医療専門家向け Late Effects of Treatment for Childhood Cancer (PDQ®)

ご利用について

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the late effects of treatment for childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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General Information About Late Effects of Treatment for Childhood Cancer

During the past five decades, dramatic progress has been made in the development of curative therapy for pediatric malignancies. Long-term survival into adulthood is the expectation for more than 80% of children with access to contemporary therapies for pediatric malignancies.[ 1 ][ 2 ] The therapy responsible for this survival can also produce adverse long-term health-related outcomes, referred to as late effects, which manifest months to years after completion of cancer treatment.

A variety of approaches have been used to advance knowledge about the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have utilized a spectrum of resources including investigation of data from the following:

Studies reporting outcomes in survivors who have been well characterized regarding clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality data to establish the occurrence and risk profiles for late cancer treatment–related toxicity. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings reported.

Prevalence of Late Effects in Childhood Cancer Survivors

Late effects are commonly experienced by adults who have survived childhood cancer; the prevalence of late effects increases as time from cancer diagnosis elapses. Population-based studies support excess hospital-related morbidity among childhood and young adult cancer survivors compared with age- and sex-matched controls.[ 3 ][ 4 ][ 5 ][ 10 ][ 11 ][ 12 ][ 13 ][ 14 ]

Research has demonstrated that among adults treated for cancer during childhood, late effects contribute to a high burden of morbidity, including the following:[ 6 ][ 8 ][ 9 ][ 15 ][ 16 ][ 17 ][ 18 ]

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 the St. Jude Lifetime Cohort experienced an average of 17.1 chronic health conditions, 4.7 of which were severe/disabling, life threatening, or fatal.[ 17 ] This is in contrast to 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 (refer to Figure 1).[ 17 ]

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

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 (refer to Figure 2).[ 6 ]

The presence of serious, disabling, and life-threatening chronic health conditions adversely affects the health status of aging survivors, with the greatest impact 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.[ 19 ] Female survivors demonstrate a steeper trajectory of age-dependent decline in health status than do male survivors.[ 20 ] The even-higher prevalence of late effects among clinically ascertained cohorts is related to the subclinical and undiagnosed conditions detected by screening and surveillance measures.[ 9 ]

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CCSS investigators also evaluated the impact of race and ethnicity on late outcomes by comparing late mortality, subsequent neoplasms, and chronic health conditions in Hispanic (n = 750) and non-Hispanic black (n = 694) participants with non-Hispanic white participants (n = 12,397).[ 21 ] The following results were observed:

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 based on a variety of clinical, biological, and sometimes genetic factors. The CCSS reported that with decreased cumulative dose and frequency of therapeutic radiation use over treatment decades from 1970 to 1999, survivors have experienced a significant decrease in risk of subsequent neoplasms.[ 23 ] With the exception of survivors requiring intensive multimodality therapy, sometimes including hematopoietic cell transplantation, for aggressive or 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 neurologic 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. 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, 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 (refer to Figure 3 for more information).[ 24 ]

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Mortality

Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer as observed in the following:

Despite high premature morbidity rates, overall mortality has decreased over time.[ 25 ][ 33 ][ 34 ][ 35 ][ 36 ] This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from subsequent cancers or treatment-related toxicities. The former reflects improvements in therapeutic efficacy, and the latter reflects changes in therapy made subsequent to studying the causes of late effects. The expectation that mortality rates in survivors will continue to exceed those in the general population is based on the long-term sequelae that are likely to increase with attained age. If patients treated on therapeutic protocols are followed up for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.

Survivors of adolescent and young adult cancers

Little information is available on the conditional probabilities of death among adolescent and young adult cancer patients who survive more than 5 years after their diagnosis. Using SEER data, conditional relative survival up to 25 years after diagnosis was studied in a cohort of adolescent and young adult patients (N = 205,954) diagnosed with a first malignant cancer (thyroid, melanoma, testicular, breast, lymphoma, leukemia, and central nervous system [CNS] tumors). For all cancer types combined, among individuals who survived up to 5 years, subsequent 5-year relative survival exceeded 95% by 7 years after diagnosis. According to this study, most adolescent and young adult cancer patients who survived at least 7 years after diagnosis experienced little difference in survival from that of the general population. For specific cancer types, including CNS tumors, female breast cancer, Hodgkin lymphoma, and leukemia, evidence of excess mortality risk persisted, or re-emerged, more than 10 years after a cancer diagnosis. Conditional relative survival was lowest for adolescent and young adult patients with CNS tumors, although patients aged 15 to 29 years demonstrated a higher survival rate than did patients aged 30 to 39 years at the time of diagnosis of their CNS tumors.[ 37 ]

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. The results of these studies have played an important role in the following areas:[ 25 ][ 33 ]

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

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. Factors that should be considered in the risk assessment for a given late effect include the following:

Resources to Support Survivor Care

Risk-based screening

The need for long-term follow-up for childhood cancer survivors is supported by the American Society of Pediatric Hematology/Oncology, the International Society of Pediatric Oncology, the American Academy of Pediatrics, the Children’s Oncology Group (COG), and the Institute of Medicine. A risk-based medical follow-up is recommended, which includes a systematic plan for lifelong screening, surveillance, and prevention that incorporates risk estimates based on the following:[ 38 ]

Part of long-term follow-up is also focused on appropriate screening of educational and vocational progress. Specific treatments for childhood cancer, especially those that directly impact nervous system structures, may result in sensory, motor, and neurocognitive deficits that may have adverse consequences on functional status, educational attainment, and future vocational opportunities.[ 39 ] In support of this, a CCSS investigation observed the following:[ 40 ]

These data emphasize the importance of facilitating survivor access to remedial services, which has been demonstrated to have a positive impact on education achievement,[ 41 ] which may in turn enhance vocational opportunities.

In addition to risk-based screening for medical late effects, the impact of health behaviors on cancer-related health risks is also emphasized. Health-promoting behaviors are stressed for survivors of childhood cancer. Targeted educational efforts appear to be worthwhile in the following areas:[ 42 ]

Proactively addressing unhealthy and risky behaviors is pertinent, as several research investigations confirm that long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects.[ 42 ][ 43 ][ 44 ]

Access to risk-based survivor care

Most childhood cancer survivors do not receive recommended risk-based care. The CCSS observed the following:

Access to health insurance appears to play an important role in risk-based survivor care.[ 49 ][ 50 ] Lack of access to health insurance affects the following:

Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors.[ 52 ][ 53 ] Legislation, including the Health Insurance Portability and Accountability Act (HIPAA),[ 54 ][ 55 ] has improved access and retention of health insurance among survivors, although the quality and limitations associated with these policies have not been well studied.

Transition to Survivor Care

Long-term follow-up programs

Transition of care from the pediatric to adult health care setting is necessary for most childhood cancer survivors in the United States.

When available, multidisciplinary long-term follow-up programs in the pediatric cancer center work collaboratively with community physicians to provide care for childhood cancer survivors. This type of shared care has been proposed as the optimal model to facilitate coordination between the cancer center oncology team and community physician groups providing survivor care.[ 56 ]

An essential service of long-term follow-up programs is the organization of an individualized survivorship care plan that includes the following:

A CCSS investigation that evaluated perceptions of future health and cancer risk highlighted the importance of continuing education of survivors during long-term follow-up evaluations. A substantial subgroup of adult survivors reported a lack of concern about future health (24%) and subsequent cancer risks (35%), even after exposure to treatments associated with increased risks. These findings present concerns that survivors may be less likely to engage in beneficial screenings and risk-reduction activities.[ 57 ]

For survivors who have not been provided with this information, the COG offers a template that can be used by survivors to organize a personal treatment summary (refer to the COG Survivorship Guidelines, Appendix 1).

COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers

To facilitate survivor and provider access to succinct information to guide risk-based care, COG investigators have organized a compendium of exposure- and risk-based health surveillance recommendations, with the goal of standardizing the care of childhood cancer survivors.[ 58 ]

The compendium of resources includes the following:

Information concerning late effects is summarized in tables throughout this summary.

Several groups have undertaken research to evaluate the yield from risk-based screening as recommended by the COG and other pediatric oncology cooperative groups.[ 9 ][ 73 ][ 74 ] Pertinent considerations in interpreting the results of these studies include:

Collectively, these studies demonstrate that screening identifies a substantial proportion of individuals with previously unrecognized, treatment-related health complications of varying degrees of severity. Study results have also identified low-yield evaluations that have encouraged revisions of screening recommendations. Ongoing research is evaluating cost effectiveness of screening in the context of consideration of benefits, risks, and harms.

参考文献

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42. Nathan PC, Ford JS, Henderson TO, et al.: Health behaviors, medical care, and interventions to promote healthy living in the Childhood Cancer Survivor Study cohort. J Clin Oncol 27 (14): 2363-73, 2009.[PUBMED Abstract]
43. Schultz KA, Chen L, Chen Z, et al.: Health and risk behaviors in survivors of childhood acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 55 (1): 157-64, 2010.[PUBMED Abstract]
44. Tercyak KP, Donze JR, Prahlad S, et al.: Multiple behavioral risk factors among adolescent survivors of childhood cancer in the Survivor Health and Resilience Education (SHARE) program. Pediatr Blood Cancer 47 (6): 825-30, 2006.[PUBMED Abstract]
45. Nathan PC, Greenberg ML, Ness KK, et al.: Medical care in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 26 (27): 4401-9, 2008.[PUBMED Abstract]
46. Nathan PC, Ness KK, Mahoney MC, et al.: Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Ann Intern Med 153 (7): 442-51, 2010.[PUBMED Abstract]
47. Casillas J, Oeffinger KC, Hudson MM, et al.: Identifying Predictors of Longitudinal Decline in the Level of Medical Care Received by Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Health Serv Res 50 (4): 1021-42, 2015.[PUBMED Abstract]
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50. 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]
51. 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]
52. Crom DB, Lensing SY, Rai SN, et al.: Marriage, employment, and health insurance in adult survivors of childhood cancer. J Cancer Surviv 1 (3): 237-45, 2007.[PUBMED Abstract]
53. Pui CH, Cheng C, Leung W, et al.: Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 349 (7): 640-9, 2003.[PUBMED Abstract]
54. 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]
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63. Liles A, Blatt J, Morris D, et al.: Monitoring pulmonary complications in long-term childhood cancer survivors: guidelines for the primary care physician. Cleve Clin J Med 75 (7): 531-9, 2008.[PUBMED Abstract]
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65. Nathan PC, Patel SK, Dilley K, et al.: Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group. Arch Pediatr Adolesc Med 161 (8): 798-806, 2007.[PUBMED Abstract]
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Subsequent Neoplasms

Subsequent neoplasms (SNs), which may be benign or malignant, are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. Childhood cancer survivors have an increased risk of developing SNs that varies according to the following:

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 ]

The excess risk of SNs has been described in several studies.[ 3 ]

Evidence (excess risk of SN after age 40 years):

1. In a CCSS cohort, at the age of 55 years, the cumulative incidence of any new SN (including malignant neoplasms, NMSCs, benign meningiomas, and other benign neoplasms) occurring after age 40 years was 34.6%. The incidence of malignant SNs was 16.3%. Female sex and therapeutic radiation exposure were associated with an increased risk of developing SNs in multivariate analysis. Moreover, prolonged follow-up has established that multiple SNs are common among aging childhood cancer survivors.[ 4 ][ 5 ]
2. The CCSS also reported that individuals treated in more recent treatment eras experienced decreased risk of SNs (including subsequent malignancies, NMSCs, and benign meningiomas) compared with those treated earlier, and this was associated with decreased exposure to therapeutic radiation; however, individuals treated in the 1990s remain at increased risk of SNs compared with the general population.[ 6 ]
3. A follow-up CCSS study evaluated morbidity and mortality associated with meningioma among 4,221 participants treated with cranial radiation therapy.[ 7 ]
4. CCSS investigators have also evaluated associations between chemotherapy and subsequent malignant neoplasms (SMNs) among nonirradiated, long-term survivors.[ 8 ]
5. Dutch investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001 (median follow-up, 20.7 years).[ 9 ]
6. St. Jude Lifetime Cohort Study investigators assessed the contribution of pathogenic and likely pathogenic mutations in cancer predisposition genes to SN risk in childhood cancer survivors.[ 10 ]
7. A study of 4,905 1-year survivors of allogeneic hematopoietic cell transplantation (HCT) who underwent transplant between 1969 and 2014 for malignant or nonmalignant diseases and followed for a median 12.5 years, demonstrated a strong effect of TBI dose and dose fractionation on risk of SNs.[ 11 ]

The development of an SN is likely multifactorial in etiology and results from a combination of influences including gene-environment and gene-gene interactions. Outcome after the diagnosis of an SN is variable, as treatment for some histological subtypes may be compromised if childhood cancer therapy included cumulative doses of agents and modalities at the threshold of tissue tolerance.[ 12 ]

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 Myelodysplastic Syndrome and Leukemia

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) has been reported after treatment of Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), and sarcomas, with the cumulative incidence approaching 2% at 15 years after therapy.[ 13 ][ 14 ][ 15 ][ 16 ][ 17 ]

Characteristics of t-MDS/AML include the following:[ 13 ][ 18 ][ 19 ]

t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types of t-MDS/AML are recognized by the World Health Organization classification:[ 20 ]

Therapy-Related Solid Neoplasms

Therapy-related solid SNs represent 80% of all SNs and demonstrate a strong relationship with radiation exposure and are characterized by a latency that exceeds 10 years. The risk of solid SNs continues to increase with longer follow-up. The risk of solid SNs is highest when the following occur:[ 2 ][ 17 ]

The histological subtypes of solid SNs encompass a neoplastic spectrum ranging from benign and low-grade malignant lesions (e.g., NMSC, meningiomas) to high-grade malignancies (e.g., breast cancers, glioblastomas).[ 2 ][ 15 ][ 23 ][ 24 ][ 25 ][ 26 ][ 27 ]

Solid SNs in childhood cancer survivors most commonly involve the following: [ 2 ][ 13 ][ 15 ][ 17 ][ 24 ][ 28 ][ 29 ]

With more prolonged follow-up of adult survivors of childhood cancer cohorts, epithelial neoplasms have been observed in the following:[ 2 ][ 13 ][ 23 ][ 30 ]

Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors who were treated with radiation therapy for childhood cancer.[ 2 ][ 24 ][ 25 ]

In addition to radiation exposure, exposure to certain anticancer agents may result in solid SNs. In recipients of an HCT conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), the cumulative incidence of new solid cancers appears to be similar regardless of exposure to radiation. In a registry-based, retrospective, cohort study, Bu-Cy conditioning without TBI was associated with higher risks of solid SNs than in the general population. Chronic graft-versus-host disease increased the risk of SNs, especially those involving the oral cavity.[ 31 ]

Some well-established solid SNs are described in the following sections.[ 32 ]

Breast cancer

Breast cancer is the most common therapy-related solid SN after HL, largely due to the high dose of chest radiation used to treat HL (SIR of subsequent breast cancer, 25–55).[ 13 ][ 33 ] The following has been observed in female survivors of childhood HL:

Radiation-induced breast cancer has been reported in one population-based study to have more adverse clinicopathological features, as evidenced by a twofold increased risk of estrogen receptor–negative, progesterone receptor–negative breast cancer observed among 15-year HL survivors, compared with women who had sporadic breast cancer.[ 38 ] Several studies that have investigated the clinical characteristics of subsequent breast cancers arising in women treated with radiation for childhood cancer have observed a higher proportion of more histologically aggressive subtypes (e.g., triple-negative breast cancer) than age-matched sporadic invasive cancers.[ 39 ][ 40 ] These findings are in contrast to other smaller hospital-based, case-control studies of breast cancer among HL survivors that have not identified a significant variation in hormone receptor status when compared with primary breast cancer controls. Previous studies have also not demonstrated significant difference in overall risk of high-grade versus low-grade tumors.[ 41 ][ 42 ][ 43 ]

Treatment of childhood HL with higher cumulative doses of alkylating agents and ovarian radiation of 5 Gy or higher (exposures predisposing to premature menopause) have been correlated with reductions in breast cancer risk, underscoring the potential contribution of hormonal stimulation on breast carcinogenesis.[ 36 ][ 44 ][ 45 ]

Most data describing the risk of radiation-associated breast cancer are based on patients treated for HL, with doses ranging from 15 Gy to 50 Gy. However, the risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer metastatic to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue:

1. In 116 children in the CCSS cohort treated with 2 Gy to 20 Gy to the lungs (median, 14 Gy), the SIR for breast cancer was 43.6 (95% CI, 27.1–70.1).[ 46 ]
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.[ 47 ]

Although currently available evidence is insufficient to demonstrate a survival benefit from the initiation of breast cancer surveillance in women treated with radiation therapy to the chest for childhood cancer, interventions to promote detection of small and early-stage tumors may improve prognosis, particularly for those who may have more limited treatment options because of previous exposure to radiation or anthracyclines.

1. Childhood sarcoma or leukemia survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.[ 48 ]
2. Dutch investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[ 9 ]
3. The St. Jude Lifetime Cohort Study assessed 1,467 women cancer survivors for the risk of developing subsequent breast cancer and evaluated whether surveillance imaging affects breast cancer outcomes.[ 49 ]

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, 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 as a result of other health-related causes, including other subsequent malignant neoplasms 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).[ 50 ]

Thyroid cancer

Thyroid cancer is observed after the following:[ 2 ][ 13 ][ 51 ]

The risk of thyroid cancer among survivors of Hodgkin disease has been reported to be 18-fold that of the general population.[ 52 ] Significant modifiers of the radiation-related risk of thyroid cancer include the following:[ 53 ][ 54 ]

(Refer to the Thyroid nodules section of this summary for information on detecting thyroid nodules and thyroid cancer.)

CNS tumors

Brain tumors develop after cranial irradiation for histologically distinct brain tumors [ 24 ] or for management of disease among ALL or non-Hodgkin lymphoma patients.[ 14 ][ 56 ] SIRs reported for subsequent CNS neoplasms after treatment for childhood cancer range from 8.1 to 52.3 across studies.[ 57 ]

The risk of subsequent brain tumors demonstrates a linear relationship with radiation dose.[ 2 ][ 24 ]

Despite the well-established increased risk of subsequent CNS neoplasms among childhood cancer survivors treated with cranial irradiation, the current literature is insufficient to evaluate the potential harms and benefits of routine screening for these lesions.[ 57 ]

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.[ 62 ][ 63 ][ 64 ][ 65 ][ 66 ]

A population-based study of 69,460 5-year survivors of cancer diagnosed before age 20 years observed the following:

Radiation therapy is associated with a linear dose-response relationship.[ 62 ][ 67 ] After adjustment for radiation therapy, treatment with alkylating agents has also been linked to bone cancer, with the risk increasing with cumulative drug exposure.[ 62 ] These data from earlier studies concur with the following data observed by the CCSS and other investigators:

1. In a CCSS cohort, an increased risk of subsequent bone or soft tissue sarcoma was associated with radiation therapy, a primary diagnosis of sarcoma, a history of other SNs, and treatment with higher doses of anthracyclines or alkylating agents.[ 68 ] 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.[ 68 ]
2. Dose-risk modeling was used to study the risk of bone sarcoma in a retrospective cohort of 4,171 survivors of a childhood solid cancer treated between 1942 and 1986 (median follow-up, 26 years).[ 67 ]
3. Dutch investigators studied the risk of sarcoma in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[ 9 ]
4. In survivors of bilateral retinoblastoma, the most common SNs seen are sarcomas, specifically osteosarcoma.[ 69 ][ 70 ][ 71 ][ 72 ] 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.[ 63 ]
5. In a cohort of 952 irradiated survivors of hereditary retinoblastoma diagnosed between 1914 and 2006, CCSS investigators observed that elevated risks of bone and soft tissue sarcomas differed by age, location, and sex.[ 73 ]
6. In a retrospective study of 160 irradiated hereditary retinoblastoma patients, no correlation was identified between age (before or after 12 months) at which external-beam radiation therapy was given and development of subsequent malignancy. Patients with and without subsequent malignancies did not differ by RB1 mutation type. Also, there was no association with mutation type and location of SMN, or SMN type and age at diagnosis. The study showed that patients who have a low penetrance mutation and receive external-beam radiation therapy remain at risk of SMNs and should be cautiously monitored.[ 66 ]

Soft tissue sarcomas can be of various histologic subtypes, including nonrhabdomyosarcoma soft tissue sarcomas, rhabdomyosarcoma, malignant peripheral nerve sheath tumors, Ewing/primitive neuroectodermal tumors, and other rare types. The CCSS reported the following on 105 cases and 422 matched controls in a nested case-control study of 14,372 childhood cancer survivors:[ 74 ]

Skin cancer

Nonmelanoma skin cancers (NMSCs) represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation therapy.[ 75 ] The CCSS has observed the following:

In 5,843 childhood cancer survivors in the Dutch Childhood Oncology Group (DCOG)-LATER cohort, investigators found that childhood cancer survivors had a 30-fold increased risk of developing BCCs. After a first BCC diagnosis, 46.7% of patients had more BCCs later. This risk was associated with any radiation therapy to the original radiation field (HR,14.32) and with estimated percentage of in-field skin surface area (26%–75%: HR, 1.99; 76%–100%: HR, 2.16 vs. 1%–25% exposed; 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).[ 77 ]

The occurrence of an NMSC as the first SN has been reported to identify a population at high risk of a future invasive malignant SN.[ 4 ] CCSS investigators observed a cumulative incidence of a malignant neoplasm of 20.3% (95% CI, 13.0%–27.6%) at 15 years among radiation-exposed survivors who developed NMSC as a first SN compared with 10.7% (95% CI, 7.2%–14.2%) whose first SN was an invasive malignancy.

