Long-term survival after treatment of gastric cancer with S-1 plus oxaliplatin regimen and sintilimab: A case report

Abstract

BACKGROUND

Treatment of metastatic gastric cancer (mGC) relies primarily on chemotherapy, which can be effectively combined with immunotherapy. Despite these interventions, overall survival remains suboptimal.

CASE SUMMARY

We report a patient with mGC who received S-1 plus oxaliplatin with sintilimab as first-line therapy, followed by maintenance therapy with S-1 and sintilimab. After 6 months, a partial response was observed, with a 71.7% reduction in the target lesion. After 13 months, the reduction reached 76.3%. Treatment was temporarily paused for 6 months due to a pulmonary infection. Upon re-evaluation 6 months later, the tumor continued to regress, with a 79.4% reduction in the target lesion. The original regimen was then resumed. From diagnosis to date, progression-free survival has reached 23 months.

CONCLUSION

Sintilimab combined with chemotherapy demonstrated improved progression-free survival and warrants further investigation in mGC.

Key Words: Metastatic gastric cancer; Sintilimab; Immunotherapy; Chemotherapy; Progression-free survival; Case report

Core Tip: Chemotherapy combined with immunotherapy is the standard first-line treatment for metastatic gastric cancer. However, the first-line median progression-free survival is only about 7 months. This article reports a case of metastatic gastric cancer in which the patient received S-1 plus oxaliplatin regimen with sintilimab, followed by maintenance therapy with S-1 and sintilimab. The patient achieved a partial response and a progression-free survival of 23 months. Moreover, the treatment was temporarily paused for 6 months due to pneumonia. However, upon re-evaluation 6 months later, the tumor continued to regress. This combination therapy has shown encouraging results and warrants further study.

INTRODUCTION

Gastric cancer (GC) is a common malignant tumor of the digestive tract. According to the International Agency for Research on Cancer, in 2022, there were 968350 new cases of GC and 659853 deaths worldwide, ranking fifth among malignant tumors for both incidence and mortality[1]. Currently, chemotherapy remains the mainstay for treating metastatic GC (mGC), with specific agents including fluorouracil, platinum compounds, taxanes, and irinotecan. However, the efficacy of chemotherapy alone is relatively low, with a median overall survival (mOS) of only one year[2]. Although the ToGA study established the role of trastuzumab in advanced human epidermal growth factor receptor 2 (HER-2)-positive GC patients, the mOS was only extended to 14 months, and only about 15% of HER-2-positive patients benefited from this drug[3]. In recent years, advancements in immunotherapy have led to studies such as CheckMate-649[4], KEYNOTE-859[5], RATIONALE-305[6], and ORIENT-16[7], which have established the roles of nivolumab, pembrolizumab, tislelizumab, and sintilimab in mGC, with mOS ranging from 12.9 months to 15.2 months and median progression-free survival (mPFS) ranging from 6.9 months to 7.7 months. Compared with chemotherapy alone, the combination of immunotherapy and chemotherapy has been shown to prolong patient survival; however, substantial room for improvement remains. We report a case of metachronous mGC treated with the S-1 plus oxaliplatin (SOX) regimen combined with sintilimab as first-line therapy. The patient achieved a partial response (PR) and progression-free survival (PFS) reaching 23 months. Moreover, metastatic lesions in the liver continued to shrink during a 6-month interruption of antitumor therapy. To our knowledge, a response of this duration to sintilimab has not been previously reported.

CASE PRESENTATION

Chief complaints

A 77-year-old male was admitted to our hospital with abdominal pain for three days in September 2022.

History of present illness

The patient experienced upper abdominal pain 3 days after eating. The pain was dull and intermittent, occurring 8 to 10 times daily, with each episode lasting approximately 5 to 10 minutes. Pain intensity was rated 3 to 4 on the numeric rating scale and resolved spontaneously. The patient reported no acid reflux, belching, nausea, vomiting, abdominal distension, or melena.

History of past illness

This patient was diagnosed with hypertension based on the symptoms of dizziness and abnormal elevation of blood pressure in 2017.

Personal and family history

He smoked about 20 cigarettes per day for 15 years and quit smoking 5 years ago. He had no history of alcohol abuse. His family history was notable for his father’s death from GC and his brother’s similar demise, whereas the cause of his mother’s death remained unknown.

Physical examination

All vital signs were stable, and physical examination revealed no notable abnormalities.

Laboratory examinations

Laboratory findings showed slightly decreased hemoglobin (99 g/L) and otherwise normal blood counts.

