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

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

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

Prevalence of Late Effects in Childhood Cancer Survivors

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Monitoring for Late Effects

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

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

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

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

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

Cancer-related factors:

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

Treatment-related factors:

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

Host-related factors:

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

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References

1. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
2. Lorenzi MF, Xie L, Rogers PC, et al.: Hospital-related morbidity among childhood cancer survivors in British Columbia, Canada: report of the childhood, adolescent, young adult cancer survivors (CAYACS) program. Int J Cancer 128 (7): 1624-31, 2011. [PUBMED Abstract]
3. Rebholz CE, Reulen RC, Toogood AA, et al.: Health care use of long-term survivors of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol 29 (31): 4181-8, 2011. [PUBMED Abstract]
4. Armstrong GT, Kawashima T, Leisenring W, et al.: Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 32 (12): 1218-27, 2014. [PUBMED Abstract]
5. Teepen JC, Kok JL, Feijen EAM, et al.: Questionnaire- and linkage-based outcomes in Dutch childhood cancer survivors: Methodology of the DCCSS LATER study part 1. Cancer Med 12 (6): 7588-7602, 2023. [PUBMED Abstract]
6. Geenen MM, Cardous-Ubbink MC, Kremer LC, et al.: Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 297 (24): 2705-15, 2007. [PUBMED Abstract]
7. Hudson MM, Ness KK, Gurney JG, et al.: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309 (22): 2371-81, 2013. [PUBMED Abstract]
8. Feijen EAM, Teepen JC, van Dulmen-den Broeder E, et al.: Clinical evaluation of late outcomes in Dutch childhood cancer survivors: Methodology of the DCCSS LATER 2 study. Pediatr Blood Cancer 70 (5): e30212, 2023. [PUBMED Abstract]
9. Kurt BA, Nolan VG, Ness KK, et al.: Hospitalization rates among survivors of childhood cancer in the Childhood Cancer Survivor Study cohort. Pediatr Blood Cancer 59 (1): 126-32, 2012. [PUBMED Abstract]
10. Zhang Y, Lorenzi MF, Goddard K, et al.: Late morbidity leading to hospitalization among 5-year survivors of young adult cancer: a report of the childhood, adolescent and young adult cancer survivors research program. Int J Cancer 134 (5): 1174-82, 2014. [PUBMED Abstract]
11. Sørensen GV, Winther JF, de Fine Licht S, et al.: Long-Term Risk of Hospitalization Among Five-Year Survivors of Childhood Leukemia in the Nordic Countries. J Natl Cancer Inst 111 (9): 943-951, 2019. [PUBMED Abstract]
12. Emerson MA, Olshan AF, Chow EJ, et al.: Hospitalization and Mortality Outcomes Among Childhood Cancer Survivors by Race, Ethnicity, and Time Since Diagnosis. JAMA Netw Open 5 (6): e2219122, 2022. [PUBMED Abstract]
13. Streefkerk N, Tissing WJE, Korevaar JC, et al.: A detailed insight in the high risks of hospitalizations in long-term childhood cancer survivors-A Dutch LATER linkage study. PLoS One 15 (5): e0232708, 2020. [PUBMED Abstract]
14. Berbis J, Michel G, Chastagner P, et al.: A French cohort of childhood leukemia survivors: impact of hematopoietic stem cell transplantation on health status and quality of life. Biol Blood Marrow Transplant 19 (7): 1065-72, 2013. [PUBMED Abstract]
15. Phillips SM, Padgett LS, Leisenring WM, et al.: Survivors of childhood cancer in the United States: prevalence and burden of morbidity. Cancer Epidemiol Biomarkers Prev 24 (4): 653-63, 2015. [PUBMED Abstract]
16. Bhakta N, Liu Q, Ness KK, et al.: The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). Lancet 390 (10112): 2569-2582, 2017. [PUBMED Abstract]
17. Salloum R, Chen Y, Yasui Y, et al.: Late Morbidity and Mortality Among Medulloblastoma Survivors Diagnosed Across Three Decades: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 37 (9): 731-740, 2019. [PUBMED Abstract]
18. Streefkerk N, Teepen JC, Feijen EAM, et al.: The cumulative burden of self-reported, clinically relevant outcomes in long-term childhood cancer survivors and implications for survivorship care: A DCCSS LATER study. Cancer 130 (8): 1349-1358, 2024. [PUBMED Abstract]
19. Esbenshade AJ, Lu L, Friedman DL, et al.: Accumulation of Chronic Disease Among Survivors of Childhood Cancer Predicts Early Mortality. J Clin Oncol 41 (20): 3629-3641, 2023. [PUBMED Abstract]
20. Ehrhardt MJ, Williams AM, Liu Q, et al.: Cumulative burden of chronic health conditions among adolescent and young adult survivors of childhood cancer: Identification of vulnerable groups at key medical transitions. Pediatr Blood Cancer 68 (6): e29030, 2021. [PUBMED Abstract]
21. Vuotto SC, Krull KR, Li C, et al.: Impact of chronic disease on emotional distress in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 123 (3): 521-528, 2017. [PUBMED Abstract]
22. Hudson MM, Oeffinger KC, Jones K, et al.: Age-dependent changes in health status in the Childhood Cancer Survivor cohort. J Clin Oncol 33 (5): 479-91, 2015. [PUBMED Abstract]
23. Liu Q, Leisenring WM, Ness KK, et al.: Racial/Ethnic Differences in Adverse Outcomes Among Childhood Cancer Survivors: The Childhood Cancer Survivor Study. J Clin Oncol 34 (14): 1634-43, 2016. [PUBMED Abstract]
24. Ehrhardt MJ, Bhakta N, Liu Q, et al.: Absence of Basal Cell Carcinoma in Irradiated Childhood Cancer Survivors of Black Race: A Report from the St. Jude Lifetime Cohort Study. Cancer Epidemiol Biomarkers Prev 25 (9): 1356-60, 2016. [PUBMED Abstract]
25. Turcotte LM, Liu Q, Yasui Y, et al.: Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015. JAMA 317 (8): 814-824, 2017. [PUBMED Abstract]
26. Gibson TM, Mostoufi-Moab S, Stratton KL, et al.: Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 19 (12): 1590-1601, 2018. [PUBMED Abstract]
27. Ness KK, Hudson MM, Jones KE, et al.: Effect of Temporal Changes in Therapeutic Exposure on Self-reported Health Status in Childhood Cancer Survivors. Ann Intern Med 166 (2): 89-98, 2017. [PUBMED Abstract]
28. Armstrong GT, Chen Y, Yasui Y, et al.: Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. N Engl J Med 374 (9): 833-42, 2016. [PUBMED Abstract]
29. Holmqvist AS, Chen Y, Wu J, et al.: Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report. Blood 131 (24): 2720-2729, 2018. [PUBMED Abstract]
30. Bagnasco F, Caruso S, Andreano A, et al.: Late mortality and causes of death among 5-year survivors of childhood cancer diagnosed in the period 1960-1999 and registered in the Italian Off-Therapy Registry. Eur J Cancer 110: 86-97, 2019. [PUBMED Abstract]
31. Byrne J, Schmidtmann I, Rashid H, et al.: Impact of era of diagnosis on cause-specific late mortality among 77 423 five-year European survivors of childhood and adolescent cancer: The PanCareSurFup consortium. Int J Cancer 150 (3): 406-419, 2022. [PUBMED Abstract]
32. Kilsdonk E, van Dulmen-den Broeder E, van Leeuwen FE, et al.: Late Mortality in Childhood Cancer Survivors according to Pediatric Cancer Diagnosis and Treatment Era in the Dutch LATER Cohort. Cancer Invest 40 (5): 413-424, 2022. [PUBMED Abstract]
33. Dixon SB, Liu Q, Chow EJ, et al.: Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet 401 (10386): 1447-1457, 2023. [PUBMED Abstract]
34. Mertens AC, Yong J, Dietz AC, et al.: Conditional survival in pediatric malignancies: analysis of data from the Childhood Cancer Survivor Study and the Surveillance, Epidemiology, and End Results Program. Cancer 121 (7): 1108-17, 2015. [PUBMED Abstract]
35. Fidler MM, Reulen RC, Winter DL, et al.: Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: population based cohort study. BMJ 354: i4351, 2016. [PUBMED Abstract]
36. Holmqvist AS, Chen Y, Wu J, et al.: Assessment of Late Mortality Risk After Allogeneic Blood or Marrow Transplantation Performed in Childhood. JAMA Oncol 4 (12): e182453, 2018. [PUBMED Abstract]
37. Dixon SB, Chen Y, Yasui Y, et al.: Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 38 (29): 3418-3429, 2020. [PUBMED Abstract]
38. Turcotte LM, Whitton JA, Leisenring WM, et al.: Chronic conditions, late mortality, and health status after childhood AML: a Childhood Cancer Survivor Study report. Blood 141 (1): 90-101, 2023. [PUBMED Abstract]
39. Ehrhardt MJ, Liu Q, Dixon SB, et al.: Association of Modifiable Health Conditions and Social Determinants of Health With Late Mortality in Survivors of Childhood Cancer. JAMA Netw Open 6 (2): e2255395, 2023. [PUBMED Abstract]
40. Chen C, Qin N, Wang M, et al.: Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study. Lancet Oncol 24 (10): 1147-1156, 2023. [PUBMED Abstract]
41. Anderson C, Smitherman AB, Nichols HB: Conditional relative survival among long-term survivors of adolescent and young adult cancers. Cancer 124 (14): 3037-3043, 2018. [PUBMED Abstract]
42. Anderson C, Nichols HB: Trends in Late Mortality Among Adolescent and Young Adult Cancer Survivors. J Natl Cancer Inst 112 (10): 994-1002, 2020. [PUBMED Abstract]
43. Suh E, Stratton KL, Leisenring WM, et al.: Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 21 (3): 421-435, 2020. [PUBMED Abstract]
44. Armenian SH, Xu L, Cannavale KL, et al.: Cause-specific mortality in survivors of adolescent and young adult cancer. Cancer 126 (10): 2305-2316, 2020. [PUBMED Abstract]
45. Chao C, Bhatia S, Xu L, et al.: Chronic Comorbidities Among Survivors of Adolescent and Young Adult Cancer. J Clin Oncol 38 (27): 3161-3174, 2020. [PUBMED Abstract]
46. Hudson MM, Armenian SH, Armstrong GT, et al.: Optimization of Health and Extension of Lifespan Through Childhood Cancer Survivorship Research. J Clin Oncol 36 (21): 2133-2134, 2018. [PUBMED Abstract]
47. Kremer LC, Mulder RL, Oeffinger KC, et al.: A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatr Blood Cancer 60 (4): 543-9, 2013. [PUBMED Abstract]
48. Dixon SB, Bjornard KL, Alberts NM, et al.: Factors influencing risk-based care of the childhood cancer survivor in the 21st century. CA Cancer J Clin 68 (2): 133-152, 2018. [PUBMED Abstract]
49. Kirchhoff AC, Leisenring W, Krull KR, et al.: Unemployment among adult survivors of childhood cancer: a report from the childhood cancer survivor study. Med Care 48 (11): 1015-25, 2010. [PUBMED Abstract]
50. Mitby PA, Robison LL, Whitton JA, et al.: Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 97 (4): 1115-26, 2003. [PUBMED Abstract]
51. Lan T, Wang M, Ehrhardt MJ, et al.: Adherence to healthy diet and risk of cardiovascular disease in adult survivors of childhood cancer in the St. Jude Lifetime Cohort: a cross-sectional study. BMC Med 21 (1): 242, 2023. [PUBMED Abstract]
52. Barlow-Krelina E, Chen Y, Yasui Y, et al.: Consistent Physical Activity and Future Neurocognitive Problems in Adult Survivors of Childhood Cancers: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 38 (18): 2041-2052, 2020. [PUBMED Abstract]
53. Tonorezos ES, Ford JS, Wang L, et al.: Impact of exercise on psychological burden in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 125 (17): 3059-3067, 2019. [PUBMED Abstract]
54. Lown EA, Hijiya N, Zhang N, et al.: Patterns and predictors of clustered risky health behaviors among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 122 (17): 2747-56, 2016. [PUBMED Abstract]
55. Gibson TM, Liu W, Armstrong GT, et al.: Longitudinal smoking patterns in survivors of childhood cancer: An update from the Childhood Cancer Survivor Study. Cancer 121 (22): 4035-43, 2015. [PUBMED Abstract]
56. Devine KA, Mertens AC, Whitton JA, et al.: Factors associated with physical activity among adolescent and young adult survivors of early childhood cancer: A report from the childhood cancer survivor study (CCSS). Psychooncology 27 (2): 613-619, 2018. [PUBMED Abstract]
57. Mueller EL, Park ER, Kirchhoff AC, et al.: Insurance, chronic health conditions, and utilization of primary and specialty outpatient services: a Childhood Cancer Survivor Study report. J Cancer Surviv 12 (5): 639-646, 2018. [PUBMED Abstract]
58. Yan AP, Chen Y, Henderson TO, et al.: Adherence to Surveillance for Second Malignant Neoplasms and Cardiac Dysfunction in Childhood Cancer Survivors: A Childhood Cancer Survivor Study. J Clin Oncol 38 (15): 1711-1722, 2020. [PUBMED Abstract]
59. Casillas J, Oeffinger KC, Hudson MM, et al.: Identifying Predictors of Longitudinal Decline in the Level of Medical Care Received by Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Health Serv Res 50 (4): 1021-42, 2015. [PUBMED Abstract]
60. Ford JS, Tonorezos ES, Mertens AC, et al.: Barriers and facilitators of risk-based health care for adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 126 (3): 619-627, 2020. [PUBMED Abstract]
61. Casillas J, Castellino SM, Hudson MM, et al.: Impact of insurance type on survivor-focused and general preventive health care utilization in adult survivors of childhood cancer: the Childhood Cancer Survivor Study (CCSS). Cancer 117 (9): 1966-75, 2011. [PUBMED Abstract]
62. Keegan TH, Tao L, DeRouen MC, et al.: Medical care in adolescents and young adult cancer survivors: what are the biggest access-related barriers? J Cancer Surviv 8 (2): 282-92, 2014. [PUBMED Abstract]
63. Kirchhoff AC, Lyles CR, Fluchel M, et al.: Limitations in health care access and utilization among long-term survivors of adolescent and young adult cancer. Cancer 118 (23): 5964-72, 2012. [PUBMED Abstract]
64. Nathan PC, Huang IC, Chen Y, et al.: Financial Hardship in Adult Survivors of Childhood Cancer in the Era After Implementation of the Affordable Care Act: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 41 (5): 1000-1010, 2023. [PUBMED Abstract]
65. Kirchhoff AC, Kuhlthau K, Pajolek H, et al.: Employer-sponsored health insurance coverage limitations: results from the Childhood Cancer Survivor Study. Support Care Cancer 21 (2): 377-83, 2013. [PUBMED Abstract]
66. Kuhlthau KA, Nipp RD, Shui A, et al.: Health insurance coverage, care accessibility and affordability for adult survivors of childhood cancer: a cross-sectional study of a nationally representative database. J Cancer Surviv 10 (6): 964-971, 2016. [PUBMED Abstract]
67. Park ER, Kirchhoff AC, Zallen JP, et al.: Childhood Cancer Survivor Study participants' perceptions and knowledge of health insurance coverage: implications for the Affordable Care Act. J Cancer Surviv 6 (3): 251-9, 2012. [PUBMED Abstract]
68. Warner EL, Park ER, Stroup A, et al.: Childhood cancer survivors' familiarity with and opinions of the Patient Protection and Affordable Care Act. J Oncol Pract 9 (5): 246-50, 2013. [PUBMED Abstract]
69. Jacobs LA, Shulman LN: Follow-up care of cancer survivors: challenges and solutions. Lancet Oncol 18 (1): e19-e29, 2017. [PUBMED Abstract]
70. Gibson TM, Li C, Armstrong GT, et al.: Perceptions of future health and cancer risk in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 124 (16): 3436-3444, 2018. [PUBMED Abstract]
71. Landier W, Bhatia S, Eshelman DA, et al.: Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22 (24): 4979-90, 2004. [PUBMED Abstract]
72. Eshelman D, Landier W, Sweeney T, et al.: Facilitating care for childhood cancer survivors: integrating children's oncology group long-term follow-up guidelines and health links in clinical practice. J Pediatr Oncol Nurs 21 (5): 271-80, 2004 Sep-Oct. [PUBMED Abstract]
73. Landier W, Armenian SH, Lee J, et al.: Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. J Clin Oncol 30 (35): 4401-8, 2012. [PUBMED Abstract]
74. Wasilewski-Masker K, Mertens AC, Patterson B, et al.: Severity of health conditions identified in a pediatric cancer survivor program. Pediatr Blood Cancer 54 (7): 976-82, 2010. [PUBMED Abstract]

Subsequent neoplasms (SNs) are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. SNs may be benign or malignant. Childhood cancer survivors have increased risks of developing SNs that are multifactorial in etiology and vary according to the following:

SNs are the leading cause of nonrelapse late mortality (standardized mortality ratio, 15.2; 95% confidence interval [CI], 13.9–16.6).[1] The Childhood Cancer Survivor Study (CCSS) reported the following 30-year cumulative incidence rates:[2]

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

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

Evidence (excess risk of SNs):

The incidence and type of SNs depend on the following:

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

Therapy-Related Solid SNs

Therapy-related solid SNs represent 80% of all SNs, demonstrate a strong relationship with radiation exposure, and are characterized by a latency that exceeds 10 years. The risk of solid SNs continues to increase with longer follow-up. The risk of solid SNs is highest when the following occur:[4,13]

• Younger age at time of radiation exposure.
• High total dose of radiation.
• Longer period of follow-up after radiation exposure.

The histological subtypes of solid SNs encompass a neoplastic spectrum ranging from benign and low-grade malignant lesions (e.g., NMSC, meningiomas) to high-grade malignancies (e.g., breast cancers, glioblastomas) (see Figure 4).[4,13,22,23]

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

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

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

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

Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors who were treated with radiation therapy for childhood cancer.[4,10,29]

Subsequent neoplasms after hematopoietic stem cell transplant (HSCT)

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

• Among 4,318 first-time allogeneic HSCT recipients treated for AML and chronic myeloid leukemia between 1986 and 2005, and conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), 66 solid cancers were reported at a median of 6 years post-HSCT.[30]
  • The cumulative incidence of new solid cancers was 0.9% at 5 years and 2.4% at 10 years and appears to be similar, regardless of exposure to radiation.
  • Bu-Cy conditioning without TBI was associated with higher risks of solid SNs than in the general population.
  • Chronic graft-versus-host disease increased the risk of SNs, especially those involving the oral cavity.
• A study of 4,905 1-year survivors of allogeneic HSCT who underwent transplant between 1969 and 2014 for malignant or nonmalignant diseases, and were followed for a median 12.5 years, demonstrated a strong effect of TBI dose and dose fractionation on risk of SNs.[31]
  • The 20-year cumulative incidence of SN after HSCT for individuals treated at younger than 20 years was 8.1%.
  • SN risk was highest in survivors exposed to high-dose, single-fraction TBI (6–12 Gy) or very high-dose fractionated TBI (14.4–17.5 Gy).
  • With low-dose TBI (2–4.5 Gy), the SN risk was comparable to the risk with chemotherapy alone, although it was still twofold higher than in the general population.
  • Among individuals treated at younger than 20 years, the number of SNs was 12.5-fold higher than expected in the general population, and the excess absolute risk was 10.6 per 1,000 person-years. Survivors treated with HSCT at this young age were more likely to develop SNs than were survivors who were treated after age 50 years (HR, 2.3).

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

Breast cancer

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

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

Evidence (excess risk of breast cancer):

1. Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[17,33] The following has been observed in female survivors of childhood Hodgkin lymphoma:
   • Excess risk of breast cancer has been reported in survivors treated with high-dose, extended-volume radiation at age 30 years or younger.[37]
   • Data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[38]
   • Patients who received limited volume supradiaphragmatic radiation therapy (excluding the axillae) had a significantly lower risk of subsequent breast cancers than patients who received full mantle-field radiation therapy.[36]
   • For patients treated with radiation therapy to the chest before age 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years.[17]
   • The latency period after chest irradiation ranges from 8 to 10 years, and the risk of subsequent breast cancer increases in a linear fashion with radiation dose (P for trend < .001).[39]
   • Treatment with higher cumulative doses of alkylating agents and ovarian radiation of 5 Gy or higher (exposures predisposing to premature menopause) have been correlated with reductions in breast cancer risk, underscoring the potential contribution of hormonal stimulation on breast carcinogenesis.[36,40,41]
   • The observed number of invasive breast cancer cases among young (aged <30 years) survivors, compared with what is expected in the general population, has decreased over recent treatment eras (1970s SIR, 55.0 vs. 1990s SIR, 14.3).[35]
2. The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue:
   1. In 116 children in the CCSS cohort treated with 2 Gy to 20 Gy to the lungs (median, 14 Gy), the SIR for breast cancer was 43.6 (95% CI, 27.1–70.1).[34]
   2. A report of 2,492 female participants in the National Wilms Tumor Studies 1 through 4 (1969–1995) addressed the excess risk of breast cancer.[42]
      • Sixteen of 369 women who received chest irradiation for metastatic Wilms tumor developed invasive breast cancer (cumulative risk at age 40 years, 14.8% [95% CI, 8.7%–24.5%]). The SIR of 27.6 (95% CI, 16.1–44.2) was based on 5,010 person-years of follow-up.
      • Of the 369 patients, radiation doses to the chest were less than 12 Gy in 4%, 12 Gy in 64%, 13 Gy to 15 Gy in 19%, and more than 15 Gy in 13% of patients.
      • For all patients who developed breast cancer (with or without chest irradiation), the median age at first breast cancer diagnosis was 34.3 years (range, 15.5–48.4) and the median time from Wilms tumor diagnosis was 27.1 years (range, 7.9–35.7).
3. An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[43]
   • Doxorubicin was associated with a dose-dependent increase of subsequent breast cancer risk (HR per 100 mg/m2, 1.24; 95% CI, 1.18–1.31).
   • There was a more-than-twofold increased risk for survivors treated with 200 mg/m2 or higher cumulative doxorubicin dose, compared with no doxorubicin (HR, 2.50 for 200–299 mg/m2; HR, 2.33 for 300–399 mg/m2; HR, 2.78 for ≥400 mg/m2).
   • The associations were not statistically significant for daunorubicin, whereas epirubicin was associated with increased subsequent breast cancer risk (exposure yes vs. no: HR, 3.25; 95% CI, 1.59–6.63).
   • The HRs per 100 mg/m2 of doxorubicin were 1.11 (95% CI, 1.02–1.21) for patients treated with chest radiation therapy and 1.26 (95% CI, 1.17–1.36) for patients who did not receive chest radiation therapy.
4. The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[32]
   • For the study group, the median age of first cancer diagnosis was 15 years and the median age at breast cancer diagnosis was 39 years.
   • The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5–6.5) and was similar for estrogen receptor–positive and estrogen receptor–negative cancers.
   • The OR per 10 Gy to the breast was higher for women who received ovarian doses less than 1 Gy (OR, 6.8; 95% CI, 3.9–12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0–6.4).
   • The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09–1.39; P < .01 for trend).
   • There was an additive interaction between radiation therapy and anthracycline treatment. The OR was 19.1 (95% CI, 7.6–48.0) for the combined association of anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) versus 9.6 (95% CI, 4.4–20.7) without anthracycline therapy.
5. Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.
   1. The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[24]
      • In women who received neither chest radiation nor anthracyclines, the cumulative incidence of breast cancer was 2% at age 35 years and 15% at age 50 years. For women who were treated with 250 mg/m2 or higher of anthracyclines, the rates were 7% at age 35 years and 46% at age 50 years.
      • Anthracycline doses of 250 mg/m2 or higher remained significantly associated with increased risk of breast cancer in models, excluding survivors with cancer predisposition gene variants, chest radiation of 10 Gy or higher, or both.
      • Breast cancers detected by imaging and/or prophylactic mastectomy were more likely to be in situ carcinomas, be smaller masses, have no lymph node involvement, and be treated without chemotherapy, compared with breast cancers detected by physical findings.
      • Dual imaging with mammography and breast magnetic resonance imaging (MRI) in this cohort was a sensitive and specific approach to identify breast cancers that require less aggressive therapy than breast cancers detected by physical findings.
   2. A CCSS investigation examined the breast cancer risk of 3,768 female participants who did not receive chest radiation.[44]
      • A fourfold excess risk (SIR, 4.0; 95% CI, 3.0–5.3) of breast cancer was observed compared with rates in the general population.
      • Breast cancer risk was highest among survivors of sarcoma (SIR, 5.3; 95% CI, 3.6–7.8) and leukemia (SIR, 4.1; 95% CI, 2.4–6.9), for whom the cumulative incidence of breast cancer was estimated to be 5.8% and 6.3%, respectively, by age 45 years.
      • Treatment with alkylating agents and anthracyclines increased the risk of breast cancer in a dose-dependent manner.
   3. CCSS investigators also examined SN risk among 7,448 participants who were treated with chemotherapy only.[12]
      • Breast cancer incidence was 4.6-fold greater than what would be expected in the general population (SIR, 4.6; 95% CI, 3.5–6.0).
      • A linear dose response was demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95% CI, 1.2–1.6).
   4. DCOG-LATER investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[13]
      • Survivors treated with doxorubicin exhibited a dose-dependent increased risk of breast cancer (HR, 3.1; 95% CI, 1.4–6.5 among survivors treated with anthracycline doses of 250 mg/m2 or higher).
      • The doxorubicin–breast cancer dose response was stronger for survivors of Li-Fraumeni–associated cancers (leukemia, CNS, and sarcomas other than Ewing) than for survivors of other cancers.
6. A SEER Program–based study evaluated trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer among women who were treated with radiation therapy for Hodgkin lymphoma before age 30 years and diagnosed with a subsequent breast cancer between 1990 and 2016.[45]
   • Overall, 263 (89.2%) women presented with unilateral breast cancer, 50 of whom (19.0%) underwent breast-conserving surgery and 213 of whom (81.0%) underwent mastectomy (40.5% bilateral).
   • The 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% (95% CI, 5.6%–15.4%), increasing to 20.2% (95% CI, 13.7%–29.2%) at 10 years and 29.9% (95% CI, 20.8%–41.9%) at 15 years. This finding underscores the importance of ongoing breast cancer surveillance and consideration of prophylactic mastectomy.

