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: The transforming growth factor-beta (TGF- ß) pathway has been implicated in proliferation, migration and invasion of various cancers. Endoglin is a TGF-ß accessory receptor that modulates signalling. We identified Endoglin as an epigenetically silenced tumour-suppressor gene in lung cancer by means of a genome-wide screening approach, then sought to characterise its effect on lung cancer progression. METHODS: Methylation microarray and RNA sequencing were carried out on lung cancer cell lines. Epigenetic silencing of Endoglin was confirmed by methylation and expression analyses. An expression vector and a 20-gene expression panel were used to evaluate Endoglin function. Pyrosequencing was carried out on two independent cohorts comprising 112 and 202 NSCLC cases, respectively, and the impact of Endoglin methylation on overall survival (OS) was evaluated. RESULTS: Methylation in the promoter region resulted in silencing of Endoglin, which could be reactivated by demethylation. Increased invasion coupled with altered EMT marker expression was observed in cell lines with an epithelial-like, but not those with a mesenchymal-like, profile when Endoglin was absent. Methylation was associated with decreased OS in stage I but not in stages II-III disease. CONCLUSIONS: We show that Endoglin is a common target of epigenetic silencing in lung cancer. We reveal a link between Endoglin silencing and EMT progression that might be associated with decreased survival in stage I disease.
Assuntos
Antígenos CD/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Inativação Gênica , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Receptores de Superfície Celular/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Endoglina , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metilação , Regiões Promotoras Genéticas , Análise Serial de Proteínas , Análise de Sequência de DNA/métodosRESUMO
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.
RESUMO
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
BACKGROUND: Calcium is an important intracellular messenger that mediates many biological processes that are relevant to the malignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in human cancer. METHODS: We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatory subunit α(2)δ-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions. RESULTS: Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5' regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffected in cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapse with loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-α (ER)-positive and -negative cases. Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system. CONCLUSION: Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Metilação de DNA , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/patologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG/genética , Feminino , Humanos , Células MCF-7 , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , RNA Mensageiro/genética , Sequências Reguladoras de Ácido NucleicoRESUMO
BACKGROUND: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastro-intestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous system (CNS) metastatic breast cancer is not known. METHODS: In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53 determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres. RESULTS: We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast carcinoma to brain metastasis. CONCLUSION: Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias do Sistema Nervoso Central/secundário , Genes p53 , Mutação , Sequência de Bases , Neoplasias da Mama/patologia , Neoplasias do Sistema Nervoso Central/genética , Primers do DNA , Feminino , HumanosRESUMO
BACKGROUND: The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process. METHODS: We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing. RESULTS: Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis. CONCLUSION: CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Ilhas de CpG/genética , Metilação de DNA , Metástase Neoplásica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Regulação para Baixo , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , RecidivaRESUMO
BACKGROUND: Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known. METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas. RESULTS: NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01). CONCLUSION: Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.
Assuntos
5'-Nucleotidase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Epigênese Genética/genética , Melanoma/genética , Melanoma/patologia , 5'-Nucleotidase/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/genética , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Inativação Gênica , Humanos , Especificidade de Órgãos , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In the light of existing preclinical and clinical data, we studied NT5E (5'-nucleotidase, ecto) expression and NT5E CpG island methylation in breast cancer. METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines and primary and breast carcinomas. RESULTS: NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series, patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P=0.003, OR=0.34, 95% CI: 0.17-0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patients progressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primary tumours (P=0.01, OR=11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS) (P=0.001, HR=2.7) and overall survival (OS) (P=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in oestrogen receptor negative (P=0.011, HR=3.27, 95% CI: 1.31-8.12) and in triple negative cases (P=0.004; HR=6.2, 95% CI: 1.9-20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whose tumours were positive for NT5E CpG island methylation: DFS (P=0.0016, HR=5.1, 95% CI: 1.8-14.37) and OS (P=0.0005, HR=7.4, 95% CI: 2.416-23.08). CONCLUSION: NT5E CpG island methylation is a promising breast cancer biomarker.
Assuntos
5'-Nucleotidase/genética , Biomarcadores Tumorais/análise , Neoplasias da Mama/genética , Metilação de DNA , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ilhas de CpG , Intervalo Livre de Doença , Feminino , Proteínas Ligadas por GPI/genética , Inativação Gênica , Humanos , Metástase Neoplásica/genética , Prognóstico , Regiões Promotoras GenéticasRESUMO
BACKGROUND: Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at http://www.genenames.org/ and Entrez database at http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable α subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant ß subunit encoded by P4HB. METHODS: We used RT-PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow. RESULTS: C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt's lymphoma. CONCLUSIONS: Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.
