Late Effects of Treatment for Childhood Cancer (PDQ®)

As a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, a core part of our mission is to educate patients and the community about cancer. The following summary is trusted information from the NCI.

General Information

During the past 5 decades, dramatic progress has been made in the development of curative therapy for pediatric malignancies. Long-term survival into adulthood is the expectation for 80% of children with access to contemporary therapies for pediatric malignancies. The therapy responsible for this survival can also produce adverse long-term health-related outcomes, referred to as "late effects," that manifest months to years after completion of cancer treatment. Late effects are commonly experienced by adults who have survived childhood cancer and demonstrate an increasing prevalence associated with longer time elapsed from cancer diagnosis.

Research has clearly demonstrated that late effects contribute to a high burden of morbidity among adults treated for cancer during childhood, with at least two-thirds developing one or more chronic health conditions and at least one-third experiencing severe or life-threatening complications during adulthood. 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. With the exception of survivors requiring intensive multimodal therapy for aggressive or refractory/relapsed malignancies, life-threatening treatment effects are relatively uncommon after contemporary therapy. However, survivors still frequently experience life-altering morbidity related to effects of cancer treatment affecting endocrine, reproductive, musculoskeletal, and neurologic function.

Mortality

Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer. Several studies of very large cohorts of survivors have reported early mortality among individuals treated for childhood cancer compared with age- and gender-matched general population controls.; [Level of evidence: 3iA] Relapsed/refractory primary cancer remains the most frequent cause of death, followed by excess cause-specific mortality from second primary cancers and cardiac and pulmonary toxicity. Despite high premature morbidity rates, overall mortality has decreased over time. This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from second 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 for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.

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 changing pediatric cancer therapeutic approaches and reducing treatment-related mortality among survivors treated in more recent eras. These investigations have also informed the development of risk counseling and health screening recommendations of long-term survivors by identifying the clinical and treatment characteristics of those at highest risk for treatment complications. The common late effects of pediatric cancer encompass several broad domains including growth and development, organ function, reproductive capacity and health of offspring, and secondary carcinogenesis. In addition, survivors of childhood cancer may experience a variety of adverse psychosocial sequelae related to the primary cancer, its treatment, or maladjustment associated with the cancer experience.

Late sequelae of therapy for childhood cancer can be anticipated based on therapeutic exposures, but the magnitude of risk and the manifestations in an individual patient are influenced by numerous factors. Factors that should be considered in the risk assessment for a given late effect include the following:

  • Tumor location.
  • Direct tissue effects.
  • Tumor-induced organ dysfunction.
  • Mechanical effects.
  • Radiation therapy: total dose, fraction size, organ or tissue volume, type of machine energy.
  • Chemotherapy: agent type, dose-intensity, cumulative dose, schedule.
  • Surgery: technique, site.
  • Use of combined modality therapy.
  • Blood product transfusion.
  • Hematopoietic cell transplantation.
  • Gender.
  • Age at diagnosis.
  • Time from diagnosis/therapy.
  • Developmental status.
  • Genetic predisposition.
  • Inherent tissue sensitivities and capacity for normal tissue repair.
  • Function of organs not affected by cancer treatment.
  • Premorbid health state.
  • Socioeconomic status.
  • Health habits.

Resources to Support Survivor Care

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. Specifically, 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 previous cancer, cancer therapy, genetic predisposition, lifestyle behaviors, and comorbid conditions. Part of long-term follow-up should also be 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. A Childhood Cancer Survivor Study (CCSS) investigation observed that treatment with cranial radiation doses of 25 Gy or higher was associated with higher odds of unemployment (health related: odds ratio [OR] = 3.47; 95% confidence interval [CI], 2.54–4.74; seeking work: OR = 1.77; 95% CI, 1.15–2.71). Unemployed survivors reported higher levels of poor physical functioning than employed survivors, had lower education and income, and were more likely to be publicly insured than unemployed siblings. These data emphasize the importance of facilitating survivor access to remedial services, which has been demonstrated to have a positive impact on education achievement, 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 should also be emphasized. Health-promoting behaviors should be stressed for survivors of childhood cancer, as targeted educational efforts appear to be worthwhile. Smoking, excess alcohol use, and illicit drug use increase risk of organ toxicity and, potentially, second malignant neoplasms. Unhealthy dietary practices and sedentary lifestyle may exacerbate treatment-related metabolic and cardiovascular complications. 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.

Unfortunately, the majority of childhood cancer survivors do not receive recommended risk-based care. The CCSS reported that 88.8% of survivors were receiving some form of medical care; however, only 31.5% reported receiving care that focused on their prior cancer (survivor-focused care), and 17.8% reported receiving survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests. Among the same cohort, surveillance for new cases of cancer was very low in survivors at the highest risk for colon, breast, or skin cancer, suggesting that survivors and their physicians need education about their risks and recommended surveillance. Health insurance access appears to play an important role in access to risk-based survivor care. In a related CCSS study, uninsured survivors were less likely than those privately insured to report a cancer-related visit (adjusted relative risk [RR] = 0.83; 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR = 0.83; 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care compared with privately insured survivors. In contrast, publicly insured survivors were more likely to report a cancer-related visit (adjusted RR = 1.22; 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR = 1.41; 95% CI, 1.18–1.70) than were privately insured survivors. Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors. Legislation, like the Health Insurance Portability and Accountability Act legislation, 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 of Survivor Care

Transition of care from the pediatric to the adult health care setting is necessary for most childhood cancer survivors in the United States. When available, multidisciplinary long-term follow-up (LTFU) 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. An essential service of LTFU programs is the organization of an individualized survivorship care plan that includes details about therapeutic interventions undertaken for childhood cancer and their potential health risks, personalized health screening recommendations, and information about lifestyle factors that modify risks. 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 (see the COG Survivorship Guidelines Appendix 1).

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. The COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers are appropriate for asymptomatic survivors presenting for routine exposure-based medical follow-up 2 or more years after completion of therapy. Patient education materials called ''Health Links'' provide detailed information on guideline-specific topics to enhance health maintenance and promotion among this population of cancer survivors. Multidisciplinary system-based (e.g., cardiovascular, neurocognitive, and reproductive) task forces who are responsible for monitoring the literature, evaluating guideline content, and providing recommendations for guideline revisions as new information becomes available have also published several comprehensive reviews that address specific late effects of childhood cancer. Information concerning late effects is summarized in tables throughout this summary.

References:
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  • Cox CL, Montgomery M, Rai SN, et al.: Supporting breast self-examination in female childhood cancer survivors: a secondary analysis of a behavioral intervention. Oncol Nurs Forum 35 (3): 423-30, 2008.
  • 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.
  • 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.
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Second Malignant Neoplasms

Second malignant neoplasms (SMNs) are defined as histologically distinct malignancies developing at least 2 months after completion of treatment for the primary malignancy. The cumulative incidence of SMNs exceeds 20% at 30 years after diagnosis of the primary cancer; factors that influence the incidence of SMNs include the type of primary cancer, treatment, and genetic predisposition to cancer. This represents a 6-fold increased risk of SMNs among cancer survivors, compared with the general population. SMNs are the leading cause of non-relapse late mortality (standardized mortality ratio [SMR] = 15.2; 95% CI, 13.9–16.6). The risk of SMNs remains elevated for more than 30 years from diagnosis of the primary cancer. The incidence and type of SMNs differ with the primary cancer diagnosis, type of therapy received, and presence of genetic conditions. Unique associations with specific therapeutic exposures have resulted in the classification of SMNs into the following two distinct groups:

  • Chemotherapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML).
  • Radiation-related solid SMNs.

Characteristics of t-MDS/AML include a short latency (<3 years from primary cancer diagnosis) and association with alkylating agents and/or topoisomerase II inhibitors. Solid SMNs have a strong and well-defined association with radiation and are characterized by a latency that exceeds 10 years. Furthermore, the risk of solid SMNs continues to climb with increasing follow-up, whereas the risk of t-MDS/AML plateaus after 10 to 15 years.

Therapy-Related Leukemia

Therapy-related myelodysplasia 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. t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types are recognized by the World Health Organization (WHO) classification:

  • Alkylating agent-related type: Alkylating agents associated with t-MDS/AML include cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, nitrosoureas, chlorambucil, and dacarbazine. The risk of alkylating agent–related t-MDS/AML is dose dependent, with a latency of 3 to 5 years after exposure; it is associated with abnormalities involving chromosomes 5 (-5/del[5q]) and 7 (-7/del[7q]).
  • Topoisomerase II inhibitor-related type: Most of the translocations observed in patients exposed to topoisomerase II inhibitors disrupt a breakpoint cluster region between exons 5 and 11 of the band 11q23 and fuse mixed lineage leukemia (MLL) with a partner gene. Topoisomerase II inhibitor-related t-AML presents as overt leukemia after a latency of 6 months to 3 years and is associated with balanced translocations involving chromosome bands 11q23 or 21q22.

The rate of second cancers in childhood ALL survivors, even after salvage therapy, does not appear to be high.

Therapy-Related Solid Second Malignant Neoplasms

Therapy-related solid SMNs demonstrate a strong relationship with ionizing radiation. The risk of solid SMNs is highest when the exposure occurs at a younger age, increases with the total dose of radiation, and with increasing follow-up after radiation. Eighty percent of all SMNs are solid SMNs. Some of the well-established radiation-related solid SMNs include the following:

  • Breast cancer: Breast cancer is the most common therapy-related solid SMN after HL, largely because of the high-dose chest radiation used to treat HL (standardized incidence ratio [SIR] of second breast cancer = 25 to 55). For female HL patients treated with chest radiation at younger than 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years. The latency period after chest radiation ranges from 8 to 10 years, and the risk of second breast cancer increases in a linear fashion with radiation dose (P for trend <.001). Radiation-induced breast cancer has been reported to have more adverse clinicopathological features compared with breast cancer in age-matched population controls.
  • Thyroid cancer: Thyroid cancer is observed after neck radiation for HL, ALL, brain tumors, and after total-body irradiation for hematopoietic stem cell transplantation. The risk of thyroid cancer has been reported to be 18-fold that of the general population. Radiation therapy at a young age is the major risk factor for the development of second thyroid cancers. A linear dose-response relationship between thyroid cancer and radiation is observed up to 29 Gy, with a decline in the odds ratio (OR) at higher doses, especially in children younger than 10 years at treatment, demonstrating evidence for a cell kill effect.
  • Brain tumors: Brain tumors develop after cranial radiation for histologically distinct brain tumors or for management of disease among ALL or non-Hodgkin lymphoma patients. The risk for second brain tumors also demonstrates a linear relationship with radiation dose.
  • Bone tumors: The risk of second bone tumors has been reported to be 133-fold that of the general population, with an estimated 20-year cumulative risk of 2.8%. Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk. Radiation therapy is associated with a linear dose-response relationship. After adjustment for radiation therapy, treatment with alkylating agents has also been linked to bone cancer, with the risk increasing with cumulative drug exposure.
  • Lung cancer: Lung cancer has been reported after chest irradiation for HL. The risk rises with increasing follow-up. Smoking has been linked with the occurrence of lung cancer developing after radiation for HL. The increase in risk of lung cancer with increasing radiation dose is greater among patients who smoke after exposure to radiation than among those who refrain from smoking (P = .04).

Second Malignant Neoplasms and Genetic Susceptibility

Literature clearly supports the role of chemotherapy and radiation in the development of SMNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome. Previous studies have demonstrated that childhood cancer survivors with either a family history of cancer, but more so, presence of Li-Fraumeni syndrome, carry an increased risk of developing an SMN. The risk of SMNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome). However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes. The interindividual variability in risk of SMNs 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. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase-1 (NQO1), and others. The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.

