• Using SEER data, conditional relative survival up to 25 years after diagnosis was studied in a cohort of AYA patients (N = 205,954) diagnosed with a first malignant cancer (thyroid, melanoma, testicular, breast, lymphoma, leukemia, and CNS tumors).[41]
  • For all cancer types combined, among individuals who survived up to 5 years, the subsequent 5-year relative survival rate exceeded 95% by 7 years after diagnosis.
  • Most AYA cancer patients who survived at least 7 years after diagnosis experienced little difference in survival compared with the general population.
  • For specific cancer types, including CNS tumors, female breast cancer, Hodgkin lymphoma, and leukemia, evidence of excess mortality risk persisted, or re-emerged, more than 10 years after a cancer diagnosis.
  • Conditional relative survival was lowest for AYA patients with CNS tumors, although patients aged 15 to 29 years demonstrated a higher survival rate than did patients aged 30 to 39 years at the time of diagnosis of their CNS tumors.
• A separate analysis of 5-year survivors of AYA cancer (aged 15–39 years at diagnosis), also using SEER data (N = 282,969), demonstrated the following:[42]
  • The 10-year all-cause mortality rate decreased from 8.3% for those diagnosed between 1975 and 1984 to 5.4% for those diagnosed between 2005 and 2011.
  • The decrease in mortality primarily resulted from fewer deaths from the initial cancer.
• CCSS investigators compared chronic health conditions and all-cause and cause-specific mortality among 5,804 survivors of early-AYA cancer survivors (cancer diagnosis, age 15–20 years; median age, 42 years) and 5,804 childhood cancer survivors (cancer diagnosis, age <15 years; median age, 34 years) matched on primary cancer diagnosis.[43]
  • The SMR was 5.9 (95% CI, 5.5–6.2) for early-AYA survivors and 6.2 (95% CI, 5.8–6.6) for younger childhood cancer survivors, compared with the general population.
  • Early-AYA survivors had lower SMRs for death from health-related causes than did childhood cancer survivors (SMR, 4.8 [95% CI, 4.4–5.1] vs. 6.8 [95% CI, 6.2–7.4]), which was primarily evident more than 20 years after cancer diagnosis.
  • Early-AYA and childhood cancer survivors were at greater risk of developing severe and disabling, life-threatening, or fatal (grades 3–5) health conditions than were siblings of the same age (HR, 4.2 [95% CI, 3.7–4.8] for early-AYA and 5.6 [95% CI, 4.9–6.3] for childhood cancer survivors), although the risk was lower for early-AYA survivors than for childhood cancer survivors.
• In a retrospective, population-based cohort study from Kaiser Permanente, cause-specific mortality in 2-year survivors (N = 10,574) of AYA cancers (patients aged 13–39 years who were diagnosed between 1990 and 2012) was examined and compared with individuals without cancer.[45]
  • AYA cancer survivors were at a 10.4-fold increased risk of death compared with the matched noncancer cohort, and this risk remained elevated at more than 20 years after diagnosis (incidence rate ratio [IRR], 2.9).
  • Beginning at 15 years after diagnosis, the incidence of second cancer–related mortality exceeded the rate of recurrence-related mortality.
  • Mortality risk of suicide was doubled in AYA cancer survivors compared with the noncancer cohort.
• Chronic comorbidities were investigated in a retrospective, population-based cohort study of 6,778 2-year AYA cancer survivors diagnosed and monitored at Kaiser Permanente.[46]
  • Approximately 17% of the survivors developed more than one comorbidity. The most common comorbidities were dyslipidemia (22 per 1,000 person-years), hypertension (16 per 1,000 person-years), diabetes (10 per 1,000 person-years), thyroid disorders (9 per 1,000 person-years), and severe depression or anxiety (8 per 1,000 person-years).
  • IRRs were higher in survivors than in controls without a history of cancer for avascular necrosis (IRR, 8.25), followed by osteoporosis (IRR, 5.75), joint replacement (IRR, 3.89), stroke (IRR, 3.19), premature ovarian failure (IRR, 2.87), and cardiomyopathy or heart failure (IRR, 2.64).
  • For survivors of AYA cancer, the prevalence of multiple comorbidities approached 40% at 10 years after index date (a 2-year time point from diagnosis), compared with 20% for those without cancer (P < .001).

• Previous cancer.
• Cancer therapy.
• Genetic predisposition.
• Lifestyle behaviors.
• Comorbid conditions.
• Sex.

• Treatment with cranial radiation doses of 25 Gy or higher was associated with higher odds of unemployment (health related: OR, 3.47; 95% CI, 2.54–4.74; seeking work: OR, 1.77; 95% CI, 1.15–2.71).
• Unemployed survivors reported higher levels of poor physical functioning than employed survivors, had lower education and income, and were more likely to be publicly insured than unemployed siblings.

• Abstinence from smoking, excess alcohol use, and illicit drug use to reduce the risk of organ toxicity and, potentially, subsequent neoplasms.
• Healthy dietary practices (e.g., a diet rich in plant foods and moderate in animal foods) [52] and active lifestyle to reduce treatment-related metabolic and cardiovascular complications.
• Regular physical activity to reduce neurocognitive problems and enhance psychological outcomes.[53,54]
  • Survivors who engaged in consistent physical activity over time had fewer neurocognitive problems, including difficulties with task efficiency, emotional regulation, organization, and memory. They also experienced larger neurocognitive improvements, compared with those who had inconsistent activity levels.[53]
  • Vigorous exercise in survivors has been associated with a lower prevalence of depression and somatization, as well as less impairment in physical functioning, general health and vitality, emotional role limitations, and mental health quality-of-life domains.[54]

• 92.8% of survivors reported receiving some form of medical care in the previous year.[58]
• Nearly 40% reported receiving care that focused on their previous cancer (survivor-focused care).[58]
• Surveillance for new cases of cancer was very low in survivors at the highest risk of colon, breast, or skin cancer, suggesting that survivors and their physicians need education about the risk of subsequent neoplasms and recommended surveillance.[59]
• Sociodemographic factors have been linked to declining rates of follow-up care over time from diagnosis. CCSS participants who were male, had a household income of less than $20,000 per year, and had lower educational attainment (high school education or less) were more likely to report no care at their most recent follow-up survey. This trend is concerning because the prevalence of chronic health conditions increases with longer elapsed time from cancer diagnosis in adults treated for cancer during childhood.[60]
• A study that included 975 adult survivors of childhood cancer identified factors associated with attending the recommended risk-based, cancer-related medical visits. The relative risk of having a cancer-related visit was higher among survivors who:[61]
  • Assigned a greater importance to these visits.
  • Perceived a greater susceptibility to health problems.
  • Had experienced a cancer-related chronic health problem that was moderate to life-threatening.
  • Were seeing a primary care provider for a cancer-related problem.
  • Had received a cancer treatment care plan.
  • Expressed greater confidence in physicians’ abilities to address questions and concerns.

• Cancer-related visits. In the CCSS, uninsured survivors were less likely than those privately insured to report a cancer-related visit (adjusted relative risk, 0.83; 95% CI, 0.75–0.91) or a cancer center visit (adjusted relative risk, 0.83; 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care than privately insured survivors. In contrast, publicly insured survivors were more likely to report a cancer-related visit (adjusted relative risk, 1.22; 95% CI, 1.11–1.35) or a cancer center visit (adjusted relative risk, 1.41; 95% CI, 1.18–1.70) than were privately insured survivors.[62]
• Health care outcomes. In a study comparing health care outcomes for long-term AYA cancer survivors with young adults who have no cancer history, the proportion of uninsured survivors did not differ between the two groups.[64]
• Financial burden. Subgroups of adult survivors of childhood cancer may be at additional risk of health care barriers due to financial hardship. Younger survivors (aged 20–29 years), females, non-White survivors, and survivors reporting poorer health faced more cost barriers, which may inhibit the early detection of late effects.[64] Survivors are more likely than their siblings to forego needed medical care related to financial challenges.[65]

• Details about therapeutic interventions undertaken for childhood cancer and their potential health risks (e.g., chemotherapy type and cumulative dose, radiation treatment fields and dose, surgical procedures, blood product transfusions, and HSCT).
• Personalized health screening recommendations.
• Information about lifestyle factors that modify risks.

• 27% of survivors and 20% of primary care providers (PCP) had a survivorship care plan. Survivors treated after 1990 were more likely to have a survivorship care plan.
• Survivorship care plan possession by high-risk survivors was associated with increased adherence to COG-recommended breast (22% vs. 8%), skin (35% vs. 23%), and cardiac (67% vs. 33%) surveillance. PCP survivorship care plan possession was associated with increased adherence to skin surveillance (40% vs. 23%).
• Among high-risk survivors, adherence increased for colorectal (14% to 41%, P < .001) and cardiac (22% to 38%, P < .001) surveillance and decreased for breast surveillance (38% to 13%, P < .001) between 2007 and 2016.
• For average-risk survivors, better adherence to American Cancer Society recommendations for breast (57%), cervical (84%), and colorectal (69%) screening was observed than with COG recommendations. PCP survivorship care plan possession was associated with increased adherence to breast and colorectal screening. Survivors were less adherent to breast screening than the general population and less adherent to cervical screening than siblings.

• Long-Term Follow-Up Guidelines. COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are appropriate for asymptomatic survivors presenting for routine exposure-based medical evaluation 2 or more years after completion of therapy.
• Health Links. Patient education materials called Health Links provide detailed information on guideline-specific topics to enhance health maintenance and promotion among this population of cancer survivors.[73]

• Variability in the cohort’s age at treatment.
• Age at screening.
• Time from cancer treatment.
• Participation bias.

• 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.[31]
  • 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.[32]
  • 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).

• 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.[18,33–36]
• 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.[33,35,37]

1. Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] 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.[38]
   • Data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[39]
   • 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.[37]
   • 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.[18]
   • 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).[40]
   • 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.[37,41,42]
   • 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).[36]
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).[35]
   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.[43]
      • 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.[44]
   • 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.[33]
   • 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.[25]
      • 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.[45]
      • 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.[46]
   • 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.

• 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.

• 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.[24,28,59]

• The risk of meningioma after radiation increases with radiation dose,[9,61] and in some studies is further potentiated with increased exposure to intrathecal methotrexate.[26] 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.[64–66]

• 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.

• In 69,460 survivors, 279 developed gliomas, and 761 developed meningiomas.
• Gliomas and meningiomas were most frequently observed after any CNS tumor or leukemia, accounting for more than 70% of all observed gliomas and 80% of all meningiomas.
• Among patients with known cranial radiation status who developed a glioma, 61% had received prior cranial radiation therapy. Among patients who developed a meningioma, 64.7% had received cranial radiation therapy.
• CNS tumor survivors treated with cranial radiation therapy were at the highest risk of developing gliomas, at 27 times the risk of the general population (95% CI, 21.5–33.2). CNS tumor survivors who did not receive cranial radiation were at 8.3 times the risk of the general population (95% CI, 4.9–14.1).
• Among CNS tumor survivors, the relative risk for patients who received cranial radiation therapy was 13 times the risk for patients who did not receive cranial radiation therapy (95% CI, 6.7–25.4). Among leukemia survivors, those who received cranial radiation therapy were at a 5-fold increased risk compared with those treated without cranial radiation therapy (95% CI, 2.9–9.9).

