Subsequent cancers within 5 years from initial diagnosis of childhood cancer. Patterns and risks in the population of Great Britain.

BACKGROUND: Patterns and risks of subsequent primary tumours (SPTs) among long-term survivors of childhood cancer have been extensively described, but much less is known about early SPTs (ESPTs) occurring within 5 years after initial diagnosis. PROCEDURE: We carried out a population-based study of ESPTs following childhood cancer throughout Britain, using the National Registry of Childhood Tumours. The full study series comprised all ESPTs occurring among 56,620 children whose initial cancer diagnosis was in the period 1971-2010. Frequencies of ESPT were calculated for the entire cohort. For analyses of risk, follow-up began 92 days after initial diagnosis. RESULTS: ESPT developed in 0.4% of children overall, 0.52% of those initially diagnosed at age less than 1 year and 0.38% of those diagnosed at age 1-14 years. Standardised incidence ratio (SIR) was 7.7 (95% confidence interval [CI]: 6.7-8.9), overall 9.5 (95% CI: 7.1-12.5) for children initially diagnosed in 1981-1990 and 6.5-7.5 for those from earlier and later decades. SIR by type of first cancer ranged from 4.4 (95% CI: 1.8-9.1) for Wilms tumour to 13.1 (95% CI: 7.7-21.0) for non-Hodgkin lymphoma. SIR by type of ESPT ranged from 2.0 (95% CI: 1.0-3.4) for acute lymphoblastic leukaemia to 66.6 (95% CI: 52.3-83.6) for acute myeloid leukaemia. Predisposition syndromes were known to be implicated in 21% of children with ESPT and suspected in another 5%. CONCLUSIONS: This study provides an overview of the patterns and risks of ESPTs in a large population where many children received therapy that is still in widespread use. Further research will be needed to monitor and understand changes in risk as childhood cancer treatment continues to evolve.

Combined resistance and aerobic exercise intervention improves fitness, insulin resistance and quality of life in survivors of childhood haemopoietic stem cell transplantation with total body irradiation.

PURPOSE: To investigate the effects of a supervised combined resistance and aerobic training programme on cardiorespiratory fitness, body composition, insulin resistance and quality of life (QoL) in survivors of childhood haematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI). PARTICIPANTS: HSCT/TBI survivors (n = 20; 8 females). Mean (range) for age at study and time since HSCT/TBI was 16.7 (10.9-24.5) and 8.4 (2.3-16.0) years, respectively. METHODS: After a 6-month run-in, participants undertook supervised 45- to 60-minute resistance and aerobic training twice weekly for 6 months, with a 6-month follow-up. The following assessments were made at 0, 6 (start of exercise programme), 12 (end of exercise programme) and 18 months: Body composition via dual energy X-ray absorptiometry, homeostatic model assessment of insulin resistance (HOMA-IR), cardiorespiratory fitness (treadmill-based peak rate of oxygen uptake (VO2 peak) test), QoL questionnaires (36-Item Short Form Health Survey (SF-36) and Minneapolis-Manchester Quality of Life Instrument (MMQL). RESULTS: Results expressed as mean (standard deviation) or geometric mean (range). There were significant improvements in VO2 peak (35.7 (8.9) vs 41.7 (16.1) mL/min/kg, P = 0.05), fasted plasma insulin (16.56 (1.48-72.8) vs 12.62 (1.04-54.97) mIU/L, P = 0.03) and HOMA-IR (3.65 (0.30-17.26) vs 2.72 (0.22-12.89), P = 0.02) after the exercise intervention. There were also significant improvements in the SF-36 QoL general health domain (69.7 (14.3) vs 72.7 (16.0), P = 0.001) and the MMQL school domain (69.1 (25.2) vs (79.3 (21.6), P = 0.03) during the exercise intervention. No significant changes were observed in percentage body fat, fat mass or lean mass. CONCLUSION: The supervised 6-month combined resistance and aerobic exercise programme significantly improved cardiorespiratory fitness, insulin resistance and QoL in childhood HSCT/TBI survivors, with no change in body composition, suggesting a metabolic training effect on muscle. These data support a role for targeted physical rehabilitation services in this group at high risk of diabetes and cardiovascular disease.

