3.9–9.9), and soft tissue sarcoma (SIR, 5.0; 95% CI, 3.0–8.5).
• Observed specific treatment associations with oral second primary neoplasms included radiation therapy and salivary gland neoplasms (SIR, 33; 95% CI, 25.3–44.5) and chemotherapy (any exposure) and tongue neoplasms (SIR, 15.9; 95% CI, 10.6–23.7).
• Data were not available to assess the contributions of health behaviors (smoking, alcohol intake) and human papillomavirus (HPV) infection status to the development of oral second primary neoplasms.

Urogenital cancers

Development of subsequent primary urogenital cancers in childhood and adolescent cancer survivors is rare.

Using SEER data of 43,991 patients (aged <20 years) diagnosed with a first primary cancer from 1975 to 2016, the risk of urinary system cancer was higher for both females (SIR, 5.18; 95% CI, 3.65–7.14) and males (SIR, 2.80; 95% CI, 1.94–3.92), compared with the general population.[97]

• Females were more likely than males to develop a subsequent urinary system cancer (SIR, 1.86; 95% CI, 1.13–3.03) and kidney cancer (SIR, 1.97; 95% CI, 1.11–3.53).
• Females with any first cancer had higher risks than the general population for developing cancers of the corpus uteri (SIR, 2.32; 95% CI, 1.49–3.45) and vulva (SIR, 4.27; 95% CI, 1.38–9.95).

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.[28,98,99] Underlying genetic predisposition may also play a role in the risk of developing renal carcinomas because rare cases of renal carcinoma have been observed in children with tuberous sclerosis.[98] 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.[100-102]

Evidence (excess risk of renal carcinoma):

1. 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.[98]
   1. 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).[98] Radiation has been hypothesized to predispose children with high-risk neuroblastoma to renal carcinoma.[103]
      • Those treated with renal-directed radiation therapy of 5 Gy or higher (RR, 3.8; 95% CI, 1.6–9.3).[98]
      • Those treated with platinum-based chemotherapy (RR, 3.5; 95% CI, 1.0–11.2).[98]

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Cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, has been reported to be the leading cause of premature mortality among long-term childhood cancer survivors.[1-3]

Evidence (excess risk of premature cardiovascular mortality):

The specific late effects covered in this section include the following:

This section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes. However, this section will not provide a detailed review of those conditions as a consequence of childhood cancer treatment. A comprehensive review of long-term cardiovascular toxicity in childhood and young adult survivors of cancer has been published.[7]

Evidence (selected cohort studies describing cardiovascular outcomes):

