Gastric Cancer (GC)BNIHGCNCT07622693
Beta-Blockers on Neoadjuvant Immunochemotherapy for Hypertensive Patients With Gastric Cancer
An observational study of Gastric Cancer (GC), run by Nanfang Hospital, Southern Medical University at 1 site in China.
Trial summary
Study Population: Patients with locally advanced gastric cancer complicated by primary hypertension, who received neoadjuvant immunochemotherapy followed by curative gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025. Read more about this study
- Who is it for?
- Ages 18 to 85 years
- Conditions the study is for
- Gastric Cancer (GC)
- How many people
- 80 participants
- Where
- 1 siteChina
- Study dates
- 10 May 2026to 31 Dec 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: This study population consists of patients with locally advanced gastric adenocarcinoma complicated by primary hypertension, who received neoadjuvant immunochemotherapy followed by curative laparoscopic gastrectomy.
Who may be able to join
- Aged between 18 and 85 years;
- No restriction on gender;
- Patients with a standardized histopathological diagnosis of gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017);
- Patients who received neoadjuvant immunochemotherapy followed by curative gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025.
Who cannot join
- Pregnant or breastfeeding women;
- Severe psychiatric disorders;
- Previous history of chemotherapy, radiotherapy, or targeted therapy prior to study treatment;
- History of other malignant tumors within the past 5 years;
- dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
- Active infection, active or refractory autoimmune disease, or uncontrolled systemic disease;
- Patients judged by the investigator to be unsuitable for participation in this study.
Trial locations and contacts
1 site in 1 country.
China1 site
Nanfang Hospital, Southern Medical University
Guangzhou, Guangdong, 510515
About this study
Official title: Beta-blockers Combined With Neoadjuvant Immunochemotherapy Significantly Improve Pathological Remission in Locally Advanced Gastric Cancer: a Multicenter Controlled Study Based on Hypertensive Patients
Study Population: Patients with locally advanced gastric cancer complicated by primary hypertension, who received neoadjuvant immunochemotherapy followed by curative gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025.
Primary Objective: To investigate the impact of beta-blocker use versus non-beta-blocker antihypertensive agents on the efficacy of neoadjuvant immunochemotherapy in patients with locally advanced gastric cancer and hypertension.
Read more
Secondary Objective: To investigate the impact of beta-blocker use versus non-beta-blocker antihypertensive agents on the incidence of immune-related adverse events (irAEs).
Study Groups: Patients are divided into two groups based on antihypertensive medication use during immunotherapy: the exposed group (patients continuously using beta-blockers during neoadjuvant immunochemotherapy) and the control group (patients continuously receiving non-beta-blocker antihypertensive agents, including ACEI/ARB, CCB, or diuretics, during the same period).
Study Design: This is a multicenter, retrospective, observational cohort study.
Study Duration: May 2026 - December 2026
Sample Size: A total of 80 eligible patients are planned for inclusion, with 40 patients in the beta-blocker exposed group and 40 patients in the non-beta-blocker control group.
Inclusion Criteria:
- Voluntarily provided informed consent for data use;
- Age between 18 and 85 years;
- No restriction on gender;
- Histopathologically confirmed gastric adenocarcinoma from the primary lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017);
- Received neoadjuvant immunochemotherapy followed by curative gastrectomy between April 2021 and December 2025.
Exclusion Criteria:
- Pregnant or breastfeeding women;
- Severe psychiatric disorders;
- Previous history of chemotherapy, radiotherapy, or targeted therapy;
- History of other malignant tumors within the past 5 years;
- dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
- Active infection, active/refractory autoimmune disease, or uncontrolled systemic disease;
- Patients judged by the investigator to be unsuitable for participation in this study.
