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The Role of Positron Emission Tomography–Computed Tomography in the Workup of Non–Small Cell Lung Cancer

The Role of Positron Emission Tomography–Computed Tomography in the Workup of Non–Small Cell Lung... Invited Commentary | Oncology The Role of Positron Emission Tomography–Computed Tomography in the Workup of Non–Small Cell Lung Cancer Martin A. Walter, MD Non–small cell lung cancer (NSCLC) remains a significant global health burden and is a leading cause Related article of cancer-related death. The correct staging of patients with NSCLC is a key step in selecting an Author affiliations and article information are adequate treatment regimen, and combined positron emission tomography–computed tomography listed at the end of this article. (PET-CT) with fluorine 18–labeled fluorodeoxyglucose (FDG) is increasingly used for staging and treatment monitoring of patients with NSCLC. The principal strengths of PET-CT with FDG in staging NSCLC include the assessment of intrathoracic lymph nodes and the detection of unanticipated stage IV disease. However, data on the effects of PET-CT with FDG on cancer-related mortality in NSCLC remain sparse. The article by Vella et al aims to provide such data on cancer-related mortality. The authors examined the association of the use of PET-CT with NSCLC mortality in 64 103 patients treated in the US Department of Veterans Affairs from 2000 to 2013. They found that PET-CT use increased over 1 1 this 13-year period, while mortality decreased. Vella et al concluded that PET-CT was associated with both a higher level of care and decreased mortality for veterans with NSCLC. To appreciate the contribution of this study in the context of the existing body of literature, it is worthwhile to summarize its main strengths and limitations. Strengths of the study by Vella et al include a highly relevant research question, ie, the association of PET-CT with survival in one of the most frequent cancers today; a large patient number; and the choice of survival as the main clinical end point, which is arguably the most relevant clinical outcome in oncology. As does every study, the study by Vella et al has limitations, which are openly discussed in the article. An association such as that shown in the study does not prove or even indicate a causal relationship, and it is entirely possible that continued improvement in the available therapeutic options for NSCLC is responsible for the yearly decreasing mortality in these patients. Also, the comparability of the PET-CT group and the no PET-CT group is unclear, eg, whether the decision to perform or not perform a PET-CT may have been influenced by a confounder that also influenced survival, such as a concomitant disease. Finally, depending on the disease stage, only 45% to 62% of patients with NSCLC who received PET-CT in the study by Vella et al went on to receive stage- appropriate treatment. Thus, it is unclear how representative the cohort is in relation to the general population and if conclusions from the present cohort can be easily translated to patient groups outside the Veterans Affairs system. Nevertheless, the article by Vella et al is an important piece within the evolving body of data on 2,3 PET-CT in patients with NSCLC. So far, 2 randomized clinical trials have been performed to assess whether the use of PET or PET-CT with FDG could improve the selection of surgically curable patients with NSCLC. Despite different distributions of clinical stages, both trials found similar results, ie, that the addition of PET with FDG to the diagnostic workup prevented futile surgery in approximately 20% of patients with suspected NSCLC. However, 1 trial did not find a survival benefit, while the other trial did not investigate survival outcomes. In this context, the survival results represent a key strength of the study by Vella et al. The current literature has also been summarized by a variety of systematic reviews and meta- analyses. A 2018 meta-analysis found that PET-CT with FDG had a high diagnostic performance for detecting distant metastasis in patients with NSCLC at initial staging. On the other hand, a 2014 Cochrane review found significant variation in the accuracy of PET-CT with FDG in NSCLC, leading to Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2019;2(11):e1915873. doi:10.1001/jamanetworkopen.2019.15873 (Reprinted) November 20, 2019 1/3 JAMA Network Open | Oncology Positron Emission Tomography–Computed Tomography and Non–Small Cell Lung Cancer the conclusion that management should not be based on PET-CT with FDG alone. Instead, the authors