Comparative assessment of quality of life in patients receiving intraperitoneal aerosol chemotherapy under pressure for gastric cancer with peritoneal dissemination

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List of abbreviations

PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy);

95% CI (95% confidence interval)

SPCT/sPCT (polychemotherapy / systemic polychemotherapy).

CTCAE v.5.0 (Common Terminology Criteria for Adverse Events Version 5.0)—Standardized classification criteria for the registration of drug- or treatment-related adverse effects.

Cy(-)/Cy(+) (cytological examination)—Negative/positive result of peritoneal fluid cytology

ECOG (Eastern Cooperative Oncology Group)—Patient General Functional Status Assessment Scale

EORTC QLQ-C30 (The European Organisation for Research and Treatment of Cancer, quality of life questionnaire core 30)—Quality of Life Questionnaire

FLOT/mFLOT (fluorouracil plus leucovorin, oxaliplatin, and docetaxel)—Chemotherapy regimen including fluorouracil, leucovorin, oxaliplatin, and docetaxel, and its modified version

HER2/neu (Human Epidermal growth factor Receptor 2)—Cell membrane receptor protein involved in the regulation of the cell cycle

QoL—Quality of Life

PAI—Peritoneal Adhesion Index

PCI—Peritoneal Cancer Index

PCI 1-7 / PCI 8-15—Low to moderate extent of peritoneal carcinomatosis

PD-L1—programmed death ligand 1

Siewert J.R.—(Siewert classification)—classification of adenocarcinomas of the esophagogastric junction theoretical basis

BACKGROUND

As the fifth leading cause of cancer incidence and mortality worldwide, gastric cancer remains a major clinical concern [1]. According to a large study from a specialized centre [2], peritoneal carcinomatosis—a condition defined as secondary peritoneal involvement, was identified in 32.1% of patients undergoing primary diagnostic laparoscopy for suspected localized, potentially resectable gastric cancer, highlighting the substantial clinical challenge in managing these cases.

Current clinical guidelines recommend palliative therapy at this disease stage, with the dual goals of extending survival and preserving quality of life. For patients with stage IV gastric cancer and peritoneal carcinomatosis on first-line chemotherapy with a satisfactory performance status (ECOG 0–1; Eastern Cooperative Oncology Group scale), comprehensive rehabilitation is an essential part of management.

The rehabilitation focuses on physical and social adaptation, prehabilitation, and nutritional and psychological support. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a minimally invasive local treatment that delivers pressurized aerosolized chemotherapy agents into the abdominal cavity during laparoscopy.

The technique features enhanced tumour penetration and uniform drug distribution, enabling a substantial dose reduction of chemotherapy to mitigate systemic complications [4]. In a pilot study [5], cisplatin and doxorubicin administered at ~10% of standard systemic doses induced histologically confirmed regression of peritoneal carcinomatosis in chemoresistant patients, demonstrating the technique’s potent local antitumour activity even with low-dose regimens.

Standardized quality-of-life questionnaire (The EORTC QLQ-C30) is used to evaluate the impact of PIPAC on quality of life in peritoneal carcinomatosis patients [6]. Its validity in this context is confirmed by a comprehensive systematic review and meta-analysis [7].

Due to variable clinical courses and treatment responses of peritoneal carcinomatosis across cancer types, the analysis considered separate patient cohorts—those with secondary peritoneal disease originating from a single primary tumour type.

Such an approach enables the acquisition of highly precise and clinically meaningful data for each disease entity. Specifically, in gastric cancer, a meta-analysis involving 31 patients demonstrated that PIPAC did not compromise quality of life: scores remained statistically unchanged across 13 of 14 assessment scales. Notably, the global health status—a critical composite measure reflecting the patient’s self-reported overall well-being (on a 0–100 scale)—showed stable mean values (53.2, 49.9 and 48.0) prior to treatment cycles 1–3, underscoring the treatment’s favourable impact on patient-reported outcomes [7].

Notably, PIPAC maintains quality of life in patients with gastric cancer-associated peritoneal carcinomatosis—a key advantage in the context of palliative management. This finding underscores the patient-centred

Benefits of the technique, particularly when curative options are limited. A comparative analysis versus cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) revealed a distinct advantage of PIPAC in managing disease-related symptoms. Patients treated with local intraperitoneal chemotherapy achieved significantly better outcomes on 9 symptom-specific scales of the quality-of-life questionnaire. In contrast, the CRS/ HIPEC group demonstrated superior performance on functional domains and the overall health status score, highlighting complementary strengths of these approaches in palliative care.

According to the review authors, most of the included studies were associated with a moderate risk of bias, with selection bias being a key concern. Specifically, patients experiencing poorer health outcomes were disproportionately likely to discontinue participation, which may have introduced an upward bias in the reported quality-of-life metrics. This limitation should be considered when interpreting the findings [7].

