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. 2023 Dec 4;115(2):507–528. doi: 10.1111/cas.16021

Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan

Seiki Hasegawa 1,✉, Yasushi Shintani 2, Teruhisa Takuwa 1, Keisuke Aoe 3, Katsuya Kato 4, Nobukazu Fujimoto 5, Yasuhiro Hida 6, Masahiro Morise 7, Yasumitsu Moriya 8, Takao Morohoshi 9, Hidemi Suzuki 10, Masayuki Chida 11, Shunsuke Endo 12, Mitsutaka Kadokura 13, Meinoshin Okumura 2, Satoshi Hattori 14, Hiroshi Date 15, Ichiro Yoshino 10
PMCID: PMC10859622  PMID: 38047872

Abstract

Due to the scarcity of large‐sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44–88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non‐surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non‐surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Keywords: chemotherapy, database, pleural mesothelioma, staging system, surgery

The median overall survival and survival rates at 1, 2, and 3 years were 32.2 months and 81.8%, 61.3%, and 41.9%, respectively, for the surgery group; at 14.0 months and 56.5%, 32.3%, and 17.2%, respectively, for the non‐surgical treatment group; and at 3.8 months and 22.9%, 17.8%, and 11.4% for the best supportive care group, respectively.

graphic file with name CAS-115-507-g002.jpg

Abbreviations

AJCC

American Joint Commission on Cancer

BSC

best supportive care

CI

confidence intervals

EPP

extrapleural pneumonectomy

ET

exploratory thoracotomy

FDG‐PET

fluorodeoxyglucose‐positron emission tomography

IASLC

International Association for the Study of Lung Cancer

IMIG

International Mesothelioma Interest Group

IQR

interquartile range

JJCLCR

the Japanese Joint Committee for Lung Cancer Registry

MCR

macroscopic complete resection

MTT

maximum tumor thickness

NOS

not otherwise specified

OS

overall survival

P/D

pleurectomy/decortication.

PFS

progression‐free survival

PM

pleural mesothelioma

PP

partial pleurectomy

PS

performance status

RT

radiation therapy

STLT

sum of three‐level thickness

SUV

standardized uptake value

UICC

Union for International Cancer Control

1. INTRODUCTION

Pleural mesothelioma (PM) is an aggressive cancer caused by exposure to asbestos. Although many developed countries have banned the use of asbestos, middle‐ and low‐income countries continue to utilize asbestos. 1 The estimated number of global mesothelioma deaths is currently up to 38,000 per year and increasing. 2

The largest database of PM is the International Association for the Study of Lung Cancer (IASLC) database. The IASLC, in collaboration with the International Mesothelioma Interest Group (IMIG), developed its first international database in 2009 3 , 4 to update the IMIG staging system introduced in 1994. 5 The staging systems based on the first and second IASLC databases were accepted in the seventh and eighth editions of the Union for International Cancer Control UICC/American Joint Commission on Cancer (AJCC) manuals, respectively. 3 , 6 , 7 , 8

The majority of the large number of available retrospective nationwide databases 9 , 10 , 11 , 12 , 13 , 14 , 15 are used for epidemiological purposes, while few have complete data on patient treatment, clinical courses, and patient outcomes. Retrospective studies focused on patient prognosis factors, 9 , 16 , 17 , 18 , 19 , 20 , 21 , 22 but only a few were prospective, multicenter studies. 23 , 24 These limitations lead to difficulties in decision‐making regarding treatment strategies for newly diagnosed/untreated PM patients.

Therefore, in our study, we conducted a nationwide prospective registry of newly diagnosed, untreated PM. To the best of our knowledge, this is the first nationwide prospective registry. This study was conducted as the ninth project of the Japanese Joint Committee for Lung Cancer Registry (JJCLCR). 25 JJCLCR has contributed to the establishment of the staging system of lung cancer through several nationwide registries, 26 , 27 , 28 , 29 , 30 including a prospective one. 29

The main study aims were to clarify the following issues in newly diagnosed/untreated PM patients in Japan: current status of surgical and non‐surgical treatment; surgery completion rate, mortality and morbidity and survival for all patients undergoing surgical intervention; macroscopic complete resection (MCR) as the goal of curative‐intent surgery; tumor shape, tumor thickness, and the sum of three‐level thickness (STLT) as possible prognostic factors; and feature and prognostic power of the seventh and eighth staging systems.

2. PATIENTS AND METHODS

2.1. Study setting

The JJCLCR conducted a prospective observational cohort study enrolling patients first diagnosed with PM between April 1, 2017, and March 31, 2019, in Japan.

The study protocol is described in Supplementary File S1. 25

2.2. Inclusion criteria

All patients newly diagnosed according to pathological (including cytology) findings including any subtype of PM in Japan between April 1, 2017, and March 31, 2019, were included. Patients were not given any treatment before registration.

2.3. Variables

The case report form is shown in Supplementary File S2. 25 The following data were collected and analyzed: (i) demographic characteristics including date of registration, sex, and date of birth; (ii) preoperative status including Eastern Cooperative Oncology Group performance status (PS), preoperative comorbidities (e.g., asbestos exposure and smoking), laboratory values (including tumor markers), radiological findings (tumor shape, tumor thickness, and maximum standardized uptake value of the pleura on fluorodeoxyglucose‐positron emission tomography), and respiratory function tests; (iii) details of diagnosis (e.g., date of diagnosis, diagnostic method, immunohistochemical evaluation results, histologic type, and clinical stage based on both seventh and eighth AJCC/UICC staging systems); (iv) surgical treatments, including induction therapy, surgical interventions, combined resection, status of residual tumor, and postoperative morbidity; (v) postoperative pathological diagnosis and stage based on both seventh and eighth AJCC/UICC staging systems; (vi) chemotherapy regimen; (vii) radiotherapy characteristics, including irradiated sites and type of radiation therapy (RT); and (viii) follow‐up data including date of last follow‐up, vital signs and symptoms during last follow‐ up, and date and location of initial relapse.

2.4. Definitions

2.4.1. Radiological examination

Localized PM was defined according to Allen's criteria. 31 All the cases were classified into three categories according to the radiological appearance of the tumor: minimal, nodular, or rindlike. 8 Tumor thickness was measured in accordance with the IASLC report. 8 Briefly, measurements of tumor thickness perpendicular to the chest wall or mediastinum on axial imaging were made, representing the upper, middle, and lower third of the hemithorax. 8

2.4.2. Diagnosis at registration

In the cases where PM was diagnosed by only cytology, the date of diagnosis was recorded as the date of thoracentesis. In cases where biopsy was performed, the date of diagnosis was the date of biopsy regardless of precedent cytological diagnosis.

2.4.3. Final diagnosis

In non‐surgical cases, diagnosis at registration was the final diagnosis. In surgical cases, the final diagnosis was the diagnosis based on the surgical specimen collected and the date of the final diagnosis was the date of surgery.

2.4.4. Surgical nomenclature

Surgical nomenclature was defined according to the IASCL/IMIG consensus report. 32

In this study, MCR was divided into two subgroups: R0‐1 was defined as the absence of microscopic tumor cells at the surgical margin, while R1 was defined as microscopic residual tumor cells confirmed at the surgical margin. R2 resection was defined as completion of surgery with macroscopic residual disease. Because both partial pleurectomy (PP) and exploratory thoracotomy (ET) were indicated as incomplete surgery, they were merged into a PP/ET group.

2.5. Assessments of survival and relapse

Overall survival (OS) was defined as the period from the date of diagnosis at registration to death. Progression‐free survival (PFS), defined as the period from surgery to disease progression or death, was calculated in patients who underwent surgery with MCR. Relapse pattern was defined according to Kostron et al. 33

2.6. Enrollment and study periods

Patients were enrolled from April 1, 2017, to March 31, 2019.

The study period was between April 1, 2017, and March 31, 2026.

2.7. Ethics Statement

This study was approved by the institutional review board of Osaka University Hospital, where the registry office is located, on October 11, 2016 (approval number 16038). The registry and the study using the registered data were approved by each institutional review board of all participating institutions. Written informed consent was obtained from all study participants.

