Use of Neoadjuvant Immunotherapy in Malignant Peritoneal Mesothelioma as a Bridge to Surgical Intervention: A Case Report

Introduction

Malignant mesothelioma (MM) is a rare disease arising from mesothelial surfaces of the pleura, pericardium, or abdominal peritoneum. Malignant peritoneal mesothelioma (MPM) accounts for 10% to 20% of all MM [1], a disease known for its poor survival rate [2]. Three main histological subtypes of MPM are described in literature: the epithelioid subtype is the least aggressive and carries the best prognosis, whereas the sarcomatoid, and biphasic (mixed) subtypes are considered highly aggressive and are associated with rapid local progression and therefore poorer outcomes [3]. While development of pleural mesothelioma is highly correlated with asbestos exposure in up to 70% of patients, the role of asbestos as a risk factor in the development of peritoneal mesothelioma is unclear, although it has been reported by patients in approximately 33% of cases [4–6]. Diagnosis of MPM is largely based on collective data on patient presentation, physical examination, radiologic imaging (most commonly computed tomography (CT) of abdomen/pelvis), and ultimately biopsy of lesions amenable to pathologic examination. Patients can present nonspecifically with generalized abdominal pain, early satiety, weight loss, and increased abdominal girth secondary to large-volume ascites [7]. Due to the non-specific nature of symptomatology, diagnosis of MPM is often delayed. Imaging via CT abdomen/pelvis will demonstrate the expansive nature of MPM with wide spread of heterogeneously-appearing lesions, involvement of the mesenteric or parietal epithelium, thickening of the omentum (“caking”), and ascites [8,9]. A distinguishing feature of MPM is the lack of extra-abdominal metastases and inability to identify a primary site of malignancy [10].

Guidelines from the Peritoneal Surface Oncology Group International (PSOGI) and the National Comprehensive Cancer Network® (NCCN®) support CRS with HIPEC as the recommended treatment for operable MPM [11–13]. However, despite recent advances, MPM remains poorly understood and underrepresented in clinical trials, with no standardized treatment protocol for unresectable or borderline resectable disease. As such, treatment decisions in borderline or inoperable scenarios rely heavily on extrapolated data from pleural mesothelioma studies. Many studies have demonstrated the benefit of immunotherapy in treating unresectable malignant pleural mesothelioma [5,14–19]. Notably, nivolumab and ipilimumab have been shown to lead to a statistically significant and clinically meaningful benefit in overall survival (OS) when compared to platinum-based doublet chemotherapy in the first-line setting. Additionally, the MERIT study, a Japanese phase II trial, has contributed to a growing body of evidence to support the potential for immunotherapy agents such as nivolumab to effectively and safely treat patients with pleural mesothelioma [20].

Furthermore, studies have illustrated the importance of understanding the tumor immune microenvironment (eg, PD-L1 expression, TIL profiles) and its role in prognostication and response prediction in MPM [21]. Unfortunately, however, while all this is promising, this practice has not been formally investigated for the management of inoperable MPM, as this rarer disease site was excluded from pivotal trials. There is currently no consensus on the use of immunotherapy as part of the systemic therapy regimen, sequence, or duration of treatment in the setting of inoperable or borderline resectable MPM. Given the rarity of this disease, trials done exclusively for MPM have been uncommon and it is generally accepted that systemic therapy strategies used in malignant pleural mesothelioma can be extrapolated to this disease process [13,22] despite their differing genomic and immunologic landscape [23]. Thus, the challenges associated with management of MPM emphasize a critical need for innovative therapeutic approaches and better-defined criteria for patient selection and timing of surgical intervention.

The aim of this case report is to explore the role of immunotherapy as a treatment option for MPM, especially in patients with inoperable or borderline resectable disease that can potentially be converted to operable disease in the setting of adequate disease control with improved systemic therapy. We report a case of a 63-year-old woman with MPM treated with perioperative immunotherapy followed by CRS and HIPEC, with prolonged OS. To our knowledge, this is among the first reported cases to demonstrate such an outcome, emphasizing the potential role of immune checkpoint inhibitors as conversion therapy in MPM.