A retrospective analysis [8] evaluated data from a cohort of 91 patients presenting with primary malignancies of diverse aetiology, including gastric cancer (32%), ovarian cancer (27%), and colorectal cancer (15%), all featuring peritoneal dissemination. The retrospective study design encompassed 158 PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy) interventions. Notably, quality-of-life assessment was performed using the validated EORTC QLQ-C30 instrument, enabling comprehensive patient-reported outcome evaluation.

Notably, the study methodology incorporated serial pre-procedure evaluations prior to each PIPAC administration, facilitating longitudinal monitoring of clinical parameters in a subgroup of 48 patients who underwent ≥2 cycles. This approach revealed robust baseline quality-of-life metrics, with particularly strong performance in cognitive domains (83±23%) compared to physical (75±28%) and emotional (62±27%) functioning. These findings suggest preserved patient-reported outcomes even in advanced disease stages.

Quantitative analysis revealed that the global physical health metric experienced a moderate, time-limited reduction following the inaugural PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy) intervention (82% to 75%), with restoration to 89% documented after the second treatment cycle. Importantly, gastrointestinal symptomatology demonstrated stability throughout the course of PIPAC therapy, as evidenced by unchanged scores on scales assessing nausea/vomiting, constipation, diarrhoea, and anorexia. Pain metrics exhibited a transient elevation post-first procedure (28% to 37%), subsequently normalizing to 32% prior to the next intervention, thereby supporting the favourable safety profile of the treatment modality.

The authors highlight that pressurized intraperitoneal aerosol chemotherapy (PIPAC) does not elicit the adverse reactions commonly observed with systemic chemotherapy regimens, specifically mucositis, paraesthesias, and alopecia. Consequently, the study provides evidence that PIPAC may be safely implemented in the management of patients with peritoneal carcinomatosis, with no clinically significant impact on quality-of-life metrics [8].

Notably, PIPAC demonstrates a multifaceted positive impact, fostering an optimal environment for rehabilitation efforts in patients with gastric cancer and peritoneal dissemination. Robust evidence from extensive meta-analyses and prospective clinical trials underscores the therapy’s ability to effectively manage debilitating symptoms, thereby preserving and potentially enhancing patients’ functional capacity.

According to a meta-analysis of 18 investigations involving 671 patients diagnosed with disseminated peritoneal malignancy, PIPAC (Pressurized intraperitoneal aerosol chemotherapy) was associated with ascites resolution in 13.1% of cases (95% CI: 7.0–20.7). The treatment demonstrated a favourable toxicity profile, with an overall adverse event rate of 17.1% (95% CI: 5.3–33.4) and a low incidence of severe complications (CTCAE grade III–V, version 5.0: 3.6%, 95% CI: 1.4–6.6). These findings substantiate the safety of PIPAC and support its consideration as a therapeutic modality for managing ascites in patients with peritoneal dissemination, minimizing additional symptomatic burden [9].

According to a prospective single-centre investigation [10], in a cohort of 24 patients diagnosed with peritoneal carcinomatosis, 11 out of 14 patients (78.6%) who underwent two or more cycles of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) demonstrated control of ascites (reduction or stabilization). This outcome was associated with maintained physical comfort and exercise capacity. Standardized assessment using the EORTC QLQ-C30 questionnaire confirmed stability of the global health status metric: 52±5.9 points at baseline, 51±8.3 points prior to the second cycle, and 48±14 points prior to the third cycle. These data substantiate the role of PIPAC as a viable therapeutic option for ascites management in peritoneal carcinomatosis, with minimal impact on patient-reported quality of life [10].

On the diarrhoea scale, values decreased sequentially: 40±9,8 points before the first procedure, 29±13 points before the second, and 20±13 points before the third. A similar improvement trend was observed on the constipation scale: baseline level 13±5,1 points, before the second procedure 13±8,8 points, and before the third 7±6,7 points. Nausea and vomiting scores remained stable: 24±7,3 points before the first procedure, 21±8,2 points before the second, and 20±12 points before the third procedure. Physical functioning demonstrated the following values: 78±4,8, 66±7,5, and 63±13 points, respectively.

A review [11] of 10 studies (n=425 patients with peritoneal carcinomatosis, including 92 [21.6%] with gastric cancer) showed stable global health scores on EORTC QLQ-C30 during PIPAC: 47,1 (95% CI: 40,2–53,9) pre-first procedure, increasing to 60,4 (95% CI: 18,0–102,9) pre-sixth procedure [11].

Critically, even within a palliative care framework and among a high-risk patient cohort, PIPAC demonstrates a favourable safety profile. Specifically, the incidence of severe adverse events remains low (9.6% for CTCAE grade III; 1.6% for grade IV, version 5.0), with minimal procedure-related mortality of just 0.7%. This safety advantage is particularly noteworthy given the vulnerability of the patient population. Consequently, these findings strongly support the incorporation of PIPAC into multidisciplinary care pathways, where it can contribute to preserving functional status and enhancing quality of life for patients with peritoneal carcinomatosis [11].

