RESUMO
PURPOSE: To investigate the safety of accelerated hypofractionated radiation therapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The primary objectives were to define the maximally tolerable course of accelerated radiation therapy and to describe toxicities of therapy. Total radiation therapy remained at 60 Gy. The number of once-daily fractions in each successive cohort was reduced as follows: cohort 1, 60 Gy in 27 fractions; cohort 2, 60 Gy in 24 fractions; cohort 3, 60 Gy in 22 fractions; and cohort 4, 60 Gy in 20 fractions. Concurrent treatment consisted of weekly carboplatin area under the curve (AUC) 2 and paclitaxel 45 mg/m2. Consolidation treatment consisted of carboplatin AUC 6 and paclitaxel 200 mg/m2 every weeks × 2 cycles. Maximum tolerated dose: Of 6 patients/cohort, ≤2 patients experienced grade ≥3 toxicity, and ≤1 patient experienced grade ≥4 toxicity. RESULTS: 22 patients were accrued; of those, 21 patients were evaluable between July 2012 and May 2014. Grade 5 toxicity occurred in 3 patients: 1 patient in cohort 2 (hemoptysis), 2 patients in cohort 3 (hemoptysis, pneumonitis). The maximum tolerated dose (MTD) was defined by cohort 2 (60 Gy in 2.5 Gy/fraction). Time to grade 5 toxicity was 9 months, 6 months, and 9 months after the start of treatment. The median follow-up time was 23.0 months (range, 7.6-30.6 months) in living patients, the median overall survival was 19.3 months (95% confidence interval [CI] 9.3-34.0 months), and the median progression-free survival was 12.2 months (95% CI 6.1-22.5 months). CONCLUSIONS: Only modest hypofractionation was achievable as a result of long-term toxicities. Nevertheless, the MTD of 60 Gy given at 2.5 Gy/fraction allows completion of RT in 20% fewer treatments than conventional therapy. Further investigation of AHRT may help to better define the therapeutic index.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Hipofracionamento da Dose de Radiação , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Quimioterapia de Consolidação/métodos , Feminino , Hemoptise/etiologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Pneumonite por Radiação/etiologiaRESUMO
Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non-small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ≥ 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ≥ 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ≥ 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ≥ 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Ciclo-Oxigenase 2/biossíntese , Neoplasias Pulmonares/tratamento farmacológico , Carboplatina/administração & dosagem , Carcinoma de Células Pequenas/enzimologia , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/urina , Celecoxib/administração & dosagem , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Dinoprostona/urina , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede/administração & dosagem , Taxa de SobrevidaRESUMO
PURPOSE: The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. MATERIALS AND METHODS: Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)-log HROS and log HRPFS-measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. RESULTS: The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8-3.5 months) and the median OS was 7.2 months (95% CI, 6.5-8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. CONCLUSIONS: The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:189-198Implications for Practice: For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.
Assuntos
Neoplasias Pulmonares/mortalidade , Mesotelioma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
INTRODUCTION: Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib. METHODS: Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10. RESULTS: From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance. CONCLUSIONS: Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib , Feminino , Humanos , Quimioterapia de Indução , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Quinazolinas/administração & dosagem , Dosagem Radioterapêutica , Radioterapia AdjuvanteRESUMO
BACKGROUND: Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) improves survival modestly but new strategies are needed. This trial was designed to evaluate an antivascular endothelial growth factor strategy with or without standard chemotherapy in previously treated NSCLC. METHODS: Patients with stage IIIB/IV NSCLC with performance status 0 to 1 progressive after first-line chemotherapy were eligible for randomization to pemetrexed, sunitinib, or the combination. Patients were stratified by performance status, stage, and sex. Primary objective was 18-week progression-free survival (PFS) rate; secondary objectives included response, overall survival (OS), and toxicity. Target accrual was 225. The study was terminated early because of decreasing accrual rates. RESULTS: Between April 2008 and September 2011, 130 patients were registered and randomized; of this, 125 patients were treated. Baseline characteristics in the three arms were well balanced. Toxicity was higher in the sunitinib-containing arms. The 18-week