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Pleural IMRT after Lung-Sparing Cytoreduction for Mesothelioma: Mature Enough to Randomize
EDITORIAL
Pleural IMRT after Lung-Sparing Cytoreduction for Mesothelioma: Mature Enough to Randomize Harvey I. Pass, MD* I do not think that there are any questions now about whether you can deliver radiation therapy (RT) safely after lung-sparing maximal cytoreductive surgery for pleural mesothelioma. Shaikh et al. from Rimner’s group have been the leaders in perfecting these complicated intensity-modulated RT (IMRT) techniques, and their results are now maturing so that the everyday mesothelioma practitioner as well as individuals who design the next series of multi-institutional prospective randomized trials can be assured that the planning can be standardized.1 The safety of the technique depends on the expertise of the center, and as defined in this report, there is always going to be some pneumonitis that could lead to death in 2% to 3% of those receiving IMRT. Just like surgical mortality rates in mesothelioma, with proper patient selection and further standardization and refinement of techniques, this rate will improve over time. The real issue, however, is efficacy, and frankly, I am still perplexed about the magnitude of added value of pleural IMRT with regard to overall survival. In its report, Rimner’s group has published a 20.2-month median survival from the completion of the RT in his cohort of 78 patients.1 Moreover, according to the authors, the RT was always the last therapy given in those cases where chemotherapy was delivered either preoperatively or postoperatively. How does this compare to anything in the literature???? Well, all the induction trials with neoadjuvant chemotherapy and surgery (extrapleural pneumonectomy [EPP]) with or without postoperative IMRT have reported median intent-totreat survival times of about 19 to 25 months from the start of the chemotherapy.2–4 At least up until recently, Memorial Sloan Kettering Cancer Center was giving preoperative chemotherapy and then postoperative IMRT in the pleurectomy situation, and in the original publication of the IMPRINT therapy,5 the median survival from the completion of IMRT was 23.7 months. From this comparison, one would conclude that the results of Rimner’s group are at least as good as the early multimodality induction trials with EPP. But we have moved on from always performing EPP, and at many centers lung sparing is a first option.6 Are these
promising results due just to patient selection? If you can do a lung-sparing operation on patients with mesothelioma, those patients usually have lower-volume disease, and for the most part, you are selecting for better long-term survivors. Obviously, biology plays a big part, and as pointed out by Bueno et al. and Kiyotani et al.,7,8 even epithelial mesothelioma is heterogeneous with regard to its survival. Nevertheless, many institutions have moved to performing surgery as a first treatment option for patients who are meticulously staged and thought to be free of nodal or chest wall involvement instead of delivering the chemotherapy in a neoadjuvant setting. Hence, the clock is being reset, and first treatment becomes surgery, so that overall survival becomes the interval from surgical maximal cytoreduction to death. The same issues that have perpetually “dogged” the induction trials will now have to be looked at if we are to routinely add IMRT in the postoperative setting, and the whole issue of intent to treat remains important. It is difficult from this report, as well as from the original IMPRINT trial, to delineate what the potential falloff for patients chosen to have lung-sparing cytoreducible disease will be, because some of the patients will already have had pleurectomy before the trial and others will have been deemed inoperable.5 If the new trifecta is surgery, chemotherapy, and then radiation or surgery followed by radiation and then by chemotherapy, we will need to know how many patients can actually get the whole package. Are we talking about a prospective trial here with potential randomization? Absolutely. Essentially,
*Corresponding author. New York University Langone Medical Center, New York, New York. Disclosure: The author declares no conflict of interest. Address for correspondence: Harvey I. Pass, MD, Department of Cardiothoracic Surgery, New York University Langone Medical Center, 530 First Ave., Suite 9V, New York, NY 10016. E-mail: harvey.pass@ med.nyu.edu ª 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2017.04.013
Journal of Thoracic Oncology
Vol. 12 No. 6: 919-921
920 Pass