• A significant dose-response relationship was reported for CNS subsequent meningiomas (excess relative ratio [ERR]/Gy, 0.44).
• Younger age at the time of primary diagnosis was associated with a higher risk of subsequent meningiomas.
• Females had a higher risk of subsequent meningiomas than males (odds ratio, 1.46; P < .0001).
• Median latency time to the development of meningiomas was 21 years.

• 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%.

• Radiation therapy is associated with a linear dose-response relationship.[75,76]
• In a PENTEC investigation on subsequent malignancies, the estimated pooled ERR/Gy for subsequent sarcomas was 0.045. There was a possible biphasic dose response, with higher rates of relapse and subsequent sarcomas above 55 Gy. After 20 Gy and anthracyclines, the absolute excess risk is predicted to be 0.24% at 50 years and 0.86% at 75 years. The median latency time to the development of sarcomas was 11 years (range, 4–23 years).[61]
• After adjustment for radiation therapy, treatment with alkylating agents [13,61] and anthracyclines [77] have both been linked to sarcoma, with the risk increasing with cumulative drug exposure.[77]
• 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.

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.[78]
   • 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:[71,72]
   • 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.[71]
   • The observed excess numbers of subsequent primary bone cancer declined with both age and years from diagnosis.[71]
   • 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%.[72]
   • The median time from diagnosis to occurrence of a soft tissue sarcoma was 19 years.[72]
   • The most commonly observed soft tissue sarcomas were leiomyosarcoma, fibromatous neoplasms, and malignant peripheral nerve sheath tumors.[72]
   • 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.[72]
   • 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).[72]
   • 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.[72]
     • 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.[27]
   • 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).[75]
   • 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.[79–81] 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.[70]
   • 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:[77]
   • 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.[81]
   • 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.[73]
   • 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.

1. An updated analysis of the CCSS confirmed an increased risk of KCs in participants with histories of radiation therapy. Compared with participants who did not receive radiation therapy, CCSS participants treated with radiation therapy had a 4.5-fold increased risk of KCs (95% CI, 3.5–5.9).[83]
   • The risk of KCs increased with higher radiation therapy doses. Per 10 Gy of radiation therapy at the KC site, the RR was similar for head/neck (1.0; 95% CI, 1.0–1.1) and extremity sites (1.0; 95% CI, 0.7–1.3). The RR was slightly higher for trunk sites (1.1; 95% CI, 1.0–1.3).
   • Allogeneic and autologous HSCT were associated with an increased risk of KCs (RR for allogeneic HSCT, 3.4; 95% CI, 2.4–4.8 and RR for autologous HSCT, 2.3; 95% CI, 1.2–4.2).
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.[30]
   • 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 a KC 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 a KC as a first SN, compared with 10.7% (95% CI, 7.2%–14.2%) among survivors whose first SN was an invasive malignancy.

• Radiation therapy (>40 Gy).
• Alkylating agents.
• Bleomycin.

1. Investigators assessed the incidence, risk factors, and outcomes for patients with melanoma in the CCSS cohort (n = 25,716).[85]
   • There were 160 survivors (median attained age, 33 years) who developed 177 melanomas (110 invasive, 62 in situ cutaneous, 5 ocular).
   • The 40-year cumulative incidence was 1.1% for all participants and 1.5% for those who received cumulative radiation doses of 40 Gy or higher. The standard incidence ratios were 2.0 when compared with the general population.
   • An increase in cutaneous melanomas was associated with a cumulative radiation dose of 40 Gy or higher to the site of the melanoma (HR, 2.0), cumulative cyclophosphamide equivalent dose of 20,000 mg/m2 or higher (HR, 1.9), and bleomycin exposure (HR, 2.2).
   • The presence of an invasive melanoma was associated with a twofold risk of death.
2. 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.[86]
   • 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.

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).[88]
   • 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.[89]
   • 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.[89]
   • 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).

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.[93]
   • 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.[92]
   • 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).[90]
   • 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:[91]
   • 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.[94]
   • 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.[95]
   • 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.[96]
   • 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).[97]
   • 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 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.

• 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).

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.[100]
   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).[100] Radiation has been hypothesized to predispose children with high-risk neuroblastoma to renal carcinoma.[105]
      • Those treated with renal-directed radiation therapy of 5 Gy or higher (RR, 3.8; 95% CI, 1.6–9.3).[100]
      • Those treated with platinum-based chemotherapy (RR, 3.5; 95% CI, 1.0–11.2).[100]

• Among 4,402 survivors who underwent whole-genome sequencing, 495 (11.2%) developed 1,269 SNs.
• Among 508 survivors (11.5%), 538 pathogenic germline variants were identified in 98 DNA repair pathways (e.g., POLG, MUTYH, ERCC2, and BRCA2).

  The following three groups were identified to have an elevated risk of SNs:

  • Female survivors with variants in homologous recombination genes who were treated with high doses (≥20 Gy) of chest radiation (RR, 4.4; 95% CI, 1.6–12.4) or a cumulative dose of anthracyclines in the second or third tertile (RR, 4.4; 95% CI, 1.7–11.4) had a significantly increased risk of breast cancer.
  • Survivors with variants in homologous recombination genes who received alkylating agent doses in the third tertile had an increased rate of subsequent sarcomas (RR, 14.9; 95% CI, 4.0–38.0).
  • Survivors with variants in nucleotide excision repair genes who were treated with neck radiation (≥30 Gy) had an increased risk of subsequent thyroid cancer (RR, 12.9; 95% CI, 1.6–46.6).

• In survivors of predominantly European ancestry, standardized PRS were significantly associated with the risk of subsequent BCCs (OR, 1.37; n = 958), female breast cancers (OR, 1.42; n = 360), thyroid cancers (OR, 1.48; n = 259), squamous cell carcinomas (OR, 1.20; n = 127), and melanomas (OR, 1.60; n = 103). The association between colorectal cancer PRS and subsequent colorectal cancer risk did not reach the threshold for statistical significance (OR, 1.19; n = 67).
• Childhood cancer survivors with a higher PRS and who received radiation therapy had more-than-additive increased risks of developing BCCs, breast cancers, and thyroid cancers.
• For female survivors who were exposed to chest radiation therapy (>10 Gy), those with high PRS had an increased cumulative incidence of subsequent breast cancer by age 50 years, compared with those with low PRS.

• The most frequent SMNs developing in 1,594 survivors included BCC (n = 822), breast cancer (n = 235), and thyroid cancer (n = 221).
• SMN risk associations with the PRS were extremely modest in survivors with European ancestry who were exposed to radiation therapy (HR, 1.22; n = 4,630).
• Among survivors with European ancestry who did not receive radiation therapy (n = 4,322), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant for those treated with alkylating agents (17% vs. 6%; HR, 2.46; P < .01), anthracyclines (20% vs. 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% vs. 1%; HR, 12.20; P < .001), or platinums (46% vs. 7%; HR, 8.58; P < .01).
• Among survivors with African ancestry who did not receive radiation therapy (n = 414), the PRS also significantly predicted epipodophyllotoxin-related SMN risk. The greatest improvements in risk prediction were for survivors who were exposed to epipodophyllotoxins (HR, 2.68; P < .01).

• Cumulative dose, particularly greater than 250 to 300 mg/m2.
• Younger age at time of exposure, particularly children younger than 5 years.
• Increased time from exposure.
• While there is no definitive safe lower dose threshold, doses in excess of 250 to 300 mg/m2 have been associated with a substantially increased risk of cardiomyopathy, with cumulative incidences exceeding 5% after 20 years of follow-up, and in some subgroups, reaching or exceeding 10% cumulative incidence by age 40 years.[18,19,32]
• Concurrent chest or heart radiation therapy also further increases risk of cardiomyopathy,[10,28,34] as does the presence of other cardiometabolic traits such as hypertension.[8,35]
• While development of clinical heart failure can occur within a few years after anthracycline exposure, in most survivors—even those who received very high doses—clinical manifestations may not occur for decades.

• Various cancer treatment exposures may also directly or indirectly influence the development of hypertension, diabetes mellitus, and dyslipidemia.
• These conditions remain important among cancer survivors, as they do in the general population, in that they are independent risk factors in the development of cardiomyopathy, ischemic heart disease, and cerebrovascular disease.[8,69–72]
• Childhood cancer survivors should be closely monitored for the development of these cardiovascular conditions because they represent potentially modifiable targets for intervention.
• Related conditions such as obesity and various endocrinopathies (e.g., hypothyroidism, hypogonadism, growth hormone deficiency) that may be more common among subsets of childhood cancer survivors also need to be monitored. If these conditions are untreated/uncontrolled, they may be associated with a metabolic profile that increases cardiovascular risk.[9] For more information, see the Risk prediction for cardiovascular diseases section.

• There is no clear evidence (at least through age 50 years or 30–40 years posttreatment) that a plateau in risk occurs after a certain time among survivors exposed to cancer treatments associated with cardiovascular late effects.[90,91] Thus, life-long surveillance is recommended by one group, even if the cost-effectiveness of certain screening strategies remains unclear.[33,92–94]
  

  Table 2. Risk Groups and Cardiomyopathy Surveillance Recommendations for Survivors of Childhood, Adolescent, and Young Adult Cancera

  Risk Group	Anthracycline (mg/m2)	Chest-Directed Radiation Therapy (Gy)	Anthracycline (mg/m2) + Chest-Directed Radiation Therapy (Gy)	Is Screening Recommended?	At What Interval?
  NA = not applicable.
  aAdapted from Ehrhardt et al.[33]
  High risk	≥250	≥30	≥100 and ≥15	Yes	2 years
  Moderate risk	100 to <250	15 to <30	NA	Maybe	5 years
  Low risk	>0 to <100	>0 to <15	NA	No	No screening

• A growing body of literature is beginning to establish the yield from these screening studies, which will help inform future guidelines.[9,95–97] In these studies, for example, among adult-aged survivors of childhood cancer, evidence for cardiomyopathy on the basis of echocardiographic changes was found in approximately 6% of at-risk survivors. Overall, in a cohort of more than 1,000 survivors (median age, 32 years), nearly 60% of screened at-risk survivors had some clinically ascertained cardiac abnormality identified.[9]
• Given the growing evidence that conventional cardiovascular conditions such as hypertension, dyslipidemia, and diabetes substantially increase the risk of more serious cardiovascular disease among survivors, clinicians should carefully consider baseline and follow-up screening and treatment of these comorbid conditions that impact cardiovascular health (see Table 3).[8,57,69,98]
• There is also emerging evidence that adoption of healthier lifestyle factors may decrease future cardiovascular morbidity in at-risk survivors.[99,100] Thus, similar to the general population, survivors should be counseled about maintaining a healthy weight, participating in regular physical activity, adhering to a heart-healthy diet, and abstaining from smoking.
• The COG has organized handouts on cardiovascular disease and related topics, including lifestyle choices, written for a lay audience to facilitate counseling and education of survivors. For more information, see the COG Survivorship Guidelines.

