RESUMEN
5-day/5-drug (5D/5D) is a novel high-dose regimen administered with autologous hematopoietic SCT (HSCT). It was designed to maximize cytoreduction via high dosing of synergistically interacting agents, while minimizing morbidity in patients with resistant neuroblastoma (NB) and ineligible for clinical trials due to myelosuppression from previous therapy. 5D/5D comprises carboplatin 500 mg/m(2)/day on days 1-2, irinotecan 50 mg/m(2)/day on days 1-3, temozolomide 250 mg/m(2)/day on days 1-3, etoposide 200 mg/m(2)/day on days 3-5 and cyclophosphamide 70 mg/kg/day on days 4-5. HSCT is on day 8. Sixteen patients received 21 courses. Treatment was in the outpatient clinic. Responses were noted against progressive disease (PD) that had developed while patients were off, or receiving only low-dose, chemotherapy but not against PD that emerged despite high-dose chemotherapy. Responses were also seen in patients with PD or stable disease after (131)I-metaiodobenzylguanidine therapy. Grade 3 toxicities were limited to transient elevations in liver enzymes (three courses) and hyponatremia (one course). Bacteremia occurred in 2/21 (10%) courses. Hematological recovery allowed patients to be enrolled on clinical trials. In conclusion, 5D/5D (including HSCT) spares vital organs, entails modest morbidity, shows activity against resistant NB and helps patients meet eligibility requirements for formal clinical trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/cirugía , Terapia Recuperativa/métodos , 3-Yodobencilguanidina , Adolescente , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carboplatino/administración & dosificación , Niño , Preescolar , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Etopósido/administración & dosificación , Femenino , Humanos , Irinotecán , Masculino , Neuroblastoma/diagnóstico por imagen , Pacientes Ambulatorios , Cintigrafía , Radiofármacos , Estudios Retrospectivos , TemozolomidaRESUMEN
We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, x 4 days; thiotepa 300 mg/m2/day, x 3 days; and carboplatin approximately 500 mg/m2/day, x 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, +/-oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.+/-8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Nervioso Central/terapia , Recurrencia Local de Neoplasia/prevención & control , Neuroblastoma/terapia , Adolescente , Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Neoplasias del Sistema Nervioso Central/mortalidad , Niño , Preescolar , Terapia Combinada/métodos , Terapia Combinada/mortalidad , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia/mortalidad , Neuroblastoma/mortalidad , Tiotepa/administración & dosificación , Tiotepa/efectos adversos , Topotecan/administración & dosificación , Topotecan/efectos adversos , Insuficiencia del TratamientoRESUMEN
PURPOSE: To describe oncolytic effects of treatment with anti-G(D2) monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with neuroblastoma (NB). PATIENTS AND METHODS: Patients were eligible for 3F8/GM-CSF if intensive therapy had not eradicated potentially lethal NB. One cycle consisted of GM-CSF (subcutaneous bolus) on days 1 through 5, 11, and 12, and GM-CSF (2-hour intravenous [IV] infusion) followed after a 1-hour interval by 3F8 (1.5-hour IV infusion) on days 6 through 10 and 13 through 17. GM-CSF was dosed at 250 microg/m(2)/d on days 1 through 7 and at 500 microg/m(2)/d on days 8 through 17. 3F8 was dosed at 10 mg/m(2)/d (100 mg/m(2)/cycle). 3F8 was given with an opiate and an antihistamine. Patients without progressive disease (PD) or elevated human antimouse antibody titers could be treated again beginning 3 weeks after completion of a cycle. RESULTS: Among 19 patients treated for NB resistant to induction therapy, 12 of 15 had complete remission (CR) of bone marrow (BM) disease, and three others who had less than partial responses achieved prolonged progression-free survival (one remains on study at 21+ months, two had PD at 12 and 17 months). Among patients treated for recurrent NB resistant to retrieval therapy, five of 10 had CR in BM. The 15 patients treated for PD fared poorly, although two had scintigraphic findings suggestive of a short-term response. Side effects were limited to readily manageable pain and, less commonly, rash of short duration; hence, patients were treated as outpatients. CONCLUSION: 3F8/GM-CSF is well tolerated and shows promise for treatment of minimal residual NB in BM.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Médula Ósea/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico , Gangliósidos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Inmunoglobulina G/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Adolescente , Adulto , Anticuerpos Monoclonales de Origen Murino , Citotoxicidad Celular Dependiente de Anticuerpos , Niño , Preescolar , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Infusiones Intravenosas , MasculinoRESUMEN
Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m2 by 30-min intravenous (i.v.) infusion on days -8, -7, -6, -5, -4; thiotepa 300 mg/m2 by 3 h i.v. infusion on days -8, -7, -6; and carboplatin by 4 h i.v. infusion on days -5, -4, -3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min ( approximately 500 mg/m2/day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post-transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carboplatino/administración & dosificación , Neuroblastoma/tratamiento farmacológico , Tiotepa/administración & dosificación , Topotecan/administración & dosificación , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Neuroblastoma/complicaciones , Neuroblastoma/terapia , Radioterapia Adyuvante , Inducción de Remisión , Resultado del TratamientoRESUMEN
PURPOSE: Although positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ((18)F-FDG) has a major impact on the treatment of adult cancer, the reported experience with extracranial tumors of childhood is limited. We describe a role for PET in patients with neuroblastoma (NB). PATIENTS AND METHODS: In 51 patients with high-risk NB, 92 PET scans were part of a staging evaluation that included iodine-123 or iodine-131 metaiodobenzylguanidine (MIBG) scan, bone scan, computed tomography (and/or magnetic resonance imaging), urine catecholamine measurements, and bone marrow (BM) examinations. The minimum number of tests sufficient to detect NB was determined. RESULTS: Of 40 patients who were not in complete remission, only 1 (2.5%) had NB that would have been missed had a staging evaluation been limited to PET and BM studies, and 13 (32.5%) had NB detected by PET but not by BM and urine tests. PET was equal or superior to MIBG scans for identifying NB in soft tissue and extracranial skeletal structures, for revealing small lesions, and for delineating the extent and localizing sites of disease. In 36 evaluations of 22 patients with NB in soft tissue, PET failed to identify only two long-standing MIBG-negative abdominal masses. PET and MIBG scans showed more skeletal lesions than bone scans, but the normally high physiologic brain uptake of FDG blocked PET visualization of cranial vault lesions. Similar to MIBG, FDG skeletal uptake was diffusely increased with extensive or progressing BM disease but faint or absent with minimal or nonprogressing BM disease. CONCLUSION: In the absence or after resolution of cranial vault lesions, and once the primary tumor is resected, PET and BM tests suffice for monitoring NB patients at high risk for progressive disease in soft tissue and bone/BM.
Asunto(s)
Neoplasias Óseas/diagnóstico por imagen , Neuroblastoma/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Tomografía Computarizada de Emisión , 3-Yodobencilguanidina , Adolescente , Adulto , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Niño , Preescolar , Femenino , Fluorodesoxiglucosa F18 , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/secundario , Radiofármacos , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/secundario , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Gangliosicle GD2 is abundant on human neuroblastoma (NB). Monoclonal antibody 3F8 targeted to GD2 may have imaging and therapeutic potential. Antigen-negative clones can escape immune-mediated attack leading to clinical resistance or recurrence. PROCEDURE: Among 95 evaluable patients treated intravenously with 3F8 (94 Stage 4, 1 Stage 3), 66 received nonradiolabeled 3F8, 11 received 131-iodine-labeled-3F8 (8-28 mCi/kg) with autologous bone marrow rescue, and 18 received both forms of treatment. Prior to treatment, 90 patients tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 68), tumor immunohistochemistry (n = 20), or diagnostic radioimmunoscintigraphy (n = 2). RESULTS: Of 62 patients who had refractory or recurrent neuroblastoma following 3F8 treatment, 61 (98%) tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 51) or tumor immunohistochemistry (n = 10). The sole tumor that lost GD2 expression underwent phenotypic transformation into a pheochromocytoma-like tumor. CONCLUSIONS: The persistence of GD2 expression in refractory or recurrent NB suggests that complete antigen loss is an uncommon event and cannot account for treatment failure.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Gangliósidos/análisis , Inmunización Pasiva , Inmunoconjugados/uso terapéutico , Inmunoglobulina G/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Neuroblastoma/terapia , Radioinmunoterapia , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Especificidad de Anticuerpos , Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/inmunología , Trasplante de Médula Ósea , Linaje de la Célula , Preescolar , Terapia Combinada , Resultado Fatal , Femenino , Ganglioneuroblastoma/diagnóstico por imagen , Ganglioneuroblastoma/tratamiento farmacológico , Ganglioneuroblastoma/inmunología , Ganglioneuroblastoma/radioterapia , Ganglioneuroblastoma/terapia , Gangliósidos/inmunología , Humanos , Inmunoglobulina G/inmunología , Masculino , Metástasis de la Neoplasia , Neuroblastoma/inmunología , Neuroblastoma/patología , Neuroblastoma/radioterapia , Radioinmunodetección , Inducción de Remisión , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
