RESUMO
BACKGROUND: Oxaliplatin neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. PATIENTS AND METHODS: From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. RESULTS: Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03). Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%) without grade 3-4 events. CONCLUSION: Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.
Assuntos
Antineoplásicos/efeitos adversos , Cicloexanóis/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Compostos Organoplatínicos/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Cloridrato de VenlafaxinaRESUMO
BACKGROUND: Diarrhea is a serious side effect that may prevent the administration of high doses of the antitumor drug Irinotecan (CPT-11). PURPOSE: Intensive, high-dose loperamide was used in an attempt to control or downstage CPT-11-induced diarrhea and thus permit the use of higher dose intensities of CPT-11. METHODS: Twenty-three patients with various cancers were treated with doses of CPT-11 ranging from 400 to 600 mg/m2, administered as a 30-minute intravenous infusion every 3 weeks. Starting 8 hours or more after the administration of CPT-11, any episode of diarrhea was treated with 2 mg of loperamide taken every 2 hours. Patients stopped taking loperamide only after a 12-hour diarrhea-free period. If diarrhea was not controlled after 3 consecutive days of nonstop loperamide intake, or if the patient was dehydrated, loperamide was stopped and the patient was hospitalized for intravenous fluids. If blood or mucus were found in the stools at any time during diarrhea, loperamide was stopped and the patient was hospitalized. RESULTS: Seventeen of 23 patients had diarrhea while on CPT-11 treatment. Eighty-two CPT-11 cycles were administered to these 17 patients, and diarrhea occurred in 49 of these cycles, at a median time-to-onset of 6 days after CPT-11 administration. The loperamide protocol was followed in 46 of the 49 episodes of diarrhea, with 21 capsules of loperamide the median number being taken (range, 5-72). Only one patient was hospitalized for failure to respond to loperamide, and no major toxicity was associated with loperamide use. Fourteen of the 17 patients who experienced diarrhea were rechallenged with CPT-11 three or more times, and seven patients six or more times. CONCLUSIONS: High-dose loperamide controlled diarrhea in patients receiving CPT-11 and allowed administration of higher doses of CPT-11. IMPLICATIONS: The effectiveness of CPT-11 might be increased by higher dose intensities, which can be made tolerable by control of diarrhea with loperamide.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/análogos & derivados , Diarreia/prevenção & controle , Loperamida/uso terapêutico , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Diarreia/induzido quimicamente , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológicoRESUMO
Intraarterial chemotherapy with Adriamycin (ADM) has shown limited advantages over i.v. administration, with no reduction in systemic toxicities and modest decrease in peripheral plasma levels. In an effort to improve the selectivity of i.a. anthracycline chemotherapy, we compared pirarubicin (4'-O-tetrahydropyranyladriamycin, THP) and ADM in the surgically implanted VX2 rabbit tumor model. Both drugs were administered at the same dose (0.5 mg/kg) either by the intraarterial hepatic route (i.a.h.) or by the i.v. route. Anthracycline plasma and tissue levels were determined by high-performance liquid chromatography with fluorescence detection. ADM peak plasma concentration and area under the curve were not significantly reduced after i.a.h. administration compared to the i.v. route; however, ADM tumor concentration was 1.9-fold higher following i.a.h. administration compared to the i.v. infusion. After THP administration by the i.a.h. route, systemic exposure (area under the curve) was markedly reduced (8-fold) compared to the same dose administered i.v. These findings correlated well with the very low concentration of the drug in heart tissue following i.a.h. infusion. After i.a.h. administration, tumor THP concentrations were 10.5 times higher compared to the i.v. route. The pharmacokinetic advantage of i.a.h. administration of THP also led to a better antitumoral effect, as shown by a significantly lower tumor growth rate [3 +/- 2% (SD)] in the i.a.h.-treated animals compared to the i.v.-treated groups (58 +/- 9%). Administration of ADM by the i.a.h. route was also inferior to i.a.h. THP. Taken together, our results suggest a clear-cut advantage of THP over ADM for i.a.h. locoregional chemotherapy, because of higher local tumor concentrations, greater antitumoral effect, and lower systemic exposure following the i.a.h. administration of THP. This anthracycline analogue could also be of therapeutic advantage in tumors partially resistant to anthracyclines that would become vulnerable to the high local concentrations achieved with i.a.h. administration. Based on these encouraging results, clinical trials using THP administered by the i.a.h. route were initiated.
