Neoadjuvant Pressurized Intraperitoneal Aerosol Chemotherapy for Conversion to Cytoreductive Surgery in Unresectable Malignant Peritoneal Mesothelioma: A Report of 2 Cases

Abstract

Case series

Patients: Male, 47-year-old Male, 43-year-old

Final Diagnosis: Advanced and unresectable peritoneal mesothelioma

Symptoms: Unspecific abdominal distension partial bowel obstruction weight loss nausea

Clinical Procedure: —

Specialty: Oncology

Objective: Rare disease

Background

Peritoneal mesothelioma (PM) is the second most common presentation site of malignant mesothelioma. The standard of care for PM is cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Because of its insidious manifestations, PM is often diagnosed at advanced, unresectable stages, precluding optimal cytoreduction and diminishing long-term survivability.

Case Reports

We report 2 cases of advanced and unresectable PM (stages III and IV) presenting with symptomatic with low-grade epithelioid disease. Both cases had a high peritoneal cancer index (PCI >30) and extensive small-bowel involvement. The patients underwent pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin as downstaging conversion therapy. Patient 1 was a 47-year-old man with a laparoscopic PCI of 34 and progression of disease despite 5 months of systemic intravenous chemotherapy. After 2 cycles of PIPAC, the patient showed disease regression and complete resolution of large ascites; CRS-HIPEC was feasible with complete cytoreduction (CC-0). The patient was discharged after a 60-day hospital stay. Patient 2 was a 43-year-old man with a laparoscopic PCI of 30 and no prior lines of therapy. After a single PIPAC cycle, there was clear disease regression (PCI=23), allowing CRS-HIPEC with optimal cytoreduction (CC-1). The patient was discharged after 10 days.

Conclusions

PIPAC is established as a suitable option for palliation of massive ascites in PM; however, in selected candidates with favorable prognostic biomarkers and appropriate fitness for surgery, the procedure can serve as a bridge to definitive open surgery (CRS-HIPEC) aimed at achieving complete cytoreduction.

Introduction

Malignant mesothelioma is a rare neoplasm arising from lining epithelia, and the peritoneum is the second most common primary site, with incidence rates ranging between 7% and 30% [1]. Malignant peritoneal mesothelioma (PM) manifests as locoregional thickening and development of metastases or peritoneal carcinomatosis, with subsequent mass effect on circulation within the abdomen leading to development of bulking and ascites. Symptoms involve abdominal distension, pain, nausea, anorexia, and bowel obstruction. The most common histological subtype of PM is epithelioid, accounting for approximately 60% of cases. The disease is often confined to the peritoneal cavity, while extraperitoneal lymphatic involvement and hematogenous spread are rare [2]. A thorough histopathological examination can define the subtype and help estimate prognosis and treatment. Furthermore, substantial literature review addresses the role of biomarkers in overall survivability, including Ki-67, p16, and BAP1 mutations. A higher Ki-67 index is associated with poorer prognosis in patients with PM who undergo cytoreduction surgery plus hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) [3–5]. Although a definitive index threshold has not been established, with reported values ranging between 9% and 17%, the most robust study correlating survival with CRS-HIPEC identified a Ki-67 index cutoff of less than 9% and low disease volume (peritoneal cancer index [PCI] <17) as associated with better surgical prognostic [3–5].

Advanced PM is characterized by infiltrative or miliary/coalescent tumor deposits in the visceral and parietal peritoneum, with size and distribution varying depending on peritoneal fluid dynamics. Because lymph node involvement and solid-organ metastases are rare, TNM staging may not be useful, while the PCI is preferred [6]. The PCI can be estimated on imaging scans or during diagnostic laparoscopy, which offers the advantage of providing samples for pathology and performing immunohistochemistry. Biopsies can also be obtained percutaneously. PCI scores of 1–10 are classified as stage I; 11–20, stage II; 21–30, stage III; and ≥31, stage IV. The gold-standard treatment for PM is CRS-HIPEC, which has well-established long-term survival benefits [7,8]. Because of its insidious and oligosymptomatic manifestations, PM is often diagnosed at advanced stages (III and IV), with high disease volume and/or unresectable implants. Patients usually already present with refractory ascites and are limited to receiving systemic chemotherapy with low bioavailability to the peritoneum.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) involves the direct application of chemotherapeutic agents to the peritoneal membrane under pressure by laparoscopic CO₂ insufflation. A standardized regimen of intraperitoneal cisplatin and doxorubicin, offering direct and high bioavailability, can be used for palliative management of refractory ascites in patients with PM who are not clinically fit for surgery [9]. However, in patients with a higher PCI, favorable biomarker panels, and unresectable tumor distribution, PIPAC can also be proposed as a form of conversion therapy, aiming at regression of tumor deposits as a bridge to definitive surgery [7].

