{"paper_id":"2a481911-9bb5-4e3f-bb21-8a31e47e82e8","body_text":"Impact of first-line nivolumab plus chemotherapy on conversion surgery rate for advanced gastric/esophagogastric junction cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of first-line nivolumab plus chemotherapy on conversion surgery rate for advanced gastric/esophagogastric junction cancer Akihiko Sano, Nobuhiro Nakazawa, Kengo Kuriyama, Takuhisa Okada, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7634092/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Systemic chemotherapy plus nivolumab is a first-line treatment in unresectable advanced gastric cancer; however, the ideal determination of conversion surgery eligibility remains unclear. This study identified predictors and prognostic factors related to conversion surgery, including the effects of first-line nivolumab. Methods : This single-institutional retrospective study included 129 patients who received systemic chemotherapy for advanced gastric or esophagogastric junction cancer. Data were compared between treatments with and without first-line nivolumab and 1:2 propensity score matching was performed to adjust for baseline differences. Results : Conversion surgery was performed in 17 (13.2%) patients. With nivolumab plus chemotherapy, the conversion surgery rate was 36.8% (7/19). In a multivariate analysis, the combination of nivolumab as first-line treatment was an independent predictor of conversion surgery both before and after matching. Minimally invasive surgery was performed on seven patients, six of whom were patients receiving nivolumab with R0 resection. An Eastern Cooperative Oncology Group Performance Status of ≥1, presence of liver metastasis, and conversion surgery were independent prognostic factors in advanced gastric cancer. Conclusions : First-line nivolumab combination chemotherapy improved eligibility for conversion surgery in advanced gastric or esophagogastric junction cancer. Understanding the prognostic factors identified herein may help guide treatment selection and improve patient outcomes. advanced gastric cancer nivolumab plus chemotherapy conversion surgery propensity score-matched analysis prognostic factors Figures Figure 1 Figure 2 Introduction In Japan, the incidence and mortality rates of stomach cancer in 2020 were 86.9 and 33.4 per 100,000 people, respectively. Gastric cancer was the most common type of digestive cancer when colon and rectal cancers were counted separately [ 1 ]. The Japanese Gastric Cancer Treatment Guidelines [ 2 ] recommend systemic chemotherapy for prolonging survival and alleviating symptoms in patients with unresectable advanced gastric cancer (AGC). Recently, a combination of oxaliplatin-based chemotherapy and nivolumab, an immune checkpoint inhibitor, was reported to improve overall survival (OS) and progression-free survival (PFS) rates when used as a first-line treatment for advanced gastric or esophagogastric junction cancer (AGEJC) [ 3 , 4 ]. A 3-year follow-up report from the CheckMate 649 [ 5 ] showed that PFS in the subset with a combined positive score of ≥ 5 was significantly longer in the nivolumab plus chemotherapy group (median 8.3 vs. 6.1 months; hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60–0.81). The OS was also significantly longer (median 14.4 vs. 11.1 months; HR 0.70, 95% CI 0.61–0.81), and the objective response rate was also higher in the nivolumab plus chemotherapy group (60% vs. 45%). Based on the results of these clinical trials, a combination of nivolumab and chemotherapy is recommended as the first-line treatment for HER2-negative unresectable advanced or recurrent gastric cancer or esophagogastric junction cancer. In patients with AGC, reduction surgery, defined as gastrectomy performed in patients with incurable factors such as unresectable liver and peritoneal metastases, did not show a survival benefit in an international randomized controlled trial (RCT) [ 6 ]. However, in recent years, it has been reported that patients with AGC can expect long-term survival after undergoing conversion surgery (CS) if chemotherapy is effective. Yoshida et al. [ 7 ] reported that the median survival time of all patients who underwent CS was 36.7 months, and those who underwent R0, R1, and R2 resection were 56.6, 25.8, and 21.7 months, respectively. CS is safe and could be a new therapeutic strategy for improving the survival of patients with AGEJC, particularly those undergoing R0 resection. Although the advisability of minimally invasive surgery (MIS) as a CS is controversial, MIS after preoperative chemotherapy has been reported to be feasible and safe for AGEJC [ 8 ]. While systemic chemotherapy is administered to patients with AGEJC, the factors that determine the suitability of CS in these patients remain unclear. This study aimed to identify the clinicopathological characteristics and prognostic factors of patients who underwent systemic chemotherapy, including the effects of nivolumab as a first-line treatment and the significance of CS. Additionally, this study aimed to review the perioperative outcomes in patients who underwent CS. These findings may help to determine whether CS should be performed and can improve the prognosis of patients with AGEJC. Patients and Methods Patients and Data Collection This single-center retrospective study included 161 patients with unresectable advanced gastric and esophagogastric junction cancer, histologically confirmed as adenocarcinoma, who underwent systemic chemotherapy between January 2011 and September 2023 at Gunma University Hospital. Among them, 32 patients who received non-standard chemotherapy were excluded. Finally, 129 patients with AGEJC who underwent the recommended multidrug chemotherapy were included in this study (Fig. 1). Data on patient demographics and clinical characteristics were extracted from the medical records, including sex, age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), primary site (gastric or esophagogastric junction), histological type (Lauren classification), site of metastasis, number of organs with metastasis, and treatment regimens. In the patients included in this study, after nivolumab combination chemotherapy became eligible for insurance coverage, it was administered to HER2-negative patients regardless of programmed death ligand 1 (PD-L1) CPS. Among patients enrolled after 2022, only two received S-1 plus oxaliplatin therapy without nivolumab due to poor ECOG PS. P ropensity Score-Matched Analysis We performed propensity score matching to reduce selection bias and balance the baseline characteristics of patients with and without nivolumab in first-line treatment. Propensity scores were estimated using a logistic regression model that included the following covariates: sex, age, ECOG PS, tumor location, Lauren classification, distant lymph node metastasis, peritoneal dissemination, liver metastasis, lung metastasis, and number of organs with metastasis. Patients were matched at a 1:2 ratio using nearest-neighbor matching without replacement and with a caliper width of 0.20 standard deviations of the logit of the propensity score (n=48). After matching, the distribution of propensity scores was well balanced between the groups. Indication Criteria and Extent of Resection for Conversion Surgery The indication criteria for CS are that drug therapy for clinical Stage IV gastric cancer and esophagogastric junction cancer is effective, and that R0 resection can be achieved. The extent of resection when performing CS involves gastrectomy with D2 dissection, including resection of metastatic lesions. In cases of para-aortic lymph node