Current Development and Research Trend of Chemotherapeutic Agents for Head and Neck Squamous Cell Carcinoma / 대한이비인후과학회지

After FDA approval of cetuximab at 2006, receptor tyrosine kinase, including an epidermal growth factor receptor, blocking agents have been evaluated for head and neck squamous cell carcinoma (HNSCC). Agents targeting PI3K/Akt/mTOR, IL-6/JAK/STAT3, vascular endothelial growth factor receptor, and cyclin D-CDK-4/6-INK4/Rb pathway have developed. Most of them have failed to demonstrate better treatment outcome in recurrent and/or metastatic (R/M) HNSCC than conventional chemotherapy. Since a pivotal role of PD-1/PD-L1 pathway in immunological tumor microenvironment was revealed, the immune checkpoint inhibitors, including pembrolizumab and nivolumab, have opened new paradigm of cancer treatment modality and propagates other immune-based therapies for R/M HNSCC. Various types of combination trials consisting of immunotherapy with other class of immunotherapy, targeted agents, radiation therapy, or conventional chemotherapy have been under investigation to improve treatment outcome. Biomarker studies to find an optimal candidate for the newly developed agents are accompanied. These clinical trials lead to tailored approach based on immunotherapy with precision medicine is expected to lead to promising results.

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models

Abstract Purpose: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. Methods: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. Results: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. Conclusion: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.

Cetuximabe para o tratamento do câncer colorretal metastático RAS selvagem com doença limitada ao fígado em primeira linha / Cetuximabe for or treatment of metastatic colorectal cancer RAS selvagem com doença limited ao fígado em primeira linha

INTRODUÇÃO: O câncer colorretal (CCR) acomete o intestino grosso, o cólon e o reto, sendo mais frequente aos 60 anos de idade. No Brasil, para 2016, foram estimados 16.660 casos novos de câncer de cólon e reto em homens e de 17.620 em mulheres. O fígado é considerado o local mais comum de metástases com estimativa de afetar aproximadamente metado dos pacientes com CCR em todo mundo a cada ano. As mutações no gene RAS, presentes em 44% destes pacientes, foram associadas a diminuição nas taxas de repostas ao tratamento com anticorpos anti-EGFR, como o cetuximabe. Dessa forma sua atividade é restrita aos tumores RAS selvagem. Os tratamentos disponíveis no Sistema Único de Saúde (SUS) para os pacientes com CCRm com metástases hepáticas irressecáveis são o tratamento quimioterápico baseado em 5- fluorouracil e leucovorin (5-fluorouracil (5-FU) infusional, leucovorin e oxaliplatina ­ FOLFOX ou irinotecano - FOLFIRI) para a redução tumoral. TECNOLOGIA: cetuximabe (Erbitux®). INDICAÇÃO: Tratamento do câncer colorretal metastático RAS selvagem com doença limitada ao fígado em primeira linha. PERGUNTA: O uso de cetuximabe em associação com a quimioterapia citotóxica é eficaz, seguro e custo-efetivo em pacientes com CCR metastático RAS selvagem com doença limitada ao fígado na primeira linha de tratamento quando comparado ao uso da quimioterapia citotóxica isolada? EVIDÊNCIAS CIENTÍFICAS: A evidência é proveniente de um ensaio clínico randomizado de baixa qualidade metodológica que demonstrou que o tratamento com cetuximabe em adição ao esquema quimioterápico FOLFIRI ou FOLFOX proporcionou que um número maior de pacientes fossem submetidos à ressecção com intenção curativa, e aumento na sobrevida global e na sobrevida livre de progressão, quando avaliada a população por intenção de tratar. No entanto quando considerados apenas os pacientes submetidos à cirurgia, que alcançaram a ressecção R0, não houve significância estatística entre os grupos. AVALIAÇÃO ECONÔMICA: A avaliação de custo-efetividade da adição de cetuximabe à quimioterapia em pacientes com CCRm RAS selvagem com doença limitada ao fígado, em primeira linha de tratamento apresentou RCEI de R$ 56.750 por ano de vida ganho quando comparado à quimioterapia isolada. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário estimou um valor acumulado superior à R$ 326 milhões em cinco anos, após a incorporação de cetuximabe. A análise de sensibilidade demonstrou que esse valor porde variar de R$ 153 milhões a R$ 491 milhões em cinco anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: existe um grande número de tecnologias sendo estudadas para o tratamento do CCR, com diferentes mecanismos de ação e diferentes vias de administração, inclusive oral. RECOMENDAÇÃO PRELIMINAR DA CONITEC: o procedimento APAC de tratamento do câncer de cólon e reto não inviabiliza o uso do medicamento cetuximabe no âmbito do SUS, que deve ser definido pelo médico em conjunto com o paciente, cujo reembolso será o valor proposto para as APACs disponíveis. A matéria será disponibilizada em consulta pública com recomendação preliminar de não incorporação do cetuximabe para pacientes com CCRm RAS selvagem com doença limitada ao fígado em primeira linha de tratamento. CONSULTA PÚBLICA: Foram recebidas 209 contribuições técnico-científicas e 323 contribuições de experiência e opinião, sendo 92% discordante com a recomendação preliminar da CONITEC. As contribuições se referiram principalmente à existência de evidências clínicas e científicas comprovadas e melhoria da qualidade de vida e sobrevida dos pacientes. A evidência citada foi descrita e discutida no relatório técnico que subsidiou a recomendação da CONITEC. Evidências adicionais apresentadas não foram consideradas uma vez que não respondem à pergunta PICO proposta pelo demandante. A CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação preliminar. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 09 de novembro de 2017 deliberaram por não recomendar o cetuximabe para o tratamento do câncer colorretal metastático RAS selvagem com doença limitada ao fígado em primeira linha. Foi assinado o Registro de Deliberação nº 306/2017. DECISÃO: Não incorporar o cetuximabe para primeira linha para pacientes com câncer colorretal metastático (CCRm) RAS selvagem, com doença limitada ao fígado, em combinação com os regimes quimioterápicos Folfiri ou Folfox, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria nº 4, publicada no DOU nº 18, do dia 25 de janeiro de 2018, seção 1, pág. 123.(AU)