A comprehensive analysis of available clinical trial data substantiates that pressurized intraperitoneal aerosol chemotherapy (PIPAC) is associated with effective symptom control and a low incidence of complications. These characteristics enable significant stabilization of patient-reported quality of life metrics in individuals with disseminated peritoneal disease. Consequently, PIPAC is well-suited for integration into multidisciplinary rehabilitation pathways, where it can support the maintenance of functional capacity and promote successful patient recovery [11].

Due to the absence of standardized PIPAC protocols in current guidelines, further study of treatment outcomes and quality of life (during/after treatment) is needed. Objective assessment of PIPAC’s effect on quality of life will clarify its role in gastric cancer with peritoneal dissemination. Therefore, a randomized trial with standardized interval quality-of-life assessment in comparable gastric cancer/peritoneal carcinomatosis groups, using PIPAC as first-line adjunct therapy, is justified.

Aim: to comprehensively evaluate patient-reported quality of life across treatment phases (pre-, intra-, and post-treatment) in stage IV gastric cancer with peritoneal dissemination (Cy+ and/or PCI ≤15). Two therapeutic approaches will be compared: systemic polychemotherapy (sPCT) versus sPCT combined with pressurized intraperitoneal aerosol chemotherapy (PIPAC). A key component of the analysis will be the stratification of patients by peritoneal carcinomatosis burden (Cy+ status; PCI scores: 1–7 vs. 8–15), enabling a nuanced understanding of how disease severity influences treatment-related quality of life changes.

METHODS

Study Design

This prospective single-site cohort investigation (n=72; protocol NCT06313801) aims to compare the safety profile and therapeutic efficacy of two first-line treatment strategies for primary stage IV gastric cancer complicated by peritoneal carcinomatosis (Cy+ and/or PCI ≤15). The study contrasts standard FLOT regimen (6 cycles) with an innovative combined approach: FLOT for 3 cycles, followed by modified FLOT (mFLOT) for 3 additional cycles, supplemented with dPIPAC (dosed PIPAC using intraperitoneal docetaxel). This design addresses a critical clinical need to optimize treatment for patients with peritoneal dissemination.

The clinical trial has a prospective design with randomization in a 1:1 ratio between treatment groups and stratification according to the severity of peritoneal carcinomatosis (Cy+: PCI 1–7, PCI 8-15). Patient recruitment and treatment under the protocol are ongoing. One of the protocol’s control points is the assessment of quality of life using the EORTC QLQ-C30 questionnaire. The assessment is conducted at five timepoints: before treatment, after three treatment cycles, after six treatment cycles, and 3- and 6-months post-treatment.

Study Setting

This prospective study was implemented at the Research Institute Of Clinical Oncology “Nizhny Novgorod Regional Clinical Oncological Dispensary”, Nizhny Novgorod, Russia. The patient inclusion period spanned June 2023 – June 2025. Patients diagnosed with stage IV gastric cancer and confirmed peritoneal dissemination, meeting the predefined inclusion criteria, were invited to take part in clinical trial NCT06313801 after undergoing diagnostic laparoscopy. Outcomes were monitored before, during, and up to 6 months after treatment.

Eligibility Criteria

Inclusion Criteria: signed informed voluntary consent obtained from the patient; age ≥18 and ≤75 years at the time of enrolment; Eastern Cooperative Oncology Group (ECOG) performance status ≤1; histologically confirmed gastric cancer or type III esophagogastric junction cancer according to the J.R. Siewert classification (adenocarcinoma, signet-ring cell carcinoma); HER2/neu-negative tumour status; microsatellite-stable tumour status; absence of PD-L1 overexpression; sole manifestation of distant metastases (M1 in the TNM classification) as follows: cytology-positive (Cy+) findings in the initial peritoneal lavage, and/or verified peritoneal dissemination with a peritoneal Cancer Index (PCI) <16; Peritoneal Adhesion Index (PAI) <16; no active infectious diseases, psychiatric disorders, severe allergic conditions, or other significant comorbidities; adequate organ function, as assessed by laboratory parameters at screening, including: haemoglobin concentration; neutrophil count; platelet count; alanine aminotransferase (ALT) level; aspartate aminotransferase (AST) level; total bilirubin level; urea level; creatinine level.

Exclusion criteria: patient has not provided signed informed voluntary consent; age <18 or >75 years at the time of inclusion; objective performance status according to the Eastern Cooperative Oncology Group (ECOG) scale ≥2; histological types excluding adenocarcinoma and signet-ring cell carcinoma of the stomach or type III esophagogastric junction cancer (per the J.R. Siewert classification)); HER2/neu-positive (3+) tumour status; microsatellite-unstable (MSI-H) tumour status; presence of PD-L1 overexpression; distant metastases (M1), except in cases where Cy+ is detected in the initial peritoneal lavage fluid and/or documented peritoneal spread (peritoneal cancer index is below 16 (PCI <16)), presence of distant metastases, including metastases to supraclavicular, mediastinal, or para-aortic lymph nodes; peritoneal cancer index (PCI) ≥16; peritoneal adhesion index (PAI) ≥16; contraindications for performing diagnostic laparoscopy; complications related to the primary tumour (bleeding, decompensated stenosis, grade III–IV dysphagia) if condition has not been corrected; decompensated comorbidities; synchronous primary tumours; any prior specific antineoplastic treatment for any malignant tumour; prior specialized treatment for gastric cancer; known individual intolerance to drugs included in the protocol; pregnancy; breastfeeding.

