Outcomes of Microscopic Residual Tumor after Curative-Intent Surgery in Adenocarcinoma of Esophagogastric Junction

Chawisa Nampoolsuksan, M.D.1,2, Khajohnsak Bhocksombud, M.D.1, Thammawat Parakonthun, M.D.1,2,*, Tharathorn Suwatthanarak, M.D.1, Thikhamporn Tawantanakorn, M.D.1, Nicha Srisuworanan, M.D.1, Voraboot Taweerutchana, M.D.1, Atthaphorn Trakarnsanga, M.D.1, Chainarong Phalanusitthepha, M.D.1, Jirawat Swangsri, M.D.1,2, Thawatchai Akaraviputh, M.D.1, Asada Methasate, M.D.1,2, Vitoon Chinswangwatanakul, M.D.1

1Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, 2Siriraj Upper GI Cancer Center, Faculty

of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

*Corresponding author: Thammawat Parakonthun E-mail: t.parakonthun@gmail.com

Received 28 May 2024 Revised 26 August 2024 Accepted 26 August 2024 ORCID ID:http://orcid.org/0000-0002-2990-0649 https://doi.org/10.33192/smj.v76i11.269480

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

INTRODUCTION

Patients with cancer originating at the transition zone between the stomach and esophagus are diagnosed with esophagogastric junction cancer regardless of the histopathologic type.1-3 Most of these cancers are adeno carcinomas.2,3 Currently, complete resection with adequate lymphadenectomy is the standard curative management for patients. Proximal submucosal extension may occur in adenocarcinomas, necessitating optimal esophageal resection.4 The surgical treatment of adenocarcinomas of esophagogastric junction (AEG) is determined by the tumor location, classified according to Siewert classification and presence of lymph node metastasis. Surgery aims to achieve complete resection with microscopically negative for residual tumor (Residual-, R0) and minimize postoperative morbidity.5,6

In case of Siewert type I tumors, a transthoracic approach is chosen to ensure sufficient proximal margins and adequate mediastinal lymph node harvesting. In case of Siewert type II tumors, transhiatal esophagogastrectomy or extended total gastrectomy is preferred if complete tumor-free esophageal resection is feasible. In case of Siewert type III tumors, total gastrectomy together with D2 lymphadenectomy is the recommended.7,8

Although R0 resection is attempted in all patients, recurrences occur in 40% to 80% of patients.9-11 Advanced disease stage, lymph node involvement, and microscopic residual tumor are associated with predictive factors.12,13

Distant metastasis is the most common recurrence and often cannot be resected, typically resulting in a shorter survival time. Therefore, perioperative systemic therapy has become the standard treatment for locally advanced disease to improve surgical outcomes and life expectancy.14-17 Our study focused on oncologic outcomes after curative-intent surgery with microscopic residual tumor to demonstrate the adverse consequences of Residual+ (R1) resection specifically on AEG. Determining associated factors of poor survival outcome would facilitate prognosis prediction and enhance further intensive surveillance.

MATERIALS AND METHODS

This study was approved by the Siriraj Institutional Review Board (CoA no. Si 552/2018) and was retrospectively registered with the Thai Clinical Trials Registry (TCTR20220721004). We reviewed the medical records and operative notes of patients aged over 18 years who were diagnosed with adenocarcinomas of the esophagogastric junction through tissue biopsy via esophagogastroduodenoscopy. These patients underwent curative-intent surgery between January 2005 and August 2018 at the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Tumor location was classified according to Siewert based on endoscopic findings.5,6 Chest and abdominal computed tomography were performed for disease staging in every patient. Exclusion were patients who underwent palliative surgery, who underwent R2

resection, or who received neoadjuvant chemotherapy. The following clinical and pathological characteristics were recorded age, gender, tumor size and location, operative approach, pathological staging according to the TNM classification, associated pathological findings, and lymph node involvement.

Patients were divided into 2 groups: the R0 and the R1 group. The R0 group was determined by the absence of microscopic residual tumor. The R1 group included cases with presence of microscopic residual tumor, confirmed by histopathological examination of either a positive surgical resection margin or malignant cells from peritoneal washing fluid. Positive intraoperative frozen section which had undergone reresection to achieve a negative margin were classified into the R0 group. Adjuvant treatment, including chemotherapy and radiotherapy, was offered in cases of locally advanced pathological stage or the presence of microscopic residual tumors. Routine postoperative surveillance was conducted to evaluate both locoregional and distant recurrence.

Statistical analyses

Statistical analyses were performed by using IBM SPSS Statistics, version 21 (IBM Corp, Armonk, NY, USA). The quantitative data are presented as the n (%) and mean ± SD for data with normal distribution or as the median (P25, P75) for data with nonnormal distribution. Comparisons of patient clinical and pathological characteristics between groups were analyzed using chi-square tests for categorical variables and independent t tests or Mann-Whitney U test for continuous variables. Survival analysis was conducted using the Kaplan–Meier method and log rank test. Cox regression analysis was used to identify associating factors of poor survival outcome. P-value less than 0.05 was considered to indicate statistical significance.

