Adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) in suboptimally cytoreduced advanced ovarian cancer: a randomized phase II trial (PIPAC-OVA)

Abstract

Purpose

Patients with advanced epithelial ovarian cancer (EOC) who undergo suboptimal primary cytoreductive surgery (PCS) have poor outcomes with standard platinum–taxane chemotherapy. This randomized controlled trial evaluated whether adding adjuvant Pressurized Intraperitoneal Aerosol Chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) to first-line systemic therapy improves survival in this high-risk population.

Methods

In this single-center, open-label trial, patients with advanced EOC and residual disease > 1 cm after PCS were randomly assigned (1:1) to receive six cycles of carboplatin/paclitaxel alone (control arm) or the same chemotherapy plus three adjuvant PIPAC C/D procedures (intervention arm). No patient received neoadjuvant chemotherapy. The primary endpoint was progression-free survival (PFS) from PCS. Secondary end points included overall survival (OS), CA-125 response, peritoneal disease control assessed macroscopically and histologically, and safety. Trial registration: ISRCTN15843444.

Results

A total of 186 patients were randomized. After excluding four after definitive histology, 182 comprised the mITT population (control, n = 91; PIPAC, n = 91). Median PFS was significantly longer with PIPAC (19.7 vs 12.5 months; HR, 0.31; 95% CI, 0.23–0.42; P < 0.001), as was OS (46.2 vs 38.1 months; HR, 0.48; 95% CI, 0.32–0.72; P < 0.001). In the PIPAC group, complete macroscopic regression occurred in 98.8% (83/84 treated patients), complete pathological regression in 85.7%, and ascites control in 98.8%. Treatment was well tolerated with no increase in grade 3–4 toxicity and minimal procedure-related morbidity.

Conclusion

In patients with suboptimally debulked advanced EOC, the addition of adjuvant PIPAC C/D to first-line chemotherapy significantly improved PFS and OS while maintaining a favorable safety profile. These findings support further evaluation of PIPAC C/D as a component of primary treatment in this high-risk subgroup in confirmatory phase III trials.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-026-16285-8.

Context

Patients with advanced epithelial ovarian cancer (EOC) who undergo suboptimal primary cytoreductive surgery have poor outcomes with standard platinum–taxane chemotherapy, and effective consolidative strategies for residual peritoneal disease are lacking.

Key objective

To our knowledge, this is the first randomized controlled study to evaluate the addition of adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin to first-line systemic chemotherapy in patients with suboptimally debulked advanced EOC.

Introduction

The high lethality of epithelial ovarian cancer (EOC) stems from its common presentation at an advanced stage with pervasive peritoneal dissemination [1, 2]. While complete macroscopic resection during primary cytoreductive surgery (PCS) followed by systemic chemotherapy is the treatment cornerstone and key prognostic determinant, it is often unachievable, leading to poor outcomes [3–7]. Residual peritoneal disease after suboptimal PCS correlates with rapid recurrence and diminished chemotherapy efficacy, highlighting an urgent need for innovative therapies [8, 9].

Recently, the OVHIPEC-1 trial demonstrated that hyperthermic intraperitoneal chemotherapy (HIPEC) during interval surgery improves survival after interval cytoreductive surgery with minimal residual disease (CC0/1) [10]. This underscores the therapeutic value of intensifying treatment within the peritoneal cavity. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) represents a technological evolution in this domain [11]. It utilizes a pressurized aerosol to achieve superior, homogeneous drug distribution and deeper tissue penetration, and applies a reduced dose to minimize systemic drug exposure. PIPAC’s favorable safety profile and promising activity, including in platinum-resistant EOC, have been demonstrated in early-phase clinical studies [12, 13].

However, these early data leave a crucial clinical question unanswered: can PIPAC improve outcomes when integrated into first-line treatment immediately after suboptimal primary surgery? Robust, randomized evidence for this specific application is absent. Therefore, to evaluate this novel strategy, we conducted a randomized controlled trial. This study evaluates whether adding adjuvant PIPAC with low-dose cisplatin and doxorubicin to standard first-line platinum–taxane chemotherapy improves progression-free survival (PFS) in patients with advanced EOC after suboptimal PCS.