We report 2 cases of epithelioid PM (stages III and IV), with bulging ascites and extensive small-bowel involvement, in which PIPAC was successfully used as conversion therapy to subsequent CRS-HIPEC. We present these cases in accordance with the CARE reporting checklist.

Case Reports

Both patients presented herein were treated in 2023 in a hospital in Brazil, in a specialized center for peritoneal carcinomatosis. PIPAC has been performed at our center since January 2018 and has become a well-established practice, with improved biosafety protocols, technical and operational training, and fully standardized techniques.

All procedures were performed in accordance with the ethical standards of the institutional research ethics committee and with the Helsinki Declaration (as revised in 2013).

PIPAC Technique

The use of standardized techniques and validated equipment is essential for safe and successful PIPAC. The cytostatic regimen of choice in PM consists of cisplatin 10.5 mg/m² in 150 mL of 0.9% saline solution plus doxorubicin 2.1 mg/m² in 50 mL of 0.9% saline, for a total volume of 200 mL, to be instilled over 45 minutes [9]. This dual-agent strategy is extrapolated on evidence from CRS-HIPEC, in which overall survival is higher with dual-agent rather than single-agent regimens.

The procedure begins by entering the abdominal cavity at midline, followed by aspiration and measurement of total ascitic fluid. The exposure of surfaces is mandatory for calculation of the laparoscopic PCI as well to ensure clear sites for cytostatic agent penetration. We did not repeat peritoneal biopsies for assessment of the Peritoneal Regression Score (PRGS) in either case, since both patients had previously documented low-grade Ki-67 indices and low-mitotic baseline samples. While palliative PIPAC can be offered to all patients to control ascites using the same chemotherapeutic regimen, we highlight that patients with low biomarkers can and must be followed closely between cycles, as they can present visual regression of disease and be positively selected for CRS-HIPEC. We allocate using main and auxiliary trocars in the midline for aspirators and forceps, facilitating subsequent abdominal wall resection if surgery becomes feasible. In the past 2 years, we have adopted and validated the MCR-4 Topol surgical micro-atomizer system (SKALA-Medica, Czech Republic), placed through a 10-mm disposable trocar with 5-mm reducer for drug aerosolization. The chemotherapeutic agents are instilled with an intra-abdominal pressure of 12 mm Hg in a continuous CO₂ flow of 2 L/min at room temperature (normothermic). Therapeutic capnoperitoneum is maintained for 30 minutes and subsequently evacuated into a closed aerosol waste system equipped with HEPA filters (marVac, KLS Martin, Germany).

Case 1

A 47-year-old man from Goiânia, Brazil, presented with unspecific abdominal distension, weight loss, and nausea. The patient had no relevant occupational history and no comorbidities other than grade III obesity, with a body mass index (BMI) of 39. The Karnofsky Performance Score (KPS) was 100%, and Eastern Cooperative Oncology Group (ECOG) performance status was 0–1. Diagnosis was obtained through computed tomography (CT) scans showing irregular and extensive peritoneal thickening, omental cake, and large-volume ascites. The patient underwent screening for other primary malignancies with colonoscopy and endoscopy; however, diagnosis was obtained with percutaneous biopsy. Histopathological analysis confirmed PM and was consistent with low-grade epithelioid PM (Ki-67 index 5%, mitotic count <1 per mm², and loss of BAP1 expression). PCI was estimated radiologically at 30 (stage III). After diagnosis, the patient underwent a 5-month course of systemic Pemetrexed, but had signs of disease progression and was referred to our center.

