Extensive Intraoperative Peritoneal Lavage Research Articles

105: SURGICAL DISSECTION DOES NOT INCREASE FREE CANCER CELLS (FCC) IN PERITONEAL LAVAGE OF PATIENTS FOLLOWING D2 GASTRECTOMY

Abstract Background and aim Peritoneal free cancer cells (FCC) in patients with gastric cancer (GC) is poor prognostic factor. D2 gastrectomy dissection may induce exfoliated FCC spread from primary tumour or involved lymph nodes (LN). Conventional cytology for FCC detection has several limitations, and prophylactic use of extensive intraoperative peritoneal lavage (IPL) does not improve survival. A prospective single-arm observational study was conducted to verify whether D2 gastrectomy causes an increase of FCC in peritoneal lavage as in patients with GC following D2 gastrectomy. Methods Thirty GC patients underwent D2 gastrectomy, followed by objective quantitative measurements of CK19 mRNA level reflecting FCC with One-Step Nucleic Acid Amplification (OSNA) assay. The IPL with 3000 cc of saline was performed twice after: (1) gastrectomy with D2 lymphadenectomy; and (2) alimentary tract reconstruction. The IPL samples were analysed by initial cytology and four (1–4) consecutive OSNA assays (Figure 1). Three patients were excluded due to positive cytology in samples obtained after laparotomy. Results Initial OSNA measurement (1) revealed positive results (≥24.6 cCP/μl) in 7 (29.6%) patients. Subsequent OSNA measurements revealed a significant decrease in the FCC level after removal of the primary tumour with regional LNs (D2 gastrectomy) (1 vs 2; medians [95%CI]: 4.6 [1.1–18.5] vs. 0.00004 [0–0.2] cCP/μl; P = 0.0012). The first IPL induced non-significant increase in the FCCs (2 vs 3, medians [95%CI]: 0.00004 [0–0.2] vs 0 [0–0.5] cCP/μl; P = 0.3300), but the second IPL reversed it to normal levels (3 vs 4, medians [95%CI]: 0 [0–0.5] vs 0 [0–0] cCP/μl; P = 0.0.0574). At this point of operation, additional finding was a trend toward temporal increase of FCC in patients with LN involvement (pN1–3)(2 vs 3; medians [95%CI]: 0 [0–0.2] vs 0 [0–42.8] cCP/μl; P = 0.0674). One patient was still positive (FCC) at the end of operation as measured by OSNA (4). Conclusion D2 Gastrectomy does not induce increase in the peritoneal FCCs. Temporal intraoperative increase in peritoneal FCC after the IPL may be observed, especially in tumours with LN metastases. At least two consecutive IPLs (with min. 3000 mL of saline) are necessary to reverse temporal increase of peritoneal FCC.

Three-year outcomes of the randomized phase III SEIPLUS trial of extensive intraoperative peritoneal lavage for locally advanced gastric cancer

Whether extensive intraoperative peritoneal lavage (EIPL) after gastrectomy is beneficial to patients with locally advanced gastric cancer (AGC) is not clear. This phase 3, multicenter, parallel-group, prospective randomized study (NCT02745509) recruits patients between April 2016 and November 2017. Eligible patients who had been histologically proven AGC with T3/4NxM0 stage are randomly assigned (1:1) to either surgery alone or surgery plus EIPL. The results of the two groups are analyzed in the intent-to-treat population. A total of 662 patients with AGC (329 patients in the surgery alone group, and 333 in the surgery plus EIPL group) are included in the study. The primary endpoint is 3-year overall survival (OS). The secondary endpoints include 3-year disease free survival (DFS), 3-year peritoneal recurrence-free survival (reported in this manuscript) and 30-day postoperative complication and mortality (previously reported). The trial meets pre-specified endpoints. Estimated 3-year OS rates are 68.5% in the surgery alone group and 70.6% in the surgery plus EIPL group (log-rank p = 0.77). 3-year DFS rates are 61.2% in the surgery alone group and 66.0% in the surgery plus EIPL group (log-rank p = 0.24). The pattern of disease recurrence is similar in the two groups. In conclusion, EIPL does not improve the 3-year survival rate in AGC patients.

