RESUMO
BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placeboâpemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Determinação de Ponto Final/estatística & dados numéricos , Neoplasias Pulmonares/tratamento farmacológico , Futilidade Médica , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bioestatística , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Interpretação Estatística de Dados , Intervalo Livre de Doença , Término Precoce de Ensaios Clínicos/estatística & dados numéricos , Humanos , Indóis/administração & dosagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Modelos Estatísticos , Pemetrexede/administração & dosagem , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patologia , Técnicas de Diagnóstico Molecular/métodos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genéticaRESUMO
BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
Quantitative assessments of tumor burden and modeling of longitudinal growth could improve phase II oncology trials. To identify obstacles to wider use of quantitative measures we obtained recorded linear tumor measurements from three published lung cancer trials. Model-based parameters of tumor burden change were estimated and compared with similarly sized samples from separate trials. Time-to-tumor growth (TTG) was computed from measurements recorded on case report forms and a second radiologist blinded to the form data. Response Evaluation Criteria in Solid Tumors (RECIST)-based progression-free survival (PFS) measures were perfectly concordant between the original forms data and the blinded radiologist re-evaluation (intraclass correlation coefficient = 1), but these routine interrater differences in the identification and measurement of target lesions were associated with an average 18-week delay (range, -20 to 55 weeks) in TTG (intraclass correlation coefficient = 0.32). To exploit computational metrics for improving statistical power in small clinical trials will require increased precision of tumor burden assessments.
Assuntos
Determinação de Ponto Final , Modelos Biológicos , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Tomografia Computadorizada por Raios X , Proliferação de Células , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Humanos , Cinética , Controle de Qualidade , Carga TumoralRESUMO
7-Hydroxystaurosporine (UCN-01), a protein kinase inhibitor in clinical development, demonstrates potent antineoplastic activity. To determine whether specific genetic abnormalities would modulate the response to UCN-01, a model of human non-small cell lung carcinoma (NSCLC) cell lines with differential abnormalities of p16CDKN2, RB, and p53 was used for these studies. Cell growth was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and cell cycling was studied using flow cytometric analysis of DNA content. Changes in protein levels and phosphorylation were assessed by Western blotting. In cell lines expressing wild-type RB (A549 and Calul), UCN-01 treatment resulted in dose-dependent growth inhibition, arrest of cells in G1, and a reduction of cells in S phase. p16CDKN2-null cells showed similar growth inhibition to normal fetal lung fibroblasts. UCN-01-induced growth arrest was accompanied by induction of p21CDKN1 and a shift of Rb to the hypophosphorylated state in both p53 wild-type and mutant cell lines. In contrast, UCN-01 treatment of the RB-null cell line H596 resulted in less growth inhibition. To test the role of RB in response to UCN-01, effects of treatment were examined in two human isogenic models of RB expression: the bladder cancer cell line 5637 (RB-null) and the prostate cancer cell line DU-145 (RB-mutant). In the Rb-expressing 5637 subline (RB5), UCN-01 treatment resulted in Rb hypophosphorylation and an accumulation in G1 in contrast to the parent line. Similarly, the wild-type Rb-expressing DU-145 sublines (DU1.1 and B5) showed increased G1 arrest compared with the parent cells. We conclude that UCN-01-induced G1 arrest can occur in cells null for p53 and p16CDKN2, and that RB status influences the ability of UCN-01 to induce a G1 arrest. These data suggest that the molecular profile of cell cycle regulating genes in individual tumors may predict responsiveness and provide insight into optimal therapeutic application of this new antineoplastic agent.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Genes do Retinoblastoma/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidores Enzimáticos/farmacologia , Fase G1/efeitos dos fármacos , Genes p53/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Fosforilação , Proteína do Retinoblastoma/biossíntese , Proteína do Retinoblastoma/genética , Estaurosporina/análogos & derivados , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genéticaRESUMO
Cryptosporidiosis is increasingly recognized as a significant human pathogen. Previous reports have emphasized the benign, self-limited nature of the illness in the immunocompetent adult. In contrast, immunodeficient hosts have severe, frequently unremitting illness. We describe a case in which an individual, with no evidence of immunodeficiency and negative human immunodeficiency virus serologic findings, was admitted with a five-week history of severe diarrhea, marked weight loss, and renal failure probably as a consequence of cryptosporidiosis. The patient's renal function returned to normal with hydration, and his diarrhea resolved without specific therapy. At a six-month follow-up, the patient was in excellent health.
