Impact of proper surgical treatment on the survival of patients with epithelial ovary cancer.

OBJECTIVE: to evaluate the quality of surgical treatment of ovarian cancer patients and assess the impact of adequate surgical oncological treatment on disease-free survival and overall survival of patients with advanced epithelial ovarian cancer. METHODS: this is an observational, retrospective study with quantitative analysis, with the collection of data in medical records of a temporal convenience sample of patients diagnosed with ovarian cancer admitted to a High Complexity Oncology Unit, in Belo Horizonte, from the period of 2014 to 2020. RESULTS: a total of 91 patients diagnosed with ovarian cancer were evaluated, with the epithelial histopathological type being the most frequent (85%). Of this total, 68 patients (74.7%) had advanced-stage ovarian cancer. Appropriate surgical treatment was performed in 30.9% of patients with advanced epithelial ovarian cancer and the type of performed surgery was statistically significant for overall survival. This low proportion of appropriate surgical oncological treatment was not related to surgical specially or surgeon competence, but mainly to advanced disease related to patient flow at UNACON. It was not possible to confirm if the advanced-stage disease was related to tumor biology or losing time from diagnosis to oncological surgery. CONCLUSION: overall survival of advanced-stage epithelial ovarian cancer patients is directly influenced by appropriate surgical treatment, however, in this study, the percentage of advanced ovarian cancer receiving adequate surgical treatment was much lower than the rates reported in the literature. To improve these outcomes, we believe that surgeons should keep following patients during neoadjuvant chemotherapy to point to a better time for surgery, and clinical oncologists should better consider adequate oncological surgery as one of the pillars of ovarian cancer treatment and get more involved in facilitating surgeries.

Characteristics of patients diagnosed with cervical cancer in Brazil: preliminary results of the prospective cohort EVITA study (EVA001/LACOG 0215).

OBJECTIVES: Cervical cancer is the fourth most common cancer in women worldwide. Epidemiological and quality of life (QoL) data in patients with cervical cancer from low- and middle-income countries are scarce. We aimed to describe sociodemographic and clinicopathological characteristics and quality of life of patients with cervical cancer at diagnosis in Brazil. METHODS: EVITA is a prospective cohort study of newly diagnosed patients with cervical cancer from May 2016 to December 2017, stages I-IVB, from 16 Brazilian sites representing the five Brazilian regions. At baseline, medical evaluation was performed and European Organization for Research and Treatment of Cancer (EORTC) QLQ-CX24/C30 questionnaires were administered. RESULTS: A total of 631 patients were included. Mean±SD age was 49.3±13.9 years; skin color was non-white in 65.3%, and 68.0% had ≤8 years of formal education. In total, 85.1% of patients had a Pap smear. The main reasons reported by patients for not having a Pap smear were: lack of interest (46.9%), shame or embarrassment (19.7%), lack of knowledge (19.7%), and difficulty with access (9.1%). Most patients were diagnosed with locally advanced or metastatic disease (FIGO clinical stage II-IV in 81.8%- stage II in 35.2%, stage III in 36.1%, and stage IV in 10.5%). Patients with clinical stage III-IV had worse physical functioning and role functioning. CONCLUSIONS: Cervical cancer in Brazil is usually diagnosed at an advanced stage. Most patients have low formal education and are unemployed. Lack of interest was identified as a main reason for not having a screening test, and limited access was reported as a reason by <10% of the patients. Awareness campaigns must be a governmental priority, specially focused on the needy population, along with wide access to treatment.

Impact of proper surgical treatment on the survival of patients with epithelial ovary cancer / Impacto do tratamento cirúrgico adequado na sobrevida de mulheres com carcinoma epitelial ovariano