PFS rate in the pemetrexed, sunitinib, and combination arms was 54% (95% confidence interval [CI], 40-71), 37% (95% CI, 25-54), and 48% (95% CI, 35-66), respectively (p = 0.25). Median PFS in the pemetrexed, sunitinib, and combination arms in months was 4.9 (2.1-8.8), 3.3 (2.3-4.2), and 3.7 (2.5-5.8), respectively (p = 0.18). There was an overall statistically significant difference in OS between the three arms: median OS in months was 10.5 (8.3-20.2) for pemetrexed, 8.0 (6.8-13.5) for sunitinib, and 6.7 (4.1-10.1) for the combination (p = 0.03). CONCLUSION: Pemetrexed had a superior toxicity profile to either sunitinib or the combination of pemetrexed and sunitinib. The 18-week PFS rate was not significantly different between the arms. OS was significantly better with pemetrexed alone compared with the two sunitinib-containing arms, with the doublet performing worst for OS.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Indóis/administração & dosagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede , Prognóstico , Pirróis/administração & dosagem , Indução de Remissão , Sunitinibe , Taxa de SobrevidaRESUMO
INTRODUCTION: Standard therapy for limited-stage small-cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy (RT) followed by prophylactic cranial radiotherapy. Although many consider the standard RT regimen to be 45 Gy in 1.5 Gy twice-daily fractions, this has failed to gain widespread acceptance. We pooled data of patients assigned to receive daily RT of 70 Gy from three, consecutive prospective Cancer and Leukemia Group B L-SCLC cancer trials and report the results here. METHODS: All patients from consecutive Cancer and Leukemia Group B L-SCLC trials (39808, 30002, and 30206) using high-dosage daily RT with concurrent chemotherapy were included, and analyzed for toxicity, disease control, and survival. Overall survival (OS) and progression-free survival (PFS) were modeled using Cox proportional hazards models. Prognostic variables for OS-rate and PFS-rate were assessed using logistic regression model. RESULTS: Two hundred patients were included. The median follow-up was 78 months. Grade 3 or greater esophagitis was 23%. The median OS for pooled population was 19.9 months (95% confidence interval [CI]: 16.7-22.3), and 5-year OS rate was 20% (95% CI: 16-27%). The 2-year PFS was 26% (95% CI: 21-32%). Multivariate analysis found younger age (p = 0.02; hazard ratio [HR]: 1.023; 95% CI: 21-32), and female sex (p = 0.02; HR:0.69; 95% CI: 0.50-0.94) independently associated with improved overall survival. CONCLUSION: Two-Gy daily RT to a total dosage of 70 Gy was well tolerated with similar survival to 45 Gy (1.5 Gy twice-daily). This experience may aid practitioners decide whether high-dosage daily RT with platinum-based chemotherapy is appropriate outside of a clinical trial.
Assuntos
Quimiorradioterapia , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/terapia , Adulto , Idoso , Carboplatina/administração & dosagem , Irradiação Craniana , Progressão da Doença , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Platina/uso terapêutico , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Carcinoma de Pequenas Células do Pulmão/mortalidadeRESUMO
INTRODUCTION: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. METHODS: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. RESULTS: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. CONCLUSIONS: This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/diagnóstico , Carcinoma de Pequenas Células do Pulmão/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalos de Confiança , Desidratação/induzido quimicamente , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Esofagite/induzido quimicamente , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Irinotecano , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Carcinoma de Pequenas Células do Pulmão/secundárioRESUMO
BACKGROUND: Cytokeratin 19 and its soluble fragment CYFRA have been studied as markers that may be associated with response to therapy and survival in non-small-cell lung cancer (NSCLC). As a prospective correlative study of Cancer and Leukemia Group B 30203, a randomized phase II trial of carboplatin/gemcitabine with eicosanoid modulators (celecoxib, zileuton, or both) in advanced NSCLC, serum CYFRA levels were obtained before and during treatment. METHODS: Serum CYFRA levels were measured at baseline and after the first cycle of treatment using an electrochemoluminescent assay. Paired specimens were available from 88 patients. The logarithms of the initial concentration and of the difference in concentrations were analyzed for association with overall survival (OS) and failure-free survival (FFS). RESULTS: Lower baseline CYFRA levels were associated with both longer OS and FFS (p < 0.0001 and p = 0.0003). In addition, larger reductions in CYFRA levels correlated with longer OS and FFS (p = 0.0255 and p = 0.0068). CONCLUSION: CYFRA and change in CYFRA were found to be reliable markers for response to chemotherapy for NSCLC; however, a precise threshold to mark response has yet to be determined.
Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Queratina-19/sangue , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos ProspectivosRESUMO
INTRODUCTION: We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment. METHODS: Patients with unresectable MM and no symptomatic effusions were given dasatinib 70 mg twice daily as part of a 28-day cycle. We also measured plasma vascular endothelial growth factor and platelet-derived growth factor b and colony stimulating factor 1 (CSF-1) and mesothelin-related protein at baseline and during therapy. RESULTS: Forty-six patients were enrolled in this study. Fifty percent of the first 12 patients enrolled experienced ≥grade 3 treatment-related adverse events, and therefore, the starting dose was reduced to 50 mg twice daily. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). The overall disease control rate was 32.6%, and progression-free survival at 24 weeks was 23% (95% confidence interval: 13.5-40.0%). Survival was markedly longer in patients with lower pretreatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy. DISCUSSION: Single-agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population.
Assuntos
Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe , Intervalo Livre de Doença , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/sangue , Masculino , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Neoplasias Pleurais/mortalidade , Pirimidinas/efeitos adversos , Tiazóis/efeitos adversosRESUMO
PURPOSE: The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: Patients with ES-SCLC received cisplatin 30 mg/m(2) and irinotecan 65 mg/m(2) on days 1 and 8 plus bevacizumab 15 mg/kg on day 1 every 21 days for six cycles on this phase II study. The primary end point was to differentiate between 50% and 65% 12-month survival rates. RESULTS: Seventy-two patients were enrolled between March 2005 and April 2006; four patients canceled, and four were ineligible. Grade 3 or 4 toxicities included neutropenia (25%), all electrolyte (23%), diarrhea (16%), thrombocytopenia (10%), fatigue (10%), nausea (10%), hypertension (9%), anemia (9%), infection (7%), vascular access thrombosis (2%), stroke (2%), and bowel perforation (1%). Three deaths (5%) occurred on therapy as a result of pneumonitis (n = 1), stroke (n =1), and heart failure (n = 1). Complete response, partial response, and stable disease occurred in three (5%), 45 (70%), and 11 patients (17%), respectively. Progressive disease occurred in one patient (2%). Overall response rate was 75%. Median progression-free survival (PFS) was 7.0 months (95% CI, 6.4 to 8.4 months). Median overall survival (OS) was 11.6 months (95% CI, 10.5 to 15.1 months). Hypertension ≥ grade 1 was associated with improved OS after adjusting for performance status (PS) and age (hazard ratio [HR], 0.55; 95% CI, 0.31 to 0.97; P = .04). Lower vascular endothelial growth factor levels correlated with worse PFS after adjusting for age and PS (HR, 0.90; 95% CI, 0.83 to 0.99; P = .03). CONCLUSION: PFS and OS times were higher compared with US trials in ES-SCLC with the same chemotherapy. However, the primary end point of the trial was not met. Hypertension was associated with improved survival after adjusting for age and PS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma de Células Pequenas/mortalidade , Cisplatino/administração & dosagem , Humanos , Irinotecano , Neoplasias Pulmonares/mortalidade , Fator de Crescimento Derivado de Plaquetas/análise , Modelos de Riscos Proporcionais , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
INTRODUCTION: Eicosanoids, including PGE-2 and 5-HETE, can increase levels of plasma vascular endothelial growth factor (VEGF). Overexpression of COX-2 or 5-LOX increases levels of PGE-2 and 5-HETE, respectively. Elevated levels of VEGF are common in patients with non-small cell lung cancer (NSCLC). We prospectively measured VEGF in serum collected from patients enrolled in Cancer and Leukemia Group B 30203, a randomized phase II study of eicosanoid modulation in addition to chemotherapy in patients with advanced NSCLC, to determine whether these levels had prognostic significance and whether they correlated with COX-2 expression and/or responded to inhibition of COX-2 or 5-LOX. METHODS: Pre- and post-treatment serum was collected from patients enrolled in CALGB 30203. Serum VEGF levels were determined using enzyme-linked immunosorbent assay methodology. Statistical analyses were performed to determine the correlation between pretreatment serum VEGF levels and time of overall survival. Pretreatment formalin fixed tissue was stained for 5-LOX and COX-2 by immunohistochemistry. RESULTS: The median baseline VEGF level was 502 pg/ml (range, 55-3453 pg/ml). Dichotomized serum VEGF levels at median