RESUMO
The feasibility of symptom-limited cardiopulmonary exercise testing (CPET) prior to allo-SCT was assessed in addition to the prognostic value of CPET-derived measures. CPET was performed prospectively on 21 patients with hematologic malignancies, with assessments of peak (for example, peak oxygen consumption, VO2peak) and submaximal (for example, ventilatory threshold (VT)) measures of cardiopulmonary function. No serious adverse events were observed during CPET procedures, with 95% of patients achieving criteria for a peak test. Mean VO2peak was 24.7±6.4 mL kg(-1 )min(-1) (range: 10.9-35.5), equivalent to 29%±17% below that of age-matched healthy controls. All patients proceeded with the conditioning regimen followed by allo-SCT. Median follow-up was 25 months. During this period, 11 (52.4%) patients died (n=6, relapsed disease; n=5, non-relapse mortality (NRM)); 9 patients (43%) developed pulmonary toxicity. In univariate analyses, both peak and submaximal markers of cardiopulmonary function were predictors of OS, pulmonary toxicity and NRM. For OS, the HR for VO2peak and VT were 0.89 (95% CI, 0.8-0.99, P=0.04) and 0.84 (95% CI, 0.71-0.98, P=0.03), respectively. In conclusion, CPET is safe and feasible prior to allo-SCT. Patients have marked impairments in cardiopulmonary function prior to allo-SCT. CPET-derived metrics may complement conventional measures to improve risk stratification.
Assuntos
Teste de Esforço/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Bevacizumab , Progressão da Doença , Esquema de Medicação , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: This phase II study evaluated the efficacy and safety of the irinotecan/gemcitabine combination in patients with relapsed/refractory small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with measurable tumor who had received one previous chemotherapy or chemotherapy/radiation regimen were eligible. Gemcitabine 1000 mg/m(2) was administered i.v. over 30 min followed immediately by irinotecan 100 mg/m(2) i.v. over 90 min, both on days 1 and 8 every 21 days. Patients were stratified based on response to initial treatment [i.e. primary sensitive disease with progression >or=3 months (group A), or refractory disease (group B)]. RESULTS: Seventy-three patients were enrolled but one never received treatment and one ineligible patient did not have SCLC. Median patient ages of the remaining patients were 61 and 63 years in groups A (n = 35) and B (n = 36), respectively, with performance status of 0 or 1 in 85% of 71 patients. Primary grade 3/4 toxic effects in groups A versus B were neutropenia (36% versus 43%), thrombocytopenia (36% versus 26%), nausea (12% versus 11%), vomiting (0 versus 11%), diarrhea (12% versus 9%), and pulmonary (12% versus 12%). Two patients had fatal events including pneumonitis (n = 1) and acute respiratory distress syndrome (n = 1). Responses occurred in 11 group A [two complete responses and nine partial responses (PRs)] and four group B (all PRs) patients, for response rates of 31% [95% confidence interval (CI) 17%, 49%) and 11% (95% CI 3%, 26%), respectively. Median survival and progression-free survival times were 7.1 (95% CI 6, 10.5) versus 3.5 (95% CI 3.1, 5.7) months, and 3.1 (95% CI 1.6, 5.3) versus 1.6 (95% CI 1.4, 2.8) months for group A versus B. CONCLUSION: The irinotecan/gemcitabine combination is active and well tolerated as second-line therapy in SCLC patients. Additional studies are warranted as second-line therapy in patients who progressed 90 days or more after first-line therapy. However, the observed efficacy results in refractory SCLC patients indicate that this regimen should not be further explored in this population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma de Células Pequenas/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Irinotecano , Neoplasias Pulmonares/secundário , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , GencitabinaRESUMO
Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oxigênio/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/fisiologia , Feminino , Humanos , Mesilato de Imatinib , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Microscopia de Fluorescência/métodos , Modelos Biológicos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Fosforilação/efeitos dos fármacos , Piperazinas/uso terapêutico , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Pressão , Pirimidinas/uso terapêutico , Distribuição Aleatória , Receptor beta de Fator de Crescimento Derivado de Plaquetas/análise , Fator A de Crescimento do Endotélio Vascular/análise , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Combined