DNA repair

DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and oncogenes that can lead to cancer initiation and progression. An individual's DNA repair capacity appears to be genetically determined. A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity. Mismatch repair (MMR) corrects mismatched DNA base pairs that arise as a result of misincorporation errors that have avoided polymerase proofreading during DNA replication. Approximately 50% of t-MDS/AML patients have microsatellite instability, associated with methylation of the MMR family member MLH1, low expression of MSH2, or polymorphisms in MSH2. RAD51 is one of the central proteins in the homologous repair (HR) pathway, functioning to bind to DNA and promote ATP-dependent homologous pairing and strand transfer reactions. RAD51 G135C polymorphism is significantly over-represented in patients with t-MDS/AML compared with controls (allele: OR = 2.7). XRCC3 also functions in the HR DSB repair pathway by directly interacting with and stabilizing RAD51. XRCC3 is a paralog of RAD51, also essential for genetic stability. Although XRCC3 Thr241Met was not associated with t-MDS/AML (OR = 1.4; 95% confidence interval [CI], 0.7–2.9), a synergistic effect resulting in an 8-fold increased risk of t-MDS/AML (OR = 8.1; 95% CI, 2.2–29.7) was observed in the presence of XRCC3 Thr241Met and RAD51 G135C allele in patients with t-MDS/AML compared with controls. Base excision repair (BER) pathway corrects individually damaged bases occurring as a result of ionizing radiation and exogenous xenobiotic exposure. The XRCC1 protein plays a central role in the BER pathway and also in the repair of single strand breaks, by acting as a scaffold and recruiting other DNA repair proteins. The presence of XRCC1 399Gln has been shown to be protective for t-MDS/AML.

Screening and Follow-up for Second Malignant Neoplasms

Vigilant screening is important for those at risk:

  • Screening for leukemia: t-MDS/AML usually manifests within 10 years following exposure. Recommendations include monitoring with annual complete blood count for 10 years after exposure to alkylating agents or topoisomerase II inhibitors.
  • Screening for early-onset colorectal cancer: Screening of those at risk for early-onset colorectal cancer (i.e., radiation doses of 30 Gy or higher to the abdomen, pelvis, or spine) should include colonoscopy every 5 years beginning at age 35 years or 10 years following radiation (whichever occurs last).
  • Screening after radiation exposure: Most other SMNs are associated with radiation exposure. Screening recommendations include careful annual physical examination of the skin and underlying tissues in the radiation field. Since outcome after breast cancer is closely linked to stage at diagnosis, close surveillance resulting in early diagnosis should confer survival advantage. Mammography, the most widely accepted screening tool for breast cancer in the general population, may not be the ideal screening tool by itself for radiation-related breast cancers occurring in relatively young women with dense breasts; hence, the American Cancer Society recommends including adjunct screening with magnetic resonance imaging (MRI). Thus, the recommendations for females who received radiation with potential impact to the breast (i.e., radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields) include monthly breast self-examination beginning at puberty; annual clinical breast examinations beginning at puberty until age 25 years; and a clinical breast examination every 6 months, with annual mammograms and MRIs beginning 8 years after radiation or at age 25 years (whichever occurs later).
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Late Effects of the Cardiovascular System

Radiation, chemotherapy, and biologic agents, both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer; in fact, cardiovascular disease is the leading cause of noncancer mortality in select cancers such as Hodgkin lymphoma (HL). Therapeutic exposures conferring the highest risk are the anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone) and thoracic radiation. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.

The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. However, the pathogenesis of injury differs, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes. Late effects of radiation to the heart include the following:

  • Delayed pericarditis, which can present abruptly or as a chronic pericardial effusion.
  • Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
  • Myopathy (in the absence of significant pericardial disease).
  • Coronary artery disease (CAD), usually involving the left anterior descending artery.
  • Functional valve injury, often aortic.
  • Conduction defects.

In a recent report, detailed dose-response evaluations for both radiation therapy and anthracycline administration were conducted for the risks (self-reported) of congestive heart failure (CHF), myocardial infarction (MI), pericardial disease, and valvular abnormalities.

Compared with siblings, survivors of childhood cancer were significantly more likely to report CHF (hazard ratio [HR] = 5.9; 95% confidence interval [CI], 3.4–9.6), MI (HR = 5.0; 95 % CI, 2.3–10.4), pericardial disease (HR = 6.3; 95 % CI, 3.3–11.9), or valvular abnormalities (HR = 4.8; 95 % CI, 3.0–7.6). Cardiac radiation exposure of 15 Gy or more increased the risk of CHF, MI, pericardial disease, and valvular abnormalities by 2- to 6-fold compared with nonirradiated survivors. There was no evidence for increased risk following doses less than 5 Gy, and slight elevations in risk were not statistically significant following doses between 5 to 15 Gy. The HR for the four self-reported cardiac conditions ranged from 3.6 to 5.5 for cardiac doses greater than 35 Gy. Exposure to 250 mg/m2 or more of anthracyclines also increased the risk of CHF, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 years after diagnosis and ranged from about 2% to slightly over 4% overall, but to much higher cumulative percentages for those receiving the highest cardiac radiation doses and the highest cumulative dose of anthracyclines. In a report from the Netherlands that assessed subclinical cardiac function, of 601 eligible childhood cancer survivors, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF). The median overall LVSF in the whole group of childhood cancer survivors was 33.1% (range, 13.0%–56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF. Vincristine was associated with a nonsignificant decrease in cardiac function (P = .07).

Hodgkin Lymphoma

Hodgkin lymphoma (HL) continues to be the pediatric malignancy associated with the greatest risk of cardiovascular disease, with a 13.1 excess absolute risk per 10,000 person years for cardiovascular death. However, with current techniques and reduced doses of radiation therapy, these effects are unlikely following treatment for childhood cancer.

Recent data from the German-Austrian DAL-HD studies show a dose response for cardiac diseases in children treated for HL with combined radiation and anthracycline-based chemotherapy (cumulative doxorubicin dose was uniformly 160 mg/m2). The 25-year cumulative incidence of cardiac diseases was 3% with no radiation therapy, 5% after 20 Gy, 6% after 25 Gy, 10% after 30 Gy, and 21% after 36 Gy. An older study of 635 patients treated for childhood HL confirms the risks that occur after higher-dose radiation therapy. The actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute MI; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. In an analysis of 48 patients treated for Hodgkin lymphoma from 1970 to 1991 with mediastinal therapy (median dose 40 Gy), 43% had unsuspected valvular abnormalities, 75% had a conduction abnormality or arrhythmia, and 30% had reduced VO2 during exercise tests. These abnormalities were noted at a mean of 15.5 years posttherapy suggesting that survivors of HL treated with these doses of mediastinal radiation therapy require long-term cardiology follow-up. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.

Cardiac radiation using sophisticated treatment planning and careful blocking to doses of 25 Gy or less is generally safe, and 40 Gy may be safely administered to small cardiac regions. The risk of delayed CAD after lower radiation doses, however, requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD—such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia—are likely to impact the frequency of disease.

Other Malignancies

Data from the Childhood Cancer Survivor Study (CCSS) demonstrate the significant cardiovascular morbidity that occurs across a number of other childhood cancer survivor diagnostic groups, with the caveat that the data is based on self-report. A study of self-reported late effects among 1,607 survivors of childhood brain tumors showed that 18% of survivors reported a heart or circulatory late effect. Risk was highest among those treated with surgery, radiation therapy, and chemotherapy compared to surgery and radiation therapy alone, suggesting a potential additive vascular injury from chemotherapy. Children who receive spinal radiation for treatment of central nervous system tumors have been demonstrated to show low maximal cardiac index on exercise testing and pathologic Q-waves in inferior leads on electrocardiogram (ECG) testing, and higher posterior-wall stress. In another report of acute lymphoblastic leukemia (ALL) survivors reporting a chronic medical condition in the CCSS cohort, the risk of a cardiac condition was nearly 7-fold higher compared with the siblings. No significant association was identified based on radiation exposure. A similar analysis among acute myeloid leukemia (AML) survivors in the cohort found the 20-year cumulative incidence of cardiac disease to be 4.7. Twenty-one percent of rhabdomyosarcoma survivors reported at least one cardiac sequelae compared with siblings. Among survivors of non-Hodgkin lymphoma, the standard mortality ratio for cardiac disease was 6.9. A recent follow-up study of Wilms tumor survivors reported a cumulative risk of congestive heart failure of 4.4% at 20 years for those who received doxorubicin as part of their initial therapy and 17.4% at 20 years where doxorubicin was received as part of therapy for relapsed disease. Risk factors for congestive heart failure in this cohort included female gender, lung irradiation with doses 20 Gy or higher, left-sided abdominal irradiation, and doxorubicin dosage of 300 mg/m2 or more. Finally, cardiac complications after bone marrow transplantation may occur, with arrhythmias, pericarditis, and myopathies predominating. High-dose cyclophosphamide clearly is a causative agent; total-body irradiation is a secondary contributing factor.

Doxorubicin

Increased risk of doxorubicin-related cardiomyopathy is associated with the following:

  • Female gender.
  • Cumulative doses greater than 200 mg/m2 to 300 mg/m2.
  • Younger age at time of exposure.
  • Increased time from exposure.

Schedule of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48 hour) versus bolus (1 hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m2 for treatment of ALL and found no difference in the degree or spectrum of cardiotoxicity in the two groups. Because the follow-up time in this study was relatively short, it is not yet clear whether the frequency of progressive cardiomyopathy will differ between the two groups over time. Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one-third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups. Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.

A number of studies have examined cardiac function after radiation therapy and doxorubicin exposure using cardiopulmonary exercise stress tests and have found abnormalities in exercise endurance, cardiac output, aerobic capacity, echocardiography during exercise testing, and ectopic rhythms. Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of left ventricular (LV) contractility. It remains unclear whether these abnormalities will have clinical impact. Asymptomatic cardiotoxicity can be demonstrated in patients who have normal clinical assessments, and abnormalities can be linked to lower self-reported health and New York Heart Association cardiac function scores. Clearly, additional studies with long-term follow-up will be necessary to determine optimal screening modalities and frequencies.

Prevention or amelioration of doxorubicin-induced cardiomyopathy is clearly important because the continued use of doxorubicin is required in cancer therapy. Dexrazoxane (DZR) is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with doxorubicin. Studies suggest that DZR is safe and does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; however, at this time, this should not preclude treatment with DZR.

Two closed Pediatric Oncology Group therapeutic phase III studies for HL measured myocardial toxicity clinically and sequentially over time by echocardiography and electrocardiography, and by determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage. The angiotensin-converting enzyme inhibitor enalapril has been used in the attempt to ameliorate doxorubicin-induced LV dysfunction. Although a transient improvement in LV function and structure was noted in 18 children, LV wall thinning continued to deteriorate; thus the intervention with enalapril was not considered successful. For this reason, studies to date in doxorubicin-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity.

Rhythm disturbances have also been reported after doxorubicin exposure. One study looked at ECG in 52 long-term survivors of childhood cancer who had been treated with doxorubicin. Prolongation of corrected QT interval (QTc) of more than 0.43 was noted in 6 of 22 patients who received cumulative doxorubicin doses greater than 300 mg/m2, compared with 0 of 15 patients who received lower doxorubicin doses. Thoracic radiation therapy increased the risk in both groups, though the higher doxorubicin dose group still demonstrated a higher frequency of prolongation of QTc. Exercise further prolonged the QTc in 6 of 10 patients evaluated.