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

Subsequent versus de novo breast cancer

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

• In one population-based study, radiation-induced breast cancer was noted to have more adverse clinicopathological features, as evidenced by a twofold increased risk of estrogen receptor–negative, progesterone receptor–negative breast cancer observed among 15-year Hodgkin lymphoma survivors, compared with women who had sporadic breast cancer.[47]
• Other studies have observed a higher proportion of more histologically aggressive subtypes (e.g., triple-negative breast cancer) than age-matched sporadic invasive cancers.[48,49]
• These findings are in contrast to other smaller, hospital-based, case-control studies of breast cancer among Hodgkin lymphoma survivors that have not identified a significant variation in hormone receptor status when compared with primary breast cancer controls. Previous studies have also not demonstrated a significant difference in overall risk of high-grade versus low-grade tumors.[50,51]
• A study using SEER Program data evaluated the clinicopathological features of 321 breast cancers diagnosed in 257 women (median age, 22 years; range, 18–26 years at Hodgkin lymphoma diagnosis) who were previously treated with radiation for Hodgkin lymphoma.[52]
  • Women who developed breast cancer after radiation for Hodgkin lymphoma were younger than women diagnosed with breast cancer without a prior malignancy (43 vs. 60 years) and were less likely to present with ductal carcinoma in situ (0.4% vs. 14.9%).
  • Radiation was not associated with poorer biological features, compared with breast cancers diagnosed in similarly aged women with no prior malignancy. However, higher proportions of upper outer quadrant and smaller tumors (≤2 cm) were found.
  • Most tumors in survivors of Hodgkin lymphoma were hormone sensitive (nearly two-thirds were estrogen receptor–positive/HER2-negative). This finding suggests that endocrine prevention may be an option for this high-risk population.

Mortality after subsequent breast cancer

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

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

Although current evidence does not show a survival benefit from the initiation of breast cancer surveillance in women treated with radiation therapy to the chest for childhood cancer, interventions to promote detection of small and early-stage tumors may improve prognosis. Those with more limited treatment options because of previous exposure to radiation or anthracyclines may especially benefit.

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

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

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

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

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

Thyroid cancer

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

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

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

• Female sex.
• Younger age at exposure.
• Longer time since exposure.
• Radiation dose. A linear dose-response relationship between radiation exposure and thyroid cancer is observed up to 10 Gy, with a leveling off between 10 Gy and 30 Gy, and a decline in the OR at higher doses, especially in children younger than 10 years at treatment, suggesting a cell killing effect of the target cells at higher doses.[23,27,58]

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

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

CNS tumors

Subsequent CNS tumors represent a spectrum of histological subtypes, from high-grade gliomas to benign meningiomas. A comprehensive Pediatric Normal Tissue Effects in the Clinic (PENTEC) review analyzed the risk of SNs. The study reported a 10-year median latency period for the development of a malignant CNS neoplasm and a 21-year median latency period for the development of a meningioma.[60] Accurate assessment of the prevalence of low-grade and benign lesions is challenging because of the variable opinions and practices related to neuroimaging versus symptom surveillance in long-term survivors treated with cranial irradiation. Therefore, the prevalence of these tumors is likely higher than proven.

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

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

• The risk of meningioma after radiation increases with radiation dose,[9,60] and in some studies is further potentiated with increased exposure to intrathecal methotrexate.[25] However, this finding has not been consistently replicated.[10]
• Cavernomas have also been reported with considerable frequency after CNS irradiation but have been speculated to result from angiogenic processes as opposed to true tumorigenesis.[63-65]

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

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

The European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) investigators described findings in childhood cancer survivors who developed meningiomas or gliomas:[66]

• 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 PENTEC analysis of CNS SNs included 32 published studies of 1,035 subsequent meningiomas after previous radiation therapy in childhood cancer survivors.[60]

• 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.

Neurological sequelae associated with meningiomas can include seizures, auditory-vestibular-visual deficits, focal neurological dysfunction, and severe headaches.[9] Despite the well-established increased risk of subsequent CNS neoplasms among childhood cancer survivors treated with cranial irradiation and the growing recognition of associated morbidity, the current literature is insufficient to evaluate the potential harms and benefits of routine screening for these lesions.[67] The decision to initiate surveillance should be shared by the cancer survivor and health care provider after carefully considering the potential harms and benefits of surveillance for CNS neoplasms, such as meningioma.

Proton radiation therapy for pediatric medulloblastoma is associated with low rates of brain stem injury and secondary malignancies. The long-term effects were reported in 178 pediatric patients with medulloblastoma who were treated with surgery, proton radiation therapy, and chemotherapy between 2002 and 2016 (median follow-up, 9.3 years).[68]

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

Bone and soft tissue tumors

Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk of developing subsequent bone and soft tissue tumors.[69-73]

• Radiation therapy is associated with a linear dose-response relationship.[74,75]
• 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).[60]
• After adjustment for radiation therapy, treatment with alkylating agents [13,60] and anthracyclines [76] have both been linked to sarcoma, with the risk increasing with cumulative drug exposure.[76]
• Soft tissue sarcomas can be of various histological subtypes, including nonrhabdomyosarcoma soft tissue sarcomas, rhabdomyosarcoma, malignant peripheral nerve sheath tumors, Ewing/primitive neuroectodermal tumors, and other rare tumor types.

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

1. A nested case-control study included 228 cases and 228 matched controls within a cohort of 69,460 5-year survivors of childhood cancer. The study investigated the risks of subsequent primary bone cancer by different levels of cumulative radiation exposure and dose-response relationships according to different specific types of chemotherapy.[77]
   • 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:[70,71]
   • 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.[70]
   • The observed excess numbers of subsequent primary bone cancer declined with both age and years from diagnosis.[70]
   • 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%.[71]
   • The median time from diagnosis to occurrence of a soft tissue sarcoma was 19 years.[71]
   • The most commonly observed soft tissue sarcomas were leiomyosarcoma, fibromatous neoplasms, and malignant peripheral nerve sheath tumors.[71]
   • 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.[71]
   • 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).[71]
   • 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.[71]
     • Retinoblastoma survivors were at the highest risk (SIR, 342.9), followed by Wilms tumor survivors (SIR, 74.2).
     • 90% of leiomyosarcomas observed after a Wilms tumor diagnosis developed within the irradiated tissue.
3. In a CCSS cohort, an increased risk of subsequent bone or soft tissue sarcoma was associated with radiation therapy, a primary diagnosis of sarcoma, a history of other SNs, and treatment with higher doses of anthracyclines or alkylating agents.[26]
   • The 30-year cumulative incidence of subsequent sarcoma in CCSS participants was 1.08% for survivors who received radiation therapy and 0.5% for survivors who did not receive radiation therapy.
4. Dose-risk modeling was used to study the risk of bone sarcoma in a retrospective cohort of 4,171 survivors of a childhood solid cancer treated between 1942 and 1986 (median follow-up, 26 years).[74]
   • 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.[78-80] 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.[69]
   • 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:[76]
   • 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.[80]
   • 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.[72]
   • Patients with and without subsequent malignancies did not differ by RB1 variant type. Also, there was no association with variant type and location of SMN, or SMN type and age at diagnosis.
   • The study showed that patients who have a low penetrance variant and receive external-beam radiation therapy remain at risk of SMNs and should be cautiously monitored.

Skin cancer

Nonmelanoma skin cancers (NMSCs) are one of the most common SNs among childhood cancer survivors and show a strong association with radiation therapy.[4,81] Adherence to sun protection behaviors can reduce exposure to UV radiation that may exacerbate risk.

The CCSS performed a randomized, controlled, comparative effectiveness trial to test methods to improve early detection of skin cancer among survivors of childhood cancer at high risk after radiation therapy exposure. Participants were randomly assigned to the experimental arm, which included print materials in combination with mHealth strategies (text messages and use of the Advancing Survivors’ Knowledge website), or the control arm. Screening rates improved by 1.5-fold in the experimental arm. Rates of physician skin examination increased from baseline to 12 months, and rates of self-examination increased from baseline to 18 months in all three intervention groups. However, the increase in rates did not differ between the intervention groups.[82]

Evidence (excess risk of NMSCs):

1. Compared with participants who did not receive radiation therapy, CCSS participants treated with radiation therapy had a 6.3-fold increased risk of NMSCs (95% CI, 3.5–11.3).[83]
   • 90% of tumors occurred within the radiation field.
   • A CCSS case-control study of the same cohort reported on subsequent basal cell carcinomas (BCCs). Children who received 35 Gy or more to the skin site had an almost 40-fold excess risk of developing BCCs (OR, 39.8; 95% CI, 8.6–185), compared with those who did not receive radiation therapy. Results were consistent with a linear dose-response relationship, with an excess OR per Gy of 1.09 (95% CI, 0.49–2.64).
2. In 5,843 childhood cancer survivors in the DCOG-LATER cohort, investigators found that childhood cancer survivors had a 30-fold increased risk of developing BCCs.[29]
   • After a first BCC diagnosis, 46.7% of patients developed additional BCCs.
   • BCC risk was associated with any radiation therapy to the relevant radiation field (site of BCC) (HR, 14.32) and with estimated percentage of exposed skin surface area (26%–75%: HR, 1.99; 76%–100%: HR, 2.16 vs. 1%–25% exposed; P_trend among exposed = .002).
   • BCC risk was not associated with prescribed radiation dose and likelihood of sun-exposed skin area.
   • Of all chemotherapy groups examined, only vinca alkaloids increased the BCC risk (HR, 1.54).
3. The occurrence of an NMSC as the first SN has been reported to identify a population at high risk of a future invasive malignant SN.[7]
   • CCSS investigators observed a cumulative incidence of a malignant neoplasm of 20.3% (95% CI, 13.0%–27.6%) at 15 years among radiation-exposed survivors who developed an NMSC as a first SN, compared with 10.7% (95% CI, 7.2%–14.2%) among survivors whose first SN was an invasive malignancy.

Malignant melanoma has also been reported as an SN in childhood cancer survivor cohorts, although at a much lower incidence than NMSCs.

Risk factors for malignant melanoma identified among these studies include the following:[84]

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

Evidence (excess risk of melanoma):

1. A systematic review that included data from 19 original studies (total N = 151,575 survivors; median follow-up of 13 years) observed an incidence of 10.8 cases of malignant melanoma per 100,000 childhood cancer survivors per year.[84]
   • Melanomas most frequently developed in survivors of Hodgkin lymphoma, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors. However, the relatively small number of survivors represented in the relevant studies preclude assessment of melanoma risk among other types of childhood cancer.
2. CCSS investigators observed an approximate 2.5-fold increased risk (SIR, 2.42; 95% CI, 1.77–3.23) of melanoma among members of their cohort (median time to development, 21 years).[85]
   • The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% (95% CI, 0.37%–0.73%), and the absolute excess risk was 0.10 per 1,000 person-years (95% CI, 0.05–0.15).
   • Family history of cancer, demographic characteristics, or treatment-related factors did not predict risk of melanoma.

Skin cancer risk after retinoblastoma

The incidence of melanoma and NMSC was evaluated in a cohort of 1,851 long-term, White survivors of retinoblastoma (1,020 hereditary and 831 nonhereditary) who were diagnosed from 1914 to 2006 and monitored through 2016.[86]

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

Lung cancer

Among childhood cancer survivor cohorts, lung cancer represents a relatively uncommon SN. A PENTEC systematic review reported a median latency period of 25 years (range, 19–29 years) between the childhood cancer diagnosis and the development of a lung SN.[60] The ERR/Gy was 0.068, compared with background cumulative risks. After 20 Gy, the excess absolute risk was predicted to be 0.27% at 50 years. After 50 Gy, the excess absolute risk was predicted to be 0.7% at 50 years.[60]

Evidence (excess risk of lung cancer):

1. The 30-year cumulative incidence of lung cancer among CCSS participants was 0.16% (95% CI, 0.09%–0.23%), representing a SIR of 4.0 (95% CI, 2.9–5.4).[87]
   • 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.[88]
   • 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.[88]
   • The increase in risk of lung cancer with increasing radiation dose is greater among patients who smoke after exposure to radiation than among those who refrain from smoking (P = .04).

Gastrointestinal (GI) cancer

There is substantial evidence that childhood cancer survivors develop GI malignancies more frequently and at a younger age than the general population. This evidence supports the need for early initiation of colorectal carcinoma surveillance.[89-91]

Evidence (excess risk of GI cancer):

1. In a French and British cohort-nested, case-control study of childhood solid tumor survivors diagnosed before age 17 years, the risk of developing a digestive organ SN varied with therapy.[92]
   • 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.[91]
   • 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).[89]
   • 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:[90]
   • 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.[93]
   • 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.[94]
   • 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.[95]
   • 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).[96]
   • The median interval between Hodgkin lymphoma diagnosis and subsequent colorectal cancer was 25.7 years (range, 18.2–31.6 years).
   • Treatment with subdiaphragmatic radiation therapy (RR, 2.4; 95% CI, 1.4–4.1) and more than 8.4 g/m2 of procarbazine (RR, 2.5; 95% CI, 1.3–5.0) were associated with increased rates of colorectal cancer on univariable analysis.
   • Colorectal cancer rate increased linearly with mean radiation therapy dose to the whole large bowel and dose to the affected bowel segment. The dose response became steeper with higher doses of procarbazine and increased 1.2-fold (95% CI, 1.1–1.3) for each 1 g/m2 increase in procarbazine.

Oral cancers

The PanCareSurFup consortium reported on risks of oral second primary neoplasms (validated through pathology reports) in a cohort of 69,460 5-year childhood cancer survivors in Europe.[97]

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

Urogenital cancers

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

Using SEER data of 43,991 patients (aged <20 years) diagnosed with a first primary cancer from 1975 to 2016, the risk of urinary system cancer was higher for both females (SIR, 5.18; 95% CI, 3.65–7.14) and males (SIR, 2.80; 95% CI, 1.94–3.92), compared with the general population.[98]

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

Renal carcinoma

Consistent with reports among survivors of adult-onset cancer, an increased risk of renal carcinoma has been observed in survivors of childhood cancer.[28,99,100] Underlying genetic predisposition may also play a role in the risk of developing renal carcinomas because rare cases of renal carcinoma have been observed in children with tuberous sclerosis.[99] Cases of secondary renal carcinoma associated with Xp11.2 translocations and TFE3 gene fusions have also been reported and suggest that cytotoxic chemotherapy may contribute to renal carcinogenesis.[101-103]

Evidence (excess risk of renal carcinoma):

1. CCSS investigators reported a significant excess of subsequent renal carcinoma among 14,358 5-year survivors in the cohort (SIR, 8.0; 95% CI, 5.2–11.7) compared with the general population.[99]
   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).[99] Radiation has been hypothesized to predispose children with high-risk neuroblastoma to renal carcinoma.[104]
      • Those treated with renal-directed radiation therapy of 5 Gy or higher (RR, 3.8; 95% CI, 1.6–9.3).[99]
      • Those treated with platinum-based chemotherapy (RR, 3.5; 95% CI, 1.0–11.2).[99]

