Edorium Journal of

Surgery

 
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Editorial
 
Can the peritoneal recurrence be prevented after curative surgery?
Shinya Shimada1, Masafumi Kuramoto2, Takashi Marutsuka3, Satoshi Ikeshima4, Kenichiro Yamamoto4, Hideo Baba5
1Director, Kumamoto General Hospital, Japan Community Health Care Organization, Yatsushiro, Kumamoto, Japan.
2Chief, Department of Surgery, Kumamoto General Hospital, Japan Community Health Care Organization, Yatsushiro, Kumamoto, Japan.
3Chief, Department of Surgery, Kumamoto Chuo Hospital, Minami-ku, Kumamoto, Japan.
4Senior Surgeon, Department of Surgery, Kumamoto General Hospital, Japan Community Health Care Organization, Yatsushiro, Kumamoto, Japan.
5Professor and Chairman, Department of Gastroenterological Surgery, Faculty of Life Sciences, Kumamoto University, Japan.

Article ID: 100005S05SS2015
doi:10.5348/S05-2015-5-ED-3

Address correspondence to:
Shinya Shimada
MD, FACS Director, Kumamoto General Hospital
Japan Community Health Care Organization, 10-10 Tohricho, Yatsushiro City
Kumamoto 866-8660, Japan, Yatsushiro City, Kumamoto
Japan-866-8660
Phone: +81-965-32-7111
Fax: +81-965-32-2772

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Shimada S, Kuramoto M, Marutsuka T, Ikeshima S, Yamamoto K, Baba H. Can the peritoneal recurrence be prevented after curative surgery? Edorium J Surg 2015;2:9–11.


Although advances in diagnosis and surgical techniques have improved the conditions of patients with gastric cancer, peritoneal recurrence is still the most frequent cause of death, and the prognosis of patients with peritoneal metastasis of gastric cancer is extremely poor [1] [2]. In patients with pancreatic cancer, besides, one of the major features is its early peritoneal recurrence as well as liver metastasis after curative surgical treatment [3].

The most likely cause of peritoneal recurrence in patients with serosa-invasive gastric cancer is the presence of intra-peritoneal free cancer cells from the serosal surface of the primary cancer and their implantation on the peritoneum. Furthermore, it has been proved that lymph node dissection opened the lymphatic channel and spread viable cancer cells into the peritoneal cavity, using CEA and CK20 specific ultra-rapid quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in combination with an automated mRNA extractor [4]. This CEA and CK20 specific RT-PCR study demonstrated that free cancer cells were found in 0.0%, 14.3% and 26.7% of the lavage fluid after lymph node dissection from patients with mucosal (M), sub mucosal (SM) and muscularis propria (MP) tumors, respectively, and that the number of free cancer cells, calculated by the standard, were 0.0 (M), 3.5±3.7 (SM, mean ± SD) and 12.1 ± 9.6 (MP) cells per 100 ml in the lavage. Yu et al. [5] also verified that lymphadenectomy can disseminate cancer cells into the cavity which leads to increased risk of peritoneal recurrence using cytological analysis by smearing and immunohistochemistry. These data could explain the main cause of the peritoneal recurrence after curative surgery for patients with non serosa-invasive gastric cancer. Consequently, it is very important to prevent peritoneal metastasis prior to the fixation and progression of free cancer cells to the peritoneum.

We have developed a powerful method for reducing the number of free cancer cells in peritoneal cavity to potentially zero, based on the law of "limiting dilution", namely EIPL (Extensive Intraoperative Peritoneal Lavage) [4] [6] [7]. The EIPL is a very simple, little time-consuming, inexpensive and practical intra-operative technique. This therapy can easily be performed anywhere and anytime, and it does not require any special techniques or devices. After the potentially curative operation, the peritoneal cavity was extensively shaken and washed, which was then followed by the complete aspiration of the fluid. This procedure was done 10 times using 1 liter of physiological saline. For example, ten washes of a 1:10 dilution resulted in just one cancerous cell from 1010 cells in the container based on the 'limiting dilution theory'. Furthermore, sufficient shaking and washing of the peritoneal cavity could remove the cancer cells which merely adhere to the peritoneum. Actually, the effectiveness of the EIPL has been confirmed in patients with peritoneal cytology-positive free cancer cells without macroscopic peritoneal dissemination (CY1/P0) by the ultra-rapid quantitative RT-PCR, that is, sequential washing of intraperitoneal free cancer cells of 3.8 × 105 ± 1.4 × 105/100 ml of lavage decreased the number to 2.8 ± 1.5 cells by 6 to 8 washes. Free cancer cells were not detected in washing fluid after that.

