High health-related quality of life among long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Health-related quality of life (HRQoL) was assessed in a cohort of long-term childhood acute lymphoblastic leukemia (ALL) survivors. PROCEDURE: Rand-36-Item health Survey (RAND-36) was used to assess subjective HRQoL in 74 survivors of ALL an average of 20 years after the diagnosis. Cranial irradiation had been administered to 46 of the survivors, while 28 survivors had solely been treated with chemotherapy. The control group consisted of 146 healthy young adults selected from local population registry. Survivors were examined by a physician and late effects were graded using the Common Terminology Criteria for Adverse Events (CTCAEv3). RESULTS: ALL survivors achieved significantly higher scores than the controls on three of the eight HRQoL subscales; role limitations due to emotional problems (P = 0.030), mental health (P = 0.030) and vitality (P = 0.004). In comparison to controls, survivors with a follow-up of more than 20 years had significantly higher scores on vitality (P = 0.006) and mental health (P = 0.011). Survivors with severe (grade 3 and 4) late effects scored significantly better than controls on vitality (P = 0.043) and mental health (P = 0.040). Patients who had been treated for an ALL relapse and had received the most intensive chemo- and radiotherapy had significantly higher scores on mental health (P = 0.004) and vitality (P = 0.004) than the controls. CONCLUSIONS: Long-term survivors of childhood ALL reported equal or better HRQoL in RAND-36. Higher HRQoL scores were associated with more severe late effects and intensive therapy. Our findings support the idea of response bias.

Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Despite the extensive literature on neuropsychological sequelae after treatment of childhood acute lymphoblastic leukemia (ALL), the very-long-term neurocognitive outcome of the survivors is poorly studied. We assessed neuropsychological functioning in a population-based cohort of young adult childhood ALL survivors. PROCEDURE: Neuropsychological testing was performed on 64 survivors an average of 20 years after the diagnosis. The test battery included verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ), memory function, orientation and attention as well as motor performance. Cranial irradiation had been administered to 44 survivors as part of ALL treatment, whereas 20 survivors had been treated solely with chemotherapy. A control group consisted of 45 healthy young adults. Earlier neuropsychological test results of 45 of the survivors were available for comparison. RESULTS: The ALL survivors attained significantly lower test scores than the controls in all the neuropsychological function areas. The mean VIQ test scores were 91, 100, and 109 (P < 0.001), and the mean PIQ test scores 100, 111, and 118 (P < 0.001) for the irradiated survivors, non-irradiated survivors and controls, respectively. Memory and motor functions were impaired among the irradiated survivor group compared with the controls. A significant decline in PIQ and VIQ test scores was observed in the irradiated survivor group during the follow-up period, but only in VIQ in the non-irradiated group. CONCLUSIONS: Survivors of childhood ALL suffer from long-lasting progressive neuropsychological impairment, especially when treatment includes cranial irradiation.

Radiation-induced meningiomas: a shadow in the success story of childhood leukemia.

While the prognosis of acute childhood leukemia has improved, long-term survivors are increasingly experiencing late effects of the treatment. Cranially irradiated survivors are predisposed to the development of CNS tumors. Our aim was to describe the incidence of secondary brain tumors and to define the significance of treatment-related risk factors and host characteristics in a cohort of childhood leukemia survivors. Our cohort consisted of 60 consecutive cranially irradiated adult survivors of childhood leukemia treated in Oulu University Hospital (Oulu, Finland); MRI of the brain was performed on 49. The sites of the tumors, their histology, and details of the leukemia treatment were determined. Of the 49 patients, 11 (22%) 1-8 years of age at the time of diagnosis developed meningioma later in life, while no other brain tumors were seen. In this cohort, the development of meningioma seemed to show undisputable linkage with long latency periods (mean, 25 years; range, 14-34 years) and an increasing incidence 20 years after the treatment (47%). Three patients had multiple meningiomas, two had recurrent disease, and one had an atypical meningioma. Age at the time of irradiation, gender, or cumulative doses of chemotherapeutic agents showed no significant association with the development of meningiomas. The high incidence of meningiomas in this study was associated with long follow-up periods. Although the cohort is small, it seems probable that the increasing incidence of meningioma will shadow the future of cranially irradiated leukemia survivors. Systematic brain imaging after the treatment is therefore justifiable.