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62. Fullerton HJ, Stratton K, Mueller S, et al.: Recurrent stroke in childhood cancer survivors. Neurology 85 (12): 1056-64, 2015. [PUBMED Abstract]
63. Chow EJ, Chen Y, Hudson MM, et al.: Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer. J Clin Oncol 36 (1): 44-52, 2018. [PUBMED Abstract]
64. El-Fayech C, Haddy N, Allodji RS, et al.: Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries. Int J Radiat Oncol Biol Phys 97 (2): 278-286, 2017. [PUBMED Abstract]
65. Bright CJ, Hawkins MM, Guha J, et al.: Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study). Circulation 135 (13): 1194-1210, 2017. [PUBMED Abstract]
66. Mueller S, Kline CN, Buerki RA, et al.: Stroke impact on mortality and psychologic morbidity within the Childhood Cancer Survivor Study. Cancer 126 (5): 1051-1059, 2020. [PUBMED Abstract]
67. Walker AJ, Grainge MJ, Card TR, et al.: Venous thromboembolism in children with cancer - a population-based cohort study. Thromb Res 133 (3): 340-4, 2014. [PUBMED Abstract]
68. Madenci AL, Weil BR, Liu Q, et al.: Long-Term Risk of Venous Thromboembolism in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol : JCO2018784595, 2018. [PUBMED Abstract]
69. Mueller S, Fullerton HJ, Stratton K, et al.: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86 (4): 649-55, 2013. [PUBMED Abstract]
70. Chao C, Xu L, Bhatia S, et al.: Cardiovascular Disease Risk Profiles in Survivors of Adolescent and Young Adult (AYA) Cancer: The Kaiser Permanente AYA Cancer Survivors Study. J Clin Oncol 34 (14): 1626-33, 2016. [PUBMED Abstract]
71. Winther JF, Bhatia S, Cederkvist L, et al.: Risk of cardiovascular disease among Nordic childhood cancer survivors with diabetes mellitus: A report from adult life after childhood cancer in Scandinavia. Cancer 124 (22): 4393-4400, 2018. [PUBMED Abstract]
72. van Dalen EC, Mulder RL, Suh E, et al.: Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Eur J Cancer 156: 127-137, 2021. [PUBMED Abstract]
73. Lipshultz SE, Lipsitz SR, Kutok JL, et al.: Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 119 (19): 3555-62, 2013. [PUBMED Abstract]
74. Visscher H, Ross CJ, Rassekh SR, et al.: Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr Blood Cancer 60 (8): 1375-81, 2013. [PUBMED Abstract]
75. Wang X, Liu W, Sun CL, et al.: Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group. J Clin Oncol 32 (7): 647-53, 2014. [PUBMED Abstract]
76. Wang X, Sun CL, Quiñones-Lombraña A, et al.: CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children's Oncology Group Genome-Wide Association Study. J Clin Oncol 34 (8): 863-70, 2016. [PUBMED Abstract]
77. Aminkeng F, Bhavsar AP, Visscher H, et al.: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 47 (9): 1079-84, 2015. [PUBMED Abstract]
78. Visscher H, Rassekh SR, Sandor GS, et al.: Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children. Pharmacogenomics 16 (10): 1065-76, 2015. [PUBMED Abstract]
79. Singh P, Wang X, Hageman L, et al.: Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report. Cancer 126 (17): 4051-4058, 2020. [PUBMED Abstract]
80. Sapkota Y, Ehrhardt MJ, Qin N, et al.: A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors. J Natl Cancer Inst 114 (8): 1109-1116, 2022. [PUBMED Abstract]
81. Davies SM: Getting to the heart of the matter. J Clin Oncol 30 (13): 1399-400, 2012. [PUBMED Abstract]
82. Lewey J, Haythe J: Cardiomyopathy in pregnancy. Semin Perinatol 38 (5): 309-17, 2014. [PUBMED Abstract]
83. Hines MR, Mulrooney DA, Hudson MM, et al.: Pregnancy-associated cardiomyopathy in survivors of childhood cancer. J Cancer Surviv 10 (1): 113-21, 2016. [PUBMED Abstract]
84. Chait-Rubinek L, Mariani JA, Goroncy N, et al.: A Retrospective Evaluation of Risk of Peripartum Cardiac Dysfunction in Survivors of Childhood, Adolescent and Young Adult Malignancies. Cancers (Basel) 11 (8): , 2019. [PUBMED Abstract]
85. Liu S, Aghel N, Belford L, et al.: Cardiac Outcomes in Pregnant Women With Treated Cancer. J Am Coll Cardiol 72 (17): 2087-2089, 2018. [PUBMED Abstract]
86. Bottinor W, Im C, Doody DR, et al.: Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer. J Am Coll Cardiol 83 (8): 827-838, 2024. [PUBMED Abstract]
87. Dietz AC, Seidel K, Leisenring WM, et al.: Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 20 (10): 1420-1431, 2019. [PUBMED Abstract]
88. Brouwer CA, Postma A, Hooimeijer HL, et al.: Endothelial damage in long-term survivors of childhood cancer. J Clin Oncol 31 (31): 3906-13, 2013. [PUBMED Abstract]
89. Maraldo MV, Jørgensen M, Brodin NP, et al.: The impact of involved node, involved field and mantle field radiotherapy on estimated radiation doses and risk of late effects for pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 61 (4): 717-22, 2014. [PUBMED Abstract]
90. Tukenova M, Guibout C, Oberlin O, et al.: Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 28 (8): 1308-15, 2010. [PUBMED Abstract]
91. Armstrong GT, Kawashima T, Leisenring W, et al.: Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 32 (12): 1218-27, 2014. [PUBMED Abstract]
92. Chen AB, Punglia RS, Kuntz KM, et al.: Cost effectiveness and screening interval of lipid screening in Hodgkin's lymphoma survivors. J Clin Oncol 27 (32): 5383-9, 2009. [PUBMED Abstract]
93. Wong FL, Bhatia S, Landier W, et al.: Cost-effectiveness of the children's oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med 160 (10): 672-83, 2014. [PUBMED Abstract]
94. Yeh JM, Nohria A, Diller L: Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects. Ann Intern Med 160 (10): 661-71, 2014. [PUBMED Abstract]
95. Landier W, Armenian SH, Lee J, et al.: Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. J Clin Oncol 30 (35): 4401-8, 2012. [PUBMED Abstract]
96. Ramjaun A, AlDuhaiby E, Ahmed S, et al.: Echocardiographic Detection of Cardiac Dysfunction in Childhood Cancer Survivors: How Long Is Screening Required? Pediatr Blood Cancer 62 (12): 2197-203, 2015. [PUBMED Abstract]
97. Spewak MB, Williamson RS, Mertens AC, et al.: Yield of screening echocardiograms during pediatric follow-up in survivors treated with anthracyclines and cardiotoxic radiation. Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
98. Chen Y, Chow EJ, Oeffinger KC, et al.: Traditional Cardiovascular Risk Factors and Individual Prediction of Cardiovascular Events in Childhood Cancer Survivors. J Natl Cancer Inst 112 (3): 256-265, 2020. [PUBMED Abstract]
99. Scott JM, Li N, Liu Q, et al.: Association of Exercise With Mortality in Adult Survivors of Childhood Cancer. JAMA Oncol 4 (10): 1352-1358, 2018. [PUBMED Abstract]
100. Schindera C, Zürcher SJ, Jung R, et al.: Physical fitness and modifiable cardiovascular disease risk factors in survivors of childhood cancer: A report from the SURfit study. Cancer 127 (10): 1690-1698, 2021. [PUBMED Abstract]
101. Rueegg CS, Zürcher SJ, Schindera C, et al.: Effect of a 1-year physical activity intervention on cardiovascular health in long-term childhood cancer survivors-a randomised controlled trial (SURfit). Br J Cancer 129 (8): 1284-1297, 2023. [PUBMED Abstract]

