RESUMO
Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor cyclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m-2 combined with CsA 10 mg kg-1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m-2 week-1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ciclosporina/administração & dosagem , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração Oral , Adulto , Idoso , Antraciclinas/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. PATIENTS AND METHODS: One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. RESULTS: The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. CONCLUSIONS: Irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina , Estudos de Coortes , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/análogos & derivados , Humanos , Irinotecano , Masculino , Pessoa de Meia-IdadeRESUMO
The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adenocarcinoma/secundário , Adolescente , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/farmacocinética , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Inibidores da Topoisomerase I , Resultado do TratamentoRESUMO
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetics of topotecan administered as a 30-min intravenous (i.v.) infusion over 5 days in combination with a 1-h i.v. infusion of ifosfamide (IF) for 3 consecutive days every 3 weeks. Patients with advanced malignancies refractory to standard therapy were entered into the study. The starting dose of topotecan was 0.4 mg x m(-2) day(-1) x 5 days. Ifosfamide was administered at a fixed dose of 1.2 g x m(-2) day(-1) x 3 days. In all, 36 patients received 144 treatment courses. Owing to toxicities, the schedule of topotecan administration was reduced from 5 to 3 days. The MTD was reached at topotecan 1.2 mg x m(-2) day(-1) x 3 days with IF 1.2 g x m(-2) day(-1) x 3 days. Haematological toxicities were dose limiting. Neutropenia was the major toxicity. Thrombocytopenia and anaemia were rare. Nonhaematological toxicities were relatively mild. Partial responses were documented in three patients with ovarian cancer dosed below the MTD. Topotecan and IF did not appear to interact pharmacokinetically. The relationships between the exposure to topotecan lactone and total topotecan, and the decrease in absolute neutrophil count and the decrease in thrombocytes, were described with sigmoidal-E(max) models. The combination of 1.0 mg m(-2) day(-1) topotecan administered as a 30-min i.v. infusion daily times three with 1.2 g x m(-2) day(-1) IF administered as a 1-h i.v. infusion daily times three every 3 weeks was feasible. However, the combination schedule of topotecan and IF did result in considerable haematological toxicity and in conjunction with previously reported pronounced nonhaematological toxicities and treatment related deaths, it may be concluded that this is not a favourable combination.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Ifosfamida/farmacocinética , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamente , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinéticaRESUMO
BACKGROUND: Irinotecan is an effective treatment for metastatic colorectal cancer. However, its use may be associated with troublesome adverse effects such as delayed diarrhoea, acute cholinergic syndrome and neutropenic infection. The manufacturer decided to release irinotecan for compassionate use in The Netherlands prior to its regulatory approval (June 1998) and first introduction for second-line treatment of metastatic colorectal cancer. In view of the drug's adverse effect profile this was done in a carefully controlled manner. METHODS: Irinotecan was made available to patients with colorectal cancer with elaborate precautions. Treating physicians requesting irinotecan for compassionate use received a protocol, providing recommendations for the proper use and the prevention/management of potentially troublesome adverse events. Limited demographic, toxicity and efficacy data were collected. RESULTS: Between June 1997 and September 1998, 112 patients were registered for this programme, 103 of whom actually received irinotecan. The percentage of patients experiencing grade 3-4 adverse effects was relatively low: delayed diarrhoea in 17%, nausea and vomiting 17%, acute cholinergic syndrome 6%, febrile neutropenia 4% and neutropenic infection 2%. Five partial tumour responses and a high proportion of patients with 'no change' were noted. CONCLUSIONS: The carefully controlled release of irinotecan for compassionate use with a very detailed protocol for guidance and advice on safety precautions seems to have contributed to the relatively safe use of the drug outside the setting of a formal clinical trial.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/efeitos adversos , Aprovação de Drogas , Feminino , Seguimentos , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Países Baixos , Avaliação de Programas e Projetos de Saúde , Resultado do TratamentoRESUMO
Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Adulto , Idoso , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Ifosfamida/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de SobrevidaRESUMO
Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m(-2) day(-1). Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m(-2) day(-1) and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1-3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4-5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.
