CURRENT READINGS
Current Readings: Improvements in IntensityModulated Radiation Therapy for Malignant Pleural Mesothelioma Kenneth E. Rosenzweig, MD The treatment of malignant pleural mesothelioma with radiation therapy has always been a technical challenge. Early experience with intensity-modulated radiation therapy demonstrated troubling toxicity. Recent reports from institutions have demonstrated that with greater experience, intensity-modulated radiation therapy can be delivered safely, both in the setting of pneumonectomy or pleurectomy. After pneumonectomy, the dose to the contralateral lung must be minimized, preferably with a volume of lung receiving 20 Gy (V20) to less than 5% and a mean lung dose of approximately 10%. In the setting of 2 intact lungs, the mean lung dose can be as high as 20 Gy. Expected rates of grade 3 or worse radiation pneumonitis are 12%-20%. The rates of fatal pneumonitis are approximately 3%-8% in these studies, which demonstrate the considerable toxicity of treatment, even with improved technique. Semin Thoracic Surg 25:245–250 I 2013 Elsevier Inc. All rights reserved. Keywords mesothelioma, intensity-modulated radiation therapy, radiation pneumonitis, radiotherapy
INTRODUCTION As malignant pleural mesothelioma (MPM) is most often confined to the ipsilateral pleura, local control is the primary concern, particularly after surgical resection. Radiation therapy has traditionally been used in many malignancies as an adjuvant treatment in an effort to decrease the rate of local failure. Yet, treating the entire pleura requires a large radiation field and increases the risks of toxicity. Initially, when administering radiotherapy as adjuvant therapy following extrapleural pneumonectomy (EPP) or pleurectomy or decortication (PD), patients were treated with conventional radiation techniques using anterior or posterior fields with matching electrons. Over the past 15 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, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Address reprint requests to Kenneth Rosenzweig, MD, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, One Gustav L Levy Place, Box 1236, New York, NY 10029. E-mail: [email protected]
1043-0679/$-see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2013.10.004
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.1 Areas of underdosing or overdosing are readily recognizable and can be corrected in the planning phase. A potential disadvantage of IMRT in mesotheliomas is dose inhomogeneity and the dose of radiation delivered to the contralateral lung, which potentially leads to a higher risk of pneumonitis. Allen et al2 from Dana-Farber Cancer Institute, reported a 46% risk of fatal toxicity from radiation pneumonitis in patients treated with IMRT after EPP. This led many to question the use of this form of radiation therapy. 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.3-5 More recently, improved IMRT techniques for the treatment of MPM have been explored, with early outcomes suggesting acceptable safety in appropriately selected patients. There are two distinct situations for the use of IMRT; one where the diseased lung has been surgically removed and the other where it is intact. Here, we review some of the recent publications exploring new modalities of radiation therapy for MPM for both situations. 245
MALIGNANT PLEURAL MESOTHELIOMA TREATMENT AFTER EXTRAPLEURAL PNEUMONECTOMY Two types of surgical procedures are commonly performed for MPM-EPP and PD. EPP involves en bloc resection of the entire pleura, lung and diaphragm, and ipsilateral half of the pericardium. PD involves resection of gross tumor without resecting the lung. Although it is still technically challenging, radiation therapy after EPP is facilitated by the removal of the lung.6 In fact, part of the rationale for EPP was to allow for the use of postoperative radiation therapy. In the advent of 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 as none of the radiation beams were delivered at an angle, which is standard practice for IMRT. Some recent publications have updated their experience with IMRT after EPP. PATTERNS OF FAILURE, TOXICITY, AND SURVIVAL AFTER EXTRAPLEURAL PNEUMONECTOMY AND HEMITHORACIC RADIATION THERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA Gomez DR, Hong DS, Allen PK, et al. J Thorac Oncol 8:238-245, 2013
Figure 1. Fused PET or CT scans and radiation isodose curves (left) and diagnostic PET scans (right) of treatment failures in 2 different patients after extrapleural pneumonectomy followed by intensity-modulated radiation therapy for malignant pleural mesothelioma. (A) Arrows indicate failure within a cold spot where the isodose lines curved inward along the chest wall and thus compromised target coverage in this portion of the radiation field. (B) Recurrence in high-dose region and within subcutaneous tissues adjacent to the surgical scar. CT, computed tomography; PET, positron emission tomography. (Color version of figure is available online at http://www.semthorcardiovascsurg.com.). Reprinted with permission from Gomez DR, Hong DS, Allen PK, et al, Patterns of Failure, Toxicity, and Survival After Extrapleural Pneumonectomy and Hemithoracic Radiation Therapy for Malignant Pleural Mesothelioma, J Thorac Oncol, 8, 238–245, 2013.
