Pleural Mesothelioma

Background

Mesothelioma arises in the pleura most frequently, but can also be found in the peritoneum, pericardium and tunical vaginalis. The highest risk factor for developing mesothelioma is asbestos exposure. Asbestos is commonly found in insulation material, brake pads and shipyards. Friable asbestos is the most dangerous (dust). Radiation has also been associated with mesothelioma (Thorotrast -- thorium dioxide exposure). Disease latency times between asbesto dust exposure and appearance more than 15 years with a peak at 30 - 40 years. The median latency time was 32 years. There are two forms of asbestos: amphiboles (rod-like) and chrysotile (serpentine). Amphiboles are "blue" asbestos crocidolite types. Crocidolyte are needle like rods that burrow into tissue and are more associated with the development of mesothelioma than chrysolite which is a serpentine type asbestos. 70% - 80% of cases have documented asbestos exposure. The lifetime risk with occupational asbestos exposure is about 10%.

Mesotheliomas affect 2,500 - 3,000 per year, in the US. The incidence has begun a slow decline as regulations initiated in the 1930s in the US and UK with a peak incidence in the US/UK in 2004 and a decline in rates since then. In the developing world, the rates have not yet peaked but will be expected to peak in the next 10 - 20 years.

Smoking per se does not cause mesothelioma, but smoking increases the risks associated with asbestos exposure, and was used in a cigarette filter for a period in the 20th century. Males are more commonly affected, largely due to the occupational exposure risk in the largely male dominated shipbuilding industries, and mining and manufacturing industries. There is no age peak with mesothelioma, risk continouously increases with age.

Pathology and Genetics

There are three most common histologic subtypes of mesothelioma seen:

1. Epitheliod (40%)
2. mixed/biphasic (35%)
3. sarcomatous/mesenchymal (25%) (worst prognosis)

Malignant mesothelioma may be associated with loss of p16, p14 and NF-2 tumor suppressor genes.

Workup and Staging

The most common presenting symptoms are dyspnea and non-pleuritic chest pain. The most common presentation of mesothelioma is recurrent pleural effusion and/or pleural thickening seen incidentally on CXR.

If a pleural based mass is seen on initial imaging, the following workup should be performed:

1. H&P
2. Labs: CBS, CMP, seum soluble mesothelin related peptide and osteopontin levels (optional)
3. Imaging: CT Chest with contrast
4. Thoracentesis for cytology and pleural biopsy
5. Consider talc pleurodesis or catheter for management of effusion

Pleural biopsy is preferably obtained via VATS, or can also be obtained with open biopsy or CT guided core needle biopsy.

Once a tissue diagnosis of malignant mesothelioma is in hand, PETCT and CT of the chest, abdomen and pelvis is necessary with contrast to identify chest wall or diaphragmatic invasion. MRI of the chest may also be indicated. Consider an medistinoscopy or endobronchial ultrasound for suspicious nodes. Laparoscopy should be considered if there is risk of transdiaphragmatic extension. VATS is helpful to rule out contralateral mediastinal disease. PFTs are necessary to assess lung function.

Other diseases in the pleural include metastatic disease, sarcomas as well as mesotheliomas.

Malignant mesotheliomas appear on chest CT as a pleural thickening with involvement of the interlobar fissures, or atelectasis with possible pleural plaques and calcification.

Pleural thorocentesis has a relatively poor diagnostic yield, finding only 23% of disease. Core needle biopsy mesothelioma can be mistaken for adenocarcinoma. Therefore special stains are indicated to confirm the diagnosis.

Staging

AJCC T Staging

T1a	Tumor limited to ipsilateral parietal pleura ± medastinal pleural involvement ± diaphragm involvement: no invovlement of visceral pleura
T1b	with involvement of visceral pleura
T2	tumor involving each of the ipsilateral pleural surfaces (parietal, medastinal, diaphragmatic and visceral pleura with at least one of these features: involvement of diaphragm tumor extension from visceral pleura into the underlying pulmonary parenchyma
T3	Locally advanced, potentially resectable tumor involving all of the surfaces of the ipsilateral pleura (parietal, mediastinal, diaphragmatic and visceral: involvement of the endthoracic fascia extension into the mediastinal fat solitary completely resectable focus of tumor extending into the soft tissues of the chest wall non-transmural involvment of the pericardium
T4	Locally advanced, technically unresectable tumor diffuse extension or multifocal masses of tumor in the chest wall ± associated rib destruction direct transdiaphragmatic extension into the peritoneum direct extension into the contralateral pleura direct extension of tumor into the mediastinal organs direct extension of tumor into the spine tumor extending through the internal surface of the pericardium ± pericardial effusion or tumor involving the myocardium.