References

1. Mertens AC, Liu Q, Neglia JP, et al.: Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 100 (19): 1368-79, 2008. [PUBMED Abstract]
2. Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract]
3. Turcotte LM, Whitton JA, Friedman DL, et al.: Risk of Subsequent Neoplasms During the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort. J Clin Oncol 33 (31): 3568-75, 2015. [PUBMED Abstract]
4. Turcotte LM, Liu Q, Yasui Y, et al.: Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015. JAMA 317 (8): 814-824, 2017. [PUBMED Abstract]
5. Stiller CA, Bunch KJ, Bayne AM, et al.: Subsequent cancers within 5 years from initial diagnosis of childhood cancer. Patterns and risks in the population of Great Britain. Pediatr Blood Cancer 70 (5): e30258, 2023. [PUBMED Abstract]
6. Withrow DR, Anderson H, Armstrong GT, et al.: Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer. JAMA Oncol 8 (12): 1756-1764, 2022. [PUBMED Abstract]
7. Armstrong GT, Liu W, Leisenring W, et al.: Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 29 (22): 3056-64, 2011. [PUBMED Abstract]
8. van Eggermond AM, Schaapveld M, Lugtenburg PJ, et al.: Risk of multiple primary malignancies following treatment of Hodgkin lymphoma. Blood 124 (3): 319-27; quiz 466, 2014. [PUBMED Abstract]
9. Bowers DC, Moskowitz CS, Chou JF, et al.: Morbidity and Mortality Associated With Meningioma After Cranial Radiotherapy: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 35 (14): 1570-1576, 2017. [PUBMED Abstract]
10. Kok JL, Teepen JC, van Leeuwen FE, et al.: Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort: contributions of radiation dose, exposed cranial volume, and age. Neuro Oncol 21 (3): 392-403, 2019. [PUBMED Abstract]
11. Verbruggen LC, Kok JL, Teepen JC, et al.: Clinical characteristics of subsequent histologically confirmed meningiomas in long-term childhood cancer survivors: A Dutch LATER study. Eur J Cancer 150: 240-249, 2021. [PUBMED Abstract]
12. Turcotte LM, Liu Q, Yasui Y, et al.: Chemotherapy and Risk of Subsequent Malignant Neoplasms in the Childhood Cancer Survivor Study Cohort. J Clin Oncol 37 (34): 3310-3319, 2019. [PUBMED Abstract]
13. Teepen JC, van Leeuwen FE, Tissing WJ, et al.: Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy. J Clin Oncol 35 (20): 2288-2298, 2017. [PUBMED Abstract]
14. Wang Z, Wilson CL, Easton J, et al.: Genetic Risk for Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer. J Clin Oncol 36 (20): 2078-2087, 2018. [PUBMED Abstract]
15. Allodji RS, Hawkins MM, Bright CJ, et al.: Risk of subsequent primary leukaemias among 69,460 five-year survivors of childhood cancer diagnosed from 1940 to 2008 in Europe: A cohort study within PanCareSurFup. Eur J Cancer 117: 71-83, 2019. [PUBMED Abstract]
16. Allodji RS, Tucker MA, Hawkins MM, et al.: Role of radiotherapy and chemotherapy in the risk of leukemia after childhood cancer: An international pooled analysis. Int J Cancer 148 (9): 2079-2089, 2021. [PUBMED Abstract]
17. Bhatia S, Yasui Y, Robison LL, et al.: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol 21 (23): 4386-94, 2003. [PUBMED Abstract]
18. Nottage K, Lanctot J, Li Z, et al.: Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study. Blood 117 (23): 6315-8, 2011. [PUBMED Abstract]
19. Khoury JD, Solary E, Abla O, et al.: The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36 (7): 1703-1719, 2022. [PUBMED Abstract]
20. Thirman MJ, Larson RA: Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 10 (2): 293-320, 1996. [PUBMED Abstract]
21. Pedersen-Bjergaard J, Philip P: Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II. Blood 78 (4): 1147-8, 1991. [PUBMED Abstract]
22. Kok JL, Teepen JC, van der Pal HJ, et al.: Incidence of and Risk Factors for Histologically Confirmed Solid Benign Tumors Among Long-term Survivors of Childhood Cancer. JAMA Oncol 5 (5): 671-680, 2019. [PUBMED Abstract]
23. Inskip PD, Sigurdson AJ, Veiga L, et al.: Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects. Int J Radiat Oncol Biol Phys 94 (4): 800-7, 2016. [PUBMED Abstract]
24. Ehrhardt MJ, Howell CR, Hale K, et al.: Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE). J Clin Oncol 37 (19): 1647-1656, 2019. [PUBMED Abstract]
25. Taylor AJ, Little MP, Winter DL, et al.: Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol 28 (36): 5287-93, 2010. [PUBMED Abstract]
26. Henderson TO, Whitton J, Stovall M, et al.: Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 99 (4): 300-8, 2007. [PUBMED Abstract]
27. Veiga LH, Holmberg E, Anderson H, et al.: Thyroid Cancer after Childhood Exposure to External Radiation: An Updated Pooled Analysis of 12 Studies. Radiat Res 185 (5): 473-84, 2016. [PUBMED Abstract]
28. Reulen RC, Frobisher C, Winter DL, et al.: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 305 (22): 2311-9, 2011. [PUBMED Abstract]
29. Teepen JC, Kok JL, Kremer LC, et al.: Long-Term Risk of Skin Cancer Among Childhood Cancer Survivors: A DCOG-LATER Cohort Study. J Natl Cancer Inst 111 (8): 845-853, 2019. [PUBMED Abstract]
30. Majhail NS, Brazauskas R, Rizzo JD, et al.: Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood 117 (1): 316-22, 2011. [PUBMED Abstract]
31. Baker KS, Leisenring WM, Goodman PJ, et al.: Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood 133 (26): 2790-2799, 2019. [PUBMED Abstract]
32. Veiga LH, Curtis RE, Morton LM, et al.: Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use: A Report From the Childhood Cancer Survivor Study. JAMA Pediatr 173 (12): 1171-1179, 2019. [PUBMED Abstract]
33. Kenney LB, Yasui Y, Inskip PD, et al.: Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med 141 (8): 590-7, 2004. [PUBMED Abstract]
34. Moskowitz CS, Chou JF, Wolden SL, et al.: Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol 32 (21): 2217-23, 2014. [PUBMED Abstract]
35. Henderson TO, Liu Q, Turcotte LM, et al.: Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study (CCSS). JAMA Oncol : , 2022. [PUBMED Abstract]
36. Schaapveld M, Aleman BM, van Eggermond AM, et al.: Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma. N Engl J Med 373 (26): 2499-511, 2015. [PUBMED Abstract]
37. Travis LB, Hill D, Dores GM, et al.: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 97 (19): 1428-37, 2005. [PUBMED Abstract]
38. O'Brien MM, Donaldson SS, Balise RR, et al.: Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol 28 (7): 1232-9, 2010. [PUBMED Abstract]
39. Inskip PD, Robison LL, Stovall M, et al.: Radiation dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol 27 (24): 3901-7, 2009. [PUBMED Abstract]
40. Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003. [PUBMED Abstract]
41. van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 95 (13): 971-80, 2003. [PUBMED Abstract]
42. Lange JM, Takashima JR, Peterson SM, et al.: Breast cancer in female survivors of Wilms tumor: a report from the national Wilms tumor late effects study. Cancer 120 (23): 3722-30, 2014. [PUBMED Abstract]
43. Wang Y, Ronckers CM, van Leeuwen FE, et al.: Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer. Nat Med 29 (9): 2268-2277, 2023. [PUBMED Abstract]
44. Henderson TO, Moskowitz CS, Chou JF, et al.: Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 34 (9): 910-8, 2016. [PUBMED Abstract]
45. Eisenberg ER, Weiss A, Prakash I, et al.: Surgical Management and Contralateral Breast Cancer Risk in Women with History of Radiation Therapy for Hodgkin Lymphoma: Results from a Population-Based Cohort. Ann Surg Oncol 29 (11): 6673-6680, 2022. [PUBMED Abstract]
46. Moskowitz CS, Ronckers CM, Chou JF, et al.: Development and Validation of a Breast Cancer Risk Prediction Model for Childhood Cancer Survivors Treated With Chest Radiation: A Report From the Childhood Cancer Survivor Study and the Dutch Hodgkin Late Effects and LATER Cohorts. J Clin Oncol 39 (27): 3012-3021, 2021. [PUBMED Abstract]
47. Dores GM, Anderson WF, Beane Freeman LE, et al.: Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy. Br J Cancer 103 (7): 1081-4, 2010. [PUBMED Abstract]
48. Horst KC, Hancock SL, Ognibene G, et al.: Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma. Ann Oncol 25 (4): 848-51, 2014. [PUBMED Abstract]
49. Demoor-Goldschmidt C, Supiot S, Mahé MA, et al.: Clinical and histological features of second breast cancers following radiotherapy for childhood and young adult malignancy. Br J Radiol 91 (1086): 20170824, 2018. [PUBMED Abstract]
50. Castiglioni F, Terenziani M, Carcangiu ML, et al.: Radiation effects on development of HER2-positive breast carcinomas. Clin Cancer Res 13 (1): 46-51, 2007. [PUBMED Abstract]
51. Gaffney DK, Hemmersmeier J, Holden J, et al.: Breast cancer after mantle irradiation for Hodgkin's disease: correlation of clinical, pathologic, and molecular features including loss of heterozygosity at BRCA1 and BRCA2. Int J Radiat Oncol Biol Phys 49 (2): 539-46, 2001. [PUBMED Abstract]
52. Wong SM, Ajjamada L, Weiss AC, et al.: Clinicopathologic features of breast cancers diagnosed in women treated with prior radiation therapy for Hodgkin lymphoma: Results from a population-based cohort. Cancer 128 (7): 1365-1372, 2022. [PUBMED Abstract]
53. Moskowitz CS, Chou JF, Neglia JP, et al.: Mortality After Breast Cancer Among Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 37 (24): 2120-2130, 2019. [PUBMED Abstract]
54. Yeh JM, Lowry KP, Schechter CB, et al.: Clinical Benefits, Harms, and Cost-Effectiveness of Breast Cancer Screening for Survivors of Childhood Cancer Treated With Chest Radiation : A Comparative Modeling Study. Ann Intern Med 173 (5): 331-341, 2020. [PUBMED Abstract]
55. Vivanco M, Dalle JH, Alberti C, et al.: Malignant and benign thyroid nodules after total body irradiation preceding hematopoietic cell transplantation during childhood. Eur J Endocrinol 167 (2): 225-33, 2012. [PUBMED Abstract]
56. Friedman DN, Goodman PJ, Leisenring WM, et al.: Impact of risk-based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 116 (6): 885-894, 2024. [PUBMED Abstract]
57. Michaelson EM, Chen YH, Silver B, et al.: Thyroid malignancies in survivors of Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 88 (3): 636-41, 2014. [PUBMED Abstract]
58. Sigurdson AJ, Ronckers CM, Mertens AC, et al.: Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365 (9476): 2014-23, 2005 Jun 11-17. [PUBMED Abstract]
59. Clement SC, Lebbink CA, Klein Hesselink MS, et al.: Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study. Eur J Endocrinol 183 (2): 169-180, 2020. [PUBMED Abstract]
60. Casey DL, Vogelius IR, Brodin NP, et al.: Risk of Subsequent Neoplasms in Childhood Cancer Survivors After Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 640-654, 2024. [PUBMED Abstract]
61. Hijiya N, Hudson MM, Lensing S, et al.: Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297 (11): 1207-15, 2007. [PUBMED Abstract]
62. Neglia JP, Robison LL, Stovall M, et al.: New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 98 (21): 1528-37, 2006. [PUBMED Abstract]
63. Faraci M, Morana G, Bagnasco F, et al.: Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: a cross sectional, single center study. Pediatr Blood Cancer 57 (2): 240-6, 2011. [PUBMED Abstract]
64. Vinchon M, Leblond P, Caron S, et al.: Radiation-induced tumors in children irradiated for brain tumor: a longitudinal study. Childs Nerv Syst 27 (3): 445-53, 2011. [PUBMED Abstract]
65. Koike T, Yanagimachi N, Ishiguro H, et al.: High incidence of radiation-induced cavernous hemangioma in long-term survivors who underwent hematopoietic stem cell transplantation with radiation therapy during childhood or adolescence. Biol Blood Marrow Transplant 18 (7): 1090-8, 2012. [PUBMED Abstract]
66. Heymer EJ, Hawkins MM, Winter DL, et al.: Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study. Br J Cancer 130 (6): 976-986, 2024. [PUBMED Abstract]
67. Bowers DC, Verbruggen LC, Kremer LCM, et al.: Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 22 (5): e196-e206, 2021. [PUBMED Abstract]
68. Baliga S, Gallotto S, Bajaj B, et al.: Decade-long disease, secondary malignancy, and brainstem injury outcomes in pediatric and young adult medulloblastoma patients treated with proton radiotherapy. Neuro Oncol 24 (6): 1010-1019, 2022. [PUBMED Abstract]
69. Wong JR, Morton LM, Tucker MA, et al.: Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol 32 (29): 3284-90, 2014. [PUBMED Abstract]
70. Fidler MM, Reulen RC, Winter DL, et al.: Risk of Subsequent Bone Cancers Among 69 460 Five-Year Survivors of Childhood and Adolescent Cancer in Europe. J Natl Cancer Inst 110 (2): , 2018. [PUBMED Abstract]
71. Bright CJ, Hawkins MM, Winter DL, et al.: Risk of Soft-Tissue Sarcoma Among 69 460 Five-Year Survivors of Childhood Cancer in Europe. J Natl Cancer Inst 110 (6): 649-660, 2018. [PUBMED Abstract]
72. Chaussade A, Millot G, Wells C, et al.: Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy. Eur J Med Genet 62 (3): 217-223, 2019. [PUBMED Abstract]
73. Kube SJ, Blattmann C, Bielack SS, et al.: Secondary malignant neoplasms after bone and soft tissue sarcomas in children, adolescents, and young adults. Cancer 128 (9): 1787-1800, 2022. [PUBMED Abstract]
74. Schwartz B, Benadjaoud MA, Cléro E, et al.: Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment. Radiat Environ Biophys 53 (2): 381-90, 2014. [PUBMED Abstract]
75. Bielack SS, Blattmann C, Hassenpflug W, et al.: Osteosarcoma Arising After Ewing Sarcoma or Vice Versa: A Report of 20 Affected Patients from the Cooperative Osteosarcoma Study Group (COSS). Anticancer Res 43 (11): 4975-4981, 2023. [PUBMED Abstract]
76. Henderson TO, Rajaraman P, Stovall M, et al.: Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys 84 (1): 224-30, 2012. [PUBMED Abstract]
77. Reulen RC, Winter DL, Diallo I, et al.: Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study. J Clin Oncol 41 (21): 3735-3746, 2023. [PUBMED Abstract]
78. MacCarthy A, Bayne AM, Brownbill PA, et al.: Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 108 (12): 2455-63, 2013. [PUBMED Abstract]
79. Temming P, Arendt M, Viehmann A, et al.: Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center. Pediatr Blood Cancer 64 (1): 71-80, 2017. [PUBMED Abstract]
80. Kleinerman RA, Schonfeld SJ, Sigel BS, et al.: Bone and Soft-Tissue Sarcoma Risk in Long-Term Survivors of Hereditary Retinoblastoma Treated With Radiation. J Clin Oncol 37 (35): 3436-3445, 2019. [PUBMED Abstract]
81. Thorsness SL, Freites-Martinez A, Marchetti MA, et al.: Nonmelanoma Skin Cancer in Childhood and Young Adult Cancer Survivors Previously Treated With Radiotherapy. J Natl Compr Canc Netw 17 (3): 237-243, 2019. [PUBMED Abstract]
82. Geller AC, Coroiu A, Keske RR, et al.: Advancing Survivors Knowledge (ASK Study) of Skin Cancer Surveillance After Childhood Cancer: A Randomized Controlled Trial in the Childhood Cancer Survivor Study. J Clin Oncol 41 (12): 2269-2280, 2023. [PUBMED Abstract]
83. Watt TC, Inskip PD, Stratton K, et al.: Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 104 (16): 1240-50, 2012. [PUBMED Abstract]
84. Braam KI, Overbeek A, Kaspers GJ, et al.: Malignant melanoma as second malignant neoplasm in long-term childhood cancer survivors: a systematic review. Pediatr Blood Cancer 58 (5): 665-74, 2012. [PUBMED Abstract]
85. Pappo AS, Armstrong GT, Liu W, et al.: Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Pediatr Blood Cancer 60 (3): 461-6, 2013. [PUBMED Abstract]
86. Kleinerman RA, Schonfeld SJ, Abramson DH, et al.: Increased Risk of Skin Cancer in 1,851 Long-Term Retinoblastoma Survivors. J Invest Dermatol 141 (12): 2849-2857.e3, 2021. [PUBMED Abstract]
87. Ghosh T, Chen Y, Dietz AC, et al.: Lung Cancer as a Subsequent Malignant Neoplasm in Survivors of Childhood Cancer. Cancer Epidemiol Biomarkers Prev 30 (12): 2235-2243, 2021. [PUBMED Abstract]
88. van Leeuwen FE, Klokman WJ, Stovall M, et al.: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 87 (20): 1530-7, 1995. [PUBMED Abstract]
89. Henderson TO, Oeffinger KC, Whitton J, et al.: Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study. Ann Intern Med 156 (11): 757-66, W-260, 2012. [PUBMED Abstract]
90. Nottage K, McFarlane J, Krasin MJ, et al.: Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 30 (20): 2552-8, 2012. [PUBMED Abstract]
91. Heymer EJ, Jóźwiak K, Kremer LC, et al.: Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study. J Clin Oncol 42 (3): 336-347, 2024. [PUBMED Abstract]
92. Tukenova M, Diallo I, Anderson H, et al.: Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study. Int J Radiat Oncol Biol Phys 82 (3): e383-90, 2012. [PUBMED Abstract]
93. Daly PE, Samiee S, Cino M, et al.: High prevalence of adenomatous colorectal polyps in young cancer survivors treated with abdominal radiation therapy: results of a prospective trial. Gut 66 (10): 1797-1801, 2017. [PUBMED Abstract]
94. Teepen JC, Kok JL, van Leeuwen FE, et al.: Colorectal Adenomas and Cancers After Childhood Cancer Treatment: A DCOG-LATER Record Linkage Study. J Natl Cancer Inst 110 (7): 758-767, 2018. [PUBMED Abstract]
95. Reulen RC, Wong KF, Bright CJ, et al.: Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study. Gut : , 2020. [PUBMED Abstract]
96. Geurts YM, Shakir R, Ntentas G, et al.: Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma. JAMA Oncol 9 (4): 481-489, 2023. [PUBMED Abstract]
97. Sunguc C, Hawkins MM, Winter DL, et al.: Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study. Br J Cancer 128 (1): 80-90, 2023. [PUBMED Abstract]
98. Liu JJ, De Vivo I, Wu CY, et al.: Subsequent primary urogenital cancers among childhood and adolescent cancer survivors in the United States. Urol Oncol 40 (2): 65.e11-65.e18, 2022. [PUBMED Abstract]
99. Wilson CL, Ness KK, Neglia JP, et al.: Renal carcinoma after childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 105 (7): 504-8, 2013. [PUBMED Abstract]
100. de Vathaire F, Scwhartz B, El-Fayech C, et al.: Risk of a Second Kidney Carcinoma Following Childhood Cancer: Role of Chemotherapy and Radiation Dose to Kidneys. J Urol 194 (5): 1390-5, 2015. [PUBMED Abstract]
101. Hedgepeth RC, Zhou M, Ross J: Rapid development of metastatic Xp11 translocation renal cell carcinoma in a girl treated for neuroblastoma. J Pediatr Hematol Oncol 31 (8): 602-4, 2009. [PUBMED Abstract]
102. Argani P, Laé M, Ballard ET, et al.: Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 24 (10): 1529-34, 2006. [PUBMED Abstract]
103. Ma J, Pan C, Yin M: Translocation Renal Cell Carcinoma in a Child Previously Treated for Infantile Fibrosarcoma. Pediatr Dev Pathol 21 (4): 418-422, 2018 Jul-Aug. [PUBMED Abstract]
104. Fleitz JM, Wootton-Gorges SL, Wyatt-Ashmead J, et al.: Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood. Pediatr Radiol 33 (8): 540-5, 2003. [PUBMED Abstract]
105. Henderson TO, Fowler BW, Hamann HA, et al.: Subsequent malignant neoplasms in the Childhood Cancer Survivor Study: Occurrence of cancer types in which human papillomavirus is an established etiologic risk factor. Cancer 128 (2): 373-382, 2022. [PUBMED Abstract]
106. Ou JY, Bennion N, Parker K, et al.: Risk Factors and Trends for HPV-Associated Subsequent Malignant Neoplasms among Adolescent and Young Adult Cancer Survivors. Cancer Epidemiol Biomarkers Prev 32 (5): 625-633, 2023. [PUBMED Abstract]
107. Brown AL, Arroyo VM, Agrusa JE, et al.: Survival disparities for second primary malignancies diagnosed among childhood cancer survivors: A population-based assessment. Cancer 125 (20): 3623-3630, 2019. [PUBMED Abstract]
108. Archer NM, Amorim RP, Naves R, et al.: An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population-Based Evidence for a Cancer Predisposition Syndrome? Pediatr Blood Cancer 63 (2): 196-201, 2016. [PUBMED Abstract]
109. Wang X, Sun CL, Hageman L, et al.: Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study. J Clin Oncol 35 (32): 3688-3696, 2017. [PUBMED Abstract]
110. Waespe N, Belle FN, Redmond S, et al.: Cancer predisposition syndromes as a risk factor for early second primary neoplasms after childhood cancer - A national cohort study. Eur J Cancer 145: 71-80, 2021. [PUBMED Abstract]
111. Andersson A, Enblad G, Tavelin B, et al.: Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma. Br J Cancer 98 (5): 1001-5, 2008. [PUBMED Abstract]
112. Hisada M, Garber JE, Fung CY, et al.: Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 90 (8): 606-11, 1998. [PUBMED Abstract]
113. de Andrade KC, Khincha PP, Hatton JN, et al.: Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol 22 (12): 1787-1798, 2021. [PUBMED Abstract]
114. Bhatia S, Chen Y, Wong FL, et al.: Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1. J Clin Oncol 37 (32): 3050-3058, 2019. [PUBMED Abstract]
115. de Blank P, Li N, Fisher MJ, et al.: Late morbidity and mortality in adult survivors of childhood glioma with neurofibromatosis type 1: report from the Childhood Cancer Survivor Study. Genet Med 22 (11): 1794-1802, 2020. [PUBMED Abstract]
116. Strahm B, Malkin D: Hereditary cancer predisposition in children: genetic basis and clinical implications. Int J Cancer 119 (9): 2001-6, 2006. [PUBMED Abstract]
117. Cullinan N, Schiller I, Di Giuseppe G, et al.: Utility of a Cancer Predisposition Screening Tool for Predicting Subsequent Malignant Neoplasms in Childhood Cancer Survivors. J Clin Oncol 39 (29): 3207-3216, 2021. [PUBMED Abstract]
118. Goudie C, Witkowski L, Cullinan N, et al.: Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes. JAMA Oncol 7 (12): 1806-1814, 2021. [PUBMED Abstract]
119. Qin N, Wang Z, Liu Q, et al.: Pathogenic Germline Mutations in DNA Repair Genes in Combination With Cancer Treatment Exposures and Risk of Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer. J Clin Oncol 38 (24): 2728-2740, 2020. [PUBMED Abstract]
120. Collins A, Harrington V: Repair of oxidative DNA damage: assessing its contribution to cancer prevention. Mutagenesis 17 (6): 489-93, 2002. [PUBMED Abstract]
121. Gibson TM, Karyadi DM, Hartley SW, et al.: Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors. Nat Med 30 (3): 690-698, 2024. [PUBMED Abstract]
122. Im C, Sharafeldin N, Yuan Y, et al.: Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report. J Clin Oncol 41 (27): 4381-4393, 2023. [PUBMED Abstract]
123. Landier W, Bhatia S, Eshelman DA, et al.: Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22 (24): 4979-90, 2004. [PUBMED Abstract]
124. Kremer LC, Mulder RL, Oeffinger KC, et al.: A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatr Blood Cancer 60 (4): 543-9, 2013. [PUBMED Abstract]
125. Mulder RL, Hudson MM, Bhatia S, et al.: Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group. J Clin Oncol 38 (35): 4194-4207, 2020. [PUBMED Abstract]
126. Kriege M, Brekelmans CT, Boetes C, et al.: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351 (5): 427-37, 2004. [PUBMED Abstract]
127. Leach MO, Boggis CR, Dixon AK, et al.: Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 365 (9473): 1769-78, 2005 May 21-27. [PUBMED Abstract]
128. Tieu MT, Cigsar C, Ahmed S, et al.: Breast cancer detection among young survivors of pediatric Hodgkin lymphoma with screening magnetic resonance imaging. Cancer 120 (16): 2507-13, 2014. [PUBMED Abstract]
129. Saslow D, Boetes C, Burke W, et al.: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57 (2): 75-89, 2007 Mar-Apr. [PUBMED Abstract]
130. Berrington de Gonzalez A, Berg CD, Visvanathan K, et al.: Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers. J Natl Cancer Inst 101 (3): 205-9, 2009. [PUBMED Abstract]
131. Young KC, Burch A, Oduko JM: Radiation doses received in the UK Breast Screening Programme in 2001 and 2002. Br J Radiol 78 (927): 207-18, 2005. [PUBMED Abstract]
132. Spelic DC: Trends in Mammography Dose and Image Quality 1974-2005. Silver Spring, Md: U.S. Food and Drug Administration, 2006. Available online. Last accessed August 21, 2023.
133. Clement SC, Kremer LCM, Verburg FA, et al.: Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63: 28-39, 2018. [PUBMED Abstract]

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

Evidence (excess risk of premature cardiovascular mortality):

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

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

Evidence (selected cohort studies describing cardiovascular outcomes):