Ressonância magnética com difusão para a avaliação da resposta terapêutica de metástases hepáticas de câncer colorretal em pacientes submetidos à quimioterapia de 1ª e 2ª linhas associada à Cetuximabe ou Bevacizumabe / Early prediction of pathological response using MR diffusion weighted imaging in patients with breast cancer submitted to neoadjuvant chemotherapy

O câncer colorretal é a terceira neoplasia maligna mais comum, sendo o fígado um órgão comumente acometido por metástases. Portanto, uma avaliação acurada do envolvimento hepático é vital para o planejamento do tratamento. O prognóstico dos. pacientes com câncer colorretal metastático mudou drasticamente nos últimos anos,. principalmente devido aos novos agentes citotóxicos e biológicos. À medida que se. caminha para melhor compreensão do uso destes medicamentos na prática clínica, observa-se a necessidade de identificar biomarcadores relacionados ao prognóstico.. A ressonância magnética (RM) com difusão é uma ferramenta promissora para o. diagnóstico e avaliação da resposta. Objetivos: Avaliar a efetividade do monitoramento da resposta terapêutica ao tratamento quimioterápico em pacientes. portadores de adenocarcinoma colorretal metastático, em tratamento de 1ª (primeira). linha ou 2ª (segunda) linha com Folfox ou Folfiri e anticorpos monoclonais. (Bevacizumabe ou Cetuximabe), utilizando-se a ressonância magnética com a técnica de difusão através da análise quantitativa do coeficiente de difusão aparente (ADC) e verificar a correlação com o método RECIST. Materiais e Métodos: Estudo prospectivo, onde foram recrutados pacientes adultos portadores de câncer colorretal metastático ao diagnóstico ou recidivado, atendidos no Departamento de Oncologia Clínica do A.C. Camargo Cancer Center no período de um ano, os quais foram submetidos ao tratamento quimioterápico de 1ª e 2ª linhas para doença metastática com Folfox ou Folfiri associado a anticorpo monoclonal (Cetuximabe ou Bevacizumabe). Foi realizado um exame de ressonância magnética do abdome superior com difusão pré-tratamento e exames adicionais ao final do 4º, 8º e 12º ciclos de quimioterapia, para avaliação de resposta das lesões hepáticas metastáticas ao tratamento proposto. Foi realizada conjuntamente a avaliação das metástases hepáticas pelo método RECIST para comparação com a avaliação quantitativa obtida pela Ressonância Magnética com difusão através do ADC. Resultados: Nove pacientes foram avaliados neste estudo. A média de idade dos pacientes foi 57,2 anos (dp=13,8), sendo a idade mínima de 34 e a máxima de 80 anos, com 5 pacientes do sexo feminino e 4 do sexo masculino. O Folfox foi utilizado em 6 pacientes e o Folfiri em 3 pacientes, sendo 6 pacientes de 1ª linha e 3 de 2ª linha de tratamento. Quanto ao Anticorpo monoclonal, 5 pacientes fizeram uso do Cetuximabe e 4 usaram o Bevacizumabe. O número de metástases hepáticas observadas em um mesmo. paciente variou de 1 até 8 lesões, com um total de 24 lesões analisadas. O tamanho. médio das lesões foi de 36,6 mm (± 21,1 mm). Seis (66,7%) dos 9 pacientes tiveram. resposta parcial (RP), 2 (22,2%) foram classificados como doença estável (DE) e 1. paciente (11,1%) apresentou progressão de doença (PD). Nenhum caso de resposta completa (RC) foi observado no follow-up. Correlação RECIST e ADC: Baseado na avaliação das lesões pelo método RECIST, as lesões foram agrupadas como respondedoras quando houve resposta completa (RC) e resposta parcial (RP) e como não respondedoras quando houve progressão de doença (PD) e doença estável (DE), para comparação com a avaliação pelo ADC. Seis pacientes responderam à quimioterapia e 3 pacientes não responderam. Em relação às lesões, 14 lesões responderam ao tratamento e 10 lesões não responderam. Na análise entre as lesões que responderam e as que não responderam ao tratamento quimioterápico de acordo com o padrão de resposta pelo RECIST não foi observada significância estatística em relação ao ADC basal (p=0,940 (após o 4º ciclo) e p=0,909 (após o 8º ciclo)). Não foi observada diferença estatística na análise das variações após o 4º ciclo de quimioterapia (p=0,245 e percentual com p=0,144), como também não observamos correlação entre a redução final do tamanho tumoral e o valor do ADC basal(p=0,869). Identificamos o melhor ponto de corte (cutoff) de ADC entre as lesões que responderam à quimioterapia e as que não responderam ao tratamento. O cutoff de ADC absoluto foi de 0,05 x 10-3 mm²/sec (AUC=0,66), e o cutoff de ADC percentual foi de 3,8% (AUC=0,70). Considerando-se o Cutoff de ADC percentual de 3,8%, não observamos significância estatística entre as lesões que responderam e as que não responderam à quimioterapia (p=0,057. Conclusões: A RM com difusão, por meio da análise quantitativa do ADC, demonstrou ser um método útil para monitorizar as lesões hepáticas de câncer colorretal metastático em tratamento com quimioterapia. A variação de ADC correlacionou-se com o RECIST, sendo que o aumento do ADC esteve associado com a redução do tamanho das lesões (resposta parcial/respondedores). No entanto, não houve significância estatística, muito provavelmente devido à amostragem limitada. Conseguimos identificar um ponto de. corte através da curva ROC que poderá ser validado em estudos posteriores com uma. maior casuística

