Table 1.
Examples of preclinical and clinical studies on the efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).
| Active Pharmaceutical Compounds | Type of PIPAC | Experimental Model/Ex Vivo, In Vivo, Clinical Trial | Cancer Type | Outcome | Reference |
|---|---|---|---|---|---|
| 1. Tracers and chemotherapeutics | |||||
| Doxorubicin | PIPAC | Pig/ex vivo | Fresh tissue samples of swine peritoneum | The study evidenced a heterogeneous drug distribution pattern of ex vivo PIPAC, indicating a significantly higher penetration depth of the drug in tissues directly exposed to the aerosol jet in comparison with the ones placed on the side wall and the top of the box. | [43] |
| Doxorubicin | PIPAC | Pig/ex vivo | Fresh postmortem swine peritoneum | Ex vivo data suggested that a higher drug dose and a closer positioning of the Micropump towards the tissue samples could assist in a superior drug penetration. Nevertheless, an increase in internal pressure did not significantly change the penetration depth of doxorubicin. Furthermore, changing the drug concentration and position of the nozzle, as well as increasing the pressure, cannot noticeably give rise to a more homogenous drug distribution pattern. | [46] |
| Methylene blue | PIPAC | Pig/in vivo | Healthy animal | Significant improvement in both the biodistribution and penetration of the test substance in the peritoneal cavity in a large animal model compared to peritoneal lavage. | [21] |
| Methylene blue | PIPAC | Pig/in vivo | Healthy animal | First description and development of basic principles of the PIPAC procedure in vivo. This study showed that all exposed peritoneal surfaces were stained by the methylene blue, indicating the partial distribution of this active substance within the peritoneal cavity. | [31] |
| 99mTc-Pertechnetate (isotopes of the radioactive element technetium) | PIPAC | Pig/in vivo | Healthy animal | Using scintigraphic peritoneography, this study revealed the inhomogenous intra-abdominal distribution pattern of aerosol during the PIPAC procedure in a postmortem swine model. | [45] |
| Tracer substances (toluidine blue and DT01) | ePIPAC | Pig/in vivo | Healthy animal | Obtained data showed that electrostatic precipitation of aerosolized substances was technically feasible in all electrostatic PIPAC (ePIPAC) animals. Generally, ePIPAC affords homogenous staining of peritoneal surfaces and enhanced tissue uptake of tracers (up to tenfold) compared to PIPAC. | [37] |
| 99mTc-Pertechnetate/Doxorubicin/Methylene blue | HINAT | Pig/in vivo | Healthy animal | Hyperthermic intracavitary nanoaerosol therapy (HINAT) was introduced as an enhanced approach of PIPAC, generating hyperthermic unipolar-charged nanosized aerosols which can in turn provide a more uniform drug deposition throughout the peritoneal cavity along with significantly deeper drug penetration. | [47] |
| Indocyanine green/Cisplatin | H-PAC | Pig/in vivo | Healthy animal | In this study, a constant hyperthermic capnoperitoneum was created using a heating apparatus. The feasibility and safety of hyperthermic PIPAC (H-PAC) were shown in the porcine survival model. | [48] |
| Doxorubicin | PIPAC | Pig/in vivo | Healthy animal | Aerosolized drugs can reach all areas within the peritoneal cavity, although the highest penetration depth was observed in the peritoneal surfaces around the Micropump. | [44] |
| Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Advanced PC from gastric, appendiceal, and ovarian origin | Superior antitumor activity with a high local concentration and low systemic toxicity. Regression of peritoneal carcinomatosis (PC) in chemo-resistant tumors was observed using 10% of an usual systemic dose. | [20] |
| Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Recurrent, platinum-resistant ovarian, fallopian, or peritoneal cancer with peritoneal carcinomatosis | Safety and activity of PIPAC were assessed in patients. This approach resulted in an objective tumor response and histological tumor regression along with acceptable local and systemic toxicity. In general, 62% of patients in this trial achieved the clinical benefit. | [32] |
| Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Gastric peritoneal metastasis | PIPAC procedure was safe and induced an objective tumor response in 50% of selected patients. | [33] |