modality therapy (CMT) is the standard of care for patients with unresectable stage III non-small-cell lung cancer (NSCLC); however, insufficient data are available regarding prognostic factors in this disease setting. PATIENTS AND METHODS: Six hundred and ninety-four patients included in five trials conducted by the Cancer and Leukemia Group B evaluating CMT in stage III NSCLC were included in this analysis. The primary objective was to identify factors that were predictors of survival and selected radiation-related toxicities using Cox regression models and logistic regression analysis. RESULTS: The Cox model shows that performance status (PS) 1 [hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.06-1.45; P=0.009] and thoracic radiation therapy (TRT) only (HR 1.58; 95% CI 1.22-2.05; P=0.001) predicted for poorer survival, while baseline hemoglobin >/=12 g/dl predicted for improved survival (HR 0.67; 95% CI 0.55-0.81; P =0.0001). Multivariate logistic regression showed an increase of grade 3 + esophagitis among patients with PS 0 [odds ratio (OR) 1.7; 95% CI 1.1-2.7; P=0.029), >5% weight loss (OR 2.9; 95% CI 1.3-6.6; P=0.008) and patients receiving concurrent chemoradiation (OR 7.3; 95% CI 3.4-15.6; P=0.0001). CONCLUSIONS: Baseline hemoglobin and PS, as well as the use of CMT, have the greatest effect on survival in unresectable stage III NSCLC. The use of concurrent chemoradiation increases the risk of esophagitis, which remains the primary radiation-related toxicity.
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/efeitos adversos , Esofagite/induzido quimicamente , Feminino , Hemoglobinas/análise , Hemoglobinas/efeitos dos fármacos , Humanos , Modelos Logísticos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: To evaluate the activity and tolerability of gemcitabine plus irinotecan or docetaxel as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients with chemotherapy-naïve stage IIIB or IV NSCLC were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8, plus either irinotecan 100 mg/m2 or docetaxel 40 mg/m2 on days 1 and 8. Treatment was administered every 3 weeks. RESULTS: Of the 80 enrolled patients with stage IIIB or IV NSCLC, 78 were evaluable for activity and safety. Overall response rates, consisting of partial responses, were 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine-irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine-docetaxel. Median overall survival was 7.95 months (95% CI 5.2-10.2) and 12.8 months (95% CI 7.9-17.1) for gemcitabine-irinotecan and gemcitabine-docetaxel, respectively. The corresponding estimated 1-year survivals were 23% and 51%, respectively. The 2-year survival rate in arm A (gemcitabine-irinotecan) is not currently estimable. The 2-year survival rate for arm B (gemcitabine-docetaxel) is 22% (95% CI 6% to 37%). Both combinations were well tolerated; the most common hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm. CONCLUSIONS: These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-naïve advanced NSCLC. The survival data with the combination gemcitabine-docetaxel are promising. Gemcitabine-docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Terapia Combinada , Desoxicitidina/administração & dosagem , Docetaxel , Feminino , Humanos , Irinotecano , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento , GencitabinaRESUMO
The purposes of this study were 2-fold: to evaluate the impact of the schedule dependency of etoposide (3-day IV short course vs. a 21-day oral prolonged course) with cisplatin on the quality of life of small-cell lung cancer (SCLC) patients; and to examine the effect of baseline quality of life variables on long-term survival, after adjustment for known demographic and clinical prognostic factors. Participants were 70 patients enrolled in the cancer and leukemia group B (CALGB) protocol 9033. Quality of life was assessed at baseline, 6 and 12 weeks by: the EORTC QLQ-30, the Centers for epidemiology studies--Depression short form, the medical outcomes study (MOS) social support questionnaire, and a scale of sleep quality. Contrary to expectations, study results suggested no significant differences in the patients' life quality and treatment response based on whether they received etoposide in a 3-day IV vs. a 21-day oral regimen. The use of the baseline variables in predicting overall survival indicated that patients who were non-white and with liver involvement had decreased survival. Brain involvement, being male, and higher depressive symptoms were also found to be borderline significant in predicting decreased survival in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Qualidade de Vida , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/mortalidade , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