AJCC 2010 N Staging

N1	Ipsilateral bronchopulmonary or hilar lymph nodes
N2	Subcarinal or ipsilateral mediastinal nodes
N3	Contralateral mediastinal, internal mammmary nodes; any supraclavicular nodes

M Staging

M0	No mets
M1	distant mets

AJCC Stage Groupings

AJCC Stage Grouping

T	N0	N1	N2	N3	M1
T1a	IA	III	III	IV	IV
T1b	IB	III	III	IV	IV
T2	II	III	III	IV	IV
T3	III	III	III	IV	IV
T4	IV	IV	IV	IV	IV

Prognosis

EORTC prognosis factors identified four prognostic factors predicting poor prognosis:

The estimated survival for malignant mesothelioma is poor. The median survival overall is 4 - 12 months. Death usually results from local progression resulting in respiratory failure or untreatable progressive infection.

The estimates of survival for low and high risk mesothelioma are:

1. Low Risk: OS-1: 40%; OS-2: 14%
2. High Risk: OS-1: 12%; OS-2: 0%

Treatment and Outcomes

The general treatment paradigm for Resectable malignant mesothelioma is:

1. Extrapleural pneumonectomy → chemotherapy → hemi-thorax radiation --or--
2. Alternatively: Neoadjuvant chemotherapy → extrapleural pneumonectomy → hemithorax radiation

The general treatment paradigm for unresectable malignant mesothelioma combination chemotherapy.

Surgery

The vast majority of mesotheliomas are unresectable. Less than 5% are found to be resectable at diagnosis. Stage T1-T3 N0-1 are considred technically resectable, but medistinoscopy is essential to insure there are no N2/N3 nodes which would make the disease unresectable.

An Extrapulmonary pneumonectomy removes the parietal pleura, lung, mediastinal lymph nodes, pericardium and ipsilateral diaphragm. A graft is placed in the excised diaphragm to prevent herniation of abdominal contents into the chest cavity. Mediastinal LND should be performed.

The mortality rate for EPP ranges from 4% to 31% and depends on proper patient selection and the experience of the center. Median survival in most series is 4 - 20 months.

Extrapulmonary pneumonectomy has high morbidity. It should be reserved for patients who are favorable candidates for better post-operative prognosis. Poor pre-operative prognostic factors indicating poor disease free survival and overall survival may not benefit from extrapleural pneumonectomy and should be spared the procedure. Palliative procedures should be considered in the alternative. Factors which portend poor prognosis and outcomes are: sarcomatoid and mixed histologies, mediastinal lymphadenopathy, large tumor burden, extracapsular site extension. If a patients is not a good candidate or will have no substantial benefit from EPP, then decortication pleurectomy should be considered.

A decortication/pleurectomy is preferred over EPP in patients with more advanced disease. More advanced disease is defined as excess nodal disease, areas of local invasion, mixed histology, and medically high risk patients. Peri-operative mortality is 2% - 5%. Decortication pleurectomy involves stripping of the pleura from the lung apex to the diaphragm including the pericardium and parietal pleura. Median survival is 6.7 - 21 months.

Decortication has a high local recurrence rates. For this reason, adjuvant radiation is advocated. (Gupta 2005 IJROBP) studed 125 patients treated with pleurectomy → interstitial RT or EBRT at MSKCC: He found MS 13.5 months and OS-2 was 23% Earlier stage and epitheliod disease did better. Patients receiving < 40 Gy or left sided disease or implant radiotherapy did worse.

Post decortication radiotherapy had increased rates of toxicity in Gupta's study. 12/125 patients had pneumonitis, 8 with pericarditis, 2 died from grade 5 toxicity within 1 month of treatment.

