RESUMO
BACKGROUND: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER: NCT02184195.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Qualidade de VidaRESUMO
BACKGROUND: The goal of this study was to create a comprehensive model for malignant pleural mesothelioma patient survival utilizing continuous, time-varying estimates of disease volume from computed tomography (CT) imaging in conjunction with clinical covariates. PATIENTS AND METHODS: Serial CT scans were obtained during the course of clinically standard chemotherapy for 81 patients. The pleural disease volume was segmented for each of the 281 CT scans, and relative changes in disease volume from the baseline scan were tracked over the course of serial follow-up imaging. A prognostic model was built using time-varying disease volume measurements in conjunction with clinical covariates. RESULTS: Over the course of treatment, disease volume decreased by an average of 19%, and median patient survival was 12.6 months from baseline. In a multivariate survival model, changes in disease volume were significantly associated with patient survival along with disease histology, Eastern Cooperative Oncology Group performance status, and presence of dyspnea. CONCLUSIONS: Analysis of the trajectories of disease volumes during chemotherapy for patients with mesothelioma indicates that increasing disease volume was significantly and independently associated with poor patient prognosis in both univariate and multivariate survival models.
Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/diagnóstico por imagem , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Pemetrexede , Neoplasias Pleurais/patologia , Prognóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS: Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Placebos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/imunologia , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Paclitaxel/farmacocinéticaRESUMO
One of the most widely used drugs in cancer chemotherapy is 5-fluorouracil (5-FU). 5-FU is optimally delivered via continuous iv. infusion, which is both cumbersome and expensive. Prolonged oral dosing of 5-FU could mimic continuous infusion with less inconvenience and cost. However, oral administration of 5-FU has been hampered by incomplete and erratic bioavailability due to substantial variability in the activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism. Eniluracil (ethynyluracil, GlaxoWellcome, USA), a uracil analogue, which irreversibly inhibits DPD, increases the oral bioavailability of 5-FU to 100%, facilitating uniform absorption and predictable toxicity. Cytotoxicity is enhanced one- to five-fold in cell lines treated with eniluracil plus 5-FU compared with 5-FU alone. Though eniluracil is neither toxic nor active as a single agent in animals, it improves the antitumour efficacy and therapeutic index of 5-FU. In Phase I trials, eniluracil markedly reduced the maximum tolerated dose of oral 5-FU, increased the half-life 20-fold and decreased the clearance 22-fold. DPD is completely inactivated within 1 h of eniluracil administration. Two dosing schedules have been evaluated in combination with oral 5-FU: a 5-day schedule every 28 days and a 28-day schedule every 35 days. The dose-limiting toxicity on the first schedule is myelosuppression with diarrhoea being dose-limiting on the 28-day schedule. Phase II trials employing the 28-day schedule have been completed in cancers of the colon, breast, liver and pancreas. Phase III trials in colorectal and pancreatic carcinoma have been completed and await analysis. Eniluracil is a promising drug, which permits reliable and safe administration of oral 5-FU and has the potential to overcome 5-FU resistance mediated by overexpression of DPD.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Oxirredutases/farmacologia , Uracila/análogos & derivados , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Ensaios Clínicos como Assunto , Di-Hidrouracila Desidrogenase (NADP) , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Oxirredutases/uso terapêutico , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/farmacologia , Uracila/uso terapêuticoRESUMO
PURPOSE: The CALGB conducted a phase II multicenter trial to evaluate the activity of gemcitabine in malignant mesothelioma (CALGB protocol 9530). PATIENTS AND METHODS: Seventeen patients were accrued between February 1996 and May 1996 and received gemcitabine 1500 mg/m(2) by intravenous infusion over 30 min weekly for 3 weeks, followed by a 1 week break. Eligibility included a performance status of 0-2 by CALGB criteria, and no prior chemotherapy. Nine patients had epithelial cell type and eight had mixed or sarcomatoid cell types. There were 11 cases with measurable disease and six with evaluable disease. RESULTS: There were no complete or partial responders. Eight patients had stable disease, seven developed progressive disease, and two were not evaluable for tumor response. Two patients had minor responses. Median survival from study entry was 4.7 months (95% CI 3.1-12.9 months); one year survival was 24% (95% CI 10-55%). One patient remains alive at 37 months. There were two early deaths, one from disease progression and one from pneumonia. Toxicity was mild and included anemia, lymphopenia and infection; no patient experienced grades three or four thrombocytopenia. CONCLUSION: No antitumor activity was observed for single-agent gemcitabine in patients with malignant mesothelioma in this multicenter phase II study.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/farmacologia , Mesotelioma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Feminino , Humanos , Infusões Intravenosas , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Resultado do Tratamento , GencitabinaRESUMO
Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiopatias/induzido quimicamente , Mesotelioma/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Razoxano/administração & dosagem , Trombocitopenia/induzido quimicamenteRESUMO
5-Fluorouracil (5-FU) has been utilized as part of standard chemotherapy for treatment of early-stage and metastatic colorectal cancer for more than 4 decades. The oral fluoropyrimidines have been studied extensively as an alternative to intravenous 5-FU. The goal of such an approach is to simplify drug administration and to improve the toxicity profile while maintaining efficacy that is at least equivalent to intravenous therapy. The goal of this article is to review the features of the main oral 5-FU prodrugs, which include capecitabine, uracil and tegafur (UFT)/leucovorin, S-1, and BOF-A2 and to describe their potential efficacy in treating colorectal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fluoruracila/administração & dosagem , Pró-Fármacos/administração & dosagem , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Capecitabina , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Combinação de Medicamentos , Fluoruracila/efeitos adversos , Fluoruracila/metabolismo , Fluoruracila/farmacologia , Humanos , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Ácido Oxônico/administração & dosagem , Cooperação do Paciente , Piridinas/administração & dosagem , Tegafur/administração & dosagem , Resultado do TratamentoRESUMO
Topotecan (9-dimethylaminoethyl-10-hydroxycamptothecin) is a topoisomerase I inhibitor. Twenty-six patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) who had received no prior chemotherapy were treated in a multicenter study with topotecan 0.6 mg/m2/day for 21 days by continuous intravenous infusion every 28 days; this starting dose was decreased to 0.5 mg/m2/day in the last 23 patients because of myelosuppression. There was one partial response, for a response rate of 4% (95% confidence interval, 0.1%-19.6%). Median survival was 9 months. One-year survival was 39%. Of the 58 lung cancer symptoms at baseline, 40% were resolved by the end of best response (all in the partial response patient, 62% in stable disease patients, 26% in progressive disease patients). Catheter-related infections complicated 19% of courses. Red-cell transfusions were given in 50% of courses. Toxicity included grade 4 neutropenia (4%), grade 3-4 anemia (19%), grade 4 thrombocytopenia (8%), and catheter-related infections (19% courses). Although the major objective response rate was only 4%, patients treated with topotecan given as a 21-day continuous intravenous infusion experienced a decrease in cancer-related symptoms and a 1-year survival of 39%.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Topotecan/administração & dosagem , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Feminino , Humanos , Bombas de Infusão , Infusões Intravenosas , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Inibidores da Topoisomerase I , Topotecan/uso terapêuticoRESUMO
BACKGROUND: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin. METHODS: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months. RESULTS: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501. CONCLUSIONS: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Mesotelioma/mortalidade , Mesotelioma Maligno , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede , Fragmentos de Peptídeos/administração & dosagem , Resultado do Tratamento , Fosfatases cdc25/administração & dosagemRESUMO
BACKGROUND: This randomized phase III study compared the overall survival (OS) of pemetrexed plus gemcitabine (PG) versus standard gemcitabine (G) in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with unresectable locally advanced or metastatic pancreatic cancer and no prior systemic therapy (including 5-fluorouracil as a radiosensitizer) were randomized to receive either 1,250 mg/m(2) gemcitabine on days 1 and 8 plus pemetrexed 500 mg/m(2) after gemcitabine on day 8 (PG arm) of each 21-day cycle, or gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of each 28-day cycle (G arm). RESULTS: Five hundred and sixty-five patients with well-balanced baseline characteristics were randomly assigned (283 PG, 282 G). OS was not improved on the PG arm (6.2 months) compared with the G arm (6.3 months) (P=0.8477). Progression-free survival (3.9 versus 3.3 months; P=0.1109) and time to treatment failure (3 versus 2.2 months; P=0.2680) results were similar. Tumor response rate (14.8% versus 7.1%; P=0.004) was significantly better on the PG arm. Grade 3 or 4 neutropenia (45.1% versus 12.8%), thrombocytopenia (17.9% versus 6.2%), anemia (13.9% versus 2.9%), febrile neutropenia (9.9% versus 0.4%; all P <0.001) and fatigue (15% versus 6.6%; P=0.002) were significantly more common on the PG arm. Four treatment-related deaths occurred on the PG arm and none in the G arm. CONCLUSIONS: Pemetrexed plus gemcitabine therapy did not improve OS. Single-agent gemcitabine remains the standard of care for advanced pancreatic cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Neoplasias Pancreáticas/patologia , Pemetrexede , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
