Application of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy in curative surgery for esophageal cancer:A metaanalysis

BACKGROUND The effectiveness of neoadjuvant therapy in esophageal cancer(EC)treatment is still a subject of debate.AIM To compare the clinical efficacy and toxic side effects between neoadjuvant chemoradiotherapy(nCRT)and neoadjuvant chemotherapy(nCT)for locally advanced EC(LAEC).METHODS A comprehensive search was conducted using multiple databases,including PubMed,EMBASE,MEDLINE,Science Direct,The Cochrane Library,China National Knowledge Infrastructure,Wanfang Database,Chinese Science and Technology Journal Database,and Chinese Biomedical Literature Database Article.Studies up to December 2022 comparing nCRT and nCT in patients with EC were selected.RESULTS The analysis revealed significant differences between nCRT and nCT in terms of disease-free survival.The results indicated that nCRT provided better outcomes in terms of the 3-year overall survival rate(OSR)[odds ratio(OR)=0.95],complete response rate(OR=3.15),and R0 clearance rate(CR)(OR=2.25).However,nCT demonstrated a better 5-year OSR(OR=1.02)than nCRT.Moreover,when compared to nCRT,nCT showed reduced risks of cardiac complications(OR=1.15)and pulmonary complications(OR=1.30).CONCLUSION Overall,both nCRT and nCT were effective in terms of survival outcomes for LAEC.However,nCT exhibited better performance in terms of postoperative complications.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Effects of neoadjuvant chemotherapy vs chemoradiotherapy in the treatment of esophageal adenocarcinoma:A systematic review and meta-analysis

BACKGROUND Neoadjuvant therapy is an essential modality for reducing the clinical stage of esophageal cancer;however,the superiority of neoadjuvant chemotherapy(nCT)or neoadjuvant chemoradiotherapy(nCRT)is unclear.Therefore,a discussion of these two modalities is necessary.AIM To investigate the benefits and complications of neoadjuvant modalities.METHODS To address this concern,predefined criteria were established using the PICO protocol.Two independent authors performed comprehensive searches using predetermined keywords.Statistical analyses were performed to identify significant differences between groups.Potential publication bias was visualized using funnel plots.The quality of the data was evaluated using the Risk of Bias Tool 2(RoB2)and the GRADE approach.RESULTS Ten articles,including 1928 patients,were included for the analysis.Significant difference was detected in pathological complete response(pCR)[P<0.001;odds ratio(OR):0.27;95%CI:0.16-0.46],30-d mortality(P=0.015;OR:0.4;95%CI:0.22-0.71)favoring the nCRT,and renal failure(P=0.039;OR:1.04;95%CI:0.66-1.64)favoring the nCT.No significant differences were observed in terms of survival,local or distal recurrence,or other clinical or surgical complications.The result of RoB2 was moderate,and that of the GRADE approach was low or very low in almost all cases.CONCLUSION Although nCRT may have a higher pCR rate,it does not translate to greater long-term survival.Moreover,nCRT is associated with higher 30-d mortality,although the specific cause for postoperative complications could not be identified.In the case of nCT,toxic side effects are suspected,which can reduce the quality of life.Given the quality of available studies,further randomized trials are required.

Effects of VEP neoadjuvant chemotherapy before esophageal cancer surgery on the malignant biological behaviors of tumor cells

Objective: To study the effects of VEP neoadjuvant chemotherapy before esophageal cancer surgery on the malignant biological behaviors of tumor cells. Methods: Patients who were diagnosed with locally advanced esophageal cancer in Dangyang People's Hospital between March 2015 and March 2017 were selected as the research objects and randomly divided into the VEP group who received preoperative VEP (etoposide + 5-fluorouracil + cisplatin) chemotherapy and the control group who accepted routine preoperative preparation. The serum contents of tumor markers were determined at diagnosis and 1 d before surgery;the expression of proliferation genes and invasion genes in tumor tissue were determined after surgical resection. Results: One day before surgery, serum CEA, CA125, CYFRA21-1 and SCC-Ag levels of VEP group were significantly lower than those at diagnosis, and serum CEA, CA125, CYFRA21-1 and SCC-Ag levels of control group were not significantly different from those at diagnosis;after surgical resection, PTEN, Smac and PTPN14 mRNA expressions in the tumor tissue of VEP group were significantly higher than those of control group whereas CyclinB1, CDK1, Grp94, MMP2, β-catenin, Slug, Vimentin and N-cadherin mRNA expressions were significantly lower than those of control group. Conclusions: VEP neoadjuvant chemotherapy before esophageal cancer surgery can reduce the growth of tumor cells and inhibit the proliferation and invasion of tumor cells in the lesion.

