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LUNG & CHEST TUMOURS 2020

ESMO POCKET GUIDELINES

LUNG & CHEST

TUMOURS

2020

MA-LAR-ALL-0258-1

GUIDELINES COMMITTEE
Chair: Giuseppe Curigliano; Deputy Chair: Cristiana Sessa; Steering Committee Members: Christian Buske,
Paolo G. Casali, Nathan Cherny, Nicoletta Colombo, Silke Gillessen, Karin Jordan, Sibylle Loibl, Rolf A. Stahel,
Arndt Vogel; Subject Editors: Eric Baudin, Alfredo Berruti, Jean-Yves Blay, Michel Ducreux, Nicolas Girard,
Mats Jerkeman, Jonathan Ledermann, Jean-Pascal Machiels, Erika Martinelli, Ulrich Mey, Olivier Michielin,
Shani Paluch-Simon, Thomas Powles, Matthias Preusser, Martin Reck, Carla Ripamonti, Daniele Santini,
Florian Scotté, Elzbieta Senkus-Konefka, Elizabeth Smyth, Jean-Charles Soria, Silvia Stacchiotti, Michael Weller;
International Coordinator of Guidelines Adaptation in Asia Pacific: Takayuki Yoshino; Staff: Claire Bramley,
Sarah Escuin, Louise Green, Lone Kristoffersen, Svetlana Jezdic, Jennifer Lamarre, Keith McGregor,
George Pentheroudakis, Francesco Rho.
ESMO CLINICAL PRACTICE GUIDELINES
Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up
Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD
and Peters S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2018;295(Suppl 4):iv194–237
https://www.annalsofoncology.org/article/S0923-7534(19)31710-7/fulltext
Living guideline: https://www.esmo.org/guidelines/lung-and-chest-tumours/clinical-practice-living-guidelines-
metastatic-non-small-cell-lung-cancer
2nd ESMO Consensus Conference on Lung Cancer: pathology and molecular biomarkers
for non-small-cell lung cancer
Kerr KM, Bubendorf L, Edelman MJ, Marchetti A, Mok T, Novello S, O’Byrne K, Stahel R, Peters S, Felip E
and Panel Members
Ann Oncol 2014;25:1681–90
https://www.annalsofoncology.org/article/S0923-7534(19)35089-6/fulltext
2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second
and further lines of treatment in advanced disease
Besse B, Adjei A, Baas P, Meldgaard P, Nicolson M, Paz-Ares L, Reck M, Smit EF, Syrigos K, Stahel R, Felip E,
Peters S and Panel Members
Ann Oncol 2014;25:1475–84
https://www.annalsofoncology.org/article/S0923-7534(19)34808-2/fulltext
Distributed with support by an educational grant from Bayer.
Bayer has not influenced the content of this publication.
2 3
Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up
Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA, Vansteenkiste J, Escriu C and Peters S, on behalf of
the ESMO Guidelines Committee
Ann Oncol 2017;28(Suppl 4):iv1–21
https://www.annalsofoncology.org/article/S0923-7534(19)42150-9/fulltext
eUpdate – Early and Locally Advanced Non-Small-Cell Lung Cancer (NSCLC) Treatment
Recommendations (May 2020)
ESMO Guidelines Committee
https://www.esmo.org/guidelines/lung-and-chest-tumours/early-stage-and-locally-advanced-non-metastatic-
non-small-cell-lung-cancer/eupdate-early-and-locally-advanced-non-small-cell-lung-cancer-nsclc-treatment-
recommendations
2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer
consensus on diagnosis, treatment and follow-up
Vansteenkiste J, Crinò L, Dooms C, Douillard JY, Faivre-Finn C, Lim E, Rocco G, Senan S, Van Schil P,
Veronesi G, Stahel R, Peters S, Felip E and Panel Members
Ann Oncol 2014;25:1462–74
https://www.annalsofoncology.org/article/S0923-7534(19)34805-7/fulltext
2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell
lung cancer
Eberhard WEE, De Ruysscher D, Weder W, Le Péchoux C, De Leyn P, Hoffmann H, Westeel V, Stahel R,
Felip E, Peters S and Panel Members
Ann Oncol 2015;26:1573–88
https://www.annalsofoncology.org/article/S0923-7534(19)31841-1/fulltext
Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Früh M, De Ruysscher D, Popat S, Crinò L, Peters S and Felip E, on behalf of the ESMO Guidelines Working Group
Ann Oncol 2013;24(Suppl 6):vi99–105
https://www.annalsofoncology.org/article/S0923-7534(19)31548-0/fulltext
Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up
Baas P, Fennell D, Kerr K, Van Schil PE, Haas RL and Peters S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2015;26(suppl 5):v31–9
https://www.annalsofoncology.org/article/S0923-7534(19)47170-6/fulltext
Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up
Girard N, Ruffini E, Marx A, Faivre-Finn C and Peters S, on behalf of the ESMO Guidelines Committee
Ann Oncol 2015;26(Suppl 5):v40–55
https://www.annalsofoncology.org/article/S0923-7534(19)47177-9/fulltext
 ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE
FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN
EASILY ACCESSIBLE FORMAT.
This quick reference booklet provides you with the most important content of
the full ESMO Clinical Practice Guidelines (CPGs) and consensus statements on
the management of lung cancers (early-stage, locally advanced and metastatic
non-small cell lung cancer [NSCLC], and small cell lung cancer [SCLC]) and
chest tumours (malignant pleural mesothelioma and thymic epithelial tumours).
Key content includes diagnostic criteria, staging of disease, treatment plans and
follow-up. The ESMO CPGs and consensus statements on lung & chest tumours
are intended to provide you with a set of recommendations for the best standards
of care for lung & chest tumours, using evidence-based medicine. Implementation
of ESMO CPGs and consensus statements facilitates knowledge uptake and helps
you to deliver an appropriate quality of focused care to your patients.
The approval and licensed indication of drugs mentioned in this pocket guideline
may vary in different countries. Please consult your local prescribing information.
This booklet can be used as a quick reference guide to access key content
on evidence-based management of lung & chest tumours.
Please visit http://www.esmo.org or http://oncologypro.esmo.org to view
the full guidelines.
4 5
8–46
METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)
DIAGNOSIS ..............................................................................................................8
Pathology/molecular biology....................................................................................8
STAGING AND RISK ASSESSMENT .......................................................................11
Laboratory .............................................................................................................11
Radiology ...............................................................................................................11
MANAGEMENT OF ADVANCED/METASTATIC NSCLC.............................................15
First-line treatment of EGFR- and ALK-negative NSCLC, PD-L1 ≥ 50% .................15
First-line treatment of EGFR- and ALK-negative NSCLC disease,
regardless of PD-L1 status ....................................................................................15
First-line treatment of NSCLC without actionable oncogenic driver, with
contraindications to use of immunotherapy ...........................................................16
First-line treatment of SCC .....................................................................................16
First-line treatment of NSCC ..................................................................................17
Maintenance...........................................................................................................22
PS 2 and beyond ....................................................................................................23
Elderly patients ......................................................................................................23
Second-line treatment of NSCLC without actionable oncogenic driver ..................23
Treatment of EGFR-mutated NSCLC .......................................................................24
Treatment of ALK-rearranged NSCLC .....................................................................26
Treatment of ROS1-rearranged NSCLC ..................................................................28
Treatment of BRAF-mutated NSCLC .......................................................................30
Treatment of NSCLC with other actionable oncogenic drivers................................30
Role of RT in stage IV NSCLC ................................................................................31
Focus on brain metastases ....................................................................................32
Focus on LM carcinomatosis .................................................................................33
Role of surgery in stage IV NSCLC ........................................................................33
Treatment of oligometastatic disease .....................................................................34
Focus on bone metastases .....................................................................................35
Role of minimally invasive procedures in stage IV NSCLC .....................................35
Role of palliative care in stage IV NSCLC ...............................................................35
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP .........................35
SUMMARY RECOMMENDATIONS FOR METASTATIC NON-SMALL
CELL LUNG CANCER ...................................................................... 36
 47–71
EARLY AND LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)
SCREENING ...........................................................................................................47
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY .........................................47
The solitary pulmonary nodule...............................................................................49
STAGING AND RISK ASSESSMENT .......................................................................49
Locoregional staging..............................................................................................49
Staging for locally advanced (stage III) NSCLC ......................................................53
Pretreatment risk assessment ................................................................................54
TREATMENT...........................................................................................................58
Early (stages I and II) NSCLC.................................................................................58
Locally advanced (stage III) NSCLC .......................................................................61
PERSONALISED MEDICINE ...................................................................................63
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP .........................64
SUMMARY RECOMMENDATIONS FOR EARLY AND LOCALLY ADVANCED
NON-SMALL CELL LUNG CANCER (NSCLC) ........................................... 65
72–78
SMALL CELL LUNG CANCER (SCLC)
DIAGNOSIS ............................................................................................................72
STAGING ................................................................................................................72
TREATMENT...........................................................................................................73
Localised disease ...................................................................................................74
Metastatic disease..................................................................................................75
PERSONALISED MEDICINE ...................................................................................76
FOLLOW-UP...........................................................................................................76
SUMMARY RECOMMENDATIONS FOR SMALL CELL LUNG CANCER (SCLC) .... 77
TREATMENT...........................................................................................................83
Front-line and maintenance therapy for mesothelioma ..........................................83
Second-line therapy for mesothelioma ..................................................................83
Radiotherapy ..........................................................................................................84
Surgery ..................................................................................................................85
RESPONSE EVALUATION AND FOLLOW-UP ..........................................................86
SUMMARY RECOMMENDATIONS FOR MALIGNANT PLEURAL
MESOTHELIOMA (MPM) ................................................................. 87
91–112
THYMIC EPITHELIAL TUMOURS
DIAGNOSIS ............................................................................................................91
STAGING AND RISK ASSESSMENT .......................................................................93
TREATMENT...........................................................................................................97
Resectable disease ...............................................................................................102
Advanced disease ................................................................................................104
Primary/induction ChT .........................................................................................104
Recurrences .........................................................................................................106
PERSONALISED MEDICINE .................................................................................106
FOLLOW-UP AND LONG-TERM IMPLICATIONS ..................................................106
SUMMARY RECOMMENDATIONS FOR THYMIC EPITHELIAL TUMOURS ........108
113–115
GLOSSARY

79–90
MALIGNANT PLEURAL MESOTHELIOMA (MPM)
DIAGNOSIS ............................................................................................................79
PATHOLOGY ..........................................................................................................80
STAGING ................................................................................................................81
6 7
 A PERSONALISED MEDICINE SYNOPSIS TABLE FOR METASTATIC NSCLC
METASTATIC NON-SMALL CELL LUNG CANCER
BIOMARKER METHOD USE
EGFR mutation Any appropriate, validated method, subject To select those patients with EGFR-
DIAGNOSIS to external quality assurance sensitising mutations most likely to
respond to EGFR TKI therapy
• High-volume centres and multidisciplinary teams are recommended
• In case of distant accessible lesions, core biopsy, under imaging guidance
ALK rearrangement Any appropriate, validated method, subject To select those patients with ALK gene
[typically computed tomography (CT)] can be proposed to external quality assurance. FISH is rearrangements most likely to respond to
• Bronchoscopy is ideally suited to central lesions and can be used for bronchial the historical standard but IHC is now ALK TKI therapy
becoming the primary therapy-determining
washing, brushing, and bronchial and transbronchial biopsy test, provided the method is validated
• Fibre optic bronchoscopy allows evaluation of regional lymph nodes by against FISH or some other orthogonal test
approach. NGS is an emerging technology
endobronchial ultrasound (EBUS) and/or endoscopic ultrasound (EUS)
ROS1 rearrangement FISH is the trial-validated standard. IHC may To select those patients with ROS1 gene
• EBUS-guided transbronchial needle aspiration is less invasive and at least as be used to select patients for confirmatory rearrangements most likely to respond to
accurate as mediastinoscopy FISH testing but currently lacks specificity. ROS1 TKI therapy
• For peripheral lesions, transthoracic percutaneous fine needle aspiration and/or NGS is an emerging technology. External
quality assurance is essential
core biopsy under imaging guidance (typically CT) is recommended
BRAF mutation Any appropriate, validated method, subject To select those patients with BRAF
• In the presence of a pleural effusion, thoracentesis may be both diagnostic and palliative to external quality assurance V600-sensitising mutations most likely
to respond to BRAF inhibitor, with or
• Image-guided pleural biopsy or surgical thoracoscopy is required where fluid without MEK inhibitor therapy
cytology examination is negative
NTRK rearrangement Screening by IHC or RNA NGS. A positive To select those patients with NTRK gene
• More invasive, surgical approaches, such as mediastinoscopy, mediastinotomy, with the former requires confirmation by a fusions most likely to respond to TRK
thoracoscopy and video-assisted thorascopic surgery (VATS) in the diagnostic work- molecular method (FISH, NGS). The latter inhibitor therapy
up should be considered when the previously described techniques are insufficient should probably be validated by IHC

Pathology/molecular biology PD-L1 expression IHC to identify PD-L1 expression at the To enrich for those patients more
Histological diagnosis appropriate level and on the appropriate cell likely to benefit from anti-PD-1 or
population(s) as determined by the intended anti-PD-L1 therapy. For pembrolizumab,
• Pathological diagnosis should be made according to the 2015 World Health drug and line of therapy. Only specific trial testing is a companion diagnostic; for
Organization (WHO) classification assays are validated. Internal and external nivolumab and atezolizumab, testing is
quality assurance are essential complementary
• Most patients with non-small cell lung cancer (NSCLC) present with advanced
stage unresectable disease and treatment-determining diagnoses must be made ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridisation; IHC,
on small biopsy and/or cytology-type samples from the primary tumour or immunohistochemistry; MEK, mitogen-activated protein kinase kinase; NGS, next-generation sequencing; NSCLC, non-small cell
lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor
accessible metastases
• Where specific subtyping is not possible by morphology alone,
immunohistochemistry (IHC) is recommended for subtype determination and • All patients with advanced, possible, probable or definite adenocarcinoma should
to reduce the NSCLC-not otherwise specified (NSCLC-NOS) rate to < 10% of be tested for oncogenic drivers
cases diagnosed • Molecular testing is not recommended in squamous cell carcinoma (SCC), except
Molecular diagnostics in never-, long-time ex- or light-smokers (< 15 pack-years)
• A personalised medicine synopsis is shown in the table on the next page • Epidermal growth factor receptor (EGFR) mutation status should be
systematically analysed in advanced non-squamous cell carcinoma (NSCC)
8 9
 • EGFR mutation status testing must cover exon 19 deletions and the exon 21
L858R substitution mutation and complete coverage of exons 18–21
is recommended
• T790M testing is mandatory for relapsed disease; if cell-free DNA blood tests are
negative, a tissue biopsy is required
• Testing for anaplastic lymphoma kinase (ALK) rearrangement should be
systematically carried out in advanced non-squamous NSCLC
IHC is an alternative to fluorescent in situ hybridisation (FISH) for ALK testing,
provided the method is validated against FISH or some other orthogonal
test approach
• Testing for ROS1 rearrangement should be systematically carried out in
advanced NSCLC
FISH is the standard approach for ROS testing; IHC can be used as a screening
approach but is not recommended as the primary treatment-determining test
• Systematic analysis of BRAF V600 mutation status for the prescription of
BRAF/mitogen-activated protein kinase kinase (MEK) inhibitors is required in
advanced NSCLC
• Screening for NTRK rearrangement should be systematically carried out and may
use IHC or NGS, with appropriate testing follow-up to validate a positive result
• Multiplex, next-generation sequencing (NGS) is becoming the standard approach
to molecular testing but does not address biomarkers requiring testing at the
protein level (requiring IHC) and the question of whether NGS-detected fusion
genes require an orthogonal test (IHC, FISH) for confirmation remains open
• Adequate internal validation and quality control measures are mandatory and
laboratories must perform adequately in external quality assurance schemes for
each test
• Programmed death-ligand 1 (PD-L1) expression testing is recommended for all
patients with newly diagnosed advanced NSCLC
The PD-L1 IHC 22C3 assay and trial-validated assays based on the 28-8 and • NSCLC is staged according to the American Joint Committee on Cancer (AJCC)/
SP263 PD-L1 IHC clones are recommended
For pembrolizumab, the mandatory treatment threshold is a tumour proportion
score (TPS) ≥ 50% in first line and ≥ 1% in second line
PD-L1 testing is not required for nivolumab and atezolizumab in second line
10
PD-L1 testing is not required for pembrolizumab when combined with platinum
and pemetrexed
• Detection in peripheral blood of genomic alterations or factors associated with
treatment resistance will facilitate disease monitoring and will become more
commonplace as techniques improve
STAGING AND RISK ASSESSMENT
• A complete medical history, with comorbidities, weight loss, performance status
(PS), smoking history and physical examination, is required
Laboratory
• Standard tests including routine haematology, renal and hepatic function and
bone biochemistry tests are required
• Routine use of serum tumour markers is not recommended
Radiology
Baseline imaging
• A contrast-enhanced CT scan of the chest and upper abdomen, including
complete assessment of liver, kidneys and adrenal glands, should be carried out
at diagnosis
• Central nervous system (CNS) imaging should be considered at diagnosis for
all patients with metastatic disease and is required for patients with neurological
symptoms or signs
Magnetic resonance imaging (MRI) is more sensitive than CT scan
• Where leptomeningeal disease (LMD) is suspected, diagnostic imaging should
include the brain and the spinal cord
• Where bone metastases are clinically suspected, a bone scan or positron
emission tomography (PET), ideally coupled with CT, is recommended
PET-CT is the most sensitive modality for detecting bone metastasis
Union for International Cancer Control (UICC) system (8th edition) as shown in
the tables on the next pages
• Where there is a solitary metastatic lesion on imaging studies, including pleural
11
 and pericardial effusion, cytological or histological confirmation of stage IV Distant Metastasis (M)
disease is recommended
M0 No distant metastasis
CLINICAL CLASSIFICATION UICC TNM 8 M1 Distant metastasis

PRIMARY TUMOUR (T) Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodules or
M1a
malignant pleural or pericardial effusion||
Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in
TX M1b Single extrathoracic metastasis in a single organ¶
sputum or bronchial washings but not visualised by imaging or bronchoscopy
T0 No evidence of primary tumour M1c Multiple extrathoracic metastasis in a single or multiple organs

Tis Carcinoma in situ* *

Tis includes adenocarcinoma in situ and squamous carcinoma in situ
†
The uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may
Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without extend proximal to the main bronchus, is also classified as T1a
T1 bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main ‡
Solitary adenocarcinoma (not more than 3 cm in greatest dimension), with a predominantly lepidic pattern and not more than 5
bronchus)† mm invasion in greatest dimension in any one focus
§
T2 tumours with these features are classified T2a if 4 cm or less, or if size cannot be determined and T2b if greater than 4 cm
T1mi Minimally invasive adenocarcinoma‡ but not larger than 5 cm
||
Most pleural (pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple microscopic
T1a Tumour 1 cm or less in greatest dimension† examinations of pleural (pericardial) fluid are negative for tumour, and the fluid is non-bloody and is not an exudate. Where
these elements and clinical judgment dictate that the effusion is not related to the tumour, the effusion should be excluded as a
T1b Tumour more than 1 cm but not more than 2 cm in greatest dimension† staging descriptor
T1c Tumour more than 2 cm but not more than 3 cm in greatest dimension†
¶
This includes involvement of a single non-regional node
TNM, tumour, node, metastasis; UICC, Union for International Cancer Control
Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features§ Brierley JD et al. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2017. Reprinted with permission.
– Involves main bronchus regardless of distance to the carina, but without involvement of the
carina
T2
– Invades visceral pleura
– Associated with atelectasis or obstructive pneumonitis that extends to the hilar region either
involving part of or the entire lung
T2a Tumour more than 3 cm but not more than 4 cm in greatest dimension
T2b Tumour more than 4 cm but not more than 5 cm in greatest dimension
Tumour more than 5 cm but not more than 7 cm in greatest dimension or one that directly
T3 invades any of the following: Parietal pleura, chest wall (including superior sulcus tumours)
phrenic nerve, parietal pericardium; or separate tumour nodule(s) in the same lobe as the primary
Tumour more than 7 cm or of any size that invades any of the following: Diaphragm,
T4 mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body,
carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary
N1
nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or
N3
supraclavicular lymph node(s)

12 13
 STAGING AND STAGE GROUPING UICC TNM 8 • The adequacy of RECIST in evaluating response to EGFR or ALK tyrosine kinase
inhibitors (TKIs) in respective genetically-driven NSCLC is debatable but it should
Occult carcinoma TX N0 M0 still be used in clinical practice
Stage 0 Tis N0 M0 Immune-related RECIST (irRECIST), immune-RECIST (iRECIST) and immune-
Stage IA T1 N0 M0 modified RECIST (imRECIST) have been developed but require further
T1mi N0 M0 evaluation before being used in clinical practice
Stage IA1
T1a N0 M0 MANAGEMENT OF ADVANCED/METASTATIC NSCLC
Stage IA2 T1b N0 M0 • The treatment strategy should consider histology, molecular pathology, age,
Stage IA3 T1c N0 M0 PS, comorbidities and the patient’s preferences and should be discussed in a
multidisciplinary tumour board
Stage IB T2a N0 M0
Stage IIA T2b N0 M0 • Systemic therapy should be offered to all stage IV patients with PS 0–2
T1a-c T2a,b N1 M0 • Smoking cessation can improve outcome at any stage of NSCLC and should be
Stage IIB strongly encouraged
T3 N0 M0
First-line treatment of EGFR- and ALK-negative NSCLC, PD-L1 ≥ 50%
T1a-c T2a,b N2 M0
• Pembrolizumab is a standard first-line option for advanced NSCLC in patients
Stage IIIA T3 N1 M0
with PD-L1 expression ≥ 50% and without contraindications to immunotherapy
T4 N0, N1 M0 (such as severe autoimmune disease or organ transplantation)
Stage IIIB T1a-c T2a,b N2 M0 • Atezolizumab represents a promising first-line treatment option in patients with
Stage IIIC T3, T4 N3 M0 PD-L1-high NSCLC (not EMA-approved)
Stage IV Any T Any N M1 First-line treatment of EGFR- and ALK-negative NSCLC disease, regardless of
Stage IVA Any T Any N M1a, M1b PD-L1 status
Stage IVB Any T Any N M1c • Pembrolizumab in combination with pemetrexed and platinum-based ChT should be
considered a standard option in first-line therapy in metastatic non-squamous NSCLC
TNM, tumour, node, metastasis; UICC, Union for International Cancer Control
Overall survival (OS) benefit is apparent across PD-L1 expression levels
Brierley JD et al. TNM Classification of Malignant Tumours, 8 edition. Oxford: John Wiley & Sons, Inc. 2017. Reprinted with permission.
th

