Multi-institutional survey of malignant pleural mesothelioma patients in the Hokushin region

Malignant pleural mesothelioma (MPM) is a major occupational and environmental neoplasm. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis, and initial treatment among MPM patients in the Hokushin region. We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals. A total of 166 MPM cases were newly diagnosed. These patients consisted of 136 men and 30 women, with a median age of 69 years. We estimated the incidence rate for MPM to be 0.55 cases per 100,000 person-years in this study. The ratio per 100,000 population-years was 0.39 in Fukui, 0.60 in Ishikawa, 1.02 in Toyama and 0.35 in Nagano. Forty-five patients were discovered when diagnosed incidentally in patients under observations for other diseases. Forty-six cases were diagnosed as localized disease, while 13 had accompanying regional lymph node metastasis. Furthermore, 44 cases showed infiltration into adjacent organs. A histo-cytological diagnosis was made in 164 cases (98.8%). A surgical approach, chemotherapy, and radiotherapy were performed for 33, 88, and 6 patients, respectively, while 44 patients (26.5%) received best supportive care. Multimodality therapy was conducted in just 3.0% of the MPM patients MPM has a tragically rapid progression if discovered under observations for other diseases. Workers in health-related fields should be on high alert for aggressive MPM. Better evaluation and multi-disciplinary approaches to MPM in these regions are needed to optimize multimodality therapy.


Introduction
Malignant pleural mesothelioma (MPM) is a lethal cancer primarily caused by the inhalation of asbestos particles, with a latency period of up to several decades and a poor survival (Lanphear and Buncher 1992). Over 70% of MPM cases in Japan are associated with asbestos exposure (Gemba et al. 2012). In Europe, the MPM incidence rates have been expected to peak around the year 2020 in some countries, and a deceleration or decrease in the incidence may have already have begun in the United States of America (Pelucchi et al. 2004;Henley et al. 2013). However, asbestos remains a subject of public interest in Japan. The spraying of asbestos was outlawed in 1975, and the manufacture of asbestos cement pipes ended in 1985. Asbestos disorder prevention regulations were established in 2005, and in principle, the manufacturing, import, and use of asbestos products are prohibited. However, millions of old buildings including asbestos in their makeup are likely still standing in Japan. As such buildings are ultimately destined for dismantling, a process by which asbestos can be easily spread, the number of cases in Japan is likely to peak around 20 years from now, according to predictions made by the Ministry of the Environment. In fact, the number of deaths due to MPM has increased threefold in the past 20 years. However, investigations concerning MPM are limited because of the rarity of the disease as well as its highly aggressive potential. Furthermore, while the role of chemotherapy has been partially established (Vogelzang et al. 2003;Zalcman et al. 2016), the roles of surgery (Hasegawa and Tanaka 2008;Rice 2011) and radiotherapy (Price 2011;Cho et al. 2021) remain controversial. Several studies have focused on surgery (Rintoul et al. 2014), chemotherapy (Vogelzang et al. 2003), or immunotherapy (Baas et al. 2021) in MPM patients; however, the data on patients who do not visit the hospital are scarce. Recently, the Japanese Joint Committee of Lung Cancer Registry (JJCLCR) established a project to develop a prospective registry database of patients with MPM with the goal of clarifying the epidemiology, pretreatment laboratory values, immunohistochemical evaluation, respiratory function, postoperative morbidity, and follow-up characteristics of MPM (Shintani et al. 2018). This effort started in 2017 and will be conducted until 2026, so its findings have not yet been made public. Therefore, a finegrained analysis of a wide area performed over a moderate duration is expected to provide useful data in the interim.
The Hokushin region of Japan comprises the Hokuriku region (Ishikawa, Toyama and Fukui Prefectures) and Nagano Prefecture, which all have relatively old populations and snowy climates during the winter (Fig. 1). We created a database based on cancer registration in the Hokushin region, referred to as the Hokushin Ganpro database, to clarify the circumstances concerning cancer patients in a super-aging society, which not only Japan but also countries all over the world will be faced with soon, as the risk of cancer increases with age. We surveyed retrospective data containing hospital-based cancer registries (HBCRs) and information on clinical epidemiological factors of MPM using the Hokushin Ganpro database.