RESULTS

Patient clinicopathological characteristics

A total of 395 patients were diagnosed with gastric and esophagogastric junction adenocarcinoma. After excluding 324 patients of gastric origin, 71 patients who underwent curative-intent surgery with adequate systematic lymph node dissection were included in our study (Fig 1). Nineteen (26.7%) patients had microscopic residual tumors after surgery (R1 group). In this group, 8 (11.3%) patients had a positive resection margin, 10 (14.0%) patients had malignant cells in the peritoneal washing fluid, and 1 (1.4%) patient had both positive results. The remaining 52 (73.2%) patients had no microscopic residual tumors (R0 group). There were no statistical differences in age, gender, preoperative serum albumin level, tumor size, Siewert classification, operative approach, or the number of harvested nodes between groups. Significantly more advanced pathological stages, greater metastatic lymph node involvement, and lymphovascular and perineural invasion were observed in the R1 group. Similar postoperative complications, severity grades according to the Clavien–Dindo classification, and length of admission were observed in both groups (Table 1).

After surgery, 24 (47%) patients in the R0 group underwent adjuvant treatment according to their pathological stage. Specifically, 13 (25.5%) patients received chemotherapy, 2 (3.9%) patients underwent radiation therapy, and 9 (17.6%) patients were administered both. In the R1 group, a greater percentage, up to 89.4% (17 patients), were given adjuvant treatment. Of these, 10 (52.6%) patients received chemotherapy, and 5 (25.3%) patients underwent chemoradiation therapy. Two (10.5%) patients had only radiation therapy due to poor performance status. Additionally, two (10.6%) patients declined adjuvant treatment and requested best supportive care.

Fig 1. Flow diagram of patient cohort

This flow diagram demonstrates all cases of adenocarcinoma of gastric and esophagogastric junction. The diagnosis was made according to the location of tumor by definitions from Japanese Gastric Cancer Association.1 Classification of AEG was divided into 3 groups by Siewert classification.5,6

TABLE 1. Characteristics of the study population.

Abbreviations: R0 group=absence of microscopic residual tumors after surgery, R1 group=presence of microscopic residual tumors after surgery

Values are presented in n(%), mean ± SD for normally distributed data, and median (P25, P75) for non-normally distributed data. Comparisons between groups were analyzed using chi-square tests for categorical variables and independent t tests or Mann-Whitney U test for continuous variables.

Outcomes

Twenty-four (34%) patients experienced disease recurrence during follow-up, with 17 (70%) of these recurrences occurring within 12 months after surgery. Median follow-up time was 14 months for R0 group and

7.7 months for R1 group. The recurrence rates were 28% (15 patients) and 48% (9 patients), respectively. Most common site of recurrence was distant metastasis in both groups. In the R0 group, 8 (53.3%) patients had distant metastasis, 5 (33.3%) patients had locoregional recurrence, 1 (6.7%) patient had both locoregional and peritoneal recurrence, and 1 (6.7%) patient had locoregional recurrence with distant metastasis. In the R1 group, 5 (55.6%) patients had distant metastasis, 2 (22.2%) patients had peritoneal metastasis, and 2 (22.2%) patients had both locoregional and peritoneal metastasis (Fig 2).

The median overall survival (OS) in R0 group was significantly higher than in the R1 group (31.3 (12.3, 91.7) vs 11.9 (5.3, 16.7) months, P = 0.003). In

R0 group, the 5-year OS rate was 26.2%, and the 3-year

disease-free survival (DFS) rate was 24.4%. In contrast, in the R1 group, these percentages were only 11.9% (P = 0.015) and 9.8% (P = 0.003), respectively (Fig 3). Additionally, the median OS was greatest for patients who had Siewert type I tumors (68.5 months), followed by 15.6 months for type II tumors and 31.3 months for type III tumors (P = 0.09) in the R0 group. Conversely, in the R1 group, the median OS was greatest for type II tumors (28 months), followed by type I tumors (9.8 months) and type III tumors (6.8 months; P = 0.389). Presence of lymphovascular invasion was the independent factors for associating factors of poor survival outcome from multivariate analysis (Table 2).

After subgroup analysis according to the Siewert classification, the median OS of Siewert type III tumors was 53.5 months in R0 group, which was significantly superior to 6.8 months in R1 group (P = 0.003). Other two subtypes did not differ significantly between the two groups.

Fig 2. Patterns of disease recurrence.

Fig 3. Kaplan–Meier survival analysis.

Abbreviations: R0 group=absence of microscopic residual tumors after surgery, R1 group=presence of microscopic residual tumors after surgery, AEG=adenocarcinoma of esophagogastric junction

TABLE 2. Associating factors for poor survival outcome.