PIPAC was performed to control the ascites, and the first cycle consisted of 3 instillations within a 30-day interval. The first procedure was performed in April 2023, yielding 3900 mL of citrine-yellow ascitic fluid and a laparoscopic PCI of 34 (stage IV). Multiple miliary implants were distributed throughout the small-bowel surface and mesentery. The postoperative course was uneventful. The second session took place in June 2023, yielding 1650 mL of ascites and an estimated PCI of 33. The third instillation was in July 2023; with 2300 mL of oscillating ascites and an estimated PCI of 28. Since patient tolerated the first cycle, with symptom improvement, we proposed a second cycle be followed between August and September 2023. Visual evidence of tumor regression was observed at each new instillation, with gross evidence of desmoplastic response in the small-bowel territories. Ascites decreased to 900 mL and was altogether absent at the last instillation. No nephrotoxicity or myelotoxicity was observed. The mean length of hospital stay was 48 hours after each PIPAC.

In November 2023, CRS-HIPEC was proposed. In brief, previous surgical scars and midline portals were resected. The surgical PCI was determined as 34. A broad desmoplastic reaction was observed, with a visual mesenchymal membrane covering areas previously exposed to PIPAC (Figure 1). (No such reaction was observed in unexposed areas or recesses.) The largest tumor remnants were found at the sigmoid fixation in the left paracolic gutter (requiring resection of the spermatic cord), omental bursa, and mesentery of the proximal jejunum, which was consistent with the mechanics of intra-abdominal peritoneal fluid circulation and areas of difficult exposure to aerosol. To complete the cytoreduction of the small-bowel mesentery, a pneumodissection technique was used (Figure 2). For the HIPEC stage, the peritoneal cavity was perfused for 90 minutes with cisplatin (10.5 mg/m²) and doxorubicin (2.1 mg/m²) in peritoneal dialysis solution. A Performer HT intraperitoneal hyperthermia system (RanD Biotech, Italy) was used. The total operative time was 14 hours, attributable to the degree of technical difficulty and the goal of achieving optimal completeness of cytoreduction (CC-0) (Figure 3). The patient needed rectosigmoidectomy and right hemicolectomy, with primary anastomosis and a protective ostomy. The patient had a long postoperative stay, developing recurrent early respiratory and superficial surgical site infections requiring broad-spectrum antibiotics. The patient was extubated successfully after tracheostomy. Complications were classified as Clavien-Dindo IIIa, did not require reoperation, and no major abdominal complications were observed. The patient remained in intensive care and on total parenteral nutrition for more than 14 days, developing extensive gastroparesis and metabolic ileus. We attributed the long hospital stay to a preexisting elevated BMI and postoperative systemic inflammatory response syndrome. After rehabilitation, decannulation, and resumption of oral intake, the patient was discharged on postoperative day 60.

Figure 1.

Initial intraoperative appearance of Patient 1 during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), demonstrating a broad desmoplastic reaction of the greater omentum (arrow) following pressurized intraperitoneal aerosol chemotherapy (PIPAC) cycles.

Figure 2.

Pneumodissection of the small-bowel mesentery was performed using fine-needle insufflation.

Figure 3.

Final cytoreduction outcome of Patient 1 demonstrating complete cytoreduction (CC-0). Exposed small-bowel mesentery is indicated by black arrows, the stomach greater curvature following radical omentectomy by the dotted arrow, and the liver in the right upper quadrant.

Eighteen surgical specimens were sent for histopathological examination. All confirmed low-grade extensive multifocal epithelioid mesothelioma with infiltrative behavior, and PRGS was not applicable. Splenic hilar and pericolic lymph node dissection were indicated no lymph-node metastases. At 3 and 6 months after discharge, control CT scans showed no remnant disease or recurrence sites. Patient is fully active, KPS 100%, and while experiencing weight and muscle loss during recovery, he was within normal range BMI with recovering sarcopenia. No signs of thrombocytosis or serum tumor markers (CA 125) were at rise. Patient remains under strict multidisciplinary team follow-up.

Case 2

A 43-year-old man from São Paulo, Brazil, presented with abdominal distension and partial bowel obstruction. The patient had no relevant comorbidities, a KPS of 100%, and an ECOG performance status of 0. Imaging demonstrated extensive small-bowel involvement with multiple partial luminal obstructions, while colon and small-bowel adenocarcinomas were excluded. A subsequent percutaneous biopsy of the omental cake bulk established the diagnosis of low-grade epithelioid mesothelioma with a Ki-67 index of 5%, WT1 positivity, and loss of BAP1 and BRCA1 expression. No systemic regimen was proposed prior to PIPAC.