Read the detailed description
- Research Background 1.1 Disease Burden of Gastric Cancer, Hypertension Comorbidity and Treatment Challenges Gastric carcinoma (GC) is one of the most common malignant tumors worldwide, ranking fifth in incidence and fourth in mortality globally. A large proportion of GC patients in China are diagnosed at an advanced stage, leading to short survival and poor quality of life. Notably, hypertension is one of the most prevalent comorbidities in advanced GC patients, with clinical data showing that approximately 30%-40% of such patients have primary hypertension. These patients not only face difficulties in blood pressure control due to excessive sympathetic nervous system activation, but also suffer from a deteriorated tumor microenvironment caused by abnormal neuro-immune crosstalk. In recent years, immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) have brought new hope for advanced GC treatment by relieving tumor-induced immune suppression and activating the body's anti-tumor immune response, demonstrating significant efficacy in a subset of patients. However, only 10%-15% of GC patients achieve long-term benefits from current immunotherapy, and the response rate may be even lower in patients with hypertension due to sympathetic activation. Most patients still develop primary or acquired resistance. This low response rate has driven research into combination strategies to enhance immunotherapy efficacy, and the potential immunomodulatory effects of beta-blockers (BBs), a commonly used antihypertensive drug, have become a research focus. 1.2 Core Role of Sympathetic Nervous System Regulation in the Tumor Microenvironment and the Impact of Hypertension With advances in tumor immunology, the immunosuppressive role of the sympathetic nervous system in the tumor microenvironment has been gradually revealed. In GC patients with hypertension, persistent excessive sympathetic activation caused by long-term abnormal blood pressure releases large amounts of catecholamine neurotransmitters (mainly norepinephrine), forming a tumor immunosuppressive cycle that critically impairs immunotherapy efficacy. Basic research has confirmed that norepinephrine participates in tumor immune escape by binding to β-adrenergic receptors (ADRBs, especially the ADRB1 subtype) on immune cells. A 2024 study published in *Nature* by the Salk Institute revealed that exhausted CD8⁺ cytotoxic T cells highly express ADRB1, making them highly sensitive to norepinephrine, which inhibits T cell proliferation and reduces effector molecule secretion, ultimately leading to T cell exhaustion. A landmark study in *Science* further elucidated this mechanism: norepinephrine activates the cAMP/PKA signaling pathway through ADRB1, inducing high expression of exhaustion markers such as PD-1 and TIM-3 on T cells and weakening anti-tumor immune responses. Beta-blockers can competitively block ADRB1 and reverse T cell exhaustion, providing direct mechanistic support for their combination with immunotherapy. In addition, the nerve density in gastric cancer tissues is significantly higher than that in normal tissues, and increased catecholamine release in patients with hypertension further enhances ADRB-mediated immunosuppression and exacerbates T cell exhaustion, laying an important theoretical foundation for targeting the β-receptor pathway. 1.3 Anti-Tumor Mechanisms, Clinical Evidence of Beta-Blockers and Research Gaps As classic cardiovascular drugs, beta-blockers are mainly used for the treatment of primary hypertension. By blocking β-adrenergic receptors to inhibit excessive catecholamine signaling, they not only control blood pressure but also exert potential anti-tumor effects by regulating immunosuppressive pathways in the tumor microenvironment. Numerous basic experiments and clinical studies have verified the anti-tumor activity of BBs: non-selective beta-blockers can inhibit the proliferation of gastric cancer cells and induce apoptosis in animal models; catecholamines released by host sympathetic activation can suppress CD8⁺ T cell activity via ADRB-mediated cAMP/PKA signaling, while BBs can enhance the efficacy of PD-1 inhibitors by upregulating PD-L1 expression on tumor-associated macrophages and blocking the synergistic inhibitory signals of the LRRC33/TGFβ1 axis and PD-1. In head and neck squamous cell carcinoma and non-small cell lung cancer, the combination of BBs and immunotherapy can improve patient survival, but relevant clinical data in gastric cancer remain limited. Our team previously enrolled 25 eligible patients from 5 hospitals across China, all of whom underwent radical resection. The distribution of postoperative pathological tumor regression grade (TRG) was as follows: TRG 0 in 10 patients (40%), TRG 1 in 4 patients (16%), TRG 2 in 11 patients (44%), and TRG 3 in 0 patients. The proportion of TRG 0/1 (pathological complete or near-complete response) was 56% (14/25), comparable to the immunotherapy plus chemotherapy group of the NEOSUMMIT-01 study; the proportion of TRG 3 (pathological non-response) was 0, significantly lower than the same group of the NEOSUMMIT-01 study. No serious beta-blocker-related adverse events were observed during treatment in the cohort. Based on the above research background and unresolved questions, this study intends to use a nationwide multicenter retrospective cohort data of advanced GC patients with primary hypertension, compare the efficacy of beta-blockers versus non-beta-blocker antihypertensive agents during immunotherapy, and systematically evaluate the unique synergistic effect of beta-blockers. This study aims to provide high-level evidence for combination immunotherapy strategies in GC patients with hypertension, and promote the development of neuro-immuno-oncology in gastric cancer, opening a new avenue to improve the prognosis of this special patient population.
