RESUMO
BACKGROUND: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far. PROCEDURE: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria. RESULTS: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence. CONCLUSION: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Ifosfamida/efeitos adversos , Nefropatias/induzido quimicamente , Sarcoma/tratamento farmacológico , Abdome/efeitos da radiação , Adolescente , Fatores Etários , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/epidemiologia , Ifosfamida/administração & dosagem , Ifosfamida/farmacologia , Ifosfamida/uso terapêutico , Incidência , Lactente , Nefropatias/epidemiologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos da radiação , Masculino , Vigilância de Produtos Comercializados , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteinúria/induzido quimicamente , Proteinúria/epidemiologia , Radioterapia/efeitos adversos , Fatores de Risco , Sarcoma/complicaçõesRESUMO
BACKGROUND: Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland. PROCEDURE: The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2). RESULTS: In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval. CONCLUSIONS: After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.
Assuntos
Cardiomiopatias/induzido quimicamente , Doxorrubicina/efeitos adversos , Vigilância de Produtos Comercializados , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Áustria/epidemiologia , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos , Sarcoma/epidemiologia , Suíça/epidemiologia , TempoRESUMO
PURPOSE: Up to now, cardiotoxicity of epirubicin has been studied almost exclusively in adult cancer patients. The aim of this study was to investigate epirubicin in children and adolescents, in comparison with doxorubicin. METHODS: About 172 soft tissue sarcoma patients (mean age at diagnosis: 8.3 years), treated with epirubicin (median cumulative dose: 450 mg/m2) or doxorubicin (median cumulative dose: 240 mg/m2) within the high-risk group of the CWS-96 study, were examined in a prospective multicentre study. Heart function was analysed by echocardiography, measuring left-ventricular fractional shortening (FS). The median follow up was 27.7 months. RESULTS: Incidence of clinically manifest cardiomyopathy was 0% (0/60; 95% CI: 0-6.0%) in patients treated with epirubicin, and 0.9% (1/108; 95% CI: 0-5.1%) in patients treated with doxorubicin. A further three patients showed subclinical cardiomyopathy. There was no difference in FS between the two treatment arms. CONCLUSIONS: Cardiotoxicity was low in our study. For the short term, cardiotoxicity seems to be only a minor problem in patients treated with epirubicin as applied in this cohort.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiomiopatia Restritiva/induzido quimicamente , Doxorrubicina/efeitos adversos , Epirubicina/efeitos adversos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Sarcoma/tratamento farmacológico , Adolescente , Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiomiopatia Restritiva/fisiopatologia , Criança , Pré-Escolar , Doxorrubicina/administração & dosagem , Ecocardiografia , Epirubicina/administração & dosagem , Feminino , Testes de Função Cardíaca , Humanos , Incidência , Masculino , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
PURPOSE: Final results are presented from two consecutive European studies for patients with metastatic rhabdomyosarcoma (RMS) to identify prognostic variables and determine the value of high-dose chemotherapy (HDCT) in complete remission. PATIENTS AND METHODS: A total of 174 patients aged 3 months to 18 years participated. From 1989 to 1991, patients received four cycles of intensive multiagent chemotherapy. From 1991 to 1995, patients achieving complete remission received consolidation with HDCT. All received local therapy (surgery, radiation therapy) according to response. RESULTS: At a median follow-up of 8 years, 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 24% and 20%, respectively. No statistical difference was found between HDCT and standard chemotherapy (5-year OS, 36% v 27%; EFS 29% v 23%). Univariate analysis identified primary tumor in parameningeal, extremity, or other sites; age younger than 1 year and older than 10 years; bone or bone marrow metastases; multiple metastases; and multiple sites of metastases as unfavorable prognostic factors for OS and EFS. Multivariate analysis identified unfavorable site, bone or bone marrow involvement, and unfavorable age as independently unfavorable factors. Two subgroups were identified. Those with fewer than two unfavorable factors had 5-year EFS and OS of 40% and 