Radiotherapy Treatment for Malignant Pleural Mesothelioma
Heading
Neoplastic pathologies are treated using different approaches depending on the stage of the disease; hence, there are early-stage tumours attacked by radical therapies, such as, for example, surgery and radiotherapy, and there are advanced-stage or metastatic tumours which are usually treated with palliative therapies, such as chemotherapy, immunotherapy or radiotherapy.
Malignant Pleural Mesothelioma (MPM) generally has an unlucky prognosis, and it is usually diagnosed at a late phase, when the disease is already in an advanced stage and cannot be subjected to radical treatment through a surgical approach. Therefore, most patients affected by MPM are treated with systemic chemotherapy or experimental protocols, which have nevertheless a merely palliative purpose, in addition to aiming at making the disease a chronic one for as long as possible.
However, radiotherapy also plays a role in the treatment of MPM, and can be used in different settings and even for opposite purposes.
This bibliographic review aims to evaluate the last studies published in scientific reviews which investigate the role of radiotherapy in the treatment of MPM.
Introduction
MPM is considered to be a radiotherapy-resistant neoplasia. Indeed, several studies have shown minimum benefits of this approach combined with the other standard treatments usually implemented in this area1 . Moreover, very often the use of radiotherapy is postponed due to the significant toxicity which this treatment can have on the lung itself.
In fact, a common collateral effect is represented by post-actinic pneumonias2. Already back in 1991, studies were published highlighting the pulmonary toxicity caused by radiotherapy applied at the level of the entire hemi-thorax: this data underscores how this treatment entails a moderate-severe and irreversible pulmonary damage in most patients subjected to radiotherapy3.
Therefore, radiotherapy has been mainly considered within the setting of palliative treatments, such as, for example, pain management4.
However, recent publications have determined that this recommendation should be changed as it has been observed that patients subjected to radiotherapy for palliative purposes also showed a good response depending on the administration of specific dosages5.
In vitro studies were also conducted assessing the usefulness of radiotherapy on the cell lines of malignant mesothelioma6. This data described the cellular sensitivity of mesothelioma to radiotherapy treatments, and it was shown that after two dosages of 2 Gy of radiation were administered, about 60-80% of the mesothelioma cells suffered a damage resulting in the inability to generate new colonies7.
With regards to this, experiments were also carried out on cell lines of murine models, which have demonstrated cellular survival in only 10% of the cases after 5 Gy of radiotherapy were administered8.
It is interesting to observe that some authors also proved the existence of a systemic activation and an increase in the proliferation of immune system cells (T-cells), in murine models in which cells previously irradiated in vitro with 5-15 Gy were injected under the skin9 .
If this research conducted on murine cells is applied to human cells, we can observe that sensitivity to radiotherapy is closely dependent upon the histological sub-type of the MPM. For instance, administering 25 Gy in vitro determines an increase in the release of damage signals, such as, for example, HMGB1 (High Mobility Group box 1), especially in the case of epithelioid MPA cells and not of sarcomatoid MPA cells. Since the release of HMGB1 is considered a pro-inflammatory factor able to activate dendritic cells and induce an immunotherapy response against the tumour, the absence of HMGB1 in sarcomatoid MPM might explain the different sensitivity of the two histological subtypes to radiotherapy10.
Medicines that act on the cell cycle could increase sensibility to radiotherapy, and this was tested on MPM cell lines MPM11 12 13. Indeed, the radiotherapy treatment causes damage at the DNA level through the generation of oxygen free radicals, consequently causing the cells to die14 15. Treatments that inhibit DNA repair or increase death of the cells therefore work in synergy with the radiotherapy.
In this case as well, however, the data is inconsistent since this was observed above all in the epithelioid MPM cell lines and not in sarcomatoid MPM cell lines. This difference may be tied to the fact that sarcomatoid tumours have such a resilience that allows them to better defend themselves against the DNA damage due to the sarcomatoid histotypes. Another explanation for the resistance of the sarcomatoid phenotype seems to be tied to the influence of the expression and of the release of fibroblasts growth factor16.
