letters to the editor
pN Categories Based on Metastatic Lymph Node Counts are Still the Cornerstone in Operable Esophageal Cancer To the Editor: Recently, we are interested to read the article by Tan et al.1 regarding the prognostic significance of lymph node ratio (LNR) in patients with esophageal cancer. The authors conclude that the LNR is an independent prognostic factor and prognosticates long-term outcomes of esophageal cancer after tri-incisional esophagectomy. We appreciated the authors on their excellent study, but we have some comments regarding their conclusions. First, we are puzzled about the authors’ conclusion that the number of LN metastasis is not an independent prognostic factor. Most of the studies2,3 have shown that the number of LN metastasis is an independent prognostic factor in esophageal cancer patients after esophagectomy. We observed that the number of metastatic LNs was significantly correlated to that of retrieved LNs in the authors’ article. And our experience also suggests the number of metastatic LNs is closely related to the number of stations of metastatic LNs. If there is strong correlation between variables in cox model, estimation of cox model parameters will be affected, and some variables affecting prognosis will be excluded from the model for multi-collinearity.4 So principal components analysis or r-type clustering analysis should be used to eliminate the influence of multi-collinearity.4 However, authors’ inclusion of factors with close
Address for correspondence: Hong-lei Pei, MS, Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China. E-mail: [email protected] Disclosure: The authors declare no conflict of interest. DOI: 10.1097/JTO.0000000000000458 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1003-0e13
correlation in multivariate analysis, without statistical adjustment, comes to conclusion that the number of LN metastasis is not an independent prognostic factor. Second, patients with the number of retrieved LNs less than 15 accounted for 53.7% (376 of 700), which means LNs dissection in more than half of patients is insufficient. The authors’ results that higher LNR indicates poor prognosis can be explained that insufficient LNs dissection can miss occult metastatic LNs which lead to stage migration and overestimating the patients’ prognosis. Third, we find the numbers of patients with stage N2 and N3 are only 69 and 28, respectively, which makes few patients included in subgroup analysis. As Table 4 of the authors’ article shows, the number of patients with stage N2 and N3 in T1 and T2 subgroup is too small to achieve sufficient statistical power. We think it is not sufficient to draw the conclusion by authors that no significant survival difference is observed in pN categories stratified by tumor status. Therefore, we should stick to the point that LNR is still not enough to replace the pN categories based on metastatic LN counts in the tumor-node metastasis classification system for esophageal cancer.
3. Rice TW, Rusch VW, Ishwaran H, Blackstone EH; Worldwide Esophageal Cancer Collaboration. Cancer of the esophagus and esophagogastric junction: Data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer Cancer Staging Manuals. Cancer 2010;116:3763–3773. 4. Johnson RA, Wichern DW, Education P. Applied Multivariate Statistical Analysis. Englewood Cliffs, NJ: Prentice Hall, 2007.
Pulmonary Metastasectomy
Where is the Evidence?
REFERENCES
To the Editor: The October 2014 issue (Vol. 9, no. 10) contained two articles about the management of “oligometastatic disease” which need comment. The first is a “concise review” of the role of stereotactic ablative radiotherapy in the management of pulmonary oligometastases and oligometastatic disease.1 A review published in a respected peer review journal should give some indication of how the evidence was identified, appraised, and used. In this case, there was no information on methods and it would appear that no systematic search was carried out as papers questioning the value of pulmonary metastasectomy were not cited. Although the issue of selection bias in the current literature, which is composed entirely of retrospective case series, was briefly discussed in the introduction, later when discussing “Future Trials and Conclusion,” selection bias was referred to as a “specter.” This implies that it is a ghostly illusion that needs exorcising, not a very real limitation to the available evidence.
1. Tan Z, Ma G, Yang H, Zhang L, Rong T, Lin P. Can lymph node ratio replace pn categories in the tumor-node-metastasis classification system for esophageal cancer? J Thorac Oncol 2014;9:1214–1221. 2. Chen YJ, Schultheiss TE, Wong JY, Kernstine KH. Impact of the number of resected and involved lymph nodes on esophageal cancer survival. J Surg Oncol 2009;100:127–132.
