ABSTRACT
Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
Subject(s)
Bone Neoplasms/therapy , Cooperative Behavior , Interdisciplinary Communication , Sarcoma, Ewing/therapy , Soft Tissue Neoplasms/therapy , Antineoplastic Combined Chemotherapy Protocols , Bone Neoplasms/mortality , Child , Clinical Trials as Topic , Combined Modality Therapy , Disease Progression , Humans , Neoadjuvant Therapy , Osteotomy , Radiotherapy, Adjuvant , Sarcoma, Ewing/mortality , Soft Tissue Neoplasms/mortality , Survival RateABSTRACT
Teenagers and young adults (TYA) cancer contributes substantially to morbidity and mortality in a population with much to offer society. TYA place distinct challenges upon cancer care services, many reporting feeling marginalized and their needs not being met in adult or paediatric cancer services. Bone tumours such as osteosarcoma and Ewing sarcoma, because of their age at presentation and the complexity of their care, are where challenges in managing (TYA) with cancer have often been most readily apparent. Bone sarcomas may be managed by paediatric or medical oncologists, and require fastidious attention to protocol. A lack of recent improvement in survival in TYA with bone tumours may be linked to a lack of specialist care, poor concordance with therapy in some situations and TYA-specific pharmacology. Participation in clinical trials, particularly of young adults, is low, hindering progress. All these requirements may be best met by a concerted effort to create collaborative care between adult and paediatric experts in bone sarcoma, working together to meet TYA patients' needs.
Subject(s)
Bone Neoplasms , Osteosarcoma , Adolescent , Adult , Age of Onset , Bone Neoplasms/epidemiology , Bone Neoplasms/therapy , Consensus , Humans , Osteosarcoma/epidemiology , Osteosarcoma/therapy , Sarcoma, Ewing/epidemiology , Sarcoma, Ewing/therapy , Young AdultABSTRACT
A scoping exercise to define the preferred competencies of professionals involved in teenage and young adult (TYA) cancer care. Data were generated during two workshops with health professionals. In groups, they ranked skills, knowledge and attitudes, previously identified through a literature search, onto a diamond template. Data were also used from an education day with TYA professionals, who generated lists of key skills, knowledge and attitudes. Individually, professionals then selected the top five areas of competence to care for young people with cancer. The workshops generated three diamonds, which exhibited agreement of 13 principle skills, knowledge and attitudes. The top two being: 'expertise in treating paediatric and adult cancers' and 'understanding cancer'. The data from the education day suggested communication, technical knowledge and teamwork as being core role features for professionals who care for young people with cancer. Integration of both datasets; one derived inductively, the other deductively provides a comprehensive outline of core skills health professionals require to be proficient in young people's cancer care. These results will form the basis of future discussion around workforce strategies and inform a Delphi survey.
Subject(s)
Clinical Competence/standards , Health Knowledge, Attitudes, Practice , Health Personnel/psychology , Neoplasms/therapy , Adolescent , England , Female , Health Personnel/standards , Humans , Male , Personality , Physician-Patient Relations , Professional Role , Young AdultABSTRACT
INTRODUCTION: Several studies have shown differences in survival trends between ethnic groups across adults with cancer in the UK. It is unclear whether these differences exist exclusively in the older adult population or whether they begin to emerge in children and young adults. METHODS: Subjects (n=3534) diagnosed with cancer under 30 years of age in Yorkshire between 1990 and 2005 were analysed. Differences in survival rates for diagnostic subgroups were estimated by ethnic group (south Asian or not) using Kaplan-Meier estimation and Cox regression. RESULTS: When compared to non-south Asians (all other ethnic groups excluding south Asians) a significant increased risk of death was seen for south Asians with leukaemia (hazard ratio (HR)=1.75; 95% confidence interval (CI)=1.11-2.76) and lymphoma (HR=2.05; 95% CI=1.09-3.87), whereas south Asians with solid tumours other than central nervous system tumours had a significantly reduced risk of death(HR=0.50; 95% CI=0.28-0.89). This was independent of socioeconomic deprivation. CONCLUSION: We found evidence of poorer survival outcomes for south Asians compared to non-south Asian children and young adults with leukaemia and lymphoma, but better outcomes for south Asian children and young adults with other solid tumours. This needs to be explained, and carefully addressed in the on-going development of cancer services.