- Study Objectives 2.1 Primary Objective To investigate the impact of combined use of beta-blockers (compared with non-beta-blocker antihypertensive agents) on the efficacy of immunotherapy in patients with advanced gastric cancer complicated by primary hypertension. 2.2 Secondary Objective To investigate the impact of combined use of beta-blockers (compared with non-beta-blocker antihypertensive agents) on the incidence of immune-related adverse events (irAEs).
- Study Design This is a retrospective, multicenter, observational study. Eligible gastric cancer patients with primary hypertension who received neoadjuvant chemoradiotherapy combined with immunotherapy followed by gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025, with complete follow-up data, will be enrolled. Patients will be divided into an exposed group and a non-exposed group according to the use of beta-blockers antihypertensive drugs during immunotherapy:
- Exposed group: Patients who continuously used beta-blockers during neoadjuvant immunochemotherapy
- Control group: Patients who continuously received non-beta-blocker antihypertensive agents (e.g., ACEI/ARB/CCB, diuretics, observation) during the same period Propensity score matching (PSM) will be used to control baseline confounding factors, including age, metastatic burden, CPS score, number of immunotherapy cycles, and hypertension grade. No randomization or study protocol-driven treatment will be administered to participants. All treatment decisions and regimens will be determined by the treating physician based on clinical indications.
- Study Population The study population consists of patients with locally advanced gastric cancer complicated by hypertension who are scheduled to undergo laparoscopic gastrectomy after immunotherapy. 4.1 Diagnostic Criteria
- Gastric cancer diagnosed in accordance with the 15th edition of the Japanese Classification of Gastric Carcinoma (2017)
- Hypertension diagnosed in accordance with the Chinese Guidelines for the Prevention and Treatment of Hypertension 2023 (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg)
- Inclusion and Exclusion Criteria 5.1 Inclusion Criteria
- Age 18-85 years
- No gender restriction
- Histopathologically confirmed gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma(2017)
- Patients who received neoadjuvant immunochemotherapy followed by gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025 5.2 Exclusion Criteria
- Pregnant or breastfeeding women
- Severe psychiatric disorders
- Previous history of chemotherapy, radiotherapy, or targeted therapy
- History of other malignant tumors within the past 5 years
- dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
- Active infection, active or refractory autoimmune disease, or uncontrolled systemic disease
- Patients judged by the investigator to be unsuitable for this study
- Sample Size This study is designed as an observational study. A total of 80 eligible patients admitted to the Department of Gastrointestinal Surgery at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025 will be enrolled, with 40 patients in each of the beta-blocker exposed group and the non-exposed group.
- Data Collection Procedures Data collection will be conducted in three phases: 7.1 Baseline Phase (First Patient Visit)
- Demographic data: gender, age, patient initials
- Medical history and physical examination: height, weight, BMI, underlying diseases, ID number, hospital record number, operation date 7.2 Routine Diagnosis and Treatment Phase
- Laboratory test results: pathological tumor stage, pathological type, histological type, tumor size, tumor location, pathological TRG grade, immunotherapy-related immunohistochemical indicators (CPS, EBER, HER2, PMS2, MLH1, MSH2, MSH6)
- Imaging findings: abdominal computed tomography (CT)
- Antihypertensive medication data: start time, duration, type and dosage of beta-blockers and non-beta-blocker antihypertensive agents 7.3 Follow-up Phase A 3-year telephone follow-up will be performed once a year to record overall survival (OS) and recurrence-free survival (RFS).