metastasis, only metastatic lymph nodes are removed, and systematic D3 dissection is not performed. Outcomes and Survival Assessment Perioperative data, including the chemotherapy period before CS, surgical procedure, approach, associated resected organs, operative time, and blood loss, were extracted from medical records. The severity of postoperative complications was evaluated according to the Clavien–Dindo classification (C–D) [9], and adverse events were defined as C–D grade ≥IIIa. Pathological responses were evaluated based on the Japanese classification of gastric carcinomas [10]. The median OS was calculated using the Kaplan–Meier method. OS was assessed from the date of first-line treatment initiation until death from any cause or censored at the latest follow-up for surviving patients. Statistical Analysis Differences between groups were compared using Fisher’s exact test for categorical variables and the Mann–Whitney U test for continuous variables. Univariate and multivariate logistic analyses were performed to identify the predictors of CS. OS estimates were obtained using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards regression model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Factors associated with OS were identified using univariate analyses, and those identified as statistically significant in the univariate analyses (p<0.05) were included in multivariate models. All data were analyzed using EZR, a freely available, easy-to-use medical statistical software package (available at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) [11]. The threshold for statistical significance was set at p<0.05. Ethics Approval and Consent to Participate This study was conducted according to the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the Gunma University Hospital (approval number: HS 2022–022). The details of the regimen, possible adverse events, expected effects of systemic chemotherapy, surgical details, and possible adverse events after surgery for gastric or esophagogastric junction cancer were explained, and informed consent was obtained from all patients. Results Clinical Characteristics of Patients CS was performed in 17 (13.2%) patients with AGEJC who underwent multidrug chemotherapy. The baseline characteristics of the patients who did or did not receive first-line nivolumab are summarized in Table 1. The results showed that, among patients receiving first-line nivolumab (n=19), most received SOX-based regimens (18/19; 94.7%). Notably, first-line nivolumab plus chemotherapy significantly increased the number of patients who underwent CS compared to prior chemotherapy alone (p=0.004) before propensity score matching. With the introduction of nivolumab plus chemotherapy as the first-line treatment for AGC, the conversion surgery rate increased to 36.8% (7/19). After matching, patient characteristics were confirmed to be well balanced. Similar to pre-matching, CS was significantly more prevalent in the first-line nivolumab group after matching (31.2% vs. 6.2%; p=0.033). Clinical Characteristics of Patients with Nivolumab Combination in First-Line Treatment (n=19) In patients receiving nivolumab (n=19), microsatellite instability status was not measured before treatment; however, PD-L1 combined positive score (CPS) was measured in seven patients. Of these, one patient had a CPS<1, four patients had a 1<CPS<5, and two patients had a CPS ≥5. Immune-related adverse events (irAEs) were observed in five patients. Grade ≥3 irAEs included adrenal insufficiency in one patient, pituitary insufficiency in one patient, and liver failure in one patient. Univariate and Multivariable Logistic Analyses or Predictors of CS for Patients with AGEJC Predictors of CS in patients with AGEJC were evaluated using univariate and multivariate logistic analyses (Table 2). In multivariate analysis, the combination of nivolumab as first-line treatment (p=0.002) was an independent predictor of CS, along with an ECOG PS of 0 (p=0.042), and only one organ with metastasis (p=0.013). After matching, first-line treatment with nivolumab (p=0.026) was identified as independent predictor of CS. Perioperative and Pathological Outcomes of Patients who Underwent CS The details of the patients who underwent CS are shown in Table 3. MIS was performed in seven (33.3%) patients, six of whom were patients receiving nivolumab (p<0.001), with R0 resection in all cases. The median duration of chemotherapy before CS was 4.9 months, compared with 7.1 months in the nivolumab group and 4.2 months in the chemotherapy alone group. In the patients who received first-line nivolumab, the estimated blood loss was significantly lower than that in those who did not receive first-line nivolumab (48.5 vs 385.5 ml, p=0.009). One patient experienced a postoperative complication of grade ≥3, which was pancreatic leakage in the first-line nivolumab group. Pathological response assessment revealed that grade 3 (i.e., pathological complete response) was observed in two patients (11.8%) in the nivolumab group. Chemotherapy was administered after CS in all 17 patients. The standard policy was to resume the drug therapy administered before CS. S-1 therapy was administered most frequently in nine patients (52.9%). In the first-line nivolumab (n=7), S-1 therapy was administered in three patients, and S-1 plus nivolumab therapy in another three patients. One patient who responded to paclitaxel plus ramucirumab therapy as second-line treatment after first-line nivolumab and subsequently underwent CS, resumed paclitaxel plus ramucirumab therapy after CS. Prognostic Factors for OS OS was significantly longer in patients who received nivolumab as first-line chemotherapy than in those who did not, both before (p=0.015) and after (p=0.019) propensity score matching (Fig. 2a and b). Similarly, patients who underwent CS had significantly better OS than those who underwent chemotherapy alone, both before (median OS 68.99 vs 17.58 months, p=0.004) and after (median OS NA vs 17.61 months, p=0.004) propensity score matching (Fig. 2c and d). In the univariate and multivariate Cox proportional hazards regression analyses for OS (Table 4), female sex (p=0.008), ECOG-PS ≥1 (p<0.001), presence of liver metastasis (p=0.036), and metastasis in two or more organs (p=0.03) were associated with poor prognosis in univariate analysis. The patients who underwent CS (p=0.007) and nivolumab treatment (p=0.021) had a significantly better prognosis. In multivariate analysis, an ECOG-PS ≥1 (HR=2.411, 95% CI: 1.436–4.046, p<0.001), presence of liver metastasis (HR=1.969, 95% CI: 1.103–3.516, p=0.022) and CS (HR=0.513, 95% CI: 0.177–0.683, p=0.007) were identified as independent prognostic factors in patients with AGEJC. Discussion In this single-institution retrospective study, 17 (13.2%) patients underwent CS after receiving the recommended multidrug chemotherapy. The introduction of nivolumab plus chemotherapy as a first-line treatment was revealed to be a strong predictor of CS in AGEJC even after propensity score matching. The addition of nivolumab increased the CS rate to 36.8% (7/19), indicating a strong effect. Patients who underwent CS had a significantly better prognosis, reaffirming the importance of surgery without residual cancer. MIS was performed in seven (41.2%) patients, with R0 resection in all patients. The present data demonstrates that nivolumab combination chemotherapy is a predictor of CS in AGEJC. In Japan, approximately 4 years have passed since nivolumab plus chemotherapy became the standard therapy for the first-line treatment of AGC based on the results of Checkmate 649 [3] and ATTRACTION 