47%, respectively. Patients with > or = two unfavorable factors had 5-year EFS and OS of 7.5% and 9%, respectively. CONCLUSION: A minority of patients with metastatic RMS have better survival than overall results for this population suggest. Those in the highest risk group have such poor survival that they are candidates for first-line novel therapies. There is no evidence that consolidation with HDCT improves outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/secundário , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/mortalidade , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Terapia Combinada , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Metástase Neoplásica , Estadiamento de Neoplasias , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Rabdomiossarcoma/terapia , Medição de Risco , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Procedimentos Cirúrgicos Operatórios , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Chromosomal translocations t(11;22) (q24;q12) are characteristic of about 80-90 % of Ewing's sarcoma family of tumors [bone and soft tissue Ewing's sarcoma and peripheral neuroectodermal tumors (PNET)]. They generate ews/fli1 rearrangements showing great diversity in breakpoint exon combination. In about 5 % of Ewing's tumors, ews is fused to the erg gene at 21q22. The various chimeric proteins encoded may function as aberrant oncogenic transcription factors. These specific translocations can be used for exact molecular diagnosis in these poorly differentiated small round-cell tumors. Moreover, the prognostic relevance of different translocational variants has been previously suggested. Furthermore, the sensitive molecular detection of minimal metastatic and residual disease and its clinical significance can be evaluated. To address these questions more definitively in the large number of patients registered in multicenter studies, it is often necessary to access archival paraffin-embedded tumor tissue if no fresh or frozen tumor material is available for analysis by RT (reverse transcription)-PCR. Specific problems arise from formalin-fixed and paraffin-embedded tissue due to the degradation of RNA and insufficient extraction efficiency. Therefore, primer distance and product size are limited for successful PCR amplification. This conflicts with the requirement for identification of various possible exon combinations by PCR simultaneously using one single primer pair with larger distance. PATIENTS: We examined paraffin embedded soft part tumor tissue samples from 47 Ewing's tumor patients. Patients were treated according to either CWS (Cooperative Weichteilsarkomstudie, CWS-91 or CWS-96) or Euro-E.W.I.N.G. 99 therapy protocols. METHOD: We established a novel RT-PCR method, using 3 different exon specific sets of PCR primer pairs, selected according to the coding ews and fli1 nucleotide sequences (NCBI database), suitable for RT-PCR identification of variant ews/fli1 fusion transcripts in RNA isolated from formalin-fixed, paraffin-embedded tissue. For use in combination with ews -primer, an erg specific primer was selected to alternatively test for ews/erg fusion transcripts. As positive control for the integrity of isolated mRNA, we used the ubiquitously expressed gapdh transcript for RT-PCR amplification in each sample. RESULTS: In 31 cases (= 66 %) of 47 paraffin samples of Ewing's tumors analysed, gapdh control indicated adequate quality of RNA. In 16 cases no gapdh control fragment was amplifiable, nevertheless in 2 of these 16 samples distinct ews fusion products could be detected. In 23 cases we identified ews fusion transcripts. Thereof in 65 % ews exon 7 being fused to fli1 exon 6 (fusion type I), in 22 % to fli1 exon 5 (fusion type II). In 4 % each ews exon 10 being juxtaposed to fli1 either exon 6 or exon 5, respectively. An ews/erg fusion was detected in 4 % ( ews exon 7 fused to erg exon 6). In 10 samples, a gapdh fragment was amplified, but no ews/fli1 or - erg fusion transcript could be identified. The reference pathological review (I. L., Kiel, Germany) disproved the primary histopathology in 5 cases. CONCLUSIONS: Using our different sets of exon specific primer pairs, it was possible to detect 4 different breakpoints of ews/fli1 fusion transcripts and the ews/erg fusion by RT-PCR in RNA isolates from formalin-fixed, paraffin-embedded Ewing's tumor tissue. This method can be a very useful alternative in clinical situations (to ensure diagnosis and perform minimal metastatic and residual disease investigations) and in order to assess prognostic significance of translocation subtypes when no fresh tumor tissue is available.
