Macroscopic Peritoneal Metastasis Research Articles

OGC P07 A Preoperative Predictive Tool to Assess the Need for Staging Laparoscopy in Oesophagogastric Cancer Patients

Abstract Background Staging laparoscopy (SL) has become commonplace in the preoperative staging pathway for oesophagogastric (OG) cancer due to the tendency for peritoneal carcinomatosis (PC) to be present, which may be macroscopic peritoneal metastases (PM) or positive peritoneal cytology (PPC). The aim of this study was to develop an objective risk scoring system to predict both PM and PPC at SL. Methods A prospectively collected and maintained database of all OG cancer patients treated between 2006-2020 was reviewed. Univariate and multivariate analyses were performed to identify risk factors for both PM and PPC at SL. A risk score was then produced for both PM and PPC, then internally validated. Results Amongst 968 patients who underwent SL, 96 (9.9%) patients had PM and 81 (8.4%) had PPC at SL. Tumour site (p<0.001), CT T stage (p<0.001) and N stage (p=0.029) were significantly associated with PM at SL. (p<0.001). Tumour site (p<0.001), biopsy histology (p=0.041) CT T stage (p<0.001) and N stage (p<0.001) were significantly associated with PPC. The risk scoring model for PM included cancer site and CT T stage. This was successfully tested on the validation set (AUROC = 0.730). The risk scoring model for PPC included cancer site, CT T and N stage. This was successfully tested on the validation set (AUROC = 0.773). Conclusions The present risk scores are valid tools with which to predict the risk PM and PPC in patients undergoing SL for OG cancer and may help to avoid subjecting patients to unnecessary SL.

Looking for a strategy in treating peritoneal gastric cancer carcinomatosis: an Italian multicenter Gastric Cancer Research group\u2019s analysis

BackgroundThe present study provides a snapshot of Italian patients with peritoneal metastasis from gastric cancer treated by surgery in Italian centers belonging to the Italian Research Group on Gastric Cancer. Prognostic factors affecting survival in such cohort of patients were evaluated with the final aim to identify patients who may benefit from radical intent surgery.MethodsIt is a multicentric retrospective study based on a prospectively collected database including demographics, clinical, surgical, pathological, and follow-up data of patients with gastric cancer and synchronous macroscopic peritoneal metastases. Patients were surgically treated from January 2005 to January 2017. We focused on patients with macroscopic peritoneal carcinomatosis (PC) treated with upfront surgery in order to provide homogeneous evidences.ResultsOur results show that patients with peritoneal carcinomatosis cannot be considered all lost. Strictly selected cases (R0/R1 and P1 patients) could benefit from an aggressive surgical approach performing an extended lymphadenectomy and HIPEC treatment.ConclusionThe main result of the study is that GC patients with limited peritoneal involvement can have a survival benefit from a surgery with “radical oncological intent”, that means extended lymphadenectomy and R0 resection. The retrospective nature of this study is an important bias, and for this reason, we have started a prospective multicentric study including Italian stage IV patients that hopefully will give us more answers.

Review of management and treatment of peritoneal metastases from gastric cancer origin.

Gastric cancer (GC) is the third cause of cancer-related deaths in the world, with less than 25% survivors at 5 years. These results are largely related to the high incidence of peritoneal metastases (PM) in these patients. Nowadays, the standard treatment for GC with PM is palliative systemic chemotherapy (SCT) with a survival of 6 months. From the 2000s, the combination of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been gaining popularity for different neoplastic diseases that involve the peritoneal surface. The use of CRS and HIPEC has been studied for GC with PM, with promising results in selected patients, obtaining survival rates never seen before. Moreover, HIPEC and other intraperitoneal chemotherapy techniques have been used to prevent peritoneal recurrences in patients diagnosed on locally advanced GC without macroscopic PM (adjuvant or prophylactic HIPEC). Even, intraperitoneal chemotherapy [laparoscopic HIPEC and neoadjuvant intraperitoneal and systemic chemotherapy (NIPS)] has been used as neoadjuvant treatment to reduce peritoneal disease burden in order to improve the rate of patients in whom complete cytoreduction can be achieved. Finally, patients with high volume peritoneal disease can be treated by palliative intraperitoneal chemotherapy to control the symptoms resulting from malignant ascites, using laparoscopic HIPEC or pressurized intraperitoneal aerosol chemotherapy (PIPAC). This review aims to update the management of PM from GC origin in these different clinical scenarios, based on the literature and the experience of the authors.

Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Oxaliplatin as Induction Therapy for Patients with Advanced Gastric Cancer with Peritoneal Metastases

BackgroundIntraperitoneal (IP) administration of paclitaxel (PTX) has a great pharmacokinetic advantage to control peritoneal lesions and can be combined with various systemic chemotherapies. In this study, we evaluate the efficacy and tolerability of a combination of IP-PTX and systemic S-1/oxaliplatin (SOX) for induction chemotherapy for patients with peritoneal metastases (PM) from gastric cancer (GC).Patients and MethodsPatients with GC who were diagnosed as macroscopic PM (P1) or positive peritoneal cytology (CY1) by staging laparoscopy between 2016 and 2019 were enrolled. PTX was IP administered at 40 mg/m2 on days 1 and 8. Oxaliplatin was IV administered at 100 mg/m2 on day 1, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, repeated every 21 days. Survival time and toxicities were retrospectively explored.ResultsForty-four patients received SOX + IP-PTX with a median (range) of 16 (1–48) courses, although oxaliplatin was suspended due to the hematotoxicity or intolerable peripheral neuropathy in many patients. The 1-year overall survival (OS) rate was 79.5% (95% CI 64.4–88.8%) with median survival time of 25.8 months. Gastrectomy was performed in 20 (45%) patients who showed macroscopic shrinkage of PM with a 1-year OS rate of 100% (95% CI 69.5–100%). Grade 2 and 3 histological responses was achieved in four (20%) and one (5%) patients. Grade 3/4 toxicities included neutropenia (11%), leukopenia (39%), and anemia (14%). There were no treatment-related deaths.ConclusionsCombination chemotherapy using SOX + IP-PTX regimen is highly effective and recommended as induction chemotherapy for patients with PM from GC.

The relationship between retroperitoneal lymphadenectomy and survival in advanced ovarian cancer patients

BackgroundSystematic retroperitoneal lymphadenectomy has been widely used in the surgical treatment of advanced ovarian cancer patients. Nevertheless, the corresponding therapeutic may not provide a survival benefit. The aim of this study was to assess the effect of systematic retroperitoneal lymphadenectomy in such patients.MethodsPatients with advanced ovarian cancer (stage III-IV, according to the classification presented by the International Federation of Gynecology and Obstetrics) who were admitted and treated in Zhejiang Cancer Hospital from January 2004 to December 2013 were enrolled and reviewed retrospectively. All patients were optimally or suboptimally debulked (absent or residual tumor < 1 cm) and divided into two groups. Group A (no-lymphadenectomy group, n = 170): patients did not undergo lymph node resection; lymph nodes resection or biopsy were selective. Group B (n = 240): patients underwent systematic retroperitoneal lymphadenectomy.ResultsA total of 410 eligible patients were enrolled in the study. The patients’ median age was 51 years old (range, 28–72 years old). The 5-year overall survival (OS) and 2-year progression-free survival (PFS) rates were 78 and 24% in the no-lymphadenectomy group and 76 and 26% in the lymphadenectomy group (P = 0.385 and 0.214, respectively). Subsequently, there was no significant difference in 5-year OS and 2-year PFS between the two groups stratified to histological types (serous type or non-serous type), the clinical evaluation of negative lymph nodes or with macroscopic peritoneal metastasis beyond pelvic (IIIB-IV). Multivariate Cox regression analysis indicated that systematic retroperitoneal lymphadenectomy was not a significant factor influencing the patients’ survival. Patients in the lymphadenectomy group had a higher incidence of postoperative complications (incidence of infection treated with antibiotics was 21.7% vs. 12.9% [P = 0.027]; incidence of lymph cysts was 20.8% vs. 2.4% [P < 0.001]).ConclusionsOur study showed that systematic retroperitoneal lymphadenectomy did not significantly improve survival of advanced ovarian cancer patients with residual tumor < 1 cm or absent after cytoreductive surgery, and were associated with a higher incidence of postoperative complications.

Minimally invasive surgery is feasible after preoperative chemotherapy for stage IV gastric cancer.