4 [4]. Nakazawa et al. [12] reported that CS after chemotherapy plus nivolumab as the first-line treatment for patients with AGEJC was performed in 11.5% of patients, with R0 resection in all patients, and that the low-risk Gustave Roussy Immune Score may be a predictor of CS. Similarly, Liang et al. [13] reported that the R0 resection rate for CS after immunochemotherapy as a first-line treatment in AGEJC was 90.5%, with perioperative complications including abdominal abscess (7.1%). In contrast, Hojo et al. [14] reported that chemotherapy with and without immune checkpoint inhibitors (ICIs) during primary treatment were not associated with CS achievement (p=0.590). However, they note that the efficacy of ICIs may have been underestimated because the number of patients receiving chemotherapy with ICIs was small. In our study, multivariate analysis showed that the combination of nivolumab as a first-line treatment, along with an ECOG PS of 0, and only one organ with metastasis, were significant predictors of CS. Therefore, it is plausible that administering nivolumab as a first-line treatment is greatly beneficial to patients with AGEJC, as it can extend their prognosis. While there are cases in which R0 resection is possible through conversion surgery and long-term prognosis can be expected, there is currently no consensus on how to predict early postoperative recurrence or the advisability of postoperative chemotherapy. Morito et al. [15] reported that recurrence within 6 months after CS, referred to as very early recurrence, correlates with a poor prognosis; thus, clinicians need to carefully consider the indications for CS, particularly in patients with poor nutritional status and liver metastases. Furthermore, Takeno et al. [16] reported that pathologically positive lymph node metastases and pathological T4 stage were poor prognostic factors in patients who underwent R0 resection. Currently, JCOG2301 has started as a randomized phase III trial to confirm whether CS after palliative chemotherapy has additional benefits versus palliative chemotherapy alone [17]. Micrometastasis will likely remain even if R0 resection was achieved after conversion surgery. In this study, all patients resumed chemotherapy after CS. Chemotherapy performed before CS was continued after CS; however, oxaliplatin was often administered 6–8 times before CS, making it difficult to continue after CS. Further verification is needed regarding the appropriateness of chemotherapy after CS, as no randomized controlled trials or even retrospective studies have been reported to date. MIS has been recognized as an effective treatment option for early gastric cancer with fewer postoperative complications, less pain, and early recovery [18,19]. The effectiveness of MIS has also been reported in patients with AGC, and the postoperative complications [20–22] and long-term outcomes [23] are equivalent to those of conventional open surgery. However, no large-scale RCTs have reported the MIS of CS for AGEJC. In a retrospective study comparing open surgery and MIS for resection after chemotherapy in stage IV gastric cancer, Yamamoto et al. [24] reported that MIS for cStage IV gastric cancer had a longer operative time than open surgery (339 vs. 266 min, p=0.039) but had less blood loss (10 mL vs. 520 mL, p<0.0001), shorter hospital stay (8 days vs. 12 days, p<0.0001), better median recurrence-free survival (31.0 months vs. 11.3 months, p=0.022), and better median OS (52.7 months vs. 22.4 months, p=0.0028). Furthermore, MIS was not a significant negative prognostic factor for OS after resection in multivariate analysis (HR 0.44, 95% CI: 0.15–1.10, p=0.081). These results suggest that the introduction of MIS in CS for cStage IV gastric cancer is expected to reduce bleeding and postoperative complications and may enable earlier resumption of postoperative chemotherapy, leading to an improved prognosis. Therefore, conversion surgery with MIS may be considered a potential treatment option for stage IV gastric cancer. However, further studies are required to verify this contention. Results from the SPOTLIGHT [25] and GLOW [26] trials demonstrate that zolbetuximab, a monoclonal antibody targeting claudin 18.2, significantly improved PFS and OS when combined with chemotherapy as the first-line treatment of HER2-negative and Claudin-positive AGC. In addition, the KEYNOTE-859 trial [27] reported that pembrolizumab and chemotherapy combination therapy, as immune checkpoint inhibitors in the first-line treatment of HER2-negative AGC, improved OS and PFS compared to chemotherapy alone. Furthermore, bemarituzumab, a monoclonal antibody against fibroblast growth factor receptor 2b, may improve PFS and OS in combination with mFOLFOX6 therapy for HER2-negative, FGFR2b-positive AGC [28], and confirmatory phase 3 trials are currently ongoing. In contrast, the KEYNOTE-811 trial reported that the combination of pembrolizumab, trastuzumab, and chemotherapy significantly improved PFS in patients with HER2-positive AGC [29]. As these drugs become available for use in clinical practice, the outcomes of first-line treatment are expected to continue to improve, leading to an increase in the CS rate and improved prognosis. This study has some limitations. First, this was a retrospective, single-center, observational study with a small sample size; therefore, the findings may have been affected by a selection bias. Although multivariate analysis was performed, the small sample size raises the possibility of overfitting and type II error. Second, although based on the gastric cancer treatment guidelines, several chemotherapy regimens were determined according to the clinical preferences of each investigator. In this study, the introduction of nivolumab as first-line treatment significantly improved the CS rate, and the results are expected to improve prognosis. However, because the MIS rate in the CS group was significantly higher, an RCT should be conducted to demonstrate the efficacy of CS. In conclusion, this study demonstrated that the introduction of nivolumab combination chemotherapy as first-line treatment significantly increased the rate of CS in AGEJC. In addition, an ECOG-PS of 0, metastasis to one organ, and CS were identified as independent prognostic factors in patients with AGEJC. It is imperative to perform CS while minimizing postoperative complications. Laparoscopic or robot-assisted surgery may contribute to the early initiation of chemotherapy after CS, which may ultimately lead to improved prognosis. Further investigation is needed to determine the chemotherapy regimens that are effective for cStage IV gastric cancer when CS is considered, the safety and efficacy of MIS for CS, and the optimal chemotherapy regimen after CS. Declarations Acknowledgments We want to thank Editage (www.editage.com) for the English language editing. Competing interests and funding All authors declare that they have no conflict of interest. This research study did not receive funding from the public, private sector, or non-profit entities. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. References Higashi T, Kurokawa Y. Incidence, mortality, survival, and treatment statistics of cancers in digestive organs-Japanese cancer statistics 2024. Ann Gastroenterol Surg 2024;8:958–965. https://doi.org/ 10.1002/ags3.12835 Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer 2023;26:1–25. https://doi.org/10.1007/s10120-022-01331-8 Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. 