Methods

Study design and participants

This was a single-center, randomized, open-label, controlled phase II trial conducted at the Moscow Regional Oncological Dispensary (Balashikha, Russian Federation) in collaboration with the P.A. Hertsen Moscow Oncology Research Institute. The study was approved by the local Ethics Committee and the Scientific Council of the P.A. Hertsen Moscow Cancer Research Institute (protocol #661, April 9, 2021) and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Eligible patients were women aged 18–75 years with histologically confirmed advanced epithelial ovarian cancer and peritoneal metastases who underwent suboptimal primary cytoreductive surgery, defined as residual disease > 1 cm. Key exclusion criteria included extra-peritoneal metastases, malignant pleural effusion, parenchymal organ metastases, Eastern Cooperative Oncology Group (ECOG) performance status 4, and synchronous malignancies. No patient received neoadjuvant chemotherapy (Table 1).

Table 1.

Baseline Characteristics and Treatment (ITT Population, N = 186)

	Control (n = 93)	PIPAC (n = 93)	p-value
Patient characteristics
Age, years	56.7 ± 9.8	56.5 ± 10.3	0.89
Performance status (ECOG)			0.62
0	20 (21.5%)	21 (22.6%)
1	13 (14.0%)	7 (7.5%)
2	38 (40.9%)	41 (44.1%)
3	22 (23.7%)	24 (25.8%)
FIGO Stage			0.41
IIIB	13 (14.0%)	17 (18.3%)
IIIC	80 (86.0%)	76 (81.7%)
Histology			0.96*
HGSOC	81 (87.1%)	81 (87.1%)
LGSOC	10 (10.8%)	10 (10.8%)
Other histology (non-Epithelial Ovarian Cancer)	2 (2.2%)	2 (2.2%)
PCI Score	23.7 ± 8.6	23.2 ± 9.6	0.74
Ascites at baseline, mL	1940 ± 1840	1740 ± 1950	0.61
CA-125 at baseline, U/mL	1400 ± 2150	1420 ± 2120	0.95
Treatment
Total hysterectomy, adnexectomy, omentectomy	93 (100%)	93 (100%)	1.0
PIPAC sessions performed	—	252
Patients receiving all 3 PIPAC cycles	—	84 (90.3%)
Chemotherapy cycles (total)	510	504	0.79
Median follow-up (months)	43.5	44.8	0.86

^*p-value for HGSOC vs. LGSOC comparison (excluding other histology)

^†Includes 4 patients with incorrect definitive histology (not epithelial ovarian cancer; 2 in each arm)

Treatment

All patients underwent primary cytoreductive surgery (PCS) including total hysterectomy, bilateral adnexectomy, and omentectomy, with peritoneal biopsies obtained at laparotomy. In this trial, "suboptimal PCS" was defined as residual macroscopic disease > 1 cm after these standard procedures. No extended cytoreductive procedures (e.g., bowel resection, peritonectomy, multivisceral resection) were performed. This decision was based on institutional policy and patient-related considerations, including disease distribution, surgical morbidity, frailty, comorbidities, and overall operability. This approach allowed us to define a homogeneous population of patients with extensive peritoneal disease burden in whom complete cytoreduction (CC0/1) was not achievable at the time of primary surgery, representing a subgroup with particularly poor prognosis and limited therapeutic options.

Patients were randomly assigned (1:1) intraoperatively to receive either standard systemic chemotherapy alone or systemic chemotherapy plus adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) (Fig. 1A).

Fig. 1.

A Study design. All patients underwent primary cytoreductive surgery (total hysterectomy, bilateral adnexectomy, and omentectomy) with intraoperative staging, PCI assessment, and peritoneal biopsies. Patients were randomized intraoperatively (1:1) to receive systemic chemotherapy alone or systemic chemotherapy plus adjuvant PIPAC (intensified therapy). Chemotherapy consisted of paclitaxel (175 mg/m²) and carboplatin (AUC 5–7) every 3 weeks for six cycles. In the experimental arm, three PIPAC procedures with cisplatin (10.5 mg/m2) and doxorubicin (2.1 mg/m2) were administered immediately after cytoreduction and before the third and fifth chemotherapy cycles. Tumor response was assessed by imaging, CA-125, laparoscopic reassessment, and histology, with 6-month follow-up. B CONSORT diagram. Among 190 patients assessed for eligibility, 186 underwent intraoperative randomization (1:1) to intensified therapy (PIPAC plus systemic chemotherapy) or standard systemic chemotherapy alone. Four patients were excluded from the ITT analysis due to incorrect definitive histology. Thirteen patients did not receive allocated treatment due to withdrawal/relocation, COVID-19, or intercurrent medical events. Detailed reasons for exclusions and analysis populations are provided in the text