Withdrawal criteria: unacceptable toxicity (Grade ≥4 according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE v.5.0); complications of the surgical component (Grade ≥IV according to the Clavien–Dindo classification); withdrawal of informed voluntary consent by the patient; clear evidence of disease progression as determined by the research team; pregnancy; severe non-compliance.

Intervention

In the control group, patients underwent initial diagnostic laparoscopy followed by 6 cycles of FLOT chemotherapy. Tumor response was evaluated after 3 and 6 cycles, with mandatory control diagnostic laparoscopy performed after completion of chemotherapy. For patients demonstrating complete regression of peritoneal metastases and negative cytology (Cy−) in peritoneal lavage, management options included either regular follow-up or optional cytoreductive surgery, as determined by the multidisciplinary team. Patients with an incomplete response were managed with dynamic observation until evidence of disease progression. Upon progression, treatment options included second-line chemotherapy regimens or tailored palliative care strategies, selected according to the specific clinical context. In the study arm, patients underwent initial diagnostic laparoscopy followed by a sequential chemotherapy regimen of 6 cycles: standard FLOT (cycles 1, 3, 5) and mFLOT; (cycles 2, 4, 6), totaling 6 (3 + 3 cycles). Assessment will be performed every 3 cycles (after the 3rd and 6th cycles), including sessions of hyperthermic intraperitoneal aerosol chemotherapy (PIPAC) with docetaxel. Docetaxel is thereby excluded from systemic administration during cycles 2, 4, 6 of perioperative chemotherapy. Group 2 does not undergo scheduled control diagnostic laparoscopy. Instead, the assessment is integrated into the surgical procedure during the hyperthermic intraperitoneal aerosol chemotherapy (PIPAC) session administered at the 6th cycle of perioperative chemotherapy. This timing aligns with the follow-up interval established in the control group. In case of complete regression of peritoneal lesions and negative cytology (Cy(−)) in peritoneal lavage, dynamic observation or optional cytoreductive surgery is considered. In case of incomplete response, dynamic observation until disease progression is recommended. In case of progression, second-line chemotherapy or optimal palliative care options are initiated, depending on the clinical situation.

Standard treatment according to the FLOT regimen: docetaxel 50 mg/m² as a 1-hour intravenous (IV) infusion on Day 1, plus oxaliplatin 85 mg/m² on Day 1, plus calcium folinate 200 mg/m² as a 2-hour IV infusion on Day 1, plus fluorouracil 2600 mg/m² as a 24-hour IV infusion on Day 1 (an infusion of the same total dose of fluorouracil over 48 hours is acceptable).

In the study group, during treatment cycles 2, 4, and 6, when docetaxel was delivered via pressurized intraperitoneal aerosol chemotherapy (PIPAC), systemic chemotherapy followed the mFLOT regimen. This study-defined abbreviation reflects the strategic transfer of docetaxel from systemic administration to intraperitoneal aerosol delivery under pressure. The mFLOT protocol consisted of the following agents, all given on Day 1: oxaliplatin at 85 mg/m² IV, calcium folinate (leucovorin) at 200 mg/m² via 2-hour IV infusion, and fluorouracil (5-FU) at 2600 mg/m² via 24-hour IV infusion. Notably, the same total dose of fluorouracil could alternatively be administered over a 48-hour infusion period. In this case, docetaxel was delivered at a systemically equivalent dosage via the PIPAC method rather than through standard intravenous administration. The PIPAC procedure was conducted under standardized conditions: an administration rate of 30 mL per minute and a maximum injector system pressure of 250 PSI, with continuous visual monitoring throughout the manipulation. Following the aerosol spraying phase, a 30-minute exposure period was implemented while maintaining the specified intraperitoneal pressure to facilitate optimal drug distribution and tissue penetration. Upon completion of the exposure phase, only the residual gas component was evacuated from the peritoneal cavity, ensuring prolonged contact of the chemotherapeutic agent with peritoneal surfaces.

Study Ou tcomes

Main study outcome:The study outcome is the assessment of quality of life (QoL) prior to treatment initiation, throughout the entire treatment period, and up to 6 months following treatment completion.

Outcomes registration.Patient surveys and quality of life (QoL) assessment were performed using a cumulative group analysis of five study visits (summary score for each time point): QOL1: prior to treatment; QOL2: after three treatment cycles; QOL3: after six treatment cycles; QOL4: 3 months after treatment completion; QOL5: 6 months after treatment completion. The standardized EORTC QLQ-C30 questionnaire (Version 3.0), with an official Russian translation, was used for the assessment. This questionnaire was developed by the European Organisation for Research and Treatment of Cancer (EORTC). The third version is the current standard for QoL assessment in research and is suitable for post-treatment study patients.