This study was registered at the UMIN Clinical Trials Registry as UMIN 000024664 (http://www.umin.ac.jp/ctr/index.htm). This study adhered to the ethical guidelines for epidemiologic studies published jointly by the Japan Ministry of Science, Culture, and Education and the Japan Ministry of Health, Labor, and Welfare on June 17, 2002, and revised on February 28, 2017.

2.8. Data collection and data analysis

The methods of data management have been previously described. 25 Briefly, patient data were retrieved from the JJCLCR website using a USB drive with a coded institution‐individual serial key. Data on survival were collected in April 2021.

2.8.1. Statistical analysis

Patients’ characteristics were summarized with median, interquartile range (IQR) and range (minimum, maximum) for continuous variables and frequencies for categorical variables. For summary statistics, two‐tailed 95% confidence intervals (CI) were presented. Survival functions were estimated using the Kaplan–Meier method and their 95% CIs were calculated by using the Greenwood variance with the complementary log–log transformation. Comparisons among multiple groups were made using the log‐rank test, which is referred to as the omnibus test. For ordinal groups, the log‐rank test with the linear scores attached was used, referred to as the trend test. Differences between survival functions were evaluated using the log‐rank method. Statistical analyses were performed after excluding cases with missing values for relevant variables. No multiplicity adjustment was applied and a p‐value of less than 0.05 was considered statistically significant. The SAS version 9.4 (SAS Institute, Cary, NC) and R version 4.1.2 (R Core Team; https://www.R‐project.org/) were used for statistical analyses. To draw the graphs for the Kaplan–Meier estimates, the survminer package for R was used.

3. RESULTS

3.1. Clinical characteristics of patients

Between April 1, 2017, and March 31, 2019, a total of 348 cases of PM were registered from 54 institutions. One duplicate case and another case with multiple missing values were removed. The remaining 346 cases were included for analysis (Figure 1).

FIGURE 1.

FIGURE 1

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CONSORT diagram. Between April 1, 2017, and March 31, 2019, a total of 348 cases of pleural mesothelioma (PM) were registered from 54 institutions. One duplicate case and another case with multiple missing values were removed. The remaining 346 cases were included for analysis. BSC, best supportive care; JJCLCR, Japanese Joint Committee for Lung Cancer Registry; NOS, not otherwise specified.

The clinical characteristics of the 346 patients are shown in Table 1. The median age was 71.0 years (range, 44–88 years). The cohort included 285 men (82.3%) and 61 women (17.7%). Most patients (93.7%) had a good PS score (0 or 1). Asbestos exposure was detected in 67.1% of the patients, and 73.2% of patients were current/former smokers.

TABLE 1.

Patient's clinical characteristics.

Characteristic Total (n = 346) Surgery (n = 138) Non‐surgical Tx (n = 164) BSC (n = 44)
Sex — Number (%)
Female 61 (17.6) 21 (15.2) 33 (20.1) 7 (15.9)
Male 285 (82.4) 117 (84.8) 131 (79.9) 37 (84.1)
Age — Number (%)
40–49 5 (1.4) 1 (0.7) 4 (2.4) 0 (0.0)
50–59 27 (7.8) 13 (9.4) 10 (6.1) 4 (9.1)
60–69 114 (32.9) 66 (47.8) 44 (26.8) 4 (9.1)
70–79 154 (44.5) 51 (37.0) 85 (51.8) 18 (40.9)
80–89 46 (13.3) 7 (5.1) 21 (12.8) 18 (40.9)
Age
Total number 346 138 164 44
Median 71.0 68.5 73.0 78.0
Range 44–88 44–88 45–88 51–88
IQR 66.0–77.0 64.0–73.0 67.0–78.0 71.0–82.0
PS — Number (%)
0 185 (53.5) 103 (74.6) 69 (42.1) 13 (29.5)
1 139 (40.2) 33 (23.9) 89 (54.3) 17 (38.6)
2 16 (4.6) 1 (0.7) 6 (3.7) 9 (20.5)
3 4 (1.2) 0 (0.0) 0 (0.0) 4 (9.1)
4 2 (0.6) 1 (0.7) 0 (0.0) 1 (2.3)
Asbestos exposure — Number (%)
Yes 232 (67.1) 94 (68.1) 107 (65.2) 31 (70.5)
No 71 (20.5) 26 (18.8) 36 (22.0) 9 (20.5)
Unknown 43 (12.4) 18 (13.0) 21 (12.8) 4 (9.1)
Smoking — Number (%)
Never 91 (26.3) 29 (21.0) 46 (28.0) 16 (36.4)
Former 231 (66.8) 95 (68.8) 110 (67.1) 26 (59.1)
Current 22 (6.4) 13 (9.4) 7 (4.3) 2 (4.5)
Unknown 2 (0.6) 1 (0.7) 1 (0.6) 0 (0.7)
Laterality — Number (%)
Right 209 (60.4) 74 (53.6) 109 (66.5) 26 (59.1)
Left 137 (39.6) 64 (46.4) 55 (33.5) 18 (40.9)
Histology at registration— Number (%)
Epithelioid 241 (69.7) 112 (81.2) 106 (64.6) 23 (52.3)
Biphasic 32 (9.2) 9 (6.5) 17 (10.4) 6 (13.6)
Sarcomatoid 60 (17.3) 11 (8.0) 36 (22.0) 13 (29.5)
NOS 4 (1.2) 0 (0.0) 2 (1.2) 2 (4.5)
NA (cytology only) 9 (2.6) 6 (4.3) 3 (1.8) 0 (0.0)
Final histology— Number (%)
Epithelioid 240 (69.4) 111 (80.4) 106 (64.6) 23 (52.3)
Biphasic 35 (10.1) 12 (8.7) 17 (10.4) 6 (13.6)
Sarcomatoid 63 (18.2) 14 (10.1) 36 (22.0) 13 (29.5)
NOS 5 (1.4) 1 (0.7) 2 (1.2) 2 (4.5)
NA (cytology only) 3 (0.9) 0 (0.0) 3 (1.8) 0 (0.0)
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Abbreviations: BSC, best supportive care; IQR, interquartile range; NA, not available; NOS, not otherwise specified; Tx, treatment.

3.2. Diagnosis and pathological findings

Diagnosis at registration was made using biopsy specimens in 97.4% of patietns (337/346) and cell blocks in 2.6% (9/346) (Table 1; Figure 2). Methods of biopsy included open surgery (2.1%, 7/337), video‐assisted thoracoscopy under general anesthesia (74.5%, 251/337), thoracoscopy under local anesthesia (11.3%, 38/337), needle biopsy (8.9%, 30/337), and others (3.3%, 11/337). Histological subtype at registration comprised epithelioid (71.5%, 241/337), biphasic (9.5%, 32/337), sarcomatoid (17.8%, 60/337), and not otherwise specified (NOS, 1.2%, 4/337) categories.

FIGURE 2.

FIGURE 2

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Pathological diagnosis at registration and final diagnosis. Pathological diagnosis at registration and final diagnosis are shown. We observed and corrected a discrepancy between preoperative and postoperative subtype diagnostics in 8.7% (12/132). NOS, not otherwise specified.

Postoperative pathological analysis of surgical specimens was performed in all 138 surgical cases. Diagnosis at registration was made using cell block specimens in six patients, which turned out to be epithelioid (n = 5) and biphasic (n = 1) subtypes defined during postoperative analysis. In the remaining 132 cases, diagnosis at registration was made using biopsy specimens. We observed and corrected a discrepancy between preoperative and postoperative subtype diagnostics in 8.7% of patients (12/132) as follows: epithelioid to biphasic (n = 5), epithelioid to sarcomatoid (n = 3), biphasic to epithelioid (n = 1), biphasic to sarcomatoid (n = 1), biphasic to NOS (n = 1), and sarcomatoid to epithelioid (n = 1). Consequently, the final diagnosis of 343 patients who underwent biopsy and/or surgery was epithelioid (70.0%, 240/343), biphasic (10.2%, 35/343), sarcomatoid (18.4%, 63/343), and NOS (1.5%, 5/343).