Malignant melanoma has also been reported as an SN in childhood cancer survivor cohorts, although at a much lower incidence than NMSCs. A systematic review including data from 19 original studies (total N = 151,575 survivors; median follow-up of 13 years) observed an incidence of 10.8 cases of malignant melanoma per 100,000 childhood cancer survivors per year.[ 78 ]

Risk factors for malignant melanoma identified among these studies include the following:[ 78 ]

Melanomas most frequently developed in survivors of HL, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors, but the relatively small number of survivors represented in the relevant studies preclude assessment of melanoma risk among other types of childhood cancer.[ 78 ]

CCSS investigators observed an approximate 2.5-fold increased risk (SIR, 2.42; 95% CI, 1.77–3.23) of melanoma among members of their cohort (median time to development, 21.0 years). The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% (95% CI, 0.37%–0.73%), and absolute excess risk was 0.10 per 1,000 person-years (95% CI, 0.05–0.15). Family history of cancer, demographic, or treatment-related factors did not predict risk of melanoma.[ 79 ]

Lung cancer

Lung cancer: Among childhood cancer survivor cohorts, lung cancer represents a relatively uncommon SN; the 30-year cumulative incidence of lung cancer among CCSS participants was 0.1% (95% CI, 0.0%–0.2%).[ 2 ] The following has been observed in adult survivors of childhood HL:[ 80 ]

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.[ 13 ][ 81 ][ 82 ][ 83 ][ 84 ]

The following has been observed in adult survivors of childhood cancer:

1. The Late Effects Study Group reported a 63.9-fold increased risk of gastric cancers and 36.4-fold increased risk of colorectal cancers in adult survivors of childhood HL. In addition to previous radiation therapy, younger age (0–5 years) at the time of the primary cancer therapy significantly increased risk.[ 13 ]
2. In a French and British cohort-nested, case-control study of childhood solid cancer survivors diagnosed before age 17 years, the risk of developing an SN in the digestive organs varied with therapy. The following was also observed:[ 81 ]
3. CCSS investigators reported a 4.6-fold higher risk of GI SNs among their study participants than in the general population (95% CI, 3.4–6.1). They also reported the following:[ 82 ]
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:[ 83 ]
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.[ 85 ]
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.[ 86 ]
7. In a large series from two institutions, 2,053 patients with retinoblastoma (diagnosed between 1914 and 2016) were identified.[ 87 ]

Collectively, these studies support the need for initiation of colorectal carcinoma surveillance at a young age among survivors receiving high-risk exposures.[ 13 ][ 81 ][ 82 ][ 83 ][ 88 ]

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.[ 30 ][ 89 ][ 90 ]

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.[ 89 ] 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:

Underlying genetic predisposition may also play a role because rare cases of renal carcinoma have been observed in children with tuberous sclerosis.[ 89 ]

Survival Outcomes after SNs

Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, individuals younger than 60 years with first primary malignancies (n = 1,332,203) were compared with childhood cancer survivors (n = 1,409) who had a second primary malignancy. Survivors of childhood cancer diagnosed with a second primary malignancy experienced poorer overall survival than did their peers without a history of cancer (HR, 1.86; 95% Cl, 1.72–2.02) after the study had accounted for cancer type, age, sex, race, and decade of diagnosis. A history of childhood cancer was consistently associated with a twofold to threefold increased risk of death for the most commonly diagnosed second primary malignancies, including breast cancer, thyroid cancer, acute myelogenous leukemia, brain cancer, melanoma, bone cancer, and soft tissue sarcoma.[ 94 ]

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, 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 as a result of 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).[ 50 ]

Subsequent Neoplasms and Genetic Susceptibility

Literature clearly supports the role of chemotherapy and radiation therapy in the development of SNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome.[ 95 ][ 96 ] Previous studies have demonstrated that childhood cancer survivors with a family history of Li-Fraumeni syndrome in particular, or a family history of cancer, carry an increased risk of developing an SN.[ 97 ][ 98 ]

The risk of SNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome).[ 98 ] However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes.

Likewise, children with neurofibromatosis type 1 (NF1) who develop a primary tumor are at an increased risk of SNs compared with childhood cancer survivors without NF1. Treatment with radiation, but not alkylating agents, increases the risk of SNs in survivors with NF1.[ 99 ]

Table 1 summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.

Table 1. Selected Syndromes of Inherited Cancer Predisposition^a

Syndrome	Major Tumor Types	Affected Gene	Mode of Inheritance
AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation.
aAdapted from Strahm et al.[ 100 ]
bDominant in a fraction of patients, spontaneous mutations can occur.
Adenomatous polyposis of the colon	Colon, hepatoblastoma, intestinal cancers, stomach, thyroid cancer	APC	Dominant
Ataxia-telangiectasia	Leukemia, lymphoma	ATM	Recessive
Beckwith-Wiedemann syndrome	Adrenal carcinoma, hepatoblastoma, rhabdomyosarcoma, Wilms tumor	CDKN1C/NSD1	Dominant
Bloom syndrome	Leukemia, lymphoma, skin cancer	BLM	Recessive
Diamond-Blackfan anemia	Colon cancer, osteogenic sarcoma, AML/MDS	RPS19 and other RP genes	Dominant, spontaneousb
Fanconi anemia	Gynecological tumors, leukemia, squamous cell carcinoma	FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG	Recessive
Juvenile polyposis syndrome	Gastrointestinal tumors	SMAD4/DPC4	Dominant
Li-Fraumeni syndrome	Adrenocortical carcinoma, brain tumor, breast carcinoma, leukemia, osteosarcoma, soft tissue sarcoma	TP53	Dominant
Multiple endocrine neoplasia 1	Pancreatic islet cell tumor, parathyroid adenoma, pituitary adenoma	MEN1	Dominant
Multiple endocrine neoplasia 2	Medullary thyroid carcinoma, pheochromocytoma	RET	Dominant
Neurofibromatosis type 1	Neurofibroma, optic pathway glioma, peripheral nerve sheath tumor	NF1	Dominant
Neurofibromatosis type 2	Vestibular schwannoma	NF2	Dominant
Nevoid basal cell carcinoma syndrome	Basal cell carcinoma, medulloblastoma	PTCH	Dominant
Peutz-Jeghers syndrome	Intestinal cancers, ovarian carcinoma, pancreatic carcinoma	STK11	Dominant
Retinoblastoma	Osteosarcoma, retinoblastoma	RB1	Dominant
Tuberous sclerosis	Hamartoma, renal angiomyolipoma, renal cell carcinoma	TSC1/TSC2	Dominant
von Hippel-Lindau syndrome	Hemangioblastoma, pheochromocytoma, renal cell carcinoma, retinal and central nervous system tumors	VHL	Dominant
WAGR syndrome	Gonadoblastoma, Wilms tumor	WT1	Dominant
Wilms tumor syndrome	Wilms tumor	WT1	Dominant
Xeroderma pigmentosum	Leukemia, melanoma	XPA, XPB, XPC, XPD, XPE, XPF, XPG, POLH	Recessive

Drug-metabolizing enzymes and DNA repair polymorphisms

The interindividual variability in risk of SNs is more likely related to common polymorphisms in low-penetrance genes that regulate the availability of active drug metabolites or are responsible for DNA repair. Gene-environment interactions may magnify subtle functional differences resulting from genetic variations.

Drug-metabolizing enzymes

Metabolism of genotoxic agents occurs in two phases.

1. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes.
2. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST) enzymes, NAD(P)H:quinone oxidoreductase-1 (NQO1) enzyme, and others.

The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.

DNA repair polymorphisms

DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and oncogenes that can lead to cancer initiation and progression. An individual’s DNA repair capacity appears to be genetically determined.[ 101 ] A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity.[ 101 ] Evaluation of the contribution of polymorphisms influencing DNA repair to the risk of SN represents an active area of research.

Screening and Follow-up for Subsequent Neoplasms

Vigilant screening is important for childhood cancer survivors at risk.[ 102 ] Because of the relatively small size of the pediatric cancer survivor population and the prevalence and time to onset of therapy-related complications, undertaking clinical studies to assess the impact of screening recommendations on the morbidity and mortality associated with the late effect is not feasible.

Well-conducted studies on large populations of childhood cancer survivors have provided compelling evidence linking specific therapeutic exposures and late effects. This evidence has been used by several national and international cooperative groups (Scottish Collegiate Guidelines Network, Children’s Cancer and Leukaemia Group, Children's Oncology Group [COG], DCOG) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors.[ 103 ]

All pediatric cancer survivor health screening guidelines employ a hybrid approach that is both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with the intensity of the screening recommendations). The screening recommendations in these guidelines represent a statement of consensus from a panel of experts in the late effects of pediatric cancer treatment.[ 102 ][ 103 ]

The COG Guidelines for malignant SNs indicate that certain high-risk populations of childhood cancer survivors merit heightened surveillance because of predisposing host, behavioral, or therapeutic factors.[ 102 ]

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53. 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]
54. 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]
55. 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]
56. Neglia JP, Friedman DL, Yasui Y, et al.: Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 93 (8): 618-29, 2001.[PUBMED Abstract]
57. Bowers DC, Nathan PC, Constine L, et al.: Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol 14 (8): e321-8, 2013.[PUBMED Abstract]
58. 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]
59. 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]
60. 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]
61. 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]
62. Hawkins MM, Wilson LM, Burton HS, et al.: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88 (5): 270-8, 1996.[PUBMED Abstract]
63. 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]
64. 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]
65. 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]
66. 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]
67. 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]
68. 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]
69. Shinohara ET, DeWees T, Perkins SM: Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 61 (1): 116-9, 2014.[PUBMED Abstract]
70. 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]
71. Yu CL, Tucker MA, Abramson DH, et al.: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst 101 (8): 581-91, 2009.[PUBMED Abstract]
72. 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]
73. 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]
74. 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]
75. Daniëls LA, Krol AD, Schaapveld M, et al.: Long-term risk of secondary skin cancers after radiation therapy for Hodgkin's lymphoma. Radiother Oncol 109 (1): 140-5, 2013.[PUBMED Abstract]
76. 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]
77. 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]
78. 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]
79. 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]
80. 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]
81. 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]
82. 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]
83. Nottage K, McFarlane J, Krasin MJ, et al.: Secondary colorectal carcinoma after childhood cancer. J Clin Oncol 30 (20): 2552-8, 2012.[PUBMED Abstract]
84. Allodji RS, Haddy N, Vu-Bezin G, et al.: Risk of subsequent colorectal cancers after a solid tumor in childhood: Effects of radiation therapy and chemotherapy. Pediatr Blood Cancer 66 (2): e27495, 2019.[PUBMED Abstract]
85. 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]
86. 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]
87. Kleinerman RA, Tucker MA, Sigel BS, et al.: Patterns of Cause-Specific Mortality Among 2053 Survivors of Retinoblastoma, 1914-2016. J Natl Cancer Inst 111 (9): 961-969, 2019.[PUBMED Abstract]
88. Rigter LS, Spaander MCW, Aleman BMP, et al.: High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors. Cancer 125 (6): 990-999, 2019.[PUBMED Abstract]
89. 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]
90. 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]
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92. 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]
93. 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]
94. 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]
95. 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]
96. 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]
97. 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]
98. 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]
99. 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]
100. Strahm B, Malkin D: Hereditary cancer predisposition in children: genetic basis and clinical implications. Int J Cancer 119 (9): 2001-6, 2006.[PUBMED Abstract]
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Late Effects of the Cardiovascular System

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 ][ 2 ][ 3 ]

Evidence (excess risk of premature cardiovascular mortality):

1. Among more than 20,000 North American 5-year survivors of childhood cancer (in the Childhood Cancer Survivor Study [CCSS]) treated from 1970 to 1986, participants had a standardized mortality ratio of 7.0 (95% confidence interval [CI], 5.9–8.2) for cardiac mortality, which translated to 0.36 excess deaths per 1,000 person-years.[ 4 ] Late cardiac mortality in children who were treated more recently (i.e., in the 1990s) appears to have decreased (e.g., the cumulative incidence was 0.5% in 1970–1974 vs. 0.1% in 1990–1994).[ 1 ]
2. Cardiac disease becomes increasingly important as childhood cancer survivors reach mature adulthood, as observed in the population-based British Childhood Cancer Survivor Study, comprised of 34,489 5-year survivors of childhood cancer diagnosed from 1940 to 2006.[ 2 ][ 5 ]

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

The section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes in relation to these late effects, but not directly review in detail 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, issued by the American Heart Association, has been published.[ 6 ]

Sources of Evidence for Cardiovascular Outcomes

Evidence (selected cohort studies describing cardiovascular outcomes):

1. CCSS investigators reported on major cardiac events among participants diagnosed with childhood cancer between 1970 and 1999.[ 17 ]
2. In the CCSS, data from 24,214 5-year survivors diagnosed between 1970 and 1999 were used to assess the impacts of radiation therapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on the risk of late-onset cardiac disease (refer to Figure 4).[ 18 ]

   

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3. A multicenter French cohort of 3,162 5-year survivors treated between 1942 and 1986 were monitored for a median of 26 years.[ 9 ]
4. A Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors (median attained age, 29.1 years) were monitored from diagnosis for a median of 22.2 years.[ 19 ]
5. The CCSS demonstrated that the cumulative incidence of serious cardiac events (myocardial infarction, congestive heart failure, pericardial disease, and valvular abnormalities) in childhood cancer survivors continues to increase beyond age 45 years.[ 7 ]
6. Of 670 survivors of Hodgkin lymphoma who were treated at St. Jude Children’s Research Hospital (SJCRH) and have lived 10 or more years, 348 patients were clinically assessed in the St. Jude Lifetime Cohort Study.[ 20 ]
7. Another St. Jude Lifetime Cohort Study compared the prevalence of major and minor electrocardiography (ECG) abnormalities among 2,715 participants and 268 community controls.[ 21 ]
8. In the Teenage and Young Adult Cancer Survivor Study, cardiac mortality was investigated in more than 200,000 5-year survivors of adolescent and young adult cancer (aged 15–39 years).[ 3 ]

Treatment Risk Factors

Chemotherapy (in particular, anthracyclines and anthraquinones) along with radiation therapy both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer and are considered to be the most important risk factors contributing to premature cardiovascular disease in this population (refer to Figure 5).[ 19 ]

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Anthracyclines and related agents

Anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and anthraquinones (e.g., mitoxantrone) are known to directly injure cardiomyocytes through inhibition of topoisomerase 2-beta in cardiomyocytes and formation of reactive oxygen species, resulting in activation of cell-death pathways and inhibition of mitochondrial apoptosis.[ 22 ][ 23 ] The downstream results of cell death are changes in heart structure, including wall thinning, which leads to ventricular overload and pathologic remodeling that, over time, leads to dysfunction and eventual clinical heart failure.[ 24 ][ 25 ]

Risk factors for anthracycline-related cardiomyopathy include the following:[ 18 ][ 26 ]

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Anthracycline dose equivalency

Traditionally, anthracycline dose equivalence has largely been based on acute hematologic toxicity equivalence rather than late cardiac toxicity.[ 29 ]

1. Most pediatric professional societies and groups have generally considered daunorubicin equivalent, or nearly equivalent, to doxorubicin, although historically lower ratios have been proposed as well.[ 30 ][ 31 ]
2. Analyses that pooled more than 28,000 long-term childhood cancer survivors monitored through age 40 years (resulting in 399 cardiomyopathy cases) have challenged those previous assumptions.[ 31 ][ 32 ]

Anthracycline cardioprotection

Cardioprotective strategies that have been explored include the following:

1. New, less cardiotoxic agents and liposomal formulations. In general, data on whether liposomal formulations of anthracyclines reduce cardiac toxicity in children are limited.[ 33 ][ 34 ]
2. Prolonged infusion time. Prolonged infusion time has been associated with reduced heart failure in adult patients, but not in children.[ 35 ][ 36 ]
3. Concurrent administration of cardioprotectants. A variety of agents have been tested as cardioprotectants (amifostine, acetylcysteine, calcium channel blockers, carvedilol, coenzyme Q10, and L-carnitine), but none have been definitively shown to be beneficial and are not considered standard of care.[ 37 ][ 38 ]
4. Dexrazoxane. There are more data for dexrazoxane as a cardioprotectant, but mainly in adult cancer patients, for whom it is approved by the U.S. Food and Drug Administration for women with metastatic breast cancer who have received 300 mg/m² of anthracyclines and who may benefit from further anthracycline-based therapy.[ 37 ]

Radiation therapy

While anthracyclines directly damage cardiomyocytes, radiation therapy primarily affects the fine vasculature of affected organs.[ 6 ]

Cardiovascular disease

Late effects of radiation therapy to the heart specifically include the following:

These cardiac late effects are related to the following:

Patients who were exposed to both radiation therapy affecting the cardiovascular system and cardiotoxic chemotherapy agents are at even greater risk of late cardiovascular outcomes.[ 9 ][ 18 ]

Cerebrovascular disease

Cerebrovascular disease after radiation therapy exposure is another potential late effect observed in survivors.

Evidence (selected studies describing prevalence of and risk factors for cerebrovascular accident [CVA]/vascular disease):

1. In a multicenter retrospective Dutch study, among 2,201 5-year survivors of Hodgkin lymphoma diagnosed before age 51 years (25% pediatric-aged patients), with a median follow-up of 18 years, 96 patients developed cerebrovascular disease (CVA and transient ischemic attacks [TIA]).[ 49 ]
2. French investigators observed a significant association between radiation dose to the brain and long-term cerebrovascular mortality among 4,227 5-year childhood cancer survivors (median follow-up, 29 years).[ 50 ]
3. A retrospective, single-center, cohort study of 325 survivors of pediatric cancer treated with cranial irradiation or cervical irradiation determined that cranial irradiation put survivors at a high risk of first and recurrent strokes.[ 52 ]
4. CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[ 53 ]
5. A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was constituted from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[ 55 ]
6. Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[ 56 ]

Venous thromboembolism

Children with cancer have an excess risk of venous thromboembolism within the first 5 years after diagnosis; however, the long-term risk of venous thromboembolism among childhood cancer survivors has not been well studied.[ 57 ]

CCSS investigators evaluated self-reported late-onset (5 or more years after cancer diagnosis) venous thromboembolism among cohort members (median follow-up, 21.3 years).[ 58 ]

Conventional cardiovascular conditions

Other Risk Factors

Sex. Some, but not all, studies suggest that female sex may be associated with a greater risk of anthracycline-related cardiomyopathy.[ 6 ]

Genetics. There is emerging evidence that genetic factors, such as single nucleotide polymorphisms in genes regulating drug metabolism and distribution, could explain the heterogeneity in susceptibility to anthracycline-mediated cardiac injury.[ 62 ][ 63 ][ 64 ][ 65 ][ 66 ][ 67 ] However, these genetic findings still require additional validation before integration into any clinical screening algorithm.[ 68 ]

Peripartum Cardiac Dysfunction

Long-term survivors of childhood, adolescent, and young adult malignancies with past exposure to potentially cardiotoxic treatments are at risk of peripartum cardiac dysfunction.

In the general population, peripartum cardiomyopathy (PPCM) is a rare condition characterized by heart failure during pregnancy (usually the last trimester or <5 months postpartum). The estimated incidence in the general population is 1:3,000 live births.[ 69 ]

There are limited data available about the prevalence in survivors of pediatric, adolescent, and young adult malignancies who have received cardiotoxic therapies. Peripartum cardiac assessment is recommended for at-risk patients.

Heart Transplant After Childhood Cancer

Data about the prevalence and outcomes of survivors with heart failure requiring heart transplantation is limited.

Knowledge Deficits

While much knowledge has been gained over the past 20 years in better understanding the long-term burden and risk factors for cardiovascular disease among childhood cancer survivors, many areas of inquiry remain, and include the following:

Screening, Surveillance, and Counseling

Various national groups, including the National Institutes of Health–sponsored Children's Oncology Group (COG) (refer to Table 2), have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors.[ 75 ][ 76 ][ 77 ] (Refer to COG's Long-Term Follow-Up Guidelines for more information.)

Professional groups (both pediatric and adult) have developed evidence-based health surveillance recommendations and have identified knowledge deficits to help guide future studies.[ 26 ][ 78 ]

Adult oncology professional and national groups have also issued recommendations related to cardiac toxicity monitoring.[ 79 ]

Consensus regarding evidence about screening, surveillance, and counseling

Predicting Cardiovascular Disease Risk

Risk prediction for cardiovascular diseases

1. Using data from four large, well-annotated childhood cancer survivor cohorts (CCSS, National Wilms Tumor Study Group, the Netherlands, and SJCRH), a heart failure risk calculator based on readily available demographic and treatment characteristics has been created and validated, which may provide more individualized clinical heart failure risk estimation for 5-year survivors of childhood cancer who have recently completed therapy, through age 40 years. Because of the young age of participants at the time of baseline prediction (5-year survival), this estimator is limited in that information on conventional cardiovascular conditions such as hypertension, dyslipidemia, or diabetes could not be incorporated.[ 27 ]
2. In another collaborative study, data from the CCSS, Netherlands, and SJCRH were used to develop risk-prediction models for ischemic heart disease and stroke among 5-year survivors of childhood cancer through age 50 years. Risk scores derived from a standard prediction model that included sex, chemotherapy exposure, and radiation therapy exposure identified statistically distinct low-risk, moderate-risk, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were less than 5%, compared with approximately 20% for high-risk groups and only 1% for siblings.[ 91 ]
3. Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-aged survivors of childhood cancer, as demonstrated by a CCSS investigation that constructed prediction models accounting for cardiotoxic cancer treatment exposures, combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes. Risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes information showed good performance (area under the receiver operating characteristic curve and concordance statistics ≥0.70) for predicting cardiovascular events in the models applied to the discovery and replication cohorts. The most influential exposures were anthracycline chemotherapy, radiation therapy, diabetes, and hypertension.[ 89 ]

Table 2. Cardiovascular Late Effects^a,b

Predisposing Therapy	Potential Cardiovascular Effects	Health Screening
aThe Children's Oncology Group (COG) guidelines also cover other conditions that may influence cardiovascular risk, such as obesity and diabetes mellitus/impaired glucose metabolism.
bAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Any anthracycline and/or any radiation to the heart	Cardiac toxicity (arrhythmia, cardiomyopathy/heart failure, pericardial disease, valve disease, ischemic heart disease)	Yearly medical history and physical exam
		Electrocardiogram at entry into long-term follow-up
		Echocardiogram at entry into long-term follow-up, periodically repeat based on previous exposures and other risk factors
Radiation to the neck and base of skull (especially ≥40 Gy)	Carotid and/or subclavian artery disease	Yearly medical history and physical exam; consider Doppler ultrasound 10 years after exposure
Radiation to the brain/cranium (especially ≥18 Gy)	Cerebrovascular disease (cavernomas, moyamoya, occlusive cerebral vasculopathy, stroke)	Yearly medical history and physical exam
Radiation to the abdomen	Diabetes	Diabetes screen every 2 years
Total-body irradiation (usually <14 Gy)	Dyslipidemia; diabetes	Fasting lipid profile and diabetes screen every 2 years
Heavy metals (carboplatin, cisplatin), and ifosfamide exposure; radiation to the kidneys; hematopoietic cell transplantation; nephrectomy	Hypertension (as a consequence of renal toxicity)	Yearly blood pressure; renal function laboratory studies at entry into long-term follow-up and repeat as clinically indicated