Neoadjuvant chemoradiotherapy for esophageal cancer:Impact on extracapsular lymph node involvement

AIM:To assess the effects of neoadjuvant chemoradiotherapy(CRT) on the presence of extracapsular lymph node involvement(LNI) and its prognostic value in patients with resected esophageal cancer.METHODS:Two hundred and ninety-eight patients with advanced esophageal cancer underwent esophagectomy between 1997 and 2006.One hundred and ninety patients(63.8%) were treated with neoadjuvant CRT prior to resection.A total of 986 metastatic LNs were examined.Survival of the patients was analyzed according to intra-and extra-capsular LNI.RESULTS:Five-year survival rate was 22.5% for the entire patient population.Patients with extracapsular LNI had a 5-year survival rate of 16.7%,which was comparable to the 15.8% in patients with infiltrated nodes of the celiac trunk(pM1lymph).In contrast to patients treated with surgery alone,neoadjuvant therapy resulted in signif icantly(P = 0.001) more patients with pN0/M0(51.6% vs 25.0%).In 17.6% of the patients with surgery alone vs 16.8% with neoadjuvant CRT,extracapsular LNI was detected.Neoadjuvant therapy does not reduce the occurrence of extracapsular LNI.CONCLUSION:Extracapsular LNI is an independent negative prognostic factor not influenced by neoadjuvant CRT.In a revised staging system for esophageal cancer,extracapsular LNI should be considered.

The predictive value of histological tumor regression grading (TRG) for therapeutic evaluation in locally advanced esophageal carcinoma treated with neoadjuvant chemotherapy

Response criteria remain controversial in therapeutic evaluation for locally advanced esophageal carcinoma treated with neoadjuvant chemotherapy.We aimed to identify the predictive value of tumor regression grading(TRG) in tumor response and prognosis.Fifty-two patients who underwent neoadjuvant chemotherapy followed by esophagectomy and radical 2-field lymphadenectomy between June 2007 and June 2011 were included in this study.All tissue specimens were reassessed according to the TRG scale.Potential prognostic factors,including clinicopathologic factors,were evaluated.Survival curves were generated by using the Kaplan-Meier method and compared with the log-rank test.Prognostic factors were determined with multivariate analysis by using the Cox regression model.Our results showed that of 52 cases,43(83%) were squamous cell carcinoma and 9(17%) were adenocarcinoma.TRG was correlated with pathologic T(P = 0.006) and N(P < 0.001) categories.Median overall survival for the entire cohort was 33 months.The 1-and 2-year overall survival rates were 71% and 44%,respectively.Univariate survival analysis results showed that favorable prognostic factors were histological subtype(P = 0.003),pathologic T category(P = 0.026),pathologic N category(P < 0.001),and TRG G0(P = 0.041).Multivariate analyses identified pathologic N category(P < 0.001) as a significant independent prognostic parameter.Our results indicate that histomorphologic TRG can be considered as an alternative option to predict the therapeutic efficacy and prognostic factor for patients with locally advanced esophageal carcinoma treated by neoadjuvant chemotherapy.