The influence of nutrition on clinical outcomes in children with cancer.

Adequate and appropriate nutrition is essential for growth and development in children; all put at risk in those with cancer. Overnutrition and undernutrition at diagnosis raise the risk of increased morbidity and mortality during therapy and beyond. All treatment modalities can jeopardize nutritional status with potentially adverse effects on clinical outcomes. Accurate assessment of nutritional status and nutrient balance is essential, with remedial interventions delivered promptly when required. Children with cancer in low- and middle-income countries (LMICs) are especially disadvantaged with concomitant challenges in the provision of nutritional support. Cost-effective advances in the form of ready-to-use therapeutic foods (RUTF) may offer solutions. Studies in LMICs have defined a critical role for the gut microbiome in the causation of undernutrition in children and have demonstrated a beneficial effect of selected RUTF in redressing the imbalanced microbiota and improving nutritional status. Challenges in high-income countries relate both to concerns about the potential disadvantage of preexisting obesity in those newly diagnosed and to undernutrition identified at diagnosis and during treatment. Much remains to be understood but the prospects are bright for offsetting malnutrition in children with cancer, resulting in enhanced opportunity for healthy survival.

Achieving a timely diagnosis for teenagers and young adults with cancer: the ACE "too young to get cancer?" study.

BACKGROUND: Time to diagnosis (TTD) concerns teenagers and young adults (TYA) with cancer and may affect outcome. METHODS: Healthcare records from 105 TYA in a regional cancer service were assessed to document events from 1st symptom to treatment start. Detailed pathway construction was possible for 104 patients and allowed a multidisciplinary panel review of each pathway with assessment of good practice and lessons for the future. RESULTS: 1st presentation was to primary care in 86, and 93% consulted in primary care before diagnosis. Routes to Diagnosis were 45% via urgent 2 Week Wait pathways and 38% as emergency referrals. Total Interval (time from 1st presentation to treatment start) was median 63 (range 1-559) days, varying within/between diagnoses. Patient interval (time from 1st symptom to 1st presentation) was longest for lymphoma, carcinoma and bone tumour (medians: 9, 12, 20 days). Overall, time in primary care was short (median 3, range 0-537 days) compared to secondary care (median 29, range 0-195 days) and longest for lymphoma, carcinoma, brain/CNS (medians: 10, 15, 16 days). Specialist Care interval (time from 1st specialist visit to treatment start) was longest for bone, brain/CNS, lymphoma, carcinoma (medians: 30, 33, 36, 48 days). 40% pathways were rated as showing good/best practice but 16% were less than satisfactory. Continued safety-netting/support was identified from primary care but analysis suggested opportunities for improvement in transition through secondary care. CONCLUSIONS: Previous reports of prolonged TTD have focused on delay in referral from primary care but this study suggests that this might be reduced by optimising management in secondary care.

Demographic and Treatment Variables Influencing Outcome for Localized Paratesticular Rhabdomyosarcoma: Results From a Pooled Analysis of North American and European Cooperative Groups.

