RESUMO
Background: Randomized controlled trial to evaluate synergy between taxane plus platinum chemotherapy and CADI-05, a Toll like receptor-2 agonist targeting desmocollin-3 as a first-line therapy in advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients with advanced NSCLC (stage IIIB or IV) were randomized to cisplatin-paclitaxel (chemotherapy group, N = 112) or cisplatin-paclitaxel plus CADI-05 (chemoimmunotherapy group, N = 109). CADI-05 was administered a week before chemotherapy and on days 8 and 15 of each cycle and every month subsequently for 12 months or disease progression. Overall survival was compared using a log-rank test. Computed tomography was carried out at baseline, end of two cycles and four cycles. Response rate was evaluated using Response Evaluation Criteria in Solid Tumors criteria by an independent radiologist. Results: As per intention-to-treat analysis, no survival benefit was observed between two groups [208 versus 196 days; hazard ratio, 0.86; 95% confidence interval (CI) 0.63-1.19; P = 0.3804]. In a subgroup analysis, improvement in median survival by 127 days was observed in squamous NSCC with chemoimmunotherapy (hazard ratio, 0.55; 95% CI 0.32-0.95; P = 0.046). In patients receiving planned four cycles of chemotherapy, there was improved median overall survival by 66 days (299 versus 233 days; hazard ratio, 0.64; 95% CI 0.41 to 0.98; P = 0.04) in the chemoimmunotherapy group compared with the chemotherapy group. This was associated with the improved survival by 17.48% at the end of 1 year, in the chemoimmunotherapy group. Systemic adverse events were identical in both the groups. Conclusion: There was no survival benefit with the addition of CADI-05 to the combination of cisplatin-paclitaxel in patients with advanced NSCLC; however, the squamous cell subset did demonstrate a survival advantage.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas Bacterianas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Desmocolinas/antagonistas & inibidores , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Modelos de Riscos Proporcionais , Receptor 2 Toll-Like/agonistas , Resultado do TratamentoRESUMO
BACKGROUND: This phase Ib study evaluated volociximab, an anti-α5ß1 integrin antibody, in combination with carboplatin (Eli Lilly and Co., Indianapolis, IN) and paclitaxel (Taxol) in advanced, untreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Three cohorts were treated with volociximab (10, 20, or 30 mg/kg) for up to six 3-week cycles in combination with carboplatin-paclitaxel chemotherapy and continued as maintenance therapy for patients with stable disease (SD) or better. Dose-limiting toxic effects, adverse events (AEs), pharmacokinetics, and anti-volociximab antibodies were assessed. RESULTS: A maximum tolerated dose was not reached up to the maximum planned dose of 30 mg/kg. In 29 patients who received volociximab, the most common grade≥3 AEs were neutropenia (24%), hyponatremia (17%), and fatigue (10%). Three patients experienced volociximab-related serious AEs. No hemorrhages were observed. Of 33 patients enrolled, 8 (24%) achieved a partial response and 17 (52%) had SD. The median progression-free survival was 6.3 months (95% confidence interval 5.5-8.1). Levels of potential biomarkers of angiogenesis or metastasis were reduced following six cycles of treatment. CONCLUSIONS: Volociximab combined with carboplatin and paclitaxel was generally well-tolerated and showed preliminary evidence of efficacy in advanced NSCLC.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Integrina alfa5beta1/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Carboplatina/administração & dosagem , Estudos de Coortes , Humanos , Dose Máxima Tolerável , Paclitaxel/administração & dosagemRESUMO