Assuntos
Doxorrubicina/análogos & derivados , Neoplasias Hepáticas/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Feminino , Artéria Hepática , Injeções Intra-Arteriais , Injeções Intravenosas , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Transplante de Neoplasias , Coelhos , Células Tumorais CultivadasRESUMO
PURPOSE: A phase I study was undertaken to determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacokinetics of the novel topoisomerase I inhibitor irinotecan (CPT-11). PATIENTS AND METHODS: Sixty-four patients meeting standard phase I eligibility criteria were included (24 women, 40 men; median age, 51 years; primary sites: colon, head and neck, lung, pleura; 60 of 64 had been previously treated). Pharmacokinetics was determined by high-performance liquid chromatography (HPLC). RESULTS: One hundred ninety CPT-11 courses were administered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to 750 mg/m2). Grade 3 to 4 nonhematologic toxicities included diarrhea (16%; three hospitalizations), nausea and vomiting (9%), asthenia (14%), alopecia (53%), elevation of hepatic transaminases (8%), and one case of skin toxicity. An acute cholinergic syndrome was observed during CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg/m2, but this was circumvented by using a high-dose loperamide protocol that allowed dose escalation. Dose-dependent, reversible, noncumulative granulocytopenia was the dose-limiting toxicity (nadir, days 6 to 9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in 9% of patients. One patient died during the study, 8 days after CPT-11 treatment. Two complete responses (cervix, 450 mg/m2; head and neck, 750 mg/m2) and six partial responses in fluorouracil (5-FU)-refractory colon cancer were observed (260 to 600 mg/m2). Pharmacokinetics of CPT-11 and active metabolite SN-38 were performed in 60 patients (94 courses). CPT-11 plasma disposition was bi- or triphasic, with a mean terminal half-life of 14.2 +/- 0.9 hours (mean +/- SEM). The mean volume of distribution (Vdss) was 157 +/- 8 L/m2, and total-body clearance was 15 +/- 1 L/m2/h. The CPT-11 area under the plasma concentration versus time curves (AUC) and SN-38 AUC increased linearly with dose. SN-38 plasma decay had an apparent half-life of 13.8 +/- 1.4 hours. Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granulocytopenia, with grade 2 diarrhea, and with nausea and vomiting. CONCLUSION: The MTD of CPT-11 administered as a 30-minute IV infusion every 3 weeks is 600 mg/m2, with granulocytopenia being dose-limiting. At 350 mg/m2, diarrhea appeared dose-limiting, but high-dose loperamide reduced this toxicity and allowed dose escalation. For safety reasons, the recommended dose is presently 350 mg/m2 every 3 weeks; more experience must be gained to establish the feasibility of a higher dose in large multicentric phase II studies. However, when careful monitoring of gastrointestinal toxicities is possible, a higher dose of 500 mg/m2 could be recommended in good-risk patients. The activity of this agent in 5-FU-refractory colorectal carcinoma makes it unique and mandates expedited phase II testing.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Agranulocitose/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/farmacologia , Diarreia/induzido quimicamente , Esquema de Medicação , Feminino , Gastroenteropatias/induzido quimicamente , Meia-Vida , Humanos , Infusões Intravenosas , Irinotecano , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program. PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks. RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H-related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred. CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia de Células T/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/efeitos adversos , Antineoplásicos/efeitos adversos , Qualidade de Produtos para o Consumidor , Feminino , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Humanos , Infusões Intravenosas , Leucemia de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/induzido quimicamente , Infecções Oportunistas/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE: A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships. PATIENTS AND METHODS: Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection. RESULTS: The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome. CONCLUSION: Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , Adulto , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: To assess, on a multicenter basis, the feasibility of treating advanced cancer patients with high-dose irinotecan. PATIENTS AND METHODS: Thirty-five patients who met the usual phase I criteria (26 men and nine women) were included. Primary tumor sites were colon, head and neck, unknown primary, kidney, liver, and