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MALIGNANT PLEURAL MESOTHELIOMA M.D. Anderson Cancer Center recently updated their experience in treating MPM with IMRT after EPP.7 In this report, Gomez et al retrospectively analyzed 86 patients who underwent hemithoracic IMRT after EPP. Almost all patients had gastrointestinal symptoms, consisting primarily of nausea and esophagitis. Grade 3 or worse pulmonary toxicity occurred in 11.6% of patients. There were 5 fatal cases of pulmonary toxicity, 3 from radiation pneumonitis and 2 bronchopleural fistula. At 2 years, the rates of overall survival, local control, and distant control were 32%, 55%, and 40%, respectively. Fourteen patients (16%) experienced local failure and only 2 of these patients had local failure alone. Distant metastases were seen in 51 patients (59%) and included failures in the contralateral hemithorax and the abdomen. Figure 1 shows a typical radiation treatment plan for two different patients. One patient had a local failure within an area of underdosing and the other had local failure despite receiving a full dose of radiation to this region (Fig. 1). EFFECT OF INCREASING EXPERIENCE ON DOSIMETRIC AND CLINICAL OUTCOMES IN THE MANAGEMENT OF MALIGNANT PLEURAL MESOTHELIOMA WITH INTENSITY-MODULATED RADIATION THERAPY Patel PR, Yoo S, Broadwater G, et al. Int J Radiat Oncol Biol Phys 83:362-368, 2012 This review from the University of North Carolina (UNC) examined 30 patients who received IMRT following EPP.8 The median dose to the ipsilateral hemithorax was 45 Gy with a 8-25 Gy boost in 9
patients. The 2-year local control, disease-free survival, and overall survival rates were 47%, 34%, and 50% respectively (Fig. 2). Four patients (13%) developed radiation pneumonitis, including a fatality (3%). The UNC group also examined whether increased experience with this modality of treatment led to improvements in outcome. 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 staff, and therapy staff is of great value in producing high-quality treatment delivery. HELICAL TOMOTHERAPY FOR RESECTED MALIGNANT PLEURAL MESOTHELIOMA: DOSIMETRIC EVALUATION OF TOXICITY Giraud P, Sylvestre A, Zefkili S, et al. Radiother Oncol 101:303-306, 2011 Giraud and colleagues reported the largest experience in using helical tomotherapy, a specialized form of IMRT, in the treatment of mesothelioma as adjuvant treatment after EPP. Helical tomotherapy (HT) is a type of IMRT wherein the radiation is delivered through a gantry that is able to rotate 3601 around the patient. Simultaneously with the movement, the treatment couch and multileaf collimator leaves also move, allowing precise dose distributions in the tumor and theoretically shielding normal tissues, especially the lung. Additionally, image
Figure 2. Kaplan-Meier estimates of local control (dotted line), disease-free survival (black line), and overall survival (gray line). Tic marks represent censoring events. Reprinted from Int J Radiat Oncol Biol Phys, 83, Patel PR, Yoo S, Broadwater G, et al, Effect of Increasing Experience on Dosimetric and Clinical Outcomes in the Management of Malignant Pleural Mesothelioma With Intensity-Modulated Radiation Therapy, 362-368, Copyright (2012), with permission from Elsevier.
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Figure 3. Isodense beam distribution showing example of typical isodose distribution using 8 angles equally spaced over 2001-2401 sector encompassing the ipsilateral lung. Area within green lines depicts target volume. (Color version of figure is available online at http://www.semthorcardiovascsurg.com.). Reprinted from Int J Radiat Oncol Biol Phys, 83, Rosenzweig KE, Zauderer MG, Laser B, et al, Pleural IntensityModulated Radiotherapy For Malignant Pleural Mesothelioma, 1278-1283, Copyright (2012), with permission from Elsevier.
