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The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Colite , Gastroenteropatias , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Gastroenteropatias/induzido quimicamente , Colite/induzido quimicamente , Colite/tratamento farmacológico , Fígado , PrognósticoRESUMO
INTRODUCTION: The VELOUR study evaluated the efficacy and safety of adding aflibercept to FOLFIRI (fluorouracil, leucovorin, irinotecan) in second-line therapy for metastatic colorectal cancer (mCRC). However, a nomogram that can stratify patients according to prognosis is unavailable, and the frequency and effect of the pragmatic use of modified schedules in actual practice remains unknown. METHOD: The sample consists of 250 patients with mCRC treated with aflibercept and irinotecan-based chemotherapy at nine Spanish academic centers between January 2013 and September 2015. The result of a Cox proportional hazards model regression for overall survival (OS), adjusted for covariates available in daily practice, was represented as a nomogram and web-based calculator. Harrell's c-index was used to assess discrimination. RESULTS: The prognostic nomogram for OS includes six variables: Eastern Cooperative Oncology Group performance status, tumor location, number of metastatic sites, mutational status, better response to previous treatment(s), and carcinoembryonic antigen. The model is well calibrated and has acceptable discriminatory capacity (optimism-corrected c-index, 0.723; 95% confidence interval [CI], 0.666-0.778). Median OS was 6.1 months (95% CI, 5.1-8.8), 12.4 months (95% CI, 9.36-14.8), and 22.9 months (95% CI, 16.6-not reached) for high-, intermediate-, and low-risk groups, respectively. Age, comorbidity, or use of modified FOLFIRI regimens did not affect prognosis in this series. Grade 3-4 adverse events were less common following modified schedules. The admission rate because of toxicity was higher in ≥65 years (9.7% vs. 19.6%; odds ratio, 2.26; p = .029). CONCLUSION: We have developed and internally validated a prognostic model for use in individuals with colorectal cancer initiating therapy with FOLFIRI-aflibercept to predict both OS and the effect of pragmatic modifications of the classic regime on efficacy and safety. This can aid in decision making and in designing future trials. IMPLICATIONS FOR PRACTICE: In this study, the authors developed and conducted the internal validation of a prognostic nomogram that makes it possible to stratify patients who are eligible for second-line FOLFIRI-aflibercept based on their probability of survival. This model was developed in a multicenter sample from nine Spanish hospitals. Furthermore, to increase the study's validity, the practical use of aflibercept in this setting was investigated, including doses or pragmatic modifications. The results suggest that the modified schedules often used in this daily clinical practice-based patient population are associated with less severe toxicity without apparent detriment to survival endpoints. It is believed that these data complement the information provided by the VELOUR trial and are relevant for the oncologist in treating colon cancer in the second-line setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Nomogramas , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Análise de Dados , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: The assessment of the state of immunosurveillance (the ability of the organism to prevent the development of neoplasias) in the blood has prognostic implications of interest in colorectal cancer. We evaluated and quantified a possible predictive character of the disease in a blood test using a mathematical interaction index of several blood parameters. The predictive capacity of the index to detect colorectal cancer was also assessed. METHODS: We performed a retrospective case-control study of a comparative analysis of the distribution of blood parameters in 266 patients with colorectal cancer and 266 healthy patients during the period from 2009 to 2013. RESULTS: Statistically significant differences (p < 0.05) were observed between patients with colorectal cancer and the control group in terms of platelet counts, fibrinogen, total leukocytes, neutrophils, systemic immunovigilance indexes (neutrophil to lymphocyte ratio and platelet to lymphocyte ratio), hemoglobin, hematocrit and eosinophil levels. These differences allowed the design of a blood analytical profile that calculates the risk of colorectal cancer. This risk profile can be quantified via a mathematical formula with a probabilistic capacity to identify patients with the highest risk of the presence of colorectal cancer (area under the ROC curve = 0.85). CONCLUSIONS: We showed that a colorectal cancer predictive character exists in blood which can be quantified by an interaction index of several blood parameters. The design and development of interaction indexes of blood parameters constitutes an interesting research line for the development and improvement of programs for the screening of colorectal cancer.
