Primary care physicians will be providing longitudinal health care for long-term survivors of childhood acute lymphoblastic leukemia (ALL) with increasing frequency. Late effects (sequelae) secondary to treatment with radiation or chemotherapeutic agents are frequent and may be serious. Depending on treatment exposures, this at-risk population may experience life-threatening late effects, such as cirrhosis secondary to hepatitis C or late-onset anthracycline-induced cardiomyopathy, or life-changing late effects, such as cognitive dysfunction. Many survivors of childhood ALL will develop problems such as obesity and osteopenia at a young age, which will significantly affect their risk for serious health outcomes as they grow olden
The goal of our review is to assist primary care physicians in providing longitudinal health care for long-term survivors of childhood ALL. We also highlight areas needing further investigation, including the prevalence of different late effects, determination of risk factors associated with a late effect, a better understanding of the potential impact of late effects on the premature development of common adult health problems, and the value and timing of different tests for screening asymptomatic survivors.
* KEYWORDS Leukemia, lymphoblastic, acute; survivors; late effects [non-MESH]; screening [non-MESH]. (J Fam Pract 2000; 49: 1133-1146)
Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, accounts for almost one fourth of childhood cancers. The incidence of ALL has shown a moderate increase in the past 20 years. It is generally considered a cancer of younger children, with a peak incidence between the ages of 2 and 5 years. It is approximately 30% more common in boys than girls and approximately twice as common in white children as in black children. Improvements in ALL treatment during the past 20 years have increased the overall survival rate to approximately 80%. Thus, success in "curing" this childhood disease has resulted in a growing population of long-term survivors.
Since it is anticipated that the majority of long-term survivors of childhood ALL will seek health care from primary care physicians, it is important to understand the potential health problems that these patients may experience secondary to their cancer treatment.[2-4] However, there are no articles in peer-reviewed family practice journals concerning the long-term follow-up of survivors of childhood ALL. Our clinical review briefly describes the evolution of the treatment for ALL, potential late effects of treatment, and recommendations for screening asymptomatic long-term survivors. Because this field of investigation is rapidly advancing and much of the available information is from cross-sectional and small cohort studies, these recommendations should not be viewed as a set of guidelines. Instead, our review is intended to contribute a foundation for primary care physicians providing longitudinal health care for ALL survivors while highlighting the areas needing further investigation. Also, because of the evolving changes in treatment protocols--and rims in potential late effects--it is essential to frequently communicate with our colleagues who specialize in the treatment of children with cancer.
EVOLUTION OF TREATMENT FOR CHILDHOOD ALL
During the 1940s childhood leukemias had a uniformly rapid fatal course over a short period of time, thus the designation of the term "acute." In the late 1940s, Farber and colleagues found that aminopterin (a folic acid antagonist) could induce temporary remissions in leukemia. This discovery opened the era of clinical investigation into the uses of combined chemotherapy in treating childhood ALL (Figure 1). The use of antimetabolite therapy for prolonged periods started in the late 1950s and early 1960s and suggested that it was possible for children to have an extended period of remission and possibly be cured. The addition of anthracydines such as daunorubicin in the 1970s and the discovery that the enzyme L-asparaginase was useful in ALL therapy for depleting cells of the essential amino acid L-asparagine further boosted the ability to induce and sustain remission.
[Figure 1 ILLUSTRATION OMITTED]
A significant factor in morbidity and mortality from childhood ALL was the development of leukemia within the central nervous system (CNS). Left untreated, more than half the children with ALL developed leukemia in the CNS, even when bone marrow remission was sustained. In most patients, CNS relapse was followed by bone marrow relapse. Prophylactic radiation to the head and spine, introduced in the early 1970s, significantly decreased the incidence of CNS leukemia and resulted in significant advancement in long-term survival. However, in the early 1980s--as a consequence of the appreciation of neurodevelopmental delays and cognitive dysfunction secondary to relatively higher-dose (24 Gy) cranial irradiation (CRT), different methods of CNS treatment and prophylaxis evolved, either using lower-dose CRT (18 Gy), intensification of systemic methotrexate (MTX) dosaging, or intrathecal medications.[8-11]
Current treatment regimens divide therapy into remission induction, consolidation and CNS prophylaxis, and maintenance or continuous treatment. Induction chemotherapy (aimed at an initial reduction in blast cell percentage in the bone marrow to 5% or lower) consists of a 1-month schedule of vincristine, prednisone, and L-asparaginase alone or with other agents. Following induction, a consolidation phase consisting of an intensified period of treatment combines the use of antimetabolites and other agents with intrathecal chemotherapy for CNS prophylaxis. Maintenance therapy continues for a period of approximately 2 years and relies heavily on the use of methotrexate and 6-mercaptopurine. During the past 2 decades, recognized differences in the phenotype of the leukemic cells have resulted in protocol modifications to improve outcome and reduce toxicity. Increasingly, the T-cell phenotype of childhood ALL has been treated more effectively with intensified regimens that include cyclophosphamide, cytarabine, and anthracylines.[12-13]
LATE EFFECTS OF TREATMENT FOR CHILDHOOD ALL
A late effect is defined as any chronic or late occurring physical or psychosocial outcome persisting or developing more than 5 years after diagnosis of the cancer. In this section we describe potential late effects in order from more common or serious health problems to less common or serious ones (Table 1). Many of these late effects may have long asymptomatic intervals before end-stage disease or serious health outcomes, such as survivors with hepatitis C who develop cirrhosis or those with a late-onset cardiomyopathy who present in congestive heart failure. Included in each section is a discussion about the screening tests commonly used in long-term follow-up programs that include asymptomatic survivors (Table 2). It should be stressed that the value of most of these tests has not been studied in this population in a prospective or a well-designed retrospective manner with adequate sample sizes, which limits the strength of the recommendations. Clinicians should be selective in ordering tests and providing preventive services and should actively incorporate the patient's concerns and fears when arriving at an individualized decision on whether to perform a test. Figure 2 is a compilation of information pertinent to the follow-up of a survivor of childhood ALL, provided as a single-page template for clinical use.
Long-Term Follow-up of Survivors of Childhood ALL
Potential Late Effects of Treatment for Childhood ALL
CRT denotes cranial irradiation; CNS, central nervous system; t-AML, treatment-related acute myelogenous leukemia.
Screening and Counseling Asymptomatic ALL Survivors
CBC denotes complete blood count; ALT, alanine aminotransferase; TSH, thyroid stimulating hormone;
(*) Every 1 to 3 years; FSH, follicle stimulating hormone; LH, luteinizing hormone.
Because bone marrow transplantation (BMT) is a relatively new therapy affecting a much smaller number of ALL survivors, our review does not include the late effects related to total body irradiation and BMT.