Despite innumerable trials of surgery, radiotherapy, and countless chemotherapeutic drugs, it is unclear whether any intervention has had a significant impact on more than a few highly selected patients with malignant pleural mesothelioma. Because most patients die of respiratory failure from extensive disease progression in the thorax, treatment usually includes attempts at local control. Unfortunately, radiotherapy is associated with significant complications in pleural mesothelioma, and surgery is feasible in only a small percentage of patients. Although there have been several single-institution reports of combined-modality therapy with extrapleural pneumonectomy, postoperative radiation, and chemotherapy in which prolonged survival has been observed, most patients with malignant pleural mesothelioma have locally advanced disease, advanced age, or comorbid medical illnesses that preclude aggressive surgery. Therefore, the use of a systemic anticancer agent is the only treatment option for most patients with malignant pleural mesothelioma. Evaluation of effective chemotherapy regimens for this disease has been hampered by many factors. Because mesothelioma is an uncommon malignancy, most studies have enrolled small numbers of patients, and few trials have been randomized. The disease is heterogeneous, yet until recently there was no single staging system that could reliably predict survival, nor is there a universally accepted set of prognostic criteria for selecting a uniform group of patients. Response assessment has been limited by the inherent difficulties of reproducibly measuring pleural-based disease. The real impact of systemic chemotherapy on the natural history of malignant mesothelioma is still uncertain because phase III trials comparing chemotherapy with best supportive care have not yet been completed. Although nearly every class of cytotoxic agent has been evaluated in mesothelioma, response rates of greater than 20% have not been consistently demonstrated for any drug. The most active drug classes are the antifolates, the anthracyclines, and the platinums. Doxorubicin has historically been considered the gold-standard chemotherapy, although its true response rate is likely only 15%. The most active commercially available drug for mesothelioma so far appears to be gemcitabine. Although gemcitabine has a limited role as a single agent, it is quite active in combination with a platinating agent. The impressive 48% response rate reported for the combination of gemcitabine with cisplatin in a single phase II study has made this regimen the new standard of care for off-protocol treatment of this disease, although this trial still requires validation. With the recent introduction of several new agents with definite activity in this disease, the therapeutic nihilism previously associated with malignant pleural mesothelioma is gradually being replaced by a cautious optimism. Early trials of angiogenesis inhibitors, gene therapy, and vaccines offer additional avenues for treatment. As we begin to incorporate these active new drugs with each other and in adjuvant and neoadjuvant treatment regimens, there is reason to believe that superior results for patients with malignant pleural mesothelioma can be achieved in the near future.
Assuntos
Mesotelioma/terapia , Neoplasias Pleurais/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Imunoterapia , Mesotelioma/patologia , Estadiamento de Neoplasias , Cuidados Paliativos , Neoplasias Pleurais/patologia , Prognóstico , RadioterapiaRESUMO
Despite advances in screening procedures and the use of adjuvant therapy, approximately 50% of patients with colorectal cancer eventually will develop metastatic disease. Long-term disease-free survival can be achieved in 25% to 40% of selected patients who undergo resection of liver or lung metastases. For all other patients, treatment is palliative. For decades, 5-fluorouracil was the only available drug for colorectal cancer; hence, numerous trials were performed that used various administration schedules and modulating agents to improve therapeutic efficacy. The addition of leucovorin to 5-FU improves response but not survival. Infusion schedules alter the toxicity profile but have a negligible impact on survival. Irinotecan was the first new drug to demonstrate activity in colorectal cancer. It was used initially in the second-line setting, where it was shown to improve quality of life and survival over best supportive care or infusional 5-FU. Recently, irinotecan has been incorporated into the front-line treatment of metastatic colorectal cancer in combination with 5-FU and leucovorin; this combination improves survival by approximately 3 months. Careful patient selection and adherence to strict dose adjustments are essential to prevent significant toxicity when patients are treated on this regimen. The oral fluoropyrimidine capecitabine recently has been approved for the front-line treatment of patients with colorectal cancer who are not appropriate candidates for combination therapy. Oxaliplatin, a novel DACH (diaminocyclohexane) platinum with definite activity in colorectal cancer, is approved for this disease in Europe and is undergoing phase III clinical trials in the United States. Other drugs with potential activity in colorectal cancer include raltitrexed, pemetrexed disodium, and the epothilone analog BMS-247550 (Bristol-Myers Squibb, New York, NY). Novel cytostatics with promising activity in colorectal cancer are being evaluated in clinical trials, including epidermal growth factor receptor inhibitors, such as IMC-C225 (Imclone Systems, New York, NY) and ZD1839 (AstraZeneca, London, UK), angiogenesis inhibitors such as bevacizumab and SU5416 (Sugen, San Francisco, CA), and vaccines such as CEAVac (Titan Pharmaceuticals, San Francisco, CA). For those patients whose disease is localized to the liver, there also is an emerging role for local therapies, including cryosurgery, radiofrequency ablation, and hepatic artery infusional chemotherapy, and resection. The emergence of these new drugs and new interventional modalities has allowed physicians who treat colorectal cancer to move beyond 5-FU.