3.3. Radiological findings

Computed tomography scans and tumor thickness measurements were performed in all cases: 38 (11.0%) localized PM and 299 (89.0%) diffuse PM. Patients were classified as having minimal (n = 68, 19.7%), nodular (n = 96, 27.7%), and rind‐like (n = 178, 51.4%) tumors (Table 2). The median maximum tumor thickness (MTT) and the STLT were 11 mm (IQR: 5.0–21.0) and 22 mm (IQR: 11.0–39.0), respectively.

TABLE 2.

Radiological findings.

Characteristic Total (n = 346) Surgery (n = 138) Non‐surgical Tx (n = 164) BSC (n = 44)
Diffuse/local — Number (%)
Diffuse 299 (86.4) 122 (88.4) 136 (82.9) 41 (93.2)
Localized 38 (11.0) 10 (7.2) 25 (15.2) 3 (6.8)
No data 9 (2.6) 6 (4.3) 3 (1.8) 0 (0.0)
Tumor shape — Number (%)
Minimal 68 (19.7) 32 (23.2) 29 (17.7) 7 (15.9)
Nodular 96 (27.7) 33 (23.9) 49 (29.9) 14 (31.8)
Rind‐like 178 (51.4) 71 (51.4) 86 (52.4) 21 (47.7)
Missing data 4 (1.2) 2 (1.4) 0 (0.0) 2 (4.5)
Maximum thickness
Total number 346 138 164 44
Median (IQR) 11.0 (5.0–21.0) 8.0 (4.0–17.0) 14.0 (7.0–25.0) 12.0 (7.5–18.5)
Range 0–89 0–77 0–89 0–80
Sum of three level thickness
Total number 346 138 164 44
Median (IQR) 22.0 (11.0–39.0) 18.0 (8.0–31.0) 29.0 (13.0–46.0) 26.5 (15.0–39.5)
Range 0–232 0–154 0–232 0–118
Maximum SUV on FDG‐PET
Total number 234 97 106 31
Median (IQR) 5.8 (3.4–9.6) 4.4 (2.7–7.4) 7.6 (4.0–11.2) 6.5 (3.3–9.5)
Range 0–32 0–23 0–32 0–18
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Abbreviations: BSC, best supportive care; FDG‐PET, fluorodeoxyglucose‐positron emission tomography; IQR, interquartile range; SUV, standardized uptake value; Tx, treatment.

3.4. Clinical and pathological stages

Clinical stages were defined for all patients. Similarly, for patients undergoing surgery, their pathological stages were determined according to both the seventh and eighth versions of TNM staging systems (Tables 3, 4, 5). Stage distribution in the seventh and eighth versions of the staging system is shown in Figure 3. Assessment of the discrepancy between clinical and pathological stages according to the version seventh staging system revealed the following: 54.3% (75/138) unchanged, 39.9% (55/138) upstaged, and 6.5% (9/138) down‐staged cancer cases. In contrast, according to the version eighth staging system, the results were as follows: 42.8% (59/138) unchanged, 52.2% (72/138) upstaged, and 5.1% (7/138) down‐staged cancer cases.

TABLE 3.

Clinical stages according to seventh and eighth TNM staging systems.

Characteristic Total (n = 346) Surgery (n = 138) Non‐surgical Tx (n = 164) BSC (n = 44)
T (version 7) — Number (%)
T0, T1a 89 (25.7) 56 (40.6) 25 (15.2) 8 (18.2)
T1b 30 (8.7) 9 (6.5) 18 (11.0) 3 (6.8)
T2 54 (15.6) 29 (21.0) 23 (14.0) 2 (4.5)
T3 104 (30.1) 41 (29.7) 47 (28.7) 16 (36.4)
T4 69 (19.9) 3 (2.2) 51 (31.1) 15 (34.1)
N (version 7) — Number (%)
N0 267 (77.2) 123 (89.1) 111 (67.7) 33 (75.0)
N1 12 (3.5) 4 (2.9) 7 (4.3) 1 (2.3)
N2 52 (15.0) 11 (8.0) 35 (21.3) 6 (13.6)
N3 15 (4.3) 0 (0.0) 11 (6.7) 4 (9.1)
M (version 7) — Number (%)
M0 326 (94.2) 137 (99.3) 150 (91.5) 39 (88.6)
M1 20 (5.8) 1 (0.7) 14 (8.5) 5 (11.4)
Stage (version 7) — Number (%)
Stage I 118 (34.1) 64 (46.4) 43 (26.2) 11 (25.0)
Stage II 41 (11.8) 25 (18.1) 16 (9.8) 0 (0.0)
Stage III 108 (31.2) 45 (32.6) 48 (29.3) 15 (34.1)
Stage IV 79 (22.8) 4 (2.9) 57 (34.8) 18 (40.9)
T (version 8) — Number (%)
T0, T1 148 (42.8) 80 (58.0) 57 (34.8) 11 (25.0)
T2 25 (7.2) 14 (10.1) 9 (5.5) 2 (4.5)
T3 104 (30.1) 41 (29.7) 47 (28.7) 16 (36.4)
T4 69 (19.9) 3 (2.2) 51 (31.1) 15 (34.1)
N (version 8) — Number (%)
N0 267 (77.2) 123 (89.1) 111 (67.7) 33 (75.0)
N1 64 (18.5) 15 (10.9) 42 (25.6) 7 (15.9)
N2 15 (4.3) 0 (0.0) 11 (6.7) 4 (9.1)
M (version 8) — Number (%)
M0 326 (94.2) 137 (99.3) 150 (91.5) 39 (88.6)
M1 20 (5.8) 1 (0.7) 14 (8.5) 5 (11.4)
Stage (version 8) — Number (%)
Stage IA 142 (41.0) 77 (55.8) 54 (32.9) 11 (25.0)
Stage IB 87 (25.1) 44 (31.9) 31 (18.9) 12 (27.3)
Stage II 12 (3.5) 5 (3.6) 6 (3.7) 1 (2.3)
Stage IIIA 26 (7.5) 8 (5.8) 16 (9.8) 2 (4.5)
Stage IIIB 59 (17.1) 3 (2.2) 43 (26.2) 13 (29.5)
Stage IV 20 (5.8) 1 (0.7) 14 (8.5) 5 (11.4)
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Abbreviations: BSC, best supportive care; Tx, treatment; ver., version.

TABLE 4.

Clinical stages for surgical cases by seventh and eighth TNM staging systems.

Characteristic Total (n = 138) EPP (n = 26) P/D (n = 83) PP/ET (n = 26) Other surgery (n = 3)
T (version 7) — Number (%)
T0, T1a 56 (40.6) 8 (30.8) 44 (53.0) 4 (15.4) 0 (0.0)
T1b 9 (6.5) 1 (3.8) 7 (8.4) 1 (3.8) 0 (0.0)
T2 29 (21.0) 7 (26.9) 14 (16.9) 6 (23.1) 2 (66.7)
T3 41 (29.7) 9 (34.6) 18 (21.7) 13 (50.0) 1 (33.3)
T4 3 (2.2) 1 (3.8) 0 (0.0) 2 (7.7) 0 (0.0)
N (version 7) — Number (%)
N0 123 (89.1) 25 (96.2) 75 (90.4) 20 (76.9) 3 (100.0)
N1 4 (2.9) 0 (0.0) 4 (4.8) 0 (0.0) 0 (0.0)
N2 11 (8.0) 1 (3.8) 4 (4.8) 6 (23.1) 0 (0.0)
M (version 7) — Number (%)
M0 137 (99.3) 26 (100.0) 83 (100.0) 25 (96.2) 3 (100.0)
M1 1 (0.7) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)
Stage (version 7) — Number (%)
Stage I 64 (46.4) 9 (34.6) 50 (60.2) 5 (19.2) 0 (0.0)
Stage II 25 (18.1) 7 (26.9) 10 (12.0) 6 (23.1) 2 (66.7)
Stage III 45 (32.6) 9 (34.6) 23 (27.7) 12 (46.2) 1 (33.3)
Stage IV 4 (2.9) 1 (3.8) 0 (0.0) 3 (11.5) 0 (0.0)
T (version 8) — Number (%)
T0, T1 80 (58.0) 14 (53.8) 59 (71.1) 7 (26.9) 0 (0.0)
T2 14 (10.1) 2 (7.7) 6 (7.2) 4 (15.4) 2 (66.7)
T3 41 (29.7) 9 (34.6) 18 (21.7) 13 (50.0) 1 (33.3)
T4 3 (2.2) 1 (3.8) 0 (0.0) 2 (7.7) 0 (0.0)
N (version 8) — Number (%)
N0 123 (89.1) 25 (96.2) 75 (90.4) 20 (76.9) 3 (100.0)
N1 15 (10.9) 1 (3.8) 8 (9.6) 6 (23.1) 0 (0.0)
M (version 8) — Number (%)
M0 137 (99.3) 26 (100.0) 83 (100.0) 25 (96.2) 3 (100.0)
M1 1 (0.7) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)
Stage (version 8) — Number (%)
Stage IA 77 (55.8) 14 (53.8) 56 (67.5) 7 (26.9) 0 (0.0)
Stage IB 44 (31.9) 10 (38.5) 19 (22.9) 12 (46.2) 3 (100.0)
Stage II 5 (3.6) 0 (0.0) 5 (6.0) 0 (0.0) 0 (0.0)
Stage IIIA 8 (5.8) 1 (3.8) 3 (3.6) 4 (15.4) 0 (0.0)
Stage IIIB 3 (2.2) 1 (3.8) 0 (0.0) 2 (7.7) 0 (0.0)
Stage IV 1 (0.7) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)
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Abbreviations: EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; PP/ET, patrial pleurectomy/exploratory thoracotomy; ver., version.