BACKGROUND: This was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The six symptom items' [average symptom burden index (ASBI)] mean at baseline was calculated using the lung cancer symptom scale (LCSS). Low and high symptom burden (LSB, ASBI < 25; HSB, ASBI ≥ 25) and performance status (PS: 0, 1) subgroups were analyzed for treatment effect on progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models adjusted for demographic/clinical factors. RESULTS: Significantly longer PFS and OS for pemetrexed versus placebo occurred in LSB patients [PFS: median 5.1 versus 2.4 months, hazard ratio (HR) 0.49, P < 0.0001; OS: median 17.5 versus 11.0 months, HR 0.63, P = 0.0012] and PS 0 patients (PFS: median 5.5 versus 1.7 months, HR 0.36, P < 0.0001; OS: median 17.7 versus 10.3 months, HR 0.54, P = 0.0019). Significantly longer PFS, but not OS, occurred in HSB patients (median 3.7 versus 2.8 months, HR 0.50, P = 0.0033) and PS 1 patients (median 4.4 versus 2.8 months, HR 0.60, P = 0.0002). CONCLUSIONS: ASBI and PS are associated with survival for non-squamous NSCLC patients, suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Feminino , Guanina/administração & dosagem , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Pemetrexede , Resultado do TratamentoRESUMO
Non-small-cell lung cancer (NSCLC) represents a common health issue in the elderly population. Nevertheless, the paucity of large, well-conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The present paper reviews the currently available evidence regarding treatment of all stages of NSCLC in elderly patients. Surgery remains the standard for early-stage disease, though pneumonectomy is associated with higher incidence of postoperative mortality in elderly patients. Given the lack of demonstrated benefit for the use of adjuvant radiotherapy, it is also not recommended in elderly patients. Elderly patients seem to derive the same benefit from adjuvant chemotherapy as younger patients do, with no significant increase in toxicity. For locally advanced NSCLC, concurrent chemoradiotherapy may be offered to selected elderly patients as there is a higher risk for toxicity reported in the elderly population. Third-generation single-agent treatment is considered the standard of care for patients with advanced/metastatic disease. Platinum-based combination chemotherapy needs to be evaluated in prospective trials. Unfortunately, with the exception of advanced/metastatic NSCLC, prospective elderly-specific NSCLC trials are lacking and the majority of recommendations made are based on retrospective data, which might suffer from selection bias. Prospective elderly-specific trials are needed.
Assuntos
Comitês Consultivos , Idoso , Carcinoma Pulmonar de Células não Pequenas/terapia , Geriatria/métodos , Neoplasias Pulmonares/terapia , Oncologia/métodos , Prova Pericial , Geriatria/organização & administração , Diretrizes para o Planejamento em Saúde , Humanos , Cooperação Internacional , Oncologia/organização & administração , População , Sociedades MédicasRESUMO
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
A limited sampling strategy was developed to estimate the total area under the curve of plasma cyclophosphamide concentrations versus time (AUC). The strategy was developed with a training set consisting of 29 pharmacokinetic studies in 16 patients who received 1-h i.v. infusions of cyclophosphamide at a dosage of 1000 mg/m2. The strategy was developed by applying stepwise forward multiple regression analysis to cyclophosphamide concentrations observed at each time in the training set (independent variables) versus the AUC (dependent variable). It was confirmed by applying stepwise backward elimination regression analysis to the same data set. The final sampling strategy, which utilized three time points, was: AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28 (dosage/1000), where C24, C4, and C1 represent plasma cyclophosphamide concentrations at 24, 4, and 1 h, respectively, and the dosage is in mg/m2 (r = 0.98). The strategy was validated prospectively with a test data set consisting of 14 pharmacokinetic studies in 11 patients who received 1-h i.v. infusions of cyclophosphamide at dosages of 300, 600, or 1200 mg/m2. The strategy proved highly predictive, with correlation coefficient between predicted and actual AUC of 0.94. The strategy also proved unbiased, with mean percentage of error (+/- SE) of 3.3 +/- 3.6%, and precise, with mean absolute percentage of error of 9.3 +/- 2.7%. The sampling strategy developed is being used in a multiinstitution trial of cyclophosphamide in an effort to relate cyclophosphamide pharmacokinetics, as expressed by AUC, with the toxic or therapeutic pharmacodynamic responses of the drug.
