RESUMEN
BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Adolescente , AdultoRESUMEN
BACKGROUND: Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. METHODS: We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. RESULTS: Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. CONCLUSION: A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping.
Asunto(s)
Antineoplásicos/administración & dosificación , Ensayos Clínicos Fase I como Asunto/estadística & datos numéricos , Oncología Médica/estadística & datos numéricos , Neoplasias/tratamiento farmacológico , Proyectos de Investigación/estadística & datos numéricos , Antineoplásicos/efectos adversos , Simulación por Computador , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Determinación de Punto Final/estadística & datos numéricos , Humanos , Dosis Máxima Tolerada , Modelos Estadísticos , Neoplasias/diagnóstico , Tamaño de la Muestra , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Preclinical studies demonstrated antiproliferative synergy of 1,25-D3 (calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose (RP2D) of 1,25-D3 with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer. METHODS: Patients were ≥18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D3 intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D3 were 30, 45, 60, and 80 mcg/m(2). A two-stage design was employed for phase II portion. We correlated CYP24A1 tagSNPs with clinical outcome and 1,25-D3 pharmacokinetics (PK). RESULTS: 34 patients were enrolled. At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D3 was 60 mcg/m(2). Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI 3.4, 6.5), and median overall survival 8.7 months (95 % CI 7.6, 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (P = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (P = 0.08). There was no association between 1,25-D3 PK and CYP24A1 SNPs. CONCLUSIONS: The RP2D of 1,25-D3 with docetaxel and cisplatin was 60 mcg/m(2) every 21 days. Pre-specified endpoint of 50 % confirmed RR was not met in the phase II study. Functional SNPs in CYP24A1 may inform future studies individualizing 1,25-D3.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Esteroide Hidroxilasas/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Calcitriol/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Progresión de la Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Farmacogenética , Polimorfismo de Nucleótido Simple , Tasa de Supervivencia , Taxoides/administración & dosificación , Resultado del Tratamiento , Vitamina D3 24-HidroxilasaRESUMEN
STUDY OBJECTIVES: We analyzed data from a community-based cancer database over a 26-year period in order to characterize clinicopathologic differences between black and white patients with lung cancer, and to identify relevant temporal trends in incidence and survival. DESIGN, SETTING, AND PATIENTS: Data on demographics, stage, histology, and survival were obtained on all black and white patients with primary bronchogenic carcinoma registered in the community-based metropolitan Detroit Surveillance, Epidemiology, and End Results database from 1973 to 1998. RESULTS: Of 48,318 eligible patients, 23% were black. Lung cancer incidence rates decreased for men of both races from 1985 to 1998, with a greater decline occurring in black men (p < 0.0001). Although incidence rates declined over time for men of both races < 50 years of age, this decrease was greater in white men, resulting in an increase in the racial differential in younger men. Temporal trends in incidence rates were similar for women of both races. The incidence of distant-stage disease was higher among blacks throughout the study period. The incidence of local-stage disease decreased for both races, though this decline was greater in blacks. A significant racial difference in 2-year and 5-year survival rates developed during the study period, due to a distinct lack of improvement in black patients. In a multivariate model, the relative risks of death for black patients, relative to white patients, were 1.24 (p < 0.0001) for local stage, 1.14 (p < 0.0001) for regional stage, and 1.03 (p = 0.045) for distant stage. CONCLUSION: Significant racial differences exist in the incidence and survival rates for lung cancer in metropolitan Detroit. Since 1973, several disturbing trends have developed, particularly with regard to the lack of improvement in overall survival in black patients. Further study is required to determine the factors responsible for these temporal trends.
