Pressurized Intraperitoneal Aerosol Chemotherapy: The Road from Promise to Proof

In this issue of Clinical Cancer Research, Kim and colleagues report the results of a phase I trial of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin in patients with peritoneal metastases of gastrointestinal (GI) origin (1). PIPAC has been developed as an innovative drug delivery system that uses aerosolization of chemotherapy during laparoscopy to optimize the distribution and tumor penetration of intraperitoneally delivered drugs. Peritoneal metastases are a common but challenging manifestation of advanced GI and gynecologic cancer with poor survival with systemic chemotherapy. However, the attitude toward peritoneal metastases has changed dramatically over the last 30 years, moving from hopeless to potentially curable. This conceptual change was driven primarily by the introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) that showed very promising results (2). The goal of CRS is to remove all macroscopic disease. HIPEC is administered as an adjunct to eradicate micrometastasis. CRS-HIPEC is combined in a single intraoperative treatment and is reserved for a highly selected group of patients with surgically resectable peritoneal metastasis. This unique combination of surgery and intraperitoneal chemotherapy has complicated the understanding of the specific contribution of both interventions. Moreover, it has probably rather harmed than helped in utilizing the full potential of both. In contrast to HIPEC, PIPAC is currently being developed as a treatment aimed for patients with unresectable peritoneal metastases. During PIPAC, intraperitoneal drugs are delivered more evenly and efficiently by utilizing aerosolization. Furthermore, the use of high intraabdominal pressure, produced during laparoscopy, might enhance (tumor) tissue penetration (3). The main differences between PIPAC and HIPEC are highlighted in Fig. 1. To understand and exploit the full potential of PIPAC, we should follow a staged approach required for standard drug development and avoid premature clinical adoption without sufficient evidence, as was probably the case with HIPEC. Some initial steps in this direction are already taken. In contrast to wide variation in HIPEC protocols, PIPAC is highly standardized among centers utilizing it. Yet, despite this high level of standardization, the scientific basis for the chosen drug, dose, number of cycles and whether or not to combine PIPAC with systemic chemotherapy is often unclear. Kim and colleagues should be complimented for their efforts to define the optimal dose for oxaliplatin PIPAC through a phase I clinical trial, an essential step prior to further clinical testing and adoption into standard practice.

The primary aim of the study conducted by Kim and colleagues was to establish a dose that could be recommended for phase II studies. Although the MTD was not reached, the authors recommend a dose of 120 mg/m² for future phase II studies as this dose was considered safe and tolerable. This recommendation differs from another recently published phase I oxaliplatin-based PIPAC study reporting a MTD of 90 mg/m² (4). The discrepancy is not surprising because unlike Kim and colleagues, the French investigators used systemic chemotherapy prior to and in between two PIPAC cycles which confounded the assessment of PIPAC tolerability. At the end of the HIPEC procedure, the highly concentrated chemotherapy is removed. This is particularly relevant for the short ultrahigh dose of oxaliplatin administered in HIPEC. The short exposure minimizes absorption and prevents adverse effects of high systemic exposure. During PIPAC, all aerosolized chemotherapy remains in situ. This makes PIPAC, from a pharmacologic standpoint a systemic treatment with local potential rather than a local treatment. However, the minimal invasive surgical approach and low risk for complications creates the potential to perform PIPAC multiple times, which should be considered as an advantage over HIPEC.

The major pharmacologic advantage of intraperitoneal delivery of cytotoxic drugs is the high drug concentration that can be reached at the tumor site. However, platinum-based chemotherapy that is administered by PIPAC will be almost completely absorbed systemically (4, 5). Platinum-based drugs, like oxaliplatin are known to have a high passage through the plasma-peritoneal barrier after intraperitoneal administration. Therefore, special attention should be given to dose-limiting cumulative neurotoxicity after oxaliplatin-based PIPAC, mainly after repeated PIPAC cycles and/or previous oxaliplatin-based chemotherapy. Systemic toxicity is regarded less important after low-dose cisplatin PIPAC, because only 12.5%–25% of an intravenous dose is applied during PIPAC. The dose of 120 mg/m² proposed for oxaliplatin almost equals the intravenous dose of 130 mg/m².

In addition to the potential pharmacokinetic advantages, the enthusiasm to adopt PIPAC quickly has been fueled by promising initial efficacy data. However, response was often measured with assessments such as intraoperative tumor volume scoring with the peritoneal cancer index or evidence of pathologic response expressed as the peritoneal regression grade score. These biomarkers have significant limitations and cannot replace the most reliable endpoints overall survival and progression-free survival. Survival data, coupled with quality-of-life endpoints, should be considered as the gold standard to prove the added value of PIPAC compared with standard therapy. Although phase I studies are not designed to show efficacy, the survival data in this study by Kim and colleagues are quite disappointing and significantly inferior to other PIPAC studies (3). The reasons are likely multifactorial but the combination with systemic chemotherapy and the number of PIPAC cycles might be important factors. Before PIPAC can be considered as proven therapy, evidence from well-designed prospective clinical trials confirming the potential advantages suggested by pharmacologic data should be awaited.

Undoubtedly, the study by Kim and colleagues contributes to our understanding of PIPAC. However, the recommended phase II dose of 120 mg/m² of oxaliplatin can only be adopted when no systemic therapy is given in between PIPAC cycles. An ideal target population for a phase II trial with only oxaliplatin administered by PIPAC is difficult to define. We believe that a more sound approach to continue exploring the added value of PIPAC would be to conduct additional earlier phase trials to evaluate more agents and potential combinations. In these studies, distinction should be made between patients with peritoneal metastasis from gastrointestinal and gynecologic cancer origin. Attempting to rush into phase II trials without sufficiently sound and convincing early phase results will undoubtedly lead to disappointment and prevent the possibility of ever conducting a well-designed phase III trial that is required to irrefutably demonstrate the added value of PIPAC. This challenging road can only be taken when different specialists (e.g., surgeons, medical oncologists, and pharmacologists) work on study design and conduct together, a multidisciplinary approach that many existing and proposed studies seem to lack. But without it, PIPAC risks to forever remain a promise rather than a proven treatment.

N.P. van Erp reports grants from Astellas, Janssen Cilag, Ipsen, Bayer, Sanofi, and Pfizer outside the submitted work. L. Bijelic reports personal fees from Merce Electromedicina outside the submitted work. No disclosures were reported by the other author.