TABLE 5.

Pathological stages for surgical cases by seventh and eighth TNM staging systems.

Characteristic Total (n = 138) EPP (n = 26) P/D (n = 83) PP/ET (n = 26) Other surgery (n = 3)
T (version 7) — Number (%)
T0, T1a 17 (12.3) 2 (7.7) 12 (14.5) 3 (11.5) 0 (0.0)
T1b 9 (6.5) 0 (0.0) 7 (8.4) 2 (7.7) 0 (0.0)
T2 30 (21.7) 11 (42.3) 16 (19.3) 2 (7.7) 1 (33.3)
T3 61 (44.2) 11 (42.3) 41 (49.4) 7 (26.9) 2 (66.7)
T4 21 (15.2) 2 (7.7) 7 (8.4) 12 (46.2) 0 (0.0)
N (version 7) — Number (%)
N0 107 (77.5) 20 (76.9) 62 (74.7) 22 (84.6) 3 (100.0)
N1 4 (2.9) 1 (3.8) 2 (2.4) 1 (3.8) 0 (0.0)
N2 26 (18.8) 5 (19.2) 18 (21.7) 3 (11.5) 0 (0.0)
N3 1 (0.7) 0 (0.0) 1 (1.2) 0 (0.0) 0 (0.0)
M (version 7) — Number (%)
M0 137 (99.3) 26 (100.0) 83 (100.0) 25 (96.2) 3 (100.0)
M1 1 (0.7) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)
Stage (version 7) — Number (%)
Stage1 26 (18.8) 2 (7.7) 19 (22.9) 5 (19.2) 0 (0.0)
Stage2 25 (18.1) 8 (30.8) 14 (16.9) 2 (7.7) 1 (33.3)
Stage3 64 (46.4) 14 (53.8) 42 (50.6) 6 (23.1) 2 (66.7)
Stage4 23 (16.7) 2 (7.7) 8 (9.6) 13 (50.0) 0 (0.0)
T (version 8) — Number (%)
T0, T1 35 (25.4) 5 (19.2) 25 (30.1) 5 (19.2) 0 (0.0)
T2 21 (15.2) 8 (30.8) 10 (12.0) 2 (7.7) 1 (33.3)
T3 61 (44.2) 11 (42.3) 41 (49.4) 7 (26.9) 2 (66.7)
T4 21 (15.2) 2 (7.7) 7 (8.4) 12 (46.2) 0 (0.0)
N (version 8) — Number (%)
N0 107 (77.5) 20 (76.9) 62 (74.7) 22 (84.6) 3 (100.0)
N1 30 (21.7) 6 (23.1) 20 (24.1) 4 (15.4) 0 (0.0)
N2 1 (0.7) 0 (0.0) 1 (1.2) 0 (0.0) 0 (0.0)
M (version 8) — Number (%)
M0 137 (99.3) 26 (100.0) 83 (100.0) 25 (96.2) 3 (100.0)
M1 1 (0.7) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)
Stage (version 8) — Number (%)
Stage IA 32 (23.2) 4 (15.4) 23 (27.7) 5 (19.2) 0 (0.0)
Stage IB 59 (42.8) 14 (53.8) 35 (42.2) 7 (26.9) 3 (100.0)
Stage II 5 (3.6) 3 (11.5) 2 (2.4) 0 (0.0) 0 (0.0)
Stage IIIA 19 (13.8) 3 (11.5) 15 (18.1) 1 (3.8) 0 (0.0)
Stage IIIB 22 (15.9) 2 (7.7) 8 (9.6) 12 (46.2) 0 (0.0)
Stage IV 1 (0.7) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0)
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Abbreviations: EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; PP/ET, patrial pleurectomy/exploratory thoracotomy; ver., version.

FIGURE 3.

FIGURE 3

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Stage distribution in seventh and eighth TNM staging systems. Distributions of clinical stages for all cases are shown in Figure 2A,B, respectively. There were 34.3% of c‐stage I and 31.2% of c‐stage III patients according to the version 7 staging system (A), and 66.1% cases were classified as c‐stage I in the version 8 staging system (B). In surgical cases, 46.4% and 87.7% of cases were classified as c‐stage I by version 7 and version 8 staging systems, respectively (C, D). Distributions of pathological stages for surgical cases are shown in Figure 2E,F: There were 46.4% of p‐stage III according to the version 7 staging system (E) and 66.0% of p‐stage I patients according to the version 8 staging system (F).

3.5. Treatment distribution

Among the enrolled 346 patients, 138 (39.9%) underwent surgery, 164 (47.4) underwent non‐surgical therapy (i.e., chemotherapy with or without radiation therapy), and the remaining 44 (12.7%) underwent BSC.

3.5.1. Surgical treatment

One hundred and thirty‐eight patients underwent surgery in 35 experienced centers. Of 138 surgeries, 81 (58.7%) were performed in three high‐volume centers. Surgical technique consisted of extrapleural pneumonectomy (EPP, n = 26), pleurectomy/decortication (P/D, n = 83), PP/ET (n = 26), and other surgeries (n = 3) (Tables 6 and 7). Surgery alone and surgery as part of a multimodality treatment with chemotherapy and/or radiation therapy were conducted in 29 and 109 patients, respectively. The median age of patients who underwent surgical intervention was 68.5 years (IQR: 64.0–73.0). The median value of operation time and blood loss were 406.5 min (IQR: 282.5–509.5) and 1210 g (IQR: 613.8–1855.8). The resection statuses were R0‐1 (n = 41), R1 (n = 55), and R2 (n = 42), respectively, and MCR (R0‐1 and R1) was achieved in 69.6% (96/138). Data analysis indicated that 30‐ and 90‐day postoperative deaths were 0.7% (1/138, PP/ET group) and 4.3% (6/138, EPP: 1, P/D: 2, PP/ET: 3). The causes within the 90‐day mortality range were diagnosed with interstitial pneumonia (two patients) and mesothelioma progression (four patients). Of the 37 patients with localized PM, 10 underwent surgery: P/D (n = 7), PP (n = 2), and other surgery (n = 1). Of these 10 patients, four underwent R0‐1 resection, another four underwent R1 resection, and two underwent R2 resection.

TABLE 6.

Surgical treatments.

Case No
EPP 26
EPP alone 2
EPP + AC 1
EPP + RT 8
EPP + RT + AC 2
NAC + EPP 2
NAC + EPP + RT 11
P/D 83
P/D alone 13
P/D + AC 18
NAC + P/D 31
NAC + P/D + AC 20
NAC + P/D + RT + AC 1
PP/ET 26
PP/ET alone 12
NAC + PP/ET 14
Other surgery 3
Other surgery alone 2
Other surgery + AC 1
Total 138
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Abbreviations: AC, adjuvant chemotherapy; EPP, extrapleural pneumonectomy; ET, exploratory thoracotomy; NAC, neoadjuvant chemotherapy; P/D, pleurectomy/decortication; PP, partial pleurectomy; RT, radiation therapy.

