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.

Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005).

BACKGROUND: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma. PATIENTS AND METHODS: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement. RESULTS: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions. CONCLUSION: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists. CLINICAL TRIALS NUMBER: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study.

In-transit metastases (ITM) are defined as metastatic lymph nodes or deposits occurring between the primary tumor and proximal draining lymph node basin. In extremity rhabdomyosarcoma (RMS), they have rarely been reported. This study evaluates the frequency, staging and survival of patients with ITM in distal extremity RMS. METHODS: Patients with extremity RMS distal to the elbow or knee, enrolled in the EpSSG RMS 2005 trial between 2005 and 2016 were eligible for this study. RESULTS: One hundred and nine distal extremity RMS patients, with a median age of 6.2 years (range 0-21 years) were included. Thirty seven of 109 (34%) had lymph node metastases at diagnosis, 19 of them (51%) had ITM, especially in lower extremity RMS. 18F-FDG-PET/CT detected involved lymph nodes in 47% of patients. In patients not undergoing 18F-FDG-PET/CT lymph node involvement was detected in 22%. The 5-yr EFS of patients with ITM vs proximal lymph nodes vs combined proximal and ITM was 88.9% vs 21.4% vs 20%, respectively (p = 0.01) and 5-yr OS was 100% vs 25.2% vs 15%, respectively (p = 0.003). CONCLUSION: Our study showed that in-transit metastases constituted more than 50% of all lymph node metastases in distal extremity RMS. 18F-FDG-PET/CT improved nodal staging by detecting more regional and in-transit metastases. Popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of in-transit metastases. Biopsy of these nodes is recommended especially in distal extremity RMS of the lower limb. Patients with proximal (axillary or inguinal) lymph node involvement have a worse prognosis.

Clinical outcomes and health-related quality of life (HRQOL) following haemopoietic stem cell transplantation (HSCT) for paediatric leukaemia.

BACKGROUND: Haemopoietic stem cell transplantation (HSCT) is a life-saving but intensive procedure associated with potentially severe adverse late effects. We aimed to determine morbidity and health-related quality of life (HRQOL) in a sample of survivors aged 8-18 years at least 1 year post HSCT for paediatric acute leukaemia, compared with a non-transplanted group of survivors matched for age, gender, initial disease and time since treatment. METHODS: Families (N = 54; HSCT n= 29) recruited from four UK centres completed measures of child behaviour and school attendance, HRQOL and finances. Mothers completed measures of their own well-being. Clinical outcome data were extracted from medical records. RESULTS: Children in the HSCT group had significantly more late effects and had received more tests for vision, bone, dental and skin health, and thyroid, lung, and gonadal function than the non-transplanted group. HRQOL scores for the HSCT group were significantly lower in all domains compared with the non-transplanted group and population norms, but were not significantly related to clinical indices. Mothers in the HSCT group had significantly poorer mental well-being than population norms. CONCLUSION: Significant morbidity and compromised HRQOL was found in survivors of HSCT. The burden of caring for a child after HSCT has a continuing toll on mothers' well-being.The importance of counselling families about possible long-term consequences is emphasized.

The British Childhood Cancer Survivor Study: Objectives, methods, population structure, response rates and initial descriptive information.

BACKGROUND: In Britain 75% of individuals diagnosed with childhood cancer survive at least 5 years. The British Childhood Cancer Survivor Study was established to determine the risks of adverse health and social outcomes among survivors. To be eligible individuals were diagnosed with childhood cancer in Britain between 1940 and 1991 and survived at least 5 years. The entire cohort of 17,981 form the basis of population-based studies of late mortality and the risks/causes of second malignant neoplasms using national registration systems. METHODS: A postal questionnaire was sent to survivors who were alive and aged at least 16 years via their primary care physician. RESULTS: Of the 14,836 survivors eligible to receive a questionnaire, 10,483 (71%) returned it completed. Of the 13,211 who were mailed a questionnaire by their primary care physician 10,483 (79%) returned it completed. Outline treatment information concerning initial radiotherapy, chemotherapy and surgery is available. CONCLUSIONS: This is the largest available population-based cohort of childhood cancer survivors to have included investigation of a wide spectrum of adverse outcomes (the risk of which might be increased as a result of childhood cancer or its treatment). The study should provide useful information for counselling survivors, planning long-term clinical follow-up and evaluating the long-term risks likely to be associated with proposed treatment strategies.