Assuntos
Adenocarcinoma/secundário , Neoplasias Colorretais/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/epidemiologia , Terapia Combinada , Métodos Epidemiológicos , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapiaRESUMO
BACKGROUND: Flavopiridol, a synthetic flavone that inhibits cell cycle progression, has demonstrated activity in colon cancer in xenografts and in a phase I trial. We evaluated flavopiridol in a phase II trial in patients with previously untreated advanced colorectal cancer (ACRC). PATIENTS AND METHODS: Twenty chemotherapy-naïve patients with ACRC received flavopiridol at a dose of 50 mg/m(2)/day via a 72-h continuous infusion every 14 days. Response was assessed by computed tomography or magnetic resonance imaging every 8 weeks. RESULTS: Twenty patients were enrolled; 19 were evaluable for toxicity and 18 for response. There were no objective responses. Five patients had stable disease lasting a median of 7 weeks. The median time to progression was 8 weeks. Median survival was 65 weeks. The principal grade 3/4 toxicities were diarrhea, fatigue and hyperglycemia, occurring in 21%, 11% and 11% of patients, respectively. Other common toxicities included anemia, anorexia and nausea/vomiting. CONCLUSIONS: Flavopiridol in this dose and schedule does not have single-agent activity in patients with ACRC. Recent preclinical data suggest that flavopiridol enhances apoptosis when combined with chemotherapy. Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in ACRC.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Flavonoides/administração & dosagem , Invasividade Neoplásica/patologia , Piperidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias Colorretais/mortalidade , Intervalos de Confiança , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Flavonoides/efeitos adversos , Seguimentos , Humanos , Infusões Intravenosas , Imageamento por Ressonância Magnética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Piperidinas/efeitos adversos , Probabilidade , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Azobenzenearsonate-specific cloned mouse T cells able to transfer delayed hypersensitivity reactions in vivo produced macrophage agglutination factor (MaggF) after stimulation with mitogen or antigen in vitro. Mitogen (Con A) elicited MAggF production directly from T cells. Responses to Ag were Ag-specific, required syngeneic accessory cells in addition to T cells, and were independent of T cell fine specificity for azobenzenearsonate. Mouse MAggF shared a number of biochemical and immunochemical properties with the fibronectins (FN): 1) high Mr similar to that of plasma FN; 2) binding to gelatin, heparin, and polyclonal antibodies and mAb specific for cellular and plasma FN; 3) inhibition of activity in solution by monoclonal anti-human FN directed against plasma FN gelatin-binding domain; and 4) action on peritoneal exudate macrophages mediated through a FN-receptor cross reactive with one on human monocytes. MAggF production required active protein synthesis and was associated with significant increases in gelatin-binding immunoreactive FN (Mr 440 kDa on immunoblotting) in culture supernatants and T cell lysates. Metabolically labeled peptides could be precipitated by anti-FN from culture supernatants of activated T cells. Stimulated cultures contained significantly more cells with immunohistologically demonstrable cytoplasmic FN than unstimulated control cultures. We suggest that T cell FN is a distinct species of cellular FN which may play an important role in mediating delayed hypersensitivity inflammatory reactions in vivo.
