Providing Primary Care for Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, accounts for almost one fourth of childhood cancers.¹ 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 thus 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.”⁵ In the late 1940s, Farber and colleagues⁶ 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 anthracyclines 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.⁷

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 survivors⁴Table 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.

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).⁹ 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.²³ Girls 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 girls and patients treated at a younger age.^24-27

Recent studies suggest that neurodevelopmental outcomes for survivors treated with chemotherapy alone are generally positive.²⁸ 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.²⁹ Though full-scale IQ was normal, Brown and colleagues³⁰ 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.³³

The Children’s Cancer Group investigated the impact of treatment on scholastic performance of 593 adult survivors, compared with 409 sibling controls.³⁴ 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) >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 coworkers³⁹ 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%).³⁹ Talvensaari and colleagues⁴⁰ 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.⁴¹ Maximal and submaximal exercise capacity were reduced in another cross-sectional study.⁴² 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.⁴³

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.⁴⁴ In a follow-up of this cohort, Wright and coworkers⁴⁵ reported that the ALL survivors had significantly less active 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 coworkers⁴⁰ 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.⁴⁹

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,⁵⁵ 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.⁵⁸

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.⁵⁹ Similarly, no differences were found in symptoms of anxiety and posttraumatic stress in 130 leukemia survivors and 155 controls.⁶⁰ 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.⁶¹ 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 colleagues⁶² 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 coworkers⁷² 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 children⁷³ and young adults⁷⁴ and has recently been shown by meta-analysis⁷⁵ 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.

GH deficiency

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 CRT⁸⁵ or chemotherapy alone^86,87 affect the final height to a lesser degree. Sklar and coworkers⁸⁸ 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 (<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.⁹⁰ Brennan and colleagues⁷¹ 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.⁹¹ 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.⁷¹ The consequences of GH deficiency in adulthood are not well understood. Small studies suggest that GH replacement may improve bone mineral density,⁹² body composition,⁹³ and quality of life.⁹⁴

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 (Ž350 mg/m2) 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 coworkers⁹⁵ assessed the cardiac status of 115 ALL survivors treated with doxorubicin and found that 65% of those treated with 228 mg/m2 or more had increased left ventricular afterload.⁹⁵ In a follow-up study, Lipshultz and colleagues⁹⁶ reported that female sex, younger age at treatment, higher rate of administration of doxorubicin, 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 m2.^98,99 In patients treated with cumulative doses less than 270 mg per m2, Sorensen and coworkers⁹⁸ 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 m2, 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 m2, and the use of cardioprotectants such as dexrazoxane in children is under investigation.¹⁰⁰ 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/m2 or more of an anthracycline have a screening echocardiogram every 2 to 3 years to evaluate left ventricular function and shortening fraction.¹⁰¹ It is also important to question patients regarding symptoms of congestive heart failure and to aggressively evaluate them if present.

Hepatitis C

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.¹⁰² 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).¹⁰⁶ 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.¹⁰⁷ In contrast, Paul and coworkers¹⁰⁸ 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 Prevention¹⁰² 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).¹⁰⁹ 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.¹¹⁰ 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-AML) 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.¹¹⁵ 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 dosedependent 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.¹³⁰

Ocular abnormalities

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.¹³¹ 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.¹³² 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%).¹³³ 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.¹³⁴ 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.¹³⁵ 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.

Thyroid-related disorders

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 colleagues¹³⁶ 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 colleagues¹³⁷ 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 colleagues¹³⁸ 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.^1,139-141 Littley and coworkers¹⁴² 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,¹⁴³ and ALL survivors treated with either 18 or 24 Gy CRT are at risk for secondary hypothyroidism, thyroid nodules, and thyroid carcinoma.¹¹¹ 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 coworkers¹⁴⁴ 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).⁴² 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.¹⁴⁵ 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 coworkers¹⁴⁸ 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.¹⁴⁹ 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 review¹⁵⁰ 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.¹⁵¹ Concurrent treatment with oral sodium 2-mercapatoethanesulfonate appears to markedly decrease the incidence of cyclophosphamide-induced hemorrhagic cystitis.¹⁵² In a nested case-control study of survivors of non–Hodgkin’s lymphoma, Travis and colleagues¹⁵³ 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

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.¹⁵⁴

Acknowledgement

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.

Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, accounts for almost one fourth of childhood cancers.¹ 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 thus 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.”⁵ In the late 1940s, Farber and colleagues⁶ 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 anthracyclines 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.⁷

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 survivors⁴Table 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.

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).⁹ 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.²³ Girls 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 girls and patients treated at a younger age.^24-27

Recent studies suggest that neurodevelopmental outcomes for survivors treated with chemotherapy alone are generally positive.²⁸ 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.²⁹ Though full-scale IQ was normal, Brown and colleagues³⁰ 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.³³

The Children’s Cancer Group investigated the impact of treatment on scholastic performance of 593 adult survivors, compared with 409 sibling controls.³⁴ 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) >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 coworkers³⁹ 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%).³⁹ Talvensaari and colleagues⁴⁰ 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.⁴¹ Maximal and submaximal exercise capacity were reduced in another cross-sectional study.⁴² 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.⁴³

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.⁴⁴ In a follow-up of this cohort, Wright and coworkers⁴⁵ reported that the ALL survivors had significantly less active 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 coworkers⁴⁰ 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.⁴⁹

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,⁵⁵ 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.⁵⁸

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.⁵⁹ Similarly, no differences were found in symptoms of anxiety and posttraumatic stress in 130 leukemia survivors and 155 controls.⁶⁰ 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.⁶¹ 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 colleagues⁶² 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 coworkers⁷² 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 children⁷³ and young adults⁷⁴ and has recently been shown by meta-analysis⁷⁵ 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.

GH deficiency

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 CRT⁸⁵ or chemotherapy alone^86,87 affect the final height to a lesser degree. Sklar and coworkers⁸⁸ 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 (<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.⁹⁰ Brennan and colleagues⁷¹ 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.⁹¹ 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.⁷¹ The consequences of GH deficiency in adulthood are not well understood. Small studies suggest that GH replacement may improve bone mineral density,⁹² body composition,⁹³ and quality of life.⁹⁴

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 (Ž350 mg/m2) 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 coworkers⁹⁵ assessed the cardiac status of 115 ALL survivors treated with doxorubicin and found that 65% of those treated with 228 mg/m2 or more had increased left ventricular afterload.⁹⁵ In a follow-up study, Lipshultz and colleagues⁹⁶ reported that female sex, younger age at treatment, higher rate of administration of doxorubicin, 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 m2.^98,99 In patients treated with cumulative doses less than 270 mg per m2, Sorensen and coworkers⁹⁸ 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 m2, 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 m2, and the use of cardioprotectants such as dexrazoxane in children is under investigation.¹⁰⁰ 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/m2 or more of an anthracycline have a screening echocardiogram every 2 to 3 years to evaluate left ventricular function and shortening fraction.¹⁰¹ It is also important to question patients regarding symptoms of congestive heart failure and to aggressively evaluate them if present.

Hepatitis C

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.¹⁰² 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).¹⁰⁶ 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.¹⁰⁷ In contrast, Paul and coworkers¹⁰⁸ 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 Prevention¹⁰² 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).¹⁰⁹ 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.¹¹⁰ 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-AML) 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.¹¹⁵ 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 dosedependent 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.¹³⁰

Ocular abnormalities

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.¹³¹ 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.¹³² 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%).¹³³ 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.¹³⁴ 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.¹³⁵ 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.

Thyroid-related disorders

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 colleagues¹³⁶ 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 colleagues¹³⁷ 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 colleagues¹³⁸ 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.^1,139-141 Littley and coworkers¹⁴² 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,¹⁴³ and ALL survivors treated with either 18 or 24 Gy CRT are at risk for secondary hypothyroidism, thyroid nodules, and thyroid carcinoma.¹¹¹ 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 coworkers¹⁴⁴ 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).⁴² 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.¹⁴⁵ 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 coworkers¹⁴⁸ 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.¹⁴⁹ 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 review¹⁵⁰ 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.¹⁵¹ Concurrent treatment with oral sodium 2-mercapatoethanesulfonate appears to markedly decrease the incidence of cyclophosphamide-induced hemorrhagic cystitis.¹⁵² In a nested case-control study of survivors of non–Hodgkin’s lymphoma, Travis and colleagues¹⁵³ 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

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.¹⁵⁴

Acknowledgement

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.

Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, accounts for almost one fourth of childhood cancers.¹ 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 thus 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.”⁵ In the late 1940s, Farber and colleagues⁶ 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 anthracyclines 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.⁷

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 survivors⁴Table 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.

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).⁹ 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.²³ Girls 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 girls and patients treated at a younger age.^24-27

Recent studies suggest that neurodevelopmental outcomes for survivors treated with chemotherapy alone are generally positive.²⁸ 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.²⁹ Though full-scale IQ was normal, Brown and colleagues³⁰ 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.³³

The Children’s Cancer Group investigated the impact of treatment on scholastic performance of 593 adult survivors, compared with 409 sibling controls.³⁴ 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) >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 coworkers³⁹ 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%).³⁹ Talvensaari and colleagues⁴⁰ 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.⁴¹ Maximal and submaximal exercise capacity were reduced in another cross-sectional study.⁴² 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.⁴³

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.⁴⁴ In a follow-up of this cohort, Wright and coworkers⁴⁵ reported that the ALL survivors had significantly less active 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 coworkers⁴⁰ 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.⁴⁹

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,⁵⁵ 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.⁵⁸

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.⁵⁹ Similarly, no differences were found in symptoms of anxiety and posttraumatic stress in 130 leukemia survivors and 155 controls.⁶⁰ 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.⁶¹ 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 colleagues⁶² 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 coworkers⁷² 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 children⁷³ and young adults⁷⁴ and has recently been shown by meta-analysis⁷⁵ 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.

GH deficiency

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 CRT⁸⁵ or chemotherapy alone^86,87 affect the final height to a lesser degree. Sklar and coworkers⁸⁸ 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 (<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.⁹⁰ Brennan and colleagues⁷¹ 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.⁹¹ 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.⁷¹ The consequences of GH deficiency in adulthood are not well understood. Small studies suggest that GH replacement may improve bone mineral density,⁹² body composition,⁹³ and quality of life.⁹⁴

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 (Ž350 mg/m2) 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 coworkers⁹⁵ assessed the cardiac status of 115 ALL survivors treated with doxorubicin and found that 65% of those treated with 228 mg/m2 or more had increased left ventricular afterload.⁹⁵ In a follow-up study, Lipshultz and colleagues⁹⁶ reported that female sex, younger age at treatment, higher rate of administration of doxorubicin, 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 m2.^98,99 In patients treated with cumulative doses less than 270 mg per m2, Sorensen and coworkers⁹⁸ 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 m2, 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 m2, and the use of cardioprotectants such as dexrazoxane in children is under investigation.¹⁰⁰ 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/m2 or more of an anthracycline have a screening echocardiogram every 2 to 3 years to evaluate left ventricular function and shortening fraction.¹⁰¹ It is also important to question patients regarding symptoms of congestive heart failure and to aggressively evaluate them if present.

Hepatitis C

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.¹⁰² 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).¹⁰⁶ 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.¹⁰⁷ In contrast, Paul and coworkers¹⁰⁸ 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 Prevention¹⁰² 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).¹⁰⁹ 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.¹¹⁰ 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-AML) 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.¹¹⁵ 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 dosedependent 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.¹³⁰

Ocular abnormalities

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.¹³¹ 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.¹³² 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%).¹³³ 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.¹³⁴ 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.¹³⁵ 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.

Thyroid-related disorders

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 colleagues¹³⁶ 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 colleagues¹³⁷ 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 colleagues¹³⁸ 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.^1,139-141 Littley and coworkers¹⁴² 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,¹⁴³ and ALL survivors treated with either 18 or 24 Gy CRT are at risk for secondary hypothyroidism, thyroid nodules, and thyroid carcinoma.¹¹¹ 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 coworkers¹⁴⁴ 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).⁴² 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.¹⁴⁵ 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 coworkers¹⁴⁸ 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.¹⁴⁹ 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 review¹⁵⁰ 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.¹⁵¹ Concurrent treatment with oral sodium 2-mercapatoethanesulfonate appears to markedly decrease the incidence of cyclophosphamide-induced hemorrhagic cystitis.¹⁵² In a nested case-control study of survivors of non–Hodgkin’s lymphoma, Travis and colleagues¹⁵³ 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

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.¹⁵⁴

Acknowledgement

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.