Immunotherapy in conversion therapy for gastric cancer: current status, progress, and challenges

Conversion therapy is adopted to achieve radical cure for patients with originally unresectable but potentially resectable late stage gastric cancer, who obtain partial or complete remission after systemic chemotherapy, to acquire relatively longer postoperative survival and recurrence-free survival. Some of the previous researches on conversion therapy for originally unresectable gastric cancer suggest that high chemotherapy response rate, high pathological response rate and R0 resection rate are associated with favorable prognosis. And the efficacy of patients with lymphatic metastasis is better than that of those with peritoneal metastasis. The protocol of conversional chemotherapy varies and so does its efficacy according to different reports. Latest clinical researches indicate that initially unresectable gastric cancer gained higher remission rate and better chance of R0 operation and consequently prolonged survival from paclitaxel based triplet chemotherapy. However, not all originally unresectable gastric cancer can benefit from conversion therapy due to the high heterogeneity of its biological behavior. Regarding the enormous number of originally unresectable gastric cancer patients, it will be a research hot spot in the field of surgical oncology, on screening criteria to select cases suitable for conversion. Exploration on conversion therapy for gastric cancer is still at initial stage, and reports that have been published are mostly single-centered with limited sample, lacking of sufficient evidence on its feasibility, safety and efficacy. Expert consensus on conversion indication, case selection, chemotherapy regimen, efficacy assessment and resection range is absent. So it is in urgent need for higher level clinical evidence to support and guide this practice. Such goal can never be achieved without joint efforts of all parties to carry out clinical trial to modify the practice of conversion therapy for late stage gastric cancer, and determine the proper selection of suitable candidates for conversion therapy, eventually to offer optimal strategy for originally unresectable gastric cancer patients. Thus, this article focuses on reviewing research progress of conversion therapy for originally unresectable late stage gastric cancer.

Gastric cancer with peritoneal dissemination is usually considered to be oncologically unresectable and is known to have a very poor prognosis. Despite recent advances in systemic chemotherapy, peritoneal dissemination due to advanced gastric cancer (AGC) still remains the most life-threatening type of metastasis and recurrence, which usually causes ascites accumulation, intestinal obstruction, or hydronephrosis, and then seriously impairs the quality of life. In general, the median survival time of these cases is reported to be just only 6-9 months. Recently, conversion therapy for gastric cancer with peritoneal dissemination has been highly concerned. It is defined as a conversion surgery aiming at an R0 resection after chemotherapy for both primary gastric cancer and distant metastatic cancerous foci including peritoneal dissemination, which were originally unresectable due to technical and/or oncological reasons. In numerous clinical practices, the results of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) have been reported to be more satisfactory in comparison with traditional systemic chemotherapy alone. Some clinical trials have demonstrated the clinical efficacy of intravenous and intraperitoneal administration of paclitaxel (PTX) combined with oral S-1 for peritoneal dissemination of gastric cancer with or without malignant ascites. Particularly, a longer period of survival can be expected when conversion R0 gastrectomy is successfully performed after observing significant responses of NIPS. Some clinical practice key points of conversion therapy for AGC patients with peritoneal dissemination are reviewed, including the importance of intraperitoneal and systemic synchronous chemotherapy, the reasonable choice of intraperitoneal chemotherapy drugs, the evaluation of primary gastric cancer and metastatic foci before and after conversion therapy, some special complications of NIPS, the indications of conversion surgery and the adjuvant therapy after conversion surgery, ect.