Assuntos
Acrilamidas/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/farmacocinética , Neoplasias/tratamento farmacológico , Acrilamidas/administração & dosagem , Acrilamidas/efeitos adversos , Acrilamidas/química , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Doenças da Bexiga Urinária/induzido quimicamenteRESUMO
PURPOSE: The objectives were to determine the maximum-tolerated dose, the recommended dose, the dose-limiting toxicity, the pharmacokinetics, and the activity of E7070, a novel cell-cycle inhibitor. PATIENTS AND METHODS: E7070 was given as a 1-hour intravenous infusion every 3 weeks in two groups of patients with advanced solid tumors who met prespecified eligibility criteria (group A) or who met the same eligibility criteria but in addition were less heavily pretreated and had more favorable liver functions (group B). RESULTS: Forty patients (31 patients in group A and nine patients in group B) were entered. Dose escalation proceeded through eight levels (range, 50 to 1,000 mg/m(2)). In group A, neutropenia and thrombocytopenia were dose-limiting toxicities occurring during the first cycle in two of seven patients treated at the doses of 700 mg/m(2) and two of four patients treated at 800 mg/m(2). Identical dose-limiting toxicities were observed in zero of six and two of three patients from group B at doses of 800 and 1,000 mg/m(2), respectively. Other toxicities included acne-like skin eruption, mucositis, conjunctivitis, nausea, fatigue, and alopecia. At doses greater than 400 mg/m(2), the area under the concentration-time curve increased disproportionately to the administered dose. Tumor stabilization lasting > or = 6 months was observed in six assessable patients. CONCLUSION: The recommended doses of E7070 in this schedule were 700 mg/m(2) (group A) and 800 mg/m(2) in patients who were less heavily pretreated (group B) with a moderate tumor burden. Prolonged disease stabilization observed in this study might warrant further investigation of E7070 in selected tumor types.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Toxidermias/etiologia , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinéticaRESUMO
In antimyosin scintigraphy was evaluated at various cumulative anthracycline dose levels in order to early identify patients with severe cardiac injury and increased long-term risk of cardiac dysfunction. Twenty-four patients receiving standard doses of 60-75 mg.m(-2) doxorubicin or 90-112.5 mg.m(-2) epirubicin were followed at baseline, low (two cycles), middle (four cycles), and high (six cycles) cumulative dose using (111)In antimyosin 48 h heart-to-lung ratio (HLR), left ventricle ejection fraction (LVEF) and peak filling rate (PFR). At a low cumulative dose only HLR was significantly increased (P=0.0001); at middle dose HLR (P<0.0001) and LVEF (P=0.0054), but not PFR, were significantly changed, and at high dose HLR (P<0.0001), LVEF (P=0.0001) and PFR (P=0.033) all changed significantly. Concerning individual results, HLR became abnormal in 18 patients (75%) at low, 22 (92%) at middle, and 24 (100%) at high cumulative dose whereas LVEF and PFR remained within normal limits in all patients. It is concluded that myocyte damage appears to precede left ventricle systolic and diastolic dysfunction in anthracycline treatment. (111)In antimyosin scintigraphy is very sensitive in detecting myocardial damage after cumulative dose levels even as low as 120-150 mg.m(-2) doxorubicin or 180-225 mg.m(-2) epirubicin.