inversely correlated with survival time (p = 0.008), as did VEGF levels as a continuous variable in multivariate analysis (p = 0.035). VEGF levels were significantly correlated neither with baseline COX-2 expression (Pearson r = 0.1524, p = 0.271) nor with 5-LOX expression. Treatment with COX-2 or 5-LOX inhibitors did not alter the levels. CONCLUSION: These data indicate that elevated serum VEGF is a negative prognostic variable in NSCLC. VEGF levels are neither correlated with baseline tumor COX-2 expression nor do they respond to COX-2 and/or 5-LOX inhibition plus chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Araquidonato 5-Lipoxigenase/química , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Ciclo-Oxigenase 2/química , Fator A de Crescimento do Endotélio Vascular/sangue , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Araquidonato 5-Lipoxigenase/metabolismo , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/enzimologia , Celecoxib , Ciclo-Oxigenase 2/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/enzimologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , GencitabinaRESUMO
PURPOSE: Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT). PATIENTS AND METHODS: Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m(2)) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study. RESULTS: Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy. CONCLUSION: The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cetuximab , Terapia Combinada , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/uso terapêutico , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Guanina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PemetrexedeRESUMO
PURPOSE: We designed a phase II trial to evaluate the efficacy and tolerability of high dose induction chemotherapy with carboplatin and paclitaxel with G-CSF and stem cell support followed by surgical resection and/or chest radiotherapy in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients had pathologically confirmed stage IIIA-IIIB NSCLC, adequate end-organ function, no prior chemotherapy or radiation, and performance status 0-1. Peripheral stem cells were mobilized with G-CSF stimulation on days 1-5 and collected prior to chemotherapy. Chemotherapy consisted of 2 cycles of paclitaxel 250 mg/m(2) over 3h and carboplatin at an AUC 18 on days 11 and 32, each followed by stem cell reinfusion. Stable and responding patients went on to surgical resection (in patients deemed resectable) followed by post-operative radiation, or to conventional chest radiotherapy to 66 Gy in unresectable patients. RESULTS: Twelve patients (11 eligible) were accrued from 1996 to 1999. The 11 patients were predominately male (64%), white (82%), of performance status 0 (64%), and with weight loss less than 5% (55%). The median age was 51 (range 31-63). Ten (10) patients (91%) experienced grade 4 toxicity. There were no lethal toxicities. Grade 3-4 toxicities most commonly reported included: platelets (100%), lymphocytopenia (91%), leukopenia (91%), neutropenia (73%), anemia (55%), pain (45%), and nausea (27%). Three patients (27%) had a partial response to induction chemotherapy. Of the 11 patients, 7 underwent surgical exploration, and 10 received radiation. Two patients were completely resected, 3 patients had incomplete resections, and 2 patients had no resection. There were 4 complete responses and 3 partial responses following surgery and/or radiation. The median overall survival time was 17.8 months. The median failure-free survival time was 8.3 months. One-year and 2-year overall survival are estimated at 64% and 27%, respectively. CONCLUSIONS: High dose induction chemotherapy with carboplatin and paclitaxel and stem cell support in patients with stage IIIA-IIIB NSCLC produced response rates and survival similar to standard therapy. Excessive toxicity (and cost) suggests that this approach does not merit further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Neoplasias Pulmonares/terapia , Pneumonectomia , Adulto , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimiorradioterapia , Cálculos da Dosagem de Medicamento , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Células-Tronco Hematopoéticas/patologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/cirurgia , Linfopenia/etiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Análise de Sobrevida , Tórax/efeitos da radiaçãoRESUMO
