Letters to the Editor
Secondly, there is a report of the use of whole lung perfusion after pulmonary metastasectomy for colorectal cancer or sarcoma.2 This starts by saying that the prognosis of these patients has not changed in 20 years, but their conclusion is not that perhaps metastasectomy does not make a difference, but seems to be “we need to do something more.” They report the use a toxic drug without a good track record in either tumor to perfuse the whole lung and that 44% of patients experienced grade 3 or 4 toxicity. Although there was an apparent reduction in pulmonary metastases there seemed to be no improvement in time to progression or overall survival—compared with historical series. There is an increasingly embedded view that pulmonary metastasectomy is a proven and effective surgical treatment that improves patient outcomes and so now people are investigating less invasive techniques (e.g., stereotactic ablative radiotherapy and radiofrequency ablation) or, adding locally perfused chemotherapy. Both papers cite the 1997 publication of International Registry on Lung Metastasis3 which was a landmark in pooling uncontrolled data, permitting analysis of over 5000 cases. But it contains no evidence on what might have been the survival among similarly selected patients without metastasectomy—there were no controls and that remains the case.4 Not only are the patients having metastasectomy highly selected but so too are citations in the publication.5 Pulmonary metastasectomy is a good example of how selective citation and repeated authoritative publication can create “facts” from hypotheses. There is no randomized trial evidence to support the belief that it is an effective intervention and there is reason to believe that any perceived survival benefit may simply be because of patient selection. This is an insecure foundation of which to justify ablative therapies.6 Before embarking on more, uncontrolled research into “better” ways of removing pulmonary metastases, there need to be well-conducted randomized trials investigating the value of the procedure. Fergus Macbeth, DM, FRCR, FRCP Wales Cancer Trials Unit Cardiff University Cardiff, UK
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Journal of Thoracic Oncology ® • Volume 10, Number 3, March 2015
Tom Treasure, MD, FRCS Clinical Operational Research Unit Department of Mathematics, University College London London, UK REFERENCES 1. Schultz DB, Filippi AR, Tharlat J et al. Stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer. J Thoracic Oncol 2014;9:1426–1433. 2. Den Hengst WA, Hendriks JMH, Balduck B et al. Phase II multicentre clinical trial of pulmonary metastasectomy and isolated lung perfusion with, melphalan in patients with resectable lung metastases. J Thoracic Oncol 2014;9:1547–1553. 3. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37–49. 4. Treasure T, Utley M. Surgical removal of asymptomatic pulmonary metastases: Time for better evidence. BMJ 2013;346:21–23. 5. Fiorentino F, Vasilakis C, Treasure T. Clinical reports of pulmonary metastasectomy for colorectal cancer: A citation network analysis. Br J Cancer 2011;104:1085–1097. 6. Palma DA, Salama JK, Lo SS, et al. The oligometastatic state-separating truth from wishful thinking. Nat Rev Clin Oncol 2014;11:549–557.
Reply to “Pulmonary Metastasectomy: Where is the Evidence?”
Absence of Evidence is not Evidence of Absence! In Response: Pulmonary Metastasectomy: Where is the Evidence? Absence of Evidence is not Evidence of Absence! Address for correspondence: Paul E. Van Schil, MD, PhD, Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium. E-mail: [email protected] Disclosure: The authors declare no conflict of interest. DOI: 10.1097/JTO.0000000000000451 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1003-0e14
In their Letter to the Editor, Drs. F. Macbeth and T. Treasure refer to two articles published in the October 2014 issue of Journal of Thoracic Oncology related to treatment of lung metastases.1–3 They correctly point out that there are no large randomized trials to provide a definite proof that resection of lung metastases prolongs survival in patients. They even take it one step back and propose to obtain level I evidence before performing further studies. In this regard, they could have chosen many surgical papers that were recently published in Journal of Thoracic Oncology. For most thoracic surgical procedures there is no such evidence to support them. This relates to surgery for mediastinal tumors as thymoma, mesothelioma, locally advanced lung cancer, and even early stage lung cancer! Does this mean that surgery is not a valid treatment, as the authors seem to suggest? How to approach individual patients when there is lack of level I evidence? Although not very clearly, the authors suggest that we should not continue any treatment modality until this evidence becomes available. However, they have not proven the reverse statement: “absence of evidence” does not mean “evidence of absence” as indicated in several editorials.4 They state that “there is reason to believe that any perceived survival benefit may simply be because of patient selection.” This is not a very scientific statement and not a single reference is mentioned to support this. Surgery became an accepted treatment for many tumors as it provides the opportunity to completely remove the primary tumor and draining lymph nodes although no formal comparison with conservative treatment is available. For this reason, there is an inherent problem when proposing randomized trials comparing surgery to conservative management which is often perceived as treatment withdrawal. Even when randomized trials are performed, there is still no absolute truth and a certain degree of uncertainty remains.4 Moreover, the conclusions are only valid for the study population for which strict inclusion and exclusion criteria were designed. For rare tumors as mesotheliomas and thymomas it will never be possible to perform a large randomized