Asunto(s)
Negro o Afroamericano/estadística & datos numéricos , Neoplasias Pulmonares/etnología , Población Blanca/estadística & datos numéricos , Adenocarcinoma/etnología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Carcinoma Broncogénico/etnología , Carcinoma Broncogénico/mortalidad , Carcinoma Broncogénico/patología , Carcinoma de Células Grandes/etnología , Carcinoma de Células Grandes/mortalidad , Carcinoma de Células Grandes/patología , Carcinoma de Células Pequeñas/etnología , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Escamosas/etnología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Incidencia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Michigan/epidemiología , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Programa de VERF , Tasa de Supervivencia , Población UrbanaRESUMEN
Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1; vincristine 1 mg/m2 on day 8; and ifosfamide 1.2 gm/m2 on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Pequeñas/patología , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Infusiones Intravenosas , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónAsunto(s)
Anticarcinógenos/farmacología , Transformación Celular Neoplásica , Neoplasias Pulmonares/prevención & control , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Ensayos Clínicos como Asunto , Determinación de Punto Final , Genes Supresores de Tumor/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatología , Proto-Oncogenes/genética , Retinoides/farmacología , Factores de Riesgo , beta Caroteno/farmacologíaRESUMEN
Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/clasificación , Apoptosis/efectos de los fármacos , Carcinoma de Células Pequeñas/patología , Diseño de Fármacos , Inhibidores de Crecimiento/uso terapéutico , Humanos , Neoplasias Pulmonares/patologíaRESUMEN
We evaluated incidence and survival trends of non-Hodgkin's lymphoma (NHL) in a large population-based cancer registry. Data regarding demographics, histology, incidence, and survival were obtained on all patients with NHL registered in the Metropolitan Detroit Cancer Surveillance System, a participant in the Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute. Incidence and survival trends from 1973 through 1995 were evaluated and stratified based on age at diagnosis, sex, race, and tumor grade. There were 11,978 patients diagnosed with NHL and recorded in the Metropolitan Detroit SEER registry from 1973 to 1995. The age-adjusted incidence rate increased from 8.6 to 15.8 per 100,000, leading to an overall increase in incidence of 83% and an average annual increase of 3.2% per year. Incidence increased significantly (p < 0.05) over time in all age groups except the youngest (ages 0-19) and in all demographic groups studied. Incidence was highest in white men and lowest in black women. The incidence of both low-grade and intermediate/high-grade NHL increased significantly for each age group (p < 0.05) except the youngest (ages 0-19). In the oldest patients (70+ years), the incidence of intermediate/high-grade NHL was almost double that of low-grade NHL. Five-year relative survival increased from 64% (1973-1983) to 68% (1984-1991) for patients with low-grade NHL and from 40% to 44% for those with intermediate/high-grade NHL. The increase in relative survival was only seen in whites, however, with 5-year relative survival in blacks decreased from 53% (1973-1983) to 45% (1984-1991). In metropolitan Detroit, the current NHL epidemic affects all age groups except the very young (ages 0-19), both sexes, and both whites and blacks and is due to increases in the incidence of both low-grade and intermediate/high-grade NHL. Five-year survival rates have increased for whites but not for blacks.
Asunto(s)
Linfoma no Hodgkin/epidemiología , Programa de VERF , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Población Negra , Niño , Preescolar , Estudios Epidemiológicos , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Linfoma no Hodgkin/mortalidad , Masculino , Michigan/epidemiología , Persona de Mediana Edad , Análisis de Supervivencia , Población BlancaAsunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Oligopéptidos/administración & dosificación , Anciano , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Depsipéptidos , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Standard chemotherapeutic regimens, such as cisplatin and etoposide, may improve quality of life and prolong survival in patients with incurable non-small cell lung cancer (NSCLC). This trial was designed to evaluate the activity and toxicity of a regimen combining three of the most active agents against advanced-stage NSCLC: mitomycin C, etoposide, and cisplatin (MEP). Sixty-eight patients with stage IIIB (pleural effusion) or IV NSCLC received cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2, and 3 every 3 weeks along with mitomycin C 10 mg/m2 i.v. on day 1 of the first and third cycles for a median of four cycles (range, 1-11). Median age was 59 years, and nine patients were enrolled after relapse from previously treated early-stage NSCLC. Eighty-eight percent of patients had stage IV disease, and 14 (21%) had brain metastases at diagnosis. Palliative radiotherapy was given to 10 patients (15%) before MEP and to 17 (25%) concurrent with MEP. The major toxicity of MEP was myelosuppression, with grade 3-4 neutropenia in 74% of patients. Sixteen patients (24%) had documented infections, and there were eight (12%) treatment-related deaths. Partial response was observed in 24 patients (35%) with a median duration of 4.4 months, (range 1.4-13 months). Median survival was 8.1 months (range, 1-34 months), and 1-year survival was 32%. The addition of mitomycin C to cisplatin and etoposide resulted in response and survival rates comparable with those achieved with standard regimens in patients with advanced NSCLC but was associated with substantial hematologic toxicity and unacceptable treatment-related mortality.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Estadificación de Neoplasias , Análisis de Supervivencia , Factores de TiempoRESUMEN
