Radiation Oncology: A Question-Based Review

Pleural Mesothelioma

Steven H. Lin and M. Kara Bucci

image Background

In what body sites does mesothelioma arise?

Mesothelioma commonly arises in the pleura but also occurs in the peritoneum, pericardium, and tunica vaginalis testis.

What is the most common cause of mesothelioma?

The highest risk factor for developing mesothelioma is asbestos exposure (amphiboles [rodlike] > chrysotile [serpentine form]). Asbestos is commonly found in insulation material, brake pads, and shipyards.

What is the major difference between the incidence of mesothelioma in the U.S. vs. the developing world?

B/c of early adoption of asbestos regulations, the incidence of mesothelioma in the U.S. peaked in 2004 and has subsequently declined. The incidence has not yet peaked in the developing world and is not expected for the next 10–20 yrs.

What is the estimated latency between asbestos exposure and mesothelioma?

The estimated latency between asbestos exposure and mesothelioma is 20–40 yrs. (Lanphear BP & Buncher CR, J Occup Med 1992)

Approximately how many cases of malignant mesothelioma are diagnosed in the U.S. annually?

~2,500–3,000 cases/yr of malignant mesothelioma in the U.S. (MMWR, CDC 2009)

What % of mesothelioma cases are related to asbestos exposure?

~70%–80% of cases have documented asbestos exposure.

What is lifetime risk of mesothelioma for someone with an occupational asbestos exposure Hx?

The lifetime risk with asbestos exposure ~10%.

Does smoking cause mesothelioma?

No. Smoking alone is not associated with mesothelioma, but smoking increases the risk associated with asbestos exposure.

Is there a gender predilection for mesothelioma?

Yes. Males are more commonly affected than females, likely related to occupational exposure differences.

At what age does the incidence of mesothelioma peak?

The incidence does not peak. It continuously increases with age.

What are the 3 most common histopathologic subtypes of mesothelioma in decreasing order of frequency?

Histopathologic subtypes of mesothelioma: epithelioid (40%) > mixed or biphasic (35%) > sarcomatous or mesenchymal (25%)

What are some common genetic changes seen in mesothelioma?

Loss of tumor suppressor genes p16, p14, and NF-2 are common genetic changes in mesothelioma.

image Workup/Staging

What are the 2 most common initial presenting Sx of mesothelioma?

Dyspnea and nonpleuritic chest pain

What is a common presentation of mesothelioma?

Recurrent pleural effusion and/or pleural thickening found incidentally on CXR

What should be present for the initial workup of a pleural-based mass seen on CXR?

Pleural-based mass initial workup: H&P, CBC, CMP, serum soluble mesothelin-related peptide and osteopontin levels (optional), CT chest + contrast, thoracentesis for cytology, and pleural Bx. Consider talc pleurodesis or a pleural catheter for management of effusion.

What is the preferred manner for pleural Bx in the workup of possible mesothelioma?

Video-assisted thorascopic surgery (VATS) (preferred), open Bx, or CT-guided core Bx

What additional workup should be done with a Dx of malignant mesothelioma?

Malignant mesothelioma workup: CT C/A/P + contrast, PET/CT, and MRI chest to determine if there is chest wall (CW) or diaphragmatic invasion. Consider mediastinoscopy or endobronchial US for suspicious nodes. Consider laparoscopy to r/o transdiaphragmatic extension. Use VATS to r/o contralat Dz, if necessary. PFTs are done to assess lung function.

How does malignant mesothelioma appear on a CT of the thoracic chest?

On CT of the thoracic chest, malignant mesothelioma appears as pleural thickening with involvement of interlobar fissures/atelectasis, with possible pleural plaques and calcification.

What is the DDx of tumors of the pleura?

Primary tumors (benign or malignant), or more commonly, metastatic Dz. Malignant tumors include mesothelioma, sarcomas, and mets.

What is the diagnostic yield of mesothelioma from the fluid cytology of the pleural effusion?

Fairly poor, only ~23%. Often, cytology finds atypical mesothelial cells only.