COGNITIVE DYSFUNCTION AND PERFORMANCE AT SCHOOL AND WORK
As described in the section on the evolution of treatment, 24 Gy CRT is associated with cognitive dysfunction. A meta-analysis of more than 30 retrospective and prospective studies established that 24 Gy CRT in combination with MTX resulted in a mean decrease of 10 points in full-scale intelligence quotient (IQ). Verbal scores were affected more than performance IQ, and changes were noted to be progressive. Although more than half the patients had mild to moderate learning problems, the outcomes were highly variable, and some patients experienced 20- to 30-point losses, while others had no discernable changes.[9,14] Deficits have been noted in measures of visual-spatial abilities, attention-concentration, nonverbal memory, and somatosensory functioning.[8-10,15-20] Studies have also shown that girls and patients treated with CRT before the age of 4 years are at significantly higher risk. Neuropathologic changes resulting from 24 Gy CRT include leukoencephalopathy, mineralizing microangiopathy, subacute necrotizing leukomyelopathy, and intracerebral calcifications, commonly with subsequent cerebral atrophy and microcephally.[21,22]
Treatment with 18 Gy CRT in combination with chemotherapy also affects cognition, though not as profoundly as with 24 Gy CRT. In a retrospective study of children with ALL, randomized by risk group to receive either 18 Gy CRT with chemotherapy or chemotherapy alone, 66 survivors were subsequently tested using several cognitive measures. Gifts who were treated with CRT/chemotherapy had a mean IQ 9 points lower than those treated with chemotherapy alone. All patients had impairments in verbal coding and short-term memory regardless of CRT use or MTX dose, suggesting that another agent such as glucocorticoids may be responsible. Other small prospective and retrospective studies have found a mild decrease in full-scale IQ in patients treated with 18 Gy CRT/chemotherapy, although subanalysis generally showed that changes were only significant for gifts and patients treated at a younger age.[24-27]
Recent studies suggest that neurodevelopmental outcomes for survivors treated with chemotherapy alone are generally positive. An analysis of 30 survivors whose condition was diagnosed before the age of 12 months showed no decrease in 6 cognitive and motor indices and no sex differences. Though full-scale IQ was normal, Brown and colleagues reported that girls had significantly decreased nonverbal scores in a study of 47 ALL survivors. Fine motor disturbances and manual dexterity difficulties, which may compound learning difficulties, have been seen in 25% to 33% of ALL survivors evaluated in 2 small cross-sectional studies.[31,32] Changes in cerebellar-frontal subsystems that correlate with neuropsychological deficits have also been seen in ALL patients treated with chemotherapy alone.
The Children's Cancer Group investigated the impact of treatment on scholastic performance of 593 adult survivors, compared with 409 sibling controls. Patients treated with 24 Gy CRT were more likely to enter special education or learning-disabled programs, with relative risks of 4.1 and 5.3, respectively. Previous treatment with 18 Gy CRT had less impact, with a relative risk of 4.0 to enter a special education program but no increased risk of entering a learning-disabled program. Patients treated with CRT (18 or 24 Gy) were just as likely to enter gifted and talented programs as their sibling controls. In general, survivors were as likely to finish high school and enter college as controls, but those treated with 24 Gy or treated before the age of 6 years were less likely to enter college. There were no sex differences in educational achievements.
There are no studies that explore problems in job acquisition, promotion, and retention for ALL survivors with evidence of cognitive dysfunction. Abstract thinking abilities in higher-level decision making may be problematic for some ALL survivors, particularly those treated with 24 Gy CRT. Further study is warranted, particularly in evaluating methods to assist at-risk survivors in developing job skills and applying for a job.
OBESITY, PHYSICAL INACTIVITY, AND RISK OF PREMATURE CARDIOVASCULAR DISEASE
Several retrospective cohort and cross-sectional studies have shown an increased incidence and prevalence of obesity in ALL survivors. Early studies suggested that the resulting obesity was secondary to CRT, with 38% to 57% of the survivors having a body mass index (BMI) [is greater than] 2 standard deviations (SDs) above the norm at the time of attainment of final height.[35-38] Two recent cross-sectional studies suggest that the increased prevalence of obesity may be due to other factors. Van Dongen-Melman and coworkers compared the weight gain and BMI of 113 ALL survivors who had received CRT/chemotherapy or chemotherapy alone and found that children treated with a combination of prednisone and dexamethasone had the highest prevalence of obesity (44%). Talvensaari and colleagues evaluated 50 childhood cancer survivors with a median age of 18 years (including 28 ALL patients) and found an increased prevalence of obesity in survivors that was not associated with CRT.
Obesity in ALL survivors may be due in part to reduced physical activity. In a small cross-sectional study with sibling controls, ALL survivors had decreased activity levels and total daily energy expenditures that correlated with their percentage of body fat. Maximal and submaximal exercise capacity were reduced in another cross-sectional study. Similarly, in a study of 53 ALL survivors with a longer interval from ALL diagnosis (mean=10.5 years), 25% and 31%, respectively, were unable to reach normal maximal oxygen uptake and normal oxygen uptake at the anaerobic threshold.
Changes in gross motor skills may also affect the physical activity level of ALL survivors. Balance, strength, running speed and agility, and hand grip strength were decreased in a cohort of 36 ALL survivors with a median age of 9.3 years. In a follow-up of this cohort, Wright and coworkers reported and passive dorsiflexion range of motion of the ankle than did controls. Younger age at diagnosis and female sex were significant predictors, while treatment with CRT did not increase risk. These studies suggest that ALL survivors should be assessed for gross motor deficits that might alter exercise choices.
In the general population, obesity and physical inactivity are risk factors for cardiovascular disease. Obesity (an especially important risk factor during young adulthood) enhances the development of hypertension, dyslipidemia, and insulin resistance.[46-48] Because the median age of ALL survivors is still relatively young, there are no cohort or case-control studies evaluating the treatment-related risk of premature onset of coronary artery disease. Talvensaari and coworkers reported that 50 childhood cancer survivors (including 28 ALL survivors) had an increased risk of fasting hyperinsulinemia and reduced high-density lipoprotein (HDL) cholesterol compared with 50 age- and sex-matched controls. Eight of the cancer survivors with reduced spontaneous growth hormone (GH) secretion (4/8 had received CRT) had obesity, hyperinsulinemia, and reduced HDL cholesterol, fitting the criteria for cardiac dysmetabolic syndrome, a clustering of metabolic problems associated with a markedly increased risk of cardiovascular disease.
Studies of noncancer populations may shed light on the cardiovascular risk of ALL survivors with GH deficiency. Hypopituitarism with GH deficiency in adults is associated with increased vascular mortality.[50-52] Adults with GH deficiency also have an increased prevalence of dyslipidemia[53,54] and insulin resistance, that may improve with GH therapy.[56,57]
Counseling on the benefits of proper diet and exercise is an important component of long-term care for ALL survivors. Periodic analysis of lipoproteins has not been prospectively studied in ALL survivors, but the US Preventive Services Task Force states that adolescents and young adults who have major risk factors for cardiovascular disease should be screened.
PSYCHOSOCIAL WELL-BEING OF ALL SURVIVORS
The long-term psychosocial welfare of ALL survivors is complex. A population-based sibling-matched control study of 93 ALL survivors who were at least 15 years postdiagnosis showed no difference in quality of life or mental health. Similarly, no differences were found in symptoms of anxiety and posttraumatic stress in 130 leukemia survivors and 155 controls. In contrast, a large cooperative study of the Children's Cancer Group and the National Institutes of Health evaluated 580 adult survivors and 396 sibling controls and reported that survivors had greater negative mood and reported more tension, depression, anger, and confusion. Female, minority, and unemployed survivors reported the highest total mood disturbance. Issues related to late effects, especially cognitive dysfunction, obesity, and physical inactivity, may have an impact on the mental health of survivors.
Few data are available on the risk behavior of ALL survivors. In a cohort study of 592 young adult ALL survivors and 409 sibling controls, Tao and colleagues reported that ALL survivors were less likely to start smoking, but once they started they were no more likely to quit than their siblings. Fourteen percent of the ALL survivors were smokers. Although no prospective studies have evaluated the effect of smoking on the incidence and severity of late effects of ALL treatment, it will have an impact on survivors with cardiovascular risk factors, restrictive pulmonary disease, and osteopenia. Counseling on smoking cessation is imperative in the long-term health care of ALL survivors.