Molecular Cytology by One-Step Nucleic Acid Amplification (OSNA) Assay of Peritoneal Washings during D2 Gastrectomy in Advanced Gastric Cancer Patients: Preliminary Results.

The presence of peritoneal free cancer cells (FCC) in gastric cancer (GC) patients is a poor prognostic factor. D2 gastrectomy may induce exfoliated FCC spread from the primary tumour or involved lymph nodes (LN). Conventional cytology for FCC detection has several limitations, whereas prophylactic use of extensive intraoperative peritoneal lavage (IPL) does not improve survival. A prospective single-arm observational study was conducted to verify whether D2 gastrectomy causes an intraoperative increase of FCC in peritoneal fluid. Twenty-seven GC patients underwent D2 gastrectomy, followed by objective quantitative measurements of CK19 mRNA level reflecting FCC with One-Step Nucleic Acid Amplification (OSNA) assay. The IPL with 3000 mL of saline was performed twice: (1) after gastrectomy with D2 lymphadenectomy and (2) after alimentary tract reconstruction. The IPL samples were analysed by initial cytology and four (1–4) consecutive OSNA assays. Initial OSNA measurement (1) revealed positive results (≥24.6 cCP/μL) in 7 (29.6%) patients. Subsequent OSNA measurements showed a significant decrease in the FCC level after D2 gastrectomy (1 vs. 2; p = 0.0012). The first IPL induced a non-significant increase in the FCCs (2 vs. 3, p = 0.3300), but the second IPL reversed it to normal levels (3 vs. 4, p = 0.0.0574). The OSNA assay indicates a temporal intraoperative increase in the peritoneal FCC in advanced GC patients undergoing D2 gastrectomy. Two consecutive IPLs are necessary to reverse the increase of CK19 mRNA level in peritoneal washings.

The benefits of surgery plus extensive intraoperative peritoneal lavage (EIPL) for patients with gastric cancer compared with surgery alone: a systematic review and meta-analysis.

This study aims to synthesize the benefits of surgery plus extensive intraoperative peritoneal lavage (EIPL) for patients with gastric cancer compared with surgery alone. We searched Pubmed, Embase, Web of Science, Cochrane library, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP) for randomized controlled trials from 2000 to 2021 according to the inclusion and exclusion criteria. The reference lists of studies meeting the criteria were also screened for additional studies. The quality of these studies was assessed by the Cochrane Collaboration Risk of Bias Tool. An inverse-variance random-effects model of DerSimonian and Laird was used to synthesize the HRs and corresponding 95% CIs of short-term outcomes: hospital mortality and postoperative complications. For long-term outcomes (peritoneal recurrence and 3-year or 5-year overall survival rate), narrative synthesis was used. 4 of 43 studies were included for quantitative analysis. For short-term outcomes, the pooled HRs of hospital mortality and postoperative complications are 0.422 (95%CI: 0.037, 4.790) and 0.774 (95%CI: 0.376, 1.592). For long-term outcomes, despite the inconsistent results, patients receiving EPIL did not have reduced peritoneal recurrence and 3-year or 5-year overall survival rate. Compared with surgery alone, surgery plus EIPL does not have more benefits for patients with gastric cancer.

Extensive peritoneal lavage with saline after curative gastrectomy for gastric cancer (EXPEL): a multicentre randomised controlled trial