others. All had been previously treated. Irinotecan was given at the maximum-tolerated dose (MTD) (600 mg/m2) or the level below (500 mg/m2) as a 30-minute infusion once every 3 weeks. RESULTS: Eighteen patients were entered in the four participating centers at the MTD of 600 mg/m2. This dose level was clearly shown not to be feasible: 14 patients (78%) had grade 3 to 4 neutropenia, with febrile episodes in 11 patients; grade 3 to 4 diarrhea was observed in nine patients; and one toxic death occurred. Subsequently, 17 not heavily pretreated patients were included at 500 mg/m2 and carefully monitored. The safety of this dose level was considered acceptable: 41% of patients had grade 3 to 4 neutropenia, 24% experienced grade 3 to 4 diarrhea, and no febrile granulocytopenia or toxic death occurred. Six partial responses were documented in metastatic colorectal cancer, all in patients who had previously received conventional chemotherapy, four in patients who had exhibited progressive disease under fluorouracil (5FU)-based chemotherapy. CONCLUSION: We plan to study the higher dose-intensity 500-mg/m2 level on good-risk and carefully monitored patients. This could enlarge the spectrum of tumors sensitive to irinotecan and improve the already good results observed in colorectal cancers.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Agranulocitose/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Diarreia/induzido quimicamente , Estudos de Viabilidade , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study. PATIENTS AND METHODS: Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures. RESULTS: Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02). CONCLUSION: CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.
Assuntos
Antidiarreicos/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Diarreia/induzido quimicamente , Adulto , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Diarreia/tratamento farmacológico , Diarreia/fisiopatologia , Feminino , Humanos , Irinotecano , Loperamida/efeitos adversos , Loperamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tiorfano/efeitos adversos , Tiorfano/análogos & derivados , Tiorfano/farmacocinética , Tiorfano/uso terapêuticoRESUMO
PURPOSE: To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS: Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS: Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION: CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Diarreia/induzido quimicamente , Progressão da Doença , Esquema de Medicação , Feminino , Febre/etiologia , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Indução de RemissãoRESUMO
Data of all phase II studies of pirarubicin (THP-doxorubicin) have been analysed for toxicity or activity in breast cancer and compared with published reports on doxorubicin, epirubicin or mitoxantrone used as single drugs. A graph of the 95% confidence intervals for each event was used. The results suggest that pirarubicin is as effective as other intercalating drugs in breast cancer and grossly better tolerated than doxorubicin, especially alopecia and cumulative cardiotoxicity. The equimyelotoxic doses of each drug were also estimated. The methodology and the validity of such historical comparisons is discussed: they cannot replace prospective randomised phase III studies, and do not allow definitive conclusions. However, most comparative trials of anticancer drug analogues cannot answer the right questions because their objectives are not adequate (especially for equiefficacy). But early evaluation by historical comparisons can help the conception of phase III studies.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Avaliação de Medicamentos , Epirubicina/efeitos adversos , Epirubicina/uso terapêutico , Feminino , Humanos , Mitoxantrona/efeitos adversos , Mitoxantrona/uso terapêutico , Equivalência TerapêuticaRESUMO
Intra-arterial hepatic (i.a.h.) administration of the doxorubicin analogue pirarubicin was evaluated in a phase I trial, based on preclinical studies that showed an advantage of pirarubicin over doxorubicin after locoregional hepatic administration. Pirarubicin was given to 9 patients with metastatic liver disease with intrapatient dose escalation. Of the 58 cycles evaluable for tolerance, no hepatobiliary or vascular toxicity was observed. The dose-limiting toxicity was granulocytopenia: the maximum administered doses ranged from 50 to 120 mg/m2, suggesting variable rates of pirarubicin hepatic extraction between patients. Pharmacokinetic data obtained in 7 patients, in which a direct comparison of intravenous (i.v.) and i.a.h. administration was possible, indicated a median i.v./i.a.h. ratio of 7.4 for the maximal plasma concentration, and a median ratio of 4 for the area under the plasma concentrations versus time curves, suggesting a high pirarubicin hepatic extraction. An unexpectedly high response rate was observed: two complete (colorectal carcinoma) and two partial responses. These data demonstrate that i.a.h. pirarubicin not only produced high locoregional concentrations and reduced systemic exposure, but can also achieve responses in metastatic liver disease of colorectal origin.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Agranulocitose/induzido quimicamente , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/sangue , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Humanos , Injeções Intra-Arteriais , Injeções Intravenosas , Neoplasias Hepáticas/sangue , Resultado do TratamentoRESUMO