Positron emission tomography complete metabolic response as a favorable prog-nostic predictor in esophageal cancer following neoadjuvant chemotherapy with docetaxel/cis-platin/5-fluorouracil

BACKGROUND 18F-fluorodeoxyglucose-positron emission tomography(PET)/computed tomography is useful in diagnosing lymph node and distant metastases of esophageal cancer.However,its value for predicting survival is controversial.AIM To evaluate the value of PET complete metabolic response(CMR)as a prognostic predictor for esophageal cancer.METHODS Between June 2013 and December 2017,58 patients with squamous cell esophageal cancer who underwent neoadjuvant chemotherapy(NAC)in Oita University were enrolled in this retrospective cohort study.Tumors were clinically staged using fluorodeoxyglucose-PET/computed tomography before and after NAC.After NAC,maximal standardized uptake value≤2.5 was defined as PET-CMR,and maximal standardized uptake value>2.5 was defined as non-PET-CMR.We compared short-term outcomes between the PET-CMR group and non-PET-CMR group and evaluated prognostic factors by univariate and multivariate analyses.RESULTS The PET-CMR group included 22 patients,and the non-PET-CMR group included 36 patients.There were no significant differences in intraoperative and post operative complications between the two groups.Five-year relapse-free survival and overall survival in the PET-CMR group were significantly more favorable than those in the non-PET-CMR group(38.6 mo vs 20.8 mo,P=0.021;42.8 mo vs 25.1 mo,P=0.011,respectively).PET-CMR was a significant prognostic factor in terms of relapse-free survival by univariate analysis(hazard ratio:2.523;95%confidence interval:1.034–7.063;P<0.041).Particularly,PET-computed tomography negative N was an independent prognostic factor of relapse-free survival and overall survival by multivariate analysis.CONCLUSION PET-CMR after NAC is considered a favorable prognostic factor for esophageal cancer.Evaluation by PET-computed tomography could be useful in clinical decision making for esophageal cancer.

Effect of cetuximab combined with paclitaxel + cisplatin neoadjuvant chemotherapy on esophageal cancer cell proliferation and invasion

Objective:To study the effect of cetuximab combined with paclitaxel + cisplatin neoadjuvant chemotherapy on esophageal cancer cell proliferation and invasion.Methods:A total of 62 patients with esophageal cancer who were treated in the hospital between January 2015 and December 2016 were collected and divided into control group and observation group according to random number table, with 31 cases in each group. Control group of patients received paclitaxel + cisplatin neoadjuvant chemotherapy + surgery, and observation group of patients accepted cetuximab combined with paclitaxel + cisplatin neoadjuvant chemotherapy + surgery. The differences in proliferation and invasion gene expression in the tumor tissue were compared between two groups of patients before and after chemotherapy.Results:Before chemotherapy, differences in proliferation and invasion gene expression in tumor tissue were not statistically significant between two groups of patients. After chemotherapy, pro-proliferation genes FOXA1, ABCE1, USP39 and Nestin mRNA expression in tumor tissue of observation group were significantly lower than those of control group;anti-proliferation genes PETN, KLF4, TSLC1 and AnnexinA2 mRNA expression were significantly higher than those of control group;pro-invasion genesγ-synuclein, CXCR4 and Snail mRNA expression were significantly lower than those of control group;anti-invasion genes CIAPIN1, Fez and Lrig1 mRNA expression were significantly higher than that of control group.Conclusions:Cetuximab combined with paclitaxel + cisplatin neoadjuvant chemotherapy can effectively inhibit the malignant degree of esophageal cancer cells and inhibit its proliferation and invasion.

Neoadjuvant therapy for esophageal cancer

Esophageal cancer is increasing in incidence more than any other visceral malignancy in North America. Adenocarcinoma has become the most common cell type. Surgery remains the primary treatment modality for locoregional disease. Overall survival with surgery alone has been dismal, with metastatic disease the primary mode of treatment failure after an R0 surgical resection. Cure rates with chemotherapy or radiation therapy alone have been disappointing as well. For these reasons, over the last decade multi-modality treatment has gained increasing acceptance as the standard of care. This review examines the present data and role of neoadjuvant treatment using chemotherapy and radiation therapy followed by surgery for the treatment of esophageal cancer.

