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Importance: Outcomes for patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT) have improved with adjuvant immune checkpoint inhibitors, with a reported 5-year overall survival benefit of approximately 10% for adjuvant durvalumab vs placebo after completion of CRT without progression and with preserved performance status. Starting atezolizumab prior to CRT may allow more patients to benefit from immunotherapy. Objective: To evaluate clinical outcomes of patients treated with atezolizumab before and after CRT for unresectable stage III NSCLC. Design, Setting, and Participants: This single-cohort, phase II, nonrandomized controlled trial was conducted at 11 US sites. Patients with pathologically confirmed, unresectable stage III NSCLC who were treatment naive and had good performance status were enrolled between January 3, 2018, and July 24, 2019. Data were locked on March 21, 2023. Interventions: Patients received four 21-day cycles of atezolizumab, 1200 mg intravenously, with therapy administered on day 1 of each cycle. Patients not experiencing tumor progression continued to CRT (60 Gy to involved fields) concurrent with weekly carboplatin area under the curve of 2 and paclitaxel, 50 mg/m2, followed by planned consolidation carboplatin area under the curve of 6 and paclitaxel, 200 mg/m2, for two 21-day cycles. Patients not experiencing progression continued atezolizumab, 1200 mg, every 21 days to complete 1 year of therapy. Main Outcomes and Measures: The primary end point was the disease control rate at 12 weeks. Secondary end points were progression-free survival, overall survival, overall response rate, safety, and translational science end points. Results: A total of 62 patients (median [range] age, 63.9 [38.1-86.5] years; 32 female [51.6%]) were enrolled and received at least 1 dose of atezolizumab. The disease control rate at 12 weeks was 74.2% (80% CI, 65.7%-81.4%). Median progression-free survival was 30.0 months (95% CI, 15.8 to not evaluable), and the median overall survival was not reached. The overall survival rate at 24 months was 73.7% (95% CI, 63.4%-85.7%), and the overall response rate was 66.2%. Seventeen patients (27.4%) experienced grade 3 or higher immune-related adverse events, including 1 with grade 5 pneumonitis and 1 with grade 4 Guillain-Barré syndrome. Thirty patients (48.4%) experienced grade 3 or higher treatment-related adverse events. Conclusions and Relevance: These findings suggest that neoadjuvant atezolizumab merits further study based on safety and encouraging outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT03102242.
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Introduction: Most patients with advanced NSCLC will experience disease progression and death within 2 years. Novel approaches are needed to improve outcomes. Methods: We conducted an open-label, nonrandomized, phase 2 trial in patients with treatment-naive, advanced NSCLC to assess the safety and efficacy of nivolumab 360 mg every 3 weeks, ipilimumab 1 mg/kg every 6 weeks, and four to six cycles of paclitaxel 80 mg/m2 on days 1 and 8 of every 21-day treatment. The primary end point of the study was median progression-free survival (PFS), with secondary end points of safety, objective response rate, and median overall survival (OS). Results: A total of 46 patients underwent consent and received treatment. The median age was 66 (range: 48-82) years, most had adenocarcinoma (63%), and 50% (23) had programmed death-ligand 1 greater than or equal to 1%. The median follow-up on the study as of October 2021 was 19 months. The primary end point of median PFS was 9.4 months (95% confidence interval [CI]: 5.9-16.6) in all patients regardless of programmed death-ligand 1 expression. The objective response rate for patients in the study was 47.8% (95% CI: 33.4-62.3). The 12-month OS rate was 69.5% (95% CI: 53%-81%), and median OS was not yet reached. Treatment-related grade greater than or equal to 3 adverse events was found in 54.3% of the patients. Conclusions: The toxicity observed was consistent with other reported chemo-immunotherapeutic combinations and was manageable. The primary end point of exceeding median PFS of 9 months was achieved with nivolumab, ipilimumab, and weekly paclitaxel and should be evaluated further in a randomized trial.
