Mesothelioma is an uncommon malignancy originating from mesothelial lining, affecting pleura, peritoneum, pericardium, or tunica vaginalis testis. The vast majority of mesothelioma occurs in the pleura. According to data from the CDC, among 62,000 new cases of mesothelioma diagnosed in the United States during 1999 to 2018, only 10% of these were those with peritoneal mesothelioma.1 It can be estimated that each year, 250 to 300 new cases of peritoneal mesothelioma are diagnosed in the United States, though estimates may vary by data source.
The rarity of peritoneal mesothelioma makes it challenging to generate management recommendations that are truly evidence-based. Clinical trials specific to peritoneal mesothelioma are scant due to the difficulty in accruing participants. Multiple lines of evidence suggest that the natural history of peritoneal mesothelioma may be different from pleural mesothelioma. When compared with patients with pleural mesothelioma, those with peritoneal mesothelioma are more likely to have germline mutations in cancer susceptibility genes, younger age at disease onset, and minimal or no asbestos exposure.2 Furthermore, prognosis is generally better for patients with peritoneal mesothelioma than pleural mesothelioma.3 Nonetheless, given the histologic similarity between pleural and peritoneal mesothelioma, the systemic treatment recommendations for peritoneal mesothelioma will be extrapolated from literature emanating from pleural mesothelioma.
For patients with peritoneal mesothelioma, select patients without extra-abdominal disease may undergo cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC).4 CRS attempts to remove all macroscopic diseases while HIPECs aim to further reduce remaining tumor burden in the peritoneal cavity. For the purpose of this review, HIPEC will not be covered. It is notable that, despite CRS, 75% of patients will have remaining macroscopic disease.5 As such, most patients with peritoneal mesothelioma will need systemic therapy at some point in their lifetime. It should be noted that a unique population of patients with well-differentiated papillary mesothelial tumor or multicystic mesothelioma, typically occurring among younger female patients, can experience an indolent course of disease.6
Since the last paper on this topic published in JNCCN in 2012,7 there has been remarkable progress in the systemic treatment of mesothelioma. This includes the availability of checkpoint inhibitor immunotherapy as well as the emerging role of anti–vascular endothelial growth factor (VEGF). Based on several unique characteristics of peritoneal mesothelioma, NCCN has issued a specific treatment guideline, separate from pleural mesothelioma.8 In this article, we reviewed current systemic therapy options available for peritoneal mesothelioma. We structured our review according to the Principles of Systemic Therapy available in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Peritoneal Mesothelioma (Version 2.2023; Figure 1), organized by first-line and subsequent-line therapies.8 We also summarized the proportion of patients with peritoneal mesothelioma represented in contemporary prospective trials of mesothelioma (Table 1).
Principles of systemic therapy [PEM-C 1 of 2]. NCCN Clinical Practice Guidelines in Oncology for Mesothelioma: Peritoneal, Version 2.2023.
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Mesothelioma: Peritoneal V.1.2024. © 2023 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Citation: Journal of the National Comprehensive Cancer Network 22, 8; 10.6004/jnccn.2024.7031
Treatment Regimen and Reported Results From Contemporary Clinical Trials
Nivolumab Plus Ipilimumab
In the phase III CheckMate 743 study, 713 patients with pleural mesothelioma without active autoimmune disease were randomized to receive treatment with nivolumab + ipilimumab or chemotherapy with pemetrexed plus platinum agent.9 The primary endpoint was overall survival (OS).
The median age of participants was approximately 70 years and 75% had epithelioid histology. Nivolumab + ipilimumab significantly extended the OS when compared with chemotherapy, with a median OS of 18.1 versus 14.1 months (hazard ratio [HR], 0.74; 95% CI, 0.60–0.91; P=.002). The 2-year survival rates were 41% versus 27% and the tumor response rates were 40% versus 43%, respectively (Table 1). In a subgroup analysis, patients with nonepithelioid histology, decreased performance status, or PD-L1 expression ≥1% derived the most benefit from nivolumab + ipilimumab. Specifically for patients with nonepithelioid histology, the HR was 0.46 (95% CI, 0.31–0.68) in favor of nivolumab + ipilimumab, compared with 0.86 (95% CI, 0.6–1.08) among patients with epithelioid histology. Thus, for patients with nonepithelioid histology, nivolumab + ipilimumab is strongly preferred over chemotherapy. In a longer-term follow-up, the 3-year survival rates among the overall population were 23% with nivolumab + ipilimumab, compared with 15% with chemotherapy.10
The most common adverse events from nivolumab + ipilimumab were diarrhea (20%), pruritus (16%), and rash (14%). Serious diarrhea occurred in 3% of patients. Adverse events resulting in death occurred in 1% of patients due to pneumonitis, encephalitis, or heart failure. Of note, infusion-related reactions were observed in 12% of patients, an incidence higher than the typically reported incidence of 4% to 5% when used in other cancers.