Prophylactic radiotherapy
In the case of surgery or surgical diagnostic procedures, there may be a dissemination of tumour cells at the level of the site where said approach was implemented.
The risk of local dissemination during a biopsy increases with the size of the procedure and ranges from 10% in case of transparietal biopsy, 13% in case of pleuroscopy, up to 26% in case a thoracotomy is performed17.
The metastasised tract may cause serious problems not only related to the worsening of the stage and of the prognosis, but also in terms of quality of life, since it can be the cause of several symptoms, the most frequent of which is pain.
For this reason, prophylactic therapy plays a role in these patients, since it reduces the risk of metastasis resulting from these diagnostic or therapeutic procedures.
The initial data pertaining to these findings was published in 1995; the authors proved that a reduction in this dissemination could be tied to the reduced angiogenesis and to the diminished release in tumour growth factors which occur thanks to the use of radiotherapy treatment18.
Nevertheless, this data is inconsistent, since other studies have not confirmed this research and, on the contrary, have shown a difference in terms of reduction of the risk of metastasis after an invasive procedure, between the group of patients treated with radiotherapy and the control group19 20 21 22 23 34 25 26.
Palliative radiotherapy
We speak of palliative radiotherapy for patients suffering from MPM when the treatment is aimed, for example, at the management of pain, of dysphagia, of obstruction of the upper respiratory tract and at relief of vena cava compression27. In fact, the radiotherapy treatment is able to bring about an improvement in severe symptoms for the patient and, although this setting does not entail an increase in survival, it is nevertheless an effective method for improving the quality of life.
Actually, radiotherapy can be used for palliative purposes also for the remote treatment of metastasis, such as, for example, bone or encephalic lesions. In this case, radiotherapy aims at blocking the secondary lesion, improving any symptoms that may be present, as wells as at reducing any symptoms and signs that may develop in the future due to these metastases, and that may lead to a further worsening of the patient’s quality of life28 29 30 31.
In fact, it has been demonstrated that, especially for non-sarcomatoid histology, palliative radiotherapy was useful and that sensitivity to radiotherapy was correlated to an improvement of the patient’s overall conditions and, consequently, a clear clinical benefit32 33 34.
Adjuvant radiotherapy
Adjuvant radiotherapy is the treatment administered after surgery as an “adjuvant” to the surgical approach in order to obtain the best outcome.
The Memorial Sloan Kettering Cancer Center (MSKCC, New York City, NY, USA) was a pioneer in the study of this technique35 36 37 38 39 40.
The radiotherapy approach may also be used intra-surgery. However, it was demonstrated that this option is not an effective treatment and, moreover may cause severe complications such as pleural empyema41 42 43.
The use of hemithoracic adjuvant radiotherapy at high dosages seems to entail a reduction in the risk of relapse; in fact, some authors claim that with this treatment, the risk of locoregional relapse is approximately 15%44 45 46.
Intensity-modulated radiotherapy (IMRT) has also been used as hemithoracic therapy at high dosages, and it has shown to provide a benefit in terms of relapse reduction, especially when applied at the level of the base of the ribcage, in areas with a higher risk of a relapse of the locoregional disease47 48 49.
It is important to remember that these treatments are not risk-free. For example, the literature includes cases of lethal contralateral pneumonia, especially after use of radiotherapy after an extrapleural pneumonectomy50 51 52. For this reason, a crucial factor is the proper dosage of the radiotherapy in addition to a careful evaluation of the patient’s respiratory functionality53 54 55.
Other authors, on the other hand, have demonstrated how radiotherapy, and in particular the modulated-intensity type, may be an approach that is easily tolerated by patient and featuring a not-so-high risk of post-actinic pneumonias56 57 58 59 60 61 62.
Moreover, a more innovative technique would allow a further reduction in the risk of complications: this innovative technique is called VMAT (Volumetric-Modulated Arc Therapy)63 64 65.
Increased control over the disease has been described in patients subjected to adjuvant radiotherapy66 67.