References

1. Armstrong GT, Chen Y, Yasui Y, et al.: Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. N Engl J Med 374 (9): 833-42, 2016. [PUBMED Abstract]
2. Fidler MM, Reulen RC, Winter DL, et al.: Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: population based cohort study. BMJ 354: i4351, 2016. [PUBMED Abstract]
3. Henson KE, Reulen RC, Winter DL, et al.: Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study. Circulation 134 (20): 1519-1531, 2016. [PUBMED Abstract]
4. Suh E, Stratton KL, Leisenring WM, et al.: Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 21 (3): 421-435, 2020. [PUBMED Abstract]
5. Hammoud RA, Liu Q, Dixon SB, et al.: The burden of cardiovascular disease and risk for subsequent major adverse cardiovascular events in survivors of childhood cancer: a prospective, longitudinal analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 25 (6): 811-822, 2024. [PUBMED Abstract]
6. Fidler MM, Reulen RC, Henson K, et al.: Population-Based Long-Term Cardiac-Specific Mortality Among 34 489 Five-Year Survivors of Childhood Cancer in Great Britain. Circulation 135 (10): 951-963, 2017. [PUBMED Abstract]
7. Bansal N, Blanco JG, Sharma UC, et al.: Cardiovascular diseases in survivors of childhood cancer. Cancer Metastasis Rev 39 (1): 55-68, 2020. [PUBMED Abstract]
8. Armstrong GT, Oeffinger KC, Chen Y, et al.: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 31 (29): 3673-80, 2013. [PUBMED Abstract]
9. Hudson MM, Ness KK, Gurney JG, et al.: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309 (22): 2371-81, 2013. [PUBMED Abstract]
10. Haddy N, Diallo S, El-Fayech C, et al.: Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study. Circulation 133 (1): 31-8, 2016. [PUBMED Abstract]
11. Cotton CA, Peterson S, Norkool PA, et al.: Early and late mortality after diagnosis of wilms tumor. J Clin Oncol 27 (8): 1304-9, 2009. [PUBMED Abstract]
12. Schellong G, Riepenhausen M, Bruch C, et al.: Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies. Pediatr Blood Cancer 55 (6): 1145-52, 2010. [PUBMED Abstract]
13. Green DM, Kun LE, Matthay KK, et al.: Relevance of historical therapeutic approaches to the contemporary treatment of pediatric solid tumors. Pediatr Blood Cancer 60 (7): 1083-94, 2013. [PUBMED Abstract]
14. Hudson MM, Neglia JP, Woods WG, et al.: Lessons from the past: opportunities to improve childhood cancer survivor care through outcomes investigations of historical therapeutic approaches for pediatric hematological malignancies. Pediatr Blood Cancer 58 (3): 334-43, 2012. [PUBMED Abstract]
15. de Baat EC, van Dalen EC, Mulder RL, et al.: Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Child Adolesc Health 6 (12): 885-894, 2022. [PUBMED Abstract]
16. Chow EJ, Antal Z, Constine LS, et al.: New Agents, Emerging Late Effects, and the Development of Precision Survivorship. J Clin Oncol 36 (21): 2231-2240, 2018. [PUBMED Abstract]
17. de Baat EC, Feijen EAM, Reulen RC, et al.: Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study. J Clin Oncol 41 (1): 96-106, 2023. [PUBMED Abstract]
18. Mulrooney DA, Hyun G, Ness KK, et al.: Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort. BMJ 368: l6794, 2020. [PUBMED Abstract]
19. Bates JE, Howell RM, Liu Q, et al.: Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study. J Clin Oncol 37 (13): 1090-1101, 2019. [PUBMED Abstract]
20. Bates JE, Shrestha S, Liu Q, et al.: Cardiac Substructure Radiation Dose and Risk of Late Cardiac Disease in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 41 (22): 3826-3838, 2023. [PUBMED Abstract]
21. Chow EJ, Chen Y, Armstrong GT, et al.: Underdiagnosis and Undertreatment of Modifiable Cardiovascular Risk Factors Among Survivors of Childhood Cancer. J Am Heart Assoc 11 (12): e024735, 2022. [PUBMED Abstract]
22. Goldberg JF, Hyun G, Ness KK, et al.: Dyslipidemia and cardiovascular disease among childhood cancer survivors: a St. Jude Lifetime Cohort report. J Natl Cancer Inst 116 (3): 408-420, 2024. [PUBMED Abstract]
23. Kooijmans ECM, van der Pal HJH, Pluijm SMF, et al.: Hypertension in long-term childhood cancer survivors after treatment with potentially nephrotoxic therapy; DCCSS-LATER 2: Renal study. Eur J Cancer 172: 287-299, 2022. [PUBMED Abstract]
24. Bhakta N, Liu Q, Yeo F, et al.: Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 17 (9): 1325-34, 2016. [PUBMED Abstract]
25. Mulrooney DA, Soliman EZ, Ehrhardt MJ, et al.: Electrocardiographic abnormalities and mortality in aging survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study. Am Heart J 189: 19-27, 2017. [PUBMED Abstract]
26. Feijen EAML, Font-Gonzalez A, Van der Pal HJH, et al.: Risk and Temporal Changes of Heart Failure Among 5-Year Childhood Cancer Survivors: a DCOG-LATER Study. J Am Heart Assoc 8 (1): e009122, 2019. [PUBMED Abstract]
27. Bates JE, Rancati T, Keshavarz H, et al.: Cardiac Disease in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 522-532, 2024. [PUBMED Abstract]
28. van der Pal HJ, van Dalen EC, van Delden E, et al.: High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30 (13): 1429-37, 2012. [PUBMED Abstract]
29. Zhang S, Liu X, Bawa-Khalfe T, et al.: Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18 (11): 1639-42, 2012. [PUBMED Abstract]
30. Lyu YL, Kerrigan JE, Lin CP, et al.: Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 67 (18): 8839-46, 2007. [PUBMED Abstract]
31. Hudson MM, Rai SN, Nunez C, et al.: Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol 25 (24): 3635-43, 2007. [PUBMED Abstract]
32. van der Pal HJ, van Dalen EC, Hauptmann M, et al.: Cardiac function in 5-year survivors of childhood cancer: a long-term follow-up study. Arch Intern Med 170 (14): 1247-55, 2010. [PUBMED Abstract]
33. Ehrhardt MJ, Leerink JM, Mulder RL, et al.: Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 24 (3): e108-e120, 2023. [PUBMED Abstract]
34. Chow EJ, Chen Y, Kremer LC, et al.: Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol 33 (5): 394-402, 2015. [PUBMED Abstract]
35. Armenian SH, Sun CL, Vase T, et al.: Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease. Blood 120 (23): 4505-12, 2012. [PUBMED Abstract]
36. Feijen EA, Leisenring WM, Stratton KL, et al.: Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer. J Clin Oncol 33 (32): 3774-80, 2015. [PUBMED Abstract]
37. Feijen EAM, Leisenring WM, Stratton KL, et al.: Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. JAMA Oncol 5 (6): 864-871, 2019. [PUBMED Abstract]
38. van Dalen EC, Michiels EM, Caron HN, et al.: Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev (5): CD005006, 2010. [PUBMED Abstract]
39. Krauss AC, Gao X, Li L, et al.: FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. Clin Cancer Res 25 (9): 2685-2690, 2019. [PUBMED Abstract]
40. van Dalen EC, van der Pal HJ, Caron HN, et al.: Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev (4): CD005008, 2009. [PUBMED Abstract]
41. Lipshultz SE, Giantris AL, Lipsitz SR, et al.: Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol 20 (6): 1677-82, 2002. [PUBMED Abstract]
42. Hensley ML, Hagerty KL, Kewalramani T, et al.: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27 (1): 127-45, 2009. [PUBMED Abstract]
43. van Dalen EC, Caron HN, Dickinson HO, et al.: Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev (6): CD003917, 2011. [PUBMED Abstract]
44. Wexler LH, Andrich MP, Venzon D, et al.: Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 14 (2): 362-72, 1996. [PUBMED Abstract]
45. Lipshultz SE, Scully RE, Lipsitz SR, et al.: Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11 (10): 950-61, 2010. [PUBMED Abstract]
46. Asselin BL, Devidas M, Chen L, et al.: Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol 34 (8): 854-62, 2016. [PUBMED Abstract]
47. Shaikh F, Dupuis LL, Alexander S, et al.: Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis. J Natl Cancer Inst 108 (4): , 2016. [PUBMED Abstract]
48. Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009. [PUBMED Abstract]
49. Chow EJ, Aplenc R, Vrooman LM, et al.: Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group. Cancer 128 (4): 788-796, 2022. [PUBMED Abstract]
50. Chow EJ, Aggarwal S, Doody DR, et al.: Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer. J Clin Oncol 41 (12): 2248-2257, 2023. [PUBMED Abstract]
51. Mansouri I, Allodji RS, Hill C, et al.: The role of irradiated heart and left ventricular volumes in heart failure occurrence after childhood cancer. Eur J Heart Fail 21 (4): 509-518, 2019. [PUBMED Abstract]
52. Shrestha S, Bates JE, Liu Q, et al.: Radiation therapy related cardiac disease risk in childhood cancer survivors: Updated dosimetry analysis from the Childhood Cancer Survivor Study. Radiother Oncol 163: 199-208, 2021. [PUBMED Abstract]
53. Lo AC, Liu A, Liu Q, et al.: Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children. JAMA Netw Open 7 (1): e2351062, 2024. [PUBMED Abstract]
54. Murphy ES, Xie H, Merchant TE, et al.: Review of cranial radiotherapy-induced vasculopathy. J Neurooncol 122 (3): 421-9, 2015. [PUBMED Abstract]
55. Passos J, Nzwalo H, Valente M, et al.: Microbleeds and cavernomas after radiotherapy for paediatric primary brain tumours. J Neurol Sci 372: 413-416, 2017. [PUBMED Abstract]
56. Bowers DC, Liu Y, Leisenring W, et al.: Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol 24 (33): 5277-82, 2006. [PUBMED Abstract]
57. De Bruin ML, Dorresteijn LD, van't Veer MB, et al.: Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 101 (13): 928-37, 2009. [PUBMED Abstract]
58. van Dijk IW, van der Pal HJ, van Os RM, et al.: Risk of Symptomatic Stroke After Radiation Therapy for Childhood Cancer: A Long-Term Follow-Up Cohort Analysis. Int J Radiat Oncol Biol Phys 96 (3): 597-605, 2016. [PUBMED Abstract]
59. Reulen RC, Guha J, Bright CJ, et al.: Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study. Int J Cancer 148 (3): 572-583, 2021. [PUBMED Abstract]
60. Waxer JF, Wong K, Modiri A, et al.: Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A PENTEC Normal Tissue Outcomes Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 417-430, 2024. [PUBMED Abstract]
61. Mueller S, Sear K, Hills NK, et al.: Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys 86 (4): 643-8, 2013. [PUBMED Abstract]
62. Fullerton HJ, Stratton K, Mueller S, et al.: Recurrent stroke in childhood cancer survivors. Neurology 85 (12): 1056-64, 2015. [PUBMED Abstract]
63. Chow EJ, Chen Y, Hudson MM, et al.: Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer. J Clin Oncol 36 (1): 44-52, 2018. [PUBMED Abstract]
64. El-Fayech C, Haddy N, Allodji RS, et al.: Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries. Int J Radiat Oncol Biol Phys 97 (2): 278-286, 2017. [PUBMED Abstract]
65. Bright CJ, Hawkins MM, Guha J, et al.: Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study). Circulation 135 (13): 1194-1210, 2017. [PUBMED Abstract]
66. Mueller S, Kline CN, Buerki RA, et al.: Stroke impact on mortality and psychologic morbidity within the Childhood Cancer Survivor Study. Cancer 126 (5): 1051-1059, 2020. [PUBMED Abstract]
67. Walker AJ, Grainge MJ, Card TR, et al.: Venous thromboembolism in children with cancer - a population-based cohort study. Thromb Res 133 (3): 340-4, 2014. [PUBMED Abstract]
68. Madenci AL, Weil BR, Liu Q, et al.: Long-Term Risk of Venous Thromboembolism in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol : JCO2018784595, 2018. [PUBMED Abstract]
69. Mueller S, Fullerton HJ, Stratton K, et al.: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86 (4): 649-55, 2013. [PUBMED Abstract]
70. Chao C, Xu L, Bhatia S, et al.: Cardiovascular Disease Risk Profiles in Survivors of Adolescent and Young Adult (AYA) Cancer: The Kaiser Permanente AYA Cancer Survivors Study. J Clin Oncol 34 (14): 1626-33, 2016. [PUBMED Abstract]
71. Winther JF, Bhatia S, Cederkvist L, et al.: Risk of cardiovascular disease among Nordic childhood cancer survivors with diabetes mellitus: A report from adult life after childhood cancer in Scandinavia. Cancer 124 (22): 4393-4400, 2018. [PUBMED Abstract]
72. van Dalen EC, Mulder RL, Suh E, et al.: Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Eur J Cancer 156: 127-137, 2021. [PUBMED Abstract]
73. Lipshultz SE, Lipsitz SR, Kutok JL, et al.: Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 119 (19): 3555-62, 2013. [PUBMED Abstract]
74. Visscher H, Ross CJ, Rassekh SR, et al.: Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr Blood Cancer 60 (8): 1375-81, 2013. [PUBMED Abstract]
75. Wang X, Liu W, Sun CL, et al.: Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group. J Clin Oncol 32 (7): 647-53, 2014. [PUBMED Abstract]
76. Wang X, Sun CL, Quiñones-Lombraña A, et al.: CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children's Oncology Group Genome-Wide Association Study. J Clin Oncol 34 (8): 863-70, 2016. [PUBMED Abstract]
77. Aminkeng F, Bhavsar AP, Visscher H, et al.: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 47 (9): 1079-84, 2015. [PUBMED Abstract]
78. Visscher H, Rassekh SR, Sandor GS, et al.: Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children. Pharmacogenomics 16 (10): 1065-76, 2015. [PUBMED Abstract]
79. Singh P, Wang X, Hageman L, et al.: Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report. Cancer 126 (17): 4051-4058, 2020. [PUBMED Abstract]
80. Sapkota Y, Ehrhardt MJ, Qin N, et al.: A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors. J Natl Cancer Inst 114 (8): 1109-1116, 2022. [PUBMED Abstract]
81. Davies SM: Getting to the heart of the matter. J Clin Oncol 30 (13): 1399-400, 2012. [PUBMED Abstract]
82. Lewey J, Haythe J: Cardiomyopathy in pregnancy. Semin Perinatol 38 (5): 309-17, 2014. [PUBMED Abstract]
83. Hines MR, Mulrooney DA, Hudson MM, et al.: Pregnancy-associated cardiomyopathy in survivors of childhood cancer. J Cancer Surviv 10 (1): 113-21, 2016. [PUBMED Abstract]
84. Chait-Rubinek L, Mariani JA, Goroncy N, et al.: A Retrospective Evaluation of Risk of Peripartum Cardiac Dysfunction in Survivors of Childhood, Adolescent and Young Adult Malignancies. Cancers (Basel) 11 (8): , 2019. [PUBMED Abstract]
85. Liu S, Aghel N, Belford L, et al.: Cardiac Outcomes in Pregnant Women With Treated Cancer. J Am Coll Cardiol 72 (17): 2087-2089, 2018. [PUBMED Abstract]
86. Bottinor W, Im C, Doody DR, et al.: Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer. J Am Coll Cardiol 83 (8): 827-838, 2024. [PUBMED Abstract]
87. Dietz AC, Seidel K, Leisenring WM, et al.: Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 20 (10): 1420-1431, 2019. [PUBMED Abstract]
88. Brouwer CA, Postma A, Hooimeijer HL, et al.: Endothelial damage in long-term survivors of childhood cancer. J Clin Oncol 31 (31): 3906-13, 2013. [PUBMED Abstract]
89. Maraldo MV, Jørgensen M, Brodin NP, et al.: The impact of involved node, involved field and mantle field radiotherapy on estimated radiation doses and risk of late effects for pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 61 (4): 717-22, 2014. [PUBMED Abstract]
90. Tukenova M, Guibout C, Oberlin O, et al.: Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 28 (8): 1308-15, 2010. [PUBMED Abstract]
91. Armstrong GT, Kawashima T, Leisenring W, et al.: Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 32 (12): 1218-27, 2014. [PUBMED Abstract]
92. Chen AB, Punglia RS, Kuntz KM, et al.: Cost effectiveness and screening interval of lipid screening in Hodgkin's lymphoma survivors. J Clin Oncol 27 (32): 5383-9, 2009. [PUBMED Abstract]
93. Wong FL, Bhatia S, Landier W, et al.: Cost-effectiveness of the children's oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med 160 (10): 672-83, 2014. [PUBMED Abstract]
94. Yeh JM, Nohria A, Diller L: Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects. Ann Intern Med 160 (10): 661-71, 2014. [PUBMED Abstract]
95. Landier W, Armenian SH, Lee J, et al.: Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. J Clin Oncol 30 (35): 4401-8, 2012. [PUBMED Abstract]
96. Ramjaun A, AlDuhaiby E, Ahmed S, et al.: Echocardiographic Detection of Cardiac Dysfunction in Childhood Cancer Survivors: How Long Is Screening Required? Pediatr Blood Cancer 62 (12): 2197-203, 2015. [PUBMED Abstract]
97. Spewak MB, Williamson RS, Mertens AC, et al.: Yield of screening echocardiograms during pediatric follow-up in survivors treated with anthracyclines and cardiotoxic radiation. Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
98. Chen Y, Chow EJ, Oeffinger KC, et al.: Traditional Cardiovascular Risk Factors and Individual Prediction of Cardiovascular Events in Childhood Cancer Survivors. J Natl Cancer Inst 112 (3): 256-265, 2020. [PUBMED Abstract]
99. Scott JM, Li N, Liu Q, et al.: Association of Exercise With Mortality in Adult Survivors of Childhood Cancer. JAMA Oncol 4 (10): 1352-1358, 2018. [PUBMED Abstract]
100. Schindera C, Zürcher SJ, Jung R, et al.: Physical fitness and modifiable cardiovascular disease risk factors in survivors of childhood cancer: A report from the SURfit study. Cancer 127 (10): 1690-1698, 2021. [PUBMED Abstract]
101. Rueegg CS, Zürcher SJ, Schindera C, et al.: Effect of a 1-year physical activity intervention on cardiovascular health in long-term childhood cancer survivors-a randomised controlled trial (SURfit). Br J Cancer 129 (8): 1284-1297, 2023. [PUBMED Abstract]

