Shigenobu Emoto

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.

Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2‐methacryloxyethyl phosphorylcholine‐co n‐butyl methacrylate) in peritoneal metastatic nodules

Intraperitoneal (i.p.) administration of paclitaxel nanoparticles (PTX‐30W) prepared by solubulization with the amphiphilic copolymer of 2‐methacryloxyethyl phosphorylcholine and n‐butyl methacrylate can efficiently suppress the growth of peritoneal metastasis. In this study, we characterized the drug distribution of i.p. injected PTX‐30W in peritoneal tumor and liver in a mouse model using MKN45, human gastric cancer cells. Oregon green‐conjugated PTX‐30W showed perivascular accumulation in MKN45 tumor in the peritoneum at 24 h after intravenous (i.v.) injection; however, the amount of PTX in tumor was markedly less than that in liver. In contrast, a larger amount of PTX accumulated in the peripheral area of disseminated nodules at 1 h after i.p. injection and the area gradually enlarged. The depth of PTX infiltration reached 1 mm from the tumor surface at 48 h after i.p. injection, and the fluorescence intensity was markedly greater than that in liver. Interestingly, i.p. injected PTX preferentially accumulated in relatively hypovascular areas, and many tumor cells in the vicinity of PTX accumulation showed apoptosis. This unique accumulation pattern and lesser washout in hypovascular areas are thought to be attributable to the superior penetrating activity of PTX‐30W, and thus, PTX‐30W is considered to be highly suitable for i.p. chemotherapy for peritoneal dissemination. (Cancer Sci 2011; 102: 200–205)

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel‐incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX‐Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX‐Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX‐Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX‐Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX‐Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX‐Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX‐Cre group (24 100 ± 3560 vs 108 ± 25 ng/mL, respectively; P < 0.001), as was the area under the concentration–time curve from 0 to 48 h (191 000 ± 32 100 vs 1500 ± 108 ng·h/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation. (Cancer Sci 2012; 103: 1304–1310)

Phase I Study of Biweekly Intravenous Paclitaxel plus Intraperitoneal Cisplatin and Paclitaxel for Gastric Cancer with Peritoneal Metastasis

Objectives: A phase I study of biweekly intravenous (IV) paclitaxel (PTX) plus intraperitoneal (IP) cisplatin (CDDP) and PTX was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Methods: Nine gastric cancer patients with peritoneal metastasis were enrolled. PTX was administered intravenously at a dose of 100 mg/m2 and intraperitoneally with an initial dose of 20 mg/m2 (level 1), stepped up to 30 or 40 mg/m2 depending on observed toxicity. CDDP was administered intraperitoneally at a dose of 30 mg/m2 over 24 h. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. Results: The MTD was determined to be dose level 1, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 leukopenia and grade 3 vomiting. Therefore, the doses of IV PTX, IP CDDP and IP PTX were reduced to 80, 25 and 20 mg/m2, respectively (level 0). Consequently, the RD was determined to be dose level 0, as only 1 of 6 patients experienced DLT, grade 3 nausea. Conclusions: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials.

CD90(+) Mesothelial-Like Cells in Peritoneal Fluid Promote Peritoneal Metastasis by Forming a Tumor Permissive Microenvironment

The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(−) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, α-smooth muscle actin and fibroblast activated protein-α by the stimulation with TGF-β, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.

CD90(+)CD45(-) intraperitoneal mesothelial-like cells inhibit T cell activation by production of arginase I.

In this study, we analyzed intraperitoneal cells recovered from human samples and found that CD90(+)CD45(-) cells exist as a minor population but vigorously grow in culture, showing the morphological features of mesothelial cells (MC). Interestingly, the MC highly expressed arginase I and markedly suppressed T cell proliferation with the reduction of CD3 ζ chain expression in T cells stimulated by coated anti-CD3 mAb. The addition of nor-NOHA (500 μM), or L-arginine (1 mM) mostly restored the inhibitory effect of MC on T cell proliferation as well as the reduced expression of CD3 ζ chain. The expression level of CD3 ζ chain in T cells in the peritoneal cavity was significantly down-regulated from circulating T cells. These results suggest that intraperitoneal free MC have immunomodulatory functions through the control of L-arginine level, and thus may play significant roles in the pathogenesis of various diseases in the peritoneal cavity.

