Surgery for malignant pleural mesothelioma: why we need controlled trials† Tom Treasurea,*, Michael Dusmetb, Francesca Fiorentinoc, Eric Limb, David Wallerd and Belinda Leese a b c d e
Department of Mathematics, Clinical Operational Research Unit, University College London, London, UK Department of Thoracic Surgery, Royal Brompton Hospital, London, UK Department of Cardiac Surgery, National Heart and Lung Institute, Imperial College London, London, UK Thoracic Surgery, Glenfield Hospital, Leicester, UK Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, UK
* Corresponding author. Clinical Operational Research Unit, 4 Taviton Street, London WC1H 0BT, UK. Tel: +44-1233-740378; fax; +44-1233-740378; e-mail: [email protected] (T. Treasure).
Keywords: Mesothelioma • Surgery • Randomized controlled trials • Extrapleural pneumonectomy • Pleurectomy
Two randomized controlled trials (RCTs) of surgery for mesothelioma have been reported [1, 2] and two trials of extended pleurectomy/decortication (e-P/D) are due to open [3]. The RCT is the gold standard of scientific proof, but much of surgery relies on observational evidence [4], predominately in the form of surgical follow-up studies. As a form of evidence, observational data from follow-up studies can be misleading [5], particularly, when the patients are highly selected, the operation is a component of multimodal treatment and perceived success relies on completed treatments rather than on intention to treat. RCTs are notoriously difficult in surgery. An RCT is a laborious exercise, taking years from instigation to eventual reporting to produce an answer limited to the research question. Trials need sufficient numbers to produce meaningful results, which for an uncommon disease may require international cooperation. RCTs are therefore justifiable only if the answer cannot be obtained in an easier way. Other avenues should always be explored first, as illustrated in two analyses of existing data. Besides being inconclusive in themselves, they narrow the gap between the claimed benefit of extirpative surgery and the clinical realities. (i) When mathematical analysts Utley et al. [6] examined data on 945 mesothelioma patients, they asked what is the greatest difference in survival that could be ascribed to surgery. Groups of patients who had no surgery (387), those whose thoracotomy was closed without resection (174) or those who had resection without further cancer treatment (177) had similar survival at an average of 17–18 months. The minority of patients (207/ 945) who had multimodal treatment survived longer to an average of 33 months. Possible contributors to the additional 15 months of life include the effect of selection, and then reselection, of the best patients for further treatments. A beneficial effect of the surgery is not evident from these results. (ii) When the respiratory physician Datta reviewed his patients who had extra pleural pneumonectomy (EPP), he found that †Presented at the 27th Annual Meeting of the European Association for CardioThoracic Surgery, Vienna, Austria, 8 October 2013.
most of the presumed survival difference could not be ascribed to surgery [7] (Fig. 1). The operated patients were a selected 8% (10 of 123) of patients with mesothelioma in the Cancer Registry of York Teaching Hospital. There was a difference in survival between the 10 operated and the 113 unoperated [7] patients, but among the EPP patients, there were none with sarcomatoid histology or performance status worse than 0/1 and the oldest patient was aged 76. When 11, 29 and 24 patients with these clinical features were taken out, in a stepwise fashion, to make the unoperated group more comparable with the EPP patients, the gap in survival progressively narrowed. If it were possible to correct for differences in staging, and the effect of expert clinical judgement on case selection, there might be no survival difference left.
In contrast, after interventions that are very effective, the benefits stand out starkly, for example, hip replacement, cataract surgery, structural disease of the heart and release of tension pneumothorax. There is a temporal and mechanistic relationship between the intervention and relief of the problem; RCTs were not required [4]. A simple rule of thumb is that for an intervention that really works, the more severe the clinical manifestations of the disease are, the greater the benefit will be. In mesothelioma, surgery is reserved for the less severely affected patients. After scrutiny of the observational data in these two examples, no benefit was evident [6, 7]. Randomized trials are needed. Mesothelioma and Radical Surgery-2 is an RCT comparing e-P/D and no e-P/D in the multimodality management of patients with malignant pleural mesothelioma. The trial will test the effectiveness of e-P/D in conjunction with platinum-pemetrexed chemotherapy vs chemotherapy alone in disease amenable to surgical resection. The outcomes will be survival and quality-of-life. The EORTC study will evaluate whether immediate or deferred e-P/D is the safer option [3], but since all patients will have e-P/D, and only the sequence is under test, European Organisation for Research and Treatment of Cancer cannot determine whether e-P/D itself is effective.
© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
EDITORIAL
EDITORIAL
European Journal of Cardio-Thoracic Surgery 45 (2014) 591–592 doi:10.1093/ejcts/ezu001 Advance Access publication 4 February 2014
592
T. Treasure et al. / European Journal of Cardio-Thoracic Surgery
Figure 1: The blue line is the Kaplan–Meier survival of 10 patients having EPP in each panel. The red line is Kaplan–Meier for all 113 patients not having EPP in the same time frame (A), excluding 11 patients with sarcomatoid histology (B), a further 29 with performance status other than 0/1 (C) and a further 24 patients older than 76.2 years (D).
