Treatment of malignant pleural mesothelioma with radiation therapy (RT) is extremely challenging. The target volume for treatment is very large, involving almost the entire hemithorax, and within and adjacent to this treatment volume, there are many normal structures with low tolerances to radiation. Consequently, it is very difficult to create treatment plans that deliver satisfactorily high doses to the complex target volume yet minimal doses to the adjacent radiosensitive normal organs. This chapter will review the history, current approaches, and future ideas for the treatment of pleural mesothelioma with radiotherapy in definitive, adjuvant, and palliative settings.

Definitive Radiation Therapy Alone for Mesothelioma

For the treatment of unresected gross disease, the target volume for RT includes the entire visceral and parietal pleura of one lung. These structures form a circumferential envelope around the lung, extend along fissures between lobes of the lung, and are attached to ipsilateral, pericardial, and diaphragmatic surfaces. A tumoricidal dose of RT for gross disease is >60 Gy, but the normal tissue tolerance of the adjacent organs is much lower. Whole organ tolerances for these structures are as follows: lung, 18 to 20 Gy; heart, 40 Gy; liver, 30 Gy; stomach, 50 Gy; kidney, 18 to 20 Gy; spinal cord, 45 to 50 Gy; and brachial plexus, 50 Gy.¹

Few reported series address the definitive treatment of unresected pleural mesothelioma, and none show promising results. In 1988, Alberts et al.² reported outcome for 262 patients treated with various combinations of RT, pleurectomy, and chemotherapy. RT was delivered to the entire hemithorax with doses of 45 to 80 Gy. All treatment groups had similar outcomes, with a median survival time of 9.6 months; the stepwise addition of treatment modalities was not associated with improved survival. No toxicity data were described. The authors concluded that new agents and approaches were warranted.

In 1990, Ball and Cruickshank³ reported on a series of 35 patients treated with RT at the Peter MacCallum Institute, 12 of whom received “radical RT.” Treatment comprised 40 Gy to the entire hemithorax using AP–PA fields, after which the spinal cord was blocked and the treatment continued to a total dose of 50 Gy. An anterior cardiac block was used for left-sided tumors to limit heart dose to 40 Gy; no shielding was used for lung, liver, or kidney. There were two treatment-related fatalities (17%) due to radiation hepatitis and radiation myelopathy, respectively. Median survival time was 9 months. The authors concluded that there is no role for radical RT given the unacceptable toxicity and lack of demonstrated efficacy.

A third report by Maasilta⁴ in 1991, included 34 patients with unresected mesothelioma who were treated to the entire hemithorax with three different high-dose regimens. The spinal cord was shielded after 40 Gy, the liver was partially shielded after 30 Gy, and there was no shielding of the intact lung. The three dose regimens were: 55 Gy in 2.2-Gy fractions (split course) to the hemithorax followed by a boost to gross disease to 70 Gy; 70 Gy to the hemithorax in 1.25-Gy twice-daily fractions (split course); and 35 Gy in 1.25-Gy twice-daily fractions to the hemithorax, with a boost to gross disease using 4-Gy fractions to a total dose of 71 Gy. Radiographic and clinical lung injuries were progressive in all groups and scored as severe by 6 months, very severe by 9 months and compatible with total loss of ipsilateral lung function by 12 months. No local control data were reported.

An interesting recent study from Heidelberg describes experience with “palliative RT” using the modern technique of intensity modulated radiation therapy (IMRT).⁵ IMRT refers to an advanced RT delivery technique which can achieve more conformal dose distributions around complex target volumes. IMRT divides the RT treatment fields into multiple subfields of varying dose intensities. By using many treatment angles and modulating the beam intensity across apertures, it is possible to partially shield parts of the target volume near a critical structure (and decrease the dose to the normal structure). The end result is a fairly homogeneous dose distribution to the target and shaping of the high-dose lines around and away from surrounding critical structures. The Heidelberg group treated 11 patients with IMRT to target volumes including all gross tumor to doses of 40 to 50 Gy. All patients in that report had recurrent disease at the time of RT, after prior surgery and/or chemotherapy, so the patient group is not directly comparable to those in the above accounts. Median survival following RT was 5 months. Given the small patient number and poor outcome, it is not possible to assess the efficacy or toxicity of this approach. Currently, data are lacking to support RT alone as definitive treatment for mesothelioma and this is not a recommended approach.