With a needle Bx, what entity is often confused with mesothelioma?

Adenocarcinoma (metastatic) is often confused with mesothelioma.

What pathologic features distinguish mesothelioma from adenocarcinoma?

1.     Mesothelioma is negative for periodic acid-Schiff stain, mucicarmine stain, carcinoembryonic antigen, and Leu-M1. It is positive for calretinin, vimentin, WT1, and cytokeratin.

2.     In mesothelioma, electron microscopy reveals that cells have long microvilli, in contrast to adenocarcinomas, which have short microvilli.

What biomarker is elevated in mesothelioma?

SRMP and osteopontin in serum. It may be elevated in >80% of pts.

What is the AJCC 7th edition (2009) T staging of mesothelioma?

1.     Tis: CIS

2.     T1a: limited to ipsi parietal pleura, no visceral pleural involvement

3.     T1b: +ipsi parietal pleura and focal involvement of visceral pleura

4.     T2: involves ipsi pleural surfaces with at least 1 of the following: (a) confluent visceral pleural tumor, (b) invasion of diaphragmatic muscle, or (c) invasion of lung parenchyma

5.     T3: involves any ipsi pleural surfaces with at least 1 of the following: (a) invasion of endothoracic fascia, (b) invasion into mediastinal fat, (c) solitary focus of tumor invading soft tissues of CW, and (d) nontransmural involvement of pericardium

6.     T4: involves any ipsi pleural surfaces with at least 1 of the following: (a) diffuse or multifocal invasion of soft tissues of CW, (b) any rib involvement, (c) invasion through diaphragm to peritoneum, (d) invasion of any mediastinal organs, (e) direct extension to contralat pleura, (f) invasion into spine, (g) extension to internal surface of pericardium, (h) pericardial effusion with +cytology, (i) invasion of myocardium, and (j) invasion of brachial plexus

Describe the N staging of mesothelioma.

1.     N1: mets involving bronchopulmonary or hilar nodes

2.     N2: mets to ipsi mediastinum (MN) or to subcarinal or internal mammary nodes

3.     N3: mets to contralat MN, internal mammary nodes, or hilar LNs, or to ipsi or contralat supraclavicular nodes

Describe the overall stage groupings for mesothelioma.

1.     Stage IA: T1aN0

2.     Stage IB: T1bN0

3.     Stage II: T2N0

4.     Stage III: T1-2N1-2 or T3N0-2

5.     Stage IV: T4 or N3 or M1

Which histologic subtype has a worse prognosis?

The sarcomatous type has the worse prognosis.

Name the 4 EORTC poor prognostic factors for mesothelioma.

EORTC poor prognostic factors for mesothelioma:

1.     WBC >8.3 × 109/dL

2.     Performance status (PS) 1–2

3.     Sarcomatous histology

4.     Male gender

What are the estimated 1- and 2-yr OS rates for EORTC low- and high-risk mesothelioma?

1.     Low risk: 1-yr OS 40%; 2-yr OS 14%

2.     High risk: 1-yr OS 12%; 2-yr OS 0%

What is the overall MS seen in mesothelioma?

Overall, MS is 4–12 mos.

Is death from mesothelioma usually due to local progression or DM?

Death is usually due to local progression resulting in respiratory failure or infection.

image Treatment/Prognosis

What is the Tx paradigm for resectable mesothelioma?

Resectable mesothelioma Tx paradigm:

1.     Extrapleural pneumonectomy (EPP) → chemo → hemithorax RT or

2.     Neoadj chemo → EPP → hemithorax RT

What is the Tx paradigm for unresectable mesothelioma?

Unresectable mesothelioma Tx paradigm: combination chemo

What are the typical recommended postop RT doses after resection for mesothelioma?

1.     −Margin: 50 Gy

2.     Close/+ margin: 54–60 Gy

3.     Gross Dz: >60 Gy (if possible)

What are the chemos of choice for the Tx of mesothelioma?

