派安普利单抗联合安罗替尼和化疗围手术期治疗局部进展期胃癌的探索性研究

doi:10.19401/j.cnki.1007-3639.2024.07.005

摘要/Abstract

摘要：

背景与目的：局部进展期胃癌（locally advanced gastric cancer，LAGC）的围手术期治疗已达成共识，但如何选择一种高效、安全的治疗方案仍有很多争议，既往已有相关研究证实了化疗联合免疫检查点抑制剂（immune checkpoint inhibitor，ICI）、化疗联合抗血管生成药物在LAGC围手术期治疗中的有效性，因此，本研究旨在探讨ICI联合抗血管生成药物和化疗的围手术期治疗方案，以期为LAGC患者的围手术期治疗方案的选择提供更多参考。方法：本研究为前瞻性、单臂探索性研究，旨在评估派安普利单抗联合安罗替尼和化疗围手术期治疗潜在可切除的T3 ~ 4N+M0期LAGC的有效性和安全性，选择2022年1月—2023年12月就诊于内蒙古自治区人民医院的LAGC患者作为研究对象，设置主要研究终点为病理学完全缓解（pathological complete response，pCR）率和主要病理学缓解（main pathological remission，MPR）率，次要研究终点为手术转化率、客观缓解率（objective response rate，ORR）、无病生存期（disease-free survival，DFS）、无进展生存期（progression-free survival，PFS）和不良反应等，根据欧洲癌症治疗研究组织（European Organization for Research on Treatment of Cancer，EORTC）QLQ-STO22中文版量表评估患者接受治疗前后的生活质量。本研究经内蒙古自治区人民医院伦理委员会审查批准（编号：202404604L）。结果：共有32例患者参与本研究，ORR为78.1%（25/32），其中18例患者接受了手术治疗，pCR率为22.2%（4/18），MPR率为38.9%（7/18），未行手术的患者的中位PFS为9.8个月（95% CI：7.6 ~ 13.1），中位随访时间为16.4个月（95% CI：11.7 ~ 22.5）。对于行根治性手术切除的患者，中位DFS未达到，1年DFS率为88.8%（16/18）。治疗后常见的不良反应包括骨髓抑制、肝功能异常、腹泻及神经毒性，大多数不良反应为1 ~ 2级，少数为3级，未发生4 ~ 5级不良反应。根据EORTC QLQ-STO22中文版量表评估发现，在吞咽困难、疼痛及进食受限领域有明显改善，同时，在焦虑、反流症状领域也所好转，在躯体形象领域改善不明显。结论：在LAGC围手术期治疗中，奥沙利铂＋替吉奥＋安罗替尼＋派安普利单抗的联合治疗方案，在保证安全性的同时，能够提高疗效，有望成为LAGC新的治疗方式。

关键词: 局部进展期胃癌, 围手术期治疗, 免疫治疗, 抗血管生成治疗, 疗效评价, 生活质量评估

Abstract:

Background and purpose: There is a consensus within the medical community regarding the perioperative treatment of locally advanced gastric cancer (LAGC), yet the selection of an efficient and safe treatment strategy remains a contentious issue. Previous studies have validated the effectiveness of chemotherapy in conjunction with immune checkpoint inhibitor (ICI) and anti-angiogenic agents in the perioperative treatment of LAGC. This study aimed to investigate the perioperative treatment regimen combining ICI, anti-angiogenic drugs and chemotherapy, in order to provide additional references for the selection of perioperative treatment strategies for patients with LAGC. Methods: This was a prospective, single-arm exploratory study designed to assess the efficacy and safety of perioperative treatment with penpulimab combined with anlotinib and chemotherapy for potentially resectable stage T3-4N+M0 LAGC. Patients diagnosed with LAGC at the Inner Mongolia Autonomous Region People’s Hospital from January 2022 to December 2023 were enrolled in the study. The primary endpoints were pathological complete response (pCR) rate and major pathological remission (MPR) rate, while secondary endpoints included surgical conversion rate, objective response rate (ORR), disease-free survival (DFS), progression-free survival (PFS) and adverse reactions. Quality of life before and after treatment was evaluated using the European Organization for Research on Treatment of Cancer (EORTC) QLQ-STO22 Chinese version questionnaire. This study was reviewed and approved by the Ethics Committee of Inner Mongolia Autonomous Region People’s Hospital (number: 202404604L). Results: A total of 32 patients participated in the study, with an ORR of 78.1% (25/32). Of these, 18 patients underwent surgical treatment, achieving a pCR rate of 22.2% (4/18) and a MPR rate of 38.9% (7/18). The median PFS for patients who did not undergo surgery was 9.8 months (95% CI: 7.6-13.1), and the median follow-up duration was 16.4 months (95% CI: 11.7-22.5). For patients who received radical surgical resection, the median DFS was not reached, and the 1-year DFS rate was 88.8% (16/18). Common adverse reactions following the treatment included myelosuppression, liver function abnormalities, diarrhea and neurotoxicity, with most adverse events being grade 1-2, a few grade 3 adverse events, and no grade 4 or 5 adverse events. According to the EORTC QLQ-STO22 Chinese version questionnaire, significant improvements were observed in the domains of difficulty swallowing, pain and eating restrictions. Additionally, improvements were noted in anxiety and reflux symptoms, while changes in body image were less pronounced. Conclusion: In the perioperative treatment of LAGC, the combination therapy of oxaliplatin, tegafur, anlotinib and penpulimab can improve the efficacy while ensuring safety, and is expected to become a new treatment for LAGC.