Address for correspondence: Fergus Macbeth, DM, FRCR, FRCP, Wales Cancer Trials Unit, Cardiff University, Cardiff, UK. E-mail: [email protected] Disclosure: The authors declare no conflict of interest. DOI: 10.1097/JTO.0000000000000454 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1003-0e13
Zhong-hua Ning, MS Hong-lei Pei, MS Department of Radiation Oncology The Third Affiliated Hospital of Soochow University Changzhou, China Zhong-hua Ning, MS Jiang-jin Jiang, MS Department of Tumor Biological Treatment The Third Affiliated Hospital of Soochow University Changzhou, China
Journal of Thoracic Oncology ® • Volume 10, Number 3, March 2015
e13
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
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
pN Categories Based on Metastatic Lymph Node Counts are Still the Cornerstone in Operable Esophageal Cancer To the Editor: Recently, we are interested to read the article by Tan et al.1 regarding the prognostic significance of lymph node ratio (LNR) in patients with esophageal cancer. The authors conclude that the LNR is an independent prognostic factor and prognosticates long-term outcomes of esophageal cancer after tri-incisional esophagectomy. We appreciated the authors on their excellent study, but we have some comments regarding their conclusions. First, we are puzzled about the authors’ conclusion that the number of LN metastasis is not an independent prognostic factor. Most of the studies2,3 have shown that the number of LN metastasis is an independent prognostic factor in esophageal cancer patients after esophagectomy. We observed that the number of metastatic LNs was significantly correlated to that of retrieved LNs in the authors’ article. And our experience also suggests the number of metastatic LNs is closely related to the number of stations of metastatic LNs. If there is strong correlation between variables in cox model, estimation of cox model parameters will be affected, and some variables affecting prognosis will be excluded from the model for multi-collinearity.4 So principal components analysis or r-type clustering analysis should be used to eliminate the influence of multi-collinearity.4 However, authors’ inclusion of factors with close
Address for correspondence: Hong-lei Pei, MS, Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China. E-mail: [email protected] Disclosure: The authors declare no conflict of interest. DOI: 10.1097/JTO.0000000000000458 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1003-0e13
correlation in multivariate analysis, without statistical adjustment, comes to conclusion that the number of LN metastasis is not an independent prognostic factor. Second, patients with the number of retrieved LNs less than 15 accounted for 53.7% (376 of 700), which means LNs dissection in more than half of patients is insufficient. The authors’ results that higher LNR indicates poor prognosis can be explained that insufficient LNs dissection can miss occult metastatic LNs which lead to stage migration and overestimating the patients’ prognosis. Third, we find the numbers of patients with stage N2 and N3 are only 69 and 28, respectively, which makes few patients included in subgroup analysis. As Table 4 of the authors’ article shows, the number of patients with stage N2 and N3 in T1 and T2 subgroup is too small to achieve sufficient statistical power. We think it is not sufficient to draw the conclusion by authors that no significant survival difference is observed in pN categories stratified by tumor status. Therefore, we should stick to the point that LNR is still not enough to replace the pN categories based on metastatic LN counts in the tumor-node metastasis classification system for esophageal cancer.
3. Rice TW, Rusch VW, Ishwaran H, Blackstone EH; Worldwide Esophageal Cancer Collaboration. Cancer of the esophagus and esophagogastric junction: Data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer Cancer Staging Manuals. Cancer 2010;116:3763–3773. 4. Johnson RA, Wichern DW, Education P. Applied Multivariate Statistical Analysis. Englewood Cliffs, NJ: Prentice Hall, 2007.
Pulmonary Metastasectomy
Where is the Evidence?
REFERENCES
To the Editor: The October 2014 issue (Vol. 9, no. 10) contained two articles about the management of “oligometastatic disease” which need comment. The first is a “concise review” of the role of stereotactic ablative radiotherapy in the management of pulmonary oligometastases and oligometastatic disease.1 A review published in a respected peer review journal should give some indication of how the evidence was identified, appraised, and used. In this case, there was no information on methods and it would appear that no systematic search was carried out as papers questioning the value of pulmonary metastasectomy were not cited. Although the issue of selection bias in the current literature, which is composed entirely of retrospective case series, was briefly discussed in the introduction, later when discussing “Future Trials and Conclusion,” selection bias was referred to as a “specter.” This implies that it is a ghostly illusion that needs exorcising, not a very real limitation to the available evidence.
1. Tan Z, Ma G, Yang H, Zhang L, Rong T, Lin P. Can lymph node ratio replace pn categories in the tumor-node-metastasis classification system for esophageal cancer? J Thorac Oncol 2014;9:1214–1221. 2. Chen YJ, Schultheiss TE, Wong JY, Kernstine KH. Impact of the number of resected and involved lymph nodes on esophageal cancer survival. J Surg Oncol 2009;100:127–132.
Address for correspondence: Fergus Macbeth, DM, FRCR, FRCP, Wales Cancer Trials Unit, Cardiff University, Cardiff, UK. E-mail: [email protected] Disclosure: The authors declare no conflict of interest. DOI: 10.1097/JTO.0000000000000454 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1003-0e13
Zhong-hua Ning, MS Hong-lei Pei, MS Department of Radiation Oncology The Third Affiliated Hospital of Soochow University Changzhou, China Zhong-hua Ning, MS Jiang-jin Jiang, MS Department of Tumor Biological Treatment The Third Affiliated Hospital of Soochow University Changzhou, China
Journal of Thoracic Oncology ® • Volume 10, Number 3, March 2015
e13
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
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
