Hironori Ishigami

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BACKGROUND A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Prospective Randomized Trial Comparing Billroth I and Roux-en-Y Procedures after Distal Gastrectomy for Gastric Carcinoma

To determine the clinical efficacy of Roux-en-Y reconstruction (RY) after distal gastrectomy, we compared postoperative outcomes of patients who underwent RY or conventional Billroth I reconstruction (B-I). A total of 50 patients were prospectively randomized to either B-I or RY reconstruction, and complications, postoperative course, and nutritional status were compared. Bile reflux and inflammation in the remnant stomach and lower esophagus were evaluated by postoperative follow-up endoscopy at 6 months. Operative time and blood loss as well as postoperative nutrition did not show significant differences between the two groups. As anticipated, 5 of 24 patients with RY reconstruction developed gastrojejunal stasis in the early postoperative period, which led to a longer postoperative hospital stay as compared with the B-I group (mean ± S.D; B-I; 19.0 ± 6.2, RY; 31.8 ± 21.7 days) (P < 0.05). Endoscopic examination revealed that the frequency of bile reflux (P < 0.01) and degree of inflammation in the remnant stomach (P < 0.05) were less in the RY group than in the B-I group. However, inflammatory findings in the lower esophagus were observed in 7 (27%) of B-I, and 8 (35%) of the RY group, suggesting that late phase esophagitis was not improved in the RY group. Roux-en-Y reconstruction was effective in preventing duodenogastric reflux and resulting gastritis, but it did not prevent esophagitis. Because RY reconstruction induces the frequent complication of Roux-en-Y stasis, causing longer postoperative hospital stay, this method has limited advantages over B-I anastomosis after distal gastrectomy.

Genetic Alterations in Ulcerative Colitis-associated Neoplasia Focusing on APC, K-ras Gene and Microsatellite Instability

The status of genetic alterations in ulcerative colitis (UC)‐associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is seen in a certain fraction of colorectal carcinomas, and adenomatous polyposis coli (APC) gene and K‐ras gene, in which mutations occur in the early stage of sporadic colorectal tumorigenesis. Thirty‐one UCAN from 15 UC patients who had undergone colorectal resection at our institution were investigated. There were 8 lesions of invasive carcinoma, 15 high‐grade dysplasia (HGD) and 8 low‐grade dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding non‐neoplastic tissue by a microdissection method. MSI status at 9 microsatellite loci, loss of heterozygosity (LOH) at the APC locus, and K‐ras codon 12 point mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD: 2/15 (13%), LGD: 1/8 (13%)) were MSI‐high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinoma: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI‐low (1 or 2 unstable loci). LOH at the APC locus was not found in 9 UCAN from 6 informative (heterozygous) cases. The K‐ras mutation rate of UCAN was 3/31 (9.7%) (carcinoma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8). MSI is relatively common in UCAN and is present at the early stage of tumorigenesis of UCAN, while the involvement of genetic alterations of the APC gene and K‐ras gene is small. MSI may be one of the mechanisms of the increased neoplastic risk in UC, and UCAN may develop through a different carcinogenic pathway from sporadic carcinomas.

Phase I Pharmacokinetic Study of Weekly Intravenous and Intraperitoneal Paclitaxel Combined with S-1 for Advanced Gastric Cancer

Objectives: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Patients and Methods: Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m2, and intraperitoneally with an initial dose of 20 mg/m2, stepped up to 30 or 40 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. Results: The MTD was determined to be 30 mg/m2, as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m2. The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. Conclusions: Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials.

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.

Diagnostic Primer Sets for Microsatellite Instability Optimized for a Minimal Amount of Damaged DNA From Colorectal Tissue Samples

Background: The diagnosis of microsatellite instability from a minimal amount of highly damaged DNA, extracted from formalin-fixed, paraffin-embedded tissue by the microdissection method, is difficult. Therefore, optimized primer sets were newly designed for substitution of documented ones.Methods: DNA was extracted from 15 archival colorectal carcinomas and used as templates for polymerase chain reaction. Nine standard microsatellite markers (BAT-25, BAT-26, BAT-40, D18S69, D2S123, D5S346, D10S197, D17S250, and D18S58) were selected for diagnosis of microsatellite instability in colorectal carcinomas. All polymerase chain reaction conditions for primer sets were unified to save experimental time.Results: The primer sets for the latter five markers documented in the literature were redesigned because of poor efficiency for damaged DNA. As a result, the number of DNA samples, sufficiently amplified at all markers, improved from 0% to 93%.Conclusions: Diagnostic primer sets for microsatellite instability, optimized for a minimal amount of damaged DNA from colorectal tissue samples, were established.

Intraperitoneal administration of paclitaxel solubilized with poly(2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) for peritoneal dissemination of gastric cancer

Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX‐30W), which was prepared by solubulization with water‐soluble amphiphilic polymer composed of PMB‐30W, a co‐polymer of 2‐methacryloxyethyl phosphorylcholineand n‐butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effct of i.p. administration of PTX‐30W was compared with conventional PTX dissolved in Cremophor EL (PTX‐Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX‐30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX‐Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX‐30W than in the PTX‐Cre group up to 24 h after i.p. injection. Oregon green–conjugated PTX‐30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX‐Cre. I.p. administration of PTX‐30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions. (Cancer Sci 2009; 100: 1979–1985)

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)

Different Tissue Distribution of Paclitaxel With Intravenous and Intraperitoneal Administration

PURPOSE Paclitaxel is considered to be suitable for disseminated cancer in the peritoneal cavity because of its high molecular weight and lipophilic characteristics. However, the difference in pharmacokinetics of paclitaxel after intraperitoneal (i.p.) and intravenous (i.v.) administration is not fully defined. Here, we investigated the tissue concentration of paclitaxel in various organs at various time points after i.p. or i.v. administration. METHODS Paclitaxel (5 mg/kg) was administrated in an ear vein or in the abdominal cavity of rabbits. At 0.5, 6, 24, and 48 h after administration, the rabbits were sacrificed, and organs as well as peripheral blood were harvested. The serum and tissue concentrations of paclitaxel were measured by HPLC procedure. RESULT The concentration of paclitaxel was high in the i.v. group at 0.5 h, whereas it was significantly higher in the i.p. group at 6 and 24 h. The AUC (area under the curve) was markedly higher in the omentum, mesenteric lymph nodes as well as ovary and stomach in the i.p. group. CONCLUSION Compared with i.v. administration, paclitaxel concentration was maintained at a high level in the whole body by i.p. administration. Repeated i.p. paclitaxel can produce more marked clinical effects than i.v. administration for metastatic lymph nodes and primary lesions as well as peritoneal dissemination.

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)