- Ethical Considerations This study is conducted in compliance with the Declaration of Helsinki and relevant ethical regulations. All data will be anonymized to protect patient privacy, and no additional interventions or risks will be introduced to participants due to the retrospective observational design.
- Conditions
- Gastric Cancer (GC)
- Keywords
- Gastric Cancer, Immunotherapy, Beta-Blockers, Pathological regression
- Medical subject headings
- Stomach Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Beta-blocker exposed group | Patients with locally advanced gastric cancer complicated by primary hypertension, who continuously received beta-blockers (e.g., metoprolol, bisoprolol) for antihypertensive treatment during neoadjuvant immunochemotherapy, followed by curative gastrectomy. | |
| Non-beta-blocker control group | Patients with locally advanced gastric cancer complicated by primary hypertension, who continuously received non-beta-blocker antihypertensive agents (e.g., ACEI/ARB, CCB, diuretics) for blood pressure control during neoadjuvant immunochemotherapy, with no exposure to beta-blockers, followed by curative gastrectomy. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pathological response of MPR
Major pathological response (MPR) is defined as the proportion of patients with ≤10% residual viable tumor cells in the surgically resected primary tumor following neoadjuvant therapy. MPR is assessed on the surgical specimen obtained approximately 1 week after completion of preoperative treatment. Pathological evaluation is performed according to standardized tumor regression grading (TRG) systems, with MPR corresponding to TRG 0-1 per AJCC 8th edition criteria (i.e., complete response or minimal residual disease). This endpoint will be reported descriptively with point estimate and 95% confidence interval.
Measured: From completion of neoadjuvant therapy to surgical resection; assessed on postoperative pathological specimen approximately 1 week after surgery, up to 4 months after study treatment initiation.
Secondary outcomes (6)
Pathological Complete Response (pCR) Rate
Pathological complete response (pCR) is defined as the proportion of patients with no viable tumor cells remaining in the primary tumor bed and lymph nodes (TRG 0, ypT0N0) on postoperative pathological specimens, evaluated per AJCC 8th edition criteria.
Measured: Assessed on postoperative pathological specimens, approximately 1 week after surgical resection (within 4 months after completion of neoadjuvant immunochemotherapy).
Pathological Non-Response (TRG 3) Rate
Pathological non-response is defined as the proportion of patients with Tumor Regression Grade (TRG) 3 (>50% residual viable tumor cells in the primary tumor bed) on postoperative pathological specimens, evaluated per AJCC 8th edition criteria.
Measured: Assessed on postoperative pathological specimens, approximately 1 week after surgical resection (within 4 months after completion of neoadjuvant immunochemotherapy)
Objective Response Rate (ORR)
Objective response rate (ORR) is defined as the proportion of patients achieving complete response (CR) or partial response (PR) on pre-surgical imaging (CT/MRI), evaluated per RECIST 1.1 criteria.
Measured: Assessed on pre-surgical imaging, within 1 week before surgery (approximately 3 months after initiation of neoadjuvant immunochemotherapy)
3-Year Progression-Free Survival (PFS)
Progression-free survival (PFS) is defined as the time from the date of surgical resection to the date of disease recurrence (local recurrence, regional lymph node recurrence, or distant metastasis) or death from any cause, whichever occurs first.
Measured: Assessed at 3 years after surgical resection, with annual follow-up
3-Year Overall Survival (OS)
Overall survival (OS) is defined as the time from the date of surgical resection to death from any cause.
Measured: Assessed at 3 years after surgical resection, with annual follow-up
Incidence of Immune-Related Adverse Events (irAEs)
The incidence of immune-related adverse events (irAEs) during neoadjuvant immunochemotherapy, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measured: From initiation of neoadjuvant immunochemotherapy to 30 days after completion of the last treatment cycle
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jun 2026
- Study start10 May 2026
- Primary completion31 Oct 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Gastric Cancer (GC)Studies of the same condition, open and under way.
