Lung Cancer CE/CME ACCREDITED Watch Time: 41 mins

touchMDT Continually improving care: Evolving role of the MDT in early EGFR-mutant NSCLC

Watch leading specialists from the multidisciplinary tumour board discuss optimal approaches to managing patients with early-stage NSCLC, with or without an EGFR driver mutation

 

Overview & Learning Objectives

James is a 65-year-old never-smoker diagnosed with early-stage EGFR-mutant NSCLC. How can the MDT optimize treatment choices?

Medical Oncologist, Pulmonologist and Thoracic Surgeon

A medical oncologist, pulmonologist and thoracic surgeon assess the suitability of the patient for surgery and expanding treatment options

Expert Spotlight
Dr David Planchard
Gustave Roussy, Villejuif, France
Dr Masahiro Tsuboi
National Cancer Center Hospital East, Kashiwa, Japan
Prof. Johan Vansteenkiste
Leuven University Hospital, Belgium

Dr David Planchard, a medical oncologist at Gustave Roussy, Villejuif in France, Prof. Johan Vansteenkiste, a pulmonologist from Catholic University of Leuven in Belgium, and Dr Masahiro Tsuboi, a thoracic surgeon from National Cancer Center Hospital East, Kashiwa in Japan, discuss the case of James, a 65-year-old patient with stage IIIA NSCLC, to highlight how clinical trial data on neoadjuvant and adjuvant treatment options are impacting decisions around surgical resection.

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Learn more Back to MDT Hub Time: 15:33
 
Medical Oncologist and Molecular Pathologist

A medical oncologist and a pathologist discuss the benefits of biomarker testing in early and locally advanced disease

Expert Spotlight
Dr David Planchard
Gustave Roussy, Villejuif, France
Prof. Albrecht Stenzinger
Heidelberg University, Heidelberg, Germany

Dr David Planchard, a medical oncologist at Gustave Roussy, Villejuif in France, and Prof. Albrecht Stenzinger, a molecular pathologist from Heidelberg University in Germany, review the current approaches to biomarker testing in early and locally advanced NSCLC, and how the results can be used to determine appropriate treatment options for James, a 65-year-old patient with stage IIIA NSCLC.

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Learn more Back to MDT Hub Time: 13:07
 
Medical Oncologist and Oncology Nurse Practitioner

A medical oncologist and oncology nurse practitioner discuss how to involve the patient in treatment decisions and the role of the MDT in keeping abreast of the latest data

Expert Spotlight
Dr David Planchard
Gustave Roussy, Villejuif, France
Ms Beth Sandy
University of Pennsylvania Abramson Cancer Center, Philadelphia, USA

Dr David Planchard, a medical oncologist at Gustave Roussy, Villejuif in France, and Ms Beth Sandy, a nurse practitioner specializing in thoracic medical oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia in the USA, consider when and how to discuss treatment options and potential side effects with patients receiving adjuvant targeted therapy, with a focus on the case of James, a 65-year-old patient with stage IIIA NSCLC and an EGFR mutation.

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Learn more Back to MDT Hub Time: 12:29
 
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Overview & Learning Objectives
Overview

In this activity, specialists from the multidisciplinary tumour board involved in the management of patients with NSCLC share their perspectives on the role of adjuvant EGFR-TKI therapy, the importance of biomarker testing and shared decision-making in early-stage NSCLC.

This activity is jointly provided by USF Health and touchIME. read more

Target Audience

This activity has been designed to meet the educational needs of pulmonologists, oncologists, radiation oncologists, thoracic surgeons, pathologists and oncology nurse specialists practicing worldwide.

Disclosures

All individuals in a position to influence content have disclosed to USF Health any financial relationship with an ineligible organization. USF Health has reviewed and mitigated all relevant financial relationships related to the content of the activity.  The relevant relationships are listed below. All individuals not listed have no relevant financial relationships.

Faculty

Dr David Planchard discloses: Advisory board fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Pfizer and Roche.

Dr Masahiro Tsuboi discloses: Advisory board fees from AstraZeneca KK, Chugai Pharmaceutical Co, Merck Sharp & Dohme and Novartis; grants and research support from AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb KK, Eli Lilly Japan, Merck Sharp & Dohme and Ono Pharmaceutical; speakers’ bureau for AstraZeneca KK, Bristol Myers Squibb KK, Chugai Pharmaceutical Co, Eli Lilly Japan, Johnson & Johnson Japan, Merck Sharp & Dohme, Ono Pharmaceutical and Taiho Pharma.