Response evaluation
• Response evaluation, using Response Evaluation Criteria in Solid Tumours
(RECIST) v1.1, is recommended after 2–3 cycles of chemotherapy (ChT)
or immunotherapy, using the same initial radiographic investigation that
demonstrated tumour lesions
• The same procedure and timing (every 6–9 weeks) should be applied for
the response evaluation in patients treated with targeted therapies and/or
immunotherapy
• Follow-up with PET is not routinely recommended, due to its high sensitivity and
relatively low specificity
The degree of durable benefit was limited in tumours with PD-L1 TPS < 1%
• The combination of atezolizumab and bevacizumab with carboplatin and
paclitaxel is an option in PS 0–1 patients with metastatic non-squamous
NSCLC, in the absence of immunotherapy contraindications
Improved OS with atezolizumab plus bevacizumab plus carboplatin plus
paclitaxel was observed in patients with sensitising EGFR mutations, defined
as exon 19 deletions or L858R mutations. This association defines a treatment
opportunity for this subgroup after targeted therapies have been exploited
• The combination of carboplatin or cisplatin with pemetrexed and atezolizumab is
another potential treatment opportunity, based on recently presented data from the
IMpower132 trial; it is not currently European Medicines Agency (EMA)-approved

14 15
 • The combination of pembrolizumab plus carboplatin and paclitaxel or albumin- • Addition of the anti-EGFR monoclonal antibody necitumumab to cisplatin and
bound paclitaxel (nab-P) is a standard choice in patients with metastatic gemcitabine was associated with a modest clinical improvement. It has not
squamous NSCLC been adopted as a standard in Europe for advanced SCC and its use should be
OS benefit is apparent across PD-L1 expression levels carefully evaluated
• Atezolizumab/carboplatin/nab-P is an option for patients with metastatic First-line treatment of NSCC
squamous NSCLC, although it is not EMA-approved and was shown to improve • Any platinum-based doublets with a third-generation agent including
PFS but not OS gemcitabine, vinorelbine or taxanes can be used in NSCC, as shown in the figure
• Nivolumab plus ipilimumab is an optional treatment for patients with NSCLC on pages 20–21
with a high tumour mutation burden (TMB, ≥ 10 Mut/Mb), although it is not • The combination of atezolizumab and carboplatin/nab-P followed by maintenance
EMA-approved atezolizumab represents a new standard treatment opportunity, based on recent
Nivolumab plus ipilimumab improved progression-free survival (PFS) data from the IMpower130 trial
versus ChT in patients with high TMB, irrespective of PD-L1, in both squamous • The incorporation of pemetrexed and bevacizumab into individual treatment
and non-squamous histologies; there was no difference between treatments in schedules should be considered based on the following:
PFS among patients with lower TMBs
Pemetrexed-based combination ChT should be restricted to NSCC in
First-line treatment of NSCLC without actionable oncogenic driver, with contraindi- any line of treatment in advanced disease
cations to use of immunotherapy The combination of carboplatin with pemetrexed can be an option in patients
• ChT with platinum doublets should be considered in all stage IV NSCLC patients with a contraindication to cisplatin
without an actionable oncogenic driver, without major comorbidities and PS 0–2 The combination of bevacizumab (continued until progression) with paclitaxel/
• Benefits of ChT versus best supportive care (BSC) are observed irrespective of carboplatin is an option for advanced NSCC in patients with PS 0–1 and the
age, sex, histology and PS absence of contraindications
• Two-agent are superior to one-agent ChT regimens and platinum-based doublets Bevacizumab can also be considered with platinum-based regimens beyond
are recommended in all patients with no platinum contraindications paclitaxel/carboplatin in the absence of contraindications
• Current recommendations are for 4 cycles of platinum-based doublets followed
by less-toxic maintenance monotherapy, or 4 cycles in patients not suitable for
maintenance monotherapy, up to a maximum of 6 cycles
• Treatment selection should consider the expected toxicity profile
• The carboplatin/nab-P regimen has a significantly higher objective response rate
(ORR) compared with solvent-based paclitaxel/carboplatin and less neurotoxicity,
and is an option for advanced NSCLC, particularly in patients with greater risk of
neurotoxicity, pre-existing hypersensitivity to paclitaxel or contraindications to
standard paclitaxel premedication
First-line treatment of SCC
• Platinum-based doublets with the addition of a third-generation cytotoxic agent
(gemcitabine, vinorelbine, taxanes) are recommended in advanced SCC patients
without major comorbidities and PS 0–2, as shown in the figure on pages 18–19

16 17
 TREATMENT ALGORITHM FOR STAGE IV SCC

Stage IV SCC

Never or former light PD-L1 expression**

smoker (< 15 pack-years)*

PD-L1 ≥ 50% Any expression of PD-L1

Molecular test
(ALK/EGFR/ROS1/BRAF) PS 0-1
PS 0-2**** PS 3-4
Pembrolizumab
Atezolizumab***

Positive Negative

Targeted Pembrolizumab + carboplatin/

Follow recommended PD-L1-positive PD-L1-negative BSC
therapy paclitaxel or carboplatin/
treatment in
nab-P (4 cycles), followed by
function of PD-L1
pembrolizumab
expression level
Nivolumab + ipilimumab
Nivolumab/ Nivolumab/ + ChT (2 cycles)***
ipilimumab*** ipilimumab***

Disease progression

*Molecular testing is not recommended in SCC, except in those rare circumstances when SCC is found in a never-, long-time ex- or
light-smoker (< 15 pack-years) PS 0-2 PS 3-4
**In absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-
based ChT, this strategy will be preferred to platinum-based ChT in patients with PS 0-1 and PD-L1 < 50%. Alternatively, if TMB can
accurately be evaluated, and conditioned by the registration and accessibility, nivolumab plus ipilimumab should be preferred to
platinum-based standard ChT in patients with NSCLC
Nivolumab BSC
***Not EMA-approved
Atezolizumab
****PS > 2 patients were not enrolled in available clinical trials. In the absence of contraindications and conditioned by the registration
and accessibility of anti-PD-(L)1 combinations with platinum-based ChT, this strategy might be chosen by analogy to PS 0–1 patients Pembrolizumab if PD-L1 > 1%
based on investigator opinion. Elderly patients are under-represented in available clinical trials, and frail or comorbid patients ≥ 70 Docetaxel
years old shall be evaluated with caution
Ramucirumab/docetaxel
ALK, anaplastic lymphoma kinase; BSC, best supportive care; ChT, chemotherapy; EGFR, epidermal growth factor receptor; EMA, European
Medicines Agency; IO, immuno-oncology; Mb, megabase; nab-P, albumin-bound paclitaxel; NSCLC, non-small cell lung cancer; PD-1,
Erlotinib
programmed cell death protein 1; PD-L1, programmed death-ligand 1; PS, performance status; SCC, squamous cell carcinoma; TMB, Afatinib
tumour mutation burden

18 19
 TREATMENT ALGORITHM FOR STAGE IV NSCC, MOLECULAR
TESTS NEGATIVE (ALK/BRAF/EGFR/ROS1)

Stage IV NSCC: Molecular tests negative (ALK/BRAF/EGFR/ROS1)

PD-L1 expression*

Any expression of PD-L1

PD-L1 ≥ 50%
PS 0-2***
PS 3-4

PS 0-1 Pembrolizumab Atezolizumab Atezolizumab/ Nivolumab/ipilimumab + BSC

Pembrolizumab + platinum/ + carboplatin/ bevacizumab platinum/pemetrexed
Atezolizumab** pemetrexed nab-P (4-6 + carboplatin/ (2 cycles) followed by
ChT (4 cycles), cycles), paclitaxel nivolumab/ipilimumab
followed by followed by (4-6 cycles),
pembrolizumab/ atezolizumab followed by
pemetrexed atezolizumab
/bevacizumab

PD-L1-positive PD-L1-negative

Nivolumab/ Nivolumab/
ipilimumab** ipilimumab**

Disease progression
*In absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1
combinations with platinum-based ChT, this strategy will be preferred to platinum-based ChT in patients with PS 0-2 PS 3-4
PS 0-1 and PD-L1 < 50%. Alternatively, if TMB can accurately be evaluated, and conditioned by the registration
and accessibility, nivolumab plus ipilimumab should be preferred to platinum-based standard ChT in patients
with NSCLC
**Not EMA-approved Nivolumab BSC
***PS > 2 patients were not enrolled in available randomised clinical trials platinum doublet or monotherapy Atezolizumab
gemcitabine, vinorelbine or docetaxel is sometimes alternatively proposed according to investigators’ Pembrolizumab if PD-L1 > 1%
assessment. Elderly patients are under-represented in available clinical trials, and frail or comorbid
patients ≥ 70 years old shall be evaluated with caution Docetaxel
ALK, anaplastic lymphoma kinase; BSC, best supportive care; ChT, chemotherapy; EGFR, epidermal growth factor
Pemetrexed
receptor; EMA, European Medicines Agency; IO, immuno-oncology; Mb, megabase; nab-P, albumin-bound paclitaxel; Ramucirumab/docetaxel
nab-PC, albumin-bound paclitaxel and carboplatin; NSCC, non-squamous cell carcinoma; NSCLC, non-small cell lung Nintedanib/docetaxel
cancer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PS, performance status; TMB, Erlotinib
tumour mutation burden

20 21
 TREATMENT ALGORITHM FOR STAGE IV NSCC, MOLECULAR TESTS POSITIVE PS 2 and beyond
(ALK/BRAF/EGFR/ROS1) • Compared with BSC, ChT prolongs survival and improves quality of life (QoL) in
NSCLC patients with PS 2
Stage IV NSCC: Molecular tests positive (ALK/BRAF/EGFR/ROS1)
• Platinum-based doublets (preferably carboplatin) should be considered for
eligible PS 2 patients, with single-agent gemcitabine, vinorelbine, docetaxel or
ALK translocation BRAF V600 mutation EGFR mutation ROS1 translocation pemetrexed (restricted to NSCC) being alternative options
(refer to the figure on page 27) (refer to the figure on page 30) (refer to the figure on page 25) (refer to the figure on page 29)
• Checkpoint inhibitor treatment can be considered for these patients, although
data are scarce
Safety appears to be comparable to that seen in patients with PS 0–1
Osimertinib*
Alectinib* Dabrafenib/trametinib Crizotinib
Brigatinib
Gefitinib
Erlotinib
Lorlatinib • BSC is recommended for poor PS (3–4) patients in the absence of documented
Crizotinib
Ceritinib
+/- bevacizumab
Entrectinib
Repotrectinib
sensitising alterations, such as EGFR mutations, ALK or ROS1 rearrangements
+/- ramucirumab
Ensartinib**
Afatinib or BRAF V600 mutation
Dacomitinib
Gefitinib/carboplatin/pemetrexed** Elderly patients
• Carboplatin-based doublet ChT is recommended for eligible elderly patients with
PS 0–2 and with adequate organ function
*Preferred option
**Not EMA-approved • Single-agent ChT remains the standard of care for patients not eligible for
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; doublet ChT
NSCC, non-squamous cell carcinoma
• A comprehensive geriatric assessment can be used to guide the choice of
platinum-based regimens, single-agent therapy or BSC
Maintenance
• There is no difference in response and survival with immunotherapy between
• Decisions on maintenance therapy must take into account histology, residual patients ≤ 65 years and those > 65 years, and immunotherapy should be
toxicity after first-line ChT, response to platinum doublet, PS and patient
considered according to standard recommendations in elderly patients
preference
Second-line treatment of NSCLC without actionable oncogenic driver
• In patients with NSCC and good PS (0–1), pemetrexed switch maintenance can
be considered in patients having disease control following 4 cycles of platinum- • Patients clinically or radiologically progressing after first-line therapy with PS
based ChT 0–2, should be offered second-line therapy, irrespective of administration of
maintenance treatment
• Pemetrexed continuation maintenance following completion of 4 cycles of
cisplatin/pemetrexed is recommended for NSCC, in the absence of progression • Following failure of first-line treatment with pembrolizumab, platinum-based ChT
after first-line ChT and recovery from treatment toxicities is recommended
• Continuation maintenance with gemcitabine is an option in NSCLC patients • Anti-programmed cell death protein 1 (PD-1)/PD-L1 agents are the treatment of
treated with 4 cycles of cisplatin/gemcitabine choice for most patients with advanced, previously treated, PD-L1-naive NSCLC,
irrespective of PD-L1 expression
• Maintenance treatment with erlotinib is only recommended for NSCC patients
with an EGFR-sensitising mutation • There are no major safety or efficacy differences in the standard second-line
treatments, nivolumab, pembrolizumab and atezolizumab, but choice can be
influenced by:
PD-L1 expression: Pembrolizumab is approved only in patients with PD-L1 ≥ 1%

22 23
 Approved schedules of administration: Once every 3 weeks for atezolizumab and TREATMENT ALGORITHM FOR STAGE IV LUNG CARCINOMA WITH
pembrolizumab and once every 2 weeks for nivolumab (according to the EMA; EGFR-ACTIVATING MUTATION
the United States Food and Drug Administration [FDA] has approved a
4-weekly schedule for nivolumab)
Stage IV lung carcinoma with EGFR-activating mutation
• Nivolumab improved OS compared with docetaxel in squamous NSCLC and non-
squamous NSCLC and also had better tolerability
PS 0-2
• Pembrolizumab prolonged OS compared with docetaxel in previously treated PS 3-4 for all following options
NSCLC with PD-L1 expression > 1% of tumour cells and was associated with
fewer side effects
Osimertinib*
• Atezolizumab improved OS compared with docetaxel in advanced NSCLC Gefitinib
Erlotinib
previously treated with one or two prior lines of ChT and was better tolerated +/- bevacizumab
• Single-agent ChT improves symptoms and survival compared with BSC, +/- ramucirumab
Afatinib
and docetaxel and pemetrexed (NSCC only) are second-line ChT options, Dacomitinib
with comparable efficacy, although pemetrexed has a more favourable Gefitinib/carboplatin/pemetrexed**
tolerability profile
Disease progression
• Second-line treatment duration should be individualised and treatment may be
prolonged if disease is controlled and toxicity acceptable Systemic progression
Oligoprogression
• The combination of ramucirumab and docetaxel is an option for patients with
NSCLC progressing after previous ChT or immunotherapy Exon 20 T790M mutation testing:
Local treatment
• The combination of nintedanib and docetaxel is an option for patients with (surgery or RT) Systemic progression
Re-biopsy
or
adenocarcinoma progressing after previous ChT or immunotherapy and continue targeted
cfDNA plasma testing, with re-biopsy
systemic treatment
if plasma test is negative
• The combination of paclitaxel and bevacizumab is another treatment option,
although it is not EMA-approved
• Erlotinib is a potential second-/third-line treatment option, in particular for patients
not suitable for immunotherapy or second-line ChT in unknown EGFR status or Exon 20 T790M mutation negative
Exon 20 T790M
EGFR wild-type (WT) tumours mutation positive Or re-biopsy indicated but not feasible

• Afatinib is a therapeutic option in patients with advanced SCC (PS 0–2) with
unknown EGFR status or EGFR WT unfit for ChT or immunotherapy, progressing Systemic
Platinum-based ChT
on or after ChT Osimertinib
progression
(see the figure on pages 20–21)
Carboplatin/paclitaxel/bevacizumab/
Treatment of EGFR-mutated NSCLC atezolizumab**

First-line treatment
• The EGFR TKIs erlotinib, gefitinib, afatinib and dacomitinib are standard first-line
treatments for advanced EGFR-mutated NSCLC, as shown in the figure on the next
page, with similar clinical benefits in PS 3–4 and good PS patients *Preferred option
First-line osimertinib is the preferred option for patients with sensitising **Not EMA-approved

EGFR mutations cfDNA, cell-free DNA; ChT, chemotherapy; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency;
PS, performance status; RT, radiotherapy

24 25
 • There is no consensus preferring any of the four currently available first-line T REATMENT ALGORITHM FOR STAGE IV LUNG CARCINOMA WITH
EGFR TKIs over others ALK TRANSLOCATION
• Clinically stable patients benefitting from EGFR TKIs may continue to receive the
same therapy beyond initial radiological progression
Stage IV lung carcinoma with ALK translocation
• Continuous use of EGFR TKIs in combination with ChT is not recommended
• The addition of carboplatin/pemetrexed to gefitinib improved OS and PFS
compared with gefitinib, and this combination is a first-line therapy option in
advanced EGFR-mutated NSCLC, although it is not EMA-approved Alectinib*
Crizotinib
• The addition of ramucirumab to erlotinib led to superior PFS in first-line EGFR- Ceritinib
mutated NSCLC in a phase III trial and is EMA-approved Brigatinib
Ensartinib**
• Erlotinib/bevacizumab is an EMA-approved front-line treatment option for EGFR-
mutated tumours
Disease progression
Beyond first-line treatment
• Almost all patients who benefit from EGFR TKIs will develop clinical resistance,
Oligoprogression
frequently due to acquired EGFR exon 20 T790M mutations Systemic progression
• All patients with clinical resistance to first-/second-generation EGFR TKIs should
undergo T790M mutation testing and osimertinib is the standard treatment for Local treatment
patients testing positive (surgery or RT) Systemic progression Re-biopsy recommended
and continue targeted (not mandatory for decision)
• Molecular mechanisms of resistance to EGFR TKIs in patients without T790M systemic treatment
mutations include MET amplification, human epidermal growth factor receptor
2 (HER2) amplification, PIK3CA alternations, KRAS mutation and small cell
transformation
The current standard approach in this scenario is platinum-based doublet After crizotinib:
Alectinib After at least 1 ALK TKI,
ChT, particularly in combination with atezolizumab and bevacizumab, Ceritinib other than crizotinib:
although it is not EMA-approved Brigatinib Lorlatinib

Treatment of ALK-rearranged NSCLC

First-line treatment
• First-line treatment for ALK-rearranged NSCLC is an ALK TKI, including alectinib, Systemic progression
crizotinib, certinib and brigatinib (EMA-approved) and ensartinib (not EMA-
approved), as shown in the figure on the next page
Platinum-based ChT (see the figure on pages 20–21)
Carboplatin/paclitaxel/bevacizumab/atezolizumab**
*Preferred option
**Not EMA-approved
ALK, anaplastic lymphoma kinase; ChT,
chemotherapy; EMA, European Medicines
Agency; RT, radiotherapy; TKI, tyrosine
kinase inhibitor

26 27
 • Lorlatinib is currently in phase III to investigate whether upfront treatment with TREATMENT ALGORITHM FOR STAGE IV LUNG CARCINOMA WITH ROS1
this next-generation TKI can further improve clinical outcomes for patients with TRANSLOCATION
advanced ALK-rearranged NSCLC compared with crizotinib treatment (not EMA-
approved) Stage IV lung carcinoma with ROS1 translocation
• An alternative daily dose of ceritinib (450 mg with food) to the currently approved
dose (750 mg in a fasted state) may help to reduce gastrointestinal toxicities
• Front-line use of ALK TKIs is effective in patients with CNS involvement Crizotinib
• While ceritinib represents a better treatment strategy than ChT and presumably or
Lorlatinib
crizotinib, alectinib represents a better treatment option than ChT and crizotinib Entrectinib
Beyond first-line treatment Repotrectinib

• Crizotinib improves ORR and PFS compared with second-line ChT in TKI-naive
Disease progression
patients with previously treated ALK-rearranged NSCLC and any patient with
NSCLC harbouring an ALK fusion should receive crizotinib as next-line therapy, if
not received previously Oligoprogression Systemic progression

• In ALK-rearranged patients progressing on crizotinib, treatment with next-

generation ALK TKIs, such as alectinib, ceritinib, brigatinib or lorlatinib, is Re-biopsy recommended if
Local treatment Systemic progression
recommended ROS1 TKI received in first line

• Ensartinib shows high activity against a broad range of known crizotinib-resistant

ALK mutations and CNS metastases, which also showed potential post-crizotinib
efficacy
Crizotinib
• In patients who progress after a second-generation ALK TKI, the next-generation or
ALK inhibitor lorlatinib is recommended platinum-based ChT
(see the figure on pages 20–21)
Treatment of ROS1-rearranged NSCLC if ROS1 TKI received in first line
Alternative new generation ROS1 TKIs
• Single-agent crizotinib is recommended as first- or second-line treatment in if not given in first line, e.g. lorlatinib*,
patients with stage IV NSCLC with ROS1 rearrangement, as shown in the figure *Not EMA-approved entrectinib*, repotrectinib*
on the next page ChT, chemotherapy; EMA, European Medicines Agency;
TKI, tyrosine kinase inhibitor