Assuntos
Éxons/genética , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Ewing/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genética , Translocação Genética , Eletroforese em Gel de Ágar , Humanos , Inclusão em Parafina , Proteína Proto-Oncogênica c-fli-1 , RNA Neoplásico/análise , Proteína EWS de Ligação a RNA , Transcrição GênicaRESUMO
The very heterogeneous group of paediatric soft tissue sarcomas account for approximately 7 % of all malignant childhood tumours. More than one half of all cases are rhabdomyosarcomas, some of the over 20 entities are very rare. The prognosis and biology of soft tissue sarcomas in children and adolescents vary greatly depending on histological subtype, the age of the patient, the primary site, the tumour size, tumour invasiveness and the extent of disease at diagnosis. Since 1981, 2918 children and adolescents with soft tissue sarcomas were treated prospectively according to the common treatment protocols of the Cooperative Soft Tissue Sarcoma Study Group (CWS-81 - 96). The known prognostic factors were used to develop a more and more detailed risk stratification. The multimodal treatment includes the use of surgery, chemotherapy and radiotherapy and should be planned by a multidisciplinary team. That way, an overall survival of nearly 70 % over all risk groups could be achieved.
Assuntos
Sarcoma/terapia , Adolescente , Protocolos Antineoplásicos , Criança , Pré-Escolar , Terapia Combinada , Tecido Conjuntivo/patologia , Feminino , Alemanha , Humanos , Lactente , Comunicação Interdisciplinar , Masculino , Músculo Esquelético/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Equipe de Assistência ao Paciente , Prognóstico , Estudos Prospectivos , Sarcoma/mortalidade , Sarcoma/patologia , Taxa de SobrevidaRESUMO
The aim of this study was to analyse carboplatin-induced ototoxicity in a recent study trial. Twenty patients who had received carboplatin for the treatment of soft tissue sarcoma were investigated prospectively for ototoxicity in a multi-centre trial. Hearing function was tested by audiometry. All patients but one were treated with a cumulative dose of 1500 mg/m(2), the remaining with 500 mg/m(2). We evaluated the incidence and dependencies of hearing loss, and compared hearing thresholds to those of an untreated control group (n=60). Hearing thresholds in the carboplatin treated group were only marginally poorer compared with those of the control group. After carboplatin therapy no patient (0%; 95%-KI: 0-17%) had a hearing loss >20 dB. Hearing thresholds were not dependent on age, sex or cranial irradiation. We conclude that ototoxicity after carboplatin was low in our group of patients.
Assuntos
Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Perda Auditiva/etiologia , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Audiometria , Criança , Humanos , Incidência , Estudos Prospectivos , Sarcoma/complicaçõesRESUMO
PURPOSE: To ascertain whether alveolar histology retains its adverse prognostic role in the subset of paratesticular rhabdomyosarcoma (RMS) patients, generally characterized by a very good outcome. PATIENTS AND METHODS: Twenty pediatric patients were treated over a 25-year period using the protocols of the Italian and German Soft Tissue Sarcoma Cooperative Groups. Clinical characteristics at presentation were much the same as in non-alveolar patients. RESULTS: The proportion of patients with alveolar histotype (8%) in paratesticular site was lower than in the general RMS population (20-30%). With a median follow-up of 122 months, 5-year EFS and OS were 78 and 89%, respectively. CONCLUSION: Our data suggest a distinctly better clinical behavior of paratesticular alveolar RMS than when the disease occurs at other sites. These patients were more intensively treated than the embryonal cases, however, so-although a treatment intensity reduction may be desiderable-the idea of eliminating the alkylating agents (as in low-risk embryonal paratesticular RMS) must be considered with great caution.
