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

Abstract

BACKGROUND: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. METHODS: Patients with gastric cancer who had primary tumors with macroscopic peritoneal metastasis were enrolled. PTX was administered intravenously at 50 mg/m 2 and intraperitoneally at 20 mg/m 2 on days 1 and 8, respectively. S-1 was administered at 80 mg/m 2 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. RESULTS: 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%). CONCLUSIONS: 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. Cancer 2013;119:3354-8. V C 2013 American Cancer Society.KEYWORDS: phase 2 study; paclitaxel; S-1; gastric cancer; peritoneal metastasis; intraperitoneal chemotherapy. INTRODUCTIONGastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related deaths. 1 Multimodal therapy combined with systemic chemotherapy, radiation therapy, and surgery has been developed in the treatment of advanced gastric cancer. 2 Even for noncurable gastric cancer, many clinical trials have been conducted using various newly developed anticancer drugs. In a phase 3 study using docetaxel (DTX), cisplatin, and fluorouracil for recurrent or metastatic gastric cancer patients, the 1-year overall survival (OS) rate and median survival time (MST) were 40% and 9.2 months, respectively. 3 In another phase 3 study using S-1 and cisplatin for unresectable or recurrent gastric cancer, the 1-year OS rate and MST were 54.1% and 13.0 months, respectively. 4 Among patients with noncurable gastric cancer, the prognosis of patients with peritoneal metastasis is extremely poor, 5 and no standard treatment for peritoneal metastasis has been established.One potential treatment approach is the introduction of paclitaxel (PTX), which has been shown to produce a high response rate (29%-36%) for undifferentiated-type adenocarcinoma 6,7 and can be expected to show high efficacy for peritoneal dissemination. The intraperitoneal (IP) administration of PTX was developed to reinforce the drug's effect on peritoneal metastasis. This would be accomplished by making the drug act directly on the nodules at a high concentration. In ...

Conversion therapy for pancreatic cancer with peritoneal metastases using intravenous and intraperitoneal paclitaxel with S-1

“…Additionally, S-1 is one of the oral 5-FU agents that were found to be non-inferior to gemcitabine in terms of overall survival in East-Asian patients with metastatic pancreatic cancer (3). Yamaguchi et al reported that IV and IP PTX with S-1 was well tolerated and highly effective against peritoneal metastases from gastric cancer (5), and the MPACT trial demonstrated that PTX was effective in metastatic pancreatic cancer (4). In fact, IV and IP PTX with S-1 recently exhibited promising results in gemcitabine-refractory pancreatic cancer (6).…”

“…S-1, an oral 5-fluorouracil (5-FU) derivative and paclitaxel (PTX) have been proven to be effective in the treatment of metastatic pancreatic cancer (3,4). Combination chemotherapy consisting of intravenous (IV) and intraperitoneal (IP) PTX with S-1 was well-tolerated and achieved promising results against peritoneal metastases from gastric and pancreatic cancer (5,6). However, to the best of our knowledge, a conversion of an unresectable pancreatic cancer with peritoneal metastases to a resectable one by this combination chemotherapy has not yet been reported.…”

Preoperative intraperitoneal oxaliplatin for unresectable peritoneal carcinomatosis of colorectal origin: a pilot study

“…Grade histological response of peritoneal cytology or small PC, to offer conversion to resectability of the selected patients but also to improve overall survival in patients with an initial PCI ≥ 20 [23].…”

“…Intraperitoneal regimens are administered in the adjuvant setting for ovarian cancer [12,13] and in the neoadjuvant setting for gastric cancer [14][15][16][17][18][19][20][21][22][23][24][25]. A similar evolution of peritoneal and hepatic metastases of colorectal origin was shown recently by a French group [26] but, while multiple non-optimally resectable hepatic metastases benefit from a local chemotherapy using an hepatic arterial infusion, no similar approach was proposed for PC.…”

Optimal drug delivery for intraperitoneal paclitaxel (PTX) in murine model

“…Thus, taxanes, such as paclitaxel (PTX) or docetaxel (DOC), are supposed to be ideal drugs for IP chemotherapy because of high local concentrations over a long period of time due to their hydrophobic properties [10]. In fact, we and others have recently shown that IP administration of PTX or DOC can exhibit remarkable effects against PM from gastric cancer (GC) [11][12][13][14]. However, the underlying mechanism to explain the marked shrinkage of PM is still unknown.…”