guidance is accomplished with daily imaging similar to computed tomography scans, which helps to ensure accurate treatment delivery. This study from the Curie Institute and the Rene Gauducheau Cancer Center, both in France, examined the use of helical tomotherapy after EPP.9 The investigators used 3 different clinical target volumes (CTVs). CTV1 encompassed the surgical cavity and was treated with 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 its median value in this group of patients was 4%. Overall, 24 patients were treated and 4 (16%) had grade 3 or worse radiation pneumonitis within 6 months, including 2 deaths (8%). There was only 1 case of grade 3 esophagitis. There were only 3 cases of local failure. The remaining patients had distant failure. RADIATION AFTER P/D With the growing use and potential benefit of PD instead of EPP,10 it became an increasing challenge to develop techniques to deliver therapeutic doses of radiation therapy to the entire pleura in the setting of an intact lung. Traditional delivery of hemithoracic radiotherapy using 2-dimensional (anterior-posterior) techniques has also been tested after PD. As the ipsilateral lung remains in situ after PD, 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
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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 1year local control rate of 42% and a median survival of 13.5 months.11 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 2 patients with possible grade 5 cardiac and pulmonary toxicity. Recently some centers explored the use of IMRT techniques in this setting. 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. TOMOTHERAPY AFTER PLEURECTOMY/ DECORTICATION OR BIOPSY FOR MALIGNANT PLEURAL MESOTHELIOMA ALLOWS THE DELIVERY OF HIGH DOSE RADIATION THERAPY IN PATIENTS WITH INTACT LUNG Minatel E, Trovo M, Polesel J, et al. J Thorac Oncol 7:1862-1866, 2012 This prospective study from Aviano, Italy, reported on 28 patients who were treated with HT after P/D or biopsy alone.12 All patients had 18fluoro-deoxyglucose–positron emission tomography scans after surgery for staging and were treated with an intended dose of 50 Gy. Areas that were hypermetabolic on positron emission tomography were boosted with an additional 10 Gy. The CTV
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 3
MALIGNANT PLEURAL MESOTHELIOMA Table 1. Comparison of Dosimetric Parameters, Toxicity, and Outcome in Patients Receiving IMRT After Extrapleural Pneumonectomy Reference Number of Technique Dose Boost V5 V20 Mean Lung Patients (Gy) (Gy) (%) (%) Dose (Gy) Giraud et al9 Patel et al8 Gomez et al7
Grade 3 þ Grade 5 RP (%) RP (%)
24
HT
50
4-6
99
4
11
16
8
30
IMRT
45
8-25
56
4
7.2
13
3
86
IMRT
45-50
10
8
12
6
2-Year OS (%) –
32
Gy, Gray; V5 and V20, dose of lung receiving 5 and 20 Gy, respectively; RP, radiation pneumonitis; OS, overall survival.
IMRT is a safe and feasible treatment technique for patients with MPM who have an intact lung on the affected side. This treatment option is currently under investigation at Memorial Sloan-Kettering Cancer Center as a phase II study. Additionally, pleural IMRT might provide good palliation for unresectable patients who have failed first-line chemotherapy.
extended from the lung apex to the upper abdomen and included the mediastinal lymph nodes when involved. The margin for planning target volume 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. Overall, 5 patients (18%) had respiratory toxicity, but only 2 were grade 3 (7%) and none was grade 5. Contralateral lung V5 strongly correlated with the risk of pneumonitis. This is especially interesting considering that theoretically there should be some function in the intact lung.
COMMENTARY The publication of the Dana-Farber experience almost 10 years ago was a sobering reminder of the potential dangers of new technologies for our patients. Patients with mesothelioma represent an especially difficult population to work with as their disease is related to environmental exposures that often leave them prone to other medical comorbidities. But it was especially disheartening as the patient population who had been treated had already had an EPP and had recovered sufficiently to be a candidate for radiation. If a relatively new technique such as IMRT was to be used, then novel ways to adapt the technology had to be implemented. The articles reviewed here represent the next wave of experience in the treatment of mesothelioma with IMRT. Table 1 reports the dosimetric data, rates of toxicity, and clinical outcome in the 3 studies on IMRT after EPP. The rate of pneumonitis is consistent between the studies (12%-16%) as is the rate of fatal toxicity (3%-8%). This is certainly a vast reduction from the 46% rate of death in the Dana-Farber experience. What accounts for the difference? The most obvious reason is the use of much more restrictive dose constraints for these patients. The V20 was 20%
PLEURAL INTENSITY-MODULATED RADIOTHERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA Rosenzweig KE, Zauderer MG, Laser B, et al. Int J Radiat Oncol Biol Phys 83:1278-1283, 2012 This article from Memorial Sloan-Kettering Cancer Center reviewed 36 patients treated with IMRT who underwent PD or biopsy alone.13 The purpose of the study was to establish the feasibility of pleural IMRT and assess its toxicity. A median dose of 4680 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 8 separate angles (Fig. 3). There were 7 patients (20%) with grade 3 or worse toxicity, including a fatality. Persistent pneumonitis was a long term toxicity in 5 patients (16%). The authors concluded that pleural
Table 2. Comparison of Dosimetric Parameters, Toxicity, and Outcome in Patients Receiving IMRT After Pleurectomy/Decortication or Biopsy Alone Reference Minatel et al12 Rosenzweig et al13
Number of Technique Dose Boost V5 Patients (Gy) (Gy) (%) 28
HT
50
10
36
IMRT
46.8
–
V20 (%) 36-38
56
Mean Lung Grade 3 Grade 5 Dose (Gy) þ RP (%) RP (%)
2-Year OS (%)
20-21
7
0
–
20
20
3
53
Gy, Gray; V5 and V20, dose of lung receiving 5 and 20 Gy, respectively; RP, radiation pneumonitis; OS, overall survival.