• Using data from four large, well-annotated childhood cancer survivor cohorts (CCSS, National Wilms Tumor Study Group, the Netherlands, and SJCRH), a heart failure risk calculator based on readily available demographic and treatment characteristics has been created and validated. This calculator may provide more individualized clinical heart failure risk estimation for 5-year survivors of childhood cancer who have recently completed therapy, through age 40 years. Because of the young age of participants at the time of baseline prediction (5-year survival), this estimator is limited in that information on conventional cardiovascular conditions such as hypertension, dyslipidemia, or diabetes could not be incorporated.[34]
• In another collaborative study, data from the CCSS, Netherlands, and SJCRH were used to develop risk-prediction models for ischemic heart disease and stroke among 5-year survivors of childhood cancer through age 50 years. Risk scores derived from a standard prediction model that included sex, chemotherapy exposure, and radiation therapy exposure identified statistically distinct low-risk, moderate-risk, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were less than 5%, compared with approximately 20% for high-risk groups and only 1% for siblings.[63]
• Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-aged survivors of childhood cancer. This finding was demonstrated by a CCSS investigation that constructed prediction models accounting for cardiotoxic cancer treatment exposures, combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes. Risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes information showed good performance (area under the receiver operating characteristic curve and concordance statistics ≥0.70) for predicting cardiovascular events in the models applied to the discovery and replication cohorts. The most influential exposures were anthracycline chemotherapy, radiation therapy, diabetes, and hypertension.[98]
• Physical activity has been shown to be a safe intervention against the high burden of cardiovascular late effects in childhood cancer survivors. A randomized controlled trial investigated the effect of a partially supervised, personalized, 1-year physical activity intervention on cardiovascular health in long-term survivors of childhood cancer.[101] There were 151 childhood cancer survivors randomly assigned (1:1) to either perform more than 2.5 hours of additional intense physical activity per week (intervention group) or continue exercise as usual (control group). A significant and robust reduction of the cardiovascular disease risk score was noted at 6 months and 12 months in the intervention group, compared with the control group. The difference in the reduction of the cardiovascular disease risk z-score of -0.18 (P = .003) at 12 months favored the intervention group.

• Cranial radiation therapy.
  • Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity, particularly in younger children.[3,4]
  • There is an established dose-response relationship, with patients who receive higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures.[3,4,16]
  • Radiation dose to specific regions of the brain, including the temporal lobes and hippocampi, have been shown to significantly impact longitudinal IQ scores and academic achievement scores among children treated with craniospinal irradiation for medulloblastoma.[17]
• Tumor site.[3]
• Shunted hydrocephalus.[18,19]
• Postsurgical cerebellar mutism.[20]
• Auditory difficulties, including sensorineural hearing loss.[12,18]
• History of stroke.[21]
• Seizures.[3,22]
• Socioeconomic status (SES).[23]

• The decline continues 5 to 10 years afterward, although less is known about potential stabilization or further decline of IQ scores several decades after diagnosis.[24,26]
• The decline in IQ scores over time typically reflects the child’s failure to acquire new abilities or information at a rate similar to that of his or her peers, rather than a progressive loss of skills and knowledge.[27]
• Affected children also may experience deficits in other cognitive areas, including academic domains (reading and math) and problems with attention, processing speed, memory, and visual or perceptual motor skills.[28]
• Changes in cognitive functioning may be partially explained by radiation-induced reduction of normal-appearing white matter volume or integrity of white matter pathways, as evaluated through magnetic resonance imaging (MRI).[29,30]
  • Reduced white matter integrity has been directly linked to slowed cognitive processing speed in survivors of brain tumors,[31] while greater white matter volume has been associated with better working memory, particularly in females.[30]
  • Data from contemporary protocols show that using lower doses of cranial radiation, proton beam radiation, and more targeted treatment volumes appears to reduce the severity of neurocognitive effects of therapy.[3,19]

1. A multisite, prospective, longitudinal trial evaluated predictors of cognitive performance among 139 infants with brain tumors who were treated with chemotherapy, with or without focal proton or photon radiation therapy.[32]
   • IQ, parent-reported working memory, and parent-reported adaptive functioning were worse than normative expectations at baseline, with younger age and lower SES representing predictive factors.
   • IQ remained stable over time, whereas parent-reported attention and executive dysfunction increased.
   • Cognitive outcomes did not differ by treatment exposure (chemotherapy only vs. chemotherapy with radiation therapy).
   • Changes in cognitive function were associated with supratentorial tumor location and cerebrospinal fluid diversion.
2. St. Jude Children’s Research Hospital (SJCRH) studied 78 children younger than 20 years (mean, 9.7 years) diagnosed with a low-grade glioma.[33]
   • Cognitive decline after 54 Gy of conformal cranial radiation therapy was noted (see Figure 5).
   • Age at time of cranial irradiation was more important than was cranial radiation dose in predicting cognitive decline, with children younger than 5 years estimated to experience the greatest cognitive decline.

     Enlarge

3. In a study of 51 children with low-grade gliomas and low-grade glioneural tumors diagnosed within the first year of life, the following was reported:[34]
   • Mean IQ score was 75.5; 75% of the children had IQ scores lower than 85.
   • Predictors of low IQ included a supratentorial location of the primary tumor and treatment with more chemotherapy regimens but not radiation use.
   • The child’s ability to complete age-appropriate tasks was as affected as IQ scores.
4. A study of 126 medulloblastoma survivors treated with 23.4 Gy or 36 Gy to 39.6 Gy of craniospinal radiation (with a conformal boost dose of 55.8 Gy to the primary tumor bed) assessed processing speed, attention, and memory performance.[35]
   • Processing speed scores declined significantly over time, while less decline was observed in attention and memory performance. Higher doses of radiation and younger age at diagnosis predicted slower processing speed over time.
   • Studies of working memory and academic achievement in patients enrolled on the same medulloblastoma trial (SJCRH SJMB03 [NCT00085202]) indicated that performance was largely within the age-expected range up to 5 years postdiagnosis,[36,37] although in both studies, posterior fossa syndrome, higher cranial radiation dose, and younger age at diagnosis predicted worse performance over time.
   • Serious hearing loss was associated with intellectual and academic decline over time.[37]
5. In a prospective study of 178 children with medulloblastoma, 60 (34%) developed posterior fossa syndrome. Of these patients, 40 (23%) developed complete mutism and 20 (11%) developed diminished speech.[38]
   • All children with posterior fossa syndrome had severe ataxia, and 42.5% of patients with posterior fossa syndrome and complete mutism had movement disorders.
   • Independent risk factors for posterior fossa syndrome included younger age and surgery in a low-volume surgery center. Risk was lower among children with sonic hedgehog (SHH) tumors.
   • Speech and gait returned in children with posterior fossa syndrome and complete mutism at a median of 2.3 and 0.7 months, respectively. Speech and gait returned in children with posterior fossa syndrome and diminished speech at a median of 2.1 and 1.5 months, respectively. However, with 12 months of follow-up, 12 of 27 children (44.4%) with posterior fossa syndrome and complete mutism were nonambulatory at 1 year.
   • The presence of a movement disorder or high ataxia score was associated with delayed speech recovery, whereas older age and high ataxia score were associated with delayed gait return.
   • Symptoms improved in all children, but no child with posterior fossa syndrome had a normal neurological examination at a median of 23 months after surgery.
6. A prospective study compared 36 pediatric patients with medulloblastoma who experienced posterior fossa syndrome with 36 patients with medulloblastoma who did not experience posterior fossa syndrome but were matched on treatment and age at diagnosis.[38,39]
   • The posterior fossa syndrome group demonstrated lower mean scores at 1, 3, and 5 years postdiagnosis on general intellectual ability, processing speed, working memory, and spatial relations compared with the non–posterior fossa syndrome group.
   • The group who experienced posterior fossa syndrome showed little recovery over time and further decline over time in some domains (attention and working memory), compared with the non–posterior fossa syndrome group.
7. Canadian investigators evaluated the impact of radiation (dose and boost volume) and neurological complications on patterns of intellectual functioning in a cohort of 113 medulloblastoma survivors (mean age at diagnosis, 7.5 years; mean time from diagnosis to last assessment, 6 years).[4]
   • Survivors treated with reduced-dose craniospinal radiation therapy plus tumor bed boost showed stable intellectual functioning.
   • Neurological complications, such as hydrocephalus requiring cerebrospinal fluid diversion and mutism, and treatment with higher doses and larger boost volumes of radiation resulted in intellectual declines with distinctive trajectories.
8. Studies are beginning to examine cognitive outcomes in histologically distinct subtypes of brain tumors.
   • Data from a sample of 121 medulloblastoma patients demonstrated variation in cognitive outcomes by four distinct molecular subgroups and differences in patterns of change over time.[40]
   • Future research is required to establish if neurocognitive outcomes vary across biologically distinct subtypes of childhood brain tumors.
9. SES has been shown to predict long-term cognitive outcomes in brain tumor survivors. In a prospective, longitudinal, phase II study of 248 children who were treated with conformal radiation therapy (54–59.4 Gy) for ependymoma, low-grade glioma, or craniopharyngioma, patients were monitored serially with cognitive assessment for 10 years.[23]
   • At preradiation therapy baseline, significant associations were seen between SES and IQ, reading and math scores, sustained attention, and adaptive function. Higher SES was associated with better performance (P < .005).
   • SES predicted change over time in IQ and reading and math scores. Higher SES was associated with less decline (P < .001).
   • These results suggest that higher SES is a protective factor for cognitive late effects.

1. A longitudinal study evaluated the relationship of hippocampal dose and short-term memory decline in 80 children and adolescents with low-grade gliomas (median age, 9.5 years at treatment) who received 54 Gy of radiation therapy.[41]
   • At a median neurocognitive follow-up of 9.8 years, higher hippocampal dose (volume receiving 40 Gy) was associated with a greater decline in delayed recall.
2. Among adult survivors participating in the CCSS, CNS tumor survivors (n = 802) self-reported significantly more problems with attention/processing speed, memory, emotional control, and organization than did survivors of non-CNS malignancies (n = 5,937) and sibling controls (n = 382).[42]
3. Another CCSS study evaluating patterns of late mortality and morbidity in 2,821 adult survivors of CNS tumors reported impairment on measures of attention/processing speed (42.9%–73.3%) and memory (14.3%–37.4%), with differences observed by diagnosis and cranial radiation dose.[43]
4. A study of 224 adult survivors of pediatric brain tumors participating in the St. Jude Life (SJLIFE) cohort study revealed that 20% to 30% of the survivors demonstrated severe neurocognitive impairment (defined as at least two standard deviations below normative mean) on clinical assessments of intelligence, memory, and executive function (e.g., planning, organization, and flexibility).[3]
   • Among adults in the general population, the expected impairment rate at this threshold is 2%.
   • Survivors who received whole-brain cranial irradiation were 1.5 to 3 times more likely to have severe neurocognitive impairment than were survivors who did not receive any cranial irradiation.
   • Hydrocephalus with shunt placement and seizures were also associated with increased risk of impairment.
5. In the CCSS, investigators compared long-term neuropsychological and SES outcomes of 181 adult survivors of pediatric low-grade gliomas with the outcomes of an age-matched and sex-matched sibling comparison group.[44]
   • Survivors who were treated with surgery and radiation therapy (median age at diagnosis, 7 years; median age at assessment, 41 years) scored lower on estimated IQ than did survivors who were treated with surgery only, who scored lower than siblings (surgery and radiation therapy, 93.9; surgery only, 101.2; siblings, 108.5; all P values < .0001).
   • Younger age at diagnosis was predictive of low scores for all neuropsychological outcomes except for attention/processing speed.
   • Survivors who were treated with surgery and radiation therapy had more-than-twofold–lower occupation scores, income, and education than did survivors who were treated with surgery only.
6. In a retrospective review of 528 brain tumor survivors diagnosed between 2000 and 2015, the prevalence of a clinical diagnosis of ADHD was 13.1%.[45]
   • Of the survivors, 12.1% used medications for ADHD, and 19.9% of survivors had symptoms of ADHD without a clinical diagnosis.
   • ADHD diagnosis was associated with younger age at tumor diagnosis and supratentorial tumor location, but not with sex, tumor type, or treatment type.