INTRODUCTION: Treatment of small cell lung cancer (SCLC) is initially gratifying with most patients responding to platinum-based chemotherapy. Treatment of relapsed disease gives much lower response rates of short duration. We undertook this study of the protein deacetylase inhibitor Romidepsin in chemosensitive recurrent SCLC based on preclinical data that suggested this to be an active target. METHODS: Patients had recurrent chemosensitive SCLC (relapse ≥90 days since completion of platinum-based chemotherapy). Treatment was administered as weekly infusions of Romidepsin at 13 mg/m(2) for 3 of 4 weeks. We designed a two-stage phase II study targeting a response rate of 30% (<10% response would be uninteresting and ≥30% worthy of further study). RESULTS: Sixteen patients (10 male, 6 female) were accrued to the first stage of this study. Most (11 patients, 69%) presented with extensive-stage SCLC, and all had received prior chemotherapy, with 11 having received prior radiation. Eastern Cooperative Oncology Group performance status was excellent with 0 in 6 patients (38%) and 1 in 10 patients. No objective responses were seen, and stable disease was the best response seen in 3 patients (19%). Toxicity was modest with 3 patients suffering grade 3 toxicity (lymphopenia, insomnia, nausea, vomiting, and hyponatremia) and one patient with grade 4 thrombocytopenia. Median progression-free survival was 1.8 months, and median overall survival was 6 months. CONCLUSION: Romidepsin given on a weekly schedule in patients with chemosensitive, recurrent SCLC was inactive and will not be pursued further in this setting.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase I como Assunto , Feminino , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: SRC is an oncogene with an essential role in the invasiveness and metastasis of solid tumors including small cell lung cancer. Dasatinib is a potent inhibitor of SRC as well as other tyrosine kinases. The primary objective of this study was to determine the efficacy of second-line dasatinib in patients with chemosensitive (relapse or progression > or =90 days after completing first-line therapy) small cell lung cancer. METHODS: Patients with measurable disease; performance status 0 to 1; no more than one prior platinum-based chemotherapy regimen; and adequate hematologic, hepatic, and renal function were eligible. Dasatinib was administered orally at 70 mg twice daily continuously (1 cycle = 21 days) until disease progression or unacceptable toxicity. Response was determined after every two cycles. Patients were followed until disease progression or death. The study was prospectively designed to simultaneously discriminate between complete plus partial response rates of 5% versus 20% and progression-free survival (PFS) rates at 6 weeks of 50% versus 70.7% in 53 evaluable patients with at least 92% power. The study was to be terminated early and declared negative if 1 or less objective response and 14 or fewer instances of PFS > or =6 weeks were observed among the initial 27 patients; however, patient accrual continued while the initial 27 patients were evaluated. RESULTS: Between April 2007 and December 2008, 45 patients were enrolled, but one patient never received any protocol therapy and one patient was ineligible: male/female, 17/26; white/black/unknown, 40/2/1; median age, 64 years (range, 35-84 years); and performance status 0/1, 12/31. No objective response was recorded among the 43 eligible and treated patients. Among the initial 27 patients, only 13 instances of PFS > or =6 weeks were observed. With a median follow-up time of 7.1 months, median estimated overall survival and PFS times for the 43 eligible and treated patients were 17.0 and 5.9 weeks, respectively. Common reasons for removal of patients from protocol treatment were progressive disease (65%) and adverse events (26%). Toxicity was generally mild to moderate: grade 3 events of >5% frequency included fatigue and pleural and pericardial effusions; and no grade 4 or 5 events were encountered. CONCLUSIONS: Dasatinib did not reach our specified efficacy criteria in this clinical setting, and the study was terminated.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Dasatinibe , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Terapia de Salvação , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The optimal treatment for medically inoperable stage I non-small-cell lung cancer (NSCLC) has not been defined. PATIENTS AND METHODS: Cancer and Leukemia Group B trial 39904 prospectively assessed accelerated, once-daily, three-dimensional radiotherapy for early-stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 or T2N0 NSCLC (< 4 cm) and pulmonary dysfunction. The nominal total radiotherapy dose remained at 70 Gy, while the number of daily fractions in each successive cohort was reduced. RESULTS: Thirty-nine eligible patients were accrued (eight patients each on cohorts 1 to 4 and seven patients on cohort 5) between January 2001 and July 2005. One grade 3 nonhematologic toxicity was observed in both cohort 3 (dyspnea) and cohort 4 (pain). The major response rate was 77%. After a median follow-up time of 53 months, the actuarial median survival time of all eligible patients was 38.5 months. Local relapse was observed in three patients. CONCLUSION: Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiation therapy and limited resection, with less apparent severe toxicity. Further investigation of this approach is warranted.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Pneumopatias/complicações , Neoplasias Pulmonares/radioterapia , Radioterapia Conformacional/métodos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/complicações , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Dosagem RadioterapêuticaRESUMO