TABLE 7.

Clinical characteristics of patients with PM surgery.

Characteristic Total (n = 138) EPP (n = 26) P/D (n = 83) PP/ET (n = 26) Other surgery (n = 3)
Gender — Number (%)
Female 21 (15.2) 4 (15.4) 10 (12.0) 6 (23.1) 1 (33.3)
Male 117 (84.8) 22 (84.6) 73 (88.0) 20 (76.9) 2 (66.7)
Age — Number (%)
40–49 1 (0.7) 1 (3.8) 0 (0.0) 0 (0.0) 0 (0.0)
50–59 13 (9.4) 4 (15.4) 9 (10.8) 0 (0.0) 0 (0.0)
60–69 66 (47.8) 11 (42.3) 43 (51.8) 11 (42.3) 1 (33.3)
70–79 51 (37.0) 9 (34.6) 27 (32.5) 13 (50.0) 2 (66.7)
80–89 7 (5.1) 1 (3.8) 4 (4.8) 2 (7.7) 0 (0.0)
Total number 138 26 83 26 3
Median (IQR) 68.5 (64.0–73.0) 68.0 (62.0–71.0) 68.0 (64.0–73.0) 71.0 (65.0–75.0) 73.0 (67.0–78.0)
Range 44–88 44–80 55–80 60–88 67–78
Completeness of resection— Number (%)
R0‐1 41 (29.7) 10 (38.5) 30 (36.1) 0 (0.0) 1 (33.3)
R1 55 (39.9) 12 (46.2) 41 (49.4) 1 (3.8) a 1 (33.3)
R2 42 (30.4) 4 (15.4) 12 (14.5) 25 (96.2) 1 (33.3)
Surgical time (min.)
Median (IQR) 406.5 393.0 466.0 175.5 274.0
(280.0–510.0) (357.0–487.0) (372.0–554.0) (90.0–233.0) (222.0–290.0)
Range 30–885 177–705 68–885 30–544 222–290
Blood loss (gram)
Median (IQR) 1210.0 1186.0 1450.0 290.0 270.0
(610.0–1861.0) (870.0–1700.0) (860.0–2160.0) (34.0–740.0) (120.0–670.0)
Range 1–25205 300–8036 5–25205 1–4530 120–670
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Abbreviations: EPP, extrapleural pneumonectomy; ET, exploratory thoracotomy; IQR, interquartile range; P/D, pleurectomy/decortication; PM, pleural mesothelioma; PP, partial pleurectomy.

a

Localized mesothelioma.

3.5.2. Non‐surgical treatment

First‐line treatment in 164 patients undergoing non‐surgical treatment consisted of concurrent chemoradiotherapy (4.3%, n = 7), cisplatin plus pemetrexed (51.2%, n = 84), carboplatin plus pemetrexed (28.7%, n = 47), pemetrexed alone (6.7, n = 11), and others (9.1%, n = 15) (Table 8). Of the 164 patients, 67.7% (n = 111) and 17.7% (n = 29) underwent second‐ and third‐line treatment, respectively. A total of 43 patients underwent RT. Post‐EPP hemithoracic RT was performed in 21 patients (45–54 Gy, dose unknown in 1). One patient underwent focal adjuvant RT after R2 resection of P/D. Eight patients underwent RT for postoperative recurrence.

TABLE 8.

Non‐surgical treatment.

First‐line Tx (n = 164) Second‐line Tx (n = 111) Third‐line Tx (n = 29)
Chemoradiotherapy (n = 7)
CDDP+PEM (n = 84) CDDP+PEM (n = 2) BSC (n = 2)
CBDCA+PEM (n = 8) Others (n = 2), BSC (n = 6)
PEM (n = 5) Others (n = 2), RT (n = 1), BSC (n = 2)
Others (n = 45) CDDP+PEM (n = 1), PEM (n = 1), Others (n = 4), RT (n = 1), BSC (n = 38)
RT (n = 1) Others (n = 1)
BSC (n = 23)
CBDCA+PEM (n = 47) CBDCA+PEM (n = 3) Others (n = 1), BSC (n = 2)
PEM (n = 1) BSC (n = 1)
Others (n = 19) CBDCA+PEM (n = 1), PEM (n = 2), Others (n = 2), BSC (n = 14)
RT (n = 2) Others (n = 1), BSC (n = 1)
BSC (n = 22)
PEM (n=11) Others (n = 5) Others (n = 1), BSC (n = 4)
BSC (n = 6)
Others (n=15) CDDP+PEM (n = 3) Others (n = 3)
CBDCA+PEM (n = 2) Others (n = 1), BSC (n = 1)
PEM (n = 1) BSC (n = 1)
Others (n = 7) CBDCA+PEM (n = 1), Others (n = 2), RT (n = 1), BSC (n = 3)
BSC (n = 2)
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Abbreviations: BSC, best supportive care; CBDCA, carboplatin; CDDP, cisplatin; PEM, pemetrexed; RT, radiation therapy; Tx, treatment.

3.6. Survival analysis

Among 346 patients, 242 patients died during the follow‐up period. The median follow‐up period for the 104 surviving patients was 945.5 days (range, 1–1480 days). At the time of data collection in April 2021, 229 patients died of PM, 13 died of other diseases (seven with PM, six without PM), 85 were alive with PM, and 19 were alive without PM. Median OS was 19.0 months (95% CI: 15.4–22.3). Survival rates at 1, 2, and 3 years for all patients were 62.8% (95% CI: 57.4%–67.6%), 42.3% (95% CI: 37.0%–47.5%), and 26.5% (95% CI: 21.3%–31.9%), respectively (Figure 4A).

FIGURE 4.

FIGURE 4

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Overall survival (OS). (A) Median OS and survival rates at 1, 2, and 3 years for all patients were 19.0 months and 62.8%, 42.3%, and 26.5%, respectively. (B) Median OS and survival rates at 1, 2, and 3 years were 32.2 months and 81.8%, 61.3%, and 41.9%, respectively, for the surgery group; at 14.0 months and 56.5%, 32.3%, and 17.2%, respectively, for the non‐surgical treatment group; and at 3.8 months, 22.9%, 17.8%, and 11.4% for the BSC group, respectively. (C) Median OS for multimodality therapy (n = 109) was significantly longer than surgery alone (n = 29): 34.6 months vs. 21.0 months. (D) Median OS by surgical technique were 25.0 months for EPP, 41.8 months for P/D, and 17.5 months for PP/ET. There was a significant difference in OS between P/D and PP/ET. (E) Median OS for R0‐1, R1, and R2 resection and PP/ET groups were undefined, 39.5 months, 32.2 months, and 16.8 months. OS for R0‐1 and R1 resections were significantly longer for those of R2 resection and PP/ET. There was no significant difference in OS between R0‐1 and R1. (F) The median OS for the MCR group was 41.8 months and was significantly longer than those for R2 resection and PP/ET. BSC, best supportive care; EPP, extrapleural pneumonectomy; MCR, macroscopic complete resection; OS, overall survival; P/D, pleurectomy/decortication; PP/ET, patrial pleurectomy/exploratory thoracotomy; Tx, treatment.

In the surgery group, median OS was 32.2 months. In non‐surgical treatment group, OS was 14.0 months, while in the BSC group, OS was only 3.8 months. Survival rates at 1, 2, and 3 years in the surgery group were 81.8%, 61.3%, and 41.9%, respectively. Survival rates at 1, 2, and 3 years in non‐surgical treatment group were 56.5%, 32.3%, and 17.2%, respectively. Finally, the survival rates in BSC group were 22.9%, 17.8%, and 11.4%, respectively (Figure 4B). These results show significant differences in OS among three groups.

Median OS after multimodality therapy (n = 109) was significantly longer than that in the surgery alone group (n = 29): 34.6 months vs. 21.0 months (HR = 0.53) (Figure 4C). Median OS by surgical technique is shown in Figure 4D: 25.0 months for EPP, 41.8 months for P/D, and 17.5 months for PP/ET. Survival time of P/D, not EPP, was significantly longer than that for PP/ET.