Colorectal cancer is the third most common malignancy, and the liver is an organ commonly affected by metastases. Therefore, an accurate assessment of liver involvement is vital for treatment planning. The prognosis of patients with metastatic colorectal cancer has changed dramatically in recent years, mainly due to new cytotoxic and biological agents. In order to better understand the use of these drugs in clinical practice, there is a need to identify biomarkers related to prognosis. Magnetic resonance imaging (MRI) with diffusion is a promising tool for the diagnosis and assessment of response. Objectives: To evaluate the effectiveness of the monitoring of the therapeutic response to chemotherapy treatment in patients with metastatic colorectal adenocarcinoma, in treatment of 1st (first) line or 2nd (second) line with Folfox or Folfiri and monoclonal antibodies (Bevacizumab or Cetuximab) using magnetic resonance imaging using the technique of diffusion through of the quantitative analysis of the apparent diffusion coefficient (ADC) and verify the correlation with the RECIST method. Materials and Methods: Prospective study conducted adult patients with metastatic colorectal cancer diagnosis or relapsed, assisted in the Department of Clinical Oncology of AC Camargo Cancer Center during one year, which underwent chemotherapy 1st and 2nd lines for metastatic disease with Folfox or Folfiri associated with monoclonal antibody (Cetuximab or Bevacizumab). We performed a magnetic resonance examination of the upper abdomen pretreatment and additional exams at the end of the 4th, 8th and 12th cycles of chemotherapy, to evaluate the response of metastatic liver lesions to the proposed treatment. It was performed jointly evaluating the liver metastases by RECIST method for quantitative comparison with the evaluation obtained by MRI with diffusion through ADC. Results: Nine patients were evaluated in this study. The mean age of the patients was 57.2 years (sd = 13.8), with a minimum age of 34 and a maximum of 80 years, with 5 female patients and 4 male. The Folfox was used in 6 patients and Folfiri in 3 patients, being 6 patients of 1st line and 3 of 2nd line of treatment. Regarding the use of the monoclonal antibody, 5 patients were using Cetuximab and 4 used Bevacizumab. The number of liver metastases in the same patient observed varied from one (1) to 8 lesions with a total of 24 lesions analyzed. The average size of the lesions was 36.6 mm (± 21.1 mm). Six (66.7%) of the 9 patients had partial response (PR), 2 (22.2%) were classified as stable disease (SD) and 1 patient (11.1%) presented disease progression (PD). No case of complete response (CR) was observed at follow-up. Correlation RECIST and ADC: Based on the evaluation of the lesions by the RECIST method, the lesions were grouped as responders when there was complete response (CR) and partial response (PR) and as no responders when there was disease progression (PD) and stable disease (SD), for comparison with the evaluation by the ADC. Six patients responded to chemotherapy and 3 patients did not respond. Regarding the lesions, 14 lesions responded to the treatment and 10 lesions did not respond. In the analysis between the lesions that responded and those that did not respond to the chemotherapy treatment according to the response pattern by the RECIST, no statistical significance was observed in relation to baseline ADC (p = 0.940 (after the 4th cycle) and p = 0.909 (after the 8th cycle)). No statistical difference was observed in the analysis of the variations after the 4th cycle of chemotherapy (p = 0.245 and percentage with p = 0.144), nor did we observe a correlation between final reduction of tumor size and baseline ADC (p = 0.869). We identified the best ADC cut-off between the lesions that responded to chemotherapy and those that did not respond to treatment. The absolute ADC cut-off was 0.05 x 10-3 mm²/sec (AUC = 0.66), and the percentage ADC cut-off was 3.8% (AUC = 0.70). Considering the Cut-off of ADC percentage of 3.8%, we did not observe statistical significance between the lesions that responded and those that did not respond to chemotherapy (p = 0.057). Conclusions: MRI, with its quantitative analysis of ADC, has been shown to be a useful method to monitor hepatic changes of the metastatic in treatment with chemotherapy. The variation in ADC correlated with RECIST, and the increase in ADC was associated with the reduction of lesion size (partial response / responders). However, there was no statistical significance, most likely due to limited sampling. We were able to identify a cutoff point through the ROC curve that could be validated in later studies with a larger casuistry