ABSTRACT Objective: to evaluate the quality of surgical treatment of ovarian cancer patients and assess the impact of adequate surgical oncological treatment on disease-free survival and overall survival of patients with advanced epithelial ovarian cancer. Methods: this is an observational, retrospective study with quantitative analysis, with the collection of data in medical records of a temporal convenience sample of patients diagnosed with ovarian cancer admitted to a High Complexity Oncology Unit, in Belo Horizonte, from the period of 2014 to 2020. Results: a total of 91 patients diagnosed with ovarian cancer were evaluated, with the epithelial histopathological type being the most frequent (85%). Of this total, 68 patients (74.7%) had advanced-stage ovarian cancer. Appropriate surgical treatment was performed in 30.9% of patients with advanced epithelial ovarian cancer and the type of performed surgery was statistically significant for overall survival. This low proportion of appropriate surgical oncological treatment was not related to surgical specially or surgeon competence, but mainly to advanced disease related to patient flow at UNACON. It was not possible to confirm if the advanced-stage disease was related to tumor biology or losing time from diagnosis to oncological surgery. Conclusion: overall survival of advanced-stage epithelial ovarian cancer patients is directly influenced by appropriate surgical treatment, however, in this study, the percentage of advanced ovarian cancer receiving adequate surgical treatment was much lower than the rates reported in the literature. To improve these outcomes, we believe that surgeons should keep following patients during neoadjuvant chemotherapy to point to a better time for surgery, and clinical oncologists should better consider adequate oncological surgery as one of the pillars of ovarian cancer treatment and get more involved in facilitating surgeries.

RESUMO Objetivo: avaliar a qualidade do tratamento cirúrgico de pacientes com câncer de ovário e o impacto do tratamento oncológico cirúrgico adequado na sobrevida livre de doença e sobrevida global de pacientes com câncer de ovário epitelial avançado. Métodos: Trata-se de um estudo observacional, retrospectivo, de análise quantitativo, com coleta de dados em prontuários de uma amostra de conveniência temporal de pacientes com diagnóstico de câncer de ovário internadas em uma Unidade de Oncologia de Alta Complexidade (UNACON), em Belo Horizonte, no período de 2014 a 2020. Resultados: foram avaliadas 91 pacientes diagnosticadas com câncer de ovário, sendo o tipo histopatológico epitelial o mais frequente (85%). Desse total, 68 pacientes (74,7%) apresentavam câncer de ovário em estágio avançado. O tratamento cirúrgico adequado foi realizado em 30,9% das pacientes com câncer de ovário epitelial avançado e o tipo de cirurgia realizada foi estatisticamente significativo para a sobrevida global. Essa baixa proporção de tratamento cirúrgico oncológico adequado não esteve relacionada à especialidade cirúrgica ou competência do cirurgião, mas principalmente à doença avançada relacionada ao fluxo de pacientes na UNACON. Não foi possível confirmar se a doença em estágio avançado estava relacionada à biologia tumoral ou à perda de tempo do diagnóstico para a cirurgia oncológica. Conclusão: A sobrevida global de pacientes com câncer de ovário epitelial em estágio avançado é diretamente influenciada pelo tratamento cirúrgico adequado. Porém, o percentual de câncer de ovário avançado recebendo tratamento cirúrgico adequado foi muito inferior aos índices relatados na literatura. Para melhorar esses resultados, acreditamos que os cirurgiões devem continuar acompanhando as pacientes durante a quimioterapia neoadjuvante para apontar um melhor momento para a cirurgia, e os oncologistas clínicos devem considerar melhor a cirurgia oncológica adequada como um dos pilares do tratamento do câncer de ovário e se envolver mais na facilitação das cirurgias.

Interest In and Practices Related to Gynecologic Oncology among Members of the Brazilian Federation of Associations of Gynecology and Obstetrics.

OBJECTIVE: The present study aims to obtain basic demographic information, the level of interest and of training in gynecology oncology among Brazilian obstetricians and gynecologists (OB-GYNs) to create a professional profile. METHODS: An online questionnaire was sent to 16,008 gynecologists affiliated to the Brazilian Federation of Associations of Gynecology and Obstetrics (FEBRASGO, in the Portuguese acronym). We considered gynecologists dedicated to gynecologic oncology (OB-GYNs ONCO) those who self-reported that > 50% of their daily practice consists in working with women's cancer care. RESULTS: A total of 1,608 (10%) of 16,008 FEBRASGO members responded. The OB-GYNs are concentrated in the southern and southeastern states of Brazil. Gynecologic oncology was considered the 8th greatest area of interest in gynecology among the OB-GYNs. A total of 95 (5.9%) of the OB-GYNs were considered OB-GYNs ONCO. Obstetricians and gynecologists are actively engaged in cancer care: > 60% of them dedicate up to 25% of their daily practice to oncology. The role of the physicians in screening and prevention, diagnosis, in the treatment of precancerous lesions, and in low complexity surgical procedures is notably high. Gynecologists dedicated to gynecologic oncology in Brazil have a heterogeneous, nonstandardized and short training period in gynecologic oncology. These professionals had a more significantly role in performing medium- and high-complexity operations compared with OB-GYNs (65.2% versus 34%, and 47.3% versus 8.4%, respectively). CONCLUSION: The role of OB-GYNs and of OB-GYNs ONCO appears to be complementary. Obstetricians and gynecologists act more often in screening and prevention and in low-complexity surgical procedures, whereas OB-GYNs ONCO are more involved in highly complex cases. Strategies to raise standards in cancer training and to encourage the recognition of gynecologic oncology as a subspecialty should be adopted in Brazil.

