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BACKGROUND: The purpose of this nonrandomized, open-label, phase I study (NCT01285037) was to evaluate the safety and tolerability of merestinib, an oral antiproliferative and antiangiogenic kinase inhibitor, and to determine a recommended phase II dose and schedule for patients with advanced cancer. MATERIALS AND METHODS: This was a multicenter, nonrandomized, open-label, phase I study of oral merestinib consisting of six parts: dose escalation (part A), followed by a four-cohort dose-confirmation study (part B) and subsequently a four-part dose expansion and combination safety testing of merestinib with standard doses of cetuximab (part C), cisplatin (part D), gemcitabine and cisplatin (part E), and ramucirumab (part F) in patients with specific types of advanced cancers. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated in all cohorts. RESULTS: The dose escalation, confirmation, and expansion results support the dosing of merestinib at 120 mg once daily, based on acceptable exposure and safety at this dose. One complete response was observed in a patient with cholangiocarcinoma, and three patients with cholangiocarcinoma achieved a partial response. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of stable disease. CONCLUSION: This study demonstrates that merestinib has a tolerable safety profile and potential anticancer activity and warrants further clinical investigation. IMPLICATIONS FOR PRACTICE: Merestinib treatment in patients with advanced cancer demonstrated an acceptable safety profile and potential antitumor activity, supporting its future development in specific disease populations as a monotherapy and/or in combination with other therapies.
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Colangiocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Indazoles/administración & dosificación , Niacinamida/análogos & derivados , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Proliferación Celular/efectos de los fármacos , Cetuximab/administración & dosificación , Colangiocarcinoma/patología , Cisplatino/administración & dosificación , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indazoles/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Gemcitabina , RamucirumabRESUMEN
BACKGROUND: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)-targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. METHODS: In this phase I/II study, patients received intravenous enoblituzumab (3-15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non-small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]-naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. RESULTS: Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. CONCLUSIONS: Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. TRIAL REGISTRATION NUMBER: NCT02475213.
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Antineoplásicos Inmunológicos , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antígenos B7 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/patología , Receptor de Muerte Celular Programada 1 , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
BACKGROUND: Intergroup 0139 Trial suggests an increase in mortality after pneumonectomy in patients receiving preoperative chemotherapy and radiation. We evaluate our outcomes with pneumonectomy after neoadjuvant chemotherapy and radiation. METHODS: Neoadjuvant chemotherapy and radiation consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1-5 and 29-33 given concurrently with 5,040 cGy radiation. From a prospective database, results after pneumonectomy were compared between patients receiving and not receiving neoadjuvant chemotherapy and radiation during the same time period. RESULTS: Over 7 years, 50 pneumonectomies were performed for non-small-cell carcinoma; 18 received neoadjuvant chemotherapy and radiation (group A) and 32 did not (group B). Comparing group A with group B, there was no significant difference in patient demographics, blood loss, transfusion requirements or pneumonectomy side. Group A had more patients with stage III disease [17/ 18 (94%) versus 15/32 (47%), P = 0.001] and also more often had vascularized flap for bronchial stump coverage [17/18 (94%) versus 4/32 (13%), P < 0.001]. There was no significant difference in operative morbidity or mortality. Mortality for group A was 0/18 and for group B was 2/32 (6.3%) (P = 0.530). Group A patients with IIIA(N2) disease (n = 13) had median recurrence-free survival of 12.4 months, median overall survival of 25 months, and 3- year overall survival of 22.2%. CONCLUSIONS: Using a multidisciplinary team approach at a tertiary care center, pneumonectomy can be performed successfully after neoadjuvant chemotherapy and radiation for advanced-stage lung cancer. Vascularized flap for bronchial stump coverage may be important in this regard.