Efficacy of carboplatin given in a phase II window study to children and adolescents with newly diagnosed metastatic soft tissue sarcoma.

AIM: The activity of carboplatin was evaluated in a phase II window study in previously untreated children with metastatic soft tissue sarcoma. METHODS: Children with poor-risk metastatic disease (over 10 years and/or with bone/bone marrow involvement) treated in the SIOP MMT 98 study were scheduled to receive two courses of intravenous carboplatin (area under curve [AUC] of 10), 21 days apart. RESULTS: Sixteen eligible patients were entered into the rhabdomyosarcoma (RMS) group. Response (complete remission or partial remission) was seen in five children (31%, 95% confidence interval (CI) 14-56%). Ten eligible patients with other soft tissue sarcomas were recruited into the non-RMS group. Two responses (20%, 95% CI 6-51%) were seen. Toxicity in both groups was predictable nausea, vomiting and marrow suppression and there were no toxic deaths. CONCLUSION: Single-agent carboplatin at AUC of 10 has an acceptable toxicity profile but only moderate efficacy in poor-risk metastatic soft tissue sarcoma.

Quality of life Evaluation in patients receiving Steroids (the QuESt tool): initial development in children and young people with acute lymphoblastic leukaemia.

BACKGROUND: The powerful cytotoxic and immunomodulatory effects of corticosteroids are an important element of the success that has been achieved in the treatment of acute lymphoblastic leukaemia (ALL). In addition to physical side effects, corticosteroids can adversely influence behaviour, cognitive function and mood leading to significantly impaired quality of life (QoL). A number of tools exist for assessing QoL, but none of these specifically examines changes attributable to steroids. METHODS: Children and young adults aged 8-24 years and parents of children receiving maintenance therapy for ALL from four UK centres were invited to participate. The study comprised three stages carried out over 2 years: (1) focus groups and interviews where participants were asked to describe their experiences of dexamethasone; (2) analysis of questionnaires sent to healthcare professionals and patients to evaluate the importance and relevance of the questions; and (3) cognitive interviewing. RESULTS: Interpretative phenomenological analysis of focus group and interview transcripts identified that dexamethasone adversely influenced behaviour, appetite, body image, mood and family relationships. 157 electronic survey responses were analysed leading to further item development. Cognitive interviewing confirmed face validity and internal consistency. QuESt comprises 28 questions within four domains and has three age-specific versions. CONCLUSIONS: QuESt is the first treatment-specific QoL measure for children and young adults receiving corticosteroids. It can be completed in 10-15 min by children aged ≥8 years. Further validity and reliability testing will be undertaken. Although the initial application is for ALL, QuESt may also be a valuable tool for understanding the impact of corticosteroids in other paediatric conditions.

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.

Improving the quality of life for children with cancer. European School of Oncology Advisory Group.

There are now more than one million new cases of cancer every year in the European Community (EC) including the children to whom particular needs should be addressed. Besides the disease-free survival other outcomes reflecting the impact of treatment on the patient and their families must also be assessed and include their physical, psychological and social functioning throughout their care: during therapy, after completion of treatment or, for some, in the terminal phase of their illness. To provide optimal care and thus improve the quality of life for these children needs: a) an appropriately structured Paediatric Cancer Unit; b) well trained and permanent staff members: comprising doctors, nurses, psychologists, social workers and other health care professionals; c) facilities such as a specific out-patient clinic, a hospital school, a residence for parents; d) a well defined programme for the terminally ill children; e) a well defined programme for controlling the late effects of therapy.

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.

Mothers' attitudes to the randomized controlled trial (RCT): the case of acute lymphoblastic leukaemia (ALL) in children.