• Ceritinib may be considered in crizotinib-naive patients but is currently not

EMA-approved
• Brigatinib, lorlatinib, repotrectinib and entrectinib also have a potential anti-ROS1
activity on the basis of preclinical studies and limited phase I/II encouraging
clinical data
• Patients receiving first-line crizotinib can be offered second-line platinum-based
ChT
• Entrectinib is EMA-approved for the treatment of NSCLC patients positive
for ROS1 mutations (patients who have not previously received other ROS1
inhibitors)
28 29
 Treatment of BRAF-mutated NSCLC • In contrast, selpercatinib and pralsetinib selectively block RET, avoiding other
• The EMA- and FDA-approved combination of dabrafenib and trametinib is targets and the associated treatment-limiting side effects
recommended for patients with BRAF inhibitor-naive, stage IV NSCLC with BRAF Both RET inhibitors are currently in late-stage clinical trials
V600E mutation, as shown in the figure on the next page Pralsetinib was approved by the FDA in September 2020 for the treatment of
• Vemurafenib is showing encouraging results in subsequent-line studies adults with metastatic RET fusion-positive NSCLC
• Patients receiving a first-line BRAF/MEK inhibitor combination may be offered • Multiple case series and cohorts have demonstrated durable ORRs in METex14-
second-line platinum-based ChT mutant disease with MET-targeting TKIs, including crizotinib, capmatinib and
tepotinib
TREATMENT ALGORITHM FOR STAGE IV LUNG CARCINOMA WITH BRAF
• Crizotinib has demonstrated potential clinical efficacy against the METex14 variant
V600 MUTATION
that needs to be confirmed
• More specific MET-directed TKIs are undergoing development against this target,
Stage IV lung carcinoma with BRAF V600 mutation including capmatinib, tepotinib and salvolitinib
• HER2 dysregulation is another promising target for advanced NSCLC but there
is a lack of robust data; targeting HER2 dysregulation is not recommended and
Dabrafenib/trametinib recruitment into open trials is encouraged
or Trastuzumab deruxtecan is a novel antibody-drug conjugate whose use is mainly
Platinum-based ChT restricted to clinical trials, while activity is promising
• For disease with somatic fusions involving the rare oncogenic drivers NTRK1-3
Disease progression
larotrectinib and entrectinib show promising clinical activity
Larotrectinib is the first tumour-agnostic drug to be approved in the European
Systemic progression
Union for the treatment of adult and paediatric patients with solid tumours
Oligoprogression displaying a NTRK gene fusion, who have a disease that is locally advanced,
Dabrafenib/trametinib metastatic or where surgical resection is likely to result in severe morbidity and
or who have no satisfactory treatment options
Platinum-based ChT (see the figure on pages
20–21) if BRAF/MEK inhibitors received in
In August 2020, the EMA granted a conditional marketing authorisation to
Local treatment Systemic progression
first line entrectinib as monotherapy indicated for the treatment of adult and paediatric
Consider immunochemotherapy as per patients 12 years of age and older with solid tumours expressing a NTRK
figure on pages 20–21 if smoker gene fusion:
ChT, chemotherapy; MEK, mitogen-activated protein kinase kinase
– who have a disease that is locally advanced, metastatic or where surgical
Treatment of NSCLC with other actionable oncogenic drivers resection is likely to result in severe morbidity, and
– who have not received a prior NTRK inhibitor
• Several other molecular targets have been identified harbouring somatic variants
with therapeutic potential, including RET, MET, HER2 and neurotrophic tyrosine – who have no satisfactory treatment options
receptor kinase (NTRK) Role of radiotherapy in stage IV NSCLC
• Multitarget agents, including cabozantinib, vandetanib, sunitinib, sorafenib, • External beam radiotherapy (EBRT) plays a major role in the symptom control
alectinib, lenvatinib, nintedanib, ponatinib and regorafenib, with anti-RET activity of metastases and is indicated in cases of haemoptysis and symptomatic
have shown disappointing activity in trials, although the studies are small and airway obstruction
subject to selection bias and results of heterogeneous benefit

30 31
 • Higher doses of radiotherapy (RT) do not lead to greater palliation and are
associated with higher rates of acute toxicity
• There are few data on the optimal timing of thoracic RT and systemic therapy
in stage IV disease and no evidence that the concurrent administration of ChT,
targeted agents or immunotherapy to palliative RT is beneficial
• EBRT alone is more effective than endobronchial brachytherapy (EBB) alone
for palliation
• EBB may be considered in selected cases of patients previously treated by EBRT
who are symptomatic from recurrent endobronchial central obstruction
• Neurological symptoms from spinal cord compression can be relieved by early
RT
Focus on brain metastases
• The treatment of patients with brain metastases with/without leptomeningeal
(LM) involvement, and no driver mutations, is dependent on the prognosis, based
on the Radiation Therapy Oncology Group recursive partitioning analysis (RPA)
• RPA class I patients are those < 65 years old, with a good Karnofsky Performance
Score (KPS) (≥ 70%), no other extracranial metastases and a controlled primary
tumour; class III patients have a KPS < 70%; class II represents all other patients
• BSC, and not whole-brain RT (WBRT), is recommended for RPA class III patients
because of the dismal prognosis
• WBRT can be considered for patients contingent on prognostic factors of better
survival, such as driver mutations
• The most frequent WBRT schedules are 20 Gy in 5 fractions or 30 Gy in 10
fractions, with no difference in outcome
• For most patients with symptomatic brain metastases and/or significant oedema,
dexamethasone or equivalent corticosteroid is recommended
Tapering of the dose and cessation after RT are recommended
Corticosteroids are not recommended for asymptomatic brain metastases
• Neuroprotective agents have not shown convincing benefit and are not
recommended for routine use
• Hippocampus avoidance WBRT is still undergoing trial evaluation and is not
currently recommended for routine care
• Surgical resection can be considered for single brain metastases, with
postoperative WBRT or stereotactic radiosurgery (SRS)
• SRS alone with close follow-up, without WBRT consolidation, is recommended
where there are a limited number of metastases and RPA class I and II
32
SRS is preferred due to reduced morbidity compared with WBRT, but there is
no randomised trial comparing the two approaches
• SRS should generally be considered in patients with ≤ 4 brain metastases, but
there is a move to base SRS decisions on total tumour volume because the risk
of radionecrosis increases with tumour volume
• Systemic therapy and deferred RT should be considered for patients with
asymptomatic brain metastases who have not received prior systemic therapy
• There are limited trial data on the safety and efficacy of immunotherapy in
patients with small-volume untreated CNS metastases
• In patients with a actionable oncogenic driver (e.g. EGFR, ALK), the use of CNS-
penetrant next-generation TKIs may restore control of brain disease, delay cranial
RT and reduce the incidence of new CNS metastases
Focus on LM carcinomatosis
• Diagnostic modalities include cerebrospinal MRI with contrast enhancement,
ideally before cerebrospinal fluid (CSF) intervention
• CSF sampling with cytological assessment is diagnostic but limited by low
sensitivity but high specificity
• Prognosis is poor and the treatment aim is to prolong survival with
acceptable QoL
• Patients with actionable oncogenic drivers may derive benefit from a CNS-
penetrant next-generation TKI, otherwise systemic therapy strategies vary widely
across Europe
• ChT and bevacizumab may have activity both extracranially and intracranially and
also in the context of LMD
• Intra-CSF pharmacotherapy may be considered, although consideration should
be given to patient factors, e.g. PS, extracranial control, and likely benefit
• No randomised data exist to support the role of RT for LMD, but focal RT can be
considered in exceptional cases of circumscribed, symptomatic lesions
Role of surgery in stage IV NSCLC
• Surgery may be indicated for diagnosis, evaluation of response to systemic
therapy and palliation, and highly selected patients may be considered for lung
resection with therapeutic intent or even for a salvage procedure
• When metastatic disease is suspected on PET scanning, invasive surgical
procedures, such as incisional biopsies, mediastinoscopy, thoracoscopy (VATS)
or laparoscopy, may be required to obtain adequate samples, which require
detailed routine staining, IHC and molecular genetic testing
33
 • Palliative interventions may be useful for primary tumour- or metastasis-related
local complications which cannot be managed by conservative measures, e.g.
lung abscess, empyema, massive haemoptysis, spinal cord compression and
pathological bone fractures
• There is no general consensus on the precise definition of oligometastatic
disease and clear evidence for surgical treatment is limited
• Extensive extrapleural pneumonectomy, sometimes in combination with
intraoperative ChT or hyperthermic ChT, in patients with malignant pleural
nodules or malignant pleural effusion carries a higher operative risk and
prospective studies are not available
• Pleurodesis for persisting or recurrent pleural effusions improves dyspnoea; talc
is the preferred agent and thoracoscopic poudrage may be better than injection of
talc slurry in patients with primary lung cancer
• Indwelling pleural catheters or pleuroperitoneal shunts may provide symptomatic
relief for trapped lung with a thickened visceral pleural peel
• Salvage surgery may be considered for residual or progressive disease in the
primary tumour or metastatic site when no other treatment options remain or
specific complications occur
• A surgical selection score, comprising histology, tumour size, tumour, node,
metastasis status, Charlson comorbidity index, age, race, facility type, insurance
and income, may be a good predictor of survival but requires further prospective
validation
Treatment of oligometastatic disease
• Stage IV patients with limited synchronous metastases at diagnosis may
experience long-term disease-free survival (DFS) following systemic therapy and
local consolidative therapy (LCT) (high-dose RT including stereotactic ablative
body RT [SABR] or surgery)
There are no published data on the impact of LCT on OS and long-term toxicity
These patients should be discussed within a multidisciplinary tumour board
and inclusion in clinical trials is preferred
• Although operative risk is low and long-term survival may be obtained, current
evidence for surgery in oligometastatic disease is limited and the relative contribution
of surgery versus RT as local treatment modality has not yet been established
• The specific approach to brain oligometastases is discussed under Focus on
brain metastases, below
• In patients with a solitary lesion in the contralateral lung, radical therapy is
recommended and both surgery and SRS are associated with long-term survival
34
• Stage IV patients with limited metachronous metastases may experience
long-term DFS with local treatment, although this is based mainly on
retrospective data
• Local treatment may also be used for patients with driver mutations who show
oligoprogression on molecular-targeted therapies, although data are lacking
and there is little information on the safety of combining SABR with molecularly
targeted agents
• Due to the limited evidence available, inclusion in clinical trials is the
preferred strategy for patients with synchronous, metachronous and
oligoprogessive metastases
Focus on bone metastases
• Both standard EBRT and SABR can be used to palliate painful, uncomplicated
bone pain; single fractions are not inferior to multiple fractions and are the
recommended approach
• Zoledronic acid or denosumab is recommended in selected patients with
advanced lung cancer with bone metastases
• Zoledronic acid and denosumab reduce skeletal-related events (SREs)
Denosumab shows a trend towards superiority to zoledronic acid in SRE prevention
• Both agents are associated with increased risk of osteonecrosis of the jaw
Role of minimally invasive procedures in stage IV NSCLC
• Endoscopy debulking by laser, cryotherapy or stent placement may be helpful in
symptomatic major airway obstruction or post-obstructive infection
• Endoscopy is useful in the diagnosis and treatment (endobronchial or by guiding
endovascular embolisation) of haemoptysis
• Vascular stenting might be useful in NSCLC-related superior vena cava compression
Role of palliative care in stage IV NSCLC
• Early palliative intervention is recommended, in parallel with standard oncological
care, and can significantly improve QoL
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
• Due to the aggressive nature of this disease, close follow-up, at least every 6–12
weeks after first-line therapy, is advised to allow for early initiation of second-line
therapy but should also depend on individual retreatment options
35

DIAGNOSIS
Bronchoscopy is ideally suited to central lesions and can be used with bronchial
washing, brushing, and bronchial and transbronchial biopsy
EBUS and/or EUS can be used to evaluate regional lymph nodes
Transthoracic percutaneous fine needle aspiration and/or core biopsy is
recommended for mid to peripheral lesions
Thoracentesis may be diagnostic and palliative for pleural effusion
Image-guided pleural biopsy or surgical thoracoscopy is required where fluid
cytology is negative
More invasive, surgical approaches should be considered when non-surgical
techniques do not provide a diagnosis
Pathology/molecular biology
Histological diagnosis
• Pathological diagnosis, using biopsy or cytology samples from the primary
tumour or metastases, should be made according to the 2015 WHO classification
• IHC can help to determine subtypes when morphology alone is insufficient
Molecular diagnostics
• All patients with advanced adenocarcinoma should be tested for
oncogenic drivers
• EGFR mutation status testing in NSCC must cover exon 19 deletions and the
exon 21 L858R substitution mutation and complete coverage of exons 18–21 is
recommended
• T790M testing is mandatory for relapsed disease
• Testing for ALK rearrangements should be systematically carried out in advanced
non-squamous NSCLC
• Testing for ROS1 rearrangements should be systematically carried out in
advanced NSCLC
• FISH is a standard approach for ROS1 translocation detection; IHC is not
recommended as the primary treatment-determining test
• IHC with high-performance ALK antibodies and validated assays may be used for
screening and have recently been accepted as an equivalent alternative to FISH
for ALK testing
36
• BRAF V600 mutation status should be systematically analysed in advanced
NSCLC for the prescription of BRAF/MEK inhibitors
• Screening for NTRK rearrangement should be systematically carried out and may
use IHC or NGS, with appropriate testing follow-up to validate a positive result
• Molecular EGFR and ALK testing are not recommended in patients with a
confident diagnosis of SCC, except in unusual cases, e.g. never/former light
smokers or long-time ex-smokers
• If available, multiplex platforms (NGS) for molecular testing are preferable.
Whatever testing modality is used, it is mandatory that adequate internal
validation and quality control measures are in place and that laboratories
participate in, and perform adequately in, external quality assurance schemes for
each biomarker test
• PD-L1 expression testing is recommended for all patients with newly diagnosed
advanced NSCLC; the treatment threshold for pembrolizumab is TPS ≥ 50% in
first line and ≥ 1% in second line
• Testing is required for pembrolizumab therapy but may also be informative when
nivolumab or atezolizumab are used
STAGING AND RISK ASSESSMENT
A complete medical history, with comorbidities, weight loss, PS, smoking history
and physical examination, along with routine haematology, renal and hepatic
function and bone marrow biochemistry, are required
Routine use of serum tumour markers, such as carcinoembryonic antigen, is not
recommended
Radiology
Baseline imaging
• Contrast-enhanced CT scan of the chest and upper abdomen including the liver
and the adrenal glands should be performed at diagnosis
• Imaging of CNS should be considered at diagnosis for all patients with metastatic
disease and is required for patients with neurological symptoms or signs. MRI is
more sensitive than CT scan
• Where LMD is suspected, imaging should include the brain and the spinal cord
• If bone metastases are clinically suspected, bone imaging is required
• Bone scan or PET, ideally coupled with CT, can be used for detection of bone
metastasis. PET-CT is the most sensitive modality in detecting bone metastasis
• NSCLC is staged according to the AJCC/UICC system
37

• For a solitary metastatic lesion on imaging, including pleural and pericardial
effusion, cytological or histological confirmation of stage IV disease is
recommended
Response evaluation
• Response evaluation is recommended to evaluate response after 2–3 cycles of
ChT or immunotherapy, using the same initial radiographic investigation that
demonstrated tumour lesions
• The same procedure and timing (every 6–9 weeks) should be applied for
the response evaluation in patients treated with targeted therapies and/or
immunotherapy
• Follow-up with PET is not routinely recommended
• Measurements and response assessment should follow RECIST v1.1
• At present, RECIST should also be used to evaluate response to EGFR or ALK
TKIs and other actionable oncogene alterations
• In the case of immune checkpoint inhibitor therapy, RECIST should be used,
although irRECIST, iRECIST and imRECIST may have a role in the overall
assessment of therapy
MANAGEMENT OF ADVANCED/METASTATIC NSCLC
Systemic therapy should be offered to all stage IV patients with PS 0–2
Smoking cessation should be strongly encouraged
First-line treatment of EGFR- and ALK-negative NSCLC, PD-L1 ≥ 50%
• Pembrolizumab is a standard first-line option for advanced NSCLC in patients
with PD-L1 expression ≥ 50% and without contraindications to immunotherapy
• Atezolizumab represents a promising first-line treatment option in patients with
PD-L1-high NSCLC (not EMA-approved)
First-line treatment of EGFR- and ALK-negative NSCLC disease, regardless of
PD-L1 status
• Pembrolizumab in combination with pemetrexed and platinum-based ChT is a
standard option in metastatic non-squamous NSCLC
• Atezolizumab in combination with pemetrexed and a platinum-based ChT is a
therapeutic option in metastatic non-squamous NSCLC [not EMA-approved]
38
• In metastatic non-squamous NSCLC, the combination of atezolizumab and
bevacizumab with carboplatin and paclitaxel is an option for PS 0–1 patients, in
the absence of immunotherapy contraindications
• In metastatic squamous NSCLC, options include combinations of pembrolizumab
and carboplatin with paclitaxel or nab-P and atezolizumab with carboplatin and
nab-P (not EMA-approved)
• Nivolumab plus ipilimumab is an optional treatment for patients with NSCLC,
although it is not EMA-approved
First-line treatment of NSCLC without actionable oncogenic driver, with
contraindications to use of immunotherapy
• ChT with platinum doublets should be considered in all stage IV NSCLC patients
without an actionable oncogenic driver, without major comorbidities and PS 0–2
• Current recommendations are: 4 cycles of platinum-based doublets followed
by less-toxic maintenance monotherapy, or 4 cycles in patients not suitable for
maintenance monotherapy, up to a maximum of 6 cycles
• Carboplatin/nab-P is an option for advanced NSCLC, particularly in patients
with greater risk of neurotoxicity, pre-existing hypersensitivity to paclitaxel or
contraindications to standard paclitaxel premedication
First-line treatment of SCC
• Platinum-based doublets with the addition of a third-generation cytotoxic agent
(gemcitabine, vinorelbine, taxanes) are recommended in patients without major
comorbidities and PS 0–2
• The addition of necitumumab to cisplatin/gemcitabine has not been adopted as
a standard in Europe for advanced SCC and its use should be carefully evaluated
First-line treatment of NSCC
• Any platinum-based doublets with a third-generation agent, including
gemcitabine, vinorelbine or taxanes, can be used in NSCC
• Atezolizumab and carboplatin/nab-P followed by maintenance atezolizumab
represents a new standard treatment opportunity
• Pemetrexed-based combination ChT should be restricted to NSCC in any line of
treatment in advanced disease
• The combination of carboplatin with pemetrexed is an option for patients with a
contraindication to cisplatin
• The combination of bevacizumab (continued until progression) with paclitaxel/
carboplatin is an option for advanced NSCC in patients with PS 0–1 and the
absence of contraindications
39

• Bevacizumab can also be considered with platinum-based regimens beyond
paclitaxel/carboplatin in the absence of contraindications
Maintenance
• Maintenance ChT should be offered only to patients with PS 0-1 after first-line
ChT. Decisions about maintenance should consider histology, response to
platinum-doublet ChT and remaining toxicity after first-line ChT, PS and patient’s
preference
• In patients with NSCC and good PS (0–1), pemetrexed switch maintenance can
be considered in patients having disease control following 4 cycles of platinum-
based ChT
• Pemetrexed continuation maintenance following completion of 4 cycles of
first-line cisplatin/pemetrexed ChT is recommended for NSCC, in the absence of
progression after first-line ChT
• Continuation maintenance with gemcitabine is an option in NSCLC patients
treated with 4 cycles of cisplatin/gemcitabine
• Erlotinib maintenance is only recommended for NSCC patients with an EGFR-
sensitising mutation
PS 2 and beyond
• ChT prolongs survival and improves QoL in NSCLC patients with PS 2 when
compared with BSC
• Platinum-based doublets (preferably carboplatin) should be considered
for eligible PS 2 patients, with single-agent gemcitabine, vinorelbine,
docetaxel, pemetrexed (restricted to NSCC), or checkpoint inhibitors being
alternative options
• BSC is recommended for poor PS (3–4) patients in the absence of documented
sensitising alterations
Elderly patients
• Carboplatin-based doublet ChT is recommended for eligible elderly patients with
PS 0–2 and with adequate organ function, with single-agent ChT as an option
where doublets are not feasible
• Immunotherapy should be considered according to standard
recommendations
Second-line treatment of NSCLC without actionable oncogenic driver
40
• Patients progressing after first-line therapy should be offered second-line
therapy, irrespective of maintenance treatment administration
• Platinum-based ChT is recommended following failure of first-line
pembrolizumab
• Anti-PD-1/PD-L1 agents are the treatment of choice for most patients with advanced,
previously treated, PD-L1-naive NSCLC, irrespective of PD-L1 expression
• Nivolumab is recommended for squamous NSCLC and non-squamous NSCLC
• Pembrolizumab is recommended for previously treated NSCLC with PD-L1
expression > 1% of tumour cells
• Atezolizumab is recommended for advanced NSCLC previously treated with one
or two prior lines of ChT
• Docetaxel and pemetrexed (NSCC only) are second-line ChT options, with
comparable efficacy; pemetrexed has a more favourable tolerability profile
• Ramucirumab plus docetaxel is an option for patients with NSCLC progressing
after previous ChT or immunotherapy
• Nintedanib plus docetaxel or paclitaxel plus bevacizumab (not EMA-approved)
are options for patients with adenocarcinoma progressing after previous ChT
or immunotherapy
• Erlotinib is a potential second-/third-line treatment option, in particular for
patients not suitable for immunotherapy or second-line ChT in unknown EGFR
status or EGFR WT tumours
• Afatinib is an option for patients with advanced SCC (PS 0–2) unfit for ChT or
immunotherapy, progressing on or after ChT with unknown EGFR status or EGFR WT
Treatment of EGFR-mutated NSCLC
First-line treatment
• Erlotinib, gefitinib, afatinib and dacomitinib are equally effective, standard first-
line treatments for advanced EGFR-mutated NSCLC, with similar clinical benefits
in PS 3–4 and good PS patients
• Clinically stable patients benefitting from EGFR TKIs may continue to receive
the same therapy beyond initial radiological progression
• First-line osimertinib is the preferred option for patients with sensitising
EGFR mutations
• Erlotinib/bevacizumab is an EMA-approved front-line treatment option for
EGFR-mutated tumours
• Another front-line combination option is carboplatin/pemetrexed/gefitinib (not
EMA-approved)
41