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81. Willard VW, Qaddoumi I, Chen S, et al.: Developmental and adaptive functioning in children with retinoblastoma: a longitudinal investigation. J Clin Oncol 32 (25): 2788-93, 2014. [PUBMED Abstract]
82. Willard VW, Qaddoumi I, Pan H, et al.: Cognitive and Adaptive Functioning in Youth With Retinoblastoma: A Longitudinal Investigation Through 10 Years of Age. J Clin Oncol 39 (24): 2676-2684, 2021. [PUBMED Abstract]
83. Brinkman TM, Merchant TE, Li Z, et al.: Cognitive function and social attainment in adult survivors of retinoblastoma: a report from the St. Jude Lifetime Cohort Study. Cancer 121 (1): 123-31, 2015. [PUBMED Abstract]
84. Ehrhardt MJ, Sandlund JT, Zhang N, et al.: Late outcomes of adult survivors of childhood non-Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
85. Krull KR, Sabin ND, Reddick WE, et al.: Neurocognitive function and CNS integrity in adult survivors of childhood hodgkin lymphoma. J Clin Oncol 30 (29): 3618-24, 2012. [PUBMED Abstract]
86. Hesko C, Liu W, Srivastava DK, et al.: Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study. Cancer 129 (18): 2904-2914, 2023. [PUBMED Abstract]
87. Wu NL, Phipps AI, Krull KR, et al.: Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant. Blood Adv 6 (14): 4347-4356, 2022. [PUBMED Abstract]
88. Willard VW, Leung W, Huang Q, et al.: Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation. J Clin Oncol 32 (35): 3982-8, 2014. [PUBMED Abstract]
89. Kenborg L, Winther JF, Linnet KM, et al.: Neurologic disorders in 4858 survivors of central nervous system tumors in childhood-an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study. Neuro Oncol 21 (1): 125-136, 2019. [PUBMED Abstract]
90. Wells EM, Ullrich NJ, Seidel K, et al.: Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report. Neuro Oncol 20 (1): 132-142, 2018. [PUBMED Abstract]
91. Goldsby RE, Liu Q, Nathan PC, et al.: Late-occurring neurologic sequelae in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28 (2): 324-31, 2010. [PUBMED Abstract]
92. Phillips NS, Khan RB, Li C, et al.: Seizures' impact on cognition and quality of life in childhood cancer survivors. Cancer 128 (1): 180-191, 2022. [PUBMED Abstract]
93. Jain P, Gulati S, Seth R, et al.: Vincristine-induced neuropathy in childhood ALL (acute lymphoblastic leukemia) survivors: prevalence and electrophysiological characteristics. J Child Neurol 29 (7): 932-7, 2014. [PUBMED Abstract]
94. Ness KK, Jones KE, Smith WA, et al.: Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study. Arch Phys Med Rehabil 94 (8): 1451-7, 2013. [PUBMED Abstract]
95. Kandula T, Farrar MA, Cohn RJ, et al.: Chemotherapy-Induced Peripheral Neuropathy in Long-term Survivors of Childhood Cancer: Clinical, Neurophysiological, Functional, and Patient-Reported Outcomes. JAMA Neurol 75 (8): 980-988, 2018. [PUBMED Abstract]
96. Rodwin RL, Ross WL, Rotatori J, et al.: Newly identified chemotherapy-induced peripheral neuropathy in a childhood cancer survivorship clinic. Pediatr Blood Cancer 69 (3): e29550, 2022. [PUBMED Abstract]
97. Varedi M, Lu L, Howell CR, et al.: Peripheral Neuropathy, Sensory Processing, and Balance in Survivors of Acute Lymphoblastic Leukemia. J Clin Oncol 36 (22): 2315-2322, 2018. [PUBMED Abstract]
98. Gurney JG, Kadan-Lottick NS, Packer RJ, et al.: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer 97 (3): 663-73, 2003. [PUBMED Abstract]
99. Ullrich NJ, Robertson R, Kinnamon DD, et al.: Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 68 (12): 932-8, 2007. [PUBMED Abstract]
100. Wang C, Roberts KB, Bindra RS, et al.: Delayed cerebral vasculopathy following cranial radiation therapy for pediatric tumors. Pediatr Neurol 50 (6): 549-56, 2014. [PUBMED Abstract]
101. Mueller S, Fullerton HJ, Stratton K, et al.: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86 (4): 649-55, 2013. [PUBMED Abstract]
102. Reulen RC, Guha J, Bright CJ, et al.: Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study. Int J Cancer 148 (3): 572-583, 2021. [PUBMED Abstract]
103. Fullerton HJ, Stratton K, Mueller S, et al.: Recurrent stroke in childhood cancer survivors. Neurology 85 (12): 1056-64, 2015. [PUBMED Abstract]
104. Waxer JF, Wong K, Modiri A, et al.: Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A PENTEC Normal Tissue Outcomes Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 417-430, 2024. [PUBMED Abstract]
105. Khan RB, Merchant TE, Sadighi ZS, et al.: Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors. J Neurooncol 136 (2): 379-384, 2018. [PUBMED Abstract]
106. van Kooten JAMC, Maurice-Stam H, Schouten AYN, et al.: High occurrence of sleep problems in survivors of a childhood brain tumor with neurocognitive complaints: The association with psychosocial and behavioral executive functioning. Pediatr Blood Cancer 66 (11): e27947, 2019. [PUBMED Abstract]
107. Khan RB, Hudson MM, Ledet DS, et al.: Neurologic morbidity and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross-sectional study. J Cancer Surviv 8 (4): 688-96, 2014. [PUBMED Abstract]
108. Khong PL, Leung LH, Fung AS, et al.: White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function. J Clin Oncol 24 (6): 884-90, 2006. [PUBMED Abstract]
109. Zeller B, Tamnes CK, Kanellopoulos A, et al.: Reduced neuroanatomic volumes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 31 (17): 2078-85, 2013. [PUBMED Abstract]
110. 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]
111. Phillips NS, Hillenbrand CM, Mitrea BG, et al.: Cerebral microbleeds in adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. Sci Rep 10 (1): 692, 2020. [PUBMED Abstract]
112. Rodwin RL, Chen Y, Yasui Y, et al.: Longitudinal Evaluation of Neuromuscular Dysfunction in Long-term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 30 (8): 1536-1545, 2021. [PUBMED Abstract]
113. Cooper BT, Mayo CS, Milano MT, et al.: Predictive Factors Associated With Radiation Myelopathy in Pediatric Patients With Cancer: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 494-506, 2024. [PUBMED Abstract]
114. Ness KK, Hudson MM, Jones KE, et al.: Effect of Temporal Changes in Therapeutic Exposure on Self-reported Health Status in Childhood Cancer Survivors. Ann Intern Med 166 (2): 89-98, 2017. [PUBMED Abstract]
115. Ernst M, Hinz A, Brähler E, et al.: Quality of life after pediatric cancer: comparison of long-term childhood cancer survivors' quality of life with a representative general population sample and associations with physical health and risk indicators. Health Qual Life Outcomes 21 (1): 65, 2023. [PUBMED Abstract]
116. Schulte F, Brinkman TM, Li C, et al.: Social adjustment in adolescent survivors of pediatric central nervous system tumors: A report from the Childhood Cancer Survivor Study. Cancer 124 (17): 3596-3608, 2018. [PUBMED Abstract]