Adjuvant Radiation Therapy for Mesothelioma

Adjuvant Radiation Therapy Following Pleurectomy

The delivery of curative adjuvant RT after pleurectomy poses many of the same problems as stated earlier for definitive treatment without resection—namely, it is very difficult to deliver a tumoricidal dose of RT to the complex target of the pleural envelope and fissures given the proximity of many radiosensitive normal structures, including the intact lung.

Several reports of RT after pleurectomy have shown only fair results. The group at Memorial Sloan–Kettering Cancer Center (MSKCC) pioneered a technique using a combination of photons and electrons to treat the hemithorax after pleurectomy.^6,7 The technique consists of treating anterior and posterior photon fields to cover the entire hemithorax and using blocks to protect lung, heart, liver, and stomach. The blocked areas are treated with superficial electrons matched to the photon fields and prescribed to a depth that covers the underlying pleura. Total dose is 42.5 to 45 Gy. This technique is very appealing in theory but, in reality, the cumulative dose distribution is not homogeneous; the result is that some portions of the target volume receive more and some less than the prescription dose, due to imperfect matching of photon and electron fields and other technical factors. Clinical results of patients treated in this fashion initially appeared promising, but an update of 123 patients showed a median survival time of only 13.5 months and 28% had grade 3 to 4 toxicity.^6,8 The authors concluded that this technique of adjuvant RT following pleurectomy is not effective.

Three other studies included subsets of patients treated with pleurectomy and adjuvant radiation. However, the informative value of these studies is limited as treatment and outcome details with respect to RT are not well described.^9–11 Investigators from the University of California at San Francisco reported results for 24 patients treated with pleurectomy followed by a combination of intraoperative electron therapy (median, 15 Gy) and postoperative photon therapy delivered with either a 3-dimensional (3D) conformal approach or IMRT (median, 41.4 Gy).¹² The intraoperative electrons were used to treat the major fissure, pericardium and diaphragm with the goal of improving target coverage and sparing underlying lung. Treatment-related toxicity was considered acceptable and included transient pneumonitis for four patients (17%), pericarditis for one (4%), and esophageal stricture requiring dilatation for one (4%). Median survival time was 18 months.

The use of IMRT in the post pleurectomy setting is potentially appealing. In 2002, Tobler et al.¹³ reported on a proposed rotational IMRT technique in which each of multiple beams treats a strip of pleural lining. The resulting dosimetry from this idealized technique showed homogeneous coverage of the circumferential pleural surface. This IMRT approach was considered to be superior to the matched electron–photon technique (EPT) reported by Kutcher et al.,⁷ showing both more uniform dose distribution and better sparing of underlying lung. However, this technique does not address treatment of the pleural reflections along the fissures. Rosenzweig et al. at MSKCC have treated 36 patients with IMRT to a median dose of 46.8 Gy, 20 of whom had undergone prior pleurectomy. Results are still preliminary, but acute toxicity has been acceptable.¹⁴ In sum, adjuvant RT following pleurectomy or decortication is associated with moderate toxicity and unclear efficacy. It is not standardly recommended but is worthy of further study.

