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

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.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial.

BACKGROUND: This randomized phase III study was to evaluate the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC) from gastric cancer. METHODS: Sixty-eight gastric PC patients were randomized into CRS alone (n = 34) or CRS + HIPEC (n = 34) receiving cisplatin 120 mg and mitomycin C 30 mg each in 6000 ml of normal saline at 43 ± 0.5°C for 60-90 min. The primary end point was overall survival, and the secondary end points were safety profiles. RESULTS: Major clinicopathological characteristics were balanced between the 2 groups. The PC index was 2-36 (median 15) in the CRS + HIPEC and 3-23 (median 15) in the CRS groups (P = 0.489). The completeness of CRS score (CC 0-1) was 58.8% (20 of 34) in the CRS and 58.8% (20 of 34) in the CRS + HIPEC groups (P = 1.000). At a median follow-up of 32 months (7.5-83.5 months), death occurred in 33 of 34 (97.1%) cases in the CRS group and 29 of 34 (85.3%) cases of the CRS + HIPEC group. The median survival was 6.5 months (95% confidence interval 4.8-8.2 months) in CRS and 11.0 months (95% confidence interval 10.0-11.9 months) in the CRS + HIPEC groups (P = 0.046). Four patients (11.7%) in the CRS group and 5 (14.7%) patients in the CRS + HIPEC group developed serious adverse events (P = 0.839). Multivariate analysis found CRS + HIPEC, synchronous PC, CC 0-1, systemic chemotherapy ≥ 6 cycles, and no serious adverse events were independent predictors for better survival. CONCLUSIONS: For synchronous gastric PC, CRS + HIPEC with mitomycin C 30 mg and cisplatin 120 mg may improve survival with acceptable morbidity.

Establishment and identification of a rabbit model of peritoneal carcinomatosis from gastric cancer.

BACKGROUND: Gastric cancer peritoneal carcinomatosis is a common clinical problem, but there are no suitable large animal models to study this problem. This study was to establish a stable rabbit peritoneal carcinomatosis model of gastric cancer using VX2 tumor, and analyze the clinico-pathological features. METHODS: VX2 tumor was implanted into 36 New Zealand rabbits by 3 methods: laparotomic orthotopic injection of cancer cells into the submucosal layer of the stomach (Group A), laparotomic implantation of tumor tissue into the greater omentum immediately beneath the gastric antrum (Group B), and percutaneous injection of tumor cells directly into the peritoneal cavity (Group C), 12 rabbits in each group. The animals were closely observed and detailed clinico-pathological studies were conducted. RESULTS: The success rates of peritoneal carcinomatosis formation were 100% (12/12), 91.7% (11/12) and 58.3% (7/12), respectively, for Groups A, B and C (P = 0.019, A versus C; P = 0.077, B versus C; P = 0.500, A versus B, Fisher's exact test). Two weeks after submucosal cancer cells injection in Group A, ulcerative gastric cancer with peritoneal carcinomatosis showed typical VX2 tumor pathology, with widespread intraperitoneal metastatic nodules, bloody ascites and perspicuous pulmonary metastases. The clinico-pathological progression pattern was very similar to patients of advanced gastric cancer with peritoneal carcinomatosis. Groups B and C showed similar pattern of cancer progression, but less aggressive. CONCLUSIONS: First large animal model of peritoneal carcinomatosis from gastric cancer has been established by laparotomic orthotopic injection of VX2 cancer cells into the submucosal layer of the stomach, providing a more suitable model for surgical interventional studies. The clinico-pathological features of this model resemble human peritoneal carcinomatosis.

A Logistic Regression Model for Noninvasive Prediction of AFP-Negative Hepatocellular Carcinoma.

α-Fetoprotein is commonly used in the diagnosis of hepatocellular carcinoma. However, the diagnostic significance of α-fetoprotein has been questioned because a number of patients with hepatocellular carcinoma are α-fetoprotein negative. It is therefore necessary to develop novel noninvasive techniques for the early diagnosis of hepatocellular carcinoma, particularly when α-fetoprotein level is low or negative. The current study aimed to evaluate the diagnostic efficiency of hematological parameters to determine which can act as surrogate markers in α-fetoprotein-negative hepatocellular carcinoma. Therefore, a retrospective study was conducted on a training set recruited from Zhongnan Hospital of Wuhan University-including 171 α-fetoprotein-negative patients with hepatocellular carcinoma and 102 healthy individuals. The results show that mean values of mean platelet volume, red blood cell distribution width, mean platelet volume-PC ratio, neutrophils-lymphocytes ratio, and platelet count-lymphocytes ratio were significantly higher in patients with hepatocellular carcinoma in comparison to the healthy individuals. Most of these parameters showed moderate area under the curve in α-fetoprotein-negative patients with hepatocellular carcinoma, but their sensitivities or specificities were not satisfactory enough. So, we built a logistic regression model combining multiple hematological parameters. This model presented better diagnostic efficiency with area under the curve of 0.922, sensitivity of 83.0%, and specificity of 93.1%. In addition, the 4 validation sets from different hospitals were used to validate the model. They all showed good area under the curve with satisfactory sensitivities or specificities. These data indicate that the logistic regression model combining multiple hematological parameters has better diagnostic efficiency, and they might be helpful for the early diagnosis for α-fetoprotein-negative hepatocellular carcinoma.

Oral gastrografin radiography for the evaluation of the functional impact of peritoneal carcinomatosis: Correlation with clinicopathological findings.

This study was conducted to evaluate the functional impact of peritoneal carcinomatosis (PC) on the gastrointestinal system by oral gastrografin radiography (OGR). OGR was performed on 105 patients with PC from abdominal malignancies. The OGR characteristics were analyzed and compared with intraoperative observations. OGR provided real-time dynamic information on the functional impacts of PC. The OGR findings were normal in 9 (8.6%) and abnormal in 96 (91.4%) cases. In terms of frequency, 33 cases (31.4%) exhibited mild intestinal aggregation and flattening of the intestinal mucosa; 29 cases (27.6%) exhibited limited intestinal invasion, marginally stenotic small bowel and mucosal deformities; 26 cases (24.8%) exhibited only mild mesenteric contracture and mild slowing of gastrointestinal peristalsis; 5 cases (4.8%) exhibited obvious mesenteric contracture, ball-like changes, fixed position and disappearance of the intestinal mucosa; 2 cases (1.9%) exhibited complete pyloric obstruction; and 1 case (0.9%) exhibited duodenal obstruction. Gastric PC was associated with a higher percentage of stomach filling defects and small intestinal aggregates compared with PC from other malignancies (P<0.01 for both). In 87 cases, the ORG findings were in accordance with the intraoperative findings (κ=0.726, P<0.001), whereas 17 cases (16.2%) were underestimated and 1 (0.9%) was overestimated by OGR. This study indicated that OGR may be a useful technique for the evaluation of the functional impacts of PC on the gastrointestinal system and may help optimize the selection of patients for treatment.