The first 28 questions of the questionnaire require the patient to select one of the following response options: “not at all”, “slightly”, “quite a bit”, “very much”. Questions 29 and 30 offer a 7-point scale for patient selection, where 1 = “very poor” and 7 = “excellent”. The analysis will focus on the summary score, which excludes one question (question 28) addressing the financial aspect (subjective assessment). The summary score is evaluated on a scale from 0 to 100 points, where 100 points represents the best possible outcome and 0 points the worst possible outcome. Data from EORTC QLQ-C30 patient questionnaires were entered into the clinical trial database and analysed using the standard EORTC summary score calculation method.

Statistical Analysis

Target sample size. A single-center, prospective, randomized investigator-initiated phase II clinical trial with a superiority design to compare the safety and efficacy of first-line polychemotherapy (FLOT, 6 cycles) versus polychemotherapy combined with PIPAC sessions using intraperitoneal docetaxel administration (FLOT 3 cycles + mFLOT 3 cycles + dPIPAC) in patients with primary stage IV gastric cancer and peritoneal carcinomatosis (Cy + and/or PCI ≤15). Null hypothesis- the medians of progression-free survival (PFS) do not differ between the groups and amount to 6 months in both groups. Alternative hypothesis: the median progression-free survival in the control group will be 6 months, while in the experimental group it will be 8.5 months. The sample size was calculated using the following predefined parameters: the acceptable probability of a Type I error (false positive) is 5%, or α=0,05. The probability of a Type II error (false negative) is set at 20%, or β=0,2. The statistical power is 1−β=1−0,2=0,8 (80%).

The critical values of the standard normal distribution corresponding to α=0,05 and 1−β=0,8 — denoted as Zα and Zβ, respectively—were obtained from a table of critical values for the normal distribution. They were found to be Zα=Z0,05=1,6449 and Zβ=Z0,8=0,8416. This study evaluated two treatment strategies for clinical efficacy. The active control arm (Group 1, Pc) involved 6 cycles of the FLOT regimen, yielding 36% efficacy.

The novel approach (PT) combined sequential chemotherapy with intraperitoneal therapy: 3 cycles of standard FLOT, followed by 3 cycles of mFLOT, and concluded with dPIPAC. This regimen demonstrated higher efficacy at 51%. For the purpose of the non-inferiority analysis, a margin of 10% was established a priori (θ=0,1). This defined the maximum acceptable difference in efficacy between the new treatment (PT) and the control (Pc). The following statistical hypotheses were tested:

Null hypothesis (H0): The difference in efficacy (PT−Pc) is less than or equal to 0.1 (PT−Pc≤0,1), indicating non-inferiority is not demonstrated.

Alternative hypothesis (H1): The difference in efficacy (PT−Pc) exceeds 0.1 (PT−Pc>0,1), suggesting the new treatment is non-inferior.

The required sample size for each study group was determined using the standard formula for non inferiority trials: n=(Z_α+Z_β)² × (P_c × (1-P_c)+P_T × (1-P_T))/(P_c- P_T-δ)².

Based on the sample size calculation, 53 patients are required in the control group and 53 in the experimental group to achieve sufficient statistical power to reject the null hypothesis (H0) and confirm the alternative hypothesis (H1). The calculation incorporates a 10% allowance for data loss, which may result from patient dropout, protocol deviations, or missing follow up data. Therefore, the total number of patients to be enrolled in the study is 106, with the anticipated attrition rate explicitly accounted for in the design.

Statistical methods. Data analysis was conducted in the R programming environment (open source statistical software) using the RStudio integrated development environment (IDE), version 2024.04.2+764, developed by Posit Software, PBC. This setup ensures reproducibility of the computational results.

Quality of life (QOL) scores were described using the mean and standard deviation (SD). Null hypothesis: there is no difference in quality of life between repeated measurements within groups and between groups. Multivariate normality was assessed using Mardia’s kurtosis test. In this study, the multivariate distribution did not differ from normal in all formed strata. Therefore, the hypothesis was tested using multivariate analysis of variance with repeated measures (MANOVA-RM). The between-subjects factor was the treatment group (SPCT / SPCT+PIPAC), and the within-subjects factor was repeated QOL measurements. Sphericity checked with Mauchly’s test; violations corrected via Greenhouse–Geisser and Huynh–Feldt methods. Post-hoc comparisons between time points were conducted using a linear mixed-effects model with Holm’s correction for multiple comparisons. Analysis performed separately for entire sample and three predefined strata: positive peritoneal lavage without macroscopic carcinomatosis, peritoneal carcinomatosis with PCI 1–7, peritoneal carcinomatosis with PCI 8–15. Changes in QOL across groups and repeated measures were visualised using an error bar plot.