Colorectal cancer is one of the most common cancers in the Western World. Although 50% of patients are cured by surgery alone, the outcome is poor in high-risk patients (Dukes stages B2 and C) despite adjuvant chemotherapy with 5-fluorouracil (5-FU)-based regimens. CPT-11 (irinotecan) is a promising new agent for the treatment of colorectal cancer with a unique mechanism of action. CPT-11 is a DNA topoisomerase I inhibitor, which has not demonstrated susceptibility to the P-glycoprotein-mediated multidrug-resistant phenotype. Phase II studies with CPT-11 have demonstrated definite activity against colorectal cancer in both chemotherapy-naive and pretreated patients (response rates of 15-32% observed) even with clinical evidence of resistance to 5-FU. The response rate appears to be consistent, reproducible and equivalent to that achieved with 5-FU plus folinic acid in chemotherapy-naive patients.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Inibidores da Topoisomerase I , Camptotecina/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , IrinotecanoRESUMO
The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Adulto , Idoso , Camptotecina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30-60 mg/m2 according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m2) and continuous infusions of 5-fluorouracil (750 mg/m2 daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a two-compartmental pattern, showing half-lives of 15.6 min and 16.6 h; the total plasma clearance of the drug was 140 l/h-1/m-2, and the total volume of distribution was 2,830 l/m2. A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin.
Assuntos
Antibióticos Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacologia , Células Sanguíneas/efeitos dos fármacos , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Avaliação de Medicamentos , Feminino , Meia-Vida , Humanos , Fatores de TempoRESUMO
Intra-arterial hepatic chemotherapy (IAHC) with adriamycin (ADM) has not increased its therapeutic index. For our preclinical studies, we selected pirarubicin (THP), an ADM derivative with faster cellular uptake. In rabbits with VX2 tumor in the liver we compared plasmatic and cellular pharmacokinetics of ADM and THP after i.v. and IAH therapy. For ADM, there were no differences in plasma and heart concentrations, with only a slight increase in tumoral levels after IAH compared to i.v. administration; on the other hand, with IAH THP, there was important reduction in systemic exposure with a major increase in tumoral drug distribution. In the phase I study, involving nine patients with implanted catheters, the starting dose of THP was 30 mg/m2 with a 10 mg/m2 intrapatient escalation every 3 weeks in the absence of toxicity. Pharmacokinetics were compared for i.v. and IAH administration in seven patients. The limiting toxicity was neutropenia and the maximal tolerated dose (MTD) ranged from 50 to 110 mg/m2. Moderate nausea-vomiting (grade 1-2) and alopecia (grade 1) occurred at the MTD. No arterial occlusion, gastroduodenal ulcer, hepatitis, or sclerosing cholangitis were seen. In the phase II study, in colorectal cancer patients (CRC) with metastasis confined to the liver, patients were enrolled until June 1990. THP (40 min infusion every 3 weeks) was initiated at 60 mg/m2 with 10 mg/m2 increment until grade 2 hematotoxicity. The median MTD was 85 mg/m2 (range of 60-120 mg/m2), and the median number of cycles was 7 (range of 2-11) with cumulated doses from 180 to 1,030 mg/m2. Grade 2-4 neutropenia was reached in 15 patients. Other toxicities included two arterial occlusions, one episode of gastritis, but no hepatic toxicity and no heart failure. Antitumor effect (in 18 patients) included 1 CR, 5 PR, 3 MR, 6 NC, and 3 PD. The median survival was 18+ months and 1-year survival was 73% +/- 12%. Seven patients had extrahepatic progression at this time. In conclusion, besides 5-FU or Fudr, THP is active in IAHC (probably in relation with high local extraction) on CRC liver metastases usually unresponsive to ADM. It can be given in an outpatient setting with minimal toxicity.