AimTo elucidate the safety and feasibility of minimally invasive surgery (MIS) as conversion surgery after chemotherapy for stage IV gastric cancer, we compared the background characteristics and clinical courses of patients who underwent open conversion surgery (open group) versus MIS (MIS group).MethodsWe included 94 consecutive patients with stage IV gastric cancer who received chemotherapy followed by conversion surgery gastric resection from January 2011 to October 2019 at the Osaka International Cancer Institute in this analysis.ResultsThe open group included more patients who had macroscopic peritoneal metastasis and required splenectomy. However, other background characteristics, including preoperative chemotherapy duration, were comparable. The MIS group had significantly longer operative time (266 vs 339 minutes, P = .0039) and less operative blood loss (520 vs 10 mL, P < .0001). The incidence of postoperative complication of Clavien‐Dindo grade II or higher was non‐significantly lower (24.5% vs 9.8%, P = .058) and length of postoperative hospital stay was significantly shorter in the MIS group (12 vs 8 days, P < .0001). Even though the open group included more patients with more advanced (ypT4a or higher, or N3) disease, the MIS group had better recurrence free survival and overall survival (OS). Multivariate analysis revealed that N status (hazard ratio [HR], 4.39; 95% confidence interval [CI], 2.18‐12.26; P < .0001) and T status (2.11; 1.05‐4.36; P = .036) were independent prognostic factors for OS. MIS was not a negative prognostic factor for OS (HR, 0.44; 95% CI, 0.15‐1.10; P = .081).ConclusionMIS can be safely performed as conversion surgery following chemotherapy for stage IV gastric cancer.

Gastric Cancer with Macroscopic Peritoneal Metastasis: Who Can Benefit from Up-Front Surgical Treatment

Background: Surgical management of stage IV gastric cancer patients for peritoneal metastasis has always been considered a palliative treatment. The aim of this study is to identify patients with macroscopical peritoneal involvement that, also with support of multidisciplinary approach including chemotherapy and HIPEC, could benefits from an intensive surgical treatment with curative intention

Phase I Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Cisplatin for Gastric Cancer with Peritoneal Metastasis

Introduction: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Recently, superiority of IP administration of paclitaxel (PTX) combined with S-1 and intravenous PTX over conventional systemic chemotherapy was suggested in a phase III study, although the difference in overall survival did not reach statistical significance in the primary analysis. Thus, attempts to combine IP PTX with other systemic therapies with higher efficacy are warranted. We designed a new regimen combining IP PTX with S-1 plus cisplatin (SP), which is regarded as the standard first-line treatment for metastatic GC in Japan, and subsequently carried out a dose-escalation study. Methods: The combination was a 5-weekly regimen. IP PTX was to be administered on days 1, 8, and 22 with an initial dose of 15 mg/m² at level 1 and 20 mg/m² at level 2. S-1 was to be administered orally at a fixed dose of 80 mg/m² b.i.d. for 21 days followed by a ­14-day rest. Cisplatin was to be administered intravenously at a dose of 60 mg/m² on day 8. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 (G3) febrile neutropenia, G3 thrombocytopenia, and G3 nonhematological toxicity. Results: A total of 9 patients with macroscopic PM were enrolled. No DLTs were observed among the 3 patients at level 1 and 6 patients at level 2. No adverse events or technical problems associated with the IP administration were observed. Consequently, the maximum-tolerated dose was not reached, and the dose for further clinical trials of IP PTX was determined as 20 mg/m². As for efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment. Conclusion: The present study determined the dose for further clinical trials of IP PTX to be 20 mg/m², when combined with the 5-weekly SP regimen.

Yield of Staging Laparoscopy for Incurable Factors in Chinese Patients with Advanced Gastric Cancer.