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OBJECTIVE: To determine whether surgery with adjuvant chemotherapy offers a survival advantage over concurrent chemoradiation for patients with cT1-2N0M0 small cell lung cancer (SCLC). BACKGROUND: Although surgery with adjuvant chemotherapy is the recommended treatment for patients with cT1-2N0M0 SCLC per international guidelines, there have been no prospective or retrospective studies evaluating the impact of surgery versus optimal medical management for cT1-2N0M0 SCLC. METHODS: Outcomes of patients with cT1-2N0M0 SCLC who underwent surgery with adjuvant chemotherapy or concurrent chemoradiation in the National Cancer Data Base (2003-2011) were evaluated using Cox proportional hazards analyses and propensity-score-matched analyses. RESULTS: During the study period, 681 (30%) patients underwent surgery with adjuvant chemotherapy and 1620 (70%) underwent concurrent chemoradiation. After propensity-score matching, all 14 covariates were well balanced between the surgery (n = 501) and concurrent chemoradiation (n = 501) groups. Surgery was associated with a higher overall survival (OS) than concurrent chemoradiation (5-year OS 47.6% vs 29.8%, P < 0.01). To minimize selection bias due to comorbidities, we limited the propensity-matched analysis to 492 patients with no comorbidities; surgery remained associated with a higher OS than concurrent chemoradiation (5-year OS 49.2% vs 32.5%, P < 0.01). CONCLUSIONS: In a national analysis, surgery with adjuvant chemotherapy was used in the minority of patients for early stage SCLC. Surgery with adjuvant chemotherapy for node-negative SCLC was associated with improved long-term survival when compared to concurrent chemoradiation. These results suggest a significant underuse of surgery among patients with early stage SCLC and support an increased role of surgery in multimodality therapy for cT1-2N0M0 SCLC.
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Quimioradioterapia , Neoplasias Pulmonares/terapia , Neumonectomía , Carcinoma Pulmonar de Células Pequeñas/terapia , Anciano , Terapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Estadificación de Neoplasias , Puntaje de Propensión , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/cirugía , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: The aim of this study was to evaluate efficacy of maintenance sunitinib after first-line chemotherapy for stage IIIB/IV NSCLC. METHODS: Cancer and Leukemia Group B 30607 trial was a randomized, double-blind, placebo-controlled, phase III study that enrolled patients without progression after four cycles of first-line platinum-based doublet chemotherapy with or without bevacizumab. Bevacizumab was allowed only during the four cycles of chemotherapy. Patients were randomized to receive sunitinib, 37.5 mg/d, or placebo and were treated until unacceptable adverse event(s), progression, or death. The primary end point was progression-free survival (PFS). RESULTS: A total of 210 patients were enrolled, randomized, and included in the intent-to-treat analysis. Ten patients did not receive maintenance therapy (four who received placebo and six who received sunitinib). Grade 3/4 adverse events affecting more than 5% of the patients were fatigue (25%), thrombocytopenia (12%), hypertension (12%), rash (11%), mucositis (11%), neutropenia (7%), and anemia (6%) for sunitinib and none for placebo. There were three grade 5 events in patients receiving sunitinib (one pulmonary hemorrhage, one other pulmonary event, and one death not associated with a Common Terminology Criteria for Adverse Events term) and two grade 5 events in patients receiving placebo (one other pulmonary event and one thromboembolism). Median PFS was 4.3 months for sunitinib and 2.6 months for placebo (hazard ratio = 0.62, 95% confidence interval: 0.47-0.82, p = 0.0006). Median overall survival was 11.7 months for sunitinib versus 12.1 months for placebo (hazard ratio = 0.98, 95% confidence interval: 0.73-1.31, p = 0.89). CONCLUSIONS: Maintenance sunitinib was safe and improved PFS as maintenance therapy in stage IIIB/IV NSCLC but had no impact on overall survival. There is no room for future investigations of sunitinib in this setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Indoles/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Pirroles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/secundario , Supervivencia sin Enfermedad , Método Doble Ciego , Erupciones por Medicamentos/etiología , Fatiga/inducido químicamente , Femenino , Humanos , Hipertensión/inducido químicamente , Indoles/efectos adversos , Análisis de Intención de Tratar , Neoplasias Pulmonares/patología , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Compuestos de Platino/administración & dosificación , Pirroles/efectos adversos , Calidad de Vida , Sunitinib , Tasa de Supervivencia , Trombocitopenia/inducido químicamenteRESUMEN