only patients who are thought to have a lung-sparing option at the outset should be evaluable for such a trial. Moreover, the timing of the interventions may play a role in this as well as the duration of, say, the chemotherapy. How many cycles of postoperative chemotherapy should there be before SBRT if that is the regimen, and is that better than delivering the IMRT first and then the chemotherapy? Could toxicity of the IMRT delay or prevent patients from receiving postoperative adjuvant chemotherapy, which in the International Society for the Study of Lung Cancer/ International Mesothelioma Interest Group mesothelioma registry,9 is already an independent factor for survival? There are hints of data already in the literature from Minatel et al., who used a surgerychemotherapy-IMRT sandwich in 69 patients, 35 of whom had a true macroscopic complete resection and 34 of whom did not.10 Most of the patients (53 of 69) received postoperative adjuvant chemotherapy followed by IMRT, and the median survival from surgery was approximately 30 months. As presented in the report, if one assumes that four cycles was about 4 months, followed by a 1-month period before IMRT, and the IMRT lasted 5 weeks, then the adjusted median survival from the completion of IMRT was 24 months, which is very similar to the results of Rimner’s group in 78 patients. How about the other situation: surgery, radiotherapy, and then chemotherapy? Unfortunately, the one large study that incorporates all of these in the recent literature includes hyperthermic pleural lavage with povidone (betadine), and the radiotherapy was really prophylactic to incision sites, not IMRT.11 So it is really lung sparing with postoperative chemotherapy. Their overall survival of 32 months is measured from the time of diagnosis of mesothelioma! The take-home message here is that there is so much variability in the conduct and reporting of lung-sparing multimodality mesothelioma treatment strategies from all over the world that it is impossible to have consensus on a standard regimen. The nonbelievers will say that it is patient selection (earlier-stage patients) in betterfunctioning individuals who, independent of any other therapy, would do well in a surgical setting. We need to data to confirm or refute these arguments. So, as an old mesothelioma surgeon who, fortunately or unfortunately, has seen it all, I am left to believe that there is indeed a promising efficacy signal with pleural IMRT, but I do not know which patient, when, and what else to do besides the surgery. Maybe this is where we stop fooling ourselves and realize that we need a randomized trial to try to sort out these issues. A national effort through the National Cancer Institute is already under way to develop novel trials in
Journal of Thoracic Oncology
Vol. 12 No. 6
pleural mesothelioma, and the possibility for unification of centers with surgical and IMRT experience to define treatment sequencing as well as the role of adjuvant chemotherapy with or without IMRT has never been better. Answers to these basic questions for potentially resectable mesothelioma can only be evidence based by randomization. There are no more excuses: we have enough data for IMRT, as well as for the safety of surgery in the disease to do the trial and at the same time focus efforts on the quality of life for patients having these therapies, which is another important but relatively ignored issue. The care and feeding of such a trial is a difficult pill for all of use to swallow, but who wants to keep on reading studies that do not even agree on the definition of when to start the clock for overall survival reporting????
References 1. 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. 2. 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;18:1196–1202. 3. 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: 3007–3013. 4. 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. 5. Rimner A, Zauderer MG, Gomez DR, et al. Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma. J Clin Oncol. 2016;34:2761–2768. 6. Rusch V, Baldini EH, Bueno R, et al. The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 1114, 2012, Boston, Mass. J Thorac Cardiovasc Surg. 2013;145:909–910. 7. Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–416. 8. Kiyotani K, Park JH, Inoue H, et al. Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma. Oncoimmunology. 2017;6:e1278330. 9. Pass HI, Giroux D, Kennedy C, et al. Supplementary prognostic variables for pleural mesothelioma: a report
June 2017 from the IASLC staging committee. J Thorac Oncol. 2014;9:856–864. 10. Minatel E, Trovo M, Bearz A, et al. Radical radiation therapy after lung-sparing surgery for malignant pleural mesothelioma: survival, pattern of failure, and prognostic factors. Int J Radiat Oncol Biol Phys. 2015;93:606–613.