BACKGROUND: Recently, there has been increased interest in the use of computed tomography (CT) for lung carcinoma screening. For this technique to be effective, small tumors must be detected at an earlier stage than large lesions. However, to the authors's knowledge, the relationship between the size of small primary (< or = 3 cm) neoplasms and disease stage at presentation has never been established clearly. The current study was performed to determine whether smaller lesions indeed have an earlier stage distribution compared with larger tumors. METHODS: The Duke University Medical Center Tumor Registry identified 620 patients (261 women and 359 men, with a mean age of 67 years) who presented with pathologically proven primary nonsmall cell lung carcinomas measuring < or = 3 cm between 1980-1999. Surgical, pathologic, and imaging information was reviewed retrospectively to confirm the size of the lesion and the disease stage at the time of presentation. The distribution of tumor size within each stage and the distribution of disease stage according to tumor size were determined. RESULTS: Tumors occurring in patients with TNM Stage IIIB disease were slightly larger than those found in patients with either more advanced or less advanced disease. However, there was no apparent statistically significant relation between the stage distribution and the size of the primary lesion. CONCLUSIONS: The current study data did not find a statistically significant relation between the size of small primary lung tumors and the distribution of disease stage at the time of presentation. This finding suggests that the detection of small tumors using screening CT may not result in a shift to an earlier disease stage distribution. A reduction in mortality needs to be demonstrated by appropriate clinical trials prior to the initiation of mass CT screening programs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Programas de Rastreamento , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrocitoma/tratamento farmacológico , Carmustina/administração & dosagem , Glioblastoma/tratamento farmacológico , Neoplasias Supratentoriais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Astrocitoma/patologia , Carmustina/efeitos adversos , Estudos de Coortes , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Progressão da Doença , Relação Dose-Resposta a Droga , Implantes de Medicamento , Sinergismo Farmacológico , Feminino , Glioblastoma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança , Neoplasias Supratentoriais/patologia , Temozolomida , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
Doxorubicin is the most widely studied agent for the treatment of malignant mesothelioma. In conventional doses, the response rate is approximately 17%. Higher dose doxorubicin has been successfully employed in other tumor types. Dexrazoxane has been demonstrated to reduce the cardiac toxicity associated with long term, chronic use of doxorubicin. Based upon phase I data generated by the Cancer and Leukemia Group B (CALGB) indicating that doxorubicin at a dose of 120 mg/m(2) when combined with dexrazoxane and GM-CSF could be safely administered, the CALGB undertook a phase II study of high-dose doxorubicin in patients with malignant mesothelioma. Toxicity was excessive, necessitating protocol modification and ultimately protocol termination. There were no objective responses observed. We conclude that high-dose doxorubicin administered with dexrazoxane is unacceptably toxic in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiopatias/induzido quimicamente , Mesotelioma/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Razoxano/administração & dosagem , Trombocitopenia/induzido quimicamenteRESUMO
BACKGROUND: The use of molecular markers in staging non-small cell lung cancer (NSCLC) has been supported in retrospective prognostic models but has not been evaluated in predicting sites of metastases. METHODS: Pathologic specimens were collected from 202 patients after complete resection for stage I NSCLC, who were subsequently found to have no metastases at 5 years (n = 108), isolated brain metastases (n = 25), or other distant metastases (n = 69). A panel of eight molecular markers of metastatic potential was chosen for immunohistochemical analysis of the tumor: p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin, urokinase plasminogen activator (UPA), UPA receptor, and plasminogen activator inhibitor. RESULTS: Patients with isolated brain relapse had