- More trials run by Nanfang Hospital, Southern Medical UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Nanfang Hospital, Southern Medical University
- Sponsor type
- University, hospital or other
- Collaborators
- The First Affiliated Hospital of Xiamen University, The First Medical Center of Chinese PLA General Hospital, Peking University Shenzhen Hospital, First Affiliated Hospital Xi'an Jiaotong University, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07622693
- Sponsor's protocol ID
- NFEC-2026-285
- Acronym
- BNIHGC
- Status last verified
- May 2026
- First submitted
- 28 May 2026
- Last updated
- 3 Jun 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Multicenter retrospective study; patient informed consent does not include provisions for sharing individual participant data, and data sharing is restricted by institutional privacy policies.
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Beta-blockers Combined With Neoadjuvant Immunochemotherapy Significantly Improve Pathological Remission in Locally Advanced Gastric Cancer: a Multicenter Controlled Study Based on Hypertensive Patients
- ClinicalTrials.gov ID
- NCT07622693
- Acronym / sponsor ID
- BNIHGC / NFEC-2026-285
- Conditions
- Gastric Cancer (GC)
- Keywords
- Gastric Cancer, Immunotherapy, Beta-Blockers, Pathological regression
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Nanfang Hospital, Southern Medical UniversityUniversity, hospital or other
- Collaborators
- The First Affiliated Hospital of Xiamen University, The First Medical Center of Chinese PLA General Hospital, Peking University Shenzhen Hospital, First Affiliated Hospital Xi'an Jiaotong University, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
- Study start
- 10 May 2026 (actual)
- Primary completion
- 31 Oct 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 3 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Study Population: Patients with locally advanced gastric cancer complicated by primary hypertension, who received neoadjuvant immunochemotherapy followed by curative gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025.
Primary Objective: To investigate the impact of beta-blocker use versus non-beta-blocker antihypertensive agents on the efficacy of neoadjuvant immunochemotherapy in patients with locally advanced gastric cancer and hypertension.
Secondary Objective: To investigate the impact of beta-blocker use versus non-beta-blocker antihypertensive agents on the incidence of immune-related adverse events (irAEs).
Study Groups: Patients are divided into two groups based on antihypertensive medication use during immunotherapy: the exposed group (patients continuously using beta-blockers during neoadjuvant immunochemotherapy) and the control group (patients continuously receiving non-beta-blocker antihypertensive agents, including ACEI/ARB, CCB, or diuretics, during the same period).
Study Design: This is a multicenter, retrospective, observational cohort study.
Study Duration: May 2026 - December 2026
Sample Size: A total of 80 eligible patients are planned for inclusion, with 40 patients in the beta-blocker exposed group and 40 patients in the non-beta-blocker control group.
Inclusion Criteria:
- Voluntarily provided informed consent for data use;
- Age between 18 and 85 years;
- No restriction on gender;
- Histopathologically confirmed gastric adenocarcinoma from the primary lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017);
- Received neoadjuvant immunochemotherapy followed by curative gastrectomy between April 2021 and December 2025.
Exclusion Criteria:
- Pregnant or breastfeeding women;
- Severe psychiatric disorders;
- Previous history of chemotherapy, radiotherapy, or targeted therapy;
- History of other malignant tumors within the past 5 years;
- dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
- Active infection, active/refractory autoimmune disease, or uncontrolled systemic disease;
- Patients judged by the investigator to be unsuitable for participation in this study.