recommended that PET-CT with FDG imaging be used to determine whether the next step should be endobronchial ultrasonography–guided biopsy, mediastinoscopy, or surgical resection. Systematic reviews and meta-analyses on the effect of PET-CT with FDG on the survival of patients with NSCLC are conspicuously absent from the existing literature. Based on the incomplete available evidence, eg, owing to divergent results or missing survival data, there is variation in guideline recommendations concerning PET-CT with FDG in NSCLC. The American College of Chest Physicians Clinical Practice Guidelines recommend the use of PET-CT with FDG for mediastinal and extrathoracic staging in patients with clinical stage IB to IIIB lung cancer being treated with curative intent. However, according to the guidelines, the usefulness of PET-CT with FDG is not clear in clinical stage IA but should be considered in patients with clinical stage IA lung cancer treated with a curative intent. On the other hand, the National Institute for Health and Care Excellence guideline recommends that all patients with NSCLC who could potentially be treated with curative intent receive a PET-CT with FDG prior to treatment. Finally, the guidelines of the European Society of Medical Oncology recommend PET-CT with FDG for initial staging in all patients with NSCLC. In day-to-day work, many clinicians find PET-CT with FDG highly useful in guiding management decisions for patients with NSCLC, and several randomized and nonrandomized clinical trials have confirmed this clinical reality. Recent systematic reviews have summarized the existing randomized and nonrandomized clinical trials, demonstrating both the strengths of PET-CT with FDG in NSCLC staging as well as the limitations in current practice and available knowledge, such as a high variability in diagnostic performance and absence of proven survival benefit. In light of this, it is now time to reduce these limitations by developing strategies that reduce the variation in PET-CT with FDG performance and by providing data on the survival effect of PET-CT with FDG in NSCLC. Thus, the article by Vella et al is a step in the right direction. ARTICLE INFORMATION Published: November 20, 2019. doi:10.1001/jamanetworkopen.2019.15873 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Walter MA. JAMA Network Open. Corresponding Author: Martin A. Walter, MD, Service of Nuclear Medicine, Diagnostic Department, University Hospital, University of Geneva, Rue Gabrielle Perret-Gentil 4, CH-1205 Geneva, Switzerland (martin.walter@ unige.ch). Author Affiliation: Service of Nuclear Medicine, Diagnostic Department, University Hospital, University of Geneva, Geneva, Switzerland. Conflict of Interest Disclosures: None reported. REFERENCES 1. Vella M, Meyer CS, Zhang N, et al. Association of receipt of positron emission tomography–computed tomography with non–small cell lung cancer mortality in the Veterans Affairs health care system. JAMA Netw Open. 2019;2(11):e1915828. doi:10.1001/jamanetworkopen.2019.15828 2. van Tinteren H, Hoekstra OS, Smit EF, et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet. 2002;359(9315):1388-1393. doi:10.1016/S0140-6736(02)08352-6 3. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009;361(1):32-39. doi:10.1056/NEJMoa0900043 4. Yu B, Zhu X, Liang Z, Sun Y, Zhao W, Chen K. Clinical usefulness of F-FDG PET/CT for the detection of distant metastases in patients with non-small cell lung cancer at initial staging: a meta-analysis. Cancer Manag Res. 2018; 10:1859-1864. doi:10.2147/CMAR.S155542 JAMA Network Open. 2019;2(11):e1915873. doi:10.1001/jamanetworkopen.2019.15873 (Reprinted) November 20, 2019 2/3 JAMA Network Open | Oncology Positron Emission Tomography–Computed Tomography and Non–Small Cell Lung Cancer 5. Schmidt-Hansen M, Baldwin DR, Hasler E, Zamora J, Abraira V, Roqué I Figuls M. PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer. Cochrane Database Syst Rev. 2014;(11):CD009519. doi:10.1002/14651858.CD009519.pub2 6. Silvestri GA, Gould MK, Margolis ML, et al; American College of Chest Physicians. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007;132(3) (suppl):178S-201S. 7. National Institute for Health Care Excellence. Lung cancer: diagnosis and management. https://www.nice.org.uk/ guidance/ng122. Accessed October 18, 2019. 8. Postmus PE, Kerr KM, Oudkerk M, et al; ESMO Guidelines Committee. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2017; 28(suppl 4):iv1-iv21. JAMA Network Open. 2019;2(11):e1915873. doi:10.1001/jamanetworkopen.2019.15873 (Reprinted) November 20, 2019 3/3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