BACKGROUND: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group. PATIENTS AND METHODS: A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb. RESULTS: Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia
, Neoplasias Pulmonares/terapia
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Carcinoma Pulmonar de Células não Pequenas/mortalidade
, Carcinoma Pulmonar de Células não Pequenas/patologia
, Ensaios Clínicos como Assunto
, Terapia Combinada
, Feminino
, Humanos
, Neoplasias Pulmonares/mortalidade
, Neoplasias Pulmonares/patologia
, Masculino
, Pessoa de Meia-Idade
, Estadiamento de Neoplasias
, Prognóstico
, Modelos de Riscos Proporcionais
, Resultado do Tratamento
RESUMO
PURPOSE: To assess the efficacy and toxicity of carboplatin, etoposide, and exisulind as initial therapy for extensive stage small cell lung cancer. PATIENTS AND METHODS: The Cancer and Leukemia Group B conducted a phase II study of carboplatin (area under the curve 6) day 1 and etoposide 80 mg/m(2) days 1-3 administered intravenously every 21 days with exisulind 250 mg orally twice daily in 44 evaluable patients with previously untreated extensive stage small cell lung cancer. The hypothesis was the addition of a novel cytostatic agent to standard therapy may increase survival time. The primary end point of the study was to evaluate overall survival. The secondary end points were to characterize response rates and toxicity. RESULTS: The majority of the patients were male (64%), Caucasian (95%), and had performance status 0 or 1 (77%). The median age was 61 (range 44-82) years. The percentage of patients alive at 1 year was 36.4% (95% [confidence interval] CI: 24.6-53.8%). The median overall survival was 10.6 months (95% CI: 9.1-14.7). The best overall response rate was 77% (95% CI: 62-89%) with 16% of the patients achieving complete response. The most frequent grade 3 or grade 4 hematological toxicities were neutropenia (64%), thrombocytopenia (36%), and febrile neutropenia (16%). The most common grade 3 or grade 4 nonhematological toxicities were gastrointestinal (30%) and electrolyte changes (23%). CONCLUSIONS: The addition of exisulind to a standard regimen of carboplatin and etoposide did not improve outcomes compared with historic controls treated with chemotherapy alone. Further evaluation of this regimen in small cell lung cancer is not warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/secundário , Sulindaco/administração & dosagem , Sulindaco/análogos & derivados , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Cancer and Leukemia Group B trial 9430 was a randomized phase II trial which investigated the safety and activity of four novel doublets in untreated extensive stage small cell lung cancer. The results of the paclitaxel and cisplatin arm have not been reported. PATIENTS AND METHODS: Patients received paclitaxel 230 mg/m followed by cisplatin 75 mg/m on day 1 every 21 days. All patients received granulocyte colony stimulating factor 5 microg/kg/d beginning on day 3 of each cycle. RESULTS: The patient characteristics of the 34 patients assigned to this treatment arm were: median age 61.5 years (range 41-82), male (76%), performance status 0 (41%), 1 (32%), and 2 (26%). An objective response was observed in 23 patients (68%; 95% confidence interval (CI): 49-83%); 2 complete responses (6%) and 21 partial responses (62%). Median progression-free survival time was 5.6 months (95% CI: 4.8-7.1 month), and median overall survival time was 7.7 months (95% CI: 7.2-12.6 months). The 1-year survival rate observed was 29% (95% CI: 15-45%). Grade 3/4 neutropenia and thrombocytopenia was observed in 5 (15%) and 4 (12%) patients, respectively. Two patients developed febrile neutropenia including one patient who died of neutropenic sepsis. Grade 3/4 nonhematologic observed were: sensory neuropathy in eight patients (24%); and hyperglycemia, malaise and nausea were all observed in four patients (12%). CONCLUSIONS: Cancer and Leukemia Group B will not pursue further investigation of paclitaxel and cisplatin due to the modest activity and the toxicity observed on this trial.