Editor's note: my country is the three major gastric cancer html, of which 70% are advanced gastric cancer. Recurrence of peritoneal metastasis is the most common type of metastasis after advanced gastric cancer surgery and is also the main lethal factor. It is of great clinical value to actively explore effective methods to prevent or reduce the recurrence rate of peritoneal metastasis. The 17th National Academic Conference on Gastric Cancer (CGCC 2022) held recently, , Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, , Professor Zhu Zhenggang gave a special report on the topic of "Prevention and Treatment of Peritoneal Metastasis of Gastric Cancer". "Tumor Lookout" and "Tumor Lookout-Digestible Times" specially invited Professor Zhu Zhenggang to give an in-depth explanation of the topic.
Gastric cancer is one of the main malignant tumors in my country. According to the annual report released by the China Cancer Center in 2019, the incidence rate of gastric cancer in my country is 41/100 000 and the mortality rate is 29.4/100 000, ranking second in the incidence rate of malignant tumors and third in the mortality rate in my country. A large number of clinical studies have confirmed that about 10% to 20% of patients with advanced gastric cancer, especially cT3 or cT4, when undergoing radical surgery, there are often tiny metastases that are difficult to detect in the naked eye; about 40% to 60% of patients with advanced gastric cancer, the peritoneum is the first recurrence after the operation; about 30% to 50% of patients with gastric cancer, peritoneal metastasis is an independent factor leading to death. Therefore, actively carrying out the prevention and treatment of peritoneal metastasis of gastric cancer will undoubtedly help further improve the overall efficacy of gastric cancer.
The clinical practice of nearly 30 years has shown that recurrence of peritoneal metastasis is the most common type of metastasis after advanced gastric cancer surgery and is also the main lethal factor. Therefore, actively exploring effective methods to prevent or reduce the recurrence rate of peritoneal metastasis has greater clinical value than treating postoperative recurrence of peritoneal metastasis. Patients with advanced gastric cancer should take positive measures to prevent their postoperative recurrence of peritoneal metastasis. First, high-risk patients with recurrence of peritoneal metastasis should be screened out. Among various clinical and pathological factors, once the tumor infiltrates the serosa or extraseroma, or if the preoperative laparoscopic exploration clearly shows that intraperitoneal free cancer cells (FCC) are present, the possibility of recurrence of peritoneal metastasis after surgery is significantly increased, and should be the focus of prevention. Perioperative prevention of peritoneal metastasis and recurrence of gastric cancer can be performed before, during and after surgery, mainly in preventive systemic and intraperitoneal chemotherapy. Currently, clinically effective intraperitoneal chemotherapy methods include hyperthermic intraperitoneal chemotherapy (HIPEC) and intraperitoneal chemotherapy. The surgery department of our hospital conducted prospective clinical research at the beginning of this century. After radical surgery on 96 patients with advanced gastric cancer who had no peritoneal metastasis during surgery, they were randomly divided into intraoperative HIPEC treatment group (42 cases) and simple surgical control group (54 cases). The perfusion solution of the HIPEC group was cisplatin and mitomycin. The temperature of the perfusion solution was controlled at (43.0℃±1.0℃), and the perfusion solution was continuously perfused for 60 minutes, aiming to clear the FCC in the abdominal cavity and interfere with the implantation process of the connective tissue of FCC underperitoneal exposure of . Follow-up of 6 years after surgery showed that the total postoperative recurrence rates of HIPEC and control groups were 46.2% (18/39) and 59.2% (29/49) respectively (P=0.004); the postoperative peritoneal recurrence rates were 10.3% (4/39) and 32.7% (16/49) respectively (P=0.013). The 1, 2 and 4-year survival rates of the HIPEC group were 85.7%, 81.0% and 63.9%, respectively, which was significantly better than the control group 77.3%, 61.0% and 50.8%. The average survival time in the HIPEC group (43.4±2.6) months was also significantly higher than that in the control group (41.8±3.8) months (P=0.048). In view of the above research results, the Department of Surgery of our hospital conducted a prospective study on the efficacy of intraoperative HIPEC in preventing peritoneal metastasis and recurrence after advanced gastric cancer between December 2014 and June 2015. 