• In childhood and adolescence, neurocognitive deficits have been associated with poor social adjustment, including problems with peer relations, social withdrawal, and reduced social skills.[46,47]
• CNS tumor survivors are more likely to need special education services than are survivors of other malignancies.[48]
• Adult CNS tumor survivors are less likely to live independently, marry, and graduate from college than are survivors of other malignancies and siblings.[49]

• 13% to 21% of survivors reported impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that reported in the sibling comparison group.
• Factors such as diagnosis before age 6 years, female sex, cranial radiation therapy, and hearing impediment were associated with impairment.

• CNS-treated survivors performed worse than non–CNS-treated survivors on all neurocognitive tests, and they were more likely to have global neurocognitive impairment (46.9% vs. 35.3%).
• A dose-response association was observed between severity/burden score of chronic health conditions and global neurocognitive impairment only among CNS-treated survivors (high OR, 2.24; 95% CI, 1.42–3.53; very high OR, 4.07; 95% CI, 2.30–7.17).
• Cardiovascular and pulmonary conditions were associated with cognitive outcomes (processing speed, executive function, and memory impairment) only in CNS-treated survivors with neurological conditions.

• Acute myeloid leukemia (AML). CCSS investigators compared the neurocognitive and psychosocial outcomes of 482 survivors (median age, 30 years) with those of 3,190 sibling controls (median age, 32 years).[76]
  • Compared with siblings, AML survivors were more likely to report impairment in overall emotional (RR, 2.19; 95% CI, 1.51–3.18), neurocognitive (RR, 2.03; 95% CI, 1.47–2.79), and physical quality of life (RR, 2.71; 95% CI, 1.61–4.56) outcomes.
  • Survivors were also at increased risk of psychosocial deficits, including lower educational attainment (RR, 1.15; 95% CI, 1.03–1.30), unemployment (RR, 1.41; 95% CI, 1.16–1.71), and lower income (RR, 1.39; 95% CI, 1.17–1.65).
  • Outcomes were not statistically different between survivors who were treated with transplant and survivors who were treated with intensive chemotherapy alone.
• Osteosarcoma. In a study evaluating neurocognitive function among 80 long-term survivors of osteosarcoma (mean time since diagnosis, 24.7 years), survivors demonstrated lower mean scores in reading skills, attention, memory, and processing speed than did community controls.[77]
  • The presence of cardiac, pulmonary, and endocrine conditions were significantly associated with worse performance on measures of memory and processing speed.
• Soft tissue sarcoma. A CCSS report characterized the prevalence of and risk factors for self-reported neurocognitive impairment in survivors of rhabdomyosarcoma (n = 713) and their siblings (n = 706). The report also identified risk factors associated with these outcomes in survivors.[78]
  • Compared with their siblings, more survivors reported neurocognitive impairments (task efficiency: 21.1% vs. 13.7%; emotional regulation: 16.7% vs. 11.0%; memory: 19.3% vs. 15.1%). Cranial radiation exposure increased the risk of impaired task efficiency (OR, 2.30).
  • Smoking was associated with impaired task efficiency (OR, 2.06) and memory (OR, 2.23).
  • Neurological and hearing conditions were associated with impaired memory (OR, 2.44 and OR, 1.87, respectively).

  SJLIFE study investigators evaluated neurocognitive function and health status through objective clinical assessments in 150 survivors of childhood soft tissue sarcoma (median age, 33 years; median time from diagnosis, 24 years).[79]

  • Compared with community and population controls, survivors demonstrated lower measures of verbal reasoning, mathematics, and long-term memory.
  • Cumulative anthracycline exposure (per 100 mg/m2) was found to be associated with poorer verbal reasoning, reading, and patient-reported vitality.
  • Neurological and neurosensory chronic conditions were associated with poorer mathematics scores and hearing impairment.
  • Better cognitive performance was associated with higher social attainment.
• Wilms tumor. SJLIFE study investigators examined the prevalence and predictors of neurocognitive outcomes, social attainment, emotional distress, and health-related quality of life in long-term survivors of pediatric Wilms tumor (n = 158; median time since diagnosis, 29 years; median age, 33 years) and compared the results to community controls.[80]
  • Long-term Wilms tumor survivors demonstrated lower neurocognitive function, including verbal reasoning, academics, attention, memory, and executive function, than did controls.
  • Wilms tumor survivors were less likely to graduate from college (OR, 2.23) and had more moderate-to-severe neurological conditions than did controls (18.4% vs. 8.2%; P < .001).
• Retinoblastoma. Serial assessment of cognitive and adaptive functioning in a group of retinoblastoma survivors younger than 6 years revealed declines in developmental functioning over time, with the most pronounced declines observed in patients with 13q deletions.[81]
  • Further longitudinal follow-up of this cohort identified improvement in adaptive functioning in all treatment groups and in cognitive function in survivors who were treated with enucleation alone from the age of 5 years to the age of 10 years.[82]
  • At age 10 years, overall functioning was generally within the average range, although estimated IQ was significantly below the normative mean for children who were treated with enucleation alone.[82]

  A study of very long-term adult survivors, who were on average 33 years postdiagnosis, demonstrated largely average cognitive functioning across domains of intelligence, memory, attention, and executive function.[83]

• Lymphoma. Survivors of lymphoma have not historically been considered at risk of developing neurocognitive late effects.
  • However, one report observed that more than two-thirds of survivors of childhood non-Hodgkin lymphoma experienced at least mild neurocognitive impairment, including severe deficits in executive function (13%), attention (9%), and memory (4%).[84]
  • Similarly, in a study of 62 adult survivors of childhood Hodgkin lymphoma, survivors demonstrated worse performance on measures of sustained attention, short- and long-term memory, and cognitive fluency when compared with national normative data.[85] Importantly, measures of cardiac and pulmonary function were also associated with neurocognitive impairment in this group of survivors.
• Neuroblastoma. CCSS investigators compared cognitive outcomes among 837 survivors of neuroblastoma (median age, 1 year at diagnosis; median attained age, 25 years) and a sibling cohort (median attained age, 23 years) using the CCSS Neurocognitive Questionnaire (NCQ).[86]
  • Survivors had a 50% higher risk of impairment with attention/processing speed and emotional regulation.
  • The risk of neurocognitive impairments was higher among survivors with chronic health conditions.
  • Survivors were also less likely to attain adult milestones, such as living independently.

• A survey study evaluated late neurocognitive outcomes among 199 survivors of HSCT (HSCT at age <21 years; median follow-up from HSCT, 27.6 years).[87]
  • As assessed by the CCSS NCQ, 18.9% to 32.5% of survivors reported impairments in task efficiency, memory, emotional regulation, or organization, compared with the expected rate of 10% (general population).
  • Quality of life, as assessed by Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL), among survivors (average T score, 49.6) was comparable to that of the normative population (50).
  • Independent risk factors for impaired Neuro-QoL (T score <40) included hearing issues (OR, 4.7; 95% CI, 1.96–12.6), history of stroke or seizure (OR, 4.46; 95% CI, 1.44–13.8), and sleep disturbances (OR, 6.96; 95% CI, 2.53–19.1).
• SJCRH investigators examined the influence of age and conditioning with total-body irradiation (TBI) on the trajectory of cognitive function after HSCT. Among 315 patients who completed a baseline assessment, 183 were alive at 1 year after HSCT and completed additional assessments at 1, 3, and 5 years.[88]
  • At 5 years after HSCT, younger patients (aged <3 years at baseline) who received TBI demonstrated a significantly lower IQ than those who did not receive TBI.
  • Longitudinal analyses demonstrated a significant impact of age and TBI over time with declines in cognitive functioning during the first year among the youngest patients and recovery of functioning in subsequent years among patients who did not receive TBI.
  • Young patients who received TBI failed to recover the losses experienced during the first year after HSCT, demonstrating stability in their functioning, but at a lower level.

• In 1,876 5-year survivors of CNS tumors from the CCSS, the incidence of seizures increased from 27% in survivors 5 years from diagnosis to 41% in survivors 30 years from diagnosis.[90]
  • Late-onset seizures were associated with frontal lobe radiation of 50 Gy (hazard ratio [HR], 1.8) and temporal lobe radiation in a dose-dependent fashion (HR, 1.9 for 1–49 Gy; HR, 2.2 for >50 Gy).
  • Other risk factors associated with late-onset seizures included recurrence (HR, 2.3), development of meningioma (HR, 2.6), and history of stroke (HR, 2.0).
  • The risk of seizures was elevated for survivors compared with siblings (HR, 12.7).
• Among survivors of childhood leukemia in the CCSS (N = 4,151; 64.5% treated with cranial irradiation), 6.1% reported the development of a seizure disorder, and seizures occurred more than 5 years after diagnosis in 51% of these patients.[91]
• An SJLIFE study evaluated the impact of seizure-related factors on neurocognitive, health-related quality of life (HRQOL), and social outcomes in 2,022 childhood cancer survivors (median age, 31.5 years; median time from diagnosis, 23.6 years).[92]
  • Seizures were identified in 232 survivors (11.5%; 29.9% of survivors with CNS tumors and 9.0% of survivors without CNS tumors).
  • Among CNS tumor survivors, seizures were associated with poorer (based on expected age-adjusted standard z-scores) executive function and processing speed. Seizure resolution was associated with improved attention and memory.
  • Among non-CNS tumor survivors, seizures were associated with worse function in all cognitive domains compared with survivors without seizures. Seizure severity was associated with worse processing speed, and resolution of seizures was associated with better executive function and attention.
  • Non-CNS survivors with seizures had poorer HRQOL outcomes (physical functioning, physical role limitations, and general health). Seizures in both non-CNS and CNS tumor survivors increased the risk of unemployment and part-time employment.

• Peripheral neuropathy presents during treatment and appears to improve or clinically resolve after completion of therapy.[93] However, recent studies of long-term survivors suggest that chemotherapy-induced peripheral neuropathy is likely under-ascertained.[96]
• Higher cumulative doses of vincristine and/or intrathecal methotrexate have been linked to neuromuscular impairments in long-term survivors of childhood ALL, which suggests that persistent effects of these agents may affect functional status in aging survivors.[93]
• SJLIFE study investigators observed associations between peripheral neuropathy and impairment in performance measures of movement (mobility and walking endurance) and quality of life (physical functioning, role physical, and general health) among survivors of childhood ALL.[97]
• Static-standing balance impairment (a predictor of falling within the next 90 days) was more common in survivors compared with controls but was not associated with peripheral neuropathy.[97]
• Among adult survivors of extracranial solid tumors of childhood (median time from diagnosis, 25 years), standardized assessment of neuromuscular function disclosed motor impairment in association with vincristine exposure and sensory impairment in association with cisplatin exposure.[94]
  • Survivors with sensory impairment demonstrated a higher prevalence of functional performance limitations related to poor endurance and mobility restrictions.

