Feasibility Study of Intraperitoneal Docetaxel Combined With Intravenous Cisplatin and Oral TS-ONE for Gastric Cancer Patients With Peritoneal Carcinomatosis

Peritoneal carcinomatosis (PC) is common in advanced gastric cancer, and it carries a poor prognosis; the median survival time is 3 to 6 months. Gastric cancer with PC is considered incurable and patients are subjected to non-surgical treatment, mainly chemotherapy. Currently, there is no established standard treatment for these patients.

Multidisciplinary approach to the treatment of gastric cancer including chemotherapy, radiotherapy and surgery has been developed and survival benefit has been demonstrated in the adjuvant setting. Novel chemotherapeutic agents: taxanes (paclitaxel and docetaxel), irinotecan, oxaliplatin, fluoropyrimidine (TS-ONE and capecitabine) have shown activity in gastric cancer. Various combination chemotherapy regimens for unresectable and metastatic gastric cancer are practised in different parts of the world. Epirubicin, cisplatin and 5-fluorouracil (ECF) are used in Europe, while TS-ONE and cisplatin are commonly used in Asian countries such as Japan and Korea. The median survival time (MST) with these regimens was 8.9 and 13 months, respectively. Use of docetaxel, cisplatin and 5-fluorouracil (DCF) was proposed in the V325 study, MST was 9.2 months but the toxicity (grade 3-4 neutropenia) was reported to be significantly higher in DCF group when compared with CF group. However, there are few trials to study the specific efficacy of these regimens on PC.

Systemic chemotherapy is considered to be less effective against PC due to the existence of the blood-peritoneal barrier (BPB). The barrier inhibits the movement of drugs from systemic circulation to the peritoneal cavity. Intraperitoneal (IP) chemotherapy has the advantage of maintaining a high drug concentration in the peritoneal cavity, and reduces the systemic toxicity. Paclitaxel and docetaxel have been shown to have high peritoneal concentration in animal studies and are considered ideal drugs for IP administration.

Neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) is a new bidirectional induction chemotherapy for treatment of PC from gastric cancer. The aim of NIPS is to induce a reduction of PC volume. Bidirectional means that NIPS could attack PC from both the peritoneal cavity and the subperitoneal blood vessels. Patients with good response to NIPS may undergo subsequent gastrectomy. The use of TS-ONE and IP taxane (paclitaxel/docetaxel) had been studied in phase I and II trials. Ischigami et al. reported 1-year survival rate of 78% and overall response rate of 56% using weekly intravenous and IP paclitaxel combined with TS-ONE. Fujiwara et al. reported 78% patients had negative peritoneal cytology after NIPS and 16 out of 18 patients (88.9%) underwent subsequent gastrectomy, with a MST of 24.6 months. No treatment-related mortality has been reported.

Systemic DCF is associated with significant toxicity, yet it is superior to CF alone in terms of survival (9.2 months vs. 8.6 months, p<0.02). Grade III/IV neutropenia was reported to be 82%. It is postulated that switching from intravenous docetaxel to IP docetaxel may improve its efficacy against PC and reduce the systemic toxicity. TS-ONE contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo). Dihydropyrimidine dehydrogenase (DPD), which is found in liver, rapidly degrades 5-FU. The presence of CDHP, a specific inhibitor of DPD, allows a high intraperitoneal drug concentration after oral administration of TS-ONE that has been demonstrated in an experimental model.