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MALIGNANT PLEURAL MESOTHELIOMA in the Dana-Farber report and most centers now try to keep it to less than 5%. Additionally, an acceptable mean lung dose has decreased from 15 Gy to approximately 10 Gy. Also it is important to note that although in all the reports, almost all patients received intravenous chemotherapy, in the Dana-Farber experience, 85% of patients also received heated intrapleural chemotherapy. It is unknown whether this treatment might have augmented the toxicity of the IMRT. Many thoracic surgeons have decreased their use of EPP in favor of PD 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 would be evaluating patients with two intact lungs in need of adjuvant radiation therapy. IMRT, with its ability to
1. Krayenbuehl J, Oertel S, Davis JB, et al: Combined photon and electron three-dimensional conformal versus intensity-modulated radiotherapy with integrated boost for adjuvant treatment of malignant pleural mesothelioma after pleuropneumonectomy. Int J Radiat Oncol Biol Phys 69(5):1593-1599, 2007 2. Allen AM, Czerminska M, Janne PA, et al: Fatal pneumonitis associated with intensitymodulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 65(3): 640-645, 2006 3. Kristensen CA, Nottrup TJ, Berthelsen AK, et al: Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma. Radiother Oncol 92(1):96-99, 2009 4. Miles EF, Larrier NA, Kelsey CR, et al: Intensitymodulated radiotherapy for resected mesothelioma: The Duke experience. Int J Radiat Oncol Biol Phys 71(4):1143-1150, 2008 5. Rice DC, Smythe WR, Liao Z, et al: Dosedependent pulmonary toxicity after postoperative
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6.
7.
8.
9.
deliver concave doses of radiation therapy to complex geometries is a logical solution to this problem. Both the two institutions who have reported their experience allow for higher doses of radiation to the lungs (V20 ¼ 20-21 Gy) but have fortunately demonstrated limited mortality and acceptable rates of pulmonary toxicity (Table 2). All 5 studies demonstrate that our ability to deliver IMRT has improved with experience. 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 considerable. Additionally, although the toxicity for these treatments has decreased, it is not insignificant and must be taken into consideration when treating our patients.
intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 69(2):350-357, 2007 Rusch VW, Rosenzweig K, Venkatraman E, et al: A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 122(4):788-795, 2001 Gomez DR, Hong DS, Allen PK, et al: Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensitymodulated radiation therapy for malignant pleural mesothelioma. J Thorac Oncol 8(2): 238-245, 2013 Patel PR, Yoo S, Broadwater G, et al: Effect of increasing experience on dosimetric and clinical outcomes in the management of malignant pleural mesothelioma with intensitymodulated radiation therapy. Int J Radiat Oncol Biol Phys 83(1):362-368, 2012 Giraud P, Sylvestre A, Zefkili S, et al: Helical tomotherapy for resected malignant pleural
10.
11.
12.
13.