PIPAC procedure

Carbon dioxide (CO₂) is insufflated into the abdominal cavity through a trocar to establish a capnoperitoneum, with a target intraperitoneal pressure of 12–14 mmHg. Intra-abdominal pressure and gas flow characteristics are monitored on the injector head display (radiological contrast injector) to assess adequate abdominal distension. Cisplatin and doxorubicin are diluted in 180 mL of 0.9% saline at doses of 10.5 mg/m² and 2.1 mg/m², respectively. The cytostatic solution is loaded into syringe-flasks of the angioinjector, which are then placed into the injector. Delivery parameters are set on the injector's control screen: operating pressure of 200–250 psi, with a maximum allowable pressure of 300 psi. A laparoscope is inserted through an epigastric trocar. Under video endoscopic guidance, a nebulizer is introduced through a trocar placed in the iliac region. The nebulizer trocar is positioned to maximize the distance for unobstructed aerosol formation. Before initiating the PIPAC procedure, all staff exit the operating room. The injector is activated remotely. Aerosol exposure duration is 30 min.

At the end of the exposure, video endoscopic inspection of the abdominal cavity and pelvis is performed. CO₂ insufflation is then discontinued. A vacuum aspirator is inserted through the iliac trocar, and CO₂ is aspirated under video endoscopic control without suctioning the cytostatic solution. The nebulizer, laparoscope, and trocars are then removed. No drains are placed; trocar sites are closed hermetically with sutures.

Chemotherapy

Systemic chemotherapy consisted of six cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 5–7), initiated 7–8 days after primary surgery and administered at 3-week intervals. As illustrated in Fig. 1A, patients in the experimental arm additionally received three PIPAC procedures with cisplatin and doxorubicin: the first intraoperatively immediately after cytoreductive surgery, with PIPAC #2 and #3 intercalated after cycles 2 and 4 and followed within 1–2 days by the subsequent chemotherapy cycles.

Sample size calculation

The sample size was calculated for the primary endpoint of progression-free survival. With a two-sided alpha level of 0.05, 80% power, and an assumed hazard ratio of 0.65 for progression or death in the experimental group compared with the control group, 169 events were required. To account for expected dropouts, an additional 10% (17 patients) was added, resulting in a total planned sample size of 186 patients (93 per arm). This number was considered sufficient to detect a clinically relevant treatment effect. Overall, trial recruitment for both arms combined spanned from the earliest surgery date of August 25, 2020, to the latest surgery date of November 3, 2022, for a total recruitment duration of approximately 27 months.

Randomization

Random assignment (central web-based) was performed using a computer-generated sequence with permuted blocks and a 1:1 allocation ratio. Randomization was stratified by FIGO stage (IIIB vs IIIC) and histology. The trial was open-label.

End points and assessments

The primary endpoint was progression-free survival (PFS), defined as the time from cytoreductive surgery to disease progression or death from any cause. Secondary end points included overall survival (OS), CA-125 response, local peritoneal disease control, and safety.

Radiologic assessments with CT or MRI and serum CA-125 measurements were performed at baseline, during treatment, and at regular intervals during follow-up. Six months after completion of systemic therapy, response was assessed by CT or MRI imaging in both groups. In the PIPAC group, protocol-mandated diagnostic laparoscopy at 6 months included reassessment of the peritoneal cancer index (PCI) and repeat peritoneal biopsy for histologic evaluation using a PRGS-derived score [14–17] (Fig. 1A). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

The primary efficacy analyses were conducted according to the modified intention-to-treat (mITT) principle, including all randomized patients in their assigned groups (n = 186), excluding 4 patients with a diagnosis other than EOC on definitive histology. Patients who withdrew consent were censored on the date of withdrawal (for time-to-event endpoints) and contributed follow-up time up to that date. Safety analyses were performed in the as-treated population, defined as all patients who received at least one component of the allocated treatment (n = 169).