Subject(s)
Neoplasms/mortality , Adolescent , Adult , Asia/ethnology , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Neoplasms/epidemiology , Neoplasms/ethnology , Survival Analysis , United Kingdom/epidemiology , Young AdultABSTRACT
BACKGROUND: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arm Bones/pathology , Bone Neoplasms/drug therapy , Leg Bones/pathology , Osteosarcoma/drug therapy , Survival , Adolescent , Adult , Bone Neoplasms/mortality , Bone Neoplasms/pathology , Child , Female , Humans , Kaplan-Meier Estimate , Male , Multivariate Analysis , Neoplasm Grading , Neoplasm Recurrence, Local , Osteosarcoma/mortality , Osteosarcoma/pathology , Proportional Hazards Models , Randomized Controlled Trials as Topic , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Few studies have examined epidemiological differences between ethnic groups for children and young adults with cancer. METHODS: Subjects aged 0-29 years, diagnosed between 1990 and 2005 in the former Yorkshire Regional Health Authority, were included in the analysis. Ethnicity (south Asian or not) was assigned using name analysis program and Hospital Episode Statistics data. Differences in incidence (per 1,000,000 person-years) rates and trends were analysed using joinpoint and Poisson regression analysis. RESULTS: Overall cancer incidence was similar for south Asians (12.1, 95% CI: 10.7-13.5; n=275) and non-south Asians (12.6, 95% CI: 12.2-13.1; n=3259). Annual incidence rates increased significantly by 1.9% per year on average (95% CI: 1.2-2.6%), especially for south Asians (7.0%; 95% CI: 4.2-9.9%). CONCLUSION: If present trends continue, the higher rate of increase seen among south Asians aged 0-29 years in Yorkshire will result in three times higher cancer incidence than non-south Asians by 2020.
Subject(s)
Neoplasms/ethnology , Neoplasms/epidemiology , Adolescent , Adult , Asia , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Male , United KingdomABSTRACT
This paper investigates the potential for long-term survivorship for young patients diagnosed with Ewing's sarcoma. Data are examined from two successive UKCCSG Ewing's Tumour studies (ET-1 and ET-2). Patients have been followed for up to 20 years. These studies had suggested that better 5-year survival with ET-2 over the earlier ET-1 was achieved by replacing cyclophosphamide by ifosfamide and increasing the dose of doxorubicin in a four-drug chemotherapy regimen. The updated hazard ratio, stratified for metastatic status at diagnosis, of 0.39 (95% confidence interval 0.12-0.61) confirmed the advantage of the ET-2 regimen in terms of overall survival. Cure models, based on the Weibull distribution, suggested that factors for long-term survival in addition to presence of metastases were age, primary site of tumour and study. Modelling identified the proportion cured with the ET-2 protocol as best at 70% in those who are under 10 years with a nonpelvic primary site and without metastatic disease. This contrasts to only 13% cure in those with the corresponding adverse prognostic indicators. Additionally, the risk of death remains greatest but relatively constant over the first 2 years postdiagnosis, and then declines to a lower but constant value for the next 3 years before reaching the 'cure plateau' at about 5 years. This investigation suggests that 'cure' is possible for patients with Ewing's sarcoma. This is established at approximately 5 years post diagnosis and the proportion cured depends on the presence of metastases, pelvic site and age at diagnosis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pelvic Neoplasms/drug therapy , Pelvic Neoplasms/mortality , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/mortality , Adolescent , Adult , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Pelvic Neoplasms/pathology , Sarcoma, Ewing/secondary , Survival Rate , SurvivorsABSTRACT
The burden of childhood cancer for Primary Care Trusts (PCTs) is unknown. PCTs in Yorkshire are representative of England and Wales and show little heterogeneity in the incidence rates of childhood cancer. Each PCT will expect three to five newly diagnosed children per year. A single GP is likely to see an incident case once every 20 years.