BACKGROUND: The N7 protocol for poor-risk neuroblastoma uses dose-intensive chemotherapy (as in N6 protocol [Kushner et al.: J Clin Oncol 12:2607-2613, 1994] but with lower dosing of vincristine) for induction, surgical resection and 2100 cGy hyperfractionated radiotherapy for local control, and for consolidation, targeted radioimmunotherapy with 131I-labeled anti-GD2 3F8 monoclonal antibody and immunotherapy with unlabeled/unmodified 3F8 (400 mg/m2). PROCEDURE: The chemotherapy consists of: cyclophosphamide 70 mg/kg/d x 2 and a 72-hr infusion of doxorubicin 75 mg/m2 plus vincristine 2 mg/m2, for courses 1, 2, 4, and 6; and cisplatin 50 mg/m2/d x 4 and etoposide 200 mg/m2/d x 3, for courses 3, 5, and 7. 131I-3F8 is dosed at 20 mCi/kg, which is myeloablative and therefore necessitates stem-cell support. RESULTS: Of the first 24 consecutive previously untreated patients more than 1 year old at diagnosis, 22 were stage 4 and two were unresectable stage 3 with MYCN amplification. Chemotherapy achieved CR/VGPR in 21 of 24 patients. Twenty patients to date have completed treatment with 131I-3F8, and 15 patients have completed all treatment. With a median follow-up of 19 months, 18 of 24 patients remain progression-free. CONCLUSIONS: Major toxicities were grade 4 myelosuppression and mucositis during chemotherapy, and self-limited pain and urticaria during antibody treatment. Late effects include hearing deficits and hypothyroidism.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoconjugados/uso terapéutico , Inmunoglobulina G/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Neuroblastoma/terapia , Radioinmunoterapia , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Enfermedades de la Médula Ósea/inducido químicamente , Quimioterapia Adyuvante , Niño , Preescolar , Aberraciones Cromosómicas , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Amplificación de Genes , Genes myc , Humanos , Hipotiroidismo/etiología , Inmunización Pasiva , Inmunoconjugados/efectos adversos , Radioisótopos de Yodo/efectos adversos , Proteínas de Neoplasias/sangre , Estadificación de Neoplasias , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/mortalidad , Neuroblastoma/radioterapia , Neuroblastoma/cirugía , Radioinmunoterapia/efectos adversos , Radioterapia Adyuvante , Inducción de Remisión , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% +/- 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% +/- 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for > or = 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neuroblastoma/radioterapia , Preescolar , Fraccionamiento de la Dosis de Radiación , Femenino , Genes myc , Humanos , Lactante , Metástasis Linfática , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/cirugía , Radioterapia Adyuvante , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Attempts to improve outcomes of patients with Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) metastatic to bone/bone marrow (BM) have focused on chemotherapy dose intensification strategies. We now present results achieved with that approach, as carried out at Memorial Sloan-Kettering Cancer Center (MSKCC) and as reported in the literature. PATIENTS AND METHODS: Twenty-one unselected MSKCC patients with newly diagnosed ES/PNET metastatic to bone/BM received the "P6" protocol which includes cycles of cyclophosphamide (4.2 g/m(2))/doxorubicin (75 mg/m(2))/vincristine and cycles of ifosfamide (9 g/m(2))/etoposide (500 mg/m(2)). Patients in complete/very good partial remission (CR/VGPR) after P6 received myeloablative therapy with either total-body irradiation (TBI) (hyperfractionated 15 Gy)/melphalan (180 mg/m(2)) or thiotepa (900 mg/m(2))/carboplatin (1,500 mg/m(2)). We reviewed the literature. RESULTS: Only one MSKCC patient became a long-term event-free survivor; all but one relapse was in a distant site. Initial responses to P6 were CR/VGPR in 19 patients, but eight of them plus two others developed PD while receiving or shortly after completing P6. Eight patients were treated with TBI/melphalan: four relapsed 2 to 7 months after transplantation; two died early of toxicity; one died of pulmonary failure 17 months after transplantation (no evidence