mesothelioma: Dosimetric evaluation and toxicity. Radiother Oncol 101(2):303-306, 2011 Flores RM, Pass HI, Seshan VE, et al: Extrapleural pneumonectomy versus pleurectomy/ decortication in the surgical management of malignant pleural mesothelioma: Results in 663 patients. J Thorac Cardiovasc Surg 135(3): 620-626, 2008 [626 e621-623] Gupta V, Mychalczak B, Krug L, et al: Hemithoracic radiation therapy after pleurectomy/ decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 63(4): 1045-1052, 2005 Minatel E, Trovo M, Polesel J, et al: Tomotherapy after pleurectomy/decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lung. J Thorac Oncol 7(12):1862-1866, 2012 Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 83(4):1278-1283, 2012
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 3
Current Readings: Improvements in IntensityModulated Radiation Therapy for Malignant Pleural Mesothelioma Kenneth E. Rosenzweig, MD The treatment of malignant pleural mesothelioma with radiation therapy has always been a technical challenge. Early experience with intensity-modulated radiation therapy demonstrated troubling toxicity. Recent reports from institutions have demonstrated that with greater experience, intensity-modulated radiation therapy can be delivered safely, both in the setting of pneumonectomy or pleurectomy. After pneumonectomy, the dose to the contralateral lung must be minimized, preferably with a volume of lung receiving 20 Gy (V20) to less than 5% and a mean lung dose of approximately 10%. In the setting of 2 intact lungs, the mean lung dose can be as high as 20 Gy. Expected rates of grade 3 or worse radiation pneumonitis are 12%-20%. The rates of fatal pneumonitis are approximately 3%-8% in these studies, which demonstrate the considerable toxicity of treatment, even with improved technique. Semin Thoracic Surg 25:245–250 I 2013 Elsevier Inc. All rights reserved. Keywords mesothelioma, intensity-modulated radiation therapy, radiation pneumonitis, radiotherapy
INTRODUCTION As malignant pleural mesothelioma (MPM) is most often confined to the ipsilateral pleura, local control is the primary concern, particularly after surgical resection. Radiation therapy has traditionally been used in many malignancies as an adjuvant treatment in an effort to decrease the rate of local failure. Yet, treating the entire pleura requires a large radiation field and increases the risks of toxicity. Initially, when administering radiotherapy as adjuvant therapy following extrapleural pneumonectomy (EPP) or pleurectomy or decortication (PD), patients were treated with conventional radiation techniques using anterior or posterior fields with matching electrons. Over the past 15 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, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Address reprint requests to Kenneth Rosenzweig, MD, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, One Gustav L Levy Place, Box 1236, New York, NY 10029. E-mail: [email protected]
1043-0679/$-see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2013.10.004
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.1 Areas of underdosing or overdosing are readily recognizable and can be corrected in the planning phase. A potential disadvantage of IMRT in mesotheliomas is dose inhomogeneity and the dose of radiation delivered to the contralateral lung, which potentially leads to a higher risk of pneumonitis. Allen et al2 from Dana-Farber Cancer Institute, reported a 46% risk of fatal toxicity from radiation pneumonitis in patients treated with IMRT after EPP. This led many to question the use of this form of radiation therapy. 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.3-5 More recently, improved IMRT techniques for the treatment of MPM have been explored, with early outcomes suggesting acceptable safety in appropriately selected patients. There are two distinct situations for the use of IMRT; one where the diseased lung has been surgically removed and the other where it is intact. Here, we review some of the recent publications exploring new modalities of radiation therapy for MPM for both situations. 245
MALIGNANT PLEURAL MESOTHELIOMA TREATMENT AFTER EXTRAPLEURAL PNEUMONECTOMY Two types of surgical procedures are commonly performed for MPM-EPP and PD. EPP involves en bloc resection of the entire pleura, lung and diaphragm, and ipsilateral half of the pericardium. PD involves resection of gross tumor without resecting the lung. Although it is still technically challenging, radiation therapy after EPP is facilitated by the removal of the lung.6 In fact, part of the rationale for EPP was to allow for the use of postoperative radiation therapy. In the advent of 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 as none of the radiation beams were delivered at an angle, which is standard practice for IMRT. Some recent publications have updated their experience with IMRT after EPP. PATTERNS OF FAILURE, TOXICITY, AND SURVIVAL AFTER EXTRAPLEURAL PNEUMONECTOMY AND HEMITHORACIC RADIATION THERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA Gomez DR, Hong DS, Allen PK, et al. J Thorac Oncol 8:238-245, 2013
Figure 1. Fused PET or CT scans and radiation isodose curves (left) and diagnostic PET scans (right) of treatment failures in 2 different patients after extrapleural pneumonectomy followed by intensity-modulated radiation therapy for malignant pleural mesothelioma. (A) Arrows indicate failure within a cold spot where the isodose lines curved inward along the chest wall and thus compromised target coverage in this portion of the radiation field. (B) Recurrence in high-dose region and within subcutaneous tissues adjacent to the surgical scar. CT, computed tomography; PET, positron emission tomography. (Color version of figure is available online at http://www.semthorcardiovascsurg.com.). Reprinted with permission from Gomez DR, Hong DS, Allen PK, et al, Patterns of Failure, Toxicity, and Survival After Extrapleural Pneumonectomy and Hemithoracic Radiation Therapy for Malignant Pleural Mesothelioma, J Thorac Oncol, 8, 238–245, 2013.