OSTEOPENIA AND OSTEOPOROSIS
Several well-designed small to medium-size cross-sectional studies of childhood cancer survivors[63-65] and ALL survivors[66-71] with median ages at evaluation ranging from 12 to 25 years consistently showed reduction in bone mineral density, bone mass content (BMC), and/or age-adjusted bone mass. Age at diagnosis, interval since treatment, sex, and cumulative dosages of MTX and corticosteroids have not been consistently associated with reduction in bone mass. In contrast, CRT has consistently been identified as a risk factor, although the 3 studies that evaluated GH status showed variation in the relationship of GH deficiency and reduced bone mass.[69-71] Impairment of peak bone mass is likely multifactorial in etiology, with predisposing risk factors including altered bone metabolism at the time of onset of leukemia, interference in bone metabolism by corticosteroids and MTX, and impaired bone growth and skeletal maturation caused by pituitary dysfunction/GH deficiency. In an ongoing prospective cohort study, Atkinson and coworkers reported that by 6 months of therapy for ALL, 64% of the children had a reduction from baseline measures of BMC, and by the end of 2 years of therapy 83% were osteopenic. Hypomagnesemia due to renal wasting of magnesium after treatment with high-dose corticosteroids and/or aminoglycosides was associated with the progression in changes and may be a key factor in the alteration of bone metabolism.
Reduction in peak bone mass in young adults is a significant risk factor for developing osteoporosis and subsequent fracture, and measures to prevent or reverse bone loss are important. Exercise increases bone density in obese children and young adults and has recently been shown by meta-analysis to prevent or reverse almost 1% of bone loss per year in pre- and postmenopausal women. With ALL survivors likely to be less physically active,[41-43] it is essential to counsel them on the benefits of exercise in preventing cardiovascular disease and osteoporosis and help them develop an exercise plan. Additionally, counseling on calcium intake and avoidance of smoking is important. Though bone densitometry has not been an effective screening test for the general population, it has value in high-risk groups.[76,77] Prospective randomized trials are needed to evaluate the usefulness and frequency of screening.
Cross-sectional and longitudinal studies have consistently shown that patients treated with 24 Gy CRT have a decrease in median height of approximately 1 to 1.5 SD score, or 5 to 10 cm.[37,78-84] Treatment with 18 Gy CRT or chemotherapy alone[86,87] affect the final height to a lesser degree. Sklar and coworkers reported a change in final height SD score of-0.65 for patients treated with 18 Gy CRT and -0.49 for those treated with chemotherapy alone. Girls and patients treated at a younger age ([is less than] 5 years) have the greatest growth reduction.[37,78,88,89] These changes are thought to be secondary to GH deficiency, resulting in a blunted pubertal growth spurt. The greater the deficiency, the more profound the impairment of growth. Brennan and colleagues reported a median decrement in final height of 2.1 SD in patients with severe GH deficiency. Treatment with GH in these patients usually results in near normalization of final height.
Though GH therapy is generally stopped when children reach their final height or by the age of 18 years, deficiency persists. In a small cross-sectional study of 30 ALL survivors, 9 of 15 patients who received 24 Gy CRT (median age=21.4 years) were GH deficient. In another cross-sectional analysis of the GH status of 32 ALL survivors (median age=23 years), 21 of 32 were GH deficient, including 9 who were severely deficient. The consequences of GH deficiency in adulthood are not well understood. Small studies suggest that GH replacement may improve bone mineral density, body composition, and quality of life.
LATE ONSET ANTHRACYCLINE-INDUCED CARDIOMYOPATHY
Anthracyclines (notably daunorubicin and doxorubicin) are often used during the induction phase of treatment, with some protocols using moderate to high dosages ([is greater than or equal to] 350 mg/[m.sup.2] for high-risk patients. In the past 10 years it has become apparent that childhood cancer patients treated with an anthracycline are at increased risk for developing late-onset cardiomyopathy.[95-97] Classically, anthracycline-induced cardiomyopathy is characterized by elevated afterload followed by the development of a dilated thin-walled left ventricle. Over time this can lead to a stiff and poorly compliant left ventricle. Most patients are asymptomatic, but longitudinal studies suggest that a significant proportion will experience progressive changes and may develop congestive heart failure.[96,97]
Lipshultz and coworkers assessed the cardiac status of 115 ALL survivors treated with doxorubicin and found that 65% of those treated with 228 mg/[m.sup.2] or more had increased left ventricular afterload. In a follow-up study, Lipshultz and colleagues reported that female sex, younger age at treatment, higher rate of administration of doxombicin, and cumulative dose of doxorubicin were independent risk factors for the development of altered left ventricular function. Two recent cross-sectional studies suggest that the risk of left ventricular dysfunction is uncommon in children who received cumulative doses less than 300 mg per [m.sup.2].[98,99] In patients treated with cumulative doses less than 270 mg per [m.sup.2], Sorensen and coworkers did not find that female sex and younger age at treatment were risk factors. However, because late cardiac abnormalities were seen in survivors who received only 90 mg per [m.sup.2], there might be no absolute level below which cardiotoxicity can be prevented.
Because of the concerns about cardiotoxicity, most recent protocols limit anthracycline doses to less than 300 mg per [m.sup.2], and the use of cardioprotectants such as dexrazoxane in children is under investigation. Primary care physicians who provide follow-up care for adult survivors should communicate with oncologists at the treating institution, obtain information about the cumulative dosage of anthracyclines, and discuss long-term screening. Because patients with anthracycline-induced cardiomyopathies generally have a prolonged asymptomatic interval before becoming symptomatic, interval screening is recommended. Optimal timing and testing modality for screening have not been prospectively studied. It is currently recommended that patients who received 300 mg/[m.sup.2] or more of an anthracycline have a screening echocardiogram every 2 to 3 years to evaluate left ventricular function and shortening fraction. It is also important to question patients regarding symptoms of congestive heart failure and to aggressively evaluate them if present.
Because most ALL patients receive blood products during therapy, those treated before adequate blood donor screening for hepatitis C was initiated in the early 1990s are at risk for chronic liver disease. The prevalence of circulating hepatitis C virus (HCV) ribonucleic acid (RNA) in ALL patients treated in Italy before 1990 ranges from 23% to 49%.[103-105] The natural history of ALL survivors with hepatitis C is not well understood. In an Italian study, only 4% of the 56 HCV-RNA seropositive patients had persistently elevated alanine aminotransferase (ALT) over the course of follow-up (mean=17 years). For a median of 14 years, 81 survivors of various childhood cancers who were HCV-RNA seropositive were followed, and none showed progression to liver failure. In contrast, Paul and coworkers reported that 12% of 75 leukemia survivors were anti-HCV positive, 6 of 9 had liver biopsies that showed at least moderate portal inflammation, and half had bridging fibrosis. The Centers for Disease Control and Prevention recommend universal screening with anti-HCV for all patients who received blood products before July 1992.
