Gastric cancer is one of the most common malignant tumors in China, and its morbidity and mortality rates are among the highest of all types of tumors. The postoperative recurrence rate is high, especially peritoneal recurrence is the most common, and the postoperative peritoneal recurrence rate of diffuse, hypofractionated and Borrman type IV gastric cancer is as high as 60-70%; the postoperative peritoneal recurrence rate of intestinal and highly differentiated gastric cancer is slightly lower, about 20-30%. The total peritoneal recurrence rate after surgery for progressive gastric cancer is 50%. Since traditional treatment methods, such as surgery, radiotherapy and chemotherapy, are not effective for peritoneal metastases, how to take active and effective measures to prevent and treat peritoneal metastases of gastric cancer has become an important issue to be solved urgently in today’s surgical oncology. Intraperitoneal chemo- hyperthermia (IPCH), which has been developed in recent years, is an important treatment tool that combines the anti-cancer effects of regional chemotherapy and heat therapy and makes full use of the synergistic effects of heat therapy and chemotherapy.
Whether in the prevention or treatment of postoperative metastasis or recurrence of progressive gastrointestinal cancer tumors, IPCH has significant efficacy, and has become a relatively ideal surgical adjuvant therapy because of its small toxic side effects and easy operation.
I. Mechanism of postoperative peritoneal recurrence of gastrointestinal cancer
At present, the main mechanism of postoperative peritoneal recurrence of gastrointestinal cancer is widely recognized as the “seed-soil” theory, in which cancer cells are shed into the peritoneal cavity to form the “seed” of recurrence; the peritoneum is mesothelial tissue, composed of flat mesothelial cells and connective tissue, and the connection between mesothelial cells is bridging grain and loose tissue, with abundant microvilli on the surface, followed by basement membrane and interstitial tissue composed of a large number of collagen fibers. The interstitial tissue contains fibroblasts, a few macrophages and lymphocytes. The peritoneal surface is mechanically damaged by surgical dissection, leaving the subperitoneal connective tissue exposed, forming a “soil” where cancer cells can easily grow. Free cancer cells in the peritoneal cavity have been shown to have the ability to survive. At the same time, the surgical trauma and wound healing process can promote cancer cell implantation in the peritoneum. In the early stage of wound healing, plasma fibrin exudates heavily, forming a so-called “deposit that traps tumor cells”, and the fibrin-like exudate wraps around the tumor cells to form a “protective barrier” that prevents phagocytosis by immunologically active cells of the body. During this process, the presence of adhesion molecules on the surface of cancer cells further facilitates their colonization and proliferation in the peritoneum. Integrins (integrins) promote the attachment of tumor cells to proteins; inflammatory cell infiltration and stimulation by growth factors predispose tumor cells to colonize the peritoneum and grow and proliferate. The scar tissue formed by wound healing further encapsulates and protects the tumor cells. The above factors cause conventional intraperitoneal lavage does not remove these cancer cells.
The main ways of shedding cancer cells into the peritoneal cavity include: (1) cancer tumor invades into the plasma layer, which means it may be shed into the peritoneal cavity; Mikarni et al. found that according to the new international TNM staging method for gastric cancer, no free cancer cells were found in the peritoneal cavity in 121 cases of gastric cancer limited to the mucosal layer (T1) and muscular layer (T2); while the detection rate of free cancer cells in the peritoneal cavity was 17.7% when the cancer tumor invaded the plasma layer (T3). Once the tumor penetrated to the extra-plasma membrane (T4), the detection rate increased to 75%. Kainara et al. found that the number of cancer cells shed into the peritoneal cavity was related to the extent of invasion of the gastric plasma membrane and the biological behavior of the tumor. (2) The diaphragm peritoneum and greater omentum are rich in lymphatic vessels. During surgery, the lymphatic vessels and intravascular cancer cells in the severed tissues may spill into the abdominal cavity with lymphatic fluid and blood. Clinically, it is found that some gastric cancers did not invade the plasma membrane, but later on the peritoneal implantation recurrence occurred, which is obviously related to this factor; (3) intraoperative spillage into the peritoneal cavity with gastrointestinal fluid.