Vascular Disease/Cerebrovascular Accident

A spectrum of vascular morbidities may occur after radiation therapy used to treat malignancies such as lymphomas, head and neck cancers, and brain tumors. Specifically, carotid artery and cerebrovascular injury occur after cervical and central nervous system irradiation. The relative risk for cerebrovascular accident (CVA [stroke]) in the CCSS cohort was almost ten-fold higher compared with the sibling control group; notably, risks were highest among the adult survivors of childhood ALL, brain tumors, and HL. Leukemia survivors were six times more likely to suffer a CVA compared with their siblings, whereas brain tumor survivors were 29 times more likely to suffer a CVA. Of the brain tumor cohort, 69 of 1,411 patients who had a history of radiation therapy reported a CVA (4.9%), with a cumulative incidence of 6.9% (95% CI, 4.47–9.33) at 25 years. Survivors exposed to cranial radiation therapy greater than 30 Gy had an increased risk for CVA, with the highest risk among those treated with greater than 50 Gy. Adult survivors of childhood HL who were treated with thoracic radiation therapy, including mediastinal and neck, had a 5.6-fold increased risk for CVA than their siblings (median dose 40 Gy). In another study from the Netherlands of 2,201 5-year survivors of HL (of whom 547 were younger than 21 years), and with median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 CVA, 31 transient ischemic attacks [TIA], and 10 both CVA and TIA), with a median age at diagnosis of 52 years. Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolism (24%). The standardized incidence ratio (SIR) for CVA was 2.2, and for TIA it was 3.1. The cumulative incidence of ischemic CVA or TIA 30 years after HL treatment was 7%. For patients younger than 21 years, the SIR for CVA was 3.8, and for TIA it was 7.6. Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR = 2.5; 95% CI, 1.1–5.6) versus without radiation therapy. Treatment with chemotherapy was not associated with increased risk. It is noteworthy that hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not.

Table 1. Cardiovascular Late EffectsPredisposing Therapy Potential Cardiovascular EffectsHealth ScreeningDOE = dyspnea on exertion; SOB = shortness of breath.Anthracyclines (daunorubicin, doxorubicin, idarubicin, epirubicin); mitoxantrone Cardiomyopathy; arrhythmias; subclinical left ventricular dysfunction History: SOB, DOE, orthopnea, chest pain, palpitations Cardiovascular examEchocardiogramElectrocardiogramLaboratory: lipid profile, consider troponin levelRadiation impacting the heartCongestive heart failure; cardiomyopathy; pericarditis/pericardial fibrosis; valvular disease; atherosclerotic heart disease/myocardial infarction; arrhythmia History: SOB, DOE, orthopnea, chest pain, palpitations Cardiovascular exam: signs of heart failure, arrhythmia, valve dysfunctionEchocardiogram ElectrocardiogramLaboratory: lipid profileRadiation impacting vascular structuresCarotid or subclavian artery diseaseHistory: transient/permanent neurological events Blood pressureCardiovascular exam: peripheral pulses, presence of bruitsNeurological exam Carotid ultrasound Laboratory: lipid profilePlant alkaloids (vinblastine, vincristine)Vasospastic attacks (Raynaud's phenomena); autonomic dysfunction (e.g., monotonous pulse) History: vasospasms of hands, feet, nose, lips, cheeks, or earlobes related to stress or cold temperatures Exam of affected area Electrocardiogram Platinum agents (cisplatin, carboplatin)DyslipidemiaFasting lipid profile

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

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Late Effects of the Central Nervous System

Neurocognitive

Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation or intraventricular/intrathecal (IT) chemotherapy; thus, children with CNS tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL) are most commonly affected. Deficits occur in a variety of areas that include the following:

  • General intelligence.
  • Age-appropriate developmental progress.
  • Academic achievement (especially in reading, language, and mathematics).
  • Visual and perceptual motor skills.
  • Nonverbal and verbal memory.
  • Receptive and expressive language and attention.

For both CNS tumors and ALL, younger age at time of treatment is associated with an increased neurocognitive deficit.

Some studies of children treated with cranial or craniospinal radiation therapy for CNS tumors demonstrated a significant adverse neurocognitive effect of therapy. Other studies using lower doses and more targeted volumes, however, have demonstrated improved results. One study supports the hypothesis that medulloblastoma patients demonstrate a decline in intelligence quotient (IQ) values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, not because of a loss of previously acquired information and skills. In a Danish study of 133 children treated for brain tumors, younger age at diagnosis, tumor site in the cerebral hemisphere, hydrocephalus treatment with shunt, and radiation therapy were predictors of lower cognitive functions. Similar findings were obtained in a series of 182 5-year survivors of childhood low-grade gliomas in which 34% had an IQ below average (<85), which was associated with younger age at diagnosis, epilepsy, and shunt placement. In a large cohort of CNS malignancy survivors to adulthood (n = 802) reported from the Childhood Cancer Survivor Study (CCSS), the risk of neurocognitive dysfunction was significantly associated with treatment involving cranial irradiation or placement of a ventriculoperitoneal shunt, and a history of stroke, paralysis, or auditory difficulties. CNS malignancy survivors with neurocognitive impairment from this study when compared with non-CNS malignancy and sibling control groups were found to have deficits in both information processing speed and working memory. Another study evaluated quantitative tissue volumes from magnetic resonance imaging scans, correlating these results with neurocognitive assessments for 40 long-term survivors of pediatric brain tumors treated with radiation therapy with or without chemotherapy 2.6 to 15.3 years earlier (median, 5.7 years) at an age of 1.7 to 14.8 years (median, 6.5 years). Analyses revealed significant impairments in patients' neurocognitive test performance on all measures. After statistically controlling for age at time of radiation therapy and time from radiation therapy, significant associations were found between normal-appearing white matter volumes and both attentional abilities and IQ, and between attentional abilities and IQ. These associations were also correlated with deficiencies in academic skills such as reading, spelling, and math.

For children with ALL, studies again show significant neurocognitive impairment when cranial radiation is combined with IT chemotherapy. Reduction in the cranial radiation dose may result in less neurocognitive impairment.

The effects of radiation on the brain are difficult to define, especially when cranial radiation is a part of multimodality therapy that may also include surgery, systemic chemotherapy, or IT chemotherapy. Moreover, tumor-related deficits because of direct invasion of the brain, seizures, and hydrocephalus must be recognized. The CCSS reported that in adult survivors of childhood CNS malignancies, neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between radiation therapy to the frontal and/or temporal lobes and lower rates of employment and marriage. Studies on CNS prophylaxis for ALL comparing craniospinal radiation therapy with cranial radiation therapy combined with IT methotrexate showed that children who were younger than 5 years at time of treatment and had received radiation therapy and IT chemotherapy had lower IQ scores than those who received craniospinal radiation therapy alone. Similarly, another study found a significant IQ deficit in children treated with 24 Gy of cranial radiation combined with IT methotrexate, as compared with childhood cancer survivors who received no CNS-directed therapy, with the effect greatest among those younger than 5 years. A similar effect on cognition with the addition of IT methotrexate has been found in children treated for medulloblastoma.

Systemic methotrexate in high doses and combined with radiation therapy can lead to a well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious. 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. The deleterious effects of systemic methotrexate, especially at doses above 1 g/m2 may be no different or worse than those of 18 Gy of cranial radiation therapy. At lower methotrexate doses, there does not appear to be a consistent pattern of neurocognitive deficits. One long-term study of infants who received high-dose systemic methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and who were tested 3 to 9 years posttreatment showed that cognitive function was in the average range.

Chemotherapy alone for ALL may result in cognitive dysfunction; however, these effects are subtle compared with the effects noted with radiation therapy. Global measures of cognitive dysfunction such as rates of marriage, employment, college attendance, and high school graduation appear to be similar in children treated with radiation therapy or chemotherapy alone. One study examined 48 children treated for leukemia without cranial radiation therapy and found impairment in tasks of higher-order cognitive functioning and learning disabilities in the area of mathematics. Another study showed that children, particularly females, treated with systemic and IT methotrexate for CNS leukemia prophylaxis showed impairment of verbal memory and coding. One other study reported mild visual and verbal short-term memory deficits in leukemia survivors treated with IT chemotherapy. Another study examined 20 patients treated for leukemia without cranial radiation therapy and found no significant neurocognitive deficits, even when patients were exposed to either IT or high-dose intravenous (IV) methotrexate. In general, patients who receive IT chemotherapy without cranial radiation as CNS therapy may have subtle long-term neurocognitive sequelae, and the deficits that develop represent relatively modest declines in a limited number of domains of neuropsychological functioning. This modest decline is especially seen in young children and girls. Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances, although long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization. Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies.

Neurocognitive abnormalities have been reported in other groups of cancer survivors besides patients with CNS tumors and ALL. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors had impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that in the sibling comparison. Factors such as diagnosis at age younger than 6 years, female gender, cranial radiation therapy, and hearing impairment were associated with impairment.

Cognitive and academic consequences of stem cell transplantation in children have also been evaluated. In a report from the St. Jude Children's Research Hospital in which 268 patients were treated with stem cell transplant, minimal risk of late cognitive and academic sequelae was seen. Subgroups of patients were at relatively higher risk, including those undergoing unrelated donor transplantation, receiving total-body irradiation, and those with graft-versus-host disease. However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status. Neurocognitive function of pediatric patients with hematologic malignancies who had undergone hematopoietic stem cell transplantation (HSCT) was evaluated prior to HSCT and then at 1, 3, and 5 years post-HSCT. In this series of 38 patients who had all received IT chemotherapy as part of their treatment, significant declines in visual motor skills and memory test scores were noted within the first year posttransplant. By 3 years posttransplant, there was an improvement in the visual motor development scores and memory scores, but there were new deficits seen in long-term memory scores. By 5 years posttransplant, there were progressive declines in verbal skills, performance skills, and new deficits seen in long-term verbal memory scores. The greatest decline in neurocognitive function occurred in patients who received cranial irradiation either as part of their initial therapy or as part of their HSCT conditioning. Most neurocognitive late effects 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 associated with white matter was compared with performance on measures associated with gray matter. Composite white matter scores were significantly lower than composite gray matter scores.

Other Neurologic Sequelae

In a report from the CCSS that compared 4,151 adult survivors of childhood ALL with their siblings, survivors were at an elevated risk for late-onset coordination problems, motor problems, seizures, and headaches. The overall cumulative incidence was 44% at 20 years. Serious headaches were most common, with a cumulative incidence of 25.8% at 20 years followed by focal neurologic dysfunction (21.2%) and seizures (7%). Children who were treated with regimens that included cranial radiation for ALL and those who suffer relapse were at increased risk for late-onset neurologic sequelae.

Table 2. Central Nervous System Late EffectsPredisposing TherapyNeurologic EffectsHealth ScreeningIQ = intelligence quotient; IT = intrathecal; IV = intravenous.Platinum agents (carboplatin, cisplatin) Peripheral sensory neuropathyNeurologic examPlant alkaloid agents (vinblastine, vincristine) Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias)Neurologic examMethotrexate (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 deficitsHistory: cognitive, motor, and/or sensory deficits, seizuresNeurologic examRadiation impacting cerebrovascular structures Cerebrovascular complications (stroke, moyamoya, occlusive cerebral vasculopathy)History: transient/permanent neurological events Blood pressureNeurologic exam Neurosurgery–brain Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizuresNeurologic exam Neurology evaluationNeurosurgery–brain Hydrocephalus; shunt malfunction Abdominal x-ray Neurosurgery evaluationNeurosurgery–spine Neurogenic bladder; urinary incontinence History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary streamNeurosurgery–spine Neurogenic bowel; fecal incontinenceHistory: chronic constipation, fecal soiling Rectal exam Predisposing TherapyNeuropsychological EffectsHealth ScreeningMethotrexate (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 have adverse quality of life or other adverse psychologic outcomes. 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 those 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, in whom rates of psychological maladjustment range from 25% to 93%. In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome indicators of successful adult adaptation (educational attainment, income, employment, and marital status) were most likely in survivors who report neurocognitive dysfunction.

Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post traumatic stress symptoms (PTSS) and post traumatic stress disorder (PTSD) in children with cancer, typically no higher than healthy comparison children. Patient and parent adaptive style are significant determinants of PTSD in the pediatric oncology setting. The incidence of PTSD and PTSS has been reported in 15% to 20% of young adult survivors of childhood cancer. Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than those without PTSD. A subset of adult survivors (9%) from the CCSS reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD significantly more frequently than sibling control subjects. In this study, PTSD was significantly associated with being unmarried, having an annual income of less than $20,000, being unemployed, having a high school education or less, and being older than 30 years. Survivors who underwent cranial radiation therapy at younger than 4 years were at particularly high risk for PTSD. Intensive treatment was also associated with increased risk of full PTSD.

Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceived 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.(Refer to the PDQ summary on Post-traumatic Stress Disorder for more information about PTSD in cancer patients.)

In a study of 101 adult cancer survivors of childhood cancer, psychologic 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 radiation. In this study, the instrument was shown to be feasible in the setting of a clinic visit because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to result in distress on the part on the survivors in 80% of cases. (Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information about psychological distress and cancer patients.)

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

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Late Effects of the Digestive System

Dental

Both chemotherapy and radiation therapy can cause multiple cosmetic and functional abnormalities of dentition, most predominantly in children treated before age 5 years who have not yet developed deciduous dentition. However, even older prepubertal children are at risk. Developing teeth are irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system (CNS) leukemia, nasopharyngeal cancer, and as a component of total-body irradiation (TBI). Doses of 20 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification. More than 85% of survivors of head and neck rhabdomyosarcoma who receive radiation doses greater than 40 Gy may have significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia.

Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots and enamel abnormalities. 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. TBI has been linked to the development of short, V-shaped roots, microdontia, enamel hypoplasia, and premature apical closure. Children who undergo bone marrow transplantation with TBI for neuroblastoma are at substantial risk for a spectrum of abnormalities and require close surveillance and appropriate interventions.

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. Dental caries are the most problematic consequence. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.

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. These findings give health care providers further impetus to encourage routine dental 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 and cancer patients.)

Table 3. Oral/Dental Late EffectsPredisposing TherapyOral/Dental EffectsHealth Screening/InterventionsCT = computed tomography; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.Any chemotherapy; radiation impacting oral cavity Dental developmental abnormalities; tooth/root agenesis; microdontia; root thinning/shortening; enamel dysplasia Dental evaluation and cleaning every 6 monthsRegular dental care including fluoride applications Consultation with orthodontist experienced in management of irradiated childhood cancer survivors Baseline panorex prior to dental procedures to evaluate root development Radiation impacting oral cavity Malocclusion; temporomandibular joint dysfunction Dental evaluation and cleaning every 6 monthsRegular dental care including fluoride applications Consultation with orthodontist experienced in management of irradiated childhood cancer survivors Baseline panorex prior to dental procedures to evaluate root development 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 monthsSupportive care with saliva substitutes, moistening agents, and sialogogues (pilocarpine)Regular dental care including fluoride applicationsRadiation impacting oral cavity (≥40 Gy) OsteoradionecrosisHistory: impaired or delayed healing following dental workExam: persistent jaw pain, swelling or trismus Imaging studies (x-ray, CT scan and/or MRI) may assist in making diagnosisSurgical biopsy may be needed to confirm diagnosisConsider hyperbaric oxygen treatments

Digestive Tract

Radiation and specific chemotherapeutic agents may produce gastrointestinal (GI) or hepatic toxicity that is acute and transient in the majority of patients, but rarely may be delayed and persistent. 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. In general, fractionated doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy cause bowel obstruction or chronic enterocolitis. Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.

A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation. One study comprehensively evaluated intestinal symptoms in 44 children with cancer who underwent whole-abdominal (10 Gy to 40 Gy) and involved-field (25 Gy to 40 Gy) radiation and received additional interventions predisposing them to GI tract complications including abdominal laparotomy in 43 (98%) and chemotherapy in 25 (57%) patients. Late small bowel obstruction was observed in 36% of patients surviving 19 months to 7 years, which was uniformly preceded by small bowel toxicity during therapy. Reports from the Intergroup Rhabdomyosarcoma Study evaluating GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma infrequently observed abnormalities of the irradiated bowel. Radiation-related complications occurred in approximately 10% of long-term survivors of paratesticular and bladder/prostate rhabdomyosarcoma and included intraperitoneal adhesions with bowel obstruction, chronic diarrhea, and stricture or enteric fistula formation. Children irradiated at lower doses for Wilms tumor also uncommonly develop chronic GI toxicity. Several studies have reported cases of small bowel obstruction following abdominal surgery, but the role of radiation appears to be less important as operative findings of enteritis have not consistently been observed.

Table 4. Digestive Tract Late EffectsPredisposing TherapyGastrointestinal EffectsHealth Screening/InterventionsGVHD = graft-versus-host disease; KUB = kidneys, ureter, bladder (plain abdominal radiograph).Radiation impacting esophagus; hematopoietic cell transplantation with any history of chronic GVHD Esophageal stricture History: dysphagia, heart burnEsophageal dilation, antireflux surgeryRadiation impacting bowel Chronic enterocolitis; fistula; strictures History: nausea, vomiting, abdominal pain, diarrheaSerum protein and albumin levels yearly in patients with chronic diarrhea or fistulaSurgical and/or gastroenterology consultation for symptomatic patientsRadiation impacting bowel; laparotomy Bowel obstruction History: abdominal pain, distention, vomiting, constipationExam: tenderness, abdominal guarding, distension (acute episode)Obtain KUB in patients with clinical symptoms of obstructionSurgical consultation in patients unresponsive to medical managementPelvic surgery; cystectomy Fecal incontinence History: chronic constipation, fecal soilingRectal exam

Hepatobiliary

Hepatic complications resulting from childhood cancer therapy are uncommon and observed primarily as acute treatment toxicities. Recipients of hematopoietic stem cell transplantation (HSCT) are the exception to this rule as these individuals frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and toxic etiologies. 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 has been reported in a subset of children who developed VOD/SOS following treatment with 6-thioguanine. Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors. In the transplant setting, VOD/SOS has also been observed following conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide and carmustine/cyclophosphamide/etoposide. Because high-dose cyclophosphamide is common to all of these regimens, toxic cyclophosphamide metabolites resulting from the agent's variable metabolism have been speculated as a causative factor.

Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS. In adults, where 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. Based on limited data from pediatric cohorts treated in the 1970s and 1980s, persistent radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload. The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, prior partial hepatectomy, and concomitant use of radiomimetic chemotherapy like dactinomycin and doxorubicin. 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.

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. Chronic hepatitis predisposes cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with both viruses accelerates the progression of liver disease. Since the majority of patients received some type of blood product during childhood cancer treatment and many are unaware of their transfusion history, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products. Therefore, all children who received blood transfusions before 1972 should be screened for hepatitis B and before 1993 should be screened for hepatitis C virus and referred for discussion of treatment options.

Less commonly reported hepatobiliary complications include cholelithiasis, focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), and microvesicular fatty change. In limited studies, an increased risk of cholelithiasis has been linked to ileal conduit, parenteral nutrition, abdominal surgery, abdominal radiation, and HSCT. Lesions made up of regenerating liver called FNH have been incidentally noted after chemotherapy or HSCT. These lesions are thought to be iatrogenic manifestations of vascular damage and have been associated with VOD, high-dose alkylating agents (e.g., busulfan and melphalan), and liver radiation therapy. The prevalence of this finding is unknown, noted at less than 1% in some papers; however, this is likely an underestimate. In one study of patients who were followed by magnetic resonance imaging (MRI) after transplant to assess liver iron stores, the cumulative incidence was 35% at 150 months posttransplant. The lesions can mimic metastatic or secondary tumors, but MRI imaging is generally diagnostic, and unless the lesions grow or patients have worrisome symptoms, biopsy or resection is generally not necessary.

Nodular regenerative hyperplasia (NRH) is a rare condition characterized by the development of multiple monoacinar regenerative hepatic nodules and mild fibrosis. The pathogenesis is not well established, but may represent a nonspecific tissue adaptation to heterogeneous hepatic blood flow. NRH has rarely been observed in survivors of childhood cancer treated with chemotherapy, with or without liver radiation therapy. Biopsy may be necessary to distinguish NRH from a second malignancy.

In a cohort who recently completed intensified therapy for acute lymphoblastic leukemia, histologic evidence of fatty infiltration was noted in 93% and siderosis in up to 70% of patients. Fibrosis developed in 11% and was associated with higher serum low-density lipoprotein (LDL) cholesterol. Prospective studies are needed to define whether acute posttherapy fatty liver change contributes to the development of steatohepatitis or the metabolic syndrome in this population. Likewise, information about the long-term outcomes of transfusion-related iron overload are lacking, especially among survivor cohorts who did not undergo hematopoietic cell transplantation.

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 5. Hepatobiliary Late EffectsPredisposing TherapyHepatic EffectsHealth Screening/InterventionsALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation.Methotrexate; mercaptopurine/thioguanine; HSCTHepatic dysfunction Lab: ALT, AST, bilirubin levelsFerritin in those treated with HSCTMercaptopurine/thioguanine; HSCTVeno-occlusive disease/sinusoidal obstructive syndrome Exam: scleral icterus, jaundice, ascites, hepatomegaly, splenomegalyLab: ALT, AST, bilirubin, platelet levels Ferritin in those treated with HSCTRadiation impacting liver/biliary tract; HSCTHepatic fibrosis/cirrhosis Exam: jaundice, spider angiomas, palmar erythema, xanthomata hepatomegaly, splenomegalyLab: ALT, AST, bilirubin levelsFerritin in those treated with HSCTProthrombin time for evaluation of hepatic synthetic function in patients with abnormal liver screening testsScreen for viral hepatitis in patients with persistently abnormal liver function or any patient transfused prior to 1993Gastroenterology/hepatology consultation in patients with persistent liver dysfunctionHepatitis A and B immunizations in patients lacking immunityConsider phlebotomy and chelation therapy for iron overloadRadiation impacting liver/biliary tract CholelithiasisHistory: colicky abdominal pain related to fatty food intake, excessive flatulenceExam: right upper quadrant or epigastric tenderness (acute episode)Consider gallbladder ultrasound in patients with chronic abdominal pain

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.

References:
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Late Effects of the Endocrine System

Thyroid Gland

Thyroid dysfunction, manifested by primary hypothyroidism, hyperthyroidism, goiter, or nodules, is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma (HL), brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia. Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later. Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis. The most frequently reported abnormalities include elevated thyroid-stimulating hormone (TSH), depressed thyroxine (T4), or both. Compensated hypothyroidism includes an elevated TSH with a normal T4 and is asymptomatic. The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.

The incidence of hypothyroidism should decrease with lower cumulative doses of radiation therapy employed in newer protocols. In a study of 1,677 children and adults with HL who were treated with radiation therapy between 1961 and 1989, the actuarial risk at 26 years posttreatment for overt or subclinical hypothyroidism was 47%, with a peak incidence at 2 to 3 years posttreatment. In a study of HL patients treated between 1962 and 1979, hypothyroidism occurred in 4 of 24 patients who received mantle doses less than 26 Gy but in 74 of 95 patients who received greater than 26 Gy. The peak incidence occurred at 3 to 5 years posttreatment, with a median of 4.6 years. A cohort of childhood HL survivors treated between 1970 and 1986 were evaluated for thyroid disease by use of a self-report questionnaire in the CCSS. Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality. For hypothyroidism, there was a clear dose response, with a 20-year risk of 20% for those who received less than 35 Gy, 30% for those who received 35 Gy to 44.9 Gy, and 50% for those who received greater than 45 Gy to the thyroid gland. The relative risk (RR) for hypothyroidism was 17.1; for hyperthyroidism 8.0; and for thyroid nodules, 27.0. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, where the risk increased in the first 3 to 5 years after diagnosis. For nodules, the risk increased beginning at 10 years after diagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.

(Refer to the Second Malignant Neoplasms section of this summary for information about secondary thyroid cancers.)