Subject(s)
Neoplasms/diagnosis , Neoplasms/epidemiology , Primary Health Care/statistics & numerical data , Registries/statistics & numerical data , Adolescent , Child, Preschool , Diagnosis, Differential , England/epidemiology , Epidemiologic Studies , Humans , Incidence , Infant , Infant, Newborn , Reference Values , Wales/epidemiologySubject(s)
Biomarkers, Tumor , Neuroblastoma/diagnosis , Sarcoma, Ewing/diagnosis , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Medical Oncology/methods , Neuroblastoma/genetics , Neuroblastoma/physiopathology , Neuroblastoma/therapy , Pediatrics/methods , Sarcoma, Ewing/economics , Sarcoma, Ewing/genetics , Sarcoma, Ewing/physiopathology , Sarcoma, Ewing/therapy , United KingdomABSTRACT
The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.
Subject(s)
Biomarkers, Tumor/analysis , Bone Neoplasms/diagnosis , Oncogene Proteins, Fusion/genetics , Sarcoma, Ewing/diagnosis , Transcription Factors/genetics , Bone Neoplasms/genetics , Humans , Mass Screening/methods , Prognosis , Proto-Oncogene Protein c-fli-1 , RNA-Binding Protein EWS , Sarcoma, Ewing/genetics , Software DesignABSTRACT
The highly urbanised northern English city of Bradford contains a diverse population from different ethnic backgrounds, including a high proportion of south Asians. We aimed to identify the effect of ethnic group on the incidence and temporal trends of childhood cancer in Bradford. Children (0-14 years) from the district of Bradford, who were diagnosed with a malignancy between 1974 and 1997, were selected from a population-based register. Each child was classified as south Asian (Indian, Pakistani and Bangladeshi), or not, based on their full name using 2 computer algorithms and individual inspection. Mid-year population estimates were used to calculate incidence rates and differences were assessed using Poisson regression. The study included 318 children, of whom 81 (25%) were south Asian. The incidence of all cancers in south Asian children (14.9 per 100,000 person years, 95% CI 11.6-18.2) was higher than non-south Asian children (12.0, 10.5-13.5) although not significantly so (P=0.14). Comparisons by diagnostic subgroup showed no major differences apart from significantly higher rates of acute myeloid leukaemia (AML) in south Asian children (1.9 versus 0.7, P=0.02). The age-specific incidence peaks of all childhood cancers and leukaemias were present in south Asian children aged 5-9 years compared with 0-4 years olds in the non-south Asian population. Non-significant increases of 1.4 and 1.5% in the average annual incidence of all cancers were seen for south Asians and non-south Asians respectively, with a significant rise for non-south Asians with leukaemia of 3.0% (P=0.04). Our timely study shows patterns of occurrence of childhood cancer that differ with respect to ethnic group. Differences are particularly apparent in the excess of AML and incidence peak in 5-9 year olds in south Asian children.
Subject(s)
Neoplasms/ethnology , Adolescent , Age Distribution , Asia/ethnology , Child , Child, Preschool , England/epidemiology , Female , Humans , Incidence , Infant , Infant, Newborn , Leukemia/ethnology , Male , Neoplasms/epidemiology , Regression Analysis , Sex DistributionABSTRACT
A 13-month-old girl presented with a large malignant rhabdoid liver tumor that ruptured soon after admission. Six years after an emergency right hepatectomy and subsequent chemotherapy (ifosfamide, vincristine, and actinomycin D), she remains well and disease free. Previously, these rare tumors invariably have been fatal and resistant to multimodal therapy. This is the first report of long-term survival of a patient with a malignant rhabdoid liver tumor.
Subject(s)
Liver Neoplasms/pathology , Rhabdoid Tumor/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Disease-Free Survival , Female , Hepatectomy , Humans , Infant , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Rhabdoid Tumor/drug therapy , Rhabdoid Tumor/surgery , Rupture, SpontaneousABSTRACT
BACKGROUND: Despite treatment with high-dose myeloblative chemotherapy and peripheral blood stem cell (PBSC) rescue, a high proportion of children with neuroblastoma relapse and die. Re-infusion of PBSC contaminated with tumour at the time of autologous transplantation may play a significant role in this relapse. In this study the frequency of tumour contamination in PB from children with neuroblastoma has been investigated. PROCEDURE: Minimal residual disease was measured using RT-PCR for tyrosine hydroxylase (TH) mRNA in PBSCs from patients with advanced neuroblastoma. PBSCs from 18 patients in complete clinical remission were studied. RESULTS: Studies in other cancers have suggested minimal contamination of PBSCs with tumour cells; TH mRNA was detected by RT-PCR in 50% (9/18) of PBSC harvests. Seventy-seven percent (7/9) of patients with TH mRNA in PBSC died of disease compared to 44% (4/9) who were TH mRNA-negative. CONCLUSIONS: Therefore, the presence of TH mRNA in PBSCs appeared to be associated with an unfavourable outcome, although this was not statistically significant. In summary, RT-PCR for TH mRNA is a sensitive method for the identification of tumour cells in PBSC harvest. The presence of TH mRNA in PBSC harvest may reflect disease status and be associated with an unfavourable outcome, although long-term clinical outcome studies in a larger patient cohort are required.