The positive results from this study led to its approval by the FDA in October 2020 as first-line systemic treatment for pleural mesothelioma. The FDA also considered data from a phase II study conducted in France with ipilimumab + nivolumab or single-agent nivolumab.11 It should be noted that the FDA-approved schedule was nivolumab 360 mg every 3 weeks + ipilimumab 1 mg/kg every 6 weeks. This treatment schedule was approved based on data from a pharmacokinetic simulation indicating no significant difference in efficacy or toxicity from biweekly nivolumab regimen.12
Although patients with peritoneal mesothelioma were not included in the CheckMate 743 trial, NCCN recommends this regimen as one of the first-line options for eligible patients with peritoneal mesothelioma.8 Ipilimumab + nivolumab has shown safety among patients with metastatic colorectal cancer.13 An anecdotal report has documented the activity of this regimen in a patient with peritoneal mesothelioma.14 In the absence of abundant prospective data specific to peritoneal mesothelioma at this time, there may still be unknown toxicities unique to this population, and therefore clinicians are encouraged to closely monitor patients during treatment.
Cisplatin Pemetrexed and Bevacizumab
In a phase III study conducted by the French Cooperative Thoracic Intergroup, patients with unresectable pleural mesothelioma with no cardiovascular comorbidity and not taking anticoagulation or antiplatelet medications were randomized to receive chemotherapy with cisplatin, pemetrexed + bevacizumab, an anti-VEGF, or chemotherapy alone every 3 weeks.15 Treatment was administered for a total of 6 cycles. Those randomized to receive bevacizumab continued bevacizumab maintenance until diseases progression or intolerable toxicity. The primary endpoint was OS. Because the trial allowed for enrollment of patients with no measurable disease, tumor response rates were not reported (Table 1).
Chemotherapy + bevacizumab yielded better results than chemotherapy alone. The median OS was 18.8 months compared with 16.1 months (HR, 0.77; 95% CI, 0.62–0.95; P=.017). Survival benefit was homogeneous across all patient subgroups. In the chemotherapy + bevacizumab group, there were notable adverse events specific to bevacizumab, including hypertension and hemorrhage. Most hemorrhages were mild. Pulmonary embolism occurred in 5% and proteinuria in 17% of patients. Because the study was not conducted according to FDA registrational standards, bevacizumab has never been approved for treatment of mesothelioma in the United States. Nonetheless, real-world data indicate that this regimen has indeed been used off-label.16
It should be noted that patients with peritoneal mesothelioma were excluded from this trial; however, a separate phase II study of this regimen did include 7 patients with peritoneal mesothelioma and found no safety concerns among them.17 Nonetheless, in several older studies of this regimen, chemotherapy + bevacizumab was associated with bowel fistula or perforation in patients with pleural mesothelioma despite the absence of abdominal metastasis.17,18 Currently, bevacizumab prescribing information recommends against its use among patients with ovarian cancer with bowel involvement or any symptoms of bowel obstruction.19 Although there has been no report of bowel perforation among patients with peritoneal mesothelioma to our knowledge, clinicians should exercise caution.
Cisplatin or Carboplatin + Pemetrexed
Prior to the availability of pemetrexed, single-agent cisplatin was one of the treatment options for mesothelioma. In a pivotal phase III study published in 2003, patients with pleural mesothelioma were randomized to receive pemetrexed + cisplatin or placebo + cisplatin.20 Participants in the latter part of the study also received dexamethasone and supplementation with folic acid and vitamin B12 to mitigate toxicity.21 Treatment was repeated every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was survival.
The median OS was better with pemetrexed + cisplatin than placebo + cisplatin: 12.1 versus 9.3 months, respectively. The tumor response rate was also higher: 41% versus 17% (Table 1). In a subsequent study, carboplatin was found to be a reasonable alternative to cisplatin.22 In that study, pemetrexed 500 mg/m2 + carboplatin at area under the curve (AUC) of 5 mg/mL/min was administered every 3 weeks. Although cisplatin has been considered a regulatory standard, its emetogenic potential can be especially problematic for patients with peritoneal mesothelioma. Experiences from a prospective, expanded-access program using pemetrexed alone or in combination with either cisplatin or carboplatin indicated that, among patients with peritoneal mesothelioma, carboplatin is safe and effective.23,24 Specifically among 109 patients with peritoneal mesothelioma receiving pemetrexed alone, pemetrexed + carboplatin, or pemetrexed + cisplatin, the tumor response rates were 12.5%, 24.1%, and 20.0%, respectively.