As might be expected, children treated for head and neck malignancies are also at risk for primary hypothyroidism if the neck is irradiated. The German Group of Paediatric Radiation Oncology recently reported on 1,086 patients treated at 62 centers, including 404 patients (median age, 10.9 years) who had received radiation therapy to the thyroid gland and/or hypophysis. Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values. In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients with radiation doses of 15 Gy to 25 Gy to the thyroid gland had a hazard ratio (HR) of 3.072 (P = .002) for the development of pathologic thyroid blood values. Patients with greater than 25 Gy to the thyroid gland and patients who underwent craniospinal irradiation had HR of 3.768 (P = .009) and 5.674 (P < .001), respectively. The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups.

Survivors of pediatric hematopoietic stem cell transplant are at increased risk of thyroid dysfunction, with the risk being much lower (15%–16%) after fractionated total-body irradiation (TBI), as opposed to single-dose TBI (46%–48%). Non-TBI-containing regimens historically were not associated with an increased risk. However, in a report from the Fred Hutchinson Cancer Research Center, the increased risk of thyroid dysfunction was not different between children receiving a TBI or a busulfan-based regimen (P = .48). Other high-dose therapies have not been studied. While mildly elevated TSH is common, it is usually accompanied by normal thyroxine concentration.

Table 6. Thyroid Late EffectsPredisposing Therapy Endocrine/Metabolic EffectsHealth ScreeningTSH = thyroid stimulating hormone.Radiation impacting thyroid gland; thyroidectomy Primary hypothyroidismTSH levelRadiation impacting thyroid gland HyperthyroidismFree thyroxine (Free T4) levelTSH levelRadiation impacting thyroid gland Thyroid nodulesThyroid exam Thyroid ultrasound

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

References:
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Late Effects of the Immune System

Spleen

Surgical or functional splenectomy increases risk of life-threatening invasive bacterial infection. Although staging laparotomy is no longer standard practice for pediatric Hodgkin lymphoma, patients from earlier time periods have ongoing risks. In addition, children may be rendered asplenic by radiation therapy to the spleen in doses greater than 30 Gy. Low-dose involved-field radiation (21 Gy) combined with multiagent chemotherapy did not appear to adversely affect splenic function as measured by pitted red blood cell assays. No other studies of immune status after radiation therapy are available. Functional asplenia (with Howell Jolly bodies, reduced splenic size and blood flow) after bone marrow transplantation has been attributed to graft-versus-host disease.

A pneumococcal vaccine booster is recommended for patients aged 10 years and older and more than 5 years after previous dose. Asplenic patients should also be immunized against Neisseria meningitidis and Haemophilus influenzae type B and should receive antibiotic prophylaxis for dental work.

Prophylactic antibiotics (penicillin or similar broad-spectrum agent) have been recommended for at least 2 to 3 years after splenectomy and until at least 5 years of age for young children. Randomized studies that address the benefit of daily prophylactic antibiotics have not been conducted in a pediatric oncology population; thus, these recommendations are based on extrapolated study data derived from other populations with asplenia. The benefit of prolonged antibiotic prophylaxis is also unknown. Many patients, over time, discontinue use of penicillin; consideration should be given to ensuring availability of appropriate antibiotics for use at the first onset of febrile illness in patients who are not on daily prophylaxis. Medical care should be sought promptly for fevers higher than 38.5°C.

Table 7. Spleen Late EffectsPredisposing TherapyImmunologic EffectsHealth Screening/InterventionsGVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; T = temperature.Radiation impacting spleen; splenectomy; HSCT with currently active GVHD Asplenia/hyposplenia; overwhelming post-splenectomy sepsisBlood cultures during febrile episodes (T >38.5°C); empiric antibioticsHSCT 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.

Immune System

Although the immune system appears to recover from the effects of active chemotherapy and radiation, there is some evidence that lymphoid subsets may not always normalize. Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia. Antibody levels to previous vaccinations are also reduced in patients off therapy for acute lymphoblastic leukemia for at least one year, suggesting persistence of abnormal humoral immunity and a need for revaccination in such children. Immune status is also compromised after stem cell transplantation, particularly in association with graft-versus-host disease.

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.

References:
  • Pickering LK, Peter G, Baker CJ, eds.: 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, Ill: American Academy of Pediatrics, 2000.
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  • 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.

Late Effects of the Musculoskeletal System

Essentially all forms of cancer therapy, including surgery, chemotherapy, and radiation therapy, can affect the musculoskeletal system of a growing child or adolescent. The following outcomes affecting the musculoskeletal system are discussed: bone and joint late effects (abnormal bone and muscle growth, amputation/limb-sparing surgery, joint contracture, osteoporosis/fractures, osteonecrosis) and changes in body composition (obesity and body fatness). While these late effects are discussed individually, it is important to remember that all of the components within 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.

Bone and Joint

Abnormal bone growth

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 or with radiation doses of 20 Gy or more. Soft tissue sarcomas, such as orbital rhabdomyosarcoma and retinoblastoma are two of the more common cancer groups with these radiation fields. Often, in addition to the cosmetic impact of the craniofacial abnormalities, there can be related dental and sinus problems.

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 short stature, scoliosis/kyphosis, or limb length discrepancy. Orthovoltage, commonly used before 1970, delivered higher doses of radiation to the bone and was commonly related to abnormalities in bone growth. However, even with contemporary radiation therapy, if the location of the solid tumor is near an epiphysis or the spine, alterations in normal bone development can be difficult to avoid.

Also, cranial radiation therapy damages the hypothalamic-pituitary axis (HPA) in an age- and dose-response fashion, often leading to growth hormone deficiency (GHD). If untreated during the growing years, and sometimes, even with appropriate treatment, this leads to a substantially lower final height. Patients with a central nervous system (CNS) tumor or acute lymphoblastic leukemia (ALL) treated with 18 Gy or more of cranial radiation therapy are at highest risk. Also, patients treated with total-body irradiation (TBI), particularly single fraction TBI, are at risk of GHD. In addition, 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—GHD and direct damage to the spine.

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 affects the risk of postsurgical complications. Complications in survivors treated with amputation include stump-prosthetic problems, chronic stump pain, phantom limb pain, and bone overgrowth. While limb-sparing surgeries may offer a more aesthetically pleasing outcome, complications have been reported more frequently in survivors undergoing these procedures compared with those treated with amputation. Complications after limb-sparing surgery include non-union, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, poor joint movement, and stump-prosthesis problems. Occasionally, refractory complications develop after limb-sparing surgery and require amputation. 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. Similarly, long-term quality of life outcomes among survivors undergoing amputation and limb sparing procedures have not differed substantially.

Joint contractures

Hematopoietic cell transplantation with any history of chronic graft-versus-host disease is associated with joint contractures.

Osteoporosis/fractures

Maximal peak bone mass is an important factor influencing the risk of osteoporosis and fracture associated with aging. Methotrexate has a cytotoxic effect on osteoblasts, resulting in a reduction of bone volume and formation of new bone. This effect may be exacerbated by the chronic use of corticosteroids, another class of agents routinely used in the treatment of hematological malignancies and in supportive care for a variety of pediatric cancers. Radiation-related endocrinopathies, such as GHD or hypogonadism, may contribute to ongoing bone mineral loss. In addition, suboptimal nutrition and physical inactivity may further predispose to deficits in bone mineral accretion.

Most of our knowledge about cancer and its treatment effects on bone mineralization has been derived from studies of children with ALL. 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. Antileukemic therapy causes further bone mineral density (BMD) loss which has been reported to normalize over time or to persist for many years after completion of therapy. Clinical factors predicting higher risk for low BMD include treatment with high cumulative doses of methotrexate (>40 g/m2), high cumulative doses of corticosteroids (>9 g/m2), and use of more potent glucocorticoids like dexamethasone. Investigations evaluating the contribution of cranial radiation to the risk of low BMD in childhood cancer survivors have yielded conflicting results.

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

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. 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. Symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during therapy. These symptoms may improve over time, persist, or progress in the years after completion of therapy. The prevalence of osteonecrosis has varied from 1% to 22% based on the study population, treatment protocol, method of evaluation, and time from treatment.

The most important clinical risk factor for osteonecrosis is treatment with substantial doses of glucocorticoids, as is typical in regimens used for ALL, non-Hodgkin lymphoma, and hematopoietic stem cell transplants (HSCT). Delayed intensification therapies for childhood ALL featuring the more potent glucocorticoid, dexamethasone, have been speculated to enhance risk since osteonecrosis was infrequently reported before this approach became more widely used in the 1990s. However, currently available results suggest that cumulative corticosteroid dose may be a better predictor of this complication.

Osteonecrosis is more common in adolescents than in children, with the highest risk among those who are older than 10 years. Osteonecrosis also occurs much more frequently in whites than in blacks. Studies evaluating the influence of gender on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females that has not been confirmed by others. Genetic factors influencing antifolate and glucocorticoid metabolism have also been linked to excess risk of osteonecrosis among survivors.

Osteochondroma

Approximately 5% of children undergoing myeloablative stem cell transplantation will develop osteochondroma (OC), a benign bone tumor that most commonly presents in the metaphyseal regions of long bones. OC generally occurs as a single lesion, however multiple lesions may develop in the context of hereditary multiple osteochondromatosis. A large Italian study reported a 6.1% cumulative risk of developing OC at 15 years posttransplant, with increased risk associated with younger age at transplant (≤3 yrs) and use of TBI. Growth hormone therapy may influence the onset and pace of growth of OCs. Because malignant degeneration of these lesions is exceptionally rare, clinical rather than radiological follow-up is most appropriate, and surgery for biopsy or resection is generally unnecessary.

Table 8. Bone and Joint Late EffectsPredisposing TherapyMusculoskeletal EffectsHealth ScreeningCT = computed tomography; DXA = dual-energy x-ray absorptiometry; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation.Radiation impacting musculoskeletal system Hypoplasia; fibrosis; reduced/uneven growth (scoliosis, kyphosis); limb length discrepancyExam: bones and soft tissues in radiation fields Radiation impacting head and neck Craniofacial abnormalitiesHistory: psychosocial assessment, with attention to: educational and/or vocational progress, depression, anxiety, post-traumatic stress, social withdrawal Head and neck examRadiation impacting musculoskeletal system Radiation-induced fractureExam of affected boneMethotrexate; corticosteroids (dexamethasone, prednisone); radiation impacting skeletal structures; HSCTReduced bone mineral densityBone mineral density test (DXA or quantitative CT) Corticosteroids (dexamethasone, prednisone) OsteonecrosisHistory: joint pain, swelling, immobility, limited range of motion Musculoskeletal examRadiation with impact to oral cavity OsteoradionecrosisHistory/oral exam: impaired or delayed healing following dental work, persistent jaw pain or swelling, trismusHSCT with any history of chronic GVHD Joint contractureMusculoskeletal examAmputation 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 evaluationLimb-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 integrityRadiograph of affected limbOrthopedic evaluation

Changes in Body Composition

Obesity and body fatness

To date, the primary cancer groups recognized with an increased incidence of treatment-related obesity are ALL and CNS tumor survivors treated with cranial radiation therapy. In addition, craniopharyngioma survivors also have a substantially increased risk of extreme obesity due to the tumor location and the HPA damage resulting from surgical resection.

Moderate-dose cranial radiation therapy (18–24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age. Female adult survivors of childhood ALL who were treated with cranial radiation therapy of 24 Gy prior to age 5 years are four times more likely to be obese in comparison with women who have not been treated for a cancer. In addition, women treated with 18 Gy to 24 Gy cranial radiation therapy prior to age 10 years have a substantially greater rate of increase in their body mass index (BMI) through their young adult years in comparison with women who were treated for ALL with only chemotherapy or with women in the general population. It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance. These outcomes are attenuated in males. Interestingly, among brain tumor survivors treated with higher doses of cranial radiation therapy, only females treated at a younger age appear to be at increased risk for obesity. The development of obesity following cranial radiation therapy is multifactorial, with factors including GHD, leptin sensitivity, reduced levels of physical activity, and energy expenditure.