RESULTS

Study Sample

A total of 72 patients were included in the present analysis. All patients received treatment in accordance with the specified clinical protocol. The treatment was administered at the facilities of the Research Institute Of Clinical Oncology “Nizhny Novgorod Regional Clinical Oncological Dispensary” (table 1). Patients were divided into two groups. The SPCT group included 39 patients: 12 were assigned to the Cy(+) subgroup, 13 to the PCI 1–7 subgroup, and 14 to the PCI 8–15 subgroup. The SPCT+PIPAC group comprised 33 patients: 9 were assigned to the Cy(+) subgroup, 13 to the PCI 1–7 subgroup, and 11 to the PCI 8–15 subgroup.

 

Table 1

General Characteristics of the Sample

Patient Characteristics	Group		p-value
	SPCT n=39 (%)	SPCT+PIPAC n=33 (%)
	Me (Q1; Q3)
Gender:			0.9 Pearson’s Chi-Square Test
Female	17 (44)	15 (45)
Male	22 (56)	18 (55)
Age, years	63.0 (59.0; 68.0)	64.0 (57.0; 69.0)	p=0.6 Wilcoxon Test
Strata:			0.9 Pearson’s Chi-Square Test
PCI 1-7	13 (33)	13 (39)
PCI 8-15	14 (36)	11 (33)
Cy(+)	12 (31)	9 (27)
Tumor Differentiation Grade:			0.5 Pearson’s Chi-Square Test
High-grade	28 (72)	26 (79)
Low-grade	11 (28)	7 (21)
Completion of Chemotherapy Courses:			0.5 Fisher’s Exact Test
6 courses	37 (95)	33 (100)
≤5 courses	2 (5.1)	0 (0)
maximum toxicity (CTCAE v5.0):			0.5 Fisher’s Exact Test
Grade 1	8 (21)	11 (33)
Grade 2	22 (56)	16 (48)
Grade 3	9 (23)	6 (18)
Grade 4-5	0 (0)	0 (0)

 

Primary Results

A multivariate analysis of variance (See Figure 1 for details) with repeated measures of patient’s quality of life scores across the entire sample revealed a statistically significant difference between patients who received SPCT and SPCT+PIPAC, with respect to: group effect (p=0,034), time effect (p <0,001), group by time interaction (p=0,009). Between the third and fifth measurements, significant differences in mean quality-of-life scores emerged between the groups. The SPCT+PIPAC group consistently showed higher QOL values compared to the SPCT-only group (see table 2 for details). Within-group comparison of repeated QOL assessments demonstrated a progressive decline in quality of life across both treatment arms. However, the temporal pattern and severity of this decline differed significantly: SPCT group: a marked reduction in QOL scores was observed starting from the third assessment point (QOL3), indicating a relatively early onset of quality-of-life deterioration. SPCT+PIPAC group: the decline in QOL began at a later time point and was notably less severe, suggesting a protective or mitigating effect of the combined treatment on patient well-being over time. These findings are summarised in Table 3 and support the hypothesis that SPCT+PIPAC may offer better preservation of quality of life during treatment. Multivariate analysis of repeated QOL measurements in patients with positive peritoneal lavage and no macroscopic carcinomatosis (Figure 2) showed significant group (p=0,022), time (p <0,002), and group by time interaction effects (p=0,029) between CT and CT+HIPEC groups.

 

Fig. 1. Quality of Life in Study Groups. Here and in Figs. 2–4: SPCT: polychemotherapy; SPCT+PIPAC— polychemotherapy in combination with pressurized intraperitoneal aerosol chemotherapy.

 

Table 2

Mean Quality of Life Values in Study Groups

Quality of Life	SPCT+PIPAC	SPCT	p-value
	μ±SD
QOL1	83.8±9.9	81.3±10.9	0.297
QOL2	81.9±8.6	83.4±8.3	0.537
QOL3	80.6±7.6	74.3±9.1	0.009
QOL4	77.8±7.8	71.1±9.1	0.006
QOL5	75.5±10.7	70.3±8.6	0.031

 

Table 3

Statistical Test Between Repeated Measurements of Quality-of-Life

Groups	Quality of Life	QOL1	QOL2	QOL3	QOL4
SPCT+PIPAC	QOL1	-	-	-	-
	QOL2	0.633	-	-	-
	QOL3	0.409	0.633	-	-
	QOL4	0.008	0.130	0.473	-
	QOL5	<0.001	0.004	0.033	0.603
SPCT	QOL1	-	-	-	-
	QOL2	0.403	-	-	-
	QOL3	<0.001	<0.001	-	-
	QOL4	<0.001	<0.001	0.149	-
	QOL5	<0.001	<0.001	0.059	0.630

 

Fig. 2. Quality of life in subgroups with positive peritoneal lavage.

 

The mean quality of life (QOL) scores by group, along with the results of within group comparisons, are presented in Table 4. Consistent with the findings in the total sample, statistically significant between group differences in QOL scores became apparent starting from the third measurement point (QOL3).