Key words: Locally advanced gastric cancer, Perioperative treatment, Immunotherapy, Anti-angiogenic therapy, Efficacy evaluation, Quality of life assessment

中图分类号:

R735.2

刘帅, 张凯, 张晓青, 栾巍. 派安普利单抗联合安罗替尼和化疗围手术期治疗局部进展期胃癌的探索性研究[J]. 中国癌症杂志, 2024, 34(7): 659-668.

LIU Shuai, ZHANG Kai, ZHANG Xiaoqing, LUAN Wei. An exploratory study on the perioperative treatment of locally advanced gastric cancer with combination of penpulimab, anlotinib and chemotherapy[J]. China Oncology, 2024, 34(7): 659-668.

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Number	Preoperative staging	Complication	Postoperative staging	Follow-up time
1	T3N2M0	No	ypT0N0M0	15
2	T4N1M0	Yes	ypT2N1M0	9
3	T3N1M0	No	ypT3N0M0	16
4	T4NxM0	No	ypT3N1M0	14
5	T3N2M0	No	ypT2N0M0	10
6	T4N1M0	Yes	ypT1N1M0	18
7	T3NxM0	No	ypT1N0M0	12
8	T4N1M0	No	ypT0N0M0	11
9	T3NxM0	No	ypT1N0M0	13
10	T4N1M0	Yes	ypT3N0M0	11
11	T3N2M0	No	ypT0N0M0	17
12	T4N2M0	No	ypT2N1M0	11
13	T4N1M0	Yes	ypT3N0M0	13
14	T4NxM0	No	ypT1N1M0	8
15	T3N2M0	Yes	ypT2N0M0	16
16	T4N1M0	No	ypT1N1M0	12
17	T3NxM0	No	ypT1N0M0	15
18	T4NxM0	No	ypT0N0M0	11

Treatment-related adverse reaction	Case n (%)
Reduced neutrophil count	12 (37.5)
Decreased white blood cell count	10 (31.2)
Reduced platelet count	8 (25.0)
Decreased lymphocyte count	4 (12.5)
Elevated aspartate aminotransferase	10 (31.2)
Elevated alanine aminotransferase	8 (25.0)
Elevated glutamyltransferase	8 (25.0)
Elevated blood bilirubin	4 (12.5)
Elevated blood alkaline phosphatase	6 (18.7)
Hypothyroidism	2 (6.25)
Hyperthyroidism	2 (6.25)
Elevated blood lactate dehydrogenase	8 (25.0)
Abnormal cardiac troponin	8 (25.0)
Elevated brain natriuretic peptide	10 (31.2)
Hypertension	8 (25.0)
Abnormal bleeding	4 (12.5)
Proteinuria	6 (18.7)
Rash	10 (31.2)
Diarrhea	8 (25.0)

Field	Before treatment	After treatment	t value	P value
Field of dysphagia	27.3±12.2	16.3±7.2	4.28	0.001
Field of pain	40.1±18.2	28.4±10.1	4.32	0.001
Field of reflux symptoms	24.7±11.2	14.3±6.2	3.67	0.015
Field of eating restrictions	38.4±16.4	25.9±10.7	4.11	0.001
Field of anxiety	46.4±17.3	29.3±9.7	4.54	0.001
Oral dryness	24.8±10.5	17.3±6.3	3.17	0.048
Altered taste	20.4±9.3	14.6±5.5	2.76	0.024
Body image	24.7±10.2	16.7±6.8	1.98	0.126
Hair loss	26.17±10.6	17.2±8.3	2.12	0.018