Although the role of staging laparoscopy (SL) in detecting radiologically occult M1 disease has been widely recognized, it is seldom used in China and its clinical value based on Chinese population has been rarely reported. The aim of this study is to identify the yield of SL for Chinese patients with advanced gastric cancer (AGC) and determine the proportions of patients in whom treatment plan is altered. The clinical data were retrospectively collected from 879 AGC patients who underwent SL without any definite signs of disseminated disease on imaging examination. The primary outcomes were the proportions of patients whose laparoscopy identified incurable factors (including M1 diseases and unresectable T4b diseases), and who had their treatment plan altered. SL revealed incurable factors in 130 (14.8%) patients, including macroscopic peritoneal metastasis (n = 92), positive peritoneal cytology (n = 10), liver metastasis (n = 12), para-aortic lymph node metastasis (n = 1), and unresectable T4b tumor (n = 18). After SL, treatment plans were altered in 123 (14.0%) patients, among which 82 (63.1%) patients were not offered any further procedure and referred for chemotherapy. Among 749 M0 patients who immediately proceeded to radical gastrectomy after SL, new incurable factors were found at subsequent operations in 21 (2.8%) patients. Multivariate analysis showed that tumor size ≥8 cm, Borrmann type III and IV, and tumor invasion of T4a and T4b in preoperative imaging examination were the predictive factors for peritoneal metastasis. SL detects additional incurable factors in Chinese AGC patients with potentially resectable disease and optimizes their treatments. A systematic and painstaking inspection of the whole abdominal cavity, including routine entry into the bursa omentalis, is necessary for improving the yield of SL.

Intraoperative peritoneal lavage cytology offers prognostic significance for gastric cancer patients with curative resection.

Outcomes of patients with gastric cancer who exhibit positive peritoneal lavage cytology findings (CY +) vary by diagnostic methods because of quantitative and qualitative cancer cell diversity. This study sought to establish practical diagnostic criteria for performing curative resections, based on peritoneal lavage cytology findings in gastric cancer patients. We enrolled 1028 patients with gastric cancer who underwent R0/1 (n = 911) or R2 (n = 117) resections and analyzed relationships between cancer cell findings in peritoneal lavage fluid and clinicopathological factors in the R0/1 group. We found 68 patients with CY + status. Receiver operating characteristic analyses and multivariate analyses showed that the presence of ≥1 signet ring cell, ≥5 cell clusters or ≥50 isolated cancer cells in peritoneal lavage fluid predicted poor prognoses in the 68 CY + patients. High‐risk CY + group patients with at least one of the above predictors had the highest hazard ratio (HR = 3.28, P < 0.001). The remaining (low‐risk) patients had a survival curve similar to that of patients with a normal cytology. The high‐risk CY + patients who underwent R1 resection had poor prognoses despite no macroscopic peritoneal metastasis (2% 5‐year survival)—equivalent to that of patients who underwent R2 resection. The CY + criteria defined in this study could help identify candidates for curative resection as an initial therapy for gastric cancer.

Conversion surgery after combination chemotherapy of docetaxel, cisplatin and S-1 (DCS) for far-advanced gastric cancer.

A triplet regimen of docetaxel, cisplatin, and S-1(DCS) is highly effective against metastatic gastric cancer. We performed this study to clarify the safety and efficacy of surgical resection in patients with initially unresectable gastric cancer, after down-staging or disease control was achieved by DCS chemotherapy. The subjects of this retrospective study were 31 consecutive patients with initially unresectable gastric cancer, who underwent surgical resection between October, 2006 and December, 2012, after down-staging or disease control was achieved by DCS chemotherapy. We evaluated the clinicopathological factors and clinical outcomes and assessed radiographic response based on the RECIST criteria, not by central review. Before DCS chemotherapy, 18 patients had extra-regional lymph node metastasis, 5 had liver metastasis, 8 had macroscopic peritoneal metastasis, and 8 had pancreatic head invasion. Twenty-three (74.2%) of the 31 patients underwent R0 resection. Postoperative morbidity and mortality rates were 16.1 and 0%. During chemotherapy, grade 3/4 toxicities included neutropenia (54.8%), leukopenia (32.3%), and anemia (16.1%). Median progression-free survival and median overall survival (OS) were 42.1 and 56.1 months, respectively. These results were similar for all patients, except those with locally advanced disease alone. In the multivariate analysis for OS, ypN remained an independent negative prognostic factor (p = 0.018). Surgical resection after DCS chemotherapy for initially unresectable gastric cancer was safe and provided a reasonable R0 resection rate and good mid-term survival.

Phase II study of intraperitoneal paclitaxel plus S-1/paclitaxel for gastric cancer with positive peritoneal cytology: CY-PHOENIX trial.

