Peritoneal Carcinomatosis Of Gastric Cancer Research Articles

Dual anti-cancer effects of weekly intraperitoneal docetaxel in treatment of advanced gastric cancer patients with peritoneal carcinomatosis: A feasibility and pharmacokinetic study

This study evaluated the feasibility and pharmacology of intraperitoneal docetaxel (IP docetaxel) when administered weekly for 3 consecutive weeks, followed by 1 week without treatment. A total of 24 patients with peritoneal carcinomatosis of gastric cancer (10 preoperative, 7 postoperative and 7 recurrent) were enrolled in this study. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and was administered in a 1 h dosage of 25, 35, 45 and 60 mg/m(2) to determine the maximum tolerated dose (MTD). To measure the docetaxel concentration, blood and peritoneal fluid samples were collected 0.5, 1, 2, 3, 6 and 24 h after administering the drug to 15 patients. A total of 109 chemotherapy cycles were administered, with a median of four cycles per patient (range 2-9). The MTD of the weekly IP docetaxel was defined at 60 mg/m(2). At a docetaxel dosage of 60 mg/m(2) per week, the dose-limiting events of grade 3 abdominal pain and grade 3 diarrhea, which may be associated with local toxicity, occurred. Peak concentrations of peritoneal fluid ranged from 24.5 to 68.7 microg/ml. The mean ratio of the area under concentration (AUC) in the peritoneal fluid to the plasma concentration was 515. Furthermore, the mean of plasma AUC by IP docetaxel was 5.63 microg h/ml versus that of IV docetaxel at a dose of 60 mg/m(2). The response rate of the preoperative IP docetaxel was 80% (4 CR, 4 PR, 1 NC and 1 PD), which was judged with laparoscopy and peritoneal lavage cytology. Gastrectomy, with D2 lymph node dissection, was performed on all of the patients evaluated as CR. The weekly IP docetaxel demonstrated a low toxicity and high efficacy for peritoneal carcinomatosis with dual anti-cancer effects via the peritoneal surface and capillary blood supply due to its unique pharmacokinetic property.

Chemokine receptors in cancer metastasis and cancer cell‐derived chemokines in host immune response

The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples.

Role of the CXCL12/CXCR4 Axis in Peritoneal Carcinomatosis of Gastric Cancer

Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P < 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.

Combined Cytoreductive Surgery and Early Postoperative Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Gastric Cancer.

Peritoneal seeding is the most common type of metastasis or recurrence and one of the poor prognostic factors in gastric cancer. Moreover, there are as yet no effective treatment modalities available. Recently some research groups suggested the benefit of combined cytoreductive surgery and intraperitoneal chemotherapy, but the related experiments remain in the trial stage. Therefore, we assessed the safety and evaluated the efficacy of combined cytoreductive surgery and early postoperative intraperitoneal chemotherapy (EPIC) in gastric cancer patients with peritoneal carcinomatosis of gastric cancer. From Nov. 1997 to May. 2002, eighteen cases of combined cytoreduction and EPIC were performed in the Korea Cancer Center Hospital due to gastric cancer with peritoneal carcinomatosis. The control group consisted of 33 patients who had no resection without EPIC during the same periods. After combined cytoreductive surgery and EPIC, all patients received systemic chemotheraphy with the exception of 2 patients who could not tolerate the treatment. We retrospectively investigated the clinicopathologic features and analyzed the factors affecting the prognosis. Median follow-up period was 11.9 months (range 0.5~61 months). Statistical analysis was performed by SPSS 11.0 for Windows. A P-value less than 0.05 was considered as statistically significant. There was one case of the treatment-related mortality (5.5%) and seven cases of treatment-related complications (38%) in the combined cytoreductive surgery and intraperitoneal chemotherapy group. One-, 3- and 5-year survival rates of cytoreductive surgery plus EPIC were 57.6%, 25.9% and 13.0%, respectively, and those of the control group were 18.2%, 3% and 0%, respectively. Survival of the combined cytoreductive surgery plus EPIC group was better than that of the control group (p=0.0026). In multivariate analysis of prognostic factors affecting the survival, combined cytoreductive surgery plus EPIC (p=0.02) and systemic chemotherapy (p=0.019) were independent prognostic factors. Although a small number of cases were included in this study, combined cytoreductive surgery plus EPIC showed survival benefit and retained a comparable complication rate compared with the control group.