2Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Honjo, Chuo-ku, Kumamoto, Japan
Shinya Shimada, Department of Surgery, Kumamoto General Hospital, Japan Community Health Care Organization, Kumamoto,10-10 Tohri-cho, Yatsushiro, Kumamoto 866-8660, Japan, E-mail:
We advocate extensive intraoperative peritoneal lavage (EIPL) as a useful and practical adjuvant surgical technique for gastric cancer patients who are likely to suffer from peritoneal recurrence.
In this article, we review the ability of EIPL to prevent peritoneal recurrence in patients with peritoneal free cancer cells, but not overt peritoneal metastasis (CY+/P-), and describe its potential as a prophylactic therapeutic strategy against peritoneal recurrence.
The median survival time of patients with intraperitoneal free cancer cells without overt peritoneal metastasis (CY+/P-) is no more than 3-6 months [6-8]. In addition, there is no standard treatment for peritoneal metastasis from gastric cancer [9-12].
It has been established that peritoneal metastasis occurs due to the implantation of free cancer cells (derived from tumors involving the serosa) in the peritoneal cavity via adhesion to and invasion of the peritoneal surface. On the other hand, in CY+/P- the cancer cells have not yet become implanted on the peritoneal surface. We propose that there are marked differences between CY+/P- and peritoneal metastasis, and hence, these conditions require different management strategies.
We previously demonstrated that performing extensive intraoperative peritoneal lavage (EIPL) after curative surgery for advanced gastric or pancreatic cancer is a simple technique that helps to prevent peritoneal metastasis. Sometimes, we combine this technique with intraperitoneal chemotherapy (EIPL-IPC). This combined treatment significantly reduces the number of intraperitoneal free cancer cells and can sometimes completely eradicate them. Our prospective randomized control study demonstrated that this therapy significantly improved the survival rate of patients with CY+/P- advanced gastric cancer . As we showed that this therapy was effective at reducing the number of free cancer cells in the abdominal cavity, we extended its indications to include advanced gastric cancer without CY+/P-.
In this article, we review the effectiveness of EIPL in terms of its ability to reduce the risk of peritoneal metastasis, and a treatment strategy for patients with advanced gastric cancer is proposed.
On the basis of this strategy, we have demonstrated that EIPL and EIPL+IPC are effective intraoperative strategies for reducing the number of free cancer cells in the abdominal cavity .
In EIPL, the peritoneal cavity is extensively washed after curative surgery, and the peritoneal lavage fluid is stirred. Then, the fluid is completely aspirated. This process should be performed 10 times using 1 L of sterilized saline each time. Ten washes (1:10 dilution) result in just 1 in every 1010 cells in the abdominal cavity being cancerous (Figure 1). In addition, satisfactory stirring and washing of the abdominal cavity would remove any cancer cells that had the potential to adhere to the peritoneum.
The numbers of free cancer cells in 100-ml samples of lavage fluid collected using 1 L of saline were assessed using ultra-rapid RT-PCR. The free cancer cells were serially diluted with 8 L of saline and had disappeared from the lavage fluid after the 8th wash.
Based on the above pilot study, we developed EIPL-IPC therapy. In this treatment, cisplatin (CDDP) is infused into the abdominal cavity at a dose of 100 mg/body after the EIPL, and the solution is suctioned at 1 hour after its injection. Even if a few cancer cells remained in the abdominal cavity, they would be extremely unlikely to survive or disseminate .
To verify the effects of EIPL-IPC therapy on survival, we designed a prospective randomized multicenter trial examining the use of this therapy in advanced gastric cancer patients with CY+/P-. Eighty-eight advanced gastric cancer patients with CY+/P- were enrolled in this study and were allocated to three groups: the surgery alone group, surgery plus IPC group, and surgery plus EIPL and IPC (EIPL-IPC) group. The overall 5-year survival rate of the EIPL-IPC group was 43.8%, which was significantly higher than those of the IPC group (4.6%, P < 0.0001) and the surgery alone group (0%, P < 0.0001), as shown in Figure 2. Univariate and multivariate analyses demonstrated that of all of the examined factors EIPL had the greatest impact on survival. These results clearly demonstrated that EIPL-IPC therapy is effective .
Peritoneal lavage samples were obtained from 63 patients with gastric cancer that did not involve the serosa just after laparotomy and after lymph node dissection, and the levels of carcinoembryonic antigen (CEA) and cytokeratin (CK) 20 mRNA in these samples were examined. CEA or CK20 mRNA was detected after lymph node dissection in 16 of 63 patients (25.4%), despite no CEA or CK20 mRNA being detected just after laparotomy. These molecules were not evident in patients with mucosal (M) tumors, but were detected in 3 (14.3%), 6 (46.2%), and 7 (53.8%) patients with tumors of the submucosa (SM), muscularis propria (MP), and subserosa (SS), respectively. These findings showed that free cancer cells were present in the peritoneal cavities of patients with gastric cancer that did not involve the serosa after lymph node dissection. Moreover, our previous study of 1272 gastric cancer patients revealed that 1/257 patients (0.4%) with tumors of the SM and 6/136 patients (4.4%) with tumors of the MP developed peritoneal recurrence after undergoing a potentially curative resection . These results suggest that lymph node dissection is a major factor in the spread of cancer cells into the peritoneal cavity. As patients with gastric cancer that does not involve the serosa should be at low risk of metastasis, EIPL can be used to prevent peritoneal recurrence after curative surgery.