Hokushin Ganpro database
Maintenance of an HBCR is mandated for all cancer care hospitals designated by the Ministry of Health, Labor and Welfare in Japan (Higashi 2014). These designated cancer care hospitals are expected to serve as hubs for providing standard care, including surgery, chemotherapy, and radiotherapy, to cancer patients in their respective regions and to register newly diagnosed and/or treated cancer cases at their hospitals every year (Uramoto et al. 2021). These institutions maintain HBCRs and collect basic information on all newly encountered cancer cases, such as the tumor location, histology, route of referral to the hospital, and treatment (Uramoto et al. 2021). The definition of malignancy corresponds to behavioral code 3 in the International Classification of Diseases for Oncology, third edition (ICD-O-3). All target neoplasms newly encountered at the hospitals are registered.
The Hokushin region has been considered a superaging region according to the Statistics Data, Statistics Bureau, Ministry of Internal Affairs. Hokushin Ganpro is a program supported by the cooperation of six universities located in the Hokushin region: Kanazawa University, Kanazawa Medical University, Shinshu University, Toyama University, Fukui University, and Ishikawa Prefectural Nursing University ( Fig. 1) (Uramoto et al. 2021). Hokushin Ganpro established a large-scale database based on hospital cancer registration covering this region between January 1, 2010, and December 31, 2015 (data set 1). The database includes information on the number of patients in each prefecture, the patient age, sex, process of cancer detection, pre-treatment process, basis for the diagnosis, histological diagnosis, and treatment performed for the registered patients (Uramoto et al. 2021). The present protocol was approved by the Kanazawa University Institutional Review Board (IRB) (reference number 2750-2), Kanazawa Medical University (I328), and the IRBs at the Hokushin Ganpro database project, all of which granted a waiver of consent for the study.

Study cases and analyses
We surveyed retrospective data of 152,921 cancer patients in 22 principal hospitals in the Hokushin region registered with the Hokushin Ganpro database. We collected MPM patients who were classified as code C384 (pleura) and analyzed the patients classified as code 2 (diagnosed and treated in the registering hospital) and code 3 (diagnosed in another hospital and treated at the currently registered hospital).
The extent of disease was classified as localized, regional lymph node metastasis, regional extension, or distant metastasis, defined as follows: 'localized', localized in the primary organ; 'regional lymph node metastasis', regional lymph node metastasis but no invasion to neighboring organs; 'regional extension', invasion to neighboring organs; 'distant metastasis', metastasis to other organs or distant lymph nodes (Uramoto et al. 2021). We examined the histological subtype, patient age at the diagnosis, patient sex, and treatments. In addition, we calculated the incidence rate of MPM for each individual prefecture according to the total Japanese population using the numbers of cancer cases and national population statistics for each year. Population estimates in Japan and each prefecture were obtained from the official statistics of Japan portal site (https:// www.e-stat. go. jp/).

Patient characteristics
A total of 166 MPM cases were newly diagnosed. The number of patients with MPM in each prefecture were 18 in Fukui, 41 in Ishikawa, 64 in Toyama and 43 in Nagano (Fig. 1). The incidence rate was estimated to be 3.32/100,000 over the 6-year period. Therefore, we estimated the incidence rate for MPM to be 0.55 cases per 100,000 personyears in this study. The ratio per 100,000 population-years was 0.39 in Fukui, 0.60 in Ishikawa, 1.02 in Toyama and 0.35 in Nagano. These patients were 136 (82%) men and 30 (18%) women, with a median age of 69 years old (range 45-92 years old). The age-specific number of patients during the observation period is shown in Fig. 2. The highest incidences were observed in those 60-69 years old.

The diagnosis and stage of MPM
Actual numbers of MPM patients each year were 26 in 2010, 23 in 2011, 34 in 2012, 22 in 2013, 32 in 2014, and 26 in 2015. Next, we investigated the referral pathway. Nine patients were discovered at cancer screening, 9 at health checkups, 11 in a voluntary setting, 45 under observations for other diseases, and 92 cases by introduction from another hospital (Fig. 3). One hundred and forty-nine (89.8%), 15, 1, and 1 case were diagnosed as the first, second, third, and fourth cancer, respectively. Eighty-seven, 59, and 1 case were right sided, left sided, and bilateral MPM, respectively; 19 cases had 'unknown data'. Figure 4 shows the data regarding the extent of disease. Forty-six cases were diagnosed with localized disease, while 13 had accompanying regional lymph node metastasis. Furthermore, 44 cases showed infiltration into the adjacent organs, and 47 cases had distant metastasis; 16 cases were reported to have 'unknown data'. The clinical stages were as follows: stage I (n = 39), stage II (n = 29), stage III (n = 34), and stage IV (n = 51), with 13 cases having 'unknown data'. Only two cases were diagnosed by radiological imaging

Treatment
The therapies applied for MPM are summarized (Fig. 5).
Overall, 73% of patients were recorded to have had at least one specific anti-cancer treatment (surgery, chemotherapy, or radiotherapy). A surgical approach was performed for 33 patients, with surgery alone performed in 29 and surgery plus radiotherapy in 4 cases. Chemotherapy was performed for 88 patients, including chemotherapy alone in 87 cases. Radiotherapy was performed for six patients, including radiotherapy alone and chemotherapy plus radiotherapy in one case each. Multimodality therapy (more than 2 approaches) was conducted in just 3.0% of MPM patients (5/166). Forty-four patients (26.5%) received best supportive care (BSC).

