Pneumomediastinum: a rare, impressive but benign complication of chemotherapy-induced emesis in children.
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Adolescent↗
Biomedical subjects
O Hartmann
Publications and source records attributed to O Hartmann.
[Treatment of chemotherapy induced emesis in children].
In recent years, the management of chemotherapy-induced emesis in children has been greatly modified by the introduction of a new therapeutic class: serotonin antagonists. Based on a better knowledge of mechanisms, the treatment now uses combinations of different drugs. These treatments need to be carefully adapted to the patient and to the emetic risk of the chemotherapy, also taking into account the minimal cost. A gradual treatment proposal in five steps is described.
Antiemetics↗
An open-label, multicentre, randomised phase 2 study of recombinant human granulocyte colony-stimulating factor (filgrastim) as an adjunct to combination chemotherapy in paediatric patients with metastatic neuroblastoma.
Administration of combination chemotherapy to children with metastatic neuroblastoma induces profound myelosuppression resulting in chemotherapy treatment delays and febrile neutropenic episodes. The objective of this randomised multicentre study was to assess the incidence, duration and severity of neutropenia when filgrastim is added to induction chemotherapy administered to patients with metastatic neuroblastoma. In this study, 59 patients with metastatic neuroblastoma were randomised to receive chemotherapy (control group, n = 28) or chemotherapy plus filgrastim (filgrastim group, n = 31). Chemotherapy consisted of four cycles of cyclophosphamide, vincristine and doxorubicin (CADO) alternating at 21-day intervals with cisplatin and etoposide (CDDP-VP16). Filgrastim was administered subcutaneously at a dose of 5 micrograms/kg/day from day 7 for up to 14 days. The incidence of neutropenia (absolute neutrophil count [ANC] < 0.5 x 10(9)/l) in the filgrastim group was not reduced after the first CADO course. However, significant reductions were observed after courses 2, 3 and 4. The duration of neutropenia and of intravenous antibiotic use were significantly reduced in the filgrastim group over the whole study period (9 days versus 26 days, P < 0.001; 12 days versus 20 days, P = 0.04, respectively). However, the duration of hospitalisation and the incidence of febrile neutropenia were not significantly reduced. Compliance to treatment was good and the ability to administer chemotherapy without treatment delays was significantly better in the filgrastim group (P < 0.05). Event-free survival was greater in the filgrastim than in the control group (2.4 years versus 1.3 years; P = 0.072). Filgrastim is a beneficial adjunct to combination induction chemotherapy used in the treatment of metastatic neuroblastoma.
Antineoplastic Combined Chemotherapy Protocols↗
Unresectable localized neuroblastoma: improved survival after primary chemotherapy including carboplatin-etoposide. Neuroblastoma Study Group of the Société Française d'Oncologie Pédiatrique (SFOP).
Neuroblastomas (NBs) were assessed according to INSS recommendations including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received primary chemotherapy including two courses of carboplatin-etoposide (CE) and two of vincristine-cyclophosphamide-doxorubicin (CAdO). Post-operative treatment was to be given only in children over 1 year of age at diagnosis who had residual disease or lymph node (LN) involvement. Between 1990 and 1994, 130 consecutive children were registered. In comparison with resectable primaries, these tumours were more commonly abdominal, larger and associated with N-myc amplification (NMA). Complete, very good and partial response (CR, VGPR, PR) to CE were, respectively, 1%, 7% and 44%, overall response rate (RR) to two courses of CE and two courses of CAdO was 71%, and the tumour could be removed in all but four of the children. The toxicity was manageable. The 5-year overall survival (OS) and event-free survival (EFS) were, respectively, 88% and 78% with a median follow-up of 38 months. In multivariate analysis, only NMA and LN involvement adversely influenced the outcome, particularly NMA. Children with unresectable NBs and no NMA fared as well as children with resectable ones as OS were, respectively, 95% and 99% and EFS 89% and 91%. Our data show encouraging results in localized but unresectable NBs as 90% of children may be considered as definitely cured, especially those without NMA.
Adolescent↗
Phase II study of high-dose thiotepa and hematopoietic stem cell transplantation in children with solid tumors.