II. Overview of the development and mechanism of action of IPCH
Tumor thermotherapy refers to the treatment of malignant tumors by increasing the temperature of the whole body and/or tumor tissues (locally) by various methods, using thermal effects and their secondary effects. It is a term that is both familiar and unfamiliar to everyone. The use of hot water baths to treat various diseases has been documented thousands of years ago in ancient Greece, Egypt, China and Japan. It is well known that the body becomes immune to infectious diseases after fever. Until the birth of antibiotics, heat therapy was a common method of treating various infectious diseases. Jauregg, an Austrian physician, inoculated some patients with blood from malaria patients, causing them to become infected with malaria and inducing high fever to treat syphilis infections of the central nervous system, which later became the standard treatment for syphilis infections of the central nervous system at that time and saved the lives of many patients, for which Jauregg was awarded the Nobel Prize in Medicine and Physiology in 1927. The use of Coley’s toxin injections to cause fever in tumor patients at the beginning of the last century was therapeutic for some patients. In retrospect, the history of medicine records that cases of spontaneous regression of tumors often occur after a bacterial infection with high fever. However, in the last hundred years, the treatment of tumors is still mainly based on surgery, radiotherapy and chemotherapy, and the unfamiliar term “tumor thermotherapy” is rarely seen in many textbooks. After more than a hundred years of development in obscurity, it has gradually entered the medical arena and become a noteworthy technology for tumor treatment. In 1988, Fujimoto used heat therapy to increase the efficacy of anti-cancer drugs and combined heat therapy and chemotherapy to treat gastrointestinal malignant tumors for the first time by using surgery with continuous heat-infused chemotherapy in the abdominal cavity. This broke the traditional concept of heat therapy for tumors only as a sensitizer for radiotherapy and made intraperitoneal chemohyperthermia (IPCH) gradually developed into an important integrated therapy for the prevention and treatment of peritoneal recurrence and metastasis of gastrointestinal tumors.
The main mechanism of peritoneal metastasis recurrence after gastric cancer surgery is the implantation of free cancer cells in the peritoneal surface and their proliferation into cancerous nodules. The efficacy of systemic chemotherapy via intravenous route in preventing recurrence of peritoneal metastasis is not satisfactory for two main reasons: 1) chemotherapeutic drugs in the blood cannot act directly on free cancer cells in the peritoneal cavity; 2) the lack of neovascularization in the small cancer foci implanted on the peritoneal surface makes it difficult to form an effective drug concentration environment. Yonemura et al. found that the response rates of primary cancer, liver metastases and lymph node metastases were high, reaching 75%, 81% and 71%, respectively, while the response rate of peritoneal metastases was the lowest, at 18%, and the survival of patients with peritoneal metastases could not be prolonged regardless of the systemic chemotherapy regimen. Another study found that the application of conventional intra-arterial chemotherapy for the treatment of recurrent peritoneal metastases was also difficult to achieve satisfactory results. The peritoneum is nourished by multiple arteries, with the blood supply to the visceral peritoneum mainly coming from the celiac artery, superior mesenteric artery and inferior mesenteric artery, while the mural peritoneum is supplied by the inferior diaphragmatic artery, lumbar artery, inferior abdominal artery and decubitus artery. Ohoyama et al. reported that the combined application of 5-FU, CDDP and VP-16 via the celiac artery or the left gastric artery in the treatment of a group of progressive gastric cancer showed a 32% response rate for the primary tumor, lymph node metastases and liver metastases, respectively. The response rates were 32%, 54% and 33% for the primary tumor, lymph node metastases and liver metastases, respectively, but only 14% for peritoneal metastases, and all 10 patients with peritoneal metastases died within 13 months after chemotherapy with this regimen, so the application of intra-arterial intervention for the treatment of recurrent peritoneal metastases also has major limitations.
In recent years, Spratt’s first intraperitoneal infusion chemotherapy was designed to address peritoneal metastases, but the results were not satisfactory. With the advent of new techniques such as “laparotomy” and “intracorporeal immunotherapy”, intraperitoneal chemohyperthermia (IPCH) was also introduced in the 1980s. IPCH is a combination of intraperitoneal mechanical irrigation, thermo-thermal effect and chemotherapeutic drugs.