Beyond first-line treatment
• Patients with clinical resistance to EGFR TKIs should undergo T790M mutation
testing and osimertinib is the standard treatment for patients testing positive
• In patients with other molecular mechanisms of resistance, the standard
approach is platinum-based doublet ChT, particularly in combination with
atezolizumab and bevacizumab, although it is not EMA-approved
Treatment of ALK-rearranged NSCLC
First-line treatment
• Patients with ALK-rearranged NSCLC should receive first-line ALK TKI including
alectinib, crizotinib, certinib and brigatinib (EMA-approved) and ensartinib (not
EMA-approved)
• Alectinib is associated with longer PFS and lower toxicity than crizotinib and
showed activity against CNS disease in patients previously untreated with ALK-
positive NSCLC
• Brigatinib is associated with longer PFS than crizotinib at the first interim analysis
and showed activity against CNS disease in previously untreated patients with
ALK-positive NSCLC
• In patients with CNS involvement, front-line use of ALK TKIs is effective, and
alectinib, brigatinib or ceritinib is recommended. Ceritinib represents a better
treatment strategy than ChT and presumably crizotinib; alectinib represents a better
treatment option than crizotinib; brigatinib represents a better treatment option
than crizotinib
• In ALK-rearranged NSCLC patients with localised distant progression and
ongoing systemic control, continuation of treatment with ALK TKI in combination
with local treatment of progressing metastatic sites may be considered
Beyond first-line treatment
• Any patient with NSCLC harbouring an ALK fusion should receive crizotinib as
next-line therapy, if not received previously
• In ALK-rearranged patients progressing on crizotinib, treatment with next-
generation ALK TKIs, such as alectinib, ceritinib, brigatinib or lorlatinib, is
recommended
• Ensartinib shows high activity against a broad range of known crizotinib-resistant
ALK mutations and CNS metastases
42
• In patients who progress after a second-generation ALK TKI, the next-generation
ALK inhibitor lorlatinib is recommended
Treatment of ROS1-rearranged NSCLC
• Single-agent crizotinib is recommended as first-line treatment in patients with
stage IV NSCLC with ROS1 rearrangement
• Ceritinib may be considered in crizotinib-naive patients but is currently not
EMA-approved
• In patients with ROS1-positive NSCLC, who have not received crizotinib in
the first-line setting, single-agent crizotinib may be offered as second-line therapy
• Patients receiving first-line crizotinib can be offered second-line platinum-based ChT
• Entrectinib is EMA-approved for the treatment of NSCLC patients positive for ROS1
mutations
Treatment of BRAF-mutated NSCLC
• The EMA- and FDA-approved combination of dabrafenib and trametinib is
recommended for stage IV NSCLC patients with BRAF V600E mutation
• Patients receiving a first-line BRAF/MEK inhibitor combination may be offered
second-line platinum-based ChT
Treatment of NSCLC with other actionable oncogenic drivers
• Several molecular targets have been identified harbouring somatic variants with
therapeutic potential, including RET, MET, HER2 and NTRK
• RET inhibitors selpercatinib and pralsetinib are currently in late-stage clinical trials,
and pralsetinib is FDA-approved for the treatment of adults with metastatic RET
fusion-positive NSCLC
• Crizotinib has demonstrated potential clinical efficacy for METex14 variant NSCLC
that needs to be confirmed
• More specific MET-directed TKIs are undergoing development against this target,
including capmatinib, tepotinib and salvolitinib
• Although trastuzumab deruxtecan shows promising activity, its use is mainly
restricted to clinical trials and targeting HER2 dysregulation is not recommended
and recruitment into open trials is encouraged
• Larotrectinib is EMA-approved in NTRK gene fusion patients with advanced NSCLC
who have no satisfactory treatment options
• Entrectinib is EMA-approved for the treatment of solid tumours expressing NTRK
gene fusions in patients who have no satisfactory treatment options
• KRAS(G12C)-mutant recruitment into open trials is encouraged
43

Role of RT in stage IV NSCLC
• EBRT is indicated in haemoptysis and symptomatic airway obstruction and is more
effective than EBB alone for palliation
• RT can achieve symptom control for a variety of clinical scenarios including
haemoptysis, symptomatic airway obstruction, painful chest wall disease and bone
metastasis, superior vena cava syndrome, soft tissue or neural invasion
• Administration of high-dose RT does not result in greater levels of palliation
• EBB may be considered in patients previously treated by EBRT who are symptomatic
from recurrent endobronchial central obstruction
• Early RT can relieve spinal cord compression-related neurological symptoms
Focus on brain metastases
• WBRT can be considered for patients contingent on prognostic factors of better
survival
• WBRT should not be offered in RPA class III patients in view of the dismal
prognosis; only BSC is recommended
• The most frequent WBRT schedules are 20 Gy in 5 fractions or 30 Gy in 10
fractions, with equivalent outcomes
• Dexamethasone or equivalent corticosteroid is recommended for most patients
with symptomatic brain metastases and/or significant oedema
• Neuroprotective agents or hippocampus avoidance WBRT are not recommended for
routine use
• In case of single brain metastases, surgical resection can be considered
• Postoperative WBRT or SRS is recommended after surgical resection
• SRS alone, without WBRT consolidation, is recommended where there are a
limited number of metastases and RPA class I and II
• SRS alone, without WBRT but with close MRI brain imaging follow-up, is an
alternative strategy
• The indication for SRS is based on total tumour volume rather than numbers of
metastases, as the risk of radionecrosis increases with tumour volume
• Systemic therapy and deferred RT should be considered for patients with
asymptomatic brain metastases who have not received prior systemic therapy
• In patients with an actionable oncogenic driver, CNS-penetrant next-generation
44
TKIs may restore control of brain disease and delay cranial RT
• There are currently limited trial data demonstrating safety and efficacy of
immunotherapy in patients with small-volume untreated CNS metastases
Focus on LM carcinomatosis
• A high index of suspicion should be borne for LM involvement especially in
patients with actionable oncogenic drivers having TKI treatment. CSF sampling is
diagnostic of LMD but limited by low sensitivity, albeit with high specificity
• Patients with actionable oncogenic drivers can receive CNS-penetrant
next-generation TKIs
• ChT and bevacizumab may have extra- and intra-cranial activity also in the
context of LMD
• Intra-CSF pharmacotherapy may be considered
• Focal RT can be considered in exceptional cases of circumscribed,
symptomatic lesions
Role of surgery in stage IV NSCLC
• Surgery may be indicated for diagnosis, evaluation of response to systemic
therapy and palliation
• Highly selected patients may be considered for lung resection with therapeutic
intent or even for a salvage procedure
• When metastatic disease is suspected on PET scanning, invasive surgical
procedures such as incisional biopsies, mediastinoscopy, thoracoscopy (VATS)
or laparoscopy may be required to obtain relevant biopsy samples. Adequate
samples should be provided to the pathologist for detailed routine staining, IHC
and molecular genetic testing
• Clear evidence for surgical treatment is limited
• Extensive extrapleural pneumonectomy for malignant pleural nodules or effusion
carries a higher operative risk
• Pleurodesis for persisting or recurrent pleural effusions improves dyspnoea. Talc
is the preferred agent
• Indwelling pleural catheters or pleuroperitoneal shunts may provide symptomatic
relief for trapped lung with a thickened visceral pleural peel
Treatment of oligometastatic disease
• Systemic therapy and LCT are recommended for stage IV patients with 1–3
synchronous metastases
• In patients with a solitary lesion in the contralateral lung, radical surgery or SRS
is recommended
45
 Solitary lesions in the contralateral lung should, in most cases, be considered
as synchronous secondary primary tumours and, if possible, treated with
curative-intent therapy
• Radical local treatment (high-dose RT or surgery) may also be used for patients with
driver mutations who show oligoprogression on molecular-targeted therapies
Focus on bone metastases
• Single-fraction EBRT or SABR is recommended for the palliation of
uncomplicated bone pain
Zoledronic acid or denosumab reduces SREs and are both recommended in
selected patients with advanced lung cancer with bone metastases
Role of minimally invasive procedures in stage IV NSCLC
• Endoscopy debulking by laser, cryotherapy or stent placement may be helpful in
symptomatic major airway obstruction or post-obstructive infection
• Endoscopy is useful in the diagnosis and treatment of haemoptysis
• Vascular stenting is useful in NSCLC-related superior vena cava compression
Role of palliative care in stage IV NSCLC
• Early palliative intervention is recommended, in parallel with standard oncological
care
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
Close follow-up, at least every 6–12 weeks after first-line therapy, is advised to
allow for early initiation of second-line therapy but should depend on individual
retreatment options
46
SCREENING
• Screening for non-small cell lung cancer (NSCLC) by low-dose computed
tomography (LDCT) has been shown to reduce lung cancer-related mortality in
high-risk subjects (current or former heavy smokers [≥ 30 pack-years or ≤ 15
years since cessation] aged 55–74 years)
Large-scale implementation of LDCT screening has not yet taken place as questions
persist about the definition of the at-risk population, the interval between screening,
the age at which screening should cease, the method of computed tomography
(CT), cost-effectiveness and the rate of false-positive diagnoses
A new non-invasive LDCT protocol shows promise in reducing the false-
positive detection rate
• LDCT screening may be offered to current or former heavy smokers aged 55–74
years who are well-informed about the potential benefits and risks of screening
LDCT should be performed within a dedicated programme in centres
experienced with CT
Patients requesting screening should be referred to a dedicated programme
• Periodical chest X-ray, sputum cytology or use of biomarkers are not
recommended methods of screening
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY
• The most common diagnostic test for lung cancer is fibre optic bronchoscopy,
often extended with evaluation of regional lymph nodes (LNs) by endobronchial
ultrasound (EBUS) and/or endoscopic ultrasound (EUS)
In most cases, bronchoscopy is sufficient to diagnose NSCLC, although
detailed sub-classification may not be possible
• Commonly used tests for diagnosis and staging are shown in the table on the
next page
47
 WORK-UP FOR DIAGNOSIS AND STAGING • A pretreatment pathological diagnosis is strongly recommended for all patients
before stereotactic ablative radiotherapy (SABR), unless an MDT decides that the
PARAMETER MANDATORY OPTIONAL risk-benefit ratio of the procedure is unacceptable
Medical history* In such a situation, the predicted likelihood of malignancy should preferably be
Physical examination* ≥ 85% based upon accepted criteria, for example using fluorodeoxyglucose
General
Assessing comorbidity (FDG)-positron emission tomography (PET)-CT standardised uptake values
Performance status
• The descriptive element of the recent World Health Organization (WHO)
X-ray thorax classification of (surgically resected) adenocarcinoma subtypes should be used
CT thorax* Bone scintigraphy to describe bronchoscopic and CT-guided biopsies whenever possible
Imaging
PET-CT thorax* Contrast-enhanced CT brain
MRI brain†
This classification shows differences in metastatic pattern, recurrence and
survival between histological subtypes and may highlight differences in
Blood cell counts response to post-resection adjuvant chemotherapy (ChT)
Renal function
Laboratory The revised adenocarcinoma classification may identify patient subtypes for whom
Liver enzymes
Bone parameters an anatomical sublobar resection, rather than lobectomy, would be sufficient
FVC, FEV1, DLCO • FDG-PET may contribute to the selection of patients for anatomical sublobar
Cardio-pulmonary function ECG Ejection fraction, CAG resections as low maximum standardised uptake values (SUVmax) of peripheral
If indicated: CPET tumours indicate lack of mediastinal metastases
Bronchoscopy†,‡ This diagnosis may be made intra-operatively by video-assisted thoracoscopic
Tissue procurement EBUS/EUS mediastinal nodes* Mediastinoscopy biopsy and frozen section analysis
CT-guided biopsy In isolated cases, a diagnostic anatomical sublobar resection may be acceptable
Tests needed for clinical staging
*
The solitary pulmonary nodule
†
See text on bronchoscopy in the Diagnosis and Pathology/Molecular Biology section on page 47
‡
Depending on site and size of tumour with biopsy/aspiration/brush/washing
• The diagnostic approach to non-calcified pulmonary nodules should be based
CAG, coronary angiography; CPET, cardiopulmonary exercise testing; CT, computed tomography; DLCO, diffusing capacity of the
on existing standard guidelines (such as those published by the British Thoracic
lungs for carbon monoxide; EBUS, endobronchial ultrasound; ECG, electrocardiogram; EUS, endoscopic ultrasound; FEV1, forced Society, the Fleischner Society or the clinical practice consensus guidelines for
expiratory volume in 1 second; FVC, forced vital capacity; MRI, magnetic resonance imaging; PET, positron emission tomography
Asia), although new evidence on nodule management is emerging
• In patients with clinical stage I–III lesions, a pretreatment pathological diagnosis • Likelihood of malignancy based upon risk calculation methods used in CT
is recommended prior to any curative treatment screening studies should be used only to guide the clinical assessment of
An exception to the requirement for a pretreatment diagnosis can be made if a pulmonary nodules detected in the wider population
multidisciplinary team (MDT) decides that the risks of obtaining pathology are STAGING AND RISK ASSESSMENT
unacceptable in a patient in whom the likelihood of malignancy is high based
on clinical and imaging findings Locoregional staging
Bronchoscopy is the recommended test to obtain a pathological diagnosis of • For locoregional staging, the algorithms shown on the next pages are still
centrally located tumours in stages I–III with biopsy of any visible lesion applicable
• The pathological classification ‘not otherwise specified’ (NOS) should be
used only in cases where it is impossible to obtain enough tissue for further
classification, or when steps to further classify the tumour are inconclusive

48 49
 SUGGESTED ALGORITHM FOR LOCOREGIONAL LN STAGING IN PATIENTS WITH TREATMENT RECOMMENDATIONS FOR PATIENTS WITH LOCOREGIONAL NSCLC,
NON-METASTATIC NSCLC BASED ON IMAGING, INVASIVE LN STAGING TESTS AND MULTIDISCIPLINARY
ASSESSMENT
CT and PET or PET-CT

Imaging No enlarged LNs and No enlarged N2 nodes Extensive mediastinal

CT-Scan* peripheral tumour but central tumour or N2 infiltration
hilar LNs
Mediastinal LNs negative Mediastinal LNs positive Enlarged discrete N2 LNs

cN0 cN1 Invasive Not required if negative Not

and or LN Result LNs on PET NO–N1 N2 N3 required
peripheral tumour central tumour
(outer third of the Tumour > 3 cm
lung) (mainly AdenoCa with
and FDG uptake)
tumour ≤ 3 cm (A) Category Surgery: Potentially Unresectable
of N2 unforeseen N2 resectable N2 N2

Tissue confirmation: Tissue confirmation:

EBUS/EUS EBUS/EUS
or Dedicated
VAM (C) multidisciplinary
(B) assessment

**

Mediastinal LNs Mediastinal LNs Mediastinal LNs Therapeutic Adjuvant ChT Surgical multimodality Non-surgical
negative positive negative on EBUS/EUS Approach (RT) treatment multimodality
treatment

*Category description according to CT imaging as in ACCP staging document (Silvestri GA et al. Chest 2013;143(5 Suppl):e211S–
VAM 50S); see text for more details
(D) **See text for factors involved in the choice between non-surgical and surgical multimodality treatment
ACCP, American College of Chest Physicians; ChT, chemotherapy; CT, computed tomography; LN, lymph node; NSCLC, non-small
cell lung cancer; PET, positron emission tomography; RT, radiotherapy

Multimodality Mediastinal LNs Mediastinal LNs • In non-metastatic NSCLC, the revised Union for International Cancer Control
treatment positive negative (UICC) tumour node metastasis (TNM) staging classification of malignant
tumours (8th edition; as shown on the next page) should be employed
for detailed locoregional staging. TNM 8 staging, alongside the patient’s
Surgery cardiopulmonary fitness, should be used to determine the choice of treatment

(A) In tumours > 3 cm (mainly in adenocarcinoma with high FDG uptake) invasive staging should be considered
(B) Depending on local expertise to adhere to minimal requirements for staging
(C) Endoscopic techniques are minimally invasive and are the first choice if local expertise with EBUS/EUS needle aspiration is available
(D) Due to its higher NPV, in the case of PET-positive or CT-enlarged mediastinal LNs, VAM with nodal dissection or biopsy remain
indicated when endoscopic staging is negative. Nodal dissection has an increased accuracy over biopsy
AdenoCa, adenocarcinoma; CT, computed tomography; EBUS, endoscopic bronchial ultrasound; EUS, endoscopic ultrasound; FDG,
fluorodeoxyglucose; LN, lymph node; NPV, negative predictive value; NSCLC, non-small cell lung cancer; PET, positron emission
tomography; VAM, video-assisted mediastinoscopy
De Leyn P et al. Eur J Cardiothorac Surg 2014;3:787–98. Reprinted with permission.
50 51
 STAGING AND STAGE GROUPING UICC TNM 8 OCCULT CARCINOMA Subsolid lesions require dedicated radiological expertise to evaluate the lung
lesion composition
T – PRIMARY N – REGIONAL M – DISTANT • The International Association for the Study of Lung Cancer (IASLC) has
STAGE
TUMOUR LYMPH NODES METASTISIS proposed: determining the T of multifocal ground glass/lepidic tumours by the
Occult carcinoma TX NO MO highest T-lesion, with either the number of tumours or m in parentheses to
denote the multifocal nature; and that a single N and M category be used for all
Stage 0 Tis N0 M0 these lesions collectively
T1a(mi) In daily practice, simply using m is preferred over trying to estimate the
Stage IA1 N0 M0
T1a number of ground glass opacity (GGO) areas
Stage IA2 T1b N0 M0 • For pneumonic tumours, the IASLC suggests using size (or T3) if in one lobe, T4
Stage IA3 T1c N0 M0 if involving a different ipsilateral lobe, and M1a if contralateral; in this situation,
Stage IB T2a N0 M0
the T stage will be based on the highest category in the most involved lung

Stage IIA T2b N0 M0

• CT follow-up studies have shown that incidental non-calcified non-solid lung
lesions do not need repeat CT examinations more frequently than every 1–2
T1a–c N1 years; these lesions are definitely less aggressive than solid or part-solid lesions
Stage IIB T2a–b N1 M0
and often even indolent
T3 N0
• If two lung lesions fulfil the criteria for two primaries, then these should be
T1a–c N2
T2a–b N2 evaluated, staged and treated accordingly
Stage IIIA T3 N1 M0 Concluding that two foci are indeed two different primaries is difficult; often it will be
T4 N0 impossible to come to a definitive conclusion and the role of an MDT is important
T4 N1
• The TNM 8 staging suggests leaving the N categories unchanged from TNM 7,
T1a–c N3 but suggests recording for future testing the sub-classification of single (N1a,
T2a–b N3 N2a) or multiple (N1b, N2b) affected nodes
Stage IIIB M0
T3 N2
T4 N2 • For patients with abnormal mediastinal and/or hilar LNs using CT and/or PET,
endosonography is recommended over surgical staging
T3 N3
Stage IIIC M0 The preferred first technique for pathological confirmation of suspect nodes is
T4 N3
needle aspiration under EBUS and/or EUS guidance
TNM, tumour, node, metastasis; UICC, Union for International Cancer Control
Brierley JD et al. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2017.
If EBUS and/or EUS does not reveal nodal involvement in a situation of high
Reprinted with permission. clinical suspicion, mediastinoscopy is indicated
• In the UICC TNM 8, the T stage has been further subdivided according to tumour size: Mediastinoscopy is the test with the highest negative predictive value (NPV) to
T1 into T1a ≤ 1 cm, T1b > 1 cm to ≤ 2 cm, T1c > 2 cm to ≤ 3 cm rule out mediastinal LN disease
T2 into T2a > 3 cm to ≤ 4 cm, T2b > 4 cm to ≤ 5 cm A suggested algorithm for the locoregional staging of LNs is shown on page 50
T3 > 5 cm to ≤ 7 cm • Screening for brain metastases by magnetic resonance imaging (MRI) might be
T4 > 7 cm useful in patients considered for curative therapy
• For part-solid tumours, the size of the invasive component should be used to Staging for locally advanced (stage III) NSCLC
assign the T category for clinical staging; however the whole size of the tumour • All patients planned for definitive stage III NSCLC treatment should undergo a
should also be recorded diagnostic contrast-enhanced CT scan of the chest and upper abdomen followed

52 53
 by a PET or a combined PET-CT with a CT technique with adequately high PREOPERATIVE RESPIRATORY EVALUATION
resolution for initial staging purposes, ideally within 4 weeks before the start of
treatment. These techniques assist in: Cardiac assessment:
FEV1 Both
low risk or
Ruling out detectable extrathoracic, extracranial metastasis treated patient DL,CO > 80%

Assessing potential mediastinal LN involvement

• Single PET-positive distant lesions need pathological confirmation Either one < 80%

• For patients with operable N2 disease, pathological staging of the mediastinum

is advised < 35% or Exercise testing > 75% or
< 10 mL·kg-1·min-1 Peak VO2 > 20 mL·kg-1·min-1
• All patients planned for curative stage III NSCLC treatment should receive brain
imaging for initial staging
Contrast-enhanced brain MRI is the preferred method for staging of the brain in 35–75% or
10–20 mL·kg-1·min-1
stage III disease, or if not possible, dedicated contrast-enhanced brain CT scan
is advised
Pretreatment risk assessment Split function
ppo-FEV1 Both > 30%
• A therapeutic intervention for lung cancer reduces the pulmonary and ppo-DL,CO
vascular reserve capacity, either acutely following resection, or more gradually
following radiotherapy (RT)
At least one < 30%
Functional loss needs to be estimated pre-therapy to determine whether the
patient will be able to cope and maintain an acceptable quality of life
• The risk of postoperative morbidity and mortality can be estimated using risk- < 35% or
< 10 mL·kg-1·min-1 ppo-peak VO2
specific models, although none have been validated in a cancer population
• In non-metastatic NSCLC, the cardiopulmonary fitness of the patient will > 35% or
determine the choice of treatment; before considering surgical resection, precise > 10 mL·kg-1·min-1
assessment of cardiac and pulmonary function is necessary to estimate risk of
operative morbidity
Lobectomy or pneumonectomy Resection
• Formal lung function testing should be used to estimate postoperative lung are usually nor recommended.
Resection up to
calculated extent up to
function. An example preoperative respiratory evaluation algorithm is shown on Consider other options pneumonectomy
the next page
DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 second; ppo, predicted
Surgical resection is usually acceptable if the predicted postoperative forced postoperative; VO2, oxygen consumption
expiratory volume in 1 second (FEV1) and diffusing capacity of the lungs for Brunelli A et al. Eur Respir J 2009;34:17–41. Reprinted with permission from the European Respiratory Society.
carbon monoxide (DLCO) values are > 40%
For patients with FEV1 and DLCO values > 80% of their predicted pulmonary • Standard risk assessments are not always directly applicable, as resection of
function tests and no other major comorbidities, no further investigations are poorly functioning parts of the lung might improve the situation instead of
advised before surgical resection making it worse
For others, exercise testing and split lung function are recommended; For example, in patients with limited pulmonary function due to emphysema, a
maximum oxygen consumption (VO2max) can be used to measure exercise lung volume reduction effect may be observed by resection of the lung cancer
capacity and predict postoperative complications within emphysematous lung tissue. Treatment of such patients is considered in
the algorithm on the next page
54 55
 PATIENTS WITH CLINICAL STAGE I LUNG CANCER AND LIMITED PULMONARY • For cardiac assessment, use of the recalibrated thoracic revised cardiac risk
FUNCTION DUE TO EMPHYSEMA index (RCRI) shown in the table below is recommended. The steps required
to undertake preoperative cardiac evaluation are shown in the figure on
Clinical stage I
the following page (the figure is based on the original RCRI rather than the
lung cancer recalibrated RCRI)
• Comorbidities should be evaluated and optimised before surgery
Reduced lung
function?
RECALIBRATED THORACIC REVISED CARDIAC RISK INDEX
(FEV1 < 65%)

POINTS
Weighted factors
No Yes
Ischaemic heart disease* 1.5
History of cerebrovascular disease† 1.5
Lobectomy with
confidence Evidence of Serum creatinine > 2 mg/dL 1
emphysema?
(based on TLC, RV, FEV1/FVC, CT Pneumonectomy planned 1.5
w/hyperexpansion, etc.)
Class groupings
A 0

No
Consider restrictive
pathology with higher
associated risks (ILD, IPF)
Yes B 1–1.5
C 2–2.5
D > 2.5
Moderately impaired lung Severely impaired lung
function? function?
(FEV1 30–65%) (FEV1 < 30%) *Ischaemic heart disease: history of myocardial infarction, history of positive exercise test, current complaint of chest pain
(myocardial ischaemia), nitrate therapy, ECG with pathological Q waves
Cerebrovascular disease: transient ischaemic attack, stroke
†

ECG, electrocardiogram
Consider anatomy of Consider non-surgical
emphysema, location of modalities Adapted from Brunelli A et al. Ann Thorac Surg 2010;90:199–203
mass, LVRS candidacy (SBRT, RFA)

Non-ideal LVRS Ideal LVRS

candidate candidate

Calculate COPD index Resection of mass

Predict postop FEV1 with concomitant
Consider sublobar resection LVRS

COPD, chronic obstructive pulmonary disease; CT, computed tomography; FEV1, forced expiratory volume in 1 second; FVC,
forced vital capacity; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; LVRS, lung volume reduction surgery; RFA,
radiofrequency ablation; RV, reserve volume; SBRT, stereotactic body radiotherapy; TLC, total lung capacity
Yacoub WN et al. Semin Thorac Cardiovasc Surg 2010;22:38–43. Reprinted with permission from Elsevier.