From 1987 to 1995, 22 children with refractory solid tumors entered a phase II study of high-dose thiotepa (HDT) (900 mg/m2) followed by stem cell transplantation (SCT) in the Pediatrics Department of the Institut Gustave Roussy. Tumor types were rhabdomyosarcoma (eight), osteosarcoma (seven), neuroblastoma (three), Ewing's sarcoma (three) and Burkitt's lymphoma (one). Before HDT, all had been extensively treated with conventional chemotherapy, surgical resection of the primary tumor (13/22) and of metastases (6/22), and radiotherapy of the primary tumor in three patients. All had measurable disease, at the site of the primary tumor (3 patients), of the metastases (9 patients) or both (10 patients). Toxicity from the HDT was severe but acceptable. No toxicity-related death occurred. The median duration of neutropenia and thrombocytopenia was 18 days (5-37) and 30 days (7-377), respectively. Septicemia was documented in four patients. Severe diarrhea was observed in seven patients. Mild hepatic toxicity occurred 18 times. No CR and 11/22 PR were documented: osteosarcoma 4/7, rhabdomyosarcoma 4/8, Ewing's sarcoma 2/3; 1/1 Burkitt's lymphoma progressed. We conclude that at a dose of 900 mg/m2 followed by SCT support in these heavily pretreated children, the main toxicity induced by thiotepa was digestive. The response rate observed, especially in sarcoma, is particularly encouraging. Thiotepa should be further evaluated in HDC regimens either in combination with other alkylating agents or in rapidly cycled courses of HDC with SCT.
Adolescent↗
Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.
We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.
Adolescent↗
Long-term follow up of 69 patients treated for optic pathway tumours before the chemotherapy era.
AIM: To analyse the long-term results of conservative management with radiotherapy in patients with optic pathway tumours. DESIGN: All 69 patients were symptomatic at diagnosis and most neoplasms involved the optic chiasm and hypothalamus. RESULTS: At 10 years, overall survival and progression free survival were 83% and 65.5%, respectively. After radiotherapy, vision improved in 18 patients and remained stable in 29 other patients. Cerebrovascular complications occurred in nine of 53 patients treated with radiotherapy after a median interval of two and a half years. These complications were five times more frequent in patients with neurofibromatosis type 1 (NF1). Severe intellectual disabilities were present in 18 children, most of whom underwent irradiation at a very young age (median age, 4 years). IMPLICATIONS: Radiotherapy is a valuable treatment in terms of tumour response, visual outcome, and progression free survival. However, in young children and in patients with NF1, major sequelae are encountered and new treatment strategies should be proposed for these patients.
Adolescent↗
High-dose melphalan, etoposide, and carboplatin followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms' tumor: a French Society of Pediatric Oncology study.
PURPOSE: The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease. PATIENTS AND METHODS: From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M. RESULTS: Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3). CONCLUSION: The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.
Adolescent↗
Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: a report from the European Bone Marrow Transplantation Solid Tumor Registry.
PURPOSE: The European Bone Marrow Transplantation (EBMT) Solid Tumor Registry (STR) contains detailed information on children with advanced neuroblastoma who, after standard-dose induction chemotherapy and surgery, received myeloablative megatherapy (MGT) followed by stem-cell transplantation (SCT). This data base was analyzed to identify factors that predict event-free survival (EFS). PATIENTS AND METHODS: Eligibility criteria were stage IV neuroblastoma, age over 1 year at diagnosis, and no relapse before MGT/SCT. Between February 1978 and July 1992, 549 patients were registered by 36 European transplant centers. The median age at diagnosis was 36 months (range, 13 to 216 months) and the male-female ratio was 1:45. Before MGT, 157 patients were in complete remission (CR), 156 in very good partial remission (VGPR), and 208 in partial remission (PR), whereas 24 had had only a minor response (MR). One hundred ten of 546 patients had undergone two successive MGT procedures. The median observation time was 60 months (range, 12 to 187 months). RESULTS: Actuarial EFS is 26% at 5 years. Multivariate analysis by the Cox proportional hazards regression model included 529 patients with complete data sets. After adjustment for treatment duration before MGT and double MGT procedures, two adverse, independent risk factors that influenced EFS were identified: (1) persisting skeletal lesions before MGT as defined by technetium (99TC) scans and/or meta-iodobenzylguanidine (mIBG) scans (P = .004) and (2) persisting bone marrow involvement before MGT (P = .03). CONCLUSION: After induction treatment, persisting skeletal disease as defined above and persisting bone marrow involvement may be predictive of a particularly poor outcome. Physicians may consider this an additional important tool to decide the patient's management.
