Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies

Drugs https://doi.org/10.1007/s40265-022-01828-7 REVIEW ARTICLE Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies Niels A. D. Guchelaar1 · Bo J. Noordman2 · Stijn L. W. Koolen1,3 · Bianca Mostert1 · Eva V. E. Madsen2 · Jacobus W. A. Burger4 · Alexandra R. M. Brandt‑Kerkhof2 · Geert‑Jan Creemers5 · Ignace H. J. T. de Hingh4,6 · Misha Luyer4 · Sander Bins1 · Esther van Meerten1 · Sjoerd M. Lagarde2 · Cornelis Verhoef2 · Bas P. L. Wijnhoven2 · Ron. H. J. Mathijssen1 Accepted: 12 December 2022 © The Author(s) 2023 Abstract Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease. Key Points 1 Introduction Intraperitoneal chemotherapy is a safe treatment option for patients with unresectable peritoneal surface malignancies. Solid tumors, especially gastrointestinal malignancies, and tumors of the female reproductive systems may spread to the peritoneal cavity [1–3]. Peritoneal dissemination is associated with a dismal prognosis and substantial morbidity, and survival rates are shorter than those of patients with nonperitoneal metastases [4–6]. Symptoms such as bowel obstruction and ascites have a negative impact on quality of life and overall survival. For patients with unresectable peritoneal dissemination, systemic chemotherapy is the cornerstone of the treatment, but the 5-year survival rate does not exceed 10% [7, 8]. Therefore, more effective treatments are needed [9]. The intraperitoneal effect of systemic chemotherapy is reduced by the peritoneal-plasma barrier [10]. The peritoneal-plasma barrier is a complex, three-dimensional structure of peritoneal cells, interstitial tissue space and microvessels, which regulates intraperitoneal homeostasis Several clinical studies in peritoneal metastases (e.g., gastric, ovarian, colorectal, and pancreatic cancer) suggest a survival benefit. More studies are needed to compare its efficacy to current standard (systemic) treatments and to establish the optimal treatment regime with intraperitoneal and systemic chemotherapy. Niels A. D. Guchelaar and Bo J. Noordman share first-authorship. * Niels A. D. Guchelaar Extended author information available on the last page of the article Vol.:(0123456789) N. A. D. Guchelaar et al. [11]. Already in 1955, Weisberger et al investigated the use of chemotherapy directly infused into the peritoneal cavity [12]. In this way, higher intraperitoneal concentrations of drugs can be achieved compared to intravenous administration [13, 14]. Furthermore, the peritonealplasma barrier limits absorption into the systemic circulation, thereby reducing systemic toxicity and prolonging exposure of cancer cells to the drug [15–17]. Intraperitoneal chemotherapy can be delivered in different ways. Normothermic repeated intraperitoneal chemotherapy is repeated for several cycles at the outpatient clinic, typically combined with systemic chemotherapy. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is administered in repeated cycles during laparoscopy. On the other hand, hyperthermic intraperitoneal chemotherapy (HIPEC) comprises a single heated intraperitoneal administration of anticancer drugs and is most often combined with cytoreductive surgery (CRS) [18]. Careful patient selection is essential to determine the optimal intraperitoneal treatment. Cytoreductive surgery-hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has a curative intent but is only an option for a minority of fit patients with limited resectable peritoneal disease. Intraperitoneal chemotherapy and PIPAC can be applied as palliatively intended treatment to patients with more advanced peritoneal surface malignancies, with conversion surgery as potentially curative option in selected cases [19–21]. Compared to PIPAC, intraperitoneal chemotherapy is less demanding, because it does not require serial laparoscopy and can be administered in an outpatient setting, whereas PIPAC might lead to enhanced uptake and deeper penetration into the tumor due to the pressurized application. Several reviews have focused on the use of intraperitoneal chemotherapy in combination with a resection [3, 22, 23]. This review gives an overview of intraperitoneal chemotherapy for unresectable peritoneal surface malignancies. We focus on the different intraperitoneally administered drugs and their pharmacokinetic characteristics and provide a systematic overview of the literature on the peritoneal implementable ports and clinical outcomes of intraperitoneal chemotherapy in the palliative setting. 2 Anticancer Drugs for Intraperitoneal Use Figure 1 summarizes characteristics that are pivotal for a drug to be used intraperitoneally [21, 24]. First, it is important that absorption of the drug through the peritonealplasma barrier into the systemic circulation is limited, to prevent systemic toxicity. Physical properties such as relatively high molecular weight, hydrophilic characteristics, and ionization can impede the peritoneal barrier to clear the drug rapidly [25]. Moreover, the drug should have rapid renal or hepatic clearance. In that way, the pharmacokinetic advantage of intraperitoneal chemotherapy with high local exposure and low systemic exposure is optim (...truncated)