Splenic hilar lymph node dissection enhances survival in Bormann type 4 gastric cancer – Scientific Reports

Patients

The present study included patients who underwent total gastrectomy for B-4 tumors between 2006 and 2016 in four major institutions in South Korea (Ajou University, Chonnam National University, Seoul St. Mary’s Hospital, and Yonsei University). B-4 tumors were defined as diffuse, infiltrative tumors with thickened and indurated gastric walls without marked ulceration or raised margins. We included patients based on macroscopic findings in pathologic reports and specimen photos, as available. Patients were excluded if they received preoperative chemotherapy, had a history of concomitant malignant diseases, or had incomplete medical records. We identified 748 patients who met the eligibility criteria and finally included 539 patients who underwent curative (R0) surgery (Fig. 1). We divided patients into two groups (no.10 LND group vs. no-dissection group) and compared their long-term survival. The institutional review board at each institution approved this study (Institutional Review Board of Ajou University Hospital: MDB-2021-355; Chonnam National Universtiy Hospital Biomedical Research Ethics Committee: CNUHH-2021-174; The institutional review board of the ethics committee of the College of Medicine, the Catholic University of Korea: KC23RIDI0411; and Yonsei University Health System, Severance Hospital, Institutional Review Board: 4-2022-1397), and the requirement for informed consent was waived. All methods were performed in accordance with the relevant guidelines and regulations.

Operative techniques

Patients underwent total gastrectomy and regional LND as described in the gastric cancer treatment guidelines¹² and received D1/D1+ or D2 LND at the discretions of surgeons. D2 LND included nos.7 (left gastric), 8a (common hepatic), 9 (celiac), 12a (proper hepatic), 11p (proximal splenic), 11d (distal splenic), and 10 (splenic hilum) LNs in addition to the perigastric LNs. D1 + LND included only nos.7, 8a, 9, and 11p. Removal of no.10 LNs was carried out via splenectomy, the spleen-preserving technique, or distal pancreaticosplenectomy. As this study adopted a retrospective multicenter design, a standardized protocol for performing no.10 LND was not established. Generally, surgeons tended to undertake no.10 LND in cases presenting with more advanced tumors. As for the operative technique, the principle technique for no.10 LND was the spleen preserving technique. Nonetheless, when LN metastasis was highly suspected at the splenic hilum, the decision to perform splenectomy was contingent upon surgeons’ discretion. All patients received esophagojejunostomy after total gastrectomy.

Patients underwent postoperative follow-ups every 6 months for 5 years. Abdominal computed tomography (CT) and endoscopy were routinely performed for surveillance every 6 or 12 months. Other imaging tests, such as chest CT, liver magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT scan, were performed as appropriate. Patients with pathologic stage II or higher received adjuvant chemotherapy using S-1 or capecitabine plus oxaliplatin.

Data collection

We collected clinicopathological data using a standardized case report form, which included demographics (age, sex, body mass index, comorbidity, American Society of Anesthesiologists [ASA] physical status, and past medical history), preoperative tests (CT and endoscopy findings, tumor markers, and laboratory data), operative outcomes (curability, operative techniques, operating time, operative bleeding, and extent of LND), pathological results (histologic type, lymphovascular invasion, tumor size, resection margin, tumor location, number of harvested and metastatic LNs, and tumor node metastasis [TNM] stage), postoperative outcomes (diet start, hospital stay, and complications), and follow-up data (adjuvant chemotherapy, disease recurrence, and survival).

The tumor characteristics and operative techniques were recorded based on the third English edition of the Japanese Classification of Gastric Carcinoma¹³. The pathologic stage was based on the eighth edition of the Union for International Cancer Control TNM classification of gastric carcinoma¹⁴. Curative (R0) surgery was defined as macroscopic and microscopic complete tumor removal without distant metastasis. Postoperative complications were defined as any complications that developed within 30 days of surgery. Overall survival was defined as the time from operation until death by any cause or last follow-up. Survival was ascertained using patient medical records or national cancer registry data. The last follow-up was in December 2021, and the median follow-up duration was 37 months (range 1–152 months).

Inverse probability of treatment weighting using propensity score

The propensity score was calculated with a logistic regression model incorporating 12 variables: age, sex, body mass index, comorbidity, ASA status, adjuvant chemotherapy, histologic type, lymphovascular invasion, tumor size, tumor location, pT, and pN stage. We then performed inverse probability of treatment weighting (IPTW) using the propensity score. IPTW is preferable to matching when the size of the control group is insufficient, as in our study¹⁵, as it enables estimation of the average treatment effect (ATE) using the overall sample as the reference population. In this study, the IPTW weights were defined as \({\omega }_{\iota }\text{=}\frac{{Z}_{{i}}}{{e}_{{i}}}+\frac{\left(1-{Z}_{{i}}\right)}{1-{e}_{{i}}}\) (where Z_i is an indicator variable of whether the ith subject was treated, and e_i denotes the propensity score for the ith subject), as proposed by Rosenbaum et al.¹⁶ After IPTW, the analysis set comprised 540.4 patients in the no.10 LND group and 532.69 patients in the no-dissection group (Fig. 1).

Statistics

We expressed data as mean ± standard deviation or number (%). Continuous variables were compared using the t-test, and categorical variables using the chi-square test. We calculated weighted Kaplan–Meier estimates for survival curves in the IPTW sample. We used a modified log-rank test appropriate for use with a weighted sample to compare survival. The causal effects of treatment (no.10 LND) were estimated using the Cox proportional hazards regression model. A robust, sandwich-type variance estimator was used to account for the weighted nature of the sample.

As a sensitivity analysis, we tested the treatment effect of no.10 LND in other IPTW models using different weights, such as the average treatment effects on the treated (ATT) and stabilized ATE weights, and in the propensity score matching sample. Statistical analysis was performed using SPSS 21.0 (IBM Corp., NY, USA) and R (version 4.1.2, Vienna, Austria). Two-sided p-values less than 0.05 were considered statistically significant.