Production of Cisplatin-Incorporating Hyaluronan Nanogels via Chelating Ligand-Metal Coordination.

Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand-metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or malonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand-platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.

Complications and Management of an Implanted Intraperitoneal Access Port System for Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Metastasis

OBJECTIVE The efficacy of intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis has been verified by clinical trials. To perform intraperitoneal chemotherapy safely and effectively, the appropriate management of intraperitoneal access ports is essential. The aim of this study was to investigate the occurrence of port complications during cyclically repeated intraperitoneal chemotherapy. METHODS The medical records of 131 gastric cancer patients with peritoneal metastases who received intraperitoneal paclitaxel between 2005 and 2011 were retrospectively analyzed. RESULTS The median period of intraperitoneal chemotherapy using a port system was 12.9 months (range: 0.8-61.5 months), and a total of 27 (20.6%) patients experienced port complications. Inflow obstruction (7.6%) and infection (6.9%) were the main complications, followed by reflux (3.1%), subcutaneous masses (1.5%) and fistulae (1.5%). The median interval between port implantation and port complication was 5.4 months (range: 0.3-40.9 months). Complications were controllable and chemotherapy was not terminated by complications. Survival was not affected by the presence or absence of port complications (median survival time: 22.5 vs. 17.2 months, respectively; P=0.65). CONCLUSIONS Intraperitoneal chemotherapy for gastric cancer using a port is safe and feasible under appropriate management.

Cell-free and concentrated ascites reinfusion therapy (CART) for management of massive malignant ascites in gastric cancer patients with peritoneal metastasis treated with intravenous and intraperitoneal paclitaxel with oral S-1

BACKGROUND Massive malignant ascites originating from peritoneal metastasis of gastric cancer is difficult to control and resistant to chemotherapy. Cell-free and Concentrated Ascites Reinfusion Therapy (CART) is one of the types of apheresis therapy, by which filtered and concentrated ascites containing albumin and globulin is reinfused intravenously to patients. We retrospectively studied the feasibility of intraperitoneal (IP) chemotherapy combined with CART in gastric cancer patients with massive malignant ascites. METHODS Paclitaxel (PTX) was administered via an IP access port implanted in the subcutaneous space. If patient had massive ascites at the start of treatment, paracentesis was performed through a percutaneous IP catheter and then CART was performed. PTX was administered through the catheter until the ascites diminished. RESULTS A total of 127 CART procedures in 30 patients were analyzed. The average volume of processed ascites was 3.1 L, which was concentrated to 0.33 L containing 85.5 g protein on average. Significant increases in urine volume, serum total protein and albumin level were found after the CART. Increase in body temperature (0.3°C), decrease in platelet count (3.8 × 10(4)/μl), and changes in blood pressure (2 mm Hg) were found after the CART procedure, but no clinically significant adverse event was experienced. The median survival time and 1-year survival of 30 patients who received IP chemotherapy combined with the CART procedure was 10.2 months and 43.3% respectively. CONCLUSIONS IP chemotherapy combined with CART might be a promising strategy for patients with massive malignant ascites originating from peritoneal metastasis of gastric cancer.

Flow cytometric quantification of intraperitoneal free tumor cells in patients with peritoneal metastasis.

Peritoneal metastasis (PM) is the most life‐threatening type of metastasis in abdominal malignancy. To improve the diagnostic accuracy of cytologic detection (CY) of free tumor cells (FTC) in the peritoneal cavity, we tried to quantify the FTC to leukocyte ratio using flow cytometry in patients with peritoneal metastasis.