Real-world data on Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)-directed therapy in patients with peritoneal metastases; Third annual report from the ISSPP PIPAC database

Introduction

Peritoneal metastasis (PM) is a common end-stage disease in patients with gastrointestinal or gynecological cancers. Patients with PM suffer from ascites, bowel obstruction, general fatigue, and reduced quality of life [1], 2]. Systemic chemotherapy has limited effect on PM and most patients have a bad prognosis [3]. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)-directed treatment was introduced a decade ago as a palliative treatment in patients with PM, striving to overcome some of the limitations of systemic chemotherapy [4].

In 2020, PIPAC reached stage 2b of the IDEAL framework, and a prospective international PIPAC database was launched by the International Society for the Study of the Pleura and Peritoneum (ISSPP). Information about the database and initial results have been published by the first two annual ISSPP PIPAC reports [5], 6]. These annual reports, together with several retrospective as well as phase 1 and phase 2 studies, have provided insights into the potential oncological application and effects of this treatment platform [7]. However, due to lack of comparative studies, PIPAC is still considered an experimental treatment. The ISSPP PIPAC database is, therefore, considered essential for monitoring real-world data in terms of indications, safety, and potential effects of PIPAC, while awaiting data from randomized controlled trials.

This study covers the third annual report from the ISSPP PIPAC database with an updated summary of all recorded data between launch of the database in June 2020 and November 1st, 2024. Registered data were analyzed and monitored in light of present PIPAC-related evidence.

Methods

This study analyzed data entered into the prospective ISSPP PIPAC database between the official launch on June 15th, 2020, and November 1st, 2024.

A general overview of reporting centers and patient characteristics was combined with a focus on procedure-related complications, response evaluation, follow-up, and survival. The peritoneal regression grading score (PRGS) or an unspecific “non-PRGS” classification was used for response evaluation. Surgical complications were graded using the Dindo–Clavien classification (DC) [8], and adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. We hypothesize, that data from the ISSPP PIPAC database aligns with existing literature in terms of patient selection, procedures, complications, and treatment outcomes.

Information regarding the ISSPP PIPAC database’s software, funding, governance, legal aspects, variables, and implementation have been described previously [6]. In short, the ISSPP PIPAC database is based on a REDCap platform [9] funded and hosted by Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark, in collaboration with Odense PIPAC Center (OPC).

Results

PIPAC centers

The ISSPP PIPAC database contained 1126 patients who were treated with 3224 PIPAC-directed treatments as of November 1st, 2024. Thirty-one PIPAC centers were registered, of which 17 (55 %) had reported data to the database during this time (Figure 1).

Figure 1:

PIPAC centers registered in the ISSPP PIPAC database worldwide (left) and in Europe (right). Red dots represent centers actively reporting patient data. Blue dots indicate centers that have not yet reported patient data.

Survival and PRGS

Patients with gastric cancer or colon cancer with mean PRGS ≤2 at PIPAC 1 had a longer overall survival than patients with mean PRGS >2 (Figure 2). A similar observation was made at PIPAC 2 (Figure 3) and PIPAC 3 (Figure 4, available as Supplementary data) for patients with gastric cancer, colon cancer, ovarian cancer, pancreatic cancer, and appendix cancers. No Kaplan–Meier analysis was performed in patients with colon cancers at PIPAC 3 due to no patients with minimal/no response (mean PRGS >2) (Figure 4, available as Supplementary data).

Figure 2:

Overall survival based on peritoneal regression grading score (PRGS) at PIPAC 1. Red curve shows patients with complete/major response (mean PRGS ≤2), and blue curve shows patients with minimal/no response (mean PRGS >2) for patients with gastric cancer (A) and colon cancer (B).

Figure 3:

Overall survival based on peritoneal regression grading score (PRGS) at PIPAC 2. Red curve shows patients with complete/major response (mean PRGS ≤2), and blue curve shows patients with minimal/no response (mean PRGS >2) for patients with gastric cancer, colon cancer, ovary cancer, pancreas cancer, or appendix cancer (A–E).

Discussion

The ISSPP PIPAC database is the world’s largest, noncommercial, voluntary, quality assuring PIPAC database with data from 1126 patients and 3224 PIPAC-directed treatments as of November 1st, 2024. Patients with PM from different primary tumors have been included since the official launch of the database in June 2020, and data from the first 809 patients were reported in the second annual report in 2023 [5]. Since 2023, the number of reporting PIPAC centers has increased by five, and today 31 PIPAC centers are registered as contributors and 17 are actively submitting patient data to the database.

As expected, and consistent with the findings of the second annual report, the results from this study align with recent systematic reviews with regard to the characteristics of the study population, the distribution of primary tumors, the number of PIPAC-directed treatments received by patients, and the PCI scores [10], 11]. Furthermore, the rates of nonaccess, chemotherapy dosage, flow rates, and exposure times are also consistent with existing literature [11], 12]. Variations observed regarding the chemotherapy dosage, flow rates, and exposure times may be attributed to the evolution of PIPAC-directed treatments (e.g., recommended doses) over time, variations between reporting centers as well as the introduction of new aerosolizers.