PURPOSE: Treatment recommendations for localized paratesticular rhabdomyosarcoma (PT RMS) differ in North America and Europe. We conducted a pooled analysis to identify demographic features and treatment choices that affect outcome. PATIENTS AND METHODS: We retrospectively analyzed the effect of nine demographic variables and four treatment choices on event-free survival (EFS) and overall survival (OS) from 12 studies conducted by five cooperative groups. RESULTS: Eight hundred forty-two patients with localized PT RMS who enrolled from 1988 to 2013 were included. Patients age ≥ 10 years were more likely than younger patients to have tumors that were > 5 cm, enlarged nodes (N1), or pathologically involved nodes ( P ≤ .05 each). With a median follow-up of 7.5 years, Kaplan-Meier estimates for 5-year EFS and OS were 87.7% and 94.8%, respectively. Of demographic variables, cooperative group, era of enrollment, age category, tumor size, Intergroup Rhabdomyosarcoma Study group, and T stage affected EFS ( P ≤ .05 each). Surgical assessment of regional nodes, which was performed in 23.5% of patients-usually in those age ≥ 10 years or with suspicious or N1 nodes-was the only treatment variable associated with EFS by univariable and multivariable analyses ( P ≤ .05 each) in patients age ≥ 1 year. A variable selection procedure on a proportional hazards regression model selected era of enrollment, age, tumor size, and surgical assessment of regional nodes as significant ( P ≤ .05 each) in the EFS model, and era of enrollment, age, tumor size, and histology ( P ≤ .05 each) in the OS model. CONCLUSION: Localized PT RMS has a favorable prognosis. Age ≥ 10 years at diagnosis and tumor size larger than 5 cm are unfavorable prognostic features. Surgical assessment of regional nodes is important in patients age ≥ 10 years and in those with N1 nodes as it affects EFS.

Understanding and Utilizing the Unmet Needs of Teenagers and Young Adults with Cancer to Determine Priorities for Service Development: The Macmillan On Target Programme.

Purpose: A systematic attempt to identify and address unmet needs among patients in a large regional teenagers and young adults (TYA) cancer service in the United Kingdom, including perspectives obtained from patients themselves, their families/supporters, and professionals. Methods: Questionnaires, focus groups, and interviews were undertaken with the following: patients (diagnosed ≥16 years, and aged 16-24 years at the time of study)-participation was 42 for questionnaire, 7 for focus group, and 6 for interview; family members/others in patients' lives ("networkers") (participation: 28, 0, and 4); and professionals (participation: 54, 0, and 97). Requirement management methodology was used to specify components for potential service interventions, which were then scored and prioritized. Co-creation was utilized to incorporate a deeper understanding of patient experience. Results: 42/108(39%) patients, 28/177(24%) networkers, and 122/322(38%) professionals participated. For patients, seven themes that "mattered most" (identified by >60% responders) were defined. For many, support was provided both to a lesser extent than needed and was sometimes unsatisfactory. For networkers, results identified the significant support offered by those around the patient and the impact on their own lives. For professionals, consensus was reached on interventions that could be utilized in clinical encounters with TYA to enhance care. A list of prioritized "requirements" was created to drive future service improvement. Conclusions: Areas identified for development included three specific initiatives applicable to other TYA services: a support website (www.tyahelp.co.uk); an electronic, age/developmentally specific, holistic needs assessment tool (the Integrated Assessment Map www.tyaiam.co.uk); and a portal linking use of the IAM to resources within the Help website (video illustration available at: https://vimeo.com/191019826).

Localized vaginal/uterine rhabdomyosarcoma-results of a pooled analysis from four international cooperative groups.

BACKGROUND: Vaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed. PROCEDURE: From 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty-eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG). RESULTS: Ten-year event-free (EFS) and overall survival (OS) were 74% (95% CI, 67-79%) and 92% (95% CI, 88-96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty-one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery. CONCLUSIONS: About half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy.

Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study.

BACKGROUND: Early response to induction chemotherapy is used in current European guidelines to evaluate the efficacy of chemotherapy and subsequently to adapt treatment in pediatric patients with rhabdomyosarcoma (RMS). However, existing literature on the prognostic value of early radiologic response on survival is contradictory; here the prognostic value is analyzed with data from the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor 95 (MMT-95) study. METHODS: This study examined 432 Intergroup Rhabdomyosarcoma Study Grouping III (macroscopic residue) patients enrolled in the SIOP MMT-95 study with a response assessment after 3 courses of chemotherapy (a 2-dimensional assessment). Patients with progressive disease (PD) after 3 courses of chemotherapy were excluded (n = 7). Failure-free survival (FFS) and overall survival (OS), calculated with the Kaplan-Meier method, were compared for 3 groups (complete response [CR]/partial response [PR], objective response [OR], and no response [NR]). The prognostic impact of early response was assessed through the calculation of Cox proportional hazards. RESULTS: After 3 courses of chemotherapy, 85.2% of the patients had CR/PR, 8.6% had OR, and 6.3% had NR. For all patients, the 5-year FFS and OS rates were 60% (95% confidence interval [CI], 56%-65%) and 74% (95% CI, 70%-78%), respectively. However, a Cox proportional hazards regression analysis revealed no significant difference in FFS or OS between the response groups. The adjusted hazard ratios for an OR and NR were 1.09 (95% CI, 0.63-1.88) and 0.81 (95% CI, 0.39-1.67), respectively, for FFS and 0.91 (95% CI, 0.47-1.76) and 1.27 (95% CI, 0.61-2.64), respectively, for OS. CONCLUSIONS: No evidence was found for the idea that early radiologic response to chemotherapy is prognostic for survival for patients with RMS. Treatment adaptation based on early response (except for patients with PD) should, therefore, no longer be incorporated into future studies. Cancer 2018;124:1016-24. © 2017 American Cancer Society.

