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involvement of the small bowel and its mesentery. The threshold level refers to the PCI cutoff count with a
[10]
favorable prognosis. PCI cutoff levels were reported as less than 17 by Kusamura et al. .
In DMPM patients not amenable to surgery, SC is a standard treatment [Table 1] [13-15] . Cartenni et al.
reported the results of treatment using CDDP and pemetrexed versus pemetrexed alone [13,14] . Response rates
and overall survival were significantly better in the CDDP plus pemetrexed group than those of the
pemetrexed group alone. Simon et al. studied the effects of gemcitabine plus pemetrexed and found a
superior response rate and survival to cisplatin with pemetrexed . However, this protocol showed
[15]
significantly more grade 3 and 4 adverse reactions, as well as one grade 5 reaction. Accordingly, the best
regimen is proposed to be the combination of cisplatin and pemetrexed, with gemcitabine and pemetrexed
as a second choice [13,15] . At present, a combination of cisplatin and pemetrexed is accepted as the standard
first-line SC for DMPM. Median overall survival with these treatments ranges from 8.7 to 26.8 months [13-15] ,
but with no survival for more than five years [13-16] . Recently, Sgarbura et al. started a phase II multicenter
randomized trial to evaluate the effect of pressurized intraperitoneal aerosol chemotherapy and SC versus
SC alone as first-line treatment for DMPM on survival . However, the results have not been reported yet.
[17]
[18]
In 2021, innovative treatment using nivolumab was reported by Fennel et al. . They reported the results of
a double-blind, randomized phase III trial of nivolumab for mesothelioma patients , including 316 (95.2%)
[18]
patients with pleural mesotheliomas and 16 patients with non-pleural mesotheliomas, respectively. PD-L1
status was positive in 27% and 23% of patients in the nivolumab and placebo groups, respectively. The most
frequently grade 3 or worse treatment-related adverse events were diarrhea in six (3%) of 221 in the
nivolumab group versus two (2%) in the placebo group, and there were no treatment-related deaths in
either group. The response rate in the nivolumab and placebo groups were 11% and 1%, respectively.
Additionally, the median survival time (MST) of the treatment and placebo groups were 10.2 and 6.9
months, respectively, and overall survival in the nivolumab group was significantly better than in the
[18]
placebo group (HR 0.69) . However, only 16 of 332 malignant mesothelioma patients in the study by
Fennel et al. had non-pleural mesothelioma, and the effects of nivolumab on non-pleural mesothelioma
[18]
were not described . Recently, several case reports about the effects of nivolumab on PM have been
published . However, the effects of nivolumab on PM are still unknown. Large studies of the effects of
[19]
nivolumab on PM patients are awaited. The computed tomography (CT) scan in Figure 1 shows a large
mass in the greater omentum of a patient with epithelioid-type PM before nivolumab treatment. After four
cycles of nivolumab (240 mg/dose) infusion, a PR response was obtained. The residual subcutaneous tumor
mass removed by surgical excision showed no evidence of tumor cells with necrosis. These results suggest
that nivolumab may be effective in patients with DMPM. White et al. noted that PD-L1 expression is
heterogeneous and that expression changes after chemotherapy . Figure 2 shows PD-L1 expression in an
[20]
epithelioid-type DMPM. PD-L1 is expressed on the cell membrane, but the expression is usually
heterogeneous. This observation should be considered when initiating immune checkpoint inhibitor
treatment of DMPM.

TREATMENT RATIONALE OF COMPREHENSIVE TREATMENT TO CURE PATIENTS WITH
PERITONEAL METASTASIS
Neither surgery alone nor chemotherapy alone can cure patients with peritoneal surface malignancy (PSM).
Patients with PSM treated with surgery alone will die due to the growth of residual micrometastasis on the
[21]
peritoneal surface left even after complete resection of macroscopic metastasis . After SC, multi-drug-
resistant cancer cells always regrow. In addition, chemotherapy is negated by the development of severe side
effects after several cycles. These two factors result in the treatment failure with chemotherapy.