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Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Testes Hematológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de RiscoRESUMO
BACKGROUND: Colorectal carcinoma is a common cause of cancer. Adjuvant treatments include: 5-fluorouracil administered together with folinic acid, or more recently, oral fluoropyrimidines such as capecitabine, in combination with oxaliplatin or irinotecan. Metastatic colorectal cancer patients can benefit from other additional treatments such as cetuximab or bevacizumab. METHODS: Using cell culture techniques, we isolated clonal populations from primary cultures of ascitic effusion derived from a colon cancer patient and after several passages an established cell line, HGUE-C-1, was obtained. Genetic analysis of HGUE-C-1 cells was performed by PCR of selected exons and sequencing. Cell proliferation studies were performed by MTT assays and cell cycle analyses were performed by flow cytometry. Retinoblastoma activity was measured by luciferase assays and proteins levels and activity were analysed by Western blot or immunohistochemistry. RESULTS: We have established a new cell line from ascitic efussion of a colon cancer patient who did not respond to 5-fluorouracil or irinotecan. HGUE-C-1 cells did not show microsatellite instability and did not harbour mutations in KRAS, BRAF, PI3KCA or TP53. However, these cells showed loss of heterozygosity affecting Adenomatous Polyposis Coli and nuclear staining of ß-catenin protein. The HGUE-C-1 cell line was sensitive to erlotinib, gefitinib, NVP-BEZ235, rapamycin and trichostatin, among other drugs, but partially resistant to heat shock protein inhibitors and highly resistant to AZD-6244 and oxaliplatin, even though the patient from which this cell line was derived had not been exposed to these drugs. Molecular characterization of this cell line revealed low expression levels and activity of Retinoblastoma protein and elevated basal levels of Erk1/2 activity and p70S6K expression and activity, which may be related to chemoresistance mechanisms. CONCLUSIONS: HGUE-C-1 represents a novel and peculiar colon carcinoma model to study chemoresistance to chemotherapeutic agents and to novel anti-neoplasic drugs that interrupt signalling pathways such as the APC/ßcatenin, Ras/Raf/Mek/Erk, PI3K/mTOR/p70S6K pathways as well as histone regulation mechanisms.
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Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Idoso , Antineoplásicos/farmacologia , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Expressão Gênica , Humanos , Masculino , Instabilidade de Microssatélites , Mutação , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Transdução de SinaisRESUMO
There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Claudinas/uso terapêutico , Junção Esofagogástrica/patologia , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Cell-free DNA analysis (cfDNA) holds promise for residual disease or tumor burden quantification in colorectal cancer, with reduced costs and diagnostic equipment compared to gold standard-specific tumor DNA (ctDNA) analysis. METHODS: This prospective case-control study included 46 colorectal cancer patients and healthy controls to perform cfDNA quantification by fluorometry using Quantus Fluorometer (Promega, Madison, WI) and using cell-free DNA ScreenTape assay (Agilent) and 4200 TapeStation instrument (Agilent Technologies, Inc., Santa Clara, CA, USA). cfDNA quantification results were correlated with stage, clinical and histopathological features. RESULTS: 33 localized (8 stage I, 12 stage II, and 13 stage III) and 13 advanced colorectal cancer patients were included. No differences in cfDNA quantification by fluorometry were demonstrated depending on stage or histopathological features in localized disease patients. Differences in cfDNA quantification by fluorometry could be demonstrated in patients with advanced disease depending on the presence of liver metastases and synchronous or metachronous metastatic disease. Differences in cfDNA quantification by fluorometry could be demonstrated between advanced colorectal cancer patients and both localized disease patients and healthy controls. Secondary cfDNA analysis by electrophoresis, although showing more specificity to measure ctDNA in cfDNA values, could not improve the capacity to detect differences between analyzed a groups beyond previously achieved with fluorometry. CONCLUSION: This exploratory analysis of cfDNA based on fluorometry and electrophoresis methods showed promising results discriminating colorectal cancer and non-cancer patients, as well as different colorectal cancer stages and disease profiles. Further studies are needed to increase our knowledge and to help to overcome barriers to broader implementation and applications.