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4. 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]
5. 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]
6. Lipshultz SE, Adams MJ, Colan SD, et al.: Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 128 (17): 1927-95, 2013.[PUBMED Abstract]
7. 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]
8. 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]
9. 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]
10. van Dalen EC, van der Pal HJ, Kok WE, et al.: Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42 (18): 3191-8, 2006.[PUBMED Abstract]
11. Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001.[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. Kero AE, Järvelä LS, Arola M, et al.: Cardiovascular morbidity in long-term survivors of early-onset cancer: a population-based study. Int J Cancer 134 (3): 664-73, 2014.[PUBMED Abstract]
14. 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]
15. 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]
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. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. 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]
24. 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]
25. 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]
26. Armenian SH, Hudson MM, Mulder RL, et al.: Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 16 (3): e123-36, 2015.[PUBMED Abstract]
27. 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]
28. 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]
29. Le Deley MC, Leblanc T, Shamsaldin A, et al.: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique. J Clin Oncol 21 (6): 1074-81, 2003.[PUBMED Abstract]
30. Keefe DL: Anthracycline-induced cardiomyopathy. Semin Oncol 28 (4 Suppl 12): 2-7, 2001.[PUBMED Abstract]
31. 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]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. 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]
42. 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]
43. 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]
44. Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25 (5): 493-500, 2007.[PUBMED Abstract]
45. Seif AE, Walker DM, Li Y, et al.: Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. Pediatr Blood Cancer 62 (4): 704-9, 2015.[PUBMED Abstract]
46. Chow EJ, Asselin BL, Schwartz CL, et al.: Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group. J Clin Oncol 33 (24): 2639-45, 2015.[PUBMED Abstract]
47. Murphy ES, Xie H, Merchant TE, et al.: Review of cranial radiotherapy-induced vasculopathy. J Neurooncol 122 (3): 421-9, 2015.[PUBMED Abstract]
48. 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]
49. 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]
50. Haddy N, Mousannif A, Tukenova M, et al.: Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. Brain 134 (Pt 5): 1362-72, 2011.[PUBMED Abstract]
51. 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]
52. 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]
53. Fullerton HJ, Stratton K, Mueller S, et al.: Recurrent stroke in childhood cancer survivors. Neurology 85 (12): 1056-64, 2015.[PUBMED Abstract]
54. 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]
55. 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]
56. 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]
57. 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]
58. 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]
59. 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]
60. 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]
61. 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]
62. 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]
63. 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]
64. 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]
65. 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]
66. 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]
67. 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]
68. Davies SM: Getting to the heart of the matter. J Clin Oncol 30 (13): 1399-400, 2012.[PUBMED Abstract]
69. Lewey J, Haythe J: Cardiomyopathy in pregnancy. Semin Perinatol 38 (5): 309-17, 2014.[PUBMED Abstract]
70. 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]
71. 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]
72. 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]
73. 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]
74. 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]
75. 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]
76. Skinner R, Wallace WH, Levitt GA, et al.: Long-term follow-up of people who have survived cancer during childhood. Lancet Oncol 7 (6): 489-98, 2006.[PUBMED Abstract]
77. Sieswerda E, Postma A, van Dalen EC, et al.: The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol 23 (8): 2191-8, 2012.[PUBMED Abstract]
78. Armenian SH, Lacchetti C, Barac A, et al.: Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 35 (8): 893-911, 2017.[PUBMED Abstract]
79. Lenihan DJ, Oliva S, Chow EJ, et al.: Cardiac toxicity in cancer survivors. Cancer 119 (Suppl 11): 2131-42, 2013.[PUBMED Abstract]
80. 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]
81. 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]
82. 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]
83. 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]
84. 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]
85. 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]
86. 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]
87. 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]
88. Lipshultz SE, Landy DC, Lopez-Mitnik G, et al.: Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy. J Clin Oncol 30 (10): 1050-7, 2012.[PUBMED Abstract]
89. 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]
90. 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]
91. 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]

Late Effects of the Central Nervous System

Neurocognitive

Neurocognitive late effects are most commonly observed after treatment of malignancies that require central nervous system (CNS)–directed therapies. While considerable evidence has been published about this outcome, its quality is often limited by small sample size, cohort selection and participation bias, cross-sectional versus longitudinal evaluations, and variable time of assessment from treatment exposures. CNS-directed therapies include the following:

Children with brain tumors or acute lymphoblastic leukemia (ALL) are most likely to be affected. Risk factors for the development of neurocognitive late effects include the following:[ 1 ][ 2 ][ 3 ][ 4 ][ 5 ][ 6 ][ 7 ]

The cognitive phenotypes observed in childhood survivors of ALL and CNS tumors may differ from traditional developmental disorders. For example, the phenotype of attention problems in ALL and brain tumor survivors appears to differ from developmental attention-deficit/hyperactivity disorder in that few survivors demonstrate significant hyperactivity/impulsivity, but instead have associated difficulties with processing speed and executive function.[ 8 ][ 9 ]

In addition to the direct effects of neurotoxic therapies like cranial radiation, Childhood Cancer Survivor Study (CCSS) investigators observed that chronic health conditions resulting from non-neurotoxic treatment exposures (e.g., thoracic radiation) can adversely impact neurocognitive function.[ 10 ] They hypothesized that chronic cardiopulmonary and endocrine dysfunction that develops after therapy mediates and may exacerbate the impact of neurotoxic exposures on neurocognitive function, underscoring the importance of promoting interventions to support healthy brain aging in long-term survivors.

Neurocognitive outcomes in brain tumor survivors

Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects caused by illness and associated treatments are a well-established morbidity in this group of survivors. In childhood and adolescent brain tumor survivors, risk factors for adverse neurocognitive effects include the following:

The negative impact of radiation treatment has been characterized by changes in IQ scores, which have been noted to drop about 2 to 5 years after diagnosis; the decline continues 5 to 10 years afterward, although less is known about potential stabilization or further decline of IQ scores several decades after diagnosis.[ 21 ][ 22 ][ 23 ] The decline in IQ scores over time typically reflects the child’s failure to acquire new abilities or information at a rate similar to that of his or her peers, rather than a progressive loss of skills and knowledge.[ 12 ] Affected children also may experience deficits in other cognitive areas, including academic difficulties (reading and math) and problems with attention, processing speed, memory, and visual or perceptual motor skills.[ 22 ][ 24 ][ 25 ]

These changes in cognitive functioning may be partially explained by radiation-induced reduction of normal-appearing white matter volume or integrity of white matter pathways, as evaluated through magnetic resonance imaging (MRI).[ 26 ][ 27 ][ 28 ] In fact, reduced white matter integrity has been directly linked to slowed cognitive processing speed in survivors of brain tumors,[ 29 ] while greater white matter volume has been associated with better working memory, particularly in females.[ 28 ] It should be noted that data emerging from contemporary protocols show that using lower doses of cranial radiation and more targeted treatment volumes appears to reduce the severity of neurocognitive effects of therapy.[ 14 ][ 16 ][ 30 ]

Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors.

Evidence (predictors of cognitive decline among survivors of CNS tumors):

1. St. Jude Children’s Research Hospital (SJCRH) studied 78 children younger than 20 years (mean, 9.7 years) diagnosed with low-grade glioma.[ 31 ]
2. In a study of 51 children with low-grade gliomas and low-grade glioneural tumors diagnosed within the first year of life, the mean IQ score was 75.5; 75% of the children had IQ scores lower than 85. Predictors of low IQ included a supratentorial location of the primary tumor and treatment with more chemotherapy regimens, but not radiation use. The child’s ability to complete age-appropriate tasks was as affected as IQ scores.[ 32 ]
3. A study of 126 medulloblastoma survivors treated with 23.4 Gy or 36 Gy to 39.6 Gy of craniospinal radiation (with a conformal boost dose of 55.8 Gy to the primary tumor bed) assessed processing speed, attention, and memory performance.[ 33 ]
4. A prospective study compared 36 pediatric medulloblastoma patients who experienced posterior fossa syndrome with 36 medulloblastoma patients who did not experience posterior fossa syndrome but were matched on treatment and age at diagnosis.[ 36 ]
5. Canadian investigators evaluated the impact of radiation (dose and boost volume) and neurologic complications on patterns of intellectual functioning in a cohort of 113 medulloblastoma survivors (mean age at diagnosis, 7.5 years; mean time from diagnosis to last assessment, 6 years).[ 37 ]
6. Studies are beginning to examine cognitive outcomes in histologically distinct subtypes of brain tumors. For example, data from a sample of 121 medulloblastoma patients demonstrated variation in cognitive outcomes by four distinct molecular subgroups and differences in patterns of change over time.[ 38 ] This study highlights the need for future research to consider neurocognitive outcomes across biologically distinct subtypes of childhood brain tumors.

Although adverse neurocognitive outcomes observed 5 to 10 years after treatment are presumed to be pervasive, and potentially worsen over time, few empirical data are available regarding the neurocognitive functioning in very long-term survivors of CNS tumors.

The neurocognitive consequences of CNS disease and treatment may have a considerable impact on functional outcomes for brain tumor survivors.

Cognitive outcomes after proton radiation therapy

Data are emerging regarding cognitive outcomes after proton radiation to the CNS;[ 46 ][ 47 ][ 48 ][ 49 ] however, these studies have been limited by retrospective analysis of cognitive outcomes among relatively small clinically heterogenous pediatric brain tumor cohorts and the use of historically treated photon patients or population standards as comparison groups.

Considering the relatively brief follow-up time from radiation, longitudinal follow-up is important to determine whether proton radiation provides a clinically meaningful benefit in sparing cognitive function compared with photon radiation.

Neurocognitive outcomes in acute lymphoblastic leukemia (ALL) survivors

The increase in cure rates for children with ALL over the past decades has resulted in greater attention to the neurocognitive morbidity and quality of life of survivors. The goal of current ALL treatment is to minimize adverse late effects while maintaining high survival rates. To minimize the risk of late sequelae, patients are stratified for treatment according to their risk of relapse. Cranial irradiation is reserved for the fewer than 20% of children who are considered at high risk for CNS relapse.[ 50 ]

Although low-risk, standard-risk, and most high-risk patients are treated with chemotherapy-only protocols, early reports of neurocognitive late effects for ALL patients were based on heterogeneously treated groups of survivors who received combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation therapy, and high-dose chemotherapy, making it difficult to differentiate the impact of the individual treatment components. However, outcome data are increasingly available regarding the risk of neurocognitive late effects in survivors of childhood ALL treated with chemotherapy only.

ALL and cranial radiation

In survivors of ALL, cranial radiation therapy may result in clinical and radiographic neurologic late sequelae, including the following:

ALL and chemotherapy-only CNS therapy

Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. Systemic methotrexate in high doses with or without radiation therapy can lead to an infrequent but well-described leukoencephalopathy, which has been linked to neurocognitive impairment.[ 51 ] When neurocognitive outcomes after radiation therapy and chemotherapy-only regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone, although some studies show no significant difference.[ 60 ][ 61 ] In a longitudinal analysis of 210 childhood ALL survivors, the development of acute leukoencephalopathy during chemotherapy-only CNS therapy predicted higher risks of developing long-term neurobehavioral problems (e.g., deficits in organization and task initiation [components of executive function]) and reduced white matter integrity in frontal brain regions.[ 62 ]

Compared with cranial irradiation, chemotherapy-only CNS-directed treatment produces neurocognitive deficits involving processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, visual-motor functioning, and executive functioning; global intellectual function is typically preserved.[ 54 ][ 60 ][ 63 ][ 64 ][ 65 ][ 66 ] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[ 64 ] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling, with deficits mainly affecting arithmetic performance.[ 60 ][ 67 ][ 68 ] Risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female sex.[ 66 ][ 69 ][ 70 ]

Reduced cognitive status has been observed in association with reduced integrity in neuroanatomical regions essential in memory formation (e.g., reduced hippocampal volume with increased activation and thinner parietal cortices). However, the long-term impact of these prevalent neurocognitive and neuroimaging abnormalities on functional status in aging adults treated for childhood ALL, particularly those treated with contemporary approaches using chemotherapy alone, remains an active area of research.

Evidence (neurocognitive functioning in large pediatric cancer survivor cohorts):

1. The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[ 71 ]
2. In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[ 72 ]
3. In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[ 74 ]
   1. Low-risk group: Intrathecal methotrexate versus high-dose methotrexate.
   2. High-risk group: High-dose methotrexate versus 24 Gy of cranial radiation therapy.
4. Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[ 53 ][ 56 ][ 59 ] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[ 53 ]

ALL and steroid therapy

The type of steroid used for ALL systemic treatment may affect cognitive functioning. In a study that involved long-term neurocognitive testing (mean follow-up, 9.8 years) of 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment, no meaningful differences in mean neurocognitive and academic performance scores were observed.[ 75 ] In contrast, in a study of 567 adult survivors of childhood leukemia (mean age, 33 years; mean time since diagnosis, 26 years) dexamethasone exposure was associated with increased risk of impairment in attention (RR, 2.12; 95% confidence interval [CI], 1.11–4.03) and executive function (RR, 2.42; 95% CI, 1.20–4.91), independent of methotrexate exposure. Intrathecal hydrocortisone also increased risk of attention problems (RR, 1.24; 95% CI, 1.05–1.46).[ 53 ]

Other cancers

Neurocognitive abnormalities have been reported in other groups of cancer survivors. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors reported impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that reported in the sibling comparison group. Factors such as diagnosis before age 6 years, female sex, cranial radiation therapy, and hearing impediment were associated with impairment.[ 55 ] In addition, emerging data suggest that the development of chronic health conditions in adulthood may contribute to cognitive deficits in long-term survivors of non-CNS cancers.

Neurocognitive abnormalities have been reported for the following cancers:

Stem cell transplantation

Cognitive and academic consequences of stem cell transplantation in children have also been evaluated and include, but are not limited to, the following:

1. In a report from SJCRH in which 268 patients were treated with stem cell transplantation, minimal risk of late cognitive and academic sequelae was observed.[ 84 ]
2. In a series of 38 patients who underwent hematopoietic stem cell transplantation (HSCT) and received intrathecal chemotherapy, significant declines in visual motor skills and memory scores were noted within the first year posttransplant.[ 85 ]

Most neurocognitive late effects after stem cell transplantation are thought to be related to white matter damage in the brain. This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures typically associated with white matter was compared with performance on measures thought to correlate with gray matter function. Composite white matter scores were significantly lower than composite gray matter scores, thereby supporting the belief that white matter damage contributes to neurocognitive late effects in this population.[ 86 ]

Neurologic Sequelae

Risk of neurologic complications may be predisposed by the following:

In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and secondary effects such as seizures and cerebrovascular complications. Numerous reports describe abnormalities of CNS integrity and function, but such studies are typically limited by small sample size, cohort selection and participation bias, cross-sectional ascertainment of outcomes, and variable time of assessment from treatment exposures. In contrast, relatively few studies comprehensively or systematically ascertain outcomes related to peripheral nervous system function.

CNS tumor survivors remain at higher risk of new-onset adverse neurologic events across their lifetimes than siblings. No plateau has been reached for new adverse sequelae, even 30 years from diagnosis, according to a longitudinal study of 1,876 5-year survivors of CNS tumors from the CCSS. The median time from diagnosis was 23 years and the median age of the patients studied was 30.3 years.[ 87 ]

Neurologic complications that may occur in survivors of childhood cancer include the following:

Table 3 summarizes CNS late effects and the related health screenings.

Table 3. Central Nervous System Late Effects^a

Predisposing Therapy	Neurologic Effects	Health Screening
IQ = intelligence quotient; IT = intrathecal; IV = intravenous.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Platinum agents (carboplatin, cisplatin)	Peripheral sensory neuropathy	Neurologic exam
Plant alkaloid agents (vinblastine, vincristine)	Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias)	Neurologic exam
Methotrexate (high dose IV or IT); cytarabine (high dose IV or IT); radiation impacting the brain	Clinical leukoencephalopathy (spasticity, ataxia, dysarthria, dysphagia, hemiparesis, seizures); headaches; seizures; sensory deficits	History: cognitive, motor, and/or sensory deficits, seizures
		Neurologic exam
Radiation impacting cerebrovascular structures	Cerebrovascular complications (stroke, Moyamoya disease, occlusive cerebral vasculopathy)	History: transient/permanent neurological events
		Blood pressure
		Neurologic exam
Neurosurgery–brain	Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizures	Neurologic exam
		Neurology evaluation
Neurosurgery–brain	Hydrocephalus; shunt malfunction	Abdominal x-ray
		Neurosurgery evaluation
Neurosurgery–spine	Neurogenic bladder; urinary incontinence	History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
Neurosurgery–spine	Neurogenic bowel; fecal incontinence	History: chronic constipation, fecal soiling
		Rectal exam
Predisposing Therapy	Neuropsychological Effects	Health Screening
Methotrexate (high-dose IV or IT); cytarabine (high-dose IV or IT); radiation impacting the brain; neurosurgery–brain	Neurocognitive deficits (executive function, memory, attention, processing speed, etc.); learning deficits; diminished IQ; behavioral change	Assessment of educational and vocational progress
		Formal neuropsychological evaluation

Psychosocial

Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes. Evidence for adverse psychosocial adjustment after childhood cancer has been derived from a number of sources, ranging from patient-reported or proxy-reported outcomes to data from population-based registries. The former may be limited by small sample size, cohort selection and participation bias, and variable methods and venues (clinical vs. distance-based survey) of assessments. The latter is often not well correlated with clinical and treatment characteristics that permit the identification of survivors at high risk of psychosocial deficits.

Survivors with neurocognitive deficits are particularly vulnerable to adverse psychosocial outcomes that affect achievement of expected social outcomes during adulthood.

Childhood cancer survivors are also at risk of developing symptoms of psychological distress. In a longitudinal study of more than 4,500 survivors, subgroups of survivors were found to be at risk of developing persistent and increasing symptoms of anxiety and depression during a 16-year period. Survivors who reported pain and worsening health status were at the greatest risk of developing symptoms of anxiety, depression, and somatization over time.[ 103 ]

Adult survivors of childhood cancer are also at risk of suicide ideation compared with siblings, with survivors of CNS tumors being most likely to report thoughts of suicide. In a CCSS study that evaluated the prevalence of recurrent suicidal ideation among 9,128 adult long-term survivors of childhood cancer, survivors were more likely to report late suicidal ideation (odds ratio [OR], 1.9; 95% CI, 1.5–2.5) and recurrent suicidal ideation (OR, 2.6; 95% CI, 1.8–3.8) compared with siblings. History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors.[ 104 ] In a population-based study that evaluated suicide among adults treated for cancer before age 25 years, the absolute risk of suicide was low (24 cases among 3,375 deaths), but the HR of suicide was increased among individuals treated for cancer in childhood (0–14 years; HR, 2.5; 95% CI, 1.7–3.8) and in adolescence and young adulthood (15–24 years; HR, 2.3; 95% CI, 1.2–4.6).[ 105 ]

The presence of chronic health conditions can also impact aspects of psychological health. In a study that evaluated psychological outcomes among long-term survivors treated with HSCT, 22% of survivors and 8% of sibling controls reported adverse outcomes. Somatic distress was the most prevalent condition and affected 15% of HSCT survivors, representing a threefold higher risk compared with siblings. HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress.[ 106 ] A report from the CCSS revealed that the presence of chronic pulmonary, endocrine, and cardiac conditions was associated with increased risk of psychological distress symptoms in a sample of 5,021 adult survivors of childhood cancer.[ 107 ]

In a CCSS investigation that evaluated long-term psychological and educational outcomes among survivors of neuroblastoma, survivors demonstrated elevated risks of psychological impairment, which was associated with the use of special education services and lower educational attainment. The presence of two or more chronic health conditions, but not common treatment exposures, predicted psychological impairment. Specifically, pulmonary disease predicted impairment in all five psychological domains, whereas endocrine disease and peripheral neuropathy each predicted impairment in three domains.[ 108 ]

Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of survivors with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, with the prevalence of psychological maladjustment ranging from 25% to 93%.[ 109 ] In a study of 101 adult cancer survivors of childhood cancer, psychological screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least one suicidal symptom. Risk factors for psychological distress included subjects’ dissatisfaction with physical appearance, poor physical health, and treatment with cranial irradiation. In this study, the instrument was shown to be feasible for use in the clinic visit setting because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to cause distress in the survivors in 80% of cases.[ 110 ] These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting.

(Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information about psychological distress and cancer patients.)

Post-traumatic stress after childhood cancer

Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder (PTSD) in children with cancer, typically no higher than those in healthy comparison children.[ 111 ] Patient and parent adaptive style appear to be significant determinants of PTSD in the pediatric oncology setting.[ 112 ][ 113 ]

The prevalence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with estimates varying based on criteria used to define these conditions.[ 114 ]

Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceive greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors.[ 118 ]

Psychosocial outcomes among childhood, adolescent, and young adult cancer survivors

Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood. Little is known about the specific impact of a cancer diagnosis with an onset in adolescence or the impact of childhood cancer on adolescent and young adult (AYA) psychosocial outcomes.

Evidence (psychosocial outcomes in AYA cancer survivors):

1. Adult survivors of cancer diagnosed during adolescence (aged 15–18 years) (N = 825) were compared with an age-matched sample from the general population and a comparison group of adults without cancer.[ 119 ]
2. A survey of 4,054 AYA cancer survivors and 345,592 respondents who had no history of cancer reported the following:[ 121 ]
3. The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of childhood cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, being headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence).[ 122 ]
4. Another CCSS study evaluated psychological and neurocognitive function in 2,589 long-term cancer survivors who were diagnosed during adolescence and young adulthood.[ 123 ]
5. A follow-up CCSS study evaluated profiles of symptom comorbidities in 3,993 adolescents (aged 13–17 years) treated for cancer.[ 124 ] Latent profile analysis identified four symptom profiles:

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

The diagnosis of childhood cancer may also affect psychosocial outcomes and the expected attainment of functional and social independence in adulthood. Several investigations have demonstrated that survivors of pediatric CNS tumors are particularly vulnerable.[ 125 ][ 126 ]

Evidence (functional and social independence):

1. In a study of 665 survivors of CNS tumors (54% male; 52% treated with cranial radiation therapy; median age, 15 years; and 12 years from diagnosis), CCSS investigators observed the following:[ 125 ]
2. A St. Jude Lifetime Cohort Study investigated functional and social independence in 306 CNS tumor survivors (astrocytoma [n = 130], medulloblastoma [n = 77], ependymoma [n = 36], and other [n = 63]; median age, 25 years; and time since diagnosis, 16.8 years).[ 126 ]

Social withdrawal in adolescence has been associated with adult obesity and physical inactivity.[ 127 ] As a result, these psychological problems may increase future risk for chronic health conditions and support the need to routinely screen and treat psychological problems after cancer therapy.