• Childhood CNS tumor survivors have a 43-fold elevated risk of stroke compared with siblings.[43,98]
  • Cranial radiation therapy (dose dependent), baseline atherosclerosis, hypertension, and African American ethnicity are identified risk factors.[99–101] For information about stroke, see the Cerebrovascular disease section.
• A British CCSS (n = 13,457 survivors) that included 2,885 childhood CNS tumor survivors reported the following:[102]
  • CNS tumor survivors who were treated with cranial irradiation had an increased risk of developing cerebrovascular disease between the ages of 50 years and 65 years.
  • Compared with an expected incidence of 4.2%, the cumulative incidence of cerebrovascular disease in survivors was 11.6% by age 40 years, 16% by age 50 years, and 26% by age 65 years.
• Among 271 CCSS participants with a history of stroke at a median age of 19 years, 70 reported a second stroke at a median age of 32 years.[103]
  • The 10-year cumulative incidence of late recurrent stroke was 21% overall, and 33% for those treated with 50 Gy or higher cranial radiation therapy.
  • Risk factors for recurrent stroke included the following:
    • Cranial radiation therapy 50 Gy or higher (HR, 4.4; 95% CI, 1.4–13.7).
    • Hypertension (HR, 1.9; 95% CI, 1.0–3.5).
    • Older age at first stroke (HR, 6.4; 95% CI, 1.8–23).
• A PENTEC review identified 101 of 3,989 pediatric patients who experienced at least one cerebrovascular toxicity (transient ischemic attack, stroke, moyamoya, or arteriopathy).[104]
  • Predicted incidences were based on the radiation dose to the Circle of Willis: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy.
  • At an attained age of 35 years, the predicted stroke incidence was 0.9% to 1.3% for 30 Gy, 1.8% to 2.7% for 45 Gy, and 2.8% to 4.1% for 54 Gy (compared with a baseline risk of 0.2%–1.0%).
  • At an attained age of 45 years, the predicted stroke incidence was 1.2% to 4.2% for 30 Gy, 4.5% to 8.6% for 45 Gy, and 6.7% to 13% for 54 Gy (compared with a baseline risk of 0.5%–1.0%).

• In a retrospective review of brain tumor patients treated at SJCRH, investigators identified 39 of 2,336 patients who were diagnosed with hypersomnia/narcolepsy, for a prevalence rate of 1,670 cases per 100,000, which is much higher than a prevalence rate of 20 to 50 cases per 100,000 reported in the general population.[105]
  • This may be an underestimate in childhood brain tumor survivors because many patients with mild-to-moderate symptoms, such as fatigue and sleep disturbances, may not be recognized or referred to a sleep specialist.
  • Hypersomnia/narcolepsy was diagnosed at a median of 6 years (range, 0.4–13.2 years) from tumor diagnosis and 4.7 years (range, 1.5–10.4 years) from cranial radiation.
  • Midline tumor location and antiepilepsy drug use correlated with hypersomnia/narcolepsy, while radiation dose higher than 30 Gy trended toward significance.
  • Posterior fossa tumor location was associated with a reduced risk of hypersomnia.
  • Treatment of hypersomnia/narcolepsy should be individualized and pharmacologic intervention with stimulants may be beneficial.
• In a baseline evaluation of 82 childhood CNS tumor survivors (median age, 13.8 years) participating in a randomized controlled trial of neurofeedback, 48% of survivors endorsed sleep problems and scored significantly worse than the norm on the Sleep Disturbance Scale for Children in the subscales for initiating and maintaining sleep, excessive somnolence, and total scale.[106]
  • Emotional problems and/or hyperactivity/inattention were independent potential risk factors for sleep problems. Sleep problems were also associated with worse parent-reported executive functioning.

• In a report from the CCSS that compared self-reported neurological late effects among 4,151 adult survivors of childhood ALL with siblings, survivors were at elevated risk for late-onset coordination problems, motor problems, seizures, and headaches.[91]
  • The overall cumulative incidence was 44% at 20 years. Serious headaches were most common, with a cumulative incidence of 25.8% at 20 years, followed by focal neurological dysfunction (21.2%) and seizures (7%).
  • Children who were treated with regimens that included cranial irradiation for ALL and those who suffered relapse were at increased risk for late-onset neurological sequelae.
• A cross-sectional study evaluated neurological morbidity and quality of life in 162 survivors of childhood ALL (median age at evaluation, 15.7 years; median time from completion of therapy, 7.4 years) in concert with a clinical neurological examination.[107]
  • Neurological symptoms were present in 83% of survivors, but symptom-related morbidity was low and quality of life was high in most survivors.
  • The most commonly reported symptoms included neuropathy (63%), headache (46.9%), dizziness (33.3%), and back pain (22.8%).
  • Female sex, ten doses or more of intrathecal chemotherapy, cranial irradiation, CNS leukemia at diagnosis, and history of ALL relapse were associated with neurological morbidity.
• Neuroimaging studies of irradiated and nonirradiated ALL survivors demonstrate a variety of CNS abnormalities, including leukoencephalopathy, cerebral lacunes, cerebral atrophy, and dystrophic calcifications (mineralizing microangiopathy).[53,59,108,109]
  • Among these, abnormalities of cerebral white matter integrity and volume have been correlated with neurocognitive outcomes.
• Cavernomas have also been observed in ALL survivors treated with cranial irradiation. They have been speculated to result from angiogenic processes as opposed to tumorigenesis.[110]
• In a retrospective cross-sectional study, 101 survivors of childhood ALL (mean time since diagnosis, 27.6 years) who were treated with cranial irradiation (63.4% received ≤18 Gy) underwent neurocognitive testing and 3T brain MRI.[111]
  • Small focal intracerebral hemorrhages that are only visible on exquisitely sensitive MRI sequences were identified and localized using susceptibility weighted imaging.
  • At least one microbleed was present in 85% of survivors, and they occurred more frequently in frontal lobes.
  • A radiation dose of 24 Gy conveyed a fivefold greater risk of having multiple microbleeds when compared with a dose of 18 Gy.
  • No significant difference was found in neurocognitive scores with either the absence or presence of microbleeds or their location.
• CCSS investigators evaluated treatment-related neurological sequelae in survivors of childhood CNS tumors.[90]
  • In 1,876 5-year survivors of CNS tumors from the CCSS, the cumulative incidence of headaches increased from 38% at 5 years to 53% at 30 years since diagnosis.
  • Coordination problems increased from 21% at 5 years to 53% at 30 years since diagnosis, and motor impairment increased from 21% to 35% during this same time period.
  • Increased risk of motor impairment was associated with tumor recurrence (HR, 2.6), development of a meningioma (HR, 2.3), and stroke (HR, 14.9).
  • The cumulative incidence of hearing loss increased from 9% at 5 years to 23% at 30 years, cumulative incidence of tinnitus increased from 8% at 5 years to 21% at 30 years, and cumulative incidence of vertigo increased from 9% at 5 years to 17% at 30 years.
  • Risks of motor impairment (HR, 7.6) and hearing loss (HR, 18.4) were elevated compared with siblings.
• CCSS investigators estimated the prevalence and cumulative incidence of neuromuscular dysfunction (motor or sensory dysfunction) among 25,583 childhood cancer survivors and 5,044 siblings.[112]
  • Neuromuscular dysfunction was prevalent in 14.7% of survivors 5 years after diagnosis, compared with 1.5% in siblings (prevalence ratio [PR], 9.9%; 95% CI, 7.9–12.4).
  • The prevalence of neuromuscular dysfunction was highest in survivors of CNS tumors (PR, 27.6; 95% CI, 22.1–34.6) and sarcomas (PR, 11.5; 95% CI, 9.1–14.5).
  • The 20-year cumulative incidence increased to 24.3% in survivors 20 years after diagnosis.
  • Cancer treatments associated with increased prevalence of neuromuscular dysfunction included spinal radiation therapy, increasing doses of cranial radiation therapy, and platinum agents.
  • Neuromuscular dysfunction was associated with downstream adverse outcomes, including concurrent or later obesity (PR, 1.1; 95% CI, 1.1–1.2), anxiety (PR, 2.5; 95% CI, 2.2–2.9), depression (PR, 2.1; 95% CI, 1.9–2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90–0.94) and finding employment (PR, 0.8; 95% CI, 0.8–0.9).
• SJLIFE investigators assessed motor and sensory impairment in 378 survivors of childhood CNS tumors (5 years or longer from diagnosis) and 445 age-, sex-, and race-matched controls, using the modified Total Neuropathy Score.[113]
  • Among survivors, 91 (24.1%; 95% CI, 19.8%–29.4%) had any grade 2 or higher motor or sensory impairment (motor only, 27 [7.1%]; sensory only, 40 [10.6%]; both, 24 [6.4%]).
  • Survivors were more likely than controls to have grade 2 or higher impairment (13.5% for survivors [7.7% for grade 2 and 5.8% for grade 3] vs. 0.9% for controls; P < .001).
  • Survivors of ependymoma had the highest prevalence of motor impairment (22.0%), and survivors of medulloblastoma had the highest prevalence of sensory impairment (33.3%).
  • Treatment factors associated with grade 2 or higher motor impairment in multivariable models included vinca alkaloid exposure of 15 mg/m2 or less compared with no exposure (OR, 4.38; 95% CI, 1.06–18.08) and etoposide exposure of more than 2,036 mg/m2 compared with no exposure (OR, 12.61; 95% CI, 2.19–72.72).
• Radiation myelopathy is a rare but severe complication of radiation therapy exposure. The PENTEC spinal cord task force examined the factors that potentially contribute to radiation myelitis in the pediatric population.[114]
  • Thirty-two patients (treated between 1962 and 2002) with radiation myelopathy were identified, for a crude incidence of 0.5%. The median age was 13 years, and 52% of the patients were male. No apparent association was identified for age at the time of radiation therapy. The most common cancer diagnoses were rhabdomyosarcoma, medulloblastoma, and Hodgkin lymphoma.
  • The median radiation dose was 40 Gy, and the fraction size was 1.8 Gy. The median latency period from completion of radiation therapy to development of radiation myelopathy was 7 months (range, 1–29 months), with higher radiation therapy doses correlating with longer latency periods (P = .03).
  • The most common chemotherapies given to patients with radiation myelopathy were vincristine, intrathecal (IT) methotrexate, and IT cytarabine. Ten patients received vincristine, IT methotrexate, and IT cytarabine.
  • Chemotherapy appears to reduce spinal cord tolerance to radiation. The radiation therapy dose resulting in radiation myelopathy was lower in patients who received chemotherapy than in those who did not receive chemotherapy (39.6 ± 8.7 Gy vs. 49.7 ± 8.2 Gy; P = .04).
  • Eight of the 32 cases of radiation myelopathy occurred in patients treated on a single Intergroup Rhabdomyosarcoma Study Group (treated with intensive IT methotrexate and cytarabine chemotherapy).
  • Many of the reports were from an era before CT-based treatment planning. Also, the investigators could not find any signs that the developing spinal cord is more sensitive than the adult spinal cord.