OBJETIVO: O presente estudo tem como objetivo obter informações demográficas básicas, o nível de interesse e de treinamento em ginecologia oncológica entre obstetras e ginecologistas (OB-GYNs) brasileiros para criar um perfil destes profissionais. MéTODOS: Um questionário online foi enviado a 16.008 ginecologistas filiados à Federação Brasileira de Associações de Ginecologia e Obstetrícia (FEBRASGO). Nós consideramos ginecologistas dedicados à oncologia ginecológica (OB-GYNs ONCO) aqueles que referiram atuar em > 50% de sua prática diária com o tratamento do câncer feminino. RESULTADOS: Um total de 1.608 (10%) dos 16.008 membros da FEBRASGO responderam ao questionário. Os OB-GYNs estão concentrados nos estados do sul e sudeste do Brasil. A oncologia ginecológica foi considerada a 8ª área de maior interesse em ginecologia entre os OB-GYNs. Um total de 95 (5,9%) dos OB-GYNs foram considerados ginecologistas dedicados à oncologia ginecológica (OB-GYNs ONCO). Obstetras e ginecologistas estão ativamente envolvidos no tratamento do câncer: > 60% deles dedicam até 25% de sua prática diária à oncologia. O papel dos médicos na triagem e na prevenção, no diagnóstico, no tratamento de lesões pré-cancerosas e em procedimentos cirúrgicos de baixa complexidade é notavelmente alto. Ginecologistas dedicados à oncologia ginecológica no Brasil têm um período de treinamento em oncologia ginecológica heterogêneo, não padronizado e curto. Estes profissionais tiveram um papel mais significativo na realização de operações de média e alta complexidade em comparação com OB-GYNs (65,2% versus 34%, e 47,3% versus 8,4%, respectivamente). CONCLUSãO: Os papéis dos OB-GYN e dos OB-GYNs ONCO parecem ser complementares. Os OB-GYNs frequentemente atuam em triagem e prevenção e em procedimentos cirúrgicos de baixa complexidade, enquanto os OB-GYNs ONCO estão mais envolvidos em casos de mais alta complexidade. Estratégias para elevar os padrões de treinamento em oncoginecologia e incentivar o reconhecimento da oncologia ginecológica como uma subespecialidade devem ser adotadas no Brasil.

Mutation screening of TP53, CHEK2 and BRCA genes in patients at high risk for hereditary breast and ovarian cancer (HBOC) in Brazil.

BACKGROUND: Few studies related to hereditary breast and ovarian cancer syndrome (HBOC) have been conducted in Brazil, and they are restricted to only small areas of the country. Here, we report the mutation profile of BRCA1/2, CHEK2 and TP53 genes in a cohort from Minas Gerais state. METHODS: These genes from 44 patients at high risk for HBOC were screened through high-resolution melting and/or sequencing. The pathogenicity of the alterations was checked using ClinVar database and bioinformatics programs. RESULTS: In BRCA genes we identified 46 variants, 38 without clinical significance and 8 pathogenic mutations including a new pathogenic mutation in BRCA1 gene (c.4688_4694delACCTGGAinsG). The most prevalent pathogenic mutation was c.4829_4830delTG, in the BRCA2 gene. This mutation was not described in the Brazilian population up to now and in this study, it was described with a prevalence of 6.8%. The p.R337H mutation in TP53 gene was found in one patient clinically diagnosed as HBOC and without clinical criteria for Li-Fraumeni syndrome. In CHEK2 gene, the undescribed variant c.485A > G was found and it presents as probably pathogenic through in silico analyses. Pathogenic mutations were found in 29.5% of the patients, 11.3% in BRCA1, 15.9% in BRCA2 and 2.3% in TP53 gene. CONCLUSIONS: Brazilian population is one of the most heterogeneous in the world and the mutational profile knowledge of genes related to HBOC from different regions can contribute to the definition of more cost-effective strategies for the prevention, identification and treatment of cancer.