96 Background: The presence of free cancer cells in the peritoneal cavity has been known as a poor prognostic factor in gastric cancer patients. Intraperitoneal (IP) paclitaxel (PTX) provides powerful local effects in the peritoneal cavity, and we previously reported the efficacy and safety of a regimen combining IP PTX with S-1/PTX in gastric cancer patients with peritoneal metastasis. This multicenter phase II study was conducted to evaluate the efficacy of IP PTX plus S-1/PTX for gastric cancer with positive peritoneal cytology. Methods: Eligibility criteria included pathologically confirmed gastric adenocarcinoma, intraperitoneal free cancer cells confirmed by peritoneal washing cytology, and no evidence of overt distant metastasis including macroscopic peritoneal metastasis. Patients were administered IP PTX 20 mg/m2, intravenous PTX 50 mg/m2 on days 1 and 8, and S-1 80 mg/m2/day on days 1-14, q3 weeks. The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints were response rate, negative conversion rate on peritoneal cytology and safety. Results: Thirty eight patients were enrolled and fully evaluated for OS and toxicity. The median number of courses was 12.5 (range 2-35). The 1-year OS rate was 84.2% (95 % confidence interval, 68.2-92.6%). Of 3 patients with target lesions, partial response and stable disease were obtained in 2 and 1 patient(s), respectively. The peritoneal cytology findings converted from positive to negative in 36 (94.7 %) patients. The incidences of grade 3/4 hematological and non-hematological toxicities were 45 % and 26 %, respectively. The frequent grade 3/4 toxicities included neutropenia (23%), leukopenia (7%) and anemia (8%). Regarding adverse events related to IP port, 2 patients developed swelling around the port site. Conclusions: IP PTX with S-1/PTX was suggested to be a promising option for gastric cancer with positive peritoneal cytology through the clearance of cancer cells in the peritoneal cavity. Clinical trial information: UMIN000002850.

Efficacy and safety of surgery combined with hyperthermic intraperitoneal chemotherapy in the treatment of advanced gastric cancer: a meta-analysis

To systematically evaluate the efficacy and safety of surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced gastric cancer (AGC). Clinical control trials about the efficacy and safety of surgery combined with HIPEC in the treatment of advanced gastric cancer published before June 2014 were searched in Embase, PubMed, Cochrane Library, Wanfang database and CNKI database. Quality of enrolled articles was evaluated with the guidelines from Cochrane collaborative network. All the retrieved data were analyzed by RevMan 5.3 software for meta-analysis. Sensitivity analysis was performed by exclusion of non-randomly clinical control trials. Publication bias was evaluated by failure safe number (Nfs0.05). Of the 1489 AGC cases included from 16 literature, 698 underwent surgery with HIPEC (HIPEC group) while 791 underwent surgery alone (control group). According to whether or not the patient presented macroscopic peritoneal metastasis before the surgery, the HIPEC group was further divided into the curative HIPEC (n=102) and prophylactic HIPEC groups (n=421). The results of meta-analysis showed that, compared with control group, the 1-year (OR=2.26, 95%CI:1.71 ~ 3.00, P=0.000), 3-year (OR=2.27, 95%CI:1.80 - 2.87, P=0.000) and 5-year (OR=1.58, 95%CI:1.20 - 2.07, P=0.001) survival rates of HIPEC group were significantly improved with significantly decreased overall recurrence rate of liver, lung, bone or peritoneal metastasis (OR=0.43, 95%CI:0.26 - 0.71, P=0.001) and lower peritoneal metastasis recurrence rate (OR=0.30, 95%CI:0.17 - 0.52, P=0.000). However, there was higher incidence of procedure-related morbidity in the HIPEC group (OR=1.67, 95%CI:1.13 - 2.45, P=0.009), whereby the incidences of myelotoxicity (OR=4.90, 95%CI:1.05 - 22.83, P=0.040) and renal insufficiency were higher (OR=3.59, 95%CI:1.67 - 7.74, P=0.001). While the other complications, such as anastomotic leakage, intestinal obstruction and respiratory diseases were not significantly different between the two groups(all P>0.05). Subgroup analysis showed that compared with control group, the rates of peritoneal recurrence and metastasis in the prophylactic HIPEC group were significantly lower (OR=0.34, 95%CI:0.24 - 0.48, P=0.000), while such rates were not significantly different in curative HIPEC group (OR=0.07, 95%CI:0.00 - 1.88, P=0.110). Surgery combined with HIPEC can improve survival of AGC patients and reduce the recurrence rate after surgery. However its safety should be improved in the future.

Functional vascular anatomy of the peritoneum in health and disease.