Prof. Johan Vansteenkiste discloses: Advisory board fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Merck Sharp & Dohme, Novartis, Pfizer and Roche; grants and research support from Merck Sharp & Dohme (institutional grant).

Prof. Albrecht Stenzinger discloses: Advisory board/speaker’s bureau fees/grants from AGCT, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly, Illumina, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SeaGen, Takeda and Thermo Fisher Scientific.

Beth Sandy discloses: Consultant fees from Amgen; speaker’s bureau for AstraZeneca, Merck and Takeda Pharmaceutical Co.

Content reviewer

Ryan N. Bookout, PharmD, BCOP discloses: Stocks (self-managed) from Bristol Myers Squibb, Gilead, Novartis and Spectrum Pharmaceuticals (all relationships terminated).

Touch Medical Director

Kathy Day has no financial interests/relationships or affiliations in relation to this activity.

USF Health Office of Continuing Professional Development and touchIME staff have no financial interests/relationships or affiliations in relation to this activity.

Requirements for Successful Completion

In order to receive credit for this activity, participants must review the content and complete the post-test and evaluation form. Statements of credit are awarded upon successful completion of the post-test and evaluation form.

If you have questions regarding credit please contact cpdsupport@usf.edu 

Accreditations

Physicians

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through a joint providership of USF Health and touchIME. USF Health is accredited by the ACCME to provide continuing medical education for physicians.

USF Health designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit(s)™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The European Union of Medical Specialists (UEMS) – European Accreditation Council for Continuing Medical Education (EACCME) has an agreement of mutual recognition of continuing medical education (CME) credit with the American Medical Association (AMA). European physicians interested in converting AMA PRA Category 1 Credit(s)™ into European CME credit (ECMEC) should contact the UEMS (www.uems.eu)

Advanced Practice Providers

Physician Assistants may claim a maximum of 0.75 Category 1 credits for completing this activity. NCCPA accepts AMA PRA Category 1 Credit(s)™ from organizations accredited by ACCME or a recognized state medical society.

The AANPCP accepts certificates of participation for educational activities approved for AMA PRA Category 1 Credit(s)™ by ACCME-accredited providers. APRNs who participate will receive a certificate of completion commensurate with the extent of their participation.

Date of original release: 23 September 2021. Date credits expire: 22 September 2022.

If you have any questions regarding credit please contact cpdsupport@usf.edu

Learning Objectives

After watching this activity, participants should be better able to:

  • Describe changes to best practice in early-stage NSCLC with the advent of EGFR-TKI adjuvant therapy, including the role of biomarker testing
  • Recall the latest efficacy and safety data for adjuvant therapy in EGFR-mutant NSCLC within the context of the current treatment paradigm
  • Discuss how the adoption of adjuvant EGFR-targeted therapy in NSCLC affects both patients and different specialties within the multidisciplinary team
Faculty & Disclosures
Dr David Planchard

Gustave Roussy, Villejuif, France

David Planchard, MD, PhD, is Associate Professor of Medicine and Head of the Thoracic Group in the Department of Medicine at Gustave Roussy, Villejuif in France. He is also responsible for the advancement of the mesothelioma and thoracic neuroendocrine tumor research at Gustave Roussy. read more

Dr David Planchard leads clinical trials (mainly phase I and II) in thoracic diseases. His contribution allowed the thoracic tumour group to build a long-term clinical research strategy based on molecular screening. Over the last 10 years, he has been a principal investigator and co-investigator in more than 100 phase I, II and III trials, and has published in several international peer-reviewed journals. His current research interests include genomic analysis (and high-throughput technologies) to guide the use of specific targeted agents for patients with lung cancer.

Dr Planchard is a member of the national network for thymic tumors (RYTHMIC), the national network for mesotheliomas (MESOCLIN) and the national network for the management of neuro-endocrine tumors (RENATEN). He is also a member of the European Society of Medical Oncology (ESMO), American Association of Cancer Research (AACR) and American Society of Clinical Oncology (ASCO).

Dr David Planchard discloses: Advisory board fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Merck, Novartis, Pfizer and Roche.

Dr Masahiro Tsuboi

National Cancer Center Hospital East, Kashiwa, Japan

Masahiro Tsuboi, MD, is Chair and Director of the Department of Thoracic Surgery and Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, and a visiting professor at the Department of Surgery, Yokohama City University Graduate School of Medicine in Yokohama, Japan. read more

Dr Tsuboi is a past board director of International Association for the Study of Lung Cancer (IASLC), a past chair of the Lung Cancer Surgical Study Group (LCSSG) and the Japan Clinical Oncology Group (JCOG), and a past board director of the World Association of Bronchology and Interventional Pulmonology (WABIP).