117. Vuotto SC, Wang M, Okcu MF, et al.: Neurologic morbidity and functional independence in adult survivors of childhood cancer. Ann Clin Transl Neurol 11 (2): 291-301, 2024. [PUBMED Abstract]
118. Hörnquist L, Rickardsson J, Lannering B, et al.: Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population. Neuro Oncol 17 (5): 733-40, 2015. [PUBMED Abstract]
119. Schulte F, Barrera M: Social competence in childhood brain tumor survivors: a comprehensive review. Support Care Cancer 18 (12): 1499-513, 2010. [PUBMED Abstract]
120. Papini C, Willard VW, Gajjar A, et al.: Social cognition and adjustment in adult survivors of pediatric central nervous system tumors. Cancer 129 (19): 3064-3075, 2023. [PUBMED Abstract]
121. Bonneau J, Berbis J, Michel G, et al.: Adolescence and Socioeconomic Factors: Key Factors in the Long-Term Impact of Leukemia on Scholastic Performance-A LEA Study. J Pediatr 205: 168-175.e2, 2019. [PUBMED Abstract]
122. Drabbe C, Coenraadts ES, van Houdt WJ, et al.: Impaired social functioning in adolescent and young adult sarcoma survivors: Prevalence and risk factors. Cancer 129 (9): 1419-1431, 2023. [PUBMED Abstract]
123. Ernst M, Brähler E, Wild PS, et al.: Risk factors for suicidal ideation in a large, registry-based sample of adult long-term childhood cancer survivors. J Affect Disord 265: 351-356, 2020. [PUBMED Abstract]
124. Lubas MM, Mirzaei Salehabadi S, Lavecchia J, et al.: Suicidality among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort Study. Cancer 126 (24): 5347-5355, 2020. [PUBMED Abstract]
125. Brinkman TM, Zhang N, Recklitis CJ, et al.: Suicide ideation and associated mortality in adult survivors of childhood cancer. Cancer 120 (2): 271-7, 2014. [PUBMED Abstract]
126. Gunnes MW, Lie RT, Bjørge T, et al.: Suicide and violent deaths in survivors of cancer in childhood, adolescence and young adulthood-A national cohort study. Int J Cancer 140 (3): 575-580, 2017. [PUBMED Abstract]
127. Sun CL, Francisco L, Baker KS, et al.: Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS). Blood 118 (17): 4723-31, 2011. [PUBMED Abstract]
128. Vuotto SC, Krull KR, Li C, et al.: Impact of chronic disease on emotional distress in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 123 (3): 521-528, 2017. [PUBMED Abstract]
129. Zheng DJ, Krull KR, Chen Y, et al.: Long-term psychological and educational outcomes for survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study. Cancer 124 (15): 3220-3230, 2018. [PUBMED Abstract]
130. Recklitis C, O'Leary T, Diller L: Utility of routine psychological screening in the childhood cancer survivor clinic. J Clin Oncol 21 (5): 787-92, 2003. [PUBMED Abstract]
131. Hsu TW, Liang CS, Tsai SJ, et al.: Risk of Major Psychiatric Disorders Among Children and Adolescents Surviving Malignancies: A Nationwide Longitudinal Study. J Clin Oncol 41 (11): 2054-2066, 2023. [PUBMED Abstract]
132. De R, Sutradhar R, Kurdyak P, et al.: Incidence and Predictors of Mental Health Outcomes Among Survivors of Adolescent and Young Adult Cancer: A Population-Based Study Using the IMPACT Cohort. J Clin Oncol 39 (9): 1010-1019, 2021. [PUBMED Abstract]
133. Phipps S, Klosky JL, Long A, et al.: Posttraumatic stress and psychological growth in children with cancer: has the traumatic impact of cancer been overestimated? J Clin Oncol 32 (7): 641-6, 2014. [PUBMED Abstract]
134. Stuber ML, Meeske KA, Leisenring W, et al.: Defining medical posttraumatic stress among young adult survivors in the Childhood Cancer Survivor Study. Gen Hosp Psychiatry 33 (4): 347-53, 2011 Jul-Aug. [PUBMED Abstract]
135. Phipps S, Larson S, Long A, et al.: Adaptive style and symptoms of posttraumatic stress in children with cancer and their parents. J Pediatr Psychol 31 (3): 298-309, 2006. [PUBMED Abstract]
136. Phipps S, Jurbergs N, Long A: Symptoms of post-traumatic stress in children with cancer: does personality trump health status? Psychooncology 18 (9): 992-1002, 2009. [PUBMED Abstract]
137. Rourke MT, Hobbie WL, Schwartz L, et al.: Posttraumatic stress disorder (PTSD) in young adult survivors of childhood cancer. Pediatr Blood Cancer 49 (2): 177-82, 2007. [PUBMED Abstract]
138. Schwartz L, Drotar D: Posttraumatic stress and related impairment in survivors of childhood cancer in early adulthood compared to healthy peers. J Pediatr Psychol 31 (4): 356-66, 2006. [PUBMED Abstract]
139. Stuber ML, Meeske KA, Krull KR, et al.: Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics 125 (5): e1124-34, 2010. [PUBMED Abstract]
140. Hobbie WL, Stuber M, Meeske K, et al.: Symptoms of posttraumatic stress in young adult survivors of childhood cancer. J Clin Oncol 18 (24): 4060-6, 2000. [PUBMED Abstract]
141. Dieluweit U, Debatin KM, Grabow D, et al.: Social outcomes of long-term survivors of adolescent cancer. Psychooncology 19 (12): 1277-84, 2010. [PUBMED Abstract]
142. Seitz DC, Hagmann D, Besier T, et al.: Life satisfaction in adult survivors of cancer during adolescence: what contributes to the latter satisfaction with life? Qual Life Res 20 (2): 225-36, 2011. [PUBMED Abstract]
143. Tai E, Buchanan N, Townsend J, et al.: Health status of adolescent and young adult cancer survivors. Cancer 118 (19): 4884-91, 2012. [PUBMED Abstract]
144. Schultz KA, Ness KK, Whitton J, et al.: Behavioral and social outcomes in adolescent survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 25 (24): 3649-56, 2007. [PUBMED Abstract]
145. Prasad PK, Hardy KK, Zhang N, et al.: Psychosocial and Neurocognitive Outcomes in Adult Survivors of Adolescent and Early Young Adult Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 33 (23): 2545-52, 2015. [PUBMED Abstract]
146. Brinkman TM, Li C, Vannatta K, et al.: Behavioral, Social, and Emotional Symptom Comorbidities and Profiles in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 34 (28): 3417-25, 2016. [PUBMED Abstract]
147. Karlson CW, Alberts NM, Liu W, et al.: Longitudinal pain and pain interference in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 126 (12): 2915-2923, 2020. [PUBMED Abstract]
148. Tonning Olsson I, Alberts NM, Li C, et al.: Pain and functional outcomes in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort study. Cancer 127 (10): 1679-1689, 2021. [PUBMED Abstract]
149. Frederiksen LE, Erdmann F, Mader L, et al.: Psychiatric disorders in childhood cancer survivors in Denmark, Finland, and Sweden: a register-based cohort study from the SALiCCS research programme. Lancet Psychiatry 9 (1): 35-45, 2022. [PUBMED Abstract]
150. Papini C, Mirzaei S S, Xing M, et al.: Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma. J Natl Cancer Inst 116 (2): 288-298, 2024. [PUBMED Abstract]

