Background: Standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer typically employs capecitabine or 5-fluorouracil. Gemcitabine, an alternative radiosensitizer, has a well-established immunomodulatory effect. The role of preoperative concurrent gemcitabine with radiotherapy on rectal cancer microenvironment and long-term survival has not been fully elucidated.Methods: In this phase II clinical trial update and secondary analysis, 40 adult patients with stage T3/T4 or node-positive, non-metastatic rectal cancer received neoadjuvant chemoradiotherapy consisting of external beam radiation (45–54 Gy) with weekly 24-hour infusional gemcitabine (100 mg/m2, later 75 mg/m2for toxicity) followed by surgery and adjuvant capecitabine. The protocol was amended to analyse immune cell infiltration pre- and post-treatment using immunohistochemistry. The primary endpoint was pathological complete response (pCR); secondary endpoints included R0 resection rate, toxicity, immune infiltration, disease-free survival (PFS), and overall survival (OS). Results were compared to historical controls treated with capecitabine-based chemoradiation.Results: Of the 40 enrolled patients (83% high-risk features), 32 underwent surgery, and 31 were resected. The updated median PFS was 70 months (median follow-up: 87.4 months); median OS was not reached. The estimated 5-year PFS and OS were 54.4% and 67.5%, respectively. Infusional gemcitabine induced significantly higher total immune cell infiltration in resected tumors compared to controls (p= 0.026). CD8+ T cell density increased markedly in surgical specimens (p= 0.001), and PD-L1+ immune cells rose significantly post-therapy (p= 0.032). There was a trend toward increased CD56+ NK cell infiltration. Toxicities and pCR rates aligned with established regimens.Conclusions: Neoadjuvant chemoradiotherapy with infusional gemcitabine yields durable survival and robust immune cell infiltration in locally advanced rectal cancer, comparable to modern standards. The immunomodulatory effects of gemcitabine—particularly the enrichment of CD8+ T cells and PD-L1+ immune cells—support further evaluation of combination strategies incorporating immunotherapy to enhance systemic disease control.
背景：局部进展期直肠癌的标准新辅助放化疗通常采用卡培他滨或5-氟尿嘧啶。吉西他滨作为一种替代性放射增敏剂，具有明确的免疫调节作用。术前吉西他滨联合同步放疗对直肠癌微环境及长期生存的影响尚未完全阐明。 方法：在这项II期临床试验更新及二次分析中，40例T3/T4期或淋巴结阳性、非转移性直肠癌成年患者接受了新辅助放化疗，方案包括外照射放疗（45–54 Gy）联合每周24小时持续输注吉西他滨（初始剂量100 mg/m²，后因毒性调整为75 mg/m²），随后进行手术及卡培他滨辅助化疗。研究方案经修订后，采用免疫组化方法分析治疗前后肿瘤组织的免疫细胞浸润情况。主要终点为病理完全缓解率；次要终点包括R0切除率、毒性反应、免疫浸润情况、无进展生存期和总生存期。研究结果与基于卡培他滨放化疗的历史对照组进行比较。 结果：在入组的40例患者中（83%具有高危特征），32例接受手术，31例实现切除。更新后的中位无进展生存期为70个月（中位随访时间：87.4个月）；中位总生存期尚未达到。预估5年无进展生存率和总生存率分别为54.4%和67.5%。与对照组相比，持续输注吉西他滨方案显著提高了切除肿瘤组织的总免疫细胞浸润水平（p=0.026）。手术标本中CD8+ T细胞密度显著增加（p=0.001），治疗后PD-L1+免疫细胞明显上升（p=0.032）。CD56+ NK细胞浸润呈现增加趋势。毒性反应和病理完全缓解率与现有标准方案相当。 结论：持续输注吉西他滨的新辅助放化疗方案在局部进展期直肠癌中可获得持久的生存获益和显著的免疫细胞浸润效应，疗效与现代标准方案相当。吉西他滨的免疫调节作用——特别是CD8+ T细胞和PD-L1+免疫细胞的富集——为后续评估联合免疫治疗以增强全身性疾病控制的策略提供了理论依据。
肿瘤(癌症)患者之家