The era of standardized precision immunotherapy for locally advanced gastric cancer

Author: Liang Han

Source: Chinese Journal of Digestive Surgery, 2024, 23(3)

summary

Locally advanced gastric cancer accounts for 70% of the clinically confirmed cases in mainland China, and standardized lymph node dissection is the foundation to ensure the quality of surgery, and the scope of standardized lymph node dissection for adenocarcinoma at the esophagogastric junction still needs to be further explored. Radical omentum-sparing gastric cancer still requires clinical evidence. Indocyanine green lymphatic navigation is the hallmark for precise lymph node dissection. SOX (oxaliplatin + Tigio) perioperative chemotherapy is currently the standard treatment mode for locally advanced gastric cancer in China, and perioperative immunotherapy + chemotherapy is being actively explored. In the era of immunotherapy, new breakthroughs are expected to be made in the transformation therapy of stage IV gastric cancer.

Gastric cancer is one of the most common malignant tumors in mainland China, and the latest data shows that there are >390,000 new gastric cancer patients and 280,000 death>s every year, making it the country with the highest incidence and mortality rate of gastric cancer in the world. The incidence and mortality rate of gastric cancer have long ranked among the top 3 among all malignant tumors. According to the data of the China Alliance of Gastrointestinal Surgery from 2014 to 2022, 20% of the patients were admitted to the clinic for early-stage gastric cancer, and 70% were in the locally advanced stage. Surgery is still the only way to cure gastric cancer, and in recent years, with the addition of immunotherapy, the treatment of locally advanced gastric cancer has entered the era of standardized, precise and immunotherapy.

1. Reasonable lymph node dissection for locally advanced gastric cancer

The 6th edition of the Japanese "Guidelines for the Treatment of Gastric Cancer" recommends that D2 lymph node dissection should include No.1, 3, 4sb, 4d, 5, 6, 7, 8a, 9, 11p, and 12a lymph nodes during distal gastrectomy; D2 lymph node dissection should include No.1~7, 8a, 9, 11p, 11d, and 12a lymph nodes during distal gastrectomy; D2 lymph node dissection should include No.1, 2, 3a, 4sa, 4sb, 7, 8a, 9, 11p, 11-day lymph nodes: when the tumor invades the esophagus, lymph node dissection should include No.19, 20, and 110 lymph nodes. The surgical treatment of gastric cancer has entered the era of minimally invasive, but the scope of standard lymph node dissection has not changed, and in the minimally invasive scenario, special emphasis is placed on the complete resection of en-bloc for each group of lymph nodes.

Since 70% of gastric cancers in mainland China are locally advanced, the range of lymph node metastasis often exceeds the standard D2 in clinical practice, especially the surgical indications of No.10, 13, 14a, and 16a2/b1 lymph nodes lack high-level evidence-based medical evidence. Therefore, the author's team and experts in related fields organized the compilation of relevant consensus, and reached a consensus on lymph node dissection beyond the D2 range by expert voting. The No.10 lymph node metastasis rate of upper gastric cancer was higher than that of lower gastric cancer. And when the tumor stage is late, the greater curvature of the stomach is invaded, and the length and diameter of the tumor are large, the No.10 lymph node metastasis rate is high. The results of meta-analysis of four prospective clinical studies in China showed that the metastasis rate of No.10 lymph nodes in locally advanced proximal gastric cancer was 10.3%, and the tumor was located on the side of the greater curvature of the stomach and the tumor was > in lengthThe No.10 lymph node metastasis rate of 5 cm non-gastric curvature and cN+ patients has a high rate, and laparoscopic spleen-preserving No.10 lymph node dissection is safe and reliable, which can improve the long-term prognosis of patients. The results of the retrospective study by the authors showed that the rate of No.13 lymph node metastasis in locally advanced lower gastric cancer was 9.0%, and No.13 lymph node dissection could improve the prognosis of patients with pTNM stage II.~III., so D2+No.13 lymph node dissection could be considered for stage II.~III gastric cancer that invaded the duodenum. The results of the retrospective study showed that the rate of No.14 lymph node metastasis in locally advanced distal gastric cancer was 18.5%, D2+No.14v lymph node dissection could improve the survival of patients with stage III.b/c, and No.6 and No.4d lymph node metastasis were high-risk factors for No.14v lymph node metastasis, and No.14v lymph node metastasis was an independent factor affecting stage III patients. Therefore, it is recommended to perform D2 + No. 14v lymph node dissection for patients with clinical evaluation No. 6 lymph node metastasis, because SOX (oxaliplatin + tigio) perioperative chemotherapy is currently the standard treatment for locally advanced gastric cancer. Therefore, patients with No.14v lymph node metastasis who are considered to have No.14v lymph node metastasis before surgery should undergo D2+No.14v lymph node dissection after neoadjuvant chemotherapy. Although the JCOG 9501 study negated prophylactic para-aortic lymph nodes dissection (PAND), D2+PAND was associated with improved prognosis in patients with only No.16 lymph node metastases. The results of the JCOG 0405 study showed that for patients with No. 16 lymph node metastasis in clinical evaluation, preoperative chemotherapy with cisplatin + Tigio regimen, followed by D2+PAND therapy, the objective response rate was 65%, the R0 resection rate was 82%, and the 5-year conditional survival rate was 53%. However, the use of D2+PAND after preoperative chemotherapy in these cases is still controversial and lacks high-level evidence-based evidence.

