Prognostic value of post-neoadjuvant immunochemotherapy hypercoagulation in gastric cancer patients undergoing surgery

Abstract

There is no standard treatment for patients with locally advanced gastric cancer (LAGC). Neoadjuvant immunochemotherapy (NICT) is an emerging therapeutic strategy in LAGC. The prognosis of patients undergoing NICT plus radical surgery varies. Hypercoagulation is frequently identified in cancer patients. A retrospective study by Li et al confirmed that in LAGC patients undergoing radical resection post-NICT, elevated D-dimer and fibrinogen levels were associated with poor prognosis, and their combined assessment improved predictive accuracy. This retrospective study has some limitations, and further prospective research is required to validate hypercoagulation as a prognostic indicator and develop a more precise predictive model. Establishing such a model can facilitate personalized treatment strategies for patients with LAGC.

Key Words: Locally advanced gastric cancer; Neoadjuvant immunochemotherapy; Hypercoagulation; Prognosis indicator; Radical gastrectomy

Core Tip: The prognosis of patients with locally advanced gastric cancer undergoing neoadjuvant immunochemotherapy (NICT) plus radical surgery varies. Post-NICT hypercoagulation may act as a prognostic indicator. However, standardized methods for assessing cancer-associated hypercoagulation are lacking. Future research should concentrate on identifying more precise and efficient biomarkers for assessing cancer-associated hypercoagulation to refine prognostic evaluation and guide individualized treatment.

INTRODUCTION

Gastric cancer (GC) is a common gastrointestinal malignancy and one of the deadliest cancer types worldwide. Early-stage GC mainly lacks typical clinical manifestations, and approximately 70% of GC patients are in locally advanced or advanced stages at the time of initial diagnosis[1]. Locally advanced GC (LAGC) mainly refers to the clinical stage of CT1-2N +M0 or CT3-4BNanyM0[2]. Surgical treatment of LAGC is associated with poor efficacy, and perioperative treatments have been developed[3]. However, at present, the efficacy of neoadjuvant chemotherapy is still limited, highlighting the need to explore and optimize perioperative treatment strategies to improve LAGC patients’ survival. Chemotherapy combined with immunotherapy has become the standard first-line treatment for advanced GC. Due to its success in advanced GC, immunotherapy is also receiving increasing attention in the perioperative treatment of LAGC. Studies have confirmed the superiority of neoadjuvant immunochemotherapy (NICT) in the treatment of LAGC[4,5], exhibiting its ability to improve the pathological complete response rate and potentially reduce postoperative tumor recurrence, ultimately leading to superior outcomes. However, the clinical benefits of this approach vary among individuals, and the prognosis remains poor in some patients, highlighting the urgent need for prognostic indicators that can accurately predict the efficacy of the new treatment.

RELATIONSHIP BETWEEN HYPERCOAGULATION AND GC

As early as 1865, a French doctor discovered a link between gastric malignancies and venous thrombosis[6]. Thrombosis is one of the most common manifestations of hypercoagulation in malignant tumors, and GC is associated with a high thrombotic risk[7]. The hypercoagulable state of malignancy is affected by a variety of factors, such as pathological type, biological behavior, and treatment method. Tumor cells can release procoagulant factors, such as tissue factor and cancer PR agglutinin, which interact with the fibrinolytic system to regulate plasmin formation and degradation, activate platelets, and trigger cancer-associated complement pathways, thereby promoting thrombogenesis. In addition, genetic alterations in cancer patients may contribute to a hypercoagulable state[8]. This can not only lead to asymptomatic coagulation abnormalities and venous thromboembolism, but also may enhance tumor progression. For instance, tissue factor binding to factor VII activates protease-activated receptors, receptor tyrosine kinases, and integrins, driving tumor cell proliferation, angiogenesis, and metastasis[9]. Moreover, platelets protect circulating tumor cells from anoikis, promote epithelial-to-mesenchymal transition, enhance angiogenesis, and support extravasation, ultimately increasing metastatic potential[6]. Accurate assessment of hypercoagulation and its severity in cancer patients, along with targeted monitoring and treatment, is vital for enhancing therapeutic efficacy and improving patient survival.

