An 81-year-old female patient presented with dull upper abdominal pain, loss of appetite, belching, and acid regurgitation for three months (February 2021). She had a history of hypertension and type two diabetes mellitus. Contrast-enhanced computed tomography (CT) was performed on the abdomen, showing gastric wall thickening in the lesser curvature of the antrum, gastric cavity stenosis with increased density of perigastric fat space, and multiple enlarged lymph nodes (Fig. 1A, B, C). Gastroscopy showed an ulcerative mass in the antrum, and pathology showed adenocarcinoma (Fig. 1D and Fig. 2A). According to the Eighth American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) classification of neoplasm Metastasis (TNM) staging, gastric adenocarcinoma is defined as clinical stage (cT4N2M0) and considered resectable after neoadjuvant chemotherapy. Detection of mismatch repair (MMR) protein : mismatch repair function defect (dMMR) (Fig. 3A, B, C, D), this patient could benefit from immunosuppressive therapy. MMR proteins : The expression of four common MMR proteins ( MLH1, MSH2, MSH6 and PMS2 ) was detected by immunohistochemistry. The positive expression was located in the nucleus. The absence of any one protein expression was dMMR, and all four proteins were positive for pMMIR ( mismatch repair function complete ). dMMR is equivalent to microsatellite instability high (MSI-H). No treatment was given before neoadjuvant therapy. From March 2021 to May 2021, the patients received three cycles of SOX chemotherapy (intravenous oxaliplatin 130 mg/m2 on the first day, S-1 80 mg/m2 after breakfast and dinner twice a day on the first to 14th days) without chemotherapy contraindication. At the same time, PD-1 inhibitor (Camrelizumab) 200 mg IVGTT DAY1, Q3W. Every three weeks was a cycle and repeated once. The treatment was well tolerated, and no immune-related adverse effects were observed based on tests for hematotoxicity and multiorgan function. After three cycles of treatment, an abdominal CT scan performed on June 2, 2021, showed a significant reduction of antral mass and perigastric lymph nodes. The efficacy of therapy is defined as the partial clinical response (PR) (Fig. 1E, F, G, H). After D2 operation for Gastric cancer, postoperative pathological examination showed the pathological stage and complete pathological response (pCR) of ypT0N0M0 (Fig. 2B). Regular follow-up was required after postoperative communication with the patient. In December 2021, A liver ultrasound examination showed two lesions in the liver's right anterior lobe were considered metastatic. Liver biopsy: consistent with adenocarcinoma(Fig. 2C). Radiofrequency therapy for liver tumors was performed on January 5, 2022. The patient refused chemotherapy after the operation and was followed up regularly. She died on May 2, 2022. The entire diagnosis and treatment schedule of the patient is shown in Fig. 4.
A 69-year-old female patient presented with cryptic pain in the upper abdomen and loss of appetite for five months (March 2021). The patient had no family genetic history or extraordinary medical history. Gastroscopy showed the antrum and gastric horn masses, and pathology showed heterospecific cells and signet-ring cells. Contrast-enhanced computed tomography (CT) of the abdomen showed local irregular thickening of the gastric wall in the antrum and gastric horn with clumped soft tissue shadows and enlargement of multiple lymph nodes around the stomach (Fig. 5A, B, C, D and Fig. 6A). The patient's clinical stage was cT4N1M0, and mismatch repair protein detection showed dMMR (Fig. 7A, B, C, D). No treatment was given before neoadjuvant therapy. From March 2021 to April 2021, two cycles of SOX chemotherapy regimen were administered in addition to the PD-1 inhibitor (Camrelizumab) 200 mg IVGTT DAY1, Q3W. The treatment was well tolerated, and no immune-related adverse effects were observed based on tests for hematotoxicity and multiorgan function. After two cycles of treatment, the patient underwent a CT scan of the abdomen on April 14, 2021, which showed a decrease in antral mass and lymph nodes around the stomach. The efficacy of treatment is defined as the partial clinical response (PR) (Fig. 5E, F, G, H). After Operation D2 for Gastric cancer(May 2021), postoperative pathological examination showed the pathological stage and complete pathological response (pCR) of ypT0N0M0 (Fig. 6B). Because the patient insisted on continuing postoperative treatment and could not tolerate therapy after one cycle with a PD-1 inhibitor (Camrelizumab) 200 mg IVGTT, the patient requested regular follow-up. In December 2021, the patient was given ascites due to apparent abdominal distension. Tumor cell examination showed dispersed nuclear heterogeneous cells in the ascites (Fig. 6C). The patient was treated with a combination of PD-1 inhibitor and S-1 for two cycles because of intraperitoneal metastasis. Due to gastrointestinal reaction again, the patient could not tolerate the treatment and was given regular follow-up observations such as nutritional support. The last follow-up time was October 2022. The entire diagnosis and treatment schedule of the patient is shown in Fig. 8.