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Gastric Cancer 2024;27:558–570. https://doi.org/10.1007/s10120-024-01466-w Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 2023;402:2197–2208. https://doi.org/10.1016/S0140-6736(23)02033-0 Tables Tables 1 to 4 are available in the Supplementary Files section. Supplementary Files Table1ver3.xlsx Table2ver3.xlsx Table3ver2.xlsx Table4ver2.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7634092\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":516747695,\"identity\":\"6f83ea41-6656-4fc5-8fbd-300329b8d19e\",\"order_by\":0,\"name\":\"Akihiko 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06:56:52\",\"extension\":\"html\",\"order_by\":16,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":94065,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"earlyproof.html\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/416f3a40c6be63c2eda3f2a5.html\"},{\"id\":92472886,\"identity\":\"f0e18943-831e-485f-bcaa-b11fc7bd63a5\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 06:56:51\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":873262,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlow chart of the study population selection. Abbreviations: G/EGJ, gastric/esophagogastric junction\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/829958007a4990c98cb91786.jpg\"},{\"id\":92474602,\"identity\":\"c6a4efba-cd79-453d-862e-88260c1c107f\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 07:12:52\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1403185,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan–Meier curve for overall survival according to combination with nivolumab as first-line chemotherapy before (a) and after (b) propensity score matching. Kaplan–Meier curve for overall survival in patients who underwent conversion surgery and those who received chemotherapy alone before (c) and after (d) propensity score matching.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/e7ceb84a9107b46b0ee701a7.jpg\"},{\"id\":98438060,\"identity\":\"ae1e17ca-2b6b-4a7e-a029-e1043e384ee4\",\"added_by\":\"auto\",\"created_at\":\"2025-12-17 16:58:36\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2927659,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/20607218-43b2-433b-bb38-c08233d88502.pdf\"},{\"id\":92472881,\"identity\":\"6288707d-be4c-4e91-88f9-3c7fb72c087e\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 06:56:51\",\"extension\":\"xlsx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":13511,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table1ver3.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/2b90ada8ad3800ed9eb45ec3.xlsx\"},{\"id\":92472882,\"identity\":\"a954cc2c-555c-4773-9b98-56fca41eed91\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 06:56:51\",\"extension\":\"xlsx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":11596,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table2ver3.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/584891431a3af6e417da58f1.xlsx\"},{\"id\":92472884,\"identity\":\"81bb3bf9-c080-4de0-bb76-14e35a47eb3f\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 06:56:51\",\"extension\":\"xlsx\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":12508,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table3ver2.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/aeffb111b04282481ef3cbdc.xlsx\"},{\"id\":92473344,\"identity\":\"fb133bfa-ebda-4946-b9f8-3acf8f4f57eb\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 07:04:52\",\"extension\":\"xlsx\",\"order_by\":4,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":11094,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table4ver2.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7634092/v1/3d3f65d9d26f88878019501d.xlsx\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Impact of first-line nivolumab plus chemotherapy on conversion surgery rate for advanced gastric/esophagogastric junction cancer\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eIn Japan, the incidence and mortality rates of stomach cancer in 2020 were 86.9 and 33.4 per 100,000 people, respectively. Gastric cancer was the most common type of digestive cancer when colon and rectal cancers were counted separately [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. The Japanese Gastric Cancer Treatment Guidelines [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e] recommend systemic chemotherapy for prolonging survival and alleviating symptoms in patients with unresectable advanced gastric cancer (AGC). Recently, a combination of oxaliplatin-based chemotherapy and nivolumab, an immune checkpoint inhibitor, was reported to improve overall survival (OS) and progression-free survival (PFS) rates when used as a first-line treatment for advanced gastric or esophagogastric junction cancer (AGEJC) [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. A 3-year follow-up report from the CheckMate 649 [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e] showed that PFS in the subset with a combined positive score of \\u0026ge;\\u0026thinsp;5 was significantly longer in the nivolumab plus chemotherapy group (median 8.3 vs. 6.1 months; hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60\\u0026ndash;0.81). The OS was also significantly longer (median 14.4 vs. 11.1 months; HR 0.70, 95% CI 0.61\\u0026ndash;0.81), and the objective response rate was also higher in the nivolumab plus chemotherapy group (60% vs. 45%). Based on the results of these clinical trials, a combination of nivolumab and chemotherapy is recommended as the first-line treatment for HER2-negative unresectable advanced or recurrent gastric cancer or esophagogastric junction cancer.\\u003c/p\\u003e\\u003cp\\u003eIn patients with AGC, reduction surgery, defined as gastrectomy performed in patients with incurable factors such as unresectable liver and peritoneal metastases, did not show a survival benefit in an international randomized controlled trial (RCT) [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. However, in recent years, it has been reported that patients with AGC can expect long-term survival after undergoing conversion surgery (CS) if chemotherapy is effective. Yoshida et al. [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e] reported that the median survival time of all patients who underwent CS was 36.7 months, and those who underwent R0, R1, and R2 resection were 56.6, 25.8, and 21.7 months, respectively. CS is safe and could be a new therapeutic strategy for improving the survival of patients with AGEJC, particularly those undergoing R0 resection. Although the advisability of minimally invasive surgery (MIS) as a CS is controversial, MIS after preoperative chemotherapy has been reported to be feasible and safe for AGEJC [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. While systemic chemotherapy is administered to patients with AGEJC, the factors that determine the suitability of CS in these patients remain unclear.\\u003c/p\\u003e\\u003cp\\u003eThis study aimed to identify the clinicopathological characteristics and prognostic factors of patients who underwent systemic chemotherapy, including the effects of nivolumab as a first-line treatment and the significance of CS. Additionally, this study aimed to review the perioperative outcomes in patients who underwent CS. These findings may help to determine whether CS should be performed and can improve the prognosis of patients with AGEJC.