References

1. Grill J, Kieffer V, Kalifa C: Measuring the neuro-cognitive side-effects of irradiation in children with brain tumors. Pediatr Blood Cancer 42 (5): 452-6, 2004. [PUBMED Abstract]
2. Marusak HA, Iadipaolo AS, Harper FW, et al.: Neurodevelopmental consequences of pediatric cancer and its treatment: applying an early adversity framework to understanding cognitive, behavioral, and emotional outcomes. Neuropsychol Rev 28 (2): 123-175, 2018. [PUBMED Abstract]
3. Brinkman TM, Krasin MJ, Liu W, et al.: Long-Term Neurocognitive Functioning and Social Attainment in Adult Survivors of Pediatric CNS Tumors: Results From the St Jude Lifetime Cohort Study. J Clin Oncol 34 (12): 1358-67, 2016. [PUBMED Abstract]
4. Moxon-Emre I, Bouffet E, Taylor MD, et al.: Impact of craniospinal dose, boost volume, and neurologic complications on intellectual outcome in patients with medulloblastoma. J Clin Oncol 32 (17): 1760-8, 2014. [PUBMED Abstract]
5. Krull KR, Zhang N, Santucci A, et al.: Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. Blood 122 (4): 550-3, 2013. [PUBMED Abstract]
6. Annett RD, Hile S, Bedrick E, et al.: Neuropsychological functioning of children treated for acute lymphoblastic leukemia: impact of whole brain radiation therapy. Psychooncology 24 (2): 181-9, 2015. [PUBMED Abstract]
7. van der Plas E, Qiu W, Nieman BJ, et al.: Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study. J Natl Cancer Inst 113 (5): 588-596, 2021. [PUBMED Abstract]
8. Krull KR, Khan RB, Ness KK, et al.: Symptoms of attention-deficit/hyperactivity disorder in long-term survivors of childhood leukemia. Pediatr Blood Cancer 57 (7): 1191-6, 2011. [PUBMED Abstract]
9. Kahalley LS, Conklin HM, Tyc VL, et al.: ADHD and secondary ADHD criteria fail to identify many at-risk survivors of pediatric ALL and brain tumor. Pediatr Blood Cancer 57 (1): 110-8, 2011. [PUBMED Abstract]
10. Mahajan A, Stavinoha PL, Rongthong W, et al.: Neurocognitive Effects and Necrosis in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 401-416, 2024. [PUBMED Abstract]
11. Cheung YT, Brinkman TM, Li C, et al.: Chronic Health Conditions and Neurocognitive Function in Aging Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 110 (4): 411-419, 2018. [PUBMED Abstract]
12. Bass JK, Liu W, Banerjee P, et al.: Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer. JAMA Oncol 6 (9): 1363-1371, 2020. [PUBMED Abstract]
13. Barlow-Krelina E, Chen Y, Yasui Y, et al.: Consistent Physical Activity and Future Neurocognitive Problems in Adult Survivors of Childhood Cancers: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 38 (18): 2041-2052, 2020. [PUBMED Abstract]
14. Bernal JDK, Recchia F, Yu DJ, et al.: Physical activity and exercise for cancer-related cognitive impairment among individuals affected by childhood cancer: a systematic review and meta-analysis. Lancet Child Adolesc Health 7 (1): 47-58, 2023. [PUBMED Abstract]
15. Phillips NS, Stratton KL, Williams AM, et al.: Late-onset Cognitive Impairment and Modifiable Risk Factors in Adult Childhood Cancer Survivors. JAMA Netw Open 6 (5): e2316077, 2023. [PUBMED Abstract]
16. Traunwieser T, Loos E, Ottensmeier H, et al.: Survivors of infant atypical teratoid/rhabdoid tumors present with severely impaired cognitive functions especially for fluid intelligence and visual processing: data from the German brain tumor studies. Pediatr Blood Cancer 71 (5): e30910, 2024. [PUBMED Abstract]
17. Merchant TE, Schreiber JE, Wu S, et al.: Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys 90 (3): 554-61, 2014. [PUBMED Abstract]
18. Armstrong GT, Conklin HM, Huang S, et al.: Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol 13 (2): 223-34, 2011. [PUBMED Abstract]
19. Di Pinto M, Conklin HM, Li C, et al.: Learning and memory following conformal radiation therapy for pediatric craniopharyngioma and low-grade glioma. Int J Radiat Oncol Biol Phys 84 (3): e363-9, 2012. [PUBMED Abstract]
20. Ris MD, Walsh K, Wallace D, et al.: Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961. Pediatr Blood Cancer 60 (8): 1350-7, 2013. [PUBMED Abstract]
21. Bowers DC, Liu Y, Leisenring W, et al.: Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol 24 (33): 5277-82, 2006. [PUBMED Abstract]
22. Nassar SL, Conklin HM, Zhou Y, et al.: Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia. Pediatr Blood Cancer 64 (8): , 2017. [PUBMED Abstract]
23. Torres VA, Ashford JM, Wright E, et al.: The impact of socioeconomic status (SES) on cognitive outcomes following radiotherapy for pediatric brain tumors: a prospective, longitudinal trial. Neuro Oncol 23 (7): 1173-1182, 2021. [PUBMED Abstract]
24. Mabbott DJ, Spiegler BJ, Greenberg ML, et al.: Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol 23 (10): 2256-63, 2005. [PUBMED Abstract]
25. Brière ME, Scott JG, McNall-Knapp RY, et al.: Cognitive outcome in pediatric brain tumor survivors: delayed attention deficit at long-term follow-up. Pediatr Blood Cancer 50 (2): 337-40, 2008. [PUBMED Abstract]
26. Edelstein K, Spiegler BJ, Fung S, et al.: Early aging in adult survivors of childhood medulloblastoma: long-term neurocognitive, functional, and physical outcomes. Neuro Oncol 13 (5): 536-45, 2011. [PUBMED Abstract]
27. Palmer SL, Goloubeva O, Reddick WE, et al.: Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol 19 (8): 2302-8, 2001. [PUBMED Abstract]
28. Mulhern RK, Merchant TE, Gajjar A, et al.: Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 5 (7): 399-408, 2004. [PUBMED Abstract]
29. Brinkman TM, Reddick WE, Luxton J, et al.: Cerebral white matter integrity and executive function in adult survivors of childhood medulloblastoma. Neuro Oncol 14 (Suppl 4): iv25-36, 2012. [PUBMED Abstract]
30. Jacola LM, Ashford JM, Reddick WE, et al.: The relationship between working memory and cerebral white matter volume in survivors of childhood brain tumors treated with conformal radiation therapy. J Neurooncol 119 (1): 197-205, 2014. [PUBMED Abstract]
31. Palmer SL, Glass JO, Li Y, et al.: White matter integrity is associated with cognitive processing in patients treated for a posterior fossa brain tumor. Neuro Oncol 14 (9): 1185-93, 2012. [PUBMED Abstract]
32. Ali JS, Ashford JM, Swain MA, et al.: Predictors of Cognitive Performance Among Infants Treated for Brain Tumors: Findings From a Multisite, Prospective, Longitudinal Trial. J Clin Oncol 39 (21): 2350-2358, 2021. [PUBMED Abstract]
33. Merchant TE, Conklin HM, Wu S, et al.: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27 (22): 3691-7, 2009. [PUBMED Abstract]
34. Liu APY, Hastings C, Wu S, et al.: Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life. Cancer 125 (7): 1163-1175, 2019. [PUBMED Abstract]
35. Palmer SL, Armstrong C, Onar-Thomas A, et al.: Processing speed, attention, and working memory after treatment for medulloblastoma: an international, prospective, and longitudinal study. J Clin Oncol 31 (28): 3494-500, 2013. [PUBMED Abstract]
36. Knight SJ, Conklin HM, Palmer SL, et al.: Working memory abilities among children treated for medulloblastoma: parent report and child performance. J Pediatr Psychol 39 (5): 501-11, 2014. [PUBMED Abstract]
37. Schreiber JE, Gurney JG, Palmer SL, et al.: Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro Oncol 16 (8): 1129-36, 2014. [PUBMED Abstract]
38. Khan RB, Patay Z, Klimo P, et al.: Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study. Neuro Oncol 23 (9): 1586-1596, 2021. [PUBMED Abstract]
39. Schreiber JE, Palmer SL, Conklin HM, et al.: Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study. Neuro Oncol 19 (12): 1673-1682, 2017. [PUBMED Abstract]
40. Moxon-Emre I, Taylor MD, Bouffet E, et al.: Intellectual Outcome in Molecular Subgroups of Medulloblastoma. J Clin Oncol 34 (34): 4161-4170, 2016. [PUBMED Abstract]
41. Acharya S, Wu S, Ashford JM, et al.: Association between hippocampal dose and memory in survivors of childhood or adolescent low-grade glioma: a 10-year neurocognitive longitudinal study. Neuro Oncol 21 (9): 1175-1183, 2019. [PUBMED Abstract]
42. Ellenberg L, Liu Q, Gioia G, et al.: Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology 23 (6): 705-17, 2009. [PUBMED Abstract]
43. Armstrong GT, Liu Q, Yasui Y, et al.: Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J Natl Cancer Inst 101 (13): 946-58, 2009. [PUBMED Abstract]
44. Ris MD, Leisenring WM, Goodman P, et al.: Neuropsychological and socioeconomic outcomes in adult survivors of pediatric low-grade glioma. Cancer 125 (17): 3050-3058, 2019. [PUBMED Abstract]
45. Shabason EK, Brodsky C, Baran J, et al.: Clinical diagnosis of attention-deficit/hyperactivity disorder in survivors of pediatric brain tumors. J Neurooncol 143 (2): 305-312, 2019. [PUBMED Abstract]
46. Brinkman TM, Palmer SL, Chen S, et al.: Parent-reported social outcomes after treatment for pediatric embryonal tumors: a prospective longitudinal study. J Clin Oncol 30 (33): 4134-40, 2012. [PUBMED Abstract]
47. Moyer KH, Willard VW, Gross AM, et al.: The impact of attention on social functioning in survivors of pediatric acute lymphoblastic leukemia and brain tumors. Pediatr Blood Cancer 59 (7): 1290-5, 2012. [PUBMED Abstract]
48. Mitby PA, Robison LL, Whitton JA, et al.: Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 97 (4): 1115-26, 2003. [PUBMED Abstract]
49. Brinkman TM, Ness KK, Li Z, et al.: Attainment of Functional and Social Independence in Adult Survivors of Pediatric CNS Tumors: A Report From the St Jude Lifetime Cohort Study. J Clin Oncol 36 (27): 2762-2769, 2018. [PUBMED Abstract]
50. Kahalley LS, Ris MD, Grosshans DR, et al.: Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors. J Clin Oncol 34 (10): 1043-9, 2016. [PUBMED Abstract]
51. Pulsifer MB, Sethi RV, Kuhlthau KA, et al.: Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors. Int J Radiat Oncol Biol Phys 93 (2): 400-7, 2015. [PUBMED Abstract]
52. Kahalley LS, Peterson R, Ris MD, et al.: Superior Intellectual Outcomes After Proton Radiotherapy Compared With Photon Radiotherapy for Pediatric Medulloblastoma. J Clin Oncol 38 (5): 454-461, 2020. [PUBMED Abstract]
53. Reddick WE, Glass JO, Helton KJ, et al.: Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate. AJNR Am J Neuroradiol 26 (5): 1263-9, 2005. [PUBMED Abstract]
54. Waber DP, Queally JT, Catania L, et al.: Neuropsychological outcomes of standard risk and high risk patients treated for acute lymphoblastic leukemia on Dana-Farber ALL consortium protocol 95-01 at 5 years post-diagnosis. Pediatr Blood Cancer 58 (5): 758-65, 2012. [PUBMED Abstract]
55. Krull KR, Brinkman TM, Li C, et al.: Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude lifetime cohort study. J Clin Oncol 31 (35): 4407-15, 2013. [PUBMED Abstract]
56. Reddick WE, Shan ZY, Glass JO, et al.: Smaller white-matter volumes are associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia. Cancer 106 (4): 941-9, 2006. [PUBMED Abstract]
57. Kadan-Lottick NS, Zeltzer LK, Liu Q, et al.: Neurocognitive functioning in adult survivors of childhood non-central nervous system cancers. J Natl Cancer Inst 102 (12): 881-93, 2010. [PUBMED Abstract]
58. Schuitema I, Deprez S, Van Hecke W, et al.: Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies. J Clin Oncol 31 (27): 3378-88, 2013. [PUBMED Abstract]
59. Armstrong GT, Reddick WE, Petersen RC, et al.: Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy. J Natl Cancer Inst 105 (12): 899-907, 2013. [PUBMED Abstract]
60. Spiegler BJ, Kennedy K, Maze R, et al.: Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate. J Clin Oncol 24 (24): 3858-64, 2006. [PUBMED Abstract]
61. Campbell LK, Scaduto M, Sharp W, et al.: A meta-analysis of the neurocognitive sequelae of treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer 49 (1): 65-73, 2007. [PUBMED Abstract]
62. Cheung YT, Sabin ND, Reddick WE, et al.: Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis. Lancet Haematol 3 (10): e456-e466, 2016. [PUBMED Abstract]
63. Jansen NC, Kingma A, Schuitema A, et al.: Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol 26 (18): 3025-30, 2008. [PUBMED Abstract]
64. Iyer NS, Balsamo LM, Bracken MB, et al.: Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis. Blood 126 (3): 346-53, 2015. [PUBMED Abstract]
65. Jacola LM, Krull KR, Pui CH, et al.: Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol. J Clin Oncol 34 (11): 1239-47, 2016. [PUBMED Abstract]
66. Espy KA, Moore IM, Kaufmann PM, et al.: Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study. J Pediatr Psychol 26 (1): 1-9, 2001 Jan-Feb. [PUBMED Abstract]
67. Buizer AI, de Sonneville LM, Veerman AJ: Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: a critical review of the literature. Pediatr Blood Cancer 52 (4): 447-54, 2009. [PUBMED Abstract]
68. Gandy K, Sapkota Y, Scoggins MA, et al.: Genetic variants, neurocognitive outcomes, and functional neuroimaging in survivors of childhood acute lymphoblastic leukemia. JNCI Cancer Spectr 7 (4): , 2023. [PUBMED Abstract]
69. Cole PD, Finkelstein Y, Stevenson KE, et al.: Polymorphisms in Genes Related to Oxidative Stress Are Associated With Inferior Cognitive Function After Therapy for Childhood Acute Lymphoblastic Leukemia. J Clin Oncol 33 (19): 2205-11, 2015. [PUBMED Abstract]
70. Jacola LM, Edelstein K, Liu W, et al.: Cognitive, behaviour, and academic functioning in adolescent and young adult survivors of childhood acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study. Lancet Psychiatry 3 (10): 965-972, 2016. [PUBMED Abstract]
71. Jacola LM, Conklin HM, Krull KR, et al.: The Impact of Intensified CNS-Directed Therapy on Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated Without Cranial Irradiation. J Clin Oncol 40 (36): 4218-4227, 2022. [PUBMED Abstract]
72. Krull KR, Cheung YT, Liu W, et al.: Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. J Clin Oncol 34 (22): 2644-53, 2016. [PUBMED Abstract]
73. Halsey C, Buck G, Richards S, et al.: The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI. J Hematol Oncol 4: 42, 2011. [PUBMED Abstract]
74. Kadan-Lottick NS, Brouwers P, Breiger D, et al.: A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia. Blood 114 (9): 1746-52, 2009. [PUBMED Abstract]
75. Williams AM, Cheung YT, Hyun G, et al.: Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood. Ann Neurol 89 (3): 534-545, 2021. [PUBMED Abstract]
76. Stefanski KJ, Anixt JS, Goodman P, et al.: Long-Term Neurocognitive and Psychosocial Outcomes After Acute Myeloid Leukemia: A Childhood Cancer Survivor Study Report. J Natl Cancer Inst 113 (4): 481-495, 2021. [PUBMED Abstract]
77. Edelmann MN, Daryani VM, Bishop MW, et al.: Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma. JAMA Oncol 2 (2): 201-8, 2016. [PUBMED Abstract]
78. van der Plas E, Darji H, Srivastava DK, et al.: Risk factors for neurocognitive impairment, emotional distress, and poor quality of life in survivors of pediatric rhabdomyosarcoma: A report from the Childhood Cancer Survivor Study. Cancer 130 (12): 2224-2236, 2024. [PUBMED Abstract]
79. Tonning Olsson I, Brinkman TM, Wang M, et al.: Neurocognitive and psychosocial outcomes in adult survivors of childhood soft-tissue sarcoma: A report from the St. Jude Lifetime Cohort. Cancer 126 (7): 1576-1584, 2020. [PUBMED Abstract]
80. Tonning Olsson I, Brinkman TM, Hyun G, et al.: Neurocognitive outcomes in long-term survivors of Wilms tumor: a report from the St. Jude Lifetime Cohort. J Cancer Surviv 13 (4): 570-579, 2019. [PUBMED Abstract]
81. Willard VW, Qaddoumi I, Chen S, et al.: Developmental and adaptive functioning in children with retinoblastoma: a longitudinal investigation. J Clin Oncol 32 (25): 2788-93, 2014. [PUBMED Abstract]
82. Willard VW, Qaddoumi I, Pan H, et al.: Cognitive and Adaptive Functioning in Youth With Retinoblastoma: A Longitudinal Investigation Through 10 Years of Age. J Clin Oncol 39 (24): 2676-2684, 2021. [PUBMED Abstract]
83. Brinkman TM, Merchant TE, Li Z, et al.: Cognitive function and social attainment in adult survivors of retinoblastoma: a report from the St. Jude Lifetime Cohort Study. Cancer 121 (1): 123-31, 2015. [PUBMED Abstract]
84. Ehrhardt MJ, Sandlund JT, Zhang N, et al.: Late outcomes of adult survivors of childhood non-Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
85. Krull KR, Sabin ND, Reddick WE, et al.: Neurocognitive function and CNS integrity in adult survivors of childhood hodgkin lymphoma. J Clin Oncol 30 (29): 3618-24, 2012. [PUBMED Abstract]
86. Hesko C, Liu W, Srivastava DK, et al.: Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study. Cancer 129 (18): 2904-2914, 2023. [PUBMED Abstract]
87. Wu NL, Phipps AI, Krull KR, et al.: Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant. Blood Adv 6 (14): 4347-4356, 2022. [PUBMED Abstract]
88. Willard VW, Leung W, Huang Q, et al.: Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation. J Clin Oncol 32 (35): 3982-8, 2014. [PUBMED Abstract]
89. Kenborg L, Winther JF, Linnet KM, et al.: Neurologic disorders in 4858 survivors of central nervous system tumors in childhood-an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study. Neuro Oncol 21 (1): 125-136, 2019. [PUBMED Abstract]
90. Wells EM, Ullrich NJ, Seidel K, et al.: Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report. Neuro Oncol 20 (1): 132-142, 2018. [PUBMED Abstract]
91. Goldsby RE, Liu Q, Nathan PC, et al.: Late-occurring neurologic sequelae in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28 (2): 324-31, 2010. [PUBMED Abstract]
92. Phillips NS, Khan RB, Li C, et al.: Seizures' impact on cognition and quality of life in childhood cancer survivors. Cancer 128 (1): 180-191, 2022. [PUBMED Abstract]
93. Jain P, Gulati S, Seth R, et al.: Vincristine-induced neuropathy in childhood ALL (acute lymphoblastic leukemia) survivors: prevalence and electrophysiological characteristics. J Child Neurol 29 (7): 932-7, 2014. [PUBMED Abstract]
94. Ness KK, Jones KE, Smith WA, et al.: Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study. Arch Phys Med Rehabil 94 (8): 1451-7, 2013. [PUBMED Abstract]
95. Kandula T, Farrar MA, Cohn RJ, et al.: Chemotherapy-Induced Peripheral Neuropathy in Long-term Survivors of Childhood Cancer: Clinical, Neurophysiological, Functional, and Patient-Reported Outcomes. JAMA Neurol 75 (8): 980-988, 2018. [PUBMED Abstract]
96. Rodwin RL, Ross WL, Rotatori J, et al.: Newly identified chemotherapy-induced peripheral neuropathy in a childhood cancer survivorship clinic. Pediatr Blood Cancer 69 (3): e29550, 2022. [PUBMED Abstract]
97. Varedi M, Lu L, Howell CR, et al.: Peripheral Neuropathy, Sensory Processing, and Balance in Survivors of Acute Lymphoblastic Leukemia. J Clin Oncol 36 (22): 2315-2322, 2018. [PUBMED Abstract]
98. Gurney JG, Kadan-Lottick NS, Packer RJ, et al.: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer 97 (3): 663-73, 2003. [PUBMED Abstract]
99. Ullrich NJ, Robertson R, Kinnamon DD, et al.: Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 68 (12): 932-8, 2007. [PUBMED Abstract]
100. Wang C, Roberts KB, Bindra RS, et al.: Delayed cerebral vasculopathy following cranial radiation therapy for pediatric tumors. Pediatr Neurol 50 (6): 549-56, 2014. [PUBMED Abstract]
101. Mueller S, Fullerton HJ, Stratton K, et al.: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86 (4): 649-55, 2013. [PUBMED Abstract]
102. Reulen RC, Guha J, Bright CJ, et al.: Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study. Int J Cancer 148 (3): 572-583, 2021. [PUBMED Abstract]
103. Fullerton HJ, Stratton K, Mueller S, et al.: Recurrent stroke in childhood cancer survivors. Neurology 85 (12): 1056-64, 2015. [PUBMED Abstract]
104. Waxer JF, Wong K, Modiri A, et al.: Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A PENTEC Normal Tissue Outcomes Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 417-430, 2024. [PUBMED Abstract]
105. Khan RB, Merchant TE, Sadighi ZS, et al.: Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors. J Neurooncol 136 (2): 379-384, 2018. [PUBMED Abstract]
106. van Kooten JAMC, Maurice-Stam H, Schouten AYN, et al.: High occurrence of sleep problems in survivors of a childhood brain tumor with neurocognitive complaints: The association with psychosocial and behavioral executive functioning. Pediatr Blood Cancer 66 (11): e27947, 2019. [PUBMED Abstract]
107. Khan RB, Hudson MM, Ledet DS, et al.: Neurologic morbidity and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross-sectional study. J Cancer Surviv 8 (4): 688-96, 2014. [PUBMED Abstract]
108. Khong PL, Leung LH, Fung AS, et al.: White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function. J Clin Oncol 24 (6): 884-90, 2006. [PUBMED Abstract]
109. Zeller B, Tamnes CK, Kanellopoulos A, et al.: Reduced neuroanatomic volumes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 31 (17): 2078-85, 2013. [PUBMED Abstract]
110. Faraci M, Morana G, Bagnasco F, et al.: Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: a cross sectional, single center study. Pediatr Blood Cancer 57 (2): 240-6, 2011. [PUBMED Abstract]
111. Phillips NS, Hillenbrand CM, Mitrea BG, et al.: Cerebral microbleeds in adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. Sci Rep 10 (1): 692, 2020. [PUBMED Abstract]
112. Rodwin RL, Chen Y, Yasui Y, et al.: Longitudinal Evaluation of Neuromuscular Dysfunction in Long-term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 30 (8): 1536-1545, 2021. [PUBMED Abstract]
113. Rodwin RL, Wang F, Lu L, et al.: Motor and sensory impairment in survivors of childhood central nervous system (CNS) tumors in the St. Jude Lifetime Cohort (SJLIFE). Cancer Med 13 (14): e7422, 2024. [PUBMED Abstract]
114. Cooper BT, Mayo CS, Milano MT, et al.: Predictive Factors Associated With Radiation Myelopathy in Pediatric Patients With Cancer: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 494-506, 2024. [PUBMED Abstract]
115. Ness KK, Hudson MM, Jones KE, et al.: Effect of Temporal Changes in Therapeutic Exposure on Self-reported Health Status in Childhood Cancer Survivors. Ann Intern Med 166 (2): 89-98, 2017. [PUBMED Abstract]
116. Ernst M, Hinz A, Brähler E, et al.: Quality of life after pediatric cancer: comparison of long-term childhood cancer survivors' quality of life with a representative general population sample and associations with physical health and risk indicators. Health Qual Life Outcomes 21 (1): 65, 2023. [PUBMED Abstract]
117. Schulte F, Brinkman TM, Li C, et al.: Social adjustment in adolescent survivors of pediatric central nervous system tumors: A report from the Childhood Cancer Survivor Study. Cancer 124 (17): 3596-3608, 2018. [PUBMED Abstract]
118. Vuotto SC, Wang M, Okcu MF, et al.: Neurologic morbidity and functional independence in adult survivors of childhood cancer. Ann Clin Transl Neurol 11 (2): 291-301, 2024. [PUBMED Abstract]
119. Hörnquist L, Rickardsson J, Lannering B, et al.: Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population. Neuro Oncol 17 (5): 733-40, 2015. [PUBMED Abstract]
120. Schulte F, Barrera M: Social competence in childhood brain tumor survivors: a comprehensive review. Support Care Cancer 18 (12): 1499-513, 2010. [PUBMED Abstract]
121. Papini C, Willard VW, Gajjar A, et al.: Social cognition and adjustment in adult survivors of pediatric central nervous system tumors. Cancer 129 (19): 3064-3075, 2023. [PUBMED Abstract]
122. Bonneau J, Berbis J, Michel G, et al.: Adolescence and Socioeconomic Factors: Key Factors in the Long-Term Impact of Leukemia on Scholastic Performance-A LEA Study. J Pediatr 205: 168-175.e2, 2019. [PUBMED Abstract]
123. Drabbe C, Coenraadts ES, van Houdt WJ, et al.: Impaired social functioning in adolescent and young adult sarcoma survivors: Prevalence and risk factors. Cancer 129 (9): 1419-1431, 2023. [PUBMED Abstract]
124. Ernst M, Brähler E, Wild PS, et al.: Risk factors for suicidal ideation in a large, registry-based sample of adult long-term childhood cancer survivors. J Affect Disord 265: 351-356, 2020. [PUBMED Abstract]
125. Lubas MM, Mirzaei Salehabadi S, Lavecchia J, et al.: Suicidality among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort Study. Cancer 126 (24): 5347-5355, 2020. [PUBMED Abstract]
126. Brinkman TM, Zhang N, Recklitis CJ, et al.: Suicide ideation and associated mortality in adult survivors of childhood cancer. Cancer 120 (2): 271-7, 2014. [PUBMED Abstract]
127. Gunnes MW, Lie RT, Bjørge T, et al.: Suicide and violent deaths in survivors of cancer in childhood, adolescence and young adulthood-A national cohort study. Int J Cancer 140 (3): 575-580, 2017. [PUBMED Abstract]
128. Sun CL, Francisco L, Baker KS, et al.: Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS). Blood 118 (17): 4723-31, 2011. [PUBMED Abstract]
129. Vuotto SC, Krull KR, Li C, et al.: Impact of chronic disease on emotional distress in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 123 (3): 521-528, 2017. [PUBMED Abstract]
130. Zheng DJ, Krull KR, Chen Y, et al.: Long-term psychological and educational outcomes for survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study. Cancer 124 (15): 3220-3230, 2018. [PUBMED Abstract]
131. Recklitis C, O'Leary T, Diller L: Utility of routine psychological screening in the childhood cancer survivor clinic. J Clin Oncol 21 (5): 787-92, 2003. [PUBMED Abstract]
132. Hsu TW, Liang CS, Tsai SJ, et al.: Risk of Major Psychiatric Disorders Among Children and Adolescents Surviving Malignancies: A Nationwide Longitudinal Study. J Clin Oncol 41 (11): 2054-2066, 2023. [PUBMED Abstract]
133. De R, Sutradhar R, Kurdyak P, et al.: Incidence and Predictors of Mental Health Outcomes Among Survivors of Adolescent and Young Adult Cancer: A Population-Based Study Using the IMPACT Cohort. J Clin Oncol 39 (9): 1010-1019, 2021. [PUBMED Abstract]
134. Phipps S, Klosky JL, Long A, et al.: Posttraumatic stress and psychological growth in children with cancer: has the traumatic impact of cancer been overestimated? J Clin Oncol 32 (7): 641-6, 2014. [PUBMED Abstract]
135. Stuber ML, Meeske KA, Leisenring W, et al.: Defining medical posttraumatic stress among young adult survivors in the Childhood Cancer Survivor Study. Gen Hosp Psychiatry 33 (4): 347-53, 2011 Jul-Aug. [PUBMED Abstract]
136. Phipps S, Larson S, Long A, et al.: Adaptive style and symptoms of posttraumatic stress in children with cancer and their parents. J Pediatr Psychol 31 (3): 298-309, 2006. [PUBMED Abstract]
137. Phipps S, Jurbergs N, Long A: Symptoms of post-traumatic stress in children with cancer: does personality trump health status? Psychooncology 18 (9): 992-1002, 2009. [PUBMED Abstract]
138. Rourke MT, Hobbie WL, Schwartz L, et al.: Posttraumatic stress disorder (PTSD) in young adult survivors of childhood cancer. Pediatr Blood Cancer 49 (2): 177-82, 2007. [PUBMED Abstract]
139. Schwartz L, Drotar D: Posttraumatic stress and related impairment in survivors of childhood cancer in early adulthood compared to healthy peers. J Pediatr Psychol 31 (4): 356-66, 2006. [PUBMED Abstract]
140. Stuber ML, Meeske KA, Krull KR, et al.: Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics 125 (5): e1124-34, 2010. [PUBMED Abstract]
141. Hobbie WL, Stuber M, Meeske K, et al.: Symptoms of posttraumatic stress in young adult survivors of childhood cancer. J Clin Oncol 18 (24): 4060-6, 2000. [PUBMED Abstract]
142. Dieluweit U, Debatin KM, Grabow D, et al.: Social outcomes of long-term survivors of adolescent cancer. Psychooncology 19 (12): 1277-84, 2010. [PUBMED Abstract]
143. Seitz DC, Hagmann D, Besier T, et al.: Life satisfaction in adult survivors of cancer during adolescence: what contributes to the latter satisfaction with life? Qual Life Res 20 (2): 225-36, 2011. [PUBMED Abstract]
144. Tai E, Buchanan N, Townsend J, et al.: Health status of adolescent and young adult cancer survivors. Cancer 118 (19): 4884-91, 2012. [PUBMED Abstract]
145. Schultz KA, Ness KK, Whitton J, et al.: Behavioral and social outcomes in adolescent survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 25 (24): 3649-56, 2007. [PUBMED Abstract]
146. Prasad PK, Hardy KK, Zhang N, et al.: Psychosocial and Neurocognitive Outcomes in Adult Survivors of Adolescent and Early Young Adult Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 33 (23): 2545-52, 2015. [PUBMED Abstract]
147. Brinkman TM, Li C, Vannatta K, et al.: Behavioral, Social, and Emotional Symptom Comorbidities and Profiles in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 34 (28): 3417-25, 2016. [PUBMED Abstract]
148. Karlson CW, Alberts NM, Liu W, et al.: Longitudinal pain and pain interference in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 126 (12): 2915-2923, 2020. [PUBMED Abstract]
149. Tonning Olsson I, Alberts NM, Li C, et al.: Pain and functional outcomes in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort study. Cancer 127 (10): 1679-1689, 2021. [PUBMED Abstract]
150. Frederiksen LE, Erdmann F, Mader L, et al.: Psychiatric disorders in childhood cancer survivors in Denmark, Finland, and Sweden: a register-based cohort study from the SALiCCS research programme. Lancet Psychiatry 9 (1): 35-45, 2022. [PUBMED Abstract]
151. Papini C, Mirzaei S S, Xing M, et al.: Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma. J Natl Cancer Inst 116 (2): 288-298, 2024. [PUBMED Abstract]