Copyright © 2015 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 10, Number 3, March 2015
controlled trial and well-designed prospective registries as created by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group will provide valuable information to advance the field and give a profound insight in these tumors. Although the authors state that we used a “toxic drug without a good track record” it should be emphasized that, before embarking on a multicenter phase II study, extensive experimental work on isolated lung perfusion was performed followed by a phase I study to determine dose-limiting toxicity.5 The main question in our study was not whether surgery in this setting is better than conservative treatment, which in fact was clearly proven in our experimental studies, but whether
the objective results of surgery can be improved by combined modality therapy, a point not raised by the authors. Although results of large randomized controlled trials are currently lacking for many surgical procedures, this does not mean that therapeutic nihilism should prevail. As the authors provide no convincing proof of the absence of any effect of surgical therapy in thoracic oncology, the final answer is still blowing in the wind and related burning questions, explored in well-designed experimental and clinically relevant studies should not be put on hold. Paul E. Van Schil Department of Thoracic and Vascular Surgery Antwerp University Hospital Edegem, Antwerp, Belgium
Copyright © 2015 by the International Association for the Study of Lung Cancer
Letters to the Editor
REFERENCES 1. Macbeth F, Treasure T. Pulmonary metastasectomy – where is the evidence? J Thorac Oncol 2015. 2. Schultz DB, Filippi AR, Tharlat J, et al. Stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer. J Thorac Oncol 2014; 9:1426–1433. 3. den Hengst WA, Hendriks JMH, Balduyck B, et al. Phase II multicenter trial of pulmonary metastasectomy and isolated lung perfusion with melphalan in patients with resectable lung metastases. J Thorac Oncol 2014; 9:1547–1553. 4. Alderson P. Absence of evidence is not evidence of absence. BMJ 2004;328: 476–477. 5. Hendriks JM, Grootenboers MJ, Schramel FM, et al. Isolated lung perfusion with melphalan for resectable lung metastases: A phase I clinical trial. Ann Thorac Surg 2004;78:1919–1926.
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Secondly, there is a report of the use of whole lung perfusion after pulmonary metastasectomy for colorectal cancer or sarcoma.2 This starts by saying that the prognosis of these patients has not changed in 20 years, but their conclusion is not that perhaps metastasectomy does not make a difference, but seems to be “we need to do something more.” They report the use a toxic drug without a good track record in either tumor to perfuse the whole lung and that 44% of patients experienced grade 3 or 4 toxicity. Although there was an apparent reduction in pulmonary metastases there seemed to be no improvement in time to progression or overall survival—compared with historical series. There is an increasingly embedded view that pulmonary metastasectomy is a proven and effective surgical treatment that improves patient outcomes and so now people are investigating less invasive techniques (e.g., stereotactic ablative radiotherapy and radiofrequency ablation) or, adding locally perfused chemotherapy. Both papers cite the 1997 publication of International Registry on Lung Metastasis3 which was a landmark in pooling uncontrolled data, permitting analysis of over 5000 cases. But it contains no evidence on what might have been the survival among similarly selected patients without metastasectomy—there were no controls and that remains the case.4 Not only are the patients having metastasectomy highly selected but so too are citations in the publication.5 Pulmonary metastasectomy is a good example of how selective citation and repeated authoritative publication can create “facts” from hypotheses. There is no randomized trial evidence to support the belief that it is an effective intervention and there is reason to believe that any perceived survival benefit may simply be because of patient selection. This is an insecure foundation of which to justify ablative therapies.6 Before embarking on more, uncontrolled research into “better” ways of removing pulmonary metastases, there need to be well-conducted randomized trials investigating the value of the procedure. Fergus Macbeth, DM, FRCR, FRCP Wales Cancer Trials Unit Cardiff University Cardiff, UK
e14
Journal of Thoracic Oncology ® • Volume 10, Number 3, March 2015
Tom Treasure, MD, FRCS Clinical Operational Research Unit Department of Mathematics, University College London London, UK REFERENCES 1. Schultz DB, Filippi AR, Tharlat J et al. Stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer. J Thoracic Oncol 2014;9:1426–1433. 2. Den Hengst WA, Hendriks JMH, Balduck B et al. Phase II multicentre clinical trial of pulmonary metastasectomy and isolated lung perfusion with, melphalan in patients with resectable lung metastases. J Thoracic Oncol 2014;9:1547–1553. 3. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37–49. 4. Treasure T, Utley M. Surgical removal of asymptomatic pulmonary metastases: Time for better evidence. BMJ 2013;346:21–23. 5. Fiorentino F, Vasilakis C, Treasure T. Clinical reports of pulmonary metastasectomy for colorectal cancer: A citation network analysis. Br J Cancer 2011;104:1085–1097. 6. Palma DA, Salama JK, Lo SS, et al. The oligometastatic state-separating truth from wishful thinking. Nat Rev Clin Oncol 2014;11:549–557.