OBJECTIVES: Survival rates for childhood cancer have improved substantially partly as a result of national and international randomized clinical trials (RCT). However, the decision for families is complex and emotional. Our aim was to describe the views of mothers of children newly diagnosed with ALL regarding consent to randomized controlled trials. DESIGN: Qualitative interview to explore mothers knowledge, and reasons for involving their child in RCTs. Interviews took place in mothers' homes. PARTICIPANTS: Fifty mothers of children with newly diagnosed ALL (age 4-16 years; mean = 7.4) recruited through research nurses at outpatient appointments. RESULTS: All but three families had consented for their child to be treated in the RCT, although there was wide variation in their understanding of the aims, costs and benefits. Most mothers reported the aim of the trial to compare 'old' and 'new' treatments. CONCLUSION: Despite detailed verbal and written information, mothers were poorly informed about the purpose of the trial, and possibility of side effects. Individual preferences for either standard or new treatment were routinely reported. The data raise questions about the extent to which families give truly informed consent to recruitment of their child to an RCT.

Use of a tissue expander and a polyglactic acid (Vicryl) mesh to reduce radiation enteritis: case report and literature review.

Management of stage IV rhabdomyosarcoma comprises systemic chemotherapy with local control by conservative surgery and radiotherapy. Abdominal radiotherapy may lead to radiation enteritis causing such serious morbidity as malabsorption, fistulae or stricture formation. The risk increases with the dose of radiation and length of bowel involved. Various methods have been utilised to displace the bowel from the radiation field. Usually these are applied in patients requiring pelvic irradiation. We report a case of metastatic alveolar rhabdomyosarcoma requiring radiotherapy to the right renal bed. Effective displacement of small bowel from the tumour site was achieved by a combined use of a tissue expander and Vicryl mesh. There were no complications from the surgery. This is the first report discussing combined use of a tissue expander and Vicryl mesh to aid radiotherapy to the renal fossa in a paediatric patient.

Malignant disease and the lung.

Primary lung tumours in childhood are rare. However, cancer in a child may have an impact on the lung in a number of ways. Chemotherapy and radiotherapy may be directly toxic to the lung. Young children are particularly sensitive to the effects of radiotherapy, which can cause impairment of growth of muscle, skin and bone, in addition to its direct toxic effect on the underlying lung. The lung is vulnerable to infection - particularly protozoal, viral and fungal organisms, as well as bacterial. Children undergoing bone marrow transplantation are at greater risk of lung damage, as they are profoundly immunosuppressed and have received intensive cytotoxic chemotherapy or radiotherapy. The underlying cause of lung damage may be difficult to determine because of the complexity of treatment and the additional risk of infectious complications. In a small number of children, pulmonary complications may be fatal. However, for the many survivors, although abnormalities of lung function are frequently detected, these are rarely clinically significant and, with notable exceptions, do not appear to deteriorate with time. However, data remain scanty; there is a real need for ongoing prospective studies of lung function in survivors of childhood cancer.

Developing a measure of health outcomes in survivors of childhood cancer: a review of the issues.

The success of treatment for childhood cancer has prompted greater attention to issues of quality of life for the survivors. Work on health-related quality of life has proceeded faster for adults than for children. This paper reviews the results of such work for adults and points to the potential for applications in children. Specific problems in adapting measures and in interpreting the results in the context of a child's development are discussed. An approach to the assessment of the health-related quality of life for survivors of childhood cancer is proposed.

Juxtaposed cystic nephroma and Wilms' tumor.

We report a case of juxtaposed Wilms' tumor (WT) and cystic nephroma (CN) in a 21-month-old girl which gave rise to radiological diagnostic difficulty. Preoperative chemotherapy was given, resulting in marked tumor necrosis but the cystic nephroma remained untouched. Histological examination showed characteristic features of a triphasic WT and a CN; the two lesions were separated by a thick fibrous capsule. While everybody agrees that WT and cystic partially differentiated nephroblastoma (CPDN) are closely related, there are two opposite views about their relationship to CN. One is that CN may represent the final step in maturation of WT and CPDN. Other authors argue that there is no evidence to support this theory but believe CN might have something in common with nephrogenic rests. We suggest that the two lesions in the present case may have originated from two intralobar nephrogenic rests, which would strengthen the latter view.