The Role of Positron Emission Tomography–Computed Tomography in the Workup of Non–Small Cell Lung Cancer

JAMA Network Open , Volume 2 (11) – Nov 20, 2019

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Publisher
American Medical Association
Copyright
Copyright 2019 Walter MA. JAMA Network Open.
eISSN
2574-3805
DOI
10.1001/jamanetworkopen.2019.15873
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Abstract

Invited Commentary | Oncology The Role of Positron Emission Tomography–Computed Tomography in the Workup of Non–Small Cell Lung Cancer Martin A. Walter, MD Non–small cell lung cancer (NSCLC) remains a significant global health burden and is a leading cause Related article of cancer-related death. The correct staging of patients with NSCLC is a key step in selecting an Author affiliations and article information are adequate treatment regimen, and combined positron emission tomography–computed tomography listed at the end of this article. (PET-CT) with fluorine 18–labeled fluorodeoxyglucose (FDG) is increasingly used for staging and treatment monitoring of patients with NSCLC. The principal strengths of PET-CT with FDG in staging NSCLC include the assessment of intrathoracic lymph nodes and the detection of unanticipated stage IV disease. However, data on the effects of PET-CT with FDG on cancer-related mortality in NSCLC remain sparse. The article by Vella et al aims to provide such data on cancer-related mortality. The authors examined the association of the use of PET-CT with NSCLC mortality in 64 103 patients treated in the US Department of Veterans Affairs from 2000 to 2013. They found that PET-CT use increased over 1 1 this 13-year period, while mortality decreased. Vella et al concluded that PET-CT was associated with both a higher level of care and decreased mortality for veterans with NSCLC. To appreciate the contribution of this study in the context of the existing body of literature, it is worthwhile to summarize its main strengths and limitations. Strengths of the study by Vella et al include a highly relevant research question, ie, the association of PET-CT with survival in one of the most frequent cancers today; a large patient number; and the choice of survival as the main clinical end point, which is arguably the most relevant clinical outcome in oncology. As does every study, the study by Vella et al has limitations, which are openly discussed in the article. An association such as that shown in the study does not prove or even indicate a causal relationship, and it is entirely possible that continued improvement in the available therapeutic options for NSCLC is responsible for the yearly decreasing mortality in these patients. Also, the comparability of the PET-CT group and the no PET-CT group is unclear, eg, whether the decision to perform or not perform a PET-CT may have been influenced by a confounder that also influenced survival, such as a concomitant disease. Finally, depending on the disease stage, only 45% to 62% of patients with NSCLC who received PET-CT in the study by Vella et al went on to receive stage- appropriate treatment. Thus, it is unclear how representative the cohort is in relation to the general population and if conclusions from the present cohort can be easily translated to patient groups outside the Veterans Affairs system. Nevertheless, the article by Vella et al is an important piece within the evolving body of data on 2,3 PET-CT in patients with NSCLC. So far, 2 randomized clinical trials have been performed to assess whether the use of PET or PET-CT with FDG could improve the selection of surgically curable patients with NSCLC. Despite different distributions of clinical stages, both trials found similar results, ie, that the addition of PET with FDG to the diagnostic workup prevented futile surgery in approximately 20% of patients with suspected NSCLC. However, 1 trial did not find a survival benefit, while the other trial did not investigate survival outcomes. In this context, the survival results represent a key strength of the study by Vella et al. The current literature has also been summarized by a variety of systematic reviews and meta- analyses. A 2018 meta-analysis found that PET-CT with FDG had a high diagnostic performance for detecting distant metastasis in patients with NSCLC at initial staging. On the other hand, a 2014 Cochrane review found significant variation in the accuracy of PET-CT with FDG in NSCLC, leading to Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2019;2(11):e1915873. doi:10.1001/jamanetworkopen.2019.15873 (Reprinted) November 20, 2019 1/3 JAMA Network Open | Oncology Positron Emission Tomography–Computed Tomography and Non–Small Cell Lung Cancer the conclusion that management should not be based on PET-CT with FDG alone. Instead, the