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Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Colorretais , Biomarcadores Tumorais , Estudos de Casos e Controles , HumanosRESUMO
Esophageal cancer is an aggressive tumor, and is the sixth-leading cause of death from cancer. Incidence is rising in Spain, particularly among men. Two main pathological different subtypes have been described: squamous cell carcinoma and adenocarcinoma. Growing evidence of their epidemiology and molecular differences explains their different response to novel treatments, and they are therefore likely to be treated as two separate entities in the near future. The best results are obtained with a multidisciplinary therapeutic strategy, and the introduction of immunotherapy is a promising new approach that will improve prognosis. In these guidelines, we review the evidence for the different methods of diagnosis and therapeutic strategies that form the basis of our standard of care.
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/terapia , Humanos , Imunoterapia/efeitos adversos , Masculino , PrognósticoRESUMO
Familial adenomatous polyposis (FAP) is mainly characterized by the development of a large number of polyps in the gastrointestinal tract and by the risk of developing adenocarcinomas. We present the case of a woman diagnosed with FAP and liver metastases. Histological analysis revealed both diseases to be secondary to a neuroendocrine tumor. To date, only three cases showing the simultaneous occurrence of these two entities have been published. Currently, there is no genetic basis to explain the coexistence of these two diseases, both of which have a very low prevalence.
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Polipose Adenomatosa do Colo/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/secundário , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/secundário , Evolução Fatal , Feminino , Humanos , Adulto JovemRESUMO
We have determined the effects of the IGF-1R tyrosine kinase inhibitors BMS-754807 (BMS) and OSI-906 (OSI) on cell proliferation and cell-cycle phase distribution in human colon, pancreatic carcinoma, and glioblastoma cell lines and primary cultures. IGF-1R signaling was blocked by BMS and OSI at equivalent doses, although both inhibitors exhibited differential antiproliferative effects. In all pancreatic carcinoma cell lines tested, BMS exerted a strong antiproliferative effect, whereas OSI had a minimal effect. Similar results were obtained on glioblastoma primary cultures, where HGUE-GB-15, -16 and -17 displayed resistance to OSI effects, whereas they were inhibited in their proliferation by BMS. Differential effects of BMS and OSI were also observed in colon carcinoma cell lines. Both inhibitors also showed different effects on cell cycle phase distribution, BMS induced G2/M arrest followed by cell death, while OSI induced G1 arrest with no cell death. Both inhibitors also showed different effects on other protein kinases activities. Taken together, our results are indicative that BMS mainly acts through off-target effects exerted on other protein kinases. Given that BMS exhibits a potent antiproliferative effect, we believe that this compound could be useful for the treatment of different types of tumors independently of their IGF-1R activation status.
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Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. Design, Setting, and Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. Main Outcomes and Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. Conclusions and Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited. Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/mortalidade , Oxaloacetatos/uso terapêutico , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
Hepatoid adenocarcinoma is an extrahepatic tumor characterized by morphological similarities to hepatocellular carcinoma. Hepatoid adenocarcinoma of the stomach is a cancer with an extremely poor prognosis with few cases reported. Here, we describe a 75-year-old Spanish man referred to our hospital with a history of abdominal pain, general fatigue, anorexia and sickness. Initial study revealed anemia, and computed tomography scan and abdominal ultrasonography showed multiple metastases to the liver with hepatocellular carcinoma characteristics in a liver with no cirrhotic change. Further study included a serum level of alpha-fetoprotein (AFP), which resulted markedly elevated, and a conclusive esophagogastroduodenoscopy describing an elevated tumour growing through the cardia and gastroesophageal junction with foci of necrosis and haemorrhage. Gastric biopsies of the tumor revealed poorly differenciated adenocarcinoma, with hepatoid differentiation. After a diagnosis of AFP-producing hepatoid adenocarcinoma of the stomach with multiple liver metastases was made, pallitive total gastrectomy, without liver resection, was performed. Patient recovered well after surgery, and entered into a palliative systemich chemotherapy protocol. Although this illness is recognized as having poor prognosis, the patient remains alive 8 months after the operation. Accurate diagnosis of hepatoid adenocarcinoma of the stomach is important, and should be suspected under certain circumstances. We describe this rare case of hepatoid adenocarcinoma of the stomach, and review the literature concerning the clinicopathological aspects.