Imaging examinations

A gastroscopy performed on September 7, 2022, revealed an irregular lesion at the cardia, approximately 4 cm × 5 cm, characterized by significant mucosal infiltration, bleeding, and invasion of the cardia. Pathological examination of the endoscopic biopsy confirmed moderately differentiated adenocarcinoma (Figure 1A). A subsequent contrast-enhanced computed tomography (CT) scan of the abdomen on September 22, 2022, demonstrated localized thickening of the gastric wall extending from the cardia to the lesser curvature, suggestive of GC, along with slightly enlarged lymph nodes in the hepatogastric space.

Figure 1 Pathology and immunohistochemistry of the endoscopic biopsy and resected specimen. A: Hematoxylin and eosin (HE) staining of the endoscopic biopsy showed suggestive of gastric cancer: Moderately differentiated adenocarcinoma, HE × 100 and HE × 200; B: HE staining of the resected specimen confirms the diagnosis of gastric cancer: Moderately to poorly differentiated adenocarcinoma, with infiltration through the entire thickness of the gastric wall into the serosal fibrous adipose tissue, HE × 200 and HE × 400; C: Immunohistochemistry (IHC) of the resected specimen showed programmed death ligand 1 positivity, IIHC × 200 and IHC × 400.

MULTIDISCIPLINARY EXPERT CONSULTATION

A discussion at the tumor board meeting was conducted, and radical open gastrectomy with esophagojejunostomy followed by adjuvant chemotherapy was planned.

FINAL DIAGNOSIS

The patient’s preoperative clinical stage was stage IIA GC.

TREATMENT

After providing full informed consent, the patient agreed to undergo surgical treatment. On September 27, 2022, the patient underwent open radical total gastrectomy with esophagojejunostomy. Intraoperative blood loss was approximately 100 mL. During surgery, two units of red blood cells and 140 mL of frozen plasma were transfused. The postoperative hospital stay lasted 12 days. A feeding jejunostomy was not performed. Postoperative pathology revealed moderately to poorly differentiated adenocarcinoma, measuring approximately 3.5 cm × 3.2 cm × 1 cm, with infiltration through the entire gastric wall into the serosal fibrous adipose tissue. Neural invasion and intravascular tumor thrombi were identified. Notably, the upper and lower resection margins, the submitted anastomotic site, and the omental tissue were free of tumor. No metastatic carcinoma was detected in the lymph nodes along the lesser curvature (0/10) or the greater curvature (0/2) (Figure 1B). Immunohistochemistry results indicated HER-2 (+), MutL homolog 1 (+), MutL homolog 12 (+), MutS homolog6 (+), and postmeiotic segregation increased 2 (+). Next-generation sequencing results showed programmed death ligand 1 (combined positive score = 3; tumor proportion score < 1%; Figure 1C) and a tumor mutation burden of 8.2 mutations/Mb. The patient’s postoperative tumor-node-metastasis stage was stage IIA (T3N0M0). The patient underwent two cycles of adjuvant chemotherapy using the SOX regimen at the Department of General Surgery, Jinling Hospital in November and December 2022 (oxaliplatin 200 mg IV on day 1; S-1 60 mg per os twice daily from day 1 to day 14, every 3 weeks). The patient self-reported the discontinuation of chemotherapy due to nausea and vomiting, and no further postoperative adjuvant treatment was administered thereafter.

On August 5, 2023, an upper abdominal magnetic resonance imaging revealed multiple liver lesions, the largest of which was approximately 5.2 cm. The patient was diagnosed with stage IV GC with liver metastasis. We did not perform a percutaneous biopsy of the liver lesion. From August 9, 2023, to January 9, 2024, the patient received first-line therapy consisting of the SOX regimen combined with sintilimab for six cycles (sintilimab 200 mg IV on day 1; oxaliplatin 200 mg IV on day 1; S-1 40 mg in the morning and 60 mg in the evening from day 1 to day 14, every 3 weeks). According to the National Comprehensive Cancer Network guidelines, positron emission tomography/CT is not routinely recommended for assessment of chemotherapy. Therefore, we performed contrast-enhanced CT of the chest and abdomen instead. After two cycles of first-line therapy, the evaluation indicated a PR with a target lesion reduction of 46.4%. After six cycles, the evaluation continued to show a PR with target lesion reductions of 71.7%. From February 23, 2024, to September 2, 2024, the patient received maintenance treatment with sintilimab combined with S-1 for eight cycles (sintilimab 200 mg IV on day 1; S-1 40 mg in the morning and 60 mg in the evening from day 1 to day 14, every 3 weeks). The efficacy evaluation indicated a maintained PR with a 76.3% reduction in target lesions (Figure 2).