of ES/PNET); and one remains in CR at more than 7 years. The three patients treated with thiotepa/carboplatin relapsed 3 to 4 months after transplantation. All reports on large series of unselected patients with ES/PNET metastatic to bone/BM showed similarly unsatisfactory results. Poor outcome was seen with use of active agents for ES/PNET-cyclophosphamide, ifosfamide, doxorubicin, dactinomycin, vincristine, etoposide - at standard dosages for prolonged periods of time and at higher dosages in intensive regimens for short or prolonged periods of time. No improvements in event-free survival rates occurred with successive cooperative group or large single-institutional studies that used increasingly aggressive chemotherapeutic approaches. Inclusion of ifosfamide with or without etoposide made no difference nor did consolidation of remission with myeloablative chemoradiotherapy. Secondary leukemia emerged as a major risk with dose-intensive regimens. CONCLUSION: The MSKCC experience and findings reported in the literature suggest that dose-intensive use of the chemotherapy agents with established activity against ES/PNET is reaching its efficacy and toxicity limits. A major impact on prognosis awaits the development of entirely novel therapies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Médula Ósea/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Tumores Neuroectodérmicos Primitivos/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Médula Ósea/radioterapia , Neoplasias de la Médula Ósea/secundario , Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Niño , Terapia Combinada , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Melfalán/administración & dosificación , Tumores Neuroectodérmicos Primitivos/radioterapia , Tumores Neuroectodérmicos Primitivos/secundario , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/secundario , Tiotepa/administración & dosificación , Vincristina/administración & dosificación , Irradiación Corporal TotalRESUMEN
The curative potential of mAbs in the treatment of patients with metastatic neuroblastoma is increasingly evident. The idiotype network appears to represent one component of a complex mechanism for success with mAb-based immunotherapy. Ongoing strategies to modify or reconstruct mAbs, to engage them with cytokines, or to unite them with T cells open new avenues for harnessing the unique forces of the immune system against some of the most deadly pediatric cancers.
Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia Activa/métodos , Neuroblastoma/tratamiento farmacológico , Niño , Ensayos Clínicos como Asunto , Humanos , Neuroblastoma/inmunologíaRESUMEN
BACKGROUND: The authors assessed key effects of granulocyte-colony stimulating factor (G-CSF) used prophylactically with multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy. To the authors' knowledge, no large study has focused on G-CSF in this setting, yet this kind of treatment has recently become standard for poor risk pediatric solid tumors such as neuroblastoma. PATIENTS AND METHODS. Children with neuroblastoma received cyclophosphamide 140 mg/kg (i.e., 4200 mg/m(2)), doxorubicin 75 mg/m(2), and vincristine (CAV) in cycles 1, 2, 4, and 6 and cisplatin 200 mg/m(2) and etoposide 600 mg/m(2) (P/VP) in cycles 3, 5, and 7. To maximize dose intensity, chemotherapy was begun as soon as the absolute neutrophil count (ANC) was > or = 500/microL and platelet count was > or = 100,000/microL. No cytokines were used during 1990-1994 (control group; n = 28), but G-CSF was used from 1995 to 1998 (G-CSF group; n = 30) at 5 microg/kg/day subcutaneously from 1 day after chemotherapy until the ANC was > or = 500/microL on 2 successive days or was > or = 1000/microL. RESULTS: Each cycle of CAV decreased ANCs to < 200/microL in all 58 patients; recovery to 200/microL and to 500/microL was significantly sooner with G-CSF. In contrast, P/VP did not invariably cause severe neutropenia: similar numbers of patients in each group maintained ANCs > or = 200/microL and > or = 500/microL; recovery to 500/microL (but not to 200/microL) was significantly faster in the G-CSF group. G-CSF had no impact on rates of febrile episodes. Bacterial/fungal infections were slightly less frequent in the G-CSF group with CAV (P = 0.11) but not with P/VP. Dose intensity through cycle 4 was the same in both groups. Beginning with cycle 3, G-CSF patients had slower recovery to platelet counts > or = 100,000/microL. Response rates were similar in the two groups. CONCLUSIONS: With multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy, prophylactic use of G-CSF hastened ANC recovery but did not reduce the incidence of febrile episodes, had little impact on infection rates, did not yield augmented dose intensity, was associated with prolonged thrombocytopenia, and had no effect on response rates of neuroblastoma. The data support more limited use of G-CSF.