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

Abstract

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 μg/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 μg•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.

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

“…In contrast, docetaxel has a pharmacokinetic advantage of two logs associated with its intraperitoneal delivery, and the systemic AUC after intraperitoneal administration is 2 times greater than that after standard intravenous administration [44,45]. These data indicate that docetaxel occupies a position between cisplatin and paclitaxel from the pharmacokinetic viewpoint (Figure 1).…”

“…Peritoneal metastasis is considered to be a non-measurable lesion because it is difficult to detect peritoneal metastasis by conventional radiological examinations. New response criteria for treatment against peritoneal metastasis were developed according to the findings of intraperitoneal photographs which were taken in the first and second laparoscopy [45]. In the phase II study to evaluate efficacy of S-1 plus IP docetaxel [74], the second staging laparoscopy after 2 cycles of combined chemotherapy showed response rate of 52% according to the response criteria for the treat-ment of peritoneal metastasis.…”

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes

“…The area under the curve ratios of the intra-abdominal space to the plasma after IP administration of the drug are about 1000 for PTX, 207-552 for DOC, 10-24 for MMC, and 12-21 for CDDP [23][24][25][26][27][28] . The prolonged retention of IP administered taxanes within the IP space allows the taxanes to directly penetrate into peritoneal disseminated tumors [23,[29][30][31] , which leads to the destruction of peripheral microvessels of tumor nodules [32] .…”

The Importance of Controlling the TGF-β Signaling Pathway in the Gastric Cancer Microenvironment

“…Peritoneal dissemination is a critical indicator of poor prognosis and represents the most frequent metastatic pattern in gastric cancer [2]. Although clinical outcomes for patients with gastric cancer with peritoneal dissemination have improved with advances in systemic or intraperitoneal chemotherapy, or both, acceptable outcomes have not been achieved [3][4][5][6]. Peritoneal dissemination is characterized by the infiltration of cancer cells, and their proliferation is accompanied by extensive stromal fibrosis [7].…”