Malignant pleural mesothelioma

The malignant pleural mesothelioma is an aggressively growing tumor originating in the pleura. Without therapy this tumor leads to death within a few months. About 80 percent of the cases can be connected to asbestos exposure. Although the use of asbestos is forbidden in Switzerland since the 90s it is expected that the peak of new MPM cases is yet to come in the year of 2020, as from asbestos contact to outbreak of the disease on average 40 years pass by. Additionally recently a genetic predisposition for MPM was detected.


 

A clinical diagnosis of MPM is impossible, as the occurring symptoms such as pain in the chest and respiratory distress are very unspecific. The final diagnosis is made basing on histopathologic (microscopic) examinations of tissue samples. There are three subtypes of MPM: epitheleoid subtype, sarcomatoid subtype and biphasic subtype (a mixture of the two other subtypes). According to the guidelines of the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) a thoracoscopic (by means of thoracoscopy) or open biopsy is recommended, as a cytologic (microscopic) assessment of the frequently occurring pleural effusion is often inconclusive. The performance of a talc pleurodesis at the time of diagnosis is controversially discussed, as a later surgery is thereby made difficult.

The staging is made according to the TNM classification of the International Mesothelioma Interest Group (IMIG), which is basing on the following pathological criteria: definition of expansion, recording of lymph node and distant metastases. For the clinical staging of MPM different imaging techniques are used. Most important is the computer tomography with contrast medium i.v., which typically shows a nodular thickening of the pleura. A PET/CT is preliminarily made to exclude metastases located outside the thorax or to prove that lymph node metastases are present. In total it showed that in clinical staging the local tumor extent is often underestimated. For precise lymph node staging a videomediastinoscopy or the endobronchial ultrasound (EBUS) is recommended. In case of suspicion of contralateral (located in the other part of the thorax) or intraabdominal (located in the abdominal cavity) metastases a contralateral thoracoscopy or laparoscopy should be performed.

There is no treatment recommendation standardized for the treatment of MPM – anyhow it is generally accepted that a monotherapy alone is insufficient for this aggressive tumor. After the last conference of International Mesothelioma Interest Group (IMIG) 2012 a macroscopic complete resection in a multi-modal treatment concept was published as consensus. Most of the centers combine currently the macroscopic complete resection with a neoadjuvant (before the surgery) or adjuvant (after the surgery) chemotherapy. The combination of cisplatin and pemetrexed is considered the gold standard, as thereby the best survival chances (on average twelve months with a response rate of 40%) and the best life quality can be achieved. Gemcitabine has a similar activity, but it is less tolerable.

Surgical procedure

Pleurectomy/decortication or extrapleural pneumonectomy

A macroscopic complete resection is the the overall aim of the procedure and can be achieved with a lung-preserving extended pleurectomy/decortication (P/D) or an extrapleural pneumonectomy (EPP). At the moment there is no scientifically approved answer to the question if EPP or P/D is the more superior surgical  procedure of choice for MPM. EPP, the pleura, lung and the pericardium and the diaphragm are resected. During P/D, there is a difference between the expanded P/D (extraction of pleura from chest wall and lung and resection of the diaphragm and/or the pericardium), a P/D (extraction of the pleura of chest wall and lung without resection of the diaphragm and the pericardium) and a partial pleurectomy (partial extraction of pleura from chest wall and/or lung with leaving parts of the tumor behind).

 

 PD_EPP.jpg

                  Surgical procedure extrapleural pneumonectomy (EPP) 


Clear recommendations for the choice of the surgical procedure are still missing. A lung-preserving procedure (P/D) is very promising, if a macroscopic complete resection can be achieved; but this seems to be rather possible in the early tumor stages. In cases of expanded, infiltrated growth in the lung parynchema a complete macroscopic resection seems to be only feasible in form of an EPP. However the situation is conclusive in patients with limited heart or lung function, reduced general condition or relevant concomitant diseases. In these cases P/D is the most suitable surgery, in particular in early cancer stages, to preserve the lung function. A P/D should also be performed in cases in which it is clear that not the entire tumor mass can be extracted macroscopically (stage IV). Apart from these explicit situations the decision for a P/D or EEP in the stages I, II and II should be made individually considering the tumor volume and condition of the patient. Both interventions – EPP and P/D – take about 5–8 hours and are very demanding surgeries, which should only be performed in centers with appropriate experience and expertise for the entire peri- and postoperative management.

Chemotherapy

In our center we recommend mesothelioma patients with resectable tumors and sufficient functional reserve induction chemotherapy with subsequent tumor resection, if the reevaluation (CT scan of the chestafter chemotherapy) shows a partial remission (reduction of the tumor) or a «stable disease» (consistent tumor size). In total the response to induction chemotherapy lies at about 30 - 40%, the resection rate is at about 70%. An adjuvant chemotherapy concept is also applied in many groups and the survival rates are comparable.

Radiotherapy

Also radiotherapy (RT) as local measure plays an important role in the multi-modal treatment of MPM. An adjuvant RT after an EPP has the advantage that the radiation-sensible lung has been extracted. Other critical organs such as the heart, liver, kidneys and spinal cord as well as the contralateral lung are still at risk. The definitive role of the curative postoperative hemithorax RT after neoadjuvant chemotherapy and EPP was multicentrically examined in Switzerland in a randomized protocol of the Swiss Working Group for Clinical Cancer Research (SAKK), but a definitive recommendation of RT was not concluded.
Promising new techniques such as the intensity modulated radiotherapy (IMRT) have been developed, to increase the precision of RT and to lower toxicity. In a small study in Canada good results have been achieved with an induction radiotherapy before an EPP, but these still have to be confirmed.
The prophylactic RT for prevention of a tumor cell spread along drainage or trocar channels show no significant reduction of the relevant risk of trocar metastases, as a metaanalysis showed. In advanced mesothelioma diseases there is the possibility of local radiotherapy for pain relief.

Localized intracavitary therapy

A relevant problem of MPM treatment is the high rate of local recurrences: for EPP up to 13 - 62%, after P/D even 90%. Localized intracavitary therapy for improvement of the local tumor control is an attractive option. Currently there are different studies with the aim of improving existing, established protocols, such as for example the intracavitary hyperthermic chemotherapy, photodynamic therapy or genetic therapy. These specific therapies have the aim of attacking residual tumor cells after a microscopic complete resection. We currently examine in a phase I study (INFLuenCe-Meso) the safety and efficiency of an intracavitary chemotherapy with cisplatin, coupled with a fibrin glue after P/D or EPP.

Operation sequence:

Application of the chemotherapeutic agent loaded to a fibrin glue carrier on a partially inflated lung after resection of mesothelioma.
 


 


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