SECOND MALIGNANT NEOPLASMS
Second malignant neoplasms (SMN) are rare in ALL survivors. Thirteen SMNs were diagnosed a median of 6.7 years from ALL diagnosis in a cohort study of 1597 ALL survivors and were associated with the use of radiation (8/13, CNS or head and neck) or chemotherapy (3/13, hematopoietic). The cumulative incidence of brain tumors at 20 years in a cohort of 1612 patients was only 1.39%, and more than half of these tumors were either low-grade or benign. CNS tumors did not occur in patients treated with chemotherapy alone. Thyroid tumors (predominantly papillary carcinoma) can rarely occur after treatment with cranial or craniospinal irradiation.[111,112] Cases of basal cell carcinoma along the spinal axis have also been reported in patients treated with craniospinal irradiation.[113,114]
Therapy-related acute myelogenous leukemia (t-AMD has been seen following treatment of several childhood cancers, such as ALL and Hodgkin's and non-Hodgkin's lymphoma. Cohort studies have shown that agents with leukemogenic potential include alklyating agents and epidophyllotoxin chemotherapy.[115-121] Most t-AMLs occur within 8 years of treatment, although cases occurring up to 13 years have been reported. Myelodysplasia (especially pancytopenia) generally precedes t-AML. The risk of t-AML following treatment for ALL has been small in 2 cohort studies.[109,122] However, because precancerous states (myelodysplastic changes or myelodysplastic syndrome) are usually antecedent to t-AML and early diagnosis may improve outcomes, most institutions recommend obtaining a complete blood count (CBC) with a platelet count and a white blood cell differential in the routine follow-up of ALL survivors who have been treated with an alkylating agent, such as cyclophosphamide, or an epidophyllotoxin, such as etoposide. How long and how frequently a CBC should be obtained in follow-up of an ALL survivor have not been established.
FERTILITY AND REPRODUCTION
Most antimetabolite-based treatment protocols for ALL do not affect long-term fertility for men or women.[123,124] Craniospinal and abdominal irradiation have been associated with infertility in both sexes but are no longer used for ALL.[125-127] Cyclophosphamide (an alkylating agent commonly used in earlier protocols but currently limited to high-risk patients) is also associated with infertility in a dose-dependent fashion in both sexes.[124,128,129] Resolution of germ-cell dysfunction may occur in men over time, but fertility remains poor for some. Women survivors treated with craniospinal or abdominal irradiation or with cyclophosphamide are at risk for ovarian failure and premature menopause and thus may be at increased risk for osteoporosis. If ovarian failure is suspected, measurement of follicle-stimulating hormone, luteinizing hormone, and serum estradiol and an evaluation by an endocrinologist should be considered.
ALL survivors should know that preliminary studies suggest that treatment is not associated with an increase in congenital malformations of their offspring. In a population-based prospective cohort study an increased rate of congenital defects was not found among 299 adult survivors.
Ocular abnormalities in patients treated with CRT are common but generally asymptomatic. Two studies have evaluated the effect of CRT and systemic corticosteroids on the eyes. In a study of 82 ALL survivors who were a mean of 32 months after completion of therapy, 52% of the patients had posterior subcapsular cataracts (PSC) that were generally not visually significant and were not related to age at treatment or gender. Eighty-three percent of the 18 patients who had received CRT and systemic corticosteroids were noted to have asymptomatic ocular abnormalities after a median surveillance of 4.1 years. Optical densities of the lens were seen in 13 of the 18 of the survivors. There have been no published studies evaluating long-term survivors who received systemic corticosteroids without CRT. Periodic vision and cataract screening is recommended for ALL survivors treated with CRT and should be considered for all survivors of ALL until the risk of prolonged corticosteroid use in childhood is better understood.
DENTAL AND PERIODONTAL DISEASE
ALL survivors, especially those treated with CRT, are more likely to have problems with tooth development and be at risk for periodontal disease. In a large retrospective evaluation of dental records, 39.5% of ALL survivors had a dental abnormality, including root stunting (24.4%), microdontia (18.9%), or hypodontia (8.5%). Patients who were treated at an age younger than 8 years or who received CRT had more dental abnormalities than the other groups. Similar findings were seen in 2 smaller cross-sectional studies. Abnormal dental development occurred in 95% of all patients and 100% of patients aged 5 years or younger at diagnosis. Abnormalities included tooth agenesis, arrested tooth development, microdontia, and enamel dysplasia. Patients who received CRT and those treated at an age younger than 5 years had higher severity scores. Survivors did not have increased caries. However, patients younger than 5 years who were treated with cranial irradiation were found to have higher plaque and gingivitis scores, suggesting an increased risk of periodontal disease. A periodic dental and periodontal evaluation is recommended for survivors treated with CRT or at a young age.
Following treatment with CRT, hypothyroidism infrequently occurs in ALL survivors through damage to the hypothalamic-pituitary-thyroid axis and/or the direct effect of radiation of the gland. Mohn and colleagues reported that 8 of 24 childhood ALL survivors who had received CRT (either 18 or 24 Gy) had either a low basal thyroid-stimulating hormone (TSH) or low peak TSH after thyrotropin-releasing hormone stimulation. Robison and colleagues reported that 10% of 175 ALL survivors who had been treated with either 18 or 24 Gy CRT or craniospinal radiation (CS-RT) therapy had a thyroid abnormality, including 5 children with primary hypothyroidism. Pasqualini and colleagues reported that 6 of 10 ALL survivors who received either CRT or CS-RT had subtle evidence of primary hypothyroidism. In contrast, 3 cross-sectional studies did not find evidence of primary hypothyroidism in 13, 31, and 64 patients, respectively.[139-141] Littley and coworkers suggest that hypopituitarism is commonly underdiagnosed secondary to the subtle manifestations and insidious progression of disease. Radioactive scatter to the thyroid occurs with CRT in a dose-dependent fashion, and ALL survivors treated with either 18 or 24 Gy CRT are at risk for secondary hypothyroidism, thyroid nodules, and thyroid carcinoma. Periodic screening with TSH and free T-4 are recommended in ALL survivors treated with CRT. Further screening of the asymptomatic survivor with thyrotropin-releasing hormone stimulation test or ultrasound of the thyroid gland are costly and have not been prospectively studied.
PULMONARY LATE EFFECTS
ALL survivors may have an increased prevalence of mild, generally subclinical, restrictive pulmonary disease. In a small cross-sectional study of ALL survivors, Shaw and coworkers reported mild restrictive changes, with patients treated at a younger age at higher risk. Similarly, an analysis of 70 leukemia survivors found mild but significant decreases in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV-1), total lung capacity (TLC), and transfer for carbon monoxide (DLCO). Cyclophosphamide, craniospinal irradiation, and a history of chest infections during treatment were independent variables associated with reductions in FEV-1, FVC, and TLC, while anthracyclines and craniospinal irradiation were associated with reductions in DLCO. ALL survivors also had impaired submaximal and maximal exercise capacity. These findings were further supported by analysis of a recent cross-sectional study of 128 patients a median of 7.6 years from therapy completion that reported an increased prevalence of subclinical restrictive pulmonary disease in ALL survivors. The long-term consequences and the possible role of smoking or other inhalant exposures need to be studied.
LIVER DYSFUNCTION (NON-HEPATITIS C)
During treatment with methotrexate (especially high-dose ranges) elevations of transaminases are common and generally transient. Two small longitudinal studies following ALL survivors for up to 7 years after completion of therapy did not report any patients with persistent transaminasemia, although Bessho and colleagues noted that 6 of 13 of their ALL survivors had elevated 2-hour postprandial bile acid levels, a more sensitive predictor of liver cirrhosis than transaminase level.[146,147] Farrow and coworkers found that of 114 survivors who had ALT elevations greater than 5 times the upper limit of normal during therapy, only 17 (14.9%) had elevations persistently. Eight of these patients had chronic HCV infections. Of the remaining 9 patients, only 1 had a persistently elevated transaminase of greater than 2 times normal.
