Follow-Up and Strategies After Curative Surgical Resection for Gastric Cancer
Article information
Abstract
With advances in gastric cancer treatment, survival outcomes following surgery have improved; however, recurrence remains a significant challenge. Postoperative follow-up is crucial for the early detection of recurrence, enabling timely intervention and improving long-term survival. In patients who undergo curative resection of gastric cancer, postoperative surveillance typically includes regular esophagogastroduodenoscopy, blood tests—including tumor marker assessments—and imaging studies such as computed tomography. However, there is limited evidence that such follow-up strategies contribute to improved long-term survival. Multiple international guidelines recommend postoperative follow-up schedules and strategies based on retrospective studies and expert opinions. The impact of Helicobacter pylori eradication on long-term outcomes after gastric cancer surgery remains a subject of ongoing debate. Secondary primary cancer following gastric cancer treatment is another issue during postoperative follow-up. Optimizing follow-ups using an individualized, evidence-based approach is crucial.
INTRODUCTION
According to GLOBOCAN 2022 data, gastric cancer was the fifth most commonly diagnosed cancer worldwide, with 968350 new cases, and also ranked fifth in cancer-related mortality, with 659853 deaths in 2022 [1]. In South Korea, gastric cancer also ranked as the fifth most common cancer, with 29487 new cases in 2022 [2]. With advancements in gastric cancer treatment, long-term survival after surgery has improved significantly. In South Korea, the 5-year relative survival rate for gastric cancer increased from 58.0% during 2001–2005 to 78.4% during 2018–2022 [2].
Following curative surgery for gastric cancer, strategies for secondary prevention and early detection of recurrence are essential, as they enable timely intervention and may contribute to improved long-term survival. This review aimed to provide a comprehensive overview of follow-up and strategies after curative surgery for gastric cancer.
GASTRIC CANCER RECURRENCE AFTER CURATIVE SURGERY
The overall recurrence rate for gastric cancer after curative surgery has been reported as 11.6%–46.5% [3-7]. The majority of recurrence cases occur within the first 2 years after surgery, while less than 10% arise beyond 5 years [6,8-11]. The recurrence rate of early gastric cancer has been reported to be 1%–2%, and more frequent recurrence has been observed in cases of submucosal invasion or lymph node metastases [12,13].
Gastric cancer recurrence manifests through four patterns: nodal, hematogenous, peritoneal, and locoregional [6,14-16]. The nodal pattern refers to recurrence in regional or distant lymph nodes via lymphatic spread. Hematogenous relapse is defined as recurrence in distant organs, such as the liver, lungs, or bones, through hematogenous dissemination. The peritoneal pattern involves recurrence in non-lymphatic peritoneal soft tissue or the presence of malignant ascites, resulting from intraperitoneal spread. Finally, the locoregional pattern is characterized by cancer recurrence in the surgical bed or peri-anastomotic area. These patterns may occur simultaneously, in which case the recurrence is classified as a mixed pattern.
Most cases of tumor recurrence are surgically unresectable. Patients with distant metastases through lymphatic or hematogenous spread and peritoneal carcinomatosis are not candidates for surgery. Qiu et al. [7] reported that 64.1% and 28.2% of recurrent cases involved distant and peritoneal metastases, respectively. Cho et al. [17] demonstrated that the most common pattern of recurrence was peritoneal (39.7%), followed by the hematogenous pattern (24.7%). Even in cases of surgically resectable tumor recurrences, such as local recurrences, surgery is often challenging and should be performed in selected cases when complete resection is possible [16,18]. Therefore, chemotherapy rather than additional surgery is the primary treatment modality for recurrent gastric cancer.
FOLLOW-UP STRATEGIES AFTER CURATIVE SURGERY
Postoperative follow-up is supported by limited evidence, primarily due to the lack of observed long-term outcome benefits [19-21]. Accordingly, the European Society for Medical Oncology (ESMO) [22] and Japanese Gastric Cancer Association (JGCA) [23] guidelines clearly state that there is limited evidence supporting postoperative follow-up as a means to improve survival outcomes. In addition, the Korean Gastric Cancer Association (KGCA) [24], the National Comprehensive Cancer Network (NCCN) [25], and the Chinese Society of Clinical Oncology (CSCO) [26] guidelines state that the optimal strategies for postoperative surveillance remain controversial. Follow-up modalities include esophagogastroduodenoscopy (EGD), computed tomography (CT), and assessment of tumor marker levels.
Esophagogastroduodenoscopy
EGD can help identify local recurrence in the remnant stomach or peri-anastomotic area, as well as metachronous cancer in the remnant stomach. The incidence of remnant gastric cancer has been reported to be 1%–8% in patients after gastrectomies [27,28]. The time interval from surgery to the remnant gastric cancer diagnosis varies from months to years. Jang et al. [29] retrospectively analyzed 30 patients diagnosed with remnant gastric cancer via EGD; of these, 17 underwent annual endoscopic surveillance, which was associated with earlier cancer detection (p=0.001). Endoscopic surveillance can enable early detection of local recurrence, potentially enhancing the feasibility of curative resection through either endoscopic or surgical approaches.