Assuntos
Colágeno/genética , Linfoma de Células B/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Linhagem Celular Tumoral , Colágeno/metabolismo , Ilhas de CpG/genética , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Linfoma de Células B/metabolismo , Metilação , Pró-Colágeno-Prolina Dioxigenase/metabolismoRESUMO
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 PescoçoRESUMO
BACKGROUND: Intensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab. PATIENTS AND METHODS: Eligible patients had stage III-IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m(2)/day × 5 days) and fluorouracil (200 mg/m(2)/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: Fourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3-4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients. CONCLUSIONS: The combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Cetuximab , Cisplatino/administração & dosagem , Terapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Radiodermite/induzido quimicamente , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients' awareness conducted after the first training period. PATIENTS AND METHODS: In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase. RESULTS: Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%. CONCLUSIONS: Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment.
Assuntos
Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Oncologia/educação , Neoplasias/diagnóstico , Neoplasias/terapia , Educação de Pacientes como Assunto , Relações Médico-Paciente , Revelação da Verdade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Conscientização , Compreensão , Empatia , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Direitos do Paciente , Prognóstico , Avaliação de Programas e Projetos de Saúde , Encaminhamento e Consulta , Inquéritos e Questionários , Recursos Humanos , Adulto JovemRESUMO
PURPOSE/OBJECTIVE: On September 2009: We started a randomized multicenter phase III study comparing chemoradiation (CRT) (Aldestein RTOG regimen) versus induction chemotherapy followed by Cetuximab radiation (IBRT). The main study's aim was comparison of overall survival but no formal analyses have been made between the two arms because of low accrual and high amount of missing data. The goal of this paper is to identify the reasons of difference in accrual and quality of data among participating centers. MATERIAL/METHODS: Statistic: We correlated data collection quality with relevance of the centers, accrual and number of scientific papers (both specific on HNC and other topics) of each PI. We created an HNC publishing score dividing the number of HNC specific papers for the overall number of published papers. RESULTS: We observed a strong difference in the accrual of pts as well as in the quality of data among the participating centers. The accrual was independent from the quality of data since some centers with low accrual produced high quality data with an excellent follow up. We found a correlation among both number of published papers of each PI and HNC publishing score with the quality of data. CONCLUSION: The study demonstrated that expertise in HNC is important not only to ensure a better outcomes but also to provide high quality data in phase III trials.
Assuntos
Coleta de Dados/métodos , Cetuximab/uso terapêutico , Quimiorradioterapia/métodos , Ensaios Clínicos Fase III como Assunto , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de PesquisaRESUMO
Cetuximab is a monoclonal antibody targeting the transmembrane receptor HER-1 (epidermal growth factor receptor, EGFR). In theory, inhibition of EGFR may influence tumor behavior since the receptor regulates many important tumor cell activities including tumor growth, angiogenesis, and inhibition of the apoptotic response to chemotherapy and radiotherapy. Available experimental data suggest that cetuximab may enhance the activity of chemotherapy and radiotherapy, reverse resistance to some anticancer drugs, and has itself anticancer activity. Early clinical data support the experimental results. This paper reviews the published findings on cetuximab in the treatment of advanced head and neck cancer and points out the future objectives of the clinical research on this drug.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas/radioterapia , Cetuximab , Cisplatino/efeitos adversos , Ensaios Clínicos como Assunto , Terapia Combinada , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Cuidados PaliativosRESUMO
BACKGROUND: In 1992, we reported the first analysis of a randomized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck. The results of that 3-year analysis indicated that the combined treatment had superior efficacy. PURPOSE: After an additional 2 years of follow-up, we again compared the efficacy of the two treatment regimens, with attention paid to differences in overall survival, progression-free survival, and locoregional relapse-free survival. METHODS: One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m2] and fluorouracil [200 mg/m2], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. Responses, failures, and toxic effects associated with the two treatment regimens were compared. Overall survival, progression-free survival, and locoregional relapse-free survival were calculated according to the Kaplan-Meier method; the logrank test was used to compare survival parameters between the two patient groups. Reported P values are two-sided. RESULTS: As reported previously, toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects; however, the incidence and severity of mucositis were nearly identical among patients in the two treatment arms. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group; P = .037, chi-squared test). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24% (95% confidence interval [CI] = 14%-40%) and 10% (95% CI = 4%-24%), respectively (P = .01, logrank test). The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21% (95% CI = 11%-37%) and 9% (95% CI = 3%-22%), respectively (P = .008, logrank test). Finally, the 5-year estimates of locoregional relapse-free survival were 64% (95% CI = 36%-84%) in the combined-treatment group and 32% (95% CI = 10%-65%) in the radiotherapy-only group (P = .038, logrank test). CONCLUSIONS AND IMPLICATIONS: The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years. However, additional trials must be conducted before considering the combined approach as standard therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/secundário , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Radioterapia Adjuvante , Análise de Sobrevida , Resultado do TratamentoRESUMO
A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).