\\u003c/p\\u003e\"},{\"header\":\"Patients and Methods\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePatients and Data Collection\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis single-center retrospective study included 161 patients with unresectable advanced gastric and esophagogastric junction cancer, histologically confirmed as adenocarcinoma, who underwent systemic chemotherapy between January 2011 and September 2023 at Gunma University Hospital. Among them, 32 patients who received non-standard chemotherapy were excluded. Finally, 129 patients with AGEJC who underwent the recommended multidrug chemotherapy were included in this study (Fig. 1). Data on patient demographics and clinical characteristics were extracted from the medical records, including sex, age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), primary site (gastric or esophagogastric junction), histological type (Lauren classification), site of metastasis, number of organs with metastasis, and treatment regimens. In the patients included in this study, after nivolumab combination chemotherapy became eligible for insurance coverage, it was administered to HER2-negative patients regardless of programmed death ligand 1 (PD-L1) CPS. Among patients enrolled after 2022, only two received S-1 plus oxaliplatin therapy without nivolumab due to poor ECOG PS.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e\\u003cem\\u003eropensity Score-Matched Analysis\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe performed propensity score matching to reduce selection bias and balance the baseline characteristics of patients with and without nivolumab in first-line treatment. Propensity scores were estimated using a logistic regression model that included the following covariates: sex, age, ECOG PS, tumor location, Lauren classification, distant lymph node metastasis, peritoneal dissemination, liver metastasis, lung metastasis, and number of organs with metastasis. Patients were matched at a 1:2 ratio using nearest-neighbor matching without replacement and with a caliper width of 0.20 standard deviations of the logit of the propensity score (n=48). After matching, the distribution of propensity scores was well balanced between the groups.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eIndication Criteria and Extent of Resection for Conversion Surgery\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe indication criteria for CS are that drug therapy for clinical Stage IV gastric cancer and esophagogastric junction cancer is effective, and that R0 resection can be achieved. The extent of resection when performing CS involves gastrectomy with D2 dissection, including resection of metastatic lesions. In cases of para-aortic lymph node metastasis, only metastatic lymph nodes are removed, and systematic D3 dissection is not performed.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eOutcomes and Survival Assessment\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePerioperative data, including the chemotherapy period before CS, surgical procedure, approach, associated resected organs, operative time, and blood loss, were extracted from medical records. The severity of postoperative complications was evaluated according to the Clavien\\u0026ndash;Dindo classification (C\\u0026ndash;D) [9], and adverse events were defined as C\\u0026ndash;D grade \\u0026ge;IIIa. Pathological responses were evaluated based on the Japanese classification of gastric carcinomas [10].\\u003c/p\\u003e\\n\\u003cp\\u003eThe median OS was calculated using the Kaplan\\u0026ndash;Meier method. OS was assessed from the date of first-line treatment initiation until death from any cause or censored at the latest follow-up for surviving patients.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eStatistical Analysis\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDifferences between groups were compared using Fisher\\u0026rsquo;s exact test for categorical variables and the Mann\\u0026ndash;Whitney\\u003cem\\u003e\\u0026nbsp;U\\u003c/em\\u003e test for continuous variables. Univariate and multivariate logistic analyses were performed to identify the predictors of CS. OS estimates were obtained using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards regression model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Factors associated with OS were identified using univariate analyses, and those identified as statistically significant in the univariate analyses (p\\u0026lt;0.05) were included in multivariate models. All data were analyzed using EZR, a freely available, easy-to-use medical statistical software package (available at http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) [11]. The threshold for statistical significance was set at p\\u0026lt;0.05.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eEthics Approval and Consent to Participate\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was conducted according to the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the Gunma University Hospital (approval number: HS 2022\\u0026ndash;022). The details of the regimen, possible adverse events, expected effects of systemic chemotherapy, surgical details, and possible adverse events after surgery for gastric or esophagogastric junction cancer were explained, and informed consent was obtained from all patients.\\u003c/p\\u003e\"},{\"header\":\"Results \",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eClinical Characteristics of Patients\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eCS was performed in 17 (13.2%) patients with AGEJC who underwent multidrug chemotherapy. The baseline characteristics of the patients who did or did not receive first-line nivolumab are summarized in Table 1. The results showed that, among patients receiving first-line nivolumab (n=19), most received SOX-based regimens (18/19; 94.7%). Notably, first-line nivolumab plus chemotherapy significantly increased the number of patients who underwent CS compared to prior chemotherapy alone (p=0.004) before propensity score matching. With the introduction of nivolumab plus chemotherapy as the first-line treatment for AGC, the conversion surgery rate increased to 36.8% (7/19). After matching, patient characteristics were confirmed to be well balanced. Similar to pre-matching, CS was significantly more prevalent in the first-line nivolumab group after matching (31.2% vs. 6.2%; p=0.033).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eClinical Characteristics of Patients with Nivolumab Combination in First-Line Treatment (n=19)\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn patients receiving nivolumab (n=19), microsatellite instability status was not measured before treatment; however, PD-L1 combined positive score (CPS) was measured in seven patients. Of these, one patient had a CPS\\u0026lt;1, four patients had a 1\\u0026lt;CPS\\u0026lt;5, and two patients had a CPS \\u0026ge;5. Immune-related adverse events (irAEs) were observed in five patients. Grade \\u0026ge;3 irAEs included adrenal insufficiency in one patient, pituitary insufficiency in one patient, and liver failure in one patient.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eUnivariate and Multivariable Logistic Analyses or Predictors of CS for Patients with AGEJC\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePredictors of CS in patients with AGEJC were evaluated using univariate and multivariate logistic analyses (Table 2). In multivariate analysis, the combination of nivolumab as first-line treatment (p=0.002) was an independent predictor of CS, along with an ECOG PS of 0 (p=0.042), and only one organ with metastasis (p=0.013). After matching, first-line treatment with nivolumab (p=0.026) was identified as independent predictor of CS.