Subject(s)
Biomarkers, Tumor/genetics , Hematopoietic Stem Cell Transplantation/adverse effects , Neoplasm Proteins/genetics , Neoplastic Cells, Circulating , Neuroblastoma/pathology , RNA, Messenger/blood , RNA, Neoplasm/blood , Transplantation, Autologous/adverse effects , Tyrosine 3-Monooxygenase/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Hematopoietic Stem Cell Mobilization , Humans , Infant , Life Tables , Neoplasm, Residual , Neuroblastoma/blood , Neuroblastoma/drug therapy , Neuroblastoma/mortality , Neuroblastoma/therapy , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity , Survival Analysis , Treatment Outcome , Tumor Cells, Cultured/chemistryABSTRACT
BACKGROUND: This paper reports the toxicity of OPEC/OJEC chemotherapy in stage 4 neuroblastoma patients over 1 year of age. PROCEDURE: Ninety-five patients with stage 4 neuroblastoma received alternating courses of OPEC/OJEC--vincristine 1.5 mg/m2 (O), cisplatin 80 mg/m2 (P), etoposide 200 mg/m2 (E), cyclophosphamide 600 mg/m2 (C), and carboplatin 500 mg/m2 (J), every 21 days if there was haematological recovery. RESULTS: Seventy out of ninety-five (74%) patients completed seven or more courses and were evaluable for toxicity. Of these 70 patients, 33% had more than three episodes of fever and sepsis, 35% required more than five blood or platelet transfusions, 36% had grade 2 or more gastrointestinal toxicity and 9% had neurotoxicity. There was a median reduction in GFR of 32 ml/min/1.73 m2 (-46 to 134) and there was one toxic death. CONCLUSIONS: OPEC/OJEC is a well-tolerated therapy for stage 4 neuroblastoma over 1 year of age.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Marrow Diseases/chemically induced , Gastrointestinal Diseases/chemically induced , Kidney Diseases/chemically induced , Nervous System Diseases/chemically induced , Neuroblastoma/drug therapy , 3-Iodobenzylguanidine , Abdominal Neoplasms/diagnostic imaging , Abdominal Neoplasms/drug therapy , Abdominal Neoplasms/mortality , Abdominal Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Bone Marrow Diseases/epidemiology , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Carboplatin/administration & dosage , Carboplatin/adverse effects , Child, Preschool , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Diphosphonates , Disease-Free Survival , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Gastrointestinal Diseases/epidemiology , Humans , Incidence , Infant , Iodine Radioisotopes , Kidney Diseases/epidemiology , Male , Neoplasm Staging , Nervous System Diseases/epidemiology , Neuroblastoma/diagnostic imaging , Neuroblastoma/mortality , Neuroblastoma/pathology , Neuroblastoma/secondary , Radionuclide Imaging , Radiopharmaceuticals , Remission Induction , Survival Analysis , Survival Rate , Technetium Compounds , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
The aim of this study was to investigate survival rates for adolescents with cancer and identify factors associated with differential long-term prognosis in Yorkshire, UK. A survival analysis of a population-based cohort of young adults aged 15-24 years, diagnosed with a malignancy in the former Yorkshire Regional Health Authority between 1985 and 1994 was carried out. The main outcome was death from all causes. Overall survival for the 1097 adolescents with a malignancy increased by 30% between 1985-1989 and 1990-1994 (P=0.004). This improvement was reflected in most subgroups of cancer. Large scale geographical differences in survival rates were observed across Yorkshire, with an increased risk of death in North Yorkshire and Humberside of 34% and 45%, respectively, compared with West Yorkshire. Small scale analyses showed reduced survival in areas of high population density, but no consistent trends were associated with socio-economic status. Improved survival from all cancers in young adults over the last decade is clearly seen. Reasons for differential survival by geographical area are unclear and warrant further investigation.
