RESUMEN
9-Nitrocamptothecin (9NC) is a water-insoluble topoisomerase I inhibitor with a broad antitumor activity in animal models. To determine the maximum tolerated oral dose (MTD), a phase I study was performed in patients with advanced cancer refractory to conventional chemotherapy. 9NC was administered orally with escalating doses to cohorts of five patients beginning at 1 mg/m2/day for five consecutive days every week for 4 weeks. Increments were 0.5 mg/m2/day for each cohort. Toxicity was evaluated in 28 patients diagnosed with various malignancies. Seven patients received 1 mg/m2/day for 28 weeks; 10 patients, 1.5 mg/m2/day for 68 weeks; and 26 patients, 2 mg/m2/day for 159 weeks. At 1.5 mg/m2/day or higher, the dose-limiting toxicity was hematologic, with grade 4 anemia in eight (29%); neutropenia in seven (25%) and thrombocytopenia in five (18%). Grade 2 or higher toxic effects occurred at each dose level: nausea and vomiting in 15 (54%), diarrhea in nine (32%), chemical cystitis in seven (25%), neutropenic sepsis in six (21%) and weight loss in five (18%) (N=28). Responses were observed after 2-8 weeks of therapy in five patients with pancreatic, breast, ovarian and hematologic tumors. Fourteen patients had a disease stabilization and one patient received treatment up to 18 months. The MTD of 9NC given orally has been estimated at 1.5 mg/m2/day for five consecutive days weekly. 9NC may be tolerated for sustained periods of time, but has the potential for significant hematologic, gastrointestinal and urinary bladder toxicity. Significant antitumor activity was observed, warranting further clinical investigations.
Asunto(s)
Antineoplásicos/uso terapéutico , Camptotecina/análogos & derivados , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Adulto , Anciano , Anemia/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/sangre , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Ciclohexanos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Náusea/inducido químicamente , Enfermedades del Sistema Nervioso/inducido químicamente , O-(Cloroacetilcarbamoil) Fumagilol , Terapia Recuperativa , Sesquiterpenos/administración & dosificación , Sesquiterpenos/efectos adversos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapiaRESUMEN
Single-agent paclitaxel infused over 24 hours produces response rates of 10 per cent to 20 per cent and 48 per cent respectively, for doses of 135 mg/m2 and 250 mg/m2. This suggests a dose response relationship. However, only a randomized trial comparing the 135 mg/m2 and 250 mg/m2 doses can confirm this result. Unfortunately, the median survival is comparable despite the difference in response rates. This may be secondary to a low CR noted at all doses. The apparent lack of benefit in terms of increased survival for the high dose group, with its attendant increase in incidence of toxic effects and cost (owing to both the paclitaxel and the G-CSF), suggest that the role of higher doses remains to be proven. It may be most useful in alleviating the severe cancer induced symptoms of some patients with advanced platinum resistant ovarian cancer(19). Despite the extensive international experience with paclitaxel in the ovarian cancer clinic its role still needs to be better defined both for salvage therapy and in combination with platinum as a front-line treatment.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Compuestos de Platino , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Resultado del TratamientoRESUMEN
Endogenous sex hormones seem to influence the risk of several common and debilitating diseases. With a view toward better understanding the effects of surgical removal of the ovaries and high-dose pelvic radiotherapy on plasma sex hormone levels, we measured estrogen and androgen concentrations cross-sectionally among 147 women who had been treated for cervical cancer 0.3-18.5 years previously. Pelvic radiotherapy (mean dose to ovaries, 50 Gy) and bilateral ovariectomy were associated with similarly reduced hormone concentrations relative to levels among nonirradiated women with intact ovaries, most of whom had had early-stage disease and were treated by hysterectomy. There was little evidence that radiotherapy in addition to ovariectomy further lowered concentrations below levels associated with ovariectomy alone, such as might be expected if radiation was suppressing adrenal endocrine function. Among women age 50 years or older at the time of blood drawing, the removal or irradiation of the ovaries was associated with approximately 45% lower concentrations of estradiol (mean ratio [MR], 0.55; 95% confidence interval [CI], 0.32-0.95) and testosterone (MR, 0.57; 95% CI, 0.32-0.99), and 25-30% lower concentrations of estrone (MR, 0.69; 95% CI, 0.44-1.09) and androstenedione (MR, 0.76; 95% CI, 0.47-1.23), relative to the hysterectomy-only group. Among women younger than 50, ovariectomy and radiotherapy, alone or in combination, were associated with 83% lower estradiol concentrations (MR, 0.17; 95% CI, 0.09-0.31), 46% lower estrone concentrations (MR, 0.54; 95% CI, 0.37-0.81), 23% lower androstenedione concentrations (MR, 0.77; 95% CI, 0.57-1.04), and 14% lower testosterone levels (MR, 0.86; 95% CI, 0.64-1.15).(ABSTRACT TRUNCATED AT 250 WORDS)