Trial database registration

Due to our unawareness of the requirement for prospective registration at the time of study initiation and the challenging access to international trial databases from inside the Russian Federation, the trial was entered retrospectively into a trial registry (Registry-Nr: ISRCTN15843444) on 06/03/2026.

Results

Of 190 patients assessed for eligibility, 186 underwent intraoperative randomization (1:1) to intensified therapy (PIPAC plus systemic chemotherapy) or standard systemic chemotherapy alone (93 per group) (Fig. 1B). Four patients had incorrect definitive histology (non-epithelial ovarian cancer; n = 2 in each arm). The remaining 182 patients comprised the modified intention-to-treat population (mITT) (control, n = 91; PIPAC, n = 91). An additional 13 patients (7 PIPAC, 6 control) discontinued treatment before completion due to withdrawal/relocation (n = 4), COVID-19 infection (n = 8), or deep venous thrombosis (n = 1) but were included in the mITT analysis. Consequently, 84 patients received PIPAC plus chemotherapy and 85 received chemotherapy alone, comprising the per-protocol/as-treated population (Fig. 1B).

Efficacy

Progression-free survival

At the data cutoff (15.1.2025), progression-free survival (PFS) was significantly longer in the PIPAC plus chemotherapy group than in the chemotherapy-alone group in the modified intention-to-treat population (N = 182). Median PFS was 19.7 months (95% CI, 17.0–22.4) in the PIPAC group compared with 12.5 months (95% CI, 11.7–13.2) in the control group (hazard ratio [HR], 0.31; 95% CI, 0.23–0.42; log-rank P < 0.001; Fig. 2A).

Fig. 2.

A Progression-free survival and overall survival, CA125 response. Kaplan–Meier estimates of progression-free survival (PFS) in the chemotherapy-alone group (blue) and the intensified therapy group (red). Tick marks indicate censored observations. PFS was significantly prolonged with intensified therapy (log-rank P < 0.001; HR, 0.31; 95% CI, 0.23–0.42). B Progression-free survival and overall survival, CA125 response. Kaplan–Meier estimates of overall survival (OS) in patients treated with systemic chemotherapy alone (blue) or intensified therapy consisting of pressurized intraperitoneal aerosol chemotherapy (PIPAC) plus systemic chemotherapy (red) in the modified intention-to-treat population (N = 182). Tick marks indicate censored observations. The intensified therapy group demonstrated significantly longer OS (log-rank P < 0.001; hazard ratio [HR], 0.48; 95% CI, 0.32–0.72). C Progression-free survival and overall survival, CA125 response. Serum CA-125 levels at baseline (blue) and after completion of treatment (red) in the control and PIPAC groups. Box plots show median values with interquartile ranges; whiskers represent the full range excluding outliers (circles). Post-treatment CA-125 levels were significantly lower in the PIPAC group compared with the control group (P < 0.001)

Overall survival

Overall survival was significantly longer in the PIPAC group than in the control group. Median OS was 46.2 months (95% CI, 44.3–48.1) in the PIPAC arm and 38.1 months (95% CI, 35.3–40.9) in the control arm (hazard ratio [HR], 0.48; 95% CI, 0.32–0.72; log-rank P < 0.001; Fig. 2B). The inclusion of 13 patients who discontinued treatment before initiation (censored early) did not alter the median survival estimates and resulted in a minimal shift of the hazard ratio compared to the as-treated analysis (HR, 0.47).

CA-125 Response

A higher proportion of patients in the PIPAC group achieved normalization of serum CA-125 at treatment completion compared with the control group (92.9% vs 67.1%; odds ratio, 6.8; 95% CI, 2.9–16.1; P < 0.001; Fig. 2C).