The influence of neoadjuvant chemotherapy on immunity function in elderly patients with the stages of Ⅱ and Ⅲ esophageal cancer

Objective: We aimed to study the influence of neoadjuvant chemotherapy on immunity function in elderly patients with the stages of II and III esophageal cancer. Methods: Thirty-seven elderly patients (age ranged from 60 to 75 years) with the stages of II and III esophageal cancer underwent 2 cycles chemotherapy preoperatively with single-drug regimen (docetaxel, 35 mg/m2 once a week, on days 1, 8 and 15, at interval of 2 weeks for one cycle). Surgery were performed three weeks later. Blood samples were drawn separately on the day of admission, 1 day before operation, 7 day and 1 month after operation, and we conducted the Flow Cytometry to detect the levels of CD3+, CD4+, CD8+,CD4+/CD8+ and NK cells. Results: There were no significant differences in the levels of CD3+, CD4+, CD8+, CD4+/CD8+ and NK cells between before and after chemotherapy (P > 0.05). On day 7 after operation, the levels of CD3+, CD4+, CD4+/CD8+ and NK cells were degraded and CD8+ increased significantly (P < 0.05). One month after operation, the levels of CD3, CD4+, CD4+/CD8 and NK cells were higher than normal, and CD8 was depressed significantly (P < 0.05). Conclusion: Neoadjuvant chemotherapy has no significant impact on cellular immune function in elderly patients with the stages of II and III esophageal cancer, it is an effective and safe treatment.

Effect of paclitaxel + cisplatin chemotherapy before radical operation for esophageal cancer on the malignant degree of tumor

Objective:To study the effect of paclitaxel + cisplatin chemotherapy before radical operation for esophageal cancer on the malignant degree of tumor.Methods:Patients who underwent radical operation for esophageal cancer in Zigong Third People's Hospital between March 2015 and November 2017 were selected and divided into experimental group and control group according to preoperative application of paclitaxel + cisplatin neoadjuvant chemotherapy or not in the history data. After surgery, right amount of esophageal cancer tissue was collected from the two groups of patients to extract RNA and then determine the mRNA expression of apoptosis genes Smac, Caspase-9, p21 and Spink8, invasion genes ADAMTS5, CNTN1,β-catenin, MMP9 and N-cadherin as well as angiogenesis molecules TGF-β1 and VEGF.Results:Smac, Caspase-9, p21 and Spink8 mRNA expression in surgically removed esophageal cancer tissues of experimental group were significantly higher than those of control group, ADAMTS5, CNTN1,β-catenin, MMP9 and N-cadherin mRNA expression in surgically removed esophageal cancer tissues were significantly lower than those of control group, and TGF-β1 and VEGF levels in serum as well as TGF-β1 and VEGF mRNA expression in surgically removed esophageal cancer tissues were significantly lower than those of control group.Conclusion:paclitaxel + cisplatin chemotherapy before radical operation for esophageal cancer can reduce the malignant degree of tumor by promoting the cancer cell apoptosis and inhibiting the cancer cell invasion and angiogenesis.

Effect of preoperative paclitaxel + cisplatin neoadjuvant chemotherapy on the proliferation and invasion of cancer cells in esophageal cancer

Objective: To investigate the effect of preoperative paclitaxel + cisplatin neoadjuvant chemotherapy on the proliferation and invasion of cancer cells in esophageal cancer. Methods: A total of 106 patients with esophageal cancer who underwent radical operation for esophageal cancer in our hospital between September 2014 and March 2017 were divided into the neoadjuvant chemotherapy group (n=54, receiving preoperative paclitaxel + cisplatin neoadjuvant chemotherapy) and the normal group (n=52, receiving no preoperative neoadjuvant chemotherapy) according the therapeutic regimen. The differences in the expression of proliferation genes and invasion genes in the postoperative lesion tissue specimens were compared between the two groups. Results: The proliferation genes MACC1, Nucleostemin, TRAF4 and USP39 mRNA expression in lesion tissue of neoadjuvant chemotherapy group were lower than those in lesion tissue of normal group whereas DEC1, PTPN14, KLF4 and LATS1 mRNA expression were higher than those in lesion tissue of normal group;invasion genes EphA2, MACC1, MMP-9, PFN2, Snail and SphK1 mRNA expression in lesion tissue of neoadjuvant chemotherapy group were lower than those in lesion tissue of normal group whereas PTEN and RACK1 mRNA expression were higher than those in lesion tissue of normal group. Conclusion: The paclitaxel + cisplatin neoadjuvant chemotherapy before esophageal cancer surgery can effectively inhibit the proliferation and invasion activity of esophageal cancer cells.

