MCO Molecular and Clinical Oncology 2049-9450 2049-9469 D.A. Spandidos 10.3892/mco.2016.918 MCO-0-0-918 Articles A retrospective analysis of hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis YuanMeiqin 1 WangZeng 2 HuGuinv 3 YangYunshan 1 LvWangxia 1 LuFangxiao 4 ZhongHaijun 1 Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China Department of Surgical Oncology, Dongyang People's Hospital, Dongyang, Zhejiang 322100, P.R. China Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China Correspondence to: Dr Haijun Zhong, Department of Chemotherapy, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, Zhejiang 310022, P.R. China, E-mail: zhj1712@aliyun.com 08 2016 02 06 2016 5 2 395 399 11012016 25052016 Copyright © 2016, Spandidos Publications 2016

Peritoneal metastasis (PM) is a poor prognostic factor in patients with gastric cancer. The aim of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced gastric cancer with PM by retrospective analysis. A total of 54 gastric cancer patients with positive ascitic fluid cytology were included in this study: 23 patients were treated with systemic chemotherapy combined with HIPEC (HIPEC+ group) and 31 received systemic chemotherapy alone (HIPEC- group). The patients were divided into 4 categories according to the changes of ascites, namely disappear, decrease, stable and increase. The disappear + decrease rate in the HIPEC+ group was 82.60%, which was statistically significantly superior to that of the HIPEC- group (54.80%). The disappear + decrease + stable rate was 95.70% in the HIPEC+ group and 74.20% in the HIPEC- group, but the difference was not statistically significant. In 33 patients with complete survival data, including 12 from the HIPEC+ and 21 from the HIPEC- group, the median progression-free survival was 164 and 129 days, respectively, and the median overall survival (OS) was 494 and 223 days, respectively. In patients with ascites disappear/decrease/stable, the OS appeared to be better compared with that in patients with ascites increase, but the difference was not statistically significant. Further analysis revealed that patients with controlled disease (complete response + partial response + stable disease) may have a better OS compared with patients with progressive disease, with a statistically significant difference. The toxicities were well tolerated in both groups. Therefore, HIPEC was found to improve survival in advanced gastric cancer patients with PM, but the difference was not statistically significant, which may be attributed to the small number of cases. Further studies with larger samples are required to confirm our data.

 hyperthermic intraperitoneal chemotherapy gastric cancer peritoneal metastasis Introduction

Peritoneal metastasis (PM) is the most common metastatic pattern in gastric cancer (GC) and has an extremely poor prognosis (1,2), with a median survival of 3–6 months without treatment (3). PM may lead to refractory ascites, intestinal obstruction, cachexia and eventually death. Thus far, PM is considered as stage IV disease, and treatment is non-curative.

There is currently no established consensus to direct treatment for GC patients with positive peritoneal cytology. Intraperitoneal chemotherapy (IPC) has been proposed as a treatment option, which may improve survival in GC patients patients with PM (4–8). IPC possesses a theoretical advantage over the systemic route by delivering high drug concentrations directly to the peritoneal cavity, with reduced systemic toxicity (9–11). In addition, high drug concentrations are achieved in the portal vein (12). This may be important, as the liver is a common metastatic site (13). Recently, hyperthermia has been developed as an anticancer therapy and has been shown to exert a direct cytotoxic effect on tumor cells in the peritoneal cavity in conjunction with certain chemotherapeutic agents (14). Zhao et al reported that whole-body hyperthermia combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for patients with advanced gastric malignancies (15). A meta-analysis by Sun et al demonstrated that HIPEC may improve the overall survival (OS) rate in patients who undergo resection for advanced GC, and help to prevent peritoneal local recurrence among GC patients with serosal invasion (16). HIPEC has also been suggested to be useful in treating advanced peritoneal metastatic cancer, and significantly prolonged survival following tumor resection (17,18).

The aim of this study was to evaluate the efficacy and safety of HIPEC in advanced GC patients with peritoneal dissemination by retrospective analysis.

 Patients and methods <sec> <title>Patients

The clinical records of 54 patients who were primarily diagnosed as GC with PM at the Zhejiang Cancer Hospital (Hangzhou, China) from 2008-1-1 through to 2014-12-31 were retrospectively analyzed (Table I). Patients eligible for this study had histologically confirmed GC with PM, which means positive peritoneal cytology. The patients had been treated with mono- or combination chemotherapy, which was found to be effective in GC, including S-1, S-1 + cisplatin (SP), S-1 + oxaliplatin (SOX), capecitabine + oxaliplatin (XELOX), capecitabine + docetaxel (XT), oxaliplatin + 5-fluorouracil + folinic acid (FOLFOX), docetaxel + cisplatin (DP), Doxetaxel + S1 (DS), Doxetaxel + Xeloda (capecitabine) (DX) and irinotecan (CPT-11). Finally, a total of 33 patients had complete survival data, including 12 in the HIPEC+ and 21 in the HIPEC- group.