Abbreviations: LVI=lymphovascular invasion, PNI=perineural invasion

DISCUSSION

Surgical resection remains the best curative approach for esophagogastric junction adenocarcinoma. The general principle of this procedure is to achieve complete clearance of tumor cells with minimal morbidity. After diagnosis and clinical staging, multidisciplinary care is essential for patient management. Enhanced recovery after surgery protocols improves postoperative recovery and shorten hospital stays. Treatment planning, patient counseling, and education on disease prognosis should be anticipated. Nutritional assessment should be routinely performed in all patients, and nutritional support should be provided if malnutrition is present before the operative procedure. In the early stages, upfront surgery is recommended unless the patient is unfit for surgery. For more locally advanced disease, perioperative systemic therapy may be added following a risk-benefit assessment.16-18

Previous studies have demonstrated superior survival benefits and favorable postoperative outcomes after

adequate surgery.19 Various factors have been investigated to improve survival rates. Unfortunately, advanced disease and lymph node involvement at the time of diagnosis are unavoidable factors. A potentially avoidable negative factor is microscopic residual tumor, which can be reduced by perioperative therapy and adequate surgical techniques. This is the first study in Thailand to report the survival prognosis and recurrence of microscopic residual tumors in patients who underwent curative-intent surgery for adenocarcinoma of the esophagogastric junction. Our study demonstrated worse survival outcomes and higher recurrence rates with microscopic residual tumors after curative-intent surgery than after complete curative surgery. Furthermore, achieving R0 resection did not increase postoperative morbidities or severe complications, nor

did it lengthen the duration of hospitalization.

In our study, 26.7% of patients had residual disease, which was higher than in other studies. The incidence of microscopic residual tumors in prior studies ranged

from 16% to 21.5%. Prospectively maintained database from Italian study had reported 16 of 100 patients (16%) with positive resection margins, and another multicenter retrospective analysis also reported 145 of 674 patients (21.5%) with positive resection margins.19,20; however, we included both positive resection margins and the presence of cancer cells in peritoneal washing fluid cytology. After excluding patients with positive fluid cytology, the incidence of positive surgical resection margins was 12.7%, which is lower than that reported in the studies mentioned above.

During the surveillance period, the recurrence rate of the disease differed from that reported by other studies. Common sites of recurrence include distant metastasis, peritoneal metastasis, and locoregional recurrences.9,11 Similarly, we found that distant metastasis was the most common site of recurrence in both groups. However, there was higher rate of peritoneal recurrence in R1 group compared to R0 group. Currently, there is no standard consensus or guideline for managing positive surgical resection margins. Adjuvant treatment with systemic chemotherapy or radiation therapy may be administered. Consistent with other studies, our median OS time, 5-year OS rate, and 3-year DFS rate in the R0 group were superior to those in the R1 group.

A limitation of this study that data were obtained from a single supertertiary center in Thailand, and details of treatment may differ from those of other centers. The concept of surgery and systematic lymphadenectomy has become more standardization. Additionally, variation in systemic treatment has changed over the years. Some of our patients were referred to our hospital for operation. After surgery, some had received adjuvant therapy at their primary hospital and continued the surveillance. This resulted in lack of postoperative documents for our analysis. For patients who completed their systemic course at our hospital, the majority of regimen is the doublet chemotherapy which is a combination of 5-FU/ LV and oxaliplatin.

Second, there is selection bias inherent in the retrospective study design and the small sample size. Clinical characteristics in the R1 group included higher pathological stages, lymphovascular and perineural invasion, and more lymph node metastasis. These factors may explain the poorer prognosis, higher recurrence rates, and shorter survival times in the residual tumor group. Nonetheless, this study confirmed the adverse consequences of microscopic residual tumors after surgery. Adjuvant systemic or local therapy may improve these outcomes and should be routinely offered to patients in this setting. Future research should be conducted

as a prospective multicenter study to combine entire patient’s treatment journey in order to minimize the above-mentioned limitations.

CONCLUSION

Microscopic residual tumors clearly worsen oncologic outcomes in esophagogastric junction adenocarcinoma patients. Complete resection and negative peritoneal washing cytology are essential considerations in operable patients. Tumor with lymphovascular invasion is an indicative factor for poorer survival outcome.

ACKNOWLEDGMENTS

We are thankful to Dr Saowalak Hunnangkul, Miss Wathanaphirom Mangmee, and Miss Chorlada Keatrungarun for their assistance with the statistical methods and analysis.

DECLARATION

Grants and Funding Information

This project is not funded by any external sources.

Conflict of Interests

The authors declare that they have no conflicts of interest.

Author Contributions

TP was the corresponding author and was responsible for conceptualization, study methodology, data analyses, and final manuscript editing. CN designed the study, collected and analyzed the data, and wrote the original draft of the manuscript. KB, JS, and AM reviewed and edited the manuscript. All authors approved the final manuscript.

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