Detailed description
- Research Background 1.1 Disease Burden of Gastric Cancer, Hypertension Comorbidity and Treatment Challenges Gastric carcinoma (GC) is one of the most common malignant tumors worldwide, ranking fifth in incidence and fourth in mortality globally. A large proportion of GC patients in China are diagnosed at an advanced stage, leading to short survival and poor quality of life. Notably, hypertension is one of the most prevalent comorbidities in advanced GC patients, with clinical data showing that approximately 30%-40% of such patients have primary hypertension. These patients not only face difficulties in blood pressure control due to excessive sympathetic nervous system activation, but also suffer from a deteriorated tumor microenvironment caused by abnormal neuro-immune crosstalk. In recent years, immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) have brought new hope for advanced GC treatment by relieving tumor-induced immune suppression and activating the body's anti-tumor immune response, demonstrating significant efficacy in a subset of patients. However, only 10%-15% of GC patients achieve long-term benefits from current immunotherapy, and the response rate may be even lower in patients with hypertension due to sympathetic activation. Most patients still develop primary or acquired resistance. This low response rate has driven research into combination strategies to enhance immunotherapy efficacy, and the potential immunomodulatory effects of beta-blockers (BBs), a commonly used antihypertensive drug, have become a research focus. 1.2 Core Role of Sympathetic Nervous System Regulation in the Tumor Microenvironment and the Impact of Hypertension With advances in tumor immunology, the immunosuppressive role of the sympathetic nervous system in the tumor microenvironment has been gradually revealed. In GC patients with hypertension, persistent excessive sympathetic activation caused by long-term abnormal blood pressure releases large amounts of catecholamine neurotransmitters (mainly norepinephrine), forming a tumor immunosuppressive cycle that critically impairs immunotherapy efficacy. Basic research has confirmed that norepinephrine participates in tumor immune escape by binding to β-adrenergic receptors (ADRBs, especially the ADRB1 subtype) on immune cells. A 2024 study published in *Nature* by the Salk Institute revealed that exhausted CD8⁺ cytotoxic T cells highly express ADRB1, making them highly sensitive to norepinephrine, which inhibits T cell proliferation and reduces effector molecule secretion, ultimately leading to T cell exhaustion. A landmark study in *Science* further elucidated this mechanism: norepinephrine activates the cAMP/PKA signaling pathway through ADRB1, inducing high expression of exhaustion markers such as PD-1 and TIM-3 on T cells and weakening anti-tumor immune responses. Beta-blockers can competitively block ADRB1 and reverse T cell exhaustion, providing direct mechanistic support for their combination with immunotherapy. In addition, the nerve density in gastric cancer tissues is significantly higher than that in normal tissues, and increased catecholamine release in patients with hypertension further enhances ADRB-mediated immunosuppression and exacerbates T cell exhaustion, laying an important theoretical foundation for targeting the β-receptor pathway. 1.3 Anti-Tumor Mechanisms, Clinical Evidence of Beta-Blockers and Research Gaps As classic cardiovascular drugs, beta-blockers are mainly used for the treatment of primary hypertension. By blocking β-adrenergic receptors to inhibit excessive catecholamine signaling, they not only control blood pressure but also exert potential anti-tumor effects by regulating immunosuppressive pathways in the tumor microenvironment. Numerous basic experiments and clinical studies have verified the anti-tumor activity of BBs: non-selective beta-blockers can inhibit the proliferation of gastric cancer cells and induce apoptosis in animal models; catecholamines released by host sympathetic activation can suppress CD8⁺ T cell activity via ADRB-mediated cAMP/PKA signaling, while BBs can enhance the efficacy of PD-1 inhibitors by upregulating PD-L1 expression on tumor-associated macrophages and blocking the synergistic inhibitory signals of the LRRC33/TGFβ1 axis and PD-1. In head and neck squamous cell carcinoma and non-small cell lung cancer, the combination of BBs and immunotherapy can improve patient survival, but relevant clinical data in gastric cancer remain limited. Our team previously enrolled 25 eligible patients from 5 hospitals across China, all of whom underwent radical resection. The distribution of postoperative pathological tumor regression grade (TRG) was as follows: TRG 0 in 10 patients (40%), TRG 1 in 4 patients (16%), TRG 2 in 11 patients (44%), and TRG 3 in 0 patients. The proportion of TRG 0/1 (pathological complete or near-complete response) was 56% (14/25), comparable to the immunotherapy plus chemotherapy group of the NEOSUMMIT-01 study; the proportion of TRG 3 (pathological non-response) was 0, significantly lower than the same group of the NEOSUMMIT-01 study. No serious beta-blocker-related adverse events were observed during treatment in the cohort. Based on the above research background and unresolved questions, this study intends to use a nationwide multicenter retrospective cohort data of advanced GC patients with primary hypertension, compare the efficacy of beta-blockers versus non-beta-blocker antihypertensive agents during immunotherapy, and systematically evaluate the unique synergistic effect of beta-blockers. This study aims to provide high-level evidence for combination immunotherapy strategies in GC patients with hypertension, and promote the development of neuro-immuno-oncology in gastric cancer, opening a new avenue to improve the prognosis of this special patient population.