Immunohistochemical WWOX expression and association with angiogenesis, p53 expression, cell proliferation and clinicopathological parameters in cervical cancer / Avaliação da expressão do gene WWOX por avaliação imunohistoquímica, sua associação com marcador de angiogênese, expressão do p53, proliferação celular e parâmetros clinicopatológicos no câncer de colo uterino

Abstract Objective The current study evaluated the expression of WW domain-containing oxidoreductase (WWOX), its association with clinicopathological features and with p53, Ki-67 (cell proliferation) and CD31 (angiogenesis) expression in patients with invasive cervical squamous cell carcinoma (ICSCC). To the best of our knowledge, no other study has evaluated this association. Methods Women with IB stage-ICSCC (n = 20) and women with uterine leiomyoma (n = 20) were prospectively evaluated. Patients with ICSCC were submitted to type BC1 radical hysterectomy and pelvic lymphadenectomy. Patients in the control group underwent vaginal hysterectomy. Tissue samples were stained with hematoxylin and eosin for histological evaluation and protein expression was detected by immunohistochemistry studies. Results The WWOX expression was significantly lower in the tumor compared with the expression in thebenign cervix (p = 0.019). TheWWOXexpressionwas inversely associated with the CD31 expression in the tumor samples (p = 0.018). There was no association betweentheWWOXexpression with the p53 expression (p = 0.464)or the Ki-67expression (p = 0.360) in the samples of invasive carcinoma of the cervix. There was no association between the WWOX expression and tumor size (p = 0.156), grade of differentiation (p = 0.914), presence of lymphatic vascular invasion (p = 0.155), parametrium involvement (p = 0.421) or pelvic lymph node metastasis (p = 0.310) in ICSCC tissue samples. Conclusion The results suggested that WWOX may be involved in ICSCC carcinogenesis, and this marker was associated with tumor angiogenesis.

Resumo Objetivo O presente estudo avaliou a expressão do WWOX, sua associação com características clinicopatológicas e com a expressão do p53, ki-67 (proliferação celular) e CD31 (angiogênese) em pacientes com carcinoma invasivo de células escamosas do colo uterino, ou simplesmente câncer do colo uterino (CCE). Métodos Foram avaliadas prospectivamente pacientes com CCE no estágio IB (n = 20) e mulheres com mioma uterino, no grupo controle (n = 20). As pacientes com CCE foram submetidas à histerectomia radical e à linfadenectomia pélvica do tipo B-C1. As mulheres no grupo-controle foram submetidas à histerectomia vaginal. As amostras de tecido foramcoradas comhematoxilina e eosina para avaliação histológica e a expressão das proteínas foi detectada por imuno-histoquímico. Resultados A expressão do WWOX foi significativamente menor no tumor quando comparada com sua expressão no colo do útero benigno (p = 0,019). A expressão tumoral de CD31 foi inversamente associada à expressão de WWOX (p = 0,018). Sua expressão não foi associada à expressão tumoral de p53 e Ki-67 em pacientes com CCE (p = 0,464 e p = 0,360, respectivamente). Não houve associação entre a expressão de WWOX e o tamanho do tumor (p = 0,156), grau de diferenciação (p = 0,914), presença de invasão vascular linfática (p = 0,155), comprometimento do paramétrio (p = 0,421) ou metástase dos linfonodos pélvicos (p = 0,310) em pacientes com CCE. Conclusão Os resultados sugeriram que o WWOX pode estar envolvido na carcinogênese do CICECU e esse marcador foi associado à angiogênese tumoral.

Immunohistochemical WWOX Expression and Association with Angiogenesis, p53 Expression, Cell Proliferation and Clinicopathological Parameters in Cervical Cancer.