Although there are currently no data evaluating ALL survivors for long-term liver-related complications secondary to methotrexate, studies in patients with juvenile rheumatoid arthritis show that septal and portal fibrosis can occur with weekly low-dose methotrexate treatment of durations as short as 17 months. Obesity may be an associated risk factor for the development of cirrhosis in juvenile rheumatoid arthritis patients treated with methotrexate. Because of these potential risks, periodic measurement of ALT is recommended in follow-up of ALL survivors.
UROLOGIC LATE EFFECTS
Cyclophosphamide is a long-recognized cause of hemorrhagic cystitis and a well-established bladder carcinogen. In a retrospective review of 314 children with ALL who were treated with cyclophosphamide between 1963 and 1973, 8% developed hemorrhagic cystitis. The frequency of diagnosis was not related to age or sex, but African American children were at higher risk. Cyclophosphamide-induced hemorrhagic cystitis generally presents during therapy, with children complaining of gross hematuria or irritative voiding complaints. Concurrent treatment with oral sodium 2-mercapatoethanesulfonate appears to markedly decrease the incidence of cyclophosphamide-induced hemorrhagic cystitis. In a nested case-control study of survivors of non-Hodgkin's lymphoma, Travis and colleagues reported that there was a 2.4-fold increased risk of bladder cancer in patients treated with cumulative dosages of cyclophosphamide lower than 20 g. Because of the risk of chronic hemorrhagic cystitis and bladder cancer, ALL survivors treated with cyclophosphamide should have periodic screening urinalysis, and their review of systems should include voiding problems.
Alopecia is a bothersome late effect secondary to treatment with 24 Gy CRT for which there are no available treatments. In a retrospective study of 273 ALL survivors treated with CRT, 10% had alopecia.
Dr Oeffinger received partial support for this work through the American Academy of Family Physicians Foundation Advanced Research Training Grant and the Robert Wood Johnson Foundation Generalist Physician Faculty Scholars Program.
We would like to thank Drs George Buchanan, Melissa Hudson, and Neyssa Marina for their critical review of this manuscript and Ms Laura Snell and Dr James Tysinger for their editing assistance.
[1.] Smith MA, Ries LAG, Gurney JG, Ross JA. Leukemia. In: Ries LAG, Smith MA, Gurney JG, et at, eds. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. Bethesda, MD: National Institutes of Health; 1999. NIH pub. no. 99-4649.
[2.] Oeffinger KC, Eshelman DA, Tomlinson GE, Buchanan GR. Programs for adult survivors of childhood cancer. J Clin Oncol 1998; 16:2864-67.
[3.] Rosen DS. Transition to adult health care for adolescents and young adults with cancer. Cancer 1993; 71:3411-14.
[4.] Oeffinger KC, Eshelman DA, Tomlinson GE, Buchanan GR, Foster BE. Grading of late effects in young adult survivors of childhood cancer followed in an ambulatory adult setting. Cancer 2000; 88:1687-95.
[5.] Tivey H. The natural history of untreated acute leukemia. Ann NU Acad Sci 1954; 60:322-58.
[6.] Farber S, Diamond LK, Mercer RD, et al. Temporary remissions in acute leukemia in children produced by folic acid antagonist 4-aminopteroylglutamic acid (aminopterin). N Engl J Med 1948; 238:787-93.
[7.] Clavell L, Gelber R, Cohen H, et al. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 1986; 315:657-63.
[8.] Robison LL, Nesbit ME Jr, Sather HN, Meadows AT, Ortega JA, Hammond GD. Factors associated with IQ scores in long-term survivors of childhood acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1984; 6:115-21.
[9.] Cousens P, Waters B, Said J, Stevens M. Cognitive effects of cranial irradiation in leukaemia: a survey and meta-analysis. J Child Psychol Psychiatry 1988; 29:839-52.
[10.] Hill JM, Kornblith AB, Jones D, et al. A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation. Cancer 1998; 82:208-18.
[11.] Poplack D, Reaman G, Bleyer W, et al. Successful prevention of central nervous (CNS) leukemia without cranial radiation in children with high risk acute lymphoblastic leukemia (ALL): a preliminary report. Proc Am Soc Clin Oncol 1989; 8:828.
[12.] Crist W, Shuster J, Falletta J, et al. Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: a Pediatric Onoclogy Group study. Blood 1988; 72:1891-97.
[13.] Pui CH, Behm FG, Singh B, et al. Heterogeneity of presenting features and their relation to treatment outcome in 120 children with T-cell acute lymphoblastic leukemia. Blood 1990; 75:174-79.
[14.] Kato M, Azuma E, Ido M, et al. Ten-year survey of the intellectual deficits in children with acute lymphoblastic leukemia receiving chemoimmunotherapy. Med Pediatr Oncol 1993; 21:435-40.
[15.] Waber DP, Urion DK, Tarbell NJ, Niemeyer C, Gelber R, Sallan SE. Late effects of central nervous system treatment of acute lymphoblastic leukemia in childhood are sex-dependent. Dev Med Child Neurol 1990; 32:238-48.
[16.] O'Hare AE, Aitken K, Eden OB. Computerized psychometry screening in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1988; 5:197-208.
[17.] Hertzberg H, Huk WJ, Ueberall MA, et al. CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL--an evaluation of the interferences between morphology and neuropsychological performance--the German Late Effects Working Group. Med Pediatr Oncol 1997; 28:387400.
[18.] Stehbens JA, Kaleita TA, Noll RB, et al. CNS prophylaxis of childhood leukemia: what are the long-term neurological, neuropsychological, and behavioral effects? Neuropsychol Rev 1991; 2:147-77.
[19.] Said JA, Waters BG, Cousens P, Stevens MM. Neuropsychological sequelae of central nervous system prophylaxis in survivors of childhood acute lymphoblastic leukemia. J Consult Clin Psychol 1989; 57:251-56.
[20.] Rodgers J, Horrocks J, Britton PG, Kernahan J. Attentional ability among survivors of leukaemia. Arch Dis Child 1999; 80:318-23.
[21.] Gamis AS, Nesbit ME. Neuropsychologic (cognitive) disabilities in long-term survivors of childhood cancer. Pediatrician 1991; 18:11-19.
[22.] Mulhern RK, Kovnar E, Langston J, et al. Long-term survivors of leukemia treated in infancy: factors associated with neuropsychologic status. J Clin Oncol 1992; 10:1095-102.
[23.] Waber DP, Tarbell NJ, Fairclough D, et al. Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 1995; 13:2490-96.
[24.] Rubenstein CL, Varni JW, Katz ER. Cognitive functioning in long-term survivors of childhood leukemia: a prospective analysis. J Dev Behav Pediatr 1990; 11:301-05.
[25.] Jankovic M, Brouwers P, Valsecchi MG, Van Veldhuizen A, Huisman J. Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. Lancet 1994; 344:224-27.
[26.] Smibert E, Anderson V, Godber T, Ekert H. Risk factors for intellectual and educational sequelae of cranial irradiation in childhood acute lymphoblastic leukaemia. Br J Cancer 1996; 73:825-30.
[27.] Anderson v, Godber T, Smibert E, Ekert H. Neurobehavioural sequelae following cranial irradiation and chemotherapy in children: an analysis of risk factors. Pediatr Rehabil 1997; 1:63-76.
[28.] Bleyer A. CNS chemoradiotherapy of childhood leukemia: the plot thickens but the ending bodes well. J Clin Oncol 1995; 13:2480-82.