Assuntos
Criptosporidiose , Adulto , Criptosporidiose/diagnóstico , Criptosporidiose/imunologia , Criptosporidiose/transmissão , Humanos , Imunocompetência , MasculinoRESUMO
In the first-line treatment of advanced non-small cell lung cancer (NSCLC), phase II trials of single-agent docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) at a dose of 100 mg/m2 every 3 weeks have reported encouraging results, with an overall response rate of 29% and a median survival duration of 9 months. Neutropenia is the dose-limiting toxicity but, even when severe, is usually of brief duration. Docetaxel also is active against NSCLC at doses of 60 to 75 mg/m2, which are associated with a lower incidence of neutropenia and other side effects. In patients with platinum-treated and refractory disease, docetaxel appears to be the most active chemotherapeutic agent studied to date. In a large multicenter trial of 80 platinum-treated patients, the response rate was 16%, median survival was 7 months, and the 1-year survival rate was 25%. In conclusion, single-agent docetaxel appears to be one of the most active agents in the therapy of advanced NSCLC, with response and survival data in chemonaive patients comparable to that reported for combination chemotherapy regimens and activity in platinum-refractory NSCLC superior to that reported with other agents studied to date. Further studies designed to optimize the therapeutic index of docetaxel and docetaxel-based combination chemotherapy of NSCLC are clearly indicated.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Ensaios Clínicos como Assunto , Docetaxel , Humanos , Paclitaxel/uso terapêutico , Falha de TratamentoRESUMO
Advanced transitional cell carcinoma (TCC) of the urothelial tract is usually fatal despite high response rates to platinum-based chemotherapy regimens. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated marked single-agent activity in TCC, and combinations of carboplatin and paclitaxel have been well tolerated in other solid tumors. Methotrexate is also active in TCC. Due to unexpectedly severe myelosuppression and mucositis when methotrexate and paclitaxel were combined, we undertook a phase I trial of paclitaxel, carboplatin, and escalating doses of methotrexate with granulocyte colony-stimulating factor and leucovorin support in advanced TCC to determine the feasibility of this combination. Nineteen previously untreated patients with locally advanced or metastatic TCC were eligible. Median age was 62 years. In sequence, paclitaxel 200 mg/m2 (3-hour infusion), carboplatin dosed to an area under the concentration-time curve of 6 mg/mL x min, and methotrexate 10 mg/m2, increasing in 10-mg/m2 increments, were administered on day 1 every 21 days. Granulocyte colony-stimulating factor 300 microg/d or 480 microg/d (in patients <60 kg or >60 kg, respectively) was administered on days 2 through 11 and leucovorin 15 mg orally every 6 hours for 3 days. At this time, the methotrexate dose has been escalated to 50 mg/m2. There were no dose-limiting toxicities in cycle 1. Sixty-eight cycles have been administered (range, one to eight cycles; median, three cycles). Significant hematologic toxicity including neutropenic sepsis (two episodes) occurred in subsequent cycles, but was infrequent. The major nonhematologic toxicity was neuropathy. Sixteen patients are evaluable for response. One patient has achieved a complete response, seven are partial responders, seven have stable disease, and one progressed on therapy. The overall response rate is 50% (95% confidence interval, 25% to 75%). The combination of paclitaxel, carboplatin, and methotrexate holds promise to be well tolerated and active in advanced TCC.