Neoadjuvant treatment of esophageal cancer

The management of esophageal cancer has been evolving over the past 30 years. In the United States, multimodality treatment combining chemotherapy and radiotherapy (RT) prior to surgical resection has come to be accepted by many as the standard of care, although debate about its overall effect on survival still exists, and rightfully so. Despite recent improvements in detection and treatment, the overall survival of patients with esophageal cancer remains lower than most solid tumors, which highlights why further advances are so desperately needed. The aim of this article is to provide a complete review of the history of esophageal cancer treatment with the addition of chemotherapy, RT, and more recently, targeted agents to the surgical management of resectable disease.

Multimodality approach for locally advanced esophageal cancer

Carcinoma of the esophagus is an aggressive and lethal malignancy with an increasing incidence worldwide.Incidence rates vary internationally,with the highest rates found in Southern and Eastern Africa and Eastern Asia,and the lowest in Western and Middle Africa and Central America.Patients with locally advanced disease face a poor prognosis,with 5-year survival rates ranging from 15%-34%.Recent clinical trials have evaluated different strategies for management of locoregional cancer;however,because of stage migration and changes in disease epidemiology,applying these trials to clinical practice has become a daunting task.We searched Medline and conference abstracts for randomized studies published in the last 3 decades.We restricted our search to articles published in English.Neoadjuvant chemoradiotherapy followed by surgical resection is an accepted standard of care in the United States.Esophagectomy remains an essential component of treatment and can lead to improved overall survival,especially when performed at high volume institutions.The role of adjuvant chemotherapy following curative resection is still unclear.External beam radiation therapy alone is considered palliative and is typically reserved for patients with a poor performance status.

Synchronous rectal and esophageal cancer treated with chemotherapy followed by two-stage resection

We report a case of 61-year-old male who had synchronous advanced rectal cancer involving the urinary bladder massively associated with multiple liver metastases, and esophageal cancer successfully treated by neoadjuvant chemotherapy followed by two-stage resection. Although complete resection of each of the lesions was considered possible by performing anterior pelvic exenteration, liver resection, and esophagectomy, it might be impossible for the patient to endure the stress of all of these operative procedures at once. Therefore, we planned to perform staged treatment with prioritizing consideration. First, we instituted chemotherapy with the FOLFOX(oxaliplatin + fluorouracil + leucovorin) plus cetuximab regimen, which could adequately control both rectal and esophageal cancer. After 6 cycles of chemotherapy, high anterior resection combined with cystoprostatectomy and lateral segmentectomy plus partial hepatectomy was performed followed by staged esophagectomy with three-field lymph node dissection. It was possible to use oxaliplatin and cetuximab safely as neoadjuvant therapy not only for advanced rectal cancer but for esophageal cancer, and it was effective.

Neoadjuvant chemoradiotherapy plus surgery in the treatment of potentially resectable thoracic esophageal squamous cell carcinoma

BACKGROUNDIn recent years, neoadjuvant chemoradiotherapy (NCRT) combined with surgeryhas been gradually applied in patients with locally advanced thoracic esophagealcancer, but its effectiveness and safety remains unclear. In this clinical trial, weprospectively investigated the efficacy and safety of NCRT plus surgery in thetreatment of thoracic esophageal squamous cell carcinoma (TESCC).AIMTo investigate the efficacy and safety of NCRT combined with surgery in thetreatment of potentially resectable TESCC.METHODSThirty patients with advanced TESCC hospitalized in our hospital from July2016 to June 2019 were prospectively studied. All patients received NCRT, whichincluded intensity modulated conformal radiotherapy (40-44 Gy/20-22f, 2 Gy/f)and chemotherapy (paclitaxel 150-175 mg/m2d1, 22 + lobaplatin 25-30 mg/m2d2,23 for two cycles). Surgery was performed after radiotherapy and chemotherapy.The effectiveness and safety of these treatments were observed.RESULTSAmong these 30 patients, complete response was achieved in two cases (6.7%) andpartial response in 26 cases (86.7%), yielding an objective response rate of 100%.All patients underwent radical surgery successfully. The R0 resection rate was100%, and the pathologic complete response rate was 33.3%. The incidence ofgrade III- IV granulocytopenia was 10% during the NCRT, and anastomoticleakage occurred in one patient after surgery.CONCLUSIONFor patients with potentially resectable TESCC, NCRT can effectively reduce thetumor size, increase R0 resection rate, and achieve obvious pathologicaldegradation, with mild adverse reactions. Thus, it is worthy of wider clinicalapplication.