After treatment with etoposide, two patients with lung cancer developed interstitial infiltrates and respiratory failure. Of the two, one patient responded rapidly to steroid therapy and developed recurrent symptoms on re-challenge with etoposide. Both patients had histopathologic findings consistent with drug-induced pulmonary toxicity. Etoposide-induced lung disease needs to be considered in patients who develop subacute dyspnea and interstitial infiltrates during treatment with this agent.
Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Etopósido/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Fibrosis Pulmonar/inducido químicamente , Adulto , Anciano , Diagnóstico Diferencial , Disnea/etiología , Femenino , Humanos , Masculino , Fibrosis Pulmonar/diagnósticoRESUMEN
OBJECTIVE: Although combined modality therapy appears to be superior to radiotherapy alone for the treatment of locally advanced non-small cell lung cancer (NSCLC), the optimal treatment regimen has not been determined. We designed this trial to determine the maximal tolerated doses (MTD) of continuous intravenous infusion (CI) cisplatin and etoposide that could be administered concurrently with thoracic irradiation. METHODS: 19 patients with stage IIIA or IIIB NSCLC were treated at three different dose levels of CI cisplatin and etoposide with concurrent single daily fraction thoracic radiotherapy to 4500 cGy. This chemoradiotherapy phase of treatment was followed by a 1500-2000 cGy radiotherapy boost and three cycles of standard intermittent bolus cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2 and 3. RESULTS: The MTD of CI chemotherapy was determined to be cisplatin 5 mg/m2/day plus etoposide 18 mg/m2/day for 5 days per week over 5 weeks along with thoracic irradiation. Overall, 37% of patients required breaks in the chemoradiotherapy course and 32% required attenuation of the planned duration of CI chemotherapy. Only 42% of patients received all three planned cycles of bolus chemotherapy and 16% received < 6000 cGy of thoracic irradiation. The major toxicities during concurrent chemoradiotherapy were grade 3-4 esophagitis (42%) and myelosuppression (47%). Subsequent chemotherapy was complicated by grade 3-4 myelosuppression in 38% of patients. An objective response was documented in 58% of patients (CR 11%, PR 47%). Median survival was 18 months with 2- and 5-year survival rates of 42 and 11%, respectively. CONCLUSIONS: These results demonstrate that CI cisplatin and etoposide can be administered safely to patients with locally advanced NSCLC, and that such potentially radiosensitizing strategies deserve further evaluation in this setting.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Infusiones Intravenosas/métodos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de Supervivencia , Tórax/efectos de la radiación , Resultado del TratamientoRESUMEN
The vascular endothelial growth factor (VEGF) family is a novel regulator of endothelial cell proliferation. We assessed the mRNA expression of VEGF, VEGF type C (VEGF-C) and their receptors together with the microvessel density (VD) and microlymphatic vessel density (LVD) in pursuit of their connection and prognostic value in malignant pleural mesothelioma (MPM). We used four human MPM cell lines, 54 MPM tumours and five normal pleural tissues. Expression levels for receptors and ligands were assessed by semiquantitative reverse transcriptase polymerase chain reaction analysis. Microvessels were highlighted by immunohistochemical staining for factor VIII. The discrimination of lymphatics was performed by enzyme-histochemistry for 5'-nucleotidase after adequate inhibition of non-specific activity. The expression levels of VEGF, VEGF-C and VEGFRs were high in all MPM cell lines. The percentages of tumours with higher expression compared to the mean values of normal pleural tissues were 31.5% (17/54) for VEGF, 66.7% (36/54) for VEGF-C, 20.4% (11/54) for fms-like tyrosine kinase (flt)-1, 42.6% (23/54) for kinase insert domain-containing recepter (KDR) and 59.3% (32/54) for flt-4. Significant positive correlations were found between VEGF-C and flt-4, VEGF and KDR, VEGF and flt-1 in tumour tissues. The association between LVD and VEGF-C expression level was especially strong (P< 0.0001, r= 0.63). There were also significant correlations between LVD and flt-4, and VD and VEGF. No correlation, however, was found between LVD and nodal metastasis. VD was a negative prognostic indicator in this study. The associations between VEGFNEGF-C and vessel density suggest that these factors play an important role in angiogenesis and lymphangiogenesis in this tumour, and assessment of vascularity may be a useful prognostic indicator for MPM patients.