ADAM17 knockdown increases sensitivity of SW480 cells to cetuximad / 南方医科大学学报

OBJECTIVE@#To explore the association between expression of ADAM17 and cetuximad resistance in human colorectal cancer SW480 cells.@*METHODS@#The expression of ADAM17 was detected using Western blotting in different human colorectal cancer cell lines, and the cells highly expressing ADAM17 were selected as the target cells. SW480 cells were transfected with ADAM17-siRNA 1 and ADAM17-siRNA 2 and the changes in the expression of ADAM17 protein were detected using Western blotting. SW480 cells were exposed to cetuximad for 24 h and the cell apoptosis was analyzed using flow cytometry. Transwell assay was used to examine the migration ability of SW480 cells with different expression levels of ADAM17; Western blotting was used to analyze the changes in the expressions of AKT signaling pathway-related proteins in the treated cells.@*RESULTS@#The baseline expressions of ADAM17 were significantly higher in SW480 cells than in the other human colorectal cancer cell lines tested ( < 0.05). Both ADAM17-siRNA 1 and 2 effectively reduced the expression of ADAM17 protein in SW480 cells. Knockdown of ADAM17 with siRNA 1 significantly increased the sensitivity of SW480 cells to tocetuximad ( < 0.05), obviously inhibited the cell proliferation, migration and invasion, and significantly reduced the expressions of p-EGFR and p-AKT in the cells ( < 0.001).@*CONCLUSIONS@#ADAM17 knockdown obviously inhibits EGFR-AKT signaling pathway and increases the sensitivity of SW480 cells to tocetuximad.

Immunotherapy in Head and Neck Squamous Cell Cancer

Prognosis in relapsed metastatic head and neck squamous cell cancer (RM-HNSCC) is dismal. Platinum based chemotherapy in combination with Cetuximab is used in first-line setting, while no further validated options are available at progression. Immunotherapy has produced durable clinical benefit in some patients with RM-HNSCC although the premises are several patients are nonresponders. Studies are ongoing to determine predictive factors and the ideal setting/combination of novel immunotherapies. In this paper, we discuss the past and present of immunotherapy in head and neck cancer and provide an up-to-date information regarding the potential ways to improve immunotherapy outcomes in HNSCC.

Prognostic value of FDG PET/CT during radiotherapy in head and neck cancer patients

PURPOSE: To evaluate the prognostic value of 18F-fluorodeoxyglucose positron-emission tomography (FDG PET) with computed tomography (CT) before and during radiotherapy (RT) in patients with head and neck cancer. METHODS: Twenty patients with primary head and neck squamous cell carcinoma were enrolled in this study, of whom 6 had oropharyngeal cancer, 10 had hypopharyngeal cancer, and 4 had laryngeal cancer. Fifteen patients received concurrent cisplatin and 2 received concurrent cetuximab chemotherapy. FDG PET/CT was performed before RT and in the 4th week of RT. The parameters of maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor were measured, and the prognostic significance of each was analyzed with the Cox proportional hazards model. RESULTS: Higher TLG (>19.0) on FDG PET/CT during RT was a poor prognostic factor for overall survival (OS) (p = 0.001) and progression-free survival (PFS) (p = 0.007). In the multivariate analysis, TLG during RT as a continuous variable was significantly associated with OS and PFS rate (p = 0.023 and p = 0.016, respectively). Tumor response worse than partial remission at 1 month after RT was another independent prognostic factor for PFS (p = 0.024). CONCLUSIONS: Higher TLG of the primary tumor on FDG PET/CT during RT was a poor prognostic factor for OS and PFS in patients with head and neck cancer.

The effect of near-infrared fluorescence conjugation on the anti-cancer potential of cetuximab / 한국실험동물학회지

This study investigated the anti-cancer potential of a near-infrared fluorescence (NIRF) molecule conjugated with Cetuximab (Cetuximab-NIRF) in six-week-old female BALB/c athymic (nu+/nu+) nude mice. A431 cells were cultured and injected into the animals to induce solid tumors. Paclitaxel (30 mg/kg body weight (BW)), Cetuximab (1 mg/kg BW), and Cetuximab-NIRF (0.25, 0.5 and 1.0 mg/kg BW) were intraperitoneally injected twice a week into the A431 cell xenografts of the nude mice. Changes in BW, tumor volume and weight, fat and lean mass, and diameter of the peri-tumoral blood vessel were determined after two weeks. Tumor volumes and weights were significantly decreased in the Cetuximab-NIRF (1 mg/kg BW) group compared with the control group (P < 0.001). Lean mass and total body water content were also conspicuously reduced in the Cetuximab-NIRF (1 mg/kg BW) group compared with the vehicle control group. Peri-tumoral blood vessel diameters were very thin in the Cetuximab-NIRF groups compared with those of the paclitaxel group. These results indicate that the conjugation of Cetuximab with NIRF does not affect the anti-cancer potential of Cetuximab and NIRF can be used for molecular imaging in cancer treatments.

Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells

Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

Informe de evaluación científica basada en la evidencia disponible: cáncer colorectal / Scientific evaluation report based on available evidence: colorectal cancer

INTRODUCCIÓN: El Cáncer Colorectal (CCR) es el tercer cáncer más común y el tercero como causa de muerte por cáncer en hombres y mujeres (en Chile es el segundo). La etiología de este cáncer es multifactorial, contando con una predisposición genética, además de una serie de factores que aumentarían el riesgo. Los síntomas más importantes del CCR son cambios en el hábito intestinal, sangrado rectal de corta duración (rectorragia) y sangre mezclada con las deposiciones (hematoquezia). En cuanto a la sobrevida, a 5 años el 90% de los pacientes en etapa temprana sobrevive, mientras que solo un 11% lo hace cuando el CCR es metastásico (CCRm). El oncogén viral (RAS) es una familia de genes que se encuentra comúnmente mutado en pacientes con CCR. Por otro lado, la existencia de receptores del factor de crecimiento epidérmico (EGFR) en este tipo de pacientes es frecuente en los CCR (aproximadamente un 70- 75% de los casos), lo que es fundamental para los tratamientos que se unen a este receptor. TECNOLOGÍAS SANITARIAS ANALIZADAS: Bevacizumab, cetuximab y panitumumab. -Bevacizumab: para el tratamiento de pacientes con CCRm refractarios a tratamientos de 1ª línea distintos a fluoropirimidinas (tratamiento en 1ª línea supera la disponibilidad del fondo). -Cetuximab para el tratamiento de pacientes con CCRm con RAS no mutado y con EGFR positivo en 1ª línea de tratamiento, y refractarios al tratamiento de 1ª línea con oxiplatino, irinotecán o fluoropirimidinas. -Panitumumab para el tratamiento de pacientes con CCRm con RAS no mutado y con EGFR positivo refractarios al tratamiento con oxiplatino, irinotecán o fluoropirimidinas. EFICACIA DE LOS TRATAMIENTOS: En cuanto a la eficacia de los tratamientos: Cetuximab 1ª línea: -El uso de cetuximab no disminuye la mortalidad. -El uso de cetuximab aumenta el riesgo de efectos adversos serios. Cetuximab 2ª línea: -La adición de cetuximab a la quimioterapia podría disminuir la mortalidad, pero la certeza de la evidencia es baja. -La adición de cetuximab podría aumentar los efectos adversos serios, pero la certeza de la evidencia es baja. Panitumumab 1ª línea: -No está claro si panitumumab disminuye la mortalidad porque la certeza de la evidencia es muy baja. -El uso de panitumumab aumenta el riesgo de efectos adversos serios. Panitumumab 2ª línea: -La adición de panitumumab a la quimioterapia probablemente no disminuye la mortalidad. -La adición de panitumumab aumenta el riesgo de eventos adversos serios. Bevacizumab 2ª línea: -No está claro si la adición de bevacizumab tiene un efecto sobre la mortalidad ni sobre los efectos adversos grado 3 ó más porque la certeza de la evidencia es muy baja. ANÁLISIS ECONÓMICO: Se revisaron 8 evaluaciones económicas realizadas en Reino Unido, Canadá, Bélgica y Holanda que estudiaron el tratamiento de bevacizumab en 2ª línea, cetuximab en 1ª y 2ª línea, y panitumumab en 2ª línea para el tratamiento del CCRm. En general, los estudios muestran un beneficio de bevacizumab, pero que es acompañado de un incremento sustancial de los costos. Por otro lado, algunos estudios se muestran favorables a la inclusión de cetuximab para el tratamiento de CCRm, mientras que panitumumab sería más costo-efectivo que cetuximab. Las agencias internacionales revisadas muestran resultados divergentes en cuanto a bevacizumab (Inglaterra no recomienda su uso, mientras que Colombia lo condiciona a un umbral bastante elevado). En el caso de cetuximab, también se encuentran divergencias, ya que Inglaterra no recomienda su uso en primera línea, y Canadá sí. Además, Inglaterra condiciona la recomendación de cetuximab en segunda línea a la existencia de descuentos por parte de laboratorios. Por último, panitumumab no es recomendado como terapia de primera línea por Inglaterra, no obstante, señala que es posible de recomendar en segunda línea si existen descuentos en cuanto al precio. El costo que estos tratamientos tendrían en 2018 sería de MM$5.365 (bevacizumab en 2ª línea), MM$32.244 (cetuximab en 1ª línea), MM$4.478 (cetuximab en 2ª línea), y MM$2.600 (panitumumab en 2ª línea). CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RAS Mutational analysis using a high-throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. MATERIALS AND METHODS: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. RESULTS: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). CONCLUSION: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.

Interpretation of the updates of NCCN 2017 version 1.0 guideline for colorectal cancer / 中华胃肠外科杂志

The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.

Development of radioimmunoconjugate for diagnosis and management of head-and-neck subclinical cancer and colorectal carcinoma

ABSTRACT Scientific innovations in diagnostic methods are important drivers of cancer control and prevention. Noninvasive imaging of the epidermal growth factor receptor (EGFR) in head-and-neck squamous, cell carcinoma and colorectal cancer could be valuable to select patients for EGFR-targeted therapy, as well as to monitor the efficacy and occurrence of resistance to immunotherapy. In order to develop the first Brazilian radioimmunoconjugate for diagnosis, Cetuximab has been conjugated to p-SCN-Bn-DTPA chelator and radiolabeled with Indium-111. The conjugation methodology was optimized using different mAb:DTPA molar ratios, time was then reduced for immunoconjugate preparation, besides the protein recovery' percentage increased after purification (m = 83.8 ± 0.91 %). The stability of Cetuximab-DTPA at - 20 oC was evaluated for six months, and its integrity was greater than 90% (m =93.9 ± 1.5%, N = 24). The radioimmunoconjugate with specific activity of 185 MBq/mg showed radiochemical purity above 95% (m=96.8 ± 1.31 %, N = 15). We conclude that the radioimmunoconjugate 111In-DTPA-cetuximab is stable and may be applied to the diagnosis of EGFR-positive tumors.

Analysis of Dermatologic Diseases in Patients Receiving Anticancer Treatments: A Retrospective Study of 140 Cases / 대한피부과학회지

BACKGROUND: A number of anticancer agents are known to induce many adverse reactions in the skin. Related cutaneous adverse drug reactions influence the morbidity, mortality, and anti-cancer regimen of the patients. A multidisciplinary approach to cancer management has been emphasized. OBJECTIVE: To identify the causative anticancer agents and frequency of adverse reactions in the skin. METHODS: We retrospectively reviewed the medical records of patients who consulted at the Dermatology Department of Busan Paik Hospital and Haeundae Paik Hospital from January 2013 to February 2015. RESULTS: A total of 140 patients were enrolled. Among the 45 patients treated with antimetabolite analogs (30 cytarabine, 7 gemcitabine, 3 methotrexate, 2 fludarabine, 2 doxifluridine, and 1 decitabine), exanthematous drug eruption (49.1%) was the most common reaction, followed by hand-foot syndrome (28.3%). Among the 35 patients treated with fluorouracil (22 5-fluorouracil and 13 capecitabine), hand-foot syndrome (47.2%) was the most common, followed by acneiform eruption (25.0%). Among the 24 patients treated with epidermal grow factor receptor inhibitors (10 erlotinib, 10 cetuximab, and 4 gefitinib), acneiform eruption (54.8%) was the most common, followed by xerosis (19.4%). Among the 11 patients treated with anthracyclines (9 doxorubicin, 1 daunorubicin, and 1 idarubicin), acneiform eruption (45.5%) was the most common, followed by hand-foot syndrome (36.4%). Among the 7 patients treated with taxanes (4 docetaxel and 3 paclitaxel), hand-foot syndrome (42.8%) was the most common. Among the 6 patients treated with angiogenesis-inducing inhibitors (3 sorafenib, 2 pazopanib, and 1 sunitinib), hand-foot skin reaction (66.7%) was the most common. Only 2 patients (1.4%) changed treatments due to intolerable skin reactions. CONCLUSION: Clinicians should be aware of the various skin reactions of anticancer agents and predict their clinical course effectively.

EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells

PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.