Adjuvant Radiation Therapy following Extrapleural Pneumonectomy (EPP)

Similar to the above scenarios, the role for adjuvant RT following extrapleural pneumonectomy (EPP) has not been clearly proven. However, there is suggestive evidence in the literature that RT may improve local control in this setting. Local recurrence (LR) rates following EPP alone are as high as 50%, whereas several reports of EPP and postoperative RT have demonstrated LR rates ranging from 16% to 40%.^15–25 Furthermore, Baldini et al.¹⁶ reported a trend for decreased LR among patients who underwent EPP and received adjuvant RT compared to those who did not (9% vs. 27%, respectively). De Perrot et al.²⁶ also demonstrated that among patients treated with induction chemotherapy and EPP, the use of postoperative RT was associated with lower LR rates. In that study, among patients with N2 disease, LR occurred in 1/11 patients (9%) who received RT compared to 5/9 (56%) who did not; this finding was statistically significant on multivariate analysis. Lastly, in a homogeneous cohort of 88 patients with epithelial mesothelioma who underwent EPP ± chemotherapy at Brigham and Women’s Hospital (BWH), the use of postoperative RT was a statistically significant favorable prognostic factor on multivariate analysis (W. G. Richards, personal communication). It is important to note that none of the above reports were randomized comparisons and, as such, all are subject to potential bias. Nonetheless, the data is suggestive of a potential benefit due to adjuvant RT.

In the post EPP setting the absence of the ipsilateral lung simplifies the radiation treatment planning compared to the post pleurectomy/decortication setting, in which the intact lung is in place. Despite this advantage, the design and implementation of RT to the large complex target volume of the hemithorax remains very challenging. Critical remaining normal structures within and adjacent to the target volume include heart, liver, stomach, kidneys, spinal cord, and contralateral lung. Three types of RT techniques following EPP have been implemented with varying success (see Table 118-1). These approaches include a moderate-dose photon technique (MDRT), a high-dose matched EPT, and a high-dose IMRT technique.

The MDRT technique was used at BWH and Dana–Farber Cancer Institute (BWH/DFCI) from 1987 to 2003 and consisted of anterior and posterior photon fields. The large hemithorax field received 30 Gy in 1.5-Gy fractions, the mediastinum received 40 Gy, and any areas of focally positive margins and/or positive nodes were boosted to a dose of 54 Gy using various beam angles.¹⁶ No blocks were placed over the heart, liver, stomach, or kidney. The moderate dose of 30 Gy was chosen because it is within tolerance of all of the relevant normal structures except the ipsilateral kidney, which was acknowledged to be sacrificed. Adequate contralateral kidney function was always documented prior to treatment. Baldini et al. examined the pattern of failure after the combination of EPP; adjuvant cyclophosphamide, doxorubicin, and cisplatin; and MDRT to the hemithorax for patients treated from 1987 to 1993. Treatment-related toxicity was acceptable, and the most common site of failure was the ipsilateral hemithorax, with a LR rate of 35%.¹⁶ Between 1993 and 2003, patients at BWH/DFCI were treated with the MDRT technique with the addition of concurrent chemotherapy (cisplatin, carboplatin/paclitaxel, or paclitaxel). However, local control remained a significant problem, with 12/24 locoregional recurrences reported—seven in the treatment field and five inferior to the field edge (marginal misses).²⁷ At BWH/DFCI, this MDRT technique has been abandoned for higher-dose techniques which will be described below.

Investigators at MSKCC pioneered a matched EPT to a total dose of 54 Gy.³³ This technique was fully described by Yajnik et al.³³ and involves anterior and posterior photon fields to the entire hemithorax and mediastinum to a dose of 39.6 Gy, after which the spinal cord (and thus, the mediastinum) is blocked and the dose is continued to 54 Gy. Blocks are placed over the abdomen to shield the liver and kidney for right-sided cases and to shield the stomach, kidney, and heart for left-sided cases. These blocked areas are then treated with superficial electron irradiation to cover the area at risk while minimizing the dose to the underlying normal structures. The advantage of this approach is that it delivers an appropriately high dose of RT; the disadvantage is that there are areas at risk that may not be fully covered by the prescription dose. The inferior medial pleura, mediastinum, retrocrural lymph nodes, and portions of the diaphragmatic sulcus are all potentially underdosed. Also, the regions of the match lines between the photon and electron fields contain heterogeneities, with cumulative doses both higher and lower than the prescribed 54 Gy.