Since malignant pleural mesothelioma (MPM) is most often confined to the ipsilateral pleura, local control is a primary concern, particularly after surgical resection (Figure 1). Radiation therapy (RT) has traditionally been used in many malignancies as an adjuvant treatment in an effort to decrease the rate of local failure. For example, in non-small cell lung cancer (NSCLC), post-operative radiation therapy (PORT) can reduce the risk of local failure in the mediastinum and perhaps improve survival (1). Treating the entire pleura, however, requires a large radiation field and increases the risks of toxicity.
Two types of surgery are commonly performed for MPM: extrapleural pleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). EPP involves en bloc resection of the entire pleura, lung and diaphragm, and ipsilateral half of the pericardium. P/D involves resection of all gross tumor without resecting the lung. Although it is still technically challenging, RT after EPP is facilitated by the removal of the lung (2). In fact, part of the rationale for EPP was to allow for the use of high doses of PORT.
The role of RT after surgical resection
There is limited data with regard to the use of RT as a standard treatment modality in mesothelioma. A retrospective review of 663 patients from three institutions demonstrated improved survival with the use of multimodality therapy as compared to surgery alone (3).
The role of RT has been questioned in a recent analysis of the Surveillance, Epidemiology, and End Result (SEER) database of 14,228 patients with mesothelioma (4). On multivariable analysis, female gender, younger age, early stage, and treatment with surgery were independent predictors of longer survival. In comparison to no treatment, surgery alone was associated with significant improvement in survival. However, surgery and radiation combined was associated with similar survival as surgery alone. The adjusted hazard ration for radiation was 1.14 suggesting radiation may not improve outcome in patients with MPM.
However, a subsequent analysis utilizing the National Cancer Database (NCDB) suggested a role for adjuvant RT. Ohri and colleagues reviewed 23,414 who were entered in the NCDB database between 2004 and 2013. Of these, 14,090 underwent definitive treatment and only 508 (3.6%) received definitive RT. The use of RT improved the 2-year rate of overall survival (OS) from 20% to 34%. The adjusted hazard ratio of using radiation was 0.87 (95% confidence interval 0.70–0.87) suggesting a significant benefit with the use of RT. A propensity scored analysis confirmed this result as well (5). It is important to note that population based studies such as those by SEER or NCDB can be difficult to apply to clinical care especially in a disease such as mesothelioma where there is no standardization for the surgical or radiotherapy procedures.
Radiation after extrapleural pneumonectomy
Initially, when administering radiation therapy (RT) as adjuvant therapy following extrapleural pneumonectomy (EPP) or P/D, patients were treated with conventional radiation techniques using anterior/posterior fields with matching electrons. Local failure with this technique has been reported to be above 50% by some centers (6).
Over the past twenty years, intensity modulated radiation therapy (IMRT) has been used in a variety of cancers. IMRT is a highly conformal radiation technique that allows more effective sparing of normal tissues, providing an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target. It comes with a much higher level of dosimetric control and certainty leading to better target coverage than conventional techniques (7).
A potential disadvantage of IMRT in mesothelioma is dose inhomogeneity and the dose of radiation delivered to the contralateral lung, which potentially leads to a higher risk of pneumonitis. Allen et al., from Dana-Farber Cancer Institute, reported a 46% risk of fatal toxicity from radiation pneumonitis in patients treated with IMRT after EPP (8). This led many to question the use of this form of RT. A higher mean lung dose and the volume of lung receiving 5, 10, or 20 Gy have been associated with a greater risk for lung toxicity (9-11).
After the Dana-Farber experience, further work was done by multiple investigators to establish dosimetric guidelines for the use of IMRT in mesothelioma. Clearly, the dose of radiation to the contralateral (remaining) lung was of primary importance. In the traditional photon-electron technique, the dose of radiation to the remaining lung was minimal since none of the radiation beams were delivered at an angle, which is standard practice for IMRT.
M.D. Anderson Cancer Center (MDACC) updated their experience in treating MPM with IMRT after EPP (12). Gomez et al., retrospectively analyzed 86 patients who underwent hemithoracic IMRT after EPP. Grade 3 or worse pulmonary toxicity occurred in 11.6% of patients. Almost all patients had gastrointestinal symptoms, consisting primarily of nausea and esophagitis. There were five fatal cases of pulmonary toxicity, 3 from radiation pneumonitis and 2 bronchopleural fistulas. At 2 years, the rates of OS, local control and distant control were 32%, 55% and 40% respectively. Fourteen patients (16%) experienced local failure and only two of these patients had local failure alone. Fifty-one patients (59%) had distant metastases, which included failures in the contralateral hemithorax and the abdomen.