We performed EIPL in patients with advanced pancreatic cancer, in which peritoneal recurrence often occurs and has a high mortality rate . EIPL was applied to 15 of 39 consecutive patients with pancreatic cancer who underwent curative surgery. The peritoneal recurrence rate of the EIPL group was significantly lower than that of the non-EIPL group (6.7% vs. 45.8%, p = 0.013), and EIPL was found to be an independent negative risk factor for peritoneal recurrence. On the basis of these findings, EIPL is considered to be applicable to various types of abdominal cancer that involve seeding in the abdominal cavity.
CY+/P- denote that metastatic cells have not yet become implanted on the peritoneal surface. We hypothesize there might be marked differences between CY+/P- and peritoneal metastasis, and hence, that these conditions require different management strategies. Accordingly, it is considered reasonable to focus on devising effective intraoperative techniques for preventing peritoneal recurrence that can be used in combination with appropriate radical resection. Practically, radical resection combined with D2 lymph node dissection appears to be feasible and safe [19-21]. The curative resection of gastric cancer together with a sufficient resection margin and the removal of metastatic lymph nodes is the only treatment that can cure gastric cancer [1,22]. Therefore, advanced gastric cancer should be treated with radical resection, even if it is accompanied by CY+/P- because our novel EIPL-IPC regimen is able to eradicate CY+. In a small retrospective study, we reported that CY+ is not a prognostic factor for advanced gastric cancer patients with CY+/P- that are treated with EIPL . These results suggest that EIPL might have a down-staging effect on the category of CY+/P- gastric cancer from IV to III.
On the basis of our experience in a series of studies and clinical observations, we have decided that EIPL should be applied not only to CY+/P- gastric cancer, but also to other types of CY- advanced gastric cancer, as it might prevent lymphatic invasion and the development of peritoneal metastasis.
From the viewpoint of a prophylactic strategy against peritoneal recurrence, the findings presented in this review greatly transform the surgical treatment for gastric cancer, including tumors that do not involve the serosa . We strongly advocate the adoption of the treatment protocol for gastric cancer shown in Figure 3.
PR: Peritoneal recurrence; M: Mucosal tumors; SM: Submucosal tumors; MP: Tumors exhibiting invasion into the Muscularis Propria; SS: tumors displaying Subserosal Invasion; SE: tumors demonstrating Serosal Invasion; SI: tumor invasion of adjacent structures; UL+: tumors with ulceration or Ulceration Scars; UL-: tumors without ulceration or ulceration scars; ESD: Endoscopic Submucosal Dissection; D1 operation: gastrectomy combined with the dissection of the group 1 lymph nodes; D2 operation: gastrectomy combined with the dissection of the group 1 and 2 lymph nodes; N(+): surgery-induced lymph node metastasis; N(-): no evidence of lymph node metastasis; EIPL: Extensive Intraoperative Peritoneal Lavage
Many investigators have used immunological methods involving selected monoclonal antibodies or real-time RT-PCR to detect free cancer cells in peritoneal lavage fluid during cytological examinations; however, these techniques are not generally available at the time of surgery . Despite this, cytological examinations are still commonly used to detect the existence of free cancer cells in the peritoneal cavity. From these points of view, it is only prudent that EIPL should be performed in all patients with gastric cancer involving the serosa, regardless of the presence/ absence of CY+/P-.
On the other hand, although curative surgery has been used to treat patients with gastric cancer that does not involve the serosa, some die of peritoneal recurrence. We previously reported that free cancer cells were found in the lavage fluid collected after lymph node dissection in 26.7% of patients with tumors involving muscle tissue, suggesting that the surgery itself caused the peritoneal dissemination of cancer cells. Therefore, EIPL is also strongly recommended for cases of gastric carcinoma that do not involve the serosa On the other hand, although curative surgery has been used to treat patients with gastric cancer that does not involve the serosa, some die of peritoneal recurrence. We previously reported that free cancer cells were found in the lavage fluid collected after lymph node dissection in 26.7% of patients with tumors involving muscle tissue, suggesting that the surgery itself caused the peritoneal dissemination of cancer cells. Therefore, EIPL is also strongly recommended for cases of gastric carcinoma that do not involve the serosa (including early stage gastric carcinoma), but in which surgery-induced lymphatic invasion is suspected to have occurred or a positive result is obtained during a cytological examination performed after D2 lymph node dissection (Figure 3).
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