The peritoneum consists of a layer of mesothelial cells on a connective tissue base which is perfused with circulatory and lymphatic vessels. Total effective blood flow to the human peritoneum is estimated between 60 and 100 mL/min, representing 1-2 % of the cardiac outflow. The parietal peritoneum accounts for about 30 % of the peritoneal surface (anterior abdominal wall 4 %) and is vascularized from the circumflex, iliac, lumbar, intercostal, and epigastric arteries, giving rise to a quadrangular network of large, parallel blood vessels and their perpendicular offshoots. Parietal vessels drain into the inferior vena cava. The visceral peritoneum accounts for 70 % of the peritoneal surface and derives its blood supply from the three major arteries that supply the splanchnic organs, celiac and superior and inferior mesenteric. These vessels give rise to smaller arteries that anastomose extensively. The visceral peritoneum drains into the portal vein. Drugs absorbed are subject to first-pass hepatic metabolism. Peritoneal inflammation and cancer invasion induce neoangiogenesis, leading to the development of an important microvascular network. Anatomy of neovessels is abnormal and characterized by large size, varying diameter, convolution and blood extravasation. Neovessels have a defective ultrastructure: formation of large "mother vessels" requires degradation of venular and capillary basement membranes. Mother vessels give birth to numerous "daughter vessels". Diffuse neoangiogenesis can be observed before appearance of macroscopic peritoneal metastasis. Multiplication of the peritoneal capillary surface by neoangiogenesis surface increases the part of cardiac outflow directed to the peritoneum.

Phase I study of intraperitoneal paclitaxel combined with S-1 plus cisplatin for gastric cancer with peritoneal metastasis.

115 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX was reported in a phase II study. Attempts to combine IP PTX with other systemic therapies with higher efficacy are warranted. We designed a new regimen combining IP PTX with S-1/cisplatin (SP) which is regarded as the standard first-line treatment of metastatic GC in Japan. We subsequently carried out a dose-escalation study to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: The combination was a five-week regimen. IP PTX was to be administered on days 1, 8 and 22 with an initial dose of 15 mg/m2 at level 1 and 20 mg/m2 at level 2. S-1 was to be administered orally at a fixed dose of 80 mg/m2 bid for 21 days followed by a 14-day rest. Cisplatin was to be administered intravenously at a dose of 60 mg/m2 on day 8, and was to be decreased to 50 mg/m2 (level 0) if necessary. Since the dosage of S-1 at the fixed dose and cisplatin at level 1 were identical to SP regimen, no further dose-escalation was planned. Dose-limiting toxicities (DLTs) were defined as Grade 4 (G4) leukopenia, G3 febrile neutropenia, G3 thrombocytopenia, and G3 non-hematological toxicity. The MTD was defined as the dose level at which ≥2 of 3 or 6 patients developed DLTs during the first course of treatment. The RD was defined as one level below the MTD. Results: A total of 9 patients with macroscopic PM were enrolled. No DLTs were observed among the 3 patients at level 1 and 6 patients at level 2. Furthermore, no G3 toxicities were observed in any of the patients enrolled. Anemia in 1 patient at level 2 was the only G2 toxicity observed. No adverse events or technical problems associated with the IP administration were observed. Consequently, the MTD was not reached, and the RD of IP PTX was determined as 20 mg/m2 (level 2). As for the efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment. Conclusions: Addition of IP PTX at 20 mg/m2 to the SP regimen at an established dose/schedule was safe and promising, and further evaluation in a phase II trial is underway. Clinical trial information: UMIN000013528.

Abstract 4938: In vivo visualization using two-photon laser scanning microscopy of anti-c-MET antibody in peritoneal metastatic gastric cancer