For digestive system late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

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60. Green DM, Norkool P, Breslow NE, et al.: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study. J Clin Oncol 8 (9): 1525-30, 1990. [PUBMED Abstract]
61. Sulis ML, Bessmertny O, Granowetter L, et al.: Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma. J Pediatr Hematol Oncol 26 (12): 843-6, 2004. [PUBMED Abstract]
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63. Dawson LA, Ten Haken RK: Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 15 (4): 279-83, 2005. [PUBMED Abstract]
64. Milano MT, Constine LS, Okunieff P: Normal tissue tolerance dose metrics for radiation therapy of major organs. Semin Radiat Oncol 17 (2): 131-40, 2007. [PUBMED Abstract]
65. Pan CC, Kavanagh BD, Dawson LA, et al.: Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S94-100, 2010. [PUBMED Abstract]
66. Bhanot P, Cushing B, Philippart A, et al.: Hepatic irradiation and adriamycin cardiotoxicity. J Pediatr 95 (4): 561-3, 1979. [PUBMED Abstract]
67. Flentje M, Weirich A, Pötter R, et al.: Hepatotoxicity in irradiated nephroblastoma patients during postoperative treatment according to SIOP9/GPOH. Radiother Oncol 31 (3): 222-8, 1994. [PUBMED Abstract]
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70. Hall MD, Howell RM, Jackson A, et al.: Liver Late Effects in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 575-587, 2024. [PUBMED Abstract]
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72. Pidala J, Chai X, Kurland BF, et al.: Analysis of gastrointestinal and hepatic chronic graft-versus-host [corrected] disease manifestations on major outcomes: a chronic graft-versus-host [corrected] disease consortium study. Biol Blood Marrow Transplant 19 (5): 784-91, 2013. [PUBMED Abstract]
73. Tomás JF, Pinilla I, García-Buey ML, et al.: Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant 26 (6): 649-55, 2000. [PUBMED Abstract]
74. Aricò M, Maggiore G, Silini E, et al.: Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 84 (9): 2919-22, 1994. [PUBMED Abstract]
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76. Cesaro S, Petris MG, Rossetti F, et al.: Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood 90 (3): 1315-20, 1997. [PUBMED Abstract]
77. Fink FM, Höcker-Schulz S, Mor W, et al.: Association of hepatitis C virus infection with chronic liver disease in paediatric cancer patients. Eur J Pediatr 152 (6): 490-2, 1993. [PUBMED Abstract]
78. Locasciulli A, Testa M, Pontisso P, et al.: Hepatitis C virus genotypes and liver disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 19 (3): 237-40, 1997. [PUBMED Abstract]
79. Locasciulli A, Testa M, Pontisso P, et al.: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90 (11): 4628-33, 1997. [PUBMED Abstract]
80. Paul IM, Sanders J, Ruggiero F, et al.: Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood 93 (11): 3672-7, 1999. [PUBMED Abstract]
81. Lansdale M, Castellino S, Marina N, et al.: Knowledge of hepatitis C virus screening in long-term pediatric cancer survivors: a report from the Childhood Cancer Survivor Study. Cancer 116 (4): 974-82, 2010. [PUBMED Abstract]
82. van Waas M, Neggers SJ, Raat H, et al.: Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7 (12): e52237, 2012. [PUBMED Abstract]
83. Neville KA, Cohn RJ, Steinbeck KS, et al.: Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 91 (11): 4401-7, 2006. [PUBMED Abstract]
84. Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
85. Dixon SB, Wang F, Lu L, et al.: Prediabetes and Associated Risk of Cardiovascular Events and Chronic Kidney Disease Among Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort. J Clin Oncol 42 (9): 1031-1043, 2024. [PUBMED Abstract]
86. Friedman DN, Moskowitz CS, Hilden P, et al.: Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus: A Report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 112 (5): 525-532, 2020. [PUBMED Abstract]
87. Williams HE, Howell CR, Chemaitilly W, et al.: Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study. Cancer 126 (4): 870-878, 2020. [PUBMED Abstract]
88. de Vathaire F, El-Fayech C, Ben Ayed FF, et al.: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13 (10): 1002-10, 2012. [PUBMED Abstract]
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Endocrine dysfunction is common among survivors of childhood cancer, especially in those who were treated with surgery or radiation therapy that involved hormone-producing organs and those who received alkylating agent chemotherapy.

Enlarge

The prevalence of specific endocrine disorders is affected by the following:[1-4]

Endocrinologic late effects can be broadly categorized as those resulting from hypothalamic-pituitary injury or from peripheral glandular compromise.[1-4] The former are most common after treatment for central nervous system (CNS) tumors. The prevalence of these late effects was 24.8% in a nationwide cohort study of 718 survivors who lived longer than 2 years and all hypothalamic-pituitary axes were affected.[3]

The following sections summarize research that characterizes the clinical features of survivors at risk of endocrine dysfunction that impacts pituitary, thyroid, adrenal, and gonadal function.