INTRODUCTION: We previously reported that progression-free survival (PFS) may be a candidate surrogate end point for overall survival (OS) in first-line extensive-stage small-cell lung cancer (ES-SCLC) using data from three randomized trials (Foster, Cancer 2011). In this validation study (N0424-Alliance), we assessed the patient-level and trial-level surrogacy of PFS using data from seven new first-line phase II/III ES-SCLC trials and across all 10 trials as well (seven new, three previous). METHODS: Individual patient data were utilized across the seven new trials (2259 patients) and all 10 trials (2855 patients). Patient-level surrogacy (Kendall's τ) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed through association of the log hazard ratios on OS and PFS across trials, including weighted (by trial size) least squares regression (WLS R²) of Cox model effects and correlation of the copula effects (copula R²). The minimum effect on the surrogate (MES) needed to detect a nonzero treatment effect on OS was also calculated. RESULTS: The median OS and PFS across all 10 trials were 9.8 and 5.9 months, respectively. PFS showed strong surrogacy within the 7 new trials (copula R² = 0.90 [standard error = 0.27], WLS R² = 0.83 [95% confidence interval: 0.43, 0.95]; MES = 0.67, and Kendall's τ = 0.58) and across all 10 trials (copula R² = 0.81 [standard errors = 0.25], WLS R² = 0.77 [95% confidence interval: 0.47-0.91], MES = 0.70, and Kendall's τ = 0.57). CONCLUSIONS: PFS demonstrated strong surrogacy for OS in first-line ES-SCLC based on this external validation study of individual patient data. PFS is a good alternative end point to OS and should be considered when resource constraints (time or patient) might make it useful or desirable in place of OS. Additional analyses are needed to assess its appropriateness for targeted agents in this disease setting.
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Ensayos Clínicos como Asunto/métodos , Determinación de Punto Final , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/métodos , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Carcinoma Pulmonar de Células Pequeñas/patología , Análisis de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: Previous studies suggest that cytologic analysis of cells obtained by lavage of the pleural surfaces at the time of resection of non-small cell lung cancer can identify patients at risk for recurrence. Because telomerase gene expression has been associated with worse outcome in non-small cell lung cancer, we hypothesized that identification of cells obtained from pleural lavage that express telomerase would identify patients at risk for recurrent disease. METHODS: Patients with presumed non-small cell lung cancer underwent thoracotomy with curative intent. Cells obtained by lavage of the pleural surfaces were analyzed for telomerase catalytic subunit human telomerase reverse transcriptase mRNA expression using reverse transcriptase polymerase chain reaction. RESULTS: A total of 194 patients with stage I/II non-small cell lung cancer had adequate samples, and median follow-up was 60 months (17-91 months). By using Cox models, no statistical differences were found between human telomerase reverse transcriptase-negative and positive patients in disease-free survival (hazard ratio, 1.28; 95% confidence interval, 0.85-1.94; log-rank test, P = .2349) or overall survival (hazard ratio, 1.13; 95% confidence interval, 0.72-1.79; log-rank test, P = .5912) CONCLUSIONS: Detection of human telomerase reverse transcriptase in cells obtained from pleural lavage of patients with stage I/II non-small cell lung cancer does not identify patients at risk for recurrent disease.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , ARN Mensajero/análisis , Telomerasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pleura , Pronóstico , Estudios Prospectivos , Irrigación TerapéuticaRESUMEN
