State-of-the-Art Therapy in Peritoneal Carcinomatosis Management

Simple Summary

Pressurized Intraperitoneal Aerosol Chemotherapy is a novel therapy used in those with peritoneal carcinomatosis from various cancers, such as gastric, pancreatic, ovarian, and colorectal. Cancer is considered advanced disease when it spreads to the peritoneum (the layer lining inside the abdomen) and can be challenging to treat. Invasive open abdominal surgery to remove all of the tumors and instill chemotherapy has been the standard of care when applicable; however, it exposes patients to prolonged hospital care, intensive care admission, and significant side effects. Pressurized Intraperitoneal Aerosol Chemotherapy is aimed at treating those with peritoneal carcinomatosis in a minimally invasive fashion, which promotes shorter hospital courses and fewer side effects while maintaining great efficacy. The purpose of this paper is to review the novel treatment method.

Abstract

This paper reviews the surgical management of peritoneal carcinomatosis as new surgical methods have been developed within the past few decades. Traditional methods included cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; however, a new method has been developed, Pressurized Intraperitoneal Aerosol Chemotherapy. This method is minimally invasive while allowing for promising outcomes in those who have exhausted therapy options or require palliative therapy. The goal of this paper is to compare and contrast the traditional and standard method with the newer method for intraoperative delivery of chemotherapy.

1. Introduction

Peritoneal carcinomatosis (PC) is an advanced stage of malignancy commonly associated with gastrointestinal and gynecologic cancers, including gastric, pancreatic, colorectal, and ovarian cancer [1]. Historically, the management of PC has been challenging due to its diffuse nature and limited response to systemic chemotherapy [1]. Standard treatment approaches have included cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), which has demonstrated survival benefits in patients [2]. However, HIPEC is a highly invasive procedure associated with significant perioperative morbidity and extended recovery times [3].

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as an innovative intraperitoneal drug delivery technique designed to enhance the local therapeutic effects of chemotherapy while minimizing systemic toxicity [4]. PIPAC utilizes a minimally invasive laparoscopic approach to administer aerosolized chemotherapy under pressure, achieving a more homogeneous distribution across the peritoneal cavity and deeper tissue penetration [5]. Compared to HIPEC, PIPAC allows for repeated treatment cycles and is particularly suited for patients with inoperable or chemotherapy-resistant peritoneal metastases [6].

Several studies have evaluated the feasibility, safety, and oncologic outcomes of PIPAC across various malignancies [7]. Numerous meta-analyses and clinical trials have reported promising results, particularly in patients with peritoneal metastases from ovarian, gastric, and colorectal cancer. However, although PIPAC shows potential as a disease-modifying therapy, further studies are needed to establish standardized protocols, determine optimal chemotherapeutic regimens, and compare its efficacy with conventional treatments [8].

This review aims to provide a comprehensive analysis of PIPAC, focusing on its procedural aspects, clinical applications, oncologic outcomes, and future directions in the management of peritoneal carcinomatosis.

2. Peritoneal Carcinomatosis

Peritoneal carcinomatosis is advance disease characterized as small tumor deposits localized to the inner surface of the visceral and parietal peritoneum [9]. PC is the end-stage expression of various gastrointestinal and gynecological malignancies that have disseminated their growth into the peritoneal cavity and onto the outer surfaces of abdominal and pelvic organs [1,10,11]. The peritoneum is a thin and highly vascular membrane, PC grows superficially and remains small in size; therefore, rare the risk of tumor invasion into the abdominal wall muscles and serosa is relatively low.

Single tumor cells or clusters of cells from the primary tumor lose cell–cell adhesion from the primary site and pass into the peritoneal cavity. The peritoneal fluid then transports these cells through capillary or lymphatic pathways prior to preferential seeding onto the peritoneum. Another method of PC formation comes from iatrogenic peritoneal seeding. This may occur from surgical handling or disruption of cancer-contaminated blood and lymphatic channels or by tumor cell spillage. An additional route for PC formation is through hematologic spread [11].

Preoperative diagnostic tests based on computed tomography (CT) scanning and magnetic resonance imaging (MRI) are limited in their capacity to capture localized PC due to insufficient sensitivity for the sparse volume of disease. However, direct peritoneal visualization through surgery is considered the preferential diagnostic standard of care [10]. Despite PC being limited to the peritoneal surface, surgical removal and systemic chemotherapy is not feasible due to diffuse spread, residual microscopic disease, and burden on a patients’ already advanced condition. Consequently, PC is often associated with a poor prognosis and deteriorates total survival for patients with gastrointestinal cancer [12].

