RADIATION THERAPY FOLLOWED BY SURGICAL RESECTION FOR RECTAL CANCER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在拟议的研究中，我们将联合西妥昔单抗（C225）与奥沙利铂、卡培他滨的新辅助放化疗，以及伴随的放疗。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提供了与细胞毒性治疗协同作用的机会。在临床前模型中，西妥昔单抗已显示出与铂、氟嘧啶和辐射的协同作用。此外，西妥昔单抗已经在结直肠癌晚期患者中显示出抗肿瘤活性，并在伊立替康难治性患者中与伊立替康联合使用。虽然术前放化疗已经研究了奥沙利铂联合5-FU/LV和放疗，但迄今为止还没有在该方案中用卡培他滨替代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，并在直肠癌已知的活性。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疗的I期顺序剂量递增试验，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剂量（MTD），就会提出II期试验来评估该方案的抗肿瘤活性。在研究的II期部分，患者将随机分配在第1天（A组）或第8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，不仅可以评估放化疗的效果，还可以观察分析EGFR抑制对放化疗的生物学影响。在开始治疗之前，所有患者都将通过经直肠超声和核心针活检进行内镜分期，以获得用于这些免疫组化研究的组织。所有患者将在第7天或第8天进行重复内窥镜核心针活检。对细胞凋亡和血管生成的评估，EGFR抑制可能增强放疗和诱导肿瘤消退的假定机制以及下游信号通路将在一系列活检标本上进行。

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.