Our prospective randomized controlled clinical trial clearly revealed that EIPL therapy significantly improved the five-year survival rate of advanced gastric patients with CY1/P0 [7]. Briefly, a total of 88 gastric cancer cases with CY1/P0 from 1522 patients with advanced gastric cancer at multicenter were enrolled in this study, and were randomly allocated to three groups: surgery alone group, surgery plus intra-peritoneal chemotherapy (IPC) group, and surgery plus EIPL and IPC (EIPL-IPC) group. In EIPL-IPC group, 100 mg of cisplatin (CDDP) was administered into the peritoneal cavity after the EIPL treatment. The overall five-year survival rate of the patients with EIPL-IPC was 43.8%, and this data was significantly higher than that of the IPC group (4.6%, p < 0.0001) and the surgery alone group (0 %, p < 0.0001). Among various recurrent patterns, the EIPL-IPC group had a significantly lower incidence of peritoneal recurrence than either of the other groups (p < 0.0001). Univariate and multivariate analyses clearly revealed that EIPL was the most significant impact factor. In addition, based on 39 consecutive patients with invasive ductal adenocarcinoma of the pancreas who underwent curative surgical treatment, peritoneal, hepatic, lymphatic, local, and extra-abdominal recurrent rates in EIPL and non-EIPL groups were 6.7%, 40.0%, 26.7%, 13.3%, 13.3%, and 45.8%, 50.0%, 20.8%, 29.2%, and 20.8%, respectively. Among these recurrent patterns, peritoneal recurrent rate of EIPL group were significantly lower than those of non-EIPL (p = 0.013) [8].

Finally, exploring the innovative EIPL method as a prophylactic strategy for peritoneal recurrence after curative operation, in Asian and non-Asian countries, phase II and phase III studies were planned [9] [10]. Especially, Japanese CCOG 1102 phase III study [10]; a total of 300 patients will be accrued from 20 institutions, has registered from November 2013. The promising EIPL results will be validated in such larger multi-institutional prospective randomized trials.

Keywords:Cancer cells, Lymph node dissection, Lymphadenectomy, Peritoneal metastasis, Peritoneal recurrence

References
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  2. Kodera Y, Nakanishi H, Yamamura Y, et al. Prognostic value and clinical implications of disseminated cancer cells in the peritoneal cavity detected by reverse transcriptase-polymerase chain reaction and cytology. Int J Cancer 1998 Aug 21;79(4):429–33.   [CrossRef]   [Pubmed]    Back to citation no. 2
  3. Griffin JF, Smalley SR, Jewell W, et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer 1990 Jul 1;66(1):56–61.   [Pubmed]    Back to citation no. 3
  4. Marutsuka T, Shimada S, Shiomori K, et al. Mechanisms of peritoneal metastasis after operation for non-serosa-invasive gastric carcinoma: an ultrarapid detection system for intraperitoneal free cancer cells and a prophylactic strategy for peritoneal metastasis. Clin Cancer Res 2003 Feb;9(2):678–85.   [Pubmed]    Back to citation no. 4
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  6. Shimada S, Tanaka E, Marutsuka T, et al. Extensive intraoperative peritoneal lavage and chemotherapy for gastric cancer patients with peritoneal free cancer cells. Gastric Cancer 2002;5(3):168–72.   [CrossRef]   [Pubmed]    Back to citation no. 6
  7. Kuramoto M, Shimada S, Ikeshima S, et al. Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma. Ann Surg 2009 Aug;250(2):242–6.   [CrossRef]   [Pubmed]    Back to citation no. 7
  8. Yamamoto K, Shimada S, Hirota M, Yagi Y, Matsuda M, Baba H. EIPL (extensive intraoperative peritoneal lavage) therapy significantly reduces peritoneal recurrence after pancreatectomy in patients with pancreatic cancer. Int J Oncol 2005 Nov;27(5):1321–8.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. Batista TP, Martins MR, Martins-Filho ED, Santos RL. A Phase II Trial Exploring the Extensive Intra-operative Peritoneal Lavage (EIPL) As A Prophylactic Strategy for Peritoneal Recurrence in locally advanced gastric Cancer: reporting postoperative morbidity and mortality after early closure. Arq Gastroenterol 2015 Apr-Jun;52(2):161–4.   [CrossRef]   [Pubmed]    Back to citation no. 9
  10. Misawa K, Mochizuki Y, Ohashi N, et al. A randomized phase III trial exploring the prognostic value of extensive intraoperative peritoneal lavage in addition to standard treatment for resectable advanced gastric cancer: CCOG 1102 study. Jpn J Clin Oncol 2014 Jan;44(1):101–3.   [CrossRef]   [Pubmed]    Back to citation no. 10

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Author Contributions:
Shinya Shimada – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Masafumi Kuramoto – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Takashi Marutsuka – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Satoshi Ikeshima – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Kenichiro Yamamoto – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Hideo Baba – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of submission
The corresponding author is the guarantor of submission.
Source of support
None
Conflict of interest
Authors declare no conflict of interest.
Copyright
© 2015 Shinya Shimada et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.



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