The Pharmacokinetic And Efficacy Of Intraperitoneal Chemohyperthermia With Different Platinum For Treatment Of Gastric Adenocarcinoma With Peritoneal Metastasis

Background:Peritoneal metastasis is one of the most common site of recurrence of gastriccancer, but also lead to treatment failure, one of the root causes of patient death.Patients with peritoneal metastases often associated with massive ascites, intestinalobstruction, such as performance, seriously affecting the quality of life of patients.Due to factors peritoneum barriers, poor systemic chemotherapy treatment, theprognosis is poor. Intraperitoneal hyperthermic chemotherapy for its high local drugconcentration, long duration of action, light side effects, chemotherapy andhyperthermia synergies and other characteristics make up for these shortcomings, hasgradually become an important treatment for peritoneal metastasis in with advancedgastric cancer.Intraperitoneal chemotherapy for gastric cancer, at present, there is no uniformstandard medication at home and abroad. Platinum-based drugs have good prospectsin terms of anti-tumor. Cisplatin is considered the standard drug peritonealchemotherapy of malignant ascites efficacy, side effects, but many ears, kidneys,nerves, and gastrointestinal tract, such as significant, and prone to drug resistance,limiting the application in clinic. Oxaliplatin and lobaplatin have broad spectrumanti-cancer, anti-cancer activity, and no cross-resistance with cisplatin, liver andkidney toxicity and mild gastrointestinal reactions, etc., have a significant effectagainst stomach cancer. As intraperitoneal chemotherapy drugs cisplatin in addition toother platinum-based evidence based medicine is not sufficient, pharmacokineticstudies of platinum drugs in ascites has not been reported. Previous work, we haveobserved from experiments in vitro and in vivo clinical studies to significantly inhibit gastric lobaplatin growth of cancer cells and have a synergistic effect with heat;intraperitoneal drug safety as well, with significant pharmacokinetic advantages.Objective:We intend to peritoneal metastasis of gastric cancer patients with massive ascites,were given different platinum peritoneal perfusion chemotherapy, based on previousresearch work by studying a larger sample size, further clarify several platinum,especially lobaplatin as pharmacokinetic advantages of intraperitoneal drug, cisplatin,compared the efficacy and safety; hoping to provide the patient with a high efficiency,low toxicity and good tolerance treatment plan.Methods:1. In patients with peritoneal metastasis of gastric cancer with massive ascites forthe study, after informed consent, screening Eligible subjects were12cases of clinicalobservation, were randomly divided into four cases of cisplatin, oxaliplatin group offour cases, lobaplatin group of four patients underwent peritoneal perfusionchemotherapy, and when completed in intraperitoneal infusion is completed after30min,1,2,4,6,8,10,12,24h, respectively, venous blood, ascites each5mL. Aftercentrifugation, the serum specimens and ascites supernatant pharmacokineticcharacteristics analysis.2.40cases of gastric cancer patients with pathologically confirmed with massiveascites peritoneal metastasis Bethune University First Hospital of Jilin University,admitted to join this study into a row of standard randomized to cisplatin peritonealperfusion chemotherapy group (n=14), oxaliplatin intraperitoneal hyperthermicperfusion chemotherapy group (n=13) and lobaplatin peritoneal perfusionchemotherapy group (n=13), recently conducted clinical efficacy of three platinum,long-term efficacy compare and adverse reactions.Results:1. Analysis of pharmacokinetic characteristics(1) The comparison of peritoneal fluid concentrations of total platinum amongthree groups: peritoneal fluid total platinum peak, AUC, elimination half-life andperitoneal clearance among cisplatin group, oxaliplatin group and lobaplatin group, the difference was not statistically significant by analysis of variance (P＞0.05).(2) The comparison of plasma concentrations of total platinum among threegroups: The difference was not statistically significant about AUC among cisplatingroup, oxaliplatin group and lobaplatin group (P=0.858). Ptotal plasma peak andplasma clearance rate both oxaliplatin group and lobaplatin group were significantlyhigher than cisplatin group; the elimination half-life was significantly shorter thancisplatin group. Total plasma peak and elimination half-life in lobaplatin group wereless than oxaliplatin group; lobaplatin plasma clearance rate in oxaliplatin group.2. Clinical efficacy(1) short-term efficacy：The total effective rate was significantly higher in thehyperthermic intraperitoneal chemotherapy with oxaliplatin and lobaplatin group thanin cisplatin group.The total effective rate was highest among them. There weresignificant difference compared with cisplatin group.(P=0.033).(2) long-term efficacy：All patients were followed(last time of follow-up，March2015) for24mouths.The average time to ascites reduce in cisplatin group, oxaliplatingroup and lobaplatin group were1.59months,2.45months and3.08monthsrespectively (P＞0.05). The1year survival rate among three group was8.7%、11.0%and28.3%respectively (P＜0.05). the median survival among three group was6.9months,9.7months and10.6months respectively (P＜0.05).3. Toxic and adverse resection: Nausea and vomiting, renal dysfunction ofcisplatin group were significantly higher than oxaliplatin group and lobaplatin group(P<0.05). The incidence of abdominal pain and neurotoxicity of oxaliplatin weresignificantly higher than cisplatin group and lobaplatin group. Myelosuppression,liver dysfunction incidence was no significant difference.Conclusion:1. There are obvious ascites pharmacokinetic advantages by hyperthermicintraperitoneal Cisplatin, oxaliplatin and lobaplatin chemotherapy, providing atheoretical basis for clinical application.2. Plasma total platinum peak of oxaliplatin and lobaplatin in hyperthermicintraperitoneal chemotherapy is significantly higher than cisplatin, showing high absorptivity of body to oxaliplatin and lobaplatin. And the plasma half-life of both wissignificantly shorter than cisplatin, that reduces drug-induced toxicity and improvesthe bioavailability of the drug.3. The effect in hyperthermic intraperitoneal lobaplatin chemotherapy foradvanced gastric adenocarcinoma with peritoneal metastasis is significant inimproving the response rate and1-year survival.It have the upper hand overprolonging the average time to ascites reduce and median survival than cisplatin andoxaliplatin.4. As intraperitoneal chemotherapy, adverse reactions of lobaplatin is lighter thancisplatin and oxaliplatin, but there is obvious peritoneal irritation about oxaliplatin.Lobaplatin is safest and best tolerated among the three.5. In this study，the sample size is small，less and uneven after each set of datapackets. The data is not yet representative of the whole picture of pharmacokinetics，clinical efficacy and toxic.6. Hyperthermic intraperitoneal lobaplatin chemotherapy shows a unique featureof superiority regardless of the clinical efficacy or pharmacokinetic characteristics.