Median OS for R1 resection, R2 resection, and PP/ET were 39.5 months, 32.2 months, and 16.8 months, respectively (Figure 4E). Median OS for R0‐1 group was undefined. There was no significant difference in OS time between R0‐1 and R1 groups. Median OS time for the MCR group (R0‐1 plus R1) was 41.8 months, which was significantly longer than that for R2 resection and PP/ET (Figure 4F).

The trend of survival in each clinical stage is shown in Table 9A and Figure 5A,B. A significant difference in survival between stage groups was observed using both seventh and eighth staging systems. The survival rates at each pathological stage are shown in Table 9B. No differences in survival rates were observed using the seventh staging system (p = 0.080; Figure 5C). A significant difference was observed for pathological stages using the eighth staging system approach (p = 0.005; Figure 5D).

TABLE 9.

Overall survival by clinical and pathological stages.

(A) Overall survival by clinical staging
n Event 1‐yr survival, % 2‐yr survival, % 3‐yr survival, % MST, mo HR p‐value
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
T (version 7)
T0 T1a T1b 119 73 0.771 (0.684, 0.837) 0.581 (0.487, 0.665) 0.334 (0.237, 0.433) 27.00 (21.83, 33.37) Reference <0.001 (trend)
T2 54 41 0.778 (0.642, 0.867) 0.407 (0.277, 0.534) 0.258 (0.141, 0.392) 21.03 (15.53, 28.23) 1.29 (0.88, 1.89) 0.196
T3 104 68 0.559 (0.458, 0.649) 0.402 (0.307, 0.496) 0.322 (0.228, 0.420) 18.13 (10.47, 24.03) 1.30 (0.93, 1.81) 0.122
T4 69 60 0.356 (0.244, 0.470) 0.186 (0.103, 0.288) 0.042 (0.005, 0.154) 8.00 (6.57, 11.93) 2.88 (2.03, 4.07) <0.001
N (version 7)
No 267 178 0.686 (0.626, 0.738) 0.476 (0.414, 0.534) 0.299 (0.238, 0.362) 21.83 (18.13, 26.23) Reference <0.001 (omnibus)
N1‐3 79 64 0.427 (0.316, 0.534) 0.240 (0.151, 0.341) 0.147 (0.071, 0.248) 8.87 (6.73, 15.30) 1.83 (1.37, 2.44) <0.001
M (ver.7)
Mo 326 227 0.640 (0.585, 0.690) 0.435 (0.380, 0.489) 0.267 (0.214, 0.323) 19.63 (15.77, 22.80) Reference 0.143 (omnibus)
M1 20 15 0.421 (0.204, 0.625) 0.211 (0.066, 0.410) 0.211 (0.066, 0.410) 11.57 (4.03, 23.93) 1.48 (0.88, 2.49) 0.143
Stage (ver.7)
Stage I 118 73 0.769 (0.682, 0.835) 0.578 (0.482, 0.662) 0.331 (0.235, 0.430) 27.00 (21.83, 33.37) Reference <0.001 (trend)
Stage II 41 31 0.829 (0.675, 0.915) 0.439 (0.286, 0.582) 0.243 (0.114, 0.399) 21.60 (15.53, 32.23) 1.22 (0.80, 1.86) 0.351
Stage III 108 71 0.585 (0.486, 0.672) 0.406 (0.312, 0.497) 0.325 (0.230, 0.422) 18.53 (11.27, 24.03) 1.28 (0.92, 1.77) 0.144
Stage IV 79 67 0.362 (0.257, 0.469) 0.201 (0.120, 0.298) 0.097 (0.038, 0.188) 7.87 (6.60, 11.57) 2.59 (1.86, 3.62) <0.001
T (ver.8)
T0‐1 148 94 0.782 (0.706, 0.841) 0.562 (0.477, 0.638) 0.319 (0.234, 0.406) 26.73 (21.77, 31.17) Reference <0.001 (trend)
T2 25 20 0.720 (0.501, 0.855) 0.320 (0.152, 0.502) 0.240 (0.082, 0.444) 18.43 (12.20, 35.00) 1.44 (0.89, 2.34) 0.137
T3 104 68 0.559 (0.458, 0.649) 0.402 (0.307, 0.496) 0.322 (0.228, 0.420) 18.13 (10.47, 24.03) 1.26 (0.92, 1.72) 0.145
T4 69 60 0.356 (0.244, 0.470) 0.186 (0.103, 0.288) 0.042 (0.005, 0.154) 8.00 (6.57, 11.93) 2.80 (2.01, 3.89) <0.001
N (ver.8)
N0 267 178 0.686 (0.626, 0.738) 0.476 (0.414, 0.534) 0.299 (0.238, 0.362) 21.83 (18.13, 26.23) Reference <0.001 (omnibus)
N1‐3 79 64 0.427 (0.316, 0.534) 0.240 (0.151, 0.341) 0.147 (0.071, 0.248) 8.87 (6.73, 15.30) 1.83 (1.37, 2.44) <0.001
M (ver.8)
M0 326 227 0.640 (0.585, 0.690) 0.435 (0.380, 0.489) 0.267 (0.214, 0.323) 19.63 (15.77, 22.80) Reference 0.143 (omnibus)
M1 20 15 0.421 (0.204, 0.625) 0.211 (0.066, 0.410) 0.211 (0.066, 0.410) 11.57 (4.03, 23.93) 1.48 (0.88, 2.49) 0.143
Stage (version 8)
Stage IA 142 90 0.787 (0.710, 0.846) 0.571 (0.485, 0.649) 0.320 (0.233, 0.409) 27.00 (21.83, 31.80) Reference <0.001 (omnibus)
Stage IB, II 99 65 0.629 (0.525, 0.717) 0.402 (0.305, 0.498) 0.337 (0.238, 0.439) 18.13 (12.23, 22.50) 1.22 (0.88, 1.67) 0.23
Stage IIIA‐IV 105 87 0.407 (0.312, 0.500) 0.238 (0.161, 0.324) 0.115 (0.055, 0.200) 8.87 (7.13, 11.97) 2.26 (1.68, 3.04) <0.001
(B) Overall survival by pathological stage
n Event 1‐year survival, % 2‐year survival, % 3‐year survival, % MST, mo HR p‐value
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
T (version 7)
T0T1aT1b 26 9 0.921 (0.721, 0.980) 0.757 (0.537, 0.883) 0.580 (0.336, 0.762) (26.30, NE) Reference 0.013 (trend)
T2 30 15 0.867 (0.683, 0.948) 0.733 (0.537, 0.857) 0.442 (0.241, 0.626) 32.23 (27.50, NE) 1.39 (0.61, 3.19) 0.431
T3 61 38 0.820 (0.698, 0.896) 0.525 (0.393, 0.641) 0.349 (0.215, 0.487) 24.60 (20.97, 35.63) 2.04 (0.99, 4.22) 0.055
T4 21 15 0.619 (0.381, 0.788) 0.524 (0.297, 0.709) 0.393 (0.179, 0.602) 32.03 (10.47, 38.97) 2.45 (1.07, 5.60) 0.034
N (version 7)
No 107 55 0.840 (0.756, 0.898) 0.631 (0.532, 0.715) 0.470 (0.360, 0.572) 35.57 (26.30, 39.50) Reference 0.125 (omnibus)
N1‐3 31 22 0.742 (0.550, 0.862) 0.548 (0.360, 0.703) 0.269 (0.118, 0.446) 25.60 (17.43, 34.60) 1.47 (0.90, 2.42) 0.125
M (ver.7)
Mo 137 76 0.817 (0.741, 0.872) 0.617 (0.530, 0.693) 0.422 (0.327, 0.513) 32.23 (25.60, 37.47) Reference 0.454 (omnibus)
M1 1 1 0.000 (0.000, 0.000) 0.000 (0.000, 0.000) 23.93 (NE, NE) 2.13 (0.29, 15.38) 0.454
Stage (ver.7)
Stage I 26 9 0.921 (0.721, 0.980) 0.757 (0.537, 0.883) 0.580 (0.336, 0.762) NE (26.30, NE) Reference 0.080 (trend)
Stage II 25 11 0.880 (0.673, 0.960) 0.760 (0.542, 0.884) 0.539 (0.320, 0.715) NE (27.50, NE) 1.22 (0.51, 2.95) 0.657
Stage III 64 40 0.828 (0.711, 0.901) 0.547 (0.418, 0.659) 0.340 (0.211, 0.474) 25.60 (20.97, 35.57) 2.00 (0.97, 4.12) 0.061
Stage IV 23 17 0.609 (0.383, 0.774) 0.478 (0.268, 0.661) 0.359 (0.163, 0.560) 23.93 (10.47, 38.97) 2.62 (1.17, 5.89) 0.02
T (ver.8)
T0‐1 35 12 0.942 (0.787, 0.985) 0.762 (0.580, 0.873) 0.597 (0.392, 0.752) NE (30.80, NE) Reference 0.007 (trend)
T2 21 12 0.810 (0.569, 0.924) 0.714 (0.472, 0.860) 0.337 (0.113, 0.580) 30.53 (21.83, NE) 2.02 (0.91, 4.51) 0.086
T3 61 38 0.820 (0.698, 0.896) 0.525 (0.393, 0.641) 0.349 (0.215, 0.487) 24.60 (20.97, 35.63) 2.24 (1.17, 4.30) 0.015
T4 21 15 0.619 (0.381, 0.788) 0.524 (0.297, 0.709) 0.393 (0.179, 0.602) 32.03 (10.47, 38.97) 2.69 (1.26, 5.75) 0.011
N (ver.8)
N0 107 55 0.840 (0.756, 0.898) 0.631 (0.532, 0.715) 0.470 (0.360, 0.572) 35.57 (26.30, 39.50) Reference 0.125 (omnibus)
N1‐3 31 22 0.742 (0.550, 0.862) 0.548 (0.360, 0.703) 0.269 (0.118, 0.446) 25.60 (17.43, 34.60) 1.47 (0.90, 2.42) 0.125
M (ver.8)
M0 137 76 0.817 (0.741, 0.872) 0.617 (0.530, 0.693) 0.422 (0.327, 0.513) 32.23 (25.60, 37.47) Reference 0.454 (omnibus)
M1 1 1 0.000 (0.000, 0.000) 0.000 (0.000, 0.000) 23.93 (NA, NE) 2.13 (0.29, 15.38) 0.454
Stage (version 8)
Stage IA 32 10 0.936 (0.769, 0.984) 0.772 (0.581, 0.885) 0.637 (0.422, 0.790) NE (30.80, NE) Reference 0.005 (trend)
Stage IB, II 64 37 0.828 (0.711, 0.901) 0.594 (0.463, 0.702) 0.363 (0.226, 0.501) 30.53 (20.97, 39.50) 2.22 (1.10, 4.46) 0.026
Stage IIIA‐IV 42 30 0.714 (0.552, 0.826) 0.524 (0.364, 0.661) 0.343 (0.195, 0.496) 25.07 (18.53, 35.00) 2.82 (1.38, 5.77) 0.005
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Abbreviations: HR, hazard ration; MST, median survival time; NE, not evaluable.