56 57
 PREOPERATIVE CARDIAC EVALUATION • For patients with a non-centrally located resectable tumour and absence of nodal
metastasis on both CT and PET images, surgical resection is recommended
RCRI: at least 3 weighted factors* or History • Lobectomy is still considered the standard surgical treatment of tumours ≥ 2 cm
1) Any cardiac condition requiring medications Physical examination in size that have a solid appearance on CT
2) A newly suspected cardiac condition Baseline ECG
3) Inability to climb two flights of stairs Calculate RCRI Lobectomy has a lower rate of recurrence than other more limited resection
types, including wedge resection and segmentectomy
Anatomical segmentectomy is generally considered acceptable for pure GGO
lesions or adenocarcinomas in situ or with minimal invasion
Yes No • LN dissection should conform to IASLC specifications for staging
• Either open thoracotomy or video-assisted thoracoscopic surgery (VATS) access
Cardiac consultation with can be carried out as appropriate to the expertise of the surgeon
non-invasive VATS should be the approach of choice in stage I tumours
cardiac testing treatments as per
AHA/ACC guidelines • For patients with multifocal lung cancer, complete resection is recommended
whenever possible, although combinations of resection and SABR have also been
found to be effective
Need for coronary
intervention
Continue with ongoing cardiac care All patients with multifocal lung cancer should be discussed by an MDT
Institute any needed new medical
(CABG or percutaneous interventions (i.e. beta-blockers,
coronary intervention) Systemic therapy
anticoagulants or statins)
• Adjuvant ChT should be offered to patients with resected stage II and III NSCLC
and can be considered in patients with resected stage IB disease and a primary
tumour > 4 cm
Postpone surgery Lung function tests
for ≥ 6 weeks • Decisions regarding adjuvant ChT should be undertaken by an MDT, taking into
account pre-existing comorbidity, time from surgery and postoperative recovery
*Original RCRI weighted factors: high-risk surgery (including lobectomy or pneumonectomy); ischaemic heart disease (prior
In most studies, the interval between surgery and the start of ChT was
myocardial infarction, angina pectoris); heart failure; insulin-dependent diabetes; previous stroke or TIA; creatinine > 2 mg/dL restricted to 6 weeks; however, comparable outcomes have been reported for
AHA/ACC, American Heart Association/American College of Cardiology; CABG, coronary artery bypass grafting; ECG, patients treated after a longer interval post-resection
electrocardiogram; RCRI, revised cardiac risk index; TIA, transient ischaemic attack
Brunelli A et al. Eur Respir J 2009;34:17–41. Reprinted with permission from the European Respiratory Society. • As neoadjuvant and adjuvant ChT have demonstrated equivalent improvements in
overall survival, the consistent results and broad evidence base of adjuvant ChT
support it as the timing of choice
TREATMENT Neoadjuvant ChT may be beneficial for preoperative downstaging, potentially
Early (stages I and II) NSCLC resulting in a less extensive resection
Surgery • For adjuvant ChT, a two-drug combination with cisplatin is preferable
• Surgery should be offered to all patients with stage I and II NSCLC who are In randomised studies, the attempted cumulative cisplatin dose was up to 300
willing to accept procedure-related risks mg/m2, delivered in 3 to 4 cycles
For those who are not willing to accept the risks, or who are at very high risk, The most frequently studied regimen is cisplatin–vinorelbine but other newer
curative RT should be offered, either SABR or hypofractionated high-dose RT accompanying agents with comparable efficacy can be considered, such as
docetaxel, gemcitabine and pemetrexed
Adding bevacizumab to cisplatin was not beneficial in this setting
58 59
 • Currently, the choice of adjuvant therapy should not be guided by molecular
analyses and targeted agents should not be used in the adjuvant setting
(Neo)adjuvant anti-programmed cell death protein 1 (PD-1)/programmed
death-ligand 1 (PD-L1) checkpoint inhibitors are currently being evaluated in
addition to current standard of care
Primary RT
• The non-surgical treatment of choice for stage I NSCLC is SABR (or stereotactic
body RT [SBRT])
Most commonly used in patients with comorbidities or other reasons for
inoperability with a peripherally located stage I NSCLC or in patients who refuse
surgery
The dose should be to a biologically equivalent tumour dose of ≥ 100 Gy,
prescribed at the encompassing isodose
• SABR for early-stage peripheral lung tumours is associated with low toxicity in
patients with chronic obstructive pulmonary disease (COPD) and the elderly
However, the risk of high-grade and fatal toxicity is high in patients with pre-
existing interstitial lung fibrosis and careful evaluation of the risks and benefits
of SABR should be considered by an expert tumour board
If SABR is unavailable for elderly patients, radical RT using hypofractionated
schedules is preferred over conventionally fractionated RT
• Salvage surgery, if feasible, may be offered to patients having complications
post-SABR
Salvage surgery should use the same indications as for primary surgery in
progressive disease after SABR, but surgery may be more difficult with higher
operative risk
• For medically inoperable patients with tumours > 5 cm and/or moderately
central location, radical RT using more conventional or accelerated schedules is
recommended
The IASLC has defined central tumours as those located within 2 cm in
all directions of any mediastinal structure, including the bronchial tree,
oesophagus, heart, brachial plexus, major vessels, spinal cord, phrenic nerve
and recurrent laryngeal nerve
Due to increased toxicity, SABR is not appropriate for ‘ultracentral’ tumours
(tumours with a planning target volume that overlaps the trachea or main bronchi)
For tumours located in the hilar region, SABR using risk-adapted fractionation
schemes can achieve high local control rates with limited toxicity
60
Radiofrequency ablation
• Patients with stage I NSCLC with strong contraindications for surgery and/or
SABR may be treated with radiofrequency ablation (RFA) although currently this
recommendation is only supported by observational studies
Postoperative RT
• Postoperative RT (PORT) is not recommended in completely resected early-stage
NSCLC due to evidence of detrimental effects
• In the case of R1 (microscopic tumour at the margin) resection, PORT should be
considered, although high-quality evidence is lacking
• Adjuvant ChT should be considered in patients with R1 resection of stage IB
disease and a primary tumour > 4 cm in stage II and III disease, although such
patients have not been included in randomised clinical trials
• If both ChT and RT are administered post-surgery, RT should be administered
after ChT
Locally advanced (stage III) NSCLC
Systemic therapy
• For curative-intent management, patients should undergo platinum-based ChT
(preferably cisplatin, although optimal ChT has not been studied extensively in
this setting)
• There is no beneficial role for induction ChT before chemoradiotherapy (CRT),
although in many centres (for reasons relating to planning of RT) 1 cycle will be
given prior to concurrent CRT
• When delivered perioperatively, cisplatin-based combinations are considered the
treatment of choice, in the absence of contraindications
• In the perioperative setting, 3 to 4 cycles of cisplatin-based ChT are
recommended, aiming at a total cumulative dose of at least 300 mg/m2 of
cisplatin
• (Neo)adjuvant anti-PD-(L)1 checkpoint inhibitors are currently being evaluated in
addition to current standard of care
Checkpoints inhibitors are also being evaluated after CRT as consolidation
therapy
Resectable locally advanced NSCLC
• ‘Resectable’ in locally advanced NSCLC refers to the following situations:
Single station N2 disease where other nodal stations have been biopsied and
proved to be benign; postoperative ChT should then be advised
61
 T4N0 tumours where nodal disease was excluded by invasive methods when an
R0 (no tumour at the margin) resection was considered feasible
After induction therapy, when there has been nodal downstaging and a
pneumonectomy can be avoided
• If, despite adequate mediastinal staging procedures, N2 disease is only
documented intra-operatively, surgery should be followed by adjuvant ChT
In the case of complete resection, the addition of PORT is not routinely
recommended, but may be an option following individual risk assessment
• If single station N2 disease can be demonstrated by preoperative pathological
nodal analysis, resection followed by adjuvant ChT, induction ChT followed by
surgery or induction CRT followed by surgery are options
If induction ChT alone is given preoperatively, PORT is not standard treatment,
but may be an option based on critical evaluation of locoregional relapse risks
• In multistation N2 or N3, concurrent definitive CRT is preferred
Any complex multimodality treatment strategy decision, including the role of
surgery, should be evaluated by an experienced MDT
• In potentially resectable superior sulcus tumours, concurrent CRT induction
followed by definitive surgery is the treatment of choice
The same strategy may be applied for potentially resectable T3 or T4 central
tumours in highly selected cases at experienced centres
In both situations, surgery should be carried out within 4 weeks after the end of RT
• There is no role for prophylactic cranial RT in stage III NSCLC
Unresectable locally advanced NSCLC
• ‘Unresectable’ in locally advance NSCLC refers to patients in whom – even after
induction therapy – a complete resection (R0) would not be possible based on
MDT evaluation
• Concurrent CRT is the treatment of choice in patients evaluated as unresectable
in stage IIIA and IIIB
Concurrent CRT leads to higher 5-year survival rates than sequential CRT
(induction ChT followed by RT) in patients who are fit, albeit at the cost of
higher rates of reversible oesophagitis
Early mortality rates are ~ 10% with concurrent CRT, with tumour volume and
pulmonary function as associated risk factors
If concurrent CRT is not possible, e.g. if the patient is elderly or less fit with
clinically relevant comorbidities, sequential ChT followed by definitive RT
represents a valid and effective alternative
62
• There is no role for prophylactic cranial RT in stage III NSCLC
• In the absence of contraindications, the optimal ChT to be combined with RT in
stage III NSCLC should be based on cisplatin
There are no firm conclusions supporting single-agent carboplatin as an RT
sensitiser
• Most comparative studies of concurrent CRT versus sequential administration used
cisplatin + etoposide or cisplatin + a vinca alkaloid (typically cisplatin + vinorelbine),
or cisplatin + pemetrexed in the presence of non-squamous histology
• There are no ChT comparative phase III trials using the paclitaxel/carboplatin
regimen: In the stage III disease CRT strategy, 2 to 4 cycles of concomitant ChT
should be delivered
There is no evidence to support further induction or consolidation ChT
There is no beneficial role for induction ChT before CRT, although in many
centres—for reasons relating to planning of RT—1 cycle will be given prior
to concurrent CRT
• For concurrent CRT, 60–66 Gy in 30–33 daily fractions is recommended
Maximum overall treatment time should not exceed 7 weeks
‘Biological intensification’, such as treatment acceleration, is not standard
practice in concurrent CRT schedules
• In sequential approaches, RT delivered in a short overall treatment time is
recommended
• The immune checkpoint inhibitor durvalumab is approved by the European
Medicines Agency as consolidation therapy in patients with stage III NSCLC who
did not have disease progression after two or more cycles of platinum-based CRT
radiotherapy
Studies demonstrated both a significant PFS and OS benefit
Durvalumab is recommended in whose tumours express PD-L1 on ≥ 1%
of tumour cells
PERSONALISED MEDICINE
• There is currently no role for targeted agents in stage III NSCLC outside clinical trials
• Immunotherapy is being studied in early NSCLC as (neo)adjuvant therapy and as
consolidation after CRT; data should be awaited before any clinical use
63
 FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
• Patients with NSCLC treated with radical intent are at risk of developing new
cancer-related problems and should be monitored for the following:
Treatment-related complications
Treatment of existing comorbidities
Detection of treatable relapse
Detection of second primaries
• During the first and second year after surgery, recurrence is mainly local and
rare thereafter, whereas at the end of the second year until the end of the fourth
year after surgery, recurrence is dominated by distant metastases decreasing
over time
The risk of developing a second primary lung cancer exhibits a more uniform
pattern and does not diminish over time
• As most local relapses occur within the first 2 years, surveillance every 6 months
for 2 years with a visit including history, physical examination and preferably
contrast-enhanced volume chest CT scan at least at 12 and 24 months is
recommended
Thereafter, an annual visit including history, physical examination and chest CT
scan is recommended in order to detect second primary tumours
• Follow-up with 6-monthly CT scans for 3 years is recommended for patients who
are suitable for salvage treatment (e.g. surgery or local ablative therapy)
The frequency of the follow-up visits can be tailored to the individual patient for
those not suitable for salvage treatment
• The selective use of FDG-PET is recommended when recurrence after SABR is
suspected based on serial spiral chest CT scan
Due to a high number of false-positive findings on PET, patients suitable for
salvage therapy should undergo a biopsy, whenever possible
• NSCLC patients should be offered smoking cessation, as this leads to superior
treatment outcomes
Combining behaviour techniques with pharmacotherapy is the preferred approach
64
SCREENING
Screening with LDCT has been shown to reduce lung cancer-related mortality but is
not yet ready for large-scale implementation; more research is needed
Periodical chest X-ray, sputum cytology or use of biomarkers are not
recommended methods of screening for NSCLC
LDCT screening may be offered to current or former heavy smokers (≥ 30 pack-
years or ≤ 15 years since cessation) aged 55–74 years who are well-informed
about the potential benefits and risks of screening
DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY
In patients with clinical stage I–III lesions, a pretreatment pathological diagnosis is
recommended prior to any curative treatment
An exception to the requirement for a pretreatment diagnosis can be made
if an experienced MDT decides that the risks of obtaining pathology may be
unacceptable in a patient in whom the likelihood of malignancy is high based on
clinical and imaging findings
Bronchoscopy is the recommended test to obtain a pathological diagnosis of
centrally located tumours in stages I–III with biopsy of any visible lesion
The pathological classification NOS should be used only in cases where it is
impossible to obtain enough tissue for further classification, or when steps to
further classify the tumour are inconclusive
A pretreatment pathological diagnosis is strongly recommended for all patients
before SABR, unless an MDT considers the risk-benefit ratio of the procedure to be
unacceptable
The descriptive element of the recent WHO classification of adenocarcinoma
subtypes should be used to describe bronchoscopic and CT-guided biopsies
whenever possible
FDG-PET may contribute to the selection of patients for anatomical sublobar
resections as low SUVmax values of peripheral tumours indicate lack of mediastinal
metastases
65

The diagnostic approach to non-calcified pulmonary nodules should be based
on existing standard guidelines (e.g. those of the British Thoracic Society, the
Fleischner Society or the clinical practice consensus guidelines for Asia)
STAGING AND RISK ASSESSMENT
In non-metastatic NSCLC, detailed locoregional staging according to the 8th TNM
staging system and the cardiopulmonary fitness of the patient determine the choice
of treatment
Locoregional staging
• For part-solid tumours, the size of the invasive component should be used to
assign the T category for clinical staging
• Subsolid lesions need dedicated radiological expertise to evaluate the lung lesion
composition
• If two lung lesions fulfil the criteria for two primaries these should be evaluated,
staged and treated accordingly
• For patients with abnormal mediastinal and/or hilar LNs using CT and/or PET,
endosonography is recommended over surgical staging
• The preferred first technique for pathological confirmation of suspect nodes is
needle aspiration under EBUS and/or EUS guidance
• If EBUS and/or EUS does not reveal nodal involvement in a situation of high
clinical suspicion, mediastinoscopy is indicated
• Mediastinoscopy is the test with the highest NPV to rule out mediastinal
LN disease
• Screening for brain metastases by MRI might be useful in patients considered for
curative therapy
Staging for locally advanced (stage III) NSCLC
• All patients planned for definitive stage III NSCLC treatment should undergo
a diagnostic contrast-enhanced CT scan of the chest and upper abdomen
followed by a PET or a combined PET-CT with a CT technique with adequately
high resolution for initial staging purposes to rule out detectable extrathoracic,
extracranial metastasis, and to assess potential mediastinal LN involvement,
ideally within 4 weeks before the start of treatment
• Single PET-positive distant lesions need pathological confirmation
66
• For patients with operable N2 disease, pathological staging of the mediastinum
is advised
• All patients planned for curative stage III NSCLC treatment should receive brain
imaging for initial staging
• Contrast-enhanced brain MRI is the preferred method for staging of the brain in
stage III disease
• If it is not possible to perform MRI, dedicated contrast-enhanced brain CT scan
is advised
Pretreatment risk assessment
• In non-metastatic NSCLC, the cardiopulmonary fitness of the patient will
determine the choice of treatment
• Risk of postoperative morbidity and mortality can be estimated using risk-specific
models, although none have been validated in a cancer population
• Before considering surgical resection, precise assessment of cardiac and
pulmonary function is necessary to estimate risk of operative morbidity
• For cardiac assessment, use of recalibrated RCRI is recommended
• Formal lung function testing should be undertaken to estimate postoperative
lung function
• For patients with FEV1 and DLCO values > 80% of their predicted pulmonary
function tests and no other major comorbidities, no further investigations are
advised before surgical resection
• For others, exercise testing and split lung function are recommended;
VO2max can be used to measure exercise capacity and predict
postoperative complications
• Comorbidities should be evaluated and optimised before surgery
• In patients with limited pulmonary function due to emphysema, a lung volume
reduction effect may be observed by resection of the lung cancer within
emphysematous lung tissue
TREATMENT OF EARLY STAGES (STAGES I AND II)
Surgery
• Surgery should be offered to all patients with stage I and II NSCLC as the
preferred treatment to all who are willing to accept procedure-related risks
• For patients with a non-centrally located resectable tumour and absence of nodal
metastasis on both CT and PET images, surgical resection is recommended
• Anatomical resection is preferred over wedge resection
67

• Anatomical segmentectomy is generally considered acceptable for pure GGO
lesions or adenocarcinomas in situ or with minimal invasion
• Lobectomy is still considered the standard surgical treatment of tumours ≥ 2 cm
in size that have a solid appearance on CT
• LN dissection should conform to IASLC specifications for staging
• Either open thoracotomy or VATS access can be carried out as appropriate to the
expertise of the surgeon
• VATS should be the approach of choice in stage I tumours
• For patients with multifocal lung cancer, complete resection is recommended
whenever possible. All patients with multifocal lung cancer should be discussed
by an MDT
Systemic therapy
• Adjuvant ChT should be offered to patients with resected stage II and III NSCLC
and can be considered in patients with resected stage IB disease and a primary
tumour > 4 cm. Pre-existing comorbidity, time from surgery and postoperative
recovery should be considered by an MDT
• For adjuvant ChT, a two-drug combination with cisplatin is preferable
The most frequently studied regimen is cisplatin/vinorelbine, but other agents
such as docetaxel, gemcitabine and pemetrexed can be considered
• Currently, the choice of adjuvant therapy should not be guided by molecular
analyses and targeted agents should not be used in the adjuvant setting
• In view of the equivalence of neoadjuvant and adjuvant ChT in terms of overall
survival, the consistent results and broad evidence base support adjuvant ChT as
the timing of choice
• (Neo)adjuvant anti-PD(L)-1 checkpoint inhibitors are currently being evaluated in
addition to current standard of care
Primary RT
• The non-surgical treatment of choice for stage I NSCLC is SABR/SBRT; this
should be given at a biologically equivalent tumour dose of ≥ 100 Gy, prescribed
to the encompassing isodose
• SABR for early-stage peripheral lung tumours is associated with low toxicity in
patients with COPD and the elderly
68
• Salvage surgery, if feasible, may be offered to patients having complications
post-SABR; the same indications should be used as for primary surgery but
surgery may be more difficult with higher operative risk
• For medically inoperable patients with tumours > 5 cm and/or moderately
central location, radical RT using more conventional or accelerated schedules
is recommended
Radiofrequency ablation
• Patients with stage I NSCLC with strong contraindications for surgery and/or
SABR may be treated with RFA
Postoperative RT
• PORT is not recommended in completely resected early-stage NSCLC
• In the case of R1 resection, PORT should be considered
• Adjuvant ChT should be considered in patients with R1 resection of stage IB
disease and a primary tumour > 4 cm in stage II and III
• If both ChT and RT are administered post-surgery, RT should be administered
after ChT
TREATMENT OF LOCALLY ADVANCED STAGE (STAGE III)
Systemic therapy
• For curative-intent management, patients should undergo platinum-based ChT
(preferably cisplatin)
• When delivered perioperatively, cisplatin-based combinations are considered the
treatment of choice in the absence of contraindications
• In the perioperative setting, 3 to 4 cycles of cisplatin-based ChT are
recommended, aiming at a total cumulative dose of at least 300 mg/m² of
cisplatin
• (Neo)adjuvant anti-PD-(L)1 checkpoint inhibitors are currently being evaluated
in addition to current standard of care; checkpoint inhibitors are also being
evaluated after CRT as consolidation therapy
Resectable locally advanced NSCLC
• If, despite adequate mediastinal staging procedures, N2 disease is only
documented intra-operatively, surgery should be followed by adjuvant ChT
• In the case of complete resection, the addition of PORT is not routinely
recommended, but may be an option following individual risk assessment
• If single station N2 disease can be demonstrated by preoperative pathological
nodal analysis, resection followed by adjuvant ChT, induction ChT followed by
surgery or induction CRT followed by surgery are options
69