94 patients with advanced gastric cancer who confirmed ≥cT3 by preoperative CT and ultrasound endoscopy and did not have visible peritoneal metastasis in the naked eye were studied. They were randomly divided into radical surgery + HIPEC group (HIPEC group) and radical surgery group (control group); the HIPEC perfusion solution was cisplatin, and the intraperitoneal fluid was maintained at (42.0℃±1.0℃), and the total perfusion time was 60 min.Excluding follow-ups for various reasons, 39 cases in the HIPEC group and 38 cases in the control group, with a median follow-up of 41 (37~52) months. The results showed that the total tumor recurrence rate of HIPEC group was 23.1% (9/39), of which 2 cases of recurrence of peritoneal metastasis (5.1%) were clearly identified, and the total tumor recurrence rate of control group was 39.5% (15/38), of which 11 cases of recurrence of peritoneal metastasis (28.9%) were identified. The 2-year tumor-free recurrence survival rate between the HIPEC group and the control group was 86.7% vs 67.6%; 3-year was 76.9% vs 60.5%, and the difference was statistically significant. This shows that intraoperative HIPEC can effectively reduce the recurrence of peritoneal metastasis in patients with advanced gastric cancer. The Department of Gastrosurgery at the Affiliated Cancer Hospital of Tianjin Medical University has routinely performed D2 radical surgery on 60 patients with advanced gastric cancer, and was randomly divided into intraoperative abdominal heat perfusion chemotherapy group (CHPP group, 30 cases) and simple surgery group (control group, 30 cases). Both groups were given FOLFOX4 regimen to assist chemotherapy from 4 weeks after surgery. The results showed that the 3-year survival rates of the CHPP group and the control group were 63.3% vs 40.0% (P0.05), and the 3-year tumor recurrence rate was 21.6% vs 43.5% (P0.05); it was suggested that surgery combined with CHPP can significantly reduce the postoperative tumor recurrence rate of patients with advanced gastric cancer and improve postoperative survival. Recently, the Department of Surgery of our hospital also conducted a meta-analysis of on the efficacy of HIPEC to prevent peritoneal recurrence after advanced gastric cancer. A total of 11 clinical studies were combined, with a total of 421 cases in the surgery + HIPEC group and 546 cases in the surgery group alone. Although the drugs used were different from the regimen, all prophylactic HIPEC was found to significantly reduce the recurrence rate of peritoneal metastasis after surgery (OR=0.34, 95%CI: 0.24~0.48, P0.001).
On the basis of the previous single-center research and achieving good results, our hospital's surgery department further carried out a phase 3 clinical study of multi-center prospective randomized control (Dragon Ⅱ trial). For patients with locally advanced gastric cancer in cT4N+M0, after laparoscopic exploration, peritoneal metastasis visible to the naked eye was eliminated, they were randomly assigned. The treatment group was first given laparoscopic HIPEC (L-HIPEC), and completed three courses of neoadjuvant chemotherapy for SOX regimen to suppress possible FCC in the abdominal cavity or tiny peritoneal metastasis that is difficult to detect in the naked eye, and promote the clinical decline of primary gastric cancer foci and metastatic lymph nodes. Then, D2 gastric cancer radical surgery was performed; the second HIPEC was performed at the end of the operation, aiming to eliminate FCC generated during the operation. Five courses of SOX regimens were performed sequentially after the operation, in order to further consolidate the efficacy of the surgery and prevent tumor recurrence including peritoneal metastasis after the operation. The control group did not perform preoperative neoadjuvant treatment and HIPEC, and directly performed radical D2 gastric cancer surgery, and was supplemented with 8 courses of SOX regimen after surgery. The main research endpoints were progress free survival (PFS), followed by recurrence rate and overall survival (OS). At present, the research is progressing smoothly; preliminary results show that the treatment group's effectiveness in preventing peritoneal metastasis and recurrence is satisfactory, and we look forward to the final results of the study.