OBJECTIVE: The current study evaluated the expression of WW domain-containing oxidoreductase (WWOX), its association with clinicopathological features and with p53, Ki-67 (cell proliferation) and CD31 (angiogenesis) expression in patients with invasive cervical squamous cell carcinoma (ICSCC). To the best of our knowledge, no other study has evaluated this association. METHODS: Women with IB stage-ICSCC (n = 20) and women with uterine leiomyoma (n = 20) were prospectively evaluated. Patients with ICSCC were submitted to type B-C1 radical hysterectomy and pelvic lymphadenectomy. Patients in the control group underwent vaginal hysterectomy. Tissue samples were stained with hematoxylin and eosin for histological evaluation and protein expression was detected by immunohistochemistry studies. RESULTS: The WWOX expression was significantly lower in the tumor compared with the expression in the benign cervix (p = 0.019). The WWOX expression was inversely associated with the CD31 expression in the tumor samples (p = 0.018). There was no association between the WWOX expression with the p53 expression (p = 0.464) or the Ki-67 expression (p = 0.360) in the samples of invasive carcinoma of the cervix. There was no association between the WWOX expression and tumor size (p = 0.156), grade of differentiation (p = 0.914), presence of lymphatic vascular invasion (p = 0.155), parametrium involvement (p = 0.421) or pelvic lymph node metastasis (p = 0.310) in ICSCC tissue samples. CONCLUSION: The results suggested that WWOX may be involved in ICSCC carcinogenesis, and this marker was associated with tumor angiogenesis.

OBJETIVO: O presente estudo avaliou a expressão do WWOX, sua associação com características clinicopatológicas e com a expressão do p53, ki-67 (proliferação celular) e CD31 (angiogênese) em pacientes com carcinoma invasivo de células escamosas do colo uterino, ou simplesmente câncer do colo uterino (CCE). MéTODOS: Foram avaliadas prospectivamente pacientes com CCE no estágio IB (n = 20) e mulheres com mioma uterino, no grupo controle (n = 20). As pacientes com CCE foram submetidas à histerectomia radical e à linfadenectomia pélvica do tipo B-C1. As mulheres no grupo-controle foram submetidas à histerectomia vaginal. As amostras de tecido foram coradas com hematoxilina e eosina para avaliação histológica e a expressão das proteínas foi detectada por imuno-histoquímico. RESULTADOS: A expressão do WWOX foi significativamente menor no tumor quando comparada com sua expressão no colo do útero benigno (p = 0,019). A expressão tumoral de CD31 foi inversamente associada à expressão de WWOX (p = 0,018). Sua expressão não foi associada à expressão tumoral de p53 e Ki-67 em pacientes com CCE (p = 0,464 e p = 0,360, respectivamente). Não houve associação entre a expressão de WWOX e o tamanho do tumor (p = 0,156), grau de diferenciação (p = 0,914), presença de invasão vascular linfática (p = 0,155), comprometimento do paramétrio (p = 0,421) ou metástase dos linfonodos pélvicos (p = 0,310) em pacientes com CCE. CONCLUSãO: Os resultados sugeriram que o WWOX pode estar envolvido na carcinogênese do CICECU e esse marcador foi associado à angiogênese tumoral.

Screening of the BRCA1 gene in Brazilian patients with breast and/or ovarian cancer via high-resolution melting reaction analysis.

The aim of this study was to evaluate the profile of BRCA1 mutations among cancer-affected Brazilian women from the Midwest region of Minas Gerais state with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. In this Brazilian region, the first Center for Hereditary Cancer Control began operation in 2011, and 90% of patients receive assistance from the public health service. Eighteen patients at high risk for HBOC were subjected to molecular analysis. Primers were designed for 22 coding exons of the gene; DNA was extracted; and real-time PCR followed by high-resolution melting reaction was performed. The amplicons were sequenced to confirm the identified profiles. Only exon 11 was directly sequenced due its length. Multiplex ligation-dependent probe amplification (MLPA) was performed for those patients in whom no pathogenic mutations were found. Among the 14 alterations identified in this study, the c.5263_5264insC pathogenic mutation was present in two patients (11.1%). Four alterations showed no clinical relevance; one exhibited inconclusive clinical relevance according to the examined databases; and eight alterations presented a divergent classification between the databases. No deletions or duplications were found using the MLPA technique. The HRM methodology was highly sensitive in identifying variants in the BRCA1 gene and can dramatically reduce the amount of sequencing required to identify germline mutations in BRCA genes, enabling cheaper tests and increasing their availability to Brazilian women assisted by the public health service.