FIGURE 5.

FIGURE 5

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Overall survival by clinical and pathological stages. (A, B) A significant survival difference between clinical stage groups was observed in both seventh (A) and eighth (B) staging systems. (C) There was not a significant survival difference at the seventh version pathological stages. (D) A significant survival difference was observed at the eighth version pathological stages.

The median OS for minimal (n = 68), nodular (n = 96), and rindlike (n = 178) tumor shape groups were 26.7, 21.3, and 15.0 months, respectively (Figure 6A). The survival time in minimal and nodular groups was significantly longer than that in the rindlike group (p = 0.007, p = 0.029 respectively). The median OS time (27.0 months) was significantly longer in the MTT <5.1 mm group (n = 91) than that in the MTT ≥ 5.1 mm group (n = 255) (15.5 months) (p = 0.013) (Figure 6B). The median OS time (26.3 months) for the STLT <13 mm group (n = 101) was significantly longer than that for the 13 ≤ STLT <60 mm group (n = 203) (15.5 months) (p = 0.022) and the STLT ≥60 mm group (n = 42) (12.0 months) (p = 0.008) (Figure 6C).

FIGURE 6.

FIGURE 6

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Overall survival (OS) by tumor shape and tumor thickness. (A) Median overall survival for minimal (n = 68), nodular (n = 96), and rind‐like (n = 178) groups were 26.7, 21.3, and 15.0 months, respectively. Survivals for minimal and nodular groups were significantly longer than for the rind‐like group. (B) Median OS was significantly longer in the MTT <5.1 mm group (n = 91) than that in the MTT ≥5.1 mm group (n = 255): 27.0 months vs. 15.5 months. (C) The median OS for the STLT <13 mm group (n = 101) was significantly longer than those for the 13 ≤ STLT <60 mm group (n = 203) and the STLT ≥60 mm group (n = 42): 26.3 months vs. 15.5 months and 12.0 months, respectively. MTT, maximum tumor thickness; OS, overall survival; STLT, sum of three‐level thickness.

3.7. Relapse after macroscopic complete resection

Relapse occurred in 74 (77.1%) of the 96 MCR patients and resulted in PM‐related death (n = 36), death due to other causes with PM (n = 1), and survival with PM (n = 37). Among 22 patients without recurrence, four died of other causes, while 18 survived. Relapse pattern was described in 71 of 74 relapsed patients. Initial relapse sites were local only in 53 (74.6%), distant only in eight (11.3%), and both in 10 (14.1%) (Table 10). Distant only metastasis was observed in 27.8% (5/18) of EPP patients and 5.9% (3/51) of P/D patients.

TABLE 10.

Relapse pattern and sites.

Relapse pattern Relapse site (local) Relapse site (distant)
Site No (EPP/PD/Other) Site No (EPP/PD/Other)
Local only (n = 53) Total 53 (11/40/2)
Ipsilateral chest wall 45 (9/34/2)
Ipsilateral diaphragm 1 (1/0/0)
Ipsilateral mediastinal LN 11 (0/11/0)
Ipsilateral axillar/supraclavicular LN 2 (1/1/0)
Pericardium 4 (3/1/0)
Distant only (n = 8) Total 8 (5/3/0)
Contralateral chest wall 3 (2/1/0)
Abdomen 2 (2/0/0)
Contralateral LN 1 (1/0/0)
Intrapulmonary 3 (1/2/0)
Local + distant (n = 10) Total 10 (2/8/0)
Ipsilateral chest wall 6 (2/4/0) Contralateral chest wall 1 (0/1/0)
Ipsilateral diaphragm 1 (0/1/0) Abdomen 1 (0/1/0)
Ipsilateral mediastinal LN 4 (0/4/0) Contralateral LN 1 (1/0/0)
Ipsilateral axillar/supraclavicular LN 1 (1/0/0) Intrapulmonary 8 (2/6/0)
Pericardium 1 (0/1/0)
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Abbreviation: EPP, extrapleural pneumonectomy; LN, lymph node; P/D, pleurectomy/decortication.

The PFS time was calculated in 93 of the 96 MCR cases, excluding three cases without detailed relapse information. Median PFS and survival rates at 1, 2, and 3 years for 93 MCR patients were 16.6 months, 73.1%, 29.3%, and 19.1%, respectively (Figure 7A). Median PFS and PFS rates at 1, 2, and 3 years were 13.6 months and 63.6%, 13.6%, and 13.6% for EPP patients (n = 22), and 19.4 months and 76.2%, 34.4%, and 20.7% for P/D patients (n = 68), respectively (Figure 7B).

FIGURE 7.

FIGURE 7

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Progression‐free survival. (A) Median PFS and survival rates at 1, 2, and 3 years for MCR patients (n = 93) were 16.6 months and 73.1%, 29.3%, and 19.1%, respectively. (B) Median PFS and PFS rates at 1, 2, and 3 years were 13.6 months and 63.6%, 13.6%, and 13.6% for EPP patients (n = 22), and 19.4 months and 76.2%, 34.4%, and 20.7% for P/D patients (n = 68), respectively. EPP, extrapleural pneumonectomy; MCR, macroscopic complete resection; P/D: pleurectomy/decortication; PFS, progression‐free survival.

