RESUMEN
PURPOSE: Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described. METHODS: From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62). CONCLUSION: Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.
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Antineoplásicos , Quinolinas , Neoplasias de la Tiroides , Antineoplásicos/efectos adversos , Femenino , Humanos , Radioisótopos de Yodo/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Estudios Retrospectivos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/radioterapiaAsunto(s)
Adenocarcinoma Folicular , Carcinoma Neuroendocrino , Cáncer Papilar Tiroideo , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/epidemiología , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/terapia , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/epidemiología , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/terapia , Estudios de Seguimiento , Cáncer Papilar Tiroideo/diagnóstico , Cáncer Papilar Tiroideo/epidemiología , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/terapia , Carcinoma Anaplásico de Tiroides/diagnóstico , Carcinoma Anaplásico de Tiroides/epidemiología , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/terapia , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapiaRESUMEN
BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.
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Antineoplásicos/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Tolerancia a Radiación , Radiofármacos/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Diferenciación Celular , Ensayos de Uso Compasivo , Progresión de la Enfermedad , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Compuestos de Fenilurea/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/radioterapia , Factores de Tiempo , Adulto JovenRESUMEN
AIM: Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)-positive in 67-96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18-64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. METHODS: This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. RESULTS: Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0-82.4%) and 27.7% (95% CI 18.5-36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025-0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005-0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. CONCLUSION: Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Androgénicos/metabolismo , Factores de Riesgo , Conductos Salivales , Resultado del TratamientoRESUMEN
BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Quinazolinonas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND: B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). PATIENTS AND METHODS: Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. RESULTS: A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72-1.36, P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53-1.11, P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38-1.20, P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%, P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). CONCLUSION: The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. CLINICAL TRIAL NUMBER: EudraCT# 2011-002564-24.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/secundario , Cetuximab/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Paclitaxel/administración & dosificación , Pronóstico , Tasa de SupervivenciaAsunto(s)
Compuestos de Fenilurea/administración & dosificación , Quinolinas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Anciano , Antineoplásicos/administración & dosificación , Diferenciación Celular/fisiología , Relación Dosis-Respuesta a Droga , Hemorragia/inducido químicamente , Hemorragia/terapia , Humanos , Masculino , Compuestos de Fenilurea/efectos adversos , Medicina de Precisión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Neoplasias de la Tiroides/patologíaRESUMEN
Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed.
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Carcinoma Neuroendocrino/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Inhibidores de Proteínas Quinasas/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Carcinoma Neuroendocrino/patología , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Diagnóstico Precoz , Humanos , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Neoplasias de la Tiroides/patología , Privación de TratamientoRESUMEN
BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Mucoepidermoide/tratamiento farmacológico , Mioepitelioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adulto , Anciano , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/secundario , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patología , Carcinoma Mucoepidermoide/secundario , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Erupciones por Medicamentos/etiología , Fatiga/inducido químicamente , Síndrome Mano-Pie/etiología , Humanos , Hipertensión/inducido químicamente , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mioepitelioma/metabolismo , Mioepitelioma/patología , Mioepitelioma/secundario , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/metabolismo , Niacinamida/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Proto-Oncogénicas c-ret/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Sorafenib , Tasa de Supervivencia , Resultado del Tratamiento , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto JovenRESUMEN
The aim of the study was to explore the relationship between occupational exposure, defined by occupational categories and job title, and laryngeal cancer. A systematic review and meta-analysis of 21 tobacco and alcohol-adjusted case-control studies including data from 6,906 exposed cases and 10,816 exposed controls was performed to investigate the frequency of laryngeal cancer in different occupations. Job classifications were harmonized using the International Standard Classification of Occupations. Pooled odds ratios (OR [95 % confidence intervals (CI)]) were calculated for the different occupational groups. A significantly increased risk of laryngeal cancer was observed for the occupational category of 'production-related workers, transport equipment operators, and laborers' (OR=1.3 [1.2-1.4]); particularly at risk were occupations as: miners (OR=1.6 [1.2-2.1]), tailors (OR=1.7 [1.2-2.3]), blacksmith and toolmakers (OR=1.5 [1.2-1.7]), painters (OR=1.4 [1.1-1.9]), bricklayers and carpenters (OR=1.3 [1.2-1.5]), and transport equipment operators (OR=1.3 [1.2-1.5]). Individuals working as 'professional, technical, and related workers' (OR=0.7 [0.6- 0.8]), 'administrative and managerial workers' (OR=0.6 [0.4-0.7]), or 'clerical and related workers' (OR=0.8 [0.7-0.9]) had laryngeal cancer less frequently. Occupational exposure, defined by occupational categories and job title, is likely to be an independent risk factor for laryngeal cancer. Further research on specific occupations with increased risk of laryngeal cancer is warranted to explore the underlying mechanisms.