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePerioperative and Pathological Outcomes of Patients who Underwent CS\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe details of the patients who underwent CS are shown in Table 3. MIS was performed in seven (33.3%) patients, six of whom were patients receiving nivolumab (p\\u0026lt;0.001), with R0 resection in all cases. The median duration of chemotherapy before CS was 4.9 months, compared with 7.1 months in the nivolumab group and 4.2 months in the chemotherapy alone group. In the patients who received first-line nivolumab, the estimated blood loss was significantly lower than that in those who did not receive first-line nivolumab (48.5 vs 385.5 ml, p=0.009). One patient experienced a postoperative complication of grade \\u0026ge;3, which was pancreatic leakage in the first-line nivolumab group. Pathological response assessment revealed that grade 3 (i.e., pathological complete response) was observed in two patients (11.8%) in the nivolumab group. Chemotherapy was administered after CS in all 17 patients. The standard policy was to resume the drug therapy administered before CS. S-1 therapy was administered most frequently in nine patients (52.9%). In the first-line nivolumab (n=7), S-1 therapy was administered in three patients, and S-1 plus nivolumab therapy in another three patients. One patient who responded to paclitaxel plus ramucirumab therapy as second-line treatment after first-line nivolumab and subsequently underwent CS, resumed paclitaxel plus ramucirumab therapy after CS.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003ePrognostic Factors for OS\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eOS was significantly longer in patients who received nivolumab as first-line chemotherapy than in those who did not, both before (p=0.015) and after (p=0.019) propensity score matching (Fig. 2a and b). Similarly, patients who underwent CS had significantly better OS than those who underwent chemotherapy alone, both before (median OS 68.99 vs 17.58 months, p=0.004) and after (median OS NA vs 17.61 months, p=0.004) propensity score matching (Fig. 2c and d). In the univariate and multivariate Cox proportional hazards regression analyses for OS (Table 4), female sex (p=0.008), ECOG-PS \\u0026ge;1 (p\\u0026lt;0.001), presence of liver metastasis (p=0.036), and metastasis in two or more organs (p=0.03) were associated with poor prognosis in univariate analysis. The patients who underwent CS (p=0.007) and nivolumab treatment (p=0.021) had a significantly better prognosis. In multivariate analysis, an ECOG-PS \\u0026ge;1 (HR=2.411, 95% CI: 1.436\\u0026ndash;4.046, p\\u0026lt;0.001), presence of liver metastasis (HR=1.969, 95% CI: 1.103\\u0026ndash;3.516, p=0.022) and CS (HR=0.513, 95% CI: 0.177\\u0026ndash;0.683, p=0.007) were identified as independent prognostic factors in patients with AGEJC.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this single-institution retrospective study, 17 (13.2%) patients underwent CS after receiving the recommended multidrug chemotherapy. The introduction of nivolumab plus chemotherapy as a first-line treatment was revealed to be a strong predictor of CS in AGEJC even after propensity score matching. The addition of nivolumab increased the CS rate to 36.8% (7/19), indicating a strong effect. Patients who underwent CS had a significantly better prognosis, reaffirming the importance of surgery without residual cancer. MIS was performed in seven (41.2%) patients, with R0 resection in all patients.\\u003c/p\\u003e\\n\\u003cp\\u003eThe present data demonstrates that nivolumab combination chemotherapy is a predictor of CS in AGEJC. In Japan, approximately 4 years have passed since nivolumab plus chemotherapy became the standard therapy for the first-line treatment of AGC based on the results of Checkmate 649 [3] and ATTRACTION 4 [4]. Nakazawa et al. [12] reported that CS after chemotherapy plus nivolumab as the first-line treatment for patients with AGEJC was performed in 11.5% of patients, with R0 resection in all patients, and that the low-risk Gustave Roussy Immune Score may be a predictor of CS. Similarly, Liang et al. [13] reported that the R0 resection rate for CS after immunochemotherapy as a first-line treatment in AGEJC was 90.5%, with perioperative complications including abdominal abscess (7.1%). In contrast, Hojo et al. [14] reported that chemotherapy with and without immune checkpoint inhibitors (ICIs) during primary treatment were not associated with CS achievement (p=0.590). However, they note that the efficacy of ICIs may have been underestimated because the number of patients receiving chemotherapy with ICIs was small. In our study, multivariate analysis showed that the combination of nivolumab as a first-line treatment, along with an ECOG PS of 0, and only one organ with metastasis, were significant predictors of CS. Therefore, it is plausible that administering nivolumab as a first-line treatment is greatly beneficial to patients with AGEJC, as it can extend their prognosis. While there are cases in which R0 resection is possible through conversion surgery and long-term prognosis can be expected, there is currently no consensus on how to predict early postoperative recurrence or the advisability of postoperative chemotherapy. Morito et al. [15] reported that recurrence within 6 months after CS, referred to as very early recurrence, correlates with a poor prognosis; thus, clinicians need to carefully consider the indications for CS, particularly in patients with poor nutritional status and liver metastases. Furthermore, Takeno et al. [16] reported that pathologically positive lymph node metastases and pathological T4 stage were poor prognostic factors in patients who underwent R0 resection. Currently, JCOG2301 has started as a randomized phase III trial to confirm whether CS after palliative chemotherapy has additional benefits versus palliative chemotherapy alone [17]. Micrometastasis will likely remain even if R0 resection was achieved after conversion surgery. In this study, all patients resumed chemotherapy after CS. Chemotherapy performed before CS was continued after CS; however, oxaliplatin was often administered 6\\u0026ndash;8 times before CS, making it difficult to continue after CS. Further verification is needed regarding the appropriateness of chemotherapy after CS, as no randomized controlled trials or even retrospective studies have been reported to date.\\u003c/p\\u003e\\n\\u003cp\\u003eMIS has been recognized as an effective treatment option for early gastric cancer with fewer postoperative complications, less pain, and early recovery [18,19]. The effectiveness of MIS has also been reported in patients with AGC, and the postoperative complications [20\\u0026ndash;22] and long-term outcomes [23] are equivalent to those of conventional open surgery. However, no large-scale RCTs have reported the MIS of CS for AGEJC. In a retrospective study comparing open surgery and MIS for resection after chemotherapy in stage IV gastric cancer, Yamamoto et al. [24] reported that MIS for cStage IV gastric cancer had a longer operative time than open surgery (339 vs. 266 min, p=0.039) but had less blood loss (10 mL vs. 520 mL, p\\u0026lt;0.0001), shorter hospital stay (8 days vs. 12 days, p\\u0026lt;0.0001), better median recurrence-free survival (31.0 months vs. 11.3 months, p=0.022), and better median OS (52.7 months vs. 22.4 months, p=0.0028). Furthermore, MIS was not a significant negative prognostic factor for OS after resection in multivariate analysis (HR 0.44, 95% CI: 0.15\\u0026ndash;1.10, p=0.081). These results suggest that the introduction of MIS in CS for cStage IV gastric cancer is expected to reduce bleeding and postoperative complications and may enable earlier resumption of postoperative chemotherapy, leading to an improved prognosis. Therefore, conversion surgery with MIS may be considered a potential treatment option for stage IV gastric cancer. However, further studies are required to verify this contention.