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Médula Ósea/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Esquema de Medicación , Fiebre/etiología , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Lactante , Neutropenia/etiología , Inducción de Remisión , Trombocitopenia/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: The recommended dosages of topotecan and cyclophosphamide in combination for prior-treated patients-3.75 mg/m(2) and 1,250 mg/m(2) in children, 5 mg/m(2) and 600 mg/m(2) in adults, respectively-are well below those of each agent when used singly. We tested the hypothesis that much higher dosing would meet critical goals of salvage therapy: antitumor effect and a lack of toxicity to key organs, so as not to preclude subsequent consolidative treatments needed for cure. PROCEDURE: Patients with resistant pediatric solid tumors received cyclophosphamide 4,200 mg/m(2) by 48 hr infusion, and topotecan 6 mg/m(2) by 72 hr infusion (HD-Cy/Topo). Mesna and granulocyte colony-stimulating factor were used. Cycles were repeated when neutrophil counts were >1,000/uL and platelet counts were >75,000/uL. RESULTS: Twenty-eight patients, aged 2 to 33 years (median, 14), received one (n = 4), two (n = 15), or > or =3 (n = 9) cycles of HD-Cy/Topo. All patients had previously received > or =6 cycles of other therapy, high-dose alkylator-based chemotherapy, and/or etoposide- and doxorubicin-containing regimens. HD-Cy/Topo was given in an outpatient setting. Profound myelosuppression was the major toxicity, but retreatment was possible by day 28, and preliminary results with peripheral blood stem cell collections showed a sparing effect on hemopoietic stem cells. Mucositis was uncommon. After HD-Cy/Topo, cardiac, renal, hepatic, and pulmonary function remained within the normal range. Partial or minor responses were noted in neuroblastoma, desmoplastic small round-cell tumor, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. CONCLUSIONS: Its antitumor potential and limited toxicity make HD-Cy/Topo an attractive choice for inclusion in aggressive salvage programs aimed at achieving cures of resistant tumors. It may also merit incorporation into frontline treatment protocols.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Recuperativa/métodos , Adolescente , Adulto , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Masculino , Neuroblastoma/tratamiento farmacológico , Proyectos Piloto , Sarcoma/tratamiento farmacológico , Topotecan/administración & dosificaciónRESUMEN
Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Tejido Nervioso/genética , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Proto-Oncogenes , Inhibidores de Topoisomerasa II , Factores de Transcripción , Translocación Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Secuencia de Bases , Southern Blotting , Cromosomas Humanos Par 11 , Cisplatino/efectos adversos , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Etopósido/efectos adversos , Exones , Resultado Fatal , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide/inducido químicamente , Leucemia Mieloide/genética , Masculino , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Reacción en Cadena de la Polimerasa , Factores de Tiempo , Vincristina/efectos adversosRESUMEN
PURPOSE: To evaluate the efficacy of 21 Gy hyperfractionated radiotherapy for local control in conjunction with surgery and intensive systemic therapy for patients with Stage 4 neuroblastoma. METHODS AND MATERIALS: After achieving a partial or complete remission, 47 children, ages 1-10 years, with Stage 4 neuroblastoma were treated on four consecutive institutional protocols (N4-N7) with dose-intensive multi-agent chemotherapy, maximal surgical debulking, and hyperfractionated radiotherapy (1.5 Gy twice a day to 21 Gy). Radiotherapy fields encompassed the initial tumor volume and regional lymph nodes plus a 3-cm margin. This was followed by consolidation with either autologous bone marrow transplantation (N4 and N5) or immunotherapy (N6 and N7). RESULTS: Forty-five of 47 patients had a complete response to surgery and chemotherapy prior to radiotherapy. Five-year actuarial rates of local control, progression-free survival, and overall survival were 84%, 40%, and 45%, respectively. Among 26 patients who relapsed, 1 failed only at the primary site, 22 developed distant metastases exclusively, and 3 had both local and distant failures. There were no acute complications of radiotherapy. CONCLUSION: Hyperfractionated radiotherapy to 21 Gy, in conjunction with dose-intensive systemic therapy and aggressive surgical resection, is well tolerated and is associated with durable local control for most patients with Stage 4 neuroblastoma.
