RESUMO
PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer.
Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Doenças da Medula Óssea/induzido quimicamente , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Topotecan , Resultado do TratamentoRESUMO
PURPOSE: Twenty-one-day topotecan infusion was administered as second-line therapy in patients with previously treated ovarian cancer (based on our prior favorable phase I experience) to determine its activity, time to progression, and pharmacodynamics. PATIENTS AND METHODS: Ovarian cancer patients with measurable lesions and one prior platinum-containing regimen were eligible. Topotecan 0.4 mg/m(2)/d 21-day continuous ambulatory intravenous infusion, with appropriate dose modifications for toxicity, was administered every 28 days. Weekly blood levels of topotecan and topoisomerase-1 (topo-1) levels in peripheral-blood mononuclear cells (PBMCs) were determined for pharmacodynamic correlation. RESULTS: Twenty-four patients were entered onto the study (six cisplatin-refractory, five relapsing within < 6 months and 13 relapsing > 6 months after platinum-based therapy). A total of 128 cycles of topotecan (median, four cycles per patient; range, one to 12 cycles) were administered. The major toxicity was neutropenia (29% grade 3 in all cycles and 4% grade 4). One episode of grade 4 thrombocytopenia (4%) occurred. Fifty-two percent of the patients had anemia that required transfusions. Eight of 23 patients with measurable disease (35%; 95% confidence interval [CI], 15% to 54%) had partial responses (PRs) lasting longer than 1 month. Two of these patients had minor residual computed tomographic changes but had clinical complete remissions that lasted up to 53 weeks while they were not undergoing further therapy. One patient with nonmeasurable disease had a PR (by CA-125 criteria) that lasted 6 months, for an overall response rate of 38% in nine of 24 patients (95% CI, 18% to 57%). The median time to progression was 26 weeks. Pharmacodynamic analysis demonstrated a statistically significant decrease in free PBMC topo-1 level at weeks 2 and 3 of drug administration. There was a strong statistical correlation between the decrease in free topo-1 levels and increasing area under the curve (AUC) for topotecan. This was confirmed in a pharmacodynamic model. CONCLUSION: Twenty-one-day infusion is a well-tolerated method of administering topotecan. Pharmacodynamic studies demonstrate correlations between (1) the week of infusion and the PBMC topo-1 level, (2) the AUC of topotecan and the decrease in topo-1 levels, and (3) the change in topo-1 level and the neutrophil nadir. The objective response rate of 35% to 38% (95% CI, 15% to 57%) in this small multicenter study is at the upper level for topotecan therapy in previously treated ovarian cancer. Prolonged topotecan administration therefore warrants further investigation in larger, randomized studies comparing this 21-day schedule with the once-daily-for-5-days schedule.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Topotecan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Área Sob a Curva , Cisplatino/uso terapêutico , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacologia , Resultado do TratamentoRESUMO
Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming "cleavable complex," a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 "free" topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of =20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy.