Effect of intra-operative chemotherapy with 5-fluorouracil and leucovorin on the survival of patients with colorectal cancer after radical surgery: a retrospective cohort study / 中华医学杂志(英文版)

BACKGROUND@#The effect of intra-operative chemotherapy (IOC) on the long-term survival of patients with colorectal cancer (CRC) remains unclear. In this study, we evaluated the independent effect of intra-operative infusion of 5-fluorouracil in combination with calcium folinate on the survival of CRC patients following radical resection.@*METHODS@#1820 patients were recruited, and 1263 received IOC and 557 did not. Clinical and demographic data were collected, including overall survival (OS), clinicopathological features, and treatment strategies. Risk factors for IOC-related deaths were identified using multivariate Cox proportional hazards models. A regression model was developed to analyze the independent effects of IOC.@*RESULTS@#Proportional hazard regression analysis showed that IOC (hazard ratio [HR]=0.53, 95% confidence intervals [CI] [0.43, 0.65], P  < 0.001) was a protective factor for the survival of patients. The mean overall survival time in IOC group was 82.50 (95% CI [80.52, 84.49]) months, and 71.21 (95% CI [67.92, 74.50]) months in non-IOC group. The OS in IOC-treated patients were significantly higher than non-IOC-treated patients ( P  < 0.001, log-rank test). Further analysis revealed that IOC decreased the risk of death in patients with CRC in a non-adjusted model (HR=0.53, 95% CI [0.43, 0.65], P  < 0.001), model 2 (adjusted for age and gender, HR=0.52, 95% CI [0.43, 0.64], P  < 0.001), and model 3 (adjusted for all factors, 95% CI 0.71 [0.55, 0.90], P  = 0.006). The subgroup analysis showed that the HR for the effect of IOC on survival was lower in patients with stage II (HR = 0.46, 95% CI [0.31, 0.67]) or III disease (HR=0.59, 95% CI [0.45, 0.76]), regardless of pre-operative radiotherapy (HR=0.55, 95% CI [0.45, 0.68]) or pre-operative chemotherapy (HR=0.54, 95% CI [0.44, 0.66]).@*CONCLUSIONS@#IOC is an independent factor that influences the survival of CRC patients. It improved the OS of patients with stages II and III CRC after radical surgery.@*TRIAL REGISTRATION@#chictr.org.cn, ChiCTR 2100043775.

Surgical treatment strategies for pancreatic cancer with simultaneous liver metastasis / 中华外科杂志

Objective: To explore the outcome of different treatment strategies in patients with pancreatic cancer with synchronous liver metastasis (sLMPC). Methods: A retrospective analysis of the clinical data and treatment results of 37 patients with sLMPC treated in China-Japan Friendship Hospital was performed from April 2017 to December 2022. A total of 23 males and 14 females were included,with an age(M(IQR)) of 61 (10) years (range: 45 to 74 years). Systemic chemotherapy was carried out after pathological diagnosis. The initial chemotherapy strategy included modified-Folfirinox, albumin paclitaxel combined with Gemcitabine, and Docetaxel+Cisplatin+Fluorouracil or Gemcitabine with S1. The possibility of surgical resection (reaching the standards of surgical intervention) was determined after systemic treatment,and the chemotherapy strategy was changed in the cases of failed initial chemotherapy plans. The Kaplan-Meier method was used to estimate the overall survival time and rate,while Log-rank and Gehan-Breslow-Wilcoxon tests were used to compare the differences of survival curves. Results: The median follow-up time for the 37 sLMPC patients was 39 months,and the median overall survival time was 13 months (range:2 to 64 months) with overall survival rates of 1-,3-,and 5-year of 59.5%,14.7%,and 14.7%,respectively. Of the 37 patients,97.3%(36/37) initially received systemic chemotherapy, 29 completed more than four cycles,resulting in a disease control rate of 69.4% (partial response in 15 cases,stable disease in 10 cases,and progressive disease in 4 cases). In the 24 patients initially planned for conversion surgery,the successful conversion rate was 54.2% (13/24). Among the 13 successfully converted patients,9 underwent surgery and their treatment outcomes were significantly better than those (4 patients) of those who did not undergo surgery (median survival time not reached vs. 13 months,P<0.05). Regarding the 9 patients whose conversion was unsuccessful, no significant differences were observed in median survival time between the surgical group (4 cases) and the non-surgical group (5 cases) (P>0.05). In the allowed-surgery group(n=13),the decreased in pre-surgical CA19-9 levels and the regression of liver metastases were more significant in the successful conversion sub-group than in the ineffective conversion sub-group;however, no significant differences were observed in the changes in primary lesion between the two groups. Conclusion: For highly selective patients with sLMPC who achieve partial response after receiving effective systemic treatment,the adoption of an aggressive surgical treatment strategy can significantly improve survival time;however, surgery dose not provide such survival benefits in patients who do not achieve partial response after systemic chemotherapy.

Prognostic factors affecting the success of conversion chemotherapy in patients with unresectable liver metastases from initially colorectal cancer / 中华胃肠外科杂志

Objective: To investigate the factors affecting the success of conversion therapy in patients with initially unresectable colorectal cancer liver metastases (CRLM) in order to provide evidence-based medical evidence for formulating individualized treatment strategies for patients. Methods: A retrospective case-control study was used in this study. Clinical data of 232 patients with initially unresectable CRLM receiving first-line systemic treatment in Sun Yat-sen University Cancer Center from January 2013 to January 2020 were collected, including 98 patients of successful conversion and 134 patients of failed conversion as control. Conversion therapy scheme: 38 patients received FOLFOXIRI regimen chemotherapy (irinotecan, oxaliplatin, calcium folinate and fluorouracil), 152 patients received FOLFOX regimen (oxaliplatin, calcium folinate and fluorouracil), 19 patients received FOLRIRI regimen (irinotecan, calcium folinate and fluorouracil), 23 patients received systemic chemotherapy combined with fluorouridine hepatic artery infusion chemotherapy; 168 patients received targeted therapy, including 68 of bevacizumab and 100 of cetuximab. Logistics analysis was used to compare the factors affecting the success of conversion therapy. The Kaplan-Meier method was used to calculate progression-free survival (PFS), and the Log-rank test was used for survival comparison. Results: Among 232 patients, 98 patients had successful conversions and 134 patients had failed conversions with a successful conversion rate of 42.2%, meanwhile 30 patients underwent simple hepatectomy and 68 underwent hepatectomy combined with intraoperative radiofrequency ablation. After first-line chemotherapy, 111 patients (47.8%) were partial remission, 57 patients (24.6%) were stable disease, and 64 patients (27.6%) were progression disease. During the median follow-up of 18.8 (1.0-87.9) months, 148 patients were dead or with tumor progression. The median PFS time of patients with successful conversion was longer than that of patients with failed conversion (31.0 months vs. 9.9 months, P<0.001). Univariate analysis found that the bilobar distribution of liver tumors (P=0.003), elevated baseline carcinoembryonic antigen (CEA) levels (P=0.024), tumor invasion of the portal vein (P=0.001), number of metastatic tumor>8 (P<0.001), non-FOLFOXIRI (P=0.005), and no targeted therapy (P=0.038) were high risk factors for the failed conversion therapy. The results of multivariate logistics analysis indicated that the number of metastatic tumor >8 (OR=2.422, 95%CI: 1.291-4.544, P=0.006), portal vein invasion (OR=2.727, 95%CI: 1.237-4.170, P=0.008) were the independent risk factors for failed conversion therapy, while FOLFOXIRI regimen (OR=0.300, 95%CI: 0.135-0.666, P=0.003) and targeted drugs (OR=0.411, 95%CI: 0.209-0.809, P=0.010) were independent protective factors for successful conversion therapy. Conclusions: The number of metastatic tumor and portal vein invasion are key factors that affect the outcomes of conversion therapy for initially unresectable CRLM. If a patient can tolerate chemotherapy, a combination program of three-drug and targeted therapy is preferred for the active conversion therapy.

Chinese expert consensus on the clinical application of the Chinese modified triplet combination with irinotecan, oxaliplatin and continuous infusional 5-fluorouracil/leucovorin for colorectal cancer / 中华胃肠外科杂志

Colorectal cancer is the second most common malignant tumor in China. The FOLFOXIRI regimen, which combines 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan, is a high-intensity and highly effective chemotherapy regimen. However, the original regimen is poorly tolerated in Chinese patients. In order to promote the standardized and rational application of FOLFOXIRI regimen by clinicians in China, "

Integrated care pathway for rectal cancer treatment: cross-sectional post-implementation study using a logic model framework

ABSTRACT BACKGROUND: Management of rectal cancer has become more complex with multimodality therapy (neoadjuvant chemoradiotherapy and surgery) and this has led to the need to organize multidisciplinary teams. The aim of this study was to report on the planning, implementation and evaluation of an integrated care pathway for neoadjuvant treatment of middle and lower rectal cancer. DESIGN AND SETTING: This was a cross-sectional post-implementation study that was carried out at a public university cancer center. METHODS: The Framework for Program Evaluation in Public Health of the Centers for Disease Control and Prevention (CDC) was used to identify resources and activities; link results from activities and outcomes with expected goals; and originate indicators and outcome measurements. RESULTS: The logic model identified four activities: stakeholders' engagement, clinical pathway development, information technology improvements and training programs; and three categories of outcomes: access to care, effectiveness and organizational outcomes. The measurements involved 218 patients, among whom 66.3% had their first consultation within 15 days after admission; 75.2% underwent surgery < 14 weeks after the end of neoadjuvant treatment and 72.7% completed the treatment in < 189 days. There was 100% adherence to the protocol for the regimen of 5-fluorouracil and leucovorin. CONCLUSIONS: The logic model was useful for evaluating the implementation of the integrated care pathways and for identifying measurements to be made in future outcome studies.

Effect of FOLFOX6 chemotherapy on serum VEGF expression in advanced colorectal cancer patients

SUMMARY OBJECTIVE: To explore the effect of FOLFOX6 chemotherapy on serum vascular endothelial growth factor (VEGF) expression in advanced colorectal cancer patients. METHODS: A retrospective analysis of 81 patients with advanced colorectal cancer who visited our hospital from March 2014 to February 2016 was performed. All the patients were treated with FOLFOX6 chemotherapy. On day 1, patients received oxaliplatin 100 mg/m2 ivgtt (2h), calcium folinate 200 mg/m2 ivgtt (2h), 5 fluorouracil 400 mg/m2 iv bolus and 5 fluorouracil 2500 mg/m2 ivgtt (5h). The treatment course was 2 weeks, and 4 treatment courses were required. The changes in the levels of VEGF and CRP and quality of life before and after 4 courses of chemotherapy were observed and therapeutic effects and adverse reactions after chemotherapy were evaluated. RESULTS: After treatment, the total efficiency of chemotherapy was 82.72% (67/81) with 24 cases in complete remission, 25 cases in partial response, 18 cases in stable disease and 14 cases in progressive disease. The levels of CRP and VEGF after the treatment were significantly lower than those before treatment (5.69±0.77) mg/L vs. (7.99±1.36) mg/L; (443.26±21.55) pg/mL vs. (542.83±20.44) pg/mL] (P<0.05). The KPS grade after treatment was significantly higher than that before treatment (57.84±4.6) point vs. (50.99±3.73) point] (P<0.05). Among them, 3 cases developed a rash, 5 cases experienced hair loss, and 9 cases developed nausea and vomiting. CONCLUSION: FOLFOX6 chemotherapy can decrease serum VEGF expression in patients with advanced colorectal cancer and enhance the curative effect with high safety, which is good for the improvement of patients' survival.

RESUMO OBJETIVO: Explorar o efeito da quimioterapia Folfox6 na expressão do fator de crescimento endotelial vascular sérico (VEGF) em pacientes com câncer colorretal avançado. MÉTODOS: Uma análise retrospectiva de 81 pacientes com câncer colorretal avançado que visitaram nosso hospital de março de 2014 a fevereiro de 2016 foi realizada. Todos os pacientes foram tratados com quimioterapia Folfox6. No dia 1, os doentes receberam oxaliplatina 100 mg / m2 ivgtt (2h), folinato de cálcio 200 mg/m2 ivgtt (2h), 5 fluorouracil 400 mg/m2 iv bolus e 5 fluorouracil 2.500 mg/m2 ivgtt (5h). O curso de tratamento foi de duas semanas e foram necessários quatro cursos de tratamento. Foram observadas as alterações nos níveis de VEGF e CRP e qualidade de vida antes e após quatro cursos de quimioterapia e avaliados os efeitos terapêuticos e reações adversas após a quimioterapia. RESULTADOS: Após o tratamento, a eficácia total da quimioterapia foi de 82,72% (67/81), com 24 casos em remissão completa, 25 casos em resposta parcial, 18 casos em doença estável e 14 casos em doença progressiva. Os níveis de CRP e VEGF após o tratamento foram significativamente inferiores aos do tratamento (5,69 ± 0,77) mg / L vs. (7,99 ± 1,36) mg / L; (443,26 ± 21,55) pg / mL vs. (542,83 ± 20,44) pg / mL] (P < 0,05). O grau de KPS após o tratamento foi significativamente maior do que antes do tratamento (57,84 ± 4,6 pontos) vs. (50,99 ± 3,73 pontos)] (P < 0,05). Entre eles, três casos desenvolveram erupção cutânea, cinco casos sofreram perda de cabelo e nove casos desenvolveram náuseas e vômitos. CONCLUSÃO: A quimioterapia Folfox6 pode, obviamente, diminuir a expressão de VEGF no soro em pacientes com câncer colorretal avançado e melhorar o efeito curativo com alta segurança, o que é bom para a melhoria da sobrevivência dos pacientes.

Delayed Elimination After High-dose Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

BACKGROUND: High doses of methotrexate (MTX) are often used in various chemotherapy protocols to treat acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) in children, but its delayed elimination increases the occurrence of adverse events, such as bone marrow suppression. The aim of this study was to investigate the elimination of MTX at 24 and 48 hours. METHODS: We retrospectively analyzed electronic medical records of ALL or NHL pediatric patients who received 5 g/m² MTX infusion over 24 hours (between June, 2012 and July, 2018) at the Yonsei University Health System, Korea. The delayed elimination of MTX concentrations was assessed with 100 or 150 µM MTX at 24 hours, and 2 or 5 µM at 48 hours. RESULTS: Among the 85 MTX cycles administered, 23 cycles were classified in delayed elimination group, and 62 cycles showed normal elimination. At 24 hours, the delayed elimination group with MTX concentration > 100 µM showed higher percentage than group with MTX concentration < 100 µM (45.8% vs. 19.7%, p = 0.015). However, no differences were observed at 150 µM MTX (p = 0.66). At 48 hours, the delayed elimination was higher than the normal elimination at both concentration baselines (p < 0.001 at 2 µM, p = 0.024 at 5 µM). CONCLUSIONS: MTX concentrations greater than 100 µM show high probability of delayed elimination at 24 hours. When MTX levels are above normal, leucovorin and hydration regimens should be continued to prevent delayed elimination.

Protective effect of Korean red ginseng on oxaliplatin-mediated splenomegaly in colon cancer

PURPOSE: This study investigated how adding Korean red ginseng extract (KRG) to folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy affected the rate of splenomegaly in colon cancer. METHODS: This retrospective study analyzed 42 patients who were randomly assigned to receive a FOLFOX regimen with or without KRG. Spleen volume change was assessed by computed tomography scans measured before surgery (presurgery volume) and 3 weeks after cessation of the 12th cycle of FOLFOX (postchemotherapy volume). RESULTS: All patients showed increased spleen volume. No difference was observed in median presurgery and postchemotherapy volume between the KRG and control groups. However, a ratio defined as postchemotherapy volume divided by presurgery volume was significantly lower in the KRG group than the control group (median, 1.38 [range, 1.0–2.8] in KRG group vs. median, 1.89 [range, 1.1–3.0] in control group, P = 0.028). When splenomegaly was defined as a >61% increase in spleen volume, the rate of splenomegaly was significantly lower in the KRG group than the control group (28.6% vs. 61.9%, P = 0.03). KRG consumption was inversely associated with developing splenomegaly in multivariate analysis. CONCLUSION: Adding KRG during FOLFOX chemotherapy for colon cancer might protect against oxaliplatin-induced splenomegaly. The protective effect of Korean red ginseng should be investigated with further research.

Hepatoid Carcinoma of the Pancreas Presenting as Acute Pancreatitis / 대한내과학회지

Hepatoid carcinoma is extrahepatic neoplasm showing similar morphologic, immunohistochemical features with hepatocellular carcinoma. It's a very rare disease and has been reported most frequently in the stomach. Herein, we report a case of hepatoid carcinoma of pancreas presented with acute pancreatitis. The hepatoid carcinoma was diagnosed by his needle biopsy specimen and it showed pleomorphic nuclei and predominantly eosinophilic and occasionally clear cytoplasm in hematoxylin and eosin staining, and positive for HepPar-1 and cytokeratin 19 in immunohistochemical staining. Surgical treatment seems to be the best choice, if possible. However, there is no standard regimen for palliative chemotherapy. In our case, the patient was treated with 5-Fluorouracil (5-FU), folinic acid, irinotecan, oxaliplatin (FOLFIRINOX). The response was stable disease up to 4 month of follow up.

Analysis on safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (FOLFOXIRI) in advanced colorectal cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (mFOLFOXIRI) for patients with advanced colorectal cancer (CRC).</p><p><b>METHODS</b>Data of 312 CRC patients confirmed by pathology receiving triplet drug alone or combined with target therapy between October 2012 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. CRC patients who had previously completed adjuvant therapy (or neoadjuvant therapy) within 6 months or palliative chemotherapy were excluded, meanwhile those with poor general condition (ECOG score > 2) or grade 2 neuropathy and allergy to oxaliplatin were excluded as well. Regimen of mFOLFOXIRI: oxaliplatin 85 mg/m² dissolved in 5% glucose solution 500 ml by intravenous infusion for 2 h; irinotecan 150 to 165 mg/m² dissolved in 0.9% sodium chloride 250 ml by intravenous infusion for 90 min; following intravenous infusion of leucovorin 400 mg/m² for 2 h, day 1; 5-FU 2800 mg/m², 48-h continuous intravenous infusion; once every 2 weeks. Therapy could be combined with a targeted drug, bevacizumab 5 mg/kg every two weeks; cetuximab 500 mg/m² every two weeks. Side effect was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0.3). The objective response rate was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) after administering at least four cycles of chemotherapy.</p><p><b>RESULTS</b>The median age was 52 years (range 16-73) in the whole group; 113 patients (36.2%) had locally advanced CRC, and 199 (63.8%) had metastatic CRC. Most patients (274/312, 87.8%) did not receive any treatment earlier. There were a total of 1651 chemotherapy cycles in the whole group, with a median of 6(1-19) cycles. Of these 1651 cycles, 124 cycles of chemotherapy(7.5%) were dose-adjusted; 176 cycles of chemotherapy(10.7%) were delayed for median 5(3-13) days; 124 cycles(7.5%) required dose decrease. The overall relative dose intensity was >90%; the specific drug dose intensity was 93.6%(2620 mg×m⁻²×d⁻¹) for fluorouracil, 97.8%(83 mg×m⁻²×d⁻¹) for oxaliplatin, and 94.2%(155 mg×m⁻²×d⁻¹) for irinotecan. Twenty-three patients (7 of intestinal perforation, 7 of intestinal obstruction, 1 of grade 4 hematologic toxicity, and 8 of grade 3 fatigue) refused subsequent chemotherapy due to intolerable toxicity. Main grade 3 or 4 adverse events in patients were neutropenia in 69 cases (22.1%), fatigue in 35 cases (11.2%), and anemia in 28 cases (8.9%). Twenty serious adverse events (6.4%) occurred, including 13 patients of febrile neutropenia (4.2%), 7 patients of intestinal perforation (2.2%, 4 patients in upper rectum, 2 in sigmoid colon, and 1 in transverse colon cancer), and 9 of them had subsequent sepsis (2.9%). All the patients with intestinal perforation underwent emergency operation. No treatment-related deaths occurred. In 199 patients with metastatic CRC, because 22 patients did not receive image evaluation, the preliminary efficacy of 177 patients was actually evaluated. A total of 113 objective response events were observed. The overall response rate was 63.8%(113/177), partial response rate was 61.6%(109/177), clinically complete response rate was 2.3%(4/177), stable disease was 29.9% (53/177), progressive disease was 6.2%(11/177), and the disease control rate was 93.8%(166/177). In 127 patients receiving triplet drug, objective response rate was 40.9% for those with less than four cycles and 81.1% for those with more than four cycles (P<0.001).</p><p><b>CONCLUSION</b>The mFOLFOXIRI regimen with reduced dose can be safely used in advanced CRC and has achieved promising results in terms of short-term efficacy.</p>

Respuesta histológica completa a la neoadyuvancia en carcinoma gástrico avanzado: A propósito de un caso y revisión de la literatura / Histological complete response to neoadjuvant therapy in advanced gastric carcinoma: A case report and review of literature

La presente comunicación, describe el primer caso en el Instituto Regional de Enfermedades Neoplásicas "Luis Pinillos Ganoza" IREN Norte en la que una paciente con carcinoma gástrico avanzado ha mostrado respuesta histopatológica completa a neoadyuvancia. Se presenta una paciente mujer de 70 años con diagnóstico histopatológico de adenocarcinoma gástrico tubular moderadamente diferenciado, localmente avanzado con imágenes de adenopatías perigástricas asociadas y pérdida de la interfase entre tumoración gástrica, hilio hepático y vesícula biliar. Luego de 6 cursos de quimioterapia neoadyuvante con esquema FOLFOX - 4 al 80%, se obtiene una respuesta casi completa desde el punto de vista tomográfico; por ello a la paciente se le realiza gastrectomía subtotal distal más linfadenectomía D2 más gastroyeyunoanastomosis Billroth II término lateral tipo Hofmeister Finsterer, verificándose, al examen microscópico de la pieza operatoria, sólo gastritis crónica y aguda con áreas mucosas y cambios reactivos. No se observa neoplasia maligna viable. Ganglios linfáticos: 0/33. Paciente evoluciona favorablemente. A propósito del caso se hace una revisión de la literatura médica relevante actualizada

This communication describes the first case in the Regional Institute of Neoplastic Diseases "Luis Pinillos Ganoza" IREN North in which a patient with advanced gastric carcinoma showed complete response to neoadjuvant histopathologic. We describe the case of a patient woman of 70 years old with histopathologic diagnosis of moderately differentiated tubular gastric adenocarcinoma, locally advanced associated with images of perigastric lymphadenopathy and loss of the interface between gastric tumor, hepatic hilum and gallbladder. After 6 courses of neoadjuvant chemotherapy with FOLFOX scheme - 4 to 80%, an almost complete response from the point of tomographic view is obtained, so the patient is underwent to distal subtotal gastrectomy lymphadenectomy D2 more gastrojejunoanastomosis Billroth II termino lateral type Hofmeister Finsterer verifying on microscopic examination of surgical specimen only acute and chronic gastritis with mucous areas and reactive changes. No feasible malignancy is observed. Lymph nodes: 0/33. Commenting on the case, a review of recent relevant literature is realized

Eficacia y seguridad de la adición de panitumumab a folfox o folfiri como tratamiento de primera línea en pacientes con cancer colrectal metastásico con gen kras no mutado (wild type) e irresecable / Efficacy and safety of the addition of panitumumab to folfox or folfiri as first-line treatment in patients with metastatic col- rectal cancer with non-mutated (wild type) kras gene and unresectable

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del uso de panitumumab asociado a quimioterapia como primera línea de tratamiento de cácner colorrectal metastásico. Aspectos Generales: El cáncer colorrectal es la segunda causa de muerte por cáncer en los países occidentales. Al momento del diagnóstico, alrededor del 20-25% de los pacientes presentan cáncer colorrectal metastásico (CCRm), mientras que se estima que entre el 20 y el 35% lo desarrollará durante el curso de la enfermedad. Además, entre el 80% y el 90% de los casos de CCRm son irresecables. A pesar de los avances en el tratamiento del CCRm, el propósito aún es pobre, con una tasa de sobrevida a los 5 años que varía entre el 10% al 20%. Tecnología Sanitaria de Interés: Panitumumab, es un anticuerpo monoclonal recombinante totalmente humano IgG2, que se une con gran afinidad y especialidad al EGFR humano. El EGFR es una glicoproteína transmembrana que pertenece a una subfamilia de receptores de las tirosinas quinasas de tipo I, que incluye el EGFR (HER1/c-ErbB-1), HER2, HER3, HER4. El EGFR potencia el crecimiento celular en tejidos epiteliales normales, incluidos la piel y los folículos pilosos, y se expresa en una variedad de células tumorales. La unión panitumumab al EGFR provoca la internalización del receptor, la inhibición del crecimiento celular, la inducción de la apoptosis y un descenso en la producción de interleuquina 8 y del factor de crecimiento del endotelio vascular. El EGFR juega un rol importante en el desarrollo de CCR, por lo que su inhibición podría dar la impresión de ser una estrategia prometedora de tratamiento para CCRm. METODOLOGIA: Estrategia de Búsqueda: Se llevó a cabo una búsqueda sistematica de la literatura con respecto a la eficacia y seguridad de la adición de panitumumab a FOLFOX o FOLFIRI comparado con FOLFOX o FOLFIRI, para el tratamiento de cáncer colorrectal metastásico, irresecable, KRAS no mutado, ECOG-2. La búsqueda s einició revisando la inforamción sobre el uso del medicamiento de acuerdo con entidades reguladoras como la Food and Drug Administration (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente, se revisaron las bases de datos de Pubmed, TRIPDATABASE y www.clinicals.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Helath and Care Excelence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), National Comprehensive Cancer Network (NCCN), y The Cochrane Collaboration. RESULTADOS: Sinopsis de la Eidenci: Se llevó a cabo una búsqueda de evidencia científica relacionada al uso de panitumumab asociado a quimioterapia para el tratamiento de CCRm irresecable, KRAS no mutado. CONCLUSIONES: El tratamiento para el CCRm recomendado consiste en quimioterapia sistémica con FOLFOX, FOLFIRI o XELOX, todos los cuales se encuentran disponibles en el Petitorio Farmacológico de EsSalud. De acuerdo a las GPC revisadas, la adición de panitumumab a quimioterapia es opcional y condicionada a la ausencia de mutaciones KRAS y de la ubicación de las lesiones en el lado izquierdo. La evidencia evaluada en relación a la adición de panitumumab a FOLFOX en comparación con FOLFOX solo, no muestra benefícios en términos de aumento de la sobrevida global ni de la calidad de vida. Los benefícios en términos de SLP mostrados en el dictamen son modestos y provienen de análisis de subgrupos en que se ha perdido la aleatorización. La evidencia econtrada en relación a la adición de panitumumab a FOLFIRI en comparación con FOLFIRI solo, no pudo ser considerada para el presente dictamen por que proviene de estudios fase II, sin brazo comparador. La adición de panitumumab a quimioterapia presenta una incidencia alta de toxicidad dermatológica (>90%), con un 34 % d eEA dermatológicos grado 3 y menos de 1% de EA dermatológicos grado 5. Asismismo, la incidencia de eventos adversos no dermatológicos grado 3 o 4 fue del 82% y de eventos adversos serios fue de 40%. Así, la relación riesgo benefício no es clara, por lo que, no se encontraron argumentos técnicos que justifiquen la adición de panitumumab a la quimioterapia sistémica (FOLFOX o FOLFIRI) como primera línea de tratamiento para cpancer colorrectal irresecable, KRAS no mtado. El Instituto de Evaluación de Tecnologías en Salud-IETSI, no aprueba la adición de panitumumab a quimioterapia a base de FOLFOX o FOLFIRI como tratamiento de primera línea para cáncer colorrectal metastásico, irresecable, KRAS no mutado.

Eficacia y seguridad de bevacizumab en combinación con quimioterapia folfiri en el tratamiento de segunda línea para pacientes con diagnostico de cáncer colorrectal metastásico / Efficacy and safety of bevacizumab in combination with folinic chemotherapy in second-line treatment for patients diagnosed with metastatic colorectal cancer

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de la eficacia y seguridad del uso de bevacizumab en combinación con quimioterapia FOLFIRI como tratamiento de segunda línea para pacientes de segunda línea para pacientes para pacientes con diagnóstico de cáncer colorrectal metastásico. Aspectos Generales: El cáncer colorrectal es uno de los cánceres más frecuentes a nivel mundial. Anualmente se reportan más de 1.361 millones de nuevos casos y 694.000 muertes por cáncer colorrectal constituyéndose en la tercera cuasa más frecuente de cáncer y en la cuarta causa de muerte a nivel mundial. Aproximadamente, uns 20-55% de los pacientes con cácner colorrectal presentan enfermedad metastásica al momento del diagnóstico, mientras que u 50-60% de los pacientes diagnosticados en estadios tempranos, pese a ser tratados quirúrgicamente igual desarrollarán metástasis, mayormente de localización hepática. Debido a ello, el prognóstico de los pacientes con cáncer colorrectal metastásico o recurrente en general es pobre, asociándose a una sobrevida global a los 5 años del 50%.Tecnología Sanitaria de Interés: Bevacizumab es un anticuerpo monoclonal específico contra el factor de crecimiento del endotelio vascular (VEGF) por sus siglas en inglés) humano. Al ligarse al VEGF, específicamente al VEGFp-A, actúa como una citoquina antiangiogénica previendo su interacción con los receptores del VEGFE-1 and VEGFR-2), mediando la inhibición del crecimiento y mantenimiento de los vasos sanguíneos de una variedad de células tumorales. METODOLOGIA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de bevacizumab en combinación con esquema de quimioterapia FOLFIRI como tratamiento de esegunda línea para pacientes con cáncer colorrectal metastásico. Las seguientes fuentes han sido revisadas y consultadas con la intención de buscar la mejor evidencia disponible que directamente responda a la pregunta PICO de esta evaluación. METODOLOGÍA: Sinopsis de la Evidencia: Se realizó la busqueda bibliográfica y de evidencia cientifica hasta diciembre 2016 para el sustento de uso de bevacizumab en combinación con el esquema de quimioterapia FOLFIRI como tratamiento de segunda línea para pacientes con diagnóstico de cáncer colocrrectal metastásico que hubieran recibido previamente quimioterapia a base de oxaliplatino. Se presenta la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión. CONCLUSIONES: El presente dictamen se evaluó la evidencia científica publicada hasta diciembre de 2016 en relación al uso de bevacizumab en combinación con quimioterapia FOLFIRI como una alternativa de tratamiento de segunda línea más eficaz y segura que la quimioterapia FOLFIRI, en pacientes con cácner colocrrectal metastásico que han progresado a quimioterapia a base de oxaliplatino. La mejor evidencia disponible a la fecha no permite evaluar el uso de bevacizumab más quimioterapia FOLFIRI, en comparación a quimioterapia FOLFIRI sin bevacizumab en pacientes que han progresado a regímenes de quimioterapia a base de oxaliplatino sin bevacizumab. Adicionalmente, en el Petitorio Farmacológico de EsSalud existen otras alternativas de tratamiento quimioterapéutico disponibles para pacientes que han progresado a regímenes a base de oxaliplatino, tales como irinotecán y FOLFIRI, las cuales también son considerados opciones de tratamiento de segunda línea en las GPC internacionales. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de bevacizumab en combinación en quimioterapia FOLFIRI para el tratamiento de cáncer colorrectal metastásico en pacientes que han progresado a quimioterapia a base de oxaliplatino.

The outcomes of intensified 5-fluorouracil plus leucovorin chemotherapy for preoperative chemoradiation in rectal cancers

PURPOSE: The clinical benefit of intensified neoadjuvant chemoradiotherapy (CRT) in rectal cancer has not been proved. We investigated clinical outcomes of intensified 5-fluorouracil plus leucovorin (5-FU/LV) chemotherapy.METHODS: We retrospectively analyzed 45 patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant CRT between 2010 and 2015. Intensified group took additional 1 cycle of 5-FU/LV chemotherapy after radiation completion (resting period) before surgery, compared to conventional group.RESULTS: Eighteen patients were in conventional group and 27 were in intensified group. Median follow-up duration was 33.7 months (range, 7.8–75.6 months). Complete response rate was 11.4% (5/45). Twelve patients in conventional group and 16 patients in intensified group achieved downstaging (P=0.435). In aspect of toxicity, anemia and thrombocytopenia tended to be more frequent in intensified group without statistical difference. There was also no difference in survival between two groups.CONCLUSION: The intensified CRT with additional 1 cycle of 5-FU/LV in rectal cancer revealed no clinical benefit compared to conventional regimen. Considering that the adverse event was minimal and generally acceptable, further research with additional cycles of 5-FU/LV is needed to prove a real benefit of intensified CRT.

Retrospective analysis on the clinical efficacy of bevacizumab combined with FOLFOX4 in the first line treatment of metastatic colorectal cancer / 고신대학교의과대학학술지

OBJECTIVES: The addition of bevacizumab to standard chemotherapy has been improved survival outcomes in patients with metastatic colorectal cancer. However, the combination of bevacizumab with oxaliplatin-based chemotherapy as first-line treatment showed limited survival benefit. The purpose of this study was to investigate the clinical efficacy and toxicity of the combination of bevacizumab to oxaliplatin and leucovorin (FOLFOX4) in the first-line treatment of patient with metastatic colorectal cancer. METHODS: Between December 2004 and September 2009, medical records of patients who were diagnosed with metastatic colorectal cancer and received the first line chemotherapy with bevacizumab and FOLFOX4, were retrospectively reviewed. RESULTS: A total of forty patients were analyzed. The median age of the patients was 55 years (range, 33–80), and 55% was male. The patients received a total of 206 cycles of therapy (median 4 cycles per patient; range 1 – 15 cycles). Of these 40 patients, none achieved complete response (CR) and 15 achieved a partial response (PR), for the overall response rate (ORR) 37.5% (95% CI, 22.5–52.5). Median progression free survival (PFS) was 6.9 months (95% CI, 3.4–10.5) and median overall survival (OS) was 22.6 months (95% CI, 17.3–27.8The most common grade 3 or 4 hematologic toxicity and non-hematologic toxicity were neutropenia (10.0%) and diarrhea (10.0%), respectively. Two patients experienced gastrointestinal perforation. CONCLUSIONS: In this study, the combination bevacizumab with FOLFOX4 was associated with favorable OS, but did not showed favorable PFS and ORR.

FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism. MATERIALS AND METHODS: FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines. RESULTS: Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele. CONCLUSION: The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

A Randomized Phase II Study of Leucovorin/5-Fluorouracil with or without Oxaliplatin (LV5FU2 vs. FOLFOX) for Curatively-Resected, Node-Positive Esophageal Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The optimal perioperative treatment for resectable esophageal squamous cell carcinoma (ESCC) remains controversial. We evaluated the efficacy and safety of leucovorin and 5-fluorouracil (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) combination chemotherapies administered adjuvantly for curatively-resected, node-positive ESCC. MATERIALS AND METHODS: Patients with pathologically node-positive esophageal cancer after curative R0 resection were enrolled and randomly assigned to receive LV5FU2 or FOLFOX biweekly for up to eight cycles. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2011 and 2015, 62 patients were randomized into the two treatment groups (32 in the LV5FU2 arm and 30 in the FOLFOX arm). The median age was 60 years and both groups had similar pathologic characteristics in tumor, nodal status, and location. Treatment completion rates were similarly high in both groups. The DFS rate at 12 months was 67% in the LV5FU2 group and 63% in the FOLFOX group with a hazard ratio of 1.3 (95% confidence interval [CI], 0.66 to 2.62). After a median follow-up period of 27 months, the median DFS was 29.6 months (95% CI, 4.9 to 54.2) in the LV5FU2 arm and 16.8 months (95% CI, 7.5 to 26.1) in the FOLFOX arm (p=0.428), respectively, while the median overall survival was not reached in either arm. Grade 3 or 4 neutropenia was more frequent in patients in the FOLFOX arm than the LV5FU2 arm (20.0% vs. 3.1%). CONCLUSION: The addition of oxaliplatin (FOLFOX) did not lead to better efficacy compared to LV5FU2 chemotherapy in an adjuvant setting in node-positive ESCC patients.

FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism. MATERIALS AND METHODS: FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines. RESULTS: Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele. CONCLUSION: The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

A Randomized Phase II Study of Leucovorin/5-Fluorouracil with or without Oxaliplatin (LV5FU2 vs. FOLFOX) for Curatively-Resected, Node-Positive Esophageal Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The optimal perioperative treatment for resectable esophageal squamous cell carcinoma (ESCC) remains controversial. We evaluated the efficacy and safety of leucovorin and 5-fluorouracil (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) combination chemotherapies administered adjuvantly for curatively-resected, node-positive ESCC. MATERIALS AND METHODS: Patients with pathologically node-positive esophageal cancer after curative R0 resection were enrolled and randomly assigned to receive LV5FU2 or FOLFOX biweekly for up to eight cycles. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2011 and 2015, 62 patients were randomized into the two treatment groups (32 in the LV5FU2 arm and 30 in the FOLFOX arm). The median age was 60 years and both groups had similar pathologic characteristics in tumor, nodal status, and location. Treatment completion rates were similarly high in both groups. The DFS rate at 12 months was 67% in the LV5FU2 group and 63% in the FOLFOX group with a hazard ratio of 1.3 (95% confidence interval [CI], 0.66 to 2.62). After a median follow-up period of 27 months, the median DFS was 29.6 months (95% CI, 4.9 to 54.2) in the LV5FU2 arm and 16.8 months (95% CI, 7.5 to 26.1) in the FOLFOX arm (p=0.428), respectively, while the median overall survival was not reached in either arm. Grade 3 or 4 neutropenia was more frequent in patients in the FOLFOX arm than the LV5FU2 arm (20.0% vs. 3.1%). CONCLUSION: The addition of oxaliplatin (FOLFOX) did not lead to better efficacy compared to LV5FU2 chemotherapy in an adjuvant setting in node-positive ESCC patients.

Simultaneous integrated boost intensity-modulated radiotherapy versus 3-dimensional conformal radiotherapy in preoperative concurrent chemoradiotherapy for locally advanced rectal cancer

PURPOSE: To evaluate the feasibility of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for preoperative concurrent chemoradiotherapy (PCRT) in locally advanced rectal cancer (LARC), by comparing with 3-dimensional conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: Patients who were treated with PCRT for LARC from 2015 January to 2016 December were retrospectively enrolled. Total doses of 45 Gy to 50.4 Gy with 3D-CRT or SIB-IMRT were administered concomitantly with 5-fluorouracil plus leucovorin or capecitabine. Surgery was performed 8 weeks after PCRT. Between PCRT and surgery, one cycle of additional chemotherapy was administered. Pathologic tumor responses were compared between SIB-IMRT and 3D-CRT groups. Acute gastrointestinal, genitourinary, hematologic, and skin toxicities were compared between the two groups based on the RTOG toxicity criteria. RESULTS: SIB-IMRT was used in 53 patients, and 3D-CRT in 41 patients. After PCRT, no significant differences were noted in tumor responses, pathologic complete response (9% vs. 7%; p = 1.000), pathologic tumor regression Grade 3 or higher (85% vs. 71%; p = 0.096), and R0 resection (87% vs. 85%; p = 0.843). Grade 2 genitourinary toxicities were significantly lesser in the SIB-IMRT group (8% vs. 24%; p = 0.023), but gastrointestinal toxicities were not different across the two groups. CONCLUSION: SIB-IMRT showed lower GU toxicity and similar tumor responses when compared with 3D-CRT in PCRT for LARC.