- Study Objectives 2.1 Primary Objective To investigate the impact of combined use of beta-blockers (compared with non-beta-blocker antihypertensive agents) on the efficacy of immunotherapy in patients with advanced gastric cancer complicated by primary hypertension. 2.2 Secondary Objective To investigate the impact of combined use of beta-blockers (compared with non-beta-blocker antihypertensive agents) on the incidence of immune-related adverse events (irAEs).
- Study Design This is a retrospective, multicenter, observational study. Eligible gastric cancer patients with primary hypertension who received neoadjuvant chemoradiotherapy combined with immunotherapy followed by gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025, with complete follow-up data, will be enrolled. Patients will be divided into an exposed group and a non-exposed group according to the use of beta-blockers antihypertensive drugs during immunotherapy:
- Exposed group: Patients who continuously used beta-blockers during neoadjuvant immunochemotherapy
- Control group: Patients who continuously received non-beta-blocker antihypertensive agents (e.g., ACEI/ARB/CCB, diuretics, observation) during the same period Propensity score matching (PSM) will be used to control baseline confounding factors, including age, metastatic burden, CPS score, number of immunotherapy cycles, and hypertension grade. No randomization or study protocol-driven treatment will be administered to participants. All treatment decisions and regimens will be determined by the treating physician based on clinical indications.
- Study Population The study population consists of patients with locally advanced gastric cancer complicated by hypertension who are scheduled to undergo laparoscopic gastrectomy after immunotherapy. 4.1 Diagnostic Criteria
- Gastric cancer diagnosed in accordance with the 15th edition of the Japanese Classification of Gastric Carcinoma (2017)
- Hypertension diagnosed in accordance with the Chinese Guidelines for the Prevention and Treatment of Hypertension 2023 (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg)
- Inclusion and Exclusion Criteria 5.1 Inclusion Criteria
- Age 18-85 years
- No gender restriction
- Histopathologically confirmed gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma(2017)
- Patients who received neoadjuvant immunochemotherapy followed by gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025 5.2 Exclusion Criteria
- Pregnant or breastfeeding women
- Severe psychiatric disorders
- Previous history of chemotherapy, radiotherapy, or targeted therapy
- History of other malignant tumors within the past 5 years
- dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
- Active infection, active or refractory autoimmune disease, or uncontrolled systemic disease
- Patients judged by the investigator to be unsuitable for this study
- Sample Size This study is designed as an observational study. A total of 80 eligible patients admitted to the Department of Gastrointestinal Surgery at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025 will be enrolled, with 40 patients in each of the beta-blocker exposed group and the non-exposed group.
- Data Collection Procedures Data collection will be conducted in three phases: 7.1 Baseline Phase (First Patient Visit)
- Demographic data: gender, age, patient initials
- Medical history and physical examination: height, weight, BMI, underlying diseases, ID number, hospital record number, operation date 7.2 Routine Diagnosis and Treatment Phase
- Laboratory test results: pathological tumor stage, pathological type, histological type, tumor size, tumor location, pathological TRG grade, immunotherapy-related immunohistochemical indicators (CPS, EBER, HER2, PMS2, MLH1, MSH2, MSH6)
- Imaging findings: abdominal computed tomography (CT)
- Antihypertensive medication data: start time, duration, type and dosage of beta-blockers and non-beta-blocker antihypertensive agents 7.3 Follow-up Phase A 3-year telephone follow-up will be performed once a year to record overall survival (OS) and recurrence-free survival (RFS).