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eResults from the SPOTLIGHT [25] and GLOW [26] trials demonstrate that zolbetuximab, a monoclonal antibody targeting claudin 18.2, significantly improved PFS and OS when combined with chemotherapy as the first-line treatment of HER2-negative and Claudin-positive AGC. In addition, the KEYNOTE-859 trial [27] reported that pembrolizumab and chemotherapy combination therapy, as immune checkpoint inhibitors in the first-line treatment of HER2-negative AGC, improved OS and PFS compared to chemotherapy alone. Furthermore, bemarituzumab, a monoclonal antibody against fibroblast growth factor receptor 2b, may improve PFS and OS in combination with mFOLFOX6 therapy for HER2-negative, FGFR2b-positive AGC [28], and confirmatory phase 3 trials are currently ongoing. In contrast, the KEYNOTE-811 trial reported that the combination of pembrolizumab, trastuzumab, and chemotherapy significantly improved PFS in patients with HER2-positive AGC [29]. As these drugs become available for use in clinical practice, the outcomes of first-line treatment are expected to continue to improve, leading to an increase in the CS rate and improved prognosis.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThis study has some limitations. First, this was a retrospective, single-center, observational study with a small sample size; therefore, the findings may have been affected by a selection bias.\\u0026nbsp;Although multivariate analysis was performed, the small sample size raises the possibility of overfitting and type II error. Second, although based on the gastric cancer treatment guidelines, several chemotherapy regimens were determined according to the clinical preferences of each investigator. In this study, the introduction of nivolumab as first-line treatment significantly improved the CS rate, and the results are expected to improve prognosis. However, because the MIS rate in the CS group was significantly higher, an RCT should be conducted to demonstrate the efficacy of CS.\\u003c/p\\u003e\\n\\u003cp\\u003eIn conclusion, this study demonstrated that the introduction of nivolumab combination chemotherapy as first-line treatment significantly increased the rate of CS in AGEJC. In addition, an ECOG-PS of 0, metastasis to one organ, and CS were identified as independent prognostic factors in patients with AGEJC. It is imperative to perform CS while minimizing postoperative complications. Laparoscopic or robot-assisted surgery may contribute to the early initiation of chemotherapy after CS, which may ultimately lead to improved prognosis. Further investigation is needed to determine the chemotherapy regimens that are effective for cStage IV gastric cancer when CS is considered, the safety and efficacy of MIS for CS, and the optimal chemotherapy regimen after CS.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe want to thank Editage (www.editage.com) for the English language editing.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests and funding\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors declare that they have no conflict of interest. This research study did not receive funding from the public, private sector, or non-profit entities.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData availability statement\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cbr\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n \\u003cli\\u003eHigashi T, Kurokawa Y. Incidence, mortality, survival, and treatment statistics of cancers in digestive organs-Japanese cancer statistics 2024. Ann Gastroenterol Surg 2024;8:958\\u0026ndash;965. https://doi.org/\\u0026nbsp;10.1002/ags3.12835\\u003c/li\\u003e\\n \\u003cli\\u003eJapanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer 2023;26:1\\u0026ndash;25. https://doi.org/10.1007/s10120-022-01331-8\\u003c/li\\u003e\\n \\u003cli\\u003eJanjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet 2021;398:27\\u0026ndash;40. https://doi.org/10.1016/S0140-6736(21)00797-2\\u003c/li\\u003e\\n \\u003cli\\u003eKang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC,\\u0026nbsp;et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022;23:234\\u0026ndash;47. https://doi.org/10.1016/S1470-2045(21)00692-6\\u003c/li\\u003e\\n \\u003cli\\u003eJanjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C,\\u0026nbsp;et al. First-line nivolumab plus chemotherapy for Advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the Phase III CheckMate 649 Trial. J Clin Oncol 2024;42:2012\\u0026ndash;2020. https://doi.org/10.1200/JCO.23.01601\\u003c/li\\u003e\\n \\u003cli\\u003eFujitani K, Yang HK, Mizusawa J, Kim YW, Terashima M, Han SU,\\u0026nbsp;et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol 2016;17:309\\u0026ndash;18. https://doi.org/10.1016/S1470-2045(15)00553-7\\u003c/li\\u003e\\n \\u003cli\\u003eYoshida K, Yasufuku I, Terashima M, Young Rha S, Moon Bae J, Li G,\\u0026nbsp;et al. International Retrospective Cohort Study of Conversion Therapy for Stage IV Gastric Cancer 1 (CONVO-GC-1). Ann Gastroenterol Surg 2021;6:227\\u0026ndash;240. https://doi.org/10.1002/ags3.12515\\u003c/li\\u003e\\n \\u003cli\\u003eTanaka T, Suda K, Shibasaki S, Serizawa A, Akimoto A,\\u0026nbsp;Nakauchi M, et al. Safety and feasibility of minimally invasive gastrectomy following preoperative chemotherapy for highly advanced gastric cancer. BMC Gastroenterol 2024;24:74. https://doi.org/10.1186/s12876-024-03155-5\\u003c/li\\u003e\\n \\u003cli\\u003eClavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD,\\u0026nbsp;et al. The Clavien-Dindo classification of surgical complications: Five-year experience. Ann Surg 2009;250:187\\u0026ndash;196. https://doi.org/10.1097/SLA.0b013e3181b13ca2\\u003c/li\\u003e\\n \\u003cli\\u003eJapanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 14, 101\\u0026ndash;112 (2011). https://doi.org/10.1007/s10120-011-0041-5\\u003c/li\\u003e\\n \\u003cli\\u003eKanda Y. Investigation of the freely available easy-to-use software \\u0026lsquo;EZR\\u0026rsquo; for medical statistics. Bone Marrow Transplant 2013;48:452\\u0026ndash;458. https://doi.org/10.1038/bmt.2012.244\\u003c/li\\u003e\\n \\u003cli\\u003eNakazawa N, Sohda M, Hosoi N, Watanabe T, Kumakura Y, Yamashita T,\\u0026nbsp;et al. Conversion surgery after chemotherapy plus nivolumab as the first-line treatment for unresectable advanced or recurrent gastric cancer and a biomarker study using the gustave roussy immune score: a multicenter study. Ann Surg Oncol 2024;31:9023\\u0026ndash;9029. https://doi.org/10.1245/s10434-024-16161-4\\u003c/li\\u003e\\n \\u003cli\\u003eLiang H, Yan X, Li Z, Chen X, Qiu Y, Li F,\\u0026nbsp;et al. Clinical outcomes of conversion surgery following immune checkpoint inhibitors and chemotherapy in stage IV gastric cancer. Int J Surg 2023;109:4162\\u0026ndash;4172. https://doi.org/10.1097/JS9.0000000000000738\\u003c/li\\u003e\\n \\u003cli\\u003eHojo Y, Ishida Y, Tomita T, Kurahashi Y, Nakamura T, Kitayama Y,\\u0026nbsp;et al. Treatment strategy for successful conversion surgery in clinical stage IVB gastric cancer. Eur J Surg Oncol 2024;50:107314. https://doi.org/10.1016/j.ejso.2023.107314\\u003c/li\\u003e\\n \\u003cli\\u003eMorito A, Eto K, Iwatsuki M, Toihata T, Kosumi K, Iwagami S,\\u0026nbsp;et al. Clinical impact of very early recurrence after conversion surgery for stage IV gastric cancer. Ann Gastroenterol Surg 