• If induction ChT alone is given preoperatively, PORT is not standard treatment,
but may be an option based on critical evaluation of locoregional relapse risks
• In multistation N2 or N3, concurrent definitive CRT is preferred
• Any complex multimodality treatment strategy decision, including the role of
surgery, should be evaluated by an experienced MDT
• In potentially resectable superior sulcus tumours, concurrent CRT induction
followed by definitive surgery is the treatment of choice and may also be used
for potentially resectable T3 or T4 central tumours in highly selected cases at
experienced centres. In both situations, surgery should be carried out within 4
weeks of the end of RT
• There is no role for prophylactic cranial RT in stage III NSCLC
Unresectable locally advanced NSCLC
• Concurrent CRT is the treatment of choice in patients evaluated as unresectable
in stage IIIA and IIIB
• If concurrent CRT is not possible, sequential ChT followed by definitive RT
represents a valid and effective alternative
• In the absence of contraindications, cisplatin-based ChT is optimal for
combination with RT in stage III NSCLC, but there are no conclusive data
supporting single-agent carboplatin as an RT sensitiser
• In the stage III disease CRT strategy, 2 to 4 cycles of concomitant ChT should be
delivered. There is no evidence for further induction or consolidation ChT
• For concurrent CRT, 60–66 Gy in 30–33 daily fractions is recommended and the
maximum overall treatment time should not exceed 7 weeks
• ‘Biological intensification’, such as treatment acceleration, is not standard
practice in concurrent CRT schedules
• In sequential approaches, RT delivered in a short overall treatment time is
recommended
• There is no role for prophylactic cranial RT in stage III NSCLC
• Durvalumab has demonstrated a significant PFS and OS benefit and is EMA-
approved as consolidation therapy in patients with stage III NSCLC who did not
have disease progression after two or more cycles of platinum-based CRT
70
PERSONALISED MEDICINE
There is currently no role for targeted agents in stage III NSCLC outside
clinical trials
Immunotherapy is being studied in early NSCLC as (neo)adjuvant therapy and as
consolidation after CRT; data should be awaited before any clinical use
FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP
NSCLC patients treated with radical intent should be followed for treatment-related
complications, detection of treatable relapse or occurrence of second primary
lung cancer
Surveillance every 6 months for 2 years with a visit including history, physical
examination and preferably contrast-enhanced volume chest CT scan at least at
12 and 24 months is recommended, and thereafter an annual visit including
history, physical examination and chest CT scan in order to detect second
primary tumours
Follow-up with 6-monthly CT scans for 3 years is recommended for patients who
are suitable for salvage treatment; the frequency of follow-up visits can be tailored
individually for those not suitable for salvage treatment
The selective use of FDG–PET is recommended when recurrence after SABR is
suspected based on serial spiral chest CT
Due to a high number of false-positive findings on PET, patients suitable for salvage
therapy should undergo a biopsy, whenever possible
NSCLC patients should be offered smoking cessation, as this leads to superior
treatment outcomes. Combining behaviour techniques with pharmacotherapy is the
preferred approach
71
 • For patients with a solitary metastasis, pathological confirmation should not
delay treatment
In these cases, the solitary metastasis should either be re-evaluated:
DIAGNOSIS – After two cycles of treatment using the same radiological imaging technique
• Pathological diagnosis should be made according to the World Health – Immediately using a different radiological imaging technique
Organization (WHO) classification system • If a pleural or pericardial effusion is the only site of metastasis but there are no
Immunohistochemistry is not mandatory but should be used to confirm malignant cells identified in the pleural fluid and another plausible explanation
the diagnosis in cases of any doubt is clinically suspected, treatment should be according to an M0 status
• Due to its frequent central localisation, biopsies may best be obtained by bronchoscopy TREATMENT
Other methods include mediastinoscopy, endobronchial ultrasound (EBUS), • A treatment algorithm summarising recommended treatment options for SCLC
endoscopic ultrasound (EUS), transthoracic needle aspiration or thoracoscopy is shown in the figure on the next page
• A biopsy from a metastatic lesion is preferred if this is easily and safely accessible
The least invasive approach should be used
STAGING
• The American Joint Committee for Cancer (AJCC)/Union for International Cancer
Control (UICC) tumour, node, metastasis (TNM) classification system (8th
edition) should be applied in the staging of small cell lung cancer (SCLC) see
Tables on pages 12–14
This should replace the former International Association for the Study of Lung
Cancer (IASLC) staging system
• Initial assessments should include:
Medical history (including smoking history)
Physical examination
Complete blood count, including differential count, liver enzymes, sodium,
potassium, calcium, glucose, lactate dehydrogenase (LDH) levels and renal
function tests
Lung function tests (for localised disease)
Computed tomography (CT) scan with contrast of the chest and abdomen
• Further imaging with bone scintigraphy and CT or magnetic resonance imaging
(MRI) of the brain are recommended if metastases are not obvious on the initial
CT scan or if clinical findings suggest brain or bone involvement
• A bone marrow aspiration may be indicated in cases of abnormal blood counts
or signs of blood-bone marrow barrier rupture
• Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an alternative
to CT and bone scintigraphy
• PET-CT findings that could impact on treatment decisions should be
pathologically confirmed
72 73
 SMALL CELL LUNG CANCER TREATMENT ALGORITHM Recommended as the first option in patients who are at increased risk for
perioperative complications
Small cell lung cancer
• All patients with T1–2 N0–1 M0 disease should be considered for prophylactic
cranial irradiation (PCI) if they have responded to initial treatment using the same
dose and fractionation as for patients with stage III SCLC
Palliative Curative • All other patients with T1–4 N0–3 M0 tumours and a good performance status
(PS) should be treated with concurrent ChT and thoracic RT
ChT: 4 cycles of etoposide/cisplatin (or 4–6 cycles if a once daily RT schedule is used)
RT:
T1-4 N1-3 M1a,b T1,2 N0,1 M0 T1-4 N1-3 M1a,b T1-4 N2,3 M0
multiple or solitary and – Twice-daily 1.5 Gy in 30 fractions for fit patients
confirmed not confirmed*
– Elective nodal volumes are not well-defined but may include the involved
lymph node regions, one adjacent region and the supraclavicular regions,
depending on the location of the primary tumour and the N2 or N3 nodes
ChT Surgery plus
adjuvant
Concomitant
CRT*
Concomitant
CRT
– Starting thoracic RT within 30 days of initiating ChT is preferred
ChT** Metastatic disease
First-line treatment
• Treatment of stage IV SCLC is palliative
• Combination ChT is the main treatment option
Prophylactic
cranial irradiation 4–6 cycles of etoposide/cisplatin or etoposide/carboplatin are recommended
if response***
Etoposide/cisplatin is recommended for young patients
*If no confirmation of solitary metastasis is obtained, RT may be added after first response evaluation and is omitted in case of Irinotecan/cisplatin, gemcitabine/carboplatin (in poor prognostic patients only)
obvious metastatic involvement
**Concomitant chemoradiotherapy as an alternative option or oral or intravenous (IV) topotecan/cisplatin are alternative regimens in cases
*** Or stable disease in case of localised disease
ChT, chemotherapy; CRT, chemoradiotherapy; RT, radiotherapy
where etoposide is contraindicated
Three-drug regimens or increased dose intensity regimens are
not recommended
Localised disease
• Continuing ChT beyond 4–6 cycles of first-line treatment (i.e. maintenance
• A surgical approach is justified for patients with T1–2 N0–1 M0 stage disease
therapy) is not recommended
as long as mediastinal lymph node involvement has been ruled out (i.e. negative
lymph nodes on CT scan, PET-CT scan or EBUS and/or mediastinoscopy, • Patients with any response to first-line treatment who have a reasonably good
if enlarged) PS should be evaluated for PCI
• Postoperatively, 4 cycles of adjuvant chemotherapy (ChT) should be administered The PCI dose may be 25 Gy in 10 daily fractions or 20 Gy in 5 fractions
• In cases of unforeseen N2 or N1, or in patients who have not undergone systematic • The routine use of thoracic irradiation in patients with metastatic SCLC is not
nodal dissection, postoperative radiotherapy (RT) should be considered currently recommended
Final results of the Dutch Phase III CREST trial evaluating this concept
• There is no role for surgery after induction ChT in N2 disease
are awaited
• An alternative treatment approach for patients with T1–2 N0–1 M0 disease
is combined concurrent chemoradiotherapy

74 75
 Second-line treatment
• Refractory patients (i.e. those not responding or progressing during ChT) and
resistant patients with early relapse (< 6 weeks):
The benefit of further systemic therapy is uncertain
Participation in a clinical trial or best supportive care is recommended
• Patients with resistant (< 3 months) or sensitive relapse:
Either oral or IV topotecan is recommended
Cyclophosphamide/doxorubicin/vincristine (CAV) is an alternative
treatment option
• Patients with sensitive disease:
May derive benefit from rechallenge with first-line therapy (usually
platinum/etoposide)
PERSONALISED MEDICINE
• More research is needed to identify molecular markers that could lead to
advances in personalised medicine
FOLLOW-UP
• The main goal of regular follow-up is to detect recurrence early, while the patient
still has a good PS
• The frequency of follow-up visits depends on the availability of treatment options
• Suggested follow-up:
CT scans every 2–3 months in patients with metastatic disease potentially
qualifying for further treatments
CT scans every 3–6 months for 2 years in patients with localised disease who
have received potentially curative treatment
– The follow-up interval may be lengthened after 2 years
– Due to the high risk of a second primary tumour, annual low-dose CT scans
after five years may be considered
• Smoking cessation counselling is essential
76
DIAGNOSIS
Pathological diagnosis should be made according to the WHO classification system
Biopsies are best obtained by bronchoscopy, but a biopsy from a metastatic lesion
may be preferred if the location of the metastasis is easily and safely accessible
(the least invasive approach should be used)
STAGING
Staging should be according to the AJCC/IUCC TNM classification system
(8th edition)
Initial assessments: Medical history (including smoking history); physical
examination; complete blood count, including differential count, liver enzymes,
sodium, potassium, calcium, glucose, LDH levels and renal function tests; lung
function tests (for localised disease); CT scan with contrast of the chest
and abdomen
Additional bone scintigraphy and CT or MRI of the brain are recommended
in patients with localised disease or if symptoms or clinical findings
suggest involvement
A bone marrow aspiration may be indicated in cases of abnormal blood counts
or signs of blood-bone marrow barrier rupture
FDG-PET is an alternative to CT and bone scintigraphy; PET-CT findings that could
impact on treatment decisions should be pathologically confirmed
TREATMENT
Localised disease
• Surgery is justified for patients with T1–2 N0–1 M0 stage disease as long as
mediastinal lymph node involvement has been ruled out. Surgery should be
followed by 4 cycles of adjuvant ChT
• Postoperative RT should be considered in cases of unforeseen N2
or N1, or in patients who have not undergone systematic nodal dissection
• Combined concurrent chemoradiotherapy is an alternative approach
(recommended for patients who are at increased risk of perioperative
complications)
• Patients with T1–2 N0–1 M0 disease should be considered for PCI if they have
responded to initial treatment
77
 • All other patients with T1–4 N0–3 M0 tumours and a good PS should receive
concurrent ChT (cisplatin/etoposide) and thoracic RT (twice-daily 1.5 Gy in 30
fractions, starting within 30 days of initiating ChT)
Metastatic disease
First-line treatment
• 4–6 cycles of etoposide/cisplatin or etoposide/carboplatin is recommended
• In young patients, etoposide/cisplatin is recommended
• Irinotecan/cisplatin, gemcitabine/carboplatin (in poor prognostic patients only)
or oral or IV topotecan/cisplatin are alternative regimens
• Maintenance therapy is not recommended
• Patients with any response and a reasonably good PS should be evaluated
for PCI
• The routine use of thoracic irradiation is not recommended
Second-line treatment
• Refractory patients: Participation in a clinical trial or best supportive care is
recommended
• Patients with resistant or sensitive relapse: Either oral or IV topotecan is
recommended (CAV is an alternative option)
• Patients with sensitive disease: Rechallenge with first-line therapy (usually
platinum/etoposide) may be associated with clinical benefit
PERSONALISED MEDICINE
More research is needed to identify molecular markers that could lead to advances
in personalised medicine
FOLLOW-UP
The frequency of follow-up depends on the availability of treatment options
Suggested follow-up:
• Patients with metastatic disease potentially qualifying for further treatments:
CT scans every 2–3 months
• Patients with localised disease who have received potentially curative treatment:
CT scans every 3–6 months for 2 years, with the follow-up interval lengthened
thereafter
Smoking cessation counselling is essential
78
DIAGNOSIS
• Shortness of breath, pain and weight loss are common symptoms and can occur
over many months
• Unilateral effusions are often observed on physical examination
• The work-up should include: chest X-ray, computed tomography (CT) scan
of chest and upper abdomen, thoracentesis, general laboratory blood tests and
a detailed occupational history
Plain chest radiography lacks sufficient sensitivity for routine staging as pleural
effusions of large volume can mask pleural/chest lesions or make it difficult to
detect small malignant pleural effusions
• When occupational history indicates significant asbestos exposure, or radiology
is suggestive of mesothelioma, cytology or histology can be used, although
histology is preferred
• Thoracoscopy is recommended to obtain adequate histology, to optimally stage
and to allow pleural fluid evacuation (with or without pleurodesis) and can be
performed as a pleuroscopy or as video-assisted thoracic surgery (VATS)
Biopsies of normal and abnormal tissue are recommended
Ultrasound-guided true-cut biopsies are a good alternative when thoracoscopy
is not feasible or is contraindicated
• The circulating tumour markers cyfra 21.1, fibulin-3 and mesothelin should
not be used as specific markers for mesothelioma. However, carcinoembryonic
antigen (CEA) is not increased in malignant pleural mesothelioma (MPM) and
can be used as a negative marker to rule this out if cytological/histological
analysis is inconclusive
• A summary of recommendations for diagnostic procedures is given on the next page
79
 RECOMMENDATION 1
Diagnostic procedures in MPM should encompass at least:
• Occupational history with emphasis on asbestos exposure
• CT scanning of the thorax
• In all patients who have a unilateral pleural thickening, with or without fluid and/or calcified asbestos
plaques, efforts should be made to obtain a pathological specimen, since there are no specific clinical
features of MPM
• There is no place for screening of persons exposed to asbestos
• Tumour markers alone cannot distinguish MPM
CT, computed tomography; MPM, malignant pleural mesothelioma
PATHOLOGY
• The three main subtypes of MPM (epitheloid, biphasic and sarcomatoid) have
numerous variants
• Samples for diagnosis include: pleural effusions, small (closed) pleural biopsies,
image-guided needle core biopsies, larger open surgery or VATS biopsy samples
of debulking specimens
• Significant sampling errors can occur in effusion cytology and small biopsy
samples and, less commonly, with larger surgical samples
• Blind biopsies are not recommended because of the risk of complications
• Reported diagnostic sensitivities of cytological features in effusions vary and this
is generally not recommended to establish a definitive diagnosis. When a biopsy
is not possible, appropriate clinical and radiological features may assist
in suggesting a diagnosis of MPM
• In the vast majority of cases, adequate tissue biopsy and appropriate
immunohistochemistry (IHC) is required for the definitive primary diagnosis
of MPM
 Definitive diagnosis by frozen section is not recommended
 The larger the tissue biopsy and the more targeted the sampling approach,
the more reliable and definitive the diagnosis
• Identification of the extent of invasion is crucial and can be assisted by IHC
 Early invasive mesothelioma may be suspected if there is nodular mesothelial
cell proliferation
• If definitive invasion cannot be recognised, a diagnosis of ‘atypical mesothelial
proliferation’ is appropriate and further sampling may be indicated
80
• Distinguishing MPM from organising fibrinous exudates (fibrinous/fibrous
pleurisy) requires a full thickness biopsy sample
• The most commonly used mesothelial markers are calretinin, cytokeratin 5/6,
WT1 and podoplanin (D2-40), with TTF-1, CEA and Ep-CAM (Ber-EP4) being the
most useful for (adeno)carcinoma
• Pancytokeratin markers can be useful in the diagnosis of sarcomatoid
mesothelioma, which does not express the usual mesothelial markers
• The role of fluorescent in situ hybridisation in detecting homozygous deletion
of p16 for MPM diagnosis has yet to be established
• A summary of recommendations for pathological samples used in MPM
diagnosis is given below
RECOMMENDATION 2
A. Definitive diagnosis of MPM on effusion cytology specimens
• Effusion cytology for definitive diagnosis of MPM remains a controversial topic and is still generally
not recommended
• If effusion cytology is frankly malignant, the diagnosis may be strongly suggested but confirmation by biopsy, if
possible, is recommended
• IHC is invaluable to characterise the nature of atypical effusion cells and sample preparation to facilitate IHC
should be carried out if at all possible
B. Definitive diagnosis of MPM on tissue biopsy specimens
• The recognition of tissue invasion is required for definitive diagnosis of MPM
• Larger and directly targeted biopsy samples facilitate definitive diagnosis. Surgical-type samples are preferred
for diagnosis
• A major subtype diagnosis (epithelioid, biphasic, sarcomatoid) should be given in all cases of MPM
C. IHC in the diagnosis of MPM
• IHC is recommended for all primary diagnoses of MPM
• At least two ‘mesothelial’ markers and at least two ‘(adeno)carcinoma’ markers should be used
• Sarcomatoid MPM often does not express usual ‘mesothelial’ markers
IHC, immunohistochemistry; MPM, maligant pleural mesothelioma
STAGING
• The most recent staging system for MPM, developed in 1995, is shown
on the next page
 A new tumour, node, metastasis (TNM) staging system is currently being
validated by the International Mesothelioma Interest Group (IMIG)
81
 TNM STAGING ACCORDING TO THE IMIG/UICC TREATMENT
STAGE TNM COMMENTS Front-line and maintenance therapy for mesothelioma
Ia T1a N0 M0 Primary tumour limited to ipsilateral parietal pleura • Combination doublet chemotherapy (ChT) of cisplatin and either pemetrexed or
raltitrexed has been shown to improve survival compared with cisplatin alone
Ib T1b N0 M0 As stage Ia plus focal involvement of visceral pleura
as front-line therapy in patients with unresectable MPM
II T2 N0 M0
As stage Ia or Ib plus confluent involvement of diaphragm or visceral pleura  Pemetrexed in combination with cisplatin is indicated for the treatment
or involvement of the lung of ChT-naive patients with unresectable MPM but not in the maintenance
Any T3 M0 Locally advanced tumour setting
III Any N1 M0 Ipsilateral, bronchopulmonary or hilar lymph node involvement  Carboplatin is an acceptable alternative to cisplatin and may be better tolerated
by the elderly
Any N2 M0 Subcarinal or ipsilateral mediastinal lymph node involvement
• The addition of novel agents to cisplatin doublets and the use of anti-angiogenic
Any T4 Locally advanced technically unresectable tumour
agents have not improved efficacy over standard treatment
Contralateral mediastinal, internal mammary, and ipsilateral or contralateral • Trials are investigating the use of a number of agents (including the focal adhesion
IV Any N3
supraclavicular lymph node involvement
kinase inhibitor defactinib and gemcitabine) in switch maintenance therapy
Any M1 Distant metastases
Second-line therapy for mesothelioma
IMIG, International Mesothelioma Interest Group; TNM, tumour, node, metastasis; UICC, Union for International Cancer Control
Reproduced with permission from the American College of Chest Physicians. Rusch VW. Chest 1995;108:1122–8. • There is currently no second-line standard of care and it is recommended that
patients are enrolled into clinical trials
• Disease staging according to the TNM system, when assessed by surgical  Studies have shown benefits in survival with some types of ChT but
staging, is the preferred approach pemetrexed was not associated with longer survival compared with best
supportive care
• Magnetic resonance imaging (MRI) using gadolinium may improve delineation
of the tumour and help to visualise foci that may be present in the diaphragm, • Immunotherapy – anti-programmed cell death protein 1 (PD-1)/programmed
pericardium or chest wall death-ligand 1 (PD-L1) checkpoint inhibitors, as monotherapy as well as
combinations with anti-CTLA-4 – has shown promising results in early clinical
• The use of positron emission tomography (PET) scanning is limited and still trials. Several randomised trials are currently ongoing frontline and in later lines
under debate in mesothelioma
• A summary of recommendations for staging in MPM diagnosis is given below • A summary of recommendations for the use of drug therapy in unresectable
MPM is given below
RECOMMENDATION 3
Staging for every patient with a confirmed diagnosis of MPM RECOMMENDATION 4
• In the absence of a uniform, robust and validated staging system, experts advocate the use of the most recent The first- and second-line treatment of unresectable mesothelioma
TNM-based UICC classification
• Pemetrexed/cisplatin doublet is recommended in first line
• The use of MRI is only recommended in special situations when tumour delineation is necessary • Maintenance therapy (switch or continuation) has not yet improved the overall survival and patients should
• The use of PET scanning is limited and can be used for localisation of tumour sites, distant metastases or early be included in these studies
response to treatment, as part of a study protocol
• Patients in good condition should be recommended to join studies in second line
MPM, malignant pleural mesothelioma; MRI, magnetic resonance imaging; PET, positron emission tomography; TNM, tumour,
node, metastasis; UICC, Union for International Cancer Control

