Unresectable CRC and AC metastases to the peritoneum are a complex clinical challenge with high morbidity, limited treatment options, and a poor prognosis. Although PIPAC has emerged as a novel therapeutic option, data comparing the benefit of PIPAC over ST are lacking. This is the first study to compare the efficacy of PIPAC with that of ST for patients with chemorefractory CRC-PM or AC-PM. The findings demonstrated that for patients with chemorefractory peritoneum-limited unresectable peritoneal metastases from invasive AC or CRC, PIPAC may be associated with better QoL (2.5-fold higher number of median good days at 1 year) and OS (59 % reduction in risk of death) than ST. Additionally, compared with the ST cohort, the PIPAC cohort had a lower burden of hospitalization during the course of 1 year after the start of treatment. Subjective QoL measured using EQ-5D-5L, Health Today scores, and MDASI showed preserved QoL after repeated PIPAC cycles. Finally, step-count data demonstrated a decline in activity immediately after PIPAC, which returned to baseline after 2 to 4 weeks, providing an objective benchmark for functional recovery.

Most patients with cancer nearing the end of life want to stay at home or at least be cared for at home.24 “Good days” is a composite outcome that combines survival and QoL. No previous reports describe using “good days” as an outcome measure for PIPAC, but it is a validated objective composite end point with demonstrated utility in a randomized trial of malignant bowel obstruction (S1316).16 The increase in number of good days for patients undergoing PIPAC (compared with ST) suggests a potentially meaningful clinical benefit of PIPAC in a chemorefractory setting. These observations also provide a rationale for the use of good days as a primary end point in trials of refractory peritoneal metastases.

To perform a granular assessment of HRQoL, we used two validated instruments: EQ-5D-5L and MDASI. Overall, we found no decline in HRQoL with repeated PIPAC treatment cycles. In contrast, Lurvink.et al.6 reported reversible worsening of patient-related outcomes using EQ-5D-5L in the first week after PIPAC cycle 1. The discordance can be explained by the differences in the timing of the surveys between the two studies. Several other studies have evaluated patient-centered outcomes after PIPAC for PM from various primary cancers including colorectal cancer, but have been more focused on ovarian, gastric, peritoneal mesothelioma, endometrial, and breast primary cancers.6,9,25,26,27,28,29,30,31,32,33,34,35,36 These studies used various sets of surveys and questionnaires including EQ-5D-5L, European Organization for Research and Treatment of Cancer (EORTC) QLQ-30, and Short Form 36 (SF-36; Medical Outcome Trust, Health Assessment Laboratories and QualityMetric, Lincoln, RI, USA). Our observations are in agreement with most of the prior studies that demonstrated no detriment in QoL scores with repeated PIPAC treatment cycles.25,26,27,28,29,30,37

In palliative studies, survey-based assessment of patient-reported outcomes can be confounded by significant attrition as the disease progresses. Functional assessment of patient functional recovery has previously been reported in prospective surgical cohorts, but not in chemotherapy trials. This is the first study to assess “daily number of steps” after PIPAC as a unique outcome of functional recovery. The results demonstrated that step counts decrease after PIPAC but return to near baseline 2 to 4 weeks after PIPAC administration, suggesting that PIPAC may have a limited but reversible impact on patient QoL. Unlike the QoL scores, which did not differ between the PD and SD patients, the step counts were higher at baseline for the SD patients than for the PD patients. Similarly, the SD patients demonstrated a more robust recovery to normal step counts after PIPAC than the PD patients. These observations raise the possibility that baseline functional activity, once validated in future studies, may be used to select or stratify patients in PM clinical trials.

The comparative analysis of survival between the two comparable cohorts also suggested a potential benefit of PIPAC. The median OS (5.1 months) and PFS (2.1 months) of the ST cohort were comparable with those in published trials of two major third-line systemic therapies for CRC with PM, namely, regorafenib (OS, 6.4 months; PFS, 1.9 months) and trifluridine/tipiracil (OS, 7.1 months; PFS, 2 months).4,38 The median OS (11.3 months) and PFS (2.9 months) of the PIPAC cohort compare favorably with the results from both our ST cohort and prior trials of third-line systemic chemotherapy. A shorter survival was reported by the PIPAX-OX trial (OS, 4.1 months; PFS, 1.5 months), but this decrease might be explained by the inclusion of various different primary cancers, which reflect different disease biologies. Moreover, 3 of the 16 patients in PIPAC-OX trial had prior extraperitoneal disease, and none of the patients were able to complete all three PIPAC cycles.13 Analysis of the data from two prospective trials of CRC-PM (PIPAC-OPC1 and PIPAC OPC-2) reported a longer median OS (20.5 months) from the time of the first PIPAC treatment cycle.10 However, the results are not comparable with those of the current study because the PIPAC-OPC cohorts were more heterogeneous, with a lack of strict inclusion criteria regarding prior systemic therapy. For example, although most of the patients (91 %, 22/24) had received palliative chemotherapy before enrolling in the PIPAC trial, the majority (63 %) had received only first-line chemotherapy with or without progression. In addition, one third of the patients had an extremely low disease burden (peritoneal carcinomatosis index [PCI], < 2.6). The longer survival of the PIPAC-OPC cohorts may be explained by these differences in inclusion criteria between the two studies.

This study had several limitations. Although PIPAC was associated with improved OS, this result does not prove the superiority of PIPAC over third-line systemic chemotherapy for unresectable PM. This result can be interpreted only as hypothesis-generating to evaluate PIPAC in a future randomized trial. The study also was limited by its small sample and its retrospective design. Nevertheless, it built on the results of the first in the U.S phase 1 PIPAC trial and provided a comparison group for comparing outcomes. Although the two groups had similar baseline characteristics for measured variables, we cannot rule out the possibility that the differences in outcomes could have been related to unmeasured confounders. Functional recovery and QoL analyses are limited due to small samples. A larger sample and improved participation would paint a clearer picture of the relevant trends. Nonetheless, these results provide a snapshot of QoL and functional recovery, which are important to consider and incorporate in future PIPAC studies.

In conclusion, given its safety, lack of negative impact on QoL, and improved efficacy signal, PIPAC needs to be investigated further as a treatment option for refractory, isolated peritoneal metastasis of CRC or AC origin in a randomized clinical trial against standard-of-care systemic therapy. These early promising results provide foundational evidence for the use of good days at 1 year as a primary end point for a future PIPAC trial in chemotherapy refractory setting. Finally, the results demonstrate the feasibility of integrating step-count data in prospective clinical trials of intra-peritoneal therapy as an objective surrogate for functional recovery.