Abstract
Background/Aim: Gastric cancer with gastric outlet obstruction (GOO) is generally found at an advanced stage and with an unfavorable prognosis. This study was performed to examine the prevalence of radiologically occult peritoneal carcinomatosis in GOO and determine the optimal treatment strategy. Patients and Methods: This single-center study was a retrospective review of the clinical data of 186 patients with locally advanced gastric cancer at the distal stomach who underwent surgery from 2008 to 2016. These patients were divided into two groups according to the presence or absence of GOO due to cancer progression: With GOO (n=71) and without GOO (n=115). Results: The incidence of peritoneal carcinomatosis [with macroscopic peritoneal deposits (P1)/positive peritoneal cytology (CY1)] detected at laparotomy/laparoscopy was significantly higher in the group with GOO than in the group without (32.4% vs. 9.6%, p<0.01). The R0 resection rate was lower in the group with GOO (62.0% vs. 87.0%, p<0.01). The 5-year overall survival rate was also lower in the group with GOO (43.9% vs. 68.5%, p<0.01). However, in the subset of patients who underwent R0 surgery, the 5-year rates were similar for the two groups (67.4% vs. 73.1%, p=0.91). The multivariable analysis showed that a type 3 tumor appearance (odds ratio=3.66) and presence of GOO (odds ratio=2.87) were predictors of peritoneal carcinomatosis. Conclusion: The prevalence of radiologically occult peritoneal carcinomatosis in gastric cancer with GOO exceeded 30%. Staging laparoscopy (gastrojejunal bypass, if needed) should be performed to determine the optimal treatment plan.
Gastric cancer is the fourth most common cause of cancer-related death worldwide (1). Advanced gastric cancer located at the distal stomach or the antrum is sometimes accompanied by gastric outlet obstruction (GOO) with symptoms such as nausea, vomiting, pain, and weight loss (2). Gastric cancer with GOO is generally detected at an advanced stage and is associated with an unfavorable prognosis even after curative resection (3). However, the optimal treatment strategy to improve the survival outcomes remains unclear.
Accurate clinical diagnosis of distant metastasis (M1) is obviously important when determining a treatment plan because the latest first-line chemotherapeutic regimens can be considered for such patients. Preoperative computed tomography (CT), sometimes combined with positron-emission tomography, is the benchmark for detecting M1 disease; however, its sensitivity remains unsatisfactory despite the recent remarkable progress of radiological diagnosis (4-7). Staging laparoscopy plays an important role in the detection of such radiologically occult peritoneal carcinomatosis. Even though seeded nodules are not visualized on CT, Yajima et al. reported that positive ascites on CT predicted the presence of peritoneal metastasis with 51% sensitivity and 97% specificity (8). Therefore, they claimed that the presence of peritoneal metastasis should be confirmed by diagnostic laparoscopy in patients with gastric cancer with ascites. Peritoneal metastasis in gastric cancer is classified into two subcategories: Macroscopic peritoneal deposits (P1) and positive peritoneal cytology (CY1). Despite routine use of peritoneal cytology not being recommended in the National Comprehensive Cancer Network guideline, the latest Japanese guidelines recommend staging laparoscopy in high-risk patients, such as those with linitis plastica, large type 3 tumors, or extensive lymph node metastasis (9-11). Except for these high-risk patients, staging laparotomy is not necessarily required because it places burdens on patients.
Gastric cancer with GOO has not yet been proposed as a candidate indication for staging laparoscopy. A few retrospective studies have indicated a high prevalence of peritoneal carcinomatosis as well as its unfavorable survival outcomes (2, 12). However, robust data are still lacking, and no comparison study between patients with and without GOO has been reported. Consequently, a specific treatment strategy for gastric cancer with GOO has not been established.
In this context, we conducted the present retrospective cohort study to examine the prevalence of radiologically occult peritoneal carcinomatosis (P1 and/or CY1) in gastric cancer with GOO and determine the optimal treatment strategy.
Patients and Methods
Patients. Patients who fulfilled the following criteria at the National Cancer Center Hospital East, Japan from January 2008 to December 2016 were included in this study: (i) Pathologically proven adenocarcinoma of the stomach, (ii) locally advanced gastric cancer localized to the distal stomach (cT3-4), and (iii) no distant metastasis detected by preoperative CT or positron-emission tomography-CT (i.e. radiologically cM0).Typically, contrast-enhanced CT was performed using Aquilion ONE (Toshiba Medical Systems, Otawara, Japan) and axial slices equal to 5.0 mm were evaluated.