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.

BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. FINDINGS: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. INTERPRETATION: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. FUNDING: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

Conservative strategy in infantile fibrosarcoma is possible: The European paediatric Soft tissue sarcoma Study Group experience.

BACKGROUND: Infantile fibrosarcoma (IFS) is a very rare disease occurring in young infants characterised by a high local aggressiveness but overall with a favourable survival. To try to reduce the total burden of therapy, the European pediatric Soft tissue sarcoma Study Group has developed conservative therapeutic recommendations according to initial resectability. MATERIAL AND METHODS: Between 2005 and 2012, children with localised IFS were prospectively registered. Initial surgery was suggested only if possible without mutilation. Patients with initial complete (IRS-group I/R0) or microscopic incomplete (group II/R1) resection had no further therapy. Patients with initial inoperable tumour (group III/R2) received first-line vincristine-actinomycin-D chemotherapy (VA). Delayed conservative surgery was planned after tumour reduction. Aggressive local therapy (mutilating surgery or external radiotherapy) was discouraged. RESULTS: A total of 50 infants (median age 1.4 months), were included in the study. ETV6-NTRK3 transcript was present in 87.2% of patients where investigation was performed. According to initial surgery, 11 patients were classified as group I, 8 as group II and 31 as group III. VA chemotherapy was first delivered to 25 children with IRS-III/R2 and one with IRS-II/R1 disease. Response rate to VA was 68.0%. Mutilating surgery was only performed in three cases. After a median follow-up of 4.7 years (range 1.9-9.0), 3-year event-free survival and overall survival were respectively 84.0% (95% confidence interval [CI] 70.5-91.7) and 94.0% (95% CI 82.5-98.0). CONCLUSIONS: Conservative therapy is possible in IFS as only three children required mutilating surgery, and alkylating or anthracycline based chemotherapy was avoided in 71.0% of patients needing chemotherapy. VA regimen should be first line therapy in order to reduce long term effects.

Prognostic Factors for Outcome in Localized Extremity Rhabdomyosarcoma. Pooled Analysis from Four International Cooperative Groups.

BACKGROUND: Extremity rhabdomyosarcomas do not always show satisfactory outcomes. We analyzed data from 643 patients treated in 14 studies conducted by European and North American groups between 1983 and 2004 to identify factors predictive of outcome. PROCEDURE: Clinical factors, including age; histology; site of primary (hand and foot vs. other); size; invasiveness (T stage); nodal involvement (N stage); and treatment factors, including post-surgical group; chemotherapy type and duration; radiotherapy; and treatment (before or after 1995); were evaluated for impact on overall survival (OS). RESULTS: 5-year OS were 67% (se 1.8). Multivariate analysis showed that lower OS correlated with age >3 years, T2 and N1 stage, incomplete initial surgery, treatment before 1995, and European cooperative group treatment. Patients with gross residual disease after initial incomplete resection/biopsy had similar outcomes in both continental groups. The better global survival of patients treated in American studies was accounted for by differences in outcome in the subset of those with grossly resected tumors (OS 86% [se 3] for COG patients vs. 68% [se 4] for European patients (P = 0.004)). When excluding chemotherapy duration from the model, analysis in this subset of patients showed that cooperative group (P = 0.001), site (P = 0.001), and T stage (P = 0.05) were all significant. However, after adding duration of chemotherapy (≥27 weeks) to the model, only primary site remained significant (P = 0.006). CONCLUSION: This meta-analysis confirms the role of many established prognostic factors but identifies for the first time that chemotherapy duration may have an impact on outcome in patients with grossly resected tumors.

Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes.

BACKGROUND: Survivors of childhood acute lymphoblastic leukaemia (ALL) treated with haematopoietic stem cell transplantation and total body irradiation (HSCT/TBI) have a high cardiometabolic risk despite lacking overt clinical obesity. This study characterised body composition using different methodologies and explored associations with reduced insulin sensitivities in a group of ALL survivors treated with/without HSCT/TBI. PROCEDURE: Survivors of childhood ALL treated with HSCT/TBI (n = 20,10 M) were compared with Chemotherapy-only (n = 31), and an obese non-leukaemic controls (n = 30). All subjects (aged 16-26 years) were investigated with: auxology (BMI, waist and hip circumferences), DEXA (total and regional fat, fat-free mass), abdominal MRI (subcutaneous, visceral, intramuscular fat), oral glucose tolerance tests (impaired glucose tolerance or diabetes, insulin sensitivity) and serum adiponectin. RESULTS: HSCT/TBI Group displayed a higher prevalence of abnormal glucose tolerance (45%); lower insulin sensitivity; lower lean mass with higher prevalence of reduced fat-free mass index (from DEXA); higher visceral and intramuscular, and lower subcutaneous fat on MRI, compared with the Chemotherapy-only and Obese controls. BMI was lowest in HSCT/TBI Group. Waist-to-hip and android-to-gynoid ratios were similar between HSCT/TBI and Obese Groups. Insulin sensitivity adjusted for visceral fat mass was lower in the HSCT/TBI than the Chemotherapy-only and Obese groups. Adiponectin in the HSCT/TBI Group was lower than the Chemotherapy-only group, and correlated negatively with time post HSCT/TBI. CONCLUSIONS: HSCT/TBI survivors have an increased risk of abnormal glucose tolerance and reduced insulin sensitivity with reduced subcutaneous and increased visceral fat distribution, increased total fat mass and reduced lean mass.

Recruitment of childhood leukaemia patients to clinical trials in Great Britain during 1980-2007: variation by birth weight, congenital malformation, socioeconomic status and ethnicity.

OBJECTIVE: To assess recruitment of children to national clinical trials for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in Great Britain during 1980-2007 and describe variation by some factors that might influence trial entry. DESIGN AND SETTING: Records of leukaemia patients aged 0-14 years at diagnosis were identified in the National Registry of Childhood Tumours and linked to birth registrations, Children's Cancer and Leukaemia Group records, Hospital Episode Statistics and Medical Research Council clinical trial registers. Trial entry rates were compared between categories of birth weight, congenital malformation, socioeconomic status and ethnicity. RESULTS: 9147 ALL and 1466 AML patients were eligible for national clinical trials during 1980-2007. Overall recruitment rates were 81% and 60% respectively. For ALL, rates varied significantly with congenital malformation (Down syndrome 61%, other malformations 80%, none 82%; p<0.001) and ethnicity (South Asian 78%, other minority groups 80%, white 85%; p<0.001). For AML, rates varied with birth weight (< 2500 g 48%, 2500-4000 g 69%, >4000 g 67%; p=0.001) and congenital malformation (Down syndrome 28%, other malformations 56%, none 63%; p<0.001). CONCLUSIONS: Although recruitment rates to clinical trials for childhood leukaemia are high, future trials should monitor possible variation by birth weight, ethnicity and presence of congenital malformations.

Conservative approach in localised rhabdomyosarcoma of the bladder and prostate: results from International Society of Paediatric Oncology (SIOP) studies: malignant mesenchymal tumour (MMT) 84, 89 and 95.

