Gastric cancer is the most commonly diagnosed malignant tumor in Chinese population. While radical surgery is still the first choice for the treatment of gastric cancer, worldwide overall 5-year survival rate of gastric cancer is less than 30 % (21), especially, at stage III or later phase gastric cancer patients (6). Adjuvant chemotherapy, therefore, is used in majority of the stage III or later phase gastric cancer patient. The current study demonstrated that HIPEC with cisplatin plus orally taken S-1 was superior to systemic chemotherapy of cisplatin plus orally taken S-1 treatment after D2 radical surgery in the stage III gastric cancer patients.
Several retrospective as well as prospective clinical studies have indicated that adjuvant chemotherapy benefits stage III gastric cancer patients (8, 22–24). However, while D2 radical surgery significantly reduced occurrence of lymphatic metastasis, peritoneal metastasis becomes major recurrent location after the surgery (9, 25). In this regard, a retrospective study reported that cancer cells were found in 29.7 % of T3 and 34.8 % of T4 patients’ peritoneal lavage fluid after the radical surgery; and that 59.4% of the T3 or T4 patients had peritoneal metastasis within 5 years after the surgery, while only 21.3 % had blood circulatory metastasis (9). Prognosis of the patients with peritoneal metastasis is poor, and thus, prevention of peritoneal metastasis following surgical resection of the late stage gastric cancer becomes crucial.
HIPEC has been used for the prevention of micro-transplantation of cancer cells during and after gastric surgery (18, 26). In this regard, HIPEC has been widely used during or right after cytoreductive surgery (CRS) for the prevention of peritoneal metastasis in variety kinds of cancers including gastric cancer, ovarian cancer and hepatic cancer (18, 27–30). HIPEC has also been used as palliative treatment for recurrent ascites and malignant plural effusion for the patients with variety kinds of late stage or recurrent cancers including lung cancer, breast cancer, gastric cancer and ovarian cancer (20, 31). Mechanism of HIPEC is to augment sensitivity of cancer cells to chemotherapeutic drugs at hyperthermic condition (41.5 ~ 42.5 C) in that cancer cells are more sensitive to heat than the normal cells (16, 26). In this content, it has shown that hyperthermia significantly increases efficacy of platinum-based anti-cancer drugs (32).
Gastric cancer is the most common cause of peritoneal metastasis after radical surgery. Therefore, prevention of peritoneal metastasis is crucial for the patients with gastrointestinal cancer. In this regard, studies have demonstrated that efficacy of CRS plus HIPEC is superior to surgical resection only in gastric cancer patients. Fujimoto first reported in 1988 that CRS plus HIPEC controlled malignant ascites in 9 out of 15 gastric cancer patients who had peritoneal metastasis after the surgery (28). Since then, HIPEC has been used as not only an adjuvant treatment for malignant ascites caused by variety kinds of abdominal cancers including colon cancer and ovarian cancer (33–35), but also a method of preventing peritoneal metastasis in the gastric cancer patients. In this regard, Fujimoto and colleagues reported in 1999 that CRS plus HIPEC could significantly increase survival rate for the patients with infiltration of gastric cancer into the gastric serosa by reducing peritoneal metastasis in comparison to the radical surgery only (36). Wansik Yu et al (37) reported that 248 stage II or III gastric cancer patients were randomly treated with either radical surgery only or CRS plus HIPEC (HIPEC starting on day 2 after surgery for 5 days with mitomycin plus fluorouracil), and they found that 5-year survival rate in the patients with CRS plus HIPEC (49.1 %) was significantly higher than that in the radical surgery only group (18.4 %). Yonemura et al (38) reported that 139 stage II-IV gastric patients were randomly assigned to a group treated with CRS plus HIPEC (42–43 °C) with mitomycin and cisplatin, a group treated with CRS plus intra-peritoneal chemotherapy at normal temperature (37 °C) with mitomycin and cisplatin, and a group treated with radical surgery only. They found the 5-year survival rates were 61 % (CRS + HIPEC), 43 % (CRS + 37 °C intra-peritoneal chemotherapy), and 42 % (CRS only) (38). Furthermore, they found that CRS plus HIPEC exerted most significant therapeutic effect in the patients, who had gastric serosa infiltration and local lymphatic metastasis, in comparison to CRS plus normal temperature intra-peritoneal perfusion therapy (38). A meta-analysis also indicated that HIPEC could significantly increase survival rate in the advanced gastric cancer patients who had CRS plus HIPEC during the surgery or post-surgery (39). Recently, it has been reported that DFS was significantly higher in the patients received D2-CRS plus HIPEC (93%) than that of patients treated with D2-CRS only (65%, P = 0.0054); that peritoneal metastasis rate was significantly lower in the patients had D2-CRS plus HIPEC (3%) than that of the patients without HIPEC (23%, P < 0.05) (19). Consistent with these findings, the current study demonstrated that patients with stage III gastric cancer had longer median DFS when they were treated with CRS plus HIPEC and oral S-1 (21.0 months) than the patients treated with CRS plus systemic cisplatin and oral S-1 (14.0 months), suggesting HIPEC is an effective adjuvant therapy following radical surgery in the advanced gastric cancer patients, especially for the patients suffered from Bormann’s type IV gastric cancer with neurovascular infiltration, T ≥ 3, and N3. These late stage patients were highly risk in regard of peritoneal metastasis, therefore, the current study was designed to prospectively investigate the outcomes of D2-CRS plus HIPEC in comparison to the group without HIPEC.