Methods of manifestation of PC differ among primary cancers. Gastric cancer is the third most common cause of cancer-related deaths in the world and the fifth most diagnosed cancer type. Only 25% of patients will survive for up to five years. Most patients are diagnosed in advanced stages; PC is especially frequent and present in 15–30% of patients at diagnosis [13]. When the gastric serosa is invaded by a tumor, half of the patients with advanced gastric cancer will develop peritoneal carcinomatosis despite radical surgery [10]. Additionally, 40–60% of patients treated with a curative gastrectomy and systemic chemotherapy will develop PC as the only site of recurrence [13]. PC from gastric cancer has a worse prognosis than PC from colorectal cancer (CRC) [10,14]. In actuality, PC incidence may be higher due to the relatively low rate of detection of small disease nodules by current diagnostic tools, as up to 80% of the patients who have died from CRC had PC that was not known until the autopsy [15]. About 5% of the CRC patients are diagnosed with metastatic disease to the peritoneum. Another 5% develop metastases to the peritoneum after 6 months following the resection of their primary tumor. Nearly half of the patients develop isolated peritoneal disease, i.e., without extra-abdominal metastases [16]. Interestingly, it was noted that those with mucinous cancers originating from either CRC or appendiceal cancer actually had worse outcomes when total peritonectomy and/or complete cytoreductive surgery was not achieved [17]. This further illustrates the importance of cytoreductive surgery before HIPEC.

PC from GC has a better prognosis than PC from pancreatic cancer [10,14]. Although pancreatic cancer comprises 4.5% of all cancer deaths in the world, it is one of the most fatal with a median five-year survival rate of 10%. Contributing to 85% of all diagnosis of pancreatic cancer is pancreatic ductal adenocarcinoma, which arises in the exocrine glands of the organ. One of the main metastatic pathways of pancreatic ductal adenocarcinoma is peritoneal dissemination. The peritoneum is the second most common metastatic site after the liver, and PC is present in 50% of patients with pancreatic cancer at the time of death. Approximately 9% of pancreatic ductal adenocarcinoma cases already have established peritoneal metastases at the time of diagnosis. PC was found in 33% of autopsied patients who passed away from recurrence following potentially curative resection of pancreatic ductal adenocarcinoma [11]. In other retrospective studies, PC was found in 25–50% of the patients who passed from pancreatic ductal adenocarcinoma with or without systemic treatment or surgery [11,18,19,20]. The anatomical arrangement of the primary tumor may be a determinant in the development of PC. For instance, the tail of the pancreas is situated within the intraperitoneal space while the rest is located retroperitoneally, deep within the upper abdomen in the epigastrium. When pancreatic ductal adenocarcinoma progresses, cancer cells released from the surface of the tumor can adhere and invade peritoneal tissues and organs [11].

Epithelial ovarian cancer is the most common cause of gynecologic cancer-associated death [9]. Due to the absence of symptoms of epithelial ovarian cancer in early disease, roughly 80% of patients present at the advanced stage, which is represented by widespread intra-abdominal disease with peritoneal metastases signifying PC. Recurrences of PC are frequently found in patients that relapse, causing ascites, small bowel obstruction from extrinsic compression, and infiltration of the mesentery, ultimately leading to death. The specific intra-abdominal and superficial growth pattern of epithelial ovarian cancer metastases suggests a complex interaction between peritoneal cells and epithelial ovarian cancer cells [9].

3. Treatment Options for Peritoneal Carcinomatosis

Cytoreductive surgery (CRS) is a comprehensive surgical removal of all macroscopic peritoneal disease. CRS is comprised of various visceral or parietal peritoneal procedures such as pelvic peritonectomy, omentectomy, splenectomy, and many others [2,21]. CRS is a complex, multi-step procedure aimed at attaining complete macroscopic tumor removal (complete cytoreduction). It involves a combination of peritoneal resections and visceral organ excisions, tailored to the extent and dissemination of peritoneal disease. Standard components of CRS include peritonectomy procedures which involve systematic removal of the parietal peritoneum, including pelvic, diaphragmatic, and anterior abdominal peritonectomy [22]. Additionally, visceral resections such as omentectomy, splenectomy, and bowel resections may be necessary, depending on tumor involvement. Advanced surgical techniques, including electrosurgical and ultrasonic dissection, are often used to minimize bleeding and preserve critical structures. Furthermore, intraoperative assessment using the completeness of cytoreduction (CC) score is critical in evaluating residual disease post-resection, with a CC-0 score (no visible disease) being associated with the best prognosis [23,24]. PC is largely resistant to low intraperitoneal concentrations of chemotherapy, and systemic chemotherapy is minimally effective even when combined with CRS [25,26].