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MALIGNANT PLEURAL MESOTHELIOMA M.D. Anderson Cancer Center recently updated their experience in treating MPM with IMRT after EPP.7 In this report, Gomez et al retrospectively analyzed 86 patients who underwent hemithoracic IMRT after EPP. Almost all patients had gastrointestinal symptoms, consisting primarily of nausea and esophagitis. Grade 3 or worse pulmonary toxicity occurred in 11.6% of patients. There were 5 fatal cases of pulmonary toxicity, 3 from radiation pneumonitis and 2 bronchopleural fistula. At 2 years, the rates of overall survival, local control, and distant control were 32%, 55%, and 40%, respectively. Fourteen patients (16%) experienced local failure and only 2 of these patients had local failure alone. Distant metastases were seen in 51 patients (59%) and included failures in the contralateral hemithorax and the abdomen. Figure 1 shows a typical radiation treatment plan for two different patients. One patient had a local failure within an area of underdosing and the other had local failure despite receiving a full dose of radiation to this region (Fig. 1). EFFECT OF INCREASING EXPERIENCE ON DOSIMETRIC AND CLINICAL OUTCOMES IN THE MANAGEMENT OF MALIGNANT PLEURAL MESOTHELIOMA WITH INTENSITY-MODULATED RADIATION THERAPY Patel PR, Yoo S, Broadwater G, et al. Int J Radiat Oncol Biol Phys 83:362-368, 2012 This review from the University of North Carolina (UNC) examined 30 patients who received IMRT following EPP.8 The median dose to the ipsilateral hemithorax was 45 Gy with a 8-25 Gy boost in 9
patients. The 2-year local control, disease-free survival, and overall survival rates were 47%, 34%, and 50% respectively (Fig. 2). Four patients (13%) developed radiation pneumonitis, including a fatality (3%). The UNC group also examined whether increased experience with this modality of treatment led to improvements in outcome. 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 staff, and therapy staff is of great value in producing high-quality treatment delivery. HELICAL TOMOTHERAPY FOR RESECTED MALIGNANT PLEURAL MESOTHELIOMA: DOSIMETRIC EVALUATION OF TOXICITY Giraud P, Sylvestre A, Zefkili S, et al. Radiother Oncol 101:303-306, 2011 Giraud and colleagues reported the largest experience in using helical tomotherapy, a specialized form of IMRT, in the treatment of mesothelioma as adjuvant treatment after EPP. Helical tomotherapy (HT) is a type of IMRT wherein the radiation is delivered through a gantry that is able to rotate 3601 around the patient. Simultaneously with the movement, the treatment couch and multileaf collimator leaves also move, allowing precise dose distributions in the tumor and theoretically shielding normal tissues, especially the lung. Additionally, image
Figure 2. Kaplan-Meier estimates of local control (dotted line), disease-free survival (black line), and overall survival (gray line). Tic marks represent censoring events. Reprinted from Int J Radiat Oncol Biol Phys, 83, Patel PR, Yoo S, Broadwater G, et al, Effect of Increasing Experience on Dosimetric and Clinical Outcomes in the Management of Malignant Pleural Mesothelioma With Intensity-Modulated Radiation Therapy, 362-368, Copyright (2012), with permission from Elsevier.
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 3
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Figure 3. Isodense beam distribution showing example of typical isodose distribution using 8 angles equally spaced over 2001-2401 sector encompassing the ipsilateral lung. Area within green lines depicts target volume. (Color version of figure is available online at http://www.semthorcardiovascsurg.com.). Reprinted from Int J Radiat Oncol Biol Phys, 83, Rosenzweig KE, Zauderer MG, Laser B, et al, Pleural IntensityModulated Radiotherapy For Malignant Pleural Mesothelioma, 1278-1283, Copyright (2012), with permission from Elsevier.