The scope of lymph node dissection for adenocarcinoma at the esophagogastric junction has been controversial. At the International Congress on Gastric Cancer held in Yokohama, Japan in June 2023, the follow-up data of the Japanese multicenter prospective study was announced and an international expert consensus was formulated, and the metastasis rate of No.19 lymph nodes was only 5.2%, and its event-free survival and overall survival treatment value indices were both low (0.6 and 1.2), so they were removed from the lymph nodes that were routinely dissected. The adjusted lymph node dissection range included lymph node invasion of 2~4 cm: No.1, 2, 3a, 7, 8a, 9, 11p, 11p, 110 lymph nodes, and 2 cm of esophageal ≤: No.1, 2, 3a, 7, 8a, 9, 11p.

Currently, a JCOG1711 study is underway in Japan on the comparison of preservation and removal of omentum in >T3 gastric cancer. The phase III multicenter, prospective RCT (TOP-GC: NCT04843215) of the clinical efficacy of omentectomy in radical resection of advanced gastric cancer (top-gc:) led by the author's medical center has completed the enrollment of 1 100 patients, and the preliminary results show that the safety of the two groups is comparable, and the total number of lymph nodes dissected in the experimental group and the control group [(38.81±2.56) vs. (39.77±1.95), P=0.761 6] and the number of positive lymph nodes [(4.750±). 0.854) vs. (4.710±0.738) pcs, P=0.971 4], and the difference was not statistically significant. The recurrence-free survival and overall survival data of the two groups are still being followed-up. At present, combined omentectomy is still the standard surgical method for local advanced gastric cancer, and the indications for omentectomy for advanced gastric cancer may be adjusted with the publication of relevant RCT results to meet the requirements of precision treatment in the minimally invasive era.

2. Lymphatic navigation technology helps precision surgery for gastric cancer

In a recent study published by Professor Huang Changming's team in China, the OSATS score of laparoscopic radical gastrectomy performed with indocyanine green navigation (indocyanine green navigation group) was significantly higher than that of the non-indocyanine green group [(29.6±2.6) vs. (26.6±3.6), P<0.001], and patients in the indocyanine green navigation group could dissect more lymph nodes than patients in the non-indocyanine green group [(50.5±15.9) vs. (42.0±10.3), P<0.001］。 The results of meta-analysis of 312 patients with gastric cancer from 5 studies showed that the application of indocyanine green lymphatic navigation technology in the robotic surgical system-assisted radical gastrectomy was safe and reliable, and compared with non-indocyanine green guided patients, the former could dissect more lymph nodes (P<0.05). In addition, indocyanine green lymphatic navigation could shorten the operation time (P<0.05), but there was no significant difference between intraoperative blood loss and postoperative complication rate compared with the non-indocyanine green group. In May 2023, the Chinese Anti-Cancer Association published relevant technical guidelines, which will further standardize clinical practice with the publication, lecture tour and popularization of the guidelines, so as to achieve accurate lymph node dissection for gastric cancer, comprehensively improve the surgical treatment of gastric cancer, and improve the survival of patients.

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The era of standardized precision immunotherapy for locally advanced gastric cancer