Unlike hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC) does not utilize hyperthermia. EPIC is delivered in several cycles to areas of high recurrence risk in the peritoneal cavity, through a system of catheter/subcutaneous port and outflow drain [2,21,25]. EPIC has the advantage of administering multiple cycles of chemotherapy over a 24 h period, with 23 h to interact with the tumors. The chemotherapy agent exposure of the peritoneal surface tissue is sustained over time, thus maximizing cell-cycle-phase-specific cytotoxic efficacy [25]. The most common drug used in EPIC is 5-fluorouracil, which has a high first-pass effect after portal absorption [27]. However, as the chemotherapeutic agents linger in the peritoneal cavity, there is an increased risk of systemic absorption and adverse effects. An increased risk of infection—such as surgical site infections at the incision and abdominopelvic infections—and other postoperative complications have been reported in patients who have received EPIC compared to HIPEC [25,28].

Bidirectional Intraperitoneal and Systemic Chemotherapy (BIPSC) and Neoadjuvant Intraperitoneal and Systemic Chemotherapy (NIPS) comprise the administration of both systemic and intraperitoneal chemotherapy followed by CRS. This method aims to reduce the tumor burden, excise residual macroscopic lesions with CRS and HIPEC, and destroy the remaining microscopic peritoneal deposits through EPIC [2]. NIPS is delivered via a peritoneal port or catheter system, which allows high local concentrations of the chemotherapeutic agent to be directly instilled into the abdominal cavity. This targeted delivery helps reduce the tumor burden by acting on microscopic peritoneal deposits while concurrent systemic chemotherapy addresses potential micro-metastases. In contrast, HIPEC is administered intraoperatively—immediately following CRS—where the heated chemotherapeutic solution is circulated throughout the peritoneal cavity [25,26,29,30]. There are disadvantages to this treatment option: non-uniform intraperitoneal drug delivery due to adhesions, and extensive fibrosis, which can impede surgical judgment, causing increased morbidity and mortality upon further surgical intervention. NIPS is a promising approach that may be of benefit in the management of peritoneal metastases from gastric cancer [25]. When comparing all these methods, CRS and HIPEC is, currently, considered the best therapeutic route for patients with PC. Since the introduction of these techniques, the life expectancy of patients has significantly improved, with survival increasing from 3–24 months to 40–62 months depending on the primary malignancy type [2].

4. Procedural Considerations of HIPEC

HIPEC is performed in the operating room directly following CRS and before any digestive reconstruction or diversion. Surgery without HIPEC can trigger fibrin entrapment of residual microscopic intra-abdominal disease, leading to quick recurrence and progression of PC [25]. Also, performing HIPEC following surgical recovery as opposed to directly after CRS is ineffective due to adhesions that can form barriers, causing uneven drug delivery and possible treatment failure [25].

Optimal CRS is crucial as the penetration of the chemotherapeutic agent is limited to 2–5 mm [21]. Chemotherapeutic agents are heated to 41–43 °C, then administered locoregionally into the peritoneal cavity. Constant hyperthermia of the chemotherapeutic agent is achieved through a continuous circuit with a pump and heat exchanger while performing temperature monitoring. During the procedure, temperature probes are strategically placed at varying sites of the circuit and intraperitoneal cavity (the heat generator, inflow and outflow drains, bladder, liver, and mesentery) [25]. The idea behind HIPEC is to rid the peritoneal surface of any residual microscopic disease [25]. For an even distribution of fluid into the peritoneal cavity, the patient’s abdomen is gently manipulated for roughly 1–1.5 h. Once this is completed, the fluid is drained, and the incision is closed carefully.

There are various mechanisms that explain the efficacy of HIPEC. First, high temperatures augment cytotoxicity of chemotherapeutic agents. Hyperthermia in the range of 41 to 43 °C selectively destroys malignant cells [23]. Second, there is preferential destruction of tumor cells since their mitochondria and lysosomes are more susceptible to hyperthermia. Lastly, there is an increased penetration depth of chemotherapy into tumor nodules due to the elevated temperatures [2,25]. Although the reversible impact of RNA synthesis inhibition and arrest of mitosis are indiscriminate, the hyperthermic consequence of increased lysosome numbers and lysozyme activity are partial to malignant cells, resulting in increased destructive capacity [23,31]. Also, in a hyperthermic state, most malignant tumors exhibit a decreased blood flow or even complete vascular stasis within their microcirculation relative normal tissues [23,31]. Moreover, hyperthermia imposes inhibition of tumor cell oxidative metabolism, leading to lactic acid accumulation and a decreased pH in the microenvironment of the malignant cell, which affects normal cell homeostasis. This synergism of consequences imposed by a hyperthermic environment on malignant cells results in their hastened cell death relative to normal cells [23].