Because of the challenges experienced by adolescents and young adults at cancer diagnosis and during long-term follow-up, this group may benefit from access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.[ 128 ][ 129 ]

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

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86. Anderson FS, Kunin-Batson AS, Perkins JL, et al.: White versus gray matter function as seen on neuropsychological testing following bone marrow transplant for acute leukemia in childhood. Neuropsychiatr Dis Treat 4 (1): 283-8, 2008.[PUBMED Abstract]
87. 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]
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89. 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]
90. 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]
91. 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]
92. 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]
93. 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]
94. 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]
95. 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]
96. 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]
97. 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]
98. 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]
99. 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]
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101. 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]
102. Schulte F, Barrera M: Social competence in childhood brain tumor survivors: a comprehensive review. Support Care Cancer 18 (12): 1499-513, 2010.[PUBMED Abstract]
103. Brinkman TM, Zhu L, Zeltzer LK, et al.: Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br J Cancer 109 (5): 1373-81, 2013.[PUBMED Abstract]
104. 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]
105. 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]
106. 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]
107. 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]
108. 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]
109. Fuemmeler BF, Elkin TD, Mullins LL: Survivors of childhood brain tumors: behavioral, emotional, and social adjustment. Clin Psychol Rev 22 (4): 547-85, 2002.[PUBMED Abstract]
110. 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]
111. 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]
112. 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]
113. 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]
114. 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]
115. 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]
116. 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]
117. 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]
118. 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]
119. 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]
120. 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]
121. 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]
122. 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]
123. 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]
124. 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]
125. 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]
126. 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]
127. Krull KR, Huang S, Gurney JG, et al.: Adolescent behavior and adult health status in childhood cancer survivors. J Cancer Surviv 4 (3): 210-7, 2010.[PUBMED Abstract]
128. Freyer DR: Transition of care for young adult survivors of childhood and adolescent cancer: rationale and approaches. J Clin Oncol 28 (32): 4810-8, 2010.[PUBMED Abstract]
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Late Effects of the Digestive System

Dental

Overview

Chemotherapy, radiation therapy, and local surgery can cause multiple cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment.

Oral and dental complications reported in childhood cancer survivors include the following:

Osteoradionecrosis and second cancers in the oral cavity also occur.

Abnormalities of tooth development

Abnormalities of dental development reported in childhood cancer survivors include the following:[ 1 ][ 2 ][ 3 ][ 4 ][ 5 ][ 6 ][ 7 ][ 8 ][ 9 ][ 10 ][ 11 ]

The prevalence of hypodontia has varied widely in series depending on age at diagnosis, treatment modality, and method of ascertainment.

Cancer treatments that have been associated with dental maldevelopment include the following:[ 3 ][ 11 ]

Children younger than 5 years are at greatest risk for dental anomalies, including root agenesis, delayed eruption, enamel defects, and/or excessive caries related to disruption of ameloblast (enamel producing) and odontoblast (dentin producing) activity early in life.[ 3 ]

Key findings related to cancer treatment effect on tooth development include the following:

1. Radiation therapy. Radiation directed at oral cavity or surrounding structures increases the risk of dental anomalies because ameloblasts can be permanently damaged by doses as low as 10 Gy.[ 3 ][ 5 ][ 6 ][ 12 ] However, the most significant degree of tooth aplasia or delayed eruption occurs in younger children (aged <4 years) who are exposed to radiation doses of 20 Gy or higher.[ 13 ]

   Developing teeth may be irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, brain tumors, and as a component of total-body irradiation (TBI). Doses of 10 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification.[ 14 ] Significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia have been reported in more than 85% of survivors of head and neck rhabdomyosarcoma treated with radiation doses higher than 40 Gy.[ 4 ][ 5 ]

2. Chemotherapy. Chemotherapy, especially exposure to alkylating agents, can affect tooth development.[ 3 ][ 6 ][ 7 ] Chemotherapy for the treatment of leukemia or neuroblastoma is associated with shortening and thinning of the premolar roots and enamel abnormalities.[ 15 ][ 16 ][ 17 ] Childhood Cancer Survivor Study (CCSS) investigators identified age younger than 5 years and increased exposure to cyclophosphamide as significant risk factors for developmental dental abnormalities in long-term survivors of childhood cancer.[ 3 ]
3. HSCT. HSCT conditioning, especially regimens containing TBI, may result in tooth agenesis and root malformation. Younger children who have not developed secondary teeth are most vulnerable.[ 1 ][ 2 ][ 6 ] Children who undergo HSCT with TBI may develop short V-shaped roots, microdontia, enamel hypoplasia, and/or premature apical closure.[ 1 ][ 2 ][ 8 ] The younger a patient is when treated with HSCT, the more severely disturbed dental development will be and the more deficient vertical growth of the lower face will be. These high-risk patients require close surveillance and appropriate interventions.[ 9 ] Dental abnormalities have been reported in patients who underwent HSCT without TBI, particularly in patients younger than 2 years at the time of the transplant.[ 18 ]

Salivary gland dysfunction

Xerostomia, the sensation of dry mouth, is a potential side effect after head and neck irradiation or HSCT that can severely impact quality of life. Complications of reduced salivary secretion include the following:[ 19 ][ 20 ]

The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques (patient report vs. stimulated or unstimulated salivary secretion rates).[ 21 ] In general, the prevalence of self-reported persistent posttherapy xerostomia is low among childhood cancer survivors. In the CCSS, the prevalence of self-reported xerostomia in survivors was 2.8% compared with 0.3% in siblings, with an increased risk in survivors older than 30 years.[ 3 ]

Key findings related to cancer treatment effect on salivary gland function include the following:

1. Radiation therapy. Salivary gland irradiation incidental to treatment of head and neck malignancies or Hodgkin lymphoma causes a qualitative and quantitative change in salivary flow, which can be reversible after doses of less than 40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy is also administered.[ 19 ]
2. HSCT. HSCT recipients are at increased risk of salivary gland dysfunction related to transplant conditioning or graft-versus-host disease (GVHD). GVHD can cause hyposalivation and xerostomia with resultant dental disease. In a study of pediatric HSCT survivors, 60% of those exposed to a conditioning regimen with cyclophosphamide and 10 Gy single-dose TBI had decreased salivary secretion rates, compared with 26% in those who received cyclophosphamide and busulfan.[ 22 ] In contrast, in another study, the prevalence of reduced salivary secretion did not differ among long-term survivors on the basis of the conditioning regimen (single-dose TBI, 47%; fractionated TBI, 47%; busulfan, 42%).[ 23 ]
3. Chemotherapy. The association of chemotherapy alone with xerostomia remains controversial.[ 19 ] Only one study of pediatric patients demonstrated an excess risk (odds ratio, 12.32 [2.1–74.4]) of decreased stimulated saliva flow rates among patients treated with cyclophosphamide; however, an increase in dental caries was not noted and patient-reported xerostomia was not evaluated.[ 7 ]

The impact of infectious complications and alterations in the microflora during and after therapy is not known.[ 6 ]

Abnormalities of craniofacial development

Craniofacial maldevelopment is a common adverse outcome among children treated with high-dose radiation therapy to the head and neck that frequently occurs in association with other oral cavity sequelae such as dental anomalies, xerostomia, and trismus.[ 5 ][ 24 ][ 25 ] The extent and severity of musculoskeletal disfigurement is related to age at treatment and radiation therapy volume and dose, with higher risk observed among younger patients and those who received 30 Gy or more.

Osteoradionecrosis of the jaw is a rare complication observed in childhood survivors treated with high-dose craniofacial radiation (>40 Gy), particularly after dental extractions in irradiated mandibles.[ 26 ][ 27 ]

Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions.

Posttherapy management

Some studies suggest that fluoride products or chlorhexidine rinses may be beneficial in patients who have undergone radiation therapy.[ 28 ] Dental caries are a problematic consequence of reduced salivary quality and flow. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.[ 20 ]

It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually.[ 29 ] The Children’s Oncology Group Long-term Follow-Up Guidelines recommend biannual dental cleaning and exams for all survivors of childhood cancer. These findings give health care providers further impetus to encourage routine dental care and dental hygiene evaluations for survivors of childhood treatment. (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information about oral complications in cancer patients.)

Table 4 summarizes oral and dental late effects and the related health screenings.

Table 4. Oral/Dental Late Effects^a

Predisposing Therapy	Oral/Dental Effects	Health Screening/Interventions
CT = computed tomography; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Any chemotherapy; radiation impacting oral cavity	Dental developmental abnormalities; tooth/root agenesis; microdontia; root thinning/shortening; enamel dysplasia	Dental evaluation and cleaning every 6 months
		Regular dental care including fluoride applications
		Consultation with orthodontist experienced in management of irradiated childhood cancer survivors
		Baseline Panorex x-ray before dental procedures to evaluate root development
Radiation impacting oral cavity	Malocclusion; temporomandibular joint dysfunction	Dental evaluation and cleaning every 6 months
		Regular dental care including fluoride applications
		Consultation with orthodontist experienced in management of irradiated childhood cancer survivors
		Baseline Panorex x-ray before dental procedures to evaluate root development
		Referral to otolaryngologist for assistive devices for jaw opening
Radiation impacting oral cavity; hematopoietic cell transplantation with history of chronic GVHD	Xerostomia/salivary gland dysfunction; periodontal disease; dental caries; oral cancer (squamous cell carcinoma)	Dental evaluation and cleaning every 6 months
		Supportive care with saliva substitutes, moistening agents, and sialogogues (pilocarpine)
		Regular dental care including fluoride applications
		Referral for biopsy of suspicious lesions
Radiation impacting oral cavity (≥40 Gy)	Osteoradionecrosis	History: impaired or delayed healing after dental work
		Exam: persistent jaw pain, swelling or trismus
		Imaging studies (x-ray, CT scan and/or MRI) may assist in making diagnosis
		Surgical biopsy may be needed to confirm diagnosis
		Consider hyperbaric oxygen treatments

Digestive Tract

Overview

The gastrointestinal (GI) tract is sensitive to the acute toxicities of chemotherapy, radiation therapy, and surgery. However, these important treatment modalities can also result in some long-term issues in a treatment- and dose-dependent manner. Reports published about long-term GI tract 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.

Treatment-related late effects include the following:

Digestive tract–related late effects include the following:

GI outcomes from selected cohort studies

Evidence (GI outcomes from selected cohort studies):

1. Among 5-year childhood cancer survivors participating in the CCSS, the cumulative incidence of self-reported GI conditions was 37.6% at 20 years from cancer diagnosis (25.8% for upper GI complications and 15.5% for lower GI complications), representing an almost twofold excess risk of upper GI complications (relative risk [RR], 1.8; 95% confidence interval [CI], 1.6–2.0) and lower GI complications (RR, 1.9; 95% CI, 1.7–2.2), compared with sibling controls.[ 30 ]

   Factors predicting higher risk of specific GI complications include the following:

2. A cohort study of children treated for acute myeloid leukemia with chemotherapy alone found that GI disorders were relatively rare and not significantly different from those reported by sibling controls.[ 31 ]
3. Late radiation injury to the digestive tract is attributable to vascular injury. Necrosis, ulceration, stenosis, or perforation can occur and are characterized by malabsorption, pain, and recurrent episodes of bowel obstruction, as well as perforation and infection.[ 32 ][ 33 ][ 34 ]

   In general, fractionated radiation doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy are associated with a higher risk of bowel obstruction or chronic enterocolitis.[ 35 ] Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.

Impact of cancer histology on GI outcomes

Intra-abdominal tumors represent a relatively common location for several pediatric malignancies, including rhabdomyosarcoma, Wilms tumor, lymphoma, germ cell tumors, and neuroblastoma. Intra-abdominal tumors often require multimodal therapy, occasionally necessitating resection of bowel, bowel-injuring chemotherapy, and/or radiation therapy. Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues.

A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation therapy:[ 36 ][ 37 ][ 38 ][ 39 ][ 40 ]

1. One study comprehensively evaluated intestinal symptoms in 44 children with cancer who underwent whole-abdominal (10–40 Gy) and involved-field (25–40 Gy) radiation therapy and received additional interventions predisposing them to GI tract complications, including abdominal laparotomy in 43 patients (98%) and chemotherapy in 25 patients (57%).[ 36 ]
2. The CCSS evaluated the incidence and risk of late-occurring intestinal obstruction requiring surgery in 12,316 5-year survivors (2,002 with and 10,314 without abdominopelvic tumors) and 4,023 siblings. The most common diagnoses among survivors with abdominopelvic tumors were Wilms tumors and neuroblastomas but also included soft tissue sarcomas, lymphomas, and bone tumors.[ 41 ]
3. Childhood cancer survivors are at increased risk of late anorectal disease after pelvic radiation exposure. A report from the CCSS demonstrated the following results:[ 42 ]
4. Reports from the Intergroup Rhabdomyosarcoma Study evaluating GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma infrequently observed abnormalities of the irradiated bowel.[ 37 ][ 38 ][ 40 ]

Table 5 summarizes digestive tract late effects and the related health screenings.

Table 5. Digestive Tract Late Effects^a

Predisposing Therapy	Gastrointestinal Effects	Health Screening/Interventions
GVHD = graft-versus-host disease; KUB = kidneys, ureter, bladder (plain abdominal radiograph).
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Radiation impacting esophagus; hematopoietic cell transplantation with any history of chronic GVHD	Gastroesophageal reflux; esophageal dysmotility; esophageal stricture	History: dysphagia, heart burn
		Esophageal dilation, antireflux surgery
Radiation impacting bowel	Chronic enterocolitis; fistula; strictures	History: nausea, vomiting, abdominal pain, diarrhea
		Serum protein and albumin levels yearly in patients with chronic diarrhea or fistula
		Surgical and/or gastroenterology consultation for symptomatic patients
Radiation impacting bowel; laparotomy	Bowel obstruction	History: abdominal pain, distention, vomiting, constipation
		Exam: tenderness, abdominal guarding, distension (acute episode)
		Obtain KUB in patients with clinical symptoms of obstruction
		Surgical consultation in patients unresponsive to medical management
Pelvic surgery; cystectomy	Fecal incontinence	History: chronic constipation, fecal soiling
		Rectal exam

Hepatobiliary

Overview

Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities.[ 43 ] Because many chemotherapy agents and radiation are hepatotoxic, transient liver function anomalies are common during therapy. Severe acute hepatic complications rarely occur. Survivors of childhood cancer can occasionally exhibit long-standing hepatic injury.[ 44 ]

Some general concepts regarding hepatotoxicity related to childhood cancer include the following:

Certain factors, including the type of chemotherapy, the dose and extent of radiation exposure, the influence of surgical interventions, and the evolving impact of viral hepatitis and/or other infectious complication, need additional attention in future studies.

Types of hepatobiliary late effects

Asymptomatic elevation of liver enzymes is the most common hepatobiliary complication.

Less commonly reported hepatobiliary complications include the following:

Treatment-related risk factors for hepatobiliary late effects

The type and intensity of previous therapy influences risk for late-occurring hepatobiliary effects. In addition to the risk of treatment-related toxicity, recipients of HSCT frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and other toxic etiologies.

Key findings related to cancer treatment effect on hepatobiliary complications include the following:

1. Chemotherapy. Chemotherapeutic agents with established hepatotoxic potential include antimetabolite agents like 6-mercaptopurine, 6-thioguanine, methotrexate, and rarely, dactinomycin. Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) and cholestatic disease have been observed after thiopurine administration, especially 6-thioguanine. Progressive fibrosis and portal hypertension have been reported in a subset of children who developed VOD/SOS after treatment with 6-thioguanine.[ 60 ][ 61 ][ 62 ] Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors.[ 63 ][ 64 ]

   In the transplant setting, VOD/SOS has also been observed after conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide, and carmustine/cyclophosphamide/etoposide.[ 65 ] High-dose cyclophosphamide, common to all of these regimens, is speculated to be a potential causative factor.

2. Radiation therapy. Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS.[ 66 ] In adults, the whole liver has tolerance up to 30 Gy to 35 Gy with conventional fractionation, the prevalence of radiation-induced liver disease varies from 6% to 66% based on the volume of liver involved and on hepatic reserve.[ 66 ][ 67 ]

   Radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload.[ 68 ] The dose threshold for irreversible injury is uncertain, but is being examined by the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative. The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, previous partial hepatectomy, and concomitant use of radiomimetic chemotherapy such as dactinomycin and doxorubicin.[ 69 ][ 70 ][ 71 ][ 72 ] Survivors who received radiation doses of 40 Gy to at least one-third of liver volume, doses of 30 Gy or more to whole abdomen, or an upper abdominal field involving the entire liver are at highest risk for hepatic dysfunction.[ 44 ]

3. HSCT. Chronic liver dysfunction in patients after HSCT is multifactorial in etiology. The most common etiologies for chronic liver dysfunction include iron overload, chronic GVHD, and viral hepatitis.[ 73 ] Patients with chronic GVHD of the GI tract who exhibit an elevated bilirubin have a worse prognosis and quality of life.[ 74 ] While chronic liver dysfunction may be seen in more than half of long-term stem cell transplantation survivors, and the course of the disease appears to be indolent, continued follow-up is needed to establish its long-term impact on survivor health.[ 75 ]

Infectious risk factors for hepatobiliary late effects

Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction. Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection. Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. The incidence of transfusion-related hepatitis C in childhood cancer survivors has ranged from 5% to 50% depending on the geographic location of the reporting center.[ 76 ][ 77 ][ 78 ][ 79 ][ 80 ][ 81 ][ 82 ]

Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with hepatitis B and C in combination or in co-occurrence with other hepatotrophic viruses accelerates the progression of liver disease.

Because most patients received some type of blood product during childhood cancer treatment and many are unaware of their transfusion history, screening on the basis of date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products.[ 83 ] Therefore, all survivors of childhood cancer who received treatment before 1972 should be screened for hepatitis B, and those who received treatment before 1993 should be screened for hepatitis C and referred for discussion of treatment options if screening results are positive.

Posttherapy management

Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury. Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed.

Table 6 summarizes hepatobiliary late effects and the related health screenings.

Table 6. Hepatobiliary Late Effects^a

Predisposing Therapy	Hepatic Effects	Health Screening/Interventions
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Methotrexate; mercaptopurine/thioguanine; HSCT	Hepatic dysfunction	Lab: ALT, AST, bilirubin levels
		Ferritin in those treated with HSCT
Mercaptopurine/thioguanine; HSCT	Veno-occlusive disease/sinusoidal obstructive syndrome	Exam: scleral icterus, jaundice, ascites, hepatomegaly, splenomegaly
		Lab: ALT, AST, bilirubin, platelet levels
		Ferritin in those treated with HSCT
Radiation impacting liver/biliary tract; HSCT	Hepatic fibrosis/cirrhosis; focal nodular hyperplasia	Exam: jaundice, spider angiomas, palmar erythema, xanthomata hepatomegaly, splenomegaly
		Lab: ALT, AST, bilirubin levels
		Ferritin in those treated with HSCT
		Prothrombin time for evaluation of hepatic synthetic function in patients with abnormal liver screening tests
		Screen for viral hepatitis in patients with persistently abnormal liver function or any patient transfused before 1993
		Gastroenterology/hepatology consultation in patients with persistent liver dysfunction
		Hepatitis A and B immunizations in patients lacking immunity
		Consider phlebotomy and chelation therapy for iron overload
Radiation impacting liver/biliary tract	Cholelithiasis	History: colicky abdominal pain related to fatty food intake, excessive flatulence
		Exam: right upper quadrant or epigastric tenderness (acute episode)
		Consider gallbladder ultrasound in patients with chronic abdominal pain

Pancreas

The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus.[ 84 ][ 85 ][ 86 ] While corticosteroids and asparaginase are associated with acute toxicity to the pancreas, late sequelae in the form of exocrine or endocrine pancreatic function for those who sustain acute injury have not been reported.

Evidence (risk of diabetes mellitus):

1. A retrospective cohort study, based on self-reports of 2,520 5-year survivors of childhood cancer treated in France and the United Kingdom, investigated the relationship between radiation dose to the pancreas and risk of a subsequent diabetes mellitus diagnosis.[ 87 ]
2. Another study evaluated the risk of diabetes mellitus in 2,264 5-year survivors of Hodgkin lymphoma (42% younger than 25 years at diagnosis) after a median follow-up of 21.5 years.[ 88 ]
3. CCSS investigators evaluated the risk of diabetes mellitus among 20,762 5-year childhood cancer survivors and 4,853 siblings.[ 89 ]
4. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for diabetes mellitus among 1,044 adult survivors of childhood acute lymphoblastic leukemia (mean age, 34 years) who were clinically assessed more than 10 years after treatment and 368 community controls (mean age, 35 years).[ 90 ]

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

参考文献

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Late Effects of the Endocrine System

Endocrine dysfunction is very common among childhood cancer survivors, especially those treated with surgery or radiation therapy that involves hormone-producing organs and those receiving alkylating agent chemotherapy.

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The prevalence of specific endocrine disorders is affected by the following:[ 1 ][ 2 ][ 3 ][ 4 ]

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

Thyroid Gland

Hypothyroidism

Risk factors

An increased risk of hypothyroidism has been reported among childhood cancer survivors treated with head and neck radiation exposing the thyroid gland, especially among survivors of Hodgkin lymphoma.[ 1 ][ 2 ][ 3 ][ 4 ]

Treatment with iodine I 131-metaiodobenzylguanidine (131I-MIBG) can cause primary hypothyroidism despite thyroid protection through potassium iodide, perchlorate, or the combination of potassium iodide, thyroxine (T₄) and a thiamazole, which decreases but does not entirely eliminate the risk of 131I-MIBG-induced hypothyroidism.[ 5 ]

Clinical presentation

Evidence (prevalence of and risk factors for hypothyroidism):

1. The German Group of Paediatric Radiation Oncology reported on 1,086 patients treated at 62 centers, including 404 patients (median age, 10.9 years) who received radiation therapy to the thyroid and/or pituitary gland.[ 7 ] Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values.
2. The Childhood Cancer Survivor Study (CCSS) investigated the prevalence of self-reported hypothyroidism assessed through serial questionnaires in 12,015 survivors. A total of 1,193 cases of hypothyroidism were observed, 777 (65%) of which occurred 5 or more years after cancer diagnosis.[ 8 ]
3. In a cohort of childhood Hodgkin lymphoma survivors treated between 1970 and 1986, survivors were evaluated for thyroid disease by use of a self-report questionnaire in the CCSS.[ 9 ]

   

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4. In a follow-up study from the CCSS that compared self-reported data from 14,290 survivors with data from 4,031 sibling controls.[ 2 ]
5. Continuous improvements in the precision of radiation therapy delivery carry the promise to decrease the radiation therapy dose received by the thyroid in a subset of patients, as demonstrated in a study of 189 children and young adults (aged <26 years) with brain tumors treated with proton radiation therapy.[ 10 ]

Hyperthyroidism

While less common than hypothyroidism, childhood cancer survivors also experience an increased risk of hyperthyroidism.[ 2 ][ 9 ][ 11 ]

Evidence (prevalence of and risk factors for hyperthyroidism):

1. CCSS investigators evaluated the prevalence of thyroid disease among 1,791 childhood Hodgkin lymphoma survivors treated between 1970 and 1986 and followed for a median of 14 years.[ 9 ]
2. Another CCSS study evaluated the risk of hyperthyroidism in relation to incidental therapeutic radiation dose to the thyroid and pituitary glands.[ 11 ]

Thyroid nodules

The clinical manifestation of thyroid neoplasia among childhood cancer survivors ranges from asymptomatic, small, solitary nodules to large, intrathoracic goiters that compress adjacent structures.