 

Table 4

Mean Quality of Life Values in Subgroups with Positive Peritoneal Lavage

Quality of Life	SPCT+PIPAC	SPCT	p-value
	μ±SD
QOL1	84.3±9.1	80.8±9.8	0.349
QOL2	79.6±9.4	83.2±9.1	0.349
QOL3	83.6±2.5	71.8±5.2	0.005
QOL4	78.8±5.9	68.9±7.7	0.015
QOL5	79.1±11.7	69.0±5.1	0.013

 

In the SPCT+ PIPAC group, analysis of repeated QOL measurements within the group revealed no statistically significant changes throughout all measurement points. In contrast, the SPCT group showed a statistically significant decline in QOL scores starting from the third measurement (QOL3) (see Table 5).

 

Table 5

Statistical Test Between Repeated Measurements of Quality of Life in Subgroups with Positive Peritoneal Lavage

Groups	Quality of Life	QOL1	QOL2	QOL3	QOL4
SPCT+PIPAC	QOL1	-	-	-	-
	QOL2	1.00	-	-	-
	QOL3	1.00	1.00	-	-
	QOL4	0.926	1.00	1.00	-
	QOL5	1.00	1.00	1.00	1.00
SPCT	QOL1	-	-	-	-
	QOL2	1.00	-	-	-
	QOL3	0.009	0.001	-	-
	QOL4	<0.001	<0.001	1.00	-
	QOL5	<0.001	<0.001	1.00	1.00

 

A multivariate analysis of variance with repeated quality of life measurements in patient subgroups with peritoneal dissemination (PCI 1–7 and PCI 8–15) revealed no statistically significant differences (p >0,24 for PCI 1–7; p >0,18 for PCI 8–15). As shown in Figures 3 and 4, synchronous changes in QOL were observed in both groups, with no differences in the pattern of quality of life change.

 

Fig. 3. Quality of life in subgroups with peritoneal dissemination of 1 to 7 points on the peritoneal cancer index (PCI).

 

Fig. 4. Quality of Life in Subgroups with Peritoneal Dissemination of 8 to 15 Points on the Peritoneal Cancer Index (PCI).

 

DISCUSSION

Research Results Summary

The findings illustrate the trajectory of quality of life (QOL) outcomes across the compared treatment groups and predefined patient strata. These data were collected as part of the clinical trial conducted under protocol NCT06313801.

Interpretation

At baseline, both groups had comparable initial scores for the overall quality of life measure. From the third to the fifth measurement, the SPCT+PIPAC group demonstrated significantly higher QOL scores compared to the SPCT group.

As in the overall sample, statistically significant differences between groups emerged in the subgroup with positive peritoneal lavage starting from QOL3. In contrast, no statistically significant differences were detected in either of the peritoneal dissemination subgroups: PCI score 1–7: p >0,24; PCI score 8–15: p >0,18.

The divergence in the overall quality of life score favouring the SPCT group after three treatment cycles, as observed in the graphical representation across groups and in the subgroup with positive peritoneal lavage, may be interpreted as reflecting patients’ subjective fear of additional surgical interventions. It may also be associated with additional pain and discomfort related to dressing changes of trocar incision sites. This conclusion is further supported by the results of active patient surveys conducted in the combined treatment group 6 months after treatment completion. The divergence in the overall quality of life score favouring the SPCT+PIPAC group after treatment completion and at subsequent follow up visits, statistically demonstrated both in the entire cohort and in the positive peritoneal lavage subgroup, can be interpreted as a result of reduced systemic toxicity and better treatment tolerability. This is attributed to the use of docetaxel in cycles 2, 4, and 6 of PIPAC treatment, as well as patient adaptation to the prescribed regimen and the absence or reduction of subjective fear of treatment within the clinical trial framework.

Study Limitations

The single centre nature of the study. All patients were enrolled and treated at a single institution, which limits the generalisability of the results and their extrapolation to broader populations.

Relatively small sample size and stratum dimensions. The total sample size (n=72 patients), further divided into two groups and three subgroups, resulted in a limited number of observations within individual strata, reducing statistical power. Patient recruitment for the clinical trial was ongoing at the time of manuscript preparation.

Limited inclusion criteria. The highly selective cohort restricts the generalisability of results to patients with more advanced tumour extent, poorer performance status, or different tumour biology.

This report presents an interim analysis conducted while patient recruitment for the clinical trial (NCT06313801) remains ongoing. The interim nature of the data should be considered when interpreting the results, as final conclusions may evolve with the inclusion of additional participants. Risk of attrition bias. Previous QOL studies in PIPAC report that patients with poorer baseline scores and more severe disease are more likely to drop out, potentially inflating mean QOL values and underestimating treatment related adverse effects.