In HIPEC, a chemotherapeutic agent is directly administered into the peritoneal cavity. Consequently, the agent is more concentrated than if it were administered intravenously as the chemotherapy needs to penetrate through the peritoneum–plasma barrier [21,32]. Additionally, since the chemotherapeutic agent is absorbed and circulated via the portal venous system, the chemotherapeutic agent becomes concentrated in the liver and may destroy parenchymal micro-metastases [33]. Pharmacologically, in malignant cells, heat enhances drug uptake by increasing membrane permeability and transport. The hyperthermic condition alters cellular metabolism and modifies drug pharmacokinetics and excretion-amplifying cytotoxicity. Alkylating agents like melphalan, cyclophosphamide, and ifosfamide have demonstrated additional effects such as enhanced tissue drug penetration, temperature-dependent drug action, and inhibition of cellular repair mechanisms. Although the locoregional heat application in HIPEC minimizes systemic adverse effects related to hyperthermia-enhanced drug toxicity, the chemotherapeutic agents used must display direct cytotoxic effects (cell-cycle-nonspecific) and lack significant local toxicity after intraperitoneal administration. Accordingly, agents requiring systemic metabolism for activation are unsuitable for this procedure [26,34].

HIPEC can be administered through two main methods: the open technique, commonly called the “Coliseum technique”, and the closed technique. In the closed abdomen technique, inflow and outflow lines are placed through distinct incisions. Then, the abdominal wall is closed prior to HIPEC administration. The main advantage of this method is the capacity to quickly reach and sustain hyperthermia, since there is little heat loss when the abdomen is closed. Another advantage is that this method increases intraperitoneal pressure. Thus, it may improve the ability of the chemotherapy to penetrate malignant tissue. Furthermore, the sealing of the abdominal cavity is achieved without exposure to the healthcare providers. However, there are disadvantages to the closed technique. The uneven distribution of chemotherapy, which may increase the frequency of complications and non-uniform treatment, can lead to hotspots and undertreated areas [23,25].

The uneven dispersal in the closed technique encourages the development of the open method, which allows for the manual dissemination of heat and cytotoxic solution. The open method involves the skin edges of the abdominal incision being held by a retractor through a running suture to ensure an open space within the abdominal cavity. A plastic sheet is integrated into this suture with a small opening in the center to permit the surgeon’s hand to access the abdomen and pelvis for handling during chemotherapy, typically with one inflow and two outflow catheters. Temperature probes are positioned close to the inflow catheters. Smoke evacuators are positioned to protect against any possible cytotoxic aerosol contamination. The main advantage of the Coliseum technique is the formation of a precise distribution of heat and cytotoxic drugs. The disadvantages are heat loss and potential drug leakage, increasing the possibility of exposure [23,25,35].

Drug regimens in HIPEC vary, with the choice contingent on the drug’s efficacy against the target disease and its compatibility with hyperthermia. Safety protocols for HIPEC in the operating room are imperative to protect staff from contact with the hazardous chemotherapeutic agents. Some safety practices include utilizing impermeable disposable sheets, restricting operating room entrance during HIPEC, and prominently broadcasting cautionary signs. Protective measures like double-layered gloves, non-permeable gowns, eye protection, and shoe covers are needed to ensure safety among staff. All materials exposed to the chemotherapy must be treated as biohazards and disposed of appropriately. Spills are managed hastily, anywhere from small spills needing protective garments and large spills mandating respirator masks and avoidance of aerosol production. High-power filtration masks and continuous fume hoods increase safety and ventilation. Cleaning post-HIPEC is performed with water and soap, without reactive bactericidal solutions, and all apparatuses are marked and washed carefully. These protocols ensure the least exposure risks and support rigorous practices of safety [3,23,35].

5. Outcomes After HIPEC

HIPEC performed in conjunction with CRS is a complex treatment method associated with considerable perioperative and postoperative challenges. Although the procedure offers significant survival benefits for patients who meet the strict selection criteria, the demanding nature contributes to a challenging recovery process characterized by high rates of postoperative complications and intensive care admissions [36,37].

5.1. Operative Demands of HIPEC and CRS

The combination of CRS and HIPEC is recognized as a highly demanding surgical procedure due to its complexity and duration. Depending on the extent of disease, CRS often involves the resection of multiple peritoneal and visceral structures, followed by the administration of heated chemotherapy to eliminate residual cancer cells. This process subjects patients to prolonged operative times, ranging from 5 to 10 h, with mean operative times of approximately 7 h, often complicated by significant fluid shifts, which contribute to hemodynamic instability [36,38,39]. During the procedure, there is significant intraoperative blood loss, resulting in transfusions, which are required in up to 74% of patients [40]. Consequently, patients frequently require aggressive intraoperative fluid management, with a median total volume of fluid of 11.050 L administered [41]. The operative stress is further compounded by the hyperthermic nature of the chemotherapy, which elevates core temperatures and further places metabolic strain on the patient [42]. Therefore, many patients require intensive care following surgery.