Local peritoneal disease control

In the PIPAC group, assessment at the protocol-mandated 6-month laparoscopy, performed in all 84 treated patients, showed complete macroscopic regression (peritoneal cancer index [PCI] = 0) in 83 of 84 patients (98.8%; Fig. 3A). Complete pathological regression of peritoneal metastases was observed in 72 of 84 patients (85.7%; Fig. 3B). Histologic assessment was not performed in the control group because no follow-up laparoscopy was planned.

Fig. 3.

Local disease control in the intensified therapy group with PIPAC C/D combined with systemic chemotherapy. A Representative macroscopic tumor response at laparoscopy. At baseline (PIPAC #1), extensive peritoneal metastases were present with high tumor burden (PCI 34), large-volume ascites (3,500 mL), and elevated CA-125 levels. Following successive PIPAC cycles, progressive disease regression was observed, including resolution of ascites, marked reduction in PCI, normalization of CA-125, and negative peritoneal histology. At 6-month follow-up, laparoscopy demonstrated sustained disease control with normal-appearing peritoneal surfaces. B Evolution of peritoneal cancer index (PCI) at baseline and during treatment. Repeated measurements demonstrate a progressive shift toward lower PCI scores over the course of therapy. C Distribution of ascites volume categories at baseline and during treatment. Bars represent the number of patients, stratified by ascites volume (0 mL, ≤ 1,000 mL, ≤ 2,000 mL, ≤ 3,000 mL, ≤ 4,000 mL, and > 4,000 mL) at each assessment point, illustrating a progressive reduction in ascites burden during therapy. D Histological tumor response assessed with the 4-tiered Peritoneal Regression Grading Score (PRGS) [18–21]. Stacked bar charts depict the PRGS category from 4 (vital tumor) to PRGS 1 (no residual tumor cells) assessed before PIPAC-2, before PIPAC-3, and at 6-month postoperative follow-up. A progressive shift toward lower PRGS categories, indicating increasing tumor regression, is observed over time (ANOVA, P < 0.001)

At baseline, ascites was present in nearly all patients in both groups (180 of 182 patients; 98.9% in each arm). In the PIPAC group, all 84 treated patients underwent protocol-mandated 6-month laparoscopy, which demonstrated a marked reduction in ascites with sustained control (no ascites) in 83 patients (98.8%). In the control group, among the 85 treated patients with evaluable imaging at 6 months after completion of chemotherapy, ascites was detected in 10 patients (11.8%). The remaining 7 PIPAC and 6 control patients in the mITT population discontinued treatment before initiation and were not evaluable for this secondary endpoint (Fig. 3C).

Among PIPAC-treated patients, histological response, graded by the Peritoneal Regression Grading Score (PRGS), showed a significant progressive shift toward lower (i.e., more favorable) PRGS categories over time (ANOVA, P < 0.001). The protocol-mandated 6-month laparoscopy confirmed complete pathological regression of peritoneal metastases (no vital tumor cells) in 85.7% (72/84).

Safety

The addition of PIPAC was not associated with increased systemic toxicity. Rates of grade 3 hematologic adverse events were similar between groups (7.8% in the control group vs 6.7% in the PIPAC group), and no grade 4 hematologic or nonhematologic toxicities related to PIPAC were observed.

No adhesion-related obstacles were reported, allowing full treatment delivery across the cohort. In total, 252 PIPAC procedures were successfully performed in 84 patients, indicating that all three planned PIPAC cycles were completed in all treated patients. Among 252 PIPAC procedures, three cases (1.2%) of delayed trocar-site healing (Clavien–Dindo grade I) occurred; all resolved without intervention. No PIPAC-related reoperations, organ injuries, or port-site metastases were reported (Table 2).

Table 2.