authors recommended that PET-CT with FDG imaging be used to determine whether the next step should be endobronchial ultrasonography–guided biopsy, mediastinoscopy, or surgical resection. Systematic reviews and meta-analyses on the effect of PET-CT with FDG on the survival of patients with NSCLC are conspicuously absent from the existing literature. Based on the incomplete available evidence, eg, owing to divergent results or missing survival data, there is variation in guideline recommendations concerning PET-CT with FDG in NSCLC. The American College of Chest Physicians Clinical Practice Guidelines recommend the use of PET-CT with FDG for mediastinal and extrathoracic staging in patients with clinical stage IB to IIIB lung cancer being treated with curative intent. However, according to the guidelines, the usefulness of PET-CT with FDG is not clear in clinical stage IA but should be considered in patients with clinical stage IA lung cancer treated with a curative intent. On the other hand, the National Institute for Health and Care Excellence guideline recommends that all patients with NSCLC who could potentially be treated with curative intent receive a PET-CT with FDG prior to treatment. Finally, the guidelines of the European Society of Medical Oncology recommend PET-CT with FDG for initial staging in all patients with NSCLC. In day-to-day work, many clinicians find PET-CT with FDG highly useful in guiding management decisions for patients with NSCLC, and several randomized and nonrandomized clinical trials have confirmed this clinical reality. Recent systematic reviews have summarized the existing randomized and nonrandomized clinical trials, demonstrating both the strengths of PET-CT with FDG in NSCLC staging as well as the limitations in current practice and available knowledge, such as a high variability in diagnostic performance and absence of proven survival benefit. In light of this, it is now time to reduce these limitations by developing strategies that reduce the variation in PET-CT with FDG performance and by providing data on the survival effect of PET-CT with FDG in NSCLC. Thus, the article by Vella et al is a step in the right direction. ARTICLE INFORMATION Published: November 20, 2019. doi:10.1001/jamanetworkopen.2019.15873 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Walter MA. JAMA Network Open. Corresponding Author: Martin A. Walter, MD, Service of Nuclear Medicine, Diagnostic Department, University Hospital, University of Geneva, Rue Gabrielle Perret-Gentil 4, CH-1205 Geneva, Switzerland (martin.walter@ unige.ch). Author Affiliation: Service of Nuclear Medicine, Diagnostic Department, University Hospital, University of Geneva, Geneva, Switzerland. Conflict of Interest Disclosures: None reported. REFERENCES 1. Vella M, Meyer CS, Zhang N, et al. Association of receipt of positron emission tomography–computed tomography with non–small cell lung cancer mortality in the Veterans Affairs health care system. JAMA Netw Open. 2019;2(11):e1915828. doi:10.1001/jamanetworkopen.2019.15828 2. van Tinteren H, Hoekstra OS, Smit EF, et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet. 2002;359(9315):1388-1393. doi:10.1016/S0140-6736(02)08352-6 3. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009;361(1):32-39. doi:10.1056/NEJMoa0900043 4. Yu B, Zhu X, Liang Z, Sun Y, Zhao W, Chen K. Clinical usefulness of F-FDG PET/CT for the detection of distant metastases in patients with non-small cell lung cancer at initial staging: a meta-analysis. Cancer Manag Res. 2018; 10:1859-1864. doi:10.2147/CMAR.S155542 JAMA Network Open. 2019;2(11):e1915873. doi:10.1001/jamanetworkopen.2019.15873 (Reprinted) November 20, 2019 2/3 JAMA Network Open | Oncology Positron Emission Tomography–Computed Tomography and Non–Small Cell Lung Cancer 5. Schmidt-Hansen M, Baldwin DR, Hasler E, Zamora J, Abraira V, Roqué I Figuls M. PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer. Cochrane Database Syst Rev. 2014;(11):CD009519. doi:10.1002/14651858.CD009519.pub2 6. Silvestri GA, Gould MK, Margolis ML, et al; American College of Chest Physicians. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007;132(3) (suppl):178S-201S. 7. National Institute for Health Care Excellence. Lung cancer: diagnosis and management. https://www.nice.org.uk/ guidance/ng122. Accessed October 18, 2019. 8. Postmus PE, Kerr KM, Oudkerk M, et al; ESMO Guidelines Committee. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2017; 28(suppl 4):iv1-iv21. JAMA Network Open. 2019;2(11):e1915873. doi:10.1001/jamanetworkopen.2019.15873 (Reprinted) November 20, 2019 3/3

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JAMA Network OpenAmerican Medical Association

Published: Nov 20, 2019

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