A review from the University of North Carolina group also examined whether increased experience with received IMRT following EPP led to improvements in outcome (13). They compared the first 15 patients treated with the second consecutive group of 15 patients. Target coverage (a measure of how well the treatment plan is adequately targeting the tumor) improved in the second group. Additionally, the mean dose to the normal structures of the heart and lung also improved in the second group of patients. This suggests that increased experience with this rare disease for the physicians, physics and therapy staff is of great value in producing high quality treatment delivery.
Helical tomotherapy is a type of IMRT wherein the radiation is delivered through a gantry that is able to rotate 360 degrees around the patient. Simultaneous with the movement, the treatment couch and multileaf collimator leaves are also moving, allowing precise dose distributions in the tumor and theoretically shielding normal tissues, especially the lung. Additionally, image-guidance is accomplished with daily imaging similar to CT scans which helps to ensure accurate treatment delivery.
A study from the Curie Institute and the Rene Gauducheau Cancer Center, both in France, examined the use of helical tomotherapy after EPP (14). The investigators used three different clinical target volumes (CTV). CTV1 encompassed the surgical cavity and was treated to 50–54 Gy. CTV2 was a 4–6 Gy boost to the positive margin. CTV3 represented the mediastinal structures next to the gross tumor and it received 46 Gy. Treatment planning was done to keep the V20 less than 20% and the median value of it in this group of patients was 4%.
Twenty-four patients were treated and four (16%) had grade 3 or worse radiation pneumonitis within six months, including two deaths (8%). There was one case of grade 3 esophagitis. There were only three cases of local failure. The remaining patients had distant failure.
Stahel et al. published the results of SAKK 17/04, a multi-centered Phase II randomized trial. In this trial, patients received three cycles of induction chemotherapy with cisplatin and pemetrexed (15). Patients then received extrapleural pneumonectomy and were subsequently randomized to either hemithoracic RT or no further treatment. One hundred and fifty-three patients were enrolled in the study and 113 underwent surgery. However, only 54 patients went on to randomization. There was no significant difference local-regional progression-free survival and OS between the two randomized groups. Although the authors concluded that there is no role for PORT after extrapleural pneumonectomy for mesothelioma, it is more likely that this trial was too underpowered to detect any difference between the groups.
Radiation before extrapleural pneumonectomy
Investigators from Princess Margaret Hospital (PMH) in Toronto, Canada have reported on an innovative technique to combine RT and extrapleural pneumonectomy (16). Patients received 25–30 Gy to the entire hemithorax utilizing IMRT one week before extrapleural pneumonectomy. Patients with pathologically involved mediastinal lymph nodes received adjuvant chemotherapy. Out of 62 patients, there was only one patient who died in the hospital after EPP and two patients who died after discharge for a treatment related mortality of 5%. Twenty-four patients (39%) developed grade 3 or higher toxicity which was mostly atrial fibrillation or empyema. It is important to note that once the RT has been delivered, surgery is obligatory. It can be presumed that if surgery is not performed, there would be significant radiation pneumonitis. In the PMH study, no patient underwent RT without subsequently having surgical resection. The median survival for all patients as an intention-to-treat analysis was an encouraging 36 months. An accompanying editorial suggested that an aggressive approach such as SMART should only be attempted in centers with significant surgical and radiation oncology expertise (17). When this treatment was compared to the use of neoadjuvant chemotherapy, it was found to have similar surgical risk (18).
Radiation after P/D
With the growing use and potential benefit of P/D instead of EPP (3), it became an increasing challenge to develop techniques to deliver therapeutic doses of RT to the entire pleura in the setting of an intact lung. Traditional delivery of hemithoracic RT using two-dimensional (anterior-posterior) techniques has also been tested after P/D. Since the ipsilateral lung remains in situ after P/D, a block is added for the central part of the lungs. The heart and upper abdominal organs are blocked following the same technique as for patients after EPP. Similarly, the anterior and posterior chest walls are boosted with an electron field added to treat the chest wall located underneath the heart, lung and upper abdominal blocks. Unfortunately, in the largest series analyzing this method there was a disappointing 1-year local control rate of 42% and a median survival of 13.5 months (19). Possible explanations include median radiation dose being only 42.5 Gy, and the dose uncertainties with this technique. In addition, the treatment was quite toxic, with 28% grade 3–4 toxicity and two patients with possible grade 5 cardiac and pulmonary toxicity.
Some centers have explored the use of hemithoracic pleural IMRT [also known as Intensity Modulated Pleural RadIatioN Therapy (IMPRINT)] in this setting (Figure 2). In this situation, the dose of radiation to the lung as a paired organ would be of dosimetric interest, similar to the challenges seen in the treatment of lung cancer.