Chemotherapy

The major preferred chemotherapy regimens are combination chemotherapy incorporated into tri-modality regimens using pemetrexed/cisplatin (Alimta--anti-folate) or gemcitabine/CDDP. Pemetrexid use is based on a randomized trial by Vogelzang (2003 JCO) of unresectable mesothelioma.This randomized trial examined cisplatin compared with cisplatin + Alimta and found the response rate improved from 17% to 41%, survival improved from 9 months to 12 months with pemetrexed. Because of the results of this study pemetrexed was approved for unresectable mesothelioma. Gemcitabine/cisplatin efficacy has also been noted on several Phase II trials.

Radiation Therapy

MSKCC Phase II trial of hemithorax RT to 54 Gy (Rusch 2003 IJROBP) after extrapleural pneumonectomy improved local control and overall survival compared to historical controls. OS-2 was 33% and MS was 34 months for Stage I/II and 10 months for later stages.

Harvard Retrospective Review (Sugerbaker 1999 J. Thorac. Cardiovasc. Surg) of 183 patients treated with EPP → adjuvant chemotherapy (cytoxan/adriamycin/cisplatin or carbo/taxol) + RT → adjuvant chemotherapy found improved median survival at 19 months. OS-5 was 15%. The suggested long term survival in the most favorable subgroup of OS-2 was 68%, OS-5 was 46% and median survival was 21 months. Best outcome predictors were: epithelial histology, negative margins, and negative extrapleural lymph nodes.

Radiotherapy techniques

Radiation after Extrapleural pneumonectomy is APPA or IMRT to 45- 54 Gy. A boost to 60 Gy for close or positive margins should be given. Radiation is hemi-thorax.

Borders:

• with the superior border at the top of T1
• lateral border: skin
• Medial Borders:
  • Right sided tumors: ipsilateral edge of the vertebral body or 1.5 cm beyond the vertebral body if mediastinum positive
  • Left sided tumors: 1.5 cm into ipsilateral edge of the vertebral body
• Inferior: L2

Note that there is a need to block critical structures such as the heart and liver and uninvolved lung. Supplement blocked areas with electron boost fields. For right sided tumors block the abdomen and add electrons at 1.53 Gy/fraction under the block . For left sided tumors block the kidney throughout and block the heart after 19.8 Gy. Block the cord at 41.4 Gy by shifting the medial border to the ipsilateral edge of the vertebral body. All scars should be bolused in the field and during the boost if necessary.

IMRT Fields ( MDACC Ahamad 2003 IJROBP) using 13 - 27 fields with 8 - 11 angles and approximately 100 segements per fiewld used the entire hemithorax as a target volume, including all surgical clips, all site of instrumentation, and ipsilateral mediastinum. The initial dose was 45 - 50 Gy, with a boost to 60 Gy for a close or positive margin.

OS-2 was 62% and DFS-3 was 45% for node negative epitheliod histology patients. 5 patients with Stage I disease had DFS-3 of 100%.

Palliation Radiation Therapy

Palliative RT is used only for temporary pain relief. Usual treatments are 30 Gy at 3 Gy/fraction, 20 Gy in 5 fractions, Retrospective studies indicate both fractions work equally well.

For skin nodules causing chest wall pain, doses ≥ 4 Gy appear to be more effective than < 4 Gy/fraction to a total dose of 20 - 40 Gy.

Radiation has been traditionally given after surgical procedures to avoid wound seeding. Tradiationally 7 Gy x 3 was given to a total dose of 21Gy. O'Rourke (2007 Radiother. Oncol) showed in a randomized trial that prophylactic RT to drain sites did not statistically reduce the rates of seeding of those sites.

Other palliative options for mesothelioma include talc pleurodesis for poor risk mesothelioma.

Toxicity

V20 of the contralateral (remaining) Lung:V20 is a key predictor of fatal pneumonitis. Rice MDACC 2007 Ann. Thorac. Surg) reports a relative risk of 42 for fatal pneumonitis if contralateral lung doses was > 7%.

Despite this, the generally accepted dose volume constraints in the remaining lung are V20 < 20% (preferably 10% with a Mean Lung Dose ≤ 8.5 Gy and a V5 dose < 50%

Radiation Oncology Synopsis