Subject(s)
Neoplasms/mortality , Adolescent , Adult , Cohort Studies , England/epidemiology , Female , Follow-Up Studies , Humans , Male , Proportional Hazards Models , Risk Factors , Survival RateABSTRACT
OBJECTIVE: To investigate the new onset of mitral regurgitation in patients with otherwise normal echocardiograms after anthracycline treatment and to assess its relation to other selected indicators of myocardial damage. DESIGN: Prospective echocardiographic and electrocardiographic study. SETTING: Tertiary paediatric cardiac referral centre. PATIENTS: 305 patients, aged 2-33 years (median 14 years), treated with cumulative anthracycline doses of between 150-450 mg/m(2) (median 180 mg/m(2)) for childhood malignancy. MAIN OUTCOME MEASURES: Colour flow Doppler detection of mitral regurgitation and its relation to changes in echocardiographic indices of left ventricular function (systolic and diastolic dimensions, fractional shortening) and to changes in the 12 lead ECG; and the prevalence of mitral regurgitation in the anthracycline treated patients in comparison with previously studied normal volunteers of similar age. RESULTS: 34 patients (11.6%) developed ultrasound detectable mitral regurgitation, which was not apparent clinically, during or after anthracycline treatment, compared with only 1.8% of a normal population of similar age (p < 0.0001). Nine of the 34 also developed non-specific T wave abnormalities. All 34 patients had normal systolic function at the time of initial detection of mitral regurgitation, but four later developed impaired left ventricular function (5, 11, 20, and 27 months after the first detection of mitral regurgitation). CONCLUSIONS: Mitral regurgitation occurs much more often in patients treated with anthracyclines than in the normal population. Echocardiographic detection of new mitral regurgitation with or without ECG abnormalities may be an early predictor of anthracycline cardiomyopathy.
Subject(s)
Antibiotics, Antineoplastic/adverse effects , Mitral Valve Insufficiency/chemically induced , Mitral Valve Insufficiency/diagnosis , Adolescent , Adult , Cardiomyopathies/chemically induced , Cardiomyopathies/diagnosis , Child , Child, Preschool , Echocardiography, Doppler, Color , Electrocardiography , Female , Humans , Male , Prospective Studies , Ventricular Function, LeftABSTRACT
PURPOSE: In this prospective, multicenter study, the independent prognostic power of neuroblastoma cells detected by reverse transcriptase polymerase chain reaction (RT-PCR) for tyrosine hydroxylase (TH) mRNA was evaluated. PATIENTS AND METHODS: The clinical significance of disease detected by RT-PCR in peripheral blood from children at diagnosis was compared with established prognostic markers [ie, age, lactate dehydrogenase (LDH), neuron-specific enolase, ferritin, and MYCN gene amplification] by multivariate analysis. The value of disease detection by RT-PCR during treatment and follow-up was also examined. RESULTS: TH mRNA was detected in peripheral blood from 33 of 49 (67%) children with stage 4 neuroblastoma > 1 year old at diagnosis and was a significant predictive factor for overall survival [hazard ratio (HR) = 2.40, 95% confidence interval (CI) 1.19 to 4.84, P =.014) and event-free survival (HR = 2.09, 95% CI 1.06 to 4.17, P =.034) in a multivariate analysis. Detection of disease in blood from clinically disease-free children was related to increased risk of death (HR 2.54, 95% CI 1.42 to 4.55, P =.0014). CONCLUSION: TH mRNA in peripheral blood of children with neuroblastoma is a poor prognostic indicator, reflecting the propensity for dissemination via the bloodstream. When combined with a serum LDH > 1500 IU/L, this is the most powerful poor prognostic model at diagnosis for children > 1 year old with stage 4 disease. The detection of TH mRNA in peripheral blood from clinically disease-free children is related to increased risk of relapse and death.