Its mechanism of action is based on the multiple effects of warmth on cancer cells. At the molecular level, the warming effect can induce the denaturation of proteins on the membrane of cancer cells, causing the dysfunction of certain molecular complexes such as receptors, transduction or transcriptase that maintain the intracellular self-stabilization, and interfering with protein, DNA and RNA synthesis; at the cellular level, the warming effect can activate lysosomes, disrupt cytoplasm and nucleus, and since the S and M phases of cancer cell division are particularly sensitive to warming, the warming At the tissue level, the thermo-thermal effect can interfere with the anaerobic enzymolysis of sugar in tumor tissues, resulting in the decrease of oxygen partial pressure and pH value, leading to the acidic environment in the tumor; in addition, cancer tissues affected by the thermo-thermal effect cannot dissipate heat by expanding blood vessels like normal tissues, resulting in the embolism of tiny blood vessels in tumor tissues, which in turn aggravates the hypoxia, acidosis and impaired nutrient uptake of cancer cells. This in turn aggravates cancer cell hypoxia, acidosis and nutrient uptake disorder, and eventually leads to tumor cell degeneration and necrosis.
On the other hand, because of the “peritoneal-plasma barrier”, the intraperitoneal administration of chemotherapeutic drugs can achieve high local drug concentrations while maintaining low concentrations in the peripheral vasculature, and depending on the molecular weight and lipophilicity of chemotherapeutic drugs, the difference between intraperitoneal and plasma concentrations of chemotherapeutic drugs can be several to tens of times. After warm intraperitoneal chemotherapy with 3OO mg of cisplatin (CDDP), the total and free drug concentrations at the end of the procedure were 12.2ug/ml and 10.1ug/ml, respectively, while the plasma concentrations were 2.1ug/ml and 1.0ug/ml, respectively; after lavage with 30ug of mitomycin (MMC), the intraperitoneal and plasma drug concentrations were 1.0 and 0.05ug/ml, respectively, due to the existence of such Because of such a drug concentration gradient, the intraperitoneal injection of warm chemotherapeutic drugs can not only directly enhance the tumoricidal effect, but also does not lead to serious systemic toxic side effects. In addition, the warming effect can also greatly enhance the sensitivity of tumor cells to certain chemotherapeutic drugs, and the resulting effect is not simply cumulative but multiplicative. For example, under the condition of 43℃, the uptake of MMC by tumor cells can be increased to 78%, and the cytotoxic effect of drugs can be increased from 30% to 50%.
The warming effect can also stimulate the function of the body’s immune system. Heat shock proteins produced during heat therapy can be released into the blood when the cells are necrotic, which can fully activate the body’s immune system to eliminate tumor cells in the body. Heat shock proteins themselves are not antigenic, but can act as antigenic peptide chaperones, maturation of antigen-presenting cells (APCs), and generate tumor-specific immune responses. These immune responses include the activation of natural killer cells, CD4 and CD8 cells, the release of cytokines such as IL-12, etc., thus exerting a strong killing effect on the tumor cells that are also present in the body. Heat therapy can enhance the anti-tumor activity of T-lymphocytes, B-lymphocytes and NK cells, thus enhancing the immune surveillance function of the body. Tumor cells enter the blood circulation system and face the immune response of various lymphocytes in the body. NK cells, as the first line of immune response cells, can play a non-specific killing effect without activation, so the activity of NK cells in the blood is one of the important factors determining the occurrence of blood-borne metastasis of tumor cells. Experimentally, fever-like systemic thermotherapy (Fever-Like WBH, 39.8±0.2°C) can increase the number of endogenous or exogenous NK cells within the tumor tissue and induce apoptosis. Whole-body heat therapy also induces redistribution of the body’s leukocytes. Lymphocytes need to pass through high endothelial venues to access secondary lymphoid organs (lymph nodes, spleen and Peyer’s nodes). It has been shown that heat therapy enhances immune surveillance by stimulating the adhesion of integrin-dependent lymphocytes to the high endothelial venues and facilitating the movement of lymphocytes to secondary lymphatic organs by stimulating the increase of L-selectin in lymphocytes.
