RESUMEN
Different chemotherapy drugs are generally introduced in clinical practices combining with therapy for glioma treatment. However, these chemotherapy drugs have rarely been compared with each other and the optimum drug still remains to be proved. In this research, medical databases were consulted, PubMed, Embase and Cochrane Library included. As primary outcomes, hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with their corresponding 95% credential intervals (CrI) were reported. A network meta-analysis was conducted; the surface under the cumulative ranking curve (SUCRA) was utilized for treatment rank and a cluster analysis based on SUCRA values was performed. This research includes 14 trials with 3,681 subjects and eight interventions. In terms of network meta-analysis, placebo was proved to be inferior to the combination of temozolomide (TMZ), nimustine (ACNU) and cisplatin (CDDP). Also, bevacizumab (BEV) in conjunction with TMZ were significantly more effective than placebo with an HR of 0.40. The estimated probabilities from SUCRA verified the above outcomes, confirming that the combination of TMZ, ACNU and CDDP exhibited the highest ranking probability of 0.889 with respect to OS, while BEV in combination with TMZ - with a probability of 0.772 - ranked the first place with respect to PFS. According to the results of this network meta-analysis, the combination of (1) TMZ, ACNU and CDDP; (2) BEV in combination with TMZ and (3) cilengitide in combination with TMZ, are considered as the preferable choices of chemotherapy drugs for glioma treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Quimioradioterapia , Glioma/terapia , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Teorema de Bayes , Bevacizumab/administración & dosificación , Neoplasias Encefálicas/mortalidad , Cisplatino/administración & dosificación , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Eflornitina/administración & dosificación , Glioma/mortalidad , Humanos , Mitolactol/administración & dosificación , Metaanálisis en Red , Nimustina/administración & dosificación , Probabilidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Venenos de Serpiente/administración & dosificación , Temozolomida , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: In a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients. METHODS: Continuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point. RESULTS: Patients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n=99), or to RT plus DBD/BCNU (n=94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p=0.111) and PFS (p=0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4-34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4-46.8]. CONCLUSION: No statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Adulto , Anciano , Astrocitoma/radioterapia , Carmustina/administración & dosificación , Carmustina/efectos adversos , Quimioterapia Adyuvante , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mitolactol/administración & dosificación , Mitolactol/efectos adversos , Insuficiencia del TratamientoRESUMEN
Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclosporina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Niño , Preescolar , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lactante , Cariotipificación , Recuento de Leucocitos , Masculino , Mitolactol/administración & dosificación , Inducción de Remisión , Análisis de Supervivencia , Tamoxifeno/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: This prospective semi-randomized study was undertaken to assess the effects and effectiveness of alkylating drugs in a preoperative setting. PATIENTS AND METHODS: During a 6-year period preceding February 2000, 80 patients with Stage II-IVa (AJCC 2002) squamous cell cancer of the oral cavity were treated. Thirty patients (Group N) received a combination of bleomycin, vincristine and methotrexate (BVM). In the alkylating group, thirty patients (Group A/M) received BVM and mitolactol (dibromodulcitol), while twenty patients (Group A/C) received BVM and cisplatin. Patients underwent surgery within 3 weeks after chemotherapy. Clinical response rate and tumour-free survival were investigated. RESULTS: Clinical complete response was 30%-36% (Group N-A). Partial response was 57%-56% (Group N-A). Side-effects were moderate and reversible. Nausea, anaemia and leucopenia were observed in the alkylating (A) group, while other side-effects (alopecia, mucositis, gastritis) were similar in both groups. The observation time was 36 months. Regional disease-free survival showed a significant difference, favouring the non-alkylating (N) group (p=0.03). A higher metastasis rate was observed in the alkylating (A) group. CONCLUSION: Cisplatin and mitolactol in combination with BVM showed higher local control and lower disease-free survival than BVM alone. That was mostly due to a higher rate of regional metastatis formation in the alkylating-treated patients. This may be a late side-effect caused by the immunosuppressive and myelosuppressive effect of alkylating agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Orofaríngeas/tratamiento farmacológico , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Mitolactol/administración & dosificación , Mitolactol/efectos adversos , Estudios Prospectivos , Insuficiencia del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