Assuntos
Ciclofosfamida/farmacocinética , Sarcoma/sangue , Neoplasias de Tecidos Moles/sangue , Ciclofosfamida/uso terapêutico , Humanos , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Fatores de TempoRESUMO
Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater carboplatin dosage administered, greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence +/- 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carboplatina , Hematopoese/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Contagem de Plaquetas/efeitos dos fármacosRESUMO
PURPOSE: We initiated a large multicenter phase II trial in stage IV non-small-cell lung cancer (NSCLC) to evaluate the activity and safety of an oral gelatin-based formation of vinorelbine. PATIENTS AND METHODS: Twenty-three centers participated in this uncontrolled phase II study, which accrued patients between August 1991 and March 1992. Eligible patients had previously untreated measurable or assessable stage IV NSCLC, age more than 18 years, and Karnofsky performance status > or = 70%. The treatment plan initially was to administer 100 mg/m2/wk of oral vinorelbine or 80 mg/m2/wk for patients who had received prior radiation therapy. After the observation of grade IV granulocytopenia in six of the first 25 patients, subsequent doses were reduced by 40 mg (one capsule) in all patients. RESULTS: One hundred sixty-two patients were treated: 138 with measurable and 24 with assessable disease. One hundred two patients were men and 60 women. The mean age was 62 years (range, 36 to 83). The overall response rate was 14.5% for patients with measurable disease (95% confidence interval, 9.3% to 21.7%). The median time to treatment failure (TTF) for all patients was 9 weeks. The median survival time was 29 weeks; the 1-year survival rate was 22%. Toxicities included grade 3 or 4 neutropenia in 40%, which was dependent on the vinorelbine dose. Other toxicities included mild to moderate nausea/vomiting, diarrhea, and stomatitis. The mean dose intensity of vinorelbine was 53 mg/m2. CONCLUSION: Oral vinorelbine administered once weekly is an active agent in stage IV NSCLC. The median survival time of 29 weeks is similar to that achieved with single-agent intravenous vinorelbine and more aggressive cisplatin-based combinations. Further studies of this compound in the palliative-intent care setting appear to be indicated.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Vimblastina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Cuidados Paliativos , Indução de Remissão , Taxa de Sobrevida , Estados Unidos , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , VinorelbinaRESUMO
PURPOSE: This randomized phase II study evaluated the efficacy and toxicity of etoposide phosphate when used in combination with cisplatin in the treatment of small-cell lung cancer. PATIENTS AND METHODS: Patients with previously untreated small-cell lung cancer were randomized to receive cisplatin in combination with either etoposide or etoposide phosphate. Molar-equivalent doses of etoposide and etoposide phosphate were used. Response rate, time to progression, survival, and toxicity were compared. RESULTS: Major response rates with etoposide phosphate and etoposide were 61% (95% confidence interval, 55% to 67%) and 58% (95% confidence interval, 52% to 64%), respectively (P = .85). No significant differences in median time to progression or survival were observed in patients who received etoposide phosphate versus etoposide. Grade 3 and 4 leukopenia occurred in 63% of patients who received etoposide phosphate compared with 77% who received etoposide (P = .16). CONCLUSION: The combination of etoposide phosphate and cisplatin is effective in the treatment of small-cell lung cancer, and can be administered with acceptable toxicity. Although this study was not designed to be a formal comparative trial, the efficacy and toxicity observed with this regimen were found to be similar to a standard etoposide/cisplatin regimen, using molar-equivalent etoposide doses. Because of its greater ease of administration, etoposide phosphate is preferable to etoposide for routine clinical use.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Carcinoma de Células Pequenas/mortalidade , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Análise de SobrevidaRESUMO
PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/secundário , Relação Dose-Resposta a Droga , Humanos , Metástase Neoplásica , Paclitaxel/administração & dosagemRESUMO
A postmenopausal patient with breast cancer with a left infrahilar lung mass was treated with tamoxifen. She became asymptomatic, but after having stable disease for eight months, she developed progressive increase in the size of the mass necessitating tamoxifen withdrawal. Complete resolution of the mass occurred following withdrawal of tamoxifen. Withdrawal responses, though known to occur with additive hormonal treatment, especially complete regression of metastatic disease as seen in our patient, is not widely recognized. Thus, when clinically possible, patients should be observed off treatment for up to six weeks, before initiating a new therapeutic modality.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Tamoxifeno/administração & dosagem , Carcinoma Intraductal não Infiltrante/secundário , Feminino , Humanos , Neoplasias Pulmonares/secundário , Metástase Linfática , Menopausa , Pessoa de Meia-Idade , Indução de Remissão , Síndrome de Abstinência a SubstânciasRESUMO