Dr Tsuboi is involved in numerous perioperative adjuvant and surgical clinical trials as a primary investigator or a member of the steering committee, such as: the phase III JCOG0707 trial of adjuvant chemotherapy in patients with completely resected, node-negative NSCLC; the JIPANG phase III study evaluating the efficacy and safety of postoperative cisplatin-based adjuvant chemotherapy for resected NSCLC; and JCOG0804/WJOG4607L: a phase III trial evaluating sublobar resection for small-size peripheral lung adenocarcinoma. He is a co-global primary investigator of the ADAURA trial and the Neo-ADAURA trials.

Dr Masahiro Tsuboi discloses: Advisory board fees from AstraZeneca KK, Chugai Pharmaceutical Co, Merck Sharp & Dohme and Novartis; grants and research support from AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb KK, Eli Lilly Japan, Merck Sharp & Dohme and Ono Pharmaceutical; speakers’ bureau for AstraZeneca KK, Bristol Myers Squibb KK, Chugai Pharmaceutical Co, Eli Lilly Japan, Johnson & Johnson Japan, Merck Sharp & Dohme, Ono Pharmaceutical and Taiho Pharma.

Prof. Johan Vansteenkiste

Catholic University of Leuven, Belgium

Johan Vansteenkiste is Professor of Internal Medicine in the Faculty of Medicine at the Catholic University of Leuven, Belgium, and Head of Clinic in the Respiratory Oncology Unit and its Clinical Trial Unit at the Leuven University Hospital. read more

Prof. Vansteenkiste studied medicine at the University of Leuven before becoming a board-certified pulmonologist-oncologist. He had additional training in respiratory oncology at the European School of Oncology in Milan, Italy, and in respiratory endoscopy at the Laser Centre in Marseille, France, before gaining his PhD at the University of Leuven in 1996.

Prof. Vansteenkiste is an active member of different international societies, such as the European Society of Medical Oncology (ESMO), International Association for the Study of Lung Cancer (IASLC), American Society of Clinical Oncology (ASCO), and European Respiratory Society (ERS). He is a member of the ESMO Lung Educational Group and Guidelines Group, and chaired one of the ESMO European Lung Cancer Conferences. He is a principal investigator/co-investigator for several clinical trials in the area of lung cancer.

He is an Associate Editor for the Annals of Oncology, member of the editorial board of several other journals, and author/co-author of more than 350 peer-reviewed papers and book chapters on respiratory oncology. His current Web of Science H-index is 73, and he was awarded the 2020 Highly Cited Researcher Award by Web of Science. He was also the recipient of the 2021 ESMO/IASLC Heine H. Hansen Award for outstanding contributions to education and research in lung cancer.

Prof. Johan Vansteenkiste discloses: Advisory board fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Merck Sharp & Dohme, Novartis, Pfizer and Roche; grants and research support from Merck Sharp & Dohme (institutional grant).

Prof. Albrecht Stenzinger

Heidelberg University, Heidelberg, Germany

Albrecht Stenzinger, MD, is a Professor of Molecular Tumour Pathology at Heidelberg University in Germany. He is also the Head of the Center for Molecular Pathology and serves as Deputy Director at the Institute of Pathology (IPH) in Heidelberg. read more

Prof. Stenzinger’s expertise is in molecular pathology and translational research and genetics of solid tumours, with a focus on lung cancer. He has been a principal investigator in several trials at the German Center for Lung Research.

He is a member of several scientific bodies including Working Groups Genomics and Pathology and Genomic Medicine Sweden. He has also contributed to the publication of several peer-reviewed articles.

Prof. Albrecht Stenzinger discloses: Advisory board/speaker’s bureau fees/grants from AGCT, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly, Illumina, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SeaGen, Takeda and Thermo Fisher Scientific.

Beth Sandy

University of Pennsylvania Abramson Cancer Center, Philadelphia, USA

Beth Sandy, MSN, CRNP, is a Nurse Practitioner specializing in thoracic medical oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, USA. She has been a nurse practitioner for 18 years in this field, and speaks nationally and internationally on topics related to the care of patients with lung cancer. She also serves in several editorial roles for peer-reviewed journals and newsletters in oncology.

Beth Sandy discloses: Consultant fees from Amgen; speaker’s bureau for AstraZeneca, Merck and Takeda Pharmaceutical Co.