Risk factors

The following factors are linked to an increased risk of thyroid nodule development:

1. Radiation dose, time from diagnosis, female sex.
2. Age at time of radiation therapy.
3. Exposure to 131I-MIBG.
4. Chemotherapy.

Screening for Thyroid Cancer

(Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers.)

Posttransplant thyroid dysfunction

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at increased risk of thyroid dysfunction.[ 25 ]

TSH deficiency (central hypothyroidism) is discussed with late effects that affect the pituitary gland.

Table 7 summarizes thyroid late effects and the related health screenings.

Table 7. Thyroid Late Effects^a

Predisposing Therapy	Endocrine/Metabolic Effects	Health Screening
131I-MIBG = Iodine I 131-metaiodobenzylguanidine; T4 = thyroxine; TSH = thyroid-stimulating hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Radiation exposing thyroid gland; thyroidectomy	Primary hypothyroidism	TSH level
Radiation exposing thyroid gland	Hyperthyroidism	Free T4 level
		TSH level
Radiation exposing thyroid gland, including 131I-MIBG	Thyroid nodules	Thyroid exam
		Thyroid ultrasound

Hypothalamus/Pituitary Axis

Survivors of childhood cancer are at risk of developing a spectrum of neuroendocrine abnormalities, primarily because of the effect of radiation therapy on the hypothalamus.

Although the quality of the literature regarding pituitary endocrinopathy among childhood cancer survivors is often limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment, the evidence linking this outcome with radiation therapy, surgery, and tumor infiltration is compelling because affected individuals typically present with metabolic and developmental abnormalities early in follow-up.

Central diabetes insipidus

Central diabetes insipidus may herald the diagnosis of craniopharyngioma, suprasellar germ cell tumor, or Langerhans cell histiocytosis.[ 29 ][ 30 ][ 31 ]

Anterior pituitary hormone deficiency

Deficiencies of anterior pituitary hormones and major hypothalamic regulatory factors are common late effects among survivors treated with cranial irradiation.[ 28 ]

Evidence (prevalence of anterior pituitary hormone deficiency):

1. In a single-institution study, 1,713 adult survivors of childhood cancers and brain tumors (median age, 32 years) were monitored for a median follow-up of 25 years.[ 27 ]
2. A study of 748 childhood cancer survivors treated with cranial irradiation and observed for a mean of 27.3 years reported the following:[ 4 ]

The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.

Table 8. Anterior Pituitary Hormones and Major Hypothalamic Regulatory Factors

Pituitary Hormone	Hypothalamic Factor	Hypothalamic Regulation of the Pituitary Hormone
(–) = inhibitory; (+) = stimulatory.
Growth hormone (GH)	Growth hormone–releasing hormone	+
	Somatostatin	–
Prolactin	Dopamine	–
Luteinizing hormone (LH)	Gonadotropin-releasing hormone	+
Follicle-stimulating hormone (FSH)	Gonadotropin-releasing hormone	+
Thyroid-stimulating hormone (TSH)	Thyroid-releasing hormone	+
	Somatostatin	–
Adrenocorticotropin (ACTH)	Corticotropin-releasing hormone	+
	Vasopressin	+

Growth hormone deficiency

Growth hormone deficiency is the earliest hormonal deficiency associated with cranial radiation therapy in childhood cancer survivors.

Evidence (radiation-dose response relationship of growth hormone deficiency in childhood brain tumor survivors):

1. A study of conformal radiation therapy (CRT) in children with CNS tumors indicates that growth hormone insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects.[ 34 ]
2. In a report featuring data from 118 patients with localized brain tumors who were treated with radiation therapy, peak growth hormone was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus.[ 35 ]

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Evidence (risk of growth deficits in childhood ALL survivors):

1. One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial radiation therapy.[ 36 ]
2. Survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, although the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age.[ 37 ] In a cross-sectional study, attained adult height was determined for 2,434 ALL survivors participating in the CCSS.
3. The impact of chemotherapy alone on growth in 67 survivors treated with contemporary regimens for ALL was statistically significant at -0.59 SD. The loss of growth potential did not correlate with growth hormone status in this study, further highlighting the participation of other factors in the growth impairments observed in this population.[ 38 ]
4. In a longitudinal study of 372 survivors of ALL who were treated on a single-institution chemotherapy-only trial, the following were observed:[ 39 ]

Growth after hematopoietic stem cell (HSCT)

Evidence (growth hormone deficiency in childhood HSCT survivors):

1. The late effects that occur after HSCT have been studied and reviewed by the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, the following results were observed:[ 46 ][ 47 ]
2. Growth hormone deficiency has been reported after lower doses with a single fraction of 10 Gy and fractionated doses of 12 to 18 Gy of TBI.[ 48 ]

Growth hormone replacement therapy

Evidence (subsequent neoplasm risk after growth hormone deficiency replacement therapy):

1. One study evaluated 361 growth hormone–treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of subsequent neoplasm, and risk of death among survivors who did and did not receive treatment with growth hormone.[ 52 ]
2. A review of existing data suggests that treatment with growth hormone is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia.[ 54 ]
3. A study from the CCSS reported specifically on the risk of subsequent CNS neoplasms after a longer period of follow-up.[ 55 ]

In general, the data addressing subsequent malignancies among childhood cancer survivors treated with growth hormone therapy should be interpreted with caution given the small number of events.[ 28 ][ 50 ][ 51 ][ 52 ][ 56 ]

Disorders of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

Central precocious puberty

Diagnosis of central precocious puberty

Prevalence and risk factors

Treatment and outcomes associated with central precocious puberty

LH/FSH deficiency

Prevalence, risk factors, and treatment

TSH deficiency

TSH deficiency (also referred to as central hypothyroidism) in survivors of childhood cancer can have profound clinical consequences and be underappreciated.

Clinical presentation and diagnosis

Prevalence and risk factors

Management of TSH deficiency

Adrenal-corticotropin (ACTH) deficiency

Prevalence and risk factors

Diagnosis and management

Hyperprolactinemia

Table 9 summarizes pituitary gland late effects and the related health screenings.

Table 9. Pituitary Gland Late Effects^a

Predisposing Therapy	Endocrine/Metabolic Effects	Health Screening
BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; T4 = thyroxine; TSH = thyroid-stimulating hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
bTesticular volume measurements are not reliable in the assessment of pubertal development in boys exposed to chemotherapy or direct radiation to the testes.
cAppropriate only at diagnosis. TSH levels are not useful for follow-up during replacement therapy.
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis.	Growth hormone deficiency	Assessment of nutritional status
		Height, weight, BMI, Tanner stageb
Tumor or surgery affecting hypothalamus/pituitary or optic pathways; hydrocephalus. Radiation exposing hypothalamic-pituitary axis.	Precocious puberty	Height, weight, BMI, Tanner stageb
		FSH, LH, estradiol, or testosterone levels
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis.	Gonadotropin deficiency	History: puberty, sexual function
		Exam: Tanner stageb
		FSH, LH, estradiol or testosterone levels
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis.	Central adrenal insufficiency	History: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension
		Endocrine consultation for those with radiation dose ≥30 Gy
Radiation exposing hypothalamic-pituitary axis.	Hyperprolactinemia	History/exam: galactorrhea
		Prolactin level
Radiation exposing hypothalamic-pituitary axis.	Overweight/obesity	Height, weight, BMI
		Blood pressure
	Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)	Fasting blood glucose level and lipid profile
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis.	Central hypothyroidism	TSHc free thyroxine (free T4) level

Testis and Ovary

Testicular and ovarian hormonal functions are discussed in the Late Effects of the Reproductive System section of this summary.

Metabolic Syndrome

An increased risk of metabolic syndrome or its components has been observed among childhood cancer survivors. The evidence for this outcome ranges from clinically manifested conditions that are self-reported by survivors to retrospectively assessed data in medical records and hospital registries to systematic clinical evaluations of clinically well-characterized cohorts. Studies have been limited by cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Despite these limitations, compelling evidence indicates that metabolic syndrome is highly associated with cardiovascular events and mortality.

Definitions of metabolic syndrome are evolving but generally include a combination of central (abdominal) obesity with at least two of the following features:[ 73 ]

Evidence (prevalence of and risk factors for metabolic syndrome in childhood cancer survivors):

1. A study monitored 784 long-term childhood ALL survivors (median age, 31.7 years) for a median follow-up of 26.1 years.[ 74 ]
2. French investigators evaluated the overall and age-specific prevalence of and risk factors for metabolic syndrome and its components among 650 adult survivors of childhood leukemia treated without HSCT.[ 75 ]
3. In a prospective study of 164 long-term survivors of embryonal tumors treated with abdominal radiation therapy (median follow-up, 26 years), nephroblastoma (OR, 5.2) and neuroblastoma (OR, 6.5) survivors had more components of metabolic syndrome than did controls.[ 76 ]

Lifestyle impact on modifiable risk factors

Evidence (lifestyle modifications to reduce cardiovascular risk in childhood cancer survivors):

1. Survivors participating in the St. Jude Lifetime Cohort Study who were adherent to a heart-healthy lifestyle had a lower risk of metabolic syndrome.[ 78 ]
2. A CCSS investigation evaluated the impact of exercise on cardiovascular disease risk among survivors of Hodgkin lymphoma.[ 79 ]
3. Another CCSS investigation evaluated the association of exercise with mortality in adult survivors of childhood cancer.[ 80 ]

Abnormal glucose metabolism

Abdominal radiation therapy and TBI are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors.[ 2 ][ 81 ][ 82 ][ 83 ][ 84 ][ 85 ]

Evidence (risk factors for diabetes mellitus in childhood cancer survivors):

1. A single-center cohort study of 532 long-term (median follow-up, 17.9 years) adult (median age, 25.6 years) survivors observed the following:[ 83 ]
2. A cross-sectional study evaluated cardiovascular risk factors and insulin resistance in a clinically heterogeneous cohort of 319 childhood cancer survivors 5 or more years since diagnosis and 208 sibling controls.[ 86 ]
3. In a European multicenter cohort of 2,520 childhood cancer survivors (median follow-up, 28 years), significant associations were found between diabetes mellitus and increasing doses of radiation therapy to the tail of the pancreas, supporting the contribution of radiation-induced islet cell injury to impairments of glucose homeostasis in this population.[ 84 ]
4. A report from the CCSS compared 8,599 childhood cancer survivors with 2,936 randomly selected sibling controls, and adjusted for age, BMI, and several demographic factors.[ 87 ]

Table 10 summarizes metabolic syndrome late effects and the related health screenings.

Table 10. Metabolic Syndrome Late Effects^a

Predisposing Therapy	Potential Late Effects	Health Screening
BMI = body mass index.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Abdominal irradiation; total-body irradiation.	Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)	Height, weight, BMI, blood pressure
		Labs: fasting glucose and lipids

Body Composition: Underweight, Overweight, and Obesity

Underweight

Overweight/Obesity

Evidence (risk factors for overweight/obesity):

1. CCSS investigators reported the following independent risk factors for obesity in childhood cancer survivors including treatment, lifestyle, and medication use:[ 99 ]

Body composition alterations after childhood ALL

1. Moderate-dose cranial radiation therapy (18–24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age.[ 90 ][ 92 ][ 100 ]
2. Body composition alterations appear to be attenuated in males.
3. ALL therapy regimens are associated with increases in BMI shortly after completion of therapy, and possibly with a higher risk of obesity in the long term.[ 93 ][ 94 ][ 104 ][ 105 ][ 106 ]

Evidence (body composition changes in adult survivors of childhood ALL):

1. A cohort study of 365 adult survivors of ALL (149 treated with cranial radiation therapy and 216 treated without cranial radiation therapy) compared body composition, energy balance, and fitness with age-, sex-, and race-matched peers.[ 110 ]
2. In a report from the CCSS based on self-reported height and weight measurements, adult survivors of childhood ALL treated with chemotherapy alone did not have significantly higher rates of obesity than did sibling controls,[ 90 ] nor were there differences in BMI changes between these groups after a subsequent period of follow-up that averaged 7.8 years.[ 92 ]
3. Swiss investigators evaluated self-reported weight in 1,936 adult survivors of childhood ALL and non-Hodgkin and Hodgkin lymphoma survivors (median age, 24 years; median time from diagnosis, 17 years) and compared them with siblings and the general population.[ 111 ]

Variable outcomes across studies likely relate to the use of BMI as the metric for abnormal body composition, which does not adequately assess visceral adiposity that can contribute to metabolic risk in this population.[ 112 ]

Body composition alterations after treatment for CNS tumors

Among brain tumor survivors treated with higher doses of cranial radiation therapy, the highest risk for obesity has been observed in females treated at a younger age.[ 113 ]

Craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.[ 114 ][ 115 ][ 116 ][ 117 ]

Body composition alterations after hematopoietic stem cell transplantation

Body composition and frailty

Young adult childhood cancer survivors have a higher-than-expected prevalence of frailty, a phenotype characterized by low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness.[ 122 ]

Table 11 summarizes body composition late effects and the related health screenings.

Table 11. Body Composition Late Effects^a

Predisposing Therapy	Potential Late Effects	Health Screening
BMI = body mass index.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Cranial radiation therapy	Overweight/obesity	Height, weight, BMI, blood pressure
		Labs: fasting glucose and lipids

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling.

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99. 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]
100. 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]
101. 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]
102. 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]
103. 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]
104. 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]
105. 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]
106. 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]
107. 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]
108. 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]
109. 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]
110. 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]
111. 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]
112. 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]
113. 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]
114. 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]
115. Müller HL: Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. Expert Rev Neurother 10 (4): 515-24, 2010.[PUBMED Abstract]
116. 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]
117. 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]
118. 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]
119. 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]
120. 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]
121. 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]
122. 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]
123. 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]

Late Effects of the Immune System

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.

Asplenia

Surgical or functional splenectomy increases the risk of life-threatening invasive bacterial infection:[ 1 ]

Individuals with asplenia, regardless of the reason for the asplenic state, have an increased risk of fulminant bacteremia, especially associated with encapsulated bacteria, which is associated with a high mortality rate. The risk of bacteremia is higher in younger children than in older children, and this risk may be higher during the years immediately after splenectomy. Fulminant septicemia, however, has been reported in adults up to 25 years after splenectomy.

Bacteremia may be caused by the following organisms in asplenic survivors:

Individuals with functional or surgical asplenia are also at increased risk of fatal malaria and severe babesiosis.

Posttherapy management

Clinicians should consider and encourage the administration of inactivated vaccines (e.g., influenza) and vaccines made of purified antigens (e.g., pneumococcus), bacterial components (e.g., diphtheria-tetanus-pertussis), or genetically engineered recombinant antigens (e.g., hepatitis B) in all cancer and transplant survivors according to recommended doses and schedules.[ 7 ][ 8 ][ 9 ]

Two primary doses of quadrivalent meningococcal conjugate vaccine should be administered 2 months apart to children with asplenia, from age 2 years through adolescence, and a booster dose should be administered every 5 years.[ 10 ] (Refer to the Immunization Schedules for 2019 section of the Red Book for more information.) However, the efficacy of meningococcal vaccines in children with asplenia has not been established. (Refer to the Meningococcal Infections section of the Red Book for more information.) No known contraindication exists to giving these vaccines at the same time as other required vaccines, in separate syringes, at different sites.

Pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine (PPSV) are indicated at the recommended age for all children with asplenia. Following the administration of the appropriate number of doses of PCV13, PPSV23 should be administered starting at age 24 months. A second dose should be administered 5 years later. For children aged 2 to 5 years with a complete PCV7 series who have not received PCV13, a supplemental dose of PCV13 should be administered. For asplenic individuals aged 6 to 18 years who have not received a dose of PCV13, a supplemental dose of PCV13 should be considered.[ 11 ][ 12 ] (Refer to the Pneumococcal Infections section of the Red Book for more information.) Hib immunization should be initiated at age 2 months, as recommended for otherwise healthy young children and for previously unimmunized children with asplenia.[ 11 ] (Refer to the Immunization Schedules for 2019 section of the Red Book for more information.)

Daily antimicrobial prophylaxis against pneumococcal infections is recommended for young children with asplenia, regardless of their immunization status. Although the efficacy of daily antimicrobial prophylaxis has been proven only in patients with sickle cell anemia, this experience has been extended to other high-risk children, including asplenic children with a history of malignant neoplasms or thalassemia. In general, antimicrobial prophylaxis (in addition to immunization) should be considered for all children with asplenia younger than 5 years and for at least 1 year after splenectomy.

The age at which antimicrobial prophylaxis is discontinued is an empiric decision. On the basis of a multicenter study in sickle cell disease, prophylactic penicillin can be discontinued at age 5 years among those who are receiving regular medical attention and who have not had a severe pneumococcal infection or surgical splenectomy. The appropriate duration of prophylaxis is unknown for children with asplenia attributable to other causes. Some experts continue prophylaxis throughout childhood and into adulthood for particularly high-risk patients with asplenia.

Table 12 summarizes spleen late effects and the related health screenings.

Table 12. Spleen Late Effects^a

Predisposing Therapy	Immunologic Effects	Health Screening/Interventions
GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; IgA = immunoglobulin A; T = temperature.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Radiation impacting spleen; splenectomy; HSCT with currently active GVHD	Asplenia/hyposplenia; overwhelming post-splenectomy sepsis	Blood cultures during febrile episodes (T >38.5°C); empiric antibiotics
		Immunization for encapsulated organisms (pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines)
HSCT with any history of chronic GVHD	Immunologic complications (secretory IgA deficiency, hypogammaglobulinemia, decreased B cells, T cell dysfunction, chronic infections [e.g., conjunctivitis, sinusitis, and bronchitis associated with chronic GVHD])	History: chronic conjunctivitis, chronic sinusitis, chronic bronchitis, recurrent or unusual infections, sepsis
		Exam: attention to eyes, nose/sinuses, and lungs

Refer to the Centers for Disease Control and Prevention (CDC) Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients for more information on posttransplant immunization.

Humoral Immunity

Although the immune system appears to recover from the effects of active chemotherapy and radiation therapy, there is some evidence that lymphoid subsets do not normalize in all survivors. Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia.[ 13 ] Defects in immune recovery characterized by B-cell depletion have been observed in 2-year survivors of standard-risk and intermediate-risk acute lymphoblastic leukemia (ALL).[ 14 ] Antibody levels to previous vaccinations are also reduced in patients off therapy for ALL for at least 1 year,[ 15 ][ 16 ] suggesting abnormal humoral immunity [ 17 ] and a need for revaccination in such children. Survivors of childhood cancer may remain susceptible to vaccine-preventable infections. Treatment intensity, age at diagnosis, and time from treatment are associated with the risk of losing pre-existing immunity.[ 18 ][ 19 ]

While there is a paucity of data regarding the benefits of administering active immunizations in this population, reimmunization is necessary to provide protective antibodies. The recommended reimmunization schedule will depend on previously received vaccinations and on the intensity of therapy.[ 20 ][ 21 ] In some children who received intensive treatment, consideration may be given to evaluating the antibodies against common vaccination antigens to determine the need for revaccination. (Refer to the Immunization Schedules for 2019 section of the Red Book for more information.)

Immune status is also compromised after HSCT, particularly in association with GVHD.[ 22 ] In a prospective, longitudinal study of 210 survivors treated with allogeneic HSCT, antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favorable. Factors associated with vaccine failure include older age at immunization; lower CD3, CD4, or CD19 count; higher immunoglobulin M concentration; positive recipient cytomegalovirus serology; negative titer before immunization; history of acute or chronic GVHD; and radiation conditioning.[ 23 ]

Follow-up recommendations for transplant recipients have been published by the major North American and European transplant groups, the CDC, and the Infectious Diseases Society of America.[ 24 ][ 25 ]

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

参考文献

1. Immunization in special circumstances. In: Kimberlin DW, Brady MT, Jackson MA, et al., eds.: Red Book: 2018–2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, Ill: American Academy of Pediatrics, 2018, pp 67-111.[PUBMED Abstract]
2. Kaiser CW: Complications from staging laparotomy for Hodgkin disease. J Surg Oncol 16 (4): 319-25, 1981.[PUBMED Abstract]
3. 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]
4. 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]
5. 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]
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. 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 March 20, 2020.[PUBMED Abstract]
8. 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]
9. 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]
10. Centers for Disease Control and Prevention (CDC): Recommendation of the Advisory Committee on Immunization Practices (ACIP) for use of quadrivalent meningococcal conjugate vaccine (MenACWY-D) among children aged 9 through 23 months at increased risk for invasive meningococcal disease. MMWR Morb Mortal Wkly Rep 60 (40): 1391-2, 2011.[PUBMED Abstract]
11. Kimberlin DW, Brady MT, Jackson MA, et al., eds.: Red Book: 2018–2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, Ill: American Academy of Pediatrics, 2018. Also available online. Last accessed March 20, 2020.[PUBMED Abstract]
12. 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]
13. Schwartz C L, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood Cancer: Assessment and Management. St. Louis, Mo: Mosby, 1994.[PUBMED Abstract]
14. 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]
15. Leung W, Neale G, Behm F, et al.: Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia. Cancer Epidemiol 34 (3): 303-8, 2010.[PUBMED Abstract]
16. Aytac S, Yalcin SS, Cetin M, et al.: Measles, mumps, and rubella antibody status and response to immunization in children after therapy for acute lymphoblastic leukemia. Pediatr Hematol Oncol 27 (5): 333-43, 2010.[PUBMED Abstract]
17. Brodtman DH, Rosenthal DW, Redner A, et al.: Immunodeficiency in children with acute lymphoblastic leukemia after completion of modern aggressive chemotherapeutic regimens. J Pediatr 146 (5): 654-61, 2005.[PUBMED Abstract]
18. 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]
19. 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]
20. Ruggiero A, Battista A, Coccia P, et al.: How to manage vaccinations in children with cancer. Pediatr Blood Cancer 57 (7): 1104-8, 2011.[PUBMED Abstract]
21. Patel SR, Chisholm JC, Heath PT: Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am 55 (1): 169-86, xi, 2008.[PUBMED Abstract]
22. 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]
23. 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]
24. Rizzo JD, Wingard JR, Tichelli A, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 37 (3): 249-61, 2006.[PUBMED Abstract]
25. 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]

Late Effects of the Musculoskeletal System

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 to 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 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 delivery of anticancer modalities, particularly radiation therapy, has changed over the years in response to documented toxicities.[ 1 ][ 2 ]

Abnormal Bone Growth

The effect of radiation on bone growth depends on the sites irradiated, as follows:

Radiation to the head and brain

In an age- and dose-dependent fashion, radiation can inhibit normal bone and muscle maturation and development. Radiation to the head (e.g., cranial, orbital, infratemporal, or nasopharyngeal radiation therapy) can cause craniofacial abnormalities, particularly in children treated before age 5 years who received radiation doses of 20 Gy or higher [ 3 ][ 4 ][ 5 ][ 6 ][ 7 ][ 8 ] or who were treated with concomitant chemotherapy.[ 9 ] Soft tissue sarcomas such as orbital rhabdomyosarcoma and retinoblastoma are two of the more common cancer types treated with these radiation fields. Often, in addition to the cosmetic impact of the craniofacial abnormalities, there can be related dental and sinus problems.