PURPOSE: Assessing impact of poor accrual on premature trial closure requires a relevant metric. We propose defining accrual sufficiency on apparent ability to address primary endpoints (PE) rather than attaining accrual targets. EXPERIMENTAL DESIGN: All phase III trials open January 1, 1993, to December 31, 2002, by five U.S. oncology Clinical Trials Cooperative Groups (CTCG) were evaluated for accrual sufficiency and scientific results. Sufficient accrual included meeting accrual target, CTCGs documentation attesting adequate accrual, or conclusive results at interim analysis; insufficient accrual included poor accrual as cited closure reason or other reasons rendering a trial unable to address its primary endpoints. Closure rates based on our accrual sufficiency definition are compared with rates of meeting accrual targets and addressing the primary endpoints. A percentage of target accrual above which trials commonly answer the intended scientific question was identified to serve as an alternative to meeting full target accrual in designating accrual success. RESULTS: Of 238 eligible trials, 158 (66%) closed with sufficient accrual. Among 80 trials with insufficient accrual, 70 (29%) closed specifically because of poor accrual. Inadequate accrual rates are overemphasized when defining accrual success solely by meeting accrual targets. Nearly 75% of trials conclusively addressed the primary endpoints with positive results in 39% of trials. Exceeding 80% of target accrual serves as a reliable proxy for answering the intended scientific question. CONCLUSIONS: Approximately one third of phase III trials closed with insufficient accrual to address the primary endpoints, primarily due to poor accrual. Defining accrual sufficiency broader than meeting accrual targets represents a fairer account of trial closures.
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Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Neoplasias/terapia , Proyectos de Investigación/estadística & datos numéricos , Logro , Adolescente , Benchmarking , Niño , Humanos , Selección de Paciente , Pronóstico , Estados UnidosRESUMEN
BACKGROUND: Research on barriers to accrual has typically emphasized factors influencing participation after trial activation. PURPOSE: We sought to identify factors influencing trial design and accrual predictions prior to trial activation associated with sufficient accrual. METHODS: A 30-question web-based survey was sent to the study chair and lead statistician for all 248 phase III trials open in 1993-2002 by five Clinical Trials Cooperative Groups. Questions addressed prior trial experience, trial design elements, accrual predictions, and perceived accrual influences. Accrual sufficiency categorization was derived from Clinical Trials Cooperative Group records: sufficient accrual included trials closed with complete accrual or at interim analysis, insufficient accrual included trials closed with inadequate accrual. Responses were analyzed by respondent role (study chair/lead statistician) and accrual sufficiency. RESULTS: Three hundred and nine eligible responses were included (response rate, 63%; lead statisticians, 81%; and study chairs, 45%), representing trials with sufficient (63%) and insufficient accruals (37%). Study chair seniority or lead statistician experience was not linked to accrual sufficiency. Literature review, study chair's personal experience, and expert opinion within Clinical Trials Cooperative Group most commonly influenced control arm selection. Clinical Trials Cooperative Group experience most influenced accrual predictions. These influences were not associated with accrual sufficiency. Among respondents citing accrual difficulties (41%), factors negatively influencing accrual were not consistently identified. Respondents credited three factors with positively influencing accrual: clinical relevance of study, lack of competing trials, and protocol paralleling normal practice. LIMITATIONS: Perceptions of lead statisticians and study chairs may not accurately reflect accrual barriers encountered by participating physicians or patients. Survey responses may be subject to recall bias. CONCLUSION: Consistent factors explaining poor accrual were not identified, suggesting reasons for poor accrual are not well understood and warrant further study. Alternate strategies for accrual prediction are needed since Clinical Trials Cooperative Group experience is linked to successful and unsuccessful accrual.