5.2. Long Postoperative Recovery

Patients undergoing CRS and HIPEC face an extensive recovery period, with median hospital stays of 17 days [43]. Recovery to baseline functionality may take several months, particularly for patients who experience postoperative complications, which occur in up to 40–60% of cases [44,45]. According to a review by Wajekar et. al., the most common complications include infections (15–30% of patients), gastrointestinal concerns including ileus and anastomotic leaks (10–20% of patients), and thromboembolic events (5–10% of patients) [46]. Pulmonary complications, including pleural effusions and pneumonia, occur in 5–20% of patients and are attributed to extensive fluid shifts and prolonged immobility during recovery, hence making the patient more susceptible to coagulopathy [47]. Enhanced Recovery After Surgery (ERAS) protocols have been increasingly adopted and implemented within practices to address these challenges. Studies show that ERAS protocols, which emphasize early mobilization, nutritional optimization, and multimodal pain relief, can reduce hospital stays by 2–4 days and lower complication rates by 15–20% [48,49]. However, they cannot entirely mitigate the physical and psychological toll of recovery, which often includes persistent fatigue, pain, and emotional distress [50].

5.3. ICU Admissions

Intensive Care Unit (ICU) admission is a frequent requirement following CRS and HIPEC, with rates ranging from 30% to 70% depending on institutional practices and patient selection [36,44]. The combined procedure compromises vascular and peritoneal integrity, resulting in third-spacing of fluids, hypovolemia, and substantial electrolyte disturbances [7]. To address these challenges, aggressive fluid resuscitation is frequently required to stabilize patients intra- and postoperatively [41]. Additionally, vasopressor support is necessary in approximately 20–40% of cases to maintain hemodynamic stability [46]. The average ICU stay ranges from 2 to 6 days, with extended stays occurring in the presence of complications such as abdominal sepsis, acute kidney injury, or multi-organ dysfunction [36,44]. Nosocomial infections, including pneumonia and bloodstream infections, are reported in 10–15% of ICU admissions, further complicating recovery [36,46]. Excessive fluid administration has been linked to increased rates of pulmonary complications and delayed recovery of bowel function. Recent studies advocate for restrictive fluid management approaches combined with advanced hemodynamic monitoring to optimize patient outcomes while minimizing complications [41].

6. Procedural Overview of Intraperitoneal Aerosol Chemotherapy (PIPAC)

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a minimally invasive procedure designed for the treatment of PC. Unlike conventional therapies, which often face challenges in delivering sufficient drug concentrations to peritoneal surfaces, PIPAC uses aerosolized chemotherapy under a controlled pressure to uniformly distribute the drug and enhance tissue penetration [4,5]. This approach improves local drug efficacy while reducing systemic toxicity, highlighting its effectiveness for malignancies associated with peritoneal metastases [51,52]. PIPAC employs laparoscopic techniques to administer chemotherapeutic agents in an aerosolized form. After establishing pneumoperitoneum, a nebulizer disperses the chemotherapeutic solution into a fine mist, which is delivered under a pressure of 12 mmHg at 37 degrees Celsius [4,53]. The pressurized environment ensures a consistent drug distribution across peritoneal surfaces and facilitates deeper tissue penetration, counteracting the high interstitial pressures within peritoneal metastases [4,51]. This method allows for the use of lower doses of chemotherapeutic agents, including cisplatin, doxorubicin, and oxaliplatin, while maintaining therapeutic efficacy [5,52]. Each PIPAC session lasts approximately 90 min and may be repeated every 4–6 weeks [6,51,54]. The procedure also enables intraoperative biopsies, providing opportunities for real-time evaluation of the tumor response and personalized adjustments to treatment regimens [52,55]. Figure 1 and Table 1 demonstrate the differences between HIPEC and PIPAC.

7. Outcomes After PIPAC

Within the past 20 years, the literature has steadily increased in reviewing and analyzing oncological outcomes in those who undergo PIPAC, with most being published within 2024. A wide variety of primary cancers causing peritoneal carcinomatosis were evaluated, ranging from ovarian to colorectal to gastric cancers, even pancreatic malignancies. Table 2. Depicts the differences of outcomes for those with various cancers who underwent PIPAC.

7.1. Ovarian Cancer

PIPAC has shown significant efficacy in managing peritoneal metastases from ovarian cancer. Multiple studies using cisplatin and doxorubicin have reported notable reductions in tumor burden, as reflected by lower Peritoneal Cancer Index (PCI) scores and histological regression [5,56,57]. A cohort study conducted by Tempfer et al. reported an objective tumor response (OTR) in 76% of patients and an improved PCI in 64% of patients [56]. Patients undergoing PIPAC have also reported improvements in quality of life, supporting its role in advanced-stage ovarian cancer, particularly in those with limited systemic treatment options [58].