Our aim was to investigate the effect of BCNU and DBD combined chemotherapy in patients with recurrent malignant gliomas. Forty-six patients were treated with combined chemotherapy. Out of 26 patients with anaplastic astrocytomas 11 were originally low-grade where no postoperative radiotherapy was applied. Fifteen patients with anaplastic astrocytoma responded well to the chemotherapy and 9 survived longer than one year. Median survival time was 14 months. Complete response of recurrent glioblastoma did not occur and only 4 patients survived longer than one year. Median survival time was 7 months. Ratio of patients with response and stable disease was 70 and 55 %, respectively. BCNU and DBD combination proved to be an effective combination for recurrent malignant gliomas. It was remarkable that patients' survival with primary or secondary lower grade astrocytoma were significantly longer than that in patients with glioblastomas. Treatment of lower grade tumors, even at their malignant recurrences is promising.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/administración & dosificación , Glioblastoma/tratamiento farmacológico , Mitolactol/administración & dosificación , Adulto , Anciano , Astrocitoma/mortalidad , Astrocitoma/secundario , Astrocitoma/cirugía , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/cirugía , Femenino , Glioblastoma/mortalidad , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
At the Hungarian National Institute of Neurosurgery 73 recurrent supratentorial malignant tumours were treated by chemotherapy during the last ten years. Chemotherapy was applied after postoperative radiotherapy but in some cases following reoperation only. All cases were clinically and by CT or MRI verified recurrences. Forty-three patients received BCNU-DBD (dibromodulcitol) treatment (23 anaplastic astrocytoma--AA, and 20 glioblastoma multiforme--GM): day 1. BCNU 150 mg/sq.m. in i.v. infusion, day 2. dibromdulcitol 1000 mg/sq orally was given. This course was repeated every six weeks, altogether 2-8 times. Sixteen patients with AA responded with complete or partial regression but only 6 did with GM. Median survival was 14 and 7 months, the difference proved to be significant, p = 0.0091. PCV combination (procarbazine, CCNU, vincristine) was applied to 16 patients with AA and 14 cases with recurrent oligodendroglioma (O). Treatment started with vincristine 1.5 mg/sq.m. i.v. (2.0 mg maximum), the next day CCNU 100 mg/sq.m. was given, followed by procarbazine 60 mg/sq.m. on days 8-22. and finished by the same dose of vincristine on day 30. The course was repeated after one month, mostly six times. Six patients with AA did not respond; in cases of oligodendroglioma all but one responded with complete or partial improvement. It is remarkable that no significant difference was found between the survivals of BCNU-DBD or PCV treated AA patients. Chemotherapy of supratentorial malignant glioma recurrences with nitroso-ureas and their combination proved to be efficacious. It also seems, that in recurrent cases lower grade gliomas show better response rate than glioblastomas.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Neoplasias Supratentoriales/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Astrocitoma/radioterapia , Astrocitoma/cirugía , Carmustina/administración & dosificación , Quimioterapia Adyuvante , Esquema de Medicación , Femenino , Glioblastoma/radioterapia , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Mitolactol/administración & dosificación , Recurrencia Local de Neoplasia , Procarbazina/administración & dosificación , Radioterapia Adyuvante , Reoperación , Neoplasias Supratentoriales/patología , Neoplasias Supratentoriales/radioterapia , Neoplasias Supratentoriales/cirugía , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
In recent years, there has been a dramatic increase in the number of tumors of the head and neck. Their successful treatment is one of the greatest challenges for physicians dealing with oncotherapy. An organic part of the complex therapy is preoperative or postoperative irradiation. Application of this is accompanied by a lower risk of recurrences, and by a higher proportion of cured patients. Unfortunately, irradiation also has a disadvantage: the development of osteoradionecrosis, a special form of osteomyelitis, in some patients (mainly in those cases where irradiation occurs after bone resection or after partial removal of the periosteum). Once the clinical picture of this irradiation complication has developed, its treatment is very difficult. A significant result or complete freedom from complaints can be attained only rarely. Attention must therefore be focussed primarily on prevention, and the oral surgeon, the oncoradiologist and the patient too can all do much to help prevent the occurrence of osteoradionecrosis. Through coupling of an up-to-date, functional surgical attitude with knowledge relating to modern radiology and radiation physics, the way may be opened to forestall this complication that is so difficult to cure.