Discussion
This study provided the latest data on the accurate epidemiology of MPM in a specific region of Japan. The ratios of staging recorded and actual rates of histopathological confirmation in this study were 92 and 98.8%, respectively, which is quite high compared with a recent UK report (Murphy et al. 2020;Beckett et al. 2015). These results suggest that the information obtained in this study is reliable. The incidence rates of MPM have been reported to be relatively high in some European countries (UK, the Netherlands) and Oceanian countries (Australia, New Zealand); whereas, rates in Japan and countries from central Europe have shown relatively low incidence rates (Bianchi and Bianchi 2014). In fact, the incidence rate was estimated to be 0.55 cases per 100,000 person-years in this study, which is around half of the value in the United States from 2003 to 2008 (average of 1.05 cases per 100,000 person-years) (Henley et al. 2013). Fortunately, the rates have decreased in the United States (Henley et al. 2013). However, the actual annual numbers of MPM patients have not decreased according to our data, suggesting that closer attention should be paid to this disease, even in the face of governmental regulations. Regional differences might exist concerning the incidence of MPM due to differing concentrations of asbestos-related factories. Interestingly, the incidence rate in Toyama Prefecture was almost two to three times higher than that in the nearby Nagano and Fukui Prefectures. Regarding the reason why the incidence of MPM in Toyama is so high, Toyama Prefecture has the highest mortality rate due to mesothelioma in this area (http:// www. mhlw. go. jp/ toukei/ saikin/ hw/ jinkou/ tokus yu/ chuuh isyu05/ index. html). We failed to obtain adequate data related to the differences in the usage of asbestos by prefecture. Detailed information concerning asbestos use, including the type of material, dose, time, duration, factory location, and type of factory will be essential for a proper evaluation of the geographical distribution. Furthermore, various investigations have shown a high level of asbestos exposure in Japanese shipyards on the coast facing the Pacific Ocean or sea on the mainland of Japan, such as Kure and Yokosuka city. These cities were the sites of Japanese naval shipyards before World War II (Kurumatani et al. 1999;Morinaga et al. 2001). There are fisheries grounds linked to the shipbuilding industry at Himi Bay in Toyama. The high incidence reported by fishing industry officials might, therefore, be related to the shipbuilding industry. Kishimoto et al. concluded that 79.2% of cases of mesothelioma in Japan were caused by asbestos exposure. According to their report concerning occupational history of asbestos exposure, among occupations, shipyard workers showed the second highest frequency of cases (Kishimoto et al. 2010;Gemba et al. 2012).
In the present study, we found that 45 cases were newly diagnosed during follow-up of other diseases. In general, there are more hospitals and diagnostic modalities in Japan than in Western countries. Today, Japan faces the problem of a rapidly aging population. Therefore, the high rate of discovery of MPM under observations for other diseases might be unique to Japan. One issue needs to be addressed: the ratio of localized disease reached 27.7% (46/166), but a surgical approach which specifically cytoreductive treatment as part of a multimodality approach (Waller et al. 2021), was performed in only 33 patients (19.9%). This result is unexpected because the diagnosis of one disease during followup for another is usually expected to indicate early detection. These discrepancies suggest that the Hokushin region is a reasonable example of an area with an ultra-declining birth rate and aging population. Ninety-two cases were also newly diagnosed by introduction from another hospital. These findings suggest that this disease has widely affected various area.
Unfortunately, there was a high incidence of BSC in the present study (26.5% 44/166), and 47 patients (28.3%) had distant metastasis. The age was significantly higher in the BSC group (mean 77.5 years old) than in the treatment group (mean 67.4 years old) (p < 0.0001). However, there were no significant differences between the two groups in terms of the extent of disease. Multimodality therapy was conducted in only 3.0% of MPM patients. This ratio seems to be very low from the perspective of general clinical practice and may be due to the extremely biologically malignant behavior of MPM and its rapid progression. There is some concern that most physicians do not have experience diagnosing this rare disease. Clinicians should, therefore, ask about a patient's occupational history in order to check for asbestos-related diseases, especially among patients with a history of involvement in the asbestos product industry or shipbuilding. Future directions of centralizing care or an increase in treatment knowledge in this region is needed.
Several limitations associated with the present study warrant mention. These include the retrospective nature of the study and the fact that it was carried out at domestic institution based on cancer registration data. Therefore, the survival information, treatment sequence, and therapeutic effect were unclear. The type of asbestos fibers in the pleura of the patients could not be analyzed because surgery or autopsies were not performed in these limited cases. Nevertheless, the current findings highlight an important issue, namely our study highlights the added value of a multi-institutional survey to analyze one type of rare cancer which was conducted in this area over a long period of time. Innovative modalities for curing MPM are needed. We recently conducted an observation study of a regional cancer database between 2016 and 2017 as dataset 2, including the Diagnosis Procedure Combination (DPC) survey data in the Hokushin region. A detailed examination conducting using data from a continuous study will provide new findings to help healthrelated staff monitor and control the disease through various new approaches (Baas et al. 2021).