RADIATION THERAPY FOLLOWED BY SURGICAL RESECTION FOR RECTAL CANCER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在拟议的研究中，我们将西妥昔单抗(C225)与使用奥沙利铂、卡培他滨和同期放射治疗的新辅助放化疗相结合。与内皮生长因子受体(EGFR)抑制相关的抗肿瘤活性的多种机制为细胞毒治疗提供了协同作用的机会。西妥昔单抗在临床前模型中显示出与铂、氟嘧啶和放射的协同活性。此外，西妥昔单抗已经在作为单药的晚期结直肠癌患者中显示出抗肿瘤活性，在伊立替康耐药患者中也显示了伊立替康的抗肿瘤活性。虽然术前放化疗联合奥沙利铂联合5-FU/LV和放射治疗的研究已经进行，但到目前为止还没有进行过用卡培他滨替代5-FU/LV的试验。卡培他滨提供了方便的口服剂量，良好的毒性特征，以及已知的直肠癌活性。考虑到潜在的重叠毒性，如腹泻、虚弱和皮肤变化，我们建议进行奥沙利铂和卡培他滨与固定剂量西妥昔单抗和放射治疗的I期序贯剂量递增试验，以评估该方案的安全性和耐受性。一旦确定了奥沙利铂和卡培他滨的最大耐受量(MTD)，就建议进行第二阶段试验来评估该方案的抗肿瘤活性。在研究的第二阶段，患者将被随机分配在第一天(A组)或第八天(B组)开始每周一次的西妥昔单抗治疗。这种分层将允许进行探索性相关免疫组织化学(IHC)研究，不仅评估放化疗的效果，而且还允许观察分析EGFR抑制对放化疗的生物学影响。在开始治疗之前，所有患者都将接受经直肠超声和芯针活检的内窥镜分期，以获取这些IHC研究的组织。所有患者将在第7天或第8天进行重复的内窥镜芯针活检。我们将对连续的活检标本进行细胞凋亡和血管生成的评估，以及抑制EGFR可能增强放射治疗和诱导肿瘤消退的可能机制以及下游信号通路。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the proposed study, we will combine Cetuximab (C225) with neoadjuvant chemoradiotherapy using Oxaliplatin, Capecitabine, and concomitant radiotherapy. The multiple mechanisms of antitumor activity associated with endothelial growth factor receptor (EGFR) inhibition present an opportunity for synergy with cytotoxic therapy. Cetuximab has demonstrated synergistic activity with platinums, Fluoropyrimidines and radiation in preclinical models. In addition, Cetuximab has already shown antitumor activity in colorectal cancer patients with advanced-stage disease as a single-agent as well as with Irinotecan in Irinotecan-refractory patients. While preoperative chemoradiotherapy has been studied combining Oxaliplatin with 5-FU/LV and radiotherapy, no trial has been performed to date substituting 5-FU/LV with Capecitabine in this regimen. Capecitabine provides convenient oral dosing, a favorable toxicity profile, and known activity in rectal cancer. Given the concern for potential overlapping toxicities such as diarrhea, asthenia, and skin changes, we propose a Phase I sequential dose-escalation trial of Oxaliplatin and Capecitabine with fixed-dose Cetuximab and radiotherapy to assess the safety and tolerability of this regimen. Once the maximally tolerated doses (MTD) of Oxaliplatin and Capecitabine have been established, a Phase II trial is then proposed to evaluate the antitumor activity of this regimen. During the Phase II portion of the study, patients will be randomly assigned to begin weekly Cetuximab on either day 1 (Group A) or day 8 (Group B). This stratification will allow for exploratory correlative immunohistochemical (IHC) studies to be performed to evaluate not only the effects of chemoradiotherapy, but also allow for observational analysis of the biological impact of EGFR inhibition upon chemoradiotherapy. All patients will undergo endoscopic staging with transrectal ultrasound and core-needle biopsy to obtain tissue for these IHC studies prior to beginning therapy. A repeat endoscopic core-needle biopsy will be performed on day 7 or 8 in all patients. An assessment of apoptosis and angiogenesis, the presumed mechanisms by which EGFR inhibition may enhance radiotherapy and induce tumor regression as well as downstream signaling pathways will be performed on serial biopsy specimens.