Ovarian cancer is one of the most morbid gynecological malignancies, with an estimated 5-year survival rate of 39% [59]. It tends to present with advanced-stage disease (Stages III–IV), where most patients have limited treatment options [59]. In women with peritoneal carcinomatosis, roughly 25–90% of them are not suitable for optimal cytoreduction and exploratory laparotomy [59]. One retrospective study examined 23 patients who underwent PIPAC and found that the median overall survival was 8.2 months (95% confidence interval 4.4–10.3) [60]. This study also examined quality-of-life parameters where patients reported improved emotions. Of the twenty-three PIPAC patients, only three had severe adverse reactions—two ileus and one pulmonary embolism [60]. Nakamura et al. reported observations of a sub-cohort of a phase I clinical trial, where they examined outcomes following PIPAC with cisplatin and doxorubicin [61]. Within this cohort, there were no Clavien–Dindo surgical complications. Only one patient had severe abdominal pain in the setting of baseline partial small bowel obstruction symptoms [61]. These two studies illustrate the minimal adverse effects of PIPAC postoperatively, especially in a sick population. Typically, patients who undergo CRS and HIPEC have various serious complications following surgery, such as perforations, anastomotic leaks, pancreatic fistulas, biliary fistulas, chyle leaks, pleural effusions, and pneumonia [62]. Comparing these two methods, PIPAC has a favorable outcome compared CRS and HIPEC, meaning it is beneficial for those who may not be great surgical candidates.

7.2. Colorectal Cancer

In patients with colorectal cancer and peritoneal metastases, PIPAC with oxaliplatin presents a therapeutic alternative, especially for those who have exhausted systemic chemotherapy [8,52]. Multiple studies have documented favorable histological response rates and disease stabilization, demonstrating its potential as both a palliative and disease-modifying therapy [8,51]. Specifically, a study by Demtröder et al. reported OTRs in 71% of patients in a retrospective study [63]. The localized delivery of chemotherapy through PIPAC directly targets peritoneal metastases while minimizing systemic side effects [4].

The peritoneum is the second most common location for cancer spread in colorectal cancer, with a prevalence of 4–5%. In general, the prognosis is poor, with survival ranging from 6 to 9 months without treatment [64]. While most patients with colorectal peritoneal carcinomatosis have an extensive disease burden according to the Peritoneal Carcinomatosis Index (PCI), those deemed to have resectable disease (roughly 25% of patients) [65] typically undergo CRS and HIPEC, which has been shown to have an overall 5-year survival of 40–50% [65,66].

Interestingly, overall survival in PIPAC seems to be shorter compared to CRS and HIPEC. A systematic review performed in 2024 reviewed 11 studies examining the use of PIPAC in colorectal peritoneal carcinomatosis. Of these 11 studies, 5 were randomized control trials, 5 were retrospective cohort studies, and 1 was a prospective study. Of these 11 examined studies, 8 included overall survival following PIPAC, ranging from 8 to 37.8 months [67]. The study further evaluated the chemotherapeutic agents utilized and compared the survival rates. It was noted that patients in studies that utilized oxaliplatin and 5-Flurouracil and Leucovorin (administered intravenously in conjunction with PIPAC) had an overall survival ranging from 8 to 13 months [67]. Studies that used oxaliplatin alone had survivals ranging from 9.4 to 20.5 months [67]. This shorter overall survival may be due to a greater disease burden, as the median peritoneal carcinomatosis indexes of the observed studies ranged from 10.7 to 31 [67].

Another study, which examined the use of PIPAC with palliative chemotherapy, showed promise in increasing survival for unresectable colorectal peritoneal carcinomatosis [68]. The median progression-free survival was 10.0 months, and the overall survival was 17.5 months [68]. This demonstrates that PIPAC may be useful as a palliative measure to prolong survival in patients who have advanced diseases.

A phase one clinical trial was conducted in the United States, which examined the efficacy and safety of performing PIPAC in patients with appendiceal cancer who could not undergo CRS and HIPEC. The median overall survival that was observed among the four patients in this study was 12.0 months, with a median progression-free survival of 2.9 months [69]. Another study demonstrated decreased and stable ascites volumes in patients who had colorectal, appendiceal, and small bowel cancers and underwent at least two cycles of PIPAC [70].

7.3. Gastric Cancer

PIPAC has been successfully integrated into multimodal treatment strategies for gastric cancer patients with peritoneal dissemination [5,51]. The procedure reduces the tumor burden and enhances the efficacy of systemic therapies [55]. Recent research suggests that PIPAC enhances disease control and symptom management, supporting its role in comprehensive treatment plans for advanced gastric malignancies [51,55]. Notably, a study by Nadiradze et al. reported a histological response in 50% of patients through PIPAC [5].