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

References

1. Hölttä P, Alaluusua S, Saarinen-Pihkala UM, et al.: Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children. Cancer 103 (1): 181-90, 2005. [PUBMED Abstract]
2. Hölttä P, Hovi L, Saarinen-Pihkala UM, et al.: Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer 103 (7): 1484-93, 2005. [PUBMED Abstract]
3. Kaste SC, Goodman P, Leisenring W, et al.: Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115 (24): 5817-27, 2009. [PUBMED Abstract]
4. Paulino AC, Simon JH, Zhen W, et al.: Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 48 (5): 1489-95, 2000. [PUBMED Abstract]
5. Maciel JC, de Castro CG, Brunetto AL, et al.: Oral health and dental anomalies in patients treated for leukemia in childhood and adolescence. Pediatr Blood Cancer 53 (3): 361-5, 2009. [PUBMED Abstract]
6. Hsieh SG, Hibbert S, Shaw P, et al.: Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy. Cancer 117 (10): 2219-27, 2011. [PUBMED Abstract]
7. Dahllöf G: Oral and dental late effects after pediatric stem cell transplantation. Biol Blood Marrow Transplant 14 (1 Suppl 1): 81-3, 2008. [PUBMED Abstract]
8. Hölttä P, Alaluusua S, Saarinen-Pihkala UM, et al.: Long-term adverse effects on dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous stem cell transplantation with or without total body irradiation. Bone Marrow Transplant 29 (2): 121-7, 2002. [PUBMED Abstract]
9. Effinger KE, Migliorati CA, Hudson MM, et al.: Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report. Support Care Cancer 22 (7): 2009-19, 2014. [PUBMED Abstract]
10. Kang CM, Hahn SM, Kim HS, et al.: Clinical Risk Factors Influencing Dental Developmental Disturbances in Childhood Cancer Survivors. Cancer Res Treat 50 (3): 926-935, 2018. [PUBMED Abstract]
11. Çetiner D, Çetiner S, Uraz A, et al.: Oral and dental alterations and growth disruption following chemotherapy in long-term survivors of childhood malignancies. Support Care Cancer 27 (5): 1891-1899, 2019. [PUBMED Abstract]
12. Patni T, Lee CT, Li Y, et al.: Factors for poor oral health in long-term childhood cancer survivors. BMC Oral Health 23 (1): 73, 2023. [PUBMED Abstract]
13. Thompson RF, Schneider RA, Albertini F, et al.: Dose to the developing dentition during therapeutic irradiation: organ at risk determination and clinical implications. Int J Radiat Oncol Biol Phys 86 (1): 108-13, 2013. [PUBMED Abstract]
14. Maguire A, Craft AW, Evans RG, et al.: The long-term effects of treatment on the dental condition of children surviving malignant disease. Cancer 60 (10): 2570-5, 1987. [PUBMED Abstract]
15. Paulino AC: Role of radiation therapy in parameningeal rhabdomyosarcoma. Cancer Invest 17 (3): 223-30, 1999. [PUBMED Abstract]
16. Kaste SC, Hopkins KP, Jones D, et al.: Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia 11 (6): 792-6, 1997. [PUBMED Abstract]
17. Elzembely MM, Dahlberg AE, Pinto N, et al.: Late effects in high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell rescue. Pediatr Blood Cancer 66 (1): e27421, 2019. [PUBMED Abstract]
18. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010. [PUBMED Abstract]
19. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 18 (8): 1061-79, 2010. [PUBMED Abstract]
20. Garming Legert K, Remberger M, Ringdèn O, et al.: Salivary secretion in children after fractionated or single-dose TBI. Bone Marrow Transplant 47 (3): 404-10, 2012. [PUBMED Abstract]
21. Bölling T, Weege J, Eich HT, et al.: Acute and late side effects to salivary glands and oral mucosa after head and neck radiotherapy in children and adolescents. Results of the "Registry for the evaluation of side effects after radiotherapy in childhood and adolescence". Head Neck 37 (8): 1137-41, 2015. [PUBMED Abstract]
22. Milgrom SA, van Luijk P, Pino R, et al.: Salivary and Dental Complications in Childhood Cancer Survivors Treated With Radiation Therapy to the Head and Neck: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 467-481, 2024. [PUBMED Abstract]
23. Dahllöf G, Wondimu B, Barr-Agholme M, et al.: Xerostomia in children and adolescents after stem cell transplantation conditioned with total body irradiation or busulfan. Oral Oncol 47 (9): 915-9, 2011. [PUBMED Abstract]
24. Garming-Legert K, Remberger M, Ringdén O, et al.: Long-term salivary function after conditioning with busulfan, fractionated or single-dose TBI. Oral Dis 17 (7): 670-6, 2011. [PUBMED Abstract]
25. Gevorgyan A, La Scala GC, Neligan PC, et al.: Radiation-induced craniofacial bone growth disturbances. J Craniofac Surg 18 (5): 1001-7, 2007. [PUBMED Abstract]
26. Sulaiman F, Huryn JM, Zlotolow IM: Dental extractions in the irradiated head and neck patient: a retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols, criteria, and end results. J Oral Maxillofac Surg 61 (10): 1123-31, 2003. [PUBMED Abstract]
27. Vissink A, Jansma J, Spijkervet FK, et al.: Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med 14 (3): 199-212, 2003. [PUBMED Abstract]
28. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010. [PUBMED Abstract]
29. Goldsby R, Chen Y, Raber S, et al.: Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. Gastroenterology 140 (5): 1464-71.e1, 2011. [PUBMED Abstract]
30. Bölling T, Willich N, Ernst I: Late effects of abdominal irradiation in children: a review of the literature. Anticancer Res 30 (1): 227-31, 2010. [PUBMED Abstract]
31. Churnratanakul S, Wirzba B, Lam T, et al.: Radiation and the small intestine. Future perspectives for preventive therapy. Dig Dis 8 (1): 45-60, 1990. [PUBMED Abstract]
32. Sher ME, Bauer J: Radiation-induced enteropathy. Am J Gastroenterol 85 (2): 121-8, 1990. [PUBMED Abstract]
33. Emami B, Lyman J, Brown A, et al.: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21 (1): 109-22, 1991. [PUBMED Abstract]
34. Weil BR, Murphy AJ, Liu Q, et al.: Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 41 (14): 2638-2650, 2023. [PUBMED Abstract]
35. Madenci AL, Fisher S, Diller LR, et al.: Intestinal Obstruction in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 33 (26): 2893-900, 2015. [PUBMED Abstract]
36. Madenci AL, Dieffenbach BV, Liu Q, et al.: Late-onset anorectal disease and psychosocial impact in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 125 (21): 3873-3881, 2019. [PUBMED Abstract]
37. Heyn R, Raney RB, Hays DM, et al.: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10 (4): 614-23, 1992. [PUBMED Abstract]
38. Hughes LL, Baruzzi MJ, Ribeiro RC, et al.: Paratesticular rhabdomyosarcoma: delayed effects of multimodality therapy and implications for current management. Cancer 73 (2): 476-82, 1994. [PUBMED Abstract]
39. Raney B, Heyn R, Hays DM, et al.: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study Committee. Cancer 71 (7): 2387-94, 1993. [PUBMED Abstract]
40. Asdahl PH, Oeffinger KC, Albieri V, et al.: Esophageal disease among childhood cancer survivors-A report from the Childhood Cancer Survivors Study. Pediatr Blood Cancer 68 (8): e29043, 2021. [PUBMED Abstract]
41. Mulder RL, van Dalen EC, Van den Hof M, et al.: Hepatic late adverse effects after antineoplastic treatment for childhood cancer. Cochrane Database Syst Rev (7): CD008205, 2011. [PUBMED Abstract]
42. Castellino S, Muir A, Shah A, et al.: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children's Oncology Group. Pediatr Blood Cancer 54 (5): 663-9, 2010. [PUBMED Abstract]
43. Mulder RL, Kremer LC, Koot BG, et al.: Surveillance of hepatic late adverse effects in a large cohort of long-term survivors of childhood cancer: prevalence and risk factors. Eur J Cancer 49 (1): 185-93, 2013. [PUBMED Abstract]
44. Green DM, Wang M, Krasin MJ, et al.: Serum Alanine Aminotransferase Elevations in Survivors of Childhood Cancer: A Report From the St. Jude Lifetime Cohort Study. Hepatology 69 (1): 94-106, 2019. [PUBMED Abstract]
45. Castellino SM, Hudson MM: Late gastrointestinal and hepatic effects. In: Schwartz CL, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood and Adolescent Cancer: A Multidisciplinary Approach. 3rd ed. Springer International Publishing, 2015, pp 229-52.
46. Mahmoud H, Schell M, Pui CH: Cholelithiasis after treatment for childhood cancer. Cancer 67 (5): 1439-42, 1991. [PUBMED Abstract]
47. Safford SD, Safford KM, Martin P, et al.: Management of cholelithiasis in pediatric patients who undergo bone marrow transplantation. J Pediatr Surg 36 (1): 86-90, 2001. [PUBMED Abstract]
48. Dieffenbach BV, Li N, Madenci AL, et al.: Incidence of and risk factors for late cholecystectomy in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Eur J Cancer 133: 4-13, 2020. [PUBMED Abstract]
49. Sudour H, Mainard L, Baumann C, et al.: Focal nodular hyperplasia of the liver following hematopoietic SCT. Bone Marrow Transplant 43 (2): 127-32, 2009. [PUBMED Abstract]
50. Lee MH, Yoo SY, Kim JH, et al.: Hypervascular hepatic nodules in childhood cancer survivors: clinical and imaging features. Clin Imaging 36 (4): 301-7, 2012 Jul-Aug. [PUBMED Abstract]
51. Wanless IR: Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 11 (5): 787-97, 1990. [PUBMED Abstract]
52. Brisse H, Servois V, Bouche B, et al.: Hepatic regenerating nodules: a mimic of recurrent cancer in children. Pediatr Radiol 30 (6): 386-93, 2000. [PUBMED Abstract]
53. Chu WC, Roebuck DJ: Nodular regenerative hyperplasia of the liver simulating metastases following treatment for bilateral Wilms tumor. Med Pediatr Oncol 41 (1): 85-7, 2003. [PUBMED Abstract]
54. Halonen P, Mattila J, Ruuska T, et al.: Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings. Med Pediatr Oncol 40 (3): 148-54, 2003. [PUBMED Abstract]
55. Tomita Y, Ishiguro H, Yasuda Y, et al.: High incidence of fatty liver and insulin resistance in long-term adult survivors of childhood SCT. Bone Marrow Transplant 46 (3): 416-25, 2011. [PUBMED Abstract]
56. Ruccione KS, Wood JC, Sposto R, et al.: Characterization of transfusion-derived iron deposition in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev 23 (9): 1913-9, 2014. [PUBMED Abstract]
57. Vag T, Kentouche K, Krumbein I, et al.: Noninvasive measurement of liver iron concentration at MRI in children with acute leukemia: initial results. Pediatr Radiol 41 (8): 980-4, 2011. [PUBMED Abstract]
58. Baskin-Miller J, Carson S, Jaffray J, et al.: Transfusional hemosiderosis in childhood cancer patients and survivors. Pediatr Blood Cancer 71 (10): e31220, 2024. [PUBMED Abstract]
59. Schempp A, Lee J, Kearney S, et al.: Iron Overload in Survivors of Childhood Cancer. J Pediatr Hematol Oncol 38 (1): 27-31, 2016. [PUBMED Abstract]
60. Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005. [PUBMED Abstract]
61. Green DM, Norkool P, Breslow NE, et al.: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study. J Clin Oncol 8 (9): 1525-30, 1990. [PUBMED Abstract]
62. Sulis ML, Bessmertny O, Granowetter L, et al.: Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma. J Pediatr Hematol Oncol 26 (12): 843-6, 2004. [PUBMED Abstract]
63. McDonald GB: Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology 51 (4): 1450-60, 2010. [PUBMED Abstract]
64. Dawson LA, Ten Haken RK: Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 15 (4): 279-83, 2005. [PUBMED Abstract]
65. Milano MT, Constine LS, Okunieff P: Normal tissue tolerance dose metrics for radiation therapy of major organs. Semin Radiat Oncol 17 (2): 131-40, 2007. [PUBMED Abstract]
66. Pan CC, Kavanagh BD, Dawson LA, et al.: Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S94-100, 2010. [PUBMED Abstract]
67. Bhanot P, Cushing B, Philippart A, et al.: Hepatic irradiation and adriamycin cardiotoxicity. J Pediatr 95 (4): 561-3, 1979. [PUBMED Abstract]
68. Flentje M, Weirich A, Pötter R, et al.: Hepatotoxicity in irradiated nephroblastoma patients during postoperative treatment according to SIOP9/GPOH. Radiother Oncol 31 (3): 222-8, 1994. [PUBMED Abstract]
69. Kun LE, Camitta BM: Hepatopathy following irradiation and adriamycin. Cancer 42 (1): 81-4, 1978. [PUBMED Abstract]
70. Tefft M: Radiation related toxicities in National Wilms' Tumor Study Number 1. Int J Radiat Oncol Biol Phys 2 (5-6): 455-63, 1977 May-Jun. [PUBMED Abstract]
71. Hall MD, Howell RM, Jackson A, et al.: Liver Late Effects in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 575-587, 2024. [PUBMED Abstract]
72. Levitsky J, Sorrell MF: Hepatic complications of hematopoietic cell transplantation. Curr Gastroenterol Rep 9 (1): 60-5, 2007. [PUBMED Abstract]
73. Pidala J, Chai X, Kurland BF, et al.: Analysis of gastrointestinal and hepatic chronic graft-versus-host [corrected] disease manifestations on major outcomes: a chronic graft-versus-host [corrected] disease consortium study. Biol Blood Marrow Transplant 19 (5): 784-91, 2013. [PUBMED Abstract]
74. Tomás JF, Pinilla I, García-Buey ML, et al.: Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant 26 (6): 649-55, 2000. [PUBMED Abstract]
75. Aricò M, Maggiore G, Silini E, et al.: Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 84 (9): 2919-22, 1994. [PUBMED Abstract]
76. Castellino S, Lensing S, Riely C, et al.: The epidemiology of chronic hepatitis C infection in survivors of childhood cancer: an update of the St Jude Children's Research Hospital hepatitis C seropositive cohort. Blood 103 (7): 2460-6, 2004. [PUBMED Abstract]
77. Cesaro S, Petris MG, Rossetti F, et al.: Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood 90 (3): 1315-20, 1997. [PUBMED Abstract]
78. Fink FM, Höcker-Schulz S, Mor W, et al.: Association of hepatitis C virus infection with chronic liver disease in paediatric cancer patients. Eur J Pediatr 152 (6): 490-2, 1993. [PUBMED Abstract]
79. Locasciulli A, Testa M, Pontisso P, et al.: Hepatitis C virus genotypes and liver disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 19 (3): 237-40, 1997. [PUBMED Abstract]
80. Locasciulli A, Testa M, Pontisso P, et al.: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90 (11): 4628-33, 1997. [PUBMED Abstract]
81. Paul IM, Sanders J, Ruggiero F, et al.: Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood 93 (11): 3672-7, 1999. [PUBMED Abstract]
82. Lansdale M, Castellino S, Marina N, et al.: Knowledge of hepatitis C virus screening in long-term pediatric cancer survivors: a report from the Childhood Cancer Survivor Study. Cancer 116 (4): 974-82, 2010. [PUBMED Abstract]
83. van Waas M, Neggers SJ, Raat H, et al.: Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7 (12): e52237, 2012. [PUBMED Abstract]
84. Neville KA, Cohn RJ, Steinbeck KS, et al.: Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 91 (11): 4401-7, 2006. [PUBMED Abstract]
85. Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
86. Dixon SB, Wang F, Lu L, et al.: Prediabetes and Associated Risk of Cardiovascular Events and Chronic Kidney Disease Among Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort. J Clin Oncol 42 (9): 1031-1043, 2024. [PUBMED Abstract]
87. Friedman DN, Moskowitz CS, Hilden P, et al.: Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus: A Report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 112 (5): 525-532, 2020. [PUBMED Abstract]
88. Williams HE, Howell CR, Chemaitilly W, et al.: Diabetes mellitus among adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime Cohort Study. Cancer 126 (4): 870-878, 2020. [PUBMED Abstract]
89. de Vathaire F, El-Fayech C, Ben Ayed FF, et al.: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13 (10): 1002-10, 2012. [PUBMED Abstract]
90. van Nimwegen FA, Schaapveld M, Janus CP, et al.: Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J Clin Oncol 32 (29): 3257-63, 2014. [PUBMED Abstract]

Endocrine dysfunction is common among survivors of childhood cancer, especially in those who were treated with surgery or radiation therapy that involved hormone-producing organs and those who received alkylating agent chemotherapy.