Asunto(s)
Factores de Crecimiento Endotelial/fisiología , Sistema Linfático/fisiopatología , Linfocinas/fisiología , Mesotelioma/irrigación sanguínea , Mesotelioma/metabolismo , Neovascularización Patológica/etiología , Neoplasias Pleurales/irrigación sanguínea , Neoplasias Pleurales/metabolismo , 5'-Nucleotidasa/metabolismo , Factores de Crecimiento Endotelial/biosíntesis , Humanos , Inmunohistoquímica , Sistema Linfático/metabolismo , Linfocinas/biosíntesis , Mesotelioma/cirugía , Neovascularización Patológica/metabolismo , Pleura/metabolismo , Neoplasias Pleurales/cirugía , Proteínas Proto-Oncogénicas/biosíntesis , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento Endotelial Vascular , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Coloración y Etiquetado/métodos , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: The role of thrombospondin-1 (TSP-1) in tumor angiogenesis and progression is controversial. The authors assessed the impact of TSP-1 as a prognostic indicator in malignant pleural mesothelioma (MPM). METHODS: TSP-1 expression was assessed by reverse transcriptase-polymerase chain reaction using 5 normal pleural samples, 78 MPM tumors, and 43 surrounding normal lung samples. In MPM tumors, vascular endothelial growth factor (VEGF) expression also was examined. Differences between different valuables were analyzed using the Mann-Whitney U test. Survival curves were obtained by the Kaplan-Meier method and the survival rate was assessed by the log rank test. RESULTS: TSP-1 was highly expressed in 74 of the 78 MPM tumors (95%) with a mean value of 2.27 +/- 0.42 compared with normal pleura (0.50 +/- 0.06) and surrounding normal lung (0.96 +/- 0.20) (P = 0.05 vs. normal pleura and P = 0.0006 vs. surrounding normal lung). The mean TSP-1 expression was significantly greater in high VEGF-expressing tumors (2.63 +/- 0.51) compared with low VEGF-expressing tumors (1.17 +/- 0.39; P < 0.0001) and TSP-1 expression was lower in patients with TNM Stage III/IV disease (n = 60) (1.85 +/- 0.37) than in patients with Stage I/II disease (n = 13) (4.46 +/- 1.74) (P = 0.025). The TSP-1 expression levels in tumors with lymph node metastases were significantly lower than in those without lymph node metastases (P = 0.0305). Although high TSP-1 expression was associated with good prognosis in patients with low VEGF-expressing tumors, TSP-1 itself appeared to have no overall impact on survival. The methylation status of a CpG island associated with the TSP-1 promoter was evident in MPM tumor samples despite high levels of TSP-1 mRNA expression. CONCLUSIONS: TSP-1 is overexpressed in MPM tumors but its expression is of little value as a prognostic indicator in MPM. However, the relations between TSP-1 and VEGF in MPM merit further investigation for possible innovative therapeutic interventions.
