This interim analysis of a randomized controlled trial comparing PIPAC with intravenous chemotherapy in platinum-resistant ovarian cancer (PROC) demonstrates a consistent signal favoring PIPAC across multiple clinically relevant domains, including objective response, disease control, quality of life, and treatment-related toxicity. These findings must be interpreted within the context of an underpowered, prematurely terminated study; however, the directionality and internal consistency of results merit careful consideration.

The primary endpoint of objective response rate (ORR) showed a significantly higher response in the PIPAC arm compared to intravenous chemotherapy. This finding is clinically meaningful, particularly in PROC where expected ORR with standard systemic agents such as weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan typically ranges between 10% and 20% [18]. Even with the addition of bevacizumab, response rates remain modest, as demonstrated in the AURELIA trial [11]. The magnitude of difference observed in the present analysis exceeds that reported in systemic therapy trials and aligns with prior PIPAC studies demonstrating encouraging response signals in heavily pretreated ovarian cancer populations [19,20,21]. This supports the hypothesis that locoregional delivery may overcome pharmacokinetic limitations of intravenous chemotherapy in peritoneal disease.

The improved disease control rate observed with PIPAC further reinforces this finding. Peritoneal metastasis in ovarian cancer is characterized by diffuse, poorly vascularized tumor deposits, and limiting drug penetration with systemic therapy. The aerosolized, pressurized delivery of chemotherapy in PIPAC enhances spatial distribution and tissue penetration, which has been demonstrated in pharmacokinetic and histological studies. This mechanistic advantage likely contributes to the improved local disease control observed in this study [22,23,24].

Histopathological response, as assessed by PRGS, provides an additional layer of validation. A response rate of 60% (PRGS 1–2) in the PIPAC arm is consistent with previously reported series and suggests true biological activity at the tumor level [20,21,22,23,24,25,26,27]. Importantly, histological response has been proposed as a more sensitive marker of treatment effect in peritoneal disease, where radiological assessment using RECIST may underestimate response due to the diffuse and non-measurable nature of lesions [28, 29]. The concordance between radiological and histological findings in this study strengthens the credibility of the observed treatment effect.

Quality-of-life (QoL) outcomes represent a critical endpoint in PROC, where treatment intent is largely palliative. The improvement in global health status and functional domains in the PIPAC arm, contrasted with stability or decline in the intravenous chemotherapy group, is a key finding. Systemic chemotherapy is associated with cumulative toxicity, including fatigue, neuropathy, and hematologic suppression, which significantly impact patient-reported outcomes. In contrast, PIPAC delivers lower systemic drug exposure, which is likely to contribute to better tolerability and preservation of QoL. These findings are consistent with prior studies demonstrating maintenance or improvement in QoL with PIPAC [20,21,22,23,24,25,26,27, 30].

The safety profile observed in this study further supports the feasibility of PIPAC. The significantly lower incidence of grade ≥ 3 adverse events compared to intravenous chemotherapy reflects the reduced systemic toxicity associated with this approach. Previous studies have similarly reported low perioperative morbidity and minimal systemic adverse effects with PIPAC. The absence of treatment-related mortality and short hospital stays further reinforce its applicability in a palliative setting [20,21,22,23,24,25,26,27].

An important observation is the consistency of benefit across multiple endpoints, including response, toxicity, and QoL. This integrated effect suggests that PIPAC may address the central limitation of systemic therapy in PROC, namely inadequate control of peritoneal disease. Unlike targeted therapies or antibody–drug conjugates, which are limited to biomarker-selected populations, PIPAC offers a compartment-directed approach applicable to a broader patient cohort. While agents such as mirvetuximab soravtansine have shown improved outcomes in selected patients [12], their role remains complementary rather than substitute in peritoneal-dominant disease.

It is also important to consider the biological plausibility of these findings. The peritoneal microenvironment, characterized by increased interstitial pressure and poor vascularization, represents a sanctuary site where systemic therapies are less effective. By delivering chemotherapy directly into the peritoneal cavity under pressure, PIPAC enhances local drug concentration and penetration, potentially overcoming this therapeutic barrier. This may explain the observed divergence in outcomes between the two treatment modalities.