The present study was approved by the Ethics Committee and Institutional Review Board of the Zhejiang Cancer Hospital and was conducted in compliance with the ethical principles of the Declaration of Helsinki.

 Treatment

Among the 54 patients, 23 received systemic chemotherapy combined with HIPEC (HIPEC+ group) and 31 patients received systemic chemotherapy alone (HIPEC- group). The systemic chemotherapy was a mono- or combination therapy, which was found to be effective in GC, including S1, SP, SOX, XELOX, XT, FOLFOX, DP, DS, DX and CPT-11. In the HIPEC+ group, the patients were administered cisplatin (CDDP, 50 mg/m2) through intraperitoneal perfusion during chemotherapy and then abdominal hyperthermia was applied in vitro. The doses of chemotherapy and their adjustments were made according to each patient's status.

 Adverse effects

Toxicity was measured using the National Cancer Institute Common Toxicity Criteria version 2.0 toxicity scales (19). Grade 3–4 toxicity was recorded according to the medical records.

 Assessment and statistics

Response was evaluated every two cycles of treatment using the Response Evaluation Criteria in Solid Tumors (20). The patients were divided into 4 categories according to the changes in ascites, including disappear, decrease, stable and increase. Survival time was analyzed with the Kaplan-Meier method using the SPSS software, version 15.0 (SPSS, Inc., Chicago, IL, USA).

 Results <sec> <title>Efficacy

The patients were divided into 4 categories according to the changes of ascites, namely disappear, decrease, stable and increase. In the 54 patients, the disappear + decrease rate in the HIPEC+ group was 82.60%, which was superior to that in the HIPEC- group (54.80%; P=0.043). The disappear + decrease + stable rate was 95.70% in the HIPEC+ group and 74.20% in the HIPEC- group (P=0.062). The disease control rate was 65.22% in the HIPEC+ group and 58.06% in the HIPEC- group (P=0.594). Therefore, HIPEC may effectively control ascites in advanced GC.

Of the 33 patients with complete survival data available, including 12 from the HIPEC+ and 21 from the HIPEC- group, further analysis revealed that the median progression-free survival (PFS) was 164 days in the HIPEC+ group and 129 days in the HIPEC- group (P=0.158; Fig. 1). The median OS was 494 days in the HIPEC+ and 223 days in the HIPEC- group (P=0.178), and the 1-year survival rate was 41.7 and 23.8%, respectively (P<0.001; Fig. 2). In patients with ascites disappear + decrease + stable, the OS appeared to be better compared with that in patients with ascites increase, but the difference was not statistically significant (P=0.08; Fig. 3). Patients with controlled disease [complete response (CR) + partial response (PR) + stable disease (SD)], may have a better OS compared with patients with progressive disease (P<0.001; Fig. 4). Other factors, such as gender, age, primary tumor site, pathology, and radical surgery, exhibited no obvious correlation with OS (Table II).

 Toxicity

All 54 patients were assessed for treatment safety, and no grade 3 or 4 adverse events or treatment-related deaths were recorded.

 Discussion

HIPEC has been proven to be effective in the treatment of PM in ovarian, appendiceal and colorectal cancer (21–24), but its role in GC with PM has not been established. The present study retrospectively investigated GC patients with PM from 2008-1-1 through to 2014-12-31 at the Zhejiang Cancer Hospital. The results demonstrated that the disappear + decrease rate in the HIPEC+ group was better compared with that in the HIPEC- group, which means that HIPEC may effectively control ascites and significantly improve the quality of life in GC patients with PM. This may be a major step in the fight against cancer.

In patients with complete survival data, the survival curves of the two groups were separated in Kaplan-Meier estimates of PFS and OS: The 1-year survival rate of HIPEC+ group was significantly higher compared with that of the HIPEC- group. Recent studies on GC patients with PM treated with cytoreductive surgery (CRS) and HIPEC reported 1-year OS rates ranging from 35.5 to 50% (Table III) (25–32). Our results are similar, but considered encouraging, due to the avoidance of surgical trauma. However, the difference in PFS and OS between the two groups was not statistically significant. This may be attributed to the small number of cases, which suggests that further studies with larger samples are required to confirm our data.

Further analysis in our study demonstrated that in patients with ascites disappear + decrease + similar, the OS appeared to be better compared with that in patients with ascites increase; the survival curves of the two groups were separated, but the difference was not statistically significant. In addition, patients with controlled disease (CR + PR + SD), may have a better OS compared with patients with progressive disease (P<0.001). These results indicate that short-term remission of the disease, including control of ascites, is associated with good prognosis. Further research on the association between short-term remission and the prognosis of advanced GC is planned in the near future.