With these purposes, new randomised and prospective studies on the association between chemotherapy and adjuvant radiotherapy may possibly provide data demonstrating greater efficacy68 69 70 71 72 73 74. Indeed, chemotherapy may reduce the risk of a relapse while radiotherapy may increase local control75 76 77 78 79 80 81 82 83 84 85 86.
Induction radiotherapy
Trimodal therapy consists of the application of chemotherapy, followed by extrapleural pneumonectomy and by hemithoracic adjuvant radiotherapy at high dosages.
Use of the therapy in this setting resulted in better survival and local control of the disease87. On the basis of this research, we can hypothesise that radiotherapy can also be applied at the early stages of MPM, rather than using chemotherapy: this therapy setting is known as "induction" radiotherapy88 89.
In studies on the application of radiotherapy in this setting, the surgical complications which occurred after the induction radiotherapy treatment were similar to those recorded after the adjuvant chemotherapy treatment90.
In this case too, the patients with epithelioid MPM had a better outcome compared to those affected by the other histological type91.
Several studies have underscored how the tumour volume is correlated with the outcome and how it could also be a guiding factor in the choice of whether or not to subject a patient to induction therapy92 93 94 95. On the contrary, the same data cannot be applied to the response to chemotherapy, which instead does not depend on the volume of the neoplasias, as it happens with radiotherapy and surgery96. This data indicates that patients with localised disease may be good candidates for treatment with induction radiotherapy, whilst those with a large-sized tumour would benefit instead from chemotherapy97.
Conclusions
Future prospects include the possibility to combine standard treatments for MPM, such as radiotherapy, and immune-system treatments98 99 100. In the past fifteen years, the role of radiotherapy in the treatment of MPM has grown, also supported by scientific evidence demonstrated in various treatment settings.
However, the real benefit of this method has yet to be completely defined for this type of neoplasia, but new and innovative approaches, such as IMRT at the pleural level and induction-accelerated hemithoracic radiotherapy performed after surgery may very well be feasible and well-tolerated.
New studies will make it possible to provide an answer these still unanswered questions.
Bibliography
1. Wanebo HJ, Martini N, Melamed MR, Hilaris B, Beattie EJ Jr. Pleural mesothelioma. Cancer 1976; 38: 2481–88.
2. Ball DL, Cruickshank DG. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 1990;13: 4–9.
3. Maasilta P1, Kivisaari L, Holsti LR, Tammilehto L, Mattson K. Radiographic chest assessment of lung injury following hemithorax irradiation for pleural mesothelioma. Eur Respir J 1991; 4: 76–83.
4. Gordon W Jr, Antman KH, Greenberger JS, Weichselbaum RR, Chaffey JT. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982; 8: 19–25.
5. de Graaf-Strukowska L, van der Zee J, van Putten W, Senan S. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura—a single-institution experience with 189 patients. Int J Radiat Oncol Biol Phys 1999; 43: 511–16.
6. Carmichael J, Degraff WG, Gamson J, et al. Radiation sensitivity of human lung cancer cell lines. Eur J Cancer Clin Oncol 1989; 25: 527–34.
7. Shearin JC Jr, Jackson D. Malignant pleural mesothelioma. Report of 19 cases. J Thorac Cardiovasc Surg 1976; 71: 621–27.
8. Wu L, Wu MO, De la Maza L, et al. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget 2015; 6: 12468–80.
9. Mattson K, Holsti LR, Tammilehto L, et al. Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 1992; 24: 643–50.
10. Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015; 16: e498–509.
11. Indovina P, Marcelli E, Di Marzo D, et al. Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma. Cancer Biol Ther 2014; 15: 380–88.
12. Sudo H, Tsuji AB, Sugyo A, Ogawa Y, Sagara M, Saga T. ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model. Cancer Sci 2012; 103: 203–09.
13. Verbrugge I, Wissink EH, Rooswinkel RW, et al. Combining radiotherapy with APO010 in cancer treatment. Clin Cancer Res 2009; 15: 2031–38.