Case Report

A 63-year-old female non-smoker patient with past medical history significant for type-2 diabetes mellitus, hypothyroidism, dyslipidemia, chronic lymphocytic leukemia (Rai 0), and no history of asbestos exposure sought medical attention for persistent vague abdominal discomfort lasting for a year. Additionally, she endorsed significant weight loss, fatigue, shortness of breath on exertion, night sweats, and changes in bowel habits. Physical examination was largely unremarkable, with the exception of a distended abdomen. Overall, her Eastern Cooperative Oncology Group (ECOG) performance status was 1. Initial investigations included unremarkable blood work and upper and lower gastrointestinal endoscopy. Abdominal CT revealed ascites with a subtle enhancement of the peritoneum and a diffuse thickened reticular appearance of the omentum without evidence of any nodular lesions (Figure 1). Positron emission tomography with CT (PET/CT) revealed diffuse omental uptake and a suspicious left perirectal nodule without distant metastases. A percutaneous image-guided omental biopsy reported atypical mesothelial hyperplasia for which further sampling was recommended for diagnosis. She subsequently underwent diagnostic laparoscopy revealing diffuse involvement of the peritoneal surface but relative sparing of the liver, spleen, stomach, and intestines. Based on preoperative imaging interpretation and intraoperative findings, ovarian primary neoplasm as the primary etiology leading to peritoneal carcinomatosis was the initial working diagnosis. This led to the decision to proceed with bilateral salpingectomy-oophorectomy, to which the patient had previously consented, to obtain a definitive diagnosis and guide subsequent management. Microscopic analysis and immunohistochemistry studies were positive for MTAP, BAP-1, Calretinin, WT1, and cytokeratin 5/6 and negative for BerEp4) (Figure 2). Pathology confirmed the diagnosis of MPM of diffuse epithelial subtype. She was then referred to our institution for definitive treatment. After reviewing the pathology at our institution, a multidisciplinary tumor board (MDTB) discussion, which included members of the surgical oncology, gynecologic oncology, pathology, and medical oncology teams, was conducted. The decision was made to proceed with a novel approach consisting of preoperative nivolumab and ipilimumab (3 mg/kg intravenous once every 2 weeks and 1 mg/kg intravenously once every 6 weeks, respectively). If there was some radiologic response during the course of her systemic treatment, the patient would be considered for and offered CRS and HIPEC.

This decision was reached by the MDTB panel as an extrapolation of the compelling data of the survival benefits of these agents (nivolumab and ipilimumab) in unresectable pleural mesothelioma, in the context of the patient’s favorable functional status, tumor burden, and unresectable/borderline disease resectability, contingent upon tumor response. The team recognized that while data specific to MPM are lacking, the rationale for immune checkpoint inhibition was supported by histologic subtype (epithelioid), good performance status, and a need to avoid disease progression while awaiting reassessment for surgery.

After 4 months of treatment, the patient showed good clinical response with resolution of all disease-related symptoms and excellent tolerance, with grade 1 to 2 toxicity only. Restaging images including PET and CT chest, abdomen, and pelvis revealed promising results with partial disease response and no extra-abdominal metastases (Figure 3). Since the first diagnostic laparoscopy was completed at an outside institution, the decision was made to proceed with repeat laparoscopy to confirm concordance with radiological findings, and to ensure there would be no contraindications to planned complete CRS (ie, diffuse small-bowel involvement). Diagnostic laparoscopy revealed the involvement of the peritoneal surface of the anterior abdominal wall, right diaphragmatic dome, and greater omentum, with an estimated peritoneal cancer index (PCI) ranging from 15 to 20. The small bowel was relatively spared from disease; therefore, no contraindication to proceed with CRS was present. Three weeks later, a complete CRS was performed, achieving a complete cytoreduction index (CCI) of 0, which was followed by HIPEC. The final PCI at surgery was 25, and CRS included the removal of all parietal peritoneal surfaces, including complete mesenteric peritonectomy, right hemicolectomy, cholecystectomy, total hysterectomy, and omentectomy. HIPEC was performed using oxaliplatin 460 mg/m2 for 30 minutes, and systemic 5-FU with leucovorin was simultaneously infused, a regimen shown to be effective in MPM [24]. The patient’s postoperative course was complicated by an acute urinary tract infection, which was treated with a 5-day course of antibiotics; the recovery was otherwise unremarkable. The patient was discharged on postoperative day 15. Her final pathology demonstrated an epithelioid type MPM, Ki-67 of 5%, with mild nuclear atypia, absence of necrosis and 2 mitosis/10 HPF, lymphovascular invasion, partial response to treatment, and involvement of 2 out of 7 of the right colon mesenteric lymph nodes. After discussion with the patient and MDTB, nivolumab and ipilimumab were continued following her surgery with a plan to continue for up to 2 years given the extent of her disease, partial response, and excellent tolerance.

She was followed with serial imaging, blood work, and clinical examination for a total of 18 months at 3-month intervals. The patient remains asymptomatic and in excellent functional status with ECOG 1. Her latest imaging, including PET scan and CT scans, in July 2024 showed no signs of recurrence and no evidence of M1 disease.