References

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97. Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328 (2): 87-94, 1993. [PUBMED Abstract]
98. Constine LS, Rubin P, Woolf PD, et al.: Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies. J Clin Oncol 5 (11): 1841-51, 1987. [PUBMED Abstract]
99. Melmed S, Casanueva FF, Hoffman AR, et al.: Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96 (2): 273-88, 2011. [PUBMED Abstract]
100. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106 (25): 3143-421, 2002. [PUBMED Abstract]
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104. van Waas M, Neggers SJ, Raat H, et al.: Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7 (12): e52237, 2012. [PUBMED Abstract]
105. Smith WA, Li C, Nottage KA, et al.: Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer 120 (17): 2742-50, 2014. [PUBMED Abstract]
106. Jones LW, Liu Q, Armstrong GT, et al.: Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. J Clin Oncol 32 (32): 3643-50, 2014. [PUBMED Abstract]
107. Scott JM, Li N, Liu Q, et al.: Association of Exercise With Mortality in Adult Survivors of Childhood Cancer. JAMA Oncol 4 (10): 1352-1358, 2018. [PUBMED Abstract]
108. Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
109. van Waas M, Neggers SJ, Uitterlinden AG, et al.: Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors. Eur J Cancer 49 (3): 668-75, 2013. [PUBMED Abstract]
110. de Vathaire F, El-Fayech C, Ben Ayed FF, et al.: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13 (10): 1002-10, 2012. [PUBMED Abstract]
111. Armenian SH, Chemaitilly W, Chen M, et al.: National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report. Biol Blood Marrow Transplant 23 (2): 201-210, 2017. [PUBMED Abstract]
112. Lega IC, Pole JD, Austin PC, et al.: Diabetes Risk in Childhood Cancer Survivors: A Population-Based Study. Can J Diabetes 42 (5): 533-539, 2018. [PUBMED Abstract]
113. Baker KS, Chow EJ, Goodman PJ, et al.: Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev 22 (11): 1954-63, 2013. [PUBMED Abstract]
114. Meacham LR, Chow EJ, Ness KK, et al.: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 19 (1): 170-81, 2010. [PUBMED Abstract]
115. van Santen HM, Geskus RB, Raemaekers S, et al.: Changes in body mass index in long-term childhood cancer survivors. Cancer 121 (23): 4197-204, 2015. [PUBMED Abstract]
116. Meacham LR, Gurney JG, Mertens AC, et al.: Body mass index in long-term adult survivors of childhood cancer: a report of the Childhood Cancer Survivor Study. Cancer 103 (8): 1730-9, 2005. [PUBMED Abstract]
117. Oeffinger KC, Mertens AC, Sklar CA, et al.: Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 21 (7): 1359-65, 2003. [PUBMED Abstract]
118. Sklar CA, Mertens AC, Walter A, et al.: Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation. Med Pediatr Oncol 35 (2): 91-5, 2000. [PUBMED Abstract]
119. Garmey EG, Liu Q, Sklar CA, et al.: Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 26 (28): 4639-45, 2008. [PUBMED Abstract]
120. Chow EJ, Pihoker C, Hunt K, et al.: Obesity and hypertension among children after treatment for acute lymphoblastic leukemia. Cancer 110 (10): 2313-20, 2007. [PUBMED Abstract]
121. Withycombe JS, Post-White JE, Meza JL, et al.: Weight patterns in children with higher risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer 53 (7): 1249-54, 2009. [PUBMED Abstract]
122. Nathan PC, Jovcevska V, Ness KK, et al.: The prevalence of overweight and obesity in pediatric survivors of cancer. J Pediatr 149 (4): 518-25, 2006. [PUBMED Abstract]
123. Oeffinger KC: Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer 50 (2 Suppl): 462-7; discussion 468, 2008. [PUBMED Abstract]
124. Brennan BM, Rahim A, Blum WF, et al.: Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 50 (2): 163-9, 1999. [PUBMED Abstract]
125. Pluimakers VG, van Atteveld JE, de Winter DTC, et al.: Prevalence, risk factors, and optimal way to determine overweight, obesity, and morbid obesity in the first Dutch cohort of 2338 long-term survivors of childhood cancer: a DCCSS-LATER study. Eur J Endocrinol 189 (5): 495-507, 2023. [PUBMED Abstract]
126. Green DM, Cox CL, Zhu L, et al.: Risk factors for obesity in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30 (3): 246-55, 2012. [PUBMED Abstract]
127. Veringa SJ, van Dulmen-den Broeder E, Kaspers GJ, et al.: Blood pressure and body composition in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 58 (2): 278-82, 2012. [PUBMED Abstract]
128. Janiszewski PM, Oeffinger KC, Church TS, et al.: Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab 92 (10): 3816-21, 2007. [PUBMED Abstract]
129. Oeffinger KC, Adams-Huet B, Victor RG, et al.: Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 27 (22): 3698-704, 2009. [PUBMED Abstract]
130. Jahnukainen K, Heikkinen R, Henriksson M, et al.: Increased Body Adiposity and Serum Leptin Concentrations in Very Long-Term Adult Male Survivors of Childhood Acute Lymphoblastic Leukemia. Horm Res Paediatr 84 (2): 108-15, 2015. [PUBMED Abstract]
131. Dalton VK, Rue M, Silverman LB, et al.: Height and weight in children treated for acute lymphoblastic leukemia: relationship to CNS treatment. J Clin Oncol 21 (15): 2953-60, 2003. [PUBMED Abstract]
132. Kohler JA, Moon RJ, Wright S, et al.: Increased adiposity and altered adipocyte function in female survivors of childhood acute lymphoblastic leukaemia treated without cranial radiation. Horm Res Paediatr 75 (6): 433-40, 2011. [PUBMED Abstract]
133. Zhang FF, Rodday AM, Kelly MJ, et al.: Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 61 (7): 1263-9, 2014. [PUBMED Abstract]
134. Warner JT, Evans WD, Webb DK, et al.: Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol 38 (3): 165-72, 2002. [PUBMED Abstract]
135. Miller TL, Lipsitz SR, Lopez-Mitnik G, et al.: Characteristics and determinants of adiposity in pediatric cancer survivors. Cancer Epidemiol Biomarkers Prev 19 (8): 2013-22, 2010. [PUBMED Abstract]
136. Jarfelt M, Lannering B, Bosaeus I, et al.: Body composition in young adult survivors of childhood acute lymphoblastic leukaemia. Eur J Endocrinol 153 (1): 81-9, 2005. [PUBMED Abstract]
137. Richard MA, Brown AL, Belmont JW, et al.: Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort. Cancer 127 (2): 310-318, 2021. [PUBMED Abstract]
138. Ness KK, DeLany JP, Kaste SC, et al.: Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. Blood 125 (22): 3411-9, 2015. [PUBMED Abstract]
139. Belle FN, Kasteler R, Schindera C, et al.: No evidence of overweight in long-term survivors of childhood cancer after glucocorticoid treatment. Cancer 124 (17): 3576-3585, 2018. [PUBMED Abstract]
140. Lindemulder SJ, Stork LC, Bostrom B, et al.: Survivors of standard risk acute lymphoblastic leukemia do not have increased risk for overweight and obesity compared to non-cancer peers: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (6): 1035-41, 2015. [PUBMED Abstract]
141. Gurney JG, Ness KK, Stovall M, et al.: Final height and body mass index among adult survivors of childhood brain cancer: childhood cancer survivor study. J Clin Endocrinol Metab 88 (10): 4731-9, 2003. [PUBMED Abstract]
142. Sahakitrungruang T, Klomchan T, Supornsilchai V, et al.: Obesity, metabolic syndrome, and insulin dynamics in children after craniopharyngioma surgery. Eur J Pediatr 170 (6): 763-9, 2011. [PUBMED Abstract]
143. Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010. [PUBMED Abstract]
144. Simoneau-Roy J, O'Gorman C, Pencharz P, et al.: Insulin sensitivity and secretion in children and adolescents with hypothalamic obesity following treatment for craniopharyngioma. Clin Endocrinol (Oxf) 72 (3): 364-70, 2010. [PUBMED Abstract]
145. Tosta-Hernandez PDC, Siviero-Miachon AA, da Silva NS, et al.: Childhood Craniopharyngioma: A 22-Year Challenging Follow-Up in a Single Center. Horm Metab Res 50 (9): 675-682, 2018. [PUBMED Abstract]
146. van Schaik J, van Roessel IMAA, Schouten-van Meeteren NAYN, et al.: High Prevalence of Weight Gain in Childhood Brain Tumor Survivors and Its Association With Hypothalamic-Pituitary Dysfunction. J Clin Oncol 39 (11): 1264-1273, 2021. [PUBMED Abstract]
147. Neville KA, Cohn RJ, Steinbeck KS, et al.: Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 91 (11): 4401-7, 2006. [PUBMED Abstract]
148. Nysom K, Holm K, Michaelsen KF, et al.: Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 27 (8): 817-20, 2001. [PUBMED Abstract]
149. Ketterl TG, Chow EJ, Leisenring WM, et al.: Adipokines, Inflammation, and Adiposity in Hematopoietic Cell Transplantation Survivors. Biol Blood Marrow Transplant 24 (3): 622-626, 2018. [PUBMED Abstract]
150. Inaba H, Yang J, Kaste SC, et al.: Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 30 (32): 3991-7, 2012. [PUBMED Abstract]
151. Wilson CL, Liu W, Chemaitilly W, et al.: Body Composition, Metabolic Health, and Functional Impairment among Adults Treated for Abdominal and Pelvic Tumors during Childhood. Cancer Epidemiol Biomarkers Prev 29 (9): 1750-1758, 2020. [PUBMED Abstract]
152. Ness KK, Krull KR, Jones KE, et al.: Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol 31 (36): 4496-503, 2013. [PUBMED Abstract]
153. Hayek S, Gibson TM, Leisenring WM, et al.: Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 38 (3): 232-247, 2020. [PUBMED Abstract]
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155. Williams AM, Krull KR, Howell CR, et al.: Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort. J Clin Oncol 39 (31): 3485-3495, 2021. [PUBMED Abstract]
156. van Atteveld JE, de Winter DTC, Pluimakers VG, et al.: Frailty and sarcopenia within the earliest national Dutch childhood cancer survivor cohort (DCCSS-LATER): a cross-sectional study. Lancet Healthy Longev 4 (4): e155-e165, 2023. [PUBMED Abstract]