Assuntos
Antídotos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucovorina/uso terapêutico , Metotrexato/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Oral , Adulto , Idoso , Antídotos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Carboplatina/efeitos adversos , Intervalos de Confiança , Progressão da Doença , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Doenças do Sistema Nervoso/induzido quimicamente , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Indução de Remissão , Terapia de Salvação , Sepse/etiologiaRESUMO
Gemcitabine has demonstrated single-agent activity in advanced, incurable non-small cell lung cancer, yielding response rates of > or =20%. In combination with cisplatin, response rates of 30% to 60% and encouraging survival have been observed. Carboplatin causes much less nonhematologic toxicity than cisplatin. In a phase III Eastern Cooperative Oncology Group trial, initial therapy with carboplatin yielded superior survival in advanced non-small cell lung cancer compared with cisplatin combinations and other cisplatin analogs, despite a lower response rate. Thus, studies designed to identify optimal dose schedules for a combination of gemcitabine plus carboplatin are clearly warranted. Carmichael et al from the United Kingdom have identified a maximum tolerated dose of carboplatin of area under the curve of 5.2 mg/mL/min administered on day I followed by gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. This combination produced a response rate of 31% and a median survival of 10.5 months in 13 evaluable patients. A subsequent phase I evaluation reversing the carboplatin and gemcitabine sequence (gemcitabine preceding carboplatin on day 1) demonstrated no difference in toxicities, pharmacodynamics, or maximum tolerated dose. Other investigators have identified similar promising results with this regimen, although one North American investigator has observed untoward toxicity in a small number of patients using a standard 28-day dose schedule with gemcitabine administered on days, 1, 8, and 15. Day-15 gemcitabine dosing is problematic and may contribute to excessive thrombocytopenia when gemcitabine is combined with carboplatin. The ongoing phase I/II trials reviewed here have focused on a compressed 21-day schedule, with carboplatin administered every 3 weeks and gemcitabine given on days 1 and 8 only.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/administração & dosagem , Esquema de Medicação , Humanos , GencitabinaRESUMO
BACKGROUND: Non-small cell lung cancer commonly presents as locally advanced disease. This category of tumors is heterogeneous. Although some patients clearly benefit from operative management alone, the vast majority (more than 90%) will succumb to their disease within 5 years. In the past decade a large clinical research effort has been undertaken in an attempt to improve on this outcome using a combination of chemotherapy, radiotherapy, and operation. METHODS: The English-language literature was reviewed using the headings for lung neoplasms and text words combined modality therapy and multimodality therapy. In addition, the bibliographies of relevant articles were reviewed. Emphasis was placed on prospective randomized trials and large phase II studies. We review the rationale, design, and outcome of these trials, including both operative and nonoperative approaches. RESULTS: Several prospective, randomized trials now demonstrate an advantage to combined modality management over radiotherapy or operation alone when a cisplatin-based chemotherapy regimen is incorporated into the treatment plan. This advantage was seen using both operative and nonoperative approaches. CONCLUSIONS: Combined modality therapy offers an improved outcome for patients with stage III non-small cell lung cancer. Whether both operation and radiotherapy are needed for local control, the best sequence of treatment and the optimal chemotherapy regimen remain to be defined.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Quimioterapia Adjuvante , Terapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVES: Intraoperative autotransfusion of shed blood is widely utilized in surgery. However, several studies have raised concern about the transmission of tumor cells during oncologic procedures. We compared the ability of a leukocyte depletion filter (RC-400; LDF) to a standard red blood cell filter (SBF) to remove tumor cells derived from urologic malignancies. METHODS: Cells were suspended in media and passed through a SBF or a LDF. The filtrate was evaluated for the presence of viable cells utilizing the trypan blue exclusion method as well as cell culture. In a second experiment, cells were suspended in fresh bovine blood and processed through a cell saver apparatus followed by filtration with either a SBF or a LDF. Aliquots were cultured after admixture with blood, after processing, and after filtration. RESULTS: The LDF was able to remove tumor cells completely, as demonstrated by both counting with the trypan blue exclusion test and by cell culture. In contrast, admixture with blood processing through the cell saver apparatus nor a standard red blood cell filter removed these cells. CONCLUSIONS: Tumor cells derived from urologic malignancies are easily removed with a LDF but not with a SBF. Filtration of blood salvaged at the time of uro-oncologic surgery with a LDF but not with a SBF reduces the potential for reinfusion of viable tumor cells.