14. Indovina P, Marcelli E, Di Marzo D, et al. Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma. Cancer Biol Ther 2014; 15: 380–88.
15. Verbrugge I, Wissink EH, Rooswinkel RW, et al. Combining radiotherapy with APO010 in cancer treatment. Clin Cancer Res 2009; 15: 2031–38.
16. Schelch K, Hoda MA, Klikovits T, et al. Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. Am J Respir Crit Care Med 2014; 190: 763–72.
17. Metintas M, Ak G, Parspour S, et al. Local recurrence of tumor at sites of intervention in malignant pleural mesothelioma. Lung Cancer 2008; 61: 255–61.
18. Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 1995; 108: 754–58
19. Bydder S, Phillips M, Joseph DJ, et al. A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. Br J Cancer 2004; 91: 9–10.
20. O’Rourke N, Garcia JC, Paul J, Lawless C, McMenemin R, Hill J. A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma. Radiother Oncol 2007; 84: 18–22.
21. Clive AO, Taylor H, Dobson L, 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: 1094–104.
22. Bayman N, Ardron D, Ashcroft L, et al. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention. BMJ Open 2016; 6: e010589.
23. Bayman N, Ardron D, Ashcroft L, et al. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention. BMJ Open 2016; 6: e010589.
24. Clive AO, Taylor H, Maskell NA. Prophylactic radiotherapy to prevent procedure-tract metastases—Author’s reply. Lancet Oncol 2016; 17: e419.
25. Bölükbas S, Manegold C, Eberlein M, Bergmann T, Fisseler-Eckhoff A, Schirren J. Survival after trimodality therapy for malignant pleural mesothelioma: radical pleurectomy, chemotherapy with cisplatin/pemetrexed and radiotherapy. Lung Cancer 2011; 71: 75–81.
26. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg 2015; 149: 558–65.
27. Gordon W Jr, Antman KH, Greenberger JS, Weichselbaum RR, Chaffey JT. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982; 8: 19–25.
28. Ball DL, Cruickshank DG. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 1990; 13: 4–9.
29. de Graaf-Strukowska L, van der Zee J, van Putten W, Senan S. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura—a single-institution experience with 189 patients. Int J Radiat Oncol Biol Phys 1999; 43: 511–16.
30. Davis SR, Tan L, Ball DL. Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994; 38: 212–14.
31. Bissett D, Macbeth FR, Cram I. The role of palliative radiotherapy in malignant mesothelioma. Clin Oncol (R Coll Radiol) 1991; 3: 315–17.
32. Jenkins P, Milliner R, Salmon C. Re-evaluating the role of palliative radiotherapy in malignant pleural mesothelioma. Eur J Cancer 2011; 47: 2143–49.
33. MacLeod N, Chalmers A, O’Rourke N, et al. Is radiotherapy useful for treating pain in mesothelioma?: a phase II trial. J Thorac Oncol 2015; 10: 944–50.
34. Aston M, O’Rourke N, Macleod N, Chalmers A. SYSTEMS-2: a randomised phase II trial of standard versus dose escalated radiotherapy in the treatment of pain in malignant pleural mesothelioma. Lung Cancer 2016; 91 (suppl 1): s71 (abstr 194).
35. Kutcher GJ, Kestler C, Greenblatt D, Brenner H, Hilaris BS, Nori D. Technique for external beam treatment for mesothelioma. Int J Radiat Oncol Biol Phys 1987; 13: 1747–52.
36. Hilaris BS, Nori D, Kwong E, Kutcher GJ, Martini N. Pleurectomy and intraoperative brachytherapy and postoperative radiation in the treatment of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 1984; 10: 325–31.
37. Cao C, Tian D, Park J, Allan J, Pataky KA, Yan TD. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer 2014; 83: 240–45.
38. Rimner A, Spratt DE, Zauderer MG, et al. Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2014; 90: 394–401.
39. Shaikh F, Zauderer MG, von Reibnitz D, et al. Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma. J Thorac Oncol 2017; 12: 993–1000.