Late effects of the immune system have not been well studied, especially in survivors treated with contemporary therapies. Reports published about long-term immune system outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.

For immune system late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

References

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7. de Vries S, Schaapveld M, Janus CPM, et al.: Long-Term Cause-Specific Mortality in Hodgkin Lymphoma Patients. J Natl Cancer Inst 113 (6): 760-769, 2021. [PUBMED Abstract]
8. Madenci AL, Armstrong LB, Kwon NK, et al.: Incidence and risk factors for sepsis after childhood splenectomy. J Pediatr Surg 54 (7): 1445-1448, 2019. [PUBMED Abstract]
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11. Bridges CB, Coyne-Beasley T; Advisory Committee on Immunization Practices: Advisory committee on immunization practices recommended immunization schedule for adults aged 19 years or older: United States, 2014. Ann Intern Med 160 (3): 190, 2014. [PUBMED Abstract]
12. Rubin LG, Levin MJ, Ljungman P, et al.: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 58 (3): 309-18, 2014. [PUBMED Abstract]
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17. Koskenvuo M, Ekman I, Saha E, et al.: Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment. Pediatr Blood Cancer 63 (9): 1653-6, 2016. [PUBMED Abstract]
18. Speckhart SA: MMR vaccination timing and long-term immunity among childhood cancer survivors. Pediatr Blood Cancer 70 (4): e30133, 2023. [PUBMED Abstract]
19. Fayea NY, Fouda AE, Kandil SM: Immunization status in childhood cancer survivors: A hidden risk which could be prevented. Pediatr Neonatol 58 (6): 541-545, 2017. [PUBMED Abstract]
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24. Cordonnier C, Einarsdottir S, Cesaro S, et al.: Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 19 (6): e200-e212, 2019. [PUBMED Abstract]
25. Majhail NS, Rizzo JD, Lee SJ, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Rev Bras Hematol Hemoter 34 (2): 109-33, 2012. [PUBMED Abstract]
26. Pergam SA, Englund JA, Kamboj M, et al.: Preventing Measles in Immunosuppressed Cancer and Hematopoietic Cell Transplantation Patients: A Position Statement by the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 25 (11): e321-e330, 2019. [PUBMED Abstract]
27. Maude SL, Laetsch TW, Buechner J, et al.: Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 378 (5): 439-448, 2018. [PUBMED Abstract]
28. Cordeiro A, Bezerra ED, Hirayama AV, et al.: Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol Blood Marrow Transplant 26 (1): 26-33, 2020. [PUBMED Abstract]
29. Bhoj VG, Arhontoulis D, Wertheim G, et al.: Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood 128 (3): 360-70, 2016. [PUBMED Abstract]
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The musculoskeletal system of growing children and adolescents is vulnerable to the cytotoxic effects of cancer therapies, including surgery, chemotherapy, and radiation therapy. Documented late effects include the following:

While these late effects are discussed individually, it is important to remember that the components of the musculoskeletal system are interrelated. For example, hypoplasia of a muscle group can negatively affect the function of the long bones and the resultant dysfunction can subsequently lead to disuse and osteoporosis.