Adolescent↗
Intraoperative localization of neuroblastoma in children with 123I- or 125I-radiolabeled metaiodobenzylguanidine.
BACKGROUND: This study describes a novel method of intraoperative localization of neuroblastoma with a gamma-detecting probe, to detect in situ tumor binding of radiolabeled 123I- or 125I-metaiodobenzylguanidine (MIBG) and improve the quality of tumor resection. METHODS: Fifty-eight children underwent 66 surgical procedures with intraoperative detection of radiolabeled MIBG. All patients with positive MIBG scintiscans at diagnosis were included in the study. A tumor/background ratio exceeding 2:1 at the time of operation was considered positive, indicating a significant uptake of MIBG, compatible with the presence of malignant cells. The surgeons were requested to evaluate the contribution of the method to the surgical procedure. Sensitivity and specificity of the method with either 123I-labeled MIBG or 125I-labeled MIBG, on the basis of correlations between probe findings and pathologic analysis of 288 resected specimens, were determined. RESULTS: Intraoperative detection was helpful in 65% of surgical procedures, allowing a better definition of tumor limits and extension to locoregional nodes or detection of small and nonpalpable tumors in sites with difficult surgical access, especially during operation for relapse. The detection was not contributory in 35% of the procedures (well-localized tumors, thoracic neuroblastoma for technical reasons, highly differentiated tumors as ganglioneuroma, and tumors with mainly necrosis or fibrosis). The sensitivity of 123I and 125I was the same (91% and 92%), but the specificity of 125I (85%) was significantly higher than that of 123I (55%) (p < 0.005). CONCLUSIONS: First, this study demonstrates the feasibility of intraoperative detection, with radiolabeled MIBG, of neuroblastoma in children. We advocate the use of 125I rather than 123I. Second, the method is useful to improve the quality of macroscopic resection in widespread neuroblastoma with nodal involvement, in sites with difficult access, and in operations for relapse.
3-Iodobenzylguanidine↗
[Update on pediatric oncology].
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Antineoplastic Combined Chemotherapy Protocols↗
[Oncogenic factors of metastatic dissemination in neuroblastoma].
Disseminated neuroblastoma frequently show a very poor prognosis. N-myc gene amplification, 1p deletion and lack of CD44 gene expression, are all genetic factors associated with the disease's dissemination. Human neuroblastoma xenografts in nude mice has permitted to characterize, in disseminated neuroblasts, oncogenes overexpression, inactivation of tumor suppressor genes as well as detoxifying genes activation which contributes to increase cellular resistance to chemotherapy. These genetic abnormalities permit to propose a nosology of this very aggressive pediatric solid tumor. Hopefully, this genetic classification could be of great value for new therapeutic approaches.
Animals↗
[Carboxypeptidase-G2 rescue of methotrexate intoxication].
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Adolescent↗
High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry.
