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

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.