If RCTs are the gold standard, why do those who believe in the intervention under test think RCTs come up with the wrong answer? [8] The difference between the active and control arms is rarely as large as they had hoped. The explanation is this: in follow-up studies, patients not doing well do not complete treatment and are not counted in the final tally, whereas in an RCT, independent scrutineers ensure that all patients allocated to the intervention remain on the record for intention to treat analysis. This is the common explanation for why outcomes for an operation under test in an RCT rarely appear as good as those reported in follow-up studies. For the comparator, authors of observational studies are free to choose their own from among patients populations not selected to have surgery. For mesothelioma, survival is stated to be less than 12 months [9]. In an RCT, the control group is designed to be directly comparable with those having the intervention: that is how a randomized trial works. Survival among these patients, selected exactly as if for surgery, is longer than for patients selected to not have surgery. So in the fair test of an RCT, you can expect the difference to be narrower than was anticipated from observational data, and if the treatment is ineffective the harm dominates [1, 10].
ACKNOWLEDGEMENTS Francesca Fiorentino is partly funded by the British Heart Foundation.
REFERENCES [1] Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J 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. [2] Chusteck J. MesoVATS: Improved Symptoms, Not Survival, in Mesothelioma: 29th October 2013. http://www.medscape.com/viewarticle/813384 (accessed 10 December 2013) [3] Hiddinga BI, van Meerbeeck JP. Surgery in mesothelioma—where do we go after MARS? J Thorac Oncol 2013;8:525–9. [4] Fiorentino F, Treasure T. Pulmonary metastasectomy: are observational studies sufficient evidence for effectiveness? Ann Thorac Surg 2013;96:1129–31. [5] Treasure T, Utley M. Statistics for the rest of us: ten traps for the unwary in surgical series: a case study in mesothelioma reports. J Thorac Cardiovasc Surg 2007;133:1414–8. [6] Utley M, Fiorentino F, Treasure T. Obtaining an upper estimate of the survival benefit associated with surgery for mesothelioma. Eur J Cardiothorac Surg 2010;38:241–4. [7] Datta A, Smith R, Fiorentino F, Treasure T. Surgery in the treatment of malignant pleural mesothelioma: recruitment into trials should be the default position. Thorax 2014;69:194–7. [8] Treasure T, Utley M, O’Byrne K. MARS: a sense of perspective and an inconvenient truth. J Thorac Oncol 2013;8:e48–9. [9] Cao CQ, Yan TD, Bannon PG, McCaughan BC. A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Oncol 2010;5:1692–703. [10] Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer 2012;77: 151–5.
Department of Mathematics, Clinical Operational Research Unit, University College London, London, UK Department of Thoracic Surgery, Royal Brompton Hospital, London, UK Department of Cardiac Surgery, National Heart and Lung Institute, Imperial College London, London, UK Thoracic Surgery, Glenfield Hospital, Leicester, UK Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, UK
* Corresponding author. Clinical Operational Research Unit, 4 Taviton Street, London WC1H 0BT, UK. Tel: +44-1233-740378; fax; +44-1233-740378; e-mail: [email protected] (T. Treasure).
Keywords: Mesothelioma • Surgery • Randomized controlled trials • Extrapleural pneumonectomy • Pleurectomy
Two randomized controlled trials (RCTs) of surgery for mesothelioma have been reported [1, 2] and two trials of extended pleurectomy/decortication (e-P/D) are due to open [3]. The RCT is the gold standard of scientific proof, but much of surgery relies on observational evidence [4], predominately in the form of surgical follow-up studies. As a form of evidence, observational data from follow-up studies can be misleading [5], particularly, when the patients are highly selected, the operation is a component of multimodal treatment and perceived success relies on completed treatments rather than on intention to treat. RCTs are notoriously difficult in surgery. An RCT is a laborious exercise, taking years from instigation to eventual reporting to produce an answer limited to the research question. Trials need sufficient numbers to produce meaningful results, which for an uncommon disease may require international cooperation. RCTs are therefore justifiable only if the answer cannot be obtained in an easier way. Other avenues should always be explored first, as illustrated in two analyses of existing data. Besides being inconclusive in themselves, they narrow the gap between the claimed benefit of extirpative surgery and the clinical realities. (i) When mathematical analysts Utley et al. [6] examined data on 945 mesothelioma patients, they asked what is the greatest difference in survival that could be ascribed to surgery. Groups of patients who had no surgery (387), those whose thoracotomy was closed without resection (174) or those who had resection without further cancer treatment (177) had similar survival at an average of 17–18 months. The minority of patients (207/ 945) who had multimodal treatment survived longer to an average of 33 months. Possible contributors to the additional 15 months of life include the effect of selection, and then reselection, of the best patients for further treatments. A beneficial effect of the surgery is not evident from these results. (ii) When the respiratory physician Datta reviewed his patients who had extra pleural pneumonectomy (EPP), he found that †Presented at the 27th Annual Meeting of the European Association for CardioThoracic Surgery, Vienna, Austria, 8 October 2013.
most of the presumed survival difference could not be ascribed to surgery [7] (Fig. 1). The operated patients were a selected 8% (10 of 123) of patients with mesothelioma in the Cancer Registry of York Teaching Hospital. There was a difference in survival between the 10 operated and the 113 unoperated [7] patients, but among the EPP patients, there were none with sarcomatoid histology or performance status worse than 0/1 and the oldest patient was aged 76. When 11, 29 and 24 patients with these clinical features were taken out, in a stepwise fashion, to make the unoperated group more comparable with the EPP patients, the gap in survival progressively narrowed. If it were possible to correct for differences in staging, and the effect of expert clinical judgement on case selection, there might be no survival difference left.