This multi-institutional randomized phase II study was designed to compare the efficacy and toxicity of three different weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin schedules in patients with advanced and metastatic non-small cell lung cancer. The second part of the trial evaluated the role of maintenance weekly paclitaxel for those with response or stable disease after 16 weeks of initial treatment. Patients in arm 1 received paclitaxel 100 mg/m(2)/wk for 3 weeks along with carboplatin (area under the curve of 6) on day 1 every 4 weeks. The treatment in arm 2 was the same as in arm 1 except that carboplatin was also administered weekly (area under the curve of 2) for 3 weeks. Patients in arm 3 received paclitaxel 150 mg/m(2)/wk and carboplatin (area under the curve of 2 per week) during the second 8-week cycle. The total duration of this initial therapy was 16 weeks. All regimens were well tolerated. Arm 1 has the best therapeutic index and will exceed the median survival seen in previous phase III trials with traditional schedules of paclitaxel and carboplatin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/secundário , Esquema de Medicação , Humanos , Neoplasias Pulmonares/patologia , Paclitaxel/administração & dosagemRESUMO
The options available to patients with advanced non-small cell lung cancer (NSCLC) resistant or refractory to first-line chemotherapy are very limited. The older-generation drugs (etoposide, vindesine, epirubicin, and cisplatin) that are active against previously untreated NSCLC do not achieve a response rate greater than 10% when used in the second-line setting. The newer-generation agents with activity in previously untreated NSCLC include carboplatin, paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. Although NSCLC remains relatively resistant to chemotherapy, the fact that second-line chemotherapy is being considered is tribute to the progress being made with first-line therapy. The taxanes have clearly become the agents of the 1990s. The activity of paclitaxel in the second-line setting is not well-defined, and the response rates have ranged from 0% to 3 31% using various schedules. However, docetaxel achieved response rates of 15% to 22% in five phase II trials, with a clinically meaningful survival rate of 25% at 1 year in one of the studies. Randomized trials of docetaxel versus best supportive care and of docetaxel versus vinorelbine or ifosfamide are in progress. The efficacy of vinorelbine and irinotecan in the second-line setting have been dismal. Gemcitabine demonstrated a response rate of 25% in a recently reported trial and needs further investigation. Further progress may come from a wider investigation of novel agents and their combination with biological and other selective therapies.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides , Camptotecina/uso terapêutico , Docetaxel , Humanos , Paclitaxel/análogos & derivados , Paclitaxel/uso terapêutico , Falha de Tratamento , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , VinorelbinaRESUMO
The combination of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) with cisplatin is feasible, has manageable toxicity, and is active in stage IIIB/IV non-small cell lung cancer. The four phase II trials completed to date show response rates ranging from 32% to 48% and median survival durations of 8 to 13 months. Based on these results, regimens combining 75 to 100 mg/m2 docetaxel with 75 to 100 mg/m2 cisplatin are now being assessed in randomized phase III comparisons with platinum-containing combinations. The combination of docetaxel and carboplatin also has promising activity, with response rates of 48% (1 complete response and 12 partial responses) seen in 27 evaluable patients. Overall, this combination is also well tolerated. However, it will be necessary to use both docetaxel/platinum regimens at earlier stages in the disease if a significant impact is to be made on survival.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/secundário , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Docetaxel , Humanos , Neoplasias Pulmonares/patologia , Paclitaxel/administração & dosagemRESUMO
Combined chemotherapy and thoracic radiation therapy has emerged as a primary treatment option for locally advanced, unresectable non-small cell lung cancer (NSCLC). Randomized trials and subsequent metaanalyses have shown a clear survival benefit with platinum-based combination chemotherapy administered sequentially or concurrently with hyperfractionated thoracic radiation over radiation alone. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin recently have been evaluated in numerous phase 1/11 trials at various doses in both sequential and concurrent schedules with thoracic radiation in patients with locally advanced and unresectable NSCLC. The patterns of failure in patients treated with concurrent paclitaxel/carboplatin and thoracic radiation suggest the need for additional chemotherapy either at the front end or after completion of the concurrent regimen. A large multicenter randomized study (Locally Advanced Multimodality Protocol) has been initiated to address these issues of improvement in distant control and to further refine the combined-modality approach for patients with locally advanced NSCLC. Several other combined-modality regimens incorporating a platinum compound and a novel agent like gemcitabine, vinorelbine, paclitaxel, or docetaxel have been recently completed or are in progress. The hope for the immediate future is to define an "effective" and "optimal" regimen that can be given simultaneously with thoracic radiation and can result in improved local and systemic control in patients with regionally advanced NSCLC. Numerous phase II and III trials are currently planned or under way to further define the efficacy of this novel combination of paclitaxel/carboplatin in combined-modality programs in an attempt to determine the optimal administration sequence of chemotherapy and thoracic radiation. These combined-modality programs are now being integrated into trials for early stage, potentially resectable disease. Thus, NSCLC is in fact a systemic disease requiring a multidisciplinary approach for optimal management.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Neoplasias Pulmonares/radioterapia , Paclitaxel/administração & dosagemRESUMO