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Bioestadística/métodos , Ensayos Clínicos Fase III como Asunto/métodos , Recolección de Datos , Humanos , Internet , Oncología Médica , National Cancer Institute (U.S.) , Participación del Paciente , Selección de Paciente , Proyectos de Investigación , Encuestas y Cuestionarios , Equipoise Terapéutico , Estados UnidosRESUMEN
BACKGROUND: A major challenge for randomized phase III oncology trials is the frequent low rates of patient enrollment, resulting in high rates of premature closure due to insufficient accrual. PURPOSE: We conducted a pilot study to determine the extent of trial closure due to poor accrual, feasibility of identifying trial factors associated with sufficient accrual, impact of redesign strategies on trial accrual, and accrual benchmarks designating high failure risk in the clinical trials cooperative group (CTCG) setting. METHODS: A subset of phase III trials opened by five CTCGs between August 1991 and March 2004 was evaluated. Design elements, experimental agents, redesign strategies, and pretrial accrual assessment supporting accrual predictions were abstracted from CTCG documents. Percent actual/predicted accrual rate averaged per month was calculated. Trials were categorized as having sufficient or insufficient accrual based on reason for trial termination. Analyses included univariate and bivariate summaries to identify potential trial factors associated with accrual sufficiency. RESULTS: Among 40 trials from one CTCG, 21 (52.5%) trials closed due to insufficient accrual. In 82 trials from five CTCGs, therapeutic trials accrued sufficiently more often than nontherapeutic trials (59% vs 27%, p = 0.05). Trials including pretrial accrual assessment more often achieved sufficient accrual than those without (67% vs 47%, p = 0.08). Fewer exclusion criteria, shorter consent forms, other CTCG participation, and trial design simplicity were not associated with achieving sufficient accrual. Trials accruing at a rate much lower than predicted (<35% actual/predicted accrual rate) were consistently closed due to insufficient accrual. LIMITATIONS: This trial subset under-represents certain experimental modalities. Data sources do not allow accounting for all factors potentially related to accrual success. CONCLUSION: Trial closure due to insufficient accrual is common. Certain trial design factors appear associated with attaining sufficient accrual. Defining accrual benchmarks for early trial termination or redesign is feasible, but better accrual prediction methods are critically needed. Future studies should focus on identifying trial factors that allow more accurate accrual predictions and strategies that can salvage open trials experiencing slow accrual.
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Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Neoplasias , Proyectos de Investigación/estadística & datos numéricos , Benchmarking , Humanos , Selección de Paciente , Proyectos PilotoRESUMEN
PURPOSE: A strong association between retinal degeneration and obesity has been shown in humans. However, the molecular basis of increased risk for retinal degeneration in obesity is unknown. Thus, an animal model with obesity and retinal degeneration would greatly aid the understanding of obesity-associated retinal degeneration. The retinal abnormalities in a novel rat model (WNIN-Ob) with spontaneously developed obesity are described. METHODS: Histologic and immunohistochemical examination were performed on retinal sections of 2- to 12-month-old WNIN-Ob rats, and findings were compared with those of lean littermate controls. RNA from retinas of 12-month-old WNIN-Ob and lean littermate rats was used for microarray and qRT-PCR analysis. RESULTS: The WNIN-Ob rats developed severe obesity, with an onset at approximately 35 days. Evaluation of retinal morphology in 2- to 12-month-old WNIN-Ob and age-matched lean littermate controls revealed progressive retinal degeneration, with an onset between 4 to 6 months of age. Immunohistochemical analysis with anti-rhodopsin, anti-cone opsin, and PSD-95 antibodies further confirmed retinal degeneration, particularly rod cell loss and thinner outer plexiform layer, in the obese rat retina. Gene expression by microarray analysis and qRT-PCR established activation of stress response, tissue remodeling, impaired phototransduction, and photoreceptor degeneration in WNIN-Ob rat retina. CONCLUSIONS: WNIN-Ob rats develop increased stress in retinal tissue and progressive retinal degeneration after the onset of severe obesity. The WNIN-Ob rat is the first rat model to develop retinal degeneration after the onset of obesity. This novel rat model may be a valuable tool for investigating retinal degeneration associated with obesity in humans.