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We present a case of locally advanced rectal cancer with initial optimal local control after neoadjuvant concurrent chemoradiotherapy followed by surgery; early liver recurrence then occurred and was treated again with curative intent with neoadjuvant combination chemotherapy followed by liver surgery. We reflect on this difficult problem and discuss relevant topics to this case report.
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BACKGROUND AND OBJECTIVES: Appendiceal neoplasms with extra-appendiceal spread may show different clinical patterns with pseudomyxoma peritonei (PMP) being one of them. We analyse the results in a series of patients treated in our centre. MATERIAL AND METHODS: Retrospective study of patients operated on for appendiceal peritoneal carcinomatosis from January 2012 to May 2015. RESULTS: Twenty-seven consecutive patients were included. Median age 63 years (26-73); 14 were men. Peritoneal carcinomatosis index=16±8 (3-31). The suspected preoperative origins were appendix in 23, ovary in 3 and urothelial in one. Postoperative mortality in 2 patients (7.4%). The remaining 36% presented morbidity. Major morbidity (Clavien-Dindo grades 3 and 4) occurred in 3 patients (12%). CONCLUSIONS: Mucinous adenocarcinomas with extra-appendiceal spread may present as PMP with mucinous ascites, jelly-nodular carcinomatosis without ascites, nodular or desmoplasic plates carcinomatosis without jelly mass/nodules. Histology is not correlated to clinical picture. Preoperative diagnosis of mucinous ovarian cancer in peritoneal carcinomatosis scenario may increase the doubt of their ovarian origin and force an appendiceal origin to be ruled out.
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Adenocarcinoma Mucinoso/patologia , Neoplasias do Apêndice/patologia , Neoplasias Peritoneais/patologia , Pseudomixoma Peritoneal/patologia , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/cirurgia , Prognóstico , Pseudomixoma Peritoneal/diagnóstico , Pseudomixoma Peritoneal/mortalidade , Pseudomixoma Peritoneal/cirurgia , Estudos RetrospectivosRESUMO
The currently reported 5-year survival rates for patients with resected stage II, IIIA, IIIB, and IV gastric cancer are 34%, 20%, 8%, and 7%, respectively. A subtotal or total gastrectomy with a D1 en bloc dissection of lymphatic tissue is the standard surgical treatment. Several meta-analyses of post-operative adjuvant trials have reported a significant benefit for chemotherapy-treated patients. Because most relapses occur locally, post-operative adjuvant chemoradiotherapy was studied in patients who received surgery alone or surgery followed by 5-fluorouracil and leucovorin (5-FU/LV, Mayo Clinic regimen) given before, after, and concurrently with radiotherapy in the Intergroup 0116 trial. The 3-year survival and 3-year disease-free survival rates were significantly higher in the adjuvant treatment group, making this regimen the adjuvant standard in the United States. A second trial, the MAGIC trial, also showed improved survival and disease-free survival with epirubicin, cisplatin, and 5-FU (ECF) given every 3 weeks pre- and post-operatively. Other agents in combination with perioperative radiotherapy and surgery are being investigated to treat patients with gastric cancer. New target-oriented agents, as well as tailored therapy based on the molecular profile of both the tumor and the patient, might also contribute to improved results.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/terapia , Quimioterapia Adjuvante , Fluoruracila/administração & dosagem , Gastrectomia , Humanos , Leucovorina/administração & dosagem , Radioterapia AdjuvanteRESUMO
Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with colon cancer who are more likely to benefit from adjuvant chemotherapy. We investigated the effect of single-nucleotide polymorphisms (SNP) within genes involved in oxaliplatin and fluoropyrimidines metabolism, DNA repair mechanisms, drug transport, or angiogenesis pathways on outcome for patients with stage II and III colon cancer treated with adjuvant chemotherapy. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples of 202 patients with stage II and III colon cancer receiving oxaliplatin-based adjuvant chemotherapy from January 2004 to December 2009. Genotyping was performed for 67 SNPs in 32 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 patients treated with the same chemotherapy regimens. The combination of the selectin E (SELE) rs3917412 G>A G/G and the methylentetrahydrofolate reductase (MTHFR) rs1801133 T/T genotypes was associated with a significantly increased risk for recurrence in both the training [RR = 4.103; 95% confidence interval (CI), 1.803-9.334; P = 0.001] and the validation cohorts (RR = 3.567; 95% CI, 1.253-10.151; P = 0.017) in the multiple regression