Trimodality Treatment for Malignant Pleural Mesothelioma

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Malignant pleural mesothelioma is a deadly cancer especially due to environmental asbestos and erionite exposure. It is estimated that around 30,000 people worldwide suffer from malignant pleural mesothelioma every year. It is estimated that the incidence of malignant mesothelioma disease will decrease starting from the 2030s.

Treatment Logic Of Malignant Pleural Mesothelioma

The only compromised treatment for Malignant Pleural Mesothelioma method is chemotherapy. Today’s median survival is approximately 12 months with two-drug therapy consisting of pemetrexed and cisplatin and one-year survival rate is more high. In the last studies, the response rate was %74.3 in 745 patients receiving pemetrexed and cisplatin. Only %2 of patients had complete response, and partial response was observed in %24.3.

The low rates of chemotherapy response and survival in Malignant Pleural Mesothelioma have led to the investigation of other treatment modalities.

Development of surgical methods of Malignant Pleural Mesothelioma was completed in 1990s. In a patient group who had previously undergone only pleurodesis and partial pleurectomy, radical pleurectomy and extrapleural pneumonectomy has become feasible with low mortality rates.

Trimodality treatment aims to combine surgery, radiotherapy and chemotherapy. Trimodality treatment targets macroscopic tumor as well as to achieve local control by radiotherapy and to reduce the incidence of distant metastases by chemotherapy or to eliminate micrometastases.

This treatment method is different mixtures were examined for treatment efficacy. There are two main methods of treatment of trimodality;

1. Sequential radiotherapy and chemotherapy after extrapleural pneumonectomy:

In this method, radiotherapy is applied at different doses and to the entire hemithorax, and chemotherapy and it is usually performed with gemcitabine-cisplatin or pemetrexed-cisplatin combination. This form of treatment is the most commonly used and long period follow-up is required.

2. Neoadjuvant extrapleural pneumonectomy and after chemotherapy radiotherapy:

In this method, extrapleural pneumonectomy is applied after gemcitabine or pemetrexed-cisplatin treatment and radiotherapy starts one month after surgery after neoadjuvant treatment. Extrapleural pneumonectomy is still not well accepted. Low response rates of chemotherapy in Malignant Pleural Mesothelioma causes patients to progressive during treatment.

Some experimental treatment methods such as radical pleurectomy, immunotherapy, intrapleural hot chemotherapy and anti-angiogenesis treatment are implemented by placing them in various protocols.

Choosing Of The Right Patient

The applicability of trimodality treatment in Malignant Pleural Mesothelioma is limited. Adequate pulmonary and cardiac functions and early tumor stage is necessary. This means %10-20 of the patient group would be available to receive this treatment option. In addition, trimodality treatment is a long-lasting treatment that negatively affects the quality of life for patients. Following extrapleural pneumonectomy, in the absence of a complication, the patient is rested for a month. Usually after surgery four to six weeks radiotherapy begins and hemithoracic radiotherapy lasts four to six weeks. After completion of radiotherapy the patient is rested for one month and two to four cycles of chemotherapy are applied. Therefore, this process takes six months and in the event of any complications, treatment may be interrupted or not performed at all.

In case of neoadjuvant therapy, the patient will be treated within four to six weeks following chemotherapy surgery. Patients should be initially informed about the treatment process.

Surgical staging:

For surgical staging; computed tomography, thoracic magnetic resonance (MR) imaging, positron emission tomography (PET) or PET-CT are the main radiological methods (Figure 1-4).

Preoperative irreversibility criteria are listed below:

  1. Invasion of the posterior or thoracic wall (Figure 5).
  2. Mediastinal aged tissue, large vessel, esophagus invasion (Figure 6).
  3. Invasion of transdiaphragmatic abdominal organs (Figure 7).
  4. Intrapericardial myocardial or atrial invasion (Figure 8).
  5. Cytologically tumor-positive pericardial or peritoneal effusion.

Recent research shows radiographically narrowed intercostal intervals and volume loss hemithorax may be among the criteria of irresectability. Even if there is no obvious rib invasion.

Figure 1. Diffuse pleural thickening in Malignant Pleural Mesothelioma case. Thickening is noted in the thoracic wall and mediastinal section.

Figure 2. Magnetic resonance imaging of the thorax in a patient with Malignant Pleural Mesothelioma . Tumoral thickening of the fissure is remarkable. This patient was treated with trimodality and developed abdominal recurrence at 59 months postoperatively.