Single Center Experience With Hyperthermic Intraperitoneal Chemotherapy

PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been proposed for controlling peritoneal seeding metastasis in some kinds of cancers, including those of colorectal origin, but their safety and oncological benefits are subjects of debate. We present our early experience with those procedures. METHODS: Data were retrospectively collected from all patients with peritoneal carcinomatosis (PC) and pseudomyxoma peritonei (PMP) treated using CRS and HIPEC at Yonsei Cancer Center between July 2014 and July 2015. Short-term outcomes and risk factors for postoperative complications were analyzed. RESULTS: Twenty-three patients with PC (n = 18) and PMP (n = 5) underwent CRS and HIPEC. Median follow-up and age were 2 months and 54 years, respectively. The median peritoneal carcinomatosis index score was 15, and CC0-1 was achieved in 78.3% of all patients. The median operation time and bleeding loss were 590 minutes and 570 mL, respectively. Grade-IIIa/grade-IIIb complications occurred in 4.3% (n = 1)/26.1% (n = 6) of the patients within 30 days postoperatively, and no 30-day mortalities were reported. Factors related to postoperative complications with CRS and HIPEC were number of organ resection (P = 0.013), longer operation time (P < 0.001), and amount of blood loss (P = 0.003). All patients treated with cetuximab for recurred colorectal cancer had grade-III postoperative complication. CONCLUSION: Our initial experience with CRS and HIPEC presented about 30% grade-III postoperative complications. Therefore, expert surgeons need to perform those procedures with great caution in selected patients who might benefit from it.

Eficacia y seguridad de la adición de cetuximab a folfiri como tratamiento de primera linea en pacientes con carcinoma colorrectal metastásico con gen kras no mutado (wild type) e irresecable / Efficacy and safety of the addition of cetuximab to folfiri as a first-line treatment in patients with metastatic colorectal carcinoma with non-mutated (wild type) kras gene and unresectable

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de la adición de cetuximab a FOLFIRI en el tratamiento de pacientes con diagnóstico de cáncer colorrectal metastásico e irresecable (CCRm) con estudio de KRAS WT (tipo salvaje), sin tratamiento sistémico previo en enfermedad metastásica. Aspectos Generales: El cáncer colorrectal (CCR) se origina en la parte baja del sistema digestivo, incluyendo el colon y el recto. El cáncer puede extenderse produciendo metástasis a lugares adyacentes a la lesión original, a los ganglios y también a otras partes distantes del cuerpo. Globalmente, el cáncer colorrectal (CCR) es el tercer cáncer más frecuentemente diagnosticado en hombres y el segundo en mujeres en el mundo (Torres). En el Perú, en el 2012 se estimó que la incidencia de este tipo de cáncer en hombres era de 9% a 16.1% con mortalidad alrededor del 5.8% a 9%; mientras que en mujeres la incidencia estimada fue de alrededor de 7.6% y 13.2%, con una mortalidad entre 5.3% y 6.9%(1,2). Tecnologia Sanitaria de Interés: El cetuximab (Erbitux, Merck Serono) es un anticuerpo monoclonal recombinante que bloquea el receptor del factor de crecimiento de la epidermis (EGFR), inhibiendo la proliferación de células que dependen de la activación de EGFR para crecer. Cetuximab está indicado en combinación con quimioterapia en el tratamiento de pacientes con CCRm que expresan EGFR y el tipo salvaje de KRAS (Kirsten rat sarcoma). METODOLOGIA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de la adición de cetuximab a FOLFIRI en el tratamiento de pacientes con diagnóstico de cáncer colorrectal metastásico e irresecable (CCRm) con estudio de KRAS WT no mutado (tipo salvaje), sin tratamiento sistémico previo para enfermedad metastásica. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento de la adición de cetuximab a FOLFIRI como tratamiento de primera línea en pacientes con \r\ncarcinoma colorrectal metastásico irresecable y con estudio negativo de la mutación KRAS. Se presenta la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión. CONCLUSIONES: La mayoría de los pacientes con cáncer colorrectal metastásico (CCRm) no pueden ser curados, siendo candidatos a tratamiento paliativo con quimioterapia sistémica, como FOLFIRI, XELOX o FOLFOX, los cuales se encuentran disponibles en el Petitorio Farmacológico de EsSalud. No se han encontrado reportes sobre el impacto de adicionar cetuximab a la quimioterapia en pacientes con cáncer colorrectal metastásico. Sin embargo, del estudio CRYSTAL se evidencia que la incidencia general de eventos adversos grado 3 o 4 fue mayor en el grupo cetuximab­FOLFIRI que en el grupo FOLFIRI. el Instituto de Evaluación en Tecnologías en Salud e Investigación-IETSI, no aprueba el uso de cetuximab en combinación con FOLFIRI para el tratamiento de cáncer colorrectal metastásico KRAS WT.