[29.] Kaleita TA, Reaman GH, MacLean WE, Sather HN, Whitt JK. Neurodevelopmental outcome of infants with acute lymphoblastic leukemia: a Children's Cancer Group report. Cancer 1999; 85:1859-65.
[30.] Brown RT, Madan-Swain A, Walco GA, et al. Cognitive and academic late effects among children previously treated for acute lymphocytic leukemia receiving chemotherapy as CNS prophylaxis. J Pediatr Psychol 1998; 23:333-40.
[31.] Vainionpaa L. Clinical neurological findings of children with acute lymphoblastic leukaemia at diagnosis and during treatment. Eur J Pediatr 1993; 152:115-19.
[32.] Reinders-Messelink HA, Schoemaker MM, Hofte M, et al. Fine motor and handwriting problems after treatment for childhood acute lymphoblastic leukemia. Med Pediatr Oncol 1996; 27:551-55.
[33.] Lesnik PG, Ciesielski KT, Hart BL, Benzel EC, Sanders JA. Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia. Arch Neurol 1998; 55:1561-68.
[34.] Haupt R, Fears TR, Robison LL, et al. Educational attainment in long-term survivors of childhood acute lymphoblastic leukemia. JAMA 1994; 272:1427-32.
[35.] Zee P, Chen CH. Prevalence of obesity in children after therapy for acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1986; 8:294-99.
[36.] Odame I, Reilly JJ, Gibson BE, Donaldson MD. Patterns of obesity in boys and girls after treatment for acute lymphoblastic leukaemia. Arch Dis Child 1994; 71:147-49.
[37.] Schell MJ, Ochs JJ, Schriock EA, Caller M. A method of predicting adult height and obesity in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 1992; 10:128-33.
[38.] Didi M, Didcock E, Davies HA, Ogilvy-Stuart AL, Wales JK, Shalet SM. High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood. J Pediatr 1995; 127:63-67.
[39.] Van Dongen-Melman JE, Hokken-Koelega AC, Hahlen K, De Groot A, Tromp CG, Egeler RM. Obesity after successful treatment of acute lymphoblastic leukemia in childhood, Pediatr Res 1995; 38:86-90.
[40.] Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab 1996; 81:3051-55.
[41.] Warner JT, Bell W, Webb DK, Gregory JW. Daily energy expenditure and physical activity in survivors of childhood malignancy. Pediatr Res 1998; 43:607-13.
[42.] Jenney ME, Faragher EB, Jones PH, Woodcock A. Lung function and exercise capacity in survivors of childhood leukaemia. Med Pediatr Oncol 1995; 24:222-30.
[43.] Black P, Gutjahr P, Stopfkuchen H. Physical performance in long-term survivors of acute leukaemia in childhood. Eur J Pediatr 1998; 157:464-67.
[44.] Wright MJ, Halton JM, Martin RF, Barr RD. Long-term gross motor performance following treatment for acute lymphoblastic leukemia. Med Pediatr Oncol 1998; 3:86-90.
[45.] Wright MJ, Halton JM, Barr RD. Limitation of ankle range of motion in survivors of acute lymphoblastic leukemia: a cross-sectional study. Med Pediatr Oncol 1999; 32:279-82.
[46.] Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics 1999; 103:1175-82.
[47.] Vanhala M, Vanhala P, Kumpusalo E, Halonen P, Takala J. Relation between obesity from childhood to adulthood and the metabolic syndrome: population based study. BMJ 1998; 317:319-21.
[48.] Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998; 338:1650-56.
[49.] Fagan TC, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med 1998; 105:77S-82S.
[50.] Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitism. Lancet 1990; 336:285-88.
[51.] Bates AS, Van't Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996; 81:1169-72.
[52.] Erfurth EM, Bulow B, Eskilsson J, Hagmar L. High incidence of cardiovascular disease and increased prevalence of cardiovascular risk factors in women with hypopituitarism not receiving growth hormone treatment: preliminary results. Growth Horm IGF Res 1999; 9 (suppl):21-24.
[53.] Davidson MB. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 1987; 8:115-31.
[54.] Hew FL, O'Neal D, Kamarudin N, Alford FP, Best JD. Growth hormone deficiency and cardiovascular risk. Baillieres Clin Endocrinol Metab 1998; 12:199-216.
[55.] Beshyah SA, Henderson A, Niththyananthan R, et al. The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance. J Clin Endocrinol Metab 1995; 80:356-63.
[56.] Al-Shoumer KA, Gray R, Anyaoku V, et al. Effects of four years' treatment with biosynthetic human growth hormone (GH) on glucose homeostasis, insulin secretion and lipid metabolism in GH-deficient adults. Clin Endocrinol 1998; 48:795-802.
[57.] O'Neal D, Hew FL, Sikaris K, Ward G, Alford F, Best JD. Low density lipoprotein particle size in hypopituitary adults receiving conventional hormone replacement therapy. J Clin Endocrinol Metab 1996; 81:2448-54.
[58.] US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Washington, DC: US Department of Health and Human Services; 1996.
[59.] Moe PJ, Holen A, Glomstein A, et al. Long-term survival and quality of life in patients treated with a national ALL protocol 15-20 years earlier: IDM/HDM and late effects? Pediatr Hematol Oncol 1997; 14:51324.
[60.] Kazak AE. Posttraumatic distress in childhood cancer survivors and their parents. Med Pediatr Oncol 1998; 1 (Suppl):60-68.
[61.] Zeltzer LK, Chen E, Weiss R, et al. Comparison of psychologic outcome in adult survivors of childhood acute lymphoblastic leukemia versus sibling controls: a cooperative Children's Cancer Group and National Institutes of Health study. J Clin Oncol 1997; 15:547-56.
[62.] Tao ML, Guo MD, Weiss R, et al. Smoking in adult survivors of childhood acute lymphoblastic leukemia. J Natl Cancer Inst 1998; 90:219-25.
[63.] Hesseling PB, Hough SF, Nel ED, van Riet FA, Beneke T, Wessels G. Bone mineral density in long-term survivors of childhood cancer. Int J Cancer Suppl 1998; 11:44-7.
[64.] Aisenberg J, Hsieh K, Kalaitzoglou G, et al. Bone mineral density in young adult survivors of childhood cancer. J Pediatr Hematol Oncol 1998; 20:241-45.
[65.] Vassilopoulou-Sellin R, Brosnan P, Delpassand A, Zietz H, Klein MJ, Jaffe N. Osteopenia in young adult survivors of childhood cancer. Med Pediatr Oncol 1999; 32:272-78.
[66.] Gilsanz V, Carlson ME, Roe TF, Ortega JA. Osteoporosis after cranial irradiation for acute lymphoblastic leukemia. J Pediatr 1990; 117:238-44.
[67.] Arikoski P, Komulainen J, Voutilainen R, et al. Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1998; 20:234-40.
[68.] Warner JT, Evans WD, Webb DK, Bell W, Gregory JW. Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 1999; 45:544-51.
[69.] Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. Bone mass after treatment for acute lymphoblastic leukemia in childhood. J Clin Oncol 1998; 16:3752-60.
[70.] Hoorweg-Nijman JJ, Kardos G, Rots JC, et al. Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol 1999; 50:237-44.
[71.] Brennan BM, Rahim A, Mackie EM, Eden OB, Shalet SM. Clin Endocrinol 1998; 48:777-783.
[72.] Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl 1998; 11:35-39.
[73.] Gutin B, Owens S, Okuyama T, Riggs S, Ferguson M, Litaker M. Effect of physical training and its cessation on percent fat and bone density of children with obesity. Obes Res 1999; 7:208-14.
