RESUMO
BACKGROUND: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6-12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy. PATIENTS AND METHODS: a detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted. RESULTS: similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357). CONCLUSION: the superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Recidiva , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina , Resultado do TratamentoRESUMO
PURPOSE: The study was undertaken to assess the antitumor activity of carboplatin 400 mg/m2 intravenously every 4 weeks in metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-four MBC patients without any prior exposure to chemotherapy entered the study. All patients had measurable disease in at least one site and were assessable for response and toxicity. RESULTS: Of 34 assessable patients, 12 obtained a complete (one) or partial (11) response to carboplatin, resulting in an overall response rate of 35% (95% confidence interval, 19.8% to 53.5%). The median duration of response was 8 months (range, 2+ to 12 months). Responses were seen in lymph nodes (four of six), lung (five of nine), skin and soft tissues (four of nine), breast (two of eight), and liver (three of 11), but not in measurable lytic lesions of the bone. Toxicity was mild, mainly consisting of emesis (81% of the patients; 66% of the courses), leukopenia of World Health Organization (WHO) grade 1 to 2 (47% of the patients; 18% of the courses), and thrombocytopenia (12% of the patients; 3% of the courses). There were no cases of life-threatening toxicity, although one patient developed grade 4 thrombocytopenia without bleeding. Of 22 patients who did not respond to carboplatin, 18 received salvage therapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF; 15 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; one patient); or hormones (two patients). Objective responses to CAF and hormonal therapy were seen in 11 of 15 and two of two patients, respectively. The remaining patient did not respond to CMF salvage chemotherapy. Overall, the response rate to either first-line carboplatin or second-line salvage therapy was 73.5% (25 of 34 patients). After a median follow-up time of 22 months, the median survival was 19 months. CONCLUSIONS: Carboplatin is an active drug in MBC patients without previous exposure to chemotherapy. In our study, the use of an experimental drug as first-line single-agent treatment in MBC did not have a negative influence on patient survival, as the majority of the carboplatin nonresponding patients could be salvaged with a conventional therapeutic regimen.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carboplatina/uso terapêutico , Análise Atuarial , Adulto , Idoso , Neoplasias da Mama/patologia , Carboplatina/efeitos adversos , Avaliação de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Terapia de Salvação , Análise de SobrevidaRESUMO
PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Vidarabina/uso terapêutico , Adolescente , Alemtuzumab , Anticorpos Monoclonais Humanizados , Antígenos CD/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Prolinfocítica de Células T/patologia , Masculino , Neutropenia/induzido quimicamente , Infecções Oportunistas , Projetos Piloto , Indução de Remissão , Terapia de Salvação , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Falha de Tratamento , Resultado do Tratamento , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosRESUMO
PURPOSE: This study was undertaken to assess the antitumor activity and tolerance of chronic oral etoposide (50 mg/m2/d for 21 days every 4 weeks) in metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-three consecutive metastatic breast cancer patients with at least one site of measurable disease entered the study. All patients had received prior chemotherapy (adjuvant, three patients; adjuvant plus chemotherapy for metastases, 21; chemotherapy for metastases, 19). Twenty-two and 21 patients had also received prior hormonal and radiation therapy, respectively. RESULTS: Thirty-five percent of patients (15 of 43; 95% confidence interval, 21% to 51%) had objective responses, according to an intention-to-treat analysis. Responses were seen in lymph nodes (six of 14), skin and soft tissues (eight of 16), lung (six of 14), lytic lesions of the bone (two of six), liver (four of 23), and peritoneum (one of one). The median duration of response was 7 months (range, 3+ to 12). The main toxic side effects were leukopenia (overall, 65% of patients; World Health Organization [WHO] grade 4, 21%), thrombocytopenia (21%; WHO grade 4, 5%) and anemia (51%; WHO grade 4, 5%). Nine patients (21%) required a 25% dose reduction because of myelosuppression, and one patient abandoned treatment because of gastrointestinal toxicity and severe asthenia. Ninety-one percent of patients developed alopecia, 39.5% had mucositis (WHO grade 3, 9.5%) and 60.5% had some degree of emesis (11.5% nausea, 46.5% transient vomiting, 2.5% intractable vomiting). No toxic deaths occurred. CONCLUSION: Chronic oral etoposide appears to be an active and well-tolerated regimen in MBC patients previously exposed to chemotherapy. This schedule of etoposide administration warrants further studies, alone or in combination, in MBC.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Etoposídeo/uso terapêutico , Administração Oral , Adulto , Idoso , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