IMRT after Cytoreduction for Mesothelioma
921
11. 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;149:558–565.
Pleural IMRT after Lung-Sparing Cytoreduction for Mesothelioma: Mature Enough to Randomize Harvey I. Pass, MD* I do not think that there are any questions now about whether you can deliver radiation therapy (RT) safely after lung-sparing maximal cytoreductive surgery for pleural mesothelioma. Shaikh et al. from Rimner’s group have been the leaders in perfecting these complicated intensity-modulated RT (IMRT) techniques, and their results are now maturing so that the everyday mesothelioma practitioner as well as individuals who design the next series of multi-institutional prospective randomized trials can be assured that the planning can be standardized.1 The safety of the technique depends on the expertise of the center, and as defined in this report, there is always going to be some pneumonitis that could lead to death in 2% to 3% of those receiving IMRT. Just like surgical mortality rates in mesothelioma, with proper patient selection and further standardization and refinement of techniques, this rate will improve over time. The real issue, however, is efficacy, and frankly, I am still perplexed about the magnitude of added value of pleural IMRT with regard to overall survival. In its report, Rimner’s group has published a 20.2-month median survival from the completion of the RT in his cohort of 78 patients.1 Moreover, according to the authors, the RT was always the last therapy given in those cases where chemotherapy was delivered either preoperatively or postoperatively. How does this compare to anything in the literature???? Well, all the induction trials with neoadjuvant chemotherapy and surgery (extrapleural pneumonectomy [EPP]) with or without postoperative IMRT have reported median intent-totreat survival times of about 19 to 25 months from the start of the chemotherapy.2–4 At least up until recently, Memorial Sloan Kettering Cancer Center was giving preoperative chemotherapy and then postoperative IMRT in the pleurectomy situation, and in the original publication of the IMPRINT therapy,5 the median survival from the completion of IMRT was 23.7 months. From this comparison, one would conclude that the results of Rimner’s group are at least as good as the early multimodality induction trials with EPP. But we have moved on from always performing EPP, and at many centers lung sparing is a first option.6 Are these
promising results due just to patient selection? If you can do a lung-sparing operation on patients with mesothelioma, those patients usually have lower-volume disease, and for the most part, you are selecting for better long-term survivors. Obviously, biology plays a big part, and as pointed out by Bueno et al. and Kiyotani et al.,7,8 even epithelial mesothelioma is heterogeneous with regard to its survival. Nevertheless, many institutions have moved to performing surgery as a first treatment option for patients who are meticulously staged and thought to be free of nodal or chest wall involvement instead of delivering the chemotherapy in a neoadjuvant setting. Hence, the clock is being reset, and first treatment becomes surgery, so that overall survival becomes the interval from surgical maximal cytoreduction to death. The same issues that have perpetually “dogged” the induction trials will now have to be looked at if we are to routinely add IMRT in the postoperative setting, and the whole issue of intent to treat remains important. It is difficult from this report, as well as from the original IMPRINT trial, to delineate what the potential falloff for patients chosen to have lung-sparing cytoreducible disease will be, because some of the patients will already have had pleurectomy before the trial and others will have been deemed inoperable.5 If the new trifecta is surgery, chemotherapy, and then radiation or surgery followed by radiation and then by chemotherapy, we will need to know how many patients can actually get the whole package. Are we talking about a prospective trial here with potential randomization? Absolutely. Essentially,
*Corresponding author. New York University Langone Medical Center, New York, New York. Disclosure: The author declares no conflict of interest. Address for correspondence: Harvey I. Pass, MD, Department of Cardiothoracic Surgery, New York University Langone Medical Center, 530 First Ave., Suite 9V, New York, NY 10016. E-mail: harvey.pass@ med.nyu.edu ª 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2017.04.013
Journal of Thoracic Oncology
Vol. 12 No. 6: 919-921
920 Pass
