Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials

Abstract

Introduction

An important component of treatment failure in gastric cancer (GC) is cancer dissemination within the peritoneal cavity and nodal metastasis. Intraperitoneal chemotherapy (IPC) is considered to give a fundamental contribute in treating advanced GC. The purpose of the study is to investigate the effects of IPC in patients with advanced GC.

Material and methods

A systematic review with meta-analysis of randomized controlled trials (RCTs) of IPC + surgery vs. control in patients with advanced GC was performed.

Results

Twenty prospective RCTs have been included (2145 patients: 1152 into surgery + IPC arm and 993 into control arm). Surgery + IPC improves: 1, 2 and 3-year mortality (OR = 0.31, 0.27, 0.29 respectively), 2 and 3-year mortality in patients with loco-regional nodal metastasis (OR = 0.28, 0.16 respectively), 1 and 2-year mortality rate in patients with serosal infiltration (OR = 0.33, 0.27 respectively). Morbidity rate was increased by surgery + IPC (OR = 1.82). The overall recurrence and the peritoneal recurrence rates were improved by surgery + IPC (OR = 0.46 and 0.47 respectively). There was no statistically significant difference in lymph-nodal recurrence rate. The rate of haematogenous metastasis was improved by surgery + IPC (OR = 0.63).

Conclusions

1, 2 and 3-year overall survival is incremented by the IPC. No differences have been found at 5-year in overall survival rate. 2 and 3-year mortality rates in patients with nodal invasion and 1 and 2-year mortality rates in patients with serosal infiltration are improved by the use of IPC. IPC has positive effect on peritoneal recurrence and distant metastasis. Morbidity rate is incremented by IPC. Loco-regional lymph-nodes invasion in patients affected by advanced gastric cancer is not a contraindication to IPC.

Introduction

Gastric cancer (GC) is the second leading cause of cancer death and the fourth most common cancer in the world.1, 2 GC disseminates principally through the haematic torrent or through the peritoneal fluids. It has been demonstrated as peritoneal dissemination is more frequent than haematogenous metastases. The 40% of patients died for GC have hepatic metastases, while the 53–60% showed a disease progression and died with peritoneal carcinosis (PC). The two most important factors affecting prognosis in GC are the serosal invasion and the lymphatic spread.3, 4, 5 When gastric serosa is infiltrated, PC could be considered practically unavoidable.⁶ As a consequence, up to half of the patients with advanced GC will develop PC in spite even radical surgery.8, 9, 10, 11 PC is already present in 5–20% of patients explored for potentially curative resection also in early gastric cancer.6, 7 Surgical resection associated to systemic chemotherapy is the mainstay of treatment. Systemic chemotherapy improves median survival in advanced and/or metastatic GC to not more than 12 months.12, 13, 14, 15 The same gain in term of survival has not been described with macroscopic PC16, 17, 18, 19 due to the inadequate diffusion of systemic chemotherapy into the abdominal cavity.²⁰

As many patients present with advanced-stage-disease, the research for more effective treatments is mandatory. An important component of treatment failure is cancer dissemination within the peritoneal cavity and nodal metastasis. In contrast to lymphatic and haematogenous dissemination, peritoneal spread should be regarded as a loco-regional disease extension rather than systemic metastasis.²¹ Taking the natural history of GC into account, the use of intraperitoneal chemotherapy (IPC) as a targeted adjuvant treatment after surgery may be considered a rational prophylactic/therapeutic approach. Actually IPC has been progressively more used in advanced GC due to the appealing theoretical rationales. Although many different regimens of IPC exist, they all could be considered as the different applications of the same treatment method. IPC allows to reach an high intraperitoneal drug concentration and allows the drugs to directly act on the free-tumour-cells and peritoneal nodules. Drugs absorbed through the peritoneum enter the portal vein, and also have a chemotherapeutic effect on the liver.²² It remains controversial if the IPC has a positive effect on the lymph-node metastasis. The purpose of the present meta-analysis of randomized controlled trials (RCT) investigating the effects of IPC in patients with advanced GC.