Adverse events

Parameter	Control (n = 85; 510 cycles)	PIPAC (n = 84; 504 cycles)	P-value
Surgical adverse events
Wound healing complication	0	3 (1.2%)	—
Hematologic adverse events
Anemia			0.634
Grade 1	89 (20.8%)	84 (20.7%)
Grade 2	56 (13.1%)	62 (15.4%)
Grade 3	21 (4.9%)	18 (4.4%)
Leukopenia			0.892
Grade 1	109 (25.5%)	112 (27.6%)
Grade 2	39 (9.1%)	33 (8.1%)
Grade 3	18 (4.2%)	15 (3.7%)
Thrombocytopenia			0.508
Grade 1	30 (7.0%)	25 (6.2%)
Grade 2	5 (1.2%)	4 (1.0%)
Renal adverse events
Hypercreatininemia			0.926
Grade 1	44 (10.3%)	38 (9.5%)
Grade 2	16 (3.7%)	14 (3.4%)
Grade 3	0 (0%)	0 (0%)

Note: Adverse event rates are reported per chemotherapy cycle, as patients received multiple cycles. Percentages are calculated based on the total number of cycles administered (510 in the control group, 504 in the PIPAC group). No grade 4 hematologic or nonhematologic toxicities were observed

Sensitivity analysis

To assess the robustness of the primary findings, we performed additional analyses using three populations: the strict intention-to-treat (ITT) population including all 186 randomly assigned patients; the modified ITT (mITT) population comprising 182 patients with confirmed epithelial ovarian cancer (the primary analysis population); and the per-protocol (PP) population of 169 patients who completed their allocated treatment without major protocol deviations. The results were highly consistent across all analysis sets, confirming the stability of the treatment effect (Suppl. Mat. 1). In the strict ITT analysis (n = 186), the hazard ratio for PFS was 0.31 (95% CI, 0.23–0.42; log-rank P < 0.001) and for OS was 0.48 (95% CI, 0.32–0.72; P < 0.001), virtually identical to the primary mITT estimates (HR for PFS, 0.31; 95% CI, 0.23–0.42; HR for OS, 0.48; 95% CI, 0.32–0.72). The per-protocol analysis, which included only patients who completed all planned therapy (n = 169), yielded hazard ratios of 0.30 (95% CI, 0.22–0.41) for PFS and 0.47 (95% CI, 0.31–0.71) for OS. These sensitivity analyses demonstrate that the observed survival benefits are robust and are not influenced by the inclusion of patients with incorrect histology, patients who did not complete treatment, or the choice of analysis population.

Discussion

In this randomized phase II trial, adjuvant PIPAC with cisplatin and doxorubicin (PIPAC C/D) added to first-line chemotherapy significantly improved progression-free survival (PFS) in patients with advanced epithelial ovarian cancer (EOC) after suboptimal primary cytoreductive surgery (PCS). Median PFS was 19.7 months in the PIPAC group versus 12.5 months in controls (HR 0.31; 95% CI 0.23–0.42; P < 0.001). Overall survival (OS) was also longer (46.2 vs. 38.1 months; HR 0.48; 95% CI 0.32–0.72; P < 0.001).

These outcomes were accompanied by deeper CA-125 responses (normalization 92.9% vs. 67.1%; P < 0.001) without increased severe toxicity. In the PIPAC group, high rates of locoregional disease control were observed, including complete macroscopic regression in 98.8%, complete pathological regression in 85.7%, and ascites control in 98.8%.

The robustness of the primary findings was confirmed in sensitivity analyses across ITT (n = 186), mITT (n = 182), and per-protocol (n = 169) populations, with consistent HRs for PFS (0.30–0.31) and OS (0.47–0.48).

Outcomes in the control arm were consistent with published data for patients with residual macroscopic disease after primary surgery, in whom median PFS typically ranges from 10 to 14 months [22, 23]. Our findings support the hypothesis that locoregional treatment intensification may partially mitigate the adverse prognostic impact of incomplete PCS [6, 24]. Treatment delivery and tolerability were preserved, which is particularly relevant for patients not candidates for extensive cytoreductive procedures. However, given differences in patient populations, treatment context, and surgical strategies across studies, we caution against direct cross-trial comparisons and overinterpretation of the effect size.

Although complete macroscopic resection remains the primary surgical objective in advanced EOC [4], it is not achievable in a substantial proportion of patients due to extensive peritoneal dissemination or medical frailty [7]. In this trial, suboptimal primary cytoreductive surgery (PCS) was defined as residual disease > 1 cm after hysterectomy, bilateral adnexectomy, and omentectomy, without extended procedures (e.g., bowel resection, peritonectomy). This approach—based on institutional policy and patient-related considerations (disease distribution, surgical morbidity, frailty, comorbidities, operability)—defined a homogeneous population with poor prognosis and limited options. We acknowledge that this strategy differs from maximal cytoreductive efforts in specialized centers, limiting generalizability to all patients with advanced EOC. However, our study was designed for a distinct subgroup in whom complete cytoreduction was not achievable, and both arms received identical surgical management with intraoperative randomization, ensuring balanced baseline characteristics.