Metastatic gastric cancer has a poor prognosis, especially when metastatic to the peritoneum [55]. It is proposed that the poor vascularity of the peritoneum makes it difficult for systemic chemotherapy to penetrate the peritoneal metastases, making them harder to eradicate [55]. Given this, PIPAC has become of interest for palliative treatment in patients with peritoneal metastatic gastric cancer. A newly published meta-analysis and systemic review comprising 18 studies evaluated the safety, feasibility, and overall survival of PIPAC in this patient population. It was noted that patients who underwent PIPAC had a shorter length of hospital stay for each treatment session, making it feasible for patients to undergo this procedure [55]. Twelve of the eighteen studies examined included data regarding the median overall survival, such that when combining these data, those who underwent one or two sessions had a higher mean overall survival [55]. While there is a variability in the length of survival, studies have demonstrated a median survival of 15.4 months to 20.1 months. This, therefore, showcases the utility of PIPAC as a palliative measure in peritoneal metastases from gastric cancer [71,72].

7.4. Pancreatic Cancer

While less commonly utilized in pancreatic cancer, PIPAC has shown potential in selected cases of peritoneal cancer [52,73]. The pressurized delivery system facilitates tumor control, slows disease progression, and provides symptomatic relief, particularly in patients with limited therapeutic options [51]. The ability to perform intraoperative biopsies during PIPAC also enables ongoing assessment of the disease status and treatment efficacy [51].

Pancreatic cancer is a devastating disease that is aggressive and tends to have a poor prognosis despite extensive treatment. The median overall survival of pancreatic cancer with peritoneal metastases is 7.6 months even with systemic chemotherapy given the poor blood supply [74]. A phase II controlled trial demonstrated a median overall survival of 15.6 months following PIPAC in those with peritoneal metastases. Interestingly, another study found a 50% reduction in pathological disease following PIPAC with oxaliplatin or cisplatin–doxorubicin [51,74]. Another phase II study demonstrated a median overall survival of 10 months with those who underwent PIPAC with nab-paclitaxel [75]. These phase II studies demonstrate prolonged overall survival when compared to systemic therapy; however, it appears that there is no consensus as to what chemotherapy agent should be used.

8. Safety and Tolerability

PIPAC’s minimally invasive approach results in a favorable safety profile that is associated with low procedural morbidity [4,55]. Common side effects of the procedure include mild nausea, abdominal discomfort, and fatigue [76]. Serious complications, such as bowel perforations, are rare [58]. The ability to repeat PIPAC sessions without significant cumulative toxicity further supports its utility in long-term management [51,52]. By achieving localized drug delivery with minimal systemic exposure, PIPAC offers a tolerable and effective therapeutic option for patients requiring prolonged treatment for peritoneal carcinomatosis [51,55].

9. Conclusions

PIPAC demonstrates great utility in treating peritoneal carcinomatosis in a variety of primary cancers, especially when considered for palliation. While it is a relatively new method of delivering chemotherapy, further studies are being conducted to better understand the efficacy, safety, feasibility, superiority compared to standard PC treatment (CRS and HIPEC), and survival of this treatment. From the current literature, it seems PIPAC is promising in reducing the burden of undergoing invasive surgery, reducing healthcare costs, and potentially improving patient outcomes and overall survival from devastating cancers.

Figure 1. Schematic depiction of PIPAC (left) versus HIPEC (right). Note how HIPEC (right) is carried out through a large laparotomy incision for which the skin is closed tightly after installing the instruments that deliver chemotherapy. This creates a closed circuit so that the chemotherapy can remain within the abdomen. Conversely, PIPAC has trocars inserted into the abdomen where the chemotherapy is instilled. Since the procedure is performed minimally invasively, the abdomen is essentially sealed. Created in BioRender. Kanadibhotla, S. (2025) [77].

Figure 1. Schematic depiction of PIPAC (left) versus HIPEC (right). Note how HIPEC (right) is carried out through a large laparotomy incision for which the skin is closed tightly after installing the instruments that deliver chemotherapy. This creates a closed circuit so that the chemotherapy can remain within the abdomen. Conversely, PIPAC has trocars inserted into the abdomen where the chemotherapy is instilled. Since the procedure is performed minimally invasively, the abdomen is essentially sealed. Created in BioRender. Kanadibhotla, S. (2025) [77].

Table 1. Table comparing and contrasting HIPEC and PIPAC.

Similarities	Differences
Both methods used for treatment of peritoneal cancers, including ovarian, colorectal, gastric, and mesothelioma	HIPEC: Primarily used for curative intent when combined with cytoreductive surgery
	PIPAC: Often used for palliative treatment in advanced and non-resectable cases
Both aim to minimize systemic toxicity and enhance drug penetration and distribution through direct chemotherapy application within the abdomen	HIPEC: Heated liquid chemotherapy directly applied within the abdomen
	PIPAC: Aerosolized chemotherapy sprayed under pressure
	HIPEC: Requires higher doses of chemotherapy
	PIPAC: Lower doses due to better tissue penetration
	HIPEC: Typically, a one-time treatment after cytoreductive therapy
	PIPAC: can be administered over multiple sessions
	HIPEC: Generally suitable for patients with resectable disease and who are good surgical candidates
HIPEC: Requires longer hospital stays for recovery after major surgery
PIPAC: Recovery is typically outpatient
PIPAC: Used for patients with more advanced disease or who are not surgical candidates for HIPEC

Table 1. Table comparing and contrasting HIPEC and PIPAC.