Discussion

For eligible patients with MPM, CRS followed by HIPEC is recommended after a course of perioperative chemotherapy when carrying high-risk features such as Ki-67 >9%, nodal metastasis, high tumor burden (PCI >17), borderline resectability, biphasic disease, or bicavitary disease [3]. This combination of treatments compares favorably to cytoreductive surgery alone, observation, or palliative intravenous chemotherapy [3,13,25]. Previous studies have shown a significant survival benefit with the addition of perioperative chemotherapy with pemetrexed and cisplatin in borderline resectable disease [26,27]. In patients with resectable disease such significance is diminished [11,12,28]. The discovery of immunotherapy and its promising effects has led to its use in many oncologic fields, including malignant pleural mesothelioma [16,29,30].

The combination of a programmed cell death protein 1 (PD-1) receptor inhibitor, nivolumab, with a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor, ipilimumab, has shown encouraging results when used for relapsed or unresectable MPM, prolonging OS [30,31] with durable responses. This combination has demonstrated a statistically significant and clinically meaningful benefit in OS when compared to chemotherapy in the first-line setting (hazard ratio (HR) 0.74 (96.6% CI 0.60–0.91; p=0.0020). In a subgroup analysis by histology (non-epithelioid vs epithelioid), the magnitude of benefit was greater in the non-epithelioid subgroup (HR 0.46, 95% CI 0.31–0.68 and 0.86, 95% CI 0.69–1.08), owing to a poorer response to chemotherapy in these patients, with the 2 year OS being similar in both histologies (2-year survival rates 38%, 95% CI 27.0–49.5 and 42%, 95% CI 35.0–48.1; absolute benefit of 30% and 9% compared to chemotherapy, respectively). Given these results, guideline statements have incorporated this regimen as part of the standard of care, but this option as a first-line strategy instead of platinum-based chemotherapy remains controversial in those with epithelioid histology, with differing expert opinions [13,32,33]. Furthermore, this strategy has not been investigated in a randomized trial in the context of MPM given the rarity of this disease, but immune checkpoint inhibitors have shown promising activity in this disease [34,35].

This case presents several unique features that distinguish it from previously published reports on MPM. Most notably, the use of neoadjuvant immunotherapy (nivolumab and ipilimumab) in a patient with borderline resectable MPM resulted in a favorable radiological and clinical response, enabling conversion to resectable status with complete cytoreduction (CCI of 0) followed by HIPEC. The novelty of our approach lies in the sequence and intent of immunotherapy; that is, utilizing checkpoint inhibitors not as definitive or palliative therapy but as a bridge to curative-intent surgery. This contributes to the treatment paradigm for MPM, particularly in patients who fall into the gray zone of borderline resectability, with favorable histology (epithelioid subtype), good performance status, and confined disease burden, to further expand the operable patient population. Additionally, the durability of response, with the patient remaining disease-free 30 months after surgery, adds weight to the therapeutic potential of this approach. Our decision-making process, rooted in extrapolated data and multidisciplinary consensus, highlights a flexible but rational clinical strategy that could guide future practice. These findings support the need for clinical trials or registries focused specifically on MPM, where rare but actionable observations like this may help shape future protocols.

Conclusions

The case presented above is unique with respect to using perioperative nivolumab and ipilimumab in a patient with borderline resectable disease who had significant clinical response allowing subsequent CRS and HIPEC with a CCI of 0. To the best of our knowledge, this approach has not been epithelioid previously described in MPM. While CRS-HIPEC remains the standard for resectable disease, our case suggests that immunotherapy may expand the operable population by downstaging initially unresectable tumors. In highly selected cases, borderline resectable cases can potentially be considered for surgical intervention and lead to prolonged disease control. In the case of rare diseases such as MPM where randomized trials are lacking, careful discussion in a multidisciplinary setting with peers and patients can aid in bridging the gaps by extrapolating from the available literature. Many questions remain regarding the use of immunotherapy in the context of MPM, including which biomarkers (such as PD-L1 expression or tumor-infiltrating lymphocytes) other than histology can aid in selecting patients who are most likely to benefit from these strategies over chemotherapy, and the optimal timing and duration of therapy in the unresectable cases that respond to therapy and undergo consolidative CRS/HIPEC. With respect to these important but unanswered questions, this report offers a foundational step toward rethinking how immunotherapy might be strategically incorporated in the treatment of MPM. We encourage careful multidisciplinary discussion, clinical documentation of outcomes such as these, and randomized clinical trial participation when available for all eligible patients to advance the standard of care [16,30,36].