The major strength of the published literature documenting musculoskeletal late effects among children and adolescents treated for cancer is that most studies have clearly defined outcomes and exposures. However, many studies are observational and cross-sectional or retrospective in design. Single-institution studies are common, and for some outcomes, only small convenience cohorts have been described. Thus, it is possible that studies either excluded patients with the most severe musculoskeletal effects because of death or inability to participate in follow-up testing, or they oversampled those with the most severe musculoskeletal late effects because these patients were accessible as they returned for complication-related follow-up. Additionally, some of the results reported in adult survivors of childhood cancer may not be relevant to patients currently being treated because the anticancer treatment and delivery of anticancer modalities, particularly radiation therapy, have changed over the years in response to documented toxicities.

Table 15 summarizes bone and joint late effects and the related health screenings.

For musculoskeletal system late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

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34. den Hoed MA, Pluijm SM, te Winkel ML, et al.: Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia. Haematologica 100 (12): 1564-70, 2015. [PUBMED Abstract]
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38. Bhandari R, Teh JB, Herrera C, et al.: Prevalence and risk factors for vitamin D deficiency in long-term childhood cancer survivors. Pediatr Blood Cancer 68 (7): e29048, 2021. [PUBMED Abstract]
39. Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 60 (1): 265-74, 2004. [PUBMED Abstract]
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42. Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005. [PUBMED Abstract]
43. Karimova EJ, Rai SN, Howard SC, et al.: Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol 25 (12): 1525-31, 2007. [PUBMED Abstract]
44. Campbell S, Sun CL, Kurian S, et al.: Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer 115 (18): 4127-35, 2009. [PUBMED Abstract]
45. Kawedia JD, Kaste SC, Pei D, et al.: Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 117 (8): 2340-7; quiz 2556, 2011. [PUBMED Abstract]
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48. Karimova EJ, Wozniak A, Wu J, et al.: How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res 468 (9): 2454-9, 2010. [PUBMED Abstract]
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50. te Winkel ML, Pieters R, Hop WC, et al.: Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol 29 (31): 4143-50, 2011. [PUBMED Abstract]
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52. Hernigou P, Auregan JC, Dubory A, et al.: Ankle osteonecrosis in fifty-one children and adolescent's leukemia survivors: a prospective randomized study on percutaneous mesenchymal stem cells treatment. Int Orthop 45 (9): 2383-2393, 2021. [PUBMED Abstract]
53. Faraci M, Calevo MG, Lanino E, et al.: Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica 91 (8): 1096-9, 2006. [PUBMED Abstract]
54. Relling MV, Yang W, Das S, et al.: Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol 22 (19): 3930-6, 2004. [PUBMED Abstract]
55. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED Abstract]
56. Hyakuna N, Shimomura Y, Watanabe A, et al.: Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. J Pediatr Hematol Oncol 36 (1): 22-9, 2014. [PUBMED Abstract]
57. Badhiwala JH, Nayiager T, Athale UH: The development of thromboembolism may increase the risk of osteonecrosis in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 62 (10): 1851-4, 2015. [PUBMED Abstract]
58. Li X, Brazauskas R, Wang Z, et al.: Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents. Biol Blood Marrow Transplant 20 (4): 587-92, 2014. [PUBMED Abstract]
59. Mattano LA, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000. [PUBMED Abstract]
60. Karol SE, Mattano LA, Yang W, et al.: Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood 127 (5): 558-64, 2016. [PUBMED Abstract]
61. Finkelstein Y, Blonquist TM, Vijayanathan V, et al.: A thymidylate synthase polymorphism is associated with increased risk for bone toxicity among children treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]
62. Karol SE, Yang W, Van Driest SL, et al.: Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood 126 (15): 1770-6, 2015. [PUBMED Abstract]
63. Aricò M, Boccalatte MF, Silvestri D, et al.: Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica 88 (7): 747-53, 2003. [PUBMED Abstract]
64. Elmantaser M, Stewart G, Young D, et al.: Skeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukaemia. Arch Dis Child 95 (10): 805-9, 2010. [PUBMED Abstract]
65. Chao C, Bhatia S, Xu L, et al.: Chronic Comorbidities Among Survivors of Adolescent and Young Adult Cancer. J Clin Oncol 38 (27): 3161-3174, 2020. [PUBMED Abstract]
66. Bovée JV: Multiple osteochondromas. Orphanet J Rare Dis 3: 3, 2008. [PUBMED Abstract]
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82. Beredjiklian PK, Drummond DS, Dormans JP, et al.: Orthopaedic manifestations of chronic graft-versus-host disease. J Pediatr Orthop 18 (5): 572-5, 1998 Sep-Oct. [PUBMED Abstract]
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Reproductive outcomes in childhood cancer survivors may be compromised by surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads. Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment. In particular, the literature is deficient regarding hard outcomes of reproductive potential (e.g., semen analysis in men, primordial follicle count in women) and outcomes after contemporary risk-adapted treatment approaches.[1,2]

The risk of infertility is generally related to the tissues or organs involved by the cancer and the specific type, dose, and combination of cytotoxic therapy.

The St. Jude Children's Research Hospital reported the cumulative risk of hypogonadism and infertility in a cohort of 156 pediatric patients with medulloblastomas who were treated with surgery, risk-adapted craniospinal irradiation, and dose-intensive chemotherapy in the SJMB03 study (2003–2013).[4]

In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility. Pediatric cancer treatment protocols often prescribe combined-modality therapy; thus, the additive effects of gonadotoxic exposures may need to be considered in assessing reproductive potential. Detailed information about the specific cancer treatment modalities, including specific surgical procedures, the type and cumulative doses of chemotherapeutic agents, and radiation treatment volumes and doses, are needed to estimate risks for gonadal dysfunction and infertility.

The treatment-indicated risk of infertility does not simply translate into adult fertility status. This is particularly important for patients who were unable to participate in sperm/oocyte preservation because of their young age when diagnosed and treated for cancer.