40. Pan HY, Jiang S, Sutton J, et al. Early experience with intensity modulated proton therapy for lung-intact mesothelioma: a case series. Pract Radiat Oncol 2015; 5: e345–e353.
41. Cupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005; 63: 1045–52.
42. Cupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2005; 63: 1045–52.
43. 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 2001;122: 788–95.
44. Gomez DR, Hong DS, Allen PK, et al. Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma. J Thorac Oncol 2013; 8: 238–45.
45. Thieke C, Nicolay NH, Sterzing F, et al. Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy. Radiat Oncol 2015; 10: 267.
46. 32
47. Allen AM, Czerminska M, Jänne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006; 65: 640–45.
48. Vedere nota 47
49. Forster KM, Smythe WR, Starkschall G, et al. Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int J Radiat Oncol Biol Phys 2003; 55: 606–16
50. Vedere nota 47
51. Kristensen CA, N.ttrup TJ, Berthelsen AK, et al. Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma. Radiother Oncol 2009; 92: 96–99.
52. Chi A, Liao Z, Nguyen NP, et al. Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol 2011; 6: 1132–41.
53. Rice DC, Smythe WR, Liao Z, et al. Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2007; 69: 350–57.
54. Vedere nota 52
55. 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. Int J Radiat Oncol Biol Phys 2012; 83: 362–68.
56. Thieke C, Nicolay NH, Sterzing F, et al. Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy. Radiat Oncol 2015; 10: 267.
57. Rice DC, Smythe WR, Liao Z, et al. Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2007; 69: 350–57.
58. 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. Int J Radiat Oncol Biol Phys 2012; 83: 362–68.
59. Ahamad A, Stevens CW, Smythe WR, et al. Intensity-modulated radiation therapy: a novel approach to the management of malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2003; 55: 768–75.
60. Tonoli S, Vitali P, Scotti V, et al. Adjuvant radiotherapy after extrapleural pneumonectomy for mesothelioma. Prospective analysis of a multi-institutional series. Radiother Oncol 2011; 101: 311–15
61. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallières E. Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 2009; 88: 870–75.
62. Du KL, Both S, Friedberg JS, Rengan R, Hahn SM, Cengel KA. Extrapleural pneumonectomy, photodynamic therapy and intensity modulated radiation therapy for the treatment of malignant pleural mesothelioma. Cancer Biol Ther 2010; 10: 425–29
63. Scorsetti M, Bignardi M, Clivio A, et al. Volumetric modulation arc radiotherapy compared with static gantry intensity-modulated radiotherapy for malignant pleural mesothelioma tumor: a feasibility study. Int J Radiat Oncol Biol Phys 2010; 77: 942–49.
64. Botticella A, Defraene G, Nackaerts K, et al. Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation?: A planning study. Strahlenther Onkol 2017; 193: 285–94.
65. Runxiao L, Yankun C, Lan W. A pilot study of volumetric-modulated arc therapy for malignant pleural mesothelioma. J Appl Clin Med Phys 2016; 17: 139–44.
66. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallières E. Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 2009; 88: 870–75.
67. Krayenbuehl J, Dimmerling P, Ciernik IF, Riesterer O. Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 2014; 9: 32.
68. Rea F, Marulli G, Bortolotti L, et al. Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): feasibility and results. Lung Cancer 2007; 57: 89–95.
69. Flores RM, Krug LM, Rosenzweig KE, et al. Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol 2006; 1: 289–95.
70. Batirel HF, Metintas M, Caglar HB, et al. Trimodality treatment of malignant pleural mesothelioma. J Thorac Oncol 2008; 3: 499–504.
71. Van Schil PE, Baas P, Gaafar R, et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J 2010; 36: 1362–69.
72. Hasegawa S, Okada M, Tanaka F, et al. Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan mesothelioma interest group 0601 trial. Int J Clin Oncol 2016; 21: 523–30.
73. Weder W, Stahel RA, Bernhard J, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007; 18: 1196–202.
74. Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009; 27: 3007–13.
75. Federico R, Adolfo F, Giuseppe M, et al. Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma. BMC Cancer 2013; 13: 22.
