Background and purpose: Intraperitoneal tumor recurrence caused by gastric cancer shedding cells is an important cause of treatment failure in patients with intermediate to advanced gastric cancer, and intraperitoneal chemotherapy can effectively kill abdominal shedding cells, thus becoming a popular topic in gastric cancer research. This study intends to investigate the application value of intraoperative immediate hypotonic warm intraperitoneal chemotherapy combined with early postoperative intraperitoneal chemotherapy, and to study its application method. METHODS: A total of 156 gastric cancer patients were randomly grouped. They were divided into three groups: immediate intraoperative hypotonic warm laparoscopic chemotherapy combined with early postoperative laparoscopic chemotherapy (treatment group 1), immediate intraoperative hypotonic warm laparoscopic chemotherapy alone (treatment group 2), and no laparoscopic chemotherapy group (control group). Results: (1) The 2-year survival rate was 84.44% in treatment group 1 and 65.22% in the control group, with a significant difference in statistical analysis (P<0.05); the 3-year survival rate was 71.11% in treatment group 1, which was significantly higher than that in treatment group 2 (50.00%) and the control group (45.65%) (P<0.05). (2) The incidence of liver metastasis in treatment group 1 was 7.69%, which was significantly lower than that in the control group (27.27%) (P<0.01); the incidence of liver metastasis in treatment group 2 was 10.20%, which was significantly lower than that in the control group (27.27%) (P<0.05). Conclusion: (1) Intraoperative immediate hypotonic warm intraperitoneal chemotherapy combined with early postoperative intraperitoneal chemotherapy is indeed effective for gastric cancer. (2) Abdominal chemotherapy has a definite preventive effect on postoperative liver metastasis of gastric cancer.
At present, the unsatisfactory treatment effect of middle and advanced gastric cancer and the main reasons for treatment failure are intra-abdominal recurrence and liver metastasis [1, 2]. And most of the intra-abdominal recurrences are caused by intra-abdominal dissemination of cancer cells shed by gastric cancer [3]. Modern radical surgery for gastric cancer includes adequate extent of gastrectomy, reasonable regional lymph node dissection and complete killing of free cancer cells in the abdominal cavity [4]. Surgery is not able to do anything for abdominal free cancer cells. Intraperitoneal chemotherapy as a selective regional chemotherapy has obvious pharmacokinetic advantages over peripheral intravenous chemotherapy in killing free cancer cells in the abdominal cavity [5], therefore, intraperitoneal chemotherapy has been more and more widely used in clinical practice recently. However, there are still debates on the timing of application of intraperitoneal chemotherapy, specific application methods, single or combination drugs, specific duration of treatment, whether it needs to be combined with systemic chemotherapy, and its efficacy.
1. Clinical data
(1) General data
We studied 156 cases of gastric cancer patients admitted to our hospital during January 1999~February 2001. There were 106 male cases and 50 female cases, aged 25 to 75 years, with a median age of 56 years. Among them, 134 cases (85.90%) underwent radical surgery for gastric cancer and 22 cases (14.10%) underwent palliative gastrectomy and resection of lymph node metastases.
(2) Grouping
Inclusion criteria: (1) no contraindication to surgery; (2) no contraindication to chemotherapy; (3) age < 75 years; (4) no history of intra-abdominal infection or major abdominal surgery.
Exclusion criteria: (1) intraoperative confirmation of unresectable primary foci or the presence of liver or other organ metastases; (2) unresectable lymph node metastases; (3) severe intraoperative contamination and unsatisfactory anastomosis.
Patients were randomly grouped by applying a random number table and divided into 3 groups: (1) immediate intraoperative hypotonic warm abdominal chemotherapy combined with early postoperative abdominal chemotherapy group (treatment group 1) 52 cases, including 36 males and 16 females, 45 cases (86.54%) underwent radical resection; (2) immediate intraoperative hypotonic warm abdominal chemotherapy group alone (treatment group 2) 49 cases, including 32 males and 17 females All three groups were treated with 6 courses of conventional intravenous chemotherapy starting at about 1 month after surgery. There was no statistical difference in the distribution of data on gender, age, lesion location, Borrmann’s staging, type of pathology, TNM stage and surgical method (P>0.05).
(3) Surgical method
Depending on the intraoperative exploration, D1 (perigastric station 1 lymph node dissection) (7/156), D2 (perigastric station 2 lymph node dissection) (109/156) or D3 (perigastric station 3 lymph node dissection) (18/156) surgery was performed, with D2 as the mainstay. Intraoperatively, attention was paid to tumor-free operation. If tumor was found to invade the gastric plasma membrane, bioprotein gel was routinely applied to prevent tumor cells from being shed. Operate gently and avoid pulling and squeezing the tumor as much as possible. The anterior lobe of the transverse mesentery and the pancreatic envelope were removed, and enough of the stomach was excised and the corresponding groups of lymph nodes were cleared. Silicone drainage tubes were routinely placed in the gastric bed after surgery as postoperative drainage and for early postoperative intraperitoneal chemotherapy (treatment group 1).