Cranial radiation therapy damages the hypothalamic-pituitary axis in an age- and dose-response fashion and can result in growth hormone deficiency.[ 10 ][ 11 ][ 12 ][ 13 ] If the growth hormone deficiency is not treated during the growing years and, sometimes, even with appropriate treatment, it leads to a substantially lower final height. Patients with a central nervous system (CNS) tumor [ 10 ][ 14 ] or acute lymphoblastic leukemia (ALL) [ 15 ][ 16 ][ 17 ] treated with 18 Gy or higher of cranial radiation therapy are at highest risk. Patients treated with total-body irradiation (TBI), particularly single-fraction TBI,[ 18 ][ 19 ][ 20 ][ 21 ] and those treated with cranial radiation for non-CNS solid tumors [ 22 ] are also at risk of growth hormone deficiency. If the spine is also irradiated (e.g., craniospinal radiation therapy for medulloblastoma or early ALL therapies in the 1960s), growth can be affected by two separate mechanisms—growth hormone deficiency and direct damage to the spine.

Radiation to the spine and long bones

Radiation therapy can also directly affect the growth of the spine and long bones (and associated muscle groups) and can cause premature closure of the epiphyses, leading to the following:[ 23 ][ 24 ][ 25 ][ 26 ][ 27 ][ 28 ][ 29 ][ 30 ][ 31 ]

Orthovoltage radiation therapy, commonly used before 1970, delivered high doses of radiation to bone and was commonly associated with subsequent abnormalities in bone growth. However, even with contemporary radiation therapy, if a solid tumor is located near an epiphysis or the spine, alterations in normal bone development can be difficult to avoid.

The effects of radiation therapy administered to the spine on stature in survivors of Wilms tumor have been assessed.

Evidence (effect of radiation therapy on the spine and long bones):

1. In the National Wilms Tumor Study (NWTS), studies 1 through 4, stature loss in 2,778 children was evaluated.[ 24 ] Repeated height measurements were collected during long-term follow-up. The effects of radiation dosage, age at treatment, and chemotherapy on stature were analyzed using statistical models that accounted for the normal variation in height with sex and advancing age. Predictions from the model were validated by descriptive analysis of heights measured at ages 17 to 18 years for 205 patients.
2. The effect of radiation therapy on the development of scoliosis has also been re-evaluated. In a group of 42 children treated for Wilms tumor from 1968 to 1994, scoliosis was seen in 18 patients, with only one patient needing orthopedic intervention.[ 32 ]

Osteoporosis and Fractures

Although increased rates of fracture are not reported among long-term survivors of childhood cancer,[ 33 ] maximal peak bone mass is an important factor influencing the risk of osteoporosis and fracture among older patients. Treatment-related factors that affect bone mineral loss include the following:

Most of our knowledge about cancer and treatment effects on bone mineralization has been derived from studies of children with ALL.[ 34 ][ 40 ] In this group, the leukemic process, and possibly vitamin D deficiency, may play a role in the alterations in bone metabolism and bone mass observed at diagnosis.[ 41 ] Antileukemic therapy causes additional bone mineral density loss,[ 42 ] which has been reported to normalize over time [ 43 ][ 44 ] or to persist for many years after completion of therapy.[ 45 ][ 46 ] Clinical factors predicting higher risk of low bone mineral density include treatment with the following:[ 38 ][ 45 ][ 47 ][ 48 ][ 49 ]

The development of osteonecrosis during treatment for ALL also predicts higher risk of low bone density.[ 50 ]

Clinical assessment of bone mineral density in adults treated for childhood ALL indicates that most bone mineral deficits normalize over time after discontinuing osteotoxic therapy.

Evidence (low bone mineral density):

1. A cohort of 845 adult survivors of childhood ALL were evaluated at a median age of 31 years.[ 38 ]
2. Among 862 ALL survivors (median age, 31.3 years) evaluated by quantitative computed tomography of L1 through L2 vertebrae, 30% of survivors had low bone mineral density (z-score below -1) and 18.6% met criteria for frailty or prefrailty.[ 51 ]

   The prefrail phenotype is characterized by having two of five characteristics (low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness) and the frail phenotype is characterized by having three or more of these characteristics. Modifiable factors such as growth hormone deficiency, smoking, and alcohol consumption were significant predictors for these outcomes, with varying impact on the basis of sex. These data underscore the importance of lifestyle counseling and screening for hormonal deficits during long-term survivors' follow-up evaluations.

Bone mineral density deficits that are likely multifactorial in etiology have been reported in allogeneic hematopoietic stem cell transplantation (HSCT) recipients conditioned with TBI.[ 52 ][ 53 ] French investigators observed a significant risk of lower femoral bone mineral density among adult survivors of childhood leukemia treated with HSCT who had gonadal deficiency.[ 54 ] Hormonal therapy has been shown to enhance the bone mineral density of adolescent girls diagnosed with hypogonadism after HSCT.[ 55 ]

Despite disease-related and treatment-related risks of bone mineral density deficits, the prevalence of self-reported fractures among Childhood Cancer Survivor Study (CCSS) participants was lower than that reported by sibling controls. Predictors of increased prevalence of fracture by multivariable analyses included the following:[ 33 ]

Radiation-induced fractures can occur with doses of radiation of 50 Gy or higher, as is often used in the treatment of Ewing sarcoma of the extremity.[ 56 ][ 57 ]

Data from the St. Jude Lifetime Cohort (development) and Erasmus Medical Center (validation) in the Netherlands were used to develop and validate prediction models for low and very low bone mineral density on the basis of clinical and treatment characteristics that identify adult survivors of childhood cancer who require screening by dual-energy x-ray absorptiometry. Low bone mineral density was defined as lumbar spine bone mineral density and/or total-body bone mineral density Z score of -1 or lower; very low bone mineral density was defined as a Z score of -2 or lower. Low bone mineral density was present in 51% and 45% of St. Jude Lifetime and Dutch participants, represented by survivors of both hematologic and solid malignancies, respectively, and very low bone mineral density was present in 20% and 10%, respectively. The model, which included male sex, height, weight, attained age, current smoking status, and cranial irradiation, showed good performance for predicting risk of low bone mineral density (areas under the curve of 0.72 in the St. Jude Lifetime Cohort and 0.69 in the Dutch cohort). The model, which included male sex, height, weight, attained age, cranial irradiation, and abdominal irradiation, showed good performance for predicting risk of very low bone mineral density (areas under the curve of 0.76 in the St. Jude Lifetime Cohort and 0.75 in the Dutch cohort). These models correctly identified bone mineral density status in most white adult survivors through age 40 years using easily measured patient and treatment characteristics.[ 58 ]

Osteonecrosis

Osteonecrosis (also known as aseptic or avascular necrosis) is a rare, but well-recognized skeletal complication observed predominantly in survivors of pediatric hematological malignancies treated with corticosteroids.[ 59 ][ 60 ][ 61 ] The prevalence of osteonecrosis has varied from 1% to 22% based on the study population, treatment protocol, method of evaluation, and time from treatment.[ 61 ][ 62 ][ 63 ][ 64 ][ 65 ][ 66 ][ 67 ][ 68 ]

The condition is characterized by death of one or more segments of bone that most often affects weight-bearing joints, especially the hips and knees. Longitudinal cohort studies have identified a spectrum of clinical manifestations of osteonecrosis, ranging from asymptomatic, spontaneously-resolving imaging changes to painful progressive articular collapse requiring joint replacement.[ 69 ][ 70 ] Symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during the first 2 years of therapy, particularly in patients with ALL. These symptoms may improve over time, persist, or progress in the years after completion of therapy.[ 71 ] In one series, 60% of patients continued to have symptoms at a median follow-up of 4.9 years after diagnosis of osteonecrosis.[ 72 ] Surgical procedures, including core decompression, osteotomy, and joint replacements, are sometimes performed in those with persistently severe symptoms.[ 72 ]

Factors that increase the risk of osteonecrosis include the following:

Studies evaluating the influence of sex on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females [ 69 ][ 72 ][ 80 ] that has not been confirmed by others.[ 60 ][ 69 ]

Osteochondroma

Osteochondromas are benign boney protrusions that can be spontaneous or associated with radiation therapy. They generally occur as a single lesion; however, multiple lesions may develop in the context of hereditary multiple osteochondromatosis.[ 84 ] Approximately 5% of children undergoing myeloablative HSCT will develop osteochondroma, which most commonly presents in the metaphyseal regions of long bones.[ 84 ][ 85 ]

Evidence (risk of osteochondroma):

1. A large Italian study reported a 6.1% cumulative risk of developing osteochondroma at 15 years posttransplant, with increased risk associated with younger age at transplant (≤3 years) and use of TBI.[ 86 ]
2. Osteochondromas have been reported in patients with neuroblastoma who received local radiation therapy, anti-GD2 monoclonal antibody therapy, and isotretinoin. [ 87 ]

Growth hormone therapy may influence the onset and pace of growth of osteochondromas.[ 21 ][ 88 ]

Because malignant degeneration of these lesions is exceptionally rare, clinical rather than radiological follow-up is most appropriate.[ 89 ] Surgical resection is only necessary when the lesion interferes with joint alignment and movement.[ 90 ]

Amputation and Limb-Sparing Surgery

Amputation and limb-sparing surgery prevent local recurrence of bone tumors by removal of all gross and microscopic disease. If optimally executed, both procedures accomplish an en bloc excision of tumor with a margin of normal uninvolved tissue. The type of surgical procedure, the primary tumor site, and the age of the patient affect the risk of postsurgical complications.[ 40 ] Complications in survivors treated with amputation include prosthetic fit problems, chronic pain in the residual limb, phantom limb pain, and bone overgrowth.[ 91 ][ 92 ] While limb-sparing surgeries may offer a more aesthetically pleasing outcome, complications have been reported more frequently in survivors who underwent these procedures than in those treated with amputation. Complications after limb-sparing surgery include non-union, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, and limited joint range of motion.[ 91 ][ 93 ] Occasionally, refractory complications develop after limb-sparing surgery and require amputation.[ 94 ][ 95 ]

A number of studies have compared functional outcomes after amputation and limb-sparing surgery, but results have been limited by inconsistent methods of functional assessment and small cohort sizes. Overall, data suggest that limb-sparing surgery results in better function than amputation, but differences are relatively modest.[ 91 ][ 95 ][ 96 ] Similarly, long-term quality of life outcomes among survivors undergoing amputation and limb sparing procedures have not differed substantially.[ 94 ] A longitudinal analysis of health status among extremity sarcoma survivors in the CCSS indicates an association between lower extremity amputation and increasing activity limitations with age, and an association between upper extremity amputation and lower educational attainment.[ 97 ]

Joint Contractures

HSCT with any history of chronic GVHD is associated with joint contractures.[ 98 ][ 99 ][ 100 ]

Table 13 summarizes bone and joint late effects and the related health screenings.

Table 13. Bone and Joint Late Effects^a

Predisposing Therapy	Musculoskeletal Effects	Health Screening
CT = computed tomography; DXA = dual-energy x-ray absorptiometry; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Radiation impacting musculoskeletal system	Hypoplasia; fibrosis; reduced/uneven growth (scoliosis, kyphosis); limb length discrepancy	Exam: bones and soft tissues in radiation fields
Radiation impacting head and neck	Craniofacial abnormalities	History: psychosocial assessment, with attention to: educational and/or vocational progress, depression, anxiety, posttraumatic stress, social withdrawal
		Head and neck exam
Radiation impacting musculoskeletal system	Radiation-induced fracture	Exam of affected bone
Methotrexate; corticosteroids (dexamethasone, prednisone); radiation impacting skeletal structures; HSCT	Reduced bone mineral density	Bone mineral density test (DXA or quantitative CT)
Corticosteroids (dexamethasone, prednisone)	Osteonecrosis	History: joint pain, swelling, immobility, limited range of motion
		Musculoskeletal exam
Radiation with impact to oral cavity	Osteoradionecrosis	History/oral exam: impaired or delayed healing after dental work, persistent jaw pain or swelling, trismus
Amputation	Amputation-related complications (impaired cosmesis, functional/activity limitations, residual limb integrity, chronic pain, increased energy expenditure)	History: pain, functional/activity limitations
		Exam: residual limb integrity
		Prosthetic evaluation
Limb-sparing surgery	Limb-sparing surgical complications (functional/activity limitations, fibrosis, contractures, chronic infection, chronic pain, limb length discrepancy, increased energy expenditure, prosthetic malfunction [loosening, non-union, fracture])	History: pain, functional/activity limitations
		Exam: residual limb integrity
		Radiograph of affected limb
		Orthopedic evaluation
HSCT with any history of chronic GVHD	Joint contracture	Musculoskeletal exam

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

参考文献

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Late Effects of the Reproductive System

Surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads may compromise reproductive outcomes in childhood cancer survivors. 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.

In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility. It should be noted that 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.

Testis

Cancer treatments that may impair testicular and reproductive function include the following:

Surgery affecting testicular function

Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up.[ 4 ][ 5 ] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms,[ 6 ][ 7 ] and erectile dysfunction may occur after extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.[ 8 ][ 9 ]

Radiation affecting testicular function

Among men treated for childhood cancer, the potential for gonadal injury exists if radiation treatment fields include the pelvis, gonads, or total body. The germinal epithelium is more sensitive to radiation injury than are the androgen-producing Leydig cells. A decrease in sperm counts can be seen 3 to 6 weeks after such irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20–30 Gy). Irreversible germ cell failure may occur with fractionated radiation doses of greater than 2 Gy to 4 Gy.[ 10 ] Administration of higher radiation doses, such as 24 Gy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both germ cell failure and Leydig cell dysfunction.[ 11 ]

Radiation injury to Leydig cells is related to the dose delivered and age at treatment. Testosterone production may be normal in prepubertal boys treated with less than 12 Gy fractionated testicular irradiation, but elevated plasma concentrations of luteinizing hormone observed in this group suggest subclinical injury. Gonadal failure typically results when prepubertal boys are treated with more than 20 Gy of radiation to the testes; androgen therapy is required for masculinization. Leydig cell function is usually preserved in sexually mature male patients if radiation doses do not exceed 30 Gy. Although available data suggest that Leydig cells are more vulnerable when exposed to radiation before puberty, confounding factors, such as the age at testing and the effects of both orchiectomy and chemotherapy, limit the reliability of this observation.[ 12 ]

Chemotherapy affecting testicular function

Cumulative alkylating agent (e.g., cyclophosphamide, mechlorethamine, dacarbazine) dose is an important factor in estimating the risk of testicular germ cell injury, but limited data are available that correlate results of semen analyses in clinically well-characterized cohorts.[ 13 ] In general, Leydig cell function is preserved, but germ cell failure is common in men treated with high cumulative doses of cyclophosphamide (7,500 mg/m² or more) and more than 3 months of combination alkylating agent therapy. Most studies suggest that prepubertal males are not at lower risk for chemotherapy-induced testicular damage than are postpubertal patients.[ 14 ][ 15 ][ 16 ][ 17 ]

Studies of testicular germ cell injury, as evidenced by oligospermia or azoospermia, after alkylating agent administration with or without radiation therapy, have reported the following:

Testicular function after hematopoietic stem cell transplantation (HSCT)

The risk of gonadal dysfunction and infertility related to conditioning with total-body irradiation (TBI), high-dose alkylating agent chemotherapy, or both is substantial. Because transplantation is often undertaken for relapsed or refractory cancer, previous treatment with alkylating agent chemotherapy or hypothalamic-pituitary axis or gonadal radiation therapy may confer additional risks. Age at treatment also influences the risk of gonadal injury. Young boys and adolescents treated with high-dose cyclophosphamide (200 mg/kg) will generally maintain Leydig cell function and testosterone production, but germ cell failure is common. After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure.[ 34 ]

Limited data suggest that a greater proportion of boys will retain germinal function or recovery of spermatogenesis (based on pubertal progress and gonadotropin levels) after reduced-intensity conditioning with fludarabine/melphalan than will those treated with myeloablative conditioning with busulfan/cyclophosphamide.[ 35 ]

Recovery of gonadal function

Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of 201 male survivors of childhood cancer, with a median follow-up of 15.7 years (range, 3–37 years) from diagnosis. The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.3 years (range, 0.7–11.3 years). The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal irradiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level.[ 36 ]

Inhibin B and FSH levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported.[ 37 ] Hence, male survivors should be advised that semen analysis is the most accurate assessment of adequacy of spermatogenesis.

Leydig cell function in long-term survivors of childhood cancer

Leydig cell function in childhood cancer survivors has not been well studied. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for Leydig cell failure and Leydig cell dysfunction in 1,516 men (median age, 30.8 years; median time from diagnosis, 22 years).[ 38 ]

Ovary

Cancer treatments that may impair ovarian function/reserve include the following:

Surgery affecting ovarian function

Oophorectomy performed for the management of germ cell tumors may reduce ovarian reserve. Contemporary treatments utilize fertility-sparing surgical procedures combined with systemic chemotherapy to reduce this risk.[ 39 ]

Radiation affecting ovarian function

In women treated for childhood cancer, the potential for primary gonadal injury exists if treatment fields involve the lumbosacral spine, abdomen, pelvis, or total body. The frequency of ovarian failure after abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. The ovaries of younger individuals are more resistant to radiation damage than are those of older women because of their greater complement of primordial follicles.

Whole-abdomen irradiation at doses of 20 Gy or greater is associated with the highest risk of ovarian dysfunction. Seventy-one percent of women in one series failed to enter puberty, and 26% had premature menopause after receiving whole-abdominal radiation therapy doses of 20 Gy to 30 Gy.[ 40 ] Other studies reported similar results in women treated with whole-abdomen irradiation [ 41 ] or craniospinal irradiation [ 42 ][ 43 ] during childhood.

Chemotherapy affecting ovarian function

Ovarian function may be impaired after treatment with combination chemotherapy that includes an alkylating agent and procarbazine. In general, girls maintain gonadal function at higher cumulative alkylating agent doses than do boys. Most female childhood cancer survivors who are treated with risk-adapted combination chemotherapy retain or recover ovarian function. However, the risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation therapy or dose-intensive alkylating agents for myeloablative conditioning before HSCT.[ 44 ][ 45 ][ 46 ][ 47 ][ 48 ]

Premature ovarian failure

Premature ovarian failure is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal radiation therapy.[ 44 ][ 48 ][ 49 ][ 50 ]

Studies have associated the following factors with an increased rate of premature ovarian failure (acute ovarian failure and premature menopause):

The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred.

Evidence (acute ovarian failure and premature menopause in childhood cancer survivors):

1. Of 3,390 eligible participants in the CCSS, 215 (6.3%) developed acute ovarian failure (defined as never having menses or ceased having menses within 5 years of diagnosis).[ 45 ]
2. The menopausal status of 2,930 survivors participating in the CCSS was compared with that of 1,399 siblings. Nonsurgical premature menopause was defined as sustained menses cessation occurring for more than 6 months beginning 5 years after the cancer diagnosis but before age 40 years that was not caused by pregnancy, surgery, or medications. In 110 survivors who developed nonsurgical premature menopause, the prevalence was 9.1% at age 40 years in a population with a median age of 34 years.[ 48 ]
3. A French cohort study of 1,109 female survivors of childhood solid cancer identified the following risk factors for nonsurgical menopause:[ 50 ]
   1. Exposure to and dose of alkylating agents, especially during adolescence.
   2. Radiation dose to the ovaries.
   3. Oophorectomy.
4. In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure.[ 49 ]
5. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for premature ovarian insufficiency in 921 female childhood cancer survivor participants. Premature ovarian insufficiency was clinically assessed and defined by persistent amenorrhea combined with an FSH level of 30 IU/L or higher before age 40 years.[ 51 ]

Ovarian function after HSCT

The preservation of ovarian function among women treated with HSCT is related to age at treatment, receipt of pretransplant alkylating agent chemotherapy and abdominal-pelvic radiation therapy, and transplant conditioning regimen.[ 46 ][ 52 ]

Evidence (ovarian function among women treated with HSCT):

1. Girls and young women conditioned with TBI or busulfan-based regimens appear to be at equally high risk of declining ovarian function and premature menopause compared with patients conditioned with cyclophosphamide only.[ 46 ] All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide before HSCT for aplastic anemia developed amenorrhea after transplantation.
2. TBI is especially damaging when given in a single fraction.[ 46 ] Most postpubertal women who receive TBI before HSCT develop amenorrhea.
3. Among women with leukemia, cranial irradiation before transplantation further decreased the possibility of retaining ovarian function.[ 46 ]
4. Ovarian function may be better preserved (based on pubertal progress and gonadotropin levels) in females undergoing HSCT with reduced-intensity conditioning using fludarabine/melphalan than in those undergoing conditioning with myeloablative busulfan/cyclophosphamide.[ 35 ]

Fertility

Infertility remains one of the most common life-altering treatment effects experienced by long-term childhood survivors. Pediatric cancer cohort studies have demonstrated the impact of cytotoxic therapy on reproductive outcomes. CCSS investigations have elucidated factors contributing to subfertility among childhood cancer survivors.[ 53 ][ 54 ]

Fertility was evaluated in 10,938 CCSS participants (5,640 males, 5,298 females) and 3,949 siblings.[ 53 ]

Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation.[ 6 ][ 7 ][ 55 ]

In a study of menopausal status on reproductive outcomes in 2,930 survivors from the CCSS, investigators found that for those who ultimately developed nonsurgical premature menopause, rates of pregnancy and live birth were substantially reduced before nonsurgical premature menopause between the ages of 31 and 40 years. However, pregnancy and live birth rates did not differ for those aged 21 to 30 years on the basis of ultimate menopausal status. Treatment variables significant for developing nonsurgical premature menopause by multivariable analyses included exposure to procarbazine doses higher than 4,000 mg/m², any ovarian irradiation, and stem cell transplant.[ 48 ] A cyclophosphamide equivalent dose of 6,000 mg/m² or higher that included procarbazine was significant in the univariate analysis, but did not achieve significance in the multivariable analysis.[ 48 ]

Reproduction

For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups.[ 56 ][ 57 ][ 58 ][ 59 ][ 60 ]

Evidence (pregnancy complications in adults treated for childhood cancer):

1. In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation.[ 56 ]
2. In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births.[ 62 ]
3. Another CCSS study evaluated pregnancy outcomes of partners of male survivors.[ 57 ]
4. Results from a Danish study confirm the association of uterine irradiation with spontaneous abortion, but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified.[ 58 ]
5. In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies.[ 59 ]
6. Most pregnancies reported by HSCT survivors and their partners result in live births.[ 60 ]
7. Preservation of fertility and successful pregnancies may occur after HSCT, although the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. One study evaluated pregnancy outcomes in a group of females treated with HSCT.[ 63 ]
8. A German study demonstrated that the rate of childbearing for female survivors of Hodgkin lymphoma was similar to that of the general population, although the rate of childbearing was lower for survivors who received pelvic radiation therapy.[ 64 ]
9. British CCSS investigators evaluated pregnancy and labor complications among female survivors of childhood cancer treated with abdominal radiation by linking British CCSS cohort data to a national hospital registry.[ 65 ]
10. A systematic review compared the data from published pregnancy and child health outcomes for pediatric and young adult leukemia and lymphoma survivors with the data from controls who did not have a history of cancer.[ 66 ]

Fertility preservation

Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy.[ 67 ] For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors.[ 68 ][ 69 ] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization.[ 70 ]

For females, the most successful assisted-reproductive techniques depend on harvesting and banking the postpubertal patient’s oocytes and cryopreserving unfertilized oocytes or embryos before gonadotoxic therapy.[ 71 ] Options for prepubertal patients are limited to investigational ovarian tissue cryopreservation for later autotransplantation, which may be offered to girls with nonovarian, nonhematologic cancers.[ 72 ]

Offspring of childhood cancer survivors

For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments.

