RESUMO
Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antibióticos Antineoplásicos/uso terapêutico , Ciclosporinas/uso terapêutico , Doxorrubicina/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Ciclosporinas/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , LipossomosRESUMO
BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Camptotecina/análogos & derivados , Desoxicitidina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biópsia por Agulha , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias/mortalidade , Neoplasias/patologia , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: We evaluated the impact of treatment modality on esthesioneuroblastoma. METHODS: Between 1976 and 1996, 25 patients with esthesioneuroblastoma were treated at Mallinckrodt Institute of Radiology. There were 11 male and 14 female patients; their ages ranged from 16 to 73 years (median, 57 years). The tumors were Kadish stage A in 3, Stage B in 13, C in 8, and modified D in 1 (cervical nodal metastasis). Seventeen patients were treated with surgery and radiation therapy, six were treated with irradiation alone, and two were treated with surgery only. Eight patients received neoadjuvant chemotherapy. Median follow-up was 8 years (range, 2-24 years). RESULTS: The 5-year actuarial overall survival, disease-free survival, and local tumor control rates were 66.3%, 56.3%, and 73.0%, respectively. Kadish stage was not a significant prognosticator for local control or disease-free survival. Five-year local control rates were 87.4% for the combination of surgery and radiation therapy and 51.2% for irradiation alone. Two patients with Kadish stage A and B disease underwent surgical resection alone; both failed locally. In contrast, 33.3% of patients (three of nine) with Kadish stage A or B disease who received adjuvant radiation therapy had a local recurrence develop. With adjuvant radiation therapy, the surgical margin status did not influence local tumor control. Among the eight patients who received neoadjuvant chemotherapy, six patients showed no response, one had partial response, and one showed a complete response. CONCLUSIONS: Surgical resection plus adjuvant radiation therapy yielded the best treatment outcome. More effective chemotherapy agents with a reproducible effectiveness are needed for patients with locally advanced esthesioneuroblastoma.
Assuntos
Estesioneuroblastoma Olfatório/terapia , Cavidade Nasal , Neoplasias Nasais/terapia , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Estesioneuroblastoma Olfatório/patologia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/patologia , Estadiamento de Neoplasias/métodos , Neoplasias Nasais/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: In a phase II trial of paclitaxel, cisplatin, and fluorouracil in metastatic esophageal cancer, we identified significant activity for the combination of agents, but there was severe associated toxicity. We therefore undertook a phase II trial of paclitaxel and cisplatin without fluorouracil. PATIENTS AND METHODS: Thirty-eight patients with carcinoma of the esophagus or gastroesophageal junction were treated. No patient who underwent prior chemotherapy was allowed to take part in the study. The majority (33 patients) had adenocarcinoma, and most (36 patients, 95%) had metastatic disease. Paclitaxel, 200 to 250 mg/m2, was given by 24-hour infusion on day 1, followed by cisplatin, 75 mg/m2, on day 2, with granulocyte colony stimulating factor support. Treatment was cycled every 21 days in the outpatient setting. The first 16 patients received paclitaxel at 250 mg/m2, but because of toxicity and treatment-related deaths, the dose was reduced to 200 mg/m2. RESULTS: Thirty-two patients were evaluable for response. Six patients were evaluated for toxicity after receiving only one cycle (due to toxicity or treatment-related death). Partial responses were seen in 14 patients (44%); responses occurred in 13/28 patients with adenocarcinoma (46%) and in one of four patients with squamous carcinoma (25%). Median duration of response was 3.9 months, and median survival was 6.9 months. Of twenty-five patients with dysphagia before therapy, eighteen patients (72%) had complete resolution of dysphagia, and two (8%) had partial resolution. Toxicity included grade 3/4 fatigue in 35% of patients and grade 4 neutropenia in 47% of patients. Nineteen patients (50%) required hospitalization for toxicity, and four patients (11%) died from therapy-related complications. CONCLUSION: The combination of paclitaxel and cisplatin has significant activity in esophageal adenocarcinoma. Because of hospitalization for toxicity and deaths resulting from treatment, the combination of paclitaxel and cisplatin used in this trial cannot be recommended. The optimal dose and schedule of paclitaxel/cisplatin combination therapy remain to be established.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Paclitaxel/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Cisplatino/toxicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/toxicidade , Fatores de TempoRESUMO
The Hoosier Oncology Group conducted a trial evaluating ifosfamide in patients who had recurrent or metastatic squamous cell carcinoma of the head and neck. Patients must have received no prior chemotherapy for metastatic disease. If prior adjuvant chemotherapy was given, the last cycle must have been at least six months from time of recurrence. All patients were required to have a Karnofsky performance status of > or = 50. Twenty-four patients received treatment consisting of ifosfamide, 1.5 g/m2/day for 5 days, with cycles repeated every 3 weeks. Mesna, 300 mg/m2, was administered intravenously 15 minutes before ifosfamide and 4 and 8 hours after ifosfamide on days 1 through 5. Toxicity was predominantly hematologic, with grade 3--4 neutropenia seen in 13 patients resulting in 4 episodes of neutropenic fever. One partial response was seen in 23 evaluable patients for an overall response rate of 4.3% (95% confidence interval, 0, 12.7%). In conclusion, ifosfamide would appear to have limited single-agent activity in squamous cell carcinoma of the head and neck.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Ifosfamida/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
We demonstrated in an earlier trial that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has substantial antineoplastic activity, with acceptable toxicity, in patients with advanced metastatic esophageal cancer. Preclinical and clinical data from studies in other tumors indicate substantial additive or even synergistic activity for paclitaxel/cisplatin combination chemotherapy. We encountered substantial toxicity with a cisplatin/paclitaxel/5-fluorouracil combination. To maximize paclitaxel dose, we initiated a phase II trial using cisplatin and paclitaxel alone. This report summarizes preliminary data from that trial. Paclitaxel 200 mg/m2 is given as a continuous, 24-hour infusion on day 1. On day 2, cisplatin 75 mg/m2 is given. Courses are repeated every 21 days. Dose adjustments are based on myelosuppression, neurotoxicity, and (for cisplatin) renal or auditory toxicity. All patients receive recombinant human granulocyte colony-stimulating factor to minimize the risk of neutropenic fever. The primary end point of the study is tumor regression. Secondary end points include duration of response and toxicity. Two groups of patients are being studied. Those with advanced metastatic disease receive chemotherapy alone as palliative treatment. The second group has locoregional disease that is potentially resectable. These patients receive combined-modality therapy involving induction paclitaxel/cisplatin chemotherapy followed by surgery. To date, 37 evaluable patients have been treated. Twenty had advanced metastatic disease and 17 were treated before planned surgery. Twenty-seven patients had adenocarcinoma and 10 had epidermoid carcinoma. Major objective responses were seen in 49% of all patients, with similar response rates for patients with metastatic and locoregional disease. The median duration of response for patients with metastases is 4+ months. Among 14 patients treated before surgery, one experienced a complete pathologic response, and the neoplasms of 43% were downstaged. Primary toxicity was neutropenia, which was tolerable. Surgical morbidity or mortality did not increase. Cisplatin plus paclitaxel is an active combination in the treatment of patients with advanced or locoregional esophageal cancer. Further studies with this combination both in metastatic and locally advanced disease are indicated.