Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study.

BACKGROUND: Health-related quality of life (HRQoL) from diagnosis until end of treatment for children with acute lymphoblastic leukaemia was investigated, examining effects of age, gender, risk-stratified treatment regimen, and therapy intensity (one vs. two 'delayed intensifications' [DIs]). METHOD: In a multi-centre prospective study, parents reported their child's generic and disease-specific HRQoL and their own care-giving burden at five time points. From 1,428 eligible patients, 874 parents completed questionnaires at least once during treatment. RESULTS: At each time point, generic HRQoL was significantly lower than equivalent norm scores for healthy children. HRQoL decreased significantly at the start of treatment, before recovering gradually (but remained below pre-treatment levels). Parents reported that older children worried more about side effects and their appearance, but showed less procedural anxiety than younger children. Concern for appearance was greater among girls than boys. Compared to Regimen B (i.e. additional doxorubicin during induction and additional cyclophosphamide and cytarabine during consolidation chemotherapy), patients receiving Regimen A had fewer problems with pain and nausea. There were no statistically significant differences in HRQoL by number of DI blocks received. INTERPRETATION: HRQoL is compromised at all stages of treatment, and is partly dependent on age. The findings increase understanding of the impact of therapy on children's HRQoL and parental care-giving burden, and will contribute to the design of future trials.

The neurodevelopmental sequelae of childhood leukaemia and its treatment.

The overall survival of childhood leukaemia has increased dramatically over recent decades. With the increasing number of survivors, chemotherapy protocols are designed not only to improve cure rates but also to minimise long-term sequelae. Central-nervous-system-directed therapy given as intrathecal chemotherapy and/or cranial irradiation plays a crucial part in acute leukaemia treatment but can also result in adverse effects on the developing brain. The elimination of cranial irradiation from current treatment protocols has improved the neurocognitive outcome without compromising survival rates. Although neurodevelopmental long-term sequelae after chemotherapy-only central-nervous-system-directed therapies may be more subtle, survivors of childhood leukaemia will continue to require methodical follow-up and appropriate rehabilitation.

Adaptation of the Manchester-Minneapolis Quality of Life instrument for use in the UK population.

INTRODUCTION: The availability of health-related quality of life (HRQL) measures that are reliable, valid, brief and comprehensible and appropriate for use with UK children is limited. We report the validation of a HRQL measure suitable for UK use in healthy children, children with chronic disease conditions and socially disadvantaged children. PATIENTS: A total of 1238 children took part in the study, including healthy children as controls (n = 824) and five exemplar groups: children diagnosed with asthma (n = 87), diabetes (n = 103) or inflammatory bowel disease (IBD; n = 69), children in remission from cancer (n = 68) and children in public care (n = 87). METHODS: In phase I, the Manchester-Minneapolis Quality of Life instrument (MMQL) Child Form was translated into UK English. In phases II and III, the questionnaire was shortened and validated. RESULTS: MMQL was anglicised and shortened to five components comprising 29 items. Good internal reliability was found with alpha reaching at least 0.69 for all subscales. Construct validity was established through moderate correlations with comparable PedsQL subscales (Pearson's r ranged from 0.38 to 0.58, p<0.01). Discriminant validity was also demonstrated in children with asthma and IBD, children in remission from cancer and children in public care, all of whom reported significantly lower HRQL than healthy children. Children with diabetes showed similar HRQL to their healthy peers. Good reproducibility and moderate responsiveness were demonstrated for the new measure. CONCLUSIONS: The anglicised and shortened MMQL was shown to be valid and reliable and could be a valuable new tool for the assessment of HRQL in children.

Osteopenia, excess adiposity and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukaemia without cranial irradiation.

OBJECTIVE: Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation. DESIGN AND PATIENT: Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7.5 years (range 3.4-16.7 years) were recruited. Serial dual energy X-ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans. RESULTS: Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0.01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0.05). Serum leptin concentrations increased following 24 months of therapy (P < 0.05). CONCLUSIONS: Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.

Effects of chemotherapeutic agents on the function of primary human osteoblast-like cells derived from children.