Assuntos
Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/patologia , Neoplasias Testiculares/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Alemanha , Humanos , Itália , Excisão de Linfonodo , Masculino , Estadiamento de Neoplasias , Prognóstico , Radioterapia , Rabdomiossarcoma Alveolar/terapia , Rabdomiossarcoma Embrionário/terapia , Taxa de Sobrevida , Neoplasias Testiculares/terapia , Resultado do TratamentoRESUMO
The MMT4 study was designed to explore an intensive chemotherapy regimen (MMT4-89) and the role of high-dose melphalan (MMT4-91) in children with metastatic soft tissue sarcoma, including extraosseous peripheral neuroectodermal tumor (PNET). Thirty-one patients with PNET were treated between 1989 and 1995 (11 according to MMT4-89 and 20 according to MMT4-91). Chemotherapy consisted of four CEVAIE cycles, each including three 3-week courses: CEV (carboplatin 500 mg/m(2), epirubicin 150 mg/m(2), vincristine 1.5 mg/m(2)), IVA ifosfamide 9 g/m(2), actinomycin 1.5 mg/m(2), vincristine 1.5 mg/m(2)), IVE (ifosfamide 9 g/m(2), etoposide 600 mg/m(2), vincristine 1.5 mg/m(2)). In MMT4-91 the fourth CEVAIE was replaced with melphalan 200 mg/m(2) with stem cell rescue. The CEV combination was evaluated as a window study. Surgery followed the second cycle. Radiotherapy was administered to post-surgical residual disease. The response rate was 55% after CEV, rising to 80% after the first CEVAIE. Twenty-five patients achieved complete remission (CR). Overall, the 5-year EFS was 22.6%: 36.4% and 15% for patients treated according to MMT4-89 and MMT4-91, respectively (P = 0.3). Local control was achieved in 77% of irradiated patients vs 45% of non-irradiated. Age >10 years was associated with significantly poorer outcome (P = 0.04). In conclusion, despite the high CR rate, intensive chemotherapy with or without high-dose melphalan appeared to have little impact on the survival of patients with metastatic extraosseus PNET.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Melfalan/administração & dosagem , Tumores Neuroectodérmicos/terapia , Sarcoma/terapia , Adolescente , Fatores Etários , Transplante de Medula Óssea , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Masculino , Tumores Neuroectodérmicos/mortalidade , Tumores Neuroectodérmicos/patologia , Transplante de Células-Tronco de Sangue Periférico , Indução de Remissão/métodos , Sarcoma/mortalidade , Sarcoma/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: We report the experience of the German-Italian Cooperative Group with 216 pediatric patients with paratesticular rhabdomyosarcoma treated over 20 years. PATIENTS AND METHODS: At diagnosis, 198 patients had localized disease and 18 had distant metastases. Among the nonmetastatic patients, complete tumor resection was performed in 83% of cases. Evaluation of the retroperitoneal lymph nodes changed over the years from routine surgical staging to radiologic assessment. All patients received chemotherapy, which was reduced in intensity and duration for patients with low-risk features in subsequent protocols. Radiotherapy was administered to 10% of patients. RESULTS: Among 72 patients with a negative retroperitoneal computed tomography (CT) scan, surgical assessment detected nodal involvement in only one case. Among 23 patients with enlarged nodes on CT scans, surgery confirmed nodal spread in 65% of patients. No differences in the rate of nodal involvement were observed over the years. With a median follow-up of 110 months, 5-year survival was 85.5% for the series as a whole, 94.6% for patients with localized disease, and 22.2% for metastatic cases. Retroperitoneal nodal recurrence was the major cause of treatment failure. Univariate analysis revealed the prognostic value of tumor invasiveness, size, and resectability, as well as of nodal involvement and age, in patients with localized