Computed tomography
CT can help detect intra-abdominal recurrences, including lymph node and liver metastases. In addition, the density increment of peritoneal fat, presence of peritoneal nodules or ascites, and bowel wall thickening on CT scans indicate peritoneal carcinomatosis [30]. Therefore, CT is one of the most widely used imaging modalities for postoperative follow-up.
A number of studies have shown that positron emission tomography/CT (PET/CT) is a valuable imaging modality for the diagnosis and evaluation of gastric cancer [31]. In addition, PET/CT has been shown to play a role in postoperative follow-up [32-35]. Kim et al. [32] demonstrated that the sensitivity, specificity, and accuracy of PET/CT for recurrent gastric cancer were 53.6%, 84.7%, and 78.4%, respectively, and those of CT were 64.3%, 86.5%, and 82.0%, respectively, which showed no significant difference between the two modalities. Lee et al. [33] indicated that the sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT were 84.2%, 87.7%, 43.2%, and 98.0%, respectively. A recent meta-analysis of 17 studies (1732 patients) demonstrated that the pooled sensitivity and specificity were 82% and 86%, respectively [35]. However, due to cost and radiation exposure, PET/CT is not routinely used for postoperative follow-up; instead, it is recommended for the differential diagnosis of suspected lesions detected on CT.
Tumor markers
Serum tumor marker level evaluation is simple, non-invasive, and relatively inexpensive. The most commonly used tumor markers are carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). However, the diagnostic performance of this method is limited. Takahashi et al. [36] investigated 321 patients who underwent curative gastrectomies, of whom 120 experienced recurrences. The sensitivities of CEA and CA 19-9 levels for recurrence were 65.8% and 55.0%, respectively. In a study by Lee et al. [37], the sensitivity and specificity of CEA elevation for recurrence were 40.6% and 89.5%, respectively, and those of CA 19-9 elevation were 34.2% and 93.6%, respectively, based on an analysis of 154 patients who developed recurrence. Kim et al. [38] reported the recurrence sensitivity of tumor marker levels according to early and advanced gastric cancer; in early gastric cancer, the sensitivities of CEA and CA 19-9 levels were 40.0% and 5.6%, respectively, and in advanced gastric cancer, the sensitivities of CEA and CA 19-9 levels were 100.0% and 68.2%, respectively. In patients with elevated preoperative tumor markers, tumor marker levels tend to be elevated at recurrence [36,37]. Given their cost-effectiveness, tumor marker levels are considered useful tools for postoperative follow-up.
Total gastrectomy
In the clinical setting, endoscopic surveillance is performed after gastric cancer surgery, regardless of whether a partial or total gastrectomy was performed. The primary objective of endoscopic surveillance is to detect local recurrence in the remnant stomach or perianastomotic area as early as possible. However, patients who underwent total gastrectomies do not have remnant stomachs, and peri-anastomotic recurrence has been reported to have a low incidence (0.6%–1.7%) [5,39-41]. In a retrospective observational study by Park et al. [41], four out of 267 patients (1.5%) who underwent total gastrectomies experienced anastomotic site recurrences. Additionally, two cases with duodenal stump and jejunal loop recurrences were not detected on EGD examinations. Lee et al. [39] demonstrated that only perianastomotic recurrences occurred in five of 848 patients (0.6%) who underwent total gastrectomies. The low incidence of perianastomotic recurrence following total gastrectomy has limited the justification for routine endoscopic surveillance. The NCCN guidelines recommend against routine EGDs after total gastrectomies unless patients are symptomatic [25]. However, routine EGD after total gastrectomy also serves an important role in detecting postoperative complications, such as anastomotic stenosis or reflux esophagitis [40]. Further large or multicenter studies are required to assess endoscopic surveillance following total gastrectomy.
Five years after curative surgery
Most recurrences (approximately 70%) occur in the first 2 years after curative resection, and almost all recurrences (up to 90%) occur within 5 years [6,8-11]. Therefore, curability is generally estimated based on the 5-year survival rate, and postoperative follow-up is often discontinued 5 years after surgery because of the cost-effectiveness and rarity of recurrence after this time.
A recent big-data study using the Korean National Health Insurance Big Data Base investigated 40468 patients with gastric cancer [42]. Recurrence 5–10 years post-gastrectomy occurred in 3138 patients (7.8%), and recurrence 10 years post-gastrectomy was observed in 1528 patients (9.4%). In this study, regular follow-up was associated with lower overall mortality 5 years after gastrectomy. Yago et al. [43] reported that the recurrence rate based on the year in stages I and II did not exceed 1% after 7 years, analyzing 5235 patients, and suggested that surveillance after 5 years differs according to cancer stage.
The NCCN guidelines state that follow-up after 5 years may be considered based on comorbidities and risk factors, and recommend against routine surveillance beyond 5 years.25 The JGCA guideline recommends that individualized approaches are required for follow-up after 5 years.