guidance is accomplished with daily imaging similar to computed tomography scans, which helps to ensure accurate treatment delivery. This study from the Curie Institute and the Rene Gauducheau Cancer Center, both in France, examined the use of helical tomotherapy after EPP.9 The investigators used 3 different clinical target volumes (CTVs). CTV1 encompassed the surgical cavity and was treated with 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 its median value in this group of patients was 4%. Overall, 24 patients were treated and 4 (16%) had grade 3 or worse radiation pneumonitis within 6 months, including 2 deaths (8%). There was only 1 case of grade 3 esophagitis. There were only 3 cases of local failure. The remaining patients had distant failure. RADIATION AFTER P/D With the growing use and potential benefit of PD instead of EPP,10 it became an increasing challenge to develop techniques to deliver therapeutic doses of radiation therapy to the entire pleura in the setting of an intact lung. Traditional delivery of hemithoracic radiotherapy using 2-dimensional (anterior-posterior) techniques has also been tested after PD. As the ipsilateral lung remains in situ after PD, 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
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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 1year local control rate of 42% and a median survival of 13.5 months.11 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 2 patients with possible grade 5 cardiac and pulmonary toxicity. Recently some centers explored the use of IMRT techniques in this setting. 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. TOMOTHERAPY AFTER PLEURECTOMY/ DECORTICATION OR BIOPSY FOR MALIGNANT PLEURAL MESOTHELIOMA ALLOWS THE DELIVERY OF HIGH DOSE RADIATION THERAPY IN PATIENTS WITH INTACT LUNG Minatel E, Trovo M, Polesel J, et al. J Thorac Oncol 7:1862-1866, 2012 This prospective study from Aviano, Italy, reported on 28 patients who were treated with HT after P/D or biopsy alone.12 All patients had 18fluoro-deoxyglucose–positron emission tomography scans after surgery for staging and were treated with an intended dose of 50 Gy. Areas that were hypermetabolic on positron emission tomography were boosted with an additional 10 Gy. The CTV
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 3
MALIGNANT PLEURAL MESOTHELIOMA Table 1. Comparison of Dosimetric Parameters, Toxicity, and Outcome in Patients Receiving IMRT After Extrapleural Pneumonectomy Reference Number of Technique Dose Boost V5 V20 Mean Lung Patients (Gy) (Gy) (%) (%) Dose (Gy) Giraud et al9 Patel et al8 Gomez et al7
Grade 3 þ Grade 5 RP (%) RP (%)
24
HT
50
4-6
99
4
11
16
8
30
IMRT
45
8-25
56
4
7.2
13
3
86
IMRT
45-50
10
8
12
6
2-Year OS (%) –
32
Gy, Gray; V5 and V20, dose of lung receiving 5 and 20 Gy, respectively; RP, radiation pneumonitis; OS, overall survival.
IMRT is a safe and feasible treatment technique for patients with MPM who have an intact lung on the affected side. This treatment option is currently under investigation at Memorial Sloan-Kettering Cancer Center as a phase II study. Additionally, pleural IMRT might provide good palliation for unresectable patients who have failed first-line chemotherapy.
extended from the lung apex to the upper abdomen and included the mediastinal lymph nodes when involved. The margin for planning target volume 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. Overall, 5 patients (18%) had respiratory toxicity, but only 2 were grade 3 (7%) and none was grade 5. Contralateral lung V5 strongly correlated with the risk of pneumonitis. This is especially interesting considering that theoretically there should be some function in the intact lung.
COMMENTARY The publication of the Dana-Farber experience almost 10 years ago was a sobering reminder of the potential dangers of new technologies for our patients. Patients with mesothelioma represent an especially difficult population to work with as their disease is related to environmental exposures that often leave them prone to other medical comorbidities. But it was especially disheartening as the patient population who had been treated had already had an EPP and had recovered sufficiently to be a candidate for radiation. If a relatively new technique such as IMRT was to be used, then novel ways to adapt the technology had to be implemented. The articles reviewed here represent the next wave of experience in the treatment of mesothelioma with IMRT. Table 1 reports the dosimetric data, rates of toxicity, and clinical outcome in the 3 studies on IMRT after EPP. The rate of pneumonitis is consistent between the studies (12%-16%) as is the rate of fatal toxicity (3%-8%). This is certainly a vast reduction from the 46% rate of death in the Dana-Farber experience. What accounts for the difference? The most obvious reason is the use of much more restrictive dose constraints for these patients. The V20 was 20%
PLEURAL INTENSITY-MODULATED RADIOTHERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA Rosenzweig KE, Zauderer MG, Laser B, et al. Int J Radiat Oncol Biol Phys 83:1278-1283, 2012 This article from Memorial Sloan-Kettering Cancer Center reviewed 36 patients treated with IMRT who underwent PD or biopsy alone.13 The purpose of the study was to establish the feasibility of pleural IMRT and assess its toxicity. A median dose of 4680 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 8 separate angles (Fig. 3). There were 7 patients (20%) with grade 3 or worse toxicity, including a fatality. Persistent pneumonitis was a long term toxicity in 5 patients (16%). The authors concluded that pleural
Table 2. Comparison of Dosimetric Parameters, Toxicity, and Outcome in Patients Receiving IMRT After Pleurectomy/Decortication or Biopsy Alone Reference Minatel et al12 Rosenzweig et al13
Number of Technique Dose Boost V5 Patients (Gy) (Gy) (%) 28
HT
50
10
36
IMRT
46.8
–
V20 (%) 36-38
56
Mean Lung Grade 3 Grade 5 Dose (Gy) þ RP (%) RP (%)
2-Year OS (%)
20-21
7
0
–
20
20
3
53
Gy, Gray; V5 and V20, dose of lung receiving 5 and 20 Gy, respectively; RP, radiation pneumonitis; OS, overall survival.