Ensaio clínico de fase II da combinação de erlotinibe, quimioterapia e radioterapia em pacientes com carcinoma epidermoide do colo de útero estadiamentos IIB a IIIB / [Phase II clinical trial of the combination of erlotinib, chemotherapy and radiation therapy in patients with cervical squamous cell carcinoma staging IIB a IIIB]

Introdução: o carcinoma epidermoide do colo de útero representa um problema de saúde pública em países em desenvolvimento. Apesar de frequentemente passível de cura quando detectado precocemente, elevado número de pacientes se apresenta com doença localmente avançada ao diagnóstico, cenário clínico associado a resultados terapêuticos insatisfatórios. O padrão atual de tratamento do câncer de colo de útero localmente avançado consiste na combinação de quimioterapia e radioterapia (QT/RXT). Entretanto, após os benefícios obtidos com a adição de quimioterapia baseada em platina à radioterapia, as taxas de cura atingiram um platô. Pacientes com estágios III e IVA apresentaram taxas de sobrevida em cinco anos limitadas a 40 e 15%, respectivamente, enfatizando a necessidade de desenvolvimento de novas estratégias terapêuticas. Estudos préclínicos e clínicos evidenciaram que inibidores do receptor de fator de crescimento epitelial (EGFR) desempenham atividade antitumoral, além de efeito químio e radiossensibilizantes. Erlotinibe (E) é um desses inibidores, com atividade antitumoral pela inibição reversível do EGFR em sua porção tirosino-cinase. Os resultados de estudo de fase I de E combinado a QT/RXT confirmaram a segurança de E na dose de 150 mg/dia. Objetivos: avaliar a segurança e eficácia da combinação de cisplatina, RXT e E em pacientes com carcinoma epidermoide de colo de útero localmente avançado e pesquisa de potenciais marcadores moleculares correlatos (expressão imuno-histoquímica de EGFR e número de cópias do EGFR por FISH). Metodologia: estudo de fase II, unicêntrico, não randomizado. Elegibilidade ­ pacientes com diagnóstico de carcinoma de células escamosas de colo de útero IIB e III; primeira linha terapêutica; ECOG PS 0-2. Tratamento: E 150 mg/dia iniciados uma semana pré-radioterapia e mantidos até o término da braquiterapia; cisplatina ­ 40 mg/m2 /semana/5 semanas; teleterapia (dose de 4.500 cGy) e braquiterapia (quatro inserções semanais de 600 cGy). Biópsia tumoral pré e pós-tratamento foram obtidas para análises moleculares. Avaliação de resposta após três meses do término do tratamento com ressonância magnética, tomografia computadorizada, 18 fluorodeoxiglicose ( 18FFDG), tomografia com emissão de pósitrons (PET-TC) e biópsia. Resultados: foram incluídas 41 pacientes com idade mediana de 44 anos (27-68), estágio IIB (57,9%), IIIA (2,6%) e IIIB (39,5%); 84,3% apresentaram expressão de EGFR, sendo superexpressão em 13%; apenas uma teve amplificação de EGFR por FISH; três foram excluídas; e 38 foram avaliadas para toxicidade; duas não completaram o esquema de tratamento (uma teve a cisplatina suspensa após exibir fenômeno de Raynaud e a segunda apresentou hepatotoxicidade grau IV). A duração mediana do tratamento foi de 77 dias (64-129) e o seguimento mediano atual de 59,3 meses. A combinação terapêutica foi bem tolerada. Todas as 36 pacientes avaliáveis relataram resposta objetiva; 34 (94,4%) exibiram resposta completa; e duas, resposta parcial. As sobrevidas global e livre de progressão foram de 91,7 e 80,6%, e 80 e 73,8% nas medianas de seguimento de 24 e 36 meses, respectivamente. Conclusão: a combinação de RXT/QT/E foi segura e apresentou eficácia promissora em câncer de colo de útero localmente avançado. Este é o primeiro estudo a sugerir o benefício de uma droga-alvo específica neste contexto clínico.