tumor. CONCLUSION: The outcome for patients with localized paratesticular rhabdomyosarcoma is excellent, despite the reduction in chemotherapy over the years: an alkylating agent-free and anthracycline-free regimen is adequate treatment for low-risk patients. Surgical assessment of the retroperitoneum must be reserved for patients with enlarged nodes on CT scans. Children over 10 years old carry a higher risk of nodal involvement and relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rabdomiossarcoma/patologia , Neoplasias Testiculares/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Metástase Linfática , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/cirurgia , Fatores de Risco , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/cirurgiaRESUMO
BACKGROUND: Hemangiopericytoma (HPC) is very uncommon in childhood and comprises two different clinical entities, the adult type and the infantile type, occurring in the first year of age. We report on a series of 27 pediatric patients treated from 1978 to 1999 by the Italian and German Soft Tissue Sarcoma Cooperative Group. METHODS: Seven patients had infantile HPC; complete resection was achieved in the tumors of five patients and chemotherapy was given to four patients. Twenty children had adult type HPC; nine received complete tumor resection (four patients at diagnosis and five at delayed surgery). Post-operative radiotherapy was administered to 15 patients, chemotherapy to 19. RESULTS: Six of seven patients with infantile HPC were alive in first remission; one patient died of disease. Chemotherapy achieved an objective response in four of four patients. Among the adult type HPC cases, 5-year event free survival was 64% (median follow-up 125 months); 12 patients were alive in first remission, eight patients relapsed and died of disease. Seven of 10 evaluable patients showed good response to chemotherapy. Statistically significant differences in outcome were observed in relation to Intergroup Rhabdomyosarcoma Study grouping, size, local invasiveness, and gender. CONCLUSIONS: Infantile HPC is a unique entity probably related to infantile myofibroblastic lesions and characterized by a high response to chemotherapy, which is required in case of unresectable, life-threatening tumors. In children over 1 year of age, HPC behaves like its adult counterpart; complete surgical resection remains the mainstay of treatment, but chemotherapy and radiotherapy seem effective and are recommended in all patients with incomplete tumor resection and/or locally invasive, large tumors.
Assuntos
Hemangiopericitoma/patologia , Adolescente , Adulto , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Feminino , Hemangiopericitoma/tratamento farmacológico , Hemangiopericitoma/cirurgia , Humanos , Lactente , Masculino , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Poor prognosis in childhood neuroblastoma is associated with deletions of chromosome region 1p36 and di/tetraploid DNA content. PROCEDURE: Forty-six patients with histopathologically proven neuroblastoma were investigated for in vivo expression of somatostatin receptors (SR) by 111In-pentetreotide scintigraphy. All tumors were analyzed for cytometric DNA content and chromosome 1p36 integrity. RESULTS: SR expression was detected in 28 tumors (61%) and correlated with young age, localized clinical stage, and favorable outcome. Fourteen tumors showed deletion at chromosome 1p36, thirteen of which did not show SR expression (P< 0.001). A triploid DNA content was correlated with the presence of SR (23 of 25, P< 0.001). No tumor with deletion of chromosome 1p36 and di/tetra DNA content showed SR expression (chi2 = 29.88, d.o.f. = 2, P < 0.001). CONCLUSIONS: We conclude that SR expression is related to genetic features of prognostic significance. This may be assessed with a minimally invasive scintigraphic method.