BackgroundHepatoid adenocarcinoma of the stomach (HAS) is a rare subtype of gastric cancer (GC) characterized by alpha-fetoprotein (AFP) production and invasive liver and lymph node metastases, typically associated with a poor prognosis. Although immuno-chemotherapy has made significant achievements in the conversion therapy of advanced GC in recent years, the management of HER2-negative, proficient mismatch repair (pMMR), and a programmed cell death ligand-1 (PD-L1) combined positive score (CPS)<5 cases, particularly in the context of synchronous multiple liver metastases and lymph node involvement, poses significant challenges. This is attributable not only to its rapid progression but also to its poor prognosis. We retrospectively report a case of HAS with concurrent multiple liver and lymph node metastases. Following six cycles of immuno-chemotherapy, R0 resection was achieved, and postoperative pathological examination confirmed a pathological complete response (pCR). No recurrence or metastasis was observed at the 32-month postoperative follow-up (last follow-up: April 26, 2025). To our knowledge, no previous reports have documented pCR in HER2-negative, pMMR, and PD-L1 CPS<5 patients with advanced HAS following conversion therapy with combined immuno-chemotherapy. This report aims to provide further clinical reference for the treatment of advanced HAS.Case summaryA 51-year-old male patient was diagnosed with HAS accompanied by multiple liver and lymph node metastases. Following six cycles of immunotherapy (sintilimab) combined with chemotherapy (Nab-paclitaxel, oxaliplatin, and S-1), the primary tumor exhibited significant reduction. Multiple liver metastases showed partial shrinkage or disappearance (the target lesion diameter must be less than 10 mm), and retroperitoneal lymph nodes were no longer detectable. After thorough evaluation, R0 resection was deemed achievable. Therefore, radical distal gastrectomy with D2 lymphadenectomy and liver metastasectomy were performed. Postoperative pathology confirmed pCR. The patient has remained progression-free survival (PFS) for 32 months and overall survival (OS) for 38 months, with no evidence of recurrence or metastasis.ConclusionHAS is a highly invasive malignant tumor of the stomach. The dynamic changes in AFP serve as a reliable indicator for detecting HAS, evaluating treatment efficacy, and predicting recurrence. In advanced HER-2-negative, PD-L1 CPS<5, pMMR-type HAS, employing a conversion therapy regimen combining sintilimab with Nab-paclitaxel, oxaliplatin, and S-1 may reduce tumor staging, enhance conversion therapy success rates, and prolong survival.

BackgroundPeritoneal metastasis (PM) is one of the most common forms of metastasis with a very poor prognosis in patients with gastric cancer (GC). The mechanisms, diagnosis, and management of PM remain controversial.Main bodyStephen Paget’s “seed-and-soil” hypothesis gives us an illustration of the mechanisms of PM. Recently, hematogenous metastasis and exosomes from GC are identified as novel mechanisms for PM. Diagnostic accuracy of conventional imaging modalities for PM is not satisfactory, but texture analysis may be a useful adjunct for the prediction of PM. Biological markers in peritoneal washings are helpful in identifying patients at high risk of PM, but many limitations remain to be overcome. Response of PM from systemic chemotherapy alone is very limited. However, conversion therapy is confirmed to be safe and able to prolong the survival of GC patients with PM. As an important part of conversion therapy, intraperitoneal chemotherapy with taxanes has become an ideal approach with several advantages. Additionally, gastrectomy should be considered in patients who would tolerate surgery if a remarkable response to chemotherapy was observed.ConclusionTexture analysis is a reliable adjunct for the prediction of PM, and conversion therapy provides a new choice for GC patients with PM. The underlying mechanisms and new biological markers for GC patients with PM should be the direction of future studies. Furthermore, significant aspects of conversion therapy, such as timing and method of the operation, and the indications remain to be clarified.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes. One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40mg/m2 b.i.d.) on days 1-14 and intravenous cisplatin (60mg/m2) and docetaxel (50-60mg/m2) on day 8 every 3weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery. Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8%) achieved R0 resection, and 78.8% were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8months (95% CI 28.0-88.5months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (P=0.0002). Of the patients with primarily unresectable metastases, 10% lived >5years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS. DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.

The incidence of gastric cancer is increasing year by year. Most gastric cancers are already in the advanced stage with poor prognosis when diagnosed, which means the current treatment is not satisfactory. Angiogenesis is an important link in the occurrence and development of tumors, and there are multiple anti-angiogenesis targeted therapies. To comprehensively evaluate the efficacy and safety of anti-angiogenic targeted drugs alone and in combination against gastric cancer, we systematically searched and sorted out relevant literature. In this review, we summarized the efficacy and safety of Ramucirumab, Bevacizumab, Apatinib, Fruquintinib, Sorafenib, Sunitinib, Pazopanib on gastric cancer when used alone or in combination based on prospective clinical trials reported in the literature, and sorted response biomarkers. We also summarized the challenges faced by anti-angiogenesis therapy for gastric cancer and available solutions. Finally, the characteristics of the current clinical research are summarized and suggestions and prospects are raised. This review will serve as a good reference for the clinical research of anti-angiogenic targeted drugs in the treatment of gastric cancer.