It should be noted that in a study of pharmacokinetics of pemetrexed among patients with third-space fluid, including peritoneal mesothelioma with ascites, pemetrexed clearance and central volume of distribution were not impacted by the presence of third space fluid.25 Pemetrexed is not recommended for patients with creatinine clearance <45 mL/min. There is a possible benefit of maintenance pemetrexed; however, this remains unknown and the only study on this topic was underpowered.26 The NCCN Guidelines recommend pemetrexed + cisplatin (or carboplatin) as a preferred first-line therapy option for patients with peritoneal mesothelioma (Figure 1).8
Cisplatin + Gemcitabine
Before the FDA approval of cisplatin + pemetrexed, cisplatin + gemcitabine was one of the commonly used first-line regimens. Subsequently, it is widely accepted that cisplatin + pemetrexed is superior to cisplatin + gemcitabine, even though a retrospective comparison identified no clear differences.27
Several older studies have shown the efficacy of cisplatin + gemcitabine. In a phase II study conducted in Australia including 21 patients with mesothelioma, the reported tumor response rate was 48% with a median OS of 9.5 months.28 The efficacy of this regimen as first-line treatment was more recently shown in its randomized study with or without bevacizumab.29 Although the study did not show a significant difference by adding bevacizumab, the tumor response rates were >20% in both treatment arms (Table 1). Therefore, cisplatin + gemcitabine can be considered when pemetrexed is contraindicated or single-agent pemetrexed treatment has failed. Whenever pemetrexed can be used, cisplatin + pemetrexed is the first-line doublet of choice.
Atezolizumab + Bevacizumab
In a phase II basket study of atezolizumab + bevacizumab for rare solid tumors, there was a peritoneal mesothelioma arm in which 20 patients were successfully enrolled.30 All patients had disease progression after chemotherapy but were naïve to immunotherapy. Those previously treated with anti-VEGF were allowed to participate. Treatment consisted of atezolizumab and bevacizumab every 3 weeks until disease progression or unacceptable toxicity.
The median age of trial participants was 63 years; 12 patients had a prior CRS. The tumor response rate was 40% (95% CI, 19%–64%), with the median duration of response of 12.8 months (Table 1). The most common serious adverse events were hypertension and anemia. The study is one of the largest contemporary study of patients with peritoneal mesothelioma, demonstrating the safety and efficacy of this regimen among highly selected patients. Although not currently approved by the FDA for treatment of mesothelioma, atezolizumab + bevacizumab is recommended by NCCN as an option for a subsequent line of therapy for those who are immunotherapy-naïve (Figure 1).8 Nivolumab + ipilimumab remains a preferred immunotherapy regimen, but atezolizumab + bevacizumab may be less likely to cause immune-related colitis.
Nivolumab
Single-agent nivolumab has been recommended as an option for subsequent-line treatment among patients who are immunotherapy-naïve (Figure 1).8 In a phase II noncomparative study, nivolumab produced a response rate of 19%, compared with 28% in the nivolumab + ipilimumab arm.11 In the placebo-controlled phase III CONFIRM trial, the efficacy of single-agent nivolumab has been shown to be superior to placebo.31 In this study, 5% of the study population were those with nonpleural mesothelioma. The reported median progression-free survival was 3.0 versus 1.8 months, respectively (HR, 0.67; P=.0012) (Table 1). The OS figures were also superior for the nivolumab group. Diarrhea and infusion-related reactions were the most frequently reported adverse events. Single-agent nivolumab is a reasonable treatment option for patients with peritoneal mesothelioma not previously treated with immunotherapy and not a candidate for nivolumab + ipilimumab owing to borderline performance status or comorbidities.
Gemcitabine
Prior to the emergence of pemetrexed, gemcitabine was a cornerstone drug for mesothelioma. The activity of single-agent gemcitabine among previously treated patients can be seen from a phase II study of pleural mesothelioma conducted in Italy in which patients were randomized to receive gemcitabine + ramucirumab or gemcitabine alone (Table 1).32 In both arms, gemcitabine 1,000 mg/m2 was given on day 1 and 8 every 3 weeks, and in the experimental arm, patients also received ramucirumab 10 mg/kg on day 1. The primary endpoint was OS.
Analyses included 161 patients: 80 who received gemcitabine + ramucirumab and 81 whom received gemcitabine + placebo. Results indicated that the median OS was 13.8 months versus 7.5 months, respectively (HR, 0.71; 95% CI, 0.59–0.85; P=.028). The tumor response rates were 6% versus 10%. Although ramucirumab is not FDA-approved for treatment of mesothelioma, NCCN Guidelines recommend gemcitabine + ramucirumab as a subsequent-line option for pleural mesothelioma.33 However, this regimen is not recommended as an option for peritoneal mesothelioma (Figure 1),8 mainly due to the lack of data from patients with peritoneal mesothelioma. Nonetheless, single-agent gemcitabine is a reasonable option.