- Ethical Considerations This study is conducted in compliance with the Declaration of Helsinki and relevant ethical regulations. All data will be anonymized to protect patient privacy, and no additional interventions or risks will be introduced to participants due to the retrospective observational design.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Beta-blocker exposed group | – | –Patients with locally advanced gastric cancer complicated by primary hypertension, who continuously received beta-blockers (e.g., metoprolol, bisoprolol) for antihypertensive treatment during neoadjuvant immunochemotherapy, followed by curative gastrectomy. |
| Non-beta-blocker control group | – | –Patients with locally advanced gastric cancer complicated by primary hypertension, who continuously received non-beta-blocker antihypertensive agents (e.g., ACEI/ARB, CCB, diuretics) for blood pressure control during neoadjuvant immunochemotherapy, with no exposure to beta-blockers, followed by curative gastrectomy. |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- This study population consists of patients with locally advanced gastric adenocarcinoma complicated by primary hypertension, who received neoadjuvant immunochemotherapy followed by curative laparoscopic gastrectomy.
Key inclusion criteria (4 listed)
- Aged between 18 and 85 years;
- No restriction on gender;
- Patients with a standardized histopathological diagnosis of gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017);
- Patients who received neoadjuvant immunochemotherapy followed by curative gastrectomy at Nanfang Hospital of Southern Medical University and other participating centers between April 2021 and December 2025.
Key exclusion criteria (7 listed)
- Pregnant or breastfeeding women;
- Severe psychiatric disorders;
- Previous history of chemotherapy, radiotherapy, or targeted therapy prior to study treatment;
- History of other malignant tumors within the past 5 years;
- dMMR or MSI-H status determined by immunohistochemistry or PCR-based assays
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Pathological response of MPR
Time frame: From completion of neoadjuvant therapy to surgical resection; assessed on postoperative pathological specimen approximately 1 week after surgery, up to 4 months after study treatment initiation.
Major pathological response (MPR) is defined as the proportion of patients with ≤10% residual viable tumor cells in the surgically resected primary tumor following neoadjuvant therapy. MPR is assessed on the surgical specimen obtained approximately 1 week after completion of preoperative treatment. Pathological evaluation is performed according to standardized tumor regression grading (TRG) systems, with MPR corresponding to TRG 0-1 per AJCC 8th edition criteria (i.e., complete response or minimal residual disease). This endpoint will be reported descriptively with point estimate and 95% confidence interval.
6 secondary outcomes
Pathological Complete Response (pCR) Rate
Time frame: Assessed on postoperative pathological specimens, approximately 1 week after surgical resection (within 4 months after completion of neoadjuvant immunochemotherapy).
Pathological Non-Response (TRG 3) Rate
Time frame: Assessed on postoperative pathological specimens, approximately 1 week after surgical resection (within 4 months after completion of neoadjuvant immunochemotherapy)
Objective Response Rate (ORR)
Time frame: Assessed on pre-surgical imaging, within 1 week before surgery (approximately 3 months after initiation of neoadjuvant immunochemotherapy)
3-Year Progression-Free Survival (PFS)
Time frame: Assessed at 3 years after surgical resection, with annual follow-up
3-Year Overall Survival (OS)
Time frame: Assessed at 3 years after surgical resection, with annual follow-up
Incidence of Immune-Related Adverse Events (irAEs)
Time frame: From initiation of neoadjuvant immunochemotherapy to 30 days after completion of the last treatment cycle
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jun 2026.
- Individual participant dataSharing planned: No. Multicenter retrospective study; patient informed consent does not include provisions for sharing individual participant data, and data sharing is restricted by institutional privacy policies.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Gastric Cancer (GC), run by Nanfang Hospital, Southern Medical University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 3 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pathological response of MPR (time frame: From completion of neoadjuvant therapy to surgical resection; assessed on postoperative pathological specimen approximately 1 week after surgery, up to 4 months after study treatment initiation.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2026.