Osteonecrosis in children treated for lymphoma or solid tumors.

PURPOSE: The purpose of this study was to find out the incidence of and clinical risk factors for magnetic resonance imaging (MRI)-detected osteonecrosis (ON) in children treated for lymphoma or solid tumors. PATIENTS AND METHODS: The development of ON was studied in 32 childhood cancer patients who underwent MRI scanning of the lower extremities at the end of their treatment. The underlying malignancy was Wilms tumor in 8 patients, non-Hodgkin lymphoma (NHL) in 8, Hodgkin disease (HD) in 7, rhabdomyosarcoma in 6, and other occasional solid tumors in 3 patients. RESULTS: Six of the 32 patients (19%) had ON. The mean age of the patients with ON at diagnosis was 12.7 years compared with 5.8 years for the patients without ON (P<0.001). All the patients with ON had either HD (4 patients) or NHL (2 patients). Two (33%) of the patients with ON were symptomatic. CONCLUSIONS: ON in MRI was found to be a common complication in children after treatment for HD or NHL. The risk for ON seems to be very low in patients with other solid tumors even when they receive high cumulative doses of dexamethasone.

Scholastic achievements of childhood leukemia patients: a nationwide, register-based study.

PURPOSE: Studies concerning the scholastic achievement of survivors of childhood leukemia have yielded controversial results. We studied the school marks of childhood leukemia survivors in a register-based study. PATIENTS AND METHODS: Three hundred seventy-one patients with a diagnosis of leukemia before the age of 16 years who were born between 1974 and 1986 and alive on their 16th birthday were identified from the Finnish Cancer Registry. Five matched controls were sought for each patient from the Population Register Center of Finland. Information on the ninth-grade school report was obtained from Statistics Finland. The overall mark average and the marks (scale 4 to 10) for mother tongue, foreign language, mathematics, and physical education were compared between the patients and controls. RESULTS: The ninth-grade school report was obtained by 97.6% of the patients and 98.5% of the controls. The patients whose treatment included cranial irradiation had a lower overall mark average (mean difference, -0.24; 95% CI, -0.33 to -0.15) and lower marks for all assessed school subjects compared with their controls. Of the patients treated with chemotherapy alone, only the females with leukemia diagnosed before 7 years of age had lower school marks than their controls. The biggest difference was observed in the marks for foreign language among the irradiated females diagnosed at a young age (mean difference, -1.0; 95% CI, -1.25 to -0.74). CONCLUSION: Leukemia treatment that includes cranial irradiation impairs scholastic achievement. It is noteworthy that treatment of leukemia with chemotherapy alone impairs school performance only in females diagnosed before school age.

High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia.

PURPOSE: The aim of the study was to determine the incidence of and clinical risk factors for radiographic osteonecrosis (ON) in children treated for acute lymphoblastic leukemia (ALL) using the Nordic ALL protocols. PATIENTS AND METHODS: Ninety-seven consecutive patients with childhood ALL were studied prospectively by magnetic resonance imaging (MRI) of the lower extremities at the end of the treatment. RESULTS: Twenty-three (24%) of the 97 patients had ON. Seven of the patients (30%) were symptomatic, and three patients (13%) required surgical interventions. Multiple logistic regression analysis showed that high body mass index (BMI; P = .04), female sex (P = .01), older age at diagnosis (P < .001), and higher cumulative dexamethasone dose (P = .03) were independent risk factors for radiographic ON. The cumulative prednisone dose did not differ significantly between the patients with and without ON. The incidence of radiographic ON decreased significantly, from 36% to 7%, when the duration of dexamethasone exposure during the delayed-intensification phase was shortened from 3 to 4 weeks to 2 weeks with a taper (P = .001). CONCLUSION: ON as determined by MRI was found to be a common complication in children and adolescents after treatment with the Nordic ALL protocols. Revision of the ALL protocols by shortening the single exposure to dexamethasone has diminished the risk for ON remarkably. High BMI was identified as a new significant risk factor for ON.

Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries.