BACKGROUND: The three sequential SIOP MMT studies provide the largest dataset available to date, to define the patient and tumour characteristics, treatment modalities and event-free and overall survival for children with non metastatic rhabdomyosarcoma (RMS) of the bladder and/or prostate (BP). PROCEDURE: The combined dataset of 172 patients with BP RMS treated on the SIOP MMT 84, 89 and 95 studies was reviewed to determine tumour characteristics, details of treatment and outcome. RESULTS: Median age at diagnosis was 2.5 years (range 2 months-17.8 years) and 138 (79%) were males. Median follow-up was 11.4 years (range 3 months-22 years). The 5-year overall survival of the combined cohort was 77% (CI 70-83%). The 5-year event-free survival was 63% and included 7 patients (4%) who did not achieve complete remission (CR), and 57 (33%) who relapsed. Age ≥ 10 years (RR 3.7) and alveolar pathology (RR 3.3) were identified as independent prognostic factors on multivariate analysis. Fifty-nine (50%) of the 119 survivors were cured without significant local therapy, improving from 31% in MMT84 study to 61% in MMT95 study. CONCLUSION: The clinical strategy of the MMT studies aims to minimise the burden of therapy whilst maintaining survival rates. Overall survival is comparable to that of other international groups, despite the lower use of radiotherapy and or radical surgery, although number of events experienced is higher. Further assessment of the late effects of therapy is required to confirm whether this approach results in lower morbidity in the long-term.

Cognitive function in children with brain tumors in the first year after diagnosis compared to healthy matched controls.

BACKGROUND: Improved survival of children with brain tumors (BTs) has increased focus on ameliorating morbidity. To reduce the risk of progressive cognitive decline, remedial strategies need to be instituted early, based upon accurate appraisal of need, yet few studies have investigated cognition in BT children early post-diagnosis. The study aims were to investigate cognition in children with primary BTs 1, 6, and 12 months post-diagnosis compared with healthy children, exploring the impact of disease and treatment variables. METHODS: Forty-eight children aged 2-16 years with primary BTs, referred to a Regional Neurosurgical Unit over the 2-year study period were eligible for enrollment. The "best friends" model was used to recruit matched controls. Cognition was assessed using age-appropriate Wechsler Intelligence scales; Children's Memory Scale; Test of Everyday Attention for Children, and Wechsler Quicktest. RESULTS: Patients with BTs had significantly reduced performance compared to controls early post-diagnosis in tests of Performance IQ, processing speed, verbal and visual memory, and selective attention. Improved performance over 12 months was seen in patients with BTs although also, for some measures, in controls. Significant deficits in cognitive performance were seen one year post-diagnosis for Verbal IQ; processing speed, visual and verbal immediate memory, and selective attention. Infratentorial site, high tumor grade, hydrocephalus, radiotherapy, and chemotherapy were associated with poorer functioning. CONCLUSION: Early cognitive impairment is present in BT children, sometimes prior to radiotherapy/chemotherapy treatment, and is associated with hydrocephalus, high tumor grade and infratentorial site. Future studies should investigate the role of early rehabilitation in improving cognition.

Risk of childhood cancer with symptoms in primary care: a population-based case-control study.