Asunto(s)
Enfermedades Maxilomandibulares/prevención & control , Neoplasias de la Boca/radioterapia , Osteorradionecrosis/prevención & control , Radioterapia/efectos adversos , Enfermedades Dentales/prevención & control , Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Cisplatino/administración & dosificación , Terapia Combinada , Fístula Cutánea/etiología , Fístula/etiología , Humanos , Maxilares/diagnóstico por imagen , Maxilares/patología , Maxilares/efectos de la radiación , Enfermedades Maxilomandibulares/etiología , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Mitolactol/administración & dosificación , Higiene Bucal , Procedimientos Quirúrgicos Ortognáticos , Osteotomía , Complicaciones Posoperatorias , Premedicación , Teleterapia por Radioisótopo/efectos adversos , Teleterapia por Radioisótopo/métodos , Dispersión de Radiación , Cirugía Plástica , Colgajos Quirúrgicos , Tomografía Computarizada por Rayos X , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/radioterapia , Neoplasias de la Lengua/cirugía , Enfermedades Dentales/etiología , Extracción Dental , Vincristina/administración & dosificación , Cicatrización de HeridasRESUMEN
OBJECTIVE: To study the results of combination chemotherapy of uterine sarcoma after operation and recurrent tumor. METHODS: One hundred seventy-four cases of three major pathological subtypes of uterine sarcomas were treated in the Cancer Hospital from 1960 to 1996. Clinical data were analyzed of 51 cases of uterine sarcomas treated with postoperative adjuvant chemotherapy and 38 cases with recurrent tumors received 98 courses of chemotherapy. They were divided into 4 groups according to the adjuvant chemotherapy regimen: single drug, VAC, VAD, and other regimens. Chemotherapy regimens for recurrent tumors were VAD, PA/PAC, and other combination regimens including etoposide, ifosfamide, cisplatin, adriamycin. RESULTS: The 5-year survival rate of stage I-II uterine sarcoma patients was 54.9% receiving adjuvant chemotherapy. It was 72.7% in VAD group which was significantly higher than that in other regimen groups. The survival rate was related to the number of chemotherapy course. The chemo-sensitivity of various pathological types of recurrent uterine sarcomas was not different. CONCLUSION: The 5-year survival rate does not improve in patients with stage I-II uterine sarcomas given postoperative chemotherapy. VAD is among the best regimens and at least 3 courses should be performed. The results of new treatment regimens such as EPA, IA, etc., must await further clinical observation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia Adyuvante , Doxorrubicina/administración & dosificación , Quimioterapia Combinada , Femenino , Humanos , Mitolactol/administración & dosificación , Mitomicinas/administración & dosificación , Recurrencia Local de Neoplasia/mortalidad , Periodo Posoperatorio , Estudios Retrospectivos , Sarcoma/mortalidad , Tasa de Supervivencia , Neoplasias Uterinas/mortalidadRESUMEN
We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Glioma/tratamiento farmacológico , Glioma/radioterapia , Lomustina/uso terapéutico , Mitolactol/uso terapéutico , Procarbazina/uso terapéutico , Tioguanina/uso terapéutico , Vincristina/uso terapéutico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Lomustina/administración & dosificación , Masculino , Mitolactol/administración & dosificación , Procarbazina/administración & dosificación , Análisis de Supervivencia , Tioguanina/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.