| Oxaliplatin | PIPAC | Human/clinical trial | Colorectal peritoneal metastasis | This retrospective analysis revealed that repeated PIPAC can induce considerable pathological responses in pretreated colorectal peritoneal metastases while causing less local toxicity. | [34] |
| Oxaliplatin/Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Peritoneal carcinomatosis | Safety and feasibility of PIPAC associated with systemic chemotherapy were explored. Preliminary data showed that this combination therapy did not lead to significant renal and hepatic toxicity. This combined treatment may be beneficial for patients with extraperitoneal disease or those at a high risk of disease development. | [35] |
| Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Peritoneal carcinomatosis | A retrospective cohort study assessed the objective tumor response in a pretreated population of women with peritoneal carcinomatosis. Results showed that PIPAC can preserve the quality of life; however, appropriate patient selection in terms of performance status and the number of previous surgeries should be take into consideration. | [41] |
| Doxorubicin + Cisplatin | ePIPAC | Human/clinical trial | Peritoneal metastasis of hepatobiliary-pancreatic origin | These preliminary results in human patients suggested that ePIPAC is well-tolerated and technically feasible and can induce the regression of biologically aggressive tumors. | [49] |
| Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Recurrent, platinum-resistant ovarian cancer | A preliminary clinical report on the activity of PIPAC provided evidence that PIPAC is well-tolerated in most patients and achieved an objective tumor response in 6/8 cases. | [50] |
| Doxorubicin + Cisplatin | PIPAC | Human/clinical trial | Peritoneal metastasis from pancreatic cancer | This case study reports on the activity of PIPAC through the induction of histologic regression in pretreated patients with systemic chemotherapy. | [51] |
| 2. Biomolecules and Nanoparticles | |||||
| Dbait (noncoding DNA fragments) coupled to cholesterol molecule and Cy5 | PIPAC | Human/ex vivo | Human sample of peritoneal carcinomatosis from an endometrial adenocarcinoma | The fluorescence signal was detected in the tumor nodules up to 1 mm in depth following aerosolization. On the contrary, no uptake was observed in the lavage sample. | [36] |
| Lipofectamin RNAiMAX/siRNA complexes | PIPAC | Human/ in vitro | Luciferase expressing ovarian cancer cell line (Luc SKOV3) | This study revealed the pronounced in vitro stability of complexes in ascites, as well as the noticeable transfection efficiency upon nebulization. | [52] |
| messengerMax/ Luc mRNA complexes | PIPAC | Rat/ in vivo | Healthy animal | First study demonstrating the feasibility of high-pressure nebulization of mRNA complexes to the peritoneal cavity of rats, affording a more homogenous distribution of luciferase mRNA expression in the entire peritoneal cavity compared to intraperitoneal injection. | [53] |
| Abraxane (albumin-bound paclitaxel) (FDA approved) | PIPAC | Human/clinical trial | Unresectable peritoneal metastasis from upper gastrointestinal, ovarian, or breast malignancies | Outcome to be determined. | [54] |
| 3. Nanoformulations potentially suitable for future implementation in PIPAC | |||||
| Nanotax® (nanoparticle formulation of paclitaxel) | IP administration | Human/clinical trial | Peritoneal malignacies | Compared to IV-administered paclitaxel, intraperitoneal (IP) administration of Nanotax® gives rise to higher paclitaxel (PTX) concentrations in the peritoneal cavity for a prolonged period of time, along with minimal sytemic exposure and a reduced toxicity. | [55] |
| 1. Nano-taxol (liposomal Paclitaxel) 2. Nano-platin (polymeric micelle cisplatin) 3. Nano-topotecan (polymeric micelle topotecan) 4. Doxil (pegylated liposomal Doxorubicin) (FDA approved) |
IP administration | Mouse/in vivo | Peritoneal metastasis of human ovarian cancer cell line (ES-2-luc) | This study indicated that systemic delivery of all tested nanomedicines failed to present a superior therapeutic efficacy compared with each free drug counterpart. In addition, IP delivery of these nanotherapeutics demonstrated a better antitumor activity only for Nano-taxol and Nano-topotecan when compared to corresponding free drugs. It is assumed that the structure of Abraxane and Doxil is considerably stable to release the encapsulated drug in the peritoneal cavity for the effective treatment of PC. | [56] |