ANTICANCER RESEARCH 34: 2019-2022 (2014)

The Role of Prophylactic Hyperthermic Intraperitoneal Chemotherapy in the Management of Serosal Involved Gastric Cancer

EDOARDO SALADINO, FRANCESCO FLERES, CARMELO MAZZEO, VINCENZO PRUITI, MICHELA SCOLLICA, MAURIZIO ROSSITTO, EUGENIO CUCINOTTA and ANTONIO MACRÌ

Human Pathology Department, University of Messina, Messina, Italy

Abstract. Background: Peritoneal carcinomatosis of gastric 7) and no survivors at 5 years (8, 9). The presence of peritoneal origin is associated with poor survival. The use of implants or a positive peritoneal cytology are the most common cytoreductive surgery and hyperthermic intraperitoneal reasons for failure after intensive chemotherapy (10), often chemotherapy (HIPEC) did not significantly improve the being seen as indicators of incurable disease (11). However, survival of patients with this disease. A promising approach investigators worldwide have continued to study potential can be based on the use of HIPEC as prophylaxis of treatment options for patients with gastric cancer with limited peritoneal dissemination. Patients and Methods: From our carcinomatosis, encouraged by the results of cytoreductive database, we have sampled 12 patients with advanced surgery (CRS) and hyperthermic intraperitoneal chemotherapy gastric cancer. In all cases, a D2 total gastrectomy was (HIPEC) for carcinomatosis of appendiceal and colorectal origin performed, associated with splenectomy in four cases. All that led to, in a small but meaningful number of patients, long- patients were submitted to HIPEC. Results: Morbidity and term survival (1, 12). However, in patients with PC of gastric mortality were 33.3% and 8.3%, respectively. The median origin, the results of CRS-plus-HIPEC are less encouraging survival was 24 months, with only one case (8.3%) of compared to other peritoneal malignancies (13-15). For this peritoneal recurrence. Conclusion: In light of our experience reason, nowadays there is a strong rationale for using HIPEC and supported by literature data, we can affirm that HIPEC as prophylaxis in patients submitted to primary resection for has a potential role in the prevention of gastric locally advanced gastric cancer or gastric cancer with positive carcinomatosis. Certainly further studies are required on a peritoneal washing, when the chance of PC is high but the larger scale to validate this new but promising approach. burden of disease is minimal. We report our experience on this specific area. Gastric cancer represents the second leading cause of cancer- related deaths worldwide. Approximately 25% of gastric Patients and Methods carcinomas are diagnosed while still localized to the , 30% have regional spread at diagnosis and an additional 30% From our database, we sampled 12 patients (Table I) with advanced have metastatic disease (1). The peritoneal surface is commonly gastric cancer, having a minimal follow-up of 60 months. In all involved in gastric cancer. In fact peritoneal carcinomatosis (PC) cases, total gastrectomy was performed with D2 lymphadenectomy, is a frequent event even in the early phase of the disease. It has associated in four cases with splenectomy. After intraoperative been estimated that 15% to 50% or more of patients have histological examination to confirm serosal involvement, all patients were submitted to HIPEC with the closed-abdomen peritoneal disease at surgical exploration, especially when there technique, which foresees the positioning of five abdominal is serosal involvement by the tumor (2). PC, once established, is drainages, two inflows on the right (subhepatic sheath and pelvic associated with poor survival as shown by many phase III trials pouch) and three outflows on the left (subhepatic, left that reported median survival ranging from 1 to 13.8 months (3- subdiaphragmatic, shallow pelvis), and of six thermometric probes (upper and lower abdomen, inflow, outflow, , and ), the temporary suturing of the skin and perfusion with a preheated solution for . Peritoneal temperature Correspondence to: Macrì Antonio, Human Pathology Department, was kept between 41-43˚C and the drugs were administered University of Messina, Via Consolare Valeria, 98125 Messina, Italy. according to the following schedule: i) cisplatin at 25 mg/m2/l plus Tel: +39 902212678, Fax: +39 902212633, e-mail: [email protected] mitomycin C at 3.3 mg/m2/l for 60 min. Afterward, the cytostatic solution was completely evacuated, the abdominal cavity was Key Words: Gastric cancer, HIPEC, prophylaxis. revisited and intestinal anastomosis were performed.

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Table I.

Gender Age Operative time Surgery Morbidity Mortality Peritoneal pTNM Adjuvant (years) (min) (<30 days) recurrences stage chemotherapy

1 F 77 600 D2 total gastrectomy plus splenectomy Yes Yes No T4N2M0 No 2 M 72 420 D2 total gastrectomy No No No T3N2M0 Yes 3 M 57 540 D2 total gastrectomy No No No T3N2M0 Yes 4 M 66 720 D2 total gastrectomy plus splenectomy Yes No No T4N2M0 Yes 5 F 70 430 D2 total gastrectomy No No No T4N2M0 Yes 6 M 61 540 D2 total gastrectomy No No No T3N2M0 Yes 7 M 68 500 D2 total gastrectomy No No No T3N2M0 Yes 8 M 68 660 D2 total gastrectomy plus splenectomy No No Yes T4N2M0 Yes 9 F 73 480 D2 total gastrectomy No No No T3N2M0 Yes 10 F 71 470 D2 total gastrectomy Yes No No T3N2M0 Yes 11 M 69 430 D2 total gastrectomy No No No T3N2M0 Yes 12 M 64 450 D2 total gastrectomy plus splenectomy No No No T3N2M0 Yes