Asunto(s)
Biomarcadores de Tumor/análisis , Mesotelioma/patología , Neovascularización Patológica , Neoplasias Pleurales/patología , Trombospondina 1/análisis , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Factores de Crecimiento Endotelial/biosíntesis , Femenino , Humanos , Linfocinas/biosíntesis , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Pronóstico , Estudios Prospectivos , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Trombospondina 1/biosíntesis , Trombospondina 1/genética , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
PURPOSE: Dolastatin 10 is a natural cytotoxic peptide which acts through the inhibition of microtubule assembly. Studies have suggested that such agents can induce apoptosis in association with bcl-2 phosphorylation. Since bcl-2 overexpression is common in small-cell lung cancer (SCLC), we evaluated the activity of dolastatin 10 in SCLC cell lines and xenografts. METHODS: In vitro growth inhibition was evaluated with a standardized MTT assay and apoptosis with fluorescent microscopy and a TUNEL assay. Immunoblot analysis and phosphatase digestion were used to determine bcl-2 modification. In vivo activity was evaluated in subcutaneous and metastatic SCLC xenograft models in SCID mice. RESULTS: Dolastatin 10 had growth inhibitory activity against four SCLC cell lines (NCI-H69, -H82, -H446, -H510) with IC50 values ranging from 0.032 to 0.184 nM. All four cell lines exhibited evidence of apoptosis after 48 h of exposure to 1.3 nM dolastatin 10. Immunoblot analysis revealed that 1.3 nM dolastatin 10 altered the electrophoretic mobility of bcl-2 in NCI-H69 and -H510 cells within 16 h of treatment. Incubation of protein extract from dolastatin 10-treated NCI-H69 and -H510 cells with calcineurin resulted in the disappearance of the altered mobility species, suggesting dolastatin 10-induced bcl-2 phosphorylation. In in vivo studies, 450 microg/kg of dolastatin 10 IV x 2 given after intravenous injection of NCI-H446 cells completely inhibited tumor formation. In established subcutaneous NCI-H446 xenografts, 450 microg/kg of dolastatin 10 IV induced apoptosis in the majority of tumor cells within 96 h, resulting in a log10 cell kill of 5.2 and an increase in median survival from 42 to 91 days. CONCLUSIONS: These findings suggest that dolastatin 10 has potent activity against SCLC and that the modulation of apoptotic pathways deserves further evaluation as an anticancer strategy.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Oligopéptidos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Depsipéptidos , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , Trasplante de Neoplasias , Oligopéptidos/uso terapéutico , Fosforilación , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To determine if the clinicopathologic features and survival of lung cancer patients < 50 years of age differ from those of older patients. DESIGN: Retrospective review of patients with primary bronchogenic carcinoma diagnosed at a single, multidisciplinary cancer center. SETTING: A National Cancer Institute-designated comprehensive cancer center in urban Detroit, MI. PATIENTS: All patients with primary bronchogenic carcinoma evaluated in the Multidisciplinary Lung Cancer Clinic at the Barbara Ann Karmanos Cancer Institute between 1990 and 1993. RESULTS: Of 1,012 patients with lung cancer, 126 (12.5%) were < 50 years old at diagnosis, with a median age of 44 years. The median age of the 886 patients > or = 50 years of age was 65 years. The gender (p = 0.08) and racial (p = 0.12) characteristics of the younger and older patient groups were not significantly different. More than 90% of patients in both groups were smokers. The incidence of adenocarcinoma was significantly higher in younger patients (48.4% vs 36.0%, p < 0.001), and early-stage disease was less frequently diagnosed in younger patients (4.8% vs 19.7%, p < 0.001). Younger patients were more likely than older patients to undergo treatment, including surgery and combined-modality therapy (p < 0.001). Median survival was 13 months in younger and 9 months in older patients, while overall survival was similar in younger and older patients (p = 0.13). CONCLUSIONS: Although younger patients with lung cancer present with more advanced-stage disease, their overall survival is similar to that of older patients, suggesting that lung cancer is not an inherently more aggressive disease in patients < 50 years of age.