Similarities	Differences
Both methods used for treatment of peritoneal cancers, including ovarian, colorectal, gastric, and mesothelioma	HIPEC: Primarily used for curative intent when combined with cytoreductive surgery
	PIPAC: Often used for palliative treatment in advanced and non-resectable cases
Both aim to minimize systemic toxicity and enhance drug penetration and distribution through direct chemotherapy application within the abdomen	HIPEC: Heated liquid chemotherapy directly applied within the abdomen
	PIPAC: Aerosolized chemotherapy sprayed under pressure
	HIPEC: Requires higher doses of chemotherapy
	PIPAC: Lower doses due to better tissue penetration
	HIPEC: Typically, a one-time treatment after cytoreductive therapy
	PIPAC: can be administered over multiple sessions
	HIPEC: Generally suitable for patients with resectable disease and who are good surgical candidates
HIPEC: Requires longer hospital stays for recovery after major surgery
PIPAC: Recovery is typically outpatient
PIPAC: Used for patients with more advanced disease or who are not surgical candidates for HIPEC

Table 2. Table summarizing surgical outcomes of various cancers following PIPAC.

Cancer Type	Chemotherapy Agents	Overall Survival (OS)	Key Findings	Adverse Effects
Ovarian Cancer	Cisplatin, Doxorubicin	Median OS: 8.2 months [57]	76% OTR response in a cohort study conducted by Tempfer et al. [53] Improvement in PCI in 64% of patients [53] Enhanced quality of life	Mild to moderate adverse effects Severe reactions (3 patients out of 23): 2 ileus, 1 pulmonary embolism [57] Minimal postoperative complications Reduced systemic toxicity compared to HIPEC
Colorectal Cancer	Oxaliplatin, 5-Fluorouracil (5-FU), Leucovorin	Median OS: 8–37.8 months [64]	71% OTR response in a cohort study conducted by Demtröder et. al. [60] Disease stabilization	Mild to moderate adverse effects Localized toxicity (abdominal pain) Minimal systemic side effects No significant surgical complications
Gastric Cancer	Cisplatin, Doxorubicin	Median OS: 15.4–20.1 months [68,69]	Histological response in 50% of patients in a study by Nadiradze et al. [5] Enhanced tumor control and symptom management	Mild to moderate adverse effects Post-treatment abdominal discomfort Shorter hospital stays compared to HIPEC No major systemic side effects
Pancreatic Cancer	Oxaliplatin, Cisplatin-Doxorubicin, Nab-paclitaxel	Median OS: 15.6 months [48]	50% reduction in pathological disease [71] Slower disease progression	Mild to moderate adverse effects Minor abdominal pain No major surgical complications

Table 2. Table summarizing surgical outcomes of various cancers following PIPAC.

Cancer Type	Chemotherapy Agents	Overall Survival (OS)	Key Findings	Adverse Effects
Ovarian Cancer	Cisplatin, Doxorubicin	Median OS: 8.2 months [57]	76% OTR response in a cohort study conducted by Tempfer et al. [53] Improvement in PCI in 64% of patients [53] Enhanced quality of life	Mild to moderate adverse effects Severe reactions (3 patients out of 23): 2 ileus, 1 pulmonary embolism [57] Minimal postoperative complications Reduced systemic toxicity compared to HIPEC
Colorectal Cancer	Oxaliplatin, 5-Fluorouracil (5-FU), Leucovorin	Median OS: 8–37.8 months [64]	71% OTR response in a cohort study conducted by Demtröder et. al. [60] Disease stabilization	Mild to moderate adverse effects Localized toxicity (abdominal pain) Minimal systemic side effects No significant surgical complications
Gastric Cancer	Cisplatin, Doxorubicin	Median OS: 15.4–20.1 months [68,69]	Histological response in 50% of patients in a study by Nadiradze et al. [5] Enhanced tumor control and symptom management	Mild to moderate adverse effects Post-treatment abdominal discomfort Shorter hospital stays compared to HIPEC No major systemic side effects
Pancreatic Cancer	Oxaliplatin, Cisplatin-Doxorubicin, Nab-paclitaxel	Median OS: 15.6 months [48]	50% reduction in pathological disease [71] Slower disease progression	Mild to moderate adverse effects Minor abdominal pain No major surgical complications