Evidence (children of cancer survivors not at significantly increased risk of congenital anomalies):

1. A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS observed the following:[ 73 ]
2. A study compared 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 with 4,544 offspring of sibling controls.[ 74 ]
3. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring.[ 75 ]

   In the same population-based cohort, survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.

4. In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer.[ 76 ] Data from the five-center study also indicated no excess risk of single-gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings.[ 77 ]
5. In a study that evaluated pregnancy outcomes in 19,412 allogeneic and 17,950 autologous transplant patients, European Group for Blood and Marrow Transplantation investigators did not observe an increased risk of birth defects, developmental delay, or cancer among offspring of male and female HSCT recipients.[ 60 ]
6. A nationwide Finnish population-based registry study compared the risk of congenital anomalies in the offspring of 6,862 long-term survivors of childhood, adolescent, and young adult cancer treated between 1953 and 2004 with the risk of congenital anomalies in the offspring of 35,690 siblings.[ 78 ]

Table 15 summarizes reproductive late effects and the related health screenings.

Table 15. Reproductive Late Effects^a

Predisposing Therapy	Reproductive Late Effects	Health Screening
AMH = anti-mullerian hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Alkylating agents; gonadal irradiation	Testicular hormonal dysfunction: Testosterone deficiency/insufficiency; delayed/arrested puberty	Tanner stage
		Morning testosterone
		LH
	Impaired spermatogenesis: Reduced fertility; oligospermia; azoospermia; infertility	Semen analysis
		FSH
		Inhibin B
	Ovarian hormone deficiencies: Delayed/arrested puberty; premature ovarian insufficiency/premature menopause. Reduced ovarian follicular pool: Diminished ovarian reserve; infertility.	Tanner stage
		Menstrual cycle history
		Estradiol
		FSH
		LH
		AMH
		Antral follicle count

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

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Late Effects of the Respiratory System

Respiratory function may be compromised in long-term survivors of childhood cancer who were treated with the following therapies:

The effects of early lung injury from cancer treatment may be exacerbated by the decline in lung function associated with normal aging, other comorbid chronic health conditions, or smoking. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, description of outcomes following antiquated treatment approaches, and variability in time since treatment and method of ascertainment. No large cohort studies have been performed that include clinical evaluations coupled with functional and quality-of-life assessments.

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, significant clinical disease has been observed.

Evidence (selected cohort studies describing long-term pulmonary function outcomes):

1. The incidence of self-reported pulmonary dysfunction among adults treated for central nervous system malignancies with craniospinal irradiation (per 1,000 person-years) was 9.1 (95% confidence interval, 7.8–10.6) for emphysema/obliterative bronchiolitis and more than 3.0 for asthma, chronic cough, and the need for extra oxygen. High rates of late onset pulmonary dysfunction occurring more than 5 years after diagnosis were also observed.[ 1 ]
2. Dutch investigators reported outcomes of 193 childhood cancer survivors evaluated by pulmonary function testing at a median follow-up of 18 years after diagnosis.[ 2 ]
3. In a longitudinal study evaluating the magnitude and trajectory of pulmonary dysfunction among 121 childhood cancer survivors (median time from diagnosis to last evaluation, 17.1 years) treated with potentially pulmonary-toxic therapy (e.g., bleomycin, busulfan, pulmonary radiation therapy), survivors were significantly more likely to have restrictive and diffusion defects than were healthy controls.[ 3 ]
4. Childhood Cancer Survivor Study investigators compared self-reported pulmonary outcomes and their impact on daily activities among 5-year cancer survivors (median, 25 years from diagnosis) and a sibling cohort.[ 4 ]

Respiratory complications after radiation therapy

Radiation therapy that exposes the lung parenchyma can result in pulmonary dysfunction related to reduced lung volume, impaired dynamic compliance, and deformity of both the lung and chest wall. The potential for chronic pulmonary sequelae is related to the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses.[ 5 ] Combined-modality therapy including radiation therapy and pulmonary toxic chemotherapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment.[ 2 ][ 6 ]

Chronic pulmonary complications reported after treatment for pediatric malignancies include restrictive or obstructive chronic pulmonary disease, pulmonary fibrosis, and spontaneous pneumothorax.[ 7 ] These sequelae are uncommon after contemporary therapy, which most often results in subclinical injury that is detected only by imaging or formal pulmonary function testing.

Evidence (selected cohort studies describing pulmonary outcomes):

1. A study of 48 survivors of pediatric malignant solid tumors followed for a median of 9.7 years after median whole-lung radiation doses of 12 Gy (range, 10.5–18 Gy) reported the following:[ 8 ]
2. For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, many exhibit substantial subclinical dysfunction.[ 11 ]
3. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor.[ 9 ][ 10 ]
4. Administration of bleomycin alone can produce pulmonary toxicity and, when combined with radiation therapy, can heighten radiation reactions. Chemotherapeutic agents such as doxorubicin, dactinomycin, and busulfan are radiomimetic agents and can reactivate underlying radiation damage.[ 9 ][ 10 ][ 12 ]

Respiratory complications after chemotherapy

Chemotherapy agents with potential pulmonary toxic effects commonly used in the treatment of pediatric malignancies include bleomycin, busulfan, and the nitrosoureas (carmustine and lomustine). These agents induce lung damage on their own or potentiate the damaging effects of radiation to the lung. Combined-modality therapy including pulmonary toxic chemotherapy and thoracic radiation therapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment.[ 2 ]

Evidence (outcomes among cohorts treated with pulmonary toxic chemotherapy):

1. The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses greater than 200 U/m² to 400 U/m², higher than those used in treatment protocols for pediatric malignancies.[ 12 ][ 13 ][ 14 ]
2. More current pediatric regimens for Hodgkin lymphoma using radiation therapy and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) have shown a significant incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time.[ 15 ][ 16 ][ 17 ] However, grades 3 and 4 pulmonary toxicity was reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of extended-field radiation.[ 14 ]
3. ABVD-related pulmonary toxic effects may result from fibrosis induced by bleomycin or radiation recall pneumonitis related to administration of doxorubicin.
4. Pulmonary veno-occlusive disease has been observed rarely and has been attributed to bleomycin chemotherapy.[ 18 ]

Respiratory complications associated with HSCT

Patients undergoing HSCT are at increased risk of pulmonary toxic effects related to the following:[ 19 ][ 20 ][ 21 ]

Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur and has been reported to increase in prevalence with increasing time from HSCT, based on limited data from longitudinally followed cohorts.[ 22 ][ 23 ] Obstructive disease is less common, as is late onset pulmonary syndrome, which includes the spectrum of restrictive and obstructive disease. Bronchiolitis obliterans with or without organizing pneumonia, diffuse alveolar damage, and interstitial pneumonia may occur as a component of this syndrome, generally between 6 and 12 months posttransplant. Cough, dyspnea, or wheezing may occur with either normal chest x-ray or diffuse/patchy infiltrates; however, most patients are symptom free.[ 20 ][ 24 ][ 25 ]

Other factors associated with respiratory late effects

Additional factors contributing to chronic pulmonary toxic effects include superimposed infection, underlying pneumonopathy (e.g., asthma), chest wall abnormalities, respiratory toxic effects, chronic GVHD, and the effects of chronic pulmonary involvement by tumor or reaction to tumor.[ 6 ] Lung lobectomy during childhood appears to have no significant impact on long-term pulmonary function,[ 26 ] but the long-term effect of lung surgery for children with cancer is not well defined.

Pulmonary complications may also be exacerbated by smoking cigarettes or other substances. While smoking rates in survivors of childhood cancer tend to be lower than the general population, it is still important to prevent initiation of smoking and promote cessation in this distinct population.[ 27 ]

Evidence (pulmonary dysfunction in former or current smokers):

1. Pulmonary function evaluations of 433 adult childhood cancer survivors treated with pulmonary toxic modalities demonstrated significantly higher risk of pulmonary dysfunction in smokers than in nonsmokers.[ 28 ]

Table 16 summarizes respiratory late effects and the related health screenings.

Table 16. Respiratory Late Effects^a

Predisposing Therapy	Respiratory Effects	Health Screening/Interventions
DLCO = diffusing capacity of the lung for carbon monoxide; GVHD = graft-versus-host disease.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Busulfan; carmustine (BCNU)/lomustine (CCNU); bleomycin; radiation impacting lungs; surgery impacting pulmonary function (lobectomy, metastasectomy, wedge resection)	Subclinical pulmonary dysfunction; interstitial pneumonitis; pulmonary fibrosis; restrictive lung disease; obstructive lung disease	History: cough, shortness of breath, dyspnea on exertion, wheezing
		Pulmonary exam
		Pulmonary function tests (including DLCO and spirometry)
		Chest x-ray
		Counsel regarding tobacco avoidance/smoking cessation
		In patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation before general anesthesia
		Pulmonary consultation for patients with symptomatic pulmonary dysfunction
		Influenza and pneumococcal vaccinations
Hematopoietic cell transplantation with any history of chronic GVHD	Pulmonary toxicity (bronchiolitis obliterans, chronic bronchitis, bronchiectasis)	History: cough, shortness of breath, dyspnea on exertion, wheezing
		Pulmonary exam
		Pulmonary function tests (including DLCO and spirometry)
		Chest x-ray
		Counsel regarding tobacco avoidance/smoking cessation
		In patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation before general anesthesia
		Pulmonary consultation for patients with symptomatic pulmonary dysfunction
		Influenza and pneumococcal vaccinations

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for respiratory late effects information including risk factors, evaluation, and health counseling.[ 29 ]

参考文献

1. Huang TT, Chen Y, Dietz AC, et al.: Pulmonary outcomes in survivors of childhood central nervous system malignancies: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 61 (2): 319-25, 2014.[PUBMED Abstract]
2. Mulder RL, Thönissen NM, van der Pal HJ, et al.: Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 66 (12): 1065-71, 2011.[PUBMED Abstract]
3. Armenian SH, Landier W, Francisco L, et al.: Long-term pulmonary function in survivors of childhood cancer. J Clin Oncol 33 (14): 1592-600, 2015.[PUBMED Abstract]
4. Dietz AC, Chen Y, Yasui Y, et al.: Risk and impact of pulmonary complications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 122 (23): 3687-3696, 2016.[PUBMED Abstract]
5. Huang TT, Hudson MM, Stokes DC, et al.: Pulmonary outcomes in survivors of childhood cancer: a systematic review. Chest 140 (4): 881-901, 2011.[PUBMED Abstract]
6. Kasteler R, Weiss A, Schindler M, et al.: Long-term pulmonary disease among Swiss childhood cancer survivors. Pediatr Blood Cancer 65 (1): , 2018.[PUBMED Abstract]
7. Josephson MB, Goldfarb SB: Pulmonary complications of childhood cancers. Expert Rev Respir Med 8 (5): 561-71, 2014.[PUBMED Abstract]
8. Motosue MS, Zhu L, Srivastava K, et al.: Pulmonary function after whole lung irradiation in pediatric patients with solid malignancies. Cancer 118 (5): 1450-6, 2012.[PUBMED Abstract]
9. McDonald S, Rubin P, Maasilta P: Response of normal lung to irradiation. Tolerance doses/tolerance volumes in pulmonary radiation syndromes. Front Radiat Ther Oncol 23: 255-76; discussion 299-301, 1989.[PUBMED Abstract]
10. McDonald S, Rubin P, Phillips TL, et al.: Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys 31 (5): 1187-203, 1995.[PUBMED Abstract]
11. Venkatramani R, Kamath S, Wong K, et al.: Pulmonary outcomes in patients with Hodgkin lymphoma treated with involved field radiation. Pediatr Blood Cancer 61 (7): 1277-81, 2014.[PUBMED Abstract]
12. Kreisman H, Wolkove N: Pulmonary toxicity of antineoplastic therapy. Semin Oncol 19 (5): 508-20, 1992.[PUBMED Abstract]
13. Bossi G, Cerveri I, Volpini E, et al.: Long-term pulmonary sequelae after treatment of childhood Hodgkin's disease. Ann Oncol 8 (Suppl 1): 19-24, 1997.[PUBMED Abstract]
14. Fryer CJ, Hutchinson RJ, Krailo M, et al.: Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease in children: a report from the Children's Cancer Study Group. J Clin Oncol 8 (12): 1971-80, 1990.[PUBMED Abstract]
15. Hudson MM, Greenwald C, Thompson E, et al.: Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease. J Clin Oncol 11 (1): 100-8, 1993.[PUBMED Abstract]
16. Hunger SP, Link MP, Donaldson SS: ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin's disease: the Stanford experience. J Clin Oncol 12 (10): 2160-6, 1994.[PUBMED Abstract]
17. Marina NM, Greenwald CA, Fairclough DL, et al.: Serial pulmonary function studies in children treated for newly diagnosed Hodgkin's disease with mantle radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Cancer 75 (7): 1706-11, 1995.[PUBMED Abstract]
18. Polliack A: Late therapy-induced cardiac and pulmonary complications in cured patients with Hodgkin's disease treated with conventional combination chemo-radiotherapy. Leuk Lymphoma 15 (Suppl 1): 7-10, 1995.[PUBMED Abstract]
19. Cerveri I, Fulgoni P, Giorgiani G, et al.: Lung function abnormalities after bone marrow transplantation in children: has the trend recently changed? Chest 120 (6): 1900-6, 2001.[PUBMED Abstract]
20. Leiper AD: Non-endocrine late complications of bone marrow transplantation in childhood: part II. Br J Haematol 118 (1): 23-43, 2002.[PUBMED Abstract]
21. Marras TK, Chan CK, Lipton JH, et al.: Long-term pulmonary function abnormalities and survival after allogeneic marrow transplantation. Bone Marrow Transplant 33 (5): 509-17, 2004.[PUBMED Abstract]
22. Inaba H, Yang J, Pan J, et al.: Pulmonary dysfunction in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Cancer 116 (8): 2020-30, 2010.[PUBMED Abstract]
23. Frisk P, Arvidson J, Hedenström H: A longitudinal study of pulmonary function after stem cell transplantation, from childhood to young adulthood. Pediatr Blood Cancer 58 (5): 775-9, 2012.[PUBMED Abstract]
24. Uderzo C, Pillon M, Corti P, et al.: Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties. Bone Marrow Transplant 39 (11): 667-75, 2007.[PUBMED Abstract]
25. Yoshihara S, Yanik G, Cooke KR, et al.: Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13 (7): 749-59, 2007.[PUBMED Abstract]
26. Kreisel D, Krupnick AS, Huddleston CB: Outcomes and late complications after pulmonary resections in the pediatric population. Semin Thorac Cardiovasc Surg 16 (3): 215-9, 2004.[PUBMED Abstract]
27. 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]
28. Oancea SC, Gurney JG, Ness KK, et al.: Cigarette smoking and pulmonary function in adult survivors of childhood cancer exposed to pulmonary-toxic therapy: results from the St. Jude lifetime cohort study. Cancer Epidemiol Biomarkers Prev 23 (9): 1938-43, 2014.[PUBMED Abstract]
29. Liles A, Blatt J, Morris D, et al.: Monitoring pulmonary complications in long-term childhood cancer survivors: guidelines for the primary care physician. Cleve Clin J Med 75 (7): 531-9, 2008.[PUBMED Abstract]

Late Effects of the Special Senses

Hearing

Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatin and carboplatin), cranial radiation therapy, or both. These therapeutic exposures are most common in the treatment of central nervous system (CNS) and non-CNS solid tumors. Children are more susceptible to otologic toxic effects from platinum agents than are adults.[ 1 ][ 2 ] A report from the Swiss Childhood Cancer Survivor Study (CCSS) (N = 2,061) estimated the prevalence of hearing loss in survivors at 10%, compared with 3% in siblings. Hearing loss was most common in survivors of CNS tumors (25%), neuroblastoma (23%), hepatic tumor (21%), germ cell tumor (20%), bone tumor (16%), and soft tissue sarcoma (16%).[ 3 ] Data from the Swiss CCSS indicate that the relative rate of first occurrence of auditory complications (problems hearing sounds, tinnitus, hearing loss, deafness) is greatest in the time period from diagnosis to 5 years postdiagnosis; however, during the period of 5 or more years postdiagnosis, the risk of developing such conditions for survivors remained significantly higher than for siblings.[ 4 ]

Risk factors associated with hearing loss include the following:

Hearing loss and platinum-based therapy

Platinum-related sensorineural hearing loss develops as an acute toxicity that is generally irreversible and bilateral. Hearing loss manifests initially in the high frequencies and progresses to the speech frequencies with increasing cumulative exposure. The prevalence of hearing loss has varied widely per series and is based on platinum treatment (e.g., platinum type, dose, infusion duration); host factors (e.g., age, genetic susceptibility, renal function); receipt of additional ototoxic therapy (cranial radiation therapy, aminoglycosides, loop diuretics), and the grading criteria used to report prevalence and severity of hearing loss.[ 5 ][ 6 ]

Hearing loss and cranial radiation therapy

Cranial radiation therapy, when used as a single modality, may result in otologic toxic effects that may be gradual in onset, manifesting months to years after exposure. The threshold dose for auditory toxicity after radiation therapy alone is in the range of 35 to 45 Gy for children.[ 16 ] High-frequency sensorineural hearing loss is uncommon at cumulative radiation doses below 35 Gy, and is rarely severe below doses of 45 Gy.[ 17 ] The exception is for patients with supratentorial tumors and ventriculoperitoneal shunts, in whom doses below 30 Gy may be associated with intermediate frequency (1,000–2,000 Hz) hearing loss.[ 16 ][ 18 ] To reduce the risk of hearing loss, the average cochlear dose should not exceed 30 to 35 Gy, delivered over 6 weeks. Young patient age and presence of a brain tumor and/or hydrocephalus can increase susceptibility to hearing loss.

Sensorineural hearing loss after cranial radiation therapy can progress over time. In a study of 235 pediatric brain tumor patients treated with conformal or intensity-modulated radiation therapy (without cisplatin or pre-existing hearing loss) and monitored for a median of 9 years, sensorineural hearing loss was prevalent in 14% of patients, with a median time to onset of 3.6 years from radiation therapy. Follow-up evaluations among 29 patients identified continued decline in hearing sensitivity. Risk factors for cranial radiation–associated sensorineural hearing loss included younger age at initiation of radiation, higher cochlear radiation dose, and cerebrospinal fluid shunting.[ 19 ]

When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.[ 16 ][ 20 ][ 21 ][ 22 ] In a report from the CCSS, 5-year survivors were at increased risk of problems with hearing sounds (relative risk [RR], 2.3), tinnitus (RR, 1.7), hearing loss requiring an aid (RR, 4.4), and hearing loss in one or both ears not corrected by a hearing aid (RR, 5.2), compared with siblings. Temporal lobe irradiation (>30 Gy) and posterior fossa irradiation (>50 Gy but also 30–49.9 Gy) were associated with these adverse outcomes. Exposure to platinum was associated with an increased risk of problems with hearing sounds (RR, 2.1), tinnitus (RR, 2.8), and hearing loss requiring an aid (RR, 4.1).[ 4 ]

Hearing loss and quality of life

Importantly, children treated for malignancies may be at risk of early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life.

The Children’s Oncology Group has published recommendations for the evaluation and management of hearing loss in survivors of childhood and adolescent cancers to promote early identification of at-risk survivors and timely referral for remedial services.[ 26 ]

Table 17 summarizes auditory late effects and the related health screenings.

Table 17. Auditory Late Effects^a

Predisposing Therapy	Potential Auditory Effects	Health Screening/Interventions
FM = frequency modulated.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Platinum agents (cisplatin, carboplatin); radiation impacting the ear	Otologic toxic effects; sensorineural hearing loss; tinnitus; vertigo; dehydrated ceruminosis; conductive hearing loss	History: hearing difficulties, tinnitus, vertigo
		Otoscopic exam
		Audiology evaluation
		Amplification in patients with progressive hearing loss
		Speech and language therapy for children with hearing loss
		Otolaryngology consultation in patients with chronic infection, cerumen impaction, or other anatomical problems exacerbating or contributing to hearing loss
		Educational accommodations (e.g., preferential classroom seating, FM amplification system, etc.)

Orbital and Optic

Orbital complications are common after radiation therapy for retinoblastoma and after total-body irradiation (TBI) and in children with head and neck sarcomas and CNS tumors.