Asunto(s)
Carcinoma Broncogénico/mortalidad , Neoplasias Pulmonares/mortalidad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma Broncogénico/epidemiología , Carcinoma Broncogénico/terapia , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Masculino , Michigan/epidemiología , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor beta (RAR-beta) and are resistant to the growth inhibitory activity of all-trans retinoic acid (RA). To elucidate the role of RAR-beta in the growth regulation of SCLC by retinoids, we restored RAR-beta expression in RAR-beta-negative H209 SCLC cells by retroviral transduction (H209-RAR-beta). We found that H209-RAR-beta, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA-treated H209-RAR-beta cells arrested in G1 and displayed reduced L-myc expression and cyclin-dependent kinase 2 (cdk2) activity compared with untreated cells. RA treatment of H209-RAR-beta cells was also accompanied by increased expression of the cdk inhibitor p27Kip1, whereas no differences in the expression of L-myc or p27Kip1 were detected upon RA treatment of parental H209 cells. The RA-induced growth arrest of H82 SCLC cells, which express endogenous RAR-beta, was also associated with reduced c-myc and increased p27Kip1 expression. We found that ectopic expression of p27Kip1 induced growth inhibition in both H209 and H82 cells, and that sustained myc expression in H209-RAR-beta cells promoted the induction of apoptosis upon RA addition. Our observations indicate that RAR-beta gene transfer can restore RA sensitivity in SCLC cells and suggest that myc and p27Kip1 may represent critical mediators of the RA-induced cell cycle arrest in SCLC cells expressing RAR-beta.
Asunto(s)
Antineoplásicos/farmacología , Quinasas CDC2-CDC28 , Carcinoma de Células Pequeñas/patología , Proteínas de Ciclo Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes myc , Inhibidores de Crecimiento/farmacología , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas de Neoplasias/biosíntesis , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Receptores de Ácido Retinoico/efectos de los fármacos , Tretinoina/farmacología , Proteínas Supresoras de Tumor , Quinasa 2 Dependiente de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Resistencia a Antineoplásicos , Activación Enzimática/efectos de los fármacos , Fase G1/efectos de los fármacos , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/fisiología , Proteínas Recombinantes de Fusión/fisiología , Transfección , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
PURPOSE: Fenretinide [N-(4-hydroxyphenyl)retinamide, 4HPR], a synthetic retinoid, is a potent inducer of apoptosis in small-cell lung cancer (SCLC) cell lines that may act through the generation of reactive oxygen species, suggesting that it may enhance the activity of other cytotoxic agents. In light of 4HPR's clinical potential and potent activity against SCLC cells, we evaluated the in vitro activity of 4HPR in combination with cisplatin, etoposide or paclitaxel. METHODS: The growth-inhibitory activities of single-agent 4HPR, cisplatin, etoposide or paclitaxel, and combinations of 4HPR and individual chemotherapeutic agents, were evaluated using an MTT assay in two SCLC cell lines. Each two-drug combination was studied over a range of concentrations at a fixed ratio corresponding to the ratio of the IC5 values of the individual agents. Data were analyzed by median-effect analysis as previously applied to drug combination studies. RESULTS: All four agents inhibited growth in a dose-dependent manner in the NCI-H82 and NCI-H446 SCLC cell lines. At clinically reported drug concentrations that resulted in over 50% growth inhibition, the activities of the combinations 4HPR and cisplatin and 4HPR and etoposide were more than additive in both cell lines, and the activity of 4HPR plus paclitaxel was more than additive in NCI-H446 cells. CONCLUSION: 4HPR's potent single-agent activity, minimal toxicity, and potential synergy with standard cytotoxic drugs will allow for the development of promising investigational regimens for the treatment of patients with SCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Fenretinida/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , División Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Fenretinida/administración & dosificación , Fenretinida/efectos adversos , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Células Tumorales CultivadasRESUMEN
Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3-4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC.