If new pleural effusions occur, a differential diagnosis of pleural mesothelioma should be considered as part of the etiological investigation. The diagnosis of pleural mesothelioma cannot be confirmed or excluded with sufficient certainty based on the patient's medical history, clinical symptoms and radiological procedures. Therefore, if a pleural mesothelioma is suspected, a histological examination should be performed in order to make a sufficient diagnosis. Due to the relatively low incidence of pleural mesothelioma, diagnosis and treatment planning for pleural mesothelioma should be carried out at a center specializing in this disease. If pleural mesothelioma is suspected, an occupational history of both the patient and the spouse should be taken in addition to the clinical history in order to determine possible exposure to asbestos.

In addition to the physical examination and sonography of the pleura, a chest X-ray and a CT chest with contrast medium should be performed, provided there are no contraindications [24, 25]. A pleural effusion should be clarified using video-assisted thoracoscopy (VATS) with pleural biopsy if pleural mesothelioma is suspected, in order to enable a sufficient histological diagnosis [22]. Similarly, if there is clinical and/or radiological suspicion of the possible presence of pleural mesothelioma, histological clarification using VATS should be sought even without the presence of a pleural effusion. When performing the biopsy, it is important to take the subpleural fat tissue to prove invasiveness. If possible, biopsies should be taken at different locations. If possible, the uniportal surgical access route should be placed at the level of a subsequent thoracotomy to avoid implantation metastases. Patients with a histologically confirmed diagnosis of pleural mesothelioma can undergo PET-CT prior to planned curative surgical treatment [25, 26]. If a PET-CT cannot be performed, a CT abdomen should be performed in addition to the CT thorax, in each case with contrast medium if possible. A contralateral VATS or laparoscopy should be considered if there is a radiological suspicion of contralateral or peritoneal involvement with clinical consequences. To clarify infiltration of the thoracic wall - particularly ribs or vertebral body - or to assess the presence of transmural diaphragmatic infiltration, an MRI of the thorax can be performed if there is a therapeutic consequence. Invasive lymph node staging using endobronchial ultrasound (EBUS) or, if necessary, mediastinoscopy should be performed before planned curative surgical treatment [27, 28].

Figure 4 summarizes the diagnostic procedure for suspected pleural mesothelioma.

The pathological diagnosis of pleural mesothelioma should be made histologically on a representative tumor sample and is clearly superior to a purely cytological diagnosis, e.g. from a pleural effusion. Immunohistochemically, the mesothelioma markers calretinin, cytokeratin 5/6, Wilms tumor 1 (WT-1) and D-240 should be determined for differential diagnosis against adenocarcinoma of the lung. The adenocarcinoma markers TTF1, CEA, Ber-EP4 should also be evaluated for the differential diagnosis of adenocarcinoma. At least 2 markers for pleural mesothelioma and 2 markers for carcinoma should be tested to diagnose an epithelioid subtype [29]. If a sarcomatoid subtype is suspected, cytokeratin should be tested [29]. The histological subtype of the mesothelioma should be specified, as well as a statement on the certainty of the diagnosis according to the criteria of the European Mesothelioma Panel.

Systemic therapy is of particular importance in the treatment of pleural mesothelioma, as a complete resection of the tumor is practically impossible to achieve even in localized stages, so that the treatment of systemic micro metastasis is relevant for the best possible long-term prognosis.

The first proof of efficacy of a combination therapy consisting of cisplatin and pemetrexed with a median of 6 cycles was provided in a phase III trial in non-resectable patients by Vogelzang et al. with an improvement in overall survival of 12.1 vs. 9.3 months (HR: 0.77; p-value = 0.02) and progression-free survival of 5.1 vs. 3.9 months (p-value = 0.001) and a response rate of 41.3% vs. 16.7% (p-value < 0.0001) [33].

Since then, the neoadjuvant or adjuvant application of 4 cycles of cisplatin and pemetrexed has been an empirically clinically recognized standard.

If there are contraindications to cisplatin and/or pemetrexed, pemetrexed can be replaced by vinorelbine or gemcitabine, for example, and if there are clear contraindications to cisplatin, this can be replaced by carboplatin if necessary [34, 35, 36].