It remains controversial whether contemporary ALL therapy, without cranial radiation therapy, is associated with a sustained increase in BMI. During and soon after completion of therapy, there appears to be an increase in BMI z-scores among children treated for ALL with only chemotherapy. However, investigators from the Childhood Cancer Survivor Study did not find a significant association among adult survivors of childhood ALL between chemotherapy-only protocols and risk of obesity or change in BMI over time. Notably, while there may not be an increased incidence of obesity, as measured by BMI, among adult survivors of childhood ALL, there does appear to be an increase in percent body fat and visceral adiposity.

Importantly, survivors of childhood cancer treated with TBI in preparation for an allogeneic HSCT have increased measures of body fatness (percent fat) while often having a normal BMI.

Table 9. Obesity and Body CompositionPredisposing TherapyPotential Late EffectsHealth ScreeningBMI = body mass index.Cranial radiation therapyOverweight/obesityExam (annual): height, weight, BMI, blood pressure Labs: fasting glucose and lipids every 2 years

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.

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Late Effects of the Neuroendocrine System

Survivors of childhood cancer are at risk for a spectrum of neuroendocrine abnormalities, primarily due to the effect of radiation therapy on the hypothalamus. Essentially all of the hypothalamic-pituitary axes are at risk. The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 10.

Table 10. Anterior Pituitary Hormones and Major Hypothalamic Regulatory FactorsPituitary Hormone Hypothalamic FactorHypothalamic Regulation of the Pituitary Hormone (–) = inhibitory; (+) = stimulatory.Growth hormoneGrowth hormone-releasing hormone +Somatostatin –Prolactin Dopamine–Luteinizing hormone Gonadotropin-releasing hormone+Follicle-stimulating hormone Gonadotropin-releasing hormone+Thyroid-stimulating hormoneThyroid-releasing hormone +Somatostatin –AdrenocorticotropinCorticotropin-releasing hormone +Vasopressin+

Growth hormone deficiency (GHD) is the first and most common side effect of cranial irradiation in brain tumor survivors. The risk increases with radiation dose and time after treatment. GHD is the earliest hormone deficiency and sensitive to low doses. Other hormone deficiencies require higher doses and their time to onset is much longer than for GHD. The prevalence in pooled analysis was found to be approximately 35.6%. The potential for neuroendocrine damage is likely to decrease because of the use of more focused radiation therapy and a decrease in dose for some malignancies such as medulloblastoma.

Growth Hormone Deficiency

Approximately 60% to 80% of irradiated pediatric brain tumor patients who have received doses greater than 30 Gy will have impaired serum growth hormone (GH) response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier that GH deficiency will occur after treatment. A study of conformal radiation therapy in children with central nervous system (CNS) tumors indicates that GH insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects. Children treated with CNS irradiation for leukemia are also at increased risk of GH deficiency. One study evaluated 127 patients with acute lymphocytic leukemia (ALL) treated with 24 Gy, 18 Gy, or no cranial irradiation. The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all three groups with a dose-response of -0.49 ± 0.14 for the no radiation therapy group, -0.65 ± 0.15 for the 18 Gy radiation therapy group, and -1.38 ± 0.16 for the 24 Gy group. Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, in which 74% had SDS score of -1 or greater and the remainder had -2 or greater. However, survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, though the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age. In this cross-sectional study, attained adult height was determined among 2,434 ALL survivors participating in the Childhood Cancer Survivor Study (CCSS). All survivor treatment exposure groups (chemotherapy alone and chemotherapy with cranial or craniospinal radiation therapy) had decreased adult height and an increased risk of adult short stature (height standard deviation score < -2) compared with siblings (P < .001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (odds ratio [OR] = 3.4; 95% confidence interval [CI], 1.9–6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL before puberty, higher-dose cranial radiation therapy (≥20 Gy vs. <20 Gy), any radiation therapy to the spine, and female gender.

Children who undergo hematopoietic stem cell transplantation (HSCT) with total-body irradiation (TBI) have a significant risk of both GH deficiency and the direct effects of radiation on skeletal development. Risk is increased with single-dose as opposed to fractionated TBI, pretransplant cranial irradiation, female gender, and posttreatment complications such as graft-versus-host disease (GVHD). Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies, but not others. Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial radiation for CNS leukemia prophylaxis or therapy. The late effects that occur after HSCT have been studied and reviewed by the Late Effect 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, an overall decrease in final height-SDS value was found compared with height at transplant and genetic height. The mean loss of height is estimated to be approximately 1 height-SDS (6 cm) compared with the mean height at time of HSCT and mean genetic height. The type of transplantation, GVHD, GH, or steroid treatment did not influence final height. TBI (single-dose radiation therapy more so than fractionated dose radiation therapy), male gender, and young age at transplant, were found to be major factors for long-term height loss. Most patients (140 of 181) reached adult height within the normal range of the general population.

GH deficiency should be treated with replacement therapy. Some controversy surrounds this, with a concern over increased risk of primary tumor recurrence and second malignancies. Most studies, however, are limited by selection bias and small sample size. One study evaluated 361 GH-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of secondary neoplasm, and risk of death among survivors who did and did not receive treatment with GH. The relative risk (RR) of disease recurrence was 0.83 (95% CI, 0.37–1.86) for GH-treated survivors. GH-treated subjects were diagnosed with 15 second malignant neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88–5.46), mainly because of a small excess number of second neoplasms observed in survivors of acute leukemia. With prolonged follow-up, the elevation of second cancer risk due to GH diminished. Compared with survivors not treated with GH, those who were treated had a two-fold excess risk of developing a second neoplasm (RR = 2.15; 95% CI, 1.33–3.47, P < .002), and meningiomas were the most commonly observed (9 of 20 tumors). A review of existing data suggests that treatment with GH is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia. In general, the data addressing second malignancies should be interpreted with caution given the small number of events.

Gonadal Abnormalities

Pubertal development can be adversely affected by cranial radiation. Doses greater than 50 Gy may result in gonadotropin deficiency, while doses in the range of 18 Gy to 47 Gy can result in precocious puberty. Precocious puberty has been reported in some children receiving cranial irradiation, mostly in girls who receive cranial radiation in doses of 24 Gy or higher. Earlier puberty and earlier peak height velocity, however, have been observed in girls treated with 18 Gy cranial radiation. Another study showed that the age of pubertal onset is positively correlated with age at the time of cranial irradiation. The impact of early puberty in a child with radiation-associated GH deficiency is significant, and timing of GH therapy is especially important for GH-deficient females also at risk of precocious puberty. With higher doses of cranial irradiation (>35 Gy), deficiencies in the gonadotropins can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.

Hypothyroidism

Central hypothyroidism in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism (e.g., asthenia, edema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance. Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increase in the risk of developing thyroid-stimulating hormone (TSH) deficiency, 44% ± 19% (dose >42 Gy) and 11% ± 8% (dose <42 Gy). It occurs in as many as 65% of the survivors of brain or nasopharyngeal tumors, 35% of bone marrow transplant recipients, and 10% to 15% of leukemia survivors.

Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus (e.g., radiation injury to both structures). TSH values may be elevated and, in addition, the secretory dynamics of TSH are abnormal with a blunted or absent TSH surge or a delayed peak response to thyrotropin-releasing hormone (TRH). In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 (7%) patients. Among patients who received total-body irradiation (fractionated total doses of 12–14.4 Gy) or craniospinal irradiation (fractionated total cranial doses higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children treated for medulloblastoma, 56% developed hypothyroidism, including 38% with primary hypothyroidism, and 19% with central hypothyroidism.

Adrenal-Corticotropin Deficiency

Adrenocorticotropic hormone (ACTH) deficiency is less common than other neuroendocrine deficits but should be suspected in patients who have a history of brain tumor (regardless of therapy modality), cranial irradiation, GH deficiency, or central hypothyroidism. Although uncommon, ACTH deficiency can occur in patients who have received intracranial radiation that did not exceed 24 Gy and has been reported to occur in less than 3% of patients after chemotherapy alone. Patients with partial ACTH deficiency may have only subtle symptoms unless they become ill. Illness can disrupt these patients' usual homeostasis and cause a more severe, prolonged, or complicated course than expected. As in complete ACTH deficiency, incomplete or unrecognized ACTH deficiency can be life-threatening during concurrent illness.

Hyperprolactinemia

Hyperprolactinemia has been described in patients who have received doses of radiation higher than 50 Gy to the hypothalamus or who have undergone surgery disrupting the integrity of the pituitary stalk. Hyperprolactinemia may result in delayed puberty. In adult women, hyperprolactinemia may cause galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia; in adult men, impotence and loss of libido. Primary hypothyroidism may lead to hyperprolactinemia as a result of hyperplasia of thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. The prolactin response to TRH is usually exaggerated in these patients.

Table 11. Neuroendocrine Late EffectsPredisposing Therapy Endocrine/Metabolic Effects Health ScreeningBMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone.Radiation impacting hypothalamic-pituitary axis Growth hormone deficiencyAssessment of nutritional status Height, weight, BMI, Tanner stage Radiation impacting hypothalamic-pituitary axis Precocious puberty Height, weight, BMI, Tanner stageRadiation impacting hypothalamic-pituitary axis Gonadotropin deficiencyHistory: puberty, sexual function Exam: Tanner stageFSH, LH, estradiol or testosterone levelsRadiation impacting hypothalamic-pituitary axis Central adrenal insufficiencyHistory: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension Endocrine consultation for those with radiation dose ≥30 Gy Radiation impacting hypothalamic-pituitary axis Hyperprolactinemia History/exam: galactorrhea Prolactin level Radiation impacting hypothalamic-pituitary axis Overweight/obesity; metabolic syndromeHeight, weight, BMI Blood pressureFasting blood glucose level and lipid profile Radiation impacting hypothalamic-pituitary axis Central hypothyroidismFree thyroxine (Free T4) level

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

References:
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Late Effects of the Reproductive System

The treatment of cancer in children and adolescents may adversely affect their subsequent reproductive function. Germ cell survival may be adversely affected by radiation therapy and chemotherapy. Ovarian damage results in both sterilization and loss of hormone production because ovarian hormonal production is closely related to the presence of ova and maturation of the primary follicle. These functions are not as intimately related in the testis. As a result, men may have normal androgen production in the presence of azoospermia.

Testis

Surgery, radiation therapy, and/or chemotherapy may damage testicular function. Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up. Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms, and impotence may occur following extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.

Men treated with whole-abdomen irradiation may develop gonadal dysfunction. In one study, five of ten men were azoospermic, and two were severely oligospermic when evaluated at ages 17 to 36 years following treatment with whole-abdomen irradiation for Wilms tumor at ages 1 to 11 years, with the penis and scrotum either excluded from the treatment volume, or shielded with 3 mm of lead. The testicular radiation doses varied from 796 cGy to 983 cGy. Others reported azoospermia in 100% of ten men 2 to 40 months after radiation therapy doses of 140 cGy to 300 cGy to both testes. Similarly, azoospermia was demonstrated in 100% of ten men following testicular radiation therapy doses of 118 cGy to 228 cGy. Recovery of spermatogenesis occurred after 44 to 77 weeks in 50% of the men, although three of the five with recovery had sperm counts below 20 x 106/ml. Oligospermia or azoospermia was reported in 33% of 18 men evaluated 6 to 70 months after receiving testicular radiation doses of 28 cGy to 135 cGy. In another report, none of five men who received testicular radiation doses of less than 20 cGy became azoospermic. By contrast, two who received testicular radiation doses of 55 cGy to 70 cGy developed temporary oligospermia, with recovery to sperm counts greater than 20 x 106/ml 18 to 24 months after treatment.

Administration of higher radiation doses, such as 2,400 cGy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both sterilization and Leydig cell dysfunction. Craniospinal irradiation produced primary germ cell damage in 17% of 23 children with ALL, but in none of four children with medulloblastoma. Total-body irradiation ([TBI] 950 cGy to 1575 cGy) and cyclophosphamide (60 mg/kg/day for 2 days) produced azoospermia in almost all men.