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Neuroblastoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Terapia Combinada , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasia Residual , Neuroblastoma/secundario , Neuroblastoma/cirugíaRESUMEN
Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.
Asunto(s)
Cromosomas Humanos Par 1/genética , Pérdida de Heterocigocidad , Neuroblastoma/genética , Alelos , Biomarcadores de Tumor/genética , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Standard cytogenetic techniques are time-consuming and often not informative with solid tumors. In contrast, the reverse transcriptase-polymerase chain reaction (RT-PCR) is a readily available technique that can rapidly detect tumor-specific chromosomal rearrangements, even in small biopsy specimens. We present cases depicting the importance of including molecular diagnostic studies in the routine evaluation of pediatric solid tumors. PROCEDURE: We used RT-PCR to detect chimeric transcripts specific for major pediatric solid tumors, including peripheral primitive neuroectodermal tumor (pPNET), alveolar rhabdomyosarcoma (ARMS), and desmoplastic small round-cell tumor (DSRCT). We reviewed six recent cases in which the initial diagnosis was changed by the results of RT-PCR. RESULTS: Highly unusual or nonspecific clinical and/or histopathologic findings led to the initial diagnoses of neuroblastoma in three patients and DSRCT, leukemia, and carcinoma in one patient each. The final diagnoses after RT-PCR studies were pPNET in three patients, ARMS in two patients, and DSRCT in one patient. RT-PCR results led to early corrections in the diagnosis in two patients, but four patients received treatment not considered optimal for the neoplasms ultimately diagnosed, including three who, despite presenting with localized tumors that have a >70% cure rate with standard therapy, have died or are dying of disease. CONCLUSIONS: Molecular genetic studies on solid tumors can clarify the diagnosis in seemingly straightforward as well as in overtly problematic cases. These diagnostic distinctions are now critical as disease-specific and risk-directed therapies have emerged.
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Carcinoma/diagnóstico , Leucemia/diagnóstico , Tumores Neuroectodérmicos Primitivos/diagnóstico , Rabdomiosarcoma Alveolar/diagnóstico , Sarcoma de Células Pequeñas/diagnóstico , Translocación Genética/genética , Adolescente , Biomarcadores de Tumor/biosíntesis , Carcinoma/genética , Carcinoma/metabolismo , Niño , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Lactante , Leucemia/genética , Leucemia/metabolismo , Masculino , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/metabolismo , Valor Predictivo de las Pruebas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/metabolismo , Sarcoma de Células Pequeñas/genética , Sarcoma de Células Pequeñas/metabolismoRESUMEN
PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m(2) taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m(2) to 3,935 mg/m(2) (median, 2,300 mg/m(2)). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.
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Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de la Médula Ósea/tratamiento farmacológico , Etopósido/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Administración Oral , Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Médula Ósea/patología , Niño , Preescolar , Esquema de Medicación , Etopósido/efectos adversos , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Neuroblastoma/patología , Resultado del TratamientoRESUMEN
BACKGROUND: As an alternative to high-dose irradiation, limited surgery and low-dose irradiation have been investigated as a means to achieve local control. We retrospectively examined the clinical characteristics, treatment, and outcome for 25 patients with Ewing sarcoma treated with limited surgery and low-dose irradiation. PROCEDURE: The records of 25 patients (age 4-48 years) were reviewed who were treated between 1979 and 1996 at Memorial Sloan-Kettering Cancer Center. At the time of diagnosis, 21 of the 25 patients had prognostically unfavorable tumors including the presence of metastatic disease (n = 12), an axial primary (n = 17), and a tumor measuring greater than 8 cm (n = 18). The primary tumor was completely resected (wide local excision) in 13 patients, incompletely resected (marginal excision) in 7 patients, and biopsied only in the remaining 5 patients. The median dose of irradiation to the primary site was 30 Gy. RESULTS: With a median follow-up of 67 months (range 16-189 months) for the surviving patients, 28% failed distantly, and an additional 28% suffered from the progression of previously established metastatic disease. No patient failed locally. The median overall survival was 43 months. The actuarial overall survival at 5 years was 39% (+/-11%) for all patients and 60% (+/-14%) for patients with localized disease. CONCLUSIONS: Limited surgery and postoperative irradiation are one strategy that promises to balance the goal of achieving local control with the goal of diminishing late effects. Apart from the scenario in which radiation therapy is absolutely unnecessary, low-dose irradiation may be appropriate after considering the risk for local recurrence and overall prognosis.