Peritoneal recurrence of gastric cancer after curative surgical resection is common and portends a poor prognosis. Early studies suggest that extensive intraoperative peritoneal lavage (EIPL) might reduce the risk of peritoneal recurrence and improve survival. We aimed to evaluate the survival benefit of EIPL in patients with gastric cancer undergoing curative gastrectomy. In this open-label, phase 3, multicentre randomised trial, patients aged 21-80 years with cT3 or cT4 gastric cancer undergoing curative resection were enrolled at 22 centres from South Korea, China, Japan, Malaysia, Hong Kong, and Singapore. Patients were randomly assigned to receive surgery and EIPL (EIPL group) or surgery alone (standard surgery group) via a web-based programme in random permuted blocks in varying block sizes of four and six, assuming equal allocation between treatment groups. Randomisation was stratified according to study site and the sequence was generated using a computer program and concealed until the interventions were assigned. After surgery in the EIPL group, peritoneal lavage was done with 1 L of warm (42°C) normal 0·9% saline followed by complete aspiration; this procedure was repeated ten times. The primary endpoint was overall survival. All analyses were done assuming intention to treat. This trial is registered with ClinicalTrials.gov, NCT02140034. Between Sept 16, 2012, and Aug 3, 2018, 800 patients were randomly assigned to the EIPL group (n=398) or the standard surgery group (n=402). Two patients in the EIPL group and one in the standard surgery group withdrew from the trial immediately after randomisation and were excluded from the intention-to-treat analysis. At the third interim analysis on Aug 28, 2019, the predictive probability of overall survival being significantly higher in the EIPL group was less than 0·5%; therefore, the trial was terminated on the basis of futility. With a median follow-up of 2·4 years (IQR 1·5-3·0), the two groups were similar in terms of overall survival (hazard ratio 1·09 [95% CI 0·78-1·52; p=0·62). 3-year overall survival was 77·0% (95% CI 71·4-81·6) for the EIPL group and 76·7% (71·0-81·5) for the standard surgery group. 60 adverse events were reported in the EIPL group and 41 were reported in the standard surgery group. The most common adverse events included anastomotic leak (ten [3%] of 346 patients in the EIPL group vs six [2%] of 362 patients in the standard surgery group), bleeding (six [2%] vs six [2%]), intra-abdominal abscess (four [1%] vs five [1%]), superficial wound infection (seven [2%] vs one [<1%]), and abnormal liver function (six [2%] vs one [<1%]). Ten of the reported adverse events (eight in the EIPL group and two in the standard surgery group) resulted in death. EIPL and surgery did not have a survival benefit compared with surgery alone and is not recommended for patients undergoing curative gastrectomy for gastric cancer. National Medical Research Council, Singapore.

Key points of perioperative whole-process management for patients with advanced gastric cancer

Perioperative whole-process management (WPM) for patients with advanced gastric cancer (AGC) mainly focuses on some clinical issues which are easily neglected or underappreciated. WPM is helpful in making a scientific and rational therapeutic plan, and avoiding inadequate communication in multi-disciplinary participation, so that the diagnosis, treatment and rehabilitation for AGC patients can be integrated organically. Based on the current clinical practice for AGC patients, eight key issues in WPM should be emphasized.(1) Preoperative clinical staging. An accurate preoperative staging by endoscopy and imaging technique is helpful in setting up a rational therapeutic plan, and is also a prerequisite to start WPM. (2) Indications and value of diagnostic laparoscopy. Laparoscopic exploration is beneficial to find intraperitoneal micro-metastases so as to avoid unnecessary laparotomy. For cases of AGC infiltrating serosal layer or suspected of peritoneal metastasis, preoperative laparoscopic exploration should be routinely performed. (3) Neoadjuvant therapy. Multiple RCT studies have shown that neoadjuvant chemotherapy can benefit a majority of patients with AGC, improving prognosis and prolonging their overall survival. Therefore, neoadjuvant therapy should be considered first for stage III and IVA AGC patients. (4) Prediction of efficacy in neoadjuvant chemotherapy. Endoscopy, MDCT scan, PET-CT and liquid biopsy have certain predictive value individually, which can be used together or separately to improve the accuracy of prediction. (5) Effective prevention of postoperative peritoneal metastasis. Extensive intraoperative peritoneal lavage (EIPL), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and normothermic intraperitoneal chemotherapy (NIPEC) have been shown to be of various efficacy in preventing peritoneal metastases. (6) Prediction of postoperative prognosis of AGC patients. The key pathological indicators are tumor regression grade (TRG) and ypTNM staging, especially if there is lymph node metastasis. Usually for AGC patients who received neoajuvant chemotherapy with TRG 0 or ypN0, their prognosis was comparable to that of patients with cTNM stage I.(7) Postoperative adjuvant chemotherapy. Postoperative adjuvant therapy is always an important part of the WPM management of AGC patients. Several recent RCT studies have shown that duplet chemotherapy can significantly reduce the risk of death after D2 radical gastrectomy compared to singlet chemotherapy, especially for stage III patients. (8) Perioperative nutritional support. Due to different degrees of malnutrition in AGC patients, enhanced nutritional treatment in the perioperative period can not only reduce surgical complications, but also enable patients to complete necessary course of chemotherapy, and ultimately further improve their survival rate.

