Residency · Residency · Radiation Oncology

Malignant Pleural Mesothelioma: Radiation Techniques and Hemithoracic RT

Overview

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer originating from the mesothelial cells lining the pleura. It is strongly linked to asbestos exposure, which accounts for 70-80% of cases. The disease typically manifests after a long latency period, ranging from 20 to 50 years following asbestos exposure. Histologically, MPM is classified into three main subtypes: epithelioid, which comprises 50-70% of cases and carries the best prognosis; sarcomatoid, representing 10-20% of cases and associated with the worst prognosis; and biphasic or mixed, accounting for 20-30%. Despite multimodality treatment, the median overall survival remains limited at 12 to 18 months. Radiation therapy plays a multifaceted role in managing MPM, including adjuvant treatment following surgery, definitive hemithoracic irradiation, and palliation for chest wall pain.

Surgical Approaches and Their Impact on RT

Extrapleural Pneumonectomy (EPP)

Extrapleural pneumonectomy involves an en bloc resection of the ipsilateral lung along with the parietal and visceral pleura, pericardium, and hemidiaphragm. This extensive surgery removes the entire lung, resulting in a large hemithoracic cavity. Historically, EPP has been followed by adjuvant hemithoracic radiation therapy as part of a trimodality approach. However, the MARS trial, which randomized patients to EPP versus no EPP within a trimodality protocol, found no overall survival benefit with EPP and reported higher morbidity, thereby questioning the role of this surgery. Consequently, the use of EPP has declined and has largely been replaced by pleurectomy/decortication at most centers.

Pleurectomy/Decortication (P/D)

Pleurectomy/decortication is a lung-sparing surgical technique that removes the visceral and parietal pleura while preserving the underlying lung. An extended P/D may also involve resection of the diaphragm and/or pericardium. Compared to EPP, P/D has a lower perioperative mortality rate, typically between 1-4%, versus 5-10% for EPP. The MARS-2 trial, which randomized patients to P/D plus chemotherapy versus chemotherapy alone, demonstrated that P/D did not improve overall survival. Administering adjuvant radiation therapy after P/D is technically challenging due to the presence of the remaining lung, which complicates dose delivery and increases the risk of toxicity.

Radiation Therapy Approaches

Adjuvant Hemithoracic RT After EPP

The classic trimodality treatment for MPM consists of induction chemotherapy with cisplatin and pemetrexed, followed by EPP and then hemithoracic radiation therapy. The radiation target encompasses the entire ipsilateral hemithorax, including the surgical bed, diaphragmatic reconstruction, and pericardial surface. The typical dose is 50-54 Gy delivered in 25-27 fractions using intensity-modulated radiation therapy (IMRT). The Sugarbaker series from Brigham and Women's Hospital demonstrated that this trimodality approach with adjuvant RT after EPP improved local control and overall survival, particularly in patients with the epithelioid subtype who achieved complete macroscopic resection (R1). Radiation techniques have evolved from conventional anterior-posterior/posterior-anterior or mixed photon/electron fields to IMRT, which offers improved conformality and better sparing of critical organs such as the kidneys and liver.

Intensity-Modulated Pleural Radiation Therapy (IMPRINT) After P/D

At Memorial Sloan Kettering, hemithoracic pleural radiation therapy is delivered to a dose of 50.4 Gy in 28 fractions using IMRT, targeting the ipsilateral pleura while sparing the underlying lung. This approach is extremely technically challenging because it requires delivering a therapeutic dose to the thin pleural surface while maintaining the ipsilateral lung volume receiving 20 Gy (V20) below 20% and the mean lung dose under 20 Gy. Phase II data have demonstrated the feasibility of this technique with acceptable toxicity, including a pneumonitis rate of approximately 20%. Precise delineation of the clinical target volume (CTV) is critical and involves a 5-7 mm expansion from the chest wall, mediastinal, and diaphragmatic pleural surfaces. Daily image-guided radiation therapy (IGRT) is mandatory to ensure accurate treatment delivery.

Prophylactic Drain-Site Irradiation

Historically, radiation therapy was applied prophylactically to chest tube, thoracoscopy, and surgical drain or incision sites to prevent tumor seeding along procedural tracts. However, the SMART trial, a randomized study comparing prophylactic drain-site radiation (21 Gy in 3 fractions) to observation, found no significant reduction in tract metastases with radiation. As a result, prophylactic drain-site irradiation is no longer routinely recommended.

Palliative Radiation

Palliative radiation therapy is commonly used to alleviate pain caused by chest wall invasion in MPM. Typical regimens include 20 Gy in 5 fractions or 30 Gy in 10 fractions. Although response rates are limited to about 50-60% due to the relative radioresistance of mesothelioma, palliative radiation can provide meaningful pain relief for localized chest wall masses.