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Modelos Animales de Enfermedad , Obesidad/fisiopatología , Retina/fisiopatología , Degeneración Retiniana/fisiopatología , Animales , Homólogo 4 de la Proteína Discs Large , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Regulación de la Expresión Génica/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Microscopía Fluorescente , Obesidad/genética , Obesidad/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Opsinas/metabolismo , Ratas , Ratas Wistar , Retina/metabolismo , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rodopsina/metabolismoRESUMEN
INTRODUCTION: Sentinel node mapping with radioactive technetium in non-small cell lung cancer has been shown to be feasible in several single institution reports. The Cancer and Leukemia Group B designed a phase II trial to test a standardized method of this technique in a multi-institutional setting. If validated, the technique could provide a more accurate and sensitive way to identify lymph node metastases. METHODS: Patients with clinical stage I non-small cell lung cancer amenable to resection were candidates for this trial. Intraoperatively, tumors were injected with technetium sulfur colloid (0.25 mCi). The tumor and lymph nodes were measured in vivo with a hand held Geiger counter and resection of the tumor and nodes was carried out. Sentinel nodes, all other nodes and the tumor were analyzed with standard histologic assessment. Negative sentinel nodes were also evaluated with immunohistochemistry. RESULTS: In this phase II trial, 8 surgeons participated (1-13 patients enrolled per surgeon), and 46 patients (out of a planned 150) were enrolled. Of these, 43 patients had cancer and an attempted complete resection, and 39 patients underwent sentinel node mapping. One or more sentinel nodes were identified in 24 of the 39 patients (61.5%). The sentinel node(s) were found to be accurate (no other nodes were positive for cancer if the sentinel node was negative) in 20/24 patients (83.3%). In the overall group the sentinel node mapping procedure was found to be accurate in 20/39 patients (51.2%). CONCLUSIONS: Intraoperative sentinel node mapping in lung cancer with radioisotope yielded lower accrual and worse accuracy than expected. The multi-institutional attempt at validating this technique was unsuccessful.
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Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/patología , Ganglios Linfáticos/diagnóstico por imagen , Monitoreo Intraoperatorio , Radiofármacos , Azufre Coloidal Tecnecio Tc 99m , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Carcinoma de Células Grandes/secundario , Carcinoma de Células Grandes/cirugía , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Estudios de Factibilidad , Femenino , Humanos , Neoplasias Pulmonares/cirugía , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Cintigrafía , Factores de Riesgo , Biopsia del Ganglio Linfático Centinela , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B]. CONCLUSIONS: This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Eritropoyetina/análogos & derivados , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mesna/análogos & derivados , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Adenocarcinoma Bronquioloalveolar/secundario , Adulto , Anciano , Anemia/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/secundario , Cisplatino/administración & dosificación , Darbepoetina alfa , Docetaxel , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Eritropoyetina/uso terapéutico , Estudios de Factibilidad , Femenino , Filgrastim , Hematínicos/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Mesna/uso terapéutico , Persona de Mediana Edad , Estadificación de Neoplasias , Neutropenia/tratamiento farmacológico , Polietilenglicoles , Pronóstico , Proteínas Recombinantes , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
PURPOSE: We sought to evaluate the activity and tolerance of the rationally designed sequence of paclitaxel-topotecan-etoposide, a nonplatinum regimen, as induction therapy for limited-stage small-cell lung cancer before combined chemo- and radiotherapy. PATIENTS AND METHODS: Patients with measurable disease, performance status 0 to 2, no prior therapy, and adequate organ function were eligible. Paclitaxel (110 mg/m2, administered intravenously on day 1), topotecan (1.5 mg/m2, administered orally on days 2 to 4), and etoposide (160 mg/m2, administered orally on days 5 to 7 every 21 days), with filgrastim for two cycles, were followed by chest irradiation to 70 Gy (to postinduction tumor volume) concurrent with carboplatin (area under the curve of 5, administered intravenously on