82 83
 Radiotherapy
• Radiotherapy (RT) can be considered for the treatment of pain, although no high
quality evidence exists to support this
 Short course RT (e.g. 1 × 10 Gy or 3 × 8 Gy) is recommended in cases of pain
due to infiltration of the chest wall or permeation nodules by MPM
• Prophylactic irradiation of scars following thoracoscopy and/or drainage
procedures to reduce the likelihood of seeding metastases is recommended only
in the context of a clinical trial
Pre- and postoperative RT
• In general, data on the administration of pre- or postoperative RT are limited and
the use of this approach for large fields (hemi-thoracic RT) is not recommended
outside the clinical trial setting
 Local control is poor and the field size and neighbouring vital organs involved
result in significant toxicity
 Improved 3D planning and the introduction of intensity-modulated RT (IMRT)
may help to improve the outcome of this approach
 Higher doses of radiation have been shown to lead to better local control with
trimodality therapy involving extrapleural pneumonectomy (EPP) and it is
recommended that this is carried out only in specialised centres
Choice of radiation type after EPP
• Preliminary results with IMRT in the adjuvant setting after EPP appear promising
and this approach may provide good local control with effective protection of
at-risk organs, although fatal pneumonitis remains a problem
 Dosimetric constraints may reduce the risk of pneumonitis: V20 (volume of
both lungs minus the planning target volume) should be less than 15% and
the mean lung dose should be less than 10 Gy
 Dosimetric constraints should also be used for conformal RT and should be
applied to the target volume and critical organs (contralateral lung, heart, spinal
cord, oesophagus, liver and kidneys)
• Further studies are required to better establish the role of RT
• RT technique is important for both local control and toxicity and it is therefore
recommended that RT is delivered in specialised centres
• A summary of recommendations for the use of RT in MPM is given on the
following page
84
RECOMMENDATION 5
RT can be considered in the following cases:
• For palliation of pain related to tumour growth, RT can be considered
• The use of RT to prevent growth in drainage tracts is not proven to be useful
• RT can be given in an adjuvant setting after surgery or chemo-surgery to reduce the local failure rate. However,
no evidence is available for its use as standard treatment
• When postoperative RT is applied, strict constraints must be adhered to in order to avoid toxicity
to neighbouring organs and special, tissue-sparing, techniques should be used
RT, radiotherapy
Surgery
Surgery for staging and palliation
• Thoracoscopic inspection of the pleural cavity is required for staging
• The staging intervention can also be used to control pleural effusion, using a talc
poudrage or decortication in the case of a captured lung
 In one study, VATS (partial) pleurectomy did not improve overall survival but
did improve quality of life, compared with standard talc poudrage
Surgery with radical intent
• The achievement of free resection margins is virtually impossible and the aim
is to obtain a macroscopic complete resection
• The International Association for the Study of Lung Cancer (IASLC)
recommended uniform definitions for surgical procedures dealing with
mesothelioma
 EPP implies a complete removal en bloc of the involved parietal and visceral
pleura including the whole ipsilateral lung. If required, the diaphragm and
pericardium can also be resected
 Extended pleurectomy/decortication (P/D) is the same procedure but the lung
is left in situ: macroscopic complete resection is still the goal
 P/D refers to removal of all gross tumour, without resection of the diaphragm
or the pericardium
 A partial pleurectomy entails partial removal of parietal and/or visceral pleura
leaving gross tumour behind
• In a large retrospective analysis, the operative mortality was slightly higher
for EPP than for P/D
• A trimodality approach of induction ChT, followed by EPP and subsequent RT
may be feasible
85
 A systematic review suggested that trimodality therapy may offer acceptable
perioperative outcomes and long-term survival in selected patients treated in
specialised centres
However, a randomised study of EPP vs no EPP after induction therapy
suggested that there was no benefit, and possibly even harm, associated
with trimodality therapy
A multidisciplinary team with sufficient experience should provide
recommendations on the suitability of patients for trimodality treatment
• A summary of recommendations for the use of surgery in MPM is given below
RECOMMENDATION 6
The indications for surgery are:
• For palliation of pleural effusions when chest tube drainage is not successful
• To obtain diagnostic samples of tumour tissue and to stage the patient
• To be part of a multimodality treatment, preferably as part of a study
• To perform a macroscopic complete resection by means of P/D or EPP
PP e trapleural pneumone tom P pleure tom de orti ation
RESPONSE EVALUATION AND FOLLOW-UP
• Response evaluation should be performed with CT scanning and the
examinations performed at presentation
• Follow-up will depend on local recommendations or, in the case of patients
taking part in a study, the protocol
86
DIAGNOSIS
Shortness of breath, pain and weight loss are common symptoms and unilateral
effusions are often observed on physical examination
The work-up should include: chest X-ray, CT scan of chest and upper abdomen,
thoracentesis, general laboratory blood tests and a detailed occupational history
When there is a history suggestive of significant asbestos exposure, or
radiology is suggestive of mesothelioma, cytology or histology can be
used (histology is preferred)
Pathological specimens should be obtained from patients with unilateral pleural
thickening, with or without fluid and/or calcified asbestos plaques
Thoracoscopy (pleuroscopy or VATS) is recommended to obtain adequate
histology, to optimally stage and to allow pleural fluid evacuation, with
ultrasound-guided true-cut biopsies as an alternative
Circulating tumour markers cannot distinguish MPM, but CEA, as a negative
marker, can be used to rule out MPM if cytological/histological analysis
is inconclusive
PATHOLOGY
Samples for diagnosis include: pleural effusions, small (closed) pleural biopsies,
image-guided needle core biopsies, larger open surgery or VATS biopsy samples
of debulking specimens
Significant sampling errors can occur in effusion cytology and small biopsy samples
Blind biopsies are not recommended
Effusion cytology is generally not recommended to establish a definitive diagnosis
but, if it is frankly malignant, confirmation by biopsy is recommended
When a biopsy is not possible, appropriate clinical and radiological features may
assist in suggesting a diagnosis of MPM
Adequate tissue biopsy and appropriate IHC is generally required for the definitive
primary diagnosis of MPM
Definitive diagnosis of mesothelioma by frozen section is not recommended
The larger the tissue biopsy and the more targeted the sampling approach, the
more reliable and definitive the diagnosis
Identification of the extent of invasion is crucial and can be assisted by IHC
87

A major subtype diagnosis (epithelioid, biphasic, sarcomatoid) should be given
in all cases of MPM
If definitive invasion cannot be recognised, a diagnosis of ‘atypical mesothelial
proliferation’ is appropriate and further sampling may be indicated
Distinguishing MPM from organising fibrinous exudates (fibrinous/fibrous pleurisy)
requires a full thickness biopsy sample
The most commonly used mesothelial markers are calretinin, cytokeratin 5/6, WT1 and
podoplanin (D2-40), with TTF-1, CEA and Ep-CAM (Ber-EP4) being the most useful for
(adeno)carcinoma
At least two mesothelial markers and at least two (adeno)carcinoma markers
should be used
Pancytokeratin markers can be useful in the diagnosis of sarcomatoid
mesothelioma, which does not express the usual mesothelial markers
STAGING
Disease staging according to the TNM-based UICC system, when assessed
by surgical staging, is the preferred approach
Gadolinium-based MRI may improve delineation of the tumour and help to visualise
foci that may be present in the diaphragm, pericardium or chest wall
The use of PET scanning is limited
TREATMENT
Front-line and maintenance therapy for mesothelioma
• Combination doublet ChT of cisplatin (or carboplatin as an alternative) and either
pemetrexed or raltitrexed improves survival compared with cisplatin alone as
front-line therapy in unresectable MPM
Pemetrexed in combination with cisplatin is indicated for the treatment
of ChT-naive patients with unresectable MPM but not in the maintenance setting
• The addition of novel agents to cisplatin doublets and the use of anti-angiogenic
agents have not improved efficacy over standard treatment
• Trials are investigating the use of a number of agents in switch maintenance
therapy and patients should be included in these studies
88
Second-line therapy for mesothelioma
• There is currently no second-line standard of care and it is recommended that
patients are enrolled into clinical trials
RT
• RT can be considered for the treatment of pain, although no high
quality evidence exists to support this
• Short course RT (e.g. 1×10 Gy or 3×8 Gy) is recommended in cases
of pain due to infiltration of the chest wall or permeation nodules by MPM
• Prophylactic irradiation of scars following thoracoscopy and/or drainage
procedures to reduce the likelihood of seeding metastases is recommended
only in the context of a clinical trial
Pre- and postoperative RT
• In general, the use of pre- or postoperative RT for large fields
(hemi-thoracic RT) is not recommended outside the clinical trial setting
• Local control is poor and the field size and neighbouring vital organs involved
result in significant toxicity, although the use of 3D planning and IMRT may
help to improve outcomes
• Higher doses of radiation have been shown to lead to better local control and
it is recommended that this is carried out only in specialised centres
Choice of radiation type after EPP
• Preliminary results with IMRT in the adjuvant setting after EPP appear promising
and dosimetric constraints may reduce the risk of pneumonitis and toxicity
to neighbouring at-risk organs
• As RT technique is important for both local control and toxicity
it is recommended that RT is delivered in specialised centres
Surgery
Surgery for staging and palliation
• Thoracoscopic inspection of the pleural cavity is required for staging
• The staging system can also be used to control pleural effusion, using
a talc poudrage or decortication in the case of a captured lung
Surgery with radical intent
• The achievement of free resection margins is virtually impossible and the
aim is to obtain a macroscopic resection by means of an EPP, extended
or partial pleurectomy
89
 • A trimodality approach of induction ChT followed by EPP
and subsequent RT may be feasible and may offer acceptable perioperative
outcomes and long-term survival in selected patients treated
in specialised centres
• A multidisciplinary team with sufficient experience should provide
recommendations on the suitability of patients for trimodality treatment
RESPONSE EVALUATION AND FOLLOW-UP
Response evaluation should be performed with CT scanning and the examinations
performed at presentation
Follow-up will depend on local recommendations or, in the case of patients
taking part in a study, the protocol
90
DIAGNOSIS
• Thymic epithelial tumours are classified according to the World Health
Organization (WHO) histopathological classification system
• Thymomas are sub-divided into A, AB, B1, B2, B3 and rare others based on the
morphology of epithelial tumour cells, the relative proportion of the non-tumoural
lymphocytic component and resemblance to normal thymic architecture
The term ‘benign thymoma’ should be avoided
• Thymic carcinomas are similar to their extrathymic counterparts, the most
frequent sub-type being squamous cell carcinoma
• Genetic risk factors, such as multiple endocrine neoplasia 1 (MEN1), may
participate in the development of thymomas and thymic carcinoids and
oncogenetic assessment is recommended in case of familial thymic tumours
• Diagnosis relies on differentiating between a thymic epithelial tumour and other
anterior mediastinal tumours and non-malignant thymic lesions
• Standard imaging is with intravenous contrast-enhanced computed tomography
(CT) scan of the thorax, with exploration of the mediastinum
and pleura
• Magnetic resonance imaging (MRI) can be used in difficult cases to differentiate
tumours from hyperplasia when a CT scan is doubtful or for cystic lesions
• Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is generally not
recommended to assess thymic masses
PET is optional for tumours with aggressive histology and at an advanced stage
to complete the staging work-up
• A complete history, full clinical examination (including neurological assessments)
and systematic immunological check-up, including complete blood cell counts
with reticulocytes and serum protein electrophoresis and tests for anti-
acetylcholine receptor and anti-nuclear antibodies, is recommended
• Thymoma is the most likely diagnosis when facing a mediastinal mass associated
with autoimmune disease, as shown on the next page, while thymic carcinoma
patients typically have unspecific local symptoms
91
 AUTOIMMUNE DISORDERS ASSOCIATED WITH THYMOMA
Neuromuscular
Haematological disorders
Collagen and autoimmune disorders
Immune deficiency disorders
Endocrine disorders
92
Pemphigus
Myasthenia gravis Lichen planus
Dermatological disorders
Myotonic dystrophy Chronic mucosal candidiasis
Limbic encephalitis Alopecia areata
Peripheral neuropathy Giant cell myocarditis
Nephrotic syndrome
Autonomic neuropathy
Miscellaneous
Acquired neuromyotonia Ulcerative colitis
Morvan syndrome (neuromyotonia and encephalitis) Hypertrophic osteoarthropathy
Stiff person syndrome
Cerebellar degeneration
• Pre-treatment biopsy is not required if the diagnosis of a thymic tumour is highly
Polymyositis (carcinomas) suspected and upfront surgical resection is achievable
Red cell aplasia • Biopsy is required in all other clinical situations, with percutaneous core
needle biopsy or incisional surgical biopsy through mediastinotomy or mini-
Pernicious anaemia
thoracotomy as possible options
Erythrocytosis  Deep, multiple biopsies are preferred to wide, scant biopsies
Pancytopaenia  Fine-needle aspiration is generally not recommended
Haemolytic anaemia
• Although designed for surgical resection specimens, the WHO classification
system may be used for small biopsies
Leukaemia
• Immunohistochemistry may be helpful and anti-CD117 (KIT) and anti-CD5
Multiple myeloma expression can assist in establishing the thymic origin in approximately 80% of
mediastinal carcinomas
Systemic lupus erythematosus
• In thymic tumours with more than one histological pattern, each component
Rheumatoid arthritis
should be listed and quantified in 10% increments; a thymic carcinoma
Sjogren’s syndrome component should be mentioned first
Scleroderma • For difficult cases, a second pathologist should be consulted or the case referred
to a thymic tumour pathology panel
Interstitial pneumonitis
STAGING AND RISK ASSESSMENT
Hypogammaglobulinaemia (Good syndrome)
• Thymic tumours are routinely staged with the Masaoka-Koga staging system,
T cell deficiency syndrome as shown on the next pages, a surgical pathology system that is assessable only
Multiple endocrine neoplasia after surgical resection of the tumour
Cushing’s syndrome
Thyroiditis
93
 Microscopic invasion
STAGING OF THYMIC EPITHELIAL TUMOURS AND SURVIVAL RATES
of the mediastinal

pleura (either partial or
penetrating the elastin
MASAOKA- INTERNATIONAL 10-YEAR
10-YEAR CUMULATIVE layer)
KOGA, THYMIC OVERALL INCIDENCE
Microscopic invasion of
1994 MALIGNANCY SURVIVAL OF RECURRENCE
the pericardium (either
INTEREST
GROUP, 2011*
partial in the fibrous
THYMOMA THYMIC layer or penetrating
CARCINOMA through to the serosal
layer)
Grossly and Invasion into but not
microscopically through the capsule Microscopically
completely confirmed direct
Stage In the absence of 84% penetration into the
I encapsulated (81–86%)
tumour capsule, absence Macroscopic outer elastin layer of the
of invasion into invasion into visceral pleura or into
surrounding tissues neighbouring the lung parenchyma
Stage 70%
organ (i.e., Invasion into the 29% (27–31%) 59% (44–76%)
Stage Microscopic Microscopic III (64–75%)
pericardium, phrenic or vagus
IIA transcapsular transcapsular invasion
great vessels, or nerves (microscopically
invasion (less than 3 mm)
lung) confirmed)
Macroscopic Gross extension
invasion into into normal thymus Invasion into
thymic or or perithymic fat or penetration
surrounding surrounding the tumour through major
83%
fatty tissue, (microscopically 8% (7–8%) 25% (22–29%) vascular structures
(79–87%)
Stage or grossly confirmed) (microscopically
IIB adherent to but confirmed)
not breaking Adherence to pleura
through the Adherence (i.e.
or pericardium, fibrous attachment)
mediastinal with microscopic
pleura or of lung or adjacent
confirmation of organs only if there is
pericardium perithymic invasion mediastinal pleural or
pericardial invasion
(microscopically
confirmed)

Pleural or Microscopically
pericardial confirmed separate
Stage metastasis nodules in the visceral 42% 71%
76% (58–100%)
IVA or parietal pleural, (26–58%) (34–100%)
pericardial or epicardial
surfaces

Lymphogenous Lymphogenous or
Stage or haematogenous 53%
57% (24–90%) 54% (37–67%)
IVB haematogenous metastasis (32–73%)
metastasis

*Refinement to original staging system

Information reprinted from Detterbeck F et al. J Thorac Oncol 2011;6:S1710–6, with permission from Elsevier.
94 95
 • A tumour, node, metastasis (TNM)-based staging system for thymic N - Regional Lymph Nodes
malignancies, proposed by the International Association for the Study of Lung
Cancer (IASLC) Staging Prognostic Factors Committee and the International NX Regional lymph nodes cannot be assessed
Thymic Malignancy Interest Group (ITMIG), is incorporated into the 8th edition of N0 No regional lymph node metastasis
the American Joint Committee on Cancer (AJCC)/Union for International Cancer
Control (UICC) TNM staging system of thoracic malignancies N1 Metastasis in anterior (perithymic) lymph nodes

• Assessment of tumour resectability is based mainly on the surgeon’s expertise, N2 Metastasis in deep intrathoracic or cervical lymph nodes
but discussions of indications for surgery within a multidisciplinary tumour board
Metastasis
setting are recommended
 Complete resection (R0, no tumour at the margin) is generally achievable in M0 No pleural, pericardial or distant metastasis
Masaoka-Koga stage I/II and some stage III tumours M1 Distant metastasis
• The new TNM staging may help to formalise resectability criteria, as shown below M1a Separate pleural or pericardial nodule(s)
PROPOSED TNM STAGING (8TH EDITION) AND CORRESPONDING M1b Distant metastasis beyond the pleura or pericardium
MASAOKA-KOGA STAGE
STAGE CORRESPONDING MASAOKA-KOGA
STAGE DESCRIPTORS GROUPING STAGE
T - Primary Tumour I T1 N0 M0 I, IIA, IIB, III

TX Primary tumour cannot be assessed II T2 N0 M0 III

T0 No evidence of primary tumour IIIA T3 N0 M0 III

Tumour encapsulated or extending into the mediastinal fat, IIIB T4 N0 M0 III

T1 may involve the mediastinal pleura
Any T N1 M0 IVA
T1a No mediastinal pleural involvement IVA
Any T N0,1 M1a IVB

T1b Direct invasion of the mediastinal pleura Any T N2 M0,1a IVB

IVB
Any T Any N M1b
T2 Direct invasion of the pericardium (partial or full-thickness)
TNM, tumour, node, metastasis
Direct invasion into any of the following: lung,
Brierley JD et al. TNM Classification of Malignant Tumours, 8th edition. Oxford: John Wiley & Sons, Inc. 2017.
T3 brachiocephalic vein, superior vena cava, phrenic nerve, Reprinted with permission.
chest wall or extrapericardial pulmonary artery or vein

Direct invasion into any of the following: aorta (ascending,
T4 arch or descending), arch vessels, intrapericardial
pulmonary artery, myocardium, trachea or oesophagus
• Autoimmune disorders may cause death in 25% of thymomas and the
management of such syndromes should be integrated into oncological treatment
TREATMENT
• Treatment, as shown in the figures and table on the next pages, is based on the
resectability of the tumour

96 97
 TREATMENT ALGORITHMS FOR THYMIC EPITHELIAL TUMOURS (B) UNRESECTABLE**
(A) RESECTABLE*

Upfront Surgery Biopsy

Histological Thymic Primary

Thymoma CRT ChT
type carcinoma

Resection R1 R0 R1 R0 Unresectable (Masaoka Resectable (Masaoka-Koga

-Koga stage III–IVA) stage III–IVA)
(TNM stage IIIA–IIIB–IVA) (TNM stage IIIA, IVA)

Masaoka
-Koga IIA, IIB, III I III I, IIA, IIB Any III IIB IIA I
stage Surgery

Histological
subtype Any Any Any Any Any Any Any
B2, B3 A, AB, B1 Histological
type Thymic carcinoma Thymoma Thymic carcinoma Thymoma

Postoperative Postoperative
ChT ChT Resection
B3 A, AB, B1, B2
Any R R2 R0, R1
Definitive
CRT RT

Postoperative
RT Postoperative Postoperative
Postoperative RT
ChT ChT

Definitive
CRT RT
Postoperative RT
Follow-up

Follow-up

98 99
 (C) METASTATIC*** Stage IIA Upfront surgery Upfront surgery
Biopsy No biopsy No biopsy
If R0: If R0: Consider postoperative RT (45–50 Gy)
- Type A–B2: no postoperative RT If R1: - Postoperative RT (50–54 Gy)
- Type B3: consider postoperative - Consider postoperative ChT
RT (45–50 Gy)
Definitive If R1: postoperative RT (50–54 Gy)
ChT
Upfront surgery Upfront surgery
No biopsy No biopsy
If R0: If R0: Consider postoperative RT (45–50 Gy)
Stage IIB - Type A–B1: no postoperative RT If R1: - Postoperative RT (50–54 Gy)
Histological Thymic
type Thymoma - Type B2–B3: consider - Consider postoperative ChT
carcinoma
postoperative RT (45–50 Gy)
If R1: postoperative RT (50–54 Gy)

Surgery Resectable tumour (TNM I–IIIA, Resectable tumour (TNM I–IIIA, i.e. T1–T3):
i.e. T1–T3): - Upfront surgery
- Upfront surgery - Postoperative RT (40–50 Gy), with boost on
- Postoperative RT (45–50 Gy), areas of concern
with boost on areas of concern - Consider postoperative ChT
Definitive Postoperative
RT RT Unresectable tumour (TNM IIIA–B, Unresectable tumour (TNM IIIA–B, i.e. T3–T4):
i.e. T3–T4): - Biopsy
- Biopsy - Primary ChT (preferably
- Primary ChT (preferably anthracycline-based)
anthracycline-based) - If the tumour becomes resectable:
Follow-up
- If the tumour becomes - Surgery
resectable: - Postoperative RT (45–50 Gy), with boost
*Masaoka-Koga stage I–III, TNM stage I–IIIA Stage III–IVA
- Surgery on areas of concern (R0, R1 resection)
**Masaoka-Koga stage III–IVA, TNM stage IIIA-IIIB-IVA
***Masaoka-Koga stage IVB, TNM stage IVB - Postoperative RT (45–50 - Consider postoperative ChT
ChT, chemotherapy; CRT, chemoradiotherapy; R0, no tumour at the margin; R1, microscopic tumour at the margin; Gy), with boost on areas of (R0, R1 resection)
R2, macroscopic tumour at the margin; RT, radiotherapy; TNM, tumour, node, metastasis concern (R0, R1 resection) - If the tumour remains unresectable or R2:
- If the tumour remains - Definitive RT (60 Gy)
STAGE-MATCHED THERAPEUTIC STRATEGIES unresectable or R2: - Option: CRT
- Definitive RT (60 Gy) - Option: concurrent CRT (platin and etoposide,
See the table below and on the next page for recommended fluorescent in situ - Option: CRT 60 Gy)
hybridisation regimens and RT doses/schedules - Option: concurrent CRT (platin
and etoposide, 60 Gy)
MASAOKA- THYMOMA THYMIC CARCINOMA
KOGA STAGE
Upfront surgery Upfront surgery Definitive ChT Definitive ChT
No biopsy No biopsy - If the tumour becomes
Stage I resectable, consider:
If R0: no postoperative RT If R0: consider postoperative RT (45–50 Gy) Stage IVB
If R1: postoperative RT (50–54 Gy) If R1: postoperative RT (50–54 Gy) - Surgery and
postoperative RT
- Definitive RT

