Pathologic Complete Response After Gastric Artery Chemoembolization Combined With Tislelizumab for Neoadjuvant Therapy of Locally Advanced Gastric Cancer: A Case Report

Abstract

Gastric cancer is the most common type of gastrointestinal cancer in China which about 80% of patients are locally advanced or advanced when diagnosed. Surgery along brings high recurrence rate for locally advanced gastric cancer (LAGC), and neoadjuvant therapies are needed. The use of programmed cell death-1 (PD-1)/programmed death-ligand 1 inhibitor nowadays improved the disease-free survival for LAGC, however, only <35% of patients achieved pathologic complete response (pCR) after neoadjuvant therapy nowadays. Therefore, new regimens are needed to be investigated. Gastric artery chemoembolization is applied to metastasis gastric cancer and researches showed interventional therapy can enhance the antitumor effect of PD-1 inhibitor. Here, for the first time, we combined gastric artery chemoembolization with tislelizumab (a PD-1 inhibitor) for neoadjuvant therapy of a patient with LAGC. The patient achieved pCR after a D2 resection and tumor regression grade score was 1. After surgery, the patient received tislelizumab 200 mg per 3 weeks, and showed no sign of recurrence after 6 months of follow-up. The study indicated the use of tislelizumab and gastric artery chemoembolization for neoadjuvant therapy may bring a better pCR rate and prognosis of LAGC.

Gastric cancer (GC) is the fifth common cancer and third leading cause of cancer death worldwide.¹ In China, about 80% of GC patients were locally advanced or advanced when diagnosed, leading to a poor prognosis and cancer-related death.² Studies have shown surgery along brings high recurrence rate for locally advanced gastric cancer (LAGC) and the 5-year survival rate after D2 resection is still <50%.³ Neoadjuvant therapies can downstage tumor stage, improve the R0 resection rate and reduce the recurrence rate which prolongs the disease-free survival (DFS) and overall survival (OS) of LAGC patients.⁴

With the development of neoadjuvant therapy, the treatment mode has been transformed from neoadjuvant chemotherapy to neoadjuvant radiotherapy, neoadjuvant immunotherapy and combination therapy. However, only <35% of patients achieved pathologic complete response (pCR) after neoadjuvant therapy nowadays. Therefore, new treatments are needed to be explored. Gastric artery chemoembolization has been used in LAGC bringing chemotherapeutic drugs and embolic agents together to tumor supplying artery, which can not only block up the tumor’s blood supply and can also act as targeted chemotherapy, killing tumor in both ways.⁵ However, gastric artery chemoembolization combined with immunotherapy as neoadjuvant therapy for LAGC, to our knowledge, has not been studied yet. Here, we reported a 63-year-old man of LAGC with tislelizumab [a programmed cell death-1 (PD-1) inhibitor] combined with gastric artery chemoembolization for the first time. This patient reached R0 resection and pCR, indicating this combination may enhance the R0 resection rate and improve the DFS and OS for LAGC.

CASE PRESENTATION

A 63-year-old Chinese man of Han nationality was referred to our hospital due to fatigue in June 2022. Physical examination showed no obvious abnormalities. Tumor marker of alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 199, carbohydrate antigen 724 were all negative. Abdominal contrast-enhanced computed tomography (CT) scan revealed a thickening of gastric wall. Then an fluorine-18 fluorodeoxyglucose positron tomography/CT was performed, which showed the gastric wall in the stomach body and antrum was significantly thickened. The thickness was about 14.3 mm with maximal standardized uptake value=17.5. And the invasion of regional lymph nodes was shown in fluorine-18 fluorodeoxyglucose positron tomography/CT (Fig. 1). Gastroscopical biopsy were performed and the pathologic diagnosis was gastric adenocarcinoma. Immunohistochemistry showed CD3⁺, CD4⁺, and CD8⁺ T cells were expressed, respectively 30%, 20%, and 10% in tumor stroma (Fig. 2), indicating an active tumor microenvironment (TME). Next-generation sequence showed negative expression of human epidermal growth factor receptor 2 and Epstein-Barr virus–encoded RNA’s and the microsatellite instability status was MSS. Both combined positive score and tumor proportion score were 5%. Eventually, the diagnosis of LAGC, cT4N1M0, and staged Ⅲ was given.

FIGURE 1.

Fluorine-18 fluorodeoxyglucose positron tomography/computed tomography scan for this patient before neoadjuvant therapy. A, Fluorine-18 fluorodeoxyglucose positron tomography/computed tomography scan revealed primary lesion of stomach with maximal standardized uptake value (SUV_max)=17.5 and the invasion of regional lymph nodes. B and C, Green arrows showed the specific lesions of this patient.

FIGURE 2.

Immunohistochemical staining of locally advanced gastric cancer (×100). A, Hematoxylin and eosin staining. B–D, CD3⁺, CD4⁺, and CD8⁺ T cells were expressed, respectively 30%, 20%, and 10% in tumor stroma.