In these patients, PIPAC C/D offers a repeatable, minimally invasive intraperitoneal approach integrated with standard systemic chemotherapy. At protocol-mandated follow-up laparoscopy, high rates of macroscopic regression (PCI = 0 in 98.8%), complete pathologic response (85.7%), and sustained ascites control (98.8%) were observed. These findings suggest meaningful activity against residual peritoneal disease but should be interpreted cautiously, as locoregional assessment modalities differed between arms, and our results should not be generalized to patients undergoing maximal cytoreductive surgery without appropriate validation.

The present findings should be considered alongside prior evidence supporting intraperitoneal treatment strategies in EOC [25]. The phase III OVHIPEC-1 trial demonstrated a survival benefit with HIPEC administered at interval cytoreductive surgery after neoadjuvant chemotherapy in patients with complete (CC-0) or near-complete (CC-1) cytoreduction [10, 26]. This population differs substantially from ours—OVHIPEC-1 enrolled patients with minimal residual disease after neoadjuvant treatment, whereas our trial focused on patients with extensive macroscopic residual disease (> 1 cm) after suboptimal primary surgery without neoadjuvant chemotherapy. Differences in patient selection, timing, surgical context, and extent of residual disease preclude direct comparisons. Nevertheless, these data together reinforce the broader concept that intraperitoneal treatment intensification can improve outcomes in advanced EOC [27]. Clinically, HIPEC and PIPAC may be viewed as complementary, addressing different scenarios along the disease spectrum: HIPEC in curative-intent strategies when complete/near-complete cytoreduction is achievable, and PIPAC for patients with persistent macroscopic residual disease not candidates for extensive surgery. We do not equate their curative potential but emphasize their non-overlapping indications.

The safety profile of PIPAC C/D was favorable. The addition of three PIPAC procedures did not increase grade 3–4 toxicities compared with chemotherapy alone, and procedure-related morbidity was low, consistent with prior reports of limited systemic exposure from aerosolized intraperitoneal chemotherapy [11–13]. As previously reported, adhesion-related obstacles did not compromise the feasibility of repeated PIPAC procedures [28]; all 252 planned PIPAC applications were successfully performed in the 84 patients treated (all three cycles per patient). Treatment delivery and tolerability were maintained—an important consideration given the cumulative treatment burden in this population.

These findings complement prior reports of PIPAC C/D in platinum-resistant EOC [16, 29–33], where histological major/complete response rates of approximately 60–65% and median OS of 12–15 months have been reported despite high disease burden and limited surgical eligibility [16, 17].

Several limitations merit emphasis. First, our surgical strategy—primary cytoreductive surgery without extended procedures (e.g., bowel resection, peritonectomy—differs from maximal cytoreductive efforts in other specialized centers. This approach, based on institutional policy and patient-related considerations (disease distribution, morbidity, frailty, comorbidities, operability), defined a homogeneous population with residual disease > 1 cm in whom complete cytoreduction was not achievable. However, this limits generalizability to patients undergoing maximal cytoreductive surgery, and our results should not be extrapolated to such populations without validation.

Second, no patients received NACT followed by interval cytoreductive surgery—a standard in recent international guidelines [34]. Our pathway (upfront surgery followed by adjuvant chemotherapy) reflects established national practice in the Russian Federation at the time of trial conduct. Nevertheless, the absence of a NACT/interval surgery comparator limits applicability to healthcare systems where that approach is preferred.

Third, the single-center, open-label, phase II design limits generalizability and introduces potential residual bias despite objective endpoints (PFS, OS, CA-125).