Retinoblastoma

For survivors of retinoblastoma, a small orbital volume may result from either enucleation or radiation therapy. Age younger than 1 year may increase risk, but this finding is not consistent across studies.[ 27 ][ 28 ] Progress has been made in the management of retinoblastoma, with better enucleation implants, intravenous chemoreduction, and intra-arterial chemotherapy in addition to thermotherapy, cryotherapy, and plaque radiation therapy. Longer follow-up is needed to assess the impact on vision in patients undergoing these more contemporary treatment modalities.[ 27 ][ 29 ][ 30 ] Previously, tumors located near the macula and fovea were associated with an increased risk of complications leading to vision loss, although treatment of these tumors with foveal laser ablation has shown promise in preserving vision.[ 31 ][ 32 ][ 33 ][ 34 ]

(Refer to the PDQ summary on Retinoblastoma Treatment for more information on the treatment of retinoblastoma.)

Rhabdomyosarcoma

Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia, ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision after radiation therapy doses of 30 Gy to 65 Gy. The higher dose ranges (>50 Gy) are associated with lid epitheliomas, keratoconjunctivitis, lacrimal duct atrophy, and severe dry eye. Retinitis and optic neuropathy may also result from doses of 50 Gy to 65 Gy and even at lower total doses if the individual fraction size is higher than 2 Gy.[ 35 ] Cataracts are reported after lower doses of 10 Gy to 18 Gy.[ 36 ][ 37 ][ 38 ]

(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information on the treatment of rhabdomyosarcoma in children.)

Low-grade optic pathway glioma and craniopharyngioma

Survivors of optic pathway glioma and craniopharyngioma are also at risk of visual complications, resulting in part from tumor proximity to the optic nerve.

In a retrospective cohort study of 59 pediatric patients with sporadic optic pathway gliomas diagnosed between 1990 and 2014 (median follow up, 5.2 years), there was a significant burden of long-term visual impairment. The findings showed that more than two-thirds of the patients had evidence of long-term vision loss, more than one-half had severe vision loss in at least one eye, and one-quarter of the patients had severe bilateral vision loss. Identified risk factors for poor visual outcome were postchiasmal involvement, younger age, and optic nerve pallor at presentation.[ 39 ]

Longitudinal follow-up (mean, 9 years) of 21 patients with optic pathway gliomas indicated that before treatment, 81% of patients had reduced visual acuity, 81% had optic nerve pallor, and all had reduced visual evoked potentials in one or both eyes. Treatment arrested acuity loss for 4 to 5 years. Visual acuity was stable or improved in 33% of patients at last follow-up; however, it declined on average. Visual acuity at follow-up was related to tumor volume at initial presentation.[ 40 ]

In a study of 51 children with low-grade gliomas and low-grade glioneural tumors diagnosed within the first year of life, visual acuity was decreased in 27 of 48 patients (56%), 13 (27%) of whom were legally blind. The tumor location (hypothalamic or optic pathway) was significantly associated with decreased visual acuity (P = .002).[ 41 ]

In a study of 25 patients diagnosed with craniopharyngioma, 67% had visual complications at a mean follow-up of 11 years.[ 42 ] A retrospective review of 30 children with craniopharyngioma revealed that 19 patients had vision loss before surgery; 21 patients had postsurgical vision loss. Preoperative vision loss was predicative of postoperative vision loss.[ 43 ]

CCSS investigators evaluated the impact of impaired vision on cognitive and psychosocial outcomes among 1,233 adult survivors of childhood low-grade gliomas. Some degree of visual impairment was prevalent in 22.5% of patients, and 3.8% of patients were blind in both eyes. Survivors who were blind in both eyes were more likely to be unmarried, live dependently, and be unemployed than were survivors with unimpaired vision. However, bilateral blindness did not impact self-reported cognitive or emotional outcomes. Impaired (with some remaining) vision was not associated with psychological or economic outcomes.[ 44 ]

Treatment-specific effects

Survivors of childhood cancer are at increased risk for ocular late effects related to both glucocorticoid and radiation exposure to the eye.

Evidence (ocular effects of radiation exposure):

1. The CCSS reported that survivors who were 5 or more years from diagnosis were at increased risk of developing cataracts (RR, 10.8), glaucoma (RR, 2.5), legal blindness (RR, 2.6), double vision (RR, 4.1), and dry eye (RR, 1.9), compared with siblings.[ 45 ]
2. The 15-year cumulative incidence of cataract was 4.5% among 517 survivors of childhood acute lymphoblastic leukemia (median, 10.9 years from diagnosis), systematically evaluated by slit lamp examination. CNS radiation therapy was the only treatment-related risk factor identified for cataract development, which occurred in 11.1% of irradiated survivors, compared with 2.8% of those who were not irradiated.[ 46 ]
3. A report from the CCSS provides additional data on the interval from radiation therapy and the radiation dose associated with the development of cataracts.[ 47 ]

Ocular complications, such as cataracts and dry eye syndrome, are common after stem cell transplantation in childhood.

Evidence (ocular effects of stem cell transplantation):

1. Compared with patients treated with busulfan or other chemotherapy, patients treated with single-dose or fractionated TBI are at increased risk of cataracts. Risk ranges from approximately 10% to 60% at 10 years posttreatment, depending on the total dose and fractionation, with a shorter latency period and more severe cataracts noted after single fraction and higher dose or dose-rate TBI.[ 48 ][ 49 ][ 50 ][ 51 ]
2. Patients receiving TBI doses of less than 40 Gy have a less than 10% chance of developing severe cataracts.[ 51 ]
3. Corticosteroids and graft-versus-host disease may further increase risk.[ 48 ][ 52 ]
4. The prevalence of cataracts, evaluated by serial slit lamp testing, among 271 participants (mean follow-up, 10.3 years) in the Leucémie Enfants Adolescents (LEA) program was 41.7%, with 8.1% requiring surgical intervention.[ 53 ] In this cohort, the cumulative incidence of cataracts among those treated with TBI increased over time from 30% at 5 years to 70.8% at 15 years and 78% at 20 years. The lack of a plateau in cataract incidence suggests that nearly all patients treated with TBI will develop cataracts as follow-up increases. In contrast, the 15-year cumulative incidence of cataracts was 12.5% among those conditioned with busulfan. Multivariable analysis identified high cumulative steroid dose as a potential cofactor with TBI for cataract risk.
5. Dry eye syndrome has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine.[ 54 ]

Table 18 summarizes ocular late effects and the related health screenings.

Table 18. Ocular Late Effects^a

Predisposing Therapy	Ocular/Vision Effects	Health Screening/Interventions
GVHD = graft-versus-host disease; 131I = iodine I 131.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Busulfan; corticosteroids; radiation impacting the eye	Cataracts	History: decreased acuity, halos, diplopia
		Eye exam: visual acuity, funduscopy (yearly)
		Ophthalmology consultation
Radiation impacting the eye, including radioiodine (131I)	Ocular toxicity (orbital hypoplasia, lacrimal duct atrophy, xerophthalmia [keratoconjunctivitis sicca], keratitis, telangiectasias, retinopathy, optic chiasm neuropathy, enophthalmos, chronic painful eye, maculopathy, papillopathy, glaucoma)	History: visual changes (decreased acuity, halos, diplopia), dry eye, persistent eye irritation, excessive tearing, light sensitivity, poor night vision, painful eye
		Eye exam: visual acuity, funduscopy (yearly)
		Ophthalmology consultation
Hematopoietic cell transplantation with any history of chronic GVHD	Xerophthalmia (keratoconjunctivitis sicca)	History: dry eye (burning, itching, foreign body sensation, inflammation)
		Eye exam: visual acuity, funduscopy (yearly)
Enucleation	Impaired cosmesis; poor prosthetic fit; orbital hypoplasia	Ocular prosthetic evaluation
		Ophthalmology

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for information on the late effects of special senses, including risk factors, evaluation, and health counseling.

参考文献

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23. Gurney JG, Tersak JM, Ness KK, et al.: Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group. Pediatrics 120 (5): e1229-36, 2007.[PUBMED Abstract]
24. Olivier TW, Bass JK, Ashford JM, et al.: Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors. J Clin Oncol 37 (18): 1566-1575, 2019.[PUBMED Abstract]
25. Brinkman TM, Bass JK, Li Z, et al.: Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer 121 (22): 4053-61, 2015.[PUBMED Abstract]
26. Bass JK, Knight KR, Yock TI, et al.: Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (7): 1152-62, 2016.[PUBMED Abstract]
27. Kaste SC, Chen G, Fontanesi J, et al.: Orbital development in long-term survivors of retinoblastoma. J Clin Oncol 15 (3): 1183-9, 1997.[PUBMED Abstract]
28. Peylan-Ramu N, Bin-Nun A, Skleir-Levy M, et al.: Orbital growth retardation in retinoblastoma survivors: work in progress. Med Pediatr Oncol 37 (5): 465-70, 2001.[PUBMED Abstract]
29. Shields CL, Shields JA: Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol 21 (3): 203-12, 2010.[PUBMED Abstract]
30. Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010.[PUBMED Abstract]
31. Shields CL, Shields JA: Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 36 (1): 8-18; quiz 35-6, 1999 Jan-Feb.[PUBMED Abstract]
32. Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108 (11): 2116-21, 2001.[PUBMED Abstract]
33. Shields JA, Shields CL: Pediatric ocular and periocular tumors. Pediatr Ann 30 (8): 491-501, 2001.[PUBMED Abstract]
34. Schefler AC, Cicciarelli N, Feuer W, et al.: Macular retinoblastoma: evaluation of tumor control, local complications, and visual outcomes for eyes treated with chemotherapy and repetitive foveal laser ablation. Ophthalmology 114 (1): 162-9, 2007.[PUBMED Abstract]
35. Kline LB, Kim JY, Ceballos R: Radiation optic neuropathy. Ophthalmology 92 (8): 1118-26, 1985.[PUBMED Abstract]
36. 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]
37. Oberlin O, Rey A, Anderson J, et al.: Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop. J Clin Oncol 19 (1): 197-204, 2001.[PUBMED Abstract]
38. Raney RB, Anderson JR, Kollath J, et al.: Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991. Med Pediatr Oncol 34 (6): 413-20, 2000.[PUBMED Abstract]
39. Wan MJ, Ullrich NJ, Manley PE, et al.: Long-term visual outcomes of optic pathway gliomas in pediatric patients without neurofibromatosis type 1. J Neurooncol 129 (1): 173-8, 2016.[PUBMED Abstract]
40. Kelly JP, Leary S, Khanna P, et al.: Longitudinal measures of visual function, tumor volume, and prediction of visual outcomes after treatment of optic pathway gliomas. Ophthalmology 119 (6): 1231-7, 2012.[PUBMED Abstract]
41. 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]
42. Poretti A, Grotzer MA, Ribi K, et al.: Outcome of craniopharyngioma in children: long-term complications and quality of life. Dev Med Child Neurol 46 (4): 220-9, 2004.[PUBMED Abstract]
43. Fisher PG, Jenab J, Gopldthwaite PT, et al.: Outcomes and failure patterns in childhood craniopharyngiomas. Childs Nerv Syst 14 (10): 558-63, 1998.[PUBMED Abstract]
44. de Blank PM, Fisher MJ, Lu L, et al.: Impact of vision loss among survivors of childhood central nervous system astroglial tumors. Cancer 122 (5): 730-9, 2016.[PUBMED Abstract]
45. Whelan KF, Stratton K, Kawashima T, et al.: Ocular late effects in childhood and adolescent cancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer 54 (1): 103-9, 2010.[PUBMED Abstract]
46. Alloin AL, Barlogis V, Auquier P, et al.: Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study. Br J Haematol 164 (1): 94-100, 2014.[PUBMED Abstract]
47. Chodick G, Sigurdson AJ, Kleinerman RA, et al.: The Risk of Cataract among Survivors of Childhood and Adolescent Cancer: A Report from the Childhood Cancer Survivor Study. Radiat Res 185 (4): 366-74, 2016.[PUBMED Abstract]
48. Ferry C, Gemayel G, Rocha V, et al.: Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant 40 (3): 219-24, 2007.[PUBMED Abstract]
49. Fahnehjelm KT, Törnquist AL, Olsson M, et al.: Visual outcome and cataract development after allogeneic stem-cell transplantation in children. Acta Ophthalmol Scand 85 (7): 724-33, 2007.[PUBMED Abstract]
50. Gurney JG, Ness KK, Rosenthal J, et al.: Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: results from the Bone Marrow Transplant Survivor study. Cancer 106 (6): 1402-8, 2006.[PUBMED Abstract]
51. Kal HB, VAN Kempen-Harteveld ML: Induction of severe cataract and late renal dysfunction following total body irradiation: dose-effect relationships. Anticancer Res 29 (8): 3305-9, 2009.[PUBMED Abstract]
52. Holmström G, Borgström B, Calissendorff B: Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Ophthalmol Scand 80 (2): 211-5, 2002.[PUBMED Abstract]
53. Horwitz M, Auquier P, Barlogis V, et al.: Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study. Br J Haematol 168 (4): 518-25, 2015.[PUBMED Abstract]
54. Fahnehjelm KT, Törnquist AL, Winiarski J: Dry-eye syndrome after allogeneic stem-cell transplantation in children. Acta Ophthalmol 86 (3): 253-8, 2008.[PUBMED Abstract]

Late Effects of the Urinary System

Acute toxicity of the urinary system from cancer therapy is well known. Less is known about the genitourinary outcomes in long-term survivors.[ 1 ] The evidence for long-term renal injury in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in time since treatment, and method of ascertainment. In particular, the inaccuracies of diagnosing chronic kidney dysfunction by estimating equations of glomerular dysfunction should be considered.[ 2 ] Cancer treatments predisposing to renal injury and/or high blood pressure later in life include the following:

The risk and degree of renal dysfunction depend on type and intensity of therapy, and the interpretation of the studies is compromised by variability in testing.

Few large-scale studies have evaluated late renal-health outcomes and risk factors for renal dysfunction among survivors treated with potentially nephrotoxic modalities.

Evidence (renal dysfunction in childhood cancer survivors):

1. In a large, cross-sectional study of 1,442 childhood cancer survivors (median attained age, 19.3 years; median time from diagnosis, 12.1 years), Dutch investigators assessed the presence of albuminuria, hypomagnesemia, hypophosphatemia, and hypertension, and they estimated glomerular filtration rate (GFR) among survivors treated with ifosfamide, cisplatin, carboplatin, high-dose cyclophosphamide (>1 g/m² or more per course), or high-dose methotrexate (>1 g/m² or more per course), radiation therapy to the kidney region, total-body irradiation (TBI), or nephrectomy.[ 3 ]

Therapy-related factors affecting the kidney

Cancer treatments predisposing to late renal injury and hypertension include the following:[ 4 ][ 5 ][ 6 ]

Genetic factors predisposing to renal dysfunction

Many childhood survivors of Wilms tumor who develop chronic renal failure have syndromes accompanying WT1 mutations or deletions that predispose to renal disease. Data from the National Wilms Tumor Study Group and the U.S. Renal Data System indicate that the 20-year cumulative incidence of end-stage renal disease in children with unilateral Wilms tumor and Denys-Drash syndrome is 74%, 36% for those with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome, 7% for male patients with genitourinary anomalies, and 0.6% for patients with none of these conditions.[ 28 ] For patients with bilateral Wilms tumors, the incidence of end-stage renal disease is 50% for Denys-Drash syndrome, 90% for WAGR, 25% for genitourinary anomaly, and 12% for others.[ 28 ][ 29 ] End-stage renal disease in patients with WAGR and genitourinary anomalies tended to occur relatively late, and often during or after adolescence.[ 28 ]

Therapy-related bladder complications

Pelvic or central nervous system surgery, alkylator-containing chemotherapy such as cyclophosphamide or ifosfamide, pelvic radiation therapy, and certain spinal and genitourinary surgical procedures have been associated with urinary bladder late effects, as follows:[ 30 ]

Kidney Transplant

In a study of solid organ transplants in 13,318 survivors in the Childhood Cancer Survivor Study, 71 survivors had end-stage kidney disease that warranted kidney transplants, 50 of whom received a kidney transplant. At 35 years after cancer diagnosis, the cumulative incidence of a kidney transplant was 0.39%, and the cumulative incidence of being placed on the waiting list or receiving a kidney was 0.54%. Exposure to ifosfamide and receiving TBI were associated with the highest hazard ratio for being placed on the waiting list or receiving a kidney transplant. The 5-year survival rate from the time of kidney transplant was 93.5%, which is similar to that of the general population in the same age range.[ 37 ]

Table 19 summarizes kidney and bladder late effects and the related health screenings.

Table 19. Kidney and Bladder Late Effects^a

Predisposing Therapy	Renal/Genitourinary Effects	Health Screening
BUN = blood urea nitrogen; NSAIDs = nonsteroidal anti-inflammatory drugs; RBC/HFP = red blood cells per high-field power (microscopic exam).
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
Cisplatin/carboplatin; ifosfamide; calcineurin inhibitors	Renal toxicity (glomerular injury, tubular injury [renal tubular acidosis], Fanconi syndrome, hypophosphatemic rickets)	Blood pressure
		BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
		Urinalysis
		Electrolyte supplements for patients with persistent electrolyte wasting
		Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Methotrexate; radiation impacting kidneys/urinary tract	Renal toxicity (renal insufficiency, hypertension)	Blood pressure
		BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
		Urinalysis
		Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Nephrectomy	Renal toxicity (proteinuria, hyperfiltration, renal insufficiency)	Blood pressure
		BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
		Urinalysis
		Discuss contact sports, bicycle safety (e.g., avoiding handlebar injuries), and proper use of seatbelts (i.e., wearing lap belts around hips, not waist)
		Counsel to use NSAIDs with caution
		Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Nephrectomy; pelvic surgery; cystectomy	Hydrocele	Testicular exam
Cystectomy	Cystectomy-related complications (chronic urinary tract infections, renal dysfunction, vesicoureteral reflux, hydronephrosis, reservoir calculi, spontaneous neobladder perforation, vitamin B12/folate/carotene deficiency [patients with ileal enterocystoplasty only])	Urology evaluation
		Vitamin B12 level
Pelvic surgery; cystectomy	Urinary incontinence; urinary tract obstruction	History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
		Counsel regarding adequate fluid intake, regular voiding, seeking medical attention for symptoms of voiding dysfunction or urinary tract infection, compliance with recommended bladder catheterization regimen
		Urologic consultation for patients with dysfunctional voiding or recurrent urinary tract infections
Cyclophosphamide/Ifosfamide; radiation impacting bladder/urinary tract	Bladder toxicity (hemorrhagic cystitis, bladder fibrosis, dysfunctional voiding, vesicoureteral reflux, hydronephrosis)	History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
		Urinalysis
		Urine culture, spot urine calcium/creatinine ratio, and ultrasound of kidneys and bladder for patients with microscopic hematuria (defined as ≥5 RBC/HFP on at least 2 occasions)
		Nephrology or urology referral for patients with culture-negative microscopic hematuria AND abnormal ultrasound and/or abnormal calcium/creatinine ratio
		Urology referral for patients with culture negative macroscopic hematuria

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

参考文献

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3. Knijnenburg SL, Jaspers MW, van der Pal HJ, et al.: Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors. Clin J Am Soc Nephrol 7 (9): 1416-27, 2012.[PUBMED Abstract]
4. Jones DP, Spunt SL, Green D, et al.: Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 724-31, 2008.[PUBMED Abstract]
5. Dekkers IA, Blijdorp K, Cransberg K, et al.: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 8 (6): 922-9, 2013.[PUBMED Abstract]
6. Mulder RL, Knijnenburg SL, Geskus RB, et al.: Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study. Cancer Epidemiol Biomarkers Prev 22 (10): 1736-46, 2013.[PUBMED Abstract]
7. Interiano RB, Delos Santos N, Huang S, et al.: Renal function in survivors of nonsyndromic Wilms tumor treated with unilateral radical nephrectomy. Cancer 121 (14): 2449-56, 2015.[PUBMED Abstract]
8. Marina NM, Poquette CA, Cain AM, et al.: Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol 22 (2): 112-8, 2000 Mar-Apr.[PUBMED Abstract]
9. Hartmann JT, Fels LM, Franzke A, et al.: Comparative study of the acute nephrotoxicity from standard dose cisplatin +/- ifosfamide and high-dose chemotherapy with carboplatin and ifosfamide. Anticancer Res 20 (5C): 3767-73, 2000 Sep-Oct.[PUBMED Abstract]
10. Skinner R, Parry A, Price L, et al.: Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: relevance of age and dose as risk factors. Eur J Cancer 45 (18): 3213-9, 2009.[PUBMED Abstract]
11. Skinner R, Kaplan R, Nathan PC: Renal and pulmonary late effects of cancer therapy. Semin Oncol 40 (6): 757-73, 2013.[PUBMED Abstract]
12. Stöhr W, Paulides M, Bielack S, et al.: Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. Pediatr Blood Cancer 48 (2): 140-7, 2007.[PUBMED Abstract]
13. Skinner R, Cotterill SJ, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group. Br J Cancer 82 (10): 1636-45, 2000.[PUBMED Abstract]
14. Stöhr W, Paulides M, Bielack S, et al.: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 48 (4): 447-52, 2007.[PUBMED Abstract]
15. Oberlin O, Fawaz O, Rey A, et al.: Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 27 (32): 5350-5, 2009.[PUBMED Abstract]
16. Widemann BC, Balis FM, Kim A, et al.: Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28 (25): 3979-86, 2010.[PUBMED Abstract]
17. Cohen EP, Robbins ME: Radiation nephropathy. Semin Nephrol 23 (5): 486-99, 2003.[PUBMED Abstract]
18. Dawson LA, Kavanagh BD, Paulino AC, et al.: Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S108-15, 2010.[PUBMED Abstract]
19. Mitus A, Tefft M, Fellers FX: Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics 44 (6): 912-21, 1969.[PUBMED Abstract]
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21. Peschel RE, Chen M, Seashore J: The treatment of massive hepatomegaly in stage IV-S neuroblastoma. Int J Radiat Oncol Biol Phys 7 (4): 549-53, 1981.[PUBMED Abstract]
22. Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 26 (2): 75-80, 1996.[PUBMED Abstract]
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26. Abboud I, Porcher R, Robin M, et al.: Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15 (10): 1251-7, 2009.[PUBMED Abstract]
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Changes to This Summary (04/02/2020)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Late Effects of the Cardiovascular System

This section was comprehensively reviewed and extensively revised.

Late Effects of the Endocrine System

This section was comprehensively reviewed and extensively revised.

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PDQ® Pediatric Treatment Editorial Board. PDQ Late Effects of Treatment for Childhood Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/late-effects-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389273]

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