Results penetrate poorly at this site. The experience with CRS associated with HIPEC in the management of gastric cancer The male-to-female ratio was 2:1 and the average age 68 is still limited and the results do not adequately support the years. The average operating time was 520 minutes. The use of this aggressive approach in the presence of advanced definitive histological examination documented eight PC (26). The analysis of the principal reports about the role T3N2M0 and four T4N2M0. The cytological examination of of CRS-plus-HIPEC in patients with gastric cancer (27-31) peritoneal lavage was always negative. Postoperative demonstred a median survival ranging from 7 months (31) to morbility and mortality were 33.3% and 8.3%, respectively. 10-15 months (27-30) and a 5-year survival ranging from 6% The average postoperative hospital stay was 28 days. (27, 29) to 31% (28-31). Interestingly, a multivariate analysis Overall, 11/12 patients (91.6%) were submitted to adjuvant showed that completeness of cytoreduction and absence of chemotherapy. The median survival was 24 months, with ascites were favorable prognostic factors for long-term only one case (8.3%) of peritoneal recurrence. survival. In fact in patients with CC-0 and CC-1, according to the completeness of cytoreduction score (CC score) (32), Discussion median survival ranged from 11.2 to 21.3 months (28, 29) and 5-year survival from 21% to 29.4% (28, 29, 31). It is The treatment of gastric cancer, especially if advanced, is noteworthy however that complete cytoreduction was possible characterized by poor results. In literature, it is reported that in only 44-51% of patients (27, 28). Therefore the most 40-50% of patients submitted to curative resection develop important prognostic factors for survival are the absence of locoregional recurrence 1-3 years after surgery (16), and ascites, completeness of cytoreduction with a low CC score often, even at death, the tumor remains confined to the and a low peritoneal dissemination class (2). The use of abdomen (17, 18). In particular, after extended HIPEC to minimize the risk of peritoneal recurrence in the lymphadenectomy, the peritoneal surface is, with the , the setting of patients with advanced gastric cancer presents many major site of recurrence (19-21). The ‘tumor cell entrapment advantages, especially in cases without established hypothesis’ (16) suggests that manipulation of the cancer- carcinomatosis but which are at high risk for intraperitoneal bearing organ, transection of lymphatic channels, and blood dissemination. In fact, many Institutional reports have been loss from the cancer specimen results in free intraperitoneal made exploring the use of perioperative HIPEC as an cancer cells that will be lethal in 100% of cases (22-25). The adjuvant treatment for this subgroup of patients. In 2007, Yan other mean of peritoneal dissemination is the spontaneous et al. published a systemic review and meta-analysis that exfoliation of the primary tumor, an event more frequent in compared surgery for primary gastric cancer combined with patients with tumor involving the serosal surface. These intraperitoneal chemotherapy versus surgery-alone (32). The concepts represent the rationale for using the locoregional intraperitoneal therapies used were HIPEC, normothermic approach, such as CRS-plus-HIPEC, in the prevention of intraoperative intraperitoneal chemotherapy, early peritoneal diffusion of gastric cancer. Locoregional treatment postoperative intraperitoneal chemotherapy and delayed was also proposed because the is defined as a postoperative intraperitoneal chemotherapy. The meta- ‘pharmacological sanctuary’ as intravenously injected drugs analysis showed that there was a significant improvement in

2020 Saladino et al: Prophylactic HIPEC in Gastric Cancer survival with the use of HIPEC or HIPEC plus early 8 Yonemura Y, Fujimura T, Nishimura G, FallaR, Sawa T, postoperative intraperitoneal chemotherapy, while there was Katayama K, Tsugawa K, Fushida S, Miyazaki I, Tanaka M, no statistically significant improvement with any other Endou Y and Sasaki T: Effects of intraoperative chemo- modality. hyperthermia in patients with gatsric cancer with periotneal dissemination. Surgery 119: 437-444, 1996. A more recent meta-analysis, based on the evaluation of 9 Elias D, Blot F, El Otmany A, Antoun S, Lasser P, Boige V, 280 studies, among which 31 potentially relevant and only Rougier P and Ducreux M: Curative treatment of periotoneal 10 randomized and therefore usable, evaluated the benefits carcinomatosis arising from colorectal cancer by complete of HIPEC for patients with serosal invasion in gastric cancer resection and intraperitoneal chemotherapy. Cancer 97: 71-76, (33). The results of the analysis indicated that HIPEC could 2001. potentially allow for a better prognosis in patients who 10 Ajani JA, Ota DM and Jackson DE: Current strategies in the underwent resection for advanced gastric cancer compared management of locoregional and metastatic gastric carcinoma. Cancer 67: 260-265, 1991. to the control group, without statistically significant 11 Brentrem D, Wilton A and Mazumdar M: The value of differences regarding adverse events. peritoneal cytology as a preoperative predictor in patients with In our experience, even if based on a relatively small gastric cancer carcinoma undergoing a curative resection. Ann number of patients, we recorded a good median survival (24 Surg Oncol 12: 347-353, 2005 months), higher than historically-reported in the literature (3- 12 Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: 9), with acceptable morbidity and mortality. However, we Gastric cancer. 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