Seminars in Thoracic and Cardiovascular Surgery Volume 25, Number 3
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MALIGNANT PLEURAL MESOTHELIOMA in the Dana-Farber report and most centers now try to keep it to less than 5%. Additionally, an acceptable mean lung dose has decreased from 15 Gy to approximately 10 Gy. Also it is important to note that although in all the reports, almost all patients received intravenous chemotherapy, in the Dana-Farber experience, 85% of patients also received heated intrapleural chemotherapy. It is unknown whether this treatment might have augmented the toxicity of the IMRT. Many thoracic surgeons have decreased their use of EPP in favor of PD 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 would be evaluating patients with two intact lungs in need of adjuvant radiation therapy. IMRT, with its ability to
1. Krayenbuehl J, Oertel S, Davis JB, et al: Combined photon and electron three-dimensional conformal versus intensity-modulated radiotherapy with integrated boost for adjuvant treatment of malignant pleural mesothelioma after pleuropneumonectomy. Int J Radiat Oncol Biol Phys 69(5):1593-1599, 2007 2. Allen AM, Czerminska M, Janne PA, et al: Fatal pneumonitis associated with intensitymodulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 65(3): 640-645, 2006 3. Kristensen CA, Nottrup TJ, Berthelsen AK, et al: Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma. Radiother Oncol 92(1):96-99, 2009 4. Miles EF, Larrier NA, Kelsey CR, et al: Intensitymodulated radiotherapy for resected mesothelioma: The Duke experience. Int J Radiat Oncol Biol Phys 71(4):1143-1150, 2008 5. Rice DC, Smythe WR, Liao Z, et al: Dosedependent pulmonary toxicity after postoperative
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6.
7.
8.
9.
deliver concave doses of radiation therapy to complex geometries is a logical solution to this problem. Both the two institutions who have reported their experience allow for higher doses of radiation to the lungs (V20 ¼ 20-21 Gy) but have fortunately demonstrated limited mortality and acceptable rates of pulmonary toxicity (Table 2). All 5 studies demonstrate that our ability to deliver IMRT has improved with experience. 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 considerable. Additionally, although the toxicity for these treatments has decreased, it is not insignificant and must be taken into consideration when treating our patients.
intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 69(2):350-357, 2007 Rusch VW, Rosenzweig K, Venkatraman E, et al: A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 122(4):788-795, 2001 Gomez DR, Hong DS, Allen PK, et al: Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensitymodulated radiation therapy for malignant pleural mesothelioma. J Thorac Oncol 8(2): 238-245, 2013 Patel PR, Yoo S, Broadwater G, et al: Effect of increasing experience on dosimetric and clinical outcomes in the management of malignant pleural mesothelioma with intensitymodulated radiation therapy. Int J Radiat Oncol Biol Phys 83(1):362-368, 2012 Giraud P, Sylvestre A, Zefkili S, et al: Helical tomotherapy for resected malignant pleural
10.
11.
12.
13.
mesothelioma: Dosimetric evaluation and toxicity. Radiother Oncol 101(2):303-306, 2011 Flores RM, Pass HI, Seshan VE, et al: Extrapleural pneumonectomy versus pleurectomy/ decortication in the surgical management of malignant pleural mesothelioma: Results in 663 patients. J Thorac Cardiovasc Surg 135(3): 620-626, 2008 [626 e621-623] Gupta V, Mychalczak B, Krug L, et al: Hemithoracic radiation therapy after pleurectomy/ decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 63(4): 1045-1052, 2005 Minatel E, Trovo M, Polesel J, et al: Tomotherapy after pleurectomy/decortication or biopsy for malignant pleural mesothelioma allows the delivery of high dose of radiation in patients with intact lung. J Thorac Oncol 7(12):1862-1866, 2012 Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 83(4):1278-1283, 2012
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