Assuntos
Fibronectinas/fisiologia , Linfocinas/biossíntese , Linfócitos T/metabolismo , Animais , Fracionamento Celular , Sistema Livre de Células , Células Cultivadas , Células Clonais/metabolismo , Fibronectinas/análise , Fibronectinas/imunologia , Gelatina/metabolismo , Haptenos/imunologia , Heparina/metabolismo , Imuno-Histoquímica , Linfocinas/isolamento & purificação , Linfocinas/metabolismo , CamundongosRESUMO
BACKGROUND: The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL). PATIENTS AND METHODS: Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks. RESULTS: Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%). CONCLUSIONS: Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Epotilonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Carcinoma/tratamento farmacológico , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Falha de TratamentoRESUMO
BACKGROUND: The Cancer and Leukemia Group B (CALGB) conducted sequential Phase II multicenter trials to evaluate the activity of edatrexate alone (E) or with leucovorin rescue (EL) in patients with malignant pleural mesothelioma (CALGB Protocol 9131). METHODS: Twenty patients were accrued to the E portion of the study and received edatrexate, 80 mg/m(2), intravenously over 20-30 minutes weekly. After a protocol amendment precipitated by excessive toxic events with E, 40 patients were enrolled in the EL arm and received the same dose of edatrexate with leucovorin, 15 mg orally, every 6 hours for 4 doses beginning 24 hours after edatrexate. Eligibility criteria included a CALGB performance status of 0-2 and no prior chemotherapy. A central pathology review was performed. Of the 58 patients included in this analysis (20 receiving E and 38 receiving EL), 36 had epithelial cell type and 22 had mixed or sarcomatous cell types. There were 31 patients with measurable disease and 27 with evaluable disease. RESULTS: The overall response rate was 25% for E (95% confidence interval [95% CI], 9-49%) and 16% for EL (95% CI, 6-31%). There was a 5% complete response [CR] rate, a 10% partial response [PR] rate, and a 10% regression [R] rate for E and a 0% CR rate, a 3% PR rate, and a 13% R rate for EL. The median survival duration from study entry was 9.6 months and 6.6 months, respectively, for E and EL; 1-year survival was 50% and 32%, respectively, for E and EL. There were four early deaths with the E regimen (including two from neutropenic sepsis) and one early death with the EL regimen (from progressive disease). Principal toxicities included mu cositis, myelosuppression, and rash, which were less frequent with leucovorin rescue. CONCLUSIONS: Moderate antitumor activity has been observed with both regimens. Leucovorin rescue ameliorated the mucosal, hematologic, and dermatologic toxicities of edatrexate, but also may have reduced its efficacy.
Assuntos
Aminopterina/análogos & derivados , Antineoplásicos/uso terapêutico , Leucovorina/uso terapêutico , Leucemia/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Aminopterina/efeitos adversos , Aminopterina/uso terapêutico , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Taxa de Sobrevida , Falha de TratamentoRESUMO
BACKGROUND: There were approximately 12,500 cases of esophageal carcinoma diagnosed in the US in 1992 and 12,200 deaths. The impact of chemotherapy on patients with metastatic disease is marginal with a median survival of only five months. Gemcitabine (LY188011,2,2,-difluorodeoxycytidine: dFdC), an analog of cytosine arabinoside (ara-C), is a pyrimidine antimetabolite. Gemcitabine has shown interesting clinical activity in initial phase II clinical trials in a variety of malignancies, including the aerodigestive malignancies, squamous-cell carcinoma of the head/neck and both non-small-cell and small-cell lung cancer. PATIENTS AND METHODS: A total of 21 patients with chemotherapy-naïve metastatic esophageal carcinoma were entered. Nineteen patients were evaluable for toxicity and seventeen patients were evaluable for response. Gemcitabine was administered intravenously at 1250 mg/m2 over 30-60 minutes on days 1, 8, and 15 followed by 1 week of rest. This four-week schedule defined a cycle of treatment. Patients may have received a maximum of six cycles. RESULTS: Gemcitabine was well tolerated with minimal non-hematologic toxicity and grade 3-4 anemia, granulocytopenia, and thrombocytopenia occurring in 10.5%, 21%, and 0% of patients, respectively. No responses were seen in the seventeen evaluable patients. CONCLUSIONS: At the dose and schedule studied it would appear that gemcitabine has no activity in patients with chemotherapy-naïve esophageal carcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Desoxicitidina/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/efeitos dos fármacos , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , GencitabinaRESUMO
BACKGROUND: This study was conducted to determine the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetics of the putative histone deacetylase inhibitor CI-994 in combination with capecitabine. PATIENTS AND METHODS: Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. Capecitabine was administered in twice daily divided doses, and CI-994 was given as a single daily dose. In schedule A, 26 patients were treated with capecitabine 1650 mg/m2/day and CI-994 for 2 weeks of a 3-week cycle. In schedule B, six patients received capecitabine 1650 mg/m2/day for two 3-week cycles and CI-994 for 5 of 6 weeks. In schedule C, 22 patients were treated with capecitabine 2000 mg/m2/day and CI-994 for 2 of 3 weeks. RESULTS: At the MTD, the principal dose-limiting toxicity was thrombocytopenia. The pharmacokinetics of CI-994 were unaltered by capecitabine, and there was no correlation between body surface area and major pharmacokinetic parameters. Platelet count nadir was best predicted by the observed maximal concentration (C(max)) of CI-994. CONCLUSIONS: The recommended phase II dose is 6 mg/m2 (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m2/day for 2 weeks of a 3-week cycle.