Treatment Planning Considerations

Hemithoracic IMRT After EPP

For hemithoracic IMRT following EPP, the clinical target volume includes the entire ipsilateral hemithorax, encompassing pleural reflection surfaces, diaphragmatic reconstruction, pericardium, surgical clips, and all incision and drain sites. Boost volumes may be added to areas with close or positive margins or residual disease. Organ-at-risk (OAR) constraints are critical to minimize toxicity: the contralateral lung must have a V20 less than 10% and a mean dose under 8 Gy to avoid fatal pneumonitis, which is the most feared complication. For right-sided tumors, the liver mean dose should be kept below 30 Gy with V30 under 33%. The ipsilateral kidney is often removed or non-functional if nephrectomy is performed, but the contralateral kidney must be preserved with a V20 under 33%. The heart should receive a mean dose below 26 Gy and V45 under 50%, the esophagus a mean dose below 34 Gy, and the spinal cord a maximum dose under 45 Gy. IMRT is strongly preferred over three-dimensional conformal radiation therapy (3D-CRT) for hemithoracic RT because it allows simultaneous coverage of the complex pleural target while sparing the contralateral lung, liver, and kidneys.

IMPRINT After P/D

In the IMPRINT technique after P/D, the CTV includes the ipsilateral parietal and visceral pleural surfaces, defined using pre-surgical imaging, surgical clips, and CT fusion. Particular attention is required for challenging volumes such as the diaphragmatic surface, mediastinal pleura, and costophrenic angles. The ipsilateral lung remains in place, so dose constraints are stringent: V20 should be kept below 15-20%, and the mean lung dose should be under 15-20 Gy. The contralateral lung dose should be minimized as much as possible to reduce the risk of fatal pneumonitis if lung dose constraints are exceeded.

Systemic Therapy Integration

Chemotherapy

The first-line chemotherapy regimen for MPM consists of cisplatin combined with pemetrexed, which has been shown to improve median overall survival to 12.1 months compared to 9.3 months with cisplatin alone, as demonstrated by Vogelzang et al. Neoadjuvant chemotherapy is standard before surgery in trimodality protocols. Carboplatin may be used as a substitute for cisplatin in patients who are unfit for the latter.

Immunotherapy

The CheckMate 743 trial compared nivolumab plus ipilimumab to cisplatin/pemetrexed in unresectable MPM and found an overall survival benefit with immunotherapy, with median survival of 18.1 months versus 14.1 months. The greatest benefit was observed in the non-epithelioid subtype. The integration of immunotherapy with surgery and radiation in multimodality treatment protocols is currently under investigation.

<image>A coronal CT reconstruction showing the anatomy of malignant pleural mesothelioma. The left hemithorax is encased by a rind of pleural tumor extending along the parietal and visceral pleura, diaphragmatic surface, and mediastinum. The tumor thickness varies from 5 mm to 3 cm. Key anatomic landmarks are labeled: costophrenic angle (common site of thickest disease), mediastinal pleura, and diaphragmatic crus. The contralateral lung, heart, and liver are labeled as critical organs at risk.</image>

<image>A side-by-side comparison of radiation treatment plans for mesothelioma. Left panel: hemithoracic IMRT after extrapleural pneumonectomy, showing the evacuated hemithorax treated uniformly to 50 Gy with IMRT. The contralateral lung, liver, and kidneys are contoured with dose constraints. Right panel: IMPRINT after pleurectomy/decortication, showing the ipsilateral pleural surface CTV with the lung in situ. Dose-volume histograms for the ipsilateral lung, contralateral lung, and liver are displayed for each plan.</image>

<image>A flowchart illustrating the treatment algorithm for malignant pleural mesothelioma. Starting point: histologic diagnosis and staging. Branch 1: Resectable (epithelioid or biphasic, good PS) leads to neoadjuvant cisplatin/pemetrexed followed by P/D or EPP followed by adjuvant hemithoracic RT (if EPP) or IMPRINT (if P/D). Branch 2: Unresectable or sarcomatoid leads to systemic therapy (nivolumab/ipilimumab or cisplatin/pemetrexed) with palliative RT as needed. Branch 3: Poor performance status leads to best supportive care with palliative RT for pain.</image>

Key Clinical Pearls

The trimodality approach, which combines chemotherapy, surgery, and adjuvant hemithoracic radiation therapy, remains the most intensive treatment strategy for malignant pleural mesothelioma. However, the MARS and MARS-2 trials have raised questions about the survival benefit of surgery, emphasizing the importance of careful patient selection. Hemithoracic IMRT after extrapleural pneumonectomy requires meticulous planning to maintain the contralateral lung V20 below 10%, as fatal pneumonitis is the most feared complication; sparing the contralateral lung is the single most critical constraint. IMPRINT following lung-sparing pleurectomy/decortication is feasible but technically demanding, with stringent ipsilateral lung dose constraints that are difficult to achieve while delivering an effective dose to the pleural surfaces. Prophylactic drain-site irradiation is no longer recommended based on the SMART trial, marking a significant change from longstanding practice. Given the complexity of mesothelioma management, multidisciplinary decision-making is essential, and the role and sequence of surgery, radiation, chemotherapy, and immunotherapy should be individualized at experienced centers.

References

• Treasure T et al. "Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study." Lancet Oncol. 2011;12(8):763-772.
• Lim E et al. "Extra-pleural pneumonectomy versus extended pleurectomy decortication versus no surgery in the Mesothelioma and Radical Surgery 2 (MARS 2) randomised clinical trial." Lancet. 2024.
• Clive AO et al. "Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial." Lancet Oncol. 2016;17(8):1094-1104.
• Rimner A et al. "Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma." J Clin Oncol. 2016;34(23):2761-2768.
• Baas P et al. "First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial." Lancet. 2021;397(10272):375-386.

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