Editorial commentary: Size and margin do matter, but is it the whole story? Paul A.J. Beckers, MD, Lawek Berzenji, MD,, Paul E. Van Schil, MD, PhD

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Accepted Manuscript Editorial commentary: Size and margin do matter, but is it the whole story? Paul A.J. Beckers, MD, Lawek Berzenji, MD,, Paul E. Van Schil, MD, PhD PII: S0022-5223(18)33135-0 DOI: https://doi.org/10.1016/j.jtcvs.2018.11.036 Reference: YMTC 13785 To appear in: The Journal of Thoracic and Cardiovascular Surgery Received Date: 3 November 2018 Accepted Date: 5 November 2018 Please cite this article as: Beckers PAJ, Berzenji L, Van Schil PE, Editorial commentary: Size and margin do matter, but is it the whole story?, The Journal of Thoracic and Cardiovascular Surgery (2018), doi: https://doi.org/10.1016/j.jtcvs.2018.11.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

JTCVS Editorial commentary Van Schil. 1 Size and margin do matter, but is it the whole story? Authors: Paul A.J. Beckers, MD; Lawek Berzenji, MD; Paul E. Van Schil, MD, PhD Institution: Department of Thoracic and Vascular Surgery, Antwerp University Hospital and Antwerp University, Belgium All three authors have no conflicts of interest or disclosures regarding this paper. 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 tel. + 32-3-8214360 fax: + 32-3-8214396 e-mail: paul.van.schil@uza.be

Central Message Van Schil. 2 Lung metastases: risk of recurrence depends on margin length and tumor size, but many other factors are also involved. Central Picture Figure1. Resection of lung metastasis: which margin is safe?

Size and margin do matter, but is it the whole story? Van Schil. 3 Resection of lung metastases is a hotly debated topic at major oncological and thoracic surgical conferences. The main question remains whether surgical resection significantly improves survival. Are the reported survival rates in surgical series due to interference with the oncological process or solely due to selection bias? At the present time no randomized evidence is available and results of the PulmiCC trial are awaited for 1. The largest available, retrospective series included more than 5,000 patients and was published in 1997 2. Factors proven to be significant were macroscopic complete resection, number of metastases, with a single metastasis having the best survival, and finally, disease-free interval with a better prognosis for patients with a disease-free interval longer than 3 years. As these metastases are blood-borne in contrast to bronchogenic carcinoma, several techniques were developed to remove these lesions with sparing of as much lung parenchyma as possible 3. Although these different techniques ranging from clamping and suturing to laser ablation, have been well described, a safe margin around these lesions has not yet been determined (fig. 1). In the present series of 335 patients undergoing 679 wedge resections for colorectal lung metastases, the 5-year risk of local recurrence was 20.6% 4. Two factors emerged from this study: a longer margin length decreased the risk of local recurrence, and a larger tumor size increased this risk. A pathologic margin length of at least half the tumor size was found to be safe with a local recurrence rate of less than 11%. The findings of the authors are certainly useful for daily surgical practice. However, the question remains whether size and margin are the only relevant factors? Can their conclusions also be expanded to other tumor types? It should be mentioned that not all lung nodules observed on imaging techniques are similar, and several histologic types may coexist. We recently reported a patient with a history of colon cancer and 5 lung nodules with 4 different histologic types on final pathological

Van Schil. 4 examination 5. In the present series, all lesions were removed by staplers and most probably, the results can be extrapolated to the other described techniques of local extirpation. Biology of the primary tumor and its resulting metastases is also an important factor to be considered. As already shown by Pastorino, melanoma metastases have a high tendency of intrathoracic and extrathoracic recurrences resulting in a poor prognosis 2. Although the authors tried to incorporate biological factors in the present paper, these proved not to be significant 4. Equally, the time of occurrence is relevant: synchronous metastases usually have a poorer prognosis than metachronous lesions occurring years later. As mentioned before, patients with a single metastasis have the best prognosis, probably due to a lower metastatic burden. In the 8 th TNM classification for lung cancer, the M1b category was redefined as a single metastasis in a single distant organ with an intermediate prognosis between the unchanged M1a subcategory and M1c disease, currently defined as multiple lesions in one or more distant organs 6. The category M1b corresponds to the concept of oligometastatic disease which recently has gained much interest, although oligo literally means a few and not a single one. So, it seems that there is an intermediate category with limited metastatic disease for whom combined systemic and local ablative therapy may improve overall prognosis, as shown in the recent randomized phase II trial of Gomez 7. Although the concept of oligometastatic disease was introduced more than 10 years ago, a precise definition is currently not available. This led the European Organisation for Research and Treatment of Cancer (EORTC) to create a specific task force addressing synchronous metastases. After an extensive survey and a consensus conference, a maximum of 5 metastases in no more than 3 organs was proposed at the 19 th World Conference on Lung Cancer in Toronto in September 2018 (abstracts MA25.01-03). Hopefully, this will give to a more uniform reporting of patients with a limited burden of metastatic disease.

Van Schil. 5 Pulmonary metastatic disease will remain a hot topic in the near future and the present paper is certainly a timely addition showing that the risk of recurrence is low when a margin length of half the tumor size is obtained 4. REFERENCES 1. Migliore M, Milošević M, Lees B, Treasure T, Di Maria G. Finding the evidence for pulmonary metastasectomy in colorectal cancer: the PulMicc trial. Future Oncol 2015; 11(2 Suppl):15-8. 2. Pastorino U, Buyse M, Friedel G. The International Registry of Lung Metastases. Longterm results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997; 113:37-49. 3. Van Schil PEY, den Hengst WA, Allen M,S Putnam JB Jr. Pulmonary Metastases. Chapter 108. In: LoCicero III J, Feins, RH, Colson YL, Rocco G eds. Shields General Thoracic Surgery, 8 th ed. Philadelphia: Wolters Kluwer; 2019:1383-1412. 4. Nelson DB, Tayob N, Mitchell KG et al. Surgical margins and risk of local recurrence of colorectal pulmonary metastases. J Thorac Cardiovasc Surg 2019, in press. 5. Toelen C, De Maeyer M, Van Schil P. Five lung nodules, four different pathologic findings: not all lung lesions are the same. Acta Chir Belg 2016; 116:388-9. 6. Eberhardt WE, Mitchell A, Crowley J et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015; 10:1515-22. 7. Gomez DR, Blumenschein GR, Jr., Lee JJ et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung

Van Schil. 6 cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672-82.

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