analysis considering the stage, lymphovascular invasion, and bowel perforation as covariates. The combined analysis of these polymorphisms was also significantly associated with overall survival in both cohorts (RR = 3.388; 95% CI, 0.988-11.623; P = 0.052, and RR = 3.929; 95% CI, 1.144-13.485; P = 0.020, respectively). Our findings suggest that the SELE rs3917412 and MTHFR rs1801133 SNPs could serve as pharmacogenetic predictors of tumor recurrence in patients with early-stage colon cancer treated with oxaliplatin-based adjuvant chemotherapy, thus allowing personalized selection of treatment to optimize clinical outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Compostos Organoplatínicos/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Reparo do DNA , Selectina E/genética , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Oxaliplatina , Farmacogenética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Recidiva , Análise de Regressão , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Adenocarcinoma/secundário , Neoplasias da Medula Óssea/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Vértebras Cervicais/patologia , Neoplasias Pulmonares/patologia , Neoplasias da Coluna Vertebral/secundário , Vértebras Torácicas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Neoplasias da Medula Óssea/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Irradiação Craniana , Craniotomia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Lobo Frontal/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Taxoides/administração & dosagem , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
Colorectal cancer is the first cause of cancer diagnosis in Spain. Over half of the patients are diagnosed with or will eventually develop distant metastasis. The current manuscript aims to provide synthetic practical guidelines for the therapeutic approaches in advanced disease. Available systemic therapeutic options, and integration and sequencing of chemotherapy with surgical procedures are discussed. Extent of disease, treatment objective, tumor kras mutation status, as well as patient's functional and comorbid conditions shall be considered to properly design the most adequate therapeutic strategy.
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Carcinoma/terapia , Neoplasias Colorretais/terapia , Oncologia/métodos , Guias de Prática Clínica como Assunto , Algoritmos , Carcinoma/patologia , Neoplasias Colorretais/patologia , Progressão da Doença , Humanos , Oncologia/tendências , Sociedades Médicas , EspanhaRESUMO
Based on improved safety and efficacy results, advanced colorectal cancer (CRC) treatment has recently shifted from intravenous bolus 5-fluorouracil (5-FU) monotherapy to standard combinations of prolonged intravenous 5-FU infusion with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). Capecitabine, a rationally designed oral fluoropyrimidine that is converted into 5-FU preferentially at the tumor site, could replace infusional 5-FU as the mainstay of combined chemotherapy treatment for metastatic CRC. Evidently, oral medication obviates the drawbacks of prolonged intravenous infusion. The combination of capecitabine and oxaliplatin is especially attractive owing to its favorable tolerability profile, good activity and convenient administration schedule. Phase III trials comparing capecitabine/oxaliplatin with infusional regimens of 5-FU +/- LV and oxaliplatin in advanced CRC show similar toxicity and efficacy outcomes with both regimens. Capecitabine has the potential to replace 5-FU/LV as the optimal combination partner for oxaliplatin at a higher cost. Capecitabine and oxaliplatin concomitantly with radiation therapy has been evaluated before surgery in rectal cancer treatment. The combination of capecitabine and oxaliplatin, with or without bevacizumab, a monoclonal antibody blocking VEGF, is also being evaluated in early stage colon cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Invasividade Neoplásica/patologia , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Prognóstico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Análise de SobrevidaRESUMO
The purpose of this review is to discuss the inhibition of vascular endothelial growth factor as a treatment for advanced colorectal cancer. The review will begin by summarizing the theory behind vascular endothelial growth factor inhibition and how this affects tumor angiogenesis. The major clinical trials that have examined antivascular endothelial growth factor agents to treat patients with advanced colorectal cancer will then be described. Finally, there is a commentary regarding the status of targeted agents currently in development for the treatment of advanced colorectal cancer and a discussion of the potential future considerations for the use of antivascular endothelial growth factor agents in clinical practice.