HYPERCOAGULATION AS AN EFFECTIVE PROGNOSTIC INDICATOR

Li et al[10] retrospectively analyzed the clinical data of 104 patients with LAGC who underwent surgery post-NICT. D-dimer and fibrinogen levels were measured to assess hypercoagulability in patients. Hypercoagulation was defined as either marker exceeding its respective upper limit of normal, whereas non-hypercoagulation was defined as both remaining within normal limits. D-dimer, a degradation product of cross-linked fibrin resulting from plasmin-mediated fibrinolysis, serves as a specific marker of secondary fibrinolysis. Plasma fibrinogen, a precursor of fibrin clot formation, plays a remarkable role in coagulation. Both markers can indirectly reflect the hypercoagulable state and are commonly utilized in clinical coagulation evaluation. A systematic review and meta-analysis demonstrated that elevated fibrinogen and D-dimer levels are associated with poor prognosis in digestive cancers[11]. However, factors, such as tissue injury and infection can also elevate the levels of these markers, necessitating a comprehensive interpretation that considers clinical context. Additional assessments, including conventional coagulation tests and thromboelastography, may provide a more accurate evaluation of a patient’s coagulation status[12]. The results indicated that the 3-year overall survival (OS) rate after surgery was significantly higher in the post-NICT non-hypercoagulation group than that in the hypercoagulation group. Disease-free survival (DFS) outcomes were consistent with OS findings, suggesting that a hypercoagulable state may contribute to LAGC progression. Multivariate regression analysis identified post-NICT hypercoagulation as an independent predictor of poor OS and DFS. However, no significant difference in 3-year OS was found between the pre-NICT hypercoagulation and non-hypercoagulation groups, indicating that hypercoagulation post-NICT is a stronger prognostic indicator in LAGC patients undergoing surgery. A population-based cohort study found that the risk factors for venous thrombosis in cancer patients include chemotherapy and immunotherapy[13]. Immune checkpoint inhibitors can induce systemic proinflammatory states, activate the coagulation cascade and platelets, and suppress fibrinolysis, thereby enhancing thrombogenicity[14,15]. Chemotherapy may promote thrombin production through a tissue factor-dependent mechanism[16]. These findings suggest that NICT may exacerbate hypercoagulability and highlight the need to evaluate its prognostic impact in this patient population. Previous studies have supported the prognostic significance of hypercoagulation in cancer. Giaccherini et al[17] conducted a prospective study, demonstrating that endogenous thrombin potential and D-dimer levels could predict 6-month disease progression and 1-year OS in patients with newly diagnosed metastatic gastrointestinal cancer. Kirwan et al[18] found that hypercoagulation was associated with reduced survival in metastatic breast cancer, where the coagulation system promotes tumor cell metastasis. These two studies excluded patients receiving anticoagulant therapy to minimize confounding, a methodological aspect that was not addressed in Li et al’s study[10]. Although these studies highlight the prognostic value of hypercoagulation, few have investigated its role in LAGC patients who underwent surgery post-NICT. Conflicting findings have also been reported. One study[19] demonstrated that plasma fibrinogen was not an independent prognostic factor for GC, possibly due to a low threshold for hyperfibrinogenemia, which might overestimate the prevalence of elevated fibrinogen level. Similarly, Liang et al[20] found that preoperative D-dimer level was not an independent prognostic factor for GC following radical resection, potentially due to regional variability and confounding factors.

RESEARCH LIMITATIONS

This study provided meaningful insights for optimizing the clinical management of patients undergoing NICT followed by radical surgery. However, several limitations must be acknowledged, including a small sample size, the absence of a control group, and potential confounding factors inherent to retrospective studies. These findings require validation through large-scale prospective randomized controlled trials. In addition, D-dimer and fibrinogen levels are influenced by various factors and cannot directly reflect patients’ complex and changeable coagulation status. Therefore, future research should incorporate additional biomarkers to improve the accuracy of hypercoagulation assessment and strengthen its prognostic value.

CONCLUSION

NICT has emerged as a notable approach in the perioperative treatment of LAGC. The hypercoagulable state appears to influence treatment outcomes, and post-NICT hypercoagulation may be used as a prognostic indicator for patients undergoing surgery. However, standardized methods and criteria for accurately evaluating cancer- associated hypercoagulation remain undefined. Exploring more accurate and efficient biomarkers to evaluate hypercoagulation in patient may advance individualized precision therapy, representing a critical direction for future research.