INTERNATIONAL GUIDELINES REVIEW
There is insufficient evidence regarding post-operative follow-up methods and frequencies, and the guideline recommendations vary. The KGCA and ESMO guidelines recommend follow-up after surgery, but do not mention detailed schedules [22,24]. Other guidelines (NCCN, JGCA, and CSCO) suggest 5-year follow-up schedules based on expert opinions [23,25,26]. The NCCN, JGCA, and CSCO guidelines recommend regular follow-up every 3–6 months in the early postoperative period (1–3 years) or every 6–12 months in the late postoperative period (3–5 years). The NCCN guidelines recommend EGD and blood tests only when clinically indicated for both early and advanced gastric cancer, and recommend regular CT only for advanced gastric cancer. The JGCA and CSCO guidelines recommend regular EGD, CT, and blood tests, including tumor markers. The KGCA guidelines present postoperative follow-up schedules based on survey data collected from 71 hospitals in South Korea, reflecting real-world clinical practice. Physical examinations, blood tests, tumor markers, CT, chest radiography, and EGD were mainly performed for surveillance. In early gastric cancer, regular follow-up was conducted every 6 months for the first 2–3 years and then every 6–12 months for up to 5 years. In advanced gastric cancer, regular follow-ups were performed every 3–6 months for the first year and then every 6–12 months for up to 5 years. After 5 years, annual EGD was usually performed.
Tables 1 and 2 illustrate postoperative follow-up schedules recommended by each guideline according to early or advanced gastric cancer.
Follow-up schedules for stage I cancer according to guidelines
Follow-up schedules for stage II–III cancer according to guidelines
HELICOBACTER PYLORI
Helicobacter pylori (HP) infection is a significant risk factor for gastric cancer [44]. HP eradication provides survival benefits and reduces recurrence rates in patients who undergo endoscopic resections for early gastric cancer [45,46], and multiple international guidelines recommend HP eradication after endoscopic resection of early gastric cancer. However, whether HP eradication improves outcomes in patients undergoing gastrectomies for gastric cancer remains controversial.
After gastrectomy, the remnant stomach offers a unique environment for HP compared to the intact stomach. For example, bile reflux occurs more frequently in cases of distal gastrectomies owing to the absence of the pylorus, leading to an elevated intragastric pH and an unfavorable environment for HP.
Two observational studies reported conflicting results regarding whether HP eradication results in better outcomes after gastrectomies. While Kim et al. [47] reported no statistically significant differences in long-term outcomes between patients who received HP eradication and placebos, Choi et al. [48] presented a statistically significant improvement in overall survival and gastric cancer-specific survival in patients who underwent HP eradication compared to those who did not. A recent largescale retrospective study by Zhao et al. [49] demonstrated that HP eradication significantly improved the 5-year overall survival rate (94.1% vs. 73.8%, p<0.001) in patients who underwent gastrectomies for gastric cancer. Further large-scale or multicenter studies are needed to determine whether HP eradication benefits patients following gastrectomies.
SECONDARY CANCER
To date, guidelines for the surveillance of secondary cancers after gastric cancer treatment have not been established. It has been reported that the incidence of secondary primary cancer is 1.0%–6.6% and its development mainly occurs within 2 years after gastric cancer [50]. In a Korean population-based study, the incidence was 4.7% [50]. A recent large population-based study using the Surveillance, Epidemiology, and End Results database (covering 27% of the population in the United States of America) reported that the incidence of malignancies was higher in patients who had previous gastric cancer than in the general population [51].
The gastrointestinal tract, including the esophagus and colon, is the most common site of secondary cancers after gastric cancer. Other common sites include the thyroid, pancreas, urinary bladder, and prostate [50-52]. In a Korean population-based study, the common types of secondary primary cancers were colorectal (15.7%), lung (15.3%), liver (10.1%), prostate (8.6%), and thyroid cancer (6.9%) [50].
The risk factors for secondary primary cancer after gastric cancer varied among studies. A nationwide population-based study in Taiwan reported that age ≥70 years, male sex, diabetes mellitus, chronic obstructive pulmonary disease, and liver cirrhosis were risk factors [53]. In another population-based study, individuals aged 65 years or older were associated with a higher risk. In contrast, female sex, higher grade, advanced stage, nonsurgical management, and no radiotherapy use were associated with a lower risk for secondary primary cancer after gastric cancer [51].
As the number of gastric cancer survivors increases, the incidence of secondary cancers after treatment also tends to increase. In the clinical setting, close surveillance not only for detecting gastric cancer recurrence but also for screening for secondary primary cancers may be required.
CONCLUSION
Postoperative follow-up surveillance is widely performed; however, recommendations concerning follow-up strategies are heterogeneous and lack sufficient evidence. International guidelines suggest strategies and schedules based on retrospective studies and expert opinion. Postoperative follow-up may lead to the early detection and prompt treatment of recurrence. Optimizing follow-up using an individualized, evidence-based approach is crucial. Further large-scale, prospective studies providing high-grade evidence are required to inform secondary prevention strategies after gastric cancer surgery.
Notes
Availability of Data and Material
Data sharing is not applicable to this article as no datasets were generated or analyzed during the study.
Conflicts of Interest
The author has no financial conflicts of interest.
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