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Yonemura et al. J Cancer Metastasis Treat 2022;8:43 https://dx.doi.org/10.20517/2394-4722.2022.49 Page 7 of 12

[24]
levels within the normal ranges reflect complete cytoreduction . Accordingly, serum CA125 levels could be
an important selection criterion when used as a marker for the completeness of cytoreduction and
recurrence [Figure 5].

Soluble mesothelin-related peptide (SMRP) is a circulating form of a 40 kDa glycoprotein, normally present
on mesothelial cells . Serum SMRP levels have sensitivity, specificity, and positive and negative predictive
[25]
values of 70%, 100%, 100%, and 61%, respectively. Serum SMRP levels are useful not only for diagnosis of
DMPM but also as a valuable assessment of response following drug therapy [Figure 5].

SURGICAL TREATMENT OF DMPM
The MST of DMPM patients who received no treatment was 16.2 months (2-52 months) with no five-year
[26]
survival , and the prognosis of patients receiving palliative surgery or radiation alone was poor with MST
of 1-2 months .
[27]

Additionally, the MST of DMPM patients treated with palliative SC ranged from 8.7 to 26.8 months [13-16,18] ,
and no five-year survival was reported after SC.

In contrast, CRS + intraoperative HIPEC has been considered the preferred treatment in selected DMPM
patients with low PCI, and their MST ranged from 23.4 to 66 months, with five-year survival rates of 28%-
58% and 10-year survival rates of 12%-39% [10,28-34] . Multivariate analyses revealed PCI levels, CCR-0, an
epithelioid histologic type, MIB-1 index < 10, absence of NASC, no grade 3 or 4 postoperative
complications, age ≤ 60, and female sex as independent favorable prognostic factors [28-34] [Table 2]. PCI cutoff
levels for the selection criteria to achieve a better prognosis are reported to range from ≤ 12 to ≤ 28.

Histologic classification of DMPM consists of epithelioid, sarcomatoid, and biphasic variants. The
epithelioid type shows a significantly more favorable prognosis than the biphasic and sarcomatoid variants.
Sarcomatoid mesothelioma comprises 4% (15/248) of all DMPM , and the prognosis is very poor, with an
[35]
MST of five months from diagnosis. Additionally, responses to chemotherapy are very poor, and organ
invasion is common. Accordingly, this type of DMPM should be treated with systemic chemo-
immunotherapy.

Complete cytoreduction (CCR-0) is a significantly better prognostic factor [10,28,30,31,34] . The rates of CCR-0
resection ranged from 37% to 60%, depending on the selection criteria for CRS. We experienced 84 DMPM
and 8 WDPPM, and 68 (74%) patients underwent CRS. CCR-0 resection could be performed in only 25
(37%) patients. The main reasons for incomplete cytoreduction (CCR-1) resection were high PCI levels,
diffuse involvement of the small bowel mesentery (high SB-PCI), and direct invasion of the diaphragm or
abdominal muscle. SB-PCI levels of CCR-0 and CCR-1 were 2.9 ± 3.4 (range, 0-8) and 8.0 ± 4.2 (0-12)
(P < 0.0001), respectively. Accordingly, reduction of PCI and SB-PCI by NAC is essential to increase CCR-0
resection rates, resulting in improved postoperative survival.

EFFECTS OF NASC, NEOADJUVANT LAPAROSCOPIC HIPEC, AND NIPS
Systemic chemotherapy, including pemetrexed + CDDP, gemcitabine + CDDP, or nivolumab therapy,
showed a response rate of 11%-24% [13,18] . Currently, pemetrexed-based regimens are considered as the
[30]
standard chemotherapy in DMPM patients . However, Kepenekian et al. showed a significant survival
disadvantage in patients treated with CRS + HIPEC after NASC, with five-year survival rates of 40%, 67%,
62%, and 56% for NASC, adjuvant chemotherapy, POC, and no chemotherapy before or after CRS +
HIPEC, respectively . They assumed that some NASC patients intrinsically have worse prognostic
[30]