In-vivo investigation of the cytotoxic effect of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) on human colonic cancer cells in a rodent peritoneal carcinomatosis model

腹膜癌病描述了胃肠道和妇科恶性肿瘤的晚期。大量患者在存在腹水、肠梗阻和黄疸等继发症状的情况下被诊断，这标志着他们的病情处于晚期。据报道，这些患者的平均生存期只有几个月，当局部肿瘤肿块有限，排便功能正常，一般状况良好时，可以考虑采用肿瘤细胞减灭术（CRS）联合腹腔温热化疗（HIPEC）。然而，CRS与HIPEC是一种广泛的外科手术，可能存在各种并发症。因此，这种唯一的治疗选择不适用于绝大多数患者，因为他们的身体状态或肿瘤进展可能不允许进行这种广泛的手术。在过去的几年中，一种新的实验性治疗方法，称为加压腹腔内气雾剂化疗（PIPAC），已在Marienhospital Herne推出，作为腹膜癌病的一种有价值的姑息治疗选择，正在迅速获得接受。本研究的目的是建立一种新的大鼠腹膜癌转移的体内PIPAC模型，以改善患者的预后和安全性。此外，本研究将通过组织病理学分析和客观肿瘤消退检测，密切检查所用化疗药物的渗透深度并测量其细胞毒性作用。为此，将培养市售的人结肠癌细胞以形成高度浓缩的肿瘤细胞悬液。然后通过腹膜下注射将该混悬液应用于大鼠，植入后3周，将发展为腹膜癌病。本实验将设3个研究组。第一组发生腹膜癌病，并接受三次PIPAC与奥沙利铂的应用，治疗间隔为6周。第二组发生腹膜癌病，不接受任何治疗，因此作为对照组。然后是第三组大鼠，其没有接受任何肿瘤细胞应用，也没有接受任何手术治疗，因此作为另一个对照，在第15周第三次应用PIPAC后，大鼠将不接受任何进一步的治疗，直到第22周。本研究设计的目的是唤起与人类相似的标准。在临床环境中，患者接受3个周期的PIPAC治疗，间隔6周。在第三个PIPAC周期后，患者将有三个月的PIPAC休息，并在其间接受分期检查。因此，本研究设计的目的是模拟我们患者的状况，以观察与对照大鼠相比，这种疗法是否有任何益处。此外，本研究旨在建立体内PIPAC模型。

Peritoneal Carcinomatosis describes the advanced stage of gastrointestinal and gynecological malignancies. A large number of patients is diagnosed in the presence of secondary symptoms such as ascites, bowel obstruction and icterus, which marks an advanced stage of their condition. These patients have a reported average survival of only a few months.When the local tumor mass is limited with regular bowl function present and good general state, cytoreductive surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) may be considered. However, CRS with HIPEC is an extensive surgical procedure with a wide range of possible complications. Thus, this only curative option is not applicable to the grand majority of patients as their body state or tumor progress may not allow such extensive surgery. In the last few years, a new experimental treatment alternative called Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) has been introduced at the Marienhospital Herne which is gaining rapid acceptance as a valuable palliative treatment option in peritoneal carcinomatosis. Its primary goals are ascites control and local tumor regressionTo improve patients’ outcome and safety, the aim of this study is to establish a novel in-vivo PIPAC model for peritoneal carcinomatosis in the rat. Moreover, this study will closely examine the penetration depth of the applied chemotherapeutic drug and measure its cytotoxic effect by histopathological analysis and detection of objective tumor regression. For this purpose, commercially available human colonic cancer cells will be cultivated to develop a highly concentrated tumor cell suspension. This suspension will then be applied to rats by means of a subperitoneal injection, which, 3 weeks after implantation, will develop into peritoneal carcinomatosis. There will be 3 study groups in this experiment. The first group develops peritoneal carcinomatosis and receives three applications of PIPAC with Oxaliplatin, at treatment intervals of 6 weeks. The second group develops peritoneal carcinomatosis and does not receive any treatment, and hence serves as a control group. Then there is a third group of rats which has not received any tumor cell application and does not receive any surgical treatment, and thus serves as another control.Following the third application of PIPAC in week 15, the rats will not receive any further treatment until week 22. The purpose of this study design is to evoke similar criteria as applied in humans. In the clinical setting, patients receive 3 cycles of PIPAC therapy with intervals of 6 weeks. Following the third PIPAC cycle, patients will have a three month PIPAC break and receive staging exams in between. Thus, the aim of this study design is to mimic our patients’ conditions to see whether there is any benefit to this therapy as compared to the control rats. Moreover, this study aims to establish an in-vivo PIPAC model.