Immunotherapy utilizing CAMPATH-1H for patients with chemotherapy-refractory chronic lymphocytic leukemia has yielded encouraging results with many reports of complete remission. Here we report the outcome of two patients with CD4-positive T cell prolymphocytic leukemia treated with CAMPATH-1H. Both patients responded rapidly to treatment and subsequently developed CD4 lymphopenia. One patient remained in complete remission after 14 weeks of treatment. Serial peripheral blood flow cytometry revealed that the CD52 antigen was present throughout treatment. The other patient who was initially CD52-positive, became CD52-negative after 6 weeks of treatment, and developed progressive symptoms of T cell prolymphocytic leukemia. Immunotherapy was stopped, chemotherapy proved futile, and the patient died. This change in phenotype from CD52-positive to -negative during CAMPATH-1H therapy points out a need to develop strategies for maintaining antigenic expression during monoclonal antibody therapy.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antineoplásicos/farmacologia , Antígenos CD/análise , Antígenos de Neoplasias , Resistencia a Medicamentos Antineoplásicos , Glicoproteínas/análise , Leucemia Prolinfocítica/patologia , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Antígenos CD/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Antígeno CD52 , Evolução Fatal , Feminino , Glicoproteínas/efeitos dos fármacos , Humanos , Imunofenotipagem , Leucemia Prolinfocítica/tratamento farmacológico , Leucemia Prolinfocítica/genética , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Indução de RemissãoRESUMO
This Phase I and pharmacological study was performed to assess the feasibility of administering the polycyclic aromatic hydrocarbon crisnatol in increasingly prolonged continuous i.v. infusions to patients with advanced solid malignancies. The study also sought to characterize the-principal toxicities of crisnatol on this schedule, to recommend doses for subsequent disease-directed studies, and to characterize possible associations between pharmacological parameters and toxicity. Sixteen patients were treated with 40 courses of crisnatol administered as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m2/day for 6 days, and the duration of the infusion was to be progressively increased by 3-day increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks. Moderate to severe central nervous system (CNS) toxicity precluded the administration of crisnatol 750 mg/m2/day for longer than 6 days, and, therefore, the dose of crisnatol was reduced to 600 mg/m2/day. At this dose, three of five patients receiving a 12-day infusion experienced dose-limiting toxicity, which consisted of pulmonary thromboembolism (two patients) and grade 4 thrombocytopenia (one patient). None of the six patients completing a 9-day infusion at 600 mg/m2/day developed dose-limiting toxicity during the first or second course of crisnatol. At this dose level, the plasma concentrations at steady state (Css) averaged 1607.8+/-261.1 ng/ml, which exceeds minimal inhibitory concentrations for most tumors in vitro (1000 ng/ml). In fact, the administration of crisnatol at a dose of 600 mg/m2/day for 9 days resulted in the longest duration that biologically relevant plasma crisnatol concentrations have been sustained. Plasma Css values were significantly higher in patients who experienced severe CNS toxicity compared with those who did not (2465.3+/-1213.5 versus 1342+/-447.3 ng/ml; P = 0.04). There were no relationships evident between the clearance of crisnatol and indices reflecting renal and hepatic functions. One patient with a glioblastoma multiforme experienced a partial response lasting 14 months. The relative lack of intolerable CNS toxicity at the recommended dose for Phase II studies of crisnatol, 600 mg/m2/day for 9 days, as well as the magnitude of the Css values achieved and the antitumor activity observed at this dose, are encouraging. However, the mechanisms for the apparently increased thrombogenicity observed in this trial are unclear and require further elucidation.