Toxicity is also a major concern. As HIPEC has the advantage of increasing the concentration of chemotherapeutic agents locally administered into the peritoneum with fewer systemic side effects compared with systemic chemotherapy, it may be hypothesized that the combination of heat and drug toxicity may lead to more complications, such as anastomotic leakage, intra-abdominal abscess, wound infection, pulmonary edema and adult respiratory distress syndrome (25). In this study, none of the abovementioned serious adverse effects were observed, and no other serious unacceptable adverse effects or treatment-related deaths were reported.

In summary, this study demonstrated the effectiveness and safety of HIPEC combined with systemic chemotherapy for advanced GC with peritoneal dissemination; however, large multicenter prospective randomized controlled studies and pharmacokinetic analysis are required to confirm our findings.

 Acknowledgements

The present study was supported by the General Research Program of Medical Health in Zhejiang Province (grant nos. 2011KYA032, 2014KYB039 and 2016KYB036), the Scientific Research Fund Project of Integrated Chinese and Western Medicine Institute in Zhejiang province (grant no. 2014LYK021), the Science and Technology in Zhejiang Province Chinese Medicine Program (grant nos. 2012ZA101 and 2016ZA038), the Hangzhou City Science and Technology Project Planning Guide (Social Development) (grant no. 20130733Q15) and the Hangzhou City Health Science and Technology Project (grant no. 2013A43).

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Kaplan-Meier estimates of progression-free survival (PFS) in the HIPC+ and HIPC- group. The median PFS was 164 days in the HIPC+ and 129 days in the HIPC- group. HIPEC, hyperthermic intraperitoneal chemotherapy; cum, cumulative.

Kaplan-Meier estimates of overall survival (OS) in the HIPC+ and HIPC- group. The median OS was 494 days in the HIPC+ and 223 days in the HIPC- group (P=0.178). The 1-year survival rate was 41.7% in the HIPC+ and 23.8% in the HIPC- group (P<0.001). HIPEC, hyperthermic intraperitoneal chemotherapy; cum, cumulative.

Kaplan-Meier estimates of overall survival (OS) in different groups according to the ascites control status (the OS in patients with ascites disappear + decrease + stable appeared to be better compared with that in patients with ascites increase, but the difference was not statistically significant (P=0.08).

Kaplan-Meier estimates of overall survival (OS) in different groups according to the disease control status. Patients with controlled disease [complete response (CR) + partial response (PR) + stable disease (SD)], had better OS compared with patients with progressive disease (PD; P<0.01).

Baseline characteristics of HIPEC+ and HIPEC- patients

HIPEC+ group HIPEC- group
Characteristics All (n=23) Complete survival data (n=12) All (n=31) Complete survival data (n=21)
Gender, n
  Male 7 5 11 7
  Female 16 7 20 14
Age, years
  Median 43 44.5 53 52
  Range 18–68 31–68 24–77 24–66
Primary site, n
  Esophagogastric junction 1 1 1 0
  Gastric body 9 5 14 10
  Gastric antrum 10 5 9 6
  Diffuse gastric lesions 3 1 3 2
  Unkown 0 0 4 3
Pathology, n
  Well-differentiated 0 0 0 0
  Moderately differentiated 0 0 3 2
  Poorly differentiated 18 8 27 18
  Differentiation unknown 5 4 1 1
Radical surgery, n
  Yes 4 4 8 5
  No 19 8 23 16

HIPEC, hyperthermic intraperitoneal chemotherapy.

Correlation analysis between baseline characteristics and overall survival (n=33)

Variables P-value
Gender 0.102
Age 0.967
Primary site 0.731
Pathology 0.910
Radical operation 0.178

Clinical results of GC patients with PM treated with CRS and HIPEC.

Temperature (°C)
Authors (Refs.) Publication year Country No. of patients Drug regimen Inflow Outflow Median survival (months) 1-year survival rate (%)
Fujimoto et al (25) 1997 Japan 48 MMC 44.5–45.0 43–44 54.0
Beaujard et al (26) 2000 France 42 MMC 46–49 36–43 48.0
Mussa et al (27) 2001 Italy 7 MMC 42–43 68.0
Yonemura et al (28) 2005 Japan 107 MMC, CDDP, ETP 42–43 11.5 35.5
Glehen et al (29) 2010 France 159 MMC, CDDP or OXIRI, 5-FU 40–43 9.2 43.0
Yang et al (30) 2010 China 21 Hydroxycamptochecin or CDDP, MMC 43 50.0
Yang et al (31) 2011 China 34 MMC, CDDP 43 11.0 41.2
Magge et al (32) 2013 USA 23 MMC, CDDP 42 9.5 50.0

GC, gastric cancer; PM, peritoneal metastasis; CRS, cytoreductive surgery; HIPEC, heated intraoperative intraperitoneal chemotherapy; CDDP, cisplatin; MMC, mitomycin; PT, paclitaxel; ETP, etoposide; OX, oxaliplantin; IRI, irinotecan; 5-FU, 5-flourouracil.