Extensive peritoneal lavage after curative gastrectomy for gastric cancer study (EXPEL): An international multicenter randomized controlled trial.

279 Background: Peritoneal recurrence of gastric cancer after curative surgical resection is common and portends a poor prognosis. Preliminary studies suggest extensive intraoperative peritoneal lavage (EIPL) may reduce the risk of peritoneal recurrence and improve survival. We sought to perform a randomized phase III study to definitively establish the role of performing EIPL after gastrectomy. Methods: This is a prospective, open-label, phase 3 multicentre randomised controlled trial involving 22 hospitals from Korea. China, Japan, Malaysia and Singapore. Patients aged between 21 to 80 years with cT3/4 stomach cancer undergoing curative resection were randomized to either surgery and EIPL (lavage with 10 litres of saline) or surgery alone. Comparison of DFS and OS were made via log-rank test. The cumulative incidence of peritoneal recurrence was compared using competing risks approach. All analyses were performed based on intention-to-treat. Results: Between March 2015 to August 2018, 800 patients were randomly assigned to surgery alone ( n= 402) or EIPL ( n= 398). Based on a median follow-up duration of 29 months, the 3-year cumulative incidence of all-cause mortality was 23.1% and 23.3% for EIPL and surgery alone respectively (hazard ratio [HR] = 1.09, 95% CI: 0.78 to 1.52, p = 0.615). Similarly, the 3-year cumulative incidence of recurrence were 28.0% and 25.9% respectively (HR = 1.01, 95% CI: 0.74 to 1.37, p = 0.947), and 7.9% and 6.6% respectively for peritoneal recurrence (Subdistribution HR = 1.33, 95% CI: 0.73 to 2.42, p = 0.347). Overall, the risk of adverse events was higher in EIPL as compared to surgery alone (relative risk = 1.58, 95% CI 1.07 to 2.33, p = 0.019). The most common adverse events were anastomotic leak, bleeding and intra-abdominal abscess. At the planned third interim analysis on 28 August 2019, the predictive probability of achieving even a 5% difference in 3-year OS in favour of EIPL at final analysis was &lt; 0.4%. The trial was thus recommended to terminate on the basis of futility. Conclusions: EIPL does not show any survival benefit compared with surgery alone and is not recommended for patients undergoing curative gastrectomy for cancer. Clinical trial information: NCT02140034.

Combined Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery Alone for Treatment of Locally Advanced Gastric Cancer

Peritoneal metastasis is the most frequent pattern of postoperative recurrence in patients with gastric cancer. Extensive intraoperative peritoneal lavage (EIPL) is a new prophylactic strategy for treatment of peritoneal metastasis of locally advanced gastric cancer; however, the safety and efficacy of EIPL is currently unknown. To evaluate short-term outcomes of patients with advanced gastric cancer who received combined surgery and EIPL or surgery alone. From March 2016 to November 2017, 662 patients with advanced gastric cancer receiving D2 gastrectomy were enrolled in a large, multicenter, randomized clinical trial from 11 centers across China. In total, 329 patients were randomly assigned to receive surgery alone, and 333 patients were randomly assigned to receive surgery plus EIPL. Clinical characteristics, operative findings, and postoperative short-term outcomes were compared between the 2 groups in the intent-to-treat population. Short-term postoperative complications and mortality. The present analysis included data from 550 patients, 390 men and 160 women, with a mean (SD) age of 60.8 (10.7) years in the surgery alone group and 60.6 (10.8) in the surgery plus EIPL group. Patients assigned to the surgery plus EIPL group exhibited reduced mortality (0 of 279 patients) compared with those assigned to surgery alone (5 of 271 patients [1.9%]) (difference, 1.9%; 95% CI, 0.3%-3.4%; P = .02). A significant difference in the overall postoperative complication rate was observed between patients receiving surgery alone (46 patients [17.0%]) and those receiving surgery plus EIPL (31 patients [11.1%]) (difference, 5.9%; 95% CI, 0.1%-11.6%; P = .04). Postoperative pain occurred more often following surgery alone (48 patients [17.7%]) than following surgery plus EIPL (30 patients [10.8%]) (difference, 7.0%; 95% CI, 0.8%-13.1%; P = .02). Inclusion of EIPL can increase the safety of D2 gastrectomy and decrease postoperative short-term complications and wound pain. As a new, safe, and simple procedure, EIPL therapy is easily performed anywhere and does not require any special devices or techniques. Our study suggests that patients with advanced gastric cancer appear to be candidates for the EIPL approach. ClinicalTrials.gov identifier: NCT02745509.