ChT, chemotherapy; CRT, chemoradiotherapy; R0, no tumour at the margin; R1, microscopic tumour at the margin; R2, macroscopic
tumour at the margin; RT, radiotherapy; TNM, tumour, node, metastasis

100 101
 Resectable disease
• Surgery is the first choice if R0 resection is deemed to be achievable upfront,
possibly followed by postoperative radiotherapy (RT) and, less frequently,
chemotherapy (ChT)
Surgery
• The standard approach is median sternotomy
• Complete thymectomy, including the tumour, residual thymus gland and
perithymic fat, is generally preferred to avoid the risk of local recurrences when
part of the thymus gland is left behind
• Thymomectomy, leaving residual thymic tissue and perithymic fat behind, is an
option in stage I tumours in non-myasthenic patients
• For widely invasive, stage III/IV tumours, removal en bloc of all affected
structures, including lung, parenchyma, pericardium, great vessels, nerves and
pleural implants, should be carried out
• Areas of uncertain resection margins should be marked with clips to allow
precise delivery of postoperative RT
• Phrenic nerve preservation does not affect overall survival but increases the risk of
local recurrence and should be balanced with the achievement of an R0 resection
• Frozen sections for the assessment of resection margin tumour involvement are
not recommended given the high risk of false negative results
• Minimally invasive surgery is an option for presumed stage I and possibly
stage II tumours in the hands of appropriately trained surgeons but should
not jeopardise the achievement of R0 resection, which may ultimately require
switching to an open procedure
 It is not recommended for stage III tumours due to the absence of long-term
follow-up data
• The IASLC/ITMIG TNM staging system recommends locoregional
lymphadenectomy during resection for all thymic tumour types
 Systematic lymphadenectomy (N1+N2) is strongly recommended for thymic
carcinoma due to the high rate of lymphatic spread (20% vs 3% in thymomas)
• Routine removal of anterior mediastinal nodes and anterior cervical nodes is
recommended
• Systematic sampling of other intrathoracic sites is encouraged in stage III/IV tumours
• Surgeon and pathologist input is required for the accurate staging of tumours; the
correct presentation of the pathological specimen is the surgeon’s responsibility
102
• Given the potential heterogeneity of tumours, at least five sections with one
additional block for each additional cm should be examined; if the margin is
< 1 mm, at least three additional sections through this area should be obtained
• Completeness of resection should be assessed, making the distinction between
tissues that have been cut or dissected, and a surface bounded by a space,
which should not be designated as a positive margin
Postoperative RT
• Stage and completeness of resection, followed by histology, are the most relevant
criteria in assessing the value of postoperative RT
• 3D conformal RT or intensity-modulated RT (IMRT) targeted to the tumour bed,
with a clinical target volume including the whole thymic space, the tumour and its
extensions and the anterior, superior and middle mediastinum, is recommended
• The optimal dose/schedule has yet to be defined, but a total dose of 45–50 Gy
after R0 resection and 50–54 Gy after R1 (microscopic tumour at the margin)
resection, with a boost to areas of likely residual disease, using a conventional
fractionation scheme of 1.8–2 Gy/day over a 4–6-week period, is suggested
• The field may encompass involved nodes and the site of a resected pleural
implant
• Postoperative RT should start within 3 months of surgery
• Prophylactic irradiation of supraclavicular nodes and low-dose entire
hemithoracic RT are not recommended
• Postoperative RT is not indicated after R0 resection of Masaoka-Koga stage I
tumours. It may be considered in stage II thymomas in case of aggressive
histology (B2, B3) or extensive transcapsular invasion (stage IIB)
• Postoperative RT is recommended after R0 resection of stage III/IVA thymomas
in an effort to prolong relapse-free and overall survival
• After R0 resection of thymic carcinomas, postoperative RT is optional for stage
I tumours, should be considered for stage II tumours and is recommended for
stage III/IVA tumours
• Postoperative RT is also recommended following R1 or R2 (macroscopic tumour
at the margin) thymic tumour resection, to a total dose of 50–54 Gy and 60 Gy,
respectively, with a 10 Gy boost to areas of likely residual disease
Postoperative ChT
• Postoperative ChT is not recommended after R0–R1 resection of thymomas
but may be considered for stage II/III/IV thymic carcinomas, especially if not
delivered as induction treatment
103
 Advanced disease Carbo-Px Carboplatin AUC 5–6 / 3w
• If R0 resection is not likely to be achieved upfront on the basis of imaging Paclitaxel 200–225 mg/m² / 3w
studies, a biopsy should be performed, followed by primary/induction ChT as
part of a curative-intent sequential strategy that integrates subsequent surgery Cap-GEM Capecitabine 650 mg/m² bid d1–14 / 3w
or RT Gemcitabine 1000 mg/m² d1,d8 / 3w
• Patients not eligible for local treatment should receive palliative ChT alone AUC, area under the curve; bid, twice a day; d, day; w, week
Girard N. Expert Rev Anticancer Ther 2012;12:685–95. Adapted with permission of Taylor & Francis Ltd
Primary/induction ChT
• Cisplatin-based regimens should be administered, as shown below, and
combinations of cisplatin, doxorubicin and cyclophosphamide (CAP) or cisplatin • Primary chemoradiotherapy (CRT) with PE is an option for thymic carcinomas
and etoposide (PE) are recommended options • Usually, 2–4 cycles are administered prior to imaging to assess tumour
SELECTED CHEMOTHERAPY REGIMENS FOR ADVANCED THYMIC EPITHELIAL resectability
TUMOURS ASSESSED IN PHASE II TRIALS • Surgery should be offered when R0 resection is deemed achievable; extended
resection may be required

REGIMEN AGENTS DOSES • Hyperthermic intrapleural ChT and extra-pleural pneumonectomy, followed by

ADOC Doxorubicin 40 mg/m² / 3w postoperative RT, may be discussed for stage IVA tumours

Cisplatin 50 mg/m² / 3w • Sub-total, or debulking, resection is an option for selected cases of thymoma
with the aim of facilitating subsequent definitive RT
Vincristine 0.6 mg/m² / 3w

• Debulking resection is not recommended for thymic carcinomas
Cyclophosphamide 700 mg/m² / 3w
• Postoperative CRT (PE plus RT at a total dose of 60 Gy in 30 fractions) may be
CAP Cisplatin 50 mg/m² / 3w considered after debulking/R2 resection

Doxorubicin 50 mg/m² / 3w Definitive RT

Cyclophosphamide 500 mg/m² / 3w • Definitive RT is recommended as part of a sequential CRT strategy for patients
deemed to be poor surgical candidates, either because R0 resection is unlikely
PE Cisplatin 60 mg/m² / 3w
or because the patient has poor performance status or co-existing medical
Etoposide 120 mg/m² x 3d / 3w conditions
VIP Etoposide 75 mg/m² x 4d / 3w • Combination with PE ChT may be considered

Ifosfamide 1.2 g/m² x 4d / 3w Definitive ChT

Cisplatin 20 mg/m2 x 4d / 3w • Single modality cisplatin-based combination ChT should be offered for the relief
of tumour-related symptoms to patients with advanced, unresectable, non-
CODE Cisplatin 25 mg/m² / 1w irradiable or metastatic (stage IVB) thymic epithelial tumours
Vincristine 1 mg/m² / 2w • CAP is the preferred regimen, with carboplatin and paclitaxel (Carbo-Px) as an
Doxorubicin 40 mg/m² / 2w option for thymic carcinomas
Etoposide 80 mg/m² x 3d / 2w • Surgery or RT can be used in rare, selected cases of metastatic thymoma,
although benefits on outcome are not proven

104 105
 • Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 should be used to • For stage III/IV thymomas, thymic carcinoma or after R1–2 resection, CT scans
assess response to ChT every 6 months for 2 years, then annually thereafter, are recommended
Recurrences • Follow-up should be continued for 10–15 years
• Recurrences are not uncommon (10–15% of all-stage resected tumours) and • Patients with clinical myasthenia gravis should be educated about the risks
should be managed according to the same strategy as newly diagnosed tumours of myasthenic crisis in certain situations, such as stress or following the
• R0 resection of recurrent lesions is a major predictor of favourable outcomes and administration of some drugs
is recommended for resectable recurrences • Participation in collaborative research initiatives and clinical trials, when available,
• For unresectable recurrences, several consecutive lines of ChT may be is recommended
administered and the use of a previously effective regimen should be considered
• Cardiac toxicity is increased in patients previously receiving mediastinal RT
• Preferred second-line ChT regimens include Carbo-Px and PE, with capecitabine
and gemcitabine (Cap-GEM) as an option
• Subsequent-line options include pemetrexed and oral etoposide
• Patients with octreoscan-positive thymoma, not eligible for ChT, may benefit from
octreotide ± prednisone
PERSONALISED MEDICINE
• Personalised medicine approaches are limited by the availability of validated
molecular markers with prognostic or predictive value
• KIT sequencing (exons 9–17) is an option for refractory thymic carcinomas
to assess suitability for tyrosine kinase inhibitor treatment, particularly in
clinical trials
• Imatinib should not be administered in the absence of KIT-sensitising mutations,
as it has no activity in this setting
• The angiogenesis inhibitor, sunitinib, is a second-line treatment option for thymic
carcinomas, independent of KIT mutation status
• The mammalian target of rapamycin inhibitor, everolimus, is an option for
refractory tumours
• NB: imatinib, sunitinib and everolimus do not have regulatory approval for use
in thymic malignancies
FOLLOW-UP AND LONG-TERM IMPLICATIONS
• In the absence of prospective data, follow-up recommendations are based
on expert consensus and recurrence data
• Baseline thoracic CT scans should be conducted 3–4 months after surgery
• For R0 resected stage I/II thymomas, CT scans annually for 5 years then every
2 years are recommended
106 107

DIAGNOSIS
Thymic epithelial tumours are classified according to the WHO histopathologic
classification, which may be used for small biopsies
Oncogenetic assessment, with a particular focus on MEN1, should be conducted
Differential diagnosis with other anterior mediastinal tumours and non-malignant
lesions is key
Standard imaging is intravenous contrast-enhanced CT of the thorax
MRI is recommended to differentiate tumours from hyperplasia when a CT scan
is doubtful or for cystic lesions
FDG-PET is generally not recommended to assess thymic masses
A complete history, full clinical examination and systematic immunological check-
up, including complete blood cell counts, with reticulocytes and serum protein
electrophoresis and anti-acetylcholine receptor and antinuclear antibodies tests,
is recommended
Thymoma is the first diagnosis to consider when facing a mediastinal mass
associated with autoimmune disease
Pre-treatment biopsy is not required if the diagnosis of thymic epithelial tumour
is highly suspected and upfront surgical resection is achievable
Biopsy, for example using percutaneous core-needle biopsy or incisional surgical
biopsy, is required in all other clinical situations; fine-needle aspiration is
not recommended
Immunohistochemistry with anti-CD117 (KIT) and anti-CD5 antibodies is useful to
establish the thymic primary nature of a mediastinal carcinoma
Each component of heterogeneous tumours may be quantified in 10% increments
Consultation with a second pathologist or referral to a thymic tumour pathology
panel is recommended in difficult cases
STAGING AND RISK ASSESSMENT
The 8th edition of the TNM staging system should be used
Assessment of resectability is at the surgeon’s discretion, but multidisciplinary
tumour board input is recommended
108
Autoimmune syndrome treatment should be integrated into oncological treatment
of thymomas, where appropriate
TREATMENT
Treatment strategies are based primarily on the possibility of upfront tumour
resection
Resectable disease
• Surgery is the first choice where R0 resection is achievable upfront
Surgery
• The standard approach is median sternotomy
• Complete thymectomy, including the tumour, the residual thymus gland and
perithymic fat, is preferred
• Thymomectomy alone is an option in stage I tumours in non-myasthenic
patients
• For extensive invasive tumours (stage III/IV), removal en bloc of all affected
structures, including lung parenchyma, pericardium, venous great vessels,
nerves and pleural implants, should be carried out
• Areas of uncertain margins should be marked with clips to allow precise delivery
of postoperative RT
• Phrenic nerve preservation increases the risk of local recurrence
• Frozen sections to assess resection margin tumour involvement are not
recommended
• Minimally invasive surgery is an option for stage I–II tumours but is not
recommended for stage III tumours
• Systematic lymphadenectomy (N1 + N2) is strongly recommended for thymic
carcinomas
• Routine removal of anterior mediastinal and anterior cervical nodes
is recommended
• Systematic sampling of intrathoracic sites is encouraged in stage III/IV tumours
• Communication between surgeons and pathologists is required for accurate
tumour staging
• At least five representative sections should be examined; if the margin is < 1 mm,
at least three additional sections through this area should be obtained
• Completeness of resection should be assessed, making the distinction between
tissues that have been cut or dissected, and a surface bounded by a space,
which should not be designated as a positive margin
109

Postoperative RT
• Stage and completeness of resection are the most relevant criteria in the
consideration of postoperative RT (3D conformal RT or IMRT targeted to the
tumour bed), which should start within 3 months of surgery
• Clinical target volume includes the whole thymic space, the tumour and its
extensions and the anterior, superior and middle mediastinum
• Recommended RT doses are: total dose 45–50 Gy after R0 resection and
50–54 Gy after R1 resection, using conventional fractionation (1.8–2 Gy/day over
4–6 weeks), with a boost to areas of likely residual disease
• The field may encompass involved nodes and the site of a resected pleural implant
• Prophylactic irradiation of supraclavicular nodes and low-dose entire
hemithoracic RT are not recommended
• After R0 thymoma resection, postoperative RT is not indicated for Masaoka-Koga
stage I or II disease but may be considered in case of aggressive histology for
stage IIA (type B2, B3) or stage IIB disease and is recommended for stage III/IVA
disease
• After R0 thymic carcinoma resection, postoperative RT is optional for stage I
tumours, should be considered for stage II tumours and is recommended for
stage III/IVA tumours
• Postoperative RT is recommended for R1 or R2 resected tumours (to a total dose
of 50-54 Gy and 60 Gy, respectively, with a 10 Gy boost to areas of likely residual
disease)
Postoperative ChT
• Postoperative ChT is not recommended after R0–R1 thymoma resection but may
be considered for stage II/III/IV thymic carcinomas
Advanced disease
• When R0 resection is not achievable upfront, a biopsy should be followed by
primary/induction ChT and subsequent surgery or RT
• Patients not eligible for local treatment receive palliative ChT alone
Primary/induction ChT
• Cisplatin-based combinations (CAP or PE) are recommended
• Primary CRT with PE is an option for thymic carcinomas
• Usually, 2–4 cycles are administered before imaging to reassess resectability of
the tumour
110
• Surgery should be offered when R0 resection is deemed achievable
• Hyperthermic intrapleural ChT and extra-pleural pneumonectomy, followed by RT,
may be discussed for stage IVA tumours
• Sub-total (debulking) resection is an option in selected thymoma cases but is not
recommended for thymic carcinomas
• Postoperative CRT (PE plus RT at a total dose of 60 Gy in 30 fractions) may be
considered after debulking/R2 resection
Definitive RT
• Definitive RT is recommended for poor surgical candidates as part of
sequential CRT
• Combination with PE ChT may be considered
Definitive ChT
• Cisplatin-based combination regimens should be offered for advanced,
unresectable, non-irradiable or stage IVB tumours
• CAP is the preferred regimen, with Carbo-Px as an option for thymic carcinomas
• Surgery or RT has no proven outcome benefit
• RECIST v1.1 should be used to assess response
Recurrences
• Recurrences should be managed with the same strategies as newly
diagnosed tumours
• Complete resection of recurrent lesions is recommended
• For non-resectable recurrences, consecutive lines of ChT may be administered
following tumour progression and use of a previously effective regimen should
be considered
• Preferred regimens for second-line treatment include Carbo-Px and PE; Cap-GEM
is also an option
• Subsequent-line options include pemetrexed and oral etoposide
• In patients with octreoscan-positive thymoma not eligible to receive additional
ChT, octreotide ± prednisone may be an option
PERSONALISED MEDICINE
KIT sequencing (exons 9–17) to assess suitability for specific inhibitor treatment is
an option for refractory thymic carcinomas, particularly in the context of clinical trials
Imatinib should not be administered in the absence of a KIT-sensitising mutation
Sunitinib can be used second line for thymic carcinomas, independent of KIT status
111
 Everolimus may be an option for refractory tumours ACCP, American College of Chest Physicians
NB: imatinib, sunitinib and everolimus do not have regulatory approval for use AdenoCa, adenocarcinoma
in thymic malignancies AHA/ACC, American Heart Association/American College of Cardiology
AJCC, American Joint Committee on Cancer
FOLLOW-UP AND LONG-TERM IMPLICATIONS ALK, anaplastic lymphoma kinase
Baseline thoracic CT scan should be performed 3–4 months after surgery AUC, area under the curve
BSC, best supportive care
For R0 resected stage I/II thymomas, CT scans should be performed annually
CABG, coronary artery bypass grafting
for 5 years, then every 2 years CAG, coronary angiography
For stage III/IV thymomas, thymic carcinoma or after R1–2 resection, CT scans CAP, cisplatin/doxorubicin/cyclophosphamide
should be performed every 6 months for 2 years, then annually thereafter Cap-GEM, capecitabine/gemcitabine
Follow-up should be continued for 10–15 years Carbo-Px, carboplatin/paclitaxel
CAV, cyclophosphamide/doxorubicin/vincristine
Participation in clinical trials is recommended CEA, carcinoembryonic antigen
cfDNA, cell-free DNA
ChT, chemotherapy
CNS, central nervous system
CODE, cisplatin/vincristine/doxorubicin/etoposide
COPD, chronic obstructive pulmonary disease
CPET, cardiopulmonary exercise testing
CPG, Clinical Practice Guideline
CRT, chemoradiotherapy
CSF, cerebrospinal fluid
CT, computed tomography
DFS, disease-free survival
DLCO, diffusing capacity of the lungs for carbon monoxide
EBB, endobronchial brachytherapy
EBRT, external beam radiotherapy
EBUS, endobronchial ultrasound
ECG, electrocardiogram
EGFR, epidermal growth factor receptor
EMA, European Medicines Agency
EPP, extrapleural pneumonectomy
ESMO, European Society for Medical Oncology
EUS, endoscopic ultrasound
FDA, Food and Drug Administration
FDG, fluorodeoxyglucose
FEV1, forced expiratory volume in 1 second
FISH, fluorescent in situ hybridisation
FVC, forced vital capacity
GGO, ground glass opacity
HER2, human epidermal growth factor receptor 2

112 113
 IASLC, International Association for the Study of Lung Cancer PS, performance status
IHC, immunohistochemistry QoL, quality of life
ILD, interstitial lung disease R0, no tumour at the margin
IMIG, International Mesothelioma Interest Group R1, microscopic tumour at the margin
imRECIST, immune-modified Response Evaluation Criteria in Solid Tumours R2, macroscopic tumour at the margin
IMRT, intensity-modulated radiotherapy RCRI, revised cardiac risk index
IO, immuno-oncology RECIST, Response Evaluation Criteria in Solid Tumours
IPF, idiopathic pulmonary fibrosis RFA, radiofrequency ablation
iRECIST, immune-Response Evaluation Criteria in Solid Tumours RPA, recursive partitioning analysis
irRECIST, immune-related Response Evaluation Criteria in Solid Tumours RT, radiotherapy
ITMIG, International Thymic Malignancy Interest Group RV, reserve volume
IV, intravenous SABR, stereotactic ablative body radiotherapy
KPS, Karnofsky Performance Score SBRT, stereotactic body radiotherapy
LCT, local consolidative therapy SCC, squamous cell carcinoma
LDCT, low-dose computed tomography SCLC, small cell lung cancer
LDH, lactate dehydrogenase SRE, skeletal-related event
LM, leptomeningeal SRS, stereotactic radiosurgery
LMD, leptomeningeal disease SUVmax, maximum standardised uptake value
LN, lymph node TIA, transient ischaemic attack
LVRS, lung volume reduction surgery Tis, carcinoma in situ
Mb, megabase TKI, tyrosine kinase inhibitor
MDT, multidisciplinary team TLC, total lung capacity
MEK, mitogen-activated protein kinase kinase TMB, tumour mutation burden
MEN1, multiple endocrine neoplasia 1 gene TNM, tumour, node, metastasis
MPM, malignant pleural mesothelioma TPS, tumour proportion score
MRI, magnetic resonance imaging UICC, Union for International Cancer Control
nab-P, albumin-bound paclitaxel VAM, video-assisted mediastinoscopy
nab-PC, albumin-bound paclitaxel/carboplatin VATS, video-assisted thoracoscopic surgery
NGS, next-generation sequencing VIP, etoposide/ifosfamide/cisplatin
NOS, not otherwise specified VO2, oxygen consumption
NPV, negative predictive value VO2max, maximum oxygen consumption
NSCC, non-squamous cell carcinoma WBRT, whole-brain radiotherapy
NSCLC, non-small cell lung cancer WHO, World Health Organization
NSCLC-NOS, non-small cell lung cancer-not otherwise specified WT, wild-type
NTRK, neurotrophic tyrosine receptor kinase
ORR, objective response rate
OS, overall survival
P/D, pleurectomy/decortication
PCI, prophylactic cranial irradiation
PD-1, programmed cell death protein 1
PD-L1, programmed death-ligand 1
PE, cisplatin/etoposide
PET, positron emission tomography
PFS, progression-free survival
PORT, postoperative radiotherapy
ppo, predictive postoperative

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© 2020 European Society for Medical Oncology
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LUNG & CHEST TUMOURS 2020

ESMO POCKET GUIDELINES

LUNG & CHEST

TUMOURS

2020

MA-LAR-ALL-0258-1