RESUMEN
OBJECTIVES: The feasibility, safety, and preliminary efficacy of a second-line combination therapy for oral topotecan and pegylated liposomal doxorubicin in patients with platinum-resistant or refractory epithelial ovarian, peritoneal, or tubal carcinoma were investigated in this phase I trial. METHODS: A fixed dose of oral topotecan 2.3 or 1.53 mg/m(2) on days 1 through 5 and escalating doses of pegylated liposomal doxorubicin on day 1 of a 28-day cycle were administered. Dose-limiting toxicities and maximum tolerated doses were recorded. Safety was assessed by adverse event monitoring, and complete and partial responses were recorded. RESULTS: Twenty-two patients received a total of 61 courses of therapy. The maximum tolerated dose of combination therapy was 1.53 mg/m(2) of topotecan on days 1 through 5 and 40 mg/m(2) of pegylated liposomal doxorubicin on day 1 of a 28-day cycle. Because of cumulative thrombocytopenia, the dose of topotecan was decreased by one-third from 2.3 to 1.53 mg/m(2) in an effort to increase the dose of pegylated liposomal doxorubicin. Only 5 patients completed >4 cycles of therapy. The most common grade 4 adverse events at dose level 4 were neutropenia (5/9 patients) and leukopenia (2/9 patients). Overall responses were observed in 2 of 22 patients. CONCLUSIONS: Oral topotecan and pegylated liposomal doxorubicin can be combined at doses that are active as monotherapies. However, the overall response rates after monotherapy in patients with platinum-resistant ovarian cancer are comparable to or higher than those observed in this phase I study of combination therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Compuestos Organoplatinos/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/secundario , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/secundario , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/secundario , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/secundario , Estudios de Factibilidad , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Ováricas/patología , Neoplasias Peritoneales/patología , Polietilenglicoles/administración & dosificación , Pronóstico , Tasa de Supervivencia , Topotecan/administración & dosificaciónRESUMEN
OBJECTIVE: Topotecan and carboplatin are active in relapsed ovarian cancer, but attempts to combine these agents are limited by myelotoxicity. This phase I/II trial combined weekly topotecan, which is less myelosuppressive than the standard 5-day regimen, with carboplatin in patients with potentially platinum-sensitive relapsed ovarian or peritoneal carcinoma (PS-OVCa/PCa). METHODS: Eligible patients had PS-OVCa/PCa, performance status 0-2, and normal bone marrow, renal, and hepatic functions. On day 1 of a 21-day cycle, patients received carboplatin (area under the curve [AUC] 5) followed by topotecan 2.0 mg/m2, both via 30-min intravenous infusion. Topotecan 2.0 mg/m2 also was administered on days 8 and 15. Treatment was withheld for neutropenia or thrombocytopenia on day 8 or 15. Dose escalation was planned. RESULTS: Seventeen patients received a total of 115 (median, 6) cycles of chemotherapy. With carboplatin AUC 4, neutropenia prevented dose escalation of topotecan; hematologic toxicity caused 34/105 (32%) weekly treatments to be withheld. However, carboplatin could be dose escalated to AUC 5 when the day 15 dose of topotecan was withheld. In the intent-to-treat population, there were 4 (24%) complete and 9 (53%) partial responses, 2 (12%) patients (at the carboplatin AUC 4 dose) with stable disease, and 2 (12%) nonevaluable patients. CONCLUSION: Carboplatin (AUC 5) on day 1 in combination with topotecan 2.0 mg/m2 on days 1 and 8 of a 21-day cycle is well tolerated and active in patients with PS-OVCa/PCa. A phase II trial comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer is warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Topotecan/administración & dosificación , Topotecan/efectos adversosRESUMEN
OBJECTIVE: Paclitaxel administered weekly in equal cumulative doses is associated with less hematologic and non-hematologic toxicity than an every 3-week administration. We studied weekly paclitaxel and 3-week carboplatin in potentially platinum-sensitive recurrent ovarian and peritoneal carcinoma. METHODS: Paclitaxel at a dose of 80 mg/m(2) over 1 h in combination with carboplatin at an AUC of 5 was administered on day 1. Subsequent paclitaxel doses, modified based on the day of treatment ANC, were administered on days 8 and 15. Paclitaxel dose reductions to 75% of prior dose were performed for chemotherapy delays or toxicity. RESULTS: Twenty-eight patients were studied. The median age was 59 (range 42-80). The median platinum-free interval was 12 months (range 7-129 months). A median of six courses (range 1-13) was administered. Paclitaxel dose reductions to 60 mg/m(2) were required in 85% of the patients. Grades 3 and 4 thrombocytopenia were seen in 5 and 0 patients, respectively. Grades 3 and 4 neutropenia were seen in 14 and 1 patients, respectively. One patient was hospitalized for neutropenic fever. Twenty of 26 (77%) evaluable patients have responded with 15 patients (58%) achieving a complete response. CONCLUSIONS: Weekly paclitaxel at a dose of 60 mg/m(2) in combination with carboplatin at an AUC of 5 is well tolerated and active in potentially platinum-sensitive recurrent ovarian and peritoneal carcinoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversosRESUMEN
OBJECTIVES: Although the combination of paclitaxel and carboplatin has a better therapeutic index than the combination of paclitaxel and cisplatin, peripheral neuropathy often occurs and remains the most chronic toxicity of this therapy. CASE: Six patients with ovarian or peritoneal carcinoma who developed grade 2 peripheral neuropathy during chemotherapy with paclitaxel and carboplatin had decreased or resolution of their neuropathy after their therapy was changed to docetaxel and carboplatin. CONCLUSIONS: Changing the taxane from paclitaxel to docetaxel in combination with carboplatin resulted in decreased or resolution of established peripheral neurotoxicity. This is one strategy to allow continued taxane therapy in the face of progressing peripheral neuropathy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Paclitaxel/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Taxoides/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificaciónRESUMEN
OBJECTIVE: The goal of this study was to evaluate the tolerance and effectiveness of carboplatin rechallenge using a prolonged desensitizing carboplatin infusion regimen in patients with clinically documented moderate-severe carboplatin hypersensitivity. METHOD: Patients admitted for carboplatin infusion were identified by computerized pharmacy records and retrospectively analyzed. RESULT: Thirty-three patients with recurrent ovarian (N = 27), peritoneal (N = 4), tubal (N = 1), and cervical (N = 1) cancer treated with a prolonged desensitizing carboplatin infusion regimen were identified. The patients had received a median of 10 courses of carboplatin (range 3-33) before developing the moderate-severe hypersensitivity reaction. Two hundred and fifteen courses (median 5, range 1-52) were administered. Twenty-nine patients (88%) were successfully rechallenged while four had a recurrent moderate-severe carboplatin hypersensitivity precluding further administration. Despite initial tolerance of the infusion schedule moderate-severe carboplatin hypersensitivity recurred in 3 additional patients (9%) after two, three, and six subsequent courses. Objective responses to therapy were seen in 22 of 28 evaluable patients (79%). CONCLUSIONS: A prolonged desensitizing carboplatin infusion regimen is tolerated in the majority of patients with clinically documented moderate-severe carboplatin hypersensitivity. Objective response rates seem acceptable with this schedule.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Desensibilización Inmunológica/métodos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/prevención & control , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Adulto , Anciano , Esquema de Medicación , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
OBJECTIVE: Preclinical models in an ovarian cancer cell line (A2780) demonstrate synergistic activity with the combination of gemcitabine and cisplatin compared to either single agent alone. Platinum resistance is related to expression of excision repair proteins, one of which (ERCC-1) has been identified as playing a critical role in the synergy of gemcitabine and cisplatin. We evaluated the cisplatin and gemcitabine regimen in patients with platinum refractory and multidrug refractory ovarian and peritoneal carcinoma. METHODS: Gemcitabine (750 mg/m(2)) was administered intravenously over 30 min followed by cisplatin (30 mg/m(2)) on Days 1 and 8 every 21 days. Day 8 therapy was canceled for an absolute neutrophil count <1000/mm(3) or platelet count <75,000/mm(3). Sequential dose reductions of gemcitabine to 600, 400, and 300 mg/m(2) were prescribed in the event of canceled therapy, neutropenic sepsis, or severe thrombocytopenia (platelets <20,000/m(3)). RESULTS: Thirty-six platinum- and paclitaxel-resistant patients were studied. Thirty-five were evaluable for response, of which 6 had progressed on gemcitabine as a single agent. Fifteen of the patients responded (42.9%, 95% CI 28.0-59.1%). Eleven were partial clinical responses and 4 were complete clinical responses, with 4 of the 6 patients who had failed gemcitabine as a single agent responding. Among the responding patients the median response duration was 11 months (range 4-14 months). For all patients the progression-free interval was 6 months (range 1-14 months). The median survival was 12 months. CONCLUSION: The combination of gemcitabine and cisplatin is active in patients who are platinum resistant. Additionally, activity is demonstrated even in patients who have previously been resistant to gemcitabine.