RESUMO
PURPOSE: Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR) and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumour progression and are important targets for cancer therapeutics. (18)F-FDG maximum standardized uptake value (SUVmax) on PET/CT is a marker of tumour metabolic activity. The purpose of this study was to measure percentage reductions in SUVmax (∆SUVmax%), VEGFR-2 (∆VEGFR-2%), EGFR (∆EGFR%) and COX-2 (∆COX-2%) in patients with locally advanced rectal cancer (LARC) after preoperative treatment, and to correlate the changes in these markers of response with pathological response in terms of tumour regression grade (TRG) using Rödel's scale and long-term clinical outcome. METHODS: VEGFR-2, EGFR and COX-2 were measured using a quantitative and qualitative compound immunohistochemistry analysis (immunoreactive score) of the pretreatment endoscopic biopsy and definitive surgical specimens. Composite indexes using ∆SUVmax% and the three molecules were developed to differentiate patients with metabolic and molecular responses from nonresponders. Cox proportional hazards model was used to explore associations between the tumour markers, disease-free survival (DFS) and overall survival (OS). RESULTS: The analysis included 38 patients with a median follow-up of 86 months (range 5 - 113 months). The ∆VEGFR-2%/∆SUVmax% index correctly identified 13 of 19 pathological responders (TRG 3 and 4) and 17 of 19 nonresponders (TRG 0 - 2) (sensitivity 68 %, specificity 89 %, accuracy 79 %, positive predictive value 87 %, negative predictive value 74 %). In multivariate analysis, only the ∆VEGFR-2%/∆SUVmax% index was associated with DFS (HR 0.11, p = 0.001) and OS (HR 0.15, p = 0.02). CONCLUSION: In patients with LARC the ∆VEGFR-2%/∆SUVmax% response index is associated with outcome. Determination of the optimal diagnostic cut-off level for this novel biomarker association should be explored. Evaluation in a clinical trial is required to determine whether selected patients could benefit from treatment with a VEGFR-targeted therapeutic agent.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais/metabolismo , Neoplasias Retais/terapia , Adulto , Idoso , Ciclo-Oxigenase 2/metabolismo , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Retais/patologia , Resultado do Tratamento , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: It has long been debated whether human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are associated with rectal cancer. The gene products of HCMV and EBV contribute to cell-cycle progression, mutagenesis, angiogenesis and immune evasion. The aim of this prospective study was to analyse the association between infection of a tumour by HCMV and EBV and clinical, histological, metabolic ((18)F-FDG uptake), volumetric (from CT) and molecular (KRAS status) features and long-term outcomes in a homogeneously treated group of patients with locally advanced rectal cancer. METHODS: HCMV and EBV were detected in pretreatment biopsies using polymerase chain reaction (PCR). The Cox proportional hazards regression model was used to explore associations between viral infection and disease-free survival (DFS) and overall survival (OS). RESULTS: We analysed 37 patients with a median follow-up of 74 months (range 5-173 months). Locoregional control, OS and DFS at 5 years were 93%, 74% and 71%, respectively. Patients with HCMV/EBV coinfection had a significantly higher maximum standardized uptake value than patients without viral coinfection (p = 0.02). Significant differences were also observed in staging and percentage relative reduction in tumour volume between patients with and without HCMV infection (p < 0.01) and EBV infection (p < 0.01). KRAS wildtype status was significantly more frequently observed in patients with EBV infection (p <0.01) and HCMV/EBV co-infection (p = 0.04). No significant differences were observed in OS or DFS between patients with and without EBV infection (p = 0.88 and 0.73), HCMV infection (p = 0.84 and 0.79), and EBV/CMV coinfection (p = 0.24 and 0.39). CONCLUSION: This pilot study showed that viral infections were associated with metabolic staging differences, and differences in the evolution of metabolic and volumetric parameters and KRAS mutations. Further findings of specific features will help determine the best candidates for metabolic and volumetric staging and restaging. Further toxicity profile findings will help to determine the best candidates for specific supportive treatment during pelvic chemoradiotherapy in patients with locally advanced rectal cancer.