We decided to perform a neoadjuvant therapy for this patient, due to the massive ulcer, gastric artery chemoembolization was conducted first. As shown in Figures 3A and 3B, we found the tumor supplying artery, then 150 mg oxaliplatin was injected for 45 minutes and followed embolization of left gastric artery with 100–300 μm microspheres. Considered of high expression of immune cell in tumor stroma, 3 cycles of tislelizumab were conducted. The patient received tislelizumab 200 mg per 3 weeks and the adverse effect during the treatment was grade 1 neutropenia after gastric artery chemoembolization.

FIGURE 3.

Gastric artery chemoembolization therapy for this patient and computed tomography scan after 3 cycles of programmed cell death-1 inhibitor plus chemotherapy. A and B, Gastric artery were found as tumor supplying artery and then performed a gastric artery chemoembolization. C and D, After 3 cycles therapy, the lymph nodes of this patient were significantly reduced.

After neoadjuvant therapy, CT scan showed a significantly reduce of lymph nodes (Figs. 3C, D) and according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), the evaluation results reached partial response. Then a D2 gastrectomy was performed which reached R0 resection. The primary lesions of gastric wall were all gone with only remained carcinoma in situ and tumor regression grade score was 1 (Fig. 4). All lymph nodes were all negative after treatment. Therefore, the patient reached ypN0 and pCR. After surgery, the patient received tislelizumab 200 mg per 3 weeks, and showed no sign of recurrence after 6 months of follow-up.

FIGURE 4.

Hematoxylin and eosin staining of locally advanced gastric cancer after surgery (×100).

DISCUSSION

GC is the fifth common cancer worldwide and the most common gastrointestinal cancer in China. GC was usually occult in onset and about 80% of patients in China were LAGC and advanced GC when diagnosed, which exhibits a poor OS about only 1 year.¹ In addition, the 5-year survival rate of LAGC after surgery was <50%.⁶ Researches show neoadjuvant therapy prolongs DFS of patients with LAGC, and also predict patients’ responses to drug therapy.^7,8 According to RESOLVE trial, 3-year DFS was 51.1% in the adjuvant-CapOx (oxaliplatin, capecitabine) group, 56.5% in the adjuvant-SOX (oxaliplatin, S-1) group, and 59.4% in the perioperative-SOX group.⁹ At present, the commonly used neoadjuvant therapy of LAGC were FLOT (oxaliplatin, leucovorin calcium, docetaxel, fluorouracil), SOX, CapOX, DOS (docetaxel, oxaliplatin, S-1) or concurrent chemoradiotherapy.^10,11 However, only a 2%–16% of patients achieved pCR after neoadjuvant chemotherapy.^10,12 Therefore, new neoadjuvant therapies are undergoing explored.

With the use of PD-1 or programmed death-ligand 1 (PD-L1) inhibitors in first line therapy of advanced GC, which greatly improve the OS.¹³ Therefore, PD-1/PD-L1 inhibitors combined chemotherapy were applicated to GC for perioperative treatment, which improve the pCR rate and DFS of LAGC. The interim results of the DANTE study showed that the pCR rate of FLOT group was about 16%, compared with 25% in atenlizumab (a PD-L1 inhibitor) combined FLOT group.¹⁴ Also, a phase Ⅱ clinical study in our center showed 33.3% pCR rate after camrelizumab (a PD-1 inhibitor) plus concurrent chemoradiotherapy. Major pathologic response, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0.¹⁵ However, only <35% of patients achieved pCR after neoadjuvant chemotherapy and immunotherapy, thus, new regimens need to be investigated.

Interventional therapy was widely used in liver cancer which can directly kill or inhibit tumor cell growth and release tumor antigens.¹⁶ Studies showed cell damage during gastric artery chemoembolization induces the formation of blood vessels in tumor tissue, and tumor cell necrosis can also activate immune responses, such as enhancing T-cell infiltration in TME, improving the expression of PD-L1 in tumor cells, which eventually increase the antitumor immune effect of the body,^17,18 indicating the combination of interventional therapy may enhance the efficacy of PD-1 inhibitors.

Based on these researches and the high expression of immune cells and high tumor proportion score and combined positive score in this patient, suggesting an active tumor TME and may benefit from immunotherapy. Therefore, we used PD-1 inhibitor combined with gastric artery chemoembolization in this case, which to our knowledge has not been reported yet. After gastric artery chemoembolization and 3 cycles of immunotherapy, this patient responded well and received a D2 gastrectomy, which reached R0 resection and pCR. Our treatment plan added evidence for combination therapy in neoadjuvant therapy for LAGC and also suggested a better prognosis for LAGC. The adverse effect was neutropenia which can recover after injecting granulocyte colony-stimulating factor and no surgical complications were seen in this case. The combination treatment is safe and effective.

In conclusion, this patient was first report of PD-1 inhibitor combined with gastric artery chemoembolization for neoadjuvant therapy for LAGC. The results showed this patient respond well which suggested a better pCR and R0 resection rate after this therapy, indicating a better pCR rate and DFS of LAGC. Further clinical studies need to be conducted to investigate this potential combined therapy and provide more therapeutic options for neoadjuvant therapy of patients with LAGC.

CONFLICTS OF INTEREST/FINANCIAL DISCLOSURES

Supported by the Natural Science Foundation of Xiamen, China (No. 3502Z20227111).

None reported. All authors have declared that there are no financial conflicts of interest with regard to this work.