Subject(s)
Neoplastic Cells, Circulating , Neuroblastoma/pathology , Reverse Transcriptase Polymerase Chain Reaction , Tyrosine 3-Monooxygenase/genetics , Age Factors , Child , Child, Preschool , Female , Humans , Infant , Male , Neoplasm Recurrence, Local , Neoplasm Staging , Neuroblastoma/genetics , Prognosis , Prospective Studies , RNA, Messenger/analysis , Survival Analysis , Tyrosine 3-Monooxygenase/analysis , Tyrosine 3-Monooxygenase/biosynthesisABSTRACT
A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Enzyme Inhibitors/administration & dosage , Neoplasms/drug therapy , Quinazolines/administration & dosage , Acute Disease , Adolescent , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/pharmacokinetics , Child , Child, Preschool , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Infant , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/metabolism , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Quinazolines/adverse effects , Quinazolines/pharmacokineticsABSTRACT
PURPOSE: To examine the relationship between received dose, received dose-intensity (RDI), and survival in patients with osteosarcoma. PATIENTS AND METHODS: Between 1983 and 1993, the European Osteosarcoma Intergroup (EOI) conducted two randomized trials involving patients with high-grade, nonmetastatic, biopsy-proven osteosarcoma of the extremity. These trials shared a common treatment arm of doxorubicin (DOX) 75 mg/m(2) and cisplatin (CDDP) 100 mg/m(2) planned for six cycles at 3-week intervals. Definitive surgery was scheduled at week 9, after three cycles. Survival time was calculated from 122 days, the scheduled end of chemotherapy. RESULTS: A total of 287 patients randomized to DOX/CDDP received at least one cycle of chemotherapy, and 232 (81%) received all six cycles. On average, 79% of the intended dose of DOX and 80% of the intended dose of CDDP was given. Mean time to completion of chemotherapy was 1.27 times that specified by the protocol. Mean RDI was 0.64 for DOX (SD = 0.19) and 0.65 for CDDP (SD = 0.18). Progression-free survival was lower for those who received one to five cycles compared with those who completed all six cycles (hazards ratio, 1.69; 95% confidence interval, 1.03 to 2.78). Survival and progression-free survival were lowest for patients with RDI less than 0.6, although these differences were not statistically significant at the 5% level. There was no clear evidence of preoperative dose or dose-intensity influencing histologic response. CONCLUSION: This analysis did not establish a clear survival benefit for increasing received dose or dose-intensity in the context of this two-drug regimen. The hypothesis that increasing dose-intensity may improve survival in osteosarcoma requires prospective evaluation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Osteosarcoma/drug therapy , Adolescent , Bone Neoplasms/surgery , Child , Cisplatin/administration & dosage , Disease-Free Survival , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Drug Administration Schedule , Extremities , Female , Humans , Male , Methotrexate/administration & dosage , Neoadjuvant Therapy , Osteosarcoma/surgery , Survival Rate , Treatment OutcomeABSTRACT
Ewing's sarcoma is thought to arise after developmental arrest of primitive neural cells during embryogenesis. Because basic fibroblast growth factor (bFGF) has a critical role in the regulation of cell survival, proliferation, and differentiation during embryogenesis, we have tested the hypothesis that bFGF and FGF receptors may contribute to the development of Ewing's sarcoma and may provide a mechanism for the modulation of their behavior. All four of the Ewing's sarcoma cell lines examined expressed bFGF and FGF receptors, which were detected by immunofluorescence and Western blotting. bFGF-induced a significant dose-dependent decrease in Ewing's sarcoma cell proliferation on plastic and reduced anchorage-independent growth in soft agar. Unexpectedly, this decrease in cell number reflected bFGF-induced apoptosis and necrosis, as demonstrated by electron microscopy, binding of annexin V, and staining with acridine orange. Induction of cell death was dependent on dosage of, and period of exposure to, bFGF. bFGF did not induce differentiation of Ewing's sarcoma cells in either the presence or the absence of serum or nerve growth factor. Treatment of NuNu mice with bFGF decreased growth of the highly tumorigenic Ewing's sarcoma cell lines. Histologically tumors grown in the NuNu mice treated with bFGF were less cellular than those in control mice, and showed an increased level of apoptotic nuclei. This is in contrast to the mitogenic effect bFGF has in most other cancer cells. In summary, bFGF decreases Ewing's sarcoma growth in vitro and in vivo by the induction of cell death. This novel observation may provide a new therapeutic strategy for Ewing's sarcomas.