Studies evaluating the significance of checkpoint inhibitors for this disease situation have not yet been conclusively evaluated. However, due to the efficacy of checkpoint inhibitors in the non-resectable situation, an extension/adaptation of the therapeutic approach is not unlikely once these studies have been finally evaluated.

The surgical procedure of choice today should be extended pleurectomy/decortication ((e)P/D), i.e. complete removal of the parietal and visceral pleura while preserving the lung parenchyma, possibly extended by diaphragmatic and/or pericardial resection. The aim of surgical resection is the macroscopically complete removal of the tumor in the sense of maximum possible cytoreduction. Outside of clinical studies, procedures such as extrapleural pneumonectomy (EPP) should only be considered if strictly indicated and if there is sufficient functional reserve. In justified exceptional cases, EPP can be performed at sufficiently experienced centers as part of individual therapy concepts.

Histologic confirmation and staging should be performed as described in section 5.1. Patients in a good general condition (ECOG 0) suffering from epithelioid mesothelioma in localized stage I-IIIA can be offered (e)PD either after neoadjuvant chemotherapy or primarily and followed by adjuvant chemotherapy with cisplatin and pemetrexed if pulmonary functionality is sufficient.

In this context, it should be noted that the neoadjuvant chemotherapy of 4 cycles of platinum combination can usually be applied much better than adjuvant therapy after (e)P/D, in which the dose density usually has to be reduced due to postoperative restrictions. On the other hand, it should be borne in mind that the postoperative recovery time after neoadjuvant chemotherapy is usually significantly longer. An EORTC study (NCT02436733), which had not yet been evaluated at the time of writing the guidelines, compares neoadjuvant with adjuvant application.

The therapeutic goal of the combination of surgical cytoreduction and systemic therapy is to control the disease for as long as possible while maintaining a good quality of life. A formally curative therapeutic approach with radical (R0) tumor resection is practically impossible in malignant pleural mesothelioma. In individual cases, long progression-free courses >10 years can be achieved, but in the long-term course there is practically always a mostly local recurrence. Depending on the localization and extent of the recurrence, local therapeutic approaches may then be offered again in combination with systemic therapy.

The therapeutic concept should be developed in an interdisciplinary conference in a facility experienced in the treatment of pleural mesothelioma, ideally in a DKG-certified lung cancer center with a mesothelioma unit.

In the non-resectable situation and/or in the presence of non-epithelioid histology, a therapy consisting of the combination of the checkpoint inhibitors nivolumab and ipilimumab is considered the current first-line standard. In the randomized phase III CheckMate743 trial, the checkpoint inhibitor combination showed significant superiority in overall survival in patients with non-epithelioid histology compared to cisplatin/carboplatin and pemetrexed, with an extension of the median overall survival time by 9.3 months (18.1 vs. 8.8 months; HR: 0.46)) [37]. In patients with epithelioid histology, median overall survival tended to be better compared to treatment with cisplatin/carboplatin and pemetrexed, but was not statistically significant, and amounted to 18.7 months in the checkpoint inhibitor arm and 16.5 months in the chemotherapy arm (HR: 0.86). For the entire patient population, the median overall survival of 18.1 vs. 14.1 (HR: 0.74; p-value = 0.002) months was also longer in the immunotherapy arm than in the chemotherapy arm. Regardless of the histological subtype, in a retrospective subgroup analysis, patients with PD-L1 expression of ≥ 1% on the tumor surface (TPS) benefited more from the immunotherapy combination than patients with PD-L1 expression of < 1% on the tumor surface (TPS). (PD-L1 ≥ 1% TPS: median overall survival 18.0 vs. 13.3 months (HR: 0.69); PD-L1 <1% TPS: median overall survival 17.3 vs. 16.5 months (HR: 0.94)). Due to the retrospective nature of the subgroup analysis and the small number of cases, a treatment decision based on PD-L1 status is not recommended.