Enlarge

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

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

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

References

1. Brignardello E, Felicetti F, Castiglione A, et al.: Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur J Endocrinol 168 (3): 465-72, 2013. [PUBMED Abstract]
2. Mostoufi-Moab S, Seidel K, Leisenring WM, et al.: Endocrine Abnormalities in Aging Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 34 (27): 3240-7, 2016. [PUBMED Abstract]
3. Clement SC, Schouten-van Meeteren AY, Boot AM, et al.: Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study. J Clin Oncol 34 (36): 4362-4370, 2016. [PUBMED Abstract]
4. Chemaitilly W, Li Z, Huang S, et al.: Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. J Clin Oncol 33 (5): 492-500, 2015. [PUBMED Abstract]
5. González Briceño LG, Kariyawasam D, Samara-Boustani D, et al.: High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort. J Clin Endocrinol Metab 107 (5): e2156-e2166, 2022. [PUBMED Abstract]
6. Clement SC, van Rijn RR, van Eck-Smit BL, et al.: Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. Eur J Nucl Med Mol Imaging 42 (5): 706-15, 2015. [PUBMED Abstract]
7. Clement SC, van Eck-Smit BL, van Trotsenburg AS, et al.: Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr Blood Cancer 60 (11): 1833-8, 2013. [PUBMED Abstract]
8. Bombardieri E, Giammarile F, Aktolun C, et al.: 131I/123I-metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging 37 (12): 2436-46, 2010. [PUBMED Abstract]
9. Sharp SE, Trout AT, Weiss BD, et al.: MIBG in Neuroblastoma Diagnostic Imaging and Therapy. Radiographics 36 (1): 258-78, 2016 Jan-Feb. [PUBMED Abstract]
10. Clement SC, Tytgat GAM, van Trotsenburg ASP, et al.: Thyroid function after diagnostic 123I-metaiodobenzylguanidine in children with neuroblastic tumors. Ann Nucl Med 36 (6): 579-585, 2022. [PUBMED Abstract]
11. Verloop H, Louwerens M, Schoones JW, et al.: Risk of hypothyroidism following hemithyroidectomy: systematic review and meta-analysis of prognostic studies. J Clin Endocrinol Metab 97 (7): 2243-55, 2012. [PUBMED Abstract]
12. Zatelli MC, Lamartina L, Meringolo D, et al.: Thyroid nodule recurrence following lobo-isthmectomy: incidence, patient's characteristics, and risk factors. J Endocrinol Invest 41 (12): 1469-1475, 2018. [PUBMED Abstract]
13. Chemaitilly W, Li Z, Brinkman TM, et al.: Primary hypothyroidism in childhood cancer survivors: Prevalence, risk factors, and long-term consequences. Cancer 128 (3): 606-614, 2022. [PUBMED Abstract]
14. Bölling T, Geisenheiser A, Pape H, et al.: Hypothyroidism after head-and-neck radiotherapy in children and adolescents: preliminary results of the "Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK). Int J Radiat Oncol Biol Phys 81 (5): e787-91, 2011. [PUBMED Abstract]
15. Inskip PD, Veiga LHS, Brenner AV, et al.: Hypothyroidism after Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Radiat Res 190 (2): 117-132, 2018. [PUBMED Abstract]
16. Sklar C, Whitton J, Mertens A, et al.: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85 (9): 3227-32, 2000. [PUBMED Abstract]
17. Vatner RE, Niemierko A, Misra M, et al.: Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors. J Clin Oncol 36 (28): 2854-2862, 2018. [PUBMED Abstract]
18. Aldrich KD, Horne VE, Bielamowicz K, et al.: Comparison of hypothyroidism, growth hormone deficiency, and adrenal insufficiency following proton and photon radiotherapy in children with medulloblastoma. J Neurooncol 155 (1): 93-100, 2021. [PUBMED Abstract]
19. Milano MT, Vargo JA, Yorke ED, et al.: Primary Hypothyroidism in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 482-493, 2024. [PUBMED Abstract]
20. Wheeler G, Grassberger C, Samers J, et al.: Central Endocrine Complications Among Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. Int J Radiat Oncol Biol Phys 119 (2): 457-466, 2024. [PUBMED Abstract]
21. Gleeson HK, Darzy K, Shalet SM: Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab 16 (2): 335-48, 2002. [PUBMED Abstract]
22. Inskip PD, Veiga LHS, Brenner AV, et al.: Hyperthyroidism After Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 104 (2): 415-424, 2019. [PUBMED Abstract]
23. Clausen CT, Hasle H, Holmqvist AS, et al.: Hyperthyroidism as a late effect in childhood cancer survivors - an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study. Acta Oncol 58 (2): 227-231, 2019. [PUBMED Abstract]
24. Bhatti P, Veiga LH, Ronckers CM, et al.: Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 174 (6): 741-52, 2010. [PUBMED Abstract]
25. Haddy N, El-Fayech C, Guibout C, et al.: Thyroid adenomas after solid cancer in childhood. Int J Radiat Oncol Biol Phys 84 (2): e209-15, 2012. [PUBMED Abstract]
26. Ronckers CM, Sigurdson AJ, Stovall M, et al.: Thyroid cancer in childhood cancer survivors: a detailed evaluation of radiation dose response and its modifiers. Radiat Res 166 (4): 618-28, 2006. [PUBMED Abstract]
27. Sigurdson AJ, Ronckers CM, Mertens AC, et al.: Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365 (9476): 2014-23, 2005 Jun 11-17. [PUBMED Abstract]
28. van Santen HM, Tytgat GA, van de Wetering MD, et al.: Differentiated thyroid carcinoma after 131I-MIBG treatment for neuroblastoma during childhood: description of the first two cases. Thyroid 22 (6): 643-6, 2012. [PUBMED Abstract]
29. Veiga LH, Lubin JH, Anderson H, et al.: A pooled analysis of thyroid cancer incidence following radiotherapy for childhood cancer. Radiat Res 178 (4): 365-76, 2012. [PUBMED Abstract]
30. Kovalchik SA, Ronckers CM, Veiga LH, et al.: Absolute risk prediction of second primary thyroid cancer among 5-year survivors of childhood cancer. J Clin Oncol 31 (1): 119-27, 2013. [PUBMED Abstract]
31. Vivanco M, Dalle JH, Alberti C, et al.: Malignant and benign thyroid nodules after total body irradiation preceding hematopoietic cell transplantation during childhood. Eur J Endocrinol 167 (2): 225-33, 2012. [PUBMED Abstract]
32. Li Z, Franklin J, Zelcer S, et al.: Ultrasound surveillance for thyroid malignancies in survivors of childhood cancer following radiotherapy: a single institutional experience. Thyroid 24 (12): 1796-805, 2014. [PUBMED Abstract]
33. Brignardello E, Felicetti F, Castiglione A, et al.: Ultrasound surveillance for radiation-induced thyroid carcinoma in adult survivors of childhood cancer. Eur J Cancer 55: 74-80, 2016. [PUBMED Abstract]
34. Clement SC, Kremer LCM, Verburg FA, et al.: Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Cancer Treat Rev 63: 28-39, 2018. [PUBMED Abstract]
35. Baran JA, Halada S, Bauer AJ, et al.: Thyroid Ultrasound Screening in Childhood Cancer Survivors following Radiotherapy. Horm Res Paediatr 97 (3): 243-253, 2024. [PUBMED Abstract]
36. Metzger ML, Howard SC, Hudson MM, et al.: Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma. Pediatr Blood Cancer 46 (3): 314-9, 2006. [PUBMED Abstract]
37. Francis GL, Waguespack SG, Bauer AJ, et al.: Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 25 (7): 716-59, 2015. [PUBMED Abstract]
38. Sanders JE, Hoffmeister PA, Woolfrey AE, et al.: Thyroid function following hematopoietic cell transplantation in children: 30 years' experience. Blood 113 (2): 306-8, 2009. [PUBMED Abstract]
39. Cattoni A, Molinari S, Gaiero A, et al.: Thyroid Disorders Following Hematopoietic Stem Cell Transplantation in Childhood: Impact of Conditioning Regimen on Thyroid Dysfunction, Volume Changes, and Occurrence of Nodules. Transplant Cell Ther 28 (8): 506.e1-506.e12, 2022. [PUBMED Abstract]
40. van Iersel L, Mulder RL, Denzer C, et al.: Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors. Endocr Rev 43 (5): 794-823, 2022. [PUBMED Abstract]
41. Gurney JG, Kadan-Lottick NS, Packer RJ, et al.: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer 97 (3): 663-73, 2003. [PUBMED Abstract]
42. Hudson MM, Ness KK, Gurney JG, et al.: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309 (22): 2371-81, 2013. [PUBMED Abstract]
43. Sklar CA, Antal Z, Chemaitilly W, et al.: Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 103 (8): 2761-2784, 2018. [PUBMED Abstract]
44. Ramelli GP, von der Weid N, Stanga Z, et al.: Suprasellar germinomas in childhood and adolescence: diagnostic pitfalls. J Pediatr Endocrinol Metab 11 (6): 693-7, 1998 Nov-Dec. [PUBMED Abstract]
45. Vinchon M, Baroncini M, Leblond P, et al.: Morbidity and tumor-related mortality among adult survivors of pediatric brain tumors: a review. Childs Nerv Syst 27 (5): 697-704, 2011. [PUBMED Abstract]
46. Fahrner B, Prosch H, Minkov M, et al.: Long-term outcome of hypothalamic pituitary tumors in Langerhans cell histiocytosis. Pediatr Blood Cancer 58 (4): 606-10, 2012. [PUBMED Abstract]
47. Lawson SA, Horne VE, Golekoh MC, et al.: Hypothalamic-pituitary function following childhood brain tumors: Analysis of prospective annual endocrine screening. Pediatr Blood Cancer 66 (5): e27631, 2019. [PUBMED Abstract]
48. Lebbink CA, Ringers TP, Schouten-van Meeteren AYN, et al.: Prevalence and risk factors of hypothalamic-pituitary dysfunction in infant and toddler childhood brain tumor survivors. Eur J Endocrinol 185 (4): 597-606, 2021. [PUBMED Abstract]
49. Fraser O, Crowne E, Tacey M, et al.: Correlating measured radiotherapy dose with patterns of endocrinopathy: The importance of minimizing pituitary dose. Pediatr Blood Cancer 69 (11): e29847, 2022. [PUBMED Abstract]
50. van Iersel L, Li Z, Srivastava DK, et al.: Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes. J Clin Endocrinol Metab 104 (12): 6101-6115, 2019. [PUBMED Abstract]
51. Darzy KH, Shalet SM: Hypopituitarism following radiotherapy. Pituitary 12 (1): 40-50, 2009. [PUBMED Abstract]
52. Viana MB, Vilela MI: Height deficit during and many years after treatment for acute lymphoblastic leukemia in children: a review. Pediatr Blood Cancer 50 (2 Suppl): 509-16; discussion 517, 2008. [PUBMED Abstract]
53. Merchant TE, Goloubeva O, Pritchard DL, et al.: Radiation dose-volume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 52 (5): 1264-70, 2002. [PUBMED Abstract]
54. Merchant TE, Rose SR, Bosley C, et al.: Growth hormone secretion after conformal radiation therapy in pediatric patients with localized brain tumors. J Clin Oncol 29 (36): 4776-80, 2011. [PUBMED Abstract]
55. Merchant TE, Wu S, Onar-Thomas A, et al.: Endocrinopathy After Treatment for Medulloblastoma: Results From the SJMB03 Trial of Risk-Adapted Radiation Therapy. Int J Radiat Oncol Biol Phys 116 (3): 560-568, 2023. [PUBMED Abstract]
56. van Iersel L, van Santen HM, Potter B, et al.: Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 67 (12): e28723, 2020. [PUBMED Abstract]
57. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 123 (1): 59-64, 1993. [PUBMED Abstract]
58. Chow EJ, Friedman DL, Yasui Y, et al.: Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr 150 (4): 370-5, 375.e1, 2007. [PUBMED Abstract]
59. Vandecruys E, Dhooge C, Craen M, et al.: Longitudinal linear growth and final height is impaired in childhood acute lymphoblastic leukemia survivors after treatment without cranial irradiation. J Pediatr 163 (1): 268-73, 2013. [PUBMED Abstract]
60. Browne EK, Zhou Y, Chemaitilly W, et al.: Changes in body mass index, height, and weight in children during and after therapy for acute lymphoblastic leukemia. Cancer 124 (21): 4248-4259, 2018. [PUBMED Abstract]
61. Demoor-Goldschmidt C, Allodji RS, Journy N, et al.: Risk Factors for Small Adult Height in Childhood Cancer Survivors. J Clin Oncol 38 (16): 1785-1796, 2020. [PUBMED Abstract]
62. Mizumoto M, Oshiro Y, Pan H, et al.: Height after photon craniospinal irradiation in pediatric patients treated for central nervous system embryonal tumors. Pediatr Blood Cancer 67 (10): e28617, 2020. [PUBMED Abstract]
63. Ogilvy-Stuart AL, Clark DJ, Wallace WH, et al.: Endocrine deficit after fractionated total body irradiation. Arch Dis Child 67 (9): 1107-10, 1992. [PUBMED Abstract]
64. Willi SM, Cooke K, Goldwein J, et al.: Growth in children after bone marrow transplantation for advanced neuroblastoma compared with growth after transplantation for leukemia or aplastic anemia. J Pediatr 120 (5): 726-32, 1992. [PUBMED Abstract]
65. Wingard JR, Plotnick LP, Freemer CS, et al.: Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation. Blood 79 (4): 1068-73, 1992. [PUBMED Abstract]
66. Huma Z, Boulad F, Black P, et al.: Growth in children after bone marrow transplantation for acute leukemia. Blood 86 (2): 819-24, 1995. [PUBMED Abstract]
67. Bernard F, Bordigoni P, Simeoni MC, et al.: Height growth during adolescence and final height after haematopoietic SCT for childhood acute leukaemia: the impact of a conditioning regimen with BU or TBI. Bone Marrow Transplant 43 (8): 637-42, 2009. [PUBMED Abstract]
68. Chemaitilly W, Sklar CA: Endocrine complications of hematopoietic stem cell transplantation. Endocrinol Metab Clin North Am 36 (4): 983-98; ix, 2007. [PUBMED Abstract]
69. Socié G, Salooja N, Cohen A, et al.: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101 (9): 3373-85, 2003. [PUBMED Abstract]
70. Cohen A, Rovelli A, Bakker B, et al.: Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood 93 (12): 4109-15, 1999. [PUBMED Abstract]
71. Brennan BM, Shalet SM: Endocrine late effects after bone marrow transplant. Br J Haematol 118 (1): 58-66, 2002. [PUBMED Abstract]
72. Sfeir JG, Kittah NEN, Tamhane SU, et al.: Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers. J Clin Endocrinol Metab 103 (8): 2785-2793, 2018. [PUBMED Abstract]
73. Raman S, Grimberg A, Waguespack SG, et al.: Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab 100 (6): 2192-203, 2015. [PUBMED Abstract]
74. Chemaitilly W, Robison LL: Safety of growth hormone treatment in patients previously treated for cancer. Endocrinol Metab Clin North Am 41 (4): 785-92, 2012. [PUBMED Abstract]
75. Sklar CA, Mertens AC, Mitby P, et al.: Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 87 (7): 3136-41, 2002. [PUBMED Abstract]
76. Ergun-Longmire B, Mertens AC, Mitby P, et al.: Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab 91 (9): 3494-8, 2006. [PUBMED Abstract]
77. Patterson BC, Chen Y, Sklar CA, et al.: Growth hormone exposure as a risk factor for the development of subsequent neoplasms of the central nervous system: a report from the childhood cancer survivor study. J Clin Endocrinol Metab 99 (6): 2030-7, 2014. [PUBMED Abstract]
78. Bogarin R, Steinbok P: Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review. Childs Nerv Syst 25 (3): 273-9, 2009. [PUBMED Abstract]
79. Tamhane S, Sfeir JG, Kittah NEN, et al.: GH Therapy in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 103 (8): 2794-2801, 2018. [PUBMED Abstract]
80. Thomas-Teinturier C, Oliver-Petit I, Pacquement H, et al.: Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer. Eur J Endocrinol 183 (4): 471-480, 2020. [PUBMED Abstract]
81. Boguszewski MCS, Boguszewski CL, Chemaitilly W, et al.: Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement. Eur J Endocrinol 186 (6): P35-P52, 2022. [PUBMED Abstract]
82. Chemaitilly W, Merchant TE, Li Z, et al.: Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes. Clin Endocrinol (Oxf) 84 (3): 361-71, 2016. [PUBMED Abstract]
83. Armstrong GT, Whitton JA, Gajjar A, et al.: Abnormal timing of menarche in survivors of central nervous system tumors: A report from the Childhood Cancer Survivor Study. Cancer 115 (11): 2562-70, 2009. [PUBMED Abstract]
84. Didcock E, Davies HA, Didi M, et al.: Pubertal growth in young adult survivors of childhood leukemia. J Clin Oncol 13 (10): 2503-7, 1995. [PUBMED Abstract]
85. Shalet SM, Crowne EC, Didi MA, et al.: Irradiation-induced growth failure. Baillieres Clin Endocrinol Metab 6 (3): 513-26, 1992. [PUBMED Abstract]
86. Gan HW, Phipps K, Aquilina K, et al.: Neuroendocrine Morbidity After Pediatric Optic Gliomas: A Longitudinal Analysis of 166 Children Over 30 Years. J Clin Endocrinol Metab 100 (10): 3787-99, 2015. [PUBMED Abstract]
87. Chemaitilly W, Sklar CA: Endocrine complications in long-term survivors of childhood cancers. Endocr Relat Cancer 17 (3): R141-59, 2010. [PUBMED Abstract]
88. Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of Hand and Wrist. 2nd ed. Stanford University Press, 1959.
89. Gleeson HK, Stoeter R, Ogilvy-Stuart AL, et al.: Improvements in final height over 25 years in growth hormone (GH)-deficient childhood survivors of brain tumors receiving GH replacement. J Clin Endocrinol Metab 88 (8): 3682-9, 2003. [PUBMED Abstract]
90. Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008. [PUBMED Abstract]
91. Bielamowicz K, Okcu MF, Sonabend R, et al.: Hypothyroidism after craniospinal irradiation with proton or photon therapy in patients with medulloblastoma. Pediatr Hematol Oncol 35 (4): 257-267, 2018. [PUBMED Abstract]
92. van Iersel L, Xu J, Potter BS, et al.: Clinical Importance of Free Thyroxine Concentration Decline After Radiotherapy for Pediatric and Adolescent Brain Tumors. J Clin Endocrinol Metab 104 (11): 4998-5007, 2019. [PUBMED Abstract]
93. Kazlauskaite R, Evans AT, Villabona CV, et al.: Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 93 (11): 4245-53, 2008. [PUBMED Abstract]
94. Rose SR, Danish RK, Kearney NS, et al.: ACTH deficiency in childhood cancer survivors. Pediatr Blood Cancer 45 (6): 808-13, 2005. [PUBMED Abstract]
95. Clement SC, Peeters RP, Ronckers CM, et al.: Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review. Cancer Treat Rev 41 (10): 925-34, 2015. [PUBMED Abstract]
96. Follin C, Erfurth EM: Long-Term Effect of Cranial Radiotherapy on Pituitary-Hypothalamus Area in Childhood Acute Lymphoblastic Leukemia Survivors. Curr Treat Options Oncol 17 (9): 50, 2016. [PUBMED Abstract]
97. Rensen N, Gemke RJ, van Dalen EC, et al.: Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev 11 (11): CD008727, 2017. [PUBMED Abstract]
98. Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328 (2): 87-94, 1993. [PUBMED Abstract]
99. Constine LS, Rubin P, Woolf PD, et al.: Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies. J Clin Oncol 5 (11): 1841-51, 1987. [PUBMED Abstract]
100. Melmed S, Casanueva FF, Hoffman AR, et al.: Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96 (2): 273-88, 2011. [PUBMED Abstract]
101. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106 (25): 3143-421, 2002. [PUBMED Abstract]
102. Saultier P, Auquier P, Bertrand Y, et al.: Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study. Haematologica 101 (12): 1603-1610, 2016. [PUBMED Abstract]
103. Nottage KA, Ness KK, Li C, et al.: Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia - From the St. Jude Lifetime Cohort. Br J Haematol 165 (3): 364-74, 2014. [PUBMED Abstract]
104. Oudin C, Berbis J, Bertrand Y, et al.: Prevalence and characteristics of metabolic syndrome in adults from the French childhood leukemia survivors' cohort: a comparison with controls from the French population. Haematologica 103 (4): 645-654, 2018. [PUBMED Abstract]
105. van Waas M, Neggers SJ, Raat H, et al.: Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7 (12): e52237, 2012. [PUBMED Abstract]
106. Smith WA, Li C, Nottage KA, et al.: Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer 120 (17): 2742-50, 2014. [PUBMED Abstract]
107. Jones LW, Liu Q, Armstrong GT, et al.: Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. J Clin Oncol 32 (32): 3643-50, 2014. [PUBMED Abstract]
108. Scott JM, Li N, Liu Q, et al.: Association of Exercise With Mortality in Adult Survivors of Childhood Cancer. JAMA Oncol 4 (10): 1352-1358, 2018. [PUBMED Abstract]
109. Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
110. van Waas M, Neggers SJ, Uitterlinden AG, et al.: Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors. Eur J Cancer 49 (3): 668-75, 2013. [PUBMED Abstract]
111. de Vathaire F, El-Fayech C, Ben Ayed FF, et al.: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13 (10): 1002-10, 2012. [PUBMED Abstract]
112. Armenian SH, Chemaitilly W, Chen M, et al.: National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report. Biol Blood Marrow Transplant 23 (2): 201-210, 2017. [PUBMED Abstract]
113. Lega IC, Pole JD, Austin PC, et al.: Diabetes Risk in Childhood Cancer Survivors: A Population-Based Study. Can J Diabetes 42 (5): 533-539, 2018. [PUBMED Abstract]
114. Baker KS, Chow EJ, Goodman PJ, et al.: Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev 22 (11): 1954-63, 2013. [PUBMED Abstract]
115. Meacham LR, Chow EJ, Ness KK, et al.: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 19 (1): 170-81, 2010. [PUBMED Abstract]
116. van Santen HM, Geskus RB, Raemaekers S, et al.: Changes in body mass index in long-term childhood cancer survivors. Cancer 121 (23): 4197-204, 2015. [PUBMED Abstract]
117. Meacham LR, Gurney JG, Mertens AC, et al.: Body mass index in long-term adult survivors of childhood cancer: a report of the Childhood Cancer Survivor Study. Cancer 103 (8): 1730-9, 2005. [PUBMED Abstract]
118. Tonorezos ES, Chou JF, Moskowitz CS, et al.: Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 71 (8): e31080, 2024. [PUBMED Abstract]
119. Oeffinger KC, Mertens AC, Sklar CA, et al.: Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 21 (7): 1359-65, 2003. [PUBMED Abstract]
120. Sklar CA, Mertens AC, Walter A, et al.: Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation. Med Pediatr Oncol 35 (2): 91-5, 2000. [PUBMED Abstract]
121. Garmey EG, Liu Q, Sklar CA, et al.: Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 26 (28): 4639-45, 2008. [PUBMED Abstract]
122. Chow EJ, Pihoker C, Hunt K, et al.: Obesity and hypertension among children after treatment for acute lymphoblastic leukemia. Cancer 110 (10): 2313-20, 2007. [PUBMED Abstract]
123. Withycombe JS, Post-White JE, Meza JL, et al.: Weight patterns in children with higher risk ALL: A report from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer 53 (7): 1249-54, 2009. [PUBMED Abstract]
124. Nathan PC, Jovcevska V, Ness KK, et al.: The prevalence of overweight and obesity in pediatric survivors of cancer. J Pediatr 149 (4): 518-25, 2006. [PUBMED Abstract]
125. Oeffinger KC: Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer 50 (2 Suppl): 462-7; discussion 468, 2008. [PUBMED Abstract]
126. Brennan BM, Rahim A, Blum WF, et al.: Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity? Clin Endocrinol (Oxf) 50 (2): 163-9, 1999. [PUBMED Abstract]
127. Pluimakers VG, van Atteveld JE, de Winter DTC, et al.: Prevalence, risk factors, and optimal way to determine overweight, obesity, and morbid obesity in the first Dutch cohort of 2338 long-term survivors of childhood cancer: a DCCSS-LATER study. Eur J Endocrinol 189 (5): 495-507, 2023. [PUBMED Abstract]
128. Green DM, Cox CL, Zhu L, et al.: Risk factors for obesity in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 30 (3): 246-55, 2012. [PUBMED Abstract]
129. Veringa SJ, van Dulmen-den Broeder E, Kaspers GJ, et al.: Blood pressure and body composition in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 58 (2): 278-82, 2012. [PUBMED Abstract]
130. Janiszewski PM, Oeffinger KC, Church TS, et al.: Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia. J Clin Endocrinol Metab 92 (10): 3816-21, 2007. [PUBMED Abstract]
131. Oeffinger KC, Adams-Huet B, Victor RG, et al.: Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 27 (22): 3698-704, 2009. [PUBMED Abstract]
132. Jahnukainen K, Heikkinen R, Henriksson M, et al.: Increased Body Adiposity and Serum Leptin Concentrations in Very Long-Term Adult Male Survivors of Childhood Acute Lymphoblastic Leukemia. Horm Res Paediatr 84 (2): 108-15, 2015. [PUBMED Abstract]
133. Dalton VK, Rue M, Silverman LB, et al.: Height and weight in children treated for acute lymphoblastic leukemia: relationship to CNS treatment. J Clin Oncol 21 (15): 2953-60, 2003. [PUBMED Abstract]
134. Kohler JA, Moon RJ, Wright S, et al.: Increased adiposity and altered adipocyte function in female survivors of childhood acute lymphoblastic leukaemia treated without cranial radiation. Horm Res Paediatr 75 (6): 433-40, 2011. [PUBMED Abstract]
135. Zhang FF, Rodday AM, Kelly MJ, et al.: Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 61 (7): 1263-9, 2014. [PUBMED Abstract]
136. Warner JT, Evans WD, Webb DK, et al.: Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol 38 (3): 165-72, 2002. [PUBMED Abstract]
137. Miller TL, Lipsitz SR, Lopez-Mitnik G, et al.: Characteristics and determinants of adiposity in pediatric cancer survivors. Cancer Epidemiol Biomarkers Prev 19 (8): 2013-22, 2010. [PUBMED Abstract]
138. Jarfelt M, Lannering B, Bosaeus I, et al.: Body composition in young adult survivors of childhood acute lymphoblastic leukaemia. Eur J Endocrinol 153 (1): 81-9, 2005. [PUBMED Abstract]
139. Richard MA, Brown AL, Belmont JW, et al.: Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort. Cancer 127 (2): 310-318, 2021. [PUBMED Abstract]
140. Ness KK, DeLany JP, Kaste SC, et al.: Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. Blood 125 (22): 3411-9, 2015. [PUBMED Abstract]
141. Belle FN, Kasteler R, Schindera C, et al.: No evidence of overweight in long-term survivors of childhood cancer after glucocorticoid treatment. Cancer 124 (17): 3576-3585, 2018. [PUBMED Abstract]
142. Lindemulder SJ, Stork LC, Bostrom B, et al.: Survivors of standard risk acute lymphoblastic leukemia do not have increased risk for overweight and obesity compared to non-cancer peers: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (6): 1035-41, 2015. [PUBMED Abstract]
143. Gurney JG, Ness KK, Stovall M, et al.: Final height and body mass index among adult survivors of childhood brain cancer: childhood cancer survivor study. J Clin Endocrinol Metab 88 (10): 4731-9, 2003. [PUBMED Abstract]
144. Sahakitrungruang T, Klomchan T, Supornsilchai V, et al.: Obesity, metabolic syndrome, and insulin dynamics in children after craniopharyngioma surgery. Eur J Pediatr 170 (6): 763-9, 2011. [PUBMED Abstract]
145. Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010. [PUBMED Abstract]
146. Simoneau-Roy J, O'Gorman C, Pencharz P, et al.: Insulin sensitivity and secretion in children and adolescents with hypothalamic obesity following treatment for craniopharyngioma. Clin Endocrinol (Oxf) 72 (3): 364-70, 2010. [PUBMED Abstract]
147. Tosta-Hernandez PDC, Siviero-Miachon AA, da Silva NS, et al.: Childhood Craniopharyngioma: A 22-Year Challenging Follow-Up in a Single Center. Horm Metab Res 50 (9): 675-682, 2018. [PUBMED Abstract]
148. van Schaik J, van Roessel IMAA, Schouten-van Meeteren NAYN, et al.: High Prevalence of Weight Gain in Childhood Brain Tumor Survivors and Its Association With Hypothalamic-Pituitary Dysfunction. J Clin Oncol 39 (11): 1264-1273, 2021. [PUBMED Abstract]
149. Neville KA, Cohn RJ, Steinbeck KS, et al.: Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 91 (11): 4401-7, 2006. [PUBMED Abstract]
150. Nysom K, Holm K, Michaelsen KF, et al.: Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 27 (8): 817-20, 2001. [PUBMED Abstract]
151. Ketterl TG, Chow EJ, Leisenring WM, et al.: Adipokines, Inflammation, and Adiposity in Hematopoietic Cell Transplantation Survivors. Biol Blood Marrow Transplant 24 (3): 622-626, 2018. [PUBMED Abstract]
152. Inaba H, Yang J, Kaste SC, et al.: Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 30 (32): 3991-7, 2012. [PUBMED Abstract]
153. Wilson CL, Liu W, Chemaitilly W, et al.: Body Composition, Metabolic Health, and Functional Impairment among Adults Treated for Abdominal and Pelvic Tumors during Childhood. Cancer Epidemiol Biomarkers Prev 29 (9): 1750-1758, 2020. [PUBMED Abstract]
154. Ness KK, Krull KR, Jones KE, et al.: Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol 31 (36): 4496-503, 2013. [PUBMED Abstract]
155. Hayek S, Gibson TM, Leisenring WM, et al.: Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 38 (3): 232-247, 2020. [PUBMED Abstract]
156. Delaney A, Howell CR, Krull KR, et al.: Progression of Frailty in Survivors of Childhood Cancer: A St. Jude Lifetime Cohort Report. J Natl Cancer Inst 113 (10): 1415-1421, 2021. [PUBMED Abstract]
157. Williams AM, Krull KR, Howell CR, et al.: Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort. J Clin Oncol 39 (31): 3485-3495, 2021. [PUBMED Abstract]
158. van Atteveld JE, de Winter DTC, Pluimakers VG, et al.: Frailty and sarcopenia within the earliest national Dutch childhood cancer survivor cohort (DCCSS-LATER): a cross-sectional study. Lancet Healthy Longev 4 (4): e155-e165, 2023. [PUBMED Abstract]
159. Guida JL, Hyun G, Belsky DW, et al.: Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort. Nat Cancer 5 (5): 731-741, 2024. [PUBMED Abstract]