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Terapia Neoadyuvante , Neumonectomía , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Terapia Combinada , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Dosificación Radioterapéutica , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD). METHODS AND MATERIALS: Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cc and <60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients per cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated. RESULTS: Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at <24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P<.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively. CONCLUSIONS: SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24 Gy in 2 fractions. Toxicity at the PBV is a concern but potentially can be avoided with strict dose-volume constraints.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/métodos , Fraccionamiento de la Dosis de Radiación , Neoplasias Pulmonares/terapia , Radiocirugia/métodos , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Quimioradioterapia/efectos adversos , Quimioradioterapia/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estudios Prospectivos , Radiocirugia/efectos adversos , Radiocirugia/mortalidadRESUMEN
PURPOSE: Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)-designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non-NCI-designated cancer programs. MATERIALS AND METHODS: Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board-approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers. RESULTS: Patient characteristics included a median age of 64 years, a median of two lines of prior therapy, and a predominance of GI carcinomas (58%). One hundred sixty-four of 200 patients (82%) had adequate tumor for NGS, 95% had genomic alterations identified, and 100% had variants of unknown significance. Fifteen of 164 patients (9.2%) enrolled in genotype-directed clinical trials, and three patients (1.8%) received commercially available targeted agents off clinical trials. The reasons for nonreceipt of NGS-directed therapy were no locally available matching trial (48.6%), ineligibility (33.6%) because of comorbidities or interim clinical deterioration, physician's choice of a different therapy (6.8%), or stable disease (11%). CONCLUSION: This experience demonstrates that a program enrolling patients in specific targeted agent clinical trials after NGS can be implemented successfully outside of the NCI-designated cancer program network, with comparable accrual rates. This is important because targetable genes have rare mutation rates and clinical trial accrual after NGS is low.
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Ensayos Clínicos como Asunto , Variación Genética , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/genética , Neoplasias/terapia , Adulto , Anciano , Anciano de 80 o más Años , Instituciones Oncológicas , Femenino , Perfilación de la Expresión Génica , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias/diagnóstico , Selección de Paciente , Estados UnidosAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/etnología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Etnicidad/estadística & datos numéricos , Neoplasias Pulmonares/etnología , Neoplasias Pulmonares/mortalidad , Grupos Raciales/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/secundario , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Factores de Riesgo , Programa de VERF , Análisis de Supervivencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Metastatic Merkel cell carcinoma (MCC) is a lethal, Merkel cell polyomavirus (MCPyV) cancer with no currently available effective therapy. Harnessing the immune system through an immune checkpoint blockade is an attractive option because the immune system appears to be dysfunctional in the Merkel cell tumor microenvironment. Although MCPyV is expressed in 80% of MCCs and serves as a powerful antigen for stimulating host immune response, intratumoral CD8+ T-cell infiltration is seen only in 18% of MCCs. In contrast, about 50% of MCPyV-positive MCCs express the programmed death-ligand 1 (PD-L1) on multiple cell types in the tumor microenvironment. We present a case of a young patient with MCC involving the heart and pancreas that showed an impressive response after treatment with four cycles of the anti-PD-1 monoclonal antibody, nivolumab.
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Pleuropulmonary synovial sarcoma (PPSS) is an extremely rare primary malignancy of the lung. We present a case of a middle-aged female with PPSS that was initially discovered as an incidental indeterminate nodule on chest radiograph. Following evaluation with computed tomography (CT), the patient went on to positron-emission tomography (PET)/CT for work-up of the solitary pulmonary nodule, which demonstrated mild FDG-avidity and no other evidence of FDG-avid disease. The patient then underwent thoracotomy and right upper lobectomy for definitive treatment. Only after evaluation of the gross pathology, histology, immunohistochemistry and cytogenetics was the diagnosis of synovial sarcoma made. Importantly, the preceding PET/CT, in addition to physical exam of the upper and lower extremities, helped exclude the more common extra-thoracic soft-tissue variety of synovial sarcoma, which frequently metastasizes to lung, carrying a worse prognosis. Discussion of synovial sarcoma and PPSS follows.