The patients’ clinical data were reviewed using an established in-house database. The exclusion criteria were (i) Type 4 gastric cancer involving the entire stomach, (ii) a history of preoperative chemotherapy, and (iii) the presence of other coexisting malignant disease. This study was approved by the Institutional Review Board of the National Cancer Center Hospital East (no. 2017-416). Written informed consent from each patient was waived in this retrospective observational study.
Definition and assessment of GOO. The presence of GOO was assessed by endoscopic examination and clinical symptoms. Gastric cancer with GOO was diagnosed when the following conditions were satisfied: (i) The tumor infiltrated the distal stomach wall from three-quarters to the entire circumference and (ii) difficulty was encountered when passing the endoscope through the stenosis or the patient had gastric distention with symptoms of nausea/vomiting.
Endpoints. The patients were divided into two groups according to the presence or absence of GOO. The clinical features and outcomes were compared between the two groups. The primary endpoint of this study was the incidence of radiologically occult peritoneal carcinomatosis (P1/CY1) detected at laparotomy/laparoscopy. The secondary endpoints were overall survival (OS), the R0 resection rate, surgical outcomes including postoperative complications, and sites of recurrence. TNM staging and the definitions of P1, CY1, and R0, 1, and 2 followed the Japanese Classification of Gastric Carcinoma, 3rd Edition (13). Postoperative complications were graded according to the Clavien–Dindo classification, and grade ≥III complications were recorded in this study (14).
Survival analysis. We evaluated the OS of all patients between the two groups. OS was defined as the interval between surgery and death from any cause. OS was also compared between the two groups in the subset of patients who underwent R0 surgery.
Statistical analysis. The Mann–Whitney U-test or Fisher’s exact test were used to assess the differences in characteristics between the two groups. Survival curves were made using the Kaplan–Meier method, and differences were determined by the log-rank test. To determine the risk factors for peritoneal carcinomatosis, a multivariate logistic regression analysis was performed. Differences were considered statistically significant when p<0.05. All statistical analyses were performed using Easy R (Saitama Medical Center, Jichi Medical University, Saitama, Japan; downloaded from https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (15). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.
Results
Clinicopathological characteristics. In total, 186 patients were enrolled in this study; they were divided into a group with GOO (n=71) and a group without GOO (n=115). The patient flow chart for this study is shown in Figure 1. The patients’ clinicopathological characteristics are detailed in Table I. The baseline clinical conditions and tumor features were significantly different in the following aspects. The patients in the group with GOO had a significantly lower body mass index, lower hemoglobin concentration, lower albumin concentration, and lower total protein concentration than the group without GOO, indicating a lower nutritional status. Additionally, the patients in the group with GOO had larger tumors, a higher incidence of type 3 appearance, more frequent duodenal invasion, and more clinical T4a tumors.
Flow chart depicting the patient assessment process.
Baseline patient characteristics.
Incidence of P1/CY1 and R0 resection rate. The surgical outcomes of the two groups are shown in Table II. Various surgical procedures were performed, including exploratory laparotomy, staging laparoscopy, gastrojejunostomy, distal gastrectomy, total gastrectomy, and pancreaticoduodenectomy. The incidence of occult peritoneal carcinomatosis (P1/CY1) that was not detected by CT but detected at surgery was significantly higher in the group with GOO (32.4% vs. 9.6%, p<0.01). The incidence of invasion of other organs (e.g. pancreas, mesocolon, and liver) was not different between the two groups (7.0% vs. 3.5%, p=0.31). In some patients (n=15), palliative gastrectomy was performed to control bleeding from the tumor or release outlet stenosis. In the entire patient cohort, the R0 resection rate was much lower in the group with GOO (62.0% vs. 87.0%, p<0.01).
Surgical outcomes of all patients.
Surgical and pathological outcomes. The surgical and pathological outcomes, excluding those of non-resection procedures (e.g. exploratory laparotomy, staging laparoscopy, and gastrojejunostomy) are summarized in Table III. Postoperative complications (Clavien–Dindo grade ≥III) were significantly more frequently observed in the group with GOO (18.6% vs. 4.9%, p<0.01). Pathological findings revealed significantly deeper tumor invasion, more advanced stages, and a higher incidence of duodenal invasion in the group with GOO (49.2% vs. 11.7%, p<0.01).