alpha-Fetoprotein (AFP)-producing gastric cancer is a rare tumour. It is said to have a high incidence of liver metastasis and poor prognosis. This study sought to evaluate long-term outcomes in such patients. Records of consecutive patients with gastric carcinoma who underwent preoperative measurement of serum AFP levels and gastrectomy were reviewed to identify those who satisfied the following criteria: preoperative AFP level exceeding 40 ng/ml with a decrease after gastrectomy, or raised preoperative AFP level (10-39 ng/ml) and resected tumour showing histologically characteristic features or immunohistochemically positive AFP production. Of 3374 patients with gastric cancer, 53 (1.6 per cent) met the selection criteria. Tumours were characterized by a high incidence of nodal (79 per cent) or liver (53 per cent) metastasis. Preoperative serum AFP levels showed no correlation with tumour size, depth of invasion, disease stage or survival. The 5-year survival rate was 34 per cent. Five patients survived after recurrence following multimodal treatment. A rising AFP level during follow-up always led to tumour recurrence, but the level remained normal in 11 of 31 patients with recurrence. AFP-producing tumours represent a small subgroup of gastric cancer with high metastatic potential. Postoperative serum AFP level can help predict recurrence but a normal level does not mean absence of recurrence. Prognosis is not as poor as previously thought, and multimodal treatment may be worthwhile even in patients with recurrent tumour.

Background The efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy in neoadjuvant therapy for locally advanced gastric cancer has been explored. However, limited research exists on its effectiveness in conversion therapy, and its superiority over standalone chemotherapy remains to be elucidated. This study aims to investigate the efficacy and survival outcomes of patients treated with ICIs in combination with conversion therapy for locally advanced gastric cancer. Methods Retrospective data from patients with locally advanced gastric cancer treated with either oxaliplatin + S-1(SOX) alone or in combination with ICIs in conversion therapy were collected. Clinical and pathological characteristics, disease-free survival, and efficacy assessments in nonoperable patients were compared between the 2 treatment groups. Efficacy was further evaluated through dynamic changes in serum markers, and patients’ quality of life was assessed using the QLQ-STO22 (Gastric Cancer–Specific Quality of Life Questionnaire) quality-of-life measurement scale. Results A total of 140 patients underwent conversion therapy: 80 in the SOX alone group and 60 in the SOX combined with the ICIs group. There were no significant differences in baseline characteristics between the 2 groups. Compared with the SOX alone group, the SOX combined with ICIs group exhibited a higher conversion rate (83.3% vs 75%, P = 0.23), R0 resection rate (90.0% vs 83.3%, P = 0.31), pathological complete response (pCR) rate (18% vs 5%, P = 0.02), median disease-free survival (21.4 vs 16.9 months, P = 0.007), the objective response rate in nonoperable patients (60% vs 40%, P = 0.301), and median progression-free survival time (7.9 vs 5.7 months, P = 0.009). The QLQ-STO22 quality-of-life assessment revealed statistically significant improvements in pain, swallowing difficulties, and dietary restrictions in the combination therapy group compared with those in the monotherapy group. The enhanced efficacy of immune combination with SOX is evident, as demonstrated by the significantly prolonged surgical duration in operated patients (206.6 ± 26.6 min vs 197.8 ± 19.8 min, P = 0.35) and intraoperative blood loss (158.9 ± 21.2 mL vs 148.9 ± 25.1 mL, P = 0.59). No significant differences were observed in postoperative complications. Conclusions Compared with the SOX conversion therapy regimen, SOX combined with ICIs demonstrated higher conversion rates, R0 resection rates, pathological response rates, and disease-free survival without increasing surgical difficulty or complications. Nonoperable patients also experienced longer progression-free survival and objective response rates.

Serum hyaluronic acid and laminin as potential tumor markers for upper gastrointestinal cancers

Objective: This study aims to investigate the potential of natural compounds targeting UCP2 as a foundation for molecular targeted therapy in gastric cancer. Methods: We conducted a database analysis to assess UCP2 expression in tumors, examined the correlation between UCP2 expression levels and survival rates in gastric cancer patients, and explored the association between UCP2 expression and the tumor immune microenvironment in gastric cancer. Virtual screening and molecular docking techniques were employed to identify optimal natural products targeting UCP2. Results: UCP2 is overexpressed in gastric cancer, and this overexpression is associated with poor prognosis. Additionally, UCP2 expression influences the tumor immune microenvironment. Virtual screening identified that Anhydronotoptol, Naringenin chalcone, Paliperidone, Retinoic acid, β-Anhydroicaritin, and β-Naphthoflavone exhibit strong interactions with UCP2. Conclusion: Anhydronotoptol, Naringenin chalcone, Paliperidone, Retinoic acid, β-Anhydroicaritin, and β-Naphthoflavone may offer therapeutic benefits in gastric cancer by targeting UCP2.