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Crisenos/efeitos adversos , Crisenos/farmacocinética , Neoplasias/tratamento farmacológico , Propilenoglicóis/efeitos adversos , Propilenoglicóis/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Crisenos/administração & dosagem , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Propilenoglicóis/administração & dosagem , Embolia Pulmonar/induzido quimicamente , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: To study the human pharmacokinetics and in vitro cytotoxicity of Apomine, an p.o. administered, nonmyelosuppressive agent that selectively inhibits cell proliferation and induces tumor cell apoptosis through the farnesoid X receptor. EXPERIMENTAL DESIGN: Seven solid cancer patients who participated in an ongoing Phase I study of Apomine and received the starting dose level of 125 mg/m(2)/day x 14 days every 3 weeks underwent a pharmacokinetic study on day 14 of the first course. Plasma concentrations of Apomine were assayed with a Hewlett Packard gas chromatograph using a nitrogen phosphorus detector and HP-5 15m x 0.32-mm column. Fresh human ovarian cancer tumor samples were obtained during initial exploratory laparotomy from 35 chemotherapy-naive, advanced stage epithelial ovarian cancer patients. Tumor samples were tested for sensitivity to Apomine, carboplatin, cisplatin, paclitaxel, and topotecan using an in vitro clonogenic [(3)H]thymidine end point assay. RESULTS: Pharmacokinetic analysis revealed a mean Apomine plasma C(max) of 16.4 +/- 9.1 microg/ml (29.1 microM), a mean plasma AUC(0--12 h) of 173.4 +/- 105 microg. h/ml (308 microM. h), and a mean t(1/2 (24--192 h)) of 156.2 +/- 42.9 h. In vitro assay results showed that 63 and 91% of the ovarian cancers were sensitive (i.e., >70% inhibition of tumor cell growth) to Apomine at concentrations of 10 and 20 microM. The sensitivity rates were 91% for carboplatin (270 microM), 88% for cisplatin (33 microM), 41% for paclitaxel (5.9 microM), and 85% for topotecan (2.2 microM). CONCLUSIONS: These in vitro assay results, taken together with our preliminary plasma pharmacokinetic data, suggest that Apomine should be clinically active at the 125 mg/m(2) dose level.
Assuntos
Antineoplásicos/farmacocinética , Difosfonatos/farmacocinética , Neoplasias/metabolismo , Administração Oral , Antineoplásicos/uso terapêutico , Divisão Celular/efeitos dos fármacos , Difosfonatos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Células Tumorais CultivadasRESUMO
Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivative of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for formulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly and completely converted to VP-16. Clinical development of the i.v. formulation has focused on the identification of the maximum tolerated dose (MTD) and pharmacokinetic characteristics of the drug using a 5 daily dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Data from these trials show the rapid and complete conversion of EP to VP-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppression and exposure to VP-16, and an MTD of 100 and 150 mg/m2 (molar equivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5, respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and treatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacokinetically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient administration; and ability to be given as a bolus, at high concentrations, and as a continuous infusion.
Assuntos
Etoposídeo/análogos & derivados , Neoplasias/tratamento farmacológico , Compostos Organofosforados/farmacocinética , Compostos Organofosforados/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Etoposídeo/toxicidade , Humanos , Infusões Intravenosas , Contagem de Leucócitos/efeitos dos fármacos , Compostos Organofosforados/administração & dosagemRESUMO
Phosphohexose isomerase (PHI) and carcinoembryonic antigen (CEA) were measured at the time of diagnosis in 300 patients with lung cancer. Serum levels were high in 75.7% and 53.0% of patients respectively. PHI levels were higher in large cell and small cell carcinomas (p less than 0.001). CEA levels were higher in adenocarcinomas (p less than 0.001). Metastatic carcinomas showed higher levels on PHI and CEA than localized cases. Survival was significantly longer in patients with normal PHI (p less than 0.001) and normal CEA (p less than 0.005) than in cases with elevated markers. The prognostic significance of PHI persisted in the different pathological types and stages, whereas CEA only had prognostic impact in non-small cell cases. Serial PHI determinations were useful for follow-up in 82.4% of cases with initial abnormal values and in 55.4% of cases with a normal value. Serial CEA was useful in 41% of cases with initially high value but in less than 15% of those with baseline normal. We conclude that PHI has prognostic significance independently of pathology and stage, whereas CEA was a prognostic indicator only in non-small cell cases; serial PHI determinations were useful more often than CEA for follow-up.