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

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

References

1. Centers for Disease Control and Prevention: Altered immunocompetence. In: Kroger A, Bahta L, Long S, et al.: General Best Practice Guidelines for Immunization: Best Practices Guidance. Atlanta, GA: Advisory Committee on Immunization Practices (ACIP); Centers for Disease Control and Prevention, 2023, pp 123-48. Available online. Last accessed November 3, 2023.
2. Jockovich M, Mendenhall NP, Sombeck MD, et al.: Long-term complications of laparotomy in Hodgkin's disease. Ann Surg 219 (6): 615-21; discussion 621-4, 1994. [PUBMED Abstract]
3. Coleman CN, McDougall IR, Dailey MO, et al.: Functional hyposplenia after splenic irradiation for Hodgkin's disease. Ann Intern Med 96 (1): 44-7, 1982. [PUBMED Abstract]
4. Weiner MA, Landmann RG, DeParedes L, et al.: Vesiculated erythrocytes as a determination of splenic reticuloendothelial function in pediatric patients with Hodgkin's disease. J Pediatr Hematol Oncol 17 (4): 338-41, 1995. [PUBMED Abstract]
5. Al-Eid MA, Tutschka PJ, Wagner HN, et al.: Functional asplenia in patients with chronic graft-versus-host disease: concise communication. J Nucl Med 24 (12): 1123-6, 1983. [PUBMED Abstract]
6. Weil BR, Madenci AL, Liu Q, et al.: Late Infection-Related Mortality in Asplenic Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 36 (16): 1571-1578, 2018. [PUBMED Abstract]
7. de Vries S, Schaapveld M, Janus CPM, et al.: Long-Term Cause-Specific Mortality in Hodgkin Lymphoma Patients. J Natl Cancer Inst 113 (6): 760-769, 2021. [PUBMED Abstract]
8. Madenci AL, Armstrong LB, Kwon NK, et al.: Incidence and risk factors for sepsis after childhood splenectomy. J Pediatr Surg 54 (7): 1445-1448, 2019. [PUBMED Abstract]
9. Ram S, Lewis LA, Rice PA: Infections of people with complement deficiencies and patients who have undergone splenectomy. Clin Microbiol Rev 23 (4): 740-80, 2010. [PUBMED Abstract]
10. National Center for Immunization and Respiratory Diseases: General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 60 (RR02): 1-60, 2011. Available online. Last accessed August 21, 2023.
11. Bridges CB, Coyne-Beasley T; Advisory Committee on Immunization Practices: Advisory committee on immunization practices recommended immunization schedule for adults aged 19 years or older: United States, 2014. Ann Intern Med 160 (3): 190, 2014. [PUBMED Abstract]
12. Rubin LG, Levin MJ, Ljungman P, et al.: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 58 (3): 309-18, 2014. [PUBMED Abstract]
13. Mbaeyi SA, Bozio CH, Duffy J, et al.: Meningococcal Vaccination: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Morb Mortal Wkly Rep 69 (No. RR-9): 1–41, 2020. Available online. Last accessed November 3, 2023.
14. Centers for Disease Control and Prevention (CDC): Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among children aged 6-18 years with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 62 (25): 521-4, 2013. [PUBMED Abstract]
15. Centers for Disease Control and Prevention: Child and Adolescent Immunization Schedule by Medical Indication: Recommendations for Ages 18 Years or Younger, United States, 2023. Atlanta, GA: Centers for Disease Control and Prevention, 2023. Available online. Last accessed November 3, 2023.
16. Guilcher GMT, Rivard L, Huang JT, et al.: Immune function in childhood cancer survivors: a Children's Oncology Group review. Lancet Child Adolesc Health 5 (4): 284-294, 2021. [PUBMED Abstract]
17. Koskenvuo M, Ekman I, Saha E, et al.: Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment. Pediatr Blood Cancer 63 (9): 1653-6, 2016. [PUBMED Abstract]
18. Speckhart SA: MMR vaccination timing and long-term immunity among childhood cancer survivors. Pediatr Blood Cancer 70 (4): e30133, 2023. [PUBMED Abstract]
19. Fayea NY, Fouda AE, Kandil SM: Immunization status in childhood cancer survivors: A hidden risk which could be prevented. Pediatr Neonatol 58 (6): 541-545, 2017. [PUBMED Abstract]
20. Bochennek K, Allwinn R, Langer R, et al.: Differential loss of humoral immunity against measles, mumps, rubella and varicella-zoster virus in children treated for cancer. Vaccine 32 (27): 3357-61, 2014. [PUBMED Abstract]
21. Olkinuora HA, Taskinen MH, Saarinen-Pihkala UM, et al.: Multiple viral infections post-hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts. Pediatr Transplant 14 (2): 242-8, 2010. [PUBMED Abstract]
22. Inaba H, Hartford CM, Pei D, et al.: Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation. Br J Haematol 156 (1): 109-17, 2012. [PUBMED Abstract]
23. Tomblyn M, Chiller T, Einsele H, et al.: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15 (10): 1143-238, 2009. [PUBMED Abstract]
24. Cordonnier C, Einarsdottir S, Cesaro S, et al.: Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 19 (6): e200-e212, 2019. [PUBMED Abstract]
25. Majhail NS, Rizzo JD, Lee SJ, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Rev Bras Hematol Hemoter 34 (2): 109-33, 2012. [PUBMED Abstract]
26. Pergam SA, Englund JA, Kamboj M, et al.: Preventing Measles in Immunosuppressed Cancer and Hematopoietic Cell Transplantation Patients: A Position Statement by the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 25 (11): e321-e330, 2019. [PUBMED Abstract]
27. Maude SL, Laetsch TW, Buechner J, et al.: Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 378 (5): 439-448, 2018. [PUBMED Abstract]
28. Cordeiro A, Bezerra ED, Hirayama AV, et al.: Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol Blood Marrow Transplant 26 (1): 26-33, 2020. [PUBMED Abstract]
29. Bhoj VG, Arhontoulis D, Wertheim G, et al.: Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood 128 (3): 360-70, 2016. [PUBMED Abstract]
30. Chehab L, Doody DR, Esbenshade AJ, et al.: A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors. J Clin Oncol 41 (2): 364-372, 2023. [PUBMED Abstract]

The musculoskeletal system of growing children and adolescents is vulnerable to the cytotoxic effects of cancer therapies, including surgery, chemotherapy, and radiation therapy. Documented late effects include the following:

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

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

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

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

References

1. Estilo CL, Huryn JM, Kraus DH, et al.: Effects of therapy on dentofacial development in long-term survivors of head and neck rhabdomyosarcoma: the memorial sloan-kettering cancer center experience. J Pediatr Hematol Oncol 25 (3): 215-22, 2003. [PUBMED Abstract]
2. Gevorgyan A, La Scala GC, Neligan PC, et al.: Radiation-induced craniofacial bone growth disturbances. J Craniofac Surg 18 (5): 1001-7, 2007. [PUBMED Abstract]
3. Karsila-Tenovuo S, Jahnukainen K, Peltomäki T, et al.: Disturbances in craniofacial morphology in children treated for solid tumors. Oral Oncol 37 (7): 586-92, 2001. [PUBMED Abstract]
4. Choi SY, Kim MS, Yoo S, et al.: Long term follow-up results of external beam radiotherapy as primary treatment for retinoblastoma. J Korean Med Sci 25 (4): 546-51, 2010. [PUBMED Abstract]
5. Shildkrot Y, Kirzhner M, Haik BG, et al.: The effect of cancer therapies on pediatric anophthalmic sockets. Ophthalmology 118 (12): 2480-6, 2011. [PUBMED Abstract]
6. Brownstein CM, Mertens AC, Mitby PA, et al.: Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the childhood cancer survivor study. J Clin Endocrinol Metab 89 (9): 4422-7, 2004. [PUBMED Abstract]
7. Nandagopal R, Laverdière C, Mulrooney D, et al.: Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group. Horm Res 69 (2): 65-74, 2008. [PUBMED Abstract]
8. Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 31 (5): 1113-21, 1995. [PUBMED Abstract]
9. Packer RJ, Boyett JM, Janss AJ, et al.: Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control. J Clin Oncol 19 (2): 480-7, 2001. [PUBMED Abstract]
10. Chow EJ, Friedman DL, Yasui Y, et al.: Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr 150 (4): 370-5, 375.e1, 2007. [PUBMED Abstract]
11. Bongers ME, Francken AB, Rouwé C, et al.: Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation. Pediatr Blood Cancer 45 (2): 139-43, 2005. [PUBMED Abstract]
12. Leung W, Ahn H, Rose SR, et al.: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86 (4): 215-24, 2007. [PUBMED Abstract]
13. Sanders JE: Growth and development after hematopoietic cell transplant in children. Bone Marrow Transplant 41 (2): 223-7, 2008. [PUBMED Abstract]
14. Sanders JE, Guthrie KA, Hoffmeister PA, et al.: Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood 105 (3): 1348-54, 2005. [PUBMED Abstract]
15. Shalitin S, Laur E, Lebenthal Y, et al.: Endocrine complications and components of the metabolic syndrome in survivors of childhood malignant non-brain solid tumors. Horm Res Paediatr 81 (1): 32-42, 2014. [PUBMED Abstract]
16. Silber JH, Littman PS, Meadows AT: Stature loss following skeletal irradiation for childhood cancer. J Clin Oncol 8 (2): 304-12, 1990. [PUBMED Abstract]
17. Hartley KA, Li C, Laningham FH, et al.: Vertebral body growth after craniospinal irradiation. Int J Radiat Oncol Biol Phys 70 (5): 1343-9, 2008. [PUBMED Abstract]
18. Paulino AC, Nguyen TX, Mai WY: An analysis of primary site control and late effects according to local control modality in non-metastatic Ewing sarcoma. Pediatr Blood Cancer 48 (4): 423-9, 2007. [PUBMED Abstract]
19. Oshiro Y, Mizumoto M, Pan H, et al.: Spinal changes after craniospinal irradiation in pediatric patients. Pediatr Blood Cancer 67 (12): e28728, 2020. [PUBMED Abstract]
20. Hogeboom CJ, Grosser SC, Guthrie KA, et al.: Stature loss following treatment for Wilms tumor. Med Pediatr Oncol 36 (2): 295-304, 2001. [PUBMED Abstract]
21. Paulino AC, Wen BC, Brown CK, et al.: Late effects in children treated with radiation therapy for Wilms' tumor. Int J Radiat Oncol Biol Phys 46 (5): 1239-46, 2000. [PUBMED Abstract]
22. Fiscaletti M, Samoilenko M, Dubois J, et al.: Predictors of Vertebral Deformity in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: The PETALE Study. J Clin Endocrinol Metab 106 (2): 512-525, 2021. [PUBMED Abstract]
23. Wilson CL, Dilley K, Ness KK, et al.: Fractures among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 118 (23): 5920-8, 2012. [PUBMED Abstract]
24. Davies JH, Evans BA, Jenney ME, et al.: Skeletal morbidity in childhood acute lymphoblastic leukaemia. Clin Endocrinol (Oxf) 63 (1): 1-9, 2005. [PUBMED Abstract]
25. Wilson CL, Chemaitilly W, Jones KE, et al.: Modifiable Factors Associated With Aging Phenotypes Among Adult Survivors of Childhood Acute Lymphoblastic Leukemia. J Clin Oncol 34 (21): 2509-15, 2016. [PUBMED Abstract]
26. van Atteveld JE, de Winter DTC, Pluimakers VG, et al.: Risk and determinants of low and very low bone mineral density and fractures in a national cohort of Dutch adult childhood cancer survivors (DCCSS-LATER): a cross-sectional study. Lancet Diabetes Endocrinol 11 (1): 21-32, 2023. [PUBMED Abstract]
27. van der Sluis IM, van den Heuvel-Eibrink MM, Hählen K, et al.: Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukemia. J Pediatr 141 (2): 204-10, 2002. [PUBMED Abstract]
28. Arikoski P, Komulainen J, Riikonen P, et al.: Reduced bone density at completion of chemotherapy for a malignancy. Arch Dis Child 80 (2): 143-8, 1999. [PUBMED Abstract]
29. Brennan BM, Mughal Z, Roberts SA, et al.: Bone mineral density in childhood survivors of acute lymphoblastic leukemia treated without cranial irradiation. J Clin Endocrinol Metab 90 (2): 689-94, 2005. [PUBMED Abstract]
30. Warner JT, Evans WD, Webb DK, et al.: Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45 (4 Pt 1): 544-51, 1999. [PUBMED Abstract]
31. Mandel K, Atkinson S, Barr RD, et al.: Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol 22 (7): 1215-21, 2004. [PUBMED Abstract]
32. Gurney JG, Kaste SC, Liu W, et al.: Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer 61 (7): 1270-6, 2014. [PUBMED Abstract]
33. den Hoed MA, Klap BC, te Winkel ML, et al.: Bone mineral density after childhood cancer in 346 long-term adult survivors of childhood cancer. Osteoporos Int 26 (2): 521-9, 2015. [PUBMED Abstract]
34. den Hoed MA, Pluijm SM, te Winkel ML, et al.: Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia. Haematologica 100 (12): 1564-70, 2015. [PUBMED Abstract]
35. Kvammen JA, Stensvold E, Godang K, et al.: Bone mineral density and nutrition in long-term survivors of childhood brain tumors. Clin Nutr ESPEN 50: 162-169, 2022. [PUBMED Abstract]
36. Le Meignen M, Auquier P, Barlogis V, et al.: Bone mineral density in adult survivors of childhood acute leukemia: impact of hematopoietic stem cell transplantation and other treatment modalities. Blood 118 (6): 1481-9, 2011. [PUBMED Abstract]
37. Kodama M, Komura H, Shimizu S, et al.: Efficacy of hormone therapy for osteoporosis in adolescent girls after hematopoietic stem cell transplantation: a longitudinal study. Fertil Steril 95 (2): 731-5, 2011. [PUBMED Abstract]
38. Bhandari R, Teh JB, Herrera C, et al.: Prevalence and risk factors for vitamin D deficiency in long-term childhood cancer survivors. Pediatr Blood Cancer 68 (7): e29048, 2021. [PUBMED Abstract]
39. Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 60 (1): 265-74, 2004. [PUBMED Abstract]
40. van Atteveld JE, Pluijm SMF, Ness KK, et al.: Prediction of Low and Very Low Bone Mineral Density Among Adult Survivors of Childhood Cancer. J Clin Oncol 37 (25): 2217-2225, 2019. [PUBMED Abstract]
41. Mattano LA, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9): 906-15, 2012. [PUBMED Abstract]
42. Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005. [PUBMED Abstract]
43. Karimova EJ, Rai SN, Howard SC, et al.: Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol 25 (12): 1525-31, 2007. [PUBMED Abstract]
44. Campbell S, Sun CL, Kurian S, et al.: Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer 115 (18): 4127-35, 2009. [PUBMED Abstract]
45. Kawedia JD, Kaste SC, Pei D, et al.: Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 117 (8): 2340-7; quiz 2556, 2011. [PUBMED Abstract]
46. Girard P, Auquier P, Barlogis V, et al.: Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. Haematologica 98 (7): 1089-97, 2013. [PUBMED Abstract]
47. Ali N, Gohar S, Zaky I, et al.: Osteonecrosis in children with acute lymphoblastic leukemia: A report from Children's Cancer Hospital Egypt (CCHE). Pediatr Blood Cancer 66 (1): e27440, 2019. [PUBMED Abstract]
48. Karimova EJ, Wozniak A, Wu J, et al.: How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res 468 (9): 2454-9, 2010. [PUBMED Abstract]
49. Padhye B, Dalla-Pozza L, Little D, et al.: Incidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL). Cancer Med 5 (5): 960-7, 2016. [PUBMED Abstract]
50. te Winkel ML, Pieters R, Hop WC, et al.: Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol 29 (31): 4143-50, 2011. [PUBMED Abstract]
51. DeFeo BM, Kaste SC, Li Z, et al.: Long-Term Functional Outcomes Among Childhood Survivors of Cancer Who Have a History of Osteonecrosis. Phys Ther 100 (3): 509-522, 2020. [PUBMED Abstract]
52. Hernigou P, Auregan JC, Dubory A, et al.: Ankle osteonecrosis in fifty-one children and adolescent's leukemia survivors: a prospective randomized study on percutaneous mesenchymal stem cells treatment. Int Orthop 45 (9): 2383-2393, 2021. [PUBMED Abstract]
53. Faraci M, Calevo MG, Lanino E, et al.: Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica 91 (8): 1096-9, 2006. [PUBMED Abstract]
54. Relling MV, Yang W, Das S, et al.: Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol 22 (19): 3930-6, 2004. [PUBMED Abstract]
55. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED Abstract]
56. Hyakuna N, Shimomura Y, Watanabe A, et al.: Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. J Pediatr Hematol Oncol 36 (1): 22-9, 2014. [PUBMED Abstract]
57. Badhiwala JH, Nayiager T, Athale UH: The development of thromboembolism may increase the risk of osteonecrosis in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 62 (10): 1851-4, 2015. [PUBMED Abstract]
58. Li X, Brazauskas R, Wang Z, et al.: Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents. Biol Blood Marrow Transplant 20 (4): 587-92, 2014. [PUBMED Abstract]
59. Mattano LA, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000. [PUBMED Abstract]
60. Karol SE, Mattano LA, Yang W, et al.: Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood 127 (5): 558-64, 2016. [PUBMED Abstract]
61. Finkelstein Y, Blonquist TM, Vijayanathan V, et al.: A thymidylate synthase polymorphism is associated with increased risk for bone toxicity among children treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]
62. Karol SE, Yang W, Van Driest SL, et al.: Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood 126 (15): 1770-6, 2015. [PUBMED Abstract]
63. Aricò M, Boccalatte MF, Silvestri D, et al.: Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica 88 (7): 747-53, 2003. [PUBMED Abstract]
64. Elmantaser M, Stewart G, Young D, et al.: Skeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukaemia. Arch Dis Child 95 (10): 805-9, 2010. [PUBMED Abstract]
65. Chao C, Bhatia S, Xu L, et al.: Chronic Comorbidities Among Survivors of Adolescent and Young Adult Cancer. J Clin Oncol 38 (27): 3161-3174, 2020. [PUBMED Abstract]
66. Bovée JV: Multiple osteochondromas. Orphanet J Rare Dis 3: 3, 2008. [PUBMED Abstract]
67. Bordigoni P, Turello R, Clement L, et al.: Osteochondroma after pediatric hematopoietic stem cell transplantation: report of eight cases. Bone Marrow Transplant 29 (7): 611-4, 2002. [PUBMED Abstract]
68. Taitz J, Cohn RJ, White L, et al.: Osteochondroma after total body irradiation: an age-related complication. Pediatr Blood Cancer 42 (3): 225-9, 2004. [PUBMED Abstract]
69. King EA, Hanauer DA, Choi SW, et al.: Osteochondromas after radiation for pediatric malignancies: a role for expanded counseling for skeletal side effects. J Pediatr Orthop 34 (3): 331-5, 2014 Apr-May. [PUBMED Abstract]
70. Danner-Koptik K, Kletzel M, Dilley KJ: Exostoses as a long-term sequela after pediatric hematopoietic progenitor cell transplantation: potential causes and increase risk of secondary malignancies from Ann & Robert H. Lurie Children's Hospital of Chicago. Biol Blood Marrow Transplant 19 (8): 1267-70, 2013. [PUBMED Abstract]
71. Faraci M, Bagnasco F, Corti P, et al.: Osteochondroma after hematopoietic stem cell transplantation in childhood. An Italian study on behalf of the AIEOP-HSCT group. Biol Blood Marrow Transplant 15 (10): 1271-6, 2009. [PUBMED Abstract]
72. Kushner BH, Roberts SS, Friedman DN, et al.: Osteochondroma in long-term survivors of high-risk neuroblastoma. Cancer 121 (12): 2090-6, 2015. [PUBMED Abstract]
73. Nagarajan R, Neglia JP, Clohisy DR, et al.: Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol 20 (22): 4493-501, 2002. [PUBMED Abstract]
74. Aulivola B, Hile CN, Hamdan AD, et al.: Major lower extremity amputation: outcome of a modern series. Arch Surg 139 (4): 395-9; discussion 399, 2004. [PUBMED Abstract]
75. Kaste SC, Neel MN, Rao BN, et al.: Complications of limb-sparing procedures using endoprosthetic replacements about the knee for pediatric skeletal sarcomas. Pediatr Radiol 31 (2): 62-71, 2001. [PUBMED Abstract]
76. Eiser C, Darlington AS, Stride CB, et al.: Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma 5 (4): 189-95, 2001. [PUBMED Abstract]
77. Renard AJ, Veth RP, Schreuder HW, et al.: Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone. J Surg Oncol 73 (4): 198-205, 2000. [PUBMED Abstract]
78. Fernandez-Pineda I, Hudson MM, Pappo AS, et al.: Long-term functional outcomes and quality of life in adult survivors of childhood extremity sarcomas: a report from the St. Jude Lifetime Cohort Study. J Cancer Surviv 11 (1): 1-12, 2017. [PUBMED Abstract]
79. Marina N, Hudson MM, Jones KE, et al.: Changes in health status among aging survivors of pediatric upper and lower extremity sarcoma: a report from the childhood cancer survivor study. Arch Phys Med Rehabil 94 (6): 1062-73, 2013. [PUBMED Abstract]
80. Geiger EJ, Liu W, Srivastava DK, et al.: What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report. Clin Orthop Relat Res 481 (3): 526-538, 2023. [PUBMED Abstract]
81. Dieffenbach BV, Murphy AJ, Liu Q, et al.: Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort. Lancet Oncol 24 (6): 691-700, 2023. [PUBMED Abstract]
82. Beredjiklian PK, Drummond DS, Dormans JP, et al.: Orthopaedic manifestations of chronic graft-versus-host disease. J Pediatr Orthop 18 (5): 572-5, 1998 Sep-Oct. [PUBMED Abstract]
83. Inamoto Y, Storer BE, Petersdorf EW, et al.: Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood 121 (25): 5098-103, 2013. [PUBMED Abstract]

Reproductive outcomes in childhood cancer survivors may be compromised by surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads. Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment. In particular, the literature is deficient regarding hard outcomes of reproductive potential (e.g., semen analysis in men, primordial follicle count in women) and outcomes after contemporary risk-adapted treatment approaches.[1,2]

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

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

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

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