Introduction

Although the incidence of gastric cancer decreased during the past years, it is still the fourth most common newly diagnosed cancer worldwide and the second leading cause of cancer-related death. Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression, or disease recurrence in patients with gastric cancer. It might be already present in 5% to 20% of patients undergoing gastric resection in curative intent. In a retrospective analysis of 1172 patients with gastric cancer after R0 resection, the peritoneal recurrence rate was 29%. In this study, the median time from recurrence at any location to death was 6 months. Sasako and colleagues demonstrated the peritoneum to be the most frequent first site of recurrence (38.1%) during a 5-year follow-up period after curative resection of gastric cancer. This tumor manifestation is mostly associated with poor prognosis. The multicentric prospective evolution of peritoneal carcinomatosis (EVOCAPE) 1 study reported a mean and a median overall survival for the natural course of the disease of 6.5 and 3.1 months, respectively. The mean age of the 125 included patients was 60.5 years (range 21–96 years). Most of the patients showed advanced T stage of the primary tumor (55 pT3, 62 pT4), 73 patients were diagnosed with synchronous peritoneal carcinomatosis (58.4%), and 19 patients had additional liver metastases (15.2%). Despite the significant improvement in survival of patients with advanced gastric cancer during the past 20 years with the use of palliative systemic polychemotherapy, the results remain unsatisfactory. Considering that patients with inoperable and/or locally advanced gastric cancer with or without distant and peritoneal metastases have been included, clinical trials with modern systemic chemotherapy show median survival rates ranging from 9 to 14 months. Data for patients in the appropriate clinical condition with peritoneal metastasis only are not available. However, combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as an inherent part of an interdisciplinary treatment concept might be a promising additional treatment option for a highly selected part of patients with limited peritoneal carcinomatosis arising from gastric cancer.

Pathophysiology

In contrast to hematologic or lymphatic metastasis, peritoneal carcinomatosis is mostly caused by continuous tumor growth or tumor cell dissemination. Ikeguchi and colleagues could demonstrate a strong correlation between the area of serosal invasion and the number of detectable free abdominal tumor cells. The first step in the development of peritoneal metastasis is the detachment of single tumor cells from the primary carcinoma. Based on fast tumor growth, lack of lymphatic drainage, and other mechanisms, these cells reach the abdominal cavity and are disseminated with the peritoneal fluid. Direct cell-to-cell contact via adhesion molecules such as intracellular adhesion molecule 1 and CD44 leads to binding to mesothelial cells with consecutive induction of apoptosis and breaking of their intercellular junctions. By reaching the extracellular matrix, the tumor cells bind integrins and cause degradation, leading to an invasion of submesothelial cell layers. Moreover, free tumor cells can directly bind to specific structures of the extracellular matrix or the greater omentum and cause tumor infiltration.

Pathophysiology

In contrast to hematologic or lymphatic metastasis, peritoneal carcinomatosis is mostly caused by continuous tumor growth or tumor cell dissemination. Ikeguchi and colleagues could demonstrate a strong correlation between the area of serosal invasion and the number of detectable free abdominal tumor cells. The first step in the development of peritoneal metastasis is the detachment of single tumor cells from the primary carcinoma. Based on fast tumor growth, lack of lymphatic drainage, and other mechanisms, these cells reach the abdominal cavity and are disseminated with the peritoneal fluid. Direct cell-to-cell contact via adhesion molecules such as intracellular adhesion molecule 1 and CD44 leads to binding to mesothelial cells with consecutive induction of apoptosis and breaking of their intercellular junctions. By reaching the extracellular matrix, the tumor cells bind integrins and cause degradation, leading to an invasion of submesothelial cell layers. Moreover, free tumor cells can directly bind to specific structures of the extracellular matrix or the greater omentum and cause tumor infiltration.

Clinical presentation

In most cases, peritoneal carcinomatosis is oligosymptomatic or asymptomatic during a long period and therefore often initially diagnosed intraoperatively. The development of malignant ascites might be the first specific sign of progressive peritoneal tumor dissemination. Moreover, patients with peritoneal carcinomatosis may develop abdominal pain, stenosis of canalicular structures, and paralytic or mechanic ileus. These complications may be accompanied by general symptoms of malignant diseases such as deterioration of general condition, weight loss, and fever ( Box 1 ).