History of Peritoneal Surface Malignancy Treatment in Japan.

In this review, Japanese experience of cytoreductive surgery and perioperative chemotherapy is described. The new concept of peritoneal metastasis (PM) type, i.e., trans-mesothelial, trans-lymphatic, and superficial growing metastasis type was proposed in 2012. Surgeons should perform peritonectomy according to the type of PM. Since 1980, Japanese surgical oncologists have been spearheading the use of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemoperfusion (HIPEC) as treatment for PM from gastric cancer. Two RCTs were conducted to verify the effect of HIPEC for the prophylaxis of peritoneal recurrence after curative resection of advanced gastric cancer. These two studies indicated that HIPEC is effective in preventing peritoneal recurrence of gastric cancer with serosal invasion. In 2002, intraperitoneal chemotherapy using taxans was developed for the treatment of PM from gastric cancer and led to the development of neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), which was reported in 2006. In 2009, extensive intra-operative peritoneal lavage (EIPL) was developed, and contributed to the remarkable improvement in survival of patients with positive lavage cytology as demonstrated by prospective randomized clinical trials. In 2017, the Peritoneal Surface Oncology Group International proposed the value of complete cytoreduction and peritoneal cancer index cut-off as independent prognostic factors after CRS for gastric cancer with PM. Founded in 2016, the Japanese/Asian School of Peritoneal Surface Oncology (JASPSO) trains beginners to perform CRS and HIPEC safely. Sixteen students have already graduated from JASPSO and started to perform the treatment in their home countries.

Long-term outcome of a randomized phase III trial exploring the significance of extensive intraoperative peritoneal lavage in addition to standard treatment for ≥ T3 resectable gastric cancer: CCOG 1102.

1 Background: Extensive intraoperative peritoneal lavage (EIPL) for gastric cancer reportedly improved survival by physically removing and reducing intraperitoneal-free cancer cells in a small-scale randomized trial (Ann Surg 2009). To confirm this, we conducted a multicenter randomized Phase III trial. Methods: Eligibility criteria: (i) histologically confirmed primary gastric adenocarcinoma, (ii) clinically T3(SS), T4a(SE) or T4b(SI), (iii) clinically M0, and (iv) scheduled for total or distal gastrectomy. Patients were intraoperatively randomized to either the EIPL group or the non-EIPL group after confirming the ≥T3 status and resectability. In the EIPL group, peritoneal lavage was conducted at least 10 times using 1L of saline before the closure of the abdomen. In the non-EIPL group, the lavage was conducted with ≤3L of saline. The primary end-point was disease-free survival (DFS). To detect the difference of 15% in 3-year DFS with a both-sided alpha of 5% and 80% power, the planned sample size was 300 cases. This study was registered as UMIN000005907. Results: Between July 2011 and January 2014, 314 patients were registered from 15 institutions. After excluding the R1/R2 resection cases, 295 patients (145 in the EIPL group and 150 in the non-EIPL group) were analyzed. There were no significant differences between the groups in clinicopathologic characteristics. The median volume of saline for the peritoneal lavage was 10.0 L (10 - 12) for the EIPL group and 3.0 L (1 - 4) for the non-EIPL group. No difference was observed in the incidence of postoperative complications. The 3-year DFS was 63.9% in the EIPL group and 59.7% in the non-EIPL group (p = 0.25, Hazard ratio 0.81 [95% CI 0.57-1.16]). The overall survival rate of the EIPL group and non-EIPL group were 75.0%, 73.7% (3 years), and 62.5%, 57.1% (5 years), respectively (p = 0.65). In the subset analysis, no subgroup with significant difference in survival was identified. Conclusions: Although EIPL for advanced gastric cancer was safe and suggested some efficacy, the primary endpoint designed based on the previous small-scale trial was not met. Clinical trial information: 000005907.

Extensive peritoneal lavage after curative gastrectomy for gastric cancer (EXPEL): study protocol of an international multicentre randomised controlled trial.

Peritoneal recurrence after gastrectomy for gastric cancer is common and the prognosis is dismal. Recent evidence suggests that extensive peritoneal lavage with large volume of normal saline after surgery before abdominal closure can reduce the risk of peritoneal recurrence and improve overall survival. This study aims to evaluate the benefit of extensive intraoperative peritoneal lavage. This is a prospective, open-label, multicentre randomised controlled trial involving 15 international centres in China, Korea, Japan, Malaysia and Singapore. Patients with cT3/4 stomach cancer undergoing curative resection are randomised to either extensive peritoneal lavage (10 l of saline) or standard lavage (≤2 l of saline). The primary outcome is overall survival and secondary outcomes include disease-free survival and peritoneal recurrence. The minimum sample size is 600 subjects with 300 per arm completing 3 years follow-up. The data will be analysed on an intention-to-treat basis, assuming a two-sided test with a 5% level of significance.

The effect of extensive intraoperative peritoneal lavage therapy (EIPL) on stage III B + C and cytology-positive gastric cancer patients.

The aim of this study was to investigate the effects of extensive intraoperative peritoneal lavage (EIPL) therapy on stage III B + C and CY1/P0 gastric cancer patients after potentially curative surgery. The study included 37 patients with CY1/P0 and 23 patients with stage III B + C gastric cancer who were treated with potentially curative gastrectomy and EIPL therapy between March 1995 and May 2013. D2 lymphadenectomy, R0 resection, and EIPL therapy were performed for all cases. Multivariate analysis revealed that male gender (P = 0.01) and lymph node metastasis (P = 0.03) were independent prognostic factors, while positive cytology was not (P = 0.21). There was no significant difference in overall survival rates between the CY1/P0 and stage III B + C groups (P = 0.93). There was also no significant difference in peritoneal recurrence rates, i.e., 13 (35.1%) in the CY1/P0 group and 5 (21.7%) in the stage III B + C group (P = 0.39). EIPL therapy combined with complete resection and sufficient (D2) lymphadenectomy could improve the prognosis of CY1/P0 gastric cancer and, to a similar extent, that of stage III B + C.

PREVENCIÓN DE LA RECURRENCIA PERITONEAL EN EL TRATAMIENTO QUIRÚRGICO DEL CÁNCER GÁSTRICO

Prevention of peritoneal recurrence of gastric cancer The peritoneal cavity is the main site of gastric cancer recurrence after curative surgery. When this re currence occurs, patients may experience bowel obstruction, dehydration and multiple hospital admissions. The therapeutic options that may decrease the rate of peritoneal recurrence and increase five years survival are intraoperative hyperthermic chemotherapy, extensive intraoperative peritoneal lavage and routine bursectomy. We herein review the oncological results of curative surgery for gastric cancer, its failure patterns and the risk factors for peritoneal recurrence. We also review the studies aiming to prevent peritoneal carcinomatosis.

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

A randomized controlled trial has started in Japan to evaluate the efficacy of extensive intraoperative peritoneal lavage in the treatment of resectable advanced gastric cancer. Patients with T3 or deeper carcinoma of the stomach are intraoperatively randomized to either extensive intraoperative peritoneal lavage + arm or extensive intraoperative peritoneal lavage- arm. A total of 300 patients will be accrued from 20 institutions. The primary endpoint is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events.