The aim of the study was to assess the risk with radiation therapy and chemotherapy of the first cancer in childhood and adolescence for the development of a second malignant solid tumor (SMST). Also, the role of relapse of the primary tumor was studied. It is a nested case-control study within a Nordic cohort of patients less than 20 years of age at first diagnosis 1960-1987. SMSTs were diagnosed in 1960-1991. There were 196 cases and 567 controls. The risk was increased only for radiotherapy given more than five years before the development of the SMST. A significantly increased relative risk of 1.8 was found already at doses below 1 Gy. The risk increased rapidly up to a maximum of 18.3 for doses above 30 Gy. Chemotherapy alone did not increase the risk to develop an SMST. However, in combination with radiotherapy, chemotherapy showed a significant potentiating effect. Relapse was found to be an independent risk factor for development of an SMST, with a higher relative risk for females than for males.

Perfusion MRI and SPECT of brain after treatment for childhood acute lymphoblastic leukemia.

BACKGROUND: Treatment of childhood leukemia may cause perfusion defects in the brain observed by SPECT. Perfusion MRI is a novel method to study brain perfusion which has not been used previously in this setting. This study was performed to compare SPECT with perfusion MRI in patients with acute lymphoblastic leukemia (ALL) after treatment. PROCEDURE: Nineteen children or young adults underwent perfusion MRI at the cessation of treatment (n = 9) or 4-8 years after the treatment (n = 10). Seventeen of them also underwent SPECT at the time of MRI (within 0-3 days, n = 14) or a couple of months later (1.5-6 months, n = 3). SPECT images and relative cerebral blood volume (CBV) and cerebral blood flow (CBF) maps from perfusion MRI were analyzed visually. Relative CBV ratios of gray matter to white matter and thalamus to white matter were also calculated from the perfusion MRI. RESULTS: Perfusion MRI did not show any focal perfusion defects, while small defects were observed by SPECT in five of 17 children (29%) in the basal, frontal or temporal areas on the left. No significant differences were observed by perfusion MRI in the relative CBV ratios in the different treatment groups. Time since treatment, age at diagnosis, brain irradiation, or findings in conventional MRI or SPECT did not have any effect on the relative perfusion values either. CONCLUSIONS: SPECT may show small perfusion defects after treatment for childhood leukemia which are not visible by perfusion MRI. The clinical significance or prognosis of these defects is not known.

Mucosal pathology of the upper gastrointestinal tract associated with intensive chemotherapy in children: vitamin A supplements do not prevent lesions.

Intensive chemotherapy (ICT) for a malignant disease in children may be associated with clinically significant mucosal lesions of the upper gastrointestinal tract. This prospective and randomized study was conducted to evaluate more thoroughly the mucosal damage and to find out whether vitamin A therapy might prevent the development of these lesions. Gastroduodenoscopy and non-invasive methods were used to examine a consecutive series of 20 patients (10 females, 10 males, aged 1-15 years) 4 weeks after initiating the therapy regimen. Half of the patients were randomized to take vitamin A supplements for 6 weeks. During a follow-up of 6 weeks, 13 (65%) reported some symptoms of the gastrointestinal (GI) tract, diarrhea and mouth pain being most prominent. Endoscopic abnormalities were found in 13 (65 %) subjects: esophagitis in 10, erosive duodenitis in 8, and gastritis in 7. Histologically, 11 subjects had duodenitis, 5 had gastritis, 3 had eosinophilic esophagitis, and 2 had lymphocytic esophagitis. Both endoscopic and histological abnormalities of the duodenum showed a close relationship with long-term (more than 2 weeks) granulocytopenia. The 4 patients with the most extensive endoscopic abnormalities were treated with HCl inhibitors, and re-endoscopy performed 4-8 weeks later showed complete recovery. The sugar permeability values, measured as the lactulose/mannitol ratio were comparable to the values obtained in the controls, and lactose intolerance was found in only 3 (20%) of the 15 children able to perform the breath test. Both the incidence of the reported GI symptoms and the endoscopically or histologically observed GI lesions were similar in the subjects randomized to take vitamin A supplements as in the controls. In this study, two-thirds of children with ICT showed erosive mucosal lesions of the upper gastrointestinal tract, and vitamin A therapy failed to prevent them. Endoscopic examination is recommended if a patient has severe symptoms indicative of mucosal pathology.