Because of its favorable biomarkers panel, PIPAC was proposed upfront as conversion therapy. We used the same regimen of 3 instillations of cisplatin/doxorubicin as described for Patient 1. At the first instillation, 400 mL of citrine-yellow ascitic fluid was aspirated, and the laparoscopic PCI was estimated at 30. In the following 2 sessions, ascites decreased to 80 mL and zero, and the visual distribution of implants showed regression, with PCI dropping to 27 and 23, respectively. CRS-HIPEC was performed in September 2023.

An extraperitoneal peritonectomy was done with resection of midline portals from the previous procedures, while a large implant was noted in the umbilical portal. The surgical PCI was 28. An intense desmoplastic reaction was observed in areas exposed to PIPAC, with visible response in the greater omentum, hepatic surface, diaphragm dome, and anterior surface of the small bowel. Peritonectomy was performed in the 4 abdominal quadrants and pelvis, as well as cholecystectomy, splenectomy, radical omentectomy, and exploration of peritoneal recesses. At the end of the cytoreduction stage, tumor remnants were still visible in the mesentery (<0.2-mm unresectable implants in close contact with the vessel arcades of the jejunum and ileum), thus yielding a final completeness score of CC-1. HIPEC consisted of perfusion with cisplatin and doxorubicin, as described above, and was completed uneventfully. The total operative time was 11 hours. Histopathological examination confirmed low-grade epithelioid mesothelioma in all specimens (21 samples). The patient’s postoperative course was uneventful, with no complications beyond those expected (early gastroparesis). The patient was discharged on postoperative day 10. CT scans at 3 and 6 months after surgery showed no abnormalities and no thickening of the small-bowel mesentery. At the time of this report, the CA 125 remains stable, and the patient is currently being screened for long-term survivability, with no signs of recurrence. Table 1 summarizes and compares the key data for both cases.

Table 1.

Summary of key clinical and procedural data for the 2 patients.

Variable	Case 1	Case 2
Diagnostic PCI	34	30
Grade of small bowel involvement	Regions 9, 10, 11 and 12* Larger >2.5 mm	Regions 10, 11 and 12* Seromuscular, larger >2 cm
Ki-67 index	5%	5%
PIPAC cycles	2 (5 instillations)	1 (3 instillations)
Ascites (largest account)	3900 mL	400 mL
Ascites after PIPAC	absent	absent
Post-PIPAC PCI	34	28
Visual regression of implants (+, ++, +++)	+++	++
Completeness of CRS-HIPEC	CC-0	CC-1
Length of hospital stay	60 days	10 days
Complications	– Pneumothorax – Pulmonary sepsis and tracheotomy for extubation – Gastroparesis – Superficial surgical site infection and hematoma	None
Long-term staging 6 months 1 year	No signs of recurrence	No signs of recurrence

CRS-HIPEC – cytoreduction surgery plus hyperthermic intraperitoneal chemotherapy; PCI – peritoneal cancer index; PIPAC – pressurized intraperitoneal aerosol chemotherapy.

^*Abdominopelvic regions for PCI according to Sugarbaker et al [14].

Discussion

The average survival of patients with PM treated with systemic chemotherapy alone is 15 months [10]. In this context, CRS-HIPEC has emerged as the standard of care for PM; however, late diagnosis often precludes cytoreduction, and patients with advanced disease are left with limited treatment options.

In peritoneal neoplasms, particularly those of epithelioid origin, survival is closely related to the extent of surgical resection and the completeness of cytoreduction. Severe seromuscular involvement of the small bowel is frequently the main criterion to define unresectability. Bioavailability of systemic chemotherapy is known to be poor in the peritoneum, triggering low local response; therefore, surgical alternatives are preferred when feasible [7,8]. Young, carefully selected patients with advanced peritoneal disease, such as diffuse small-bowel or extensive mesenteric involvement, can be offered neoadjuvant PIPAC as a bridge to CRS-HIPEC. While systemic chemotherapy is associated with adverse effects and low effectiveness due to its limited bioavailability in the peritoneal cavity, PIPAC applies higher doses with little to no systemic toxicity.