Standard Prophylactic Strategy against Peritoneal Dissemination Metastasis in Gastric Cancer

Peritoneal carcinomatosis is the most frequent pattern of metastasis and recurrence in patients with gastric cancer, and the prognosis of those patients with peritoneal metastasis is extremely poor. Once peritoneal metastasis is formed, it is extremely difficult to overcome. EIPL (extensive intraoperative peritoneal lavage) is a quite useful and practical adjuvant surgical technique for the gastric cancer patients who are likely to suffer from peritoneal recurrence. EIPL includes 10 times of an extensive shake and wash of abdominal cavity with saline followed by the complete aspiration of the fluid after potentially curative operation, which is supposed to have an amazing cyto-reduction power. The purpose of this article is to review the effect of EIPL on prevention of peritoneal recurrence in the patients with peritoneal free cancer cells and to evaluate its validity as a standard prophylactic strategy against peritoneal recurrence in gastric cancer.

Prophylactic Strategy for Peritoneal Recurrence after Curative Operation in Pancreatic Cancer

Even though curative surgery has been performed for patients with pancreatic cancer without peritoneal free cancer cells at laparotomy, many patients die of peritoneal recurrence. The reason for this fact is postulated that the surgical procedure itself could cause spread of cancer cells into peritoneal cavity. To identify the free cancer cells spilled in the peritoneal cavity during the operation, we have established real-time quantitative reverse transcription Polymerase Chain Reaction (RT-PCR) system. Moreover, we have devised Extensive Intraoperative Peritoneal Lavage (EIPL) therapy as a very simple and non-aggressive prophylactic treatment for peritoneal dissemination of gastric cancer patients with peritoneal free cancer cells. In this paper, we review the validity of EIPL therapy navigated by real-time quantitative RT-PCR detecting free cancer cells in the peritoneal cavity during operation, and the effect of this therapy on the survival after curative operations in patients with pancreatic cancer

Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis

Peritoneal metastasis of gastric cancer is mainly caused by the dispersion of free cancer cells from the serosal surface of the invaded stomach, from surgically transected lymphatic channels, and from tumor cell-containing blood from the primary lesion into the peritoneal cavity. Intraperitoneal chemotherapy (IPC) combined with surgery has performed for the prevention and treatment of peritoneal metastasis in gastric cancer. The efficacy of this technique is influenced by the pharmacokinetic advantage achievable with the anticancer drug, timing of administration, combination with hyperthermia, and tumor volume. The pharmacokinetic advantage for peritoneal cavity exposure relative to peripheral circulation by intraperitoneal delivery for drugs including cisplatin (10-fold advantage), mitomycin C (20- to 30-fold advantage), docetaxel (500-fold advantage), and paclitaxel (1000-fold advantage) has been confirmed. To avoid uneven drug distribution in the peritoneal cavity and the re-growth of residual tumor, it seems to be reasonable to perform IPC perioperatively; however, early perioperative intraperitoneal chemotherapy (EPIC) has a relatively high morbidity rate compared with intraoperative IPC. Hyperthermia has both cytotoxicity of itself and a synergistic effect with anticancer drugs, especially mitomycin C. In the adjuvant setting, patients with either hyperthermic intraperitoneal chemotherapy (HIPEC) or EPIC showed a significant improvement of survival compared to those with surgery alone. In addition, extensive intraoperative peritoneal lavage (EIPL) seems also to be a reasonable method to reduce free cancer cells in the peritoneal cavity. For the treatment of peritoneal metastasis, cytoreductive surgery which achieves R0 or R1 resection followed by IPC has demonstrated a survival benefit, whereas gross residual tumor (R2) treated by IPC has shown poor prognosis. Extensive cytoreductive surgery, such as peritonectomy, followed by IPC achieved long-term survival for selected patients, though this aggressive procedure led to high morbidity and mortality rates. It seems that combined chemotherapy (systemically and intraperitoneally) followed by conversion surgery can be expected to be a powerful procedure for the patients with gross peritoneal tumors.