The majority of patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) treated with conventional radiation therapy develop distant metastases and succumb to the disease. Thus, NSCLC should be viewed as a systemic disease, and attempts to control micrometastatic disease with chemotherapy should have a greater impact on survival. This does not eliminate the role of radiation therapy, as locoregional control is equally important. Combined chemoradiotherapy has become the major area of clinical research to improve long-term outcomes in patients with locally advanced NSCLC. The optimal chemoradiotherapy sequence is yet to be determined. Several randomized studies have demonstrated that sequential chemotherapy followed by definitive thoracic irradiation is superior to the same radiation therapy alone. The overall impact has been on both survival and incidence of distant metastasis. A number of pilot studies (phase II) have tested concurrent chemoradiotherapy in patients with locally advanced NSCLC. At the University of Maryland Cancer Center, we are evaluating the efficacy of thoracic radiation (60 Gy) with concurrent weekly carboplatin, which has known activity in NSCLC and also has radiosensitizing effects. Preliminary results show that the combination is feasible and well tolerated; median survival rates compare favorably to those seen in the combined-modality arms of the randomized, sequential studies. Definitive conclusions based on the results of the reported studies are not possible, yet there seems to be a potential benefit to adding chemotherapy to radiation therapy. These trials need to be confirmed before they can be used to define a "standard of care" for patients with locally advanced, unresectable NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/mortalidade , Dosagem Radioterapêutica , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de SobrevidaRESUMO
Until recently, chemotherapeutic intervention in advanced and metastatic non-small cell lung cancer (NSCLC) has been viewed with a certain degree of nihilism. Although meta-analysis of randomized clinical studies from the 1970s and 1980s comparing cisplatin-based chemotherapy to best supportive care in metastatic NSCLC showed improvement in survival, it was modest at best. A number of novel agents have been developed with significant activity against NSCLC in the past 5 to 6 years and are being incorporated into the therapy of this disease. These agents include paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. Clearly there has been improvement in response rates, and in some cases the responses have been durable with an increase in the number of 1- and 2-year survivors. The next generation of studies has evaluated combinations of these novel agents with either cisplatin or carboplatin for patients with NSCLC and the results have been provocative, with 1-year survival rates as high as 54%. A randomized phase III study of the Eastern Cooperative Oncology Group has shown the superiority of paclitaxel-cisplatin regimens over etoposide-cisplatin for patients with advanced and metastatic NSCLC. The vinorelbine-cisplatin regimen has also proven to have significant, albeit modest benefit in survival when compared with cisplatin alone. These combination regimens have now become the reference regimens in ongoing randomized studies. There is continued interest in developing new agents, or selective approaches that effect novel targets with the hope of showing improved therapeutic activity. Some of these approaches include gene therapy, monoclonal antibodies, and introduction of antisense oligodeoxynucleotides. With better understanding of the molecular and cellular biology of lung cancer, the hope for the future is to combine the mechanistic approaches with new drug development to define an effective, optimal, and definitive regimen for NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Docetaxel , Humanos , Irinotecano , Neoplasias Pulmonares/patologia , Paclitaxel/administração & dosagem , Paclitaxel/análogos & derivados , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
Lung cancer remains the leading cause of cancer deaths in industrialized countries. Efforts toward the development of new cytotoxic drugs and more active combination regimens for non-small cell lung cancer (NSCLC) are ongoing. Nevertheless, specific targeting of malignant cells poses a major challenge; toxicities of normal tissues continue to be dose limiting. Cytoprotective agents, such as amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), that can shield normal tissues from cytotoxic effects are now the subject of intense clinical investigation. Amifostine has been shown to selectively protect normal tissues when used in combination with a large number of chemotherapeutic agents, including cisplatin, carboplatin, and paclitaxel. The addition of amifostine to paclitaxel or carboplatin has been shown to reduce the dose-limiting toxicities associated with each chemotherapeutic agent. However, now the combination regimen of carboplatin/paclitaxel is commonly used in NSCLC. To improve the tolerance of this regimen, a large, phase III, multicenter, randomized trial has been initiated that compares carboplatin/paclitaxel with or without amifostine in patients with locally advanced and metastatic NSCLC. The main objective is to evaluate the impact of amifostine on myelotoxicity and neurotoxicity. The addition of cytoprotective agents such as amifostine to other active NSCLC regimens may also reduce overall toxicity and improve the therapeutic index.