[74.] Valdimarsson O, Kristinsson JO, Stefansson SO, Valdimarsson S, Sigurdsson G. Lean mass and physical activity as predictors of bone mineral density in 16-20-year old women. J Intern Med 1999; 245:489-96.
[75.] Wolff I, van Croonenborg JJ, Kemper HC, Kostense PJ, Twisk JW. The effect of exercise training programs on bone mass: a meta-analysis of published controlled trials in pre- and postmenopausal women. Osteoporos Int 1999; 9:1-12.
[76.] Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254-59.
[77.] Halley D, Sampietro-Colom L, Marshall D, Rico R, Granados A, Asua J. The effectiveness of bone density measurement and associated treatments for prevention of fractures: an international collaborative review. Int J Technol Assess Health Care 1998; 14:237-54.
[78.] Robison LL, Nesbit ME Jr, Sather HN, Meadows AT, Ortega JA, Hammond GD. Height of children successfully treated for acute lymphoblastic leukemia: a report from the Late Effects Study Committee of Children's Cancer Study Group. Med Pediatr Oncol 1985; 13:14-21.
[79.] Schriock EA, Schell MJ, Carter M, Hustu O, Ochs JJ. Abnormal growth patterns and adult short stature in 115 long-term survivors of childhood leukemia. J Clin Oncol 1991; 9:400-05.
[80.] Uruena M, Stanhope R, Chessells JM, Leiper AD. Impaired pubertal growth in acute lymphoblastic leukaemia. Arch DIS Child 1991; 66:1403-07.
[81.] Mohnike K, Dorffel W, Timme J, et al. Final height and puberty in 40 patients after antileukaemic treatment during childhood. Eur J Pediatr 1997; 156:272-76.
[82.] Sempoux P, Moell C, Cornu G, Malvaux P, Maes M. Subnormal growth during puberty in children treated for acute lymphoblastic leukemia. Pediatr Hematol Oncol 1992; 9:217-22.
[83.] Hokken-Koelega AC, van Doom JW, Hahlen K, Stijnen T, de Muinck Keizer-Schrama SM, Drop SL. Long-term effects of treatment for acute lymphoblastic leukemia with and without cranial irradiation on growth and puberty: a comparative study. Pediatr Res 1993; 33:577-82.
[84.] Katz JA, Pollock BH, Jacaruso D, Morad A. Final attained height in patients successfully treated for childhood acute lymphoblastic leukemia. J Pediatr 1993; 123:546-52.
[85.] Melin AE, Adan L, Leverger G, Souberbielle JC, Schaison G, Brauner R. Growth hormone secretion, puberty and adult height after cranial irradiation with 18 Gy for leukaemia. Eur J Pediatr 1998; 157:703-07.
[86.] Roman J, Villaizan CJ, Garcia-Foncillas J, Azcona C, Salvador J, Sierrasesumaga L. Chemotherapy-induced growth hormone deficiency in children with cancer. Med Pediatr Oncol 1995; 25:90-5.
[87.] Roman J, Villaizan CJ, Garcia-Foncillas J, Salvador J, Sierrasesumaga L. Growth and growth hormone secretion in children with cancer treated with chemotherapy. J Pediatr 1997; 131:105-12.
[88.] Sklar C, Mertens A, Walter A, et al. Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 1993; 123:59-64.
[89.] Cicognani A, Cacciari E, Rosito P, et al. Longitudinal growth and final height in long-term survivors of childhood leukaemia. Eur J Pediatr 1994; 153:726-30.
[90.] Stubberfield TG, Byrne GC, Jones TW. Growth and growth hormone secretion after treatment for acute lymphoblastic leukemia in childhood 18-Gy versus 24-Gy cranial irradiation. J Pediatr Hematol Oncol 1995; 17:167-71.
[91.] Birkebaek NH, Fisker S, Clausen N, Tuovinen V, Sindet-Pedersen S, Christiansen JS. Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood. Med Pediatr Oncol 1998; 30:351-56.
[92.] O'Halloran DJ, Tsatsoulis A, Whitehouse RW, Holmes SJ, Adams JE, Shalet SM. Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency. J Clin Endocrinol Metab 1993; 76:1344-48.
[93.] Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321:1797-803,
[94.] Burman P, Broman JE, Hetta J, et al. Quality of life in adults with growth hormone (GH) deficiency: response to treatment with recombinant human GH in a placebo-controlled 21-month trial. J Clin Endocrinol Metab 1995; 80:3585-90.
[95.] Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxombicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324:843-45.
[96.] Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and drug dose as risk factors for late cardiotoxic effects of doxombicin therapy for childhood cancer. N Engl J Med 1995; 332:1738-43.
[97.] Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 1998; 25(suppl):72-85.
[98.] Sorensen K, Levitt G, Bull C, Chessells J, Sullivan I. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. J Clin Oncol 1997; 15:61-68.
[99.] Nysom K, Holm K, Lipsitz SR, et al. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 1998; 16:545-50.
[100.] Wexler LH. Ameliorating anthracycline cardiotoxicity in children with cancer: clinical trials with dexrazoxane. Semin Oncol 1998; 25:86-92.
[101.] Steinherz LJ, Graham T, Hurwitz R, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992; 89:942-49.
[102.] Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998; 47:1-39.
[103.] Arico M, Maggiore G, Silini E, Bono F, Vigano C. Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 1994; 84:2919-22.
[104.] Dibenedetto SP, Ragusa R, Sciacca A, et al. Incidence and morbidity of infection by hepatitis C virus in children with acute lymphoblastic leukaemia. Eur J Pediatr 1994; 153:271-75.
[105.] Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997; 90:4628-33.
[106.] Locasciulli A, Alberti A. Hepatitis C virus serum markers and liver disease in children with leukemia. Leuk Lymphoma 1995; 17:245-49.
[107.] Cesaro S, Petris MG, Rossetti F, et al. Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood 1997; 90:1315-20.
[108.] Paul IM, Sanders J, Ruggiero F, Andrews T, Ungar D, Eyster ME. Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood 1953); 93:3672-77.
[109.] Kimball Dalton VM, Gelber RD, Li F, Donnelly MJ, Tarbell NJ, Sallan SE. Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol 1998; 16:2848-53.
[110.] Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital. J Clin Oncol 1998; 16:3761-67.
[111.] Black P, Straaten A, Gutjahr P. Secondary thyroid carcinoma after treatment for childhood cancer. Med Pediatr Oncol 1998; 31:91-95.
[112.] Perel Y, Leverger G, Carrere A, et al. Second thyroid neoplasms after prophylactic cranial irradiation for acute lymphoblastic leukemia. Am J Hematol 1998; 59:91-94.
[113.] Yoshihara T, Ikuta H, Hibi S, Todo S. Second cutaneous neoplasms after acute lymphoblastic leukemia in childhood. Int J Hematol 1993; 59: 67-71.
[114.] Garcia-Silva J, Velasco-Benito JA, Pena-Penabad C, Armijo M. Basal cell carcioma in a girl after cobalt irradiation to the cranium for acute lymphoblastic leukemia: case report and literature review. Pediatr Dermatol 1996; 13:54-57.
[115.] Pedersen-Bjergaard J, Philip P, Larsen SO, et al. Therapy-related myelodysplasia and acute myeloid leukemia: cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series. Leukemia 1993; 7:1975-86.
[116.] Winick N, Shuster JJ, Bowman WP, et al. Intensive oral methotrexate protects against lymphoid marrow relapse in childhood B-precursor acute lymphoblastic leukemia. J Clin Oncol 1996; 14:2803-11.