Asunto(s)
Antimetabolitos Antineoplásicos/sangre , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/tratamiento farmacológico , Etopósido/farmacología , Meduloblastoma/sangre , Meduloblastoma/tratamiento farmacológico , Metotrexato/sangre , Adolescente , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Neoplasias Encefálicas/radioterapia , Niño , Cisplatino/administración & dosificación , Terapia Combinada , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Etopósido/administración & dosificación , Etopósido/sangre , Humanos , Leucovorina/administración & dosificación , Meduloblastoma/radioterapia , Metotrexato/administración & dosificación , Mitolactol/administración & dosificación , Procarbazina/administración & dosificaciónRESUMEN
Twenty six (17 males) patients with glioblastoma (GBL), median age 55 years, median Karnofsky Index (KI) 70/100, and 11 patients (9 males) with anaplastic astrocytoma (AA), median age 56 years, median KI 70/100 were treated at recurrence with dibromodulcitol (DBD) 1400 mg/m2 on day 1, BCNU 150 mg/m2 on day 2, and procarbazine (PCZ) 150 mg/day on days 1 to 15. The course was repeated every 4 weeks, but was delayed or decreased by 25% according to hematological toxicity. Response to treatment was evaluated by the criteria of MacDonald et al. (J Clin Oncol 1990; 8: 1277-1280). All GBL-patients were followed until death. One patient with complete response (CR) survived one year, and 2 patients with partial response (PR) survived 1 and 3 years. Ten patients who stabilized (SD) survived 7.5 months, and 13 patients who progressed under chemotherapy had a median survival of 3.5 months. In AA-group 3 patients were alive at the time of the analyses. Six patients: 1 CR and 5 PR survived 6 to 40+ months. Two patients with SD survived 4 and 14 months. Three patients with progressive disease had a mean survived of less than 3 months. The response rate of 55% in AA was significantly higher (p = 0.011) than the 12% response rate seen in GBL. We conclude that the regimen tested appears particularly promising in AA. The results in GBL are comparable to those obtained with a single nitrosourea, despite an increased but reversible toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carmustina/administración & dosificación , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Mitolactol/administración & dosificación , Recurrencia Local de Neoplasia , Procarbazina/administración & dosificación , Análisis de SupervivenciaRESUMEN
Patients who have metastatic breast cancer are seldom curable. Chemotherapy given by conventional doses and schedules generally produces complete remissions in 10% to 20% of patients. This study sought to determine 1) whether a combination of dibromodulcitol, Adriamycin, vincristine, tamoxifen, Halotestin, and methotrexate with leucovorin rescue (DAVTHML) can produce a complete remission rate of 50%; and 2) the toxicity of this combination in patients with chemotherapy-naive metastatic breast cancer. Patients were treated with six 28-day cycles of DAVTHML induction chemotherapy consisting of dibromodulcitol, 135 mg/m2 perorally days 1 to 10; Adriamycin 45 mg/m2 intravenously day 1; vincristine, 2 mg intravenously day 1; tamoxifen and Halotestin, 20 mg perorally daily; methotrexate, 800 mg/m2 intravenously days 15 and 22; and leucovorin, 15 mg/m2 perorally every 6 hours for 9 doses, starting 4 hours after methotrexate. After induction, patients who had stable disease or a partial response were treated with a cyclophosphamide, methotrexate, and 5-fluorouracil-based regimen (CMF). Patients in complete remission were treated with three additional cycles of DAVTHML after achieving complete remission and then observed off therapy until relapse, when DAVTHML was to be given again. Fifty-eight patients were included in this study. During induction, 26% of eligible patients experienced a complete remission; overall response rate was 80%. The median time to treatment failure and the median survival time of eligible patients was 11.1 and 24.0 months, respectively. This did not change significantly when all the patients were included in the evaluation. The 3-year and 5-year survival rates were 37% and 11%, respectively. Ninety percent of the eligible patients experienced grade III or IV toxicity. They were leukopenia (75%), anemia (20%), thrombocytopenia (20%), and vomiting (17%). No lethal toxicity was documented during therapy; however, 1 patient later died of myelodysplastic syndrome induced by dibromodulcitol. The overall response and complete remission rates from our study were encouraging. The toxicity of DAVTHML was tolerable, with the exception of myelodysplastic syndrome from dibromodulcitol. The concept of using mid-cycle nonmyelosuppressant agents to increase complete remission rate is feasible.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Doxorrubicina/administración & dosificación , Femenino , Fluoximesterona/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Mitolactol/administración & dosificación , Metástasis de la Neoplasia , Proyectos Piloto , Inducción de Remisión , Análisis de Supervivencia , Tamoxifeno/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