Fourth, peritoneal disease burden and ascites were assessed using different modalities: the PIPAC group underwent CT and laparoscopy with histology, while controls underwent CT alone. A protocol-mandated control-arm laparoscopy was not ethically acceptable due to its invasive nature and lack of therapeutic benefit. This difference limits interpretability of exploratory locoregional endpoints (PCI, PRGS); thus, locoregional results in the PIPAC group should be considered descriptive only. Importantly, the primary endpoints (PFS, OS) were assessed uniformly across groups and are unaffected, supporting the robustness of the main conclusions.

Fifth, the study was registered retrospectively. At trial initiation, prospective registration in an international registry was not routine practice in the Russian Federation, and database access was challenging. The trial was therefore entered retrospectively (ISRCTN15843444) on 06/03/2026, reflecting local regulatory frameworks. Importantly, the protocol was predefined and ethics-approved prior to enrollment and was not modified during the trial. All key methodological details have been transparently reported.

Sixth, BRCA1/2 and HRD testing were not routinely performed, and no patients received PARP inhibitor therapy, which is increasingly part of contemporary standard care in some settings.

In conclusion, this randomized phase II trial provides prospective evidence that adjuvant PIPAC with low-dose cisplatin and doxorubicin added to standard doublet chemotherapy improves PFS and OS in patients with advanced EOC after suboptimal primary cytoreductive surgery. These findings were observed in a high-risk population characterized by extensive peritoneal disease, impaired performance status, and limited surgical options.

The magnitude of the treatment effect is notable. However, interpretation should consider the single-center, open-label design, the absence of a neoadjuvant chemotherapy comparator, the lack of molecular stratification and contemporary maintenance therapy, and a surgical strategy that differs from maximal cytoreductive approaches in other settings—all of which may limit generalizability.

While the consistency of results across multiple analysis populations supports robustness, residual bias and unmeasured confounders cannot be excluded. Accordingly, these results require confirmation in larger, multicenter, randomized phase III trials incorporating standardized treatment pathways and contemporary systemic therapies. Future studies should standardize assessment methods, incorporate molecular profiling and contemporary maintenance strategies (including PARP inhibitors [18] and antiangiogenic agents [19]), and include patient-reported outcomes [20, 21].

Within these limitations, adjuvant PIPAC C/D represents a promising locoregional strategy for patients with persistent macroscopic peritoneal disease after suboptimal primary surgery—a population with limited therapeutic options.

Abbreviations

AUC

Area Under the Curve

CA-125

Cancer Antigen 125

CI

Confidence Interval

CONSORT

Consolidated Standards of Reporting Trials

CT

Computed Tomography

ECOG

Eastern Cooperative Oncology Group

EOC

Epithelial Ovarian Cancer

FIGO

Fédération Internationale de Gynécologie et d’Obstétrique

HIPEC

Hyperthermic Intraperitoneal Chemotherapy

HR

Hazard Ratio

HGSOC

High-Grade Serous Ovarian Cancer

ITT

Intention-to-Treat

LGSOC

Low-Grade Serous Ovarian Cancer

mITT

Modified Intention-to-Treat

NACT

Neoadjuvant chemotherapy

MRI

Magnetic Resonance Imaging

OS

Overall Survival

PCI

Peritoneal Cancer Index

PCS

Primary Cytoreductive Surgery

PFS

Progression-Free Survival

PIPAC

Pressurized Intraperitoneal Aerosol Chemotherapy

PIPAC C/D

Pressurized Intraperitoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin

PP

Per-Protocol

PRGS

Peritoneal Regression Grading Score

Authors’ contributions

A.S.D. served as principal investigator, conceived the study, performed cytoreductive surgery (CRS), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and intravenous chemotherapy, conducted data analysis, and drafted the manuscript. V.M.K. was a co-investigator, contributed to the study concept, and critically reviewed the manuscript. A.V.T. participated in CRS, PIPAC, and intravenous chemotherapy administration. V.L.A. and A.A.K. were co-investigators and contributed to the study concept. S.O.G. contributed to manuscript writing. M.A.A. performed the pathology assessment. All authors read and approved the final manuscript.

Funding

This study was supported by institutional funding, with no external financial support.

Data availability

The datasets analyzed during the current study, as well as the study protocol and statistical analysis plan, are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the local Ethics Committee and the Scientific Council of the P.A. Hertsen Moscow Cancer Research Institute (protocol #661, April 9, 2021) and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.