Combination chemotherapy that includes an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium. Azoospermia occurred less frequently in adults following treatment with two, rather than six, cycles of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone). Elevation of the basal follicle-stimulating hormone (FSH) level, reflecting impaired spermatogenesis, was less frequent among patients receiving two courses of OPPA (vincristine, procarbazine, prednisone, doxorubicin) than among those who received two courses of OPPA in combination with two or more courses of COPP (cyclophosphamide, vincristine, procarbazine and prednisone).

Most studies suggest that procarbazine contributes significantly to the testicular toxicity of combination chemotherapy regimens. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported following treatment with MOPP. Most studies suggested that prepubertal males were not at lower risk for chemotherapy-induced testicular damage than were postpubertal patients.

Male survivors of non-Hodgkin lymphoma who underwent pelvic radiation therapy and received a cumulative cyclophosphamide dose greater than 9.5 g/m2 were at increased risk for failure to recover spermatogenesis; in survivors of Ewing and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia. Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide prior to undergoing bone marrow transplantation (BMT) for aplastic anemia. Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.

Ovary

The majority of postpubertal women who receive TBI prior to BMT develop amenorrhea. Recovery of normal ovarian function occurred in only 9 of 144 patients in one series and was highly correlated with age at irradiation of younger than 25 years. In a series restricted to patients who were prepubertal at the time of BMT, 44% (7 of 16) had clinical and biochemical evidence of ovarian failure.

The frequency of ovarian failure following 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. Whole-abdomen irradiation produces severe ovarian damage. Seventy-one percent of women in one series failed to enter puberty and 26% had premature menopause following whole-abdominal radiation therapy doses of 2,000 cGy to 3,000 cGy. Other studies reported similar results in women treated with whole-abdomen irradiation or craniospinal irradiation during childhood.

Ovarian function may be impaired following treatment with combination chemotherapy that includes an alkylating agent and procarbazine such as MOPP; MVPP (nitrogen mustard [mechlorethamine], vinblastine, procarbazine, and prednisone); ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); MDP (doxorubicin, prednisone, procarbazine, vincristine, and cyclophosphamide); or the combination of COP (cyclophosphamide, vincristine, and procarbazine) with ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine). Amenorrhea was reported in 11% after MOPP (2 of 18 girls treated at age 2 to 15 years), 31% after MDP (10 of 31 girls treated at age 9 to 15.2 years), and 13% after ChIVPP (3 of 23 girls treated at age 6.1 to 20 years), but in 0% after COP/ABVD (0 of 17 girls treated at age 4 to 20 years).

Ovarian function was evaluated in women treated with drug combinations that did not include procarbazine. Ovarian function was normal in all of six women treated for non-Hodgkin lymphoma with a cyclophosphamide containing drug combination. Others reported that pubertal progression was adversely affected in 5.8% of 17 patients treated before puberty compared with 33.3% of 18 patients treated during puberty or after menarche. However, the administration of cyclophosphamide did not correlate with the abnormal pubertal progression observed in these patients. Administration of ifosfamide 27 g/m2 to 90 g/m2 to 13 females resulted in evidence of impaired estrogen production in only one patient. Cisplatin administration resulted in amenorrhea in 14% of seven patients.

All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide prior to BMT for aplastic anemia developed amenorrhea following transplantation. In one series, 36 of 43 women had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of BMT.

Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure (AOF). Survivors with AOF were older (aged 13–20 years vs. aged 0–12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than survivors without AOF. Of survivors who developed AOF, 75% had received abdominal-pelvic irradiation. Radiation doses to the ovary of at least 2,000 cGy were associated with the highest rate of AOF with over 70% of such patients developing AOF. In a multivariable logistic regression model, increasing doses of ovarian irradiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for AOF.

The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred. Premature menopause is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal irradiation. A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically-induced menopause (relative risk [RR] = 0.8; 95% confidence interval [CI] = 0.52–1.23). However, the cumulative incidence of nonsurgical premature menopause was substantially higher for survivors than for siblings (8% vs. 0.8%; RR = 13.21; 95% CI, 3.26–53.51; P < .001).

A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent dose (AAD) score, and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominal-pelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%.

Fertility

Fertility was evaluated among the 6,224 male CCSS participants aged 15 to 44 years who were not surgically sterile. They were less likely to sire a pregnancy than siblings (hazard ratio [HR] 0.56; 95% CI, 0.49–0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy greater than 750 cGy to the testes (HR = 0.12; 95% CI, 0.02–0.64), higher summed AAD score or treatment with cyclophosphamide (3rd tertile - HR = 0.42; 95% CI, 0.31–0.57) or procarbazine (2nd tertile - HR = 0.48; 95% CI, 0.26–0.87; 3rd tertile – HR = 0.17; 95% CI, 0.07–0.41). The HR of siring a pregnancy was inversely related to the summed AAD score (P-value for linear trend = <.001). Those who had a summed AAD score of 2 (HR = 0.67; 95% CI, 0.51–0.88; P = .004), 3 (HR = 0.48; 95% CI, 0.36–0.65; P <.001), 4 (HR = 0.34; 95% CI, 0.22–0.52; P <.001), 5 (HR = 0.38; 95% CI, 0.22–0.66; P <.001), or 6 to 11 (HR = 0.16; 95% CI, 0.08–0.32; P <.001) were also less likely to ever sire a pregnancy compared with those who did not receive any alkylating agents. Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0 and a hypothalamic/pituitary radiation dose of 0 cGy and a testes radiation dose of 0 cGy was 0.91 (95% CI, 0.73–1.14; P = .41).

Fertility was evaluated among the 5,149 female CCSS participants and 1,441 female siblings of CCSS participants, aged 15 to 44 years. The RR for ever being pregnant was 0.81 (95% CI, 0.73–0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose of greater than 3,000 cGy (RR = 0.61; 95% CI, 0.44–0.83) or an ovarian/uterine radiation dose greater than 500 cGy were less likely to have ever been pregnant (RR = 0.56 for 500–1000 cGy; 95% CI, 0.37–0.85; RR = 0.18 for >1000 cGy; 95% CI, 0.13–0.26). A summed AAD score of 3 (RR = 0.72; 95% CI, 0.58–0.90; P = .003) or 4 (RR = 0.65; 95% CI, 0.45–0.96; P = .03) was associated with lower observed risk of pregnancy compared with those with no alkylating agent exposure. Those with a summed AAD score of 3 or 4 or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant.

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. Retrograde ejaculation occurs with a significant frequency in men who undergo bilateral retroperitoneal lymph node dissection. Uterine structure may be affected by abdominal irradiation. A recent study demonstrated that uterine length was significantly shorter in ten women with ovarian failure who had been treated with whole abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women, and through one uterine artery in three additional women.

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. 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. Risk of miscarriage was 3.6-fold higher in women treated with craniospinal radiation and 1.7-fold higher in those treated with pelvic radiation. Chemotherapy exposure alone did not increase risk of miscarriage. Compared with siblings, survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low birth weight babies. In the same cohort, another study evaluated pregnancy outcomes of partners of male survivors. Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis. Compared with partners of male siblings, there was a decreased incidence of live births (RR = 0.77), but no significant differences of pregnancy outcome by treatment. 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. Hypertension complicating pregnancy, early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank radiation, in a dose-dependent manner. Results from a Danish study confirm the association of uterine radiation with spontaneous 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. No significant differences were seen between survivors and comparison women in the proportions of livebirths, stillbirths, or all types of abortions combined. Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion. Thus, the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion.

Preservation of fertility and successful pregnancies may occur after HSCT, though the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. In a group of 21 females who had received a BMT in the prepubertal years, 12 (57%) were found to have ovarian failure when examined between ages 11 and 21 years, and the association with busulfan was significant. One study evaluated pregnancy outcomes in a group of females treated with BMT. Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant. Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant. Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination. Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination. There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function.

For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. In the reports from the National Wilms Tumor Group, congenital anomalies were marginally increased in offspring of females who had received flank radiation therapy in an early analysis and in the offspring of the partners of males who had received flank radiation therapy in a later analysis, raising the possibility that one or both findings were spurious. In a report of 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 compared with 4,544 offspring of sibling controls, there were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring. 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. 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.

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. 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information about sexuality and reproductive issues and cancer patients.)

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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  • Pryzant RM, Meistrich ML, Wilson G, et al.: Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. J Clin Oncol 11 (2): 239-47, 1993.
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Late Effects of the Respiratory System

Acute and chronic pulmonary complications reported after treatment for pediatric malignancies include radiation pneumonitis, pulmonary fibrosis, and spontaneous pneumothorax. These sequelae are uncommon following contemporary therapy and most often result in subclinical injury that is detected only by imaging or formal pulmonary function testing. Chemotherapy agents with potential pulmonary toxicity 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. Thus, the potential for acute or chronic pulmonary sequelae must be considered in the context of the specific chemotherapeutic agents and the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses.

Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow radiation therapy alone at doses greater than 40 Gy to focal lung volumes, or after lower doses when combined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after radiation therapy alone at doses to the whole lung greater than 20 Gy, but is possible after lower doses when combined with chemotherapy. Infection, graft-versus-host disease (GVHD) in the setting of bone marrow transplant (BMT), and pre-existing pulmonary compromise (e.g., asthma) all may influence this risk. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor. A dose of 12 Gy to 14 Gy reduced total lung capacity and vital capacity to about 70% of predicted values, and even lower if the patient had undergone thoracotomy. Fractionation of dose decreases this risk. 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 latent radiation damage.

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. More current pediatric regimens for Hodgkin lymphoma using radiation therapy and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) have shown a significant incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time. However, grade 3 and 4 pulmonary toxicity has been reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of radiation. In addition, ABVD-related pulmonary toxicity may result from fibrosis induced by bleomycin or "radiation recall" pneumonitis related to administration of doxorubicin. Pulmonary veno-occlusive disease has been observed rarely and has been attributed to bleomycin chemotherapy.

Patients undergoing hematopoietic stem cell transplant (HSCT) are at increased risk of pulmonary toxicity, related to (1) preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy), (2) the preparative regimen that may include cyclophosphamide, busulfan, carmustine, (3) total-body irradiation, and (4) the presence of GVHD. Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur. 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.

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

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, there is significant clinical disease. No large cohort studies have been performed with clinical evaluations coupled with functional and quality of life assessments. An analysis of self-reported pulmonary complications of 12,390 survivors of common childhood malignancies has been reported by the Childhood Cancer Survivor Study. This cohort includes children treated with both conventional and myeloablative therapies. Compared with siblings, survivors had an increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen therapy, abnormal chest wall, exercise-induced shortness of breath, and bronchitis, with RRs ranging from 1.2 to 13.0 (highest for lung fibrosis and lowest for bronchitis). The 25-year cumulative incidence of lung fibrosis was 5% for those who received chest radiation therapy and less than 1% for those who received pulmonary toxic chemotherapy. With changes in the doses of radiation therapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.

Table 12. Pulmonary Late EffectsPredisposing TherapyPulmonary EffectsHealth Screening/InterventionsDLCO = diffusing capacity of the lung for carbon monoxide; GVHD = graft-versus-host disease.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, wheezingPulmonary examPulmonary function tests (including DLCO and spirometry)Chest x-rayCounsel regarding tobacco avoidance/smoking cessationIn patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation prior to general anesthesiaPulmonary consultation for patients with symptomatic pulmonary dysfunctionInfluenza and pneumococcal vaccinationsHematopoietic cell transplantation with any history of chronic GVHD Pulmonary toxicity (bronchiolitis obliterans, chronic bronchitis, bronchiectasis)History: cough, shortness of breath, dyspnea on exertion, wheezingPulmonary examPulmonary function tests (including DLCO and spirometry)Chest x-rayCounsel regarding tobacco avoidance/smoking cessationIn patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation prior to general anesthesiaPulmonary consultation for patients with symptomatic pulmonary dysfunctionInfluenza 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.