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Neoplasias Óseas/radioterapia , Sarcoma de Ewing/radioterapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/secundario , Sarcoma de Ewing/cirugía , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Except at diagnosis and relapse, when gross disease is present, histologic evaluation is less sensitive than immunocytology (IC) of bone marrow for detecting metastatic neuroblastoma. We examined whether the chance of a positive IC from a single marrow site was comparable to an IC of pooled marrow from multiple sites. PROCEDURE: We carried out 47 marrow examinations on 29 patients with high-risk neuroblastoma on therapy. Each examination consisted of histologic evaluation of four aspirates and two biopsies (six sites), IC of a 2.5-5-mL heparinized sample from a single site (the right posterior iliac crest; IC-RPIC), as well as IC of 8-10 mL of heparinized marrow pooled from bilateral anterior and bilateral posterior iliac crests (IC-pooled). IC was performed using a panel of monoclonal antibodies specific for ganglioside GD2. RESULTS: The number of GD2-positive tumor cells detected by IC-pooled had a strong linear correlation with that by IC-RPIC (R = 0.91), although IC-pooled detected an average of 3.3 times more GD2-positive cells. Of 47 examinations, 15 tested positive by histology (6 sites), 20 by IC- pooled, and 17 by IC-RPIC. Among 29 patients, the level of agreement between IC-RPIC and IC-pooled was generally good (kappa statistic > or = 0.72), giving a false negative rate of < or = 30%. CONCLUSIONS: Compared to conventional histologic examinations, immunocytology of a single marrow aspirate generally agrees with that of marrow pooled from six sites. However, the false negative rate may be too high in the setting of examination prior to bone marrow or stem cell harvest.
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Neoplasias de la Médula Ósea/química , Neoplasias de la Médula Ósea/patología , Médula Ósea/patología , Neuroblastoma/química , Neuroblastoma/patología , Anticuerpos Monoclonales/química , Biopsia con Aguja , Médula Ósea/química , Técnica del Anticuerpo Fluorescente , Gangliósidos/inmunología , Humanos , InmunohistoquímicaRESUMEN
BACKGROUND: The identification of recently described nonrandom chromosomal defects specific for various small round-cell and spindle-cell sarcomas can eliminate diagnostic uncertainty arising from the clinical and histopathologic overlap of soft tissue neoplasms. METHODS: A 26-year-old man presented with bulky abdominal-pelvic disease. Immunohistochemical and molecular studies on tumor were performed. Treatment was instituted using cycles of high-dose cyclophosphamide (4,200 mg/m2) with doxorubicin (75 mg/m2). RESULTS: Clinical findings pointed to desmoplastic small round-cell tumor. The tumor was histologically undifferentiated and immunoreactive for vimentin but negative for other markers. Reverse transcriptase-polymerase chain reaction revealed the SYT/SSX2 fusion transcript of the synovial sarcoma t(X;18) chromosomal rearrangement. The high-dose chemotherapy, plus surgery, achieved a complete remission, but recurrent disease emerged 13 months from diagnosis. CONCLUSIONS: This clinically unique case of synovial sarcoma highlights how the use of now readily available molecular techniques will allow more accurate appraisals of the incidence and anatomic distribution of soft tissue neoplasms-information that bears upon pathogenesis and treatment. This case confirms the utility of high-dose alkylator-based therapy for synovial sarcoma. It also demonstrates that with nonlocalized solid tumors, the eradication of minimal residual disease remains an elusive goal. One alternative involves immunologic attack against markers derived from tumor-specific chromosomal defects such as those found in our patient.