Heat therapy is also effective in suppressing tumor metastasis. The metastasis and implantation of malignant tumors depend on the breakdown of extracellular matrix by cancer cells and the breakthrough of tumor basement membrane. Matrix metalloproteinases (MMP) secreted by cancer cells are important enzymes that degrade extracellular matrix during tumor invasion and metastasis, and the activity of MMP is closely related to tumor invasion and metastasis. Experimentally, heating tumor cells to 42℃/3 hours can reduce the concentration of cAMP inside tumor cells, thus significantly inhibiting the gene expression and protein synthesis of type I matrix metalloproteinases in tumor cells, and further inhibiting the activation of gelatinogenic enzyme A. Meanwhile, in vitro tumor cell invasiveness experiments showed that the thermal effect of 42℃/3 hours could significantly inhibit the invasive activity of tumor cells. Thus, the tendency of tumor metastasis was inhibited. The formation of neovascularization is the key link of tumor metastasis, through which tumor cells can be transferred to other sites and tumor tissues can obtain new nutrition and oxygen and keep growing. The generation of neovascularization is regulated by both positive and negative regulators, VEGF, bFGF and IL-8 are the promoting factors, among which VEGF is considered to be the strongest and most specific promoting factor. Experiments have proved that 42℃/4 hours can inhibit the expression of VEGF gene and the synthesis of VEGF in cancer cells. When 42℃×60 minutes×4 times (1 time/week) systemic thermotherapy was administered to tumor patients, the serum VEGF concentration of patients decreased significantly and was basically close to the normal level.
III. Introduction of IPCH operating system and commonly used drugs
From the above study results, we can see that IPCH is a new technology with only more than ten years of development process, and it is a technology with multiple efficacy for peritoneal metastasis and recurrent foci of gastric cancer. Because IPCH is a relatively new treatment technology, it is still under continuous improvement and exploration, and there are many common operation techniques and methods, but the basic steps are more or less the same, so the following is a brief introduction.
It is mainly started immediately after the resection of gastrointestinal tumors, and still needs to be performed under general anesthesia. First, the patient is given an ice bag on the head and a cold water bag on the back to lower the body temperature to 31.0°C-32.0°C. The purpose is to avoid the adverse effects of intra-abdominal warming on the nerve center of the brain. Then 3 to 5 sterile silicone tubes (0.8 cm inner diameter and 1.0 cm outer diameter) are placed in the left and right subdiaphragmatic cavity (input end) and pelvic Douglas fossa (output end), respectively, and connected to a temperature-adjustable irrigation driver, so that the irrigation driver, tubes and abdominal cavity form a circulatory system. When operating, attention should be paid to: (1) control the temperature of the irrigation fluid at the input and output ends of the abdominal cavity between 44.0℃～49.0℃ and 41.0℃～43.O℃, respectively, so that the temperature of the fluid in the abdominal cavity is constant at (43.0±1.0)℃ to ensure optimal therapeutic efficacy and safety. (2) The treatment time of IPCH is usually maintained at 1 to 2 hours, so the chemotherapeutic drugs selected should not depend on the cell proliferation cycle, but should be those with direct cytotoxic effects, such as MMC, CDDP or etoposide. Figure 1 shows the basic workflow of an intraperitoneal perfusion chemotherapy device.
Volume selection: The uniform distribution of anticancer fluids containing high concentrations in the peritoneal cavity so that the entire peritoneal cavity and the surfaces of the abdominal organs are in contact with them is the fundamental basis of intraperitoneal chemotherapy. In order to make the perfused fluid have enough contact area with the peritoneal surface to give full play to the surface effect (surface reaction) of IPCH. For this reason, peritoneal cavityexpander (PCE) is often used in clinical practice, and open perfusion is adopted to increase the fluid infused in the peritoneal cavity to more than LOL, thus greatly increasing the contact area between the peritoneal surface and the fluid and avoiding the existence of a “dead space” for IPCH infusion in the peritoneal cavity. Rosensheir et al. studied the fluid dynamics of the peritoneal cavity by injecting radioactive tracer into the peritoneal perfusion fluid and found that at least 2000 ml of fluid had to be injected to overcome the resistance to free flow of fluid in the peritoneal cavity and to ensure uniform distribution of fluid in the peritoneal cavity. uniform distribution within the peritoneal cavity. Therefore, open peritoneal perfusion has the advantages of large perfusion volume and good homogeneity, but it also has the disadvantages of easy contamination, direct contact with chemotherapeutic drugs by health care workers, and must be performed postoperatively. Closed peritoneal perfusion can overcome these disadvantages and can be repeated, but the perfusion volume is limited and the homogeneity is poor. In order to solve these problems, positive pressure perfusion in the closed abdominal cavity is being tried in the hope that a larger amount of fluid can be perfused in the closed abdominal cavity and that the perfusate is uniformly distributed in the abdominal cavity.