1.     Preferred Tx includes the combination chemo of choice incorporated into trimodality regimens utilizing antifolate agents such as pemetrexed (Alimta)/cisplatin or gemcitabine/cisplatin.

2.     Pemetrexed/cisplatin is based on an RCT (Vogelzang NJ et al., JCO 2003) of unresectable mesothelioma pts to cisplatin vs. pemetrexed/cisplatin. There was improved response rate (17% vs. 41%) and survival (9 mos vs. 12 mos) with pemetrexed/cisplatin. This trial led to FDA approval for use in unresectable Dz.

3.     Cisplatin/gemcitabine is based on several phase II studies.

What % of mesothelioma pts are surgically resectable at Dx?

<5% of pts are surgically resectable at Dx.

What TNM stage of Dz determines surgical resectability using EPP for mesothelioma?

T1-3N0-1. Therefore, mediastinoscopy to r/o N2-N3 Dz will be important.

What clinical factors are important to consider for proper pt selection for EPP?

Factors important for proper EPP pt selection:

1.     PS 0–1

2.     Predicted postop FEV1 >1.0 L

3.     PaO2 >65 mm Hg (on room air)

4.     PaCO2 <45 mm Hg (on room air)

5.     Ejection fraction >40%

6.     Mean pulmonary arterial pressure <30 mm Hg

7.     Epithelial histology

8.     No T4, N2-N3, or M1 Dz

9.     Able to tolerate trimodality therapy

What is removed with an EPP for mesothelioma?

Parietal pleura, lung, mediastinal nodes, pericardium, and ipsi diaphragm, with a graft to prevent herniation of abdominal contents through the diaphragmatic defect. Mediastinal nodal dissection should be done.

When is a decortication/pleurectomy a preferred procedure over EPP in a pt with mesothelioma?

Decortation/pleurectomy is preferred over EPP in pts with more advanced Dz (↑ nodal Dz, areas of local invasion), mixed histology, and medically high-risk pts. Periop mortality is 2%–5%.

What is the mortality rate of EPP? What is the MS for mesothelioma after EPP?

The mortality rate of EPP ranges from 4%–31% and depends largely on the experience of the center and preop selection. MS in most series is 4–20 mos.

What study supports adj RT after EPP for mesothelioma?

MSKCC phase II trial with hemithorax RT to 54 Gy after EPP improved LC and OS compared to historical controls (Rusch V et al., IJROBP 2003). 2-yr OS was 33%. MS was 34 mos for stages I–II and 10 mos for later stages.

What study supports the role of trimodality therapy for mesothelioma?

Harvard retrospective review (Sugerbaker D et al., J Thorac Cardiovc Surg 1999) of 183 pts treated with EPP + adj chemo (Cytoxan/Adriamycin/cisplatin [CAP] or carboplatin/Taxol) + RT → adj chemo. Overall MS was 19 mos; 5-yr OS was 15%. The suggested long-term survival in the most favorable subgroup of 2-yr OS was 68%, 5-yr OS was 46%, and MS was 21 mos. 3 factors predicted for best outcomes: epithelial histology, negative resection margin, and negative extrapleural nodes.

Name 2 RT techniques used for adj Tx of mesothelioma after EPP.

AP/PA or IMRT to 45–54 Gy, with a boost to 60 Gy for a close/+ margin

Describe conventional RT field borders for adj RT Tx of mesothelioma after EPP.

1.     Superior: T1

2.     Lateral: skin

3.     Medial: if right-sided, ipsi edge of vertebral body or 1.5 cm beyond edge of vertebral body if MN is positive for Dz; if left-sided, 1.5 cm into ipsi edge of vertebral body

4.     Inferior: L2

Need to block critical structures such as the heart and liver and supplement blocked areas with electrons.

For right-sided tumors, the abdominal block is present throughout with electron supplementation at 1.53 Gy/fx (+scatter).

For left-sided tumors, the kidney is blocked throughout, and the heart block is present after 19.8 Gy. The spinal cord is blocked after 41.4 Gy by shifting the medial border to the ipsi edge of the vertebral body.