Surgical and pathological outcomes excluding non-resection procedures (e.g. exploratory laparotomy, staging laparoscopy, and gastrojejunostomy).
Survival outcomes. Figure 2A shows the Kaplan–Meier survival curves for the entire patient cohort. The median follow-up period was 56.0 months. The 5-year OS rate was lower in the group with GOO (43.9% vs. 68.5%, p<0.01). However, in the subset of patients who underwent R0 surgery, the 5-year OS rates were similar for the two groups (67.4% vs. 73.1%, p=0.91) (Figure 2B). The distribution of sites of recurrence is detailed in Table IV. The group with GOO had more peritoneal recurrence than the group without GOO but without statistical significance (18.2% vs. 11.0%, p=0.29).
Kaplan–Meier curves of survival of patients with primary locally advanced distal gastric cancer. A: Overall survival (OS) of all patients. Patients with gastric outlet obstruction (GOO) had a significantly poorer 5-year OS rate than those without GOO (43.9% vs. 68.5%, p<0.01). B: OS of patients who underwent R0 resection. There was no difference in the 5-year OS rate between the two groups when limited to patients who underwent R0 surgery (67.4% vs. 73.1%, p=0.91).
Recurrence rate and site of patients who underwent R0 resection.
Predictors of radiologically occult peritoneal carcinomatosis (P1/CY1). A multivariable analysis was carried out of the entire patient cohort (n=186) to identify predictors of radiologically occult P1/CY1 (Table V). The result indicated that macroscopic type 3 tumors (odds ratio=3.66, 95% confidence interval=1.22-10.90) and the presence of GOO (odds ratio=2.87, 95% confidence interval=1.20-6.88) were independent predictors of radiologically occult P1/CY1.
Multivariate analyses of peritoneal carcinomatosis in patients with primary locally advanced distal gastric cancer.
Discussion
This study showed that the incidence of radiologically occult peritoneal carcinomatosis in gastric cancer with GOO exceeds 30%, supporting the recommendation of staging laparoscopy for this population. Notably, the R0 resection rate was lower in patients with GOO than in those without; consequently, the survival outcomes were also worse in patients with GOO. However, the survival outcomes did not differ in the subset of patients who underwent R0 resection. These findings may suggest that gastric cancer with GOO exhibits different biological behaviors and that a specific treatment strategy is therefore needed to improve survival outcomes.
Staging laparoscopy is useful for accurate staging and can prevent unnecessary laparotomy or reduce substantial morbidity (16). Some reports have described high-risk subgroups of patients with radiologically occult peritoneal carcinomatosis (10, 17, 18), with an incidence of 56% in patients with large type 3 tumors (tumor size of ≥80 mm), 54% in those with type 4 (linitis plastica), 21% in those with bulky lymph node metastasis (size of ≥30 mm) or para-aortic nodal metastasis, and 20% in radiologically suspected cases (10). Thus, staging laparoscopy is recommended in the latest Japanese guidelines for these subgroups of patients. In the present study, the incidence of occult peritoneal metastasis was 32.4% in gastric cancer with GOO, which is comparable to the above-listed subgroups. A previous report showed that the incidence was 44.9% in patients with gastric cancer presenting as GOO (12). Moreover, our multivariate analysis confirmed the presence of GOO as an independent predictor of radiologically occult peritoneal carcinomatosis.
In gastric cancer with GOO, another advantage of staging laparoscopy is expected in addition to prevention of unnecessary laparotomy: Gastrojejunostomy can be simultaneously performed to release GOO. Endoscopic stenting for gastric cancer with GOO is less invasive than gastrojejunostomy in terms of its shorter time to oral intake (19). However, gastrojejunostomy reportedly has a lower reconstruction rate, a lower reintervention rate and better survival than endoscopic stenting (20). This procedure can be performed either for palliative purposes (when P1 is recognized) or as prearrangement for subsequent neoadjuvant chemotherapy (when no obvious P1 is recognized). The REGATTA study clearly showed that palliative resection does not contribute to survival in patients with P1 (21). Improvement of oral intake may enhance the nutritional condition or compliance with administration of anticancer drugs such as S-1 or capecitabine, which are key elements in recent chemotherapeutic regimens for gastric cancer. The CONVO-GC-01 study demonstrated that conversion surgery (R0 resection) after response to chemotherapy has the potential to achieve long survival even in patients with P1 (22). In fact, in the present study, approximately 15% of patients in the group with GOO underwent gastrojejunostomy, and its incidence is currently increasing in our clinical practice because more powerful chemotherapeutic regimens have become available.