Figure 3. FDG-PET images in a patient with right Malignant Pleural Mesothelioma. Pleura widespread involvement throughout.

Figure 4. PET-CT image of Malignant Pleural Mesothelioma holding the posterior of the right hemithorax, oblique and horizantal fissures.

Figure 5. Tumor invasion of the intercostal muscles in the anterior thorax (white arrow) is seen in the patient with Malignant Pleural Mesothelioma

Figure 6. Patient who developed Malignant Pleural Mesothelioma due to erionite exposure. MR images show vena cava invasion.

Figure 7. Left Malignant Pleural Mesothelioma patient shows transdiaphragmatic and splenic invasion.

Figure 8. Intrapericardial tumor and atrium in a patient with Malignant Pleural Mesothelioma invasion.

In the presence of multislice CT, thoracic MRI is not necessary. But In cases where CT images are insufficient MRI is a very effective method for demonstrating transdiaphragmatic and chest wall invasion.

Preoperative evaluation:

Patients over 70 years of age are unsuitable for trimodality treatment. The size of the surgery and the comorbidities usually do not allow applicability of this treatment more than 70 years old.

Pulmonary function test is performed before the surgery. In the pulmonary function test, the minimum pneumonectomy criterion for the patient is should be at least 1 L/sec of forced vital capacity (FEV1) after surgery. This value is different from other pneumonectomies, since hemidiaphragm is removed when extrapleural pneumonectomy is performed and this affects the operation of the other hemidiaphragm. Electro and echocardiography are performed for cardiac evaluation and sampling is performed in the presence of pericardial effusion. Smoking and exertion test is performed in patients with a history of hypertension.

Surgical Procedure:

The idea of surgical treatment in Malignant Pleural Mesothelioma is completely remove the tumors from the affected areas because survival in Malignant Pleural Mesothelioma tumor cell is the key for the treatment.

Two surgeries method for curative treatment of Malignant Pleural Mesothelioma can be applied.

The first one is extrapleural pneumonectomy and the second is radical pleurectomy.

With extrapleural pneumonectomy:

The lung, parietal pleura, pericardium and hemidiaphram (Figure 9) is removed and reconstruction of the diaphragm and pericardium is performed.

With radical pleurectomy:

Parietal, except lung and visceral pleura, hemidiaphragm and pericardial tissue is removed. Usually no reconstruction of the diaphragm or pericardium is performed.

Macroscopic complete resection with extrapleural pneumonectomy is higher. Therefore extrapleural pneumonectomy respiratory reserve is sufficient in all Malignant Pleural Mesothelioma patients. Because when pleurectomy is performed, pulmonary fissure or lung invasion macroscopic tumor remains in the thorax. Radical pleurectomy with limited respiratory reserve in elderly and very early stage mesothelioma patients.

Radiotherapy:

High-dose radiotherapy to the hemithorax after extrapleural pneumonectomy in the treatment of trimodality local control is very important. In this method, hemithorax one section per day in 1.8 Gy radiotheraphy, 54 Gy radiotherapy five days a week is applied.

The presence of the lung in pleurectomy cases does not allow the application of radiotherapy to the thoracic cavity at the above mentioned doses and ineffective. Radiotherapy can be applied to only pleurectomy patients.

Chemotherapy:

Chemotherapy in trimodality treatment have two options:

  • Neoadjuvant
  • Adjuvant

Pemetrexed-cisplatin combination is the most effective treatment method in the primary treatment of extrapleural pneumonectomy. In a study in 2003 there are different combinations are used.

  • Gemcitabine and cisplatin,
  • Pemetrexed and cisplatin,
  • Cisplatin alone,
  • Raltitrexed and cisplatin.

Among these combinations the best median survival was 12.1 months with pemetrexed and cisplatin combination. Three cycles of pemetrexed and cisplatin as adjuvant in the treatment of trimodality combination is the most effective treatment method in today ‘s data.

Multicenter study is published in Switzerland in 2007, neoadjuvant chemotherapy was applied as a combination of gemcitabine and cisplatin with three cycles. The neoadjuvant treatment protocol using pemetrexed and cisplatin combination is multicenter in the USA and summarized the initial results. In the published study, 77 patients were included in this study and the response rate was %32.5. %46 of the patients remained stable during chemotherapy. The median survival of 57 patients with extrapleural pneumonectomy was 21.9 months. These results are promising for neoadjuvant treatment.

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