Reply to “Pulmonary Metastasectomy: Where is the Evidence?”
Absence of Evidence is not Evidence of Absence! In Response: Pulmonary Metastasectomy: Where is the Evidence? Absence of Evidence is not Evidence of Absence! Address for correspondence: Paul E. Van Schil, MD, PhD, Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium. E-mail: [email protected] Disclosure: The authors declare no conflict of interest. DOI: 10.1097/JTO.0000000000000451 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1003-0e14
In their Letter to the Editor, Drs. F. Macbeth and T. Treasure refer to two articles published in the October 2014 issue of Journal of Thoracic Oncology related to treatment of lung metastases.1–3 They correctly point out that there are no large randomized trials to provide a definite proof that resection of lung metastases prolongs survival in patients. They even take it one step back and propose to obtain level I evidence before performing further studies. In this regard, they could have chosen many surgical papers that were recently published in Journal of Thoracic Oncology. For most thoracic surgical procedures there is no such evidence to support them. This relates to surgery for mediastinal tumors as thymoma, mesothelioma, locally advanced lung cancer, and even early stage lung cancer! Does this mean that surgery is not a valid treatment, as the authors seem to suggest? How to approach individual patients when there is lack of level I evidence? Although not very clearly, the authors suggest that we should not continue any treatment modality until this evidence becomes available. However, they have not proven the reverse statement: “absence of evidence” does not mean “evidence of absence” as indicated in several editorials.4 They state that “there is reason to believe that any perceived survival benefit may simply be because of patient selection.” This is not a very scientific statement and not a single reference is mentioned to support this. Surgery became an accepted treatment for many tumors as it provides the opportunity to completely remove the primary tumor and draining lymph nodes although no formal comparison with conservative treatment is available. For this reason, there is an inherent problem when proposing randomized trials comparing surgery to conservative management which is often perceived as treatment withdrawal. Even when randomized trials are performed, there is still no absolute truth and a certain degree of uncertainty remains.4 Moreover, the conclusions are only valid for the study population for which strict inclusion and exclusion criteria were designed. For rare tumors as mesotheliomas and thymomas it will never be possible to perform a large randomized
Copyright © 2015 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 10, Number 3, March 2015
controlled trial and well-designed prospective registries as created by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group will provide valuable information to advance the field and give a profound insight in these tumors. Although the authors state that we used a “toxic drug without a good track record” it should be emphasized that, before embarking on a multicenter phase II study, extensive experimental work on isolated lung perfusion was performed followed by a phase I study to determine dose-limiting toxicity.5 The main question in our study was not whether surgery in this setting is better than conservative treatment, which in fact was clearly proven in our experimental studies, but whether
the objective results of surgery can be improved by combined modality therapy, a point not raised by the authors. Although results of large randomized controlled trials are currently lacking for many surgical procedures, this does not mean that therapeutic nihilism should prevail. As the authors provide no convincing proof of the absence of any effect of surgical therapy in thoracic oncology, the final answer is still blowing in the wind and related burning questions, explored in well-designed experimental and clinically relevant studies should not be put on hold. Paul E. Van Schil Department of Thoracic and Vascular Surgery Antwerp University Hospital Edegem, Antwerp, Belgium
Copyright © 2015 by the International Association for the Study of Lung Cancer
Letters to the Editor
REFERENCES 1. Macbeth F, Treasure T. Pulmonary metastasectomy – where is the evidence? J Thorac Oncol 2015. 2. Schultz DB, Filippi AR, Tharlat J, et al. Stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer. J Thorac Oncol 2014; 9:1426–1433. 3. den Hengst WA, Hendriks JMH, Balduyck B, et al. Phase II multicenter trial of pulmonary metastasectomy and isolated lung perfusion with melphalan in patients with resectable lung metastases. J Thorac Oncol 2014; 9:1547–1553. 4. Alderson P. Absence of evidence is not evidence of absence. BMJ 2004;328: 476–477. 5. Hendriks JM, Grootenboers MJ, Schramel FM, et al. Isolated lung perfusion with melphalan for resectable lung metastases: A phase I clinical trial. Ann Thorac Surg 2004;78:1919–1926.
e15