How to manage patients with P0CY1 remains controversial. In some studies, the survival outcomes of patients with P0CY1 were not different between those who underwent immediate surgery plus adjuvant chemotherapy and those who underwent induction chemotherapy followed by surgical resection (23). It is well known that P0CY1 changes to P0CY0 in some patients, which can be confirmed with repeat staging laparoscopy (24). Long-term survival may be expected in such patients. This issue should be further examined. However, induction chemotherapy seems to be better in gastric cancer with GOO because these patients’ nutritional condition is unsuitable for radical surgery. Given these considerations, gastrojejunostomy prior to radical surgery seems effective in patients with P0CY1 gastric cancer with GOO to improve their nutritional condition.
In the current study, more complications (Clavien–Dindo grade ≥III) were observed in the group with GOO. This may reflect the fact that most patients with GOO were in poor nutritional condition and had more advanced tumors. The incidence of invasion to other organs was not different between the two groups, but duodenal invasion was more frequently seen in the group with GOO. In such a situation, tissue inflammation around the pancreatic head is likely to be severe, which makes surgery more challenging. It is also suggested that less invasive surgery rather than radical surgery would be a better option. Currently, whether immediate surgery or neoadjuvant chemotherapy is better for patients with P0CY0 gastric cancer with GOO is controversial. Although further examination is necessary to reach definitive conclusions, we believe that neoadjuvant chemotherapy following gastrojejunostomy creation is a promising strategy considering the unfavorable oncological behavior of gastric cancer with GOO.
Interestingly, the survival outcomes were similar for the two groups in the subset of patients who underwent R0 resection. Yasufuku et al. also suggested improved survival outcomes by curative resection even in patients with GOO (12). However, few studies to date have compared survival outcomes between patients with and without GOO. Our study clearly demonstrated that R0 resection has the potential to provide the same effect in both patients with and those without GOO. Some randomized studies have revealed that the R0 resection rate can be increased by neoadjuvant chemotherapy (25, 26). As previously reported (27), we also believe that neoadjuvant chemotherapy after gastrojejunostomy should preferentially be considered for gastric cancer with GOO but further studies are needed.
This study has several limitations. Firstly, this was a single-institution retrospective study. Furthermore, even in a high-volume center, the proportion of patients with gastric cancer with GOO is small, so the study results may be biased. A further study using a larger multicenter dataset is warranted. Secondly, this study did not include patients with radiologically detected peritoneal dissemination. Therefore, our data do not comprehensively reflect the oncological behaviors of this disease. Thirdly, staging laparoscopy fundamentally includes false-negative findings. The false-negative rate reported in previous studies ranges from 11.0% to 17.2% (10, 18). Therefore, this factor might have introduced bias in the present study.
In conclusion, the prevalence of occult peritoneal carcinomatosis undetectable by CT was more than 30% in patients with gastric cancer with GOO. Staging laparoscopy (with gastrojejunostomy, if needed) should be performed to determine the optimal treatment plan for these patients. Without peritoneal carcinomatosis, subsequent R0 resection may provide survival outcomes similar to those in patients without GOO.
Acknowledgements
The data sets generated during the current study are not publicly available to protect individual patient information, but data are available from the corresponding author on reasonable request. The Authors thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this article.
Footnotes
Authors’ Contributions
Masaru Komatsu: Data curation, interpretation of data, writing-original draft. Takahiro Kinoshita: Conceptualization, methodology, interpretation of data, revising-original draft. Eigo Akimoto: Methodology, interpretation of data, writing-reviewing. Mitsumasa Yoshida: Interpretation of data, writing-reviewing. Daiki Terajima: Interpretation of data, writing-reviewing. Hiromi Nagata: Interpretation of data, writing-reviewing, Takumi Habu: Interpretation of data, writing-reviewing. Takafumi Okayama: Interpretation of data, writing-reviewing. Yuya Takabe: Interpretation of data, writing-reviewing. Junichiro Harada: Data curation, interpretation of data, writing-reviewing. Masayuki Yamaguchi: Interpretation of data, writing-reviewing. Masahiro Yura: Interpretation of data, writing-reviewing.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received September 5, 2022.
- Revision received September 23, 2022.
- Accepted September 27, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