Serial PIPAC cycles in different primary tumors can also assess the PRGS or Histological Tumor Regression Grade [9], and some centers use sequential biopsies to evaluate tumor response. In our experience, however, both cases demonstrated postoperative surgical specimens with persistent microscopic low-grade disease in all samples, which may not correlate with, or accurately reflect, the macroscopic regression observed during each PIPAC. Visual assessment and the diminishing-to-absent ascites suggest successful debulking of the celiac axis obstruction, even though biopsies would likely still have demonstrated the presence of MP. In our context, we assert that if patients exhibit tolerance to the method, no overt toxicity, and improvement of symptoms, PIPAC can be offered for longer periods with visual recognition of regression.

A 2023 cohort of 36 patients demonstrated the use of PIPAC as neoadjuvant treatment for non-resectable PM, with half of the patients receiving 3 PIPAC cycles or more [11]. However, only 9 of 22 patients had perceptible ascites, implying that the remaining still had fluid reabsorption, possibly indicating a lower bulk of disease or lymphatic micro-obstructions. Notably, 14 patients underwent subsequent CRS-HIPEC and achieved complete cytoresections. With the goal of using PIPAC as a bridge to definitive surgery, several recommendations warrant consideration. During PIPAC, concentrating the aerosol in a single area or too close to small bowel or serosa can induce iatrogenic lesions and not properly spread the agents evenly in the abdominal cavity [12]. All ascitic fluid should be completely aspirated and quantified to ensure adequate peritoneal surface exposure and to minimize the risk of leakage or trocar-site contamination during and after PIPAC. Total ascites might be an independent and observable factor correlating with treatment response, although additional data and larger patient populations are needed for independent analysis.

For CRS-HIPEC following PIPAC, surgeons must have experience and a high HIPEC learning curve owing to more challenging adhesiolysis, maneuvers to complete mesenterectomy, and thorough exploration of recesses and anatomical pitfalls such as the bursa omentalis, ligament of Treitz, foramen of Winslow, and inguinal hernial sacs. The desmoplastic adhesions observed after PIPAC appear as thin connective tissue firmly adherent to the serosa, usually covering residual disease, and must be completely removed.

When selecting these patients, PIPAC is already established as a useful tool for palliative care in peritoneal carcinomatosis and in the treatment of ascites. The decision to use PIPAC as a bridge can actively guide patient monitoring, with biomarkers such as a low Ki-67 index combined with PCI serving as prognostic indicators for outcomes after CRS-HIPEC. We have adopted critical selection criteria of a Ki-67 index less than 9% and PCI less than 17 for patients to be eligible for the PIPAC bridge to CRS-HIPEC [2,13]. BAP1 loss is relatively common in epithelioid subtypes, which generally have better overall survival than other subtypes; therefore, in epithelioid cases, BAP1 loss is not considered an independent marker for patient selection [3,4]. In our center, patients with other subtypes, such as biphasic, sarcomatoid, or bicavitary, are, for now, eligible for palliative PIPAC exclusively. Immunostaining of Ki-67 can be assessed in the first diagnostic biopsy; therefore, the index should be poignant to guide the clinical decisions from thereon.

Advanced extraperitoneal disease and lymph node involvement remain absolute contraindications to neoadjuvant PIPAC. ECOG performance status greater than 3 or performance status too poor to tolerate for surgery with curative intent are relative-to-absolute contraindications; nevertheless, PIPAC may still be offered exclusively for the palliative management of ascites.

The standardization of PIPAC is well defined in the literature, with only slight differences and preferences across centers. It is important to note that there is a learning curve, and PIPAC should only ever be performed using validated materials; improvised devices should be avoided.

Conclusions

PIPAC serves its original purpose of palliating symptomatic malignant ascites, but it can and should be considered as a viable neoadjuvant treatment option for tumor downstaging in patients with high PCI and favorable biomarker panels prior to definitive surgery. CRS-HIPEC following PIPAC should aim for optimal cytoreduction. Achieving complete cytoreduction is technically more difficult after PIPAC owing to the formation of mesenchymal adhesions, and surgeons must be familiar with multiple cytoreductive techniques. If, at any point in treatment, a patient develops disease progression, extraperitoneal or pleural disease, lymph node involvement, or failure to respond to PIPAC, the decision to pursue surgery must be reconsidered, avoiding interventions that add morbidity and mortality without survival benefit.