Figure 2 Abdominal computed tomography and magnetic resonance during the treatment and follow-up. A: Magnetic resonance imaging done at the baseline before starting the therapy showed three liver lesions, with the largest measuring 527 cm; B: Magnetic resonance imaging performed after 2 cycles of first-line therapy showed a significant reduction in the liver lesions; C: Contrast-enhanced computed tomography (CT) done after 4 cycles of first-line therapy; D: Contrast-enhanced CT after 6 cycles of first-line therapy; E: Contrast-enhanced CT after 2 cycles of maintenance treatment; F: Contrast-enhanced CT done on August 8, 2024, after 6 cycles of maintenance treatment, showing sustained partial response; G: Contrast-enhanced CT done on March 7, 2025, after 6 months of treatment interruption. Oranges arrows indicate the primary lesions.

On September 10, 2024, the patient was diagnosed with pneumonia and treated with cefoperazone sulbactam sodium combined with moxifloxacin in the Emergency Department. Subsequently, on September 23, 2024, the patient was admitted to the Respiratory Department and treated with piperacillin and tazobactam due to the worsening infection. On October 8, 2024, the patient required admission to the intensive care unit and was administered imipenem and cilastatin due to further aggravation of the infection. A chest CT scan conducted on November 4, 2024, revealed bronchiectasis with infection in the right lung. Subsequently, there was clinical and radiological improvement (Figure 3). During the anti-infective treatment, the use of sintilimab and S-1 was discontinued. Following discharge from the hospital, due to the patient’s poor physical condition, the patient requested a temporary discontinuation of antitumor treatment. After thorough communication, the patient opted for close observation and follow-up. From September 2024 to February 2025, the patient did not undergo any antitumor therapy. A CT scan on March 7, 2025, indicated that the liver lesions continued to shrink, with target lesions reduced by 79.4% (Figure 2). Subsequently, on March 12, April 9, and May 19, 2025, the patient received three cycles of maintenance therapy with sintilimab combined with S-1 (sintilimab 200 mg IV on day 1; S-1 40 mg in the morning and 60 mg in the evening from day 1 to day 14, every 3 weeks). The patient tolerated the therapy well, with the main adverse reactions being grade 1 anemia and grade 1 fatigue, which were considered primarily related to chemotherapy and not associated with sintilimab.

Figure 3 Chest computed tomography findings of the patient. A: On September 10, 2024, inflammation was observed in both lungs, accompanied by localized bronchiectasis in the right lung; B: On September 23, 2024, the findings indicated bronchiectasis and infection in the right lung, as well as inflammation in both the lower lobes; C: On October 8, 2024, the condition further deteriorated, showing bronchiectasis with infection in the right lung and inflammation in both lungs; D: On November 4, 2024, some resolution in the bronchiectasis and bilateral lung infections was noted.

OUTCOME AND FOLLOW-UP

The patient is currently undergoing maintenance therapy, maintaining a good quality of life. The case timeline is presented in Figure 4.

Figure 4 Timeline of the patient’s treatment and clinical course. PD: Progressive disease; PR: Partial response; PFS: Progression-free survival; SOX: Oxaliplatin and S-1.

DISCUSSION

mGC is associated with poor long-term survival due to a lack of effective systemic therapy. The CheckMate649 study was a multicenter trial that enrolled a total of 1581 patients, including 208 Chinese patients[4]. This study confirmed the efficacy of nivolumab combined with chemotherapy as a first-line treatment for mGC. However, GC is highly heterogeneous, exhibiting significant differences between Eastern and Western populations[8]. The ORIENT-16 study is the first randomized, double-blind, phase III trial conducted in China, demonstrating substantial benefits of immunotherapy combined with chemotherapy as a first-line treatment for mGC[7]. The results of this study showed that sintilimab combined with chemotherapy provided significant survival benefits, with a mOS of 15.2 months and a mPFS of 7.1 months, along with a median duration of response of nearly 10 months and a favorable safety profile. Based on these findings, the China State Food and Drug Administration approved sintilimab for first-line treatment of mGC in 2023. Accordingly, we administered sintilimab in combination with the SOX chemotherapy regimen to this patient.

After the first two cycles of first-line treatment, the index patient achieved a 46.4% reduction in target lesions from baseline at the first evaluation. This finding suggests that the SOX regimen combined with sintilimab demonstrates substantial tumor regression in a short timeframe. A phase II single-arm clinical study conducted by Li et al[9] also reported similar findings. This study assessed the efficacy and safety of the FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) regimen combined with sintilimab in 32 patients with mGC. It was found that after 3-4 cycles of treatment, four patients achieved a complete response (12.5%), 23 patients achieved PR (71.9%), four patients had stable disease (12.5%), and one patient had progressive disease (3.1%). The overall response rate was 84.4%, and the disease control rate was 96.9%. Furthermore, Jiang et al[10] observed the efficacy of the XELOX (capecitabine and oxaliplatin) regimen combined with sintilimab in patients with mGC. After three cycles of treatment, among six patients with measurable target lesions, four patients achieved PR, and two patients had stable disease. The overall response rate was 66.7%, whereas the disease control rate reached 100%. Although these were small-sample, phase II clinical trials, the preliminary results demonstrated that both the XELOX regimen combined with sintilimab and the FLOT regimen combined with sintilimab achieved favorable short-term efficacy, with significant tumor regression observed after only two to four cycles.