2023;8:214\\u0026ndash;220. https://doi.org/10.1002/ags3.12738\\u003c/li\\u003e\\n \\u003cli\\u003eTakeno A, Motoori M, Kishi K, Omori T, Hirao M, Masuzawa T, et al. Prognostic factors of conversion surgery for stage IV gastric cancer: A multi-institutional retrospective analysis. Ann Gastroenterol Surg 2024;8:431\\u0026ndash;442. https://doi.org/10.1002/ags3.12778\\u003c/li\\u003e\\n \\u003cli\\u003eKita R, Yasufuku I, Takahashi N, Mizusawa J, Sano Y, Fukuda H, et al. Randomized controlled phase III study comparing chemotherapy alone versus conversion surgery after a remarkable response to chemotherapy in patients with initially unresectable cStage IVB or pStage IV gastric cancer (JCOG2301, Conversion study). Jpn J Clin Oncol 2024:hyae174. https://doi.org/10.1093/jjco/hyae174\\u003c/li\\u003e\\n \\u003cli\\u003eKim W, Kim HH, Han SU, Kim MC, Hyung WJ, Ryu SW,\\u0026nbsp;et al. Decreased morbidity of laparoscopic distal gastrectomy compared with open distal gastrectomy for stage I gastric Cancer: Short-term outcomes from a Multicenter Randomized Controlled Trial (KLASS-01). Ann Surg 2016;263:28\\u0026ndash;35. https://doi.org/10.1097/SLA.0000000000001346\\u003c/li\\u003e\\n \\u003cli\\u003eKatai H, Mizusawa J, Katayama H, Morita S, Yamada T, Bando E,\\u0026nbsp;et al. Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer (JCOG0912): a multicentre, non-inferiority, phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol 2020;5:142\\u0026ndash;151. https://doi.org/10.1016/S2468-1253(19)30332-2\\u003c/li\\u003e\\n \\u003cli\\u003eInaki N, Etoh T, Ohyama T, Uchiyama K, Katada N, Koeda K,\\u0026nbsp;et al. A multi-institutional, prospective, phase ii feasibility study of laparoscopy-assisted distal gastrectomy with D2 lymph node dissection for locally advanced gastric cancer (JLSSG0901). World J Surg 2015;39:2734\\u0026ndash;2741. https://doi.org/10.1007/s00268-015-3160-z\\u003c/li\\u003e\\n \\u003cli\\u003eLee HJ, Hyung WJ, Yang HK, Han SU, Park YK, An JY, et al. Short-term outcomes of a multicenter randomized controlled trial comparing laparoscopic distal gastrectomy with D2 lymphadenectomy to open distal gastrectomy for locally advanced gastric cancer (KLASS-02-RCT). Ann Surg 2019;270:983\\u0026ndash;991. https://doi.org/10.1097/SLA.0000000000003217\\u003c/li\\u003e\\n \\u003cli\\u003eOmori T, Fujiwara Y, Yamamoto K, Yanagimoto Y, Sugimura K, Masuzawa T, et al. The safety and feasibility of single-port laparoscopic gastrectomy for advanced gastric cancer. J Gastrointest Surg 2019;23:1329\\u0026ndash;1339. https://doi.org/10.1007/s11605-018-3937-0\\u003c/li\\u003e\\n \\u003cli\\u003eYu J, Huang C, Sun Y,\\u0026nbsp;Su X, Cao H, Hu J,\\u0026nbsp;et al. Effect of laparoscopic vs open distal gastrectomy on 3-year disease-free survival in patients with locally advanced gastric cancer: the CLASS-01 randomized clinical trial. JAMA 2019;321:1983\\u0026ndash;1992. https://doi.org/10.1001/jama.2019.5359\\u003c/li\\u003e\\n \\u003cli\\u003eYamamoto K, Omori T, Hara H, Shinno N, Sugimura K, Miyata H,\\u0026nbsp;et al. Minimally invasive surgery is feasible after preoperative chemotherapy for stage IV gastric cancer. Ann Gastroenterol Surg 2020; 4:396\\u0026ndash;404. https://doi.org/10.1002/ags3.12343.\\u003c/li\\u003e\\n \\u003cli\\u003eShitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA,\\u0026nbsp;et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2023;401:1655\\u0026ndash;1668. https://doi.org/10.1016/S0140-6736(23)00620-7\\u003c/li\\u003e\\n \\u003cli\\u003eShah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D,\\u0026nbsp;et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 2023;29:2133\\u0026ndash;2141. https://doi.org/10.1038/s41591-023-02465-7\\u003c/li\\u003e\\n \\u003cli\\u003eRha SY, Oh DY, Ya\\u0026ntilde;ez P, Bai Y, Ryu MH, Lee J,\\u0026nbsp;et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1181\\u0026ndash;1195. https://doi.org/10.1016/S1470-2045(23)00515-6\\u003c/li\\u003e\\n \\u003cli\\u003eWainberg ZA, Kang YK, Lee KW, Qin S, Yamaguchi K, Kim IH, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial. Gastric Cancer 2024;27:558\\u0026ndash;570. https://doi.org/10.1007/s10120-024-01466-w\\u003c/li\\u003e\\n \\u003cli\\u003eJanjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 2023;402:2197\\u0026ndash;2208. https://doi.org/10.1016/S0140-6736(23)02033-0\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTables 1 to 4 are available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"advanced gastric cancer, nivolumab plus chemotherapy, conversion surgery, propensity score-matched analysis, prognostic factors\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7634092/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7634092/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cem\\u003e\\u003cstrong\\u003eBackground\\u003c/strong\\u003e\\u003c/em\\u003e\\u003cstrong\\u003e: \\u003c/strong\\u003eSystemic chemotherapy plus nivolumab is a first-line treatment in unresectable advanced gastric cancer; however, the ideal determination of conversion surgery eligibility remains unclear. This study identified predictors and prognostic factors related to conversion surgery, including the effects of first-line nivolumab.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003e\\u003cstrong\\u003eMethods\\u003c/strong\\u003e\\u003c/em\\u003e\\u003cstrong\\u003e: \\u003c/strong\\u003eThis single-institutional retrospective study included 129 patients who received systemic chemotherapy for advanced gastric or esophagogastric junction cancer. Data were compared between treatments with and without first-line nivolumab and 1:2 propensity score matching was performed to adjust for baseline differences.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003e\\u003cstrong\\u003eResults\\u003c/strong\\u003e\\u003c/em\\u003e\\u003cstrong\\u003e: \\u003c/strong\\u003eConversion surgery was performed in 17 (13.2%) patients. With nivolumab plus chemotherapy, the conversion surgery rate was 36.8% (7/19). In a multivariate analysis, the combination of nivolumab as first-line treatment was an independent predictor of conversion surgery both before and after matching. Minimally invasive surgery was performed on seven patients, six of whom were patients receiving nivolumab with R0 resection. An Eastern Cooperative Oncology Group Performance Status of ≥1, presence of liver metastasis, and conversion surgery were independent prognostic factors in advanced gastric cancer.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003e\\u003cstrong\\u003eConclusions\\u003c/strong\\u003e\\u003c/em\\u003e\\u003cstrong\\u003e: \\u003c/strong\\u003eFirst-line nivolumab combination chemotherapy improved eligibility for conversion surgery in advanced gastric or esophagogastric junction cancer. Understanding the prognostic factors identified herein may help guide treatment selection and improve patient outcomes.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Impact of first-line nivolumab plus chemotherapy on conversion surgery rate for advanced gastric/esophagogastric junction cancer\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-30 06:56:47\",\"doi\":\"10.21203/rs.3.rs-7634092/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"a1114df4-9b86-4df3-a7f4-32cf0e12d520\",\"owner\":[],\"postedDate\":\"September 30th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-17T03:45:33+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-09-30 06:56:47\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7634092\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7634092\",\"identity\":\"rs-7634092\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}