4. DISCUSSION

The JJLCRC generated several nationwide registries to establish the international staging system of lung cancer. 27 , 29 , 30 This study is the first investigation and analysis of a PM registry by JJLCRC. Like previous JJLCRC registries 26 , 27 , 28 , 29 , 30 this study provides reliable and critical information with few excluded cases and missing values of clinical data. According to the annual report of the Japanese Ministry of Health, Labor, and Welfares, 34 1555 and 1512 deaths were associated with PM in 2017 and 2018, respectively. According to the National Clinical Database of Japan, 622 curative‐intent surgeries for PM were performed between January 2014 and December 2017. 35 Thus, this study represents approximately 10% of all PM cases and 50% of surgical cases in Japan during the study period.

With the nationwide enrollment prospectively, the present study has provided critical information on PM treatment. We found that median OS time for non‐surgical treatment groups and BSC groups were 14.0 months and 3.8 months, respectively. These results were in line with a large‐scale retrospective study in the United States. 36 This study revealed that prognosis for unresectable PM remains poor. Furthermore, our study provided the surgery completion rate, MCR rate, mortality/morbidity rate, and postoperative survival rate of all patients undergoing surgery, which had been lacking in the literature. Surgery incompletion rate (i.e., ET/PP) in this study was 18.8%, similar to the result of a previous single‐center retrospective study. 37 However, the found rate was relatively high compared to the data from previous prospective studies. 38 , 39 , 40 , 41 , 42 The relatively high surgery incompletion rate in this study might have reflected that some of participating surgeons were not sufficiently experienced. The ambiguity of surgical nomenclature might also serve as a possible explanation of our findings. Since the distinction of R2 resection, PP, and ET in surgery‐intended cases is not clearly described in the consensus paper, 32 surgery incompletion rate might vary according to the surgeon's definition.

The median OS time (32.2 months) for all surgical cases in the present study was longer than that in previous prospective studies (up to 24.4 months). 38 , 39 , 43 , 44 , 45 , 46 , 47 The recent small‐scale phase II clinical trial reported an intent‐to‐treat basis survival of 41.4 months. 42 The present study demonstrated that the postoperative survival for all surgical cases was extending over 30 months.

This study reconfirmed that MCR is a reasonable goal for PM surgery. Since any type of curative‐intent surgery for PM provides R1 resection, MCR has become a surgical goal. 48 , 49 However, some experts were critical of the reliability of MCR, which was subject to the surgeon's discretion. 50 This study revealed that the survival of the MCR group was significantly longer than those of the R2 resection and ET/PP groups. During the planning phase of this study, we hypothesized that a part of MCR surgery might be more radical than the rest. Thus, we divided MCR into two subcategories: R0‐1 and R1. However, R0‐1 and R1 groups had similar survival rates. Thus, the results confirmed that MCR is a reliable and practical goal of PM surgery.

In the present study, P/D, not EPP, showed a significantly longer survival than PP/ET. Because this study may contain patient selection bias, including conversion from P/D to EPP, 40 it is not appropriate to draw any conclusion on the comparison of different surgical techniques. However, the results of this study might suggest that we should be cautious in indicating surgical intervention for EPP.

Our study confirmed the prognostic power of both tumor shape and tumor thickness that had been found in the previous IASLC registry. 8 The reliability of MTT and STLT was previously confirmed by single‐center studies. 51 , 52 To the best of our knowledge, this study was the first to validate that tumor shape is a reliable prognostic variable. Since tumor shape and thickness are readily accessible to practicians, they are promising candidates for the next T descriptors.

We verified and compared the prognostic power using the seventh and eighth versions of the TNM staging system. Approximately two‐thirds of patients were categorized as c‐ and p‐stage I in the eighth TNM staging system. The results of the present study concur with previously reported data of a retrospective study that validated the sixth and eighth TNM staging system using the surveillance, epidemiology, and end results (SEER) database. 53 This study revealed the “bulky stage I” issue of the eighth version as a task for the ninth version of the TNM staging system.

This study has some limitations. First, there may be sampling bias because this study did not collect all the Japanese PM cases during the study period. This study might have not reflected the real‐world situation in Japan because the majority of the participating institutions were academic centers or large hospitals. Second, the results of this study might not directly translate to other countries because of differences in racial composition, cultural habits, and medical systems. 54 Complimentary periodic medical checkups for high‐risk populations and complimentary medical interventions for patients with PM are available in Japan. Third, nivolumab treatment was not considered in the questionnaire of the case report form because registration of this study was started in April 2017, a year before the approval of nivolumab in Japan. Although most of the chemotherapeutic agents listed as “others” were presumed to be nivolumab, this cannot be verified. It is also presumed that nivolumab had an additional effect on the prognosis of both surgical and non‐surgical cases.

AUTHOR CONTRIBUTIONS

Seiki Hasegawa: Conceptualization; investigation; methodology; project administration; validation; writing – original draft; writing – review and editing. Yasushi Shintani: Data curation; validation; writing – original draft; writing – review and editing. Teruhisa Takuwa: Investigation; writing – original draft. Keisuke Aoe: Investigation. Katsuya Kato: Investigation. Nobukazu Fujimoto: Investigation. Yasuhiro Hida: Investigation. Masahiro Morise: Investigation. Yasumitsu Moriya: Investigation. Takao Morohoshi: Investigation. Hidemi Suzuki: Investigation; project administration. Masayuki Chida: Investigation. Shunsuke Endo: Data curation. Mitsutaka Kadokura: Investigation. Meinoshin Okumura: Funding acquisition; supervision. Satoshi Hattori: Data curation; formal analysis; visualization; writing – original draft. Hiroshi Date: Funding acquisition; supervision. Ichiro Yoshino: Funding acquisition; supervision; writing – original draft; writing – review and editing.

FUNDING INFORMATION

The Japanese Joint Committee for Lung Cancer Registry (JJCLCR) runs thanks to donations from participating medical associations, including the Japanese Respiratory Society, the Japanese Lung Cancer Society, the Japanese Association for Chest Surgery, the Japanese Association for Thoracic Surgery, the Japanese Society for Respiratory Endoscopy, the Japanese Association for Research on the Thymus, and the Japan Asbestos and Mesothelioma Interest Group.

CONFLICT OF INTEREST STATEMENT

Seiki Hasegawa received an endowed course from Kubota Corporation. Yasushi Shintani received grants from Immunomedicine, and Ishihara Sangyo Kaisya. Keisuke Aoe received grants from Astra Zeneka, Novartis, Phizer, Bristol‐Meyer Squib, and MSD. Masahiro Morise received grants from Behringer Ingelheim and Eli Lilly. The other authors declare that they have no conflicts of interest.

ETHICS STATEMENT

This study was approved by the institutional review board of Osaka University Hospital, where the registry office is located, on October 11, 2016 (approval number 16038). The registry and the study using the registered data were approved by each institutional review board of all participating institutions.

Informed consent statement: This study complied with the Declaration of Helsinki. Written informed consent was obtained from all study participants.

This study adhered to the ethical guidelines for epidemiologic studies published jointly by the Japan Ministry of Science, Culture, and Education and the Japan Ministry of Health, Labor, and Welfare on June 17, 2002, and revised on February 28, 2017.

Clinical Trial Registration: UMIN 000024664.

Animal Studies: N/A.

DISCLAIMER

The findings and conclusions of this study are those of the authors and do not necessarily represent the views of the Japanese Joint Committee for Lung Cancer Registry or its participating medical associations.

Supporting information

File S1.

Click here for additional data file. (63.7KB, docx)

File S2.

Click here for additional data file. (38KB, xlsx)

ACKNOWLEDGMENTS

The authors thank all patients and investigators from participating institutions.

Hasegawa S, Shintani Y, Takuwa T, et al. Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan. Cancer Sci. 2024;115:507‐528. doi: 10.1111/cas.16021

DATA AVAILABILITY STATEMENT

Under Japan's Personal Information Protection Law (Amended version in 2022), it is obligatory to obtain re‐consent from research participants when providing data to a third‐party. Since it is impossible to obtain consent again from the research participants, we cannot provide the data.

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Supplementary Materials

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Data Availability Statement

Under Japan's Personal Information Protection Law (Amended version in 2022), it is obligatory to obtain re‐consent from research participants when providing data to a third‐party. Since it is impossible to obtain consent again from the research participants, we cannot provide the data.

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