(4) Application of immediate intraoperative hypotonic warm intraperitoneal chemotherapy
At the end of surgery, the abdominal cavity was probed for no active bleeding, and each anastomosis was checked to be indeed reliable. After thorough flushing of the abdominal cavity with distilled water, a latex drainage tube was placed in the lowest part of the pelvis. After 5 min, start to aspirate the drug from the drainage tube and measure the temperature of the aspirated fluid, which is usually between 42℃ and 43℃, while replenishing new warmed fluid from the upper abdomen to maintain the temperature of the drug in the abdominal cavity at around 43℃. The temperature of the drug solution was around 43℃ and the concentration and hypotonicity of the drug solution could be relatively maintained. After 60 min of hypotonic warm chemotherapy, a drainage tube was routinely placed in the gastric bed and the abdomen was closed. In the control group, the abdominal cavity was flushed with distilled water only.
(5) Application of early postoperative intraperitoneal chemotherapy
Generally, on the 4th to 6th postoperative day, chemotherapy can be applied if the patient’s gastrointestinal function recovers, there is no abdominal pain or fever, and liver and kidney function, biochemistry and blood routine are basically normal. Chemotherapy regimen: 5-FU 1000 mg/m2, days 1~5; cisplatin (DDP) 60 mg/m2, day 1. The chemotherapy drug was dissolved in 1 L of saline and rapidly dripped from the abdominal drainage tube into the posterior clamping tube. The patient was instructed to change position.
(6) Statistical methods
SPSS11.0 software was applied, and the χ2 test was performed for statistical processing.
2. Results
The follow-up rate was 86.54% (45/52) for treatment group 1, 85.71% (42/49) for treatment group 2, and 83.64% (46/55) for the control group. The overall follow-up rate was 85.26% (133/156).
(1) Follow-up results of case survival rate in the three groups
After statistical analysis, it was found that (1) there was no significant difference in the 1-year survival rate among the 3 groups (P>0.05); (2) there was no significant difference in the 2-year survival rate of treatment group 1 relative to treatment group 2 (P>0.05), which was higher than that of the control group (P<0.05), and there was no significant difference in the 2-year survival rate of treatment group 2 and the control group (P>0.05); (3) the 3-year survival rate of treatment group 1 was higher than that of treatment group 2 and control group (P<0.05), while there was no significant difference between treatment group 2 and control group for comparison (P>0.05).
(2) Survival of patients with positive abdominal exfoliative cells
After statistical analysis, we found that among the abdominal exfoliated cell positive cases: (1) there was no significant difference in the 1-year survival rate among the 3 groups of cases (P>0.05); (2) there was no significant difference in the 2-year survival rate of treatment group 1 relative to treatment group 2 (P>0.05), while it was higher than that of the control group (P<0.05), and there was no significant difference in the 2-year survival rate between treatment group 2 and the control group (P>0.05); (3) there was no significant difference in the 3-year survival rate of treatment group 1 relative to treatment group 2 (P>0.05). (3) The 3-year survival rate of treatment group 1 was higher than that of treatment group 2 (P<0.05) and significantly higher than that of the control group (P<0.01), while there was still no significant difference between treatment group 2 and the control group for comparison (P>0.05).
(3) Survival of patients with negative abdominal exfoliative cells
After statistical analysis of the follow-up data, we found that among the abdominal exfoliative cell-negative cases: there was no significant difference in the survival rate from 1 to 3 years among the three groups (P>0.05).
We further analyzed the abdominal exfoliative cell negative stage IIIa and IIIb cases and found that: (1) there was no significant difference in the 1-year and 2-year survival rates among the 3 groups of cases (P>0.05); (2) there was no significant difference in the 3-year survival rate of treatment group 1 relative to treatment group 2 (P>0.05), but higher than the control group (P<0.05); (3) the 3-year survival rates of treatment group 2 and control group were not significant difference (P>0.05).
(4) Survival of abdominal exfoliated cell positive cases and negative cases in the 3 groups
After statistical analysis of the follow-up data (see Tables 3 and 4), we found that: (1) There was no significant difference in the survival rates from 1 to 3 years between cases with positive and negative abdominal exfoliative cells in treatment group 1. (2) There was no significant difference in the 1-year and 2-year survival rates between cases with positive and negative abdominal exfoliative cells in treatment group 2, and the 3-year survival rate was significantly lower in cases with positive abdominal exfoliative cells than in cases with negative abdominal exfoliative cells (P<0.05). (3) The 2-year survival rate of the control group showed a difference (P<0.05), and the difference in the 3-year survival rate was even more significant (P<0.01).