While majority of the previous studies have compared the outcomes of HIPEC versus radical surgery only (19, 36–39), adjuvant chemotherapy following radical surgery has become standard treatment for the gastric cancer. However, outcomes of HIPEC versus systemic chemotherapy in these patients remains to be further investigated. In this regard, a retrospective study by Shi et al (40) reported that 5-year survival rate in the patients with CRS + systemic chemotherapy + HIPEC was significantly higher than that without HIPEC (60.4 % vs 42.9 %), and median progress free survival (PFS) was 60.5 and 46.2 months, respectively. Similarly, Zhang et al (41) reported that gastric cancer patients treated with CRS + systemic chemotherapy + HIPEC had significantly higher 3-year survival rate (61.8 %) but lower local recurrent rate (23.5 %) compared to that of CRS + systemic chemotherapy only (3-year survival rate: 40.0 %; local recurrent rate: 43.3 %). Furthermore, a meta-analysis on 2299 cases of late stage gastric cancer patients in 18 randomized clinical trials found that rates of post-operational recurrence and distant metastasis were significantly lower in the patients received HIPEC plus systemic chemotherapy than that of the patients received systemic chemotherapy only; that long-term survival was increased without significant adverse effect by HIPEC plus systemic chemotherapy (42). In the current study, therefore, a prospective study on the outcomes of HIPEC plus oral administration of S-1 in comparison to that of systemic chemotherapy plus oral administration of S-1 was carried out.
S-1 is a combination of tegafur, gimeracil and oteracil potassium. Tegafur is a prodrug of the active substance fluorouracil (5-FU). Gimeracil inhibits the degradation of 5-FU by reversibly blocking the dehydrogenase enzyme dihydropyrimidine dehydrogenase (DPD), by which mechanism, higher level and prolonged half-life of 5-FU are achieved. Oteracil potassium mainly stays in the gut due to low permeability and is a highly selective inhibitor of the enzyme orotate phosphoribosyl transferase. Oteracil reduces the production of 5-FU in the gut through inhibiting phosphorylation of 5-FU, which results in a lower gastrointestinal toxicity. S-1 has been approved and used for the treatment of advanced gastric cancer by oral administration in Japan in 1999. A study, called SC-101, has been conducted in China, in which 224 cases of unresectable late phase or metastatic gastric cancer were enrolled and treated with S-1(43). It was found that tumor remission rate was significantly higher in the patients treated with S-1 plus cisplatin (37.8%) than that of 5-FU plus cisplatin (19.2%) or S-1 only (24.7%); that median survival of the patients with S-1 plus cisplatin was 433 days (14.4 months), which was longer than that of the other two groups. Therefore, S-1 was used in the current prospective study as an adjuvant chemotherapeutic drug in addition to cisplatin, and found that DFS (21.0 months versus 14.0 months, P = 0.039) as well as 2-year DFS rate (47.3% versus 29.4%) were significantly longer or higher in the patients treated with HIPEC plus S-1 oral administration than that of systemic cisplatin administration plus S-1. These findings suggested that S-1 could be used as a standard chemotherapeutic drug in gastric cancer patients in China; and that HIPEC plus S-1 might be superior to systemic chemotherapy plus S-1 oral administration for the stage III gastric cancer after D2 radical surgery.
While combination of CRS and HIPEC could significantly increase survival of the cancer patients, safety is highly concerned in HIPEC procedure during surgery because adverse events associated with HIPEC may also arise by invasive procedures, high temperature, and large amount of fluid circulation. In this regard, it has been reported that HIPEC-treated patients had higher incidence rate of severe adverse events including severe bleeding and even intestinal perforation than the patients had CRS only although incidence rate of side effects and mortality were not significantly different between the two groups (37–39). In addition, incidence of leukopenia and peritoneal infection has also been reported in the patients treated with HIPEC (37, 39). In the current study, side effects including nausea/vomiting, diarrhea, leukopenia, thrombocytopenia, and fatigue were compared in the two groups, and found that incidence of these side effects was slightly lower in this novel bedside HIPEC group compared to the control group although they were not statistically different, suggesting HIPEC might reduce side effects caused by chemotherapeutic drugs. In addition, in the current study, bedside hyperthermic intra-peritoneal perfusion and circulation of chemotherapeutic drugs was established through needle puncture technique. Consistent with our previous report (20), while this technique was safe and could be performed under local anesthesia, 2 out of 57 patients (3.5 %) had HIPEC-associated pain at the puncture points and one out of 57 patients (1.8 %) had HIPEC-associated peritoneal inflammation, suggesting cautious attention be paid on these HIPEC-associated side effects.
HIPEC, especially during CRS, has been performed under systemic anesthesia of the patients with opened abdominal cavity (18). When the patients were under systemic anesthesia, it not only takes longer time to complete the HIPEC, but also may increase the opportunity of side effects such as peritoneal infection. In addition, method of previously reported HIPEC at surgical operation room was performed only once during or right after the CRS. In the current study, however, a local anesthesia followed by puncture technique and devices were used for the HIPEC. This procedure and device are especially convenient and safe to perform repeated HIPEC for multiple therapeutic cycles after CRS for the patients with recurrent peritoneal metastasis. Average time of the HIPEC performed in the current study was less than 2 hours, which rendered the patients to be easily tolerable to the procedure and could be treated multiple cycles. Furthermore, by application of multiple cycles of HIPEC plus oral S-1, the current study demonstrated that HIPEC could not only significantly increased 2-year DFS (47.3 % vs 29.4 %), but also reduced peritoneal metastasis (10.5 % vs 21.1 %), suggesting that multiple cycles of HIPEC with puncture procedure could be safely and easily performed in the patients after RS to prevent peritoneal metastasis of gastric cancer. However, limitation of the current study was that small number of cases was enrolled into this study. A prospective and larger number of clinical trials could be performed in the future to further confirm the findings of the current study.