Current trends in perioperative treatment of resectable gastric cancer

In the last few decades,the treatment strategy for locally advanced resectable gastric cancer(GC)has shifted to a multimodal approach,which potentially decreases recurrence risk and improves survival rates.Perioperative therapy leads to downstaging,increased curative resection rates,and prolonged disease-free and overall survival,by preventing micrometastases in patients with resectable GC.Application of neoadjuvant therapy provides information about tumor biology and in vivo sensitivity.A consensus regarding the therapeutic approach for non-metastatic GC does not exist,and many clinical trials aim to clarify this aspect.Advances in precision medicine and the role of immunotherapy have been the focus of research in GC treatment.Herein,the current status and possible future developments of perioperative therapy for locally advanced resectable GC are reviewed,based on the most recent randomized clinical trials.

非小细胞肺癌新辅助免疫治疗在临床中的应用进展

肺癌的发病率和病死率普遍较高,严重威胁大众身体健康。目前,手术仍然是对能够切除的非小细胞肺癌(NSCLC)的良好干预策略。免疫检测点类的抑制药物的出现极大程度上改变了NSCLC的干预效果。随着研究深入,免疫检查点抑制剂在治疗NSCLC的安全性和可行性方面也有着优异的表现,但仍缺乏远期预后评估,以及公认合理的治疗方案和疗程等。该文将阐述新辅助免疫治疗可切除的NSCLC的发展过程、作用机制及研究现状。

食管癌新辅助免疫治疗研究进展

食管癌有着较高的发病率以及死亡率,使大众身体健康受到严重威胁。目前而言,手术仍然是治疗可切除食管癌的首选治疗方式,但是在局部晚期的食管癌患者中,单纯手术治疗的效果并不乐观,因此手术配合化疗及免疫治疗为主的综合治疗是现今公认的最佳方案。它的作用原理主要是通过阻断免疫检查点,抵抗肿瘤对免疫的抑制,起到将肿物缩小及防止复发的作用。现在有多项临床试验也正在探索新辅助免疫治疗联合化疗用于治疗食管癌患者的应用模式,但仍缺乏远期预后,而且目前也尚未明确潜在受益人群以及合理的治疗方案和疗程等问题。该文对新辅助免疫治疗在食管癌中的作用机制、研究现状以及与治疗相关常见问题进行综述。

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023

The 2023 update of the Chinese Society of Clinical Oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-based medicine,healthcare resource availability,and precision medicine.These updates address the differences in epidemiological characteristics,clinicopatho-logical features,tumor biology,treatment patterns,and drug selections between Eastern and Western gastric cancer patients.Key revisions include a structured template for imaging diagnosis reports,updated standards for molecular marker testing in pathological diagnosis,and an elevated recommendation for neoadju-vant chemotherapy in stage III gastric cancer.For advanced metastatic gastric cancer,the guidelines introduce new recommendations for immunotherapy,anti-angiogenic therapy and targeted drugs,along with updated management strategies for human epidermal growth factor receptor 2(HER2)-positive and deficient DNA mismatch repair(dMMR)/microsatellite instability-high(MSI-H)patients.Additionally,the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer.The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice,particularly in the heterogeneous healthcare landscape of China,while maintaining a commitment to scientific rigor,impartiality,and timely revisions.