RESUMEN
BACKGROUND: AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). METHODS: TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. RESULTS: Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. CONCLUSIONS: TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , ADN/administración & dosificación , Neoplasias de Cabeza y Cuello/terapia , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Quimioradioterapia , ADN/genética , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorouracilo/administración & dosificación , Terapia Genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Hidroxiurea/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada , Retratamiento , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
INTRODUCTION: Treatment of technically operable, medically fit locoregionally advanced non-small cell lung cancer (NSCLC) patients is a controversial therapeutic challenge. Our group routinely uses a trimodality approach. Recent advances in radiotherapy allow for improved tumor targeting and daily patient positioning. We hypothesized that these technologies would improve pathologic response rates. We analyzed consecutively treated stage IIIA/IIIB NSCLC patients undergoing chemoradiotherapy before major lung resection, with particular attention paid to the impact of advanced technologies. METHODS: Locoregionally advanced NSCLC patients (N2) staged in a multidisciplinary forum with mediastinoscopy were planned to receive platinum-based chemotherapy and 60Gy and major lung resection. Four-dimensional CT (4DCT) and image-guided radiotherapy (IGRT) were used as available. Survival endpoints were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using Cox proportional hazards models. RESULTS: We identified 53 patients from 2/1999 to 2/2010. Median RT dose was 59Gy. 68% underwent lobectomy. Forty-three patients were downstaged pathologically (81%), 38 experienced mediastinal sterilization (72%), and 21 (40%) had complete pathologic response (pCR). 1 and 2 year OS were 85.5% and 61.6%. Superior OS and DFS were associated with nodal downstaging and mediastinal sterilization (pN0). Treatment with IGRT/4DCT in 10 patients resulted in high rates of nodal downstaging (100% vs 77%, p=0.0452), mediastinal sterilization (90% vs 67%, p=0.0769), and pCR (60% vs 35%, p=0.0728). CONCLUSIONS: In selected patients, definitive dose CRT followed by major lung resection results in promising DFS and OS. The use of advanced radiotherapy techniques (4DCT and IGRT) appears to result in promising pathologic response rates.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neumonectomía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Quimioradioterapia , Progresión de la Enfermedad , Femenino , Tomografía Computarizada Cuatridimensional , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia Guiada por Imagen , Inducción de Remisión , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. PATIENTS AND METHODS: Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. RESULTS: Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2-54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6-8.3) and 9.5 months (95% CI 7.2-15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. CONCLUSIONS: The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/cirugía , Terapia Combinada/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Femenino , Glutamatos/administración & dosificación , Glutamatos/efectos adversos , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/análogos & derivados , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Pemetrexed , Estudios Prospectivos , Radioterapia/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello , GemcitabinaRESUMEN
INTRODUCTION: We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head and neck squamous cell cancers (HNSCC). PATIENTS AND METHODS: Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m(2)/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy. RESULTS: Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen. CONCLUSIONS: Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Terapia Combinada , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Hidroxiurea/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Dosificación Radioterapéutica , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
BACKGROUND: We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity. PATIENTS AND METHODS: Stages III-IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy. RESULTS: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027). CONCLUSIONS: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Estudios de Cohortes , Terapia Combinada , Supervivencia sin Enfermedad , Relación Dosis-Respuesta en la Radiación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Neoplasias de Cabeza y Cuello/patología , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Inducción de RemisiónRESUMEN
BACKGROUND: Randomized trials established chemoradiotherapy as standard treatment for advanced laryngeal cancer. Patients with large-volume T4 disease (LVT4) were excluded from these trials. The purpose of this study was to report T4 laryngeal cancer patient outcome, including those with LVT4 disease, treated with chemoradiotherapy. PATIENTS AND METHODS: This study is a retrospective subset analysis of 32 patients with T4 laryngeal carcinoma including LVT4 tumors treated on three consecutive protocols investigating paclitaxel (Taxol), 5-fluorouracil, hydroxyurea, and 1.5-Gy twice daily (BID) radiotherapy (TFHX). RESULTS: Median follow-up is 43 months. Four-year locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and laryngectomy-free survival (LFS) was 71%, 67%, 53%, and 86%, respectively. Four patients required laryngectomy for recurrent or persistent disease. Of disease-free patients with >or=1 year follow-up, 90% demonstrated normal or understandable speech. None required laryngectomy for complications. Among LVT4 patients, 4-year LRC, DFS, OS, and LFS was 71%, 65%, 56%, and 81%, respectively. Induction chemotherapy improved 4-year LRC (90% versus 46%, P = 0.03) and DFS (84% versus 42%, P = 0.03). CONCLUSIONS: Promising control and functional outcomes are achieved with TFHX for T4 laryngeal patients. LVT4 disease had outcomes similar to patients with less advanced disease treated on Radiation Therapy Oncology Group 91-11. Induction chemotherapy improved outcomes, warranting further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/radioterapia , Adulto , Anciano , Área Bajo la Curva , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Terapia Combinada , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Hidroxiurea/administración & dosificación , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Preservación de Órganos/métodos , Paclitaxel/administración & dosificación , Probabilidad , Calidad de Vida , Dosificación Radioterapéutica , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We studied the morphometry of 35 femora from 31 female patients with developmental dysplasia of the hip (DDH) and another 15 from 15 age- and sex-matched control patients using CT and three-dimensional computer reconstruction models. According to the classification of Crowe et al 15 of the dysplastic hips were graded as class I (less than 50% subluxation), ten as class I/III (50% to 100% subluxation) and ten as class IV (more than 100% subluxation). The femora with DDH had 10 to 14 degrees more anteversion than the control group independent of the degree of subluxation of the hip. In even the most mildly dysplastic joints, the femur had a smaller and more anteverted canal than the normal control. With increased subluxation, additional abnormalities were observed in the size and position of the femoral head. Femora from dislocated joints had a short, anteverted neck associated with a smaller, narrower, and straighter canal than femora of classes I and II/III or the normal control group. We suggest that when total hip replacement is performed in the patient with DDH, the femoral prosthesis should be chosen on the basis of the severity of the subluxation and the degree of anteversion of each individual femur.