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Neoplasias Pulmonares , Neoplasias Pleurales , Sarcoma Sinovial , Nódulo Pulmonar Solitario , Adulto , Femenino , Humanos , Hallazgos Incidentales , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirugía , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/cirugía , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/cirugía , Nódulo Pulmonar Solitario/diagnóstico , Nódulo Pulmonar Solitario/cirugíaRESUMEN
OBJECTIVES: To assess the effect on progression-free and overall survival from the addition of cetuximab to paclitaxel-based chemoradiation for patients with squamous cell head and neck cancer from Brown University Oncology Group studies. METHODS: BrUOG HN-204 patients with stage III or IV locally advanced squamous cell cancer of the head and neck without distant organ metastases received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Recurrence and survival data were compared with previous Brown University studies utilizing the same paclitaxel-based chemoradiation with and without induction chemotherapy. RESULTS: The progression-free survival and overall survival at 3 years for all 37 patients initiating chemoradiation was 54% and 57%, respectively. All surviving patients were followed for at least 3 years and the median follow-up is 4.4 years. Of 14 patients who recurred within 3 years, 7 patients recurred locally only, 5 had a systemic recurrence, and 2 recurred both locally and systemically. CONCLUSIONS: The addition of cetuximab to paclitaxel, carboplatin, and radiation achieves overall survival that is virtually identical to prior Brown University Oncology Group studies of paclitaxel-based chemoradiation without cetuximab. Improvements in locoregional control are needed despite the use of 3 agents to enhance the effects of radiation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Células Escamosas/tratamiento farmacológico , Neoplasias de Células Escamosas/mortalidad , Neoplasias de Células Escamosas/radioterapia , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carboplatino/administración & dosificación , Cetuximab , Quimioradioterapia , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias de Células Escamosas/patología , Paclitaxel/administración & dosificación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Gastric reflux can reach into the upper airway, inducing cellular damage in the epithelial lining. This condition is believed to be a risk factor for development of laryngopharyngeal squamous cell carcinoma (LPSCC), although the literature is conflicting. METHODS: To better clarify this relationship, we assessed the association of self-reported heartburn history and medication use among 631 patients with LPSCCs and 1234 control subjects (frequency-matched on age, gender, and town of residence) enrolled as part of a population-based case-control study of head and neck squamous cell carcinoma in the greater Boston area. RESULTS: After adjusting for age, gender, race, smoking, alcohol consumption, HPV16 seropositivity, education, and body mass index, subjects reporting a history of frequent heartburn and who were neither a heavy smoker nor heavy drinker had a significantly elevated risk of LPSCCs [OR, 1.78; 95% confidence interval (CI), 1.00-3.16]. Among those with a history of heartburn, there was an inverse association between antacid use and LPSCCs relative to those never taking heartburn medication (OR, 0.59; 95% CI, 0.38-0.93) that remained consistent when analyzed by smoking/drinking status, HPV16 status, or by primary tumor site. CONCLUSIONS: Our data show that gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx. Further studies are needed to clarify the possible chemopreventive role of antacid use for patients with gastric reflux. IMPACT: Elucidation of additional risk factors for head and neck cancer can allow for risk stratification and inform surveillance of high-risk patients.
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Carcinoma de Células Escamosas/complicaciones , Reflujo Gastroesofágico/etiología , Neoplasias Laríngeas/complicaciones , Neoplasias Faríngeas/complicaciones , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVES: Src family kinases (SFKs) are expressed in non-small cell lung cancer (NSCLC) and may be involved in tumor growth and metastases. Inhibition of SFK may also enhance radiation. The purpose of this study was to evaluate if a maximum dose of 100 mg of dasatinib could be safely administered with concurrent chemoradiation and then continued as maintenance for patients with newly diagnosed stage III NSCLC. METHODS: Patients with stage III locally advanced NSCLC received paclitaxel, 50 mg/m(2)/week, with carboplatin area under the curve (AUC) = 2, weekly for 7 weeks, and concurrent radiotherapy, 64.8 Gy. Three dose levels of dasatinib 50, 70, and 100 mg/day were planned. RESULTS: 11 patients with locally advanced NSCLC were entered. At the 70 mg dose level 1 patient had grade 5 pneumonitis not responsive to therapy, and one patient had reversible grade 3 pneumonitis and grade 3 pericardial effusion. Due to these toxicities the Brown University Oncology Group Data Safety Monitoring Board terminated the study. CONCLUSION: Dasatinib could not be safely combined with concurrent chemoradiation for stage 3 lung cancer due to pneumonitis.