To evaluate the role of high-dose chemotherapy (HDC) followed by autologous bone marrow transplantation (ABMT) in children with poor-prognosis Burkitt's lymphoma, the European Lymphoma BMT registry was critically reviewed. Between February 1979 and July 1991, a selected group of 89 children (78 boys and 11 girls) were considered as ABMT candidates in 12 European cancer centers for the following reasons: poor initial response (PIR) to first-line chemotherapy in 28 patients, primary refractory disease (PRD) in nine patients, sensitive relapse (SR) in 38 patients, and resistant relapse (RR) in 14 patients. The median age at ABMT was 8.2 years (range, 2.8 to 16.2 years). Thus, this report reflects data for patients surviving the salvage attempt deemed appropriate for HDC/ABMT and who then actually underwent the transplant procedure. The median follow-up period after HDC/ABMT was 4.3 years (range, 2 to 12 years). The prognosis was dismal for PRD patients and those with RR, ie, all patients died within 1 year. The 5-year event-free survival (EFS) was 56.6% (P < .0001) for patients in partial remission (PR) and 48.7% (P = .002) for patients with SR. The toxic death rate was 11.1%. Continuous complete remissions (CRs) in 39.4% of these otherwise incurable children highlight the fact that HDC/ABMT was an effective complementary procedure after conventional-dose chemotherapy protocols used during the given period. In addition, these data show that patients with PRD or RR clearly had no advantage from this aggressive and cost-intensive procedure. It has to be considered that the need for HDC/ABMT has greatly diminished in parallel with the improvement in survival using the modern intensive pulsed CCT of current protocols. To further rescue patients failing to respond to modern protocols, new approaches appear necessary, ie, combinations of HDC with antibody-targeted therapy plus allogeneic BMT for the additional benefits of the potential graft-versus-lymphoma effect.
Antineoplastic Agents↗
Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs. A randomized, controlled trial.
BACKGROUND: Previous studies have suggested that peripheral blood stem cell (PBSC) transplantation has an advantage over autologous bone marrow transplantation. OBJECTIVE: To compare the hematologic recovery and costs associated with PBSC transplantation with those associated with autologous bone marrow transplantation in patients receiving high-dose chemotherapy for solid tumors or lymphomas. DESIGN: Multicenter, randomized, controlled clinical trial. SETTING: French Federation of Cancer Centers, located in cancer facilities or public hospitals with transplantation units. PATIENTS: Children and adults with solid tumors or lymphomas who were candidates for high-dose chemotherapy. INTERVENTIONS: Bone marrow or filgrastim-mobilized PBSCs. MEASUREMENT: The major and point was the duration of thrombocytopenia (platelet count < 50 x 10(9)/L). An economic evaluation of both types of transplantation was done prospectively to measure costs and cost-effectiveness. RESULTS: 129 patients entered the trial; 64 had PBSC transplantation, and 65 had bone marrow transplantation. The median duration of thrombocytopenia was 16 days in the PBSC group and 35 days in the bone marrow group (P < 0.001). All of the other clinical end points studied (time to last platelet transfusion, duration of granulocytopenia, number of transfusion episodes, and duration of hospitalization) favored PBSC transplantation. A cost analysis showed that total cost was decreased by 17% in adults and 29% in children with PBSC transplantation; thus, PBSC transplantation was clearly more cost-effective than bone marrow transplantation for both platelet and granulocyte recovery. CONCLUSION: Transplantation of PBSCs is associated with more rapid hematologic recovery than is bone marrow transplantation after high-dose chemotherapy for solid tumors or lymphomas. Furthermore, global costs are lower and cost-effectiveness ratios are better with PBSC transplantation.
Adolescent↗
Stage IV neuroblastoma in patients over 1 year of age at diagnosis: consolidation of poor responders with combined busulfan, cyclophosphamide and melphalan followed by in vitro mafosfamide-purged autologous bone marrow transplantation.
In an attempt to improve the poor prognosis of poor responders with stage IV neuroblastoma, a new combined high-dose chemotherapy conditioning regimen was tested. Event-free and overall survival, as well as the incidence of complications, were analysed. Twenty-five children aged 12-146 months at diagnosis entered this study. All were in complete remission (CR) at the time of high-dose chemotherapy. Two or three different protocols had been necessary for them to achieve a CR. High-dose chemotherapy consisted of a combination of busulfan (600 mg/m2), cyclophosphamide (4400 mg/m2) and melphalan (140 mg/m2). It was followed by autologous bone marrow transplantation (ABMT). The bone marrow graft was purged in vitro with mafosfamide. The probability of event-free survival (EFS) at 5 years post-ABMT was 34%, compared to < 8% in a historical series. Toxicity was severe but manageable and 2 complication-related deaths were observed. Veno-occlusive disease was the most frequent extrahaematopoietic complication encountered, but its outcome was always favourable. By using a very intensive conditioning regimen consisting of a combination of three alkylating agents, the EFS of poor responders with metastatic neuroblastoma was improved and similar to that of good responders. When compared with a previously published similar series of patients, the improvement in survival appears probably related to intensification of the conditioning regimen.