significantly higher expression of p53 (p = 0.02) and UPA (p = 0.002). The quantitative expression of E-cadherin was used to predict the site of metastases using recursive partitioning: 0 of 92 patients with E-cadherin expression of 0, 1, or 2 developed isolated cerebral metastases; 0 of 33 patients with E-cadherin expression of 3 with UPA of 1 or 2 and ErbB2 of 0 developed brain metastases. Of the remaining patients at risk (UPA = 3), the risk of isolated cerebral metastases was 21 of 57 patients (37%). CONCLUSIONS: This study demonstrates that molecular markers may predict the site of relapse in early stage NSCLC. If validated in an ongoing prospective study, these results could be used to select patients with isolated brain metastases for adjuvant therapy, such as prophylactic cranial irradiation.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Técnicas Imunoenzimáticas , Pulmão/patologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica/patologia , Estadiamento de Neoplasias , Especificidade de Órgãos/genética , RiscoRESUMO
PURPOSE: The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non-small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFbeta) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFbeta level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which < or = one grade 4 (life-threatening) late toxicity and < or = two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS: Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFbeta levels. Fourteen patients whose TGFbeta levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION: It is feasible to use plasma TGFbeta levels to select patients for RT dose escalation for non-small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Seleção de Pacientes , Lesões por Radiação/prevenção & controle , Fator de Crescimento Transformador beta/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estudos Prospectivos , Dosagem Radioterapêutica , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Sensibilidade e Especificidade , Taxa de SobrevidaRESUMO
Our purpose was to determine whether peripheral blood biomarkers MUC1 and CK19 could be used to complement imaging studies in differentiating benign from malignant indeterminate pulmonary nodules or masses detected on computed tomography CT. One hundred and eighteen patients had a thoracic CT and blood drawn for tumor marker reverse transcriptase-polymerase chain reaction analysis. Thirty-five of the 118 patients had an indeterminate pulmonary nodular opacity on CT, and the findings then were correlated with the reverse transcriptase-polymerase chain reaction results. The sensitivity and specificity for the markers in determining malignancy was calculated. Thirteen of the 35 opacities on CT proved to be benign, and 22 proved to be lung cancer. Among the patients with indeterminate pulmonary abnormalities, polymorphic epithelial mucin protein 1 had a sensitivity and specificity for lung cancer of 100% and 46%, respectively. Cytokeratin 19 had a sensitivity and specificity for lung cancer of 95% and 8%, respectively. These preliminary data showed that serum biomarkers polymorphic epithelial mucin protein 1 and cytokeratin 19 were not specific for lung cancer, although patients with an indeterminate pulmonary abnormality and negative markers were unlikely to have lung cancer. Integration of imaging studies with the appropriate biomarkers may prove useful in evaluating indeterminate pulmonary nodules or masses.
Assuntos
Biomarcadores Tumorais/sangue , Queratinas/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico por imagem , Mucina-1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Humanos , Queratinas/genética , Pneumopatias/sangue , Pneumopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/genética , Projetos Piloto , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: To correlate FDG activity on PET with the expression of glucose transporter proteins Glut-1 and Glut-3 in patients with early stage non-small cell lung cancer (NSCLC). METHODS: Over a 5 year period, all patients with a PET scan and clinical stage I NSCLC underwent an immunohistochemical analysis of their tumor for Glut-1 and Glut-3 expression. The amount of FDG uptake in the primary lesion was measured by a standardized uptake ratio (SUR) and correlated with immunohistochemical results. RESULTS: Seventy-three patients with a mean age of 66 years had clinical stage I disease. The final pathologic stage showed 64 patients with stage IA/B disease, eight with stage IIA disease, and one patient with pathologic stage IIIA (T1N2) disease. Glut-1 transporter expression was significantly