The index patient not only exhibited significant tumor regression within a short period but also achieved favorable long-term efficacy. From initiation of the SOX regimen combined with sintilimab until treatment was interrupted due to pneumonia, PFS reached 13 months. After resolution of pneumonia and resumption of treatment, PFS extended to 23 months by July 2025. In contrast, large-sample randomized controlled trials have reported mPFS ranging from 6.9 months to 7.7 months, unlike the aforementioned small-sample phase II clinical studies[4-7]. The survival data for this patient exceed the median values reported in the aforementioned studies due to various factors, as discussed below.

First, the patient had an intestinal-type gastric adenocarcinoma, according to the Lauren classification. This classification, based on GC histology and morphology, has been clinically utilized for many years[11]. It categorizes GC into intestinal (50%), diffuse (30%), and mixed types (20%)[12]. The histological characteristics of intestinal type patients include a tubular glandular structure of tumor cells observable under the microscope, whereas diffuse type patients exhibit poorly differentiated tumor cells with weak cell adhesion. Patients with the intestinal type are more prone to liver metastasis and generally have a better prognosis. In contrast, those with the diffuse type are more susceptible to peritoneal and bone metastases, demonstrating greater aggressiveness and a more ominous prognosis[13].

Second, the patient had only hepatic metastases without any evidence of extrahepatic metastasis. Approximately 37% of GC patients develop liver metastasis following surgical resection, which is associated with a relatively favorable prognosis[14]. In contrast, 5% of GC patients present with peritoneal metastasis at the time of surgery, and the incidence of peritoneal metastasis after radical gastrectomy is 29%. This condition is associated with a mOS of only about 4 months, indicating a poor prognosis[15]. Furthermore, the tumor burden associated with liver metastases is also linked to prognosis. Hori et al[16] classified patients with liver metastasis from GC based on the number of liver metastases and the size of the largest diameter. The mOS was 10.2 months for patients with fewer than 4 liver metastases and a maximum diameter of less than 5 cm, compared to 3.1 months for those with 5 or more liver metastases and a maximum diameter of 5 cm or greater. In the present case, the patient had only three hepatic lesions with the maximum diameter of 5.27 cm at the baseline assessment, indicating a relatively low tumor burden and a favorable prognosis.

Moreover, the patient exhibited notable sensitivity to immunotherapy. Due to pneumonia, both immunotherapy and chemotherapy had to be suspended for a period of up to six months. However, follow-up CT scans conducted after this six-month interval revealed that the liver metastases had continued to shrink, with no new lesions detected, resulting in sustained PR. This finding suggests that once the treatment activates the body’s immune surveillance mechanism, it may function autonomously for an extended period, even after treatment cessation, thereby exerting persistent antitumor effects. Gauci et al[17] investigated the survival outcomes of 262 cancer patients following the interruption of immunotherapy. Through careful screening, 76 patients were identified as responders to immunotherapy. Among these, 39 patients had to interrupt their treatment for various reasons. Of these, 15 cases experienced disease recurrence, whereas the remaining 24 patients maintained therapeutic efficacy for at least 10 months to 20 months post-treatment discontinuation. The results indicate that, even after treatment cessation due to immune-related adverse events or in accordance with clinical study protocols, only 38% of the patients experienced disease progression, whereas 62% demonstrated sustained response. The durability of this therapeutic effect may be attributed to the capacity of immunotherapy to elicit a polyclonal and memory-adaptive antitumor immune response. This immune response can control the tumor initiation and progression, as well as kill the tumor cells, which can be maintained over the long term[18,19].

CONCLUSION

In summary, the combination of the SOX regimen with sintilimab for the treatment of mGC demonstrates favorable short-term efficacy and long-term survival. It may be related to the intestinal type, as classified by Lauren, the presence of liver-only metastasis, and notable sensitivity to immunotherapy. In clinical practice, GC patients with intestinal type and liver-only metastasis are not uncommon. Moreover, the patient demonstrated good tolerance to treatment, with no adverse reactions attributable to immunotherapy. Nevertheless, future studies with larger sample sizes are needed to validate these findings and improve survival in mGC.