Assuntos
Doxorrubicina/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Animais , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Esquema de Medicação , Avaliação de Medicamentos , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neutropenia/induzido quimicamente , CoelhosRESUMO
4'-O-Tetrahydropyranyl adriamycin (THP adriamycin) is a new anthracycline active as a single drug in advanced breast cancer. We have undertaken a phase II study as first-line treatment for metastatic disease with THP adriamycin day 1 = 40 mg/m2 i.v. bolus and 5-fluorouracil day 1 to day 5 = 750 mg/m2 as a continuous i.v. infusion. The dose of THP adriamycin was further escalated up to the maximal tolerated dose defined as grade 3 granulopenia for each patient. Thirty-nine patients were included, 37 being so far evaluable for toxicity and for efficacy. The mean number of cycles given was 5 (range: 2-12). The overall response rate (CR + PR) was 54% (95% CI: 37.9-70.1) and the CR rate 8%. Sites of response were as follows: lung 6/9, liver 11/18, breast 4/8, nodes 7/14, skin 3/8, bone 2/8. Neutropenia with grade 3 + 4 nadir values was observed in 70.2% of the patients according to the objective of the study. No severe thrombopenia or anemia occurred. Stomatitis grade 3 was seen in 27% and grade 4 in 3% of the patients. Alopecia grade 2 was seen in 18% and grade 3 in 9%. No other toxicity was observed. We conclude that this association is effective in metastatic breast cancer, giving few alopecia. A high response rate in liver metastases warrants further evaluation.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Doenças Hematológicas/induzido quimicamente , Humanos , Pessoa de Meia-IdadeRESUMO
Thirty elderly (over 70 years) women with measurable advanced breast cancer entered into this Phase II study. An initial dose of 30 mg/m2 of pirarubicin (THP) every 3 weeks was given intravenously. THP was escalated by levels of 10 mg/m2 according to the blood cell count done at day 14 and day 21 until a maximum dose per cycle of 70 mg/m2 was reached. The mean total cumulative dose of THP received was 204 mg/m2 (range 30-710 mg/m2). The mean number of cycles given was 5.5 (range 1-24). Of 28 evaluable patients, 1 achieved a complete response (CR), 6 had a partial response (PR) (CR + PR = 25%; 95% confidence interval 9-41%), 13 showed no change, and 5 had a progressive disease. The median time to progression was 3 months (range 0.5-18+ months). Of 28 patients evaluable for toxicity, the hematologic toxicity at day 15 was neutropenia grade 3 and 4 in 61% of the patients and thrombopenia grade 3 and 4, 0% of cycles. No cumulative hematologic toxicity was detected. Nonhematologic toxicities consisted of nausea and vomiting in 50% of patients (WHO grade 3 = 5%) and alopecia in 64% (WHO grade 2-3 = 36%). No stomatitis occurred. No cardiac toxicity was observed. The results of this study show that THP is an active drug in elderly patients with advanced breast cancer. Because of its safety, THP deserves further investigation in this application.