RADIATION THERAPY FOLLOWED BY SURGICAL RESECTION FOR RECTAL CANCER

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在拟定的研究中，我们将联合收割机西妥昔单抗（C225）与奥沙利铂、卡培他滨的新辅助放化疗和伴随放疗联合使用。与内皮生长因子受体（EGFR）抑制相关的多种抗肿瘤活性机制为与细胞毒性治疗协同提供了机会。在临床前模型中，西妥昔单抗与铂类、氟嘧啶类和放射治疗具有协同活性。此外，西妥昔单抗单药治疗晚期结直肠癌患者以及与伊立替康联合治疗伊立替康难治性患者已显示出抗肿瘤活性。 虽然已经研究了奥沙利铂联合5-FU/LV和放疗的术前放化疗，但迄今为止尚未进行在该方案中用卡培他滨替代5-FU/LV的试验。卡培他滨提供方便的口服给药、有利的毒性特征和已知的直肠癌活性。考虑到潜在的重叠毒性，如腹泻、无力和皮肤变化，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剂量（MTD），则建议进行II期试验以评价该方案的抗肿瘤活性。 在研究的II期部分，患者将被随机分配至开始每周一次的西妥昔单抗治疗，第1天（A组）或第8天（B组）。该分层将允许进行探索性相关免疫组化（IHC）研究，不仅评价放化疗的效果，还允许观察性分析EGFR抑制对放化疗的生物学影响。在开始治疗前，所有患者都将接受经直肠超声内镜分期和芯针活检，以获得用于这些IHC研究的组织。所有患者将在第7天或第8天重复进行内镜芯针活检。将对连续活检标本进行细胞凋亡和血管生成评估，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传导途径。

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.