Assuntos
Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/análise , Glucose-6-Fosfato Isomerase/sangue , Neoplasias Pulmonares/diagnóstico , Sobrevivência Celular , Feminino , Humanos , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de NeoplasiasRESUMO
The aim of this work was to study the possible utility of simultaneous determination of CA 125 and CA 19.9 in patients with lung cancer. Serum levels of both markers were studied in 87 patients without metastases (Mo), 72 patients with distant metastases (MT) and 15 cases without clinical evidence of disease after primary treatment (NED). Sixty-five tumors were epidermoid, 34 were adenocarcinomas, 24 were cell undifferentiated carcinomas and 51 were small-cell carcinomas. Sera from 75 healthy subjects and 20 patients with benign lung disease were used as controls. The cut-off values used were 35 and 37 U/ml for CA 125 and CA 19.9, respectively. CA 125 and CA 19.9 serum levels were within normal limits in all control patients. In NED patients these markers were not elevated, except in one with chronic liver disease who showed elevated CA 19.9 (76 U/ml). Twenty-five percent of Mo lung cancer patients and 40.3% of MT cases had CA 19.9 over 37 U/ml. Abnormally high levels of CA 125 were found in 18.7% and 22.9% of Mo and MT patients, respectively. Sixty percent of patients with large cell undifferentiated carcinoma had elevated CA 125 (mean 176 U/ml) compared to 15.4% of patients with all other histological types of tumors combined (54.3 U/ml, p less than 0.01). CA 19.9 serum levels were also more often elevated in patients with large cell undifferentiated carcinomas (50%, 7/14 cases) than in other histological types (30%, 36/120 patients), but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antígenos Glicosídicos Associados a Tumores/sangue , Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Pequenas/sangue , Carcinoma de Células Pequenas/imunologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/imunologia , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologiaRESUMO
Sixteen patients with hepatic metastases of histologically documented breast cancer were treated with etoposide (VP 16-213) and cyclophosphamide. Previously, 6 had shown relapse in the liver after adjuvant chemotherapy, 2 had failed to respond to another chemotherapy combination, and 8 had never undergone chemotherapy. Fifty percent responded to treatment, including 1 complete remission and 7 partial responses. Median survival was 16 months and median duration of response was 13 months. All patients showed alopecia and moderate leukopenia; 13 experienced moderate gastrointestinal toxicity; there was 1 mild case of anemia and 1 case of moderate hemorrhagic cystitis. This study suggests that the combination of VP 16-213 and cyclophosphamide is a well-tolerated and effective treatment in advanced breast cancer patients with liver metastases.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Sinergismo Farmacológico , Etoposídeo/administração & dosagem , Feminino , Humanos , Injeções Intravenosas , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
This bibliographic review evaluated phase II clinical trials aimed at the identification of antitumor activity of single agents in soft tissue sarcoma (STS) after failure of standard- of-care therapy including anthracyclines and ifosfamide. A total of 63 articles (on anthracyclines, ifosfamide, trabectedin and 27 investigational agents) were included (data from 1979 to 2008).Trabectedin is the most extensively studied agent in patients with STS after failure of anthracyclines and ifosfamide (457 patients), followed by ifosfamide (412), cisplatin (144), temozolomide (137), docetaxel (114), gemcitabine (112), etoposide (95) and doxorubicin (59). Dacarbazine and the remaining investigational agents have usually been tested in 50 or fewer patients, with vastly negative results not warranting further investigation. Methodological limitations are identified in the majority of the reviewed phase II studies, including small sample size, single-institution studies, lack of independent review of the antitumor responses and inadequate description of previous therapies/agents. However, all trabectedin studies fulfilled these methodological characteristics relevant for a phase II trial. A phase II randomized trial confirmed the results of 3 prior nonrandomized studies and, therefore, trabectedin is currently considered an important new option to control advanced sarcomas in patients with STS following failure of all conventional treatments.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacologia , Ensaios Clínicos Fase II como Assunto , Dioxóis/efeitos adversos , Dioxóis/farmacologia , Humanos , Farmacogenética , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/genética , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/genética , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/farmacologia , TrabectedinaRESUMO