Include scars with bolus in the field and boost if necessary.

How is IMRT delivered for the adj Tx of mesothelioma?

MDACC experience (Ahamad A et al., IJROBP 2003, 2004), using 13–27 fields with 8–11 angles, with ~100 segments/field. Target volume was the entire hemithorax, all surgical clips, all sites of instrumentation, and the ipsi MN; initial dose to 45–50 Gy, with a boost to 60 Gy for a close/+margin. 2-yr survival was 62%, and 3-yr DFS was 45% for LN–, epithelioid histology. 5 pts with stage I Dz had 3-yr DFS of 100%.

Under what circumstances should pts be spared the morbidity of an EPP?

Subhistologies of sarcomatous or mixed type, involvement of the mediastinal LNs, large tumor burden, extension to extracapsular sites. These are all poor preop factors that have very poor DFS and OS and may not benefit from EPP. Palliative procedures should be considered.

If the pt is not a good candidate for EPP, pleurectomy or decortication has been advocated by some investigators. What does the procedure entail, and what are the outcomes of the procedure?

Decortication or pleurectomy involves stripping of the pleura from the apex of the lung to the diaphragm, removing pericardium and parietal pleura. MS is 6.7–21 mos.

What is often recommended after a decortication/pleurectomy procedure for mesothelioma?

B/c of the high LR rate, adj RT is advocated (Gupta V et al., IJROBP 2005). 125 pts were treated with pleurectomy → interstitial RT or EBRT at MSKCC. MS was 13.5 mos; 2-yr OS was 23%. Those with epithelial-type or earlier-stage Dz did better. Pts receiving <40 Gy, those with left-sided Dz, those with use of an implant, or those with a nonepithelioid histology did worse. LC rate was 40%. However, there were increased rates of toxicity (12 pts with pneumonitis, 8 pts with pericarditis). 2 pts died from grade 5 toxicity within 1 mo of Tx.

What is a palliative surgical procedure to consider for the management of poor-risk mesothelioma?

Pleurodesis with talc can be considered as palliative care with poor-risk mesothelioma.

What is the Tx paradigm for unresectable mesothelioma (stage III or IV)?

Unresectable mesothelioma Tx paradigm: chemo with cisplatinum/pemetrexed or cisplatinum/gemcitabine

What is the role of RT in unresectable mesothelioma Dz?

Palliative RT is used only for temporary pain relief. Use either 30 Gy in 10 fx or 20 Gy in 5 fx. In retrospective studies, the 2 regimens gave similar palliation.

What RT doses are used for palliation of chest pain associated with skin nodules in the CW?

Daily doses <4 Gy appear more efficacious than fx dose <4 Gy, for a total dose of 20–40 Gy.

What is the role of RT after invasive procedures for mesothelioma? What study evaluated the role of prophylactic RT, and what were the results?

Historically, RT was given to areas of invasive procedure to avoid needle tract seeding with tumor. RT was 7 Gy × 3, for a total of 21 Gy. However, O–Rourke et al. (Radiother Oncol 2007) showed in a randomized trial that prophylactic RT to drain sites did not statistically reduce the rate of seeding. However, b/c recurrence is morbid and this is easy to do, it is still generally done.

image Toxicity

What is the estimated contralat lung V20 associated with the development of fatal pneumonitis in the Tx of mesothelioma?

RR was 42 for fatal pneumonitis if the V20 was >7% in the contralat intact lung based on a retrospective review from MDACC. (Rice DC et al., Ann Thorac Surg 2007)

What are the dose-volume constraints for the contralat lung in RT for mesothelioma?

In the remaining lung, with the V20 <20% (preferably <10%), mean lung dose > 8.5 Gy, V5 <50%.

What is the dose constraint for the liver? Heart? Spinal cord? Esophagus? Kidney?

1.     Liver: V30 <30%

2.     Heart: V40 <50%

3.     Spinal cord: V45 <10%, no volume >50 Gy

4.     Esophagus: V55 <30%

5.     Kidney: V15 <20%