BackgroundHepatocellular carcinoma (HCC) is a highly malignant disease with poor prognosis, and most cases were already considered unresectable at the time of presentation. Conversion therapy, as an emerging treatment, is designed to provide patients with initially unresectable hepatocellular carcinoma (uHCC) the opportunity to undergo radical resection. At present, conversion therapy for patients with uHCC remains controversial. Transarterial chemoembolization (TACE) is currently the most widely selected treatment for uHCC, but its efficacy as a conversion therapy remains controversial.MethodsWe compared and evaluated the conversion rate for and tumor response to TACE monotherapy or combination therapy. Meanwhile, postoperative complications and overall survival (OS) in uHCC patients who underwent conversion therapy were also analyzed.ResultsA total of 18 studies were included in this meta-analysis. The conversion rate for triple therapy [TACE in combination with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)] was 42% [95% confidence interval (CI), 0.29–0.56], higher than any other group [TACE monotherapy: 10% (95% CI, 0.08–0.12), bigeminy therapy: 19% (95% CI, 0.06–0.36)]. Meanwhile, triple therapy yielded a better tumor response than TACE monotherapy or bigeminy therapy. Among the patients with successful surgical resection after conversion therapy, the pooled postoperative OS rates at 1, 2, and 5 years were 90% (95% CI, 0.81–0.97), 58% (95% CI, 0.42–0.73), and 42% (95% CI, 0.26–0.60), respectively, and the major postoperative complications were biliary leakage (7%; 95% CI, 0.03–0.12) and liver failure (3%; 95% CI, 0.00–0.07).ConclusionTACE conversion therapies showed good conversion rates, especially the triple therapy of TACE in combination with TKIs and ICIs. Surgical resection after successful conversion therapy could maximize the outcome of patients with uHCC.

Photodynamic therapy may salvage chemotherapy failure in gastric cancer: A case report and a literature review

Amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein is found in 15%-20% of patients with gastric and gastroesophageal junction cancer. The degree of HER2 overexpression and amplification varies with the location of the carcinoma, with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach. Further, HER2 overexpression and amplification also seems to be related to the Lauren histological classification, with higher levels found in the intestinal phenotype compared to the diffuse and mixed types. The prognostic properties of HER2 overexpression and amplification are still under debate, but a large number of studies seem to indicate that HER2 is a negative prognostic factor. The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial, where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive 5-FU/capecitabine and cisplatin, either alone or in combination with trastuzumab. A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy. Patients with a strong overexpression of the HER2 protein (IHC3+) specifically benefited from the treatment, with a median overall survival of 17.9 mo. As a consequence of the positive results of the ToGA trial, patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2. The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab, ado-trastuzumab emtansine, lapatinib, afatinib, and dacomitinib, which are currently undergoing phase II and III clinical testing. Overall, this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.

Gastric cancer is one of the most common and deadly types of cancer in the world, and poor prognosis with treatment failure is widely reported in the literature. In this context, kinases have been considered a relevant choice for targeted therapy in gastric cancer. Here, we explore the antiproliferative and antimigratory effects of the AURKA inhibitor and the prognostic and therapeutic value as a biomarker of gastric cancer. A total of 145 kinase inhibitors were screened to evaluate the cytotoxic or cytostatic effects in the gastric cancer cell line. Using the Alamar Blue assay, flow cytometry, quantitative polymerase chain reaction, and observation of caspase 3/7 activity and cell migration, we investigated the antiproliferative, proapoptotic, and antimigratory effects of the AURKA inhibitor. Moreover, AURKA overexpression was evaluated in the gastric cell lines and the gastric tumor tissue. Out of the 145 inhibitors, two presented the highest antiproliferative effect. Both molecules can induce apoptosis by the caspases 3/7 pathway in addition to inhibiting cancer cell migration, mainly the AURKA inhibitor. Moreover, molecular docking analysis revealed that GW779439X interacts in the active site of the AURKA enzyme with similar energy as a well-described inhibitor. Our study identified AURKA overexpression in the gastric cancer cell line and gastric tumor tissue, revealing that its overexpression in patients with cancer is correlated with low survival. Therefore, it is feasible to suggest AURKA as a potential marker of gastric cancer, besides providing robust information for diagnosis and estimated survival of patients. AURKA can be considered a new molecular target used in the prognosis and therapy of gastric cancer.