Once gastric cancer occurs peritoneal metastasis, the treatment is more difficult. In addition to the biological behavior of the tumor, the effect of treatment also depends on (1) the degree and range of peritoneal metastasis, which is usually expressed as peritoneal metastasis index (PCI); (2) tumor cell reduction (CCS). The initial stage of peritoneal metastasis in gastric cancer is mostly regional metastasis, with limited metastasis and fewer other distant metastasis at the same time. Therefore, better efficacy can be achieved through tumor cell reduction (CRS) and combined with HIPEC. However, if there is obvious peritoneal metastasis in the naked eye, with a wide range and diffuse range, and there is a large amount of ascites, or it may be accompanied by distant multifocal metastasis, and radical resection is difficult to achieve surgery, it should be regarded as a systemic tumor disease, and simple local regional treatment is often difficult to work. On the surface of many clinical studies at home and abroad, once the PCI index is 12, it will be treated with CRS+HIPEC alone, and the prognosis will still be poor; similarly, if the tumor cell depletion after treatment is CC0, the efficacy will be significantly better than CC1 or CC2. The clinical guidelines for peritoneal cancer developed by the International Alliance of the Collaborative Group on Peritoneal Surface Tumors propose clinical pathways for the treatment of peritoneal metastasis for primary or recurrent gastric cancer. For patients with peritoneal metastasis of gastric cancer confirmed by laparoscopic exploration, CRS can be performed and supplemented with HIPEC.It is particularly emphasized that patients with peritoneal metastasis of gastric cancer should actively carry out intraperitoneal combined systemic chemotherapy, and it is not recommended to directly perform CRS+HIPEC. In 2017, the "Chinese Expert Consensus on Preventing and Treating Peritoneal Metastasis in Gastric Cancer" issued by the Chinese Anti-Cancer Association, proposing the treatment process for gastric cancer peritoneal metastasis. Whether patients with P1CY0/1 or P0CY1 are required to carry out HIPEC on the basis of active systemic chemotherapy. It can be seen that for patients with advanced gastric cancer with peritoneal metastasis, systemic chemotherapy and other transformational treatments must be adhered to, and regional intraperitoneal treatment should not be simply emphasized. Clinical studies have confirmed that for advanced gastric cancer with a wide range of peritoneal metastasis, it is difficult to obtain satisfactory efficacy by simply implementing CRS+HIPEC; PCI6 and CRS+HIPEC have obvious efficacy; PCI6~12 has limited efficacy; PCI12 has poor efficacy, and it must rely on a multidisciplinary team (MDT) to actively adopt comprehensive treatment plans.
In recent years, clinical research on the treatment of advanced gastric cancer in peritoneal metastasis has been in full swing, and the combination of systemic and intraperitoneal transformation treatment plans have been continuously updated. Systemic dosing regimens include different combinations of chemotherapy and molecularly targeted or immunotherapy drugs, but intraperitoneal chemotherapy is still mainly carried out in the following three forms: (1) HIPEC, which makes full use of the warming effect, mechanical lavage and chemotherapy drugs to act synergistically on peritoneal metastasis, and has good efficacy for patients with non-wide metastasis in the peritoneal period; (2) Perioperative bidirectional intraperitoneal and systemic chemotherapy, and intraperitoneal chemotherapy ports are embedded in the abdominal wall and the internal catheter of the abdominal cavity to cooperate with systemic chemotherapy. The biggest advantage is that it can maintain intraperitoneal chemotherapy for a long time. , for several years, the effect of controlling peritoneal metastasis can be achieved; (3) Intraperitoneal pressurized aerosol chemotherapy, using special aerosol atomization equipment, after laparoscopic confirmation of the peritoneal metastasis range, inserting a pressurized tube with a micropump increases the pressure in the abdominal cavity, and then injecting aerosol containing chemotherapy drugs into the abdominal cavity; compared with injecting drug liquid therapy, this therapy can quickly and evenly distribute the aerosol containing chemotherapy drugs on the surface of the peritoneal metastasis foci, and increase the concentration of drug liquid penetration into the tumor tissue under pressure to achieve therapeutic effect.
In short, once gastric cancer occurs peritoneal metastasis, the prognosis is poor. For advanced gastric cancer, attention should be paid to prevention and reduce the metastasis and recurrence of the peritoneal tissue as much as possible to further improve long-term survival; for advanced gastric cancer that has undergone peritoneal metastasis, systemic combined intraperitoneal treatment should be actively carried out to relieve the patient's symptoms, improve the quality of life and prolong the survival time.
Zhu Zhenggang
Shanghai Jiaotong UniversityDistinguished Professor, Ruijin HospitalTenior Professor
International Gastric Cancer Research Association (IGCA) Director
Academician of the American Academy of Surgery ( FACS)
Director of Shanghai Institute of Gastroenterology Surgery
Director of Shanghai Key Laboratory of Gastric Tumor Technique
Historical: ml3
Hand Vice President of Shanghai Jiaotong University, Dean of the School of Medicine, and Dean of the affiliated Ruijin Hospital
Hand Chairman of the Professor's Association of Shanghai Jiaotong University School of Medicine
Director of Surgery Department of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine
Chinese Anti-Cancer Association Executive Director and Chairman of the Gastric Cancer Professional Committee
Chinese Medical Association Executive Director, Upper Gastrointestinal Surgeon Chairman of the Special Committee
vice president of Shanghai Medical Association and chairman of the Surgery Association
Shanghai Anti-cancer Association Vice Chairman and Chairman of the Gastrointestinal Cancer Professional Committee
