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

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.