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INTRODUCTION: Pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with improved survival in solid tumors. Southwest Oncology Group 9,900 demonstrated a 9% pCR after three cycles of paclitaxel/carboplatin every 21 days. We evaluated pCR rate with intensive weekly paclitaxel in a phase II study. METHODS: Patients with non-small cell lung cancer, stage IB to IIIA, were eligible and received carboplatin, area under the curve = 6, every 21 days ×3 and paclitaxel 80 mg/m weekly ×9. Primary outcome was the pCR rate. RESULTS: Twenty patients with clinical stage IB (n = 16), IIA (n = 1), IIB (n = 1), and IIIA (n = 2) were enrolled. Mean age was 65 years. Toxicity included grade 4 neutropenia in 1 (5%), grade 3 neutropenia in 3 (15%), grade 3 neuropathy in 1 (5%), and grade 3 nausea in 1 (5%). After neoadjuvant therapy, one patient refused surgery and one died of a nontreatment-related event. Eighteen patients underwent complete resection, 15 by lobectomy, and 3 by pneumonectomy. Pathology revealed 3 (17%) patients with pCR. The median follow-up is 67 months. For clinical stage IB (n = 16), the median overall survival has not been reached, and the 5-year overall survival is 69%. All patients with pCR (n = 3) remain alive and disease-free. Improved overall survival was seen in patients who were pathologically down-staged versus patients who were not, p = 0.05. CONCLUSIONS: Neoadjuvant chemotherapy with intensive weekly paclitaxel and carboplatin is well tolerated and does not increase surgical morbidity. This intense regimen achieves rates of pCR and survival that compares favorably with other reported induction regimens and merits further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Terapia Neoadyuvante , Anciano , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Inducción de Remisión , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: A phase I study was performed to determine the maximally tolerated dose of carboplatin, ifosfamide, and docetaxel in advanced head and neck cancers. METHODS: Carboplatin (week 1) was administered with weekly docetaxel and ifosfamide for 3 weeks in an every 4-week cycle. Restaging was done after two cycles, while dose level escalation was done in cohorts of three patients. RESULTS: Fifteen patients (recurrent/metastatic disease, n = 8; bulky locally advanced disease, n = 7) were enrolled. No dose-limiting toxicities were observed. Toxicities included grade 3 neutropenia and anemia (n = 2, each), and grade 2 thrombocytopenia (n = 3). The final level of carboplatin AUC = 6 (week 1) with docetaxel 30 mg/m(2) per week and ifosfamide 1,000 mg/m(2) per week was chosen for further evaluation. CONCLUSIONS: This novel regimen of carboplatin with weekly docetaxel and ifosfamide has a favorable toxicity profile and is active in this setting. Phase II study results are awaited.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Dosis Máxima Tolerada , Adulto , Anciano , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Docetaxel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Factibilidad , Femenino , Hospitales Universitarios , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer. MATERIALS AND METHODS: Patients with stage III or IV locally advanced squamous cell cancer of the head and neck, without distant organ metastases, were eligible. Patients received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. RESULTS: Thirty-two patients were assessable for chemoradiation toxicities. Grade 3 and grade 4 mucositis occurred in 53% and 16% of patients, respectively. Grade 3 and grade 4 radiation dermatitis occurred in 44% and 9% of patients, respectively. Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy (64% vs.14%, respectively, P < 0.0001). Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6% and 3% of patients. Overall 21 patients (66%) had any grade 3 toxicity and 10 patients (31%) had any grade 4 toxicity. The percentages of the intended total dose delivered of carboplatin, cetuximab, paclitaxel, and radiation were 86%, 89%, 89%, and 96%, respectively. CONCLUSION: Cetuximab, when combined with paclitaxel, carboplatin and intensity modulated radiation therapy, increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel, carboplatin, and conventional radiation for patients with head and neck cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Erupciones Acneiformes/inducido químicamente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Células Escamosas/patología , Cetuximab , Terapia Combinada , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Mucositis/etiología , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Estudios Prospectivos , Radiodermatitis/etiología , Dosificación Radioterapéutica , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.