Peritoneal carcinomatosis from gastric carcinoma
Although the incidence of gastric cancer has 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 [
1]. Surgery comprising a subtotal or total gastrectomy with a D1.5-D2 lymphadenectomy, remains the most important tool for curative treatment of gastric carcinoma. Surgery is usually combined with systemic perioperative chemotherapy whose benefit has been demonstrated in two randomized studies: the MAGIC trial [
2] using epirubicin, cisplatin, and a continuous infusion FU regimen and the FNLCC-FFCD trial [
3] using 5-FU and cisplatin. In the latter trial, 5-year overall survival was significantly longer in patients in the perioperative chemotherapy group compared to those in the surgery alone group, respectively 38% and 24%.
In addition, despite the administration of pre- and/or postoperative systemic chemotherapy, one of the major problems with gastric carcinoma is its peritoneal tropism and the peritoneum is the major site of recurrence. Peritoneal dissemination commonly occurs in patients with gastric cancer via intracoelomic dissemination or due to tumour spillage during surgery [
4]. Peritoneal carcinomatosis is present at the diagnosis in 5-20% of the patients [
5] and can affect 60% of the patients after curative treatment [
6], and this tumour manifestation is considered a fatal disease with limited treatment options. Thus, in the multicentric prospective study of peritoneal carcinomatosis (EVOCAPE 1 study), median overall survival for the natural history of the disease was 3.1 months [
7].
Intraperitoneal chemotherapy for gastric carcinoma
A new therapeutic approach for peritoneal carcinomatosis has been under development for over twenty years. This treatment consists of complete cytoreductive surgery of peritoneal lesions followed by intraperitoneal chemotherapy. The main objective of the intraperitoneal administration of chemotherapy is to heighten the concentration and the total amount of the drug, thereby reducing plasma concentrations. This treatment increased the survival of patients with carcinomatosis of colorectal origin, from pseudomyxoma and mesothelioma [
8‐
10]. Regarding carcinomatosis of gastric origin, the results of intraperitoneal chemotherapy with conventional chemotherapeutic agents such as mitomycin C, oxaliplatin and 5FU remain disappointing. In a selected population of 159 patients with peritoneal disease alone, cytoreductive surgery plus intraperitoneal chemotherapy yielded a 5-year overall survival rate of 13% and a median overall survival rate of only 9.2 months [
11]. However, the beneficial effect of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of PC from gastric carcinoma was demonstrated in a phase III trial [
12]. Sixty-eight patients with gastric PC were randomized between complete cytoreductive surgery alone (n = 34) or complete cytoreductive surgery followed by HIPEC (n = 34) with cisplatin (120 mg) and mitomycin C (30 mg) each in 6000 ml of normal saline at 43°C over 60-90 min. Macroscopic complete cytoreduction of PC was achieved in 58.8% of the patients in each arm. Median survival was significantly increased in the group who received HIPEC, but it was only 11 months (95% confidence interval 10-11.9 months), compared to 6.5 months (95% confidence interval 4.8-8.2 months) in the surgery alone group (P = 0.046). A multivariate analysis found that complete cytoreductive surgery plus HIPEC, synchronous PC, the completeness of surgery (0-1), systemic chemotherapy ≥ 6 cycles, and no serious adverse events were independent predictors for better survival.
Thus, because of the poor prognosis of PC of gastric origin and disappointing results of treatment with complete cytoreductive surgery followed by HIPEC containing cytotoxic agents, innovative surgical therapies such as intraperitoneal immunotherapy need to be developed for the immediate postoperative period after complete cytoreductive surgery.
Intraperitoneal immunotherapy with catumaxomab in malignant ascites
Catumaxomab is a nonhumanised chimeric antibody, consisting in a mouse-derived anti-EpCAM Fab (fragment antigen-binding) region and a rat anti-CD3 Fab. Thus, catumaxomab is characterized by its unique ability to bind to three different types of cells: tumor cells expressing the epithelial cell adhesion molecule (EpCAM positive), T lymphocytes (CD3 positive) and also accessory cells (Fcγ receptor positive), such as macrophages, natural killer cells and dendritic cells, which are activated with the hybrid Fc (crystallisable fragment) region [
13,
14]).
Catumaxomab anti-tumour activity has been demonstrated in vitro, notably in ascitic fluids, resulting in a decreased rate of EpCAM + cells and the release of pro-inflammatory cytokines (Interferon- γ, tumour necrosis factor-α, interleukin (IL)-2 and IL-6) [
15].