• Adult survivors of childhood cancer participating in the CCSS who were treated with CNS-directed therapies did not achieve independence at rates comparable with survivors who did not receive CNS-directed therapies or their sibling counterparts. Associations between neurological late effects and attainment of independence were examined in adult survivors of cancer treated with (n = 7,881) and without CNS-directed therapies (n = 8,039) and a sibling cohort (n = 3,994). Compared with the other groups, survivors of childhood cancer treated with CNS-directed therapies showed three distinct patterns of functional independence: (1) moderately independent, never married, and nonindependent living (78.7%); (2) moderately independent, unable to drive (15.6%); (3) not independent (5.7%). No survivors treated with CNS-directed therapies were fully independent (a fourth identified class). In contrast, 50% of survivors who did not receive CNS treatment and 60% of siblings were classified as fully independent. Nonindependence was associated with emotional distress symptoms (i.e., depression, anxiety, somatization, and suicidal ideation).[118]
• In a population-based study of adult survivors of CNS tumors diagnosed in childhood or adolescence, survivors had significantly poorer self-perception and self-esteem than did individuals in the general population. Female sex, persistent visible physical sequelae, specific tumor type, and treatment with cranial radiation therapy predicted poor self-perception outcomes.[119]
• In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome on multiple indicators of successful adult adjustment (educational achievement, income, employment, and marital status) were most prevalent among survivors who reported neurocognitive dysfunction.[42]
• Collectively, studies evaluating psychosocial outcomes among CNS tumor survivors indicate deficits in social competence that worsen over time.[120] This includes problems with peer rejection and isolation in childhood/adolescence, and the inability to develop friendships and romantic relationships as adults.
• In an SJLIFE study of 224 survivors of CNS tumors (median current age, 26 years; median time from diagnosis, 18 years), neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and dependent living.[3]
  • Among one subgroup, significant impairments in social perceptions skills, including affect recognition, contributed to limited achievement of functional outcomes. Self-reports of social adjustment were generally within normal limits, suggesting limited self-insight into social deficits.[121]
• In a series of 1,560 adolescent survivors of childhood ALL treated with chemotherapy alone, the CCSS identified a significant proportion of survivors who still experienced problems with headstrong behavior, inattention-hyperactivity, and social withdrawal, which were associated with an increased risk of special education placement and predicted reduced adult educational attainment.[70]
• In a cross-sectional study of 855 childhood leukemia survivors (mean, 10.2 years from diagnosis) in the Leucémie de l’Enfant et de l’Adolescent (LEA) cohort, investigators identified independent factors associated with repeating a grade in school, including low parental education and household financial difficulties, emphasizing the importance of considering socioeconomic factors that may affect access to educational support. Survivors who were adolescents (aged 11–17 years) at diagnosis were also at greater risk than were survivors who were children (aged <11 years) at diagnosis.[122]
• In a population-based, cross-sectional, survivorship study, 28% of adolescent and young adult (AYA) survivors of sarcoma (aged 18–39 years at diagnosis; median time from diagnosis, 6.2 years) experienced impaired social functioning.[123] Multivariable analysis identified independent associations with impaired social functioning and unemployment (OR, 3.72; 95% CI, 1.26–10.97) and having to make lifestyle changes because of financial problems caused by an individual’s physical condition or medical treatment (OR, 3.39; 95% CI, 1.12–10.30). In contrast, better social support reduced the risk of impaired social functioning (OR, 0.74; 95% CI, 0.57–0.96).

• A CCSS report characterized the prevalence of and risk factors for self-reported emotional distress and HRQOL in survivors of rhabdomyosarcoma (n = 713) and their siblings (n = 706). The study also identified risk factors associated with these outcomes in survivors.[78]
  • Compared with their siblings, more survivors reported elevated emotional distress (somatic distress: 12.9% vs. 4.7%; anxiety: 11.7% vs. 5.9%; depression: 22.8% vs. 16.9%) and poorer HRQOL (physical functioning: 11.1% vs. 2.8%; role functioning due to physical problems: 16.8% vs. 8.2%; pain: 17.5% vs. 10.0%; vitality: 22.3% vs. 13.8%; social functioning: 14.4% vs. 6.8%; emotional functioning: 17.1% vs. 10.6%).
  • Chest and pelvic radiation exposure predicted an increased risk of impaired physical functioning (OR, 2.68 and 3.44, respectively).
  • Smoking was associated with anxiety (OR, 2.71) and depression (OR, 1.77).
  • Neurological conditions increased the risk of anxiety (OR, 2.30), and hearing conditions increased the risk of depression (OR, 1.79).
• The SJLIFE study was used to compare the risks of suicidal ideation, suicidal behaviors, and mortality in adult survivors of childhood cancer with those of the general population.[125]
  • Survivors (n = 3,096) reported a similar 12-month prevalence of suicidal ideation compared with the general population (standardized incidence ratio [SIR], 0.68) and a lower prevalence of suicidal behaviors (planning: SIR, 0.17; attempts: SIR, 0.07) and mortality (standardized mortality ratio, 0.60).
  • Among survivors, depression (RR, 12.30), anxiety (RR, 2.19), and financial stress (RR, 1.47) were found to be risk factors associated with suicidal ideation.
  • Survivors who were currently single, widowed, or divorced; who were not working full time; who reported financial stress during the previous year; and who reported sleep disturbances had an approximately 30% to 50% higher prevalence of suicidal ideation.
• A CCSS study evaluated the prevalence of recurrent suicidal ideation among 9,128 adult long-term survivors of childhood cancer.[126]
  • Survivors were more likely to report late suicidal ideation (OR, 1.9; 95% CI, 1.5–2.5) and recurrent suicidal ideation (OR, 2.6; 95% CI, 1.8–3.8) compared with siblings.
  • History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors.
• A population-based study evaluated suicide among adults treated for cancer before age 25 years.[127]
  • The absolute risk of suicide was low (24 cases among 3,375 deaths).
  • The HR of suicide was increased among individuals treated for cancer in childhood (0–14 years; HR, 2.5; 95% CI, 1.7–3.8) and in adolescence and young adulthood (15–24 years; HR, 2.3; 95% CI, 1.2–4.6).

• In a study that evaluated psychological outcomes among long-term survivors treated with HSCT, 22% of survivors and 8% of sibling controls reported adverse outcomes. Somatic distress was the most prevalent condition and affected 15% of HSCT survivors, representing a threefold higher risk compared with siblings. HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress.[128]
• A report from the CCSS revealed that the presence of chronic pulmonary, endocrine, and cardiac conditions was associated with increased risk of psychological distress symptoms in a sample of 5,021 adult survivors of childhood cancer.[129]
• In a CCSS investigation that evaluated long-term psychological and educational outcomes among survivors of neuroblastoma, survivors demonstrated elevated risks of psychological impairment, which was associated with the use of special education services and lower educational attainment. The presence of two or more chronic health conditions, but not common treatment exposures, predicted psychological impairment. Specifically, pulmonary disease predicted impairment in all five psychological domains, whereas endocrine disease and peripheral neuropathy each predicted impairment in three domains.[130]

• In a study of 101 adult survivors of childhood cancer, psychological screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute.[131]
  • On the Symptom Checklist 90 Revised, 32 survivors had a positive screen (indicating psychological distress), and 14 survivors reported at least one suicidal symptom.
  • Risk factors for psychological distress included survivors’ dissatisfaction with physical appearance, poor physical health, and treatment with cranial irradiation.
  • This instrument was shown to be feasible for use in the clinic-visit setting because the psychological screening was completed in less than 30 minutes and did not appear to cause distress in the survivors in 80% of cases.

• Survivors (mean age, 9 years; 60% were 5 or more years from diagnosis) showed increased risks of six serious mental illnesses compared with controls. These disorders included the following:
  • Autism spectrum disorder (HR, 10.42; 95% CI, 4.58–23.69).
  • ADHD (HR, 6.59; 95% CI, 4.91–8.86).
  • Bipolar disorder (HR, 2.93; 95% CI, 1.26–6.80).
  • Major depressive disorder (HR, 1.88; 95% CI, 1.26–2.79).
  • Obsessive-compulsive disorder (OCD) (HR, 3.37; 95% CI, 1.33–8.52).
  • Post-traumatic stress disorder (PTSD) (HR, 6.10; 95% CI, 1.46–25.54).
• Survivors were younger than controls at the time of diagnosis of ADHD, schizophrenia, major depressive disorder, and OCD.
• Risks of serious mental illnesses varied according to specific cancer types. The greatest number of major psychiatric disorders was observed among survivors of brain cancer and lymphatic/hematopoietic tissue cancer.

• Five-year AYA survivors experienced higher rates of outpatient mental health visits than did controls (671 vs. 506 visits per 1,000 person-years; RR, 1.3), higher risk of a severe psychiatric episode (HR, 1.2), and higher risk of a psychotic disorder–associated severe event (HR, 2.0).
• Treatment in an adult center was associated with substantially higher outpatient visit rates compared with treatment in pediatric settings (RR, 1.8).

• The prevalence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with estimates varying based on criteria used to define these conditions.[135]
• In a cohort of 5,121 childhood and adolescent cancer survivors (mean age, 9 years), the incidence of PTSD was 0.59%. Compared with controls, survivors showed a 6.10-fold elevated risk of being diagnosed with PTSD. Brain cancer survivors had the highest risk of all cancer diagnoses for PTSD (HR, 18.50; 95% CI, 2.11–162.64).[132]
• Patient and parent adaptive style appear to be significant determinants of PTSD in the pediatric oncology setting.[136,137]
• Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than did those without PTSD.[138,139]
• A subset of adult survivors (9%) from the CCSS reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD.[140]
  • PTSD was significantly more prevalent in survivors than in sibling comparisons.
  • PTSD was significantly associated with being unmarried, having an annual income of less than $20,000, being unemployed, having a high school education or less, and being older than 30 years.
  • Survivors who were treated with cranial irradiation before age 4 years were at particularly higher risk of developing PTSD.
  • Intensive cancer-directed therapy was also associated with increased risk of full PTSD.
• Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care.[141]
  • Those with PTSD perceive greater current threats to their lives or the lives of their children.
  • Other risk factors for PTSD include poor family functioning, decreased social support, and noncancer stressors.

1. Adult survivors of cancer diagnosed during adolescence (aged 15–18 years) (N = 825) were compared with an age-matched sample from the general population and a comparison group of adults without cancer.[142]
   • Female survivors of adolescent cancers achieved fewer developmental milestones related to their psychosexual development, such as having their first boyfriend, or they reached these milestones later.
   • Male survivors were more likely to live with their parents than were same-sex controls.
   • Adolescent cancer survivors were less likely to have ever married or have had children. Survivors were significantly older at their first marriage and at the birth of their first child than were their age-matched samples.
   • Survivors in this cohort were also significantly less satisfied with their general and health-related life than were people in a community-based control group. Impaired general and health-related life satisfaction were associated with somatic late effects, symptoms of depression and anxiety, and lower rates of posttraumatic growth.[143]
2. A survey of 4,054 AYA cancer survivors and 345,592 respondents who had no history of cancer reported the following:[144]
   • AYA cancer survivors were more likely to smoke (26% vs. 18%), be affected by obesity (31% vs. 27%), and have chronic conditions such as cardiovascular disease (14% vs. 7%), hypertension (35% vs. 9%), asthma (15% vs. 8%), disability (36% vs. 18%), and poor mental health (20% vs. 10%).
   • They were also less likely to receive medical care because of cost (24% vs. 15%).
3. The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of childhood cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, being headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence).[145]
   • Survivors were 1.5 times (95% CI, 1.1–2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (95% CI, 1.3–2.2) more likely than siblings to have antisocial behaviors.
   • Scores in the depression/anxiety, attention deficit, and antisocial domains were significantly elevated in adolescents treated for leukemia or CNS tumors, compared with the scores in siblings.
   • In addition, survivors of neuroblastoma had difficulty in the depression/anxiety and antisocial domains.
   • CNS-directed treatments (cranial radiation therapy and/or intrathecal methotrexate) were specific risk factors for adverse behavioral outcomes.
4. Another CCSS study evaluated psychological and neurocognitive function in 2,589 long-term cancer survivors who were diagnosed during adolescence and young adulthood.[146]
   • Compared with a sibling cohort, survivors diagnosed during adolescence and young adulthood reported higher rates of depression (OR, 1.55; 95% CI, 1.04–2.30) and anxiety (OR, 2.00; 95% CI, 1.17–3.43) and reported more cognitive problems affecting task efficiency (OR, 1.72; 95% CI, 1.21–2.43), emotional regulation (OR, 1.74; 95% CI, 1.26–2.40), and memory (OR, 1.44; 95% CI, 1.09–1.89).
   • Survivors of lymphoma and sarcoma diagnosed during later adolescence were at reduced risk of psychosocial and neurocognitive problems than were those diagnosed before age 11 years. These outcomes did not differ by age at diagnosis among CNS tumor and leukemia survivors.
   • Survivors diagnosed during adolescence and young adulthood were also significantly less likely than sibling controls to have attained a post–high school education, be working full time, be married, or be living independently; inferior social outcomes were related to neurocognitive symptoms.
5. A follow-up CCSS study evaluated profiles of symptom comorbidities in 3,993 adolescents (aged 13–17 years) treated for cancer.[147] Latent profile analysis identified four symptom profiles:
   • No significant symptoms.
   • Elevated internalizing symptoms (anxiety and/or depression, social withdrawal, and attention problems).
   • Elevated externalizing symptoms (headstrong behavior and attention problems).
   • Elevated internalizing and externalizing symptoms.