Vinorelbine
Single-agent vinorelbine has a modest activity in mesothelioma. In a randomized phase II trial of anetumab ravtansine,34 patients in the control arm received single-agent vinorelbine weekly. This was a negative study but among those receiving single-agent vinorelbine, the tumor response rate was 7% (Table 1). In a study of oral vinorelbine versus best supportive care among patients with recurrent pleural mesothelioma and good performance status, vinorelbine produced a significantly better outcome than best supportive care alone, with a median progression-free survival of 4.2 versus 2.8 months.35 It should be noted, however, that in another randomized study, which also included patients with impaired performance status, no survival advantage of vinorelbine was observed over best supportive care alone.36 The NCCN Guidelines recommend single-agent vinorelbine as a subsequent therapy option for patients with peritoneal mesothelioma (Figure 1).8
Pemetrexed
Pemetrexed is a key component in the systemic treatment of mesothelioma. Most patients with mesothelioma would have been exposed to pemetrexed from first-line or second-line treatment. Historically, single-agent pemetrexed has shown a remarkable tumor response rate of 19% among pemetrexed-naïve patients (Table 1).37 Even among patients previously exposed to pemetrexed, evidence from retrospective studies supported re-treatment with pemetrexed with or without platinum chemotherapy among patients whose disease remains under control for >6 months since the previous pemetrexed exposure.38,39 The 2018 guideline from ASCO stated that re-treatment with pemetrexed-based chemotherapy may be offered in patients with pleural mesothelioma who achieved durable (>6 months) disease control with first-line pemetrexed-based chemotherapy.40 The NCCN Guidelines recommend single-agent pemetrexed as a first-line or subsequent therapy option for patients with peritoneal mesothelioma (Figure 1).8
Targeted Therapy
Gene rearrangements involving ALK or EWSR have been reported in a rare subgroup of pediatric and young adult patients with peritoneal mesothelioma.41–44 Among those with ALK rearrangement, 3 patients with an exon 3 STRN–exon 20 ALK fusion were reportedly treated with ALK inhibitors. One was a 9-year-old female treated with crizotinib whose tumor did not respond,41 another was a 24-year-old female treated with crizotinib with a partial response lasting for only 4 months,42 and the other was a 13-year-old female treated with ceritinib with a partial response ongoing over 3 months.43 Given the potential therapeutic value of ALK inhibitors, the NCCN Guidelines recommend broad molecular tumor profiling for peritoneal mesothelioma.8
Emerging Therapies
Recent clinical trials have suggested a remarkable activity of chemoimmunotherapy in pleural mesothelioma. As first-line treatment, the regimen of durvalumab + chemotherapy (pemetrexed and platinum agent) was investigated in 2 prospective clinical trials and showed a tumor response rate of 48% and 56%, respectively.45,46 Moreover, at the 2023 ASCO Annual Meeting, a group of investigators from Canada and Europe reported data from a randomized phase III study comparing pembrolizumab + chemotherapy with chemotherapy alone as first-line treatment for pleural mesothelioma.47 Pembrolizumab + chemotherapy yielded better survival than chemotherapy alone: 17.3 versus 16.1 months (P=.03). A subgroup analysis suggested that patients with nonepithelioid histology derived a greater survival benefit from chemo-immunotherapy than those with epithelioid histology. While chemoimmunotherapy has not been approved by the FDA for treatment of mesothelioma, several clinical trials are ongoing.
Finally, the use of systemic therapy as neoadjuvant or adjuvant therapy in pleural or peritoneal mesothelioma is also a subject of ongoing investigations.48 A small retrospective study of neoadjuvant chemotherapy in peritoneal mesothelioma suggested that neoadjuvant therapy could allow for more patients to become a candidate for CRS and HIPEC; however, survival difference was not observed.49
Conclusions
In summary, this review found that most clinical trials which form the evidence for systemic therapy recommendation in peritoneal mesothelioma did not include any patients with peritoneal mesothelioma (Table 1). When available, clinical trial is preferred. For first-line therapy, patients with sarcomatoid or biphasic histology will be best treated with nivolumab + ipilimumab. Those with epithelioid histology may consider nivolumab + ipilimumab or cisplatin + pemetrexed. Bevacizumab may be added to chemotherapy. For second-line therapy, an alternate, unchosen approach above can be considered. A number of other subsequent-line options are available.
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