Assuntos
Aneuploidia , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/deficiência , Neuroblastoma/genética , Receptores de Somatostatina/deficiência , Adolescente , Fatores Etários , Criança , Pré-Escolar , Cromossomos Humanos Par 1/ultraestrutura , DNA de Neoplasias/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Radioisótopos de Índio , Lactente , Perda de Heterozigosidade , Masculino , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Prognóstico , Cintilografia , Receptores de Somatostatina/análise , Receptores de Somatostatina/genética , Somatostatina/análogos & derivadosRESUMO
Rhabdomyosarcomas (RMS) of the urinary bladder and vagina vary in their biologic and clinical behavior and require different types of treatment. Anatomically the two organs are close, and the reason for these differences in behavior is unknown. We investigated tumor specimens of 51 urinary bladder RMS and 14 vaginal RMS with regard to histologic subtype, growth pattern, differentiation, and proliferation morphologically and immunohistochemically. Recurrences and/or "second look" specimens from 15 patients after chemotherapy were compared with the primary tumors. Within the 65 specimens we found 31 "classical" embryonal RMS, 26 embryonal RMS of botryoid subtype (BRMS), 3 embryonal RMS of spindle cell subtype, and 5 alveolar RMS. BRMS is more common in the vagina (11 BRMS of 14 cases) than in the urinary bladder RMS (15 BRMS of 54 cases). Classical embryonal RMS with a polypoid (exophytic) growth pattern is associated with a more favorable prognosis (92% 10-year survival) than the same type with a diffuse intramural (endophytic) growth pattern (68% 10-year survival, p = 0.02). The proliferation rate was associated with the degree of differentiation, but neither showed a correlation with prognosis. A marked maturation after chemotherapy was seen in the majority of recurrences and SL specimens, associated with lowered proliferation activity. Two of 12 patients with recurrences showing chemotherapy-induced maturation died of the disease. In conclusion, we determined that polypoid embryonal RMS of both the urinary bladder and the vagina have a comparably good prognosis. This includes all botryoid RMS. The poorer prognosis of the group of urinary bladder RMS as a whole was caused by a high incidence of diffusely growing RMS, which have a less favorable prognosis than polypoid RMS. Maturation after chemotherapy occurs frequently in RMS. In contrast to the excellent prognosis reported in other studies, we had two patients with fatal outcome despite chemotherapy-induced maturation in the recurrences.
Assuntos
Rabdomiossarcoma/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias Vaginais/patologia , Adolescente , Divisão Celular , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Recidiva Local de Neoplasia , Sistema de Registros , Rabdomiossarcoma/metabolismo , Análise de Sobrevida , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias Vaginais/metabolismoRESUMO
PURPOSE: Cooperative Ewing's Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone. PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and > or =100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models. RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P =.92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P =.0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P =.0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Lactente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Fatores de Risco , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/cirurgia , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
PURPOSE: Orbital rhabdomyosarcoma (RMS) historically has been associated with an excellent survival rate. The majority of patients are cured with the use of both chemotherapy and radiation therapy, but a significant number experience important late sequelae of treatment. In an attempt to determine optimal therapy in relation both to cure and to sequelae, the experience of the four international collaborative groups (Intergroup Rhabdomyosarcoma Study Group [IRSG], International Society of Paediatric Oncology [SIOP] Sarcoma Committee, German Collaborative Soft Tissue Sarcoma Group [CWS], and Italian Cooperative Soft Tissue Sarcoma Group [ICG] studies) was shared at an international workshop. PATIENTS AND METHODS: A total of 306 eligible patients were identified from group records (186 from IRS, 43 from SIOP MMT, 40 from CWS, and 37 from ICG). Median age was 6.8 years, and median follow-up was 6.5 years. Eighty percent of patients received radiation therapy (RT) as part of primary therapy, but there were significant differences in the use of RT between the individual groups (93% in IRSG, 76% in ICG, and 70% in CWS, but only 37% in the SIOP MMT group). RESULTS: At 10 years, event-free and overall survival for the whole cohort were 77% (range, 71% to 81%) and 87% (range, 82% to 92%), respectively. There was no difference in overall survival between the collaborative groups regardless of differences in the use of initial RT. In total, 34 (12%) of 273 survivors had not received RT, although this varied between the different groups (41% in the SIOP MMT group, 20% in CWS, 7% in ICG, and 6% in IRSG). There was no difference in overall survival for the whole cohort regardless of whether radiotherapy was used as part of initial therapy (86% at 10 years for both). CONCLUSION: These data suggest that a subset of patients with orbital RMS can be cured without systematic local therapy, although the total burden of treatment (primary therapy and treatment for relapse) must be taken into account when assessing the implications for late sequelae.