Drug selection: Intraperitoneal chemotherapy solution is mainly composed of anticancer drugs and solvents. Isotonic solutions are more commonly used, often saline or Ringer’s solution or 1.5% Inpersol solution. Hypertonic solutions have the effect of enhancing drug distribution and are currently being tried. Anticancer drugs are guided by intraperitoneal pharmacokinetics and are selected based on the following points: (1) The drug must be able to kill tumor cells by itself or its metabolites. (2) The drug must have a low peritoneal permeability. (3) The drug must be rapidly cleared from the plasma. (4) The drug must have a strong ability to penetrate tumor tissue. According to the above principles, the most commonly used anti-cancer drugs for intraperitoneal chemotherapy of gastric cancer are cisplatin (CDDP), mitomycin (MMC), etc. A variety of chemotherapeutic agents are undergoing phase Ι and II studies, such as carboplatin, oplatin, gemcitabine CPT-11, etc. Some large molecule biologics such as interferon, interleukin-2, monoclonal antibodies, etc. are currently applied in intraperitoneal chemotherapy to enhance the anti-cancer therapeutic effect based on the characteristic that the peritoneal clearance of large molecules is slower than that of small molecules.
During the implementation of IPCH treatment, the effect of intra-abdominal warmth on the patient’s vital organs should be closely observed to ensure the safety of treatment. The focus of intraoperative monitoring is: (1) the temperature of the return heart blood flow, which can be measured by direct thermometry with a built-in catheter via the pulmonary artery or indirect thermometry with a thermometer inserted at the lower end of the esophagus, and the temperature of the return heart blood flow should not be higher than 41℃ for safety. (2) Cardiac function indicators, including blood pressure, heart rate, cardiac index (CI), etc. (3) Arterial partial pressure of oxygen, etc.
IV. Indications for IPCH
Patients with gastric cancer who have no distant metastases such as liver, lung, brain, bone cheese, no serious organ diseases such as heart, lung, liver, kidney, etc., and whose primary cancer site has been radically or palliatively resected, and who have one of the following conditions, are suitable for IPCH treatment: (1) Positive test for free cancer cells (FCC) in the abdominal cavity. (2) The cancer has infiltrated into the plasma membrane or extra-plasma membrane, or is accompanied by peritoneal implantation metastasis. (3) Patients with scattered postoperative peritoneal recurrence or low to moderate amount of cancerous ascites, who can undergo more complete cytoreductive surgery, i.e., the maximum possible removal of metastases visible to the naked eye, especially cancerous nodules implanted on the peritoneal surface. The relevant literature reports that thermal perfusion chemotherapy is only effective for tumor nodules of 3 to 5 mm. Therefore, minimizing the intra-abdominal tumor load before administering IPCH therapy is necessary to achieve better outcomes.
In order to have quantitative criteria for patient selection, researchers abroad have developed various scoring systems for primary or metastatic tumors in the abdominal cavity, and a few of the more commonly used scoring systems are described. The grading method for metastatic peritoneal cancer proposed by Francois N Gilly, a French physician, in 1994 through a retrospective study of 370 patients in 9 treatment centers is one of the more applied grading methods, and the specific scoring criteria are shown in Table 1. patients with grade 1 and 2 metastatic peritoneal cancer who underwent more thorough radical surgery or tumor reduction followed by peritoneal thermoperfusion chemotherapy had significantly higher efficacy and A shortcoming of the Gilly grading method is that it does not indicate the size of the resectability of metastatic nodes by grading.
