细胞减灭术加腹腔热灌注化疗联合靶向新药PDOX治疗胃癌腹膜癌

Experimental Study on the Efficacy and Safety of Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy Combined with Molecular Targeted Therapeutic Regimen Ac-Phe-Lys-PABC-DOX(PDOX) for Treating Peritoneal Carcinomatosis of Gastric Cancer

目的:观察细胞减灭术加腹腔热灌注化疗(CRS+HIPEC)联合靶向新药PDOX治疗胃癌腹膜癌(PC)的疗效和安全性。方法:将VX2瘤细胞注入40只新西兰兔胃窦部黏膜下,制成胃癌PC模型,随机分4组(n=10):Control组观察自然病程;HIPEC组行CRS+HIPEC;PDOX组和DOX组行CRS+HIPEC联合化疗(PDOX 50.0 mg/kg,DOX 5.0 mg/kg)。结果:模型成功率100%(40/40)。Control组中位生存期23.0 d(95%CI:19.9～26.1 d),HIPEC组41.0(36.9～45.1)d,PDOX组58.0(39.6～54.4)d,DOX组65.0(44.1～71.9)d。HIPEC组生存期较Control组延长70.0%以上(P<0.001),PDOX组和DOX组较HIPEC组延长40.0%以上(P=0.029、P=0.021)。DOX组化疗后WBC、PLT低于HIPEC组(P<0.05),各组间血液学指标差异无统计学意义(P>0.05)。结论:在CRS+HIPEC基础上,联合靶向新药PDOX可进一步延长胃癌PC模型生存期,毒性无明显增加。

Objective： This work aimed to study the efficacy and safety of cytoreductive surgery （CRS） plus hyperthermic intra -peritoneal chemotherapy （HIPEC） combined with targeting anti-tumor drug Ac-Phe-Lys- PABC-DOX （PDOX） for treating the gastric cancer rabbit models with peritoneal carcinomatosis （PC）. Methods：VX2 tumor cells were injected into the gastric sub-mucosa of 40 adult male New Zealand rabbits using a laparotomic inoculation technique and laparoscopy in order to construct the gastric cancer rabbit model with PC. The rabbits were randomly divided into 4 groups： the Control group （ n=10 ） without any treatment, the HIPEC group （n=10 ） receiving CRS plus HIPEC （docetaxel10 .0mg and carboplatin 50 .0 mg in250 mL normal saline, at42 .5 ± 0.5℃for 30 min）, the PDOX group （n=10 ） receiving systemic chemotherapy with PDOX 50 .0 mg/kg （10 .0 mg/kg every 4 d for 5 cycles） after CRS＋HIPEC, and the DOX group （n=10） receiving systemic chemotherapy with DOX 5.0 mg/kg （1.0 mg/kg every4 d for 5 cycles） after CRS＋HIPEC. The CRS＋HIPEC regimen was performed for a total of 8 d, while the systemic chemotherapy was initiated16 d after model construction. The primary endpoint was overall survival （OS）, and the secondary endpoint was safety profile.Results：Rabbit PC model was successfully established in all animals （100%,40 /40 ）. The median （95 % confidence interval [CI]） survivals were 23 .0 d （19 .9 d to 26 .1 d） in the Control group, 41 .0 d （36 .9 d to 45 .1 d） in the HIPEC group,58 .0 d （39 .6 d to 54 .4 d） in the PDOX group, and 65 .0 d （44 .1 d to 71 .9 d） in the DOX group. Compared with the Control group, the OS was extended by at least 70% in the HIPEC group （P〈0.001）. Compared with the HIPEC group, the OS was extended by at least 40 % in the PDOX and DOX groups （P=0.029, PDOX vs. HIPEC; P=0.021, DOX vs. HIPEC）. There were no differences in the blood cell count, liver and kidney functions, creatine kinase （CK）, CK-MB, and lactate dehydrogenase （LDH） between the 2 groups at the same time point. The values of white blood cell and platelet were significantly lower in the DOX than in the HIPEC group, after the systemic chemotherapy （ P〈0.05 ）. Conclusion：The regimen of CRS plus HIPEC could bring survival benefits to the gastric cancer rabbit model with PC. Furthermore, the addition of molecular targeted therapy with PDOX could bring about better survival benefits with more satisfactory drug safety.