Median progression-free survival was comparable for the entire patient population in both study arms (6.8 months in the immunotherapy arm and 7.2 months in the chemotherapy arm (HR: 1.00)). However, progression occurred more frequently in the first 6 months in the checkpoint inhibitor arm than in the chemotherapy arm [37].

The median duration of response in the entire patient population was 11.0 months in the checkpoint inhibitor arm and 6.7 months in the chemotherapy arm, meaning that patients benefited longer from a response to checkpoint inhibitor therapy. In both study arms, the objective response rate was comparable with 40% in the checkpoint inhibitor arm and 43% in the chemotherapy arm.

In the CheckMate743 study, the checkpoint inhibitor arm showed better control of the disease-associated symptoms anorexia (HR: 0.51), fatigue (HR: 0.43), pain (0.55), dyspnoea (HR: 0.75) and cough (HR: 0.78) and a better general quality of life measured in the standardized questionnaires LCSS-Meso ASBI (HR: 0.52) and LCSS-Meso 3-IGI (HR: 0.61) [38].

Since the study met the primary endpoint (improvement in overall survival in the entire study population), patients can benefit from the possibility of a longer-lasting treatment response and symptom control and quality of life were more favorable in the checkpoint inhibitor arm, treatment with nivolumab and ipilimumab can be considered as a possible treatment option for both histological subtypes. However, for patients with a high pressure of treatment and need of a remission and epithelioid histology, treatment with cisplatin and pemetrexed should continue to be used as the standard of care based on the data presented above [33]. Patients with a contraindication to checkpoint inhibitor therapy should also receive cisplatin and pemetrexed as first-line therapy if there are no contraindications [33].

In patients with very significant comorbidities, a very severely reduced general condition or refusal of therapy by the patient, it may be appropriate, as part of a joint, individual decision by the patient and therapist, not to carry out active tumor therapy but to pursue a purely palliative concept of "best supportive care". However, this is always an individual decision for which no generally valid recommendations can be made due to a lack of randomized data.

At the time of writing this guideline, there are no evaluated phase II or III studies on treatment options after progression under first-line therapy with checkpoint inhibitors.

For patients who have not received treatment with nivolumab and ipilimumab as first-line therapy in the non-operable disease situation, treatment with nivolumab and ipilimumab should be considered as part of an "off-label use" due to the overall good data from the CheckMate743 study [37], in the absence of contraindications. An application to the payer is required to secure cost coverage.

In the event of progression during/after treatment with ipilimumab and nivolumab, treatment with cisplatin and pemetrexed should be administered for up to six cycles, for which a possible overall survival of 12.1 months has been described in first-line therapy [33], see Chapter 6.1.1 Maintenance treatment with pemetrexed showed no clinically relevant or statistically significant advantage in progression-free or overall survival in a randomized phase II trial (CALGB 30901) [39] and cannot currently be recommended. Switch maintenance with gemcitabine after first-line treatment with platinum and pemetrexed showed a prolongation of median progression-free survival from 3.2 to 6.2 months (HR: 0.44; p-value <0.0001) compared to best supportive care [40]. However, the data for a general recommendation of switch maintenance therapy with gemcitabine are not yet sufficiently robust.

In a multicenter retrospective analysis, re-exposure to pemetrexed at progression showed a disease control rate of 66% with a reduction in pain in 43% of patients, a time to progression of 5.1 months and an overall survival of 13.6 months in patients with a treatment response of at least 6 months to first-line treatment with platinum and pemetrexed [41]. Another multicenter, retrospective analysis by Zucali et al. showed a disease control rate of 70.7%, a progression-free survival of 6.2 months and an overall survival of 10.6 months for patients previously treated with pemetrexed [42]. In this retrospective analysis, patients pretreated with pemetrexed also received second-line therapy consisting of pemetrexed and a platinum derivative [42]. The group of patients who were re-treated with platinum and pemetrexed achieved a longer median overall survival (13.4 vs. 4.2 months; p-value <0.001) and a longer median progression-free survival (6.4 vs. 2.4 months; p-value = 0.003) compared to patients treated with pemetrexed as a single agent.