Between March 9, 1984 and January 29, 1992, 42 children with newly diagnosed symptomatic or previously diagnosed progressive low-grade gliomas received outpatient chemotherapy as their primary treatment. This study was a single arm, phase II trial designed to estimate the time to tumor progression and toxicity of this regimen. Procarbazine, 6-thioguanine, and dibromodulcitol were given before lomustine (CCNU) and vincristine was given 1 and 3 weeks after CCNU. Patients were treated for six treatment cycles or until the tumor progressed, whichever came first. Twenty-three patients had juvenile pilocytic astrocytomas, 11 had astrocytomas, one had oligodendroglioma, one had ganglioglioma, and six had radiographically diagnosed low-grade gliomas. The mean age of the patients was 5 years (median, 3 years). The median time to treatment failure was 132 weeks (95% confidence interval: 106, 186 weeks). Only eight patients have died the estimated 5-year survival rate is 78% (95% confidence interval, 60% 87%). There were two episodes of grade 4 neutropenia, and three episodes of grade 4 thrombocytopenia. This regimen was safe, able to be delivered in the outpatient setting, and produced prolonged periods of disease stabilization in children with low-grade gliomas.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Glioma/mortalidad , Humanos , Lactante , Lomustina/administración & dosificación , Lomustina/efectos adversos , Masculino , Mitolactol/administración & dosificación , Mitolactol/efectos adversos , Procarbazina/administración & dosificación , Procarbazina/efectos adversos , Tioguanina/administración & dosificación , Tioguanina/efectos adversos , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
PURPOSE: To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of CCNU, in the treatment of recurrent metastatic brain tumors. PATIENTS AND METHODS: One hundred fifteen patients with progressive or recurrent metastatic brain tumors that failed to respond to surgery and/or radiation therapy were enrolled onto a multicenter prospective study between 1989 and 1995. Patients received TPDC-FuHu in a repeated cycle every 6 weeks until recurrence or until they completed six courses. RESULTS: Ninety-seven patients were assessable at the end of the study. Forty-eight had lung cancer (39 non-small-cell [NSCLC] and nine small-cell [SCLC]), 28 had breast cancer, nine had melanoma, and 12 had adenocarcinoma of different origins (three colon, two kidney, one bladder, one stomach, and five of unknown origin). The response and stable disease (SD) rate (overall response rate) was 52%, 66%, 60%, and 22% in patients with NSCLC, SCLC, breast cancer, and melanoma, respectively. Median time to progression (MTP) was 12, 26, 12, and 6 weeks, respectively, for the four groups. Side effects were mild to moderate in the majority of patients. Severe myelosuppression (grade 4) occurred in only 11% of the patients. CONCLUSION: TPDC-FuHu chemotherapy is an active treatment against recurrent brain metastases from breast cancer and SCLC, and to a lesser extent from NSCLC. This regimen is well tolerated and has acceptable toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Factores de Edad , Anciano , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/secundario , Progresión de la Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Hidroxiurea/administración & dosificación , Lomustina/administración & dosificación , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mitolactol/administración & dosificación , Procarbazina/administración & dosificación , Estudios Prospectivos , Tioguanina/administración & dosificaciónRESUMEN
PURPOSE: Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone. PATIENTS AND METHODS: Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival. RESULTS: CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05). CONCLUSION: CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Femenino , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Persona de Mediana Edad , Mitolactol/administración & dosificación , Mitolactol/efectos adversos , Estudios Prospectivos , Inducción de Remisión , Análisis de Supervivencia , Neoplasias del Cuello Uterino/patologíaRESUMEN
From January 1976, 50 patients with squamous cell cancer of the head and neck were treated with telecobalt preoperative irradiation followed by appropriate surgery. Another group of 50 patients, who matched in risk factors and stage of disease, were treated with preoperative chemotherapy and surgery. Chemotherapy consisted of bleomycin, vincristine, mitolactol and methotrexate. All patients received 3 courses. Surgery was performed 2-3 weeks post-chemotherapy or 4-6 weeks postradiotherapy. Forty-four percent of the patients in the radiotherapy group showed recurrences, while 30% of the patients had recurrence in the chemotherapy group. The overall 3-year survival rate was 66% in the chemotherapy group and 57% in the radiation therapy group, with no statistical difference.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Carcinoma de Células Escamosas/cirugía , Terapia Combinada , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Mitolactol/administración & dosificación , Neoplasias de la Boca/cirugía , Cuidados Preoperatorios , Vincristina/administración & dosificaciónRESUMEN
The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/farmacología , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Leucemia P388/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Mitolactol/farmacología , Animales , Peso Corporal/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Cisplatino/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Leucemia P388/genética , Masculino , Melanoma/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Mitolactol/administración & dosificación , Mitolactol/farmacocinética , Mitolactol/toxicidad , Metástasis de la Neoplasia , Trasplante de Neoplasias , Células Tumorales CultivadasRESUMEN