Asunto(s)
Neoplasias Laríngeas/etiología , Exposición Profesional/efectos adversos , Ocupaciones/estadística & datos numéricos , Humanos , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: Tumor human papillomavirus (HPV) status strongly affects overall survival (OS) of oropharyngeal cancer (OPC) patients. Recently, three groups with different outcomes were identified based on HPV status, smoking history and tumor stage. Our objective was to validate this model using a single-institutional retrospective database. PATIENTS AND METHODS: Patients (n=120) diagnosed with OPC at our institution, treated with concomitant cisplatin plus radiotherapy (RT) (n=64), induction chemotherapy followed by concomitant chemoradiation (n=39) or RT alone (n=17), were stratified in three groups with respect to the risk of death (low 26, intermediate 46 and high 49 patients) according to tumor p16 expression as surrogate of HPV status, pack-years of tobacco smoking and nodal/tumor stage. Group-stratified Kaplan-Meier OS curves were estimated and compared using the log-rank test. RESULTS: The 2-year OS estimates were 100%, 86% and 70%, respectively. The difference between the survival curves was statistically significant (P=0.009). The Harrell's concordance index was 0.70. The calibration plot showed a good concordance between our results and those observed in the original study. CONCLUSIONS: This study validates the risk grouping previously identified. Risk-driven clinical decision making and trial designs will help in better defining the most appropriate treatment in OPC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Fumar/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Supervivencia sin Enfermedad , Femenino , Genes p16 , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/terapia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: This monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein-Barr virus -related locally advanced undifferentiated nasopharyngeal cancer. PATIENTS AND METHODS: We retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, and 5-FU 750 mg/m(2)/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m(2) every 21 days for three cycles. RESULTS: Thirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3-4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3-4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%- to 100%), respectively. CONCLUSIONS: In this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones por Virus de Epstein-Barr/complicaciones , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Supervivencia sin Enfermedad , Docetaxel , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Quimioterapia de Inducción , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/administración & dosificación , Taxoides/efectos adversosRESUMEN
BACKGROUND: Mounting evidence suggests that recurrence of resected head and neck squamous cell carcinomas (HNSCCs) is due to the outgrowth of unrecognized residual tumor cells as well as to the premalignant and/or precursor-field epithelial cells. We studied the impact of processes triggered by HNSCC surgery in stimulating both residual tumor cells [demonstrated to overexpress epidermal growth factor receptor (EGFR)], and premalignant cells surrounding the resected lesion. PATIENTS AND METHODS: EGFR expression/activation by immunohistochemistry/biochemistry and gene status by FISH were investigated in 23 primary HNSCCs and surrounding tissues. The ability to induce cell proliferation of wound healing drainages collected from 12 relapsed and 11 not relapsed patients was evaluated by a colorimetric assay in squamous cell carcinoma cell lines A431 (carrying EGFR amplification) and CAL27 (carrying three EGFR copies) in the presence/absence of EGFR therapeutic inhibitors. RESULTS: Primary tumors showed intermediate/high EGFR expression (91%), EGFR phosphorylation and EGFR-positive FISH (35%). Normal, metaplastic and dysplastic epithelium surrounding the resected tumor displayed EGFR overexpression. EGFR activation and gene amplification were observed in normal and dysplastic epithelium, respectively. Each tested wound healing drainage induced the cells to proliferate and the proliferation was significantly higher in relapsed compared with not relapsed HNSCC patients (P = 0.02 and P = 0.03). Anti-EGFR treatments inhibited the drainage-induced proliferation, with the highest inhibitory efficiency by cetuximab on A431 cells, while CAL27 cell growth was more efficiently inhibited by tyrosine kinase inhibitors. CONCLUSIONS: Surgery could favor the proliferation of cells showing EGFR overexpression/activation/amplification such as residual tumor cells and/or precursor-field epithelial cells already present after surgery. Treatment with anti-EGFR reagents inhibits wound-induced stimulation, according to the EGFR family status.
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Carcinoma de Células Escamosas/patología , Receptores ErbB/biosíntesis , Neoplasias de Cabeza y Cuello/patología , Recurrencia Local de Neoplasia/patología , Cicatrización de Heridas , Adulto , Anciano , Líquidos Corporales/metabolismo , Carcinoma de Células Escamosas/cirugía , Línea Celular Tumoral , Proliferación Celular , Células Epiteliales/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/sangre , Femenino , Expresión Génica , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Proteínas Oncogénicas v-erbB/metabolismo , Receptor ErbB-2/metabolismoRESUMEN
EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for >or=6months was investigated. From April to December 2005, 30 patients [23 adenoid cystic carcinoma (ACC) and 7 non-ACC] were treated with cetuximab at 400mg/m(2)/week followed by 250mg/m(2)/week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5-54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash >or=G2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Adenoide Quístico/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/secundario , Cetuximab , Supervivencia sin Enfermedad , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Cuidados Paliativos/métodos , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Adulto JovenRESUMEN
BACKGROUND: This phase II study was conducted to determine the antitumour activity of gemcitabine in adenoid cystic carcinoma (ACC). PATIENTS AND METHODS: Patients with progressive and/or symptomatic, recurrent and/or metastatic ACC were treated with gemcitabine 1250 mg/m(2) intravenous (i.v.) on days 1 and 8 of each 21-day cycle. Each cycle was repeated every 3 weeks in the absence of disease progression for a minimum of four cycles and a maximum of 12 cycles. RESULTS: Among 21 ACC patients, there were no objective responses. Eleven patients had a stable disease, of which ten patients for more than 6 months, and eight had a progressive disease after 4 cycles. Gemcitabine was well tolerated by most patients. CONCLUSION: We conclude that gemcitabine is not an active drug in ACC.