   Overall results support that behavioral, emotional, and social symptoms frequently co-occur and are associated with treatment exposures (cranial radiation, corticosteroids, and methotrexate) and late effects (obesity, cancer-related pain, and sensory impairments) in adolescent survivors diagnosed between 1970 and 1986.

6. Another CCSS study characterized the prevalence and risk of pain, clinically significant interference in daily activities because of pain, and recurrent pain in 10,012 adult survivors of childhood cancer (median time since diagnosis, 23 years).[148]
   • A significant minority of survivors endorsed moderate to severe pain (29%), moderate to extreme pain interference (20%), and moderate to severe recurrent pain (9%).
   • Older age at diagnosis and follow-up, female sex, and presence of grades 3 to 4 chronic medical conditions were consistently associated with an increased risk of worse pain outcomes.
   • Minority racial and ethnic groups, diagnosis of CNS tumor, and treatment with platinum-based chemotherapy and cranial radiation were associated with an increased risk of late-occurrence pain and pain interference.
   • Depression and anxiety were associated with increased risk of all pain outcomes, and poor vitality mediated the effects of anxiety on high pain and pain interference.
7. An SJLIFE study evaluated the associations between comprehensive medical, neurocognitive, and physical performance assessments and self-reported pain, quality of life, and social functioning in 2,836 survivors (mean age, 32.2 years; mean time since diagnosis, 23.7 years) and 343 noncancer community controls.[149]
   • Moderate-to-very-severe pain with moderate-to-extreme daily interference was endorsed by 18% of survivors, compared with 8% of controls (P < .001).
   • Survivors of soft tissue sarcoma (OR, 9.25), non-Hodgkin lymphoma (OR, 4.13), and Ewing sarcoma and/or osteosarcoma (OR, 3.93) had the highest odds of pain with daily interference, compared with controls.
   • In multivariable models that included treatment exposures, histories of amputation (OR, 1.89) and/or limb-sparing surgery (OR, 2.30) were associated with increased odds of pain with daily interference.
   • Pain with daily interference was associated with an increased risk of impaired neurocognition (attention: RR, 1.88; memory: RR, 1.65) and physical functioning (aerobic capacity: RR, 2.29; mobility: RR, 1.71).
   • Pain with daily interference was also associated with an increased risk of impaired social functioning (inability to hold a job and/or attend school: RR, 4.46; assistance with routine and/or personal care needs: RR, 5.64), and health-related quality of life (physical: RR, 6.34; emotional: RR, 2.83).
8. A Nordic, register-based cohort study evaluated whether childhood cancer survivors (n = 18,621) were at a higher risk of developing psychiatric disorders later in life than their siblings (n = 24,775) and the general population (n = 88,630).[150]
   • The cumulative incidence of contact with a psychiatric hospital by age 30 years was 15.9% for childhood cancer survivors, 14.0% for siblings, and 12.7% for matched (by birth year, sex, and country/municipality) population controls.
   • The absolute difference was small, but survivors were still at a higher RR for any psychiatric hospital contact than their siblings (1.39) and matched controls (HR, 1.34).
9. A CCSS study evaluated associations between treatment changes and neurocognition as well as the impact of neurocognition and chronic health conditions on adult independence in 1,284 adult survivors of childhood gliomas (median age, 30 years at assessment and 22 years from diagnosis).[151]
   • Cranial radiation exposure decreased over the study period (1970s–1990s).
   • Survivors with any treatment exposures (surgery only, chemotherapy with or without surgery, cranial radiation therapy with or without chemotherapy/surgery) had an elevated risk of neurocognitive impairment, compared with siblings.
   • While most long-term glioma survivors in the cohort achieved adult independence, associations with treatment-related neurocognitive impairment and chronic health conditions were observed among those with functional nonindependence.

1. In a study of 665 survivors of CNS tumors (54% male; 52% treated with cranial radiation therapy; median age, 15 years; and 12 years from diagnosis), CCSS investigators observed the following:[117]
   • Almost 50% of survivors experienced social difficulties related to peer relationships that exceeded those of survivors of solid tumors and sibling controls.
   • Cranial radiation exposure predicted impaired social and peer relationships, and cognitive impairment mediated these associations.
2. An SJLIFE study investigated functional and social independence in 306 CNS tumor survivors (astrocytoma [n = 130], medulloblastoma [n = 77], ependymoma [n = 36], and other [n = 63]; median age, 25 years; and time since diagnosis, 16.8 years).[49]
   • Only 40% of long-term survivors in the study cohort achieved complete independence as adults.
   • Predictors of nonindependence included treatment with craniospinal irradiation, history of hydrocephalus with shunting, and younger age at diagnosis.
   • Beyond impaired IQ scores, functional limitations in aerobic capacity, flexibility, and adaptive physical function were significantly associated with nonindependence.

• head and neck cancers
• Hodgkin lymphoma
• neuroblastoma
• leukemia that spreads to the brain and spinal cord
• nasopharyngeal cancer
• brain tumors
• cancers treated with total-body irradiation (TBI) as part of a stem cell transplant

• radiation therapy to the head and neck
• TBI as part of a stem cell transplant
• chemotherapy, especially with higher doses of alkylating agents such as cyclophosphamide
• surgery in the head and neck area

• teeth that are not normal
• tooth decay (including cavities) and gum disease
• salivary glands that do not make enough saliva
• death of the bone cells in the jaw
• changes in the way the face, jaw, or skull form
• a second cancer in the mouth

• teeth are small or do not have a normal shape
• missing permanent teeth
• permanent teeth come in at a later than normal age
• teeth have less enamel than normal
• more tooth decay (cavities) and gum disease than normal
• dry mouth
• trouble chewing, swallowing, and speaking
• jaw pain
• jaws do not open and close the way they should

• Dental exam is an exam of the teeth, mouth, and jaws to check general signs of dental health, including checking for signs of disease, such as cavities or anything that seems unusual. This may also be called a dental check-up.
• Panorex x-ray is an x-ray of all of the teeth and their roots. An x-ray is a type of radiation that can go through the body and make pictures.
• X-ray of the jaws is an x-ray of the jaws. An x-ray is a type of radiation that can go through the body and make pictures.
• CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the head and neck. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
• Magnetic resonance imaging (MRI) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the head and neck. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• Biopsy is a procedure in which a sample of tissue is removed from the tumor so that a pathologist can view it under a microscope to check for signs of cancer.

• germ cell tumors
• Hodgkin lymphoma
• non-Hodgkin lymphoma
• neuroblastoma
• rhabdomyosarcoma of the bladder or prostate, or near the testicles
• Wilms tumor

• Radiation therapy to the abdomen or areas near the abdomen, such as the esophagus, bladder, prostate, or testicles, may cause digestive tract problems that begin quickly and last for a short time. In some patients, however, digestive tract problems are delayed and long-lasting. These late effects are caused by radiation therapy that damages the blood vessels. Receiving higher doses of radiation therapy or receiving chemotherapy such as dactinomycin or anthracyclines together with radiation therapy may increase this risk.
• Abdominal surgery or pelvic surgery to remove the bladder.
• Chemotherapy with alkylating agents such as cyclophosphamide, procarbazine, and ifosfamide, or with anthracyclines such as doxorubicin, daunorubicin, idarubicin, and epirubicin.
• Stem cell transplant.

• older age at diagnosis or when treatment begins
• treatment with both radiation therapy and chemotherapy
• a history of chronic graft-versus-host disease

• a narrowing of the esophagus or intestine
• the muscles of the esophagus do not work well
• reflux
• diarrhea, constipation, fecal incontinence, or blocked bowel
• bowel perforation (a hole in the intestine)
• inflammation of the intestines
• death of part of the intestine
• intestine is not able to absorb nutrients from food
• a second cancer

• trouble swallowing or feeling like food is stuck in the throat
• heartburn
• fever with severe pain in the abdomen and nausea
• pain in the abdomen
• a change in bowel habits (constipation or diarrhea)
• nausea and vomiting
• frequent gas pains, bloating, fullness, or cramps
• reflux

• Digital rectal exam is an exam where the doctor or nurse inserts a lubricated, gloved finger into the rectum to feel for lumps or anything else that seems unusual.
• Blood chemistry studies is a test that uses a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
• Kidney, ureter, and bladder x-ray is a type of radiation that can go through the body and make pictures of the abdomen, kidney, ureter, or bladder to check for signs of disease.
• CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
• Magnetic resonance imaging (MRI) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• Barium swallow is a series of x-rays of the throat, esophagus, stomach, and the first part of the small intestine (duodenum). For this procedure, the patient drinks a liquid that contains barium (a silver-white metallic compound). The barium coats the esophagus and stomach which helps them show up more clearly in x-rays. This procedure is also called an upper GI series.

• acute lymphoblastic leukemia (ALL)
• liver cancer
• Wilms tumor
• cancers treated with a stem cell transplant

• surgery to remove part of the liver or a liver transplant
• chemotherapy that includes high-dose cyclophosphamide as part of a stem cell transplant
• chemotherapy such as 6-mercaptopurine, 6-thioguanine, methotrexate, and dactinomycin
• radiation therapy to the liver and bile ducts, with the risk depending on:
  • the dose of radiation and how much of the liver is treated
  • age when treated (the younger the age, the higher the risk)
  • whether there was surgery to remove part of the liver
  • whether chemotherapy, such as doxorubicin or dactinomycin, was given together with radiation therapy
• stem cell transplant

• hepatitis B or hepatitis C infection
• history of chronic graft-versus-host disease
• liver damage caused by veno-occlusive disease/sinusoidal obstruction syndrome
• tissue and organ damage from the buildup of extra iron after having many blood transfusions

• liver dysfunction
• gallstones
• benign liver lesions
• an overgrowth of connective tissue in the liver (liver fibrosis) or cirrhosis
• fatty liver with insulin resistance (a condition in which the body makes insulin but cannot use it well)

• weight gain or weight loss
• swelling of the abdomen
• nausea and vomiting
• pain in the abdomen that may occur near the ribs, often on the right side after eating a fatty meal
• yellowing of the skin and whites of the eyes (jaundice)
• light-colored bowel movements
• diarrhea
• dark-colored urine
• a lot of gas
• lack of appetite
• feeling tired or weak

• Blood chemistry studies use a blood sample to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease. For example, there may be a higher level of bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the body if the liver has been damaged.
• Ferritin level uses a blood sample to measure the amount of ferritin. Ferritin is a protein that binds to iron and stores it for use by the body. After a stem cell transplant, a high ferritin level may be a sign of liver disease.
• Complete blood count (CBC) is when a sample of blood is drawn and checked for:
  • the number of red blood cells, white blood cells, and platelets
  • the amount of hemoglobin (the protein that carries oxygen) in the red blood cells
  • the portion of the blood sample made up of red blood cells

  This test is used to check the amount of platelets in the body.