Intraperitoneal Chemotherapy as a Multimodal Treatment for Gastric Cancer Patients with Peritoneal Metastasis

Peritoneal metastasis of gastric cancer is mainly caused by the dispersion of free cancer cells from the serosal surface of the invaded stomach, from surgically transected lymphatic channels, and from tumor cell-containing blood from the primary lesion into the peritoneal cavity. Intraperitoneal chemotherapy (IPC) combined with surgery has performed for the prevention and treatment of peritoneal metastasis in gastric cancer. The efficacy of this technique is influenced by the pharmacokinetic advantage achievable with the anticancer drug, timing of administration, combination with hyperthermia, and tumor volume. The pharmacokinetic advantage for peritoneal cavity exposure relative to peripheral circulation by intraperitoneal delivery for drugs including cisplatin (10-fold advantage), mitomycin C (20- to 30-fold advantage), docetaxel (500-fold advantage), and paclitaxel (1000-fold advantage) has been confirmed. To avoid uneven drug distribution in the peritoneal cavity and the re-growth of residual tumor, it seems to be reasonable to perform IPC perioperatively; however, early perioperative intraperitoneal chemotherapy (EPIC) has a relatively high morbidity rate compared with intraoperative IPC. Hyperthermia has both cytotoxicity of itself and a synergistic effect with anticancer drugs, especially mitomycin C. In the adjuvant setting, patients with either hyperthermic intraperitoneal chemotherapy (HIPEC) or EPIC showed a significant improvement of survival compared to those with surgery alone. In addition, extensive intraoperative peritoneal lavage (EIPL) seems also to be a reasonable method to reduce free cancer cells in the peritoneal cavity. For the treatment of peritoneal metastasis, cytoreductive surgery which achieves R0 or R1 resection followed by IPC has demonstrated a survival benefit, whereas gross residual tumor (R2) treated by IPC has shown poor prognosis. Extensive cytoreductive surgery, such as peritonectomy, followed by IPC achieved long-term survival for selected patients, though this aggressive procedure led to high morbidity and mortality rates. It seems that combined chemotherapy (systemically and intraperitoneally) followed by conversion surgery can be expected to be a powerful procedure for the patients with gross peritoneal tumors.

D2 lymphadenectomy can disseminate tumor cells into peritoneal cavity in patients with advanced gastric cancer

We sought to determine the dissemination of gastric cancer cells before and after radical D2 surgery and to determine the effectiveness of EIPL in preventing post-operative peritoneal metastasis. 64 patients were recruited with advanced gastric cancer for our final analysis. Complete curative gastrectomy with D2 lymphadenectomy was performed on the 64 patients. Before surgery, peritoneal lavage fluid was collected for cytological analysis by cell smearing and immunohistochemistry to detect disseminated cancer cells (S1). Following tumor and lymph node resection, peritoneal lavage fluid was collected for cytological examination (S2). The patients were treated by extensive intra-operative peritoneal lavage (EIPL) with normal saline (n = 31) or distilled water (n = 33). The peritoneal lavage fluid was collected for cytological examination (S3). At S1 stage, 18 patients (28.1%) were positive for disseminated cancer cells in their abdominal fluid. After D2 lymphadenectomy, 34 patients (53.1%) had disseminated cancer cells in their abdominal fluid at stage S2, which indicated that the D2 lymphadenectomy caused in an additional 16 (16/46, 34.8%) patients positive for disseminated cancer cells. After EIPL with either normal saline or distilled water at the S3 stage), all the patients were negative for disseminated cancer cells in their abdominal fluid. A total of six patients died, and four patients had recurrencent cancer. These findings indicate that D2 lymphadenectomy can disseminate gastric cancer cells, and post-operative lavage of the abdominal cavity can eliminate cancer cell dissemination and decrease the risk of peritoneal metastasis.

A Proposal of a Practical and Optimal Prophylactic Strategy for Peritoneal Recurrence

Peritoneal metastasis, which often arises in patients with advanced gastric cancer, is well known as a miserable and ill-fated disease. Once peritoneal metastasis is formed, it is extremely difficult to defeat. We advocated EIPL (extensive intraoperative peritoneal lavage) as a useful and practical adjuvant surgical technique for those gastric cancer patients who are likely to suffer from peritoneal recurrence. In this paper, we review the effect of EIPL therapy on prevention of peritoneal recurrence on patients with peritoneal free cancer cells without overt peritoneal metastasis (CY+/P−) through the prospective randomized study, and we verified its potential as an optimal and standard prophylactic therapeutic strategy for peritoneal recurrence.