Assuntos
Neoplasias Orbitárias/radioterapia , Lesões por Radiação/epidemiologia , Rabdomiossarcoma/radioterapia , Adolescente , Análise de Variância , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Neoplasias Orbitárias/tratamento farmacológico , Neoplasias Orbitárias/mortalidade , Lesões por Radiação/prevenção & controle , Radioterapia/efeitos adversos , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: High-affinity somatostatin receptors (SRs) have been characterized in neuroblastomas and may be used as target structures for in vivo detection of SR. PROCEDURE: Eighty-eight children with histologically proven neuroblastoma were investigated at diagnosis or relapse by (123)I-mIBG and (111)In-pentetreotide scintigraphy. All tumors were investigated for MYCN copy number, chromosome 1p36 status, and 68/88 also for DNA content, followed for a median follow-up of 35 months (range 1-88 months). RESULTS: SR expression was detected in 56/88 tumors and (123)I-mIBG showed positivity in 83/88. (111)In-pentetreotide was less sensitive in detecting tumor tissue than was (123)I-mIBG (64% vs. 94%, P = 0.005). Survival (SUR) and event-free survival probability (EFS) according to Kaplan-Meier was significantly better for children with positive SR scintigraphy than for the children with a negative SR scan (SUR: 90% vs. 48% at 4 years log rank P < 0.003, EFS: 83% vs. 39% at 4 years, log rank P < 0.0002). CONCLUSIONS: (123)I-mIBG scintigraphy remains the best scintigraphic method for detecting neuroblastoma tumor tissue, whereas additional SR scintigraphy is able to provide significant prognostic information with a minimum of invasiveness.
Assuntos
3-Iodobenzilguanidina , Radioisótopos de Índio , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/mortalidade , Compostos Radiofarmacêuticos , Somatostatina/análogos & derivados , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Cintilografia , Taxa de SobrevidaRESUMO
BACKGROUND: The German Neuroblastoma Screening Project is the first controlled and population-based screening study to evaluate the presumed benefit of neuroblastoma mass screening at 1 year of age (10-18 months). PROCEDURE: Screening takes place in 6 of the 16 German states; children from the remainder serve as controls. The German Childhood Cancer Registry enables a mostly complete follow-up and detection of false-negative patients. RESULTS: Up to December, 1999, 1,199,165 children were examined for urinary catecholamine metabolites and 124 cases of neuroblastoma were detected preclinically, giving a detection rate of 10.3/100,000. Within this cohort, 33 false-negative cases were found. CONCLUSIONS: The results of this screening program will be crucial for further implementation of neuroblastoma screening.
Assuntos
Programas de Rastreamento , Neuroblastoma/epidemiologia , Reações Falso-Negativas , Reações Falso-Positivas , Alemanha/epidemiologia , Humanos , Lactente , Neuroblastoma/diagnóstico , Vigilância da População , Valor Preditivo dos Testes , Avaliação de Programas e Projetos de SaúdeRESUMO
PURPOSE: The European Collaborative MMT4-91 trial was conducted as a prospective nonrandomized study to evaluate the potential benefit of high-dose melphalan as consolidation of first complete remission in children with stage IV rhabdomyosarcoma. PATIENTS AND METHODS: Fifty-two patients in complete remission after six courses of chemotherapy received "megatherapy": 42 received melphalan alone, whereas 10 received melphalan in combination with etoposide, carboplatin/etoposide, or thiotepa/busulfan and etoposide. The outcome of this group of patients was compared with that observed in 44 patients who were also in complete remission after six courses of identical chemotherapy (plus surgery or radiotherapy) but went on to receive a total of up to 12 courses of conventional chemotherapy (four cycles). No differences were found between the two groups regarding clinical characteristics, chemotherapy received before complete remission, or response to chemotherapy. In particular, there was no significant difference between the groups for site of primary tumor, histologic subtype, age at presentation, presence of bone or bone marrow metastases, or number of metastases. RESULTS: The 3-year event-free survival (EFS) and overall survival (OS) rates were 