day 1) and etoposide (100 mg/m2 on days 1 to 3 every 21 days) without filgrastim for three cycles (five chemotherapy cycles total). We aimed to determine the response rates to induction and overall therapy, overall and failure-free survival, and toxicity. The primary statistical endpoint was to differentiate between complete response rates of 50 and 70% for the overall treatment program. RESULTS: Between June 2001 and January 2003, 65 patients were enrolled, but one never started therapy, and one was ineligible. Patient characteristics included male/female, 27/36; white/black/other/unknown, 58/3/1/1; median age 62 (range, 38-78); performance status 0/1/2, 27/33/3. Induction chemotherapy resulted in six (10%) complete responses and 35 (56%) partial responses. Overall response to chemoradiotherapy included 27 (43%; 95% confidence interval [CI] 30-56%) complete responses and 24 (38%) partial responses. Median progression-free survival is 12 months (95% CI, 9-15 months). Median overall survival is 20 months (95% CI, 16-24 months). Frequent (>20%) grade 3/4 toxicities during all therapy included neutropenia, febrile neutropenia, anemia, thrombocytopenia, fatigue, and dysphagia. One patient died of febrile neutropenia, one died of febrile neutropenia and typhlitis, and one patient who declined transfusion for anemia died of cardiac ischemia. CONCLUSIONS: This treatment regimen has significant activity in limited-stage small-cell lung cancer but did not meet our prospectively defined criteria for further investigation in this setting. The addition of etoposide and the use of a sequenced administration schedule did not seem to improve overall activity beyond our prior experience with a topotecan-paclitaxel doublet.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/terapia , Neoplasias Pulmonares/terapia , Adulto , Anciano , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/radioterapia , Terapia Combinada , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Topotecan/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS: E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS: E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at approximately 10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS: E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas del Ojo/genética , Proteínas de la Membrana/genética , Mutación , Células Fotorreceptoras de Vertebrados/patología , Degeneración Retiniana/genética , Animales , Secuencia de Bases , Western Blotting , Cromatografía de Gases , Progresión de la Enfermedad , Electrorretinografía , Ácidos Grasos/metabolismo , Regulación de la Expresión Génica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Fotorreceptoras de Vertebrados/metabolismo , Reacción en Cadena de la Polimerasa , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Eliminación de SecuenciaRESUMEN
PURPOSE: Mutations in the gene Elongation of very long-chain fatty acids-4 (ELOVL4) have been shown to be associated with autosomal dominant Stargardt-like macular dystrophy (STGD3). ELOVL4 is expressed in photoreceptors and encodes a putative transmembrane protein of 314 amino acids with an endoplasmic reticulum (ER) retention signal. A 5 bp deletion in exon 6 of ELOVL4 observed in some STGD3 patients results in the truncation of the protein and loss of the ER retention signal. To understand the disease mechanism underlying STGD3 we studied the intracellular trafficking of the wild-type and a 5 bp deletion mutant of ELOVL4. METHODS: Wild-type and mutant ELOVL4 proteins with the N-terminal GFP/V5 tags were expressed in COS-7 cells. Expression and the intracellular localization of the wild-type and mutant proteins were characterized by immunocytochemistry and western blot analysis using tag- and organelle-specific antibodies. Interaction between the wild-type and mutant proteins was studied by two-dimensional gel electrophoresis and fluorescence resonance energy transfer (FRET) analysis. RESULTS: The mutant ELOVL4 protein exerted a dominant negative effect when the wild-type and 5 bp deletion mutant ELOVL4 proteins were co-expressed in COS-7 cells. Immunocytochemical analysis, two-dimensional gel electrophoresis and FRET revealed that the mutant ELOVL4 interacts with the wild-type protein, forming higher molecular mass complexes that accumulate in aggresomes. CONCLUSIONS: In the presence of mutant ELOVL4 protein, the wild-type protein was recruited into perinuclear cytoplasmic inclusions that resemble aggresomes. The interaction between the wild-type and mutant forms of ELOVL4 and the resultant alteration in the trafficking of the wild-type ELOVL4 protein suggest a mechanism for the pathogenicity observed in patients with autosomal dominant STGD3.