Assuntos
Transfusão de Sangue Autóloga/efeitos adversos , Cuidados Intraoperatórios/efeitos adversos , Leucócitos , Depleção Linfocítica/instrumentação , Inoculação de Neoplasia , Sobrevivência Celular , Estudos de Avaliação como Assunto , Filtração/instrumentação , Humanos , Masculino , Fatores de Risco , Células Tumorais Cultivadas , Neoplasias UrológicasRESUMO
A number of new drugs and drug classes have recently become available for clinical testing which demonstrate significant antitumor activity in non-small cell lung cancer. The preclinical rationale, mechanism of action, toxicity profile and results of early trials of paclitaxel, docetaxel, edatrexate, CPT-11, topotecan, vinorelbine and gemcitabine in non-small cell lung cancer are reviewed.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Ensaios Clínicos como Assunto , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Docetaxel , Humanos , Paclitaxel/análogos & derivados , Paclitaxel/uso terapêutico , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , Vinorelbina , GencitabinaRESUMO
PURPOSE: To evaluate in vitro interactions of carboplatin, gemcitabine and paclitaxel in molecularly defined non-small-cell lung cancer lines. MATERIALS AND METHODS: Three NSCLC lines, A549 (p16-,p53 wt, Rb wt), Calu-1 (p16-, p53-, Rb+) and H596 (p16 wt, p53 mut, Rb-) were utilized. Cells were exposed to carboplatin, gemcitabine and paclitaxel as individual drugs and in two- and three-drug combinations with various sequences of administration. Cytotoxicity was assessed with the MTT assay. Interactions between the drugs (additive, synergistic and antagonistic) were evaluated by median effect analysis. RESULTS: Gemcitabine and carboplatin were synergistic in all three cell lines. In the A549 line, this synergy was most pronounced when gemcitabine preceded carboplatin. For three-drug combinations, paclitaxel was synergistic with gemcitabine and carboplatin regardless of sequence of administration. CONCLUSIONS: In vitro modeling of gemcitabine and carboplatin as well as gemcitabine/carboplatin and paclitaxel demonstrates synergistic interaction regardless of p16, p53, or Rb status.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Carboplatina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Genes do Retinoblastoma/fisiologia , Genes p53/fisiologia , Humanos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas , GencitabinaRESUMO
BACKGROUND: Edatrexate and carboplatin are each active single agents in the treatment of non-small-cell lung cancer (NSCLC). Preclinical studies in NSCLC lines have demonstrated schedule-dependent synergy of edatrexate followed by carboplatin. In a phase I trial, we demonstrated the tolerability of this combination, the ability of ice-chip cryotherapy to ameliorate dose-limiting mucositis, and promising activity in NSCLC. This phase II trial (SWOG 9207) was undertaken to investigate the efficacy of this regimen in stage IV NSCLC. METHODS: A total of 24 patients with stage IV disease were accrued to this Southwest Oncology Group (SWOG) multicenter study. Treatment consisted of edatrexate 80 mg/m2 (50% dose on day 8) intravenously weekly for 5 weeks, then every other week, and carboplatin 350 mg/m2 every 28 days. RESULTS: Of the 24 patients, 23 were assessable for toxicity and response; one was ineligible for study entry. Myelosuppression was the most significant toxicity; grade 3-4 neutropenia was seen in 8/23 patients. Two patients died of neutropenic sepsis during the first cycle of therapy, in both instances associated with the presence of pleural effusions. Although mild mucositis was common, it was dose-limiting (grade 3) in only three patients. Objective response was observed in 3/23 patients (13%). The median survival time was 7 months, and 30% of patients remained alive at one year. CONCLUSIONS: This study suggests that ice-chip cryotherapy is effective in reducing the severity of mucositis typically associated with this edatrexate schedule of administration. However, unexpectedly severe myelosuppression resulted in death from neutropenic sepsis in two patients with third space fluid collections, leading to a protocol amendment to exclude such patients from study entry. Furthermore, response and median survival with this dose schedule of edatrexate and carboplatin do not appear to be improved compared to other chemotherapeutic regimens tested by SWOG in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Aminopterina/administração & dosagem , Aminopterina/efeitos adversos , Aminopterina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/efeitos dos fármacos , Neutropenia/induzido quimicamente , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. METHODS: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 micrograms was administered subcutaneously (s.c.) on days 5-14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. RESULTS: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9-18 weeks). Administration of TOPO on days 1-4 and DOC on day 4 resulted in increased neutropenia. CONCLUSIONS: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 micrograms s.c. on days 5-14. The alternative schedule with DOC given on day 4 and TOPO on days 1-4 is not recommended.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Estudos de Coortes , Docetaxel , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinéticaRESUMO
PURPOSE: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. METHODS: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. RESULTS: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. CONCLUSIONS: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Toremifeno/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Toremifeno/sangueRESUMO
PURPOSE: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status. MATERIALS AND METHODS: A phase II trial of high-dose toremifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled. RESULTS: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6-37). Median overall survival was 8.1 months (95% CI 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-epsilon overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type. CONCLUSION: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Toremifeno/administração & dosagem , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cisplatino/efeitos adversos , Feminino , Genes fos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Proteína Quinase C/metabolismo , Toremifeno/efeitos adversosRESUMO
Recent developments in the chemotherapy of advanced and metastatic non small-cell lung cancer have led to significant, albeit modest, improvements in survival and quality of life. The plethora of new agents with activity in this disease has led to questions as to how these drugs can best be added to existing regimens. Traditionally, the paradigm of combination chemotherapy has dominated this approach with new agents added to older regimens. Unfortunately, this will frequently lead to additive toxicity and necessitate reduction in the doses of individual components of the combination. The planned sequential administration of new chemotherapy agents circumvents this problem. Additionally, considerable theoretical, biological, and clinical evidence supports this approach. This paper reviews the rationale for this strategy and discusses initial data from a pilot trial of this approach.
RESUMO
Of the patients that undergo complete resection of early-stage non-small cell lung cancer (NSCLC), 30-60% will die. Postoperative adjuvant chemotherapy has yet to demonstrate an unequivocal benefit and there are significant difficulties in administering postoperative chemotherapy to patients with the significant comorbidities found in NSCLC. Currently, several trials are evaluating the role of preoperative chemotherapy in stage I and II NSCLC. This paper reviews the rationale for this approach and potential future developments.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Estadiamento de Neoplasias , RecidivaRESUMO
Platinum compounds, either cisplatin (Platinol) or carboplatin (Paraplatin), in combination with a number of new chemotherapeutic agents, have demonstrated improved response or survival compared to cisplatin alone or older platinum-based regimens. Gemcitabine (Gemzar)-platinum combinations are of particular interest because of their interactive mechanisms of action, demonstrated preclinical synergism, and the single-agent activity of gemcitabine. Indeed, gemcitabine and cisplatin regimens have proven to be among the most efficacious in the palliative treatment of advanced non-small-cell lung cancer. In view of the reduced nonhematologic toxicities associated with the platinum analogue, carboplatin, several combinations of new agents and carboplatin have been developed and incorporated into clinical practice. This article describes recent clinical trials evaluating gemcitabine plus carboplatin, and the impact of the dosing schedule on the feasibility and tolerability of this combination.