Assuntos
Anticorpos Monoclonais , Doxorrubicina/efeitos adversos , Coração/diagnóstico por imagem , Radioisótopos de Índio , Miócitos Cardíacos/diagnóstico por imagem , Miócitos Cardíacos/metabolismo , Adolescente , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Seguimentos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Radioisótopos de Índio/farmacocinética , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miosinas/imunologia , Neoplasias/tratamento farmacológico , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Sensibilidade e Especificidade , Volume Sistólico , Disfunção Ventricular EsquerdaRESUMO
Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Fosforilcolina/administração & dosagem , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Concentração Máxima Permitida , Pessoa de Meia-Idade , Neoplasias/sangue , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacocinéticaRESUMO
PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate-binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m(2) oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m(2) intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 +/- 9.6 microg.h/L without GF120918 to 78.7 +/- 20.6 microg.h/L when GF120918 was coadministered (P =.008). The mean maximum plasma concentration of total topotecan increased from 4.1 +/- 1.5 microg/L without GF120918 to 11.5 +/- 2.4 microg/L with GF120918 (P =.008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P =.008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/uso terapêutico , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Inibidores Enzimáticos/farmacocinética , Isoquinolinas/uso terapêutico , Tetra-Hidroisoquinolinas , Topotecan/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Acridinas/farmacologia , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Esquema de Medicação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Isoquinolinas/farmacologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Topotecan/administração & dosagemRESUMO
OBJECTIVES: To compare retrospectively the treatment results of surveillance and primary retroperitoneal lymph node dissection (RPLND) of patients with clinical Stage I nonseminomatous germ cell tumors of the testis (NSGCT) in two institutions in The Netherlands. METHODS: From 1982 to 1994, 90 consecutive patients with clinical Stage I NSGCT were prospectively entered in a surveillance protocol in Amsterdam (group 1). In the same period, 101 patients with clinical Stage I NSGCT underwent primary RPLND in Nijmegen (group 2). Both patient populations were comparable for patient age, presence of vascular invasion, and embryonal cell components in the primary tumor. All patients in group 1 with relapse, except for 2, were treated with cisplatin-based chemotherapy. All patients in group 2 with vital tumor in the RPLND specimen were treated with two adjuvant courses of combined chemotherapy (cisplatin, etoposide, and bleomycin). RESULTS: In group 1, at a median follow-up of 7.7 years, 23 patients (26%) had relapse. The median time to relapse was 12 months. Relapses were located retroperitoneally (n = 18, 78%), in the lung (n = 3, 13%), scrotally (n = 1, 4%), and combined in the liver, lung, and pleura (n = 1, 4%). After treatment of relapses (chemotherapy in 21 and/or surgery in 11), only 1 patient died of disseminated disease. A disease-free survival rate of 98.5% was achieved at the median follow-up. The main toxicities consisted of short-lasting leukopenia, accompanied by infection (13%). Four patients reported cardiovascular and four neuropathy complaints. In group 2, the median follow-up was 6.9 years. In 31 patients (30.7%), vital tumor was found retroperitoneally; after two courses of combined chemotherapy, none of them had a relapse. Seven patients with pathologic Stage I disease (6.4%) had a pulmonary relapse within 1 year after surgery. No retroperitoneal relapses were found. After chemotherapy, 6 patients with relapse were salvaged, and 1 died of disseminated disease. The disease-specific survival rate in group 2 was 98% at the median follow-up. The most frequent surgical complications were lymphocele (n = 3), small bowel obstruction (n = 3), and abdominal pain (n = 3). The antegrade ejaculation rate was 94%. CONCLUSIONS: Excellent treatment results in terms of disease-free survival can be achieved in Stage I NSGCT with both surveillance and primary RPLND. Patients with pathologic Stage II disease adjuvantly treated with chemotherapy did not have any relapse and consequently all survived. Most complications after both treatment strategies are reversible. The choice of treatment should be based on balanced information and not on dogmatic principles.