The inability to achieve full blinding and the influence of subjective factors constitute significant methodological limitations. The compared interventions—standard SPCT and SPCT+PIPAC—differ fundamentally in invasiveness and treatment structure, making blinding of patients and clinicians impossible; Subjective influences may affect QOL self assessments, including: patient expectations about treatment efficacy, anxiety related to laparoscopic procedures, attitudes towards clinical trial participation, communication dynamics with healthcare providers.

These factors may introduce response bias and partially distort the observed QOL outcomes.

CONCLUSION

The quality of life in patients receiving first line combination treatment for gastric cancer with peritoneal dissemination (chemotherapy + Pressurized Intraperitoneal Aerosol Chemotherapy) is comparable to that of patients undergoing standard first line chemotherapy during the treatment phase. Furthermore, it demonstrates a statistically significant improvement at the end of treatment and during follow up assessments at 3 and 6 months. These findings reflect better QOL outcomes in the immediate post treatment period and short term follow up for patients receiving combination therapy including SPCT and PIPAC with docetaxel.

Additional information

Author contributions: S.A. Klimin led the data collection process and gathered evidence, conducted data analysis and interpretation, contributed to the scientific design of the study, formulated and developed key research objectives and goals, and drafted the manuscript; Ya.I. Kolesnik managed the dataset, prepared tables and graphs, performed data analysis, and created the graphical presentation of the results; S.E. Mustafaeva conducted a comprehensive literature review and analysed relevant scientific sources to support the study’s background and discussion. N.M. Kiselev contributed to the scientific design, participated in data analysis and interpretation, and provided a critical review of the manuscript with valuable comments to improve the content; I.S. Shumskaya contributed to the scientific design, engaged in data analysis and interpretation, and conducted a critical review of the manuscript, offering valuable suggestions for refinement; V.E. Zagaynov, S.V. Gamayunov: idea formation, goal setting, critical revision, overall responsibility for the work and its integrity. All authors approved the final manuscript and agreed to be accountable for all aspects of the work, guaranteeing proper handling of accuracy and integrity issues. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval: The study received approval from the Local Ethics Committee of the Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary» (Protocol No. 21, Extract No. 11, 19 January 2023). Written informed consent was obtained from all participants, including consent for quality of life assessment using the EORTC QLQ C30 questionnaire during follow up visits.

Funding source: The study and publication of this article were funded by the personal resources of the author team. The authors declare no competing financial interests or conflicts of interest related to the funding of this work.

Disclosure of interests: The authors declare that they have no competing interests.

Statement of originality: The data presented in this article are original and are used for the stated analysis purposes for the first time.

Data availability statement: The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request, subject to patient confidentiality requirements.

Generative AI: The authors confirm that no generative artificial intelligence (AI) technologies or language models (such as ChatGPT, Gemini, Claude, etc.) were used in the preparation, writing, or editing of this manuscript. All content was developed solely by the human authors.

About the authors

Sergei A. Klimin

Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary»; Privolzhsky Research Medical University

Author for correspondence.
Email: kliminsergey7@yandex.ru
ORCID iD: 0009-0009-7832-7728
SPIN-code: 5391-1897
Russian Federation, Nizhny Novgorod; Nizhny Novgorod

Yan I. Kolesnik

Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary»; Privolzhsky Research Medical University

Email: kolesnik-y-i@yandex.ru
ORCID iD: 0000-0002-7959-1813
SPIN-code: 9540-8042

MD, PhD

Russian Federation, Nizhny Novgorod; Nizhny Novgorod

Shamama E. Mustafaeva

City Clinical Hospital named after S.S. Yudin

Email: mu1005va@gmail.com
ORCID iD: 0009-0000-8146-6379
Russian Federation, Moscow

Nikolai M. Kiselev

Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary»; Privolzhsky Research Medical University

Email: kiselev_1989@mail.ru
ORCID iD: 0000-0002-9202-1321
SPIN-code: 6113-0956

MD, PhD

Russian Federation, Nizhny Novgorod; Nizhny Novgorod

Irina S. Shumskaya

Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary»; Privolzhsky Research Medical University

Email: medicanns@mail.ru
ORCID iD: 0000-0003-4295-1843
SPIN-code: 4162-6164

MD, PhD

Russian Federation, Nizhny Novgorod; Nizhny Novgorod

Vladimir E. Zagainov

Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary»; Privolzhsky Research Medical University

Email: zagainov@xmail.ru
ORCID iD: 0000-0002-5769-0378
SPIN-code: 6477-0291

MD, PhD, Assistant Professor

Russian Federation, Nizhny Novgorod; Nizhny Novgorod

Sergey V. Gamayunov

Research Institute of Clinical Oncology «Nizhny Novgorod Regional Clinical Oncological Dispensary»; Privolzhsky Research Medical University; National Medical Research Radiological Center

Email: gamajnovs@mail.ru
ORCID iD: 0000-0002-0223-0753
SPIN-code: 9828-9522

A.F. Tsyb Medical Radiological Research Centre; MD, PhD

Russian Federation, Nizhny Novgorod; Nizhny Novgorod; Obninsk

References

Supplementary files