Therapeutic options and surgical technique

It is beyond question that the treatment of patients with advanced or recurrent gastric cancer is the domain of palliative systemic chemotherapy. Wagner and colleagues showed in a meta-analysis of several randomized clinical trials that compared chemotherapy with best supportive care a significant overall survival benefit in favor of systemic chemotherapy and combined chemotherapy, respectively. Two prospective randomized trials using epirubin, cisplatin, fluorouracil (ECF) demonstrated a median survival of 8.9 and 9.4 months, respectively. Comparable results with a median survival of 9.2 months were achieved in a randomized controlled trial using docetaxel, cisplatin, fluorouracil (DCF). Cunningham and colleagues reported a median survival of 11.2 months in a group of patients treated with EOX (epirubin, oxaliplatin, capecitabine [xeloda]) in the prospective randomized multicentric Phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer (REAL-2) trial. The addition of the anti-HER2 monoclonal antibody trastuzumab to a chemotherapeutic regimen consisting of cisplatin and 5-fluorouracil or capecitabine led to an improved overall median survival of 13.8 months in patients with HER2- positive advanced gastric cancer. Nevertheless, the oncologic outcome of the subgroup of patients with peritoneal carcinomatosis is not reported in these trials and might be expected to be worse. Thus, additional treatment options are required to improve the oncologic outcome of this subset of patients.

The goal of the combined treatment concept consisting of CRS and HIPEC is to remove all visible tumor masses from the abdominal cavity as a precondition for peritoneal perfusion with highly concentrated chemotherapy to locally treat residual microscopic tumor cells. Hyperthermia may have additional antitumoral effects and enhances the penetration ability of the intraperitoneally administered cytostatic agents. The surgical technique has been described in detail by Sugarbaker in 1995. Although the principle of HIPEC is based on continuous peritoneal perfusion using inflow and outflow drainages and a heat-exchanger/pump system, the treatment protocol is not standardized. Thus, multiple different cytostatic agents are used for HIPEC and administered in open, semiopen, or closed abdomen technique. Intraperitoneal temperature is 40° to 42°C, and perfusion time ranges from 30 to 120 minutes. A meta-analysis summarizing the results of 13 randomized trials evaluating adjuvant intraperitoneal chemotherapy (IPC) in 1648 patients (873 patients with and 775 patients without IPC) indicates an overall survival advantage for patients with IPC after curative gastric resection. Moreover, Kuramoto and colleagues could demonstrate in a prospective randomized trial comparing extensive intraperitoneal lavage and IPC with IPC and surgery only a significant 5-year survival benefit in favor of prophylactic extensive intraoperative peritoneal lavage and IPC after curative resection of gastric cancer. These data support the efficacy of HIPEC in patients with advanced gastric cancer.

Diagnostic procedures

Preoperative gastroscopy including endosonography should be performed in all patients with advanced gastric cancer to determine the resectability of the primary tumor and local lymph node status. Moreover, computed tomography (CT) scanning of the thorax and abdomen with intravenous and intraluminal contrast media is mandatory to exclude distant metastasis and to determine the extent of peritoneal tumor dissemination. Liver metastasis should be assessed with additional ultrasonography.

In patients qualifying for CRS and HIPEC, a staging laparoscopy before cytoreduction is recommended to assess the extent of peritoneal tumor dissemination and to exclude disseminated small-nodule carcinomatosis of the small bowel. Additional diagnostics such as contrast-enhanced sonography, magnetic resonance imaging, and/or positron-emission tomography (PET)/CT may be helpful in case of unclear findings and should be performed if applicable ( Box 2 ).

Diagnosis and Patient Selection

Several studies demonstrate that complete macroscopic resection (CC-0/1) is crucial for the improvement of survival after CRS and HIPEC in patients with peritoneal carcinomatosis arising from gastric cancer. Thus, the achievability of CC-0/1 resection should be assessed with preoperative diagnostics as described. Moreover, survival was influenced by the intraoperative Peritoneal Cancer Index (PCI) showing a significant survival benefit for patients with a PCI of less than 12. The PCI (Washington Cancer Center Washington, DC, USA) allows the assessment of the extent of peritoneal surface malignancy. The numerical score ranging from 0 to 39 combines lesion size and tumor localization in 13 abdominopelvic regions (regions 0–12). Esquivel and Chua showed that preoperative CT mostly underestimates the extent of peritoneal tumor dissemination. In particular, the involvement of small bowel that is common in patients with advanced gastric cancer is not sufficiently detected with CT. Thus, additional staging laparoscopy is recommended to assess the PCI before CRS and HIPEC and to allow for consistent preoperative patient selection. The main selection criteria are summarized in Box 3 . Moreover, individual patient motivation, operative risk, and the expected postoperative quality of life should be taken into account. All patients’s cases should be discussed in an interdisciplinary tumor board before the institution of CRS and HIPEC.

Box 3

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