Assuntos
Amifostina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Citoproteção , Neoplasias Pulmonares/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Amifostina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças da Medula Óssea/induzido quimicamente , Doenças da Medula Óssea/prevenção & controle , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/secundário , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Humanos , Neoplasias Pulmonares/patologia , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Substâncias Protetoras/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) and carboplatin have each shown activity against non-small cell lung cancer and they are synergistic in vitro. We thus designed a phase I study to define the maximum tolerated dose and dose-limiting toxicity of the combination with and without filgrastim support. With an initial fixed dose of paclitaxel 135 mg/m2 given as a 24-hour infusion, carboplatin was administered in escalating doses in cohorts of three patients, based on a target area under the concentration-time curve (AUC) of 5, 7, 9, or 11 using Calvert's formula: dose (mg) = target AUC x (glomerular filtration rate + 25). Dose escalations were based on course I toxicities. Filgrastim 5 micrograms/kg was administered with the first cycle only after grade 4 neutropenia occurred in two of three patients at the prior dose level. One hundred five courses of paclitaxel and carboplatin have been administered in 26 patients. Dose-limiting toxicity (grade 4 neutropenia) occurred in two patients at level 2 (cycle I). Filgrastim was instituted thereafter with cycle I for the next four levels. Grade 4 thrombocytopenia was seen at level 4; thus, the carboplatin dose was de-escalated in the next level, but the paclitaxel dose was escalated. The regimen has been well tolerated. One patient had a complete response and 12 had partial responses, for an overall response rate of 50%. There is a suggestion of a dose-response effect with both paclitaxel and carboplatin. The combination of paclitaxel and carboplatin is active in non-small cell lung cancer, and the recommended phase II doses for the combination without filgrastim support are paclitaxel 175 mg/m2 as a 24-hour infusion with the carboplatin dose based on a target AUC of 7. The phase II dose with filgrastim support will be defined as dose escalation of paclitaxel continues.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/secundário , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Carboplatina/efeitos adversos , Carboplatina/sangue , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Creatinina/urina , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Filgrastim , Taxa de Filtração Glomerular , Humanos , Infusões Intravenosas , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Paclitaxel/efeitos adversos , Paclitaxel/sangue , Proteínas Recombinantes/uso terapêutico , Indução de Remissão , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controleRESUMO
Given their known activity against non-small cell lung cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin were combined in this phase I study of patients with metastatic disease to determine the maximum tolerated dose and the dose-limiting toxicity of the combination. The initial dose of paclitaxel was fixed at 135 mg/m2 given as a 24-hour infusion with carboplatin administered in escalating doses in cohorts using Calvert's formula-dose (mg) = target AUC x (GFR + 25), where AUC is area under the concentration-time curve and GFR is glomerular filtration rate-based on target AUCs of 5, 7, 9, or 11 mg/mL.min. Dose escalations were based on cycle 1 toxicities. Filgrastim was not administered with the first cycle until two or more patients developed grade 4 or febrile neutropenia at the preceding dose level. Dose-limiting toxicity occurred in two patients at level 2 (cycle 1), and filgrastim was administered thereafter for the next four dose levels. Grade 4 thrombocytopenia was seen at level 4; thus, the carboplatin dose was de-escalated thereafter, and the paclitaxel dose escalated. Rare nonhematologic toxicities include fatigue, diarrhea, and nausea and vomiting. Among the first 30 patients, one had a complete response and 14 had partial responses, for an overall response rate of 50%. The combination of paclitaxel and carboplatin is active in non-small cell lung cancer, and the recommended phase II dose without filgrastim support is paclitaxel 175 mg/m2 via a 24-hour infusion with the carboplatin dose targeted to achieve an AUC of 7 mg/ mL.min.