RESUMEN
Patients with non-Hodgkin's lymphoma (NHL) recurrent after chemotherapy exhibit clinical characteristics compatible with the phenomenon of multidrug resistance (MDR) and frequently have detectable levels of P-glycoprotein (P-gp). Paclitaxel has been used in recurrent NHL with limited success. To test whether clinical resistance to paclitaxel can be reversed, we treated patients having paclitaxel-resistant NHL with paclitaxel plus quinine and measured the effects of quinine on paclitaxel pharmacokinetics. Eligible patients had recurrent and measurable NHL. Patients initially received paclitaxel, 120 mg/m2 (dose determined by a phase I trial of paclitaxel plus quinine), as a 20-24 h infusion every 3 weeks until there was evidence of clinical resistance. Patients then received paclitaxel at the same dose rate plus oral quinine at a fixed dose rate of 400 mg three times each day. Paclitaxel pharmacokinetics were studied in each patient using paired samples from plasma obtained at the end of the 24 h paclitaxel infusion as an estimate of the steady-state drug level. Of 14 patients treated with paclitaxel alone, one patient obtained a partial response (7%). At the time of disease progression, one patient (same patient) obtained a partial response with paclitaxel plus quinine (7%). Steady-state paclitaxel levels were obtained in 12 patients. In 11 of 12 patients the steady-state paclitaxel level was substantially lower with the addition of quinine. The average ratio of end of infusion plasma levels (paclitaxel alone/paclitaxel plus quinine) was 0.6 (range 0.31-0.97) indicating a 40% decrease in paclitaxel levels with the addition of quinine (p=0.001). We conclude that paclitaxel given by this dose and schedule has modest activity in recurrent NHL. The addition of quinine to paclitaxel also has limited activity, but the combination did reverse paclitaxel resistance in one patient, adding support to the hypothesis that clinical drug resistance can be overcome with chemosensitizers in individual patients. Pharmacokinetic studies indicate that the reversal of drug resistance in this study cannot be attributed to changes in clearance of paclitaxel (which appears to increase with quinine), but more likely to the sensitization of lymphoma cells.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Quinina/farmacocinética , Quinina/uso terapéutico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Humanos , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/prevención & control , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.
Asunto(s)
Factores Inmunológicos/uso terapéutico , Interferón gamma/uso terapéutico , Interleucina-2/uso terapéutico , Neoplasias/terapia , Adulto , Anciano , Terapia Combinada , Evaluación de Medicamentos , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Interferón gamma/efectos adversos , Interleucina-2/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
One hundred fifty-six women with axillary node-negative breast cancer and primary tumors less than or equal to 5 cm in diameter (T1N0 or T2N0) were treated with a brief course of postoperative adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide. Treatment was well tolerated and toxicity was minimal. With a median follow-up time of 58 months, there has been 1 relapse among 58 patients with T1 primary lesions and 15 relapses among 98 patients with T2 primary tumors. When compared with a matched historical control group receiving surgery alone, significant improvement was apparent in disease-free survival among the patients who received adjuvant chemotherapy. Prospective controlled trials are needed if we are to confirm this favorable experience with adjuvant chemotherapy in the treatment of women with node-negative breast cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Adulto , Anciano , Axila , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Ensayos Clínicos como Asunto , Terapia Combinada , Ciclofosfamida/toxicidad , Doxorrubicina/toxicidad , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Factores de TiempoRESUMEN
Piperazinedione given iv once every 3-4 weeks at a starting dose of 9-12 mg/m2 (4.5-12 mg/m2 for patients with myeloma) was evaluated in a Southwest Oncology Group phase II study for patients with far-advanced refractory lymphoma or multiple myeloma. Among 36 patients fully evaluable for tumor response (adequate trial), partial responses were observed in five (71%) of seven patients with Hodgkin's disease, in three (19%) of 16 patients with non-Hodgkin's lymphoma, and in none of 13 patients with multiple myeloma. Response was observed by the time of the second (five patients) or third (three patients) course. The median duration of response was 3.7 months (range, 1-17+ months). The dose-limiting toxic effects were hematologic, with 18 (50%) of 36 patients evaluable for toxicity experiencing severe leukopenia (wbc count less than 2000/mm3) and 22 (61%) experiencing severe thrombocytopenia (platelet count less than 50,000/mm3). Twenty patients had a decrease from their pretreatment hemoglobin level of greater than or equal to 2 g/100 ml. Hematologic toxic effects were often unpredictable and in several patients quite prolonged. This study indicates that piperazinedione had definite antitumor activity in patients with Hodgkin's disease and further trials in this disease using the drug at a reduced dose in combination with other effective drugs appear warranted.