Systemic pharmacokinetics of high dose (500 mg/m2), orally administered Elobromol (dibromodulcitol, DBD) were studied in 16 chemotherapeutic courses administered to five patients. Cerebrospinal fluid (CSF) DBD levels were also analyzed in two patients. Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD. The HPLC method, developed by our team, is suitable for the determination of both DBD and its main metabolites (DAD and BAD). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexitol derivatives in pediatric patients. With the exception of one patient, concentration time curves were analyzed by the one-compartment model. From 30 min following administration, DBD was detectable in all plasma samples for at least 12 h; its concentration, however, was usually undetectable by 24 h. Though highly variable in value, DAD concentrations were detectable during all but one of the therapeutic courses. The following peak concentrations were observed: DBD = 3.46-30.63 microM, DAD = 1.70-6.17 microM and BAD = 0-5.63 microM. The correlation of AUCBAD and AUCDBD values were exponential up to 200 microM h with no additional increase detectable above this limit: the distribution of AUCBAD and AUCDBD was described by a maximum curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives was detectable in CSF even if the concentration of the individual metabolite remained undetectable in plasma. DBD CSF concentrations were almost constant in the period from 2.5 to 8 h following administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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Neoplasias Encefálicas/metabolismo , Meduloblastoma/metabolismo , Mitolactol/farmacocinética , Envejecimiento/metabolismo , Biotransformación , Neoplasias Encefálicas/tratamiento farmacológico , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Circulación Enterohepática/fisiología , Femenino , Semivida , Humanos , Meduloblastoma/tratamiento farmacológico , Mitolactol/administración & dosificaciónRESUMEN
OBJECTIVE: We tested adjuvant chemotherapy combining dibromodulcitol (DBD) and bischloroethylnitrosourea (BCNU) given postoperatively to adults with newly diagnosed supratentorial malignant gliomas. METHODS: We enrolled 269 patients, 255 of whom were eligible. After surgery, we treated all patients with radiation therapy, using a median dose of 60 Gy given in 30 fractions. After randomization, patients in the chemotherapy group also received (1) six weekly courses, administered during irradiation, of DBD 700 mg/m2 and (2) one to nine (median, four) courses, administered during the first year following radiation therapy, of DBD 1,000 mg/m2 on day 1 and BCNU 150 mg/m2 on day 2, with the course being repeated every 6 weeks. RESULTS: Patients treated with radiation therapy along with DBD plus BCNU (group 2) had significantly longer survival time (p = 0.044) and time to progression (p = 0.003) than did those treated with radiation therapy alone (group 1). The median survival time was 13.0 months for group 2 and 10.4 months for group 1; the median time to progression was 8.1 months for group 2 and 6.7 months for group 1. The percentage of patients alive at 18 and 24 months was 34% and 21% in group 2 compared with 21% and 12% in group 1. CONCLUSION: DBD plus BCNU is an effective adjuvant therapy for malignant glioma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Glioma/tratamiento farmacológico , Glioma/mortalidad , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carmustina/administración & dosificación , Quimioterapia Adyuvante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitolactol/administración & dosificación , Análisis de SupervivenciaRESUMEN
PURPOSE: To investigate the therapeutic value of reinduction with the same cytostatic treatment that had been used in induction treatment for women with metastatic breast cancer. MATERIALS AND METHODS: One hundred six women with metastatic breast cancer were given dibromodulcitol (mitolactol), doxorubicin, vincristine, tamoxifen, and fluoxymesterone (DAVTH) for 6 months of induction treatment, then randomized to receive one of two chemotherapy regimens if they had obtained an induction partial response (PR) or no change (NC), or to receive observation versus chemotherapy if they had obtained an induction complete response (CR). Patients were then retreated with DAVTH reinduction after relapse. RESULTS: Seventy-four patients were eligible or had minor reasons for ineligibility. Severe or life-threatening toxicity was documented in 46%, and lethal toxicity in 4%. Eighteen percent had a response on reinduction (zero of 16 induction nonresponders, 15% induction PR, 44% induction CR). The median time to treatment failure (TTF) from reinduction was 3 months, and the median survival duration from reinduction was 14 months. In a logistic model, factors associated with more reinduction responses were observation after induction CR (P = .002) and age greater than 55 years (P = .04). Time since induction was not significant. CONCLUSION: Reinduction of response after treatment failure remains a therapeutic problem. The need for better salvage treatment underlines the importance of developing new regimens.