Nivolumab for malignant peritoneal mesothelioma

Abstract

Malignant peritoneal mesothelioma (MPeM) is a highly malignant neoplasm of the peritoneum, which carries a poor prognosis. A 70-year-old man, who was employed in the shipbuilding industry and exposed to asbestos for 50 years, was found to have a low-density lesion in the peritoneum around the liver and spleen, associated with multiple mediastinal and parasternal lymphadenopathy. Laparoscopic exploration was performed, and biopsy specimen analysis led to a diagnosis of MPeM. Initial systemic chemotherapy comprising cisplatin and pemetrexed yielded a modest cytoreductive effect. However, 4 months later, the patient presented with abdominal distension and anorexia. CT images revealed massive ascites, bowel obstruction and an enlarged intra-abdominal tumour, which was considered progression of the MPeM. The patient was treated with nivolumab. Bowel obstruction was improved after the first administration, and his sense of abdomen distension completely disappeared after the third administration. This case supports the utility of immunotherapy in MPeM.

Background

Malignant peritoneal mesothelioma (MPeM) is a highly malignant neoplasm occurring in the peritoneum, which is associated with a poor prognosis. There is no established treatment strategy for this disease, and patients with MPeM are usually treated following the strategy for malignant pleural mesothelioma. In recent years, several encouraging reports have demonstrated that malignant pleural mesothelioma shows a positive clinical response to immunocheckpoint inhibitors. However, no clinical study has examined the utility and safety of immunocheckpoint inhibitors for MPeM treatment. Here, we report a case of MPeM which showed a significant clinical response to nivolumab treatment.

Case presentation

A 70-year-old man, who had been employed in the shipbuilding industry and exposed to asbestos for 22 years between 16 and 38 years, was identified as hepatitis B virus-positive by a blood test. Further examination using abdominal CT scan revealed a low-density lesion in the peritoneum around the liver and spleen, associated with multiple mediastinal and parasternal lymphadenopathy. Positron emission tomography/CT scan revealed 18F-fluorodeoxyglucose (FDG) accumulation in the peritoneal lesion. Laparoscopic exploration was performed, and histopathological analyses of the biopsy specimen revealed a sheet-like proliferation of epithelial cells with round nuclei and conspicuous nucleoli. Immunohistochemical analyses demonstrated that these cells were positive for calretinin, D2-40 and cytokeratin 5/6, and negative for desmin, carcinoembryonic antigen and thyroid transcription factor-1. Based on these findings, the patient was diagnosed with MPeM, epithelioid subtype.

Investigations

This patient was referred to our hospital, where he received systemic chemotherapy comprising cisplatin and pemetrexed. Six cycles of this treatment yielded a modest cytoreductive effect. Four months later, the patient was admitted to another hospital due to bowel obstruction. He received conservative treatment, but continued to exhibit abdominal distension and anorexia. CT images showed massive ascites, bowel obstruction and an enlarged intra-abdominal tumour, which was considered to be the progression of the MPeM (figure 1A).

Figure 1.

(A) CT images of the abdomen reveal a soft tissue lesion on the omentum (bold arrow); lymphadenopathy adjacent to pericardium fat (arrowheads) and dilatation and fluid accumulation of the small intestine, which indicate intestinal obstruction (narrow arrows). All of these findings suggest the progression of malignant peritoneal mesothelioma. (B) CT images after the fourth administration of nivolumab reveal significant improvement of all of the previous findings.

Nivolumab therapy was initiated as a salvage treatment. After the first nivolumab administration, the bowel obstruction was improved. The patient’s sense of abdomen distension completely disappeared after the third nivolumab administration. After the fourth administration, CT images demonstrated remarkable reduction of the abdominal tumour (figure 1B). Nivolumab therapy did not result in any specific adverse event, except for grade 1 skin eruption (according to Common Toxicity Criteria of Adverse Event V.5).

Outcome and follow-up

The patient was administered 24 courses of nivolumab without disease regrowth. Further administration was suspended due to financial reasons. At this time, the patient had been progression free for 10 months after discontinuation without any cancer treatment.

Discussion

Malignant mesothelioma (MM) is mainly found in the pleura and peritoneum, with some reports indicating that 80% occur in the pleura and 10%–20% in the peritoneum.¹ MPeM arises in peritoneal mesothelium cells, and is classified into epithelioid, sarcomatoid and biphasic subtypes. Yan et al found that 92% of cases were the epithelioid subtype and 8% the biphasic subtype.² Asbestos exposure is considered a main cause of MPeM, though the association is weaker than with malignant pleural mesothelioma.³

No standard MPeM treatment has yet been established. Selected patients receive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.⁴ For patients with inoperable disease, systemic chemotherapy is the most common alternative treatment option, typically using a combination of cisplatin and pemetrexed, since pemetrexed has been approved for malignant pleural mesothelioma. One report of MPeM cases describes a chemotherapy response rate of 38%, and a median overall survival of 15.4 months.⁵ In the salvage setting after chemotherapy failure, currently available agents rarely work against MM. In Japan in 2018, nivolumab was approved for malignant pleural mesothelioma that is refractory to primary chemotherapy, based on the favourable results of a phase II clinical study.⁶ To date, no report has described the utility of immunocheckpoint inhibitors for MPeM treatment.

The drastic and durable clinical response to nivolumab in the current case of MPeM suggests the utility of immunotherapy in MPeM. A well-designed clinical study is warranted to examine whether nivolumab should be considered as a new treatment option for MPeM.

Patient’s perspective.

At diagnosis:

I had no symptoms and I was fully active, so I was very shocked when I was given the diagnosis of malignant peritoneal mesothelioma. I was exposed to asbestos when I worked at a shipyard, when I was 17–20 years old. I was afraid of what will happen to me in the future. I was getting in shape by going to the gym, so I was sure to overcome my disease. I want to set myself up as an example to other patients with mesothelioma who can survive long.

At the presentation of disease progression, small intestinal obstruction:

I was informed of the disease progression. My doctor said that there were few treatment options, and he suggested that I receive treatment with nivolumab. I thought it would be far better than doing nothing at all, so I decided to receive the nivolumab treatment.

After the third administration of nivolumab:

My abdomen has dented! I feel grateful that my doctor has treated me with nivolumab. I feel like people on the news, because I have watched the TV news that reported that the researchers who discovered programmed death-1 protein have been given the Nobel Prize. Now I can eat a lot, so I feel the benefit of nivolumab every day.

At the discontinuation of nivolumab:

I was very shocked to hear that I could not continue the nivolumab treatment because Worker’s Compensation will not support the treatment anymore. I gradually feel more positive these days, so from now on, I will proactively do what I can.

Learning points.

• There is no established treatment strategy for patients with malignant peritoneal mesothelioma (MPeM).

• Immunocheckpoint inhibitors have proven useful for malignant pleural mesothelioma in recent years.

• A well-designed clinical study is warranted to examine whether nivolumab should be considered as a new treatment option for MPeM.