Rosenzweig et al., from Memorial Sloan-Kettering Cancer Center (MSKCC) reviewed 36 patients treated with pleural IMRT who underwent P/D or biopsy alone (20). The purpose of the study was to establish the feasibility of pleural IMRT and assess its toxicity. A median dose of 4,680 cGy was delivered to the pleural surface and almost 90% of the patients had received chemotherapy, although none received it concurrently. The typical treatment plan was done via a “step and shoot” method with beams entering from eight separate angles. There were seven patients (20%) with grade 3 or worse toxicity, including one fatality. Five patients (16%) had persistent pneumonitis as a long-term toxicity. The authors concluded that pleural IMRT is a safe and feasible treatment technique for patients with MPM who have an intact lung on the affected side. Post-treatment imaging of a patient who received IMPRINT is presented in Figure 3. A recent study demonstrates that the use of advanced IMRT techniques, such as VMAT can improve the radiation dose distribution and reduce predicted toxicity (21).
An update of the MSKCC experience evaluated sixty-seven patients with MPM were treated with definitive or adjuvant hemithoracic pleural IMRT (22). Pretreatment imaging, treatment plans, and post-treatment imaging were retrospectively reviewed to determine failure location(s). Failures were categorized as in-field, marginal, out-of-field, or distant depending on the failures’ relation to the 90% and 50% isodose lines. The median follow-up was 24 months from diagnosis and the median time to in-field local failure from the end of RT was 10 months. Forty-three in-field local failures (64%) were found with a 1- and 2-year actuarial failure rate of 56% and 74%, respectively. For patients who underwent P/D versus those who received a partial pleurectomy or were deemed unresectable, the median time to in-field local failure was 14 months versus 6 months, respectively (P<0.03). The authors concluded that local failure remains the dominant form of failure pattern and that patients treated with adjuvant hemithoracic pleural IMRT after P/D experience a significantly longer time to local and distant failure than patients treated with definitive pleural IMRT.
A two-center Phase II study evaluating the use IMPRINT with chemotherapy and P/D was recently reported (23) from MSKCC and MDACC. A total of 27 patients received radiation after chemotherapy and P/D (median dose, 46.8 Gy). Six patients experienced grade 2 RP, and two patients experienced grade 3 or worse RP (no grade 4 or 5). The median progression-free survival and OS were 12.4 and 23.7 months, respectively. The 2-year OS was 59% in patients with resectable tumors and was 25% in patients with unresectable tumors. A follow-up multi-institutional study of the IMPRINT technique is currently underway.
Another study from Aviano, Italy reports on 28 patients who were treated with HT after P/D or biopsy alone (24). All patients had FDG-PET scans after surgery for staging and were treated to an intended dose of 50 Gy. Areas that were hypermetabolic on PET were boosted with an additional 10 Gy. The CTV extended from the lung apex to the upper abdomen and included the mediastinal lymph nodes when involved. The margin for planning target volume (PTV) was 5 mm from the CTV. The primary pulmonary dosimetric constraint was the contralateral lung to a mean dose of less than 7 Gy. The ipsilateral lung and the total lung did not have specific constraints.
Five patients (18%) had respiratory toxicity, but only two were grade 3 (7%) and none were grade 5. Contralateral lung V5 was strongly correlated with the risk of pneumonitis. This is especially interesting considering that theoretically there should be some function in the intact lung.
A comparison of the IMPRINT technique and conventional RT was recently performed (25). Conventional RT consisted of matched photon/electron fields and was delivered with two-dimensional RT techniques. OS was significantly higher after IMPRINT (median 20.2 vs. 12.3 months, P=0.001). Additionally, fewer patients developed grade ≥2 esophagitis after IMPRINT compared to CONV (23% vs. 47%).
Many aspects of treatment for patients with MPM are not standardized. There is still variation in the surgical technique used and the role of RT. The use of pemetrexed chemotherapy is standard, but there is still no clinically effective second line systemic treatment. Similar to other solid tumors, there has been some promising work with monoclonal antibodies and immunotoxins (26,27).
The use of RT has changed radically since the advent of advanced radiation treatment planning techniques, especially IMRT. IMRT is now part of the care for almost all patients when RT is used, despite the difficulties in some of the earliest studies. Patients with mesothelioma represent an especially difficult population with which to work with since their disease is related to environmental exposures that often leave them prone to other medical comorbidities.
Many thoracic surgeons have decreased their use of EPP in favor of P/D in an effort to decrease operative morbidity and mortality, especially considering the possibility that there is no clear difference in clinical outcome. Therefore, radiation oncologists will be evaluating patients with two intact lungs in need of adjuvant RT. IMRT, with its ability to deliver concave doses of RT to complex geometries is a logical solution to this problem.
Recent studies demonstrate that our ability to deliver IMRT has improved with experience and has excellent efficacy in single institutional reports. These represent centers with high volumes of patients when such expertise is able to be developed. The clinical issues for these patients, including contouring, treatment planning and delivery are not inconsiderable. Additionally, although the toxicity for these treatments has decreased, it is not insignificant and must be taken into consideration when treating our patients.
Conflicts of Interest: The author has no conflicts of interest to declare.
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