• Prothrombin time (PT) test measures how long it takes for the blood to clot.
• Hepatitis assay uses a blood sample to check for pieces of the hepatitis virus. The blood sample may also be used to measure how much hepatitis virus is in the blood. All patients who had a blood transfusion before 1972 should have a screening test for hepatitis B. Patients who had a blood transfusion before 1993 should have a screening test for hepatitis C.
• Ultrasound exam uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs, such as the gall bladder, and make echoes. The echoes form a picture of body tissues called a sonogram.
• CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs and tissue show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer.
• Magnetic resonance imaging (MRI) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).

• having a healthy weight
• not drinking alcohol
• getting vaccines for hepatitis A and hepatitis B viruses

• radiation therapy to the abdomen
• total-body irradiation as part of a stem cell transplant

• Insulin resistance is a condition in which the body does not use insulin the way it should. Insulin is needed to help control the amount of glucose (a type of sugar) in the body. Because the insulin does not work the way it should, glucose and fat levels rise.
• Diabetes mellitus is a disease in which the body does not make enough insulin or does not use it the way it should. When there is not enough insulin, the amount of glucose in the blood increases and the kidneys make a large amount of urine. Survivors also have an increased risk of prediabetes, which can lead to diabetes.

• frequent urination
• feeling very thirsty
• feeling very hungry
• weight loss for no known reason
• feeling very tired
• frequent infections, especially of the skin, gums, or bladder
• blurred vision
• cuts or bruises that are slow to heal
• numbness or tingling in the hands or feet

• Glycated hemoglobin (A1C) test uses a sample of blood to measure the amount of glucose that is attached to red blood cells. A higher-than-normal amount of glucose attached to red blood cells can be a sign of diabetes mellitus.
• Fasting blood sugar test uses a blood sample to measure the amount of glucose in the blood. This test is done after the patient has had nothing to eat overnight. A higher-than-normal amount of glucose in the blood can be a sign of diabetes mellitus.

• acute lymphoblastic leukemia (ALL)
• brain tumors
• head and neck cancers
• Hodgkin lymphoma
• neuroblastoma
• cancers treated with a stem cell transplant

• radiation therapy to the thyroid as part of radiation therapy to the head and neck or to the pituitary gland in the brain
• total-body irradiation or chemotherapy as part of a stem cell transplant
• MIBG (radioactive iodine) therapy for neuroblastoma
• chemotherapy such as alkylating agents, anthracyclines, or bleomycin
• surgery to remove part of the thyroid

• Hypothyroidism (not enough thyroid hormone): There is a higher risk of hypothyroidism in survivors treated with head and neck radiation involving the thyroid gland, especially survivors of Hodgkin lymphoma. This is the most common thyroid late effect. It usually occurs 2 to 5 years after treatment ends but may occur more than 25 years after radiation therapy. It is more common in girls than boys. Children, adolescents, and young adults treated with proton beam radiation therapy may have a lower risk of developing hypothyroidism.
• Hyperthyroidism (too much thyroid hormone): The risk of hyperthyroidism increases with higher doses of radiation therapy to the thyroid gland. Hyperthyroidism is less common than hypothyroidism. It usually occurs 5 years after treatment ends, but may occur more than 25 years after radiation therapy.
• Lumps in the thyroid: Higher radiation dose and longer time since diagnosis are linked to an increased risk of developing thyroid lumps. These growths may be benign (not cancerous) or malignant (cancer). It is more common in girls than boys. An enlarged thyroid (goiter) may be caused by lumps in the thyroid.

Hypothyroidism (too little thyroid hormone)

• feeling tired or weak
• being more sensitive to cold
• pale, dry skin
• coarse and thinning hair
• brittle fingernails
• hoarse voice
• puffy face
• muscle and joint aches and stiffness
• constipation
• menstrual periods that are irregular or heavier than normal
• weight gain for no known reason
• depression or trouble with memory or being able to concentrate

Hyperthyroidism (too much thyroid hormone)

• feeling nervous, anxious, or moody
• trouble sleeping
• feeling tired or weak
• having shaky hands
• having a fast heartbeat
• having red, warm skin that may be itchy
• having fine, soft hair that is falling out
• having frequent or loose bowel movements
• weight loss for no known reason
• being more sensitive to heat

• Blood hormone studies use a blood sample to measure the amounts of certain hormones released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease in the organ or tissue that makes it. The blood may be checked for abnormal levels of thyroid-stimulating hormone (TSH) or free thyroxine (T4).
• Ultrasound exam uses high-energy sound waves (ultrasound) that bounce off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. This procedure can show the size of the thyroid and whether there are nodules (lumps) on the thyroid.

• acute lymphoblastic leukemia (ALL)
• brain and spinal cord tumors
• head and neck cancers
• cancers treated with a stem cell transplant

• Growth hormone deficiency: Growth hormone helps promote growth and control metabolism. A low level of growth hormone is a common late effect of radiation to the brain in childhood cancer survivors. The higher the radiation dose and the longer the time since treatment, the greater the risk of this late effect. A low level of growth hormone may also occur in childhood ALL and stem cell transplant survivors who received radiation therapy to the brain and spinal cord and/or chemotherapy.

  A low level of growth hormone in childhood results in adult height that is shorter than normal. If the child’s bones have not fully developed, low growth hormone levels may be treated with growth hormone replacement therapy beginning one year after the end of treatment.

• Adrenocorticotropin deficiency (ACTH): Adrenocorticotropic hormone controls the making of glucocorticoids. A low level of adrenocorticotropic hormone is an uncommon late effect. It may occur in survivors:
  • of childhood brain tumors, other tumors, or blood cancers
  • with low growth hormone levels or central hypothyroidism
  • who received radiation therapy to the brain
  • who received steroid hormone therapy

  Symptoms of adrenocorticotropin deficiency may not be severe and may not be noticed. Symptoms include:

  • weight loss for no known reason
  • not feeling hungry
  • nausea
  • vomiting
  • abdominal pain
  • low blood pressure
  • feeling tired
  • dizziness
  • muscle or joint pains
  • darkening of the skin
  • pale skin
  • low blood sugar
  • craving salts

  Low levels of adrenocorticotropin may be treated with hydrocortisone therapy.

• Hyperprolactinemia: Prolactin controls the making of breast milk and has many other effects in the body. A high level of the hormone prolactin may occur after a high dose of radiation to the brain or surgery that affects part of the pituitary gland. A high level of prolactin may cause:
  • puberty at a later age than normal
  • flow of breast milk in a woman who is not pregnant or breastfeeding
  • less frequent or no menstrual periods or menstrual periods with a very light flow
  • hot flashes
  • inability to become pregnant
  • inability to have an erection needed for sexual intercourse
  • lower sex drive (in men and women)
  • low bone mineral density (osteopenia)

  Sometimes there are no signs and symptoms. Treatment is rarely needed.

• Thyroid-stimulating hormone (TSH) deficiency: Thyroid-stimulating hormone controls the making of thyroid hormones. A low level of thyroid hormone may occur very slowly over time after radiation therapy to the brain. Thyroid-stimulating hormone deficiency may also be called central hyphothyroidism.

  Sometimes the symptoms of thyroid-stimulating hormone deficiency are not noticed. Low thyroid hormone levels may cause slow growth and delayed puberty, as well as other symptoms. Learn more about the symptoms of hypothyroidism.

  A low level of thyroid hormone may be treated with thyroid hormone replacement therapy.

• Luteinizing hormone or follicle-stimulating hormone imbalance: Luteinizing hormone and follicle-stimulating hormone control reproduction. Abnormal levels of these hormones can cause different health problems. The type of problem depends on the radiation dose and whether hormone levels are higher or lower than normal.

  Childhood cancer survivors who had brain tumors near the hypothalamus or pituitary gland, who were treated with lower doses of radiation to the brain, or who have hydrocephalus may develop central precocious puberty (a condition that causes puberty to start before age 8 in girls and 9 in boys). Central precocious puberty happens when the brain releases luteinizing and follicle-stimulating hormones too soon in the child’s development. This condition may be treated with gonadotropin-releasing hormone (GnRH) agonist therapy to delay puberty and help the child’s growth.

  Childhood cancer survivors who were treated with higher doses of radiation to the brain may have low levels of luteinizing hormone or follicle-stimulating hormone. This condition may be treated with sex hormone replacement therapy. The dose will depend on the child’s age and whether the child has reached puberty.

• Central diabetes insipidus: Central diabetes insipidus may be caused by the absence of or low amounts of all of the hormones made in the front part of the pituitary gland and released into the blood. It may occur in childhood cancer survivors treated with surgery in the area of the hypothalamus or pituitary gland. Symptoms of central diabetes insipidus may include:
  • making large amounts of urine
  • feeling very thirsty
  • fatigue

  Symptoms of central diabetes insipidus in infants may include:

  • vomiting
  • diarrhea
  • irritability
  • slowed growth and development
  • weight loss for no known reason

• Blood chemistry study uses a blood sample to measure the amounts of certain substances, such as glucose, released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
• Blood hormone studies use a blood sample to measure the amounts of certain hormones released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease in the organ or tissue that makes it. The blood may be checked for abnormal levels of follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, cortisol, or free thyroxine (T4).
• Lipid profile studies use a blood sample to measure the amounts of triglycerides, cholesterol, and low- and high-density lipoprotein cholesterol in the blood.

• high blood pressure
• high levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol in the blood
• high levels of glucose (sugar) in the blood

• acute lymphoblastic leukemia (ALL)
• cancers treated with a stem cell transplant
• cancers treated with radiation to the abdomen, such as Wilms tumor or neuroblastoma

• radiation therapy to the brain, abdomen, or pelvis
• total-body irradiation (TBI) as part of a stem cell transplant
• chemotherapy, such as alkylating agents
• older age

• Blood chemistry studies use a blood sample to measure the amounts of certain substances, such as glucose, released into the blood by organs and tissues in the body. An unusual amount of a substance can be a sign of disease.
• Lipid profile studies use a blood sample to measure the amounts of triglycerides, cholesterol, and low- and high-density lipoprotein cholesterol in the blood.

• having a healthy weight
• eating a heart-healthy diet
• exercising regularly
• not smoking

• acute lymphoblastic leukemia (ALL)
• brain tumors, especially craniopharyngiomas
• bone tumors
• cancers treated with radiation to the brain, including TBI as part of a stem cell transplant

• TBI for females
• radiation therapy to the abdomen for males
• certain types of chemotherapy (alkylating agents and anthracyclines)

• being female
• having a low household income
• having a chronic illness