The complications and adverse events data recorded in the ISSPP PIPAC database also mirror the general opinion that patients scheduled for PIPAC are well selected and thus ensuring a satisfactory safety and feasibility profile [11], 12]. Also, the postoperative mortality within day 1 (0.1 %) and the 30-day mortality from last treatment (3 %) seem to align with findings in the second annual report and in two recent systematic reviews [5], 11], 13].

Patients with PM from gastric cancer had a 90-day mortality after last PIPAC-directed treatment of 31 %, which was significantly higher than for patients with other primary tumors. However, with 11.2 %, their 90-day mortality following PIPAC 1 was comparable to the mortality observed in patients with ovarian or pancreatic cancers [10], 11]. Ninety days mortality is rarely reported in PIPAC studies, but one study recorded 17 % among patients with gastric cancer treated with a bidirectional approach, and cause of death was reported to have been mainly due to disease progression and to not have been related to the PIPAC-directed treatment [14]. Data on cause of death are not available in the ISSPP PIPAC database, but since there was no difference in the rate of complications or adverse events between patients with different primary tumors, the high 90-day mortality after the last treatment reported here is probably unrelated to the PIPAC-directed treatments and instead may reflect the poor prognosis of gastric cancer patients with PM [12], 14]. Careful selection of all PM patients for PIPAC-directed therapy is still a topic of great importance. The minimum expected survival time at the time of inclusion (i.e., PIPAC 1) may vary between PIPAC centers and trials, but three out of four patients surviving at least 3 months after the last PIPAC-directed treatment seems to justify the present patient selection. One must, however, consider that pooling data from patients with different primary tumors might introduce biases and challenges for the interpretation of the results.

PRGS seems able to reflect the state of PM at different time points and thus the potential local treatment effect during PIPAC-directed or bidirectional therapy [15]. PRGS was the most commonly used tool for response evaluation, and throughout PIPAC 1–3 a mean PRGS ≤2 (i.e., a complete or major response) was observed in 57 %, 72 %, and 75 % of patients, respectively. This is comparable to data from a recent review investigating response evaluation in patients with PM treated with PIPAC, which reported a stable or improved PRGS in 18–58 % of patients [16]. The large variation in the review was due to heterogeneity of patients or a high number of discontinued treatments in the included studies [16]. The higher response rates observed in the present study may be explained by a larger study population, a more selected patient cohort, or other contributing factors.

The data we show demonstrates, that patients with PM from gastric, colon, ovarian, pancreatic, or appendix cancers, who have a mean PRGS ≤2 at PIPAC 1, 2, or 3 seem to have a longer overall survival compared with patients who have a PRGS>2. Similar observations were made in a large prospective phase II trial [15], while other studies found PRGS not to be an independent prognostic factor [17], 18]. This demonstrates that patients responding to systemic chemotherapy and PIPAC have a better prognosis. The isolated effect of PIPAC-directed treatments remains unclear, and randomized controlled trials are needed to investigate this topic. Available data suggest that PRGS and index PCI might be markers of local treatment response, but the definitive prognostic value and role of PRGS, however, requires further investigation [16].

The most frequent reason for stopping PIPAC was disease progression followed by poor general condition, and patient refusal. This was unchanged compared to the second annual PIPAC report and consistent with a recent systematic review, which reported disease progression to be the reason for stopping PIPAC in nearly 50 % of patients [10]. To provide more specific data on progression, a new database variable (location of disease progression) was launched in July 2024, and data from the first 148 patients found peritoneum to be the most frequent location of disease progression. To the best of our knowledge, this topic has not been previously explored, underscoring the need for further research.

This study shows encouraging survival results following PIPAC-directed treatment, and the results are in line with recent systematic reviews [12], 13], 19]. In addition, PIPAC and systemic chemotherapy may result in patients being long-term survivors [20], or even to be able to undergo radical resection [10], 21]. Patients with peritoneal mesothelioma, in particular, appear to benefit from PIPAC, with a median overall survival (OS) of 33.5 months [22]. This represents the longest OS ever reported for peritoneal mesothelioma patients receiving PIPAC and is nearly comparable to outcomes achieved with a combination of cytoreductive surgery and Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) [23], 24]. However, the results from systematic reviews and the ISSPP PIPAC database should be interpreted with caution due to heterogeneity regarding inclusion criteria and treatment strategies [12], 13], 19].

Recent studies suggest an increased survival with the numbers of delivered PIPAC treatments [11], 12]. In the present study, almost half of the patients had three or more PIPAC-directed treatments irrespective of their primary cancer type, and this may reflect good patient selection, treatment response, or probably a mixture of several known and unknown factors.

Conclusion

The third annual report from the ISSPP PIPAC database provides important real-world data supporting the use, safety, and effect of PIPAC-directed therapy in patients with PM from different primary tumors. Data from the ISSPP PIPAC database align with existing literature and suggest that PIPAC combined with systemic chemotherapy can induce local tumor responses and potentially prolong survival in selected cancer patients. Continuous monitoring and registration of PIPAC data in the ISSPP PIPAC database remains essential while awaiting data from randomized controlled trials