Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study

Journal of Translational Medicine, May 2011

Background Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered as a promising treatment modality for gastric cancer with peritoneal carcinomatosis (PC). However, there have also been many debates regarding the efficacy and safety of this new approach. Results from experimental animal model study could help provide reliable information. This study was to investigate the safety and efficacy of CRS + HIPEC to treat gastric cancer with PC in a rabbit model. Methods VX2 tumor cells were injected into the gastric submucosa of 42 male New Zealand rabbits using a laparotomic implantation technique, to construct rabbit model of gastric cancer with PC. The rabbits were randomized into control group (n = 14), CRS alone group (n = 14) and CRS + HIPEC group (n = 14). The control group was observed for natural course of disease progression. Treatments were started on day 9 after tumor cells inoculation, including maximal removal of tumor nodules in CRS alone group, and maximal CRS plus heperthermic intraperitoneal chemoperfusion with docetaxel (10 mg/rabbit) and carboplatin (40 mg/rabbit) at 42.0 ± 0.5°C for 30 min in CRS + HIPEC group. The primary endpoint was overall survival (OS). The secondary endpoints were body weight, biochemistry, major organ functions and serious adverse events (SAE). Results Rabbit model of gastric cancer with PC was successfully established in all animals. The clinicopathological features of the model were similar to human gastric PC. The median OS was 24.0 d (95% confidence interval 21.8 - 26.2 d ) in the control group, 25.0 d (95% CI 21.3 - 28.7 d ) in CRS group, and 40.0 d (95% CI 34.6 - 45.4 d ) in CRS + HIPEC group (P = 0.00, log rank test). Compared with CRS only or control group, CRS + HIPEC could extend the OS by at least 15 d (60%). At the baseline, on the day of surgery and on day 8 after surgery, the peripheral blood cells counts, liver and kidney functions, and biochemistry parameters were all comparable. SAE occurred in 0 animal in control group, 2 animals in CRS alone group including 1 animal death due to anesthesia overdose and another death due to postoperative hemorrhage, and 3 animals in CRS + HIPEC group including 1 animal death due to anesthesia overdose, and 2 animal deaths due to diarrhea 23 and 27 d after operation. Conclusions In this rabbit model of gastric cancer with PC, CRS alone could not bring benefit while CRS + HIPEC with docetaxel and carboplatin could significantly prolong the survival with acceptable safety.

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Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study

Journal of Translational Medicine Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study Li Tang 0 Lie-Jun Mei 0 Xiao-Jun Yang 0 Chao-Qun Huang 0 Yun-Feng Zhou 0 Yutaka Yonemura 1 Yan Li 0 0 Department of Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Clinical Cancer Study Center , Wuhan, 430071 , P.R. China 1 NPO Organization to Support Peritoneal Dissemination Treatment , Kishiwada, Osaka , Japan Background: Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered as a promising treatment modality for gastric cancer with peritoneal carcinomatosis (PC). However, there have also been many debates regarding the efficacy and safety of this new approach. Results from experimental animal model study could help provide reliable information. This study was to investigate the safety and efficacy of CRS + HIPEC to treat gastric cancer with PC in a rabbit model. Methods: VX2 tumor cells were injected into the gastric submucosa of 42 male New Zealand rabbits using a laparotomic implantation technique, to construct rabbit model of gastric cancer with PC. The rabbits were randomized into control group (n = 14), CRS alone group (n = 14) and CRS + HIPEC group (n = 14). The control group was observed for natural course of disease progression. Treatments were started on day 9 after tumor cells inoculation, including maximal removal of tumor nodules in CRS alone group, and maximal CRS plus heperthermic intraperitoneal chemoperfusion with docetaxel (10 mg/rabbit) and carboplatin (40 mg/rabbit) at 42.0 0.5C for 30 min in CRS + HIPEC group. The primary endpoint was overall survival (OS). The secondary endpoints were body weight, biochemistry, major organ functions and serious adverse events (SAE). Results: Rabbit model of gastric cancer with PC was successfully established in all animals. The clinicopathological features of the model were similar to human gastric PC. The median OS was 24.0 d (95% confidence interval 21.8 - 26.2 d ) in the control group, 25.0 d (95% CI 21.3 - 28.7 d ) in CRS group, and 40.0 d (95% CI 34.6 - 45.4 d ) in CRS + HIPEC group (P = 0.00, log rank test). Compared with CRS only or control group, CRS + HIPEC could extend the OS by at least 15 d (60%). At the baseline, on the day of surgery and on day 8 after surgery, the peripheral blood cells counts, liver and kidney functions, and biochemistry parameters were all comparable. SAE occurred in 0 animal in control group, 2 animals in CRS alone group including 1 animal death due to anesthesia overdose and another death due to postoperative hemorrhage, and 3 animals in CRS + HIPEC group including 1 animal death due to anesthesia overdose, and 2 animal deaths due to diarrhea 23 and 27 d after operation. Conclusions: In this rabbit model of gastric cancer with PC, CRS alone could not bring benefit while CRS + HIPEC with docetaxel and carboplatin could significantly prolong the survival with acceptable safety. - Background The loco-regional progression of gastric cancer usually results in peritoneal carcinomatosis (PC), characterized by the presence of tumor nodules of various size, number, and distribution on the peritoneal surface as well as malignant ascites, with very poor prognosis [1-5]. Patients with gastric PC face a dismal outcome, with a median survival of about 6 months [6]. Current treatments for such PC are systemic chemotherapy, best support care and palliative therapy. In order to tackle this problem, a new treatment modality called cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed over the past 3 decades, taking advantages of surgery to reduce visible tumor burden, and regional hyperthermic chemotherapy to eradicate micrometastases [7-10]. Although many clinical studies have been performed to test and confirm the efficacy of this combined treatment approach, there is a lack of high quality evidence from phase III randomized prospective studies. In order to more objectively evaluate such treatment, it is necessary to study this treatment modality under experimental conditions, in which most of the confounding factors could be well controlled. In this respect, suitable animal models of PC are indispensable platforms. Small animal models of PC have been established, including mouse models and rat models [11-18]. In most of these animal models, cancer cells are injected directly into the peritoneum, which will result in widespread PC in due time. Such models have been used to test various treatment modalities, including CRS and HIPEC, either alone or in combination, producing valuable information on the validity of different therapies. The small body size and delicate hemodynamic conditions are limiting factors for complex surgical interventions. Large animal models (...truncated)


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Li Tang, Lie-Jun Mei, Xiao-Jun Yang, Chao-Qun Huang, Yun-Feng Zhou, Yutaka Yonemura, Yan Li. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study, Journal of Translational Medicine, 2011, pp. 53, 9, DOI: 10.1186/1479-5876-9-53