Abstract:

Objective To explore the clinical efficacy and safety of a multimodal treatment regimen integrating radiotherapy，chemotherapy，and immunotherapy in patients with human epidermal growth factor receptor 2 （HER2）-negative locally advanced or advanced gastric cancer. Methods A total of 34 patients with unresectable，HER2-negative，locally advanced or metastatic gastric/gastroesophageal junction （G/GEJ） adenocarcinoma admitted to the Affiliated Cancer Hospital of Guizhou Medical University from September 2021 to March 2024 were selected as study objects. Participants received one cycle of either XELOX regimen （capecitabine + oxaliplatin） or SOX regimen （S-1 + oxaliplatin） with immunotherapy （sintilimab or nivolumab）. The process was succeeded by radiotherapy targeted at the primary G/GEJ tumor and regional lymph nodes. In selected cases，sequential radiotherapy was also administered for distant metastases. The primary endpoint was Objective response rate （ORR），and secondary endpoints were disease control rate （DCR），clinical symptom response，changes in Karnofsky performance status （KPS） score，progression-free survival （PFS），and adverse reactions. Clinical efficacy was assessed in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. Adverse reactions were assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and the Chinese Society of Clinical Oncology guidelines for management of immune checkpoint inhibitor-related toxicity. With a median follow-up of 7 months （range：2.3 to 30 months），the final evaluation considered the best response documented throughout follow-up. Survival curves were constructed utilizing Kaplan-Meier analysis. Results By the end of follow-up，an overall ORR of 58.8% （20/34） and DCR of 70.6% （24/34） were observed. The ORR of lesions by radiotherapy reached 73.8% （48/65） and the DCR reached 92.3% （60/65）. Univariate analysis showed that the ORR of female patients （84.6%，11/13） was higher than that of male patients （42.9%，9/21），and the ORR of patients with distant lymph node metastasis alone （83.3%，15/18） was higher than that of patients with distant lymph node metastasis combined with organ metastasis or organ metastasis alone （18.2%，2/11），with statistically significant differences （P=0.030； P=0.010）. There were no statistically significant differences in ORR among patients with different age （P=0.487），KPS score （P=0.198），primary tumor location （P=0.280），histological differentiation （P=0.668），chemotherapy regimen （P=0.728），or immunotherapy regimen （P>0.999）. Twenty-two of 23 （95.7%） patients with upper abdominal pain were relieved，10 of 21 （47.6%） patients with appetite loss were relieved，15 of 17 patients with upper abdominal distension were relieved，13 of 14 patients with melena were relieved，6 of 7 patients with eating obstruction were relieved，3 of 4 patients with metastatic site pain were relieved，and 2 patients with hematemesis were relieved. KPS score enhanced in 82.4% （28/34） of patients，remained stable in 11.8% （4/34），and declined in 5.8% （2/34）. The median PFS of the 34 patients was 7.9 months. The most common adverse reactions during radiotherapy combined with chemotherapy and immunotherapy were hematological adverse reactions，in which neutropenia accounted for the highest proportion （91.2%，31/34），followed by anemia （50.0%，17/34）. Fatigue was the most common non-hematological adverse reaction （50.0%，17/34），followed by nausea and vomiting （26.5%，9/34）. The adverse reactions of 6 patients receiving immune monotherapy maintenance were anemia，hypothyroidism，transaminase elevation，proteinuria，fatigue，and rash，all of which were grade 1-2. Conclusions Radiotherapy combined with chemotherapy and immunotherapy shows good short-term clinical efficacy in patients with HER2-negative locally advanced or advanced gastric cancer，and the overall adverse reactions are tolerable. Female or patients with distant lymph node metastasis alone may be the preferred population for this study protocol.

Key words: Stomach neoplasms, Chemoradiotherapy, Immunotherapy, Drug-related side effects and adverse reactions, Short-term efficacy