76. Minatel E, Trovo M, Polesel J, et al. Radical pleurectomy/ decortication followed by high dose of radiation therapy for malignant pleural mesothelioma. Final results with long-term follow-up. Lung Cancer 2014; 83: 78–82.
77. Cho BC, Feld R, Leighl N, et al. A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma. J Thorac Oncol 2014; 9: 397–402.
78. 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 2008; 135: 620–26.
79. Yan TD, Boyer M, Tin MM, et al. Extrapleural pneumonectomy for malignant pleural mesothelioma: outcomes of treatment and prognostic factors. J Thorac Cardiovasc Surg 2009; 138: 619–24.
80. Pass HI, Giroux D, Kennedy C, et al. Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. J Thorac Oncol 2014; 9: 856–64.
81. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A lung cancer study group trial. J Thorac Cardiovasc Surg 1991; 102: 1–9.
82. Treasure T, Lang-Lazdunski L, Waller D, 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: 763–72.
83. Vedere nota 83
84. Weder W, Stahel RA, Baas P, et al. The MARS feasibility trial: conclusions not supported by data. Lancet Oncol 2011; 12: 1093–94.
85. Rimner A, Simone CB 2nd, Zauderer MG, Cengel KA, Rusch VW. Hemithoracic radiotherapy for mesothelioma: lack of benefit or lack of statistical power? Lancet Oncol 2016; 17: e43–44.
86. Kostron A, Friess M, Crameri O, et al. Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma. Eur J Cardiothorac Surg 2016; 49: 1516–23.
87. de Perrot M, Feld R, Cho BC, et al. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009; 27: 1413–18.
88. Cho BC, Feld R, Leighl N, et al. A feasibility study evaluating surgery for mesothelioma after radiation therapy: the “SMART” approach for resectable malignant pleural mesothelioma. J Thorac Oncol 2014; 9: 397–402
89. de Perrot M, Feld R, Leighl NB, et al. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2016; 151: 468–73.
90. Mordant P, McRae K, Cho J, et al. Impact of induction therapy on postoperative outcome after extrapleural pneumonectomy for malignant pleural mesothelioma: does induction-accelerated hemithoracic radiation increase the surgical risk? Eur J Cardiothorac Surg 2016; 50: 433–38.
91. de Perrot M, Dong Z, Bradbury P, et al. Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma. Eur Respir J 2017; 49: 1601428
92. Opitz I, Friess M, Kestenholz P, et al. A new prognostic score supporting treatment allocation for multimodality therapy for malignant pleural mesothelioma: a review of 12 years’ experience. J Thorac Oncol 2015; 10: 1634–41.
93. Gill RR, Richards WG, Yeap BY, et al. Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume. AJR Am J Roentgenol 2012; 198: 359–63.
94. Rusch VW, Gill R, Mitchell A, et al. A multicenter study of volumetric computed tomography for staging malignant pleural mesothelioma. Ann Thorac Surg 2016; 102: 1059–66.
95. Pass HI, Temeck BK, Kranda K, Steinberg SM, Feuerstein IR. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998; 115: 310–17.
96. Liu F, Zhao B, Krug LM, et al. Assessment of therapy responses and prediction of survival in malignant pleural mesothelioma through computer-aided volumetric measurement on computed tomography scans. J Thorac Oncol 2010; 5: 879–84.
97. Vedere nota 96
98. Wu L, Yun Z, Tagawa T, Rey-McIntyre K, de Perrot M. CTLA-4 blockade expands infiltrating T cells and inhibits cancer cell repopulation during the intervals of chemotherapy in murine mesothelioma. Mol Cancer Ther 2012; 11: 1809–19.
99. Alley EW, Katz SI, Cengal KA, Simone CB 2nd. Immunotherapy and radiation therapy for malignant pleural mesothelioma. Transl Lung Cancer Res 2017; 6: 212–19.
100. Wu L, Wu MO, De la Maza L, et al. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget 2015; 6: 12468–80.
t 2015; 6: 12468–80.