In contrast, after interventions that are very effective, the benefits stand out starkly, for example, hip replacement, cataract surgery, structural disease of the heart and release of tension pneumothorax. There is a temporal and mechanistic relationship between the intervention and relief of the problem; RCTs were not required [4]. A simple rule of thumb is that for an intervention that really works, the more severe the clinical manifestations of the disease are, the greater the benefit will be. In mesothelioma, surgery is reserved for the less severely affected patients. After scrutiny of the observational data in these two examples, no benefit was evident [6, 7]. Randomized trials are needed. Mesothelioma and Radical Surgery-2 is an RCT comparing e-P/D and no e-P/D in the multimodality management of patients with malignant pleural mesothelioma. The trial will test the effectiveness of e-P/D in conjunction with platinum-pemetrexed chemotherapy vs chemotherapy alone in disease amenable to surgical resection. The outcomes will be survival and quality-of-life. The EORTC study will evaluate whether immediate or deferred e-P/D is the safer option [3], but since all patients will have e-P/D, and only the sequence is under test, European Organisation for Research and Treatment of Cancer cannot determine whether e-P/D itself is effective.
© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
EDITORIAL
EDITORIAL
European Journal of Cardio-Thoracic Surgery 45 (2014) 591–592 doi:10.1093/ejcts/ezu001 Advance Access publication 4 February 2014
592
T. Treasure et al. / European Journal of Cardio-Thoracic Surgery
Figure 1: The blue line is the Kaplan–Meier survival of 10 patients having EPP in each panel. The red line is Kaplan–Meier for all 113 patients not having EPP in the same time frame (A), excluding 11 patients with sarcomatoid histology (B), a further 29 with performance status other than 0/1 (C) and a further 24 patients older than 76.2 years (D).
If RCTs are the gold standard, why do those who believe in the intervention under test think RCTs come up with the wrong answer? [8] The difference between the active and control arms is rarely as large as they had hoped. The explanation is this: in follow-up studies, patients not doing well do not complete treatment and are not counted in the final tally, whereas in an RCT, independent scrutineers ensure that all patients allocated to the intervention remain on the record for intention to treat analysis. This is the common explanation for why outcomes for an operation under test in an RCT rarely appear as good as those reported in follow-up studies. For the comparator, authors of observational studies are free to choose their own from among patients populations not selected to have surgery. For mesothelioma, survival is stated to be less than 12 months [9]. In an RCT, the control group is designed to be directly comparable with those having the intervention: that is how a randomized trial works. Survival among these patients, selected exactly as if for surgery, is longer than for patients selected to not have surgery. So in the fair test of an RCT, you can expect the difference to be narrower than was anticipated from observational data, and if the treatment is ineffective the harm dominates [1, 10].
ACKNOWLEDGEMENTS Francesca Fiorentino is partly funded by the British Heart Foundation.
REFERENCES [1] Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J 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. [2] Chusteck J. MesoVATS: Improved Symptoms, Not Survival, in Mesothelioma: 29th October 2013. http://www.medscape.com/viewarticle/813384 (accessed 10 December 2013) [3] Hiddinga BI, van Meerbeeck JP. Surgery in mesothelioma—where do we go after MARS? J Thorac Oncol 2013;8:525–9. [4] Fiorentino F, Treasure T. Pulmonary metastasectomy: are observational studies sufficient evidence for effectiveness? Ann Thorac Surg 2013;96:1129–31. [5] Treasure T, Utley M. Statistics for the rest of us: ten traps for the unwary in surgical series: a case study in mesothelioma reports. J Thorac Cardiovasc Surg 2007;133:1414–8. [6] Utley M, Fiorentino F, Treasure T. Obtaining an upper estimate of the survival benefit associated with surgery for mesothelioma. Eur J Cardiothorac Surg 2010;38:241–4. [7] Datta A, Smith R, Fiorentino F, Treasure T. Surgery in the treatment of malignant pleural mesothelioma: recruitment into trials should be the default position. Thorax 2014;69:194–7. [8] Treasure T, Utley M, O’Byrne K. MARS: a sense of perspective and an inconvenient truth. J Thorac Oncol 2013;8:e48–9. [9] Cao CQ, Yan TD, Bannon PG, McCaughan BC. A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Oncol 2010;5:1692–703. [10] Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer 2012;77: 151–5.