A case series of four patients who had been treated with platinum and pemetrexed in first-line therapy described partial remission and stable disease in three cases after re-therapy with platinum and pemetrexed [43].

Another case series described a progression-free survival of 5.0 and 8.2 months in four comparable patients who responded to re-therapy with platinum and pemetrexed [44]. A single-arm observational study showed a median overall survival of 10.5 months and a median progression-free survival of 3.8 months in 31 patients who had been re-treated with platinum and pemetrexed (16 patients) (second or higher line of therapy) [45]. The duration of progression-free and overall survival correlated with the duration of response to first-line treatment with platinum and pemetrexed [45].

This means that patients who have achieved a response or disease stabilization period of at least 6 months following treatment with platinum and pemetrexed can be re-exposed to pemetrexed as a monosubstance or in combination with a platinum derivative in the event of progression. The decision as to whether treatment should be carried out as monotherapy or combination therapy should depend on the presence of side effects from the previous line of therapy, e.g. polyneuropathy or hypoacusis, as well as comorbidities and the patient's general condition.

Patients who have achieved a treatment response or disease stabilization of less than 6 months under treatment with platinum and pemetrexed, or who cannot receive treatment with pemetrexed due to contraindications, should be treated with vinorelbine or gemcitabine as monotherapy or in combination [46, 47, 48, 49, 50,51]. The advantage or disadvantage of combination therapy compared to monotherapy has not been proven by randomized data.

In the randomized phase 2 VIM study, oral vinorelbine and active symptom control provided a statistically significant benefit in progression-free survival of 4.2 versus 2.8 months [HR 0.60; p = 0.002)] [50].

For vinorelbine, a median progression-free survival of 1.7 and 2.3 months and a median overall survival of 5.4 and 6.2 months have been documented in two retrospective analyses in the second or higher line of therapy [46, 47].

In a retrospective analysis, monotherapy with gemcitabine in the second or more advanced line of therapy resulted in a progression-free survival of 1.6 months and a median overall survival of 4.9 months [46].

The randomized phase II RAMES study compared gemcitabine plus placebo with a therapy consisting of gemcitabine and the anti-VEGF antibody ramucirumab in second-line therapy [48]. In this study, the median overall survival for gemcitabine and placebo was 7.5 months compared to 13.8 months in the gemcitabine and ramucirumab study arm (HR: 0.71; p-value 0.028). In the gemcitabine and ramucirumab arm, median progression-free survival was 6.4 months compared to 3.3 months in the gemcitabine and placebo arm (HR: 0.79; p-value= 0.082).

However, at the time of writing this guideline, there is no approval for ramucirumab in pleural mesothelioma in Germany, Austria and Switzerland (off-label use).

The randomized phase III trial ETOP9-15 (PROMISE-Meso trial) compared a chemotherapy arm in which either gemcitabine or vinorelbine (investigator's choice) was administered with the PD-1 inhibitor pembrolizumab [51]. Median progression-free survival was 3.4 months in the gemcitabine or vinorelbine arm compared to 2.5 months in the pembrolizumab arm (HR: 1.06; p-value= 0.76). A median overall survival of 12.4 months was reported in the gemcitabine or vinorelbine arm compared to 10.7 months in the pembrolizumab arm (HR: 1.12; p-value = 0.59).

The anthracyclines doxorubicin and epirubicin have been described to be effective in non-resectable pleural mesothelioma [52, 53, 54, 55]. Due to more effective substances with a better study situation, doxorubicin or epirubicin are now only administered as monotherapy, if at all, in advanced therapy situations after the failure of checkpoint inhibitors, platinum derivatives with pemetrexed, gemcitabine and vinorelbine.

Doxorubicin showed a median overall survival of 8.2 and 10 months in two phase III trials in first-line therapy [52, 53]. Epirubicin showed a median overall survival of 7.5 and 10 months and a response rate of 5% and 15% in two single-arm phase II trials in first-line therapy [54, 55].

Due to the limited efficacy of treatment options in the second and later lines of therapy for pleural mesothelioma, it is generally recommended that patients be included in clinical trials.