(5) Follow-up of the incidence of liver metastases in the 3 groups
The incidence of liver metastasis was 8.89% (4/45) in treatment group 1, 11.90% (5/42) in treatment group 2, and 32.61% (15/46) in the control group. After statistical analysis, it was found that (1) there was no significant difference in the incidence of liver metastasis in treatment group 1 compared with treatment group 2 (P>0.05); (2) the incidence of liver metastasis in treatment group 1 was significantly lower than that in the control group (P<0.01); (3) the incidence of liver metastasis in treatment group 2 was lower than that in the control group (P<0.05).
3. Discussion
The ideal chemotherapy approach for gastric cancer should be able to effectively target common sites of recurrence and metastasis, such as resected areas, peritoneal implants and the liver. Pharmacokinetic studies have confirmed [5] that the peritoneal cavity drug concentration is significantly higher than that in circulating blood after transperitoneal administration of high volume anticancer drugs due to the lower permeability of the peritoneum than the plasma contouring rate. After high-dose 5-FU intraperitoneal administration, the highest drug concentration was found in the peritoneal fluid, followed by the portal vein blood concentration, the hepatic vein blood concentration was lower than the portal vein, and the femoral vein blood concentration was the lowest, forming a gradient difference from high to low blood concentrations in the peritoneal fluid, portal vein, hepatic vein, and femoral vein. The advantages of intraperitoneal chemotherapy are summarized as follows: (1) the high concentration and large volume of intraperitoneal irrigation fluid can make all organs in the abdominal cavity soak in chemotherapy drugs, which can directly kill free cancer cells and micro-metastatic lesions; (2) the action time of anti-cancer drugs with cancer cells and micro-metastatic lesions is prolonged after intraperitoneal administration due to the effect of peritoneal barrier; (3) most of anti-cancer drugs are absorbed into the liver through portal vein, which can prevent and treat (4) anti-cancer drugs are metabolized into the body circulation through the portal vein into the liver, which has less toxic side effects on the whole body, especially there is almost no interference with the hematopoietic system, and the maximum tolerated dose of drugs can be increased; (5) most of the highly concentrated chemotherapeutic drugs can enter the abdominal lymphatic network and kill cancer cells in the lymphatic system, while lymphatic metastasis is the main metastatic diffusion pathway in the gastrointestinal tract; (6) the operation is relatively simple, low-cost and easy to accept by patients. and low cost, which is easily accepted by patients.
The efficacy of various forms of intraperitoneal chemotherapy for cases of peritoneal metastasis of gastric cancer is not satisfactory. In addition to the sensitivity of anticancer agents, poor drug permeability is the main reason for the poor efficacy of intraperitoneal chemotherapy. Improving the absorption of anticancer agents by tumor tissues is the key to improve their efficacy. In order to improve the efficacy of intraperitoneal chemotherapy, some scholars have applied warming and hypotonicity to intraperitoneal chemotherapy in recent years [6, 7]. Since hypotonicity and warmth can promote the uptake of chemotherapeutic drugs by tumor cells, and warmth can also kill tumors at the molecular level, cellular level, and tissue level, good efficacy has been achieved. In addition, the timing of intraperitoneal chemotherapy is very important. The decrease of immunity of the body after surgery caused by anesthesia and surgical trauma and the reduction of tumor load of the body after surgery can make the tumor cells proliferate rapidly. At this time, tumor cells are in active phase and sensitive to cell cycle drugs, thus it is easier to kill them. In addition, the peritoneal adhesions are not heavy in the early postoperative period, and the drugs can fully contact with the peritoneum. If intraperitoneal chemotherapy is not carried out in a timely manner and tumor cells form microscopic cancer foci before postponing intraperitoneal chemotherapy, the killing effect of chemotherapeutic drugs will be greatly weakened, which will eventually lead to recurrence of intraperitoneal tumor.
Many literatures have reported the application of warm intraperitoneal chemotherapy in the postoperative period [8, 9]. However, we found in our study that warm intraperitoneal chemotherapy under non-anesthesia is very difficult to perform, and most patients have difficulty tolerating it when the temperature of the peritoneal perfusion fluid reaches 43°C. Therefore, we controlled the temperature of postoperative intraperitoneal chemotherapy perfusion fluid at about 39°C to 41°C, whichever is tolerated by the patients. The total amount of postoperative intraperitoneal chemotherapeutic perfusion fluid is recommended in the literature as 1.5 L [9]. We experienced in practice that when the total amount of perfusion fluid exceeded 1.2 L, most patients had obvious abdominal distension and some had difficulty in tolerating it to the extent that it affected the chemotherapy the next day. We analyzed the reasons and concluded that: the gastrointestinal function of patients in the early postoperative period had not fully recovered, and the distension of the intestinal canal was more obvious; in addition, the increase of peritoneal exudation in postoperative patients would affect the absorption of perfusate by the peritoneum. Therefore, the total amount of perfusion fluid we applied was generally 1~1.2 L, and 1.5 L was used in a few patients.