Seguridad y eficacia de cetuximab más irinotecán en comparación a irinotecán como monoterapia para el tratamiento de segunda línea en cáncer colorrectal metastásico con gen kras no mutado (Wild Type) / Safety and efficacy of cetuximab plus irinotecan compared to irinotecan as monotherapy for second line treatment in metastatic colorectal cancer with non-mutated kras gene (Wild Type)

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación del medicamento cetuximab en combinación con irinotecán respecto a su uso en pacientes con cáncer colorrectal metastásico y gen KRAS' no mutado (WT) con progresión a primera línea de quimioterapia basada oxaliplatino. Aspectos Generales: A nivel mundial, en cáncer colorrectal es el tercer tipo de cáncer más frecuente, representando el 9.4% de todas las incidencias de cáncer en hombres y el 10.1% en mujeres. Aproximadamente el 25% de los pacientes diagnosticados con cáncer colorrectal presentan enfermedad metastásica al momento del diagnóstico y del resto de pacientes, el 25% a 35% desarrollará metástasis en el transcurso de la enfermedad. Tecnología Sanitaria de Interés: Cetuximab: Cetuximab con nombre comercial Erbitux, es un anticuerpo monoclonal recombinante que inhibe la proliferación de células bloqueando los EGFR(15). El EGFR es uno de los cuatro receptores pertenecientes a la familia de proteínas c-erbB de receptores de tirosina quinasa (i.e., c-erb-1, c-erb-2, c-erb-3, c-erb-4). METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de cetuximab para el tratamiento de cáncer colorrectal metastásico en pacientes sin mutación el en gen KRAS (KRAS WT) en las bases de datos de MEDLINE y TRIPDATABASE. Se hizo una búsqueda adicional en www.clinicaltrials.gov, para poder identificar ensayos aún en elaboración o que no hayan sido publicados. Asimismo, se hizo una búsqueda dentro de la información generada por grupos que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library y The National Institute for Health and Care Excellence (NICE). RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso de cetuximab como tratamiento para cáncer colorrectal metastásico con KRAS no mutado (WT), en pacientes con progresión a primera línea de quimioterapia basada en fluoropirimidina y oxaliplatino. Se presenta la evidencia disponible en Guías de Práctica Clínica, Evaluación de tecnologías sanitarias, Meta-análisis/Network Meta-análisis y Ensayos clínicos. CONCLUSIONES: -\tEn la actualidad el fármaco irinotecán se encuentra incluido en el petitorio farmacológico de ESSALUD para su uso en el tratamiento de cáncer colorrectal metastásico, lo que incluye su uso como alternativa en pacientes que no hayan recibido previamente regímenes con este fármaco. Así, ESSALUD cuenta con una alternativa para pacientes con cáncer colorrectal metastásico que hayan utilizado previamente regímenes con fluoropirimidina y oxaliplatino. Es por ello que se requiere que la adición de cetuximab a irinotecán suponga un beneficio adicional para dichos pacientes. Sin embargo, hasta la fecha (i.e., Marzo 2016) no se ha encontrado evidencia sólida con relación a la hipótesis que añadir cetuximab a irinotecán, en el contexto de progresión a regímenes con fluoropirimidina y oxaliplatino, ofrezca un beneficio mayor al obtenido con regímenes a base de irinotecán como monodroga. Así, la evidencia disponible al momento no justifica el uso de cetuximab en combinación con irinotecán para el tratamiento de cáncer colorrectal metastásico en pacientes que han progresado a regímenes de quimioterapia a base de fluoropirimidina y / u oxaliplatino; ya que en el petitorio de la Institución ya se cuenta con un tratamiento utilizado para dichos pacientes. -\tPor lo expuesto, el Instituto de evaluación en Tecnologías en Salud e Investigación-IETSI, no aprueba el uso de cetuximab en combinación con irinotecán para el tratamiento de cáncer colorrectal metastásico KRAS WT, en pacientes refractarios a quimioterapia pasada en fluoropirimidina y oxaliplatino.

Target Therapy in Unresectable or Metastatic Colorectal Cancer / 대한소화기학회지

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Korea. Despite recent developments in the treatment of CRC, the median overall survival time in patients with metastatic CRC is less than 30 months. The biologic agents that target the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have proven clinical benefits in the treatment of patient with metastatic CRC. Anti-EGFR agents, including cetuximab and panitumumab, as well as anti-VEGF agents, including bevacizumab, aflibercept, ramucirumab, and regorafenib have been shown to extend survival in combination with cytotoxic chemotherapy. In particular, the addition of anti-EGFR agents has demonstrated significant efficacy in patients with the RAS wild-type metastatic CRC. In the future, building a personalized treatment strategy, according to the clinical characteristics and biologic features of patients with unresectable or metastatic CRC, will be necessary. In this review, we summarized the mechanisms of target therapy, the results of main clinical trials, and the guideline of clinical practice in patients with unresectable or metastatic CRC.