higher than Glut-3 (P<0.0001), and although there was some association between the SUR and Glut-1 (P=0.085) and SUR and Glut-3 (P=0.074) expression, this did not reach statistical significance. CONCLUSIONS: Glut-1 and Glut-3 transporter expression did not demonstrate a statistically significant correlation with FDG uptake in potentially resectable lung cancer. It appears that these transporters alone do not affect the variation in FDG activity in early stage NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fluordesoxiglucose F18 , Neoplasias Pulmonares/metabolismo , Proteínas de Transporte de Monossacarídeos/análise , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas do Tecido Nervoso , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Feminino , Transportador de Glucose Tipo 1 , Transportador de Glucose Tipo 3 , Humanos , Técnicas Imunoenzimáticas , Pulmão/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Tomografia Computadorizada de EmissãoRESUMO
Several studies have suggested that non-small cell lung cancer (NSCLC) patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of p53 and HER2 may confer relative chemotherapy resistance and shortened survival. The Cancer and Leukemia Group B performed a series of studies involving sequential chemotherapy followed by radiation for patients with unresectable stage III NSCLC. The objectives of this study were to analyze pathological specimens using immunohistochemistry for NE markers, p53 and HER2 to determine if there was a correlation between marker expression and response or survival. Of 160 eligible patients, 28 (18%) were not evaluable because of inadequate material. The percentage of specimens positive for markers was as follows: neuron-specific enolase 38%, Leu-7 2%, chromogranin A 0%, synaptophysin 5%, > or =2+NE markers 3%, p53 61%, and HER2 65%. There was no statistically significant correlation between any individual marker and response to induction chemotherapy or response to combined chemotherapy/radiation except for synaptophysin. Six of 6 (100%) synaptophysin positive tumors responded by the completion of all therapy compared with 69/125 (55%) synaptophysin negative tumors (P=0.04). None of the individual markers had a significant effect on survival in univariate analysis. Neuron-specific enolase was marginally significant in multivariate analysis (P=0.08). In conclusion, this study did not demonstrate that expression of NE markers, p53 and HER2 were predictive of response to chemotherapy, combined chemotherapy/radiation or for survival in this group of patients with stage III NSCLC. Future studies must employ either different markers or be performed on more adequate surgical specimens.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor ErbB-2/análise , Proteína Supressora de Tumor p53/análise , Antígeno Carcinoembrionário/análise , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/classificação , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/classificação , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: This study was designed to determine the prognostic value of immunohistochemical tumor marker expression in a population of patients with node-negative esophageal cancer treated with complete resection alone. METHODS: Resection specimens were collected from 61 patients with node-negative T1 (n = 31), T2 (n = 14), and T3 (n = 16) esophageal cancer. A panel of 10 tumor markers was chosen for immunohistochemical analysis, based on associations with differing oncologic mechanisms: apoptosis (p53), growth regulation (transforming growth factor-alpha, epidermal growth factor receptor, and Her2-neu), angiogenesis (factor VIII), metastatic potential (CD44), platinum resistance (p-glycoprotein and metallothionein), 5-fluorouracil resistance (thymidylate synthetase), and carcinogenic detoxification (glutathione S-transferase-pi). RESULTS: Complete resection was performed in all patients (44 adenocarcinoma, 17 squamous cell carcinoma), with no operative deaths. Multivariable analysis demonstrated a significant relationship between cancer-specific death and the following variables: low-level P-gp expression (p = 0.004), high-level expression of p53 (p = 0.04), and low-level expression of transforming growth factor-alpha (p = 0.03). In addition, the number of involved tumor markers present was strongly predictive of negative outcome (p = 0.0001). CONCLUSIONS: This study supports the prognostic value of immunohistochemical tumor markers, specifically the expression pattern of P-gp, p53, and transforming growth factor-alpha, in patients with esophageal carcinoma treated with complete resection alone.
Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/mortalidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Adenocarcinoma/química , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/química , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteínas de Neoplasias/análise , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Fator de Crescimento Transformador alfa/análise , Proteína Supressora de Tumor p53/análiseRESUMO
OBJECTIVES: The quality of life (QoL) of 44 men with HRPC and 37 partners (primary caregivers, most residing with the patient) was assessed in a multicenter Phase II trial of docetaxel, estramustine and low dose hydrocortisone (CALGB 9780). A secondary objective was to test the feasibility of assessing partners' QoL in a cooperative group setting. PATIENTS AND METHODS: Patients and partners were separately interviewed by telephone at baseline, two, four and six months by a single trained research interviewer. Patients' QoL was measured by the FACT-P, Mental Health Inventory-17 (MHI-17), Brief Pain Inventory (BPI), a two-day log of pain medications, and the OARS for co-morbid conditions. Partners' QoL was measured by the MHI-17, Caregiver Burden Interview, and co-morbid conditions. RESULTS: The QoL study refusal rates were low for patients (4%) and partners (3%). Although patients tended to experience greater treatment side effects in the first two months (FACT Physical Well-Being item, P = 0.057), their cancer-specific emotions (e.g., worrying about worsening health) significantly improved at two and four months (FACT-Emotional Well-Being, P = 0.003, P = 0.03, respectively), as did their prostate cancer-specific physical problems (e.g., urination, pain), at two and four months (FACT-P, P = 0.001, P = 0.005, respectively). Partners' anxiety significantly decreased over time (MHI, P < 0.05). Patients' quality of life at two months was significantly related to their clinical response (FACT-P total and prostate cancer-specific problems, P < 0.05), and their clinical response was significantly related to a decrease in their partners' anxiety at two months (MHI, P < 0.05). CONCLUSIONS: Despite feeling worse from side effects, patients' prostate cancer-specific problems and emotional state significantly improved in the first four months of treatment. With treatment significantly affecting both patients' and partners' lives. and the successful assessment of partners' QoL, QoL of both patients and partners could be used as important endpoints in selected clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Emoções , Paclitaxel/análogos & derivados , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Qualidade de Vida , Taxoides , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Ansiedade , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Estramustina/administração & dosagem , Estudos de Viabilidade , Feminino , Nível de Saúde , Humanos , Hidrocortisona/administração & dosagem , Infusões Intravenosas , Masculino , Saúde Mental , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Dor , Comportamento Sexual , CônjugesRESUMO
BACKGROUND: CA 125 and CEA are valuable serum tumor markers that can be used to monitor response to therapy in patients with various solid tumors. Systemic studies of CA125 and CEA have not been evaluated in lung cancer. In this study, we report the serum levels of CA 125 and compared it to CEA in newly diagnosed lung cancer and analyzed the serum levels of these markers pre- and post-therapy. MATERIALS AND METHODS: Two hundred and sixteen patients with newly diagnosed non-small lung cancer were evaluated. CA 125 and CEA levels were correlated with stage and histopathology. RESULTS: CA 125 levels and CEA levels were shown to be lower in patients with early stage disease as compared to patients with unresectable or metastatic disease. CEA levels were significantly higher among patients with adenocarcinoma, while there was no statistically significant relationship between histology and CA 125. There was a statistically significant difference in the CEA and CA 125 levels dependent on tumor size. Thirty-seven patients were analyzed for responses to chemotherapy and responders are more likely to have decreases in CA 125 or CEA. CONCLUSION: When abnormally elevated inpatients witlrlung cancer, CA 125 and CEA are useful indicators of disease extent, a useful clinical therapeutic marker, and may potentially have important prognostic value.
Assuntos
Antígeno Ca-125/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Carcinoma de Células Grandes/sangue , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Estadiamento de NeoplasiasRESUMO
The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil (5-FU) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center. Three markers of possible platinum chemotherapy association [metallothionein (MT), glutathione S-transferase-pi (GST-pi), P-glycoprotein (P-gp or multidrug resistance)] and one marker of possible 5-FU association [thymidylate synthase (TS)] were measured using immunohistochemistry. The median cancer-free survival was 25.0 months, with a significantly improved survival for the 38 patients who had a complete response (P < 0.001). High-level expression of GST-pi, P-gp, and TS were associated with a decreased survival. MT was not significant in this population. Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death. In conclusion, this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from trimodality therapy. These data need to be reproduced in a prospective investigation.