BACKGROUND: Guidelines describing symptoms in children that should alert GPs to consider cancer have been developed, but without any supporting primary-care research. AIM: To identify symptoms and signs in primary care that strongly increase the likelihood of childhood cancer, to assist GPs in selection of children for investigation. DESIGN AND SETTING: A population-based case-control study in UK general practice. METHOD: Using electronic primary care records from the UK General Practice Research Database, 1267 children aged 0-14 years diagnosed with childhood cancer were matched to 15 318 controls. Clinical features associated with subsequent diagnosis of cancer were identified using conditional logistic regression, and likelihood ratios and positive predictive values (PPVs) were estimated for each. RESULTS: Twelve symptoms were associated with PPVs of ≥0.04%, which represents a greater than tenfold increase in prior probability. The six symptoms with the highest PPVs were pallor (odds ratio, OR = 84; PPV = 0.41% (95% confidence interval [CI] = 0.12% to 1.34%), head and neck masses (OR = 17; PPV = 0.30%; 95% CI = 0.10% to 0.84%), masses elsewhere (OR = 22; PPV = 0.11%; 95% CI = 0.06% to 0.20%), lymphadenopathy (OR = 10; PPV = 0.09%; 95% CI = 0.06% to 0.13%), symptoms/signs of abnormal movement (OR = 16; PPV = 0.08%; 95% CI = 0.04% to 0.14%), and bruising (OR = 12; PPV = 0·08%; 95% CI = 0.05% to 0.13%). When each of these 12 symptoms was combined singly with at least three consultations in a 3-month period, the probability of cancer was between 11 and 76 in 10 000. CONCLUSION: Twelve features of childhood cancers were identified, each of which increased the risk of cancer at least tenfold. These symptoms, particularly when combined with multiple consultations, warrant careful evaluation in general practice.

Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.

PURPOSE: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. PATIENTS AND METHODS: From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. RESULTS: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. CONCLUSION: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

A detailed prospective longitudinal assessment of health status in children with brain tumors in the first year after diagnosis.

PURPOSE: To compare health status (HS) in children with brain tumors at 1 (t1), 6 (t6), and 12 (t12) months after diagnosis with "normal" controls. To assess the relationship between parent-report and self-report HS for patients at t12. METHODS: HS was assessed using the Health Utilities Index Mark III parent-report at all time points and self-report at t12. Twenty-nine patients and 32 controls were included in analysis of parent-report, and 21 patients and 22 controls in self-report HS at t12. Nonparametric analyses were used. RESULTS: Patients scored significantly lower than controls for global overall HS at all time points for parent-report and at t12 for self-report (Pmax=0.009). For parent-report, patients scored significantly lower than controls in the attributes of emotion, cognition, and pain at t1 and t6, in ambulation at t1 and in dexterity at t6. At t12, the difference was statistically significant for parent-report cognition only (all P<0.01). No attributes reached significance for self-report at t12. For patients, correlations between parent-report and self-report were good (rs>0.73) for all Health Utilities Index Mark 3 scores with the exception of emotion and pain. CONCLUSION: HS is significantly compromised in children with brain tumors over the first year after diagnosis, but improves with time. Parent-report and self-report differ, and both should be considered in assessing outcomes or defining interventions.

Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy.

PURPOSE: Previous studies suggest poor outcome in children with relapsed rhabdomyosarcoma (RMS). A better understanding is needed of which patients can be salvaged after first relapse. PATIENTS AND METHODS: The analysis included children with nonmetastatic RMS and embryonal sarcoma enrolled onto the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumor (MMT) 84, 89, and 95 studies who relapsed after achieving complete local control with primary therapy. All patients included in the analysis had follow-up for ≥ 3.0 years after the last event. The clinical features, initial treatment characteristics, and features of the relapse were correlated with survival in univariate and multivariate analyses. RESULTS: In all, 474 eligible patients were identified for the study. At ≥ 3.0 years from the last event, 176 (37%) were alive ("cured"). In a full-model multivariate analysis, the factors identified at first relapse that most strongly associated with poor outcome were metastatic relapse (odds ratio [OR], 4.19; 95% CI, 2.0 to 8.5), prior radiotherapy treatment (OR, 3.64; 95% CI, 2.1 to 6.4), initial tumor size > 5 cm (OR, 2.53; 95% CI, 1.5 to 4.1), and time of relapse < 18 months from diagnosis (OR, 2.20; 95% CI, 1.3 to 3.6). Unfavorable primary disease site, nodal involvement at diagnosis, alveolar histology, and previous three- or six-drug chemotherapy were also independently associated with poor outcome. To estimate chance of cure for individual patients, a nomogram was developed, which allowed for weighting of these significant factors. CONCLUSION: Some children with relapsed RMS remain curable. It is now possible to estimate the chance of salvage for individual children to direct therapy appropriately toward cure, use of experimental therapies, and/or palliation.