RESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Determinación de Punto Final/estadística & datos numéricos , Neoplasias Pulmonares/tratamiento farmacológico , Inutilidad Médica , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación/estadística & datos numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bioestadística , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Interpretación Estadística de Datos , Supervivencia sin Enfermedad , Terminación Anticipada de los Ensayos Clínicos/estadística & datos numéricos , Humanos , Indoles/administración & dosificación , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Modelos Estadísticos , Pemetrexed/administración & dosificación , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Determinación de Punto Final , Modelos Biológicos , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tomografía Computarizada por Rayos X , Proliferación Celular , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Humanos , Cinética , Control de Calidad , Carga TumoralRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patología , Técnicas de Diagnóstico Molecular/métodos , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/secundario , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Desoxicitidina/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/farmacología , Carboplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Genes de Retinoblastoma/fisiología , Genes p53/fisiología , Humanos , Paclitaxel/administración & dosificación , Células Tumorales Cultivadas , GemcitabinaRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Toremifeno/administración & dosificación , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Cisplatino/efectos adversos , Femenino , Genes fos , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Proteína Quinasa C/metabolismo , Toremifeno/efectos adversosRESUMEN
BACKGROUND: The objective of this Phase II study was to evaluate the concept of sequential chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC) by the administration of carboplatin plus gemcitabine followed by of paclitaxel. METHODS: Patients with Stage IIIB (pleural effusion) or Stage IV NSCLC and a Southwest Oncology Group (SWOG) performance status (PS) of 0--2 were eligible. Therapy consisted of three cycles of carboplatin (area under the concentration-time curve = 5.5 mg/mL per minute) on Day 1 and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days followed by three cycles of paclitaxel 225 mg/m(2) every 21 days. RESULTS: Of the 37 eligible patients, 81% had Stage IV disease, and 27% had a PS of 2; all were assessable for survival and toxicity; 32 patients were assessable for response. After treatment with carboplatin plus gemcitabine, there were no complete responses (CRs) and eight partial responses (PRs) (response rate [RR], 25%; 95% confidence interval [95% CI], 11--43%). The best overall response was two CRs and eight PRs (RR, 31%; 95% CI, 16--50%). The median survival time was 9.5 months, the 1-year survival rate was 36% (95% CI, 26--44%), the 2-year survival rate was 11% (95% CI, 3--25%), and the median time to disease progression was 4.9 months. The median survivals were 11.2 months for patients with a PS of 0--1 and 6.4 months for patients with a PS of 2. Noncumulative, reversible thrombocytopenia was the principal toxicity with carboplatin/gemcitabine therapy. Paclitaxel therapy was well tolerated, and moderate (Grade 3) neutropenia was the primary toxic effect. One cardiac death occurred, possibly related to paclitaxel. CONCLUSIONS: This study is the first to evaluate planned sequential chemotherapy in patients with NSCLC. Carboplatin plus gemcitabine followed by paclitaxel was well tolerated and resulted in promising survival in this patient population. This pilot experience forms the basis for an ongoing SWOG trial. Cancer 2001;92:146-52. Published 2001 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Proyectos Piloto , Resultado del Tratamiento , GemcitabinaRESUMEN
Combinations of gemcitabine (Gemzar) with cisplatin (Platinol) are among the most active new chemotherapy regimens developed for advanced non-small-cell lung cancer. Carboplatin (Paraplatin) is a platinum analog devoid of many of the nonhematologic toxicities associated with cisplatin. Although few direct comparisons have been made, when administered by area under the concentration-time curve (AUC) dosing, carboplatin is probably equivalent to cisplatin in advanced non-small-cell lung cancer and provides an improved therapeutic index. Based on its favorable toxicity profile, carboplatin has supplanted cisplatin for use in combination with paclitaxel in several different tumor types. Initial trials combining gemcitabine and carboplatin using standard days 1, 8, and 15 dosing of gemcitabine suggested that thrombocytopenia was problematic. More recently, 21-day schedules in which gemcitabine is administered only on days 1 and 8 have demonstrated both efficacy and improved toxicity profiles. Here we review recent studies investigating gemcitabine plus carboplatin and preliminary data regarding combinations of gemcitabine with the new platinum analog oxaliplatin.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Humanos , Compuestos de Platino/uso terapéutico , GemcitabinaRESUMEN