Introduction: Squamous cell cervical carcinoma (CC) represents an important public health concern in developing countries. Although CC is often curable if detected early, a significant number of patients present with locally advanced disease at diagnosis, a clinical scenario associated with suboptimal therapeutic benefits. Combined treatment involving radiotherapy and weekly cisplatin may be considered a reasonable standard of care. After the benefits obtained with the addition of platinum-based chemotherapy to radiotherapy, cure rates of locally advanced cell cervical carcinoma (LACC) have reached a plateau. Therapy results are sub-optimal and patients with stage III and IVA tumors have 5 year survival rates of 40% and 15%, respectively. There is a clear need to explore new strategies to improve prognosis in this group of patients.Pre-clinical and clinical data indicate that EGFR inhibition has antitumor effect itself and potentiates CRT. Erlotinib is a drug that reversibly binds to the the EGFR tyrosine Kinase domain, thereby blocking the signal transduction events, and tumorigenic effects associated with EGFR activation. We previously reported the results from a phase I trial of E administered concurrently with standard chemoradiotherapy for locally advanced cervical cancer that confirmed the safety of E at 150mg/day. Purpose: This phase II trial aims to evaluate the safety and efficacy of erlotinib combined to chemoradiotherapy in locally advanced cervical cancer patients and correlative molecular studies (EGFR IHC and copy number analysis).Methods: Phase II, non-randomised, single institutional.Eligibility - histologically proven stage IIB to IIIB squamous cell cervical carcinoma; no prior therapy; ECOG PS 0-2; adequate end-organ function. Patients received E 150mg/day one week before and combined with C (40mg/m2 , weekly, 5 cycles) and RT (external beam - 4500cGy in 25 fractions, followed by 4 fractions/600cGy/weekly of brachytherapy). Pre and pos treatment tumor tissue was obtained for molecular analysis. Response was assessed after a 3 month-interval with MRI, CT, PET and biopsy.Results: Patient characteristics: median age 44 (27-68), stage IIB 22 (57.9%), IIIA (2.6%) and IIIB 15 (39.5%). 84.3% presented EGFR expression, being 2 or 3 (+) in 13% of them; only one pt presented EGFR amplification by FISH. 41 pts were enrolled and 3 excluded. 38 patients were available for toxicity. Two patients did not complete planned treatment (one presented Raynaud's Syndrome and had C interrupted and one presented grade 4 hepatotoxicity). Of 36 pts who have completed E+CRT, median duration of treatment was 77 (64-129) days and median followup(FUP) is 59.3months(m). Overall E+CRT was well tolerated. Most common grade 3 toxicity was skin rash (13%). Of 36 evaluable for response, 34 patients, (94.4%-IC 95% 79.99- 99.03) had complete response and two patients had partial response. Cumulative OS and PFS survivals were 91.7% and 80.6% and 80% and 73.8%, at the median FUP of 24 and 36 m respectively, superior to historical control. Conclusions: E+CRT is safe and has significant activity in LACC, superior to historical control. To the best of our knowledge, this is the first study to show that a target agent has promising activity in LACC.

Delineamento do perfil molecular relacionado à via do receptor de fator de crescimento epitelial (EGFR) em estudo de fase i da combinação de Erlotinibe e quimioirradiação em portadoras decarcinoma epidermoide do colo uterino estadiamentos IIB a IIIB

Introdução: o carcinoma epidermoide do colo uterino representa um problema de saúde pública em países em desenvolvimento. A sua elevada incidência é agravada pelo fato de que a maioria das pacientes apresenta doença avançada no momento do diagnóstico. O padrão atual de tratamento do câncer de colo uterino localmente avançado consiste na combinação de quimioterapia baseada em platina e radioterapia (RXT), sendo os resultados obtidos insatisfatórios em significativo número de pacientes. O desenvolvimento de novas estratégias terapêuticas para esse subgrupo de pacientes e a identificação de preditores de resposta ao tratamento são necessários. Resultados promissores vêm sendo obtidos no tratamento de carcinomas extrapélvicos mediante o uso de inibidores do receptor de fator de crescimento epitelial (EGFR). Erlotinibe é um desses inibidores, com atividade antitumoral pela inibição do EGFR em sua porção tirosino-quinase. Seu uso combinado à cisplatina e à RXT não conferiu acréscimo significativo de toxicidade em portadores de câncer de cabeça e pescoço. Objetivos: avaliar a expressão de EGFR total tumoral, AKT fosforilada (pAKT) e MAPK fosforilada (pMAPK) para delineamento inicial do perfil molecular relacionado ao EGFR em câncer de colo uterino e avaliar a segurança e taxa de resposta da combinação do inibidor de EGFR erlotinibe, cisplatina e radioterapia em pacientes com carcinoma epidermoide de colo uterino estágios IIB, IIIA e IIIB. Metodologia: avaliação da expressão de EGFR total, pAKT e pMAPK por imunohistoquímica em amostra de tumor de colo uterino biopsiado previamente à exposição ao tratamento em pacientes portadoras de carcinoma de colo uterino IIB e III tratadas em estudo de fase I composto de três coortes consecutivas com doses progressivas de 50, 100 e 150 mg de erlotinibe associado ao tratamento padrão de cisplatina e radioterapia. Cada coorte foi composta de no mínimo três pacientes seguidas por 14 semanas. Avaliou-se a resposta terapêutica com tomografia com emissão de pósitrons, tomografia computadorizada, ressonância magnética e exame clínico após três meses do término de tratamento. Resultados: 15 pacientes foram incluídas, 3 no nível de dose de 50mg, 4 no de 100 e 8 no de 150mg. As pacientes apresentaram idade mediana de 47 anos (36-59) e estágio IIB (46,2%) e IIIB (53,8%). O perfil molecular tumoral relacionado à via do fator de crescimento epitelial (EGF) nessa coorte foi de 80% de expressão de EGFR total, 90% de pAKT e 80% de pMAPK. A combinação terapêutica mostrou-se segura e eficaz, com resposta completa em 91,7% das pacientes tratadas. Erupção cutânea e diarréia foram as toxicidades mais comumente encontradas, sendo graus 3 em 2 e 3 pacientes, respectivamente. Não foi observada toxicidade dose limitante no campo de tratamento. A dose de 150 mg de erlotinibe foi definida para exploração em estudo de fase II. Conclusão: a expressão de EGFR e a ativação de efetores da via do EGF dão suporte a novas estratégias de bloqueio direto ou indiretos dessas vias, conforme explorado neste estudo de fase I. Isso cria novas perspectivas de alvos a serem explorados, em termos da sua eficácia, no tratamento do câncer de colo uterino. Além disso, esses dados podem contribuir para o desenvolvimento de terapias que combinem radioterapia e inibidores do EGFR (IEGFR) em outras neoplasias pélvicas. As altas taxas de resposta e a segurança apresentadas justificam e respaldam a investigação dessa combinação no contexto de um estudo de fase II