Abstract Background: c-MET (hepatocyte growth factor receptor) gene is overexpressed in approximately 20% of gastric cancer. Onartuzumab, a MET-selective humanized one-armed monoclonal antibody, has been studied in metastatic Met-positive non-small cell lung cancer and expected to be introduced to MET-positive gastric cancer. Two-photon laser scanning microscopy (TPLSM) has revolutionized in vivo real-time imaging because of the benefits of higher resolution, increased tissue penetration, and reduced photodamage. We established a method of intravital imaging for intra-abdominal organs using TPLSM with an organ stabilizing system (Japanese Patent No.5268282). Aim: To visualize the binding of fluorescence labeled-antibody to its receptor of cancer cells in peritoneal metastatic xenografts of living mice using a TPLSM. Method: Human gastric cancer cell lines (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein (GFP) expressing nude mice to make macroscopic peritoneal metastases. In vitro study, the binding of Zenon Alexa Fluor 594 labeled anti-c-MET antibody to viable NUGC4 cells was imaged using fluorescence microscopy. In vivo study, the binding of fluorescence labeled-antibody to viable NUGC4 cells of peritoneal metastatic xenografts was imaged using a TPLSM. Result: Zenon Alexa Fluor 594 labeled anti-c-MET antibody (red) was bound to the surface of viable NUGC4 cells, and clearly visualized under a fluorescence microscopy. Peritoneal metastases with label-free NUGC4 cells (black) and murine stromal cells (green) were imaged under TPLSM in vivo real-time. Fluorescence labeled-antibody could be visualized within tumor vessels of peritoneal metastases after its intravenous administration. Thereafter, label-free NUGC4 cells were identified by the binding of fluorescence labeled- anti-c-MET antibody to c-MET of NUGC4 cells. Conclusion: We could visualize fluorescence labeled-antibody in peritoneal metastases of gastric cancer in living mice using a TPLSM. The binding of fluorescence labeled- anti-c-MET antibody to c-MET of viable NUGC4 cells was clearly imaged at high magnification and high resolution in vivo real-time. It is valuable to develop a method of in vivo optical pathology for therapeutic monoclonal antibodies using MPM on metastatic tumor xenografts. Citation Format: Shozo Ide, Koji Tanaka, Tadanobu Shimura, Masato Okigami, Satoru Kondo, Takahito Kitajima, Hiroki Imaoka, Yoshinaga Okugawa, Susumu Saigusa, Yuji Toiyama, Hiromi Yasuda, Masaki Ohi, Yasuhiro Inoue, Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Masato Kusunoki. In vivo visualization using two-photon laser scanning microscopy of anti-c-MET antibody in peritoneal metastatic gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4938. doi:10.1158/1538-7445.AM2014-4938

Reappraisal of Mechanical Exfoliating Cytology for the Detection of Peritoneal Dissemination during the Surgical Staging of Epithelial Ovarian Carcinomas and Borderline Tumours

Objective: This study aimed to evaluate the usability of peritoneal swabbing cytology (PSC) with cotton swabs as an effective method for the detection of peritoneal metastasis during the staging laparotomy of epithelial ovarian carcinomas and borderline tumours (EOC/BT). Study Design: One hundred and ninety-two patients with EOC/BT who underwent laparotomy at the Yokohama City University Hospital from 2004 to 2010 were analysed retrospectively. The positive rates of the PSC and ascites/peritoneal-wash cytology (A/PWC) were compared. Results and Conclusion: Both A/PWC and PSC were performed during laparotomy (n = 140). The rate of metastasis detection with A/PWC was significantly higher than with PSC (50.0 vs. 20.7%, p < 0.001 by χ² test). The superior detection ability of A/PWC was observed regardless of the presence of macroscopic peritoneal metastasis in 56 cases with macroscopic peritoneal metastasis, with A/PWC detecting 80.3% of cases versus PSC detecting 37.5% (p = 0.013). In 84 cases without macroscopic peritoneal metastasis, A/PWC detected 29.8% of cases versus 9.5% with PSC (p = 0.003). Our results suggest that PSC is insufficient to evaluate the peritoneal metastasis for the surgical staging of EOC/BT. Other procedures such as subdiaphragmatic A/PWC should be included when possible to maximize the accuracy of diagnosis.

The incremental benefit of two quadrant lavage for peritoneal cytology at staging laparoscopy for oesophagogastric adenocarcinoma