Despite unequivocal evidence of activity and tolerability, the potential contribution of vinorelbine to the management of non-small cell lung cancer (NSCLC) has been relatively unappreciated. A phase III trial of vinorelbine as a single agent in the elderly demonstrated clear benefits in terms of survival and quality of life compared with supportive care. Two other phase III trials demonstrated that vinorelbine plus platinum was superior when compared either with one of the older platinum combinations, platinum as a single agent or vinorelbine alone. New vinorelbine-based regimens appear to be active but with less toxicity than older combinations in stage IV disease. Chemotherapy plays an essential role in the management of locally advanced (i.e., stage III) disease with the weight of evidence supporting improved curability of this stage when drugs are employed either preoperatively or as part of a chemoradiotherapy regimen. It has been reported that induction therapy using carboplatin/vinorelbine or carboplatin/paclitaxel followed by accelerated conformal radiation therapy has promising results without causing undue toxicity. Clearly, vinorelbine is an active agent which is well tolerated and suitable for use in the management of NSCLC. It is likely to play a greater role in the future.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Vinblastina/análogos & derivados , Vinblastina/uso terapéutico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Neoplasias Pulmonares/radioterapia , Resultado del Tratamiento , VinorelbinaRESUMEN
The treatment of advanced non-small cell lung cancer requires histologic proof of diagnosis, careful staging, and assessment of each patient's performance status and comorbidities. For patients with stage IIIB (pleural effusion) and stage IV disease who have a Cancer and Leukemia Group B performance status (PS) of 0 to 1, appropriate management consists of combination chemotherapy with a platinum (either cisplatin or carboplatin) combined with paclitaxel, gemcitabine, vinorelbine, docetaxel, or CPT-11. Dosages and schedules previously established by large phase II or phase III studies should be followed. Variations in the toxicity patterns, schedules of administration, and economic considerations should guide the selection of the specific regimen. For patients who maintain a good performance status after first-line chemotherapy, second-line treatment may be considered. Current evidence supports the use of docetaxel as second-line treatment if the patient has not previously received this drug. Gemcitabine and paclitaxel may also have activity in this setting. Vinorelbine, ifosfamide, and CPT-11 appear to be inactive as second-line therapy for patients who have previously received platinum-based chemotherapy. For patients with a PS of 2, single-agent chemotherapy with vinorelbine, gemcitabine, or a combination of the two should be considered. Patients with poor performance status should be treated with supportive measures designed to relieve pain and acute complications because any tumor-directed therapy has limited benefit. Special situations exist in which curative therapy for metastatic disease is a possibility. Patients who present with solitary sites of metastatic disease, particularly after a long disease-free interval and in the CNS may undergo definitive surgery or radiotherapy with curative intent. Some have also reported favorable outcomes for patients with solitary adrenal or bone metastases as well. Surgical treatment or definitive radiotherapy should not be employed unless a thorough restaging evaluation is performed that includes computed tomography scan of the chest and abdomen through adrenals, brain magnetic resonance imaging, and positron emission tomography scan. A plethora of new agents targeting angiogenesis, tumor invasiveness, the hypoxic environment of tumors, and the cell cycle are currently in development.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , Invasividad Neoplásica , Metástasis de la Neoplasia , Selección de Paciente , Terapia Recuperativa , Análisis de SupervivenciaRESUMEN
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.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/clasificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Neoplasias Pulmonares/clasificación , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Ensayos Clínicos como Asunto , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirugía , Estadificación de Neoplasias , RecurrenciaRESUMEN
The combination of methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) has been the standard therapy for transitional cell carcinoma for over a decade. Despite evidence that MVAC can improve outcome in comparison with single drugs or other combinations in this disease, only a small fraction of patients (less than 4%) become long-term survivors, and the regimen is quite toxic. Attempts to improve upon the MVAC regimen have partially ameliorated its toxicity, but they have not clearly improved outcome. Recently, a number of new chemotherapeutic agents have become available. This report summarizes the current experience with these agents and combinations.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Taxoides , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Carcinoma de Células Transicionales/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Galio/uso terapéutico , Humanos , Ifosfamida/uso terapéutico , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Metástasis de la Neoplasia , Neoplasias de la Vejiga Urinaria/patología , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , GemcitabinaRESUMEN
Several new agents developed in the past decade have demonstrated activity in esophageal cancer. No single agent or combination of agents has been compared in a randomized study with the current standard, albeit limited, treatment of cisplatin and 5-FU. Recent studies employing instruments measuring pain and quality of life have demonstrated stability or improvement, indicating real patient benefit from treatment. Numerous agents with potential activity in esophageal carcinoma based on their putative mechanisms of action are in development. Only clinical trials can establish the role of these agents in the clinic.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Cisplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Humanos , Paclitaxel/uso terapéuticoRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Cuidados Paliativos , Carboplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Trombocitopenia/inducido químicamente , GemcitabinaRESUMEN
OBJECTIVES: To evaluate the feasibility and activity of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma (TCC) of the urothelium and to relate the activity of this combination to the mutational status of p53. METHODS: In the Phase I portion, paclitaxel 200 mg/m(2) (3-hour infusion), carboplatin dosed to an area under the curve (AUC) of 6 mg/mL. min, and methotrexate 10 mg/m(2), increasing in 10-mg/m(2) increments, were administered on day 1 and every 21 days thereafter with granulocyte colony-stimulating factor (G-CSF) and leucovorin support. Subsequently, a Phase II study was initiated in which the carboplatin dose was lowered to an AUC of 5 to allow treatment without G-CSF. p53 expression was evaluated using immunohistochemistry. RESULTS: Thirty-three patients were accrued. Median age was 66 years. No dose-limiting toxicities were seen in the Phase I portion despite escalation of the methotrexate to 60 mg/m(2). Principal toxicities were myelosuppression and neuropathy. The overall response rate (Phase I and II) was 56% (95% confidence interval 38% to 74%). Median survival was 15.5 months; 88% of patients overexpressed p53 at the primary site. CONCLUSIONS: Paclitaxel, carboplatin, and methotrexate were well tolerated and active in advanced TCC. The high response rate to this regimen despite frequent p53 mutation is consistent with the p53-independent mechanism of paclitaxel. Whether this regimen is superior to methotrexate/vinblastine/doxorubicin/cisplatin, other paclitaxel-based regimens, or to paclitaxel alone will require comparative trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Análisis Mutacional de ADN , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Factibilidad , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Estudios de Cohortes , Docetaxel , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/farmacocinéticaRESUMEN
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.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes de Retinoblastoma/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidores Enzimáticos/farmacología , Fase G1/efectos de los fármacos , Genes p53/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Fosforilación , Proteína de Retinoblastoma/biosíntesis , Proteína de Retinoblastoma/genética , Estaurosporina/análogos & derivados , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genéticaRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Ensayos Clínicos como Asunto , Docetaxel , Humanos , Paclitaxel/uso terapéutico , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Imbalanced amino acid diets in animals rapidly produce anorexia and weight loss. Blockade of type 3 serotonergic receptors (5HT(3)) can ameliorate anorexia in this animal model. Imbalanced plasma amino acid levels also have been documented in both animal models and human patients with cancer cachexia. Therefore a trial of the 5HT(3) receptor antagonist, ondansetron, was undertaken in the treatment of patients with cancer cachexia. METHODS: Patients with metastatic cancer who were not undergoing chemotherapy or radiotherapy and who had lost >5% of their body weight were eligible. Baseline physical examination; weight; anthropometric studies; levels of retinol binding protein, albumin, and prealbumin; and skin testing for anergy were obtained. The ability to enjoy food was assessed utilizing a seven-point hedonic category scale for specific foods. Therapy was comprised of oral ondansetron, 8 mg twice a day. RESULTS: Twenty-seven patients were enrolled; all were evaluable for toxicity and 20 patients were evaluable for response. Toxicity of ondansetron was minimal. Patients demonstrated significant weight loss prior to disease entry (mean baseline weight of 76.9 kg vs. 72. 1 kg; P < 0.000002). Patients continued to lose weight on study (Week 0: 72.5 kg vs. Week 4: 71.4 kg; P = 0.027); in addition, there was significant deterioration of midarm circumference and hand grip strength, all of which indicated worsening nutritional status. However, a significant improvement in food enjoyment was noted (P = 0.04). CONCLUSIONS: Although it apparently improved the ability of patients to enjoy food, the blockade of 5HT(3) receptors failed to prevent weight loss in patients with cancer cachexia or alter laboratory parameters of protein nutrition.