Antineoplastic Combined Chemotherapy Protocols↗
Loss of chromosome 1p may have a prognostic value in localised neuroblastoma: results of the French NBL 90 Study. Neuroblastoma Study Group of the Société Française d'Oncologie Pédiatrique (SFOP).
Between March 1990 and December 1994, 316 consecutive children with localised neuroblastoma were registered in the French NBL 90 study. In addition to the assessment of a new chemotherapy regimen in unresectable neuroblastoma, we evaluated the prognostic significance of MYCN amplification and loss of the short arm of chromosome 1 (LOH1p). MYCN was found in 22/225 children (10%) and associated with unfavourable clinical features such as age at diagnosis > 1 year and large and unresectable tumours. LOH1p was observed in 9/91 patients (10%), of whom some had favourable prognostic factors such as age at diagnosis < 1 year (n = 4), INSS stage 1 or 2 (n = 3) and no MYCN amplification (n = 4). Overall survival (OS) and event-free survival (EFS) were, respectively, 56% and 22% (median follow-up: 36 months) for children with LOH1p compared with 97% and 94% for those without (log-rank = 10(-8)). All except 1 of the 5 children with MYCN amplification and LOH1p relapsed and ultimately died of the disease. Among the 4 with LOH1p and no MYCN amplification, recurrence occurred in 3 (2 local, 1 metastatic), all alive in second remission after salvage therapy (12-19 months after the relapse). In multivariate analysis, LOH1p was the strongest prognostic indicator for subsequent relapse. LOH1p appears more discriminant than MYCN amplification for predicting the risk of recurrence in children with localised neuroblastoma. However, its analysis was possible in only 30% of our patients and its final impact on survival should be confirmed in larger, prospective studies in order to stratify subsequent treatment.
Abdominal Neoplasms↗
DNA-topoisomerase I, a new target for the treatment of neuroblastoma.
DNA-topoisomerase I is the nuclear target of new anticancer drugs, namely camptothecin and its derivatives. In order to establish the rational basis for their clinical development in paediatric oncology, the antitumour activity of irinotecan (CPT-11) and topotecan, two camptothecin water-soluble derivatives, was studied in nude mice bearing neuroblastoma xenografts. The panel was composed of 4 previously established subcutaneous xenograft lines (IGR-N835, IGR-N91, IGR-NB3, IGR-NB8) that exhibited the common biological markers of poor prognosis in children (MYCN amplification, 1p deletion, paradiploidy and/or MDR1 overexpression). Irinotecan and topotecan were administered i.v. or i.p. over 5 consecutive days in animals bearing tumours. Irinotecan (40 mg/kg/day) induced 20-100% complete regressions with tumour growth delays ranging from 20 to 46 days. Two out of 10 IGR-N91 bearing animals were tumour free more than 120 days after treatment with the top dose (50 mg/kg/day). Topotecan (2.7 mg/kg/day) induced 0-67% complete regressions with tumour growth delays ranging from 23 to 50 days. One out of 8 IGR-NB3 bearing mice was tumour free at the end of the experiment. The antitumour activity of both drugs was clearly sustained at a lower dose level. Topoisomerase I activity was assayed in 15 neuroblastomas, 3 ganglioneuroblastomas and 2 normal adrenal glands, using a DNA relaxation assay. Topoisomerase I activity ranged from 69 to 1304 arbitrary units/mg of protein, and was significantly higher in immature neuroblastomas than in ganglioneuroblastomas and adrenal glands. In conclusion, irinotecan and topotecan are active against neuroblastoma xenografts. Their target is expressed in patients' tumour samples. Clinical development of topoisomerase I inhibitors in children with neuroblastoma is warranted.
Adrenal Glands↗