Assuntos
Germinoma/secundário , Germinoma/cirurgia , Excisão de Linfonodo , Neoplasias Testiculares/cirurgia , Adolescente , Adulto , Ejaculação , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Espaço Retroperitoneal , Estudos Retrospectivos , Vigilância de Evento Sentinela , Neoplasias Testiculares/patologiaRESUMO
PURPOSE: We investigate the results of a surveillance program for stage I nonseminomatous germ cell tumors to validate a surveillance policy, and furthermore improve it by analyzing diagnostic instruments and identifying prognostic factors for relapse. MATERIALS AND METHODS: From 1982 to 1994, 90 patients with stage I nonseminomatous germ cell tumors entered a surveillance protocol after orchiectomy. Patients with relapse were treated with cisplatin based chemotherapy. A statistical analysis of possible prognostic factors for relapse was performed. RESULTS: Relapse occurred in 23 (26%) patients. Disease specific survival was 98.9%, and 1 patient died of tumor. Most relapses were located in retroperitoneal lymph nodes only (78%). Tumor markers were the most important indicators of relapse. However, in 22% of patients with relapse abdominal x-ray of lymphangiographic contrast showed the first sign of relapse. Computerized tomography located all but 1 relapse. Vascular invasion (p = 0.0001), tumor size (p = 0.0341) and presence of immature teratoma (p = 0.0154) were significantly predictive of relapse with the multivariate analysis, percentage embryonal carcinoma only by univariate analysis (p = 0.032). The relapse rate was highest (52%) when vascular invasion was present. CONCLUSIONS: With surveillance for stage I nonseminomatous germ cell tumors, excellent treatment results can be achieved that are comparable to primary retroperitoneal lymph node dissection. Tumor markers and computerized tomography are highly reliable for detecting relapse. Lymphangiography is still of staging value. Pathological factors may influence the choice of adjuvant treatment. However, relapse risks of 50% to 60% are maximally achieved with presently available prognostic factors, and so sparing morbidity of adjuvant treatment by a surveillance protocol remains a feasible option even in these patients.
Assuntos
Germinoma/patologia , Neoplasias Testiculares/patologia , Adolescente , Adulto , Seguimentos , Germinoma/epidemiologia , Germinoma/secundário , Germinoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vigilância da População , Prognóstico , Fatores de Risco , Neoplasias Testiculares/cirurgiaRESUMO
The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Glicerol/análogos & derivados , Glicerol/farmacologia , Absorção Intestinal/efeitos dos fármacos , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Administração Oral , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Ciclosporina/administração & dosagem , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Combinação de Medicamentos , Fezes/química , Humanos , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Veículos Farmacêuticos , Polissorbatos/farmacologia , Solventes/farmacologiaRESUMO
OBJECTIVE: To evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the absorption of orally administered docetaxel. METHODS: Patients (n = 9) with histological proof of solid cancer received oral docetaxel 75 mg/m2 in combination with oral CsA 15 mg/kg. RESULTS: The area under the blood concentration-time curve (AUC) of CsA when combined with docetaxel 75 mg/m2 was 31.0+/-9.3 mg/l h (mean +/- SD). Compared with literature data of the same dose of CsA, AUC values in our study appear to be substantially higher. In addition, compared with the AUC values of CsA in combination with oral paclitaxel (previously published data), AUC values in this study are approximately 1.5-fold higher. CONCLUSIONS: The higher AUC values of CsA obtained in this study compared with literature data may be explained by competitive inhibition of cytochrome P450 (CYP) 3A4-mediated metabolism of CsA by docetaxel. In addition, the higher levels of CsA with docetaxel than with paclitaxel co-administration may be explained by the fact that docetaxel is almost exclusively metabolised by CYP 3A4, whereas paclitaxel is predominantly metabolised by CYP 2C8 and to a lesser extent by CYP 3A4.