 

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Question 1/5
Your patient is a 72-year-old female, never-smoker, who has been diagnosed with stage IIIA non-small cell lung cancer. You have the opportunity to test for oncogenic driver mutations on the bioptic sample collected during the diagnostic process. What should be the next step in the management of this patient?

MDT, multidisciplinary team.
Correct

The third-generation EGFR-TKI, osimertinib, is approved by both the US Food and Drug Administration and the European Medicines Agency as targeted adjuvant therapy after tumour resection in adult patients with NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.1,2 Biomarker testing is required to confirm the presence of the EGFR mutation before administration of osimertinib in the adjuvant setting.1,2 Biomarker testing is not currently recommended for the use of neoadjuvant therapy, where chemotherapy is the standard of care.3

Surgical resection is recommended for early-stage NSCLC, and the decision to proceed with surgery is based on  radiographic assessment and a precise assessment of cardiac and pulmonary function to estimate risk of operative morbidity, not on biomarker tests.4

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

References

  1. FDA. Osimertinib. Prescribing information. 2021. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2021/208065s022lbl.pdf (accessed 27 August 2021).
  2. EMA. Osimertinib. Summary of product specifications. 2021. Available at: www.ema.europa.eu/en/documents/product-information/tagrisso-epar-product-information_en.pdf (accessed 27 August 2021).
  3. NCCN guidelines. 2021. Available at: www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (accessed 2 Sept 2021).
  4. Vansteenkiste J, et al. Ann Oncol. 2014;25:1462–74.
Question 2/5
Your patient is a 68-year-old male, never-smoker, who underwent surgical resection with curative intent for non-small cell lung cancer. Biomarker testing on resected tissue showed that the tumour is positive for PD-L1 (71% TPS) and for the EGFR exon 21 L858R mutation. Should all options be available as an approved treatment or in the setting of ongoing clinical trials, which of the following adjuvant therapy approaches would you consider?

EGFR, epidermal growth factor receptor; PD-L1, programmed-death ligand-1; TPS, tumour proportion score.
Correct

The ADAURA trial assessed the efficacy and safety of osimertinib as adjuvant therapy in completely resected EGFR-mutant NSCLC (NCT02511106, phase III).1 In patients with stage IB to IIIA EGFR-mutant NSCLC, DFS was significantly longer among those who received osimertinib, than among those who received placebo.1 The study enrolled patients who had received adjuvant chemotherapy and those who had not.1 Of note, the observed DFS benefit with osimertinib was irrespective of whether patients received adjuvant chemotherapy or not.1

Following the results of the ADAURA trial, osimertinib was approved by both the US Food and Drug Administration and the European Medicines Agency as targeted adjuvant therapy after tumour resection in adult patients with NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.2,3

Durvalumab monotherapy has been tested in patients with stage III, unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy in the PACIFIC trial (NCT02125461).4 Durvalumab significantly prolonged overall survival compared with placebo (hazard ratio, 0.68; 99.73% confidence interval, 0.47–0.997) in this cohort of patients, but the PACIFIC trial did not include patients with resectable disease to test the benefit of durvalumab in the adjuvant setting.4

The IMpower010 (NCT02486718) trial enrolled patients with completely resected stage IB–IIIA NSCLC who received cisplatin-based postoperative chemotherapy and were randomized to receive further adjuvant treatment with atezolizumab or best supportive care.5 Atezolizumab demonstrated a statistically significant DFS benefit compared with best supportive care in patients with stage II–IIIA tumour with PD-L1 expression ≥1%.5 However, in this study, patients were not selected based on the presence of oncogenic target mutations and data collected in clinical trials for advanced NSCLC showed that immunotherapy is poorly effective in patients with EGFR-mutant NSCLC.6,7 In addition, in a subgroup analysis of the IMpower010 trial, which tested atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB–IIIA NSCLC, there was no benefit with atezolizumab compared with best supportive care in patients whose tumour harboured an EGFR mutation.8

DFS, disease-free survival; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-L1, programmed-death ligand-1.

References

  1. Wu Y-L, et al. N Engl J Med. 2020;383:1711–23.
  2. FDA. Osimertinib. Prescribing information. 2021. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2021/208065s022lbl.pdf (accessed 27 August 2021).
  3. EMA. Osimertinib. Summary of product specifications. Available at: www.ema.europa.eu/en/documents/product-information/tagrisso-epar-product-information_en.pdf (accessed 27 August 2021).
  4. Antonia SJ, et al. N Engl J Med. 2018;379:2342–50.
  5. Wakelee HA, et al. J Clin Oncol. 2021;39(Suppl. 15):8500.
  6. Lisberg A, et al. J Clin Oncol. 2018;13:1138–45.
  7. Velez MA, et al. Transl Lung Cancer Res. 2019;8:S339–42.
  8. Wakelee HA, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Presented at the American Association for Clinical Oncology (ASCO) meeting on 6 June 2021. Abstract #8500.
Question 3/5
Based on the most recent clinical data and drawing from lessons learned in the use of targeted therapy and immunotherapy in the advanced/metastatic setting, in which of the following cases would you expect osimertinib to show the best efficacy and least toxicity in the adjuvant setting?

EGFR, epithelial growth factor receptor; PD-L1, programmed death-ligand-1.
Correct

The ADAURA trial assessed the efficacy and safety of osimertinib as adjuvant therapy in completely resected EGFR-mutant NSCLC (NCT02511106, phase III).1 In patients with stage IB–IIIA EGFR-mutant NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo.1

Osimertinib is approved by both the US Food and Drug Administration and the European Medicines Agency as targeted adjuvant therapy after tumour resection in adult patients with NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.2,3

Evidence collected in clinical trials for advanced NSCLC showed that immunotherapy is poorly effective in patients with EGFR-mutant NSCLC and that EGFR-TKIs administered after prior immunotherapy were associated with poor outcomes and increased toxicity.4,5 In addition, in a subgroup analysis of the IMpower010 trial, which tested atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB–IIIA NSCLC, there was no benefit with atezolizumab compared with best supportive care in patients whose tumour harbured an EGFR mutation.6

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

References

  1. Wu Y-L, et al. N Engl J Med. 2020;383:1711–23.
  2. FDA. Osimertinib. Prescribing information. 2021. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2021/208065s022lbl.pdf (accessed 27 August 2021).
  3. EMA. Osimertinib. Summary of product characteristics. Available at: www.ema.europa.eu/en/documents/product-information/tagrisso-epar-product-information_en.pdf (accessed 27 August 2021).
  4. Lisberg A, et al. J Clin Oncol. 2018;13:1138–45.
  5. Velez MA, et al. Transl Lung Cancer Res. 2019;8:S339–42.
  6. Wakelee HA, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Presented at the American Association for Clinical Oncology (ASCO) meeting on 6 June 2021. Abstract #8500.
Question 4/5
What do data from the EMERGING-CTONG 1103 trial (NCT01407822) tell us on the efficacy of first-generation EGFR-TKI therapy in the neoadjuvant and adjuvant setting?

PFS, progression-free survival; OS, overall survival.
Correct

The EMERGING-CTONG 1103 trial (NCT01407822, phase II) enrolled patients with stage IIIA–N2 NSCLC with EGFR mutations in exon 19 or 21.1 Patients were randomly assigned 1:1 to receive erlotinib or gemcitabine plus cisplatin chemotherapy as both neoadjuvant and adjuvant therapy.1 At the median follow-up of 14.1 months, median PFS was significantly longer with erlotinib (21.5 months; 95% CI, 16.7–26.3) versus chemotherapy (11.4 months; 95% CI, 7.3–15.5 months; HR, 0.39; 95% CI, 0.23–0.67; p<0.001).1

At a median follow-up of 62.5 months, the median OS was 42.2 months in the erlotinib group compared with 36.9 months in the chemotherapy group (HR, 0.83, 95% CI 0.47–1.47, p=0.513).2

The improvement in PFS observed with neoadjuvant and adjuvant erlotinib compared with platinum-based chemotherapy did not translate in a statistically significant improvement in OS.1,2

CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; PFS, progression-free survival; OS, overall survival.

References

  1. Zhong WZ, et al. J Clin Oncol. 2019;37:2235–45.
  2. Wu YL, et al. J Clin Oncol. 2021;39(Suppl. 15):8502.
Question 5/5
Your patient is a 77-year-old male, never-smoker, diagnosed with stage IIIA NSCLC. PFTs show FEV1 = 68% and TLco = 72%. What would you consider to be the best course of action for this patient?

FEV1, forced expiratory volume in the first second; NSCLC, non-small cell lung cancer; PFT, pulmonary function test; TLco, transfer factor for carbon monoxide.
Correct

Before considering surgical resection, precise assessment of cardiac and pulmonary function is necessary to estimate risk of operative morbidity.

For functional respiratory assessment, FEV1 and TLco are required; in case either one is <80%, use of additional tests for pulmonary function, such as exercise testing and split lung function, are recommended.

FEV1, forced expiratory volume in the first second; TLco, transfer factor for carbon monoxide.

Reference

Vansteenkiste J, et al. Ann Oncol. 2014;25:1462–74.

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