RESUMO
PURPOSE: This study was designed to investigate the outcome of "the liver-first" approach in patients with locally advanced rectal cancer and synchronous liver metastases. METHODS: Patients with locally advanced rectal cancer and synchronous liver metastases were primarily treated for their liver metastases. If successful, patients underwent treatment for the rectal tumor. RESULTS: Twenty-three patients were included. One patient had liver resection without neoadjuvant chemotherapy followed by chemoradiotherapy. All remaining 22 patients underwent laparotomy after chemotherapy. Eighteen patients underwent partial liver resection and subsequent chemoradiotherapy for the rectal cancer. One patient underwent in one session a partial liver resection and a low anterior resection. Six patients were not treated according to protocol because of extensive disease. Sixteen patients (73 percent) completed the full treatment protocol and all are alive after a median period of 19 (range, 7-56) months. CONCLUSIONS: This is the first sizable report on the "liver-first approach" demonstrating that it may be considered the preferred treatment schedule for patients with locally advanced rectal cancer and synchronous liver metastases. It allows most patients to undergo curative resections of both metastatic and primary disease and can avoid useless rectal surgery in patients with incurable metastatic disease.
Assuntos
Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Retais/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Hepatectomia , Humanos , Laparotomia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Retais/cirurgia , Neoplasias Retais/terapia , Falha de TratamentoRESUMO
PURPOSE: TZT-1027 [N(2)-(N,N-dimethyl-l-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide] is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m(2). For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. RESULTS: Seventeen patients received a total of >70 courses. The stopping dose was reached at 2.7 mg/m(2), with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting >54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027. CONCLUSIONS: In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m(2) given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cromatografia Líquida de Alta Pressão , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversosRESUMO
PURPOSE: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor tyrosine kinase inhibitor PKI166 in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information and characterize the effect of food intake on PKI166 pharmacokinetics. Pharmacokinetics of PKI166 were characterized after single and multiple doses at all dose levels. RESULTS: Fifty-four patients received a total of one hundred sixteen 28-day cycles of PKI166. Dose-limiting transaminase elevations were observed in two of seven and two of eight patients using 50 and 100 mg PKI166 continuously. In the second part with PKI166 once daily for 2 weeks every 4 weeks, MTD was set at 750 mg. Dose-limiting toxicity consisted of diarrhea, skin rash, and transaminase elevations. Pharmacokinetic analysis revealed fast absorption, a linear dose-response relationship without drug accumulation after multiple doses. At MTD, no significant influence of food intake on PKI166 pharmacokinetics was observed. Stable disease for more than two cycles was observed in 11 patients. CONCLUSIONS: PKI166 given once daily for 2 weeks every 4 weeks is well tolerated with linear pharmacokinetics, compatible with once daily dosing, and without significant effect of food intake on absorption. The recommended dose for further studies is 750 mg once daily for 2 weeks every 4 weeks.
Assuntos
Receptores ErbB/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/farmacocinética , Pirróis/uso terapêutico , Absorção , Adulto , Idoso , Antineoplásicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Químicos , Proteínas Tirosina Quinases/metabolismo , Software , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with oral ZD9331 given once daily (od) or twice daily (bid) for 5, 7, or 10 days; cycles were repeated every 21 days at doses ranging from 2.5 to 40 mg. For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated liquid chromatographic-tandem mass spectrometry assay. Plasma levels of 2'-deoxyuridine were measured as a surrogate marker for TS inhibition. RESULTS: Forty-two patients received a total of 166 courses. The DLTs were myelosuppression and skin rash. Dose escalation of oral ZD9331 from 2.5 to 40 mg, as a single daily dose, resulted in a less than proportional increase in the plasma area under the concentration-time curve of ZD9331. The plasma drug exposure per cycle for the schedules 20 mg od for 5 days, 10 mg od for 10 days, and 10 mg bid for 5 days, all resulting in a total dose per cycle of 100 mg, were comparable. One partial response was noted in a patient with gastric cancer. CONCLUSION: DLTs in this phase I study of oral ZD9331 were myelosuppression and skin toxicity. The recommended dose for phase II studies of oral ZD9331 is 20 mg od for 5 consecutive days, every 3 weeks.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Medula Óssea/efeitos dos fármacos , Toxidermias/etiologia , Neoplasias/tratamento farmacológico , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Timidilato Sintase/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Sob a Curva , Cromatografia Líquida , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Neoplasias/sangue , Quinazolinas/química , Quinazolinas/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination RESULTS: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent. CONCLUSIONS: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.
Assuntos
Amidinas/farmacocinética , Amidinas/toxicidade , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Indanos/farmacocinética , Indanos/toxicidade , Adulto , Idoso , Amidinas/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Colorretais/parasitologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Indanos/administração & dosagem , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pseudomixoma Peritoneal/tratamento farmacológico , Pseudomixoma Peritoneal/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Resultado do TratamentoRESUMO
PURPOSE: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients. EXPERIMENTAL DESIGN: Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection. RESULTS: Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor. CONCLUSION: Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2).