Assuntos
Antineoplásicos/farmacocinética , Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Paclitaxel/análogos & derivados , Paclitaxel/farmacocinética , Taxoides , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Área Sob a Curva , Ciclosporina/administração & dosagem , Docetaxel , Interações Medicamentosas , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagemRESUMO
The objective of this study was to evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the oral absorption of paclitaxel. Patients received oral paclitaxel in doses of 60-360 mg/m(2) in combination with a dose of oral CsA of 15 mg/kg. Dose escalation of paclitaxel from 60 to 300 mg/m(2) resulted in a significant decrease in the area under the concentration-time curve (AUC) of CsA from 24.4+/-9.9 to 17.6+/-2.8 mg/l.h (p=0.03) (n=28). In conclusion, increases in the paclitaxel dose resulted in a decrease in the AUC of CsA. This observation may be explained by the increase in the co-solvent Cremophor EL of paclitaxel causing reduced absorption of CsA.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Ciclosporina/farmacocinética , Inibidores Enzimáticos/farmacocinética , Neoplasias/metabolismo , Paclitaxel/administração & dosagem , Absorção , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Quimioterapia Combinada , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m(2), as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m(2), at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.
Assuntos
Anemia/induzido quimicamente , Doenças do Sistema Nervoso/induzido quimicamente , Paclitaxel/farmacocinética , Paclitaxel/toxicidade , Polímeros/farmacocinética , Polímeros/toxicidade , Adulto , Idoso , Área Sob a Curva , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Relação Dose-Resposta a Droga , Portadores de Fármacos , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Metacrilatos/química , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/análogos & derivados , Paclitaxel/síntese química , Paclitaxel/química , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/toxicidade , Indução de Remissão , Neoplasias Cutâneas/secundário , Solubilidade , Taxoides/análogos & derivadosRESUMO
The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m(2) oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 microM (T>0.1 microM) of oral paclitaxel. The mean (+/-SD) AUC and T>0.1 microM values of oral paclitaxel with CsA 10 mg/kg were 4.29+/-0.88 microM x h and 12.0+/-2.1 h, respectively. With CsA 5 mg/kg these values were 2.75+/-0.63 microM x h and 7.0+/-2.1 h, respectively (p=0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 microM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 microM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclosporina/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Área Sob a Curva , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Pré-Medicação , Neoplasias Gástricas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológicoRESUMO
PURPOSE: To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination. PATIENTS AND METHODS: A total of 15 patients received during course 1 two doses of oral paclitaxel (2 x 60, 2 x 90, 2 x 120, or 2 x 160 mg/m2) 7 h apart in combination with 15 mg/kg of cyclosporin A, co-administered to enhance the absorption of paclitaxel. During subsequent courses, patients received 3-weekly intravenous paclitaxel at a dose of 175 mg/m2 as a 3-h infusion. RESULTS: Toxicities observed following b.i.d. dosing of oral paclitaxel were generally mild and included toxicities common to paclitaxel administration and mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea, which occurred more often at the higher dose levels. Dose escalation of b.i.d. oral paclitaxel from 2 x 60 to 2 x 160 mg/m2 did not result in a significant increase in the area under the plasma concentration-time curve (AUC) of paclitaxel. The AUC after doses of 2 x 60, 90, 120, and 160 mg/m2 were 3.77 +/- 2.70, 4.57 +/- 2.43, 3.62 +/- 1.58, and 8.58 +/- 7.87 microM.h, respectively. The AUC achieved after intravenous administration of paclitaxel 175 mg/m2 was 17.95 +/- 3.94 microM.h. CONCLUSION: Dose increment of paclitaxel did not result in a significant additional increase in the AUC values of the drug. Dose escalation of the b.i.d. dosing regimen was therefore not continued up to DLT. As b.i.d. dosing appeared to result in higher AUC values compared with single-dose administration (data which we have published previously), we recommend b.i.d. dosing of oral paclitaxel for future studies. Although pharmacokinetic data are difficult to interpret, due to the limited number of patients at each dose level and the large interpatient variability, we recommend the dose level of 2 x 90 mg/m2 for further investigation, as this dose level showed the highest systemic exposure to paclitaxel combined with good safety.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Ciclosporina/administração & dosagem , Ciclosporina/farmacocinética , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Área Sob a Curva , Ciclosporina/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Imunossupressores/efeitos adversos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Paclitaxel/efeitos adversosRESUMO
PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2). RESULTS: The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.