All study procedures involving human participants followed institutional and National Research Council ethical standards and the Declaration of Helsinki (revised 2013). Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.
Neoadjuvant Chemotherapy:
Gastric cancer is one of the most common digestive system malignancies with high morbidity and mortality. In most gastric cancer patients, patients with advanced gastric cancer are the main body. Surgical resection is still the only curative measure at present. However, surgical treatment alone cannot achieve satisfactory results for treating locally advanced gastric cancer. With the advancement of science and technology and in-depth research on gastric cancer, adjuvant therapy for gastric cancer is also constantly improving. There have been many essential changes in the treatment mode of locally advanced gastric cancer, from surgery alone to surgery combined with postoperative adjuvant chemotherapy and then to neoadjuvant chemotherapy + surgery + postoperative adjuvant. Among them, the mode of neoadjuvant chemotherapy + surgery + postoperative adjuvant therapy has attracted more and more attention. In the past 20 years, many kinds of literature have analyzed and demonstrated the safety and efficacy of neoadjuvant chemotherapy[12–14]. The theoretical application value of neoadjuvant chemotherapy lies in 1. They were shrinking the primary tumor, reducing or disappearing the metastatic lymph nodes, inducing preoperative downstaging, and improving the surgical R0 resection rate; 2. They were eliminating potential micrometastases in the body and reducing postoperative distant Metastasis and recurrence rates; 3. According to the clinical examination data before and after neoadjuvant chemotherapy and postoperative pathological conditions, the clinical remission rate and histopathological regression grading of primary lesions can be observed; 4. Applying neoadjuvant chemotherapy can verify the sensitivity of tumors to chemotherapy drugs and guide postoperative medication according to tumor response; 5. Determine tumor biological behavior to evaluate patient prognosis[15].
Currently, neoadjuvant chemotherapy is mainly used for patients with locally advanced gastric cancer with preoperative stage T3-4 or N1-3 without distant metastasis[16]. In 1982, Feri[17] first proposed the concept of neoadjuvant chemotherapy and applied it to the treatment of solid tumors and achieved good results. In 1989, Wilke et al[18] applied neoadjuvant chemotherapy to the treatment of gastric cancer patients for the first time, and the results showed that the treatment was effective, the tumor was downstaged, and the radical resection of gastric cancer and lymph node dissection were successfully performed. Later, more and more researchers turned their attention to neoadjuvant therapy. In 2006, the MAGIC clinical trial found that the overall survival and disease progression-free survival of patients in the neoadjuvant chemotherapy group for gastric cancer were significantly higher than those of patients with surgery alone (P = 0.009, P < 0.001); the 5-year survival rate of the patients was 36.3%., higher than 23.0% of patients with surgery alone, R0 resection rate (79.3% vs 70.3%, P < 0.05)[19]. The results of this study lay the foundation for neoadjuvant chemotherapy for gastric cancer. In 2011, the FFCD9703 study further confirmed that preoperative neoadjuvant chemotherapy for gastric cancer could improve the R0 resection rate, overall survival rate, and disease progression-free survival rate[20]. The results of the multicenter phase III clinical trial FNCLCC/FFCD organized by Ychou et al also showed that the neoadjuvant chemotherapy group was significantly improved in R0 resection rate (84% vs. 73%, P = 0.04), overall survival (P = 0.02), disease Progression-free survival (P = 0.003) and 5-year survival rate (38% vs. 24%, P = 0.02) were significantly better than those in the surgery-only group. Studies have demonstrated the efficacy and safety of neoadjuvant chemotherapy for gastric cancer, and it has also become the key evidence for the process of incorporating neoadjuvant chemotherapy combined with surgery into the National Comprehensive Cancer Network (NCCN) Guidelines for the Treatment of Gastric Cancer[21].