BACKGROUND: The purpose of the study was to evaluate the effects of erlotinib on epidermal growth factor receptor (EGFR)-related signaling elements in tumor and skin from patients with advanced squamous cell carcinoma of the head and neck (HNSCC) and seek relationships between relevant clinical, biological, and pharmacokinetic parameters. PATIENTS AND METHODS: Immunostaining for EGFR, p-EGFR, p-ERK, p-Akt, and p27 were analyzed semiquantitatively in serial tumor and skin samples from participating patients. Steady-state trough concentrations of erlotinib and its metabolite OSI-420 were also determined. RESULTS: Of 25 patients enrolled, 20 (80%) paired pre- and posttreatment skin biopsies and seven (28%) paired tumor biopsies were evaluable for at least one immunohistochemical parameter. The severity of skin toxicity related to time to progression (TTP) (P = 0.048) and overall survival (P < 0.001). C(ss,min) values for erlotinib and OSI-420 also related to TTP (P = 0.042 and 0.036, respectively). Erlotinib treatment was associated with decreased p-EGFR expression in 66% of evaluable tumor samples, which seemed related to increased TTP and survival, and p27 was up-regulated in 59% of evaluable skin biopsy samples following treatment. CONCLUSIONS: The feasibility of obtaining serial evaluable biopsies of HNSCC was suboptimal. Nevertheless, erlotinib inhibited p-EGFR in HNSCC tumors, which appeared associated to clinical benefit, and induced p27 in biopsies of normal skin.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quinazolinas/uso terapêutico , Pele/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/mortalidade , Inibidor de Quinase Dependente de Ciclina p27/análise , Receptores ErbB/análise , Cloridrato de Erlotinib , MAP Quinases Reguladas por Sinal Extracelular/análise , Feminino , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Quinazolinas/efeitos adversosRESUMO
Progressive hearing loss after cisplatin therapy is relatively frequent, specially in older patients, but it is less common in children and in acute form. The case of a 17-year-old patient with an intracranial tumor who suffered sudden deafness after a single course of cisplatin is presented. This patient had a previously documented very good hearing up to 20 kHz. Although it has been suggested that children with irradiated brain tumors may have an increased susceptibility to cisplatin-induced hearing loss, in this case the patient had not been subjected to radiotherapy.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Cisplatino/efeitos adversos , Disgerminoma/tratamento farmacológico , Perda Auditiva Súbita/induzido quimicamente , Adolescente , Cisplatino/uso terapêutico , Humanos , MasculinoRESUMO
Ninety previously untreated patients with histologically documented lung cancer were treated with VP-16 and cyclophosphamide either alone (protocol I) or with methotrexate (protocol II) or Adriamycin (protocol III), with 30 patients in each protocol. The rates of objective response were 57,37, and 27%, respectively, protocol I being significantly better than protocol III (P less than 0.05). Protocol I was significantly less toxic than protocols II(P less than 0.01) and III (P less than 0.001). The overall rate of objective responses was 66% in small cell (SCC) and 22% in non-small cell carcinoma (nSCC). Median survival was 37 weeks in SCC and 21 weeks in nSCC. Median survival of responders both in SCC and in nSCC was significantly longer than in nonresponders. We conclude that VP-16 plus cyclophosphamide is a well tolerated regimen with positive effect in advanced lung cancer. The association of methotrexate or Adriamycin didn't offer any improvement over the basic combination in this study.
Assuntos
Carcinoma de Células Pequenas/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Podofilotoxina/análogos & derivados , Adulto , Idoso , Carcinoma de Células Pequenas/mortalidade , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , ProbabilidadeRESUMO
Twenty-two patients with metastatic breast carcinoma were treated with a combination of cisplatin (100 mg/m2 i.v. day 1) and etoposide (100 mg/m2 i.v. days 1-3). Eligible patients had measurable disease with normal organ functions, performance status < 3, age < 70 years and no previous chemotherapy for metastatic disease. Twenty patients were assessable for response. Objective responses were seen in 50% (95% confidence limits: 24.4-67.8). One patient achieved a complete response. Objective response was observed in patients with visceral metastatic disease and who had received anthracyclin-containing regimens in previous chemotherapy. Median survival after therapy was 55 weeks. Median time to progression was 23 weeks. Hematologic toxicity was limiting. Cisplatin plus etoposide is an active combination in advanced breast cancer.