29.7% and 40%, respectively, for those receiving high-dose melphalan or other multiagent high-dose regimens and 19.2% and 27.7%, respectively, for those receiving standard chemotherapy. The difference was not statistically significant (P =.3 and P =.2 for EFS and OS, respectively). There was a significant prolongation in the time from the last day of high-dose chemotherapy or the end of chemotherapy cycle 4 to the time of relapse in those receiving megatherapy (168 days for patients receiving megatherapy v 104 days for those receiving standard therapy; P =.05). CONCLUSION: The addition of a high-dose alkylating agent to consolidation therapy may have prolonged progression-free survival in this poor-risk patient group, but it did not significantly improve the ultimate outcome.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Transplante de Medula Óssea , Melfalan/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Transplante de Células , Criança , Pré-Escolar , Terapia Combinada , Dactinomicina/administração & dosagem , Epirubicina/administração & dosagem , Humanos , Ifosfamida/administração & dosagem , Lactente , Estudos Prospectivos , Rabdomiossarcoma/patologia , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy. PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54. 4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation). RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% +/- 3% and 69% +/- 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% +/- 5%; stage II, 69% +/- 6%; stage III, 57% +/- 4%; and stage IV, 19% +/- 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% +/- 5% v 44% +/- 6%; P =.053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site. CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Dactinomicina/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Cuidados Pré-Operatórios , Prognóstico , Recidiva , Projetos de Pesquisa , Terapia de Salvação , Sarcoma/mortalidade , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
BACKGROUND: Owing to twenty years of multicentric interdisciplinary cooperation, the COSS group has been able to collect data on a large group of osteosarcoma patients treated by neoadjuvant therapy. This paper reviews results achieved in patients with localized extremity tumors. INCLUSION CRITERIA: Registration into a completed neoadjuvant COSS-Study. Histologically confirmed, primary, localized, high-grade, central osteosarcoma of an extremity; age < 40 years; no pretreatment; interval diagnosis to chemotherapy < or = 3 weeks; no severe comorbidity. Chemotherapy: HD-methotrexate +/- doxorubicin +/- cisplatin +/- ifosfamide +/- BCD. Scheduled local therapy: Surgery. RESULTS: 925 evaluable patients from 101 institutions. Median age 15 years, m:f 1.4:1. Primary site: femur 510, tibia 251, humerus 100, fibula 51, other 13. Tumor-size < 1/3 of the involved bone 616, > or = 1/3 304. Definitive surgery in 903/925 cases, 443 limb salvage procedures. Good response (> 90% necrosis) in 469/806 (58.2%) evaluated tumors. Median follow-up for surviving patients: 5.42 years. Actuarial survival after 5 and 10 years: 72.5% (95%-CI 69.3-75.7) and 66.3% (62.5-70.0), relapse-free 62.1% (58.7-65.4) and 59.4% (55.8-63.0). 683/925 alive (601 first remission), 242 deceased (212 tumor progression, 30 other causes). 66.2% (97.3%) of all relapses within 2 (5) years. Prognosis correlates with tumor-size (< vs. > or = 1/3: 69.9% vs. 58.3% at 10 years) and -site (tibia: 74.2%, humerus: 54.5%) and -response (good vs. poor: 78.2% vs. 52.5%) (all p < 0.01). Actuarial 10-year survival by response grading I-VI according to Salzer-Kuntschik 80.9%, 82.8%, 71.1%, 60.7%, 47.7%, 27.3%. COSS-studies with preoperative 4-drug therapy more efficacious than less aggressive protocols. No impact of doxorubicin scheduling (sequential: rapid vs. 48 h-continuous infusion) or cisplatin scheduling (randomized: 5 h vs. 72 h-infusion) on prognosis detected. CONCLUSIONS: Intensive multiagent chemotherapy and delayed surgery for localized extremity osteosarcoma led to excellent oncologic results in the COSS-studies. Tumor-size, -site, and -response as well as the intensity of upfront chemotherapy correlated with outcome. Giving doxorubicin and cisplatin by continuous infusions did not result in discernible prognostic disadvantages.