A randomized study was performed in patients with symptomatic malignant ascites secondary to EpCAM + carcinomas, to evaluate the efficacy and safety of intraperitoneal administration of catumaxomab [
16]. Patients were randomly assigned to paracentesis alone, or to paracentesis plus intraperitoneal catumaxomab. The efficacy of intraperitoneal administration of catumaxomab was evaluated on puncture-free survival (primary endpoint). Two hundred and fifty-eight patients, 66 of whom had carcinomatosis of gastric origin, were included in the study. Catumaxomab was administered in four intraperitoneal infusions, each preceded by aspiration of ascites at day 0 (D0), D3, D7 and D10, and required a total of 11 days of hospitalization. Puncture-free survival was significantly longer in the group treated with catumaxomab compared to that in the control group (46
vs 11 days, p < 0.0001). Median overall survival was similar between the two groups: 72 days in the catumaxomab group
vs 68 days in the control group. The most common adverse events were related to the release of cytokines (fever, nausea, vomiting, tachycardia and hypotension). These reactions were of mild or moderate severity (grade 1 or 2) and transient, limited to the duration of catumaxomab therapy with an acceptable tolerability profile. Other treatment-related adverse events were haematological (lymphopenia, leucocytosis and anaemia) and non-haematological (abdominal pain, elevated C-reactive protein, and gamma-glutamyltransferase levels, fatigue, anorexia, elevated blood alkaline phosphatase, AST and ALT levels). This study confirmed the feasibility and efficacy of intraperitoneal infusion of catumaxomab in reducing the volume of ascites. Thus, an approval was granted to the European Union in April 2009 for the use of catumaxomab intraperitoneal infusion in patients with ascites from an EpCAM + malignancy for which standard therapy was not available or no longer feasible [
17]. This study also demonstrated that deterioration in quality of life (QoL) scores, evaluated with the EORTC QLQ-C30, appeared significantly more rapidly in the control than in the catumaxomab group for all scores (range of median times 19-26 days
vs 47-49 days, p < 0.0001) [
18].
Another randomized study was reported at ASCO congress in 2008 [
19]. Among 55 patients operated on for gastric adenocarcinoma (T2b/T3/T4, N±, M0) with a curative intent, 28 received an intraperitoneal catumaxomab infusion during the immediate postoperative period, and were compared to 27 patients who underwent resection alone. Catumaxomab was administered during surgery and then 4 times (D7, 10, 13 and 16) at increasing doses. The EpCAM antigen was present in 100% of patients. Seventy-eight percent (22/28) of the patients treated with catumaxomab received all 5 infusions. Treatment-related adverse events occurred in 40% of the patients (grade 3 in 22 patients, of whom 10 were in control arm). The most frequent adverse events in the catumaxomab group were anaemia, pyrexia, inflammatory syndrome and abdominal pain. All related serious adverse events resolved at the end of therapy except for nephropathy (one patient), which resolved leaving minor sequels. This study demonstrated that adjuvant intraperitoneal administration of catumaxomab, after gastrectomy, seems to be feasible, safe and well tolerated.
A
post hoc analysis was performed to investigate whether there was a correlation between the detection of human anti-mouse antibodies (HAMAs) 8 days after the fourth catumaxomab infusion and clinical outcome, because catumoxamab is a mouse/rat antibody [
20]. Among patients who received intraperitoneal catumaxomab, those who developed HAMAs experienced greater clinical benefits (longer puncture-free survival, longer time to the next therapeutic puncture) than those who did not develop HAMAs. In addition, median survival was significantly longer in the group of patients who developed HAMAs (129 vs 64 days, p = 0.0003; hazard ratio 0.433). These results demonstrate that there was a strong correlation between humoral immune response to catumaxomab and clinical outcome in that phase II/III study.
However, the survival benefit of immediate postoperative immunotherapy after cytoreductive surgery of peritoneal carcinomatosis has never been reported. There are strong arguments to evaluate this treatment in patients with gastric carcinomatosis: [
1] the poor prognosis of patients despite optimal treatment with a curative intent including HIPEC [
2], the expression of the EpCAM antigen in nearly 90% of gastric adenocarcinoma [
21], and [
3] peritoneum is an immunocompetent organ, [
4] peritoneal mesenchymal cells do not express the EpCAM antigen.
Due to our experience in the surgical treatment of peritoneal carcinomatosis which represents a major activity of the Department of Surgical Oncology (over 700 patients since 1993), we are poised to initiate a phase II randomised clinical trial (IIPOP), funded by a PHRC grant (Programme Hospitalier de Recherche Clinique).