Gilly grading of metastatic peritoneal cancer
Grading
Extent of metastasis
No visual peritoneal metastasis
Metastatic nodes less than 5 mm in diameter, confined to one peritoneal site
Metastatic nodules less than 5 mm in diameter, widely disseminated in the peritoneal cavity
Limited or disseminated metastatic nodes between 5 and 20 mm in diameter
Limited or disseminated metastatic nodes larger than 5 mm in diameter
Another commonly used grading method is the PCI grading method (peritoneal cancer index, PCI) developed by Jacquet and Sugarbaker. As shown in Figure 2, the abdominal and pelvic cavities were divided into 0-8, with a total of 9 regions; the proximal and distal segments of the jejunum were 9 and 10 regions, respectively, and the proximal and distal segments of the ileum were 11 and 12 regions, respectively, for a total of 13 regions. The tumor nodules in each of the 13 regions were scored: no nodule was scored as 0; nodule diameter not more than 5 mm was scored as 1; nodule diameter greater than 5 mm but less than 5 cm was scored as 2; nodule diameter greater than or equal to 5 cm was scored as 3. The scores of the 13 areas were summed, and patients with scores less than 16
Patients undergoing more thorough radical surgery or tumor reduction followed by intraperitoneal thermal perfusion chemotherapy had significantly better outcomes than those with scores greater than or equal to 16.
V. Complications and adverse effects of IPCH
Complications and adverse effects after the application of IPCH have always been the focus of attention, and their in-depth study and observation are related to the further development of IPCH. To date, there have been no reports in the literature of patient deaths due to complications after IPCH application. We can elaborate on each of the following three aspects.
Complications and adverse effects of non-surgical IPCH
Since patients are not treated surgically, complications and adverse effects in this group of patients are still mainly acute and chronic abdominal pain and digestive system reactions. Qi Chao et al. reported 31.5% acute abdominal pain, 30.3% chronic abdominal pain, one case of transient intestinal paralysis after IPCH in patients with advanced abdominopelvic malignancies, but no abnormalities were seen after opening, 5% abnormal GPT, 1.3% shock (1/76), and one case of abdominal wall hard mass. Gong Liyan et al. reported that the complications and adverse reactions in the IPCH (external heating method) + chemotherapy group for progressive gastrointestinal cancer were mainly digestive reactions, which were more common than those in the chemotherapy-only group. The incidence of III-IV nausea and vomiting reached 36.0%, which was significantly different from 15.3% in the chemotherapy-only group (P0.05), but 34.2% of patients in the IPCH group had mild or moderate abdominal pain within 10 days after surgery. Twenty-eight percent of patients had mild to moderate hypoproteinemia, all of which resolved with symptomatic supportive treatment. The abdominal pain was considered to be caused by repeated and repeated thermal perfusion chemotherapy that caused peritoneal and intestinal wall congestion, edema and chemical peritonitis, and the hypoproteinemia was probably related to the loss of large amount of protein-containing exudate during repeated thermal perfusion.
VI. Clinical efficacy of IPCH
Since IPCH has been used in clinical practice, it has achieved significant efficacy in the prevention of postoperative recurrence of gastrointestinal cancer tumors or in the treatment of advanced patients with peritoneal metastases, and has been unanimously evaluated.
Efficacy of non-surgical IPCH
(1) Artificial ascites method: this method is simple, with few complications and easy to carry out, but the temperature in the abdominal cavity is not uniform, plus the large area of the abdominal cavity and rapid heat dissipation, it is difficult to maintain the effective temperature, although it has been reported clinically, the efficacy deserves further exploration.
(2) Artificial ascites external heating method: this method is less traumatic, the intra-abdominal temperature is relatively uniform, and the effective temperature can be maintained. The results showed that the efficiency of IPCH+chemotherapy group was 56.0% (CR+PR), and the efficiency of chemotherapy group was 26.9%, and there was a significant difference between the two groups.
Clinical efficacy of intraoperative IPCH
Kainara et al. randomly divided 82 patients with gastric cancer invading the plasma membrane into two groups and conducted a control observation after radical surgery, the 5-year survival rate was 71.5% in the IPCH group and 59.7% in the control group; the postoperative peritoneal metastasis rate was 45% in the IPCH group, which was lower than that of 57% in the control group. It can be seen that IPCH has the effect of improving the survival rate and reducing the recurrence rate of postoperative patients with gastric cancer invading the plasma membrane. Most scholars believe that IPCH is less reported in cases of progressive gastrointestinal cancer that have not yet developed peritoneal metastasis, especially those invading the plasma layer, or with a small number of microperitoneal metastases (500 ml in diameter) treated with continuous circulating thermal perfusion chemotherapy. The method is relatively uniform in intra-abdominal temperature and can be performed several times in the early postoperative period.