The number of applications of postoperative peritoneal chemotherapy is inconclusive. We believe that heavy adhesions will form in the patient’s abdominal cavity about two weeks after surgery. The application of intraperitoneal chemotherapy in this situation not only fails to achieve the desired effect, but also increases the risk of laparotomy. In addition, it will inevitably delay the application of systemic chemotherapy. It is due to the special pharmacokinetic changes of intraperitoneal chemotherapy that the concentration of chemotherapeutic drugs in the blood outside the portal vein is low and insufficient to kill the tumor cells that may exist within it. Therefore, we believe that routine systemic intravenous chemotherapy administered about 1 month after surgery is essential. In this study, postoperative intraperitoneal chemotherapy was applied only once.
By analyzing the efficacy of all cases that received follow-up in this study, we observed that the 2- and 3-year survival rates were higher in treatment group 1 than in the other two groups, while there was no significant difference in the comparison between treatment group 2 and the control group. In the analysis of survival rates in cases with positive abdominal exfoliated cells, we also obtained the same conclusion, except that the elevated survival rate was more significant in treatment group 1. This tells us that in the treatment of gastric cancer, immediate intraoperative hypotonic warm intraperitoneal chemotherapy combined with early postoperative intraperitoneal chemotherapy has a real efficacy, especially for cases with positive abdominal exfoliative cells. The data in this study showed that although the 2- and 3-year survival rates were higher in the immediate intraoperative hypotonic warm laparoscopic chemotherapy alone group than in the group without laparoscopic chemotherapy, there was no significant difference in statistical analysis. The difference with literature reports is large [6, 10]. The reason for our analysis may be related to the lack of a large total number of cases in this study, but the difference in efficacy with the combined postoperative early laparoscopic chemotherapy group is positive. Therefore, it is reasonable to assume that immediate intraoperative hypotonic warm intraperitoneal chemotherapy alone is not sufficient and must be combined with early postoperative intraperitoneal chemotherapy.
In the analysis of the efficacy of abdominal exfoliative cell negative cases, we found no significant difference in the 1 to 3 year survival rate in any of the 3 groups. So is it possible that abdominal chemotherapy is ineffective in patients with negative abdominal exfoliative cells? We further analyzed the 1 to 3-year survival rates of stage IIIa and IIIb cases in this group, from which we found that there was no significant difference between the 1-year and 2-year survival rates of the 3 groups of cases. There was no significant difference in the 3-year survival rate of treatment group 1 relative to treatment group 2, which was higher than that of the control group. There was no significant difference in the 3-year survival rate between treatment group 2 and the control group. This tells us that immediate intraoperative hypo-osmotic warm intraperitoneal chemotherapy combined with early postoperative intraperitoneal chemotherapy is indeed efficacious in stage IIIa and IIIb cases, even if the abdominal cavity is negative for exfoliated cells. The reason for this is that these cases may have abdominal exfoliative cells that are just not detected or may have small metastases for which laparoscopic chemotherapy has some efficacy.
When comparing the information on the 1 to 3-year survival rates of the abdominal exfoliated cell positive and negative cases in each group separately, we observed that there was no significant difference between the 1-year and 2-year survival rates of the abdominal exfoliated cell positive and negative cases in the treatment group2 and the 3-year survival rate of the abdominal exfoliated cell positive cases was significantly lower than that of the abdominal exfoliated cell negative cases. The difference in the 2-year survival rate was shown in the control group, and the difference in the 3-year survival rate was even more significant. In contrast, there was no significant difference in the 1 to 3-year survival rate between cases with positive and negative abdominal exfoliative cells in the treatment group1. The above results further confirmed that abdominal chemotherapy has a real efficacy on abdominal exfoliated cells in gastric cancer.
By analyzing the postoperative liver metastases in the three groups of cases, we found that there was no significant difference in the incidence of liver metastases in treatment group 1 relative to treatment group 2, while the incidence of liver metastases in both treatment group 1 and treatment group 2 was lower than that in the control group. It was confirmed that intraperitoneal chemotherapy has a real effect on the prevention of liver metastasis after gastric cancer surgery.
The technique of intraperitoneal chemotherapy is relatively simple, easy to apply, characterized by highly selective regional chemotherapy, with little systemic toxic side effects, and has a positive effect on the prevention and treatment of postoperative abdominal recurrence and liver metastasis of gastric cancer, which is a promising adjuvant chemotherapy measure.