Introduction: Cervical squamous cell carcinoma represents an important public health concern in developing countries. Combined treatment involving radiotherapy and weekly cisplatin may be considered a reasonable standard of care. After the benefits obtained with the addition of platinum-based chemotherapy to radiotherapy, cure rates of locally advanced squamous cell cervical carcinoma have reached a plateau. Therapy results are sub-optimal and patients with stage III and IVA tumors have 5 year survival rates of 40% and 15%, respectively. There is a clear need to explore new strategies to improve prognosis in this group of patients and to identify predictive biomarkers. EGFR autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression. Inhibitors of EGFR have been tested in different tumor types with promising results. Erlotinib is a drug that reversibly binds to the the EGFR tyrosine Kinase domain, thereby blocking the signal transduction events, and tumorigenic effects associated with EGFR activation. The combination of erlotinib with radiotherapy and cisplatin in locally advanced head and neck cancer showed a high complete response rate with acceptable toxicity. Purpose: To check EGFR expression and AKT/MAP phosphorylation status to outline EGFR pathway molecular profile in cervical cancer and to determine the safety and response rate of erlotinib combined to chemoradiotherapy in stage IIB to IIIB cervical cancer. Methods: EGFR expression and AKT/MAPK phosphorylation status were determined by immunohistochemistry in tumor tissue samples collected before treatment. In a modified Fibonacci design, the study aimed to study three cohorts of at least three patients receiving escalating doses of erlotinib(50/100/150mg) combined with cisplatin (40mg/m2, weekly, 5 cycles) and radiotherapy (external beam 4,500cGy in 25 fractions, followed by 4 fractions/600cGy/weekly of brachytherapy). Response was assessed by PET CT, MRI, CT and clinical evaluation three months after treatment end . Results: 15 patients were enrolled, 3 at dose level (DL) 50mg, 4 at DL 100mg and 8 at DL150mg. Patients presented median age 47 (36-59), stage IIB (46.2%) and IIIB (53.8%). EGFR was expressed in 90% and phosporylation of AKT and MAPK was present in 90 and 80% of the patients, respectively. Combined treatment of erlotinib and chemoradiation was well tolerated and did not increase in field or systemic toxicities. Skin rash and diarrhea were the most common adverse events, being grade 3 in 2 and 3 patients, respectively.There was no limiting in-field toxicity. 91.7% of the patients presented complete response. Conclusions: The high expression ratios of EGFR and the activation of its major signalling routes, AKT and MAPK, create new insights to direct and indirect blocking of the EGFR pathway in cervical cancer and may be helpful, as potential biomarkers, in directing a more rationale design of future clinical trials. The high response rate and the safety of the combination support and encourage the development of a phase II trial