only patients who are thought to have a lung-sparing option at the outset should be evaluable for such a trial. Moreover, the timing of the interventions may play a role in this as well as the duration of, say, the chemotherapy. How many cycles of postoperative chemotherapy should there be before SBRT if that is the regimen, and is that better than delivering the IMRT first and then the chemotherapy? Could toxicity of the IMRT delay or prevent patients from receiving postoperative adjuvant chemotherapy, which in the International Society for the Study of Lung Cancer/ International Mesothelioma Interest Group mesothelioma registry,9 is already an independent factor for survival? There are hints of data already in the literature from Minatel et al., who used a surgerychemotherapy-IMRT sandwich in 69 patients, 35 of whom had a true macroscopic complete resection and 34 of whom did not.10 Most of the patients (53 of 69) received postoperative adjuvant chemotherapy followed by IMRT, and the median survival from surgery was approximately 30 months. As presented in the report, if one assumes that four cycles was about 4 months, followed by a 1-month period before IMRT, and the IMRT lasted 5 weeks, then the adjusted median survival from the completion of IMRT was 24 months, which is very similar to the results of Rimner’s group in 78 patients. How about the other situation: surgery, radiotherapy, and then chemotherapy? Unfortunately, the one large study that incorporates all of these in the recent literature includes hyperthermic pleural lavage with povidone (betadine), and the radiotherapy was really prophylactic to incision sites, not IMRT.11 So it is really lung sparing with postoperative chemotherapy. Their overall survival of 32 months is measured from the time of diagnosis of mesothelioma! The take-home message here is that there is so much variability in the conduct and reporting of lung-sparing multimodality mesothelioma treatment strategies from all over the world that it is impossible to have consensus on a standard regimen. The nonbelievers will say that it is patient selection (earlier-stage patients) in betterfunctioning individuals who, independent of any other therapy, would do well in a surgical setting. We need to data to confirm or refute these arguments. So, as an old mesothelioma surgeon who, fortunately or unfortunately, has seen it all, I am left to believe that there is indeed a promising efficacy signal with pleural IMRT, but I do not know which patient, when, and what else to do besides the surgery. Maybe this is where we stop fooling ourselves and realize that we need a randomized trial to try to sort out these issues. A national effort through the National Cancer Institute is already under way to develop novel trials in
Journal of Thoracic Oncology
Vol. 12 No. 6
pleural mesothelioma, and the possibility for unification of centers with surgical and IMRT experience to define treatment sequencing as well as the role of adjuvant chemotherapy with or without IMRT has never been better. Answers to these basic questions for potentially resectable mesothelioma can only be evidence based by randomization. There are no more excuses: we have enough data for IMRT, as well as for the safety of surgery in the disease to do the trial and at the same time focus efforts on the quality of life for patients having these therapies, which is another important but relatively ignored issue. The care and feeding of such a trial is a difficult pill for all of use to swallow, but who wants to keep on reading studies that do not even agree on the definition of when to start the clock for overall survival reporting????
References 1. 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. 2. 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;18:1196–1202. 3. 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: 3007–3013. 4. 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. 5. Rimner A, Zauderer MG, Gomez DR, et al. Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma. J Clin Oncol. 2016;34:2761–2768. 6. Rusch V, Baldini EH, Bueno R, et al. The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 1114, 2012, Boston, Mass. J Thorac Cardiovasc Surg. 2013;145:909–910. 7. Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–416. 8. Kiyotani K, Park JH, Inoue H, et al. Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma. Oncoimmunology. 2017;6:e1278330. 9. Pass HI, Giroux D, Kennedy C, et al. Supplementary prognostic variables for pleural mesothelioma: a report
June 2017 from the IASLC staging committee. J Thorac Oncol. 2014;9:856–864. 10. Minatel E, Trovo M, Bearz A, et al. Radical radiation therapy after lung-sparing surgery for malignant pleural mesothelioma: survival, pattern of failure, and prognostic factors. Int J Radiat Oncol Biol Phys. 2015;93:606–613.
IMRT after Cytoreduction for Mesothelioma
921
11. 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;149:558–565.