RESUMO
BACKGROUND: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. PATIENTS AND METHODS: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. RESULTS: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). CONCLUSIONS: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. CLINICAL TRIAL REGISTRATION: NCT01345682.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Metotrexato/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Quinazolinas/administração & dosagem , Administração Intravenosa , Administração Oral , Afatinib , Antimetabólitos Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/sangue , Biópsia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Physical activity (PA) reduces the risk of developing breast cancer (BC) and mortality rate in BC patients starting PA after diagnosis. Immunomodulation is considered responsible for these effects. However, limited data exist on the immunomodulation induced by moderate PA (mPA) during neoadjuvant chemotherapy (NACT). We have investigated the longitudinal change of cytokines during NACT alone or combined with mPA. MATERIALS AND METHODS: Twenty-three cytokines were analyzed in BC patients at consecutive timepoints: at baseline (T0), before starting mPA (T1), before surgery (T2), and after surgery (T3). mPA consisted of 3-weekly brisk-walking sessions for 9-10 consecutive weeks. RESULTS: Ninety-two patients were assessed: 21 patients refused mPA (untrained) and 71 agreed (trained). At T1, NACT induced significant up-regulation of interleukin (IL)-5, IL-6, IL-15, chemokine ligand (CCL)-2, interferon-γ, and C-X-C motif ligand (CXCL)-10 and reduction of expression of IL-13 and CCL-22. At T2, NACT and mPA induced up-regulation of IL-21, CCL-2, and tumor necrosis factor-α and reduction of expression of IL-8, IL-15, vascular endothelial growth factor, and soluble interleukin 6 receptor. Only CXCL-10 increased in untrained patients. A cytokine score (CS) was created to analyze, all together, the changes between T1 and T2. At T2 the CS decreased in trained and increased in untrained patients. We clustered the patients using cytokines and predictive factors and identified two clusters. The cluster A, encompassing 90% of trained patients, showed more pathological complete response (pCR) compared to the cluster B: 78% versus 22%, respectively. CONCLUSIONS: mPA interacts with NACT inducing CS reduction in trained patients not observed in untrained patients, suggesting a reduction of inflammation, notwithstanding chemotherapy. This effect may contribute to the higher rate of pCR observed in the cluster A, including most trained patients.
Assuntos
Neoplasias da Mama , Citocinas , Exercício Físico , Inflamação , Terapia Neoadjuvante , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Citocinas/metabolismo , Exercício Físico/fisiologia , Adulto , Idoso , Estudos ProspectivosRESUMO
Until a few decades ago neck dissection (ND) was the standard surgical approach for node-positive tumours. Nowadays patients with locally advanced head and neck cancer can be treated with definitive chemoradiation (CRT), which includes the treatment of the neck; however, results on residual viable tumour after conservative treatment are heterogeneous and depend on initial node stage and primary treatment. Many authors accept adjuvant surgery in patients with N2-3 disease. Regardless of the results of upfront CRT, even if there is no evidence of lymph node metastases, when the risk for persistent positive neck nodes exceeds 15-20%, elective ND might be indicated. However, despite the diffusion of innovative technologies and therapies, there are controversies about both response evaluation and surgical management of initially involved neck nodes after definitive CRT and organ preservation treatment. In this paper we will analyse state of art of neck evaluation after CRT and discuss the role of ND.
Assuntos
Carcinoma de Células Escamosas/cirurgia , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Esvaziamento Cervical , Neoplasia Residual/cirurgia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Metástase Linfática , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/radioterapia , PrognósticoRESUMO
Despite progress in the treatment of locally advanced head and neck squamous cell cancer (HNSCC), the prognosis remains dismal and 5-year survival does not exceed 40%. In metastatic and recurrent disease, in spite of the introduction of cetuximab in combination with platinum and fluorouracil, the median overall survival rate remains lower than 11 months. There are many possible reasons for these disappointing results including acquired drug resistance and tumor hypoxia. Angiogenesis plays an important role in HNSCC development and proliferation. Promising preclinical results with antiangiogenic therapies have engendered a number of clinical trials, but so far there have not been any conclusive results on the value of such treatments. This paper aims to review the role of angiogenesis in head and neck cancer and to suggest future perspectives.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Cetuximab , Humanos , Camundongos , Neovascularização Patológica/metabolismoRESUMO
BACKGROUND: Radiation dermatitis developing in patients receiving cetuximab concomitantly with radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) is now recognized to have different pathophysiological and clinical characteristics to the radiation dermatitis associated with radiotherapy or concomitant chemotherapy and radiotherapy. Current grading tools were not designed to grade this type of radiation dermatitis; their use may lead to misclassification of reactions and inappropriate management strategies, potentially compromising cancer treatment. PATIENTS AND METHODS: An advisory board of seven leading European specialists (three medical oncologists, three radiation oncologists and a dermatologist) with extensive experience of the use of cetuximab plus radiotherapy produced consensus guidelines for the grading and management of radiation dermatitis in patients receiving cetuximab plus radiotherapy. RESULTS: Modifications to the current, commonly used National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 for grading radiation dermatitis were proposed. Updated management guidelines, building on previously published guidelines from 2008, were also proposed. CONCLUSIONS: The proposed revisions to the grading system and updated management guidelines described here represent important developments toward the more appropriate grading and effective management of radiation dermatitis in patients receiving cetuximab plus radiotherapy for LA SCCHN.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Radioterapia (Especialidade)/normas , Radiodermite/etiologia , Radiodermite/patologia , Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cetuximab , Terapia Combinada/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Guias de Prática Clínica como Assunto , Radiodermite/fisiopatologia , Radiodermite/terapia , Radioterapia/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e PescoçoAssuntos
Imunoterapia , Neoplasias/terapia , Microambiente Tumoral , Antineoplásicos/uso terapêutico , Humanos , Subfamília C de Receptores Semelhantes a Lectina de Células NK/efeitos dos fármacos , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Fator de Transcrição STAT3/efeitos dos fármacos , Receptores Toll-Like/efeitos dos fármacosRESUMO
Head and neck cancer is a complex disorder that includes mostly squamous cell carcinomas that can develop in the throat, larynx, nose, sinuses, and mouth. Etiopathogenesis is due to tobacco and alcohol consumption and to infection by human papillomavirus (HPV) type 16/18. Tumors often develop within preneoplastic fields of genetically altered cells. Most head and neck cancers result from multistep accumulation of genetic alterationsm resulting in clonal outgrowth of transformed cells. These DNA changes are caused by a variety of mechanisms like endogenous mutations and exogenous mutations. Dysregulated molecular pathway includes alterations of critical inhibitor of cyclin CDK complexes, inactivating mutations of p53 gene, and activation of oncogenes and growth factors. This paper attempts to review the role of p53 and MDM2 genetic aberrations and pathways in head and neck cancer.