Li Y J, Yuan P, Zhai J N, Yao Y F, Tan L X, Li Z W, Zhang X Y, Wu A W
Gastrointestinal Cancer Center, Unit III, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Department of Endoscopy, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Zhonghua Wei Chang Wai Ke Za Zhi. 2024 Jul 25;27(7):684-693. doi: 10.3760/cma.j.cn441530-20240526-00188.
To evaluate the short-term efficacy and safety of a preoperative combination of programmed cell death protein-1 (PD-1) inhibitor with either oxaliplatin + capecitabine (CapeOx) or oxaliplatin + tegafur gimeracil oteracil potassium (SOX) in the treatment of locally advanced immunotherapy-sensitive gastric cancer (LAGC) or adenocarcinoma of the esophagogastric junction (AEG). The cohort of this retrospective descriptive case series comprised patients with LAGC or AEG whose cancers had been determined to be immunotherapy- sensitive by endoscopic biopsy before treatment in the Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital and Institute from 1 August 1 2021 to 31 January 2024. Patients with any one of the following three characteristics were immunotherapy-sensitive: (i) PD-L1 combined positive score (CPS) ≥5; (ii) microsatellite instability-high (MSI-H) / mismatch repair deficiency (dMMR); or (iii) Epstein-Barr virus-encoded RNA (EBER) positivity. All study patients received PD-1 inhibitors combined with CapeOx or SOX as a neoadjuvant or conversion treatment strategy before surgery. Patients with immune system diseases, distant metastases, or human epidermal growth factor receptor 2 positivity were excluded. Factors analyzed included pathological complete response, clinical complete response, major pathological response, R0 resection rate, surgical conversion rate, and safety of the treatment, including immune-related adverse events (irAEs) and surgical complications. The study cohort comprised 39 patients (28 men and 11 women) of median age 62 (range 44-79) years. After the above-described preoperative treatment, radical resection of the 14 tumors that were initially considered unresectable was achieved (surgical conversion rate: 14/14). Twenty-three of the remaining 25 patients underwent radical resection. The last two patients achieved clinical complete responses and opted for a "non-surgical strategy" (watch and wait). Overall, 37 patients (94.9%) underwent radical resection, with an R0 resection rate of 100% (37/37), pathological complete response rate of 48.6% (18/37), and major pathological response rate of 62.2% (23/37). Of the 24 patients with CPS ≥ 5 (non-MSI-H/dMMR and non-EBER positive), 11 achieved pathological complete responses and one with CPS=95 achieved a clinical complete response. Of the eight patients with MSI-H/dMMR, six achieved pathological complete responses and one a clinical complete response. Of the seven patients with EBER positivity, one achieved a pathological complete response. After excluding patients with major pathological complete responses, there was a statistically significant difference in CPS scores between preoperative biopsy specimens and postoperative surgical specimens in 13 patients (7.769±5.570 vs. 15.538±16.870, =2.287, =0.041). All patients tolerated preoperative immunotherapy well; nine patients (9/39, 23.1%) had Grade I-II irAEs. There were no Grade III-IV irAEs. The five patients with pyloric obstruction before treatment tolerated normal diets after treatment. The incidence of postoperative complications among all patients who underwent surgery was 18.9% (7/37), including one case of Grade IIIA anastomotic leakage, one of Grade IIIA intestinal obstruction, one of Grade II abdominal hemorrhage, two of Grade II abdominal infection, one of Grade I intestinal obstruction. Additionally, one patient developed COVID-19 postoperatively. All patients recovered with symptomatic treatment. We found that preoperative treatment of patients with LAGC or AEG of one of three types (CPS≥5, dMMR+MSI-H, and EBER positivity) with a PD-1 inhibitor combined with CapeOx or SOX chemotherapy achieved promising effectiveness and safety, with high surgical conversion, R0 resection, and complete response rates.
评估程序性细胞死亡蛋白1（PD-1）抑制剂与奥沙利铂+卡培他滨（CapeOx）或奥沙利铂+替吉奥（SOX）术前联合应用于局部晚期免疫治疗敏感型胃癌（LAGC）或食管胃交界腺癌（AEG）的短期疗效和安全性。本回顾性描述性病例系列研究队列包括2021年8月1日至2024年1月31日期间在北京肿瘤医院暨研究所胃肠肿瘤中心三区接受治疗前经内镜活检确定癌症对免疫治疗敏感的LAGC或AEG患者。具有以下三种特征之一的患者为免疫治疗敏感型：（i）PD-L1联合阳性评分（CPS）≥5；（ii）微卫星高度不稳定（MSI-H）/错配修复缺陷（dMMR）；或（iii）爱泼斯坦-巴尔病毒编码RNA（EBER）阳性。所有研究患者在手术前接受PD-1抑制剂联合CapeOx或SOX作为新辅助或转化治疗策略。排除患有免疫系统疾病、远处转移或人表皮生长因子受体2阳性的患者。分析的因素包括病理完全缓解、临床完全缓解、主要病理缓解、R0切除率、手术转化率以及治疗的安全性，包括免疫相关不良事件（irAEs）和手术并发症。研究队列包括39例患者（28例男性和11例女性），中位年龄62岁（范围44 - 79岁）。经过上述术前治疗，最初被认为无法切除的14个肿瘤实现了根治性切除（手术转化率：14/14）。其余25例患者中的23例接受了根治性切除。最后2例患者达到临床完全缓解并选择了“非手术策略”（观察等待）。总体而言，37例患者（94.9%）接受了根治性切除，R0切除率为100%（37/37），病理完全缓解率为48.6%（18/37），主要病理缓解率为62.2%（23/37）。在24例CPS≥5（非MSI-H/dMMR且非EBER阳性）的患者中，11例实现了病理完全缓解，1例CPS = 95的患者实现了临床完全缓解。在8例MSI-H/dMMR患者中，6例实现了病理完全缓解，1例实现了临床完全缓解。在7例EBER阳性患者中，1例实现了病理完全缓解。排除主要病理完全缓解的患者后，13例患者术前活检标本与术后手术标本的CPS评分存在统计学显著差异（7.769±5.570 vs. 15.538±16.870，t = 2.287，P = 0.041）。所有患者对术前免疫治疗耐受性良好；9例患者（9/39，23.1%）出现I-II级irAEs。无III-IV级irAEs。治疗前有幽门梗阻的5例患者治疗后能耐受正常饮食。所有接受手术的患者术后并发症发生率为18.9%（7/37），包括1例IIIA级吻合口漏、1例IIIA级肠梗阻、1例II级腹腔出血、2例II级腹腔感染、1例I级肠梗阻。此外，1例患者术后发生新型冠状病毒肺炎。所有患者经对症治疗后康复。我们发现，术前用PD-1抑制剂联合CapeOx或SOX化疗治疗三种类型（CPS≥5、dMMR + MSI-H和EBER阳性）之一的LAGC或AEG患者，取得了有前景的疗效和安全性，手术转化率、R0切除率和完全缓解率均较高。