Patients with positive peritoneal cytology from oesophagogastric cancer have a poor prognosis. The purpose of this study was to compare lavage cytology from the pelvis alone with the pelvis and subphrenic areas at staging laparoscopy in patients with potentially resectable oesophagogastric adenocarcinoma. Between November 2006 and November 2010, all patients with operable oesophagogastric adenocarcinoma on spiral CT considered fit for surgical resection underwent staging laparoscopy. Subphrenic and pelvic peritoneal lavage for cytology was performed followed by laparoscopic biopsy of any visible peritoneal disease. Patients were divided into groups: macroscopic peritoneal metastases (P+), no macroscopic peritoneal disease with negative cytology (P-C-), no macroscopic peritoneal disease with positive pelvic cytology (P-PC+), no macroscopic peritoneal disease with positive subphrenic cytology (P-SC+), or both (P-PSC+). A total of 316 staging laparoscopy procedures were performed; 245 patients (78 %) were P-C-, 28 (9 %) were P+, and 43 (14 %) were P-C+, of whom 29 (9 %) were P-PSC+, 10 (3 %) were P-SC+, and 4 (1 %) were P-PC+. Pelvic cytology alone had 76.7 % sensitivity for peritoneal disease, and subphrenic cytology alone had 90.7 % sensitivity. Peritoneal lavage for cytology at staging laparoscopy has an incremental benefit for staging oesophagogastric adenocarcinoma in the absence of macroscopic metastatic disease. Subphrenic washings have the highest yield of positive results. Performing isolated pelvic washings for cytology will understage 23.3 % of patients with microscopic peritoneal disease. The routine use of subphrenic in combination with pelvic lavage for cytology at staging laparoscopy in patients with oesophagogastric adenocarcinoma has an incremental benefit in detecting cytology-positive disease over either pelvic or subphrenic cytology alone.

A phase 2 trial of intravenous and intraperitoneal paclitaxel combined with S‐1 for treatment of gastric cancer with macroscopic peritoneal metastasis

The prognosis of patients with gastric cancer with peritoneal metastasis is extremely poor. This phase 2 study evaluated the benefits and tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) treatment combined with oral S-1 in patients with gastric cancer who had macroscopic peritoneal metastasis. Patients with gastric cancer who had primary tumors with macroscopic peritoneal metastasis were enrolled. PTX was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8, respectively. S-1 was administered at 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest. The primary endpoint was the 1-year overall survival (OS) rate. The secondary endpoints were the response rate, efficacy against malignant ascites, and safety. Thirty-five patients were enrolled. The median number of treatment courses was 11 (range, 2-35). The 1-year OS rate was 77.1% (95% confidence interval, 60.5-88.1). The overall response rate was 71% in 7 patients with target lesions. Malignant ascites disappeared or decreased in 15 of 22 (68%) patients. The frequent grade 3/4 toxic effects were neutropenia (34%), leukopenia (23%), and anemia (9%). Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 is well-tolerated and effective in patients with gastric cancer who have macroscopic peritoneal metastasis.

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenografts of gastric cancer using multiphoton microscopy.

e22205 Background: Peritoneal metastasis shows an extremely poor prognosis in patients with gastric cancer. Clinically, the tumor response to chemotherapeutics depends on anatomical location of metastasis. Metastatic tumor xenografts have been shown to be more resistant to chemotherapy than subcutaneous non-metastatic tumor xenografts in preclinical murine model. We have reported a method of in vivo optical pathology using multiphoton microscopy (MPM) in colorectal liver metastatic tumor xenograft model. Aim: We established a method of time-series in vivo optical pathology of peritoneal metastatic xenografts of gastric cancer using MPM. Then, we imaged and evaluated paclitaxel efficacy in the tumor microenvironment with regard to both tumor cell itself and intravascular change in tumor vessels. Methods: Red fluorescent protein (RFP) expressing human gastric cancer cell line (NUGC4) was inoculated into the peritoneal cavity of green fluorescent protein (GFP) expressing nude mice. Paclitaxel (10 mg/kg) was administered three times a week for more than three weeks. Intravital MPM was performed before and after paclitaxel treatment for the exteriorized peritoneal metastatic lesion in the same living mouse. Results: Four to six weeks later, RFP-NUGC4 cells formed macroscopic peritoneal metastases. Red-colored cancer cells and green-colored surrounding stroma with tumor vessels were clearly imaged at the cellular level (in vivooptical pathology). Their cross-sectional images were obtained from the tissue surface to the area of depth of 200 μm (z-stacks imaging). After paclitaxel treatment, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed. Within the tumor vessels, platelet aggregation and platelet adhesion to endothelial cells were observed. Conclusions: In vivo optical pathology using MPM provides histopathological information about three-dimensional tissue microarchitecture without tissue shrinkage by fixation and tissue destruction by microtome-sectioning. Our method may become a powerful tool to evaluate the tumor response to new chemotherapeutics on ‘metastatic site’ in preclinical tumor xenograft model.