References:
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Late Effects of the Special Senses

Hearing

Children treated for malignancies may be at risk for early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life. Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatin and carboplatin) and cranial irradiation. Children are more susceptible to ototoxicity from platinum agents than adults. Risk factors associated with hearing loss with platinum agents include the following:

  • Younger age.
  • Higher cumulative dose of chemotherapy.
  • Central nervous system (CNS) tumors.
  • Concomitant CNS radiation.

For cisplatin, the risk of significant hearing loss involving the speech frequencies (500–2000 Hz) usually occurs with cumulative doses that exceed 400 mg/m2 in pediatric patients. Ototoxicity after platinum chemotherapy can present or worsen years after completion of therapy. In 59 patients who had received cisplatin, 51% of them developed late-onset hearing loss (occurring at least 6 months after the last dose of cisplatin). Radiation to the posterior fossa and the use of hearing aids were associated with late-onset hearing loss. Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic. A single study observed ototoxicity after the use of non-stem cell transplant dosing of carboplatin for retinoblastoma, in that 8 children out of 175 developed hearing loss. For seven of the eight children, the onset of the ototoxicity was delayed a median of 3.7 years. With myeloablative dosing, carboplatin may cause significant ototoxicity. For carboplatin, ototoxicity has been reported to occur at cumulative doses exceeding 400 mg/m2.

Cranial radiation therapy, when used as a single modality, results in ototoxicity when cochlear dosage exceeds 32 Gy. Young patient age and presence of a brain tumor and/or hydrocephalus can increase susceptibility to hearing loss. The onset of radiation-associated hearing loss may be gradual, manifesting months to years after exposure. When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.

Table 13. Auditory Late EffectsPredisposing TherapyPotential Auditory EffectsHealth Screening/InterventionsPlatinum agents (cisplatin, carboplatin); radiation impacting the earOtotoxicity; sensorineural hearing loss; tinnitus; vertigo History: hearing difficulties, tinnitus, vertigoOtoscopic exam Audiology evaluation Amplification in patients with progressive hearing lossSpeech and language therapy for children with hearing lossOtolaryngology consultation in patients with chronic infection, cerumen impaction, or other anatomical problems exacerbating or contributing to hearing lossEducational accommodations (e.g., preferential classroom seating, FM amplification system, etc.)

Orbital and Optic

Orbital complications are common following radiation therapy for retinoblastoma, childhood head and neck sarcomas, and CNS tumors, and as part of total-body irradiation (TBI).

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 is not consistent across studies. 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. Longer follow-up is needed to assess the impact on vision in patients undergoing these treatment modalities. Previously, tumors located near the macula and fovea were associated with an increased risk of complications leading to visual loss, although treatment of these tumors with foveal laser ablation has shown promise in preserving vision. (Refer to the PDQ summary on Retinoblastoma Treatment for more information on the treatment of retinoblastoma.)

Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia, ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision following 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 greater than 2 Gy. Cataracts are reported following lower doses of 10 Gy to 18 Gy. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information on the treatment of rhabdomyosarcoma in children.)

Survivors of childhood cancer are at increased risk for ocular late effects related to both glucocorticoid and radiation exposure to the eye. The Childhood Cancer Survivor Study (CCSS) reported that survivors 5 or more years from diagnosis are at increased risk for cataracts, glaucoma, legal blindness, double vision, and dry eyes when compared with siblings. The dose of radiation to the eye is significantly associated with risk of cataracts, legal blindness, double vision, and dry eyes, in a dose-dependent manner. Risk of cataracts was associated with a radiation dose of 3,000 cGy or more to the posterior fossa, temporal lobe and exposure to prednisone. The cumulative incidence of cataracts, double vision, dry eyes, and legal blindness continued to increase up to 20 years after diagnosis for those who received more than 500 cGy to the eye.

Ocular complications such as cataracts and dry-eye syndrome are common after stem cell transplant in childhood. 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. Patients receiving TBI with biologically effective doses of less than 40 Gy have a less than 10% chance of developing severe cataracts. Corticosteroids and graft-versus-host disease (GVHD) may further increase risk. Epithelial superficial keratopathy has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine A.

Table 14. Ocular Late EffectsPredisposing TherapyOcular/Vision EffectsHealth Screening/InterventionsGVHD = graft-versus-host disease.Busulfan; corticosteroids; radiation impacting the eye CataractsHistory: decreased acuity, halos, diplopiaEye exam: visual acuity, funduscopyOphthalmology consultationRadiation impacting the eye including radioiodine (I-131) 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 eyeEye exam: visual acuity, funduscopyOphthalmology consultationHematopoietic cell transplantation with any history of chronic GVHDXerophthalmia (keratoconjunctivitis sicca) History: dry eyes (burning, itching, foreign body sensation, inflammation)Eye exam: visual acuity, funduscopyEnucleationImpaired cosmesis; poor prosthetic fit; orbital hypoplasia Ocular prosthetic evaluationOphthalmology

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.

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  • Fontanesi J, Pratt CB, Kun LE, et al.: Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol 26 (5): 297-304, 1996.
  • Shields JA, Shields CL: Pediatric ocular and periocular tumors. Pediatr Ann 30 (8): 491-501, 2001.
  • 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.
  • Kline LB, Kim JY, Ceballos R: Radiation optic neuropathy. Ophthalmology 92 (8): 1118-26, 1985.
  • Raney RB, Asmar L, Vassilopoulou-Sellin R, et al.: Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol 33 (4): 362-71, 1999.
  • 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.
  • Parsons JT, Bova FJ, Mendenhall WM, et al.: Response of the normal eye to high dose radiotherapy. Oncology (Huntingt) 10 (6): 837-47; discussion 847-8, 851-2, 1996.
  • Paulino AC: Role of radiation therapy in parameningeal rhabdomyosarcoma. Cancer Invest 17 (3): 223-30, 1999.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Fahnehjelm KT, Törnquist AL, Winiarski J: Dry-eye syndrome after allogeneic stem-cell transplantation in children. Acta Ophthalmol 86 (3): 253-8, 2008.

Late Effects of the Urinary System

Cancer treatments predisposing to late renal injury and hypertension include specific chemotherapeutic drugs (cisplatin, carboplatin, and ifosfamide), renal radiation therapy, and nephrectomy. Cisplatin can cause glomerular and tubular damage resulting in a diminished glomerular filtration rate (GFR) and electrolyte wasting (particularly magnesium, calcium, and potassium). Approximately 50% of patients may experience long-lasting hypomagnesemia. The use of ifosfamide concurrently with cisplatin increases the risk of renal injury. Carboplatin is a cisplatin analogue and is less nephrotoxic than cisplatin. The combination of carboplatin/ifosfamide may be associated with more renal damage than the combination of cisplatin/ifosfamide. As with ototoxicity, however, additional follow-up in larger numbers of survivors treated with carboplatin must be evaluated before potential renal toxicity can be better defined.

Ifosfamide can also cause glomerular and tubular toxicity, with renal tubular acidosis, and Fanconi syndrome, a proximal tubular defect characterized by impairment of resorption of glucose, amino acids, phosphate, and bicarbonate. Ifosfamide doses greater than 60 g/m2 to 100 g/m2, age younger than 5 years at time of treatment, and combination with cisplatin and carboplatin increase the risk of ifosfamide-associated renal tubular toxicity. Abnormalities in glomerular filtration are less common, and when found, are usually not clinically significant. More common are abnormalities with proximal tubular function greater than distal tubular function, though the prevalence of these findings is uncertain and further study of larger cohorts with longer follow-up is required. A French study evaluating the incidence of late renal toxicity after ifosfamide reported normal tubular function in 90% of pediatric cancer survivors (median follow-up of 10 years); 79% of the cancer survivors had normal GFR, and all had normal serum bicarbonate and calcium. Hypomagnesemia and hypophosphatemia were seen in 1% of cancer survivors. Glycosuria was detected in 37% of cancer survivors but was mild in 95% of cases. Proteinuria was observed in 12% of cancer survivors. In multivariate analysis, ifosfamide dose and interval from therapy were predictors of tubulopathy, and older age at diagnosis and interval from therapy were predictors of abnormal GFR.

High-dose methotrexate (1,000–33,000 mg/m2) has been reported to cause acute renal dysfunction in 0% to 12.4% of patients. This has resulted in delayed elimination of the drug, but long-term renal sequelae have not been described.

Irradiation to the kidney can result in radiation nephritis or nephropathy after a latent period of 3 to 12 months. Doses greater than 20 Gy can result in significant nephropathy. The effect of radiation therapy on the kidney has best been examined in survivors of pediatric Wilms tumor. Generally, studies have shown that the risk of renal insufficiency is higher among children receiving higher doses of radiation. In a cohort of Wilms tumor survivors evaluated 5 years after receiving abdominal radiation, the prevalence of renal insufficiency, as defined by hypertension, was approximately 7%. One study examined the spectrum of renal failure in 55 patients among the 5,823 patients treated for Wilms tumor. The incidence of renal failure at 16 years postdiagnosis was 0.6% for patients with unilateral disease and 13% for patients with bilateral disease. The most common etiologies of renal failure were bilateral nephrectomy for persistent or recurrent tumor, progressive tumor in the remaining kidney without nephrectomy, Denys-Drash syndrome (DDS), and radiation nephritis. In another study from the National Wilms Tumor Group of children treated from 1969 to 1995, 58 of 5,976 developed renal failure; median follow-up was 11 years. Patients with bilateral disease and unilateral disease had a 20-year renal failure incidence of 5.5% and 1.0%, respectively. Treatment for Wilms tumor without flank or abdominal radiation therapy was not associated with significant nephrotoxicity in a study of 40 Wilms tumor survivors treated in England. Patients with predisposition syndromes such as DDS, WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome, or male genitourinary anomalies had much higher incidence of renal failure at 20 years; 62.4%, 38.3%, and 10.9%, respectively.

In the setting of hematopoietic cell transplantation, fewer than 15% of children will develop chronic renal insufficiency or hypertension; the risk is related to the nephrotoxic agents used and the TBI-fractionation scheme and interfraction interval.

Childhood cancer survivors treated with pelvic or central nervous system surgery, alkylator-containing chemotherapy including cyclophosphamide or ifosfamide, or pelvic radiation therapy may experience urinary bladder late effects including hemorrhagic cystitis, bladder fibrosis, neurogenic/dysfunctional bladder, and bladder cancer.

Table 15. Kidney and Bladder Late EffectsPredisposing TherapyRenal/Genitourinary EffectsHealth ScreeningBUN = blood urea nitrogen; NSAIDs = nonsteroidal anti-inflammatory drugs; RBC/HFP = red blood cells per high-field power (microscopic exam).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 ratioUrology referral for patients with culture negative macroscopic hematuriaCisplatin/carboplatin; ifosfamide Renal toxicity (glomerular injury, tubular injury [renal tubular acidosis], Fanconi syndrome, hypophosphatemic rickets) Blood pressure BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levelsUrinalysisElectrolyte supplements for patients with persistent electrolyte wastingNephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiencyMethotrexate; radiation impacting kidneys/urinary tract Renal toxicity (renal insufficiency, hypertension)Blood pressure BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levelsUrinalysis Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiencyNephrectomy Renal toxicity (proteinuria, hyperfiltration, renal insufficiency)Blood pressure BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levelsUrinalysisDiscuss contact sports, bicycle safety (e.g., avoiding handlebar injuries), and proper use of seatbelts (i.e., wearing lapbelts around hips, not waist)Counsel to use NSAIDs with cautionNephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiencyNephrectomy; pelvic surgery; cystectomy Hydrocele Testicular examCystectomy 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 streamCounsel regarding adequate fluid intake, regular voiding, seeking medical attention for symptoms of voiding dysfunction or urinary tract infection, compliance with recommended bladder catheterization regimenUrologic consultation for patients with dysfunctional voiding or recurrent urinary tract infections

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.

References:
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