[117.] Kollmannsberger C, Hartmann JT, Kanz L, Bokemeyer C. Risk of secondary myeloid leukemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies. J Cancer Res Clin Oncol 1998; 124:207-14.
[118.] Kantarjian HM, Keating MJ. Therapy-related leukemia and myelodysplastic syndrome. Semin Oncol 1987; 14:435-43.
[119.] Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 1999; 17:569-77.
[120.] Smith MA, Rubinstein L, Cazenave L, et al. Report of the Cancer Therapy Evaluation Program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins. J Natl Cancer Inst 1993; 85:554-58.
[121.] Pui CH, Relling MV, Rivera GK, et al. Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 1995; 9:1990-96.
[122.] Kubota M, Akiyama Y, Koishi S, et al. Second malignancy following treatment of acute lymphoblastic leukemia in children. Int J Hematol 1998; 67:397401.
[123.] Nygaard R, Clausen N, Siimes MA, et al. Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring. Med Pediatr Oncol 1991; 19:459-66.
[124.] Levitt GA, Jenney ME. The reproductive system after childhood cancer. Br J Obstet Gynaecol 1998; 105:946-53.
[125.] Wallace WH, Shalet SM, Tetlow LJ, Morris-Jones PH. Ovarian function following the treatment of childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 1993; 21:333-39.
[126.] Hamre MR, Robison LL, Nesbit ME, et al. Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children's Cancer Study Group. J Clin Oncol 1987; 5:1759-65.
[127.] Sklar CA, Robison LL, Nesbit ME, et al. Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group. J Clin Oncol 1990; 8:1981-87.
[128.] Ise T, Kishi K, Imashuku S, et al. Testicular histology and function following long-term chemotherapy of acute leukemia in children and outcome of the patients who received testicular biopsy. Am J Pediatr Hematol Oncol 1986; 8:288-93.
[129.] Wallace WH, Shalet SM, Lendon M, Moms-Jones PH. Male fertility in long-term survivors of childhood acute lymphoblastic leukaemia. Int J Androl 1991; 14:312-19.
[130.] Kenney LB, Nicholson HS, Brasseux C, et at. Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia: a Children's Cancer Group/National Institutes of Health Report. Cancer 1996; 78:169-76.
[131.] Hoover DL, Smith LE, Turner SJ, Gelber RD, Sallan SE. Ophthalmic evaluation of survivors of acute lymphoblastic leukemia. Ophthalmology 1988; 95:151-55.
[132.] Weaver RG Jr, Chauvenet AR, Smith TJ, Schwartz AC. Ophthalmic evaluation of long-term survivors of childhood acute lymphoblastic leukemia. Cancer 1986; 58:963-68.
[133.] Kaste SC, Hopkins KP, Jones D, Crom D, Greenwald CA, Santana VM. Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia 1997; 11:792-96.
[134.] Sonis AL, Tarbell N, Valachovic RW, Geller R, Schwenn M, Sallan S. Dentofacial development in long-term survivors of acute lymphoblastic leukemia: a comparison of three treatment modalities. Cancer 1990; 66:2645-52.
[135.] Sonis AL, Waber DP, Sallan S, Tarbell NJ. The oral health of long-term survivors of acute lymphoblastic leukaemia: a comparison of three treatment modalities. Eur J Cancer B Oral Oncol 1995; 31:250-52.
[136.] Motto A, Chiarelli F, Di Marzio A, Impicciatore P, Marsico S, Angrilli F. Thyroid function in children treated for acute lymphoblastic leukemia. J Endocrinol Invest 1997; 20:215-19.
[137.] Robison LL, Nesbit ME, Sather HN, Meadows AT, Ortega JA, Hammond GD. Thyroid abnormalities in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Res 1985; 19:266A.
[138.] Pasqualini T, McCalla J, Berg S, et al. Subtle primary hypothyroidism in patients treated for acute lymphoblastic leukemia. Acta Endocrinol 1991; 124:375-80.
[139.] Drinnan CR, Miller JD, Guyda HJ, Esseltine DW, Chevalier LM, Freeman CR. Growth and development of long-term survivors of childhood acute lymphoblastic leukemia treated with and without prophylactic radiation of the central nervous system. Clin Invest Med 1985; 8:307-14.
[140.] Voorhess ML, Brecher ML, Glicksman AS, et al. Hypothalamic-pituitary function of children with acute lymphocytic leukemia after three forms of central nervous system prophylaxis: a retrospective study. Cancer 1986; 57:1287-91.
[141.] Carter EP, Leiper AD, Chessells JM Thyroid function in children after treatment for acute lymphoblastic leukemia. Arch Dis Child 1988; 64:631.
[142.] Littley MD, Shalet SM, Beardwell CG. Radiation and hypothalamic-pituitary function. Baillieres Clin Endocrinol Metab 1990; 4:147-75.
[143.] Bessho F, Ohta K, Akanuma A, Sakata K. Dosimetry of radiation scattered to thyroid gland from prophylactic cranial irradiation for childhood leukemia. Pediatr Hematol Oncol 1994; 11:47-53.
[144.] Shaw NJ, Tweeddale PM, Eden OB. Pulmonary function in childhood leukaemia survivors. Med Pediatr Oncol 1989; 17:149-54.
[145.] Nysom K, Holm K, Olsen JH, Hertz H, Hesse B. Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood. Br J Cancer 1998; 78:21-27.
[146.] Weber BL, Tanyer G, Poplack DG, et al. Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood. NCI Monogr 1987; 5:207-12.
[147.] Bessho F, Kinumaki H, Yokota S, Hayashi Y, Kobayashi M, Kamoshita S. Liver function studies in children with acute lymphocytic leukemia after cessation of therapy. Med Pediatr Oncol 1994; 23:111-15.
[148.] Farrow AC, Buchanan GR, Zweiner RJ, Bowman WP, Winick NJ. Serum aminotransferase elevation during and following treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 1997; 15:1560-66.
[149.] Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH. The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 1999; 134:47-52.
[150.] Lawrence HJ, Simone J, Aur RJA. Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia. Cancer 1975; 36:1572-76.
[151.] Stillwell TJ, Benson RC. Cyclophosphamide-induced hemorrhagic cystitis; a review of 100 patients. Cancer 1988; 61:451-57.
[152.] Vose JM, Reed EC, Pippert GC, et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: a randomized trial. J Clin Oncol 1993; 11:1306-10.
[153.] Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst 1995; 87:524-30.
[154.] Van der Does-van den Berg A, de Vaan GAM, van Weerden JF, Hahlen K, van Weel-Sipman M, Veerman AJP. Late effects among long-term survivors of childhood acute leukemia in the Netherlands: a Dutch Childhood Leukemia Study Group report. Pediatr Res 1995; 38:802-07.
* Submitted, revised, August 27, 2000.
From the Department of Family Practice and Community Medicine (K.C.O., MT., G.W.S.), the Center for Cancer and Blood Disorders (D.A.E.), and the Department of Pediatrics, Division of Hematology-Ontology (G.E.T.), the University of Texas Southwestern Medical Center at Dallas, and Children's Medical Center of Dallas, the After the Cancer Experience (ACE) Young Adult Program. Reprint requests should he addressed to Kevin C. Oeffinger, MD, the University of Texas Southwestern Medical Center at Dallas, Department of Family Practice and Community Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-9067. E-mail: firstname.lastname@example.org.
COPYRIGHT 2000 Appleton & Lange
COPYRIGHT 2001 Gale Group