Studies in children treated with chemotherapy suggest that chemotherapeutic agents have deleterious effects on bone metabolism. We therefore evaluated the in vitro effects of clinically relevant concentrations of chemotherapeutic agents on the synthesis of type I collagen, alkaline phosphatase (AP) activity, and mineralization by primary human osteoblast-like (HOB) cells derived from children. Because serum 1,25-dihydroxyvitamin D(3) concentrations may be reduced during treatment with chemotherapy, the effect of chemotherapeutic agents on HOB cells cultured in the presence or absence of 1,25-dihydroxyvitamin D(3) was also evaluated. Type I collagen synthesis was reduced by all agents (P < 0.01) other than methotrexate, whereas the relative AP activity was increased (P < 0.01) by all agents. The relative number of cells staining intensely for AP after culture with agents increased (P < 0.05), and AP mRNA expression was increased (P < 0.01) with vincristine. 1,25-Dihydroxyvitamin D(3) ameliorated (P < 0.01) the depletion of HOB cell numbers by chemotherapeutic agents. Furthermore, vincristine and daunorubicin inhibited 1,25-dihydroxyvitamin D(3)-mediated AP activity (P < 0.01). We conclude that chemotherapeutic agents can adversely affect HOB cell function, and we speculate that this observation may account, in part, for the osteopenia observed during and after treatment of children with chemotherapy.

In vitro effects of combination chemotherapy on osteoblasts: implications for osteopenia in childhood malignancy.

Clinical studies suggest that combination chemotherapy adversely affects bone metabolism and in vitro studies have demonstrated that a reduction in osteoblast numbers results in diminished bone formation. The aim of this study was to investigate the in vitro effects of combinations of chemotherapeutic agents on primary human osteoblast-like (hOB) cell numbers and apoptosis, and to assess the ability of hOBs and osteoprogenitor (HCC1) cells to recover from prior treatment with chemotherapy. As glucocorticoids are frequently administered during treatment with cytotoxic agents, we evaluated whether glucocorticoids influence the chemosensitivity of hOB and human osteosarcoma (MG63) cells. Culture with clinically relevant concentrations of the individual chemotherapeutic agents reduced hOB cell numbers compared with control (p < 0.01) and also increased the numbers of apoptotic cells (p < 0.05). Potentiation of cytotoxicity was observed when agents were given in combination, thus further reducing cell numbers, and this effect was greatest when vincristine was given in combination with asparaginase. Following culture with a chemotherapeutic agent, there was greater recovery of hOB compared with HCC1 cell numbers (p < 0.01). Pretreatment with glucocorticoids ameliorated the adverse effects of chemotherapeutic agents on hOB and MG63 cell numbers and apoptosis (p < 0.05). We conclude that the use of combination chemotherapy contributes to osteopenia in childhood malignancy by a reduction in osteoblast numbers. However, this effect may be attenuated by the concomitant use of glucocorticoids.

In vitro effects of chemotherapeutic agents on human osteoblast-like cells.

Osteopenia is a complicating problem that may occur during and after treatment for childhood malignancy. Clinical studies suggest that chemotherapeutic agents directly affect osteoblasts in vivo. Since combinations of agents are used for treatment, we individually investigated the chemosensitivity of human osteoblast-like cells to 11 of the chemotherapeutic agents used. The relative chemosensitivity of osteoblast-like cells representing different stages of cell differentiation was also examined. Cell numbers were evaluated following culture of an established human osteoblast-like cell line (MG63) for 3 days with clinically relevant concentrations of the chemotherapeutic agents. The chemosensitivity of MG63 cells was compared to that of a human osteoprogenitor cell line (HCC1) and primary osteoblast-like (HOB) cells derived from pediatric bone. Cell numbers were reduced by all agents in all cell types, although there was a varied response between agents at equimolar concentrations. In MG63 cells the lowest concentration of agent significantly reducing cell numbers varied between agents, for example, methotrexate (10(-7) M), vincristine (10(-9) M), and etoposide (10(-7) M) (all P <0.01). The less differentiated osteoblast phenotypes were significantly more chemosensitive at equimolar concentrations of methotrexate, vincristine, asparaginase, and dexamethasone than more differentiated phenotypes (all P <0.01). Furthermore, four agents significantly increased alkaline phosphatase (AP) activity in HOB cells. We conclude that individual chemotherapeutic agents added to osteoblast cell cultures reduce cell numbers, with osteoblast precursor cells being preferentially depleted. These results suggest that most of the agents may contribute to osteopenia in childhood malignancy by direct effects on cell numbers.