Currently, many neoadjuvant chemotherapy regimens are in clinical application, such as SOX, ECF, XELOX, FLOT-4, DOF, and FOLFOX. The SOX regimen is a chemotherapy regimen of S-1 combined with oxaliplatin. As a fluorouracil anticancer drug, S-1 can be rapidly absorbed orally, reducing the pain and associated risks of intravenous intubation and reducing infusion complications. It is easy to accept, so the SOX regimen as a safe and feasible neoadjuvant chemotherapy regimen is recommended as 2A in the CSCO gastric cancer guidelines and is widely used in clinical practice[22]. Several recent studies have shown the promising efficacy and safety of S-1 + oxaliplatin (SOX) as a neoadjuvant chemotherapy regimen [23–25]. A single-center phase II trial has confirmed that the disease control rate of SOX using neoadjuvant chemotherapy was 93.8%. The overall response rate was 68.8%. Compared with the operation group alone, the R0 resection rate and D2 lymph node clearance rate in the neoadjuvant chemotherapy group were significantly superior [26]. In addition, fluorouracil plus oxaliplatin is recommended in the Chinese Society of Clinical Oncology (CSCO) guidelines and NCCN guidelines for treating gastric cancer [16, 22]. Therefore, SOX has a good application prospect in neoadjuvant therapy for gastric cancer.
Immunity Therapy:
In recent years, the development of immune checkpoint inhibitors (ICIs) related research, such as programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, revolutionized the treatment of advanced solid cancers[27]. Adam[28] found in a comprehensive molecular characterization of gastric adenocarcinoma that PD-L1 overexpression was observed in 65% of gastric cancer tissues. The binding of PD-1 to PD-L1 inhibited effector T cell function, thereby inhibiting the Anti-tumor immune response promotes tumor growth[29], The study of this mechanism makes blocking the PD-1/PD-L1 signaling pathway a reasonable target for treating gastric cancer patients. Phase III Attraction-02 study[8] and Keynote-061 study[9] on immune checkpoint PD-1 inhibitors in patients with advanced gastric cancer confirmed their superiority in advanced gastric cancer. Regarding safety, PD-1 therapy also has the advantages of fewer adverse reactions and good tolerance. Kang et al[8] treated gastric cancer with PD-1, the incidence of TRAE > grade 3 was 10%, and there were few reports of treatment-related deaths and treatment discontinuation due to adverse reactions. Ahamadi et al[30] conducted a study and found that the pharmacokinetics of PD-1 is relatively stable, and age, gender, liver and kidney function, and concomitant use of other drugs have little effect on plasma concentrations and metabolic processes. This advantage is particularly prominent in patients with liver and kidney insufficiency, multiple concomitant diseases, or multiple medications.
Given the low efficacy of immunotherapy alone for gastric cancer, combining immunotherapy with chemotherapy or targeted therapy may be more beneficial than monotherapy. Several clinical trials have demonstrated this effectiveness. The ATTRACTION-04 study is a phase II/III clinical trial of PD-1 combined with chemotherapy (S-1/capecitabine + oxaliplatin) in first-line treatment of advanced or recurrent HER-2-negative gastric or gastroesophageal junction cancer. The study showed that the two groups of chemotherapy combined with immunotherapy had an effective rate of 67% and 71%, respectively, with a PFS of 7.1 months and 9.9 months, with good ORR and PFS[10]. Immunotherapy combined with chemotherapy and targeted therapy has also shown good clinical therapeutic effects in neoadjuvant therapy for gastric cancer. Efficacy and safety evaluation of S-1 plus oxaliplatin combined with PD-1 inhibitor and lapatinib (SOXPA) as neoadjuvant therapy in patients with locally advanced gastric cancer (LAGC). Patients showed complete response (CR), partial response (PR), and stable disease (SD) in 6.7%, 60.0%, and 33.3%, respectively. The R0 resection rate was 93.3%. The pCR rate was 20%. The target response rate (ORR) and disease control rate (DCR) was 66.7% and 100.0%, respectively. And no grade 4 adverse events occurred, with good safety[31]. In addition, the Phase III CheckMate-649 clinical study is the largest clinical study in gastric cancer, and the combination of PD-1 inhibitor and chemotherapy is compared with chemotherapy alone in OS, PFS, and acceptable safety. The advantages are obvious. PD-1 inhibitor plus chemotherapy is expected to change the first-line treatment landscape in gastric cancer and become the new standard first-line treatment for these patients[11].