clinical practice guidelines Annals of Oncology 21 (Supplement 5): v116v119, 2010

doi:10.1093/annonc/mdq189

Metastatic non-small-cell lung cancer: ESMO Clinical

Practice Guidelines for diagnosis, treatment and follow-
up
G. DAddario1, M. Fruh2, M. Reck3, P. Baumann4, W. Klepetko5 & E. Felip6
On behalf of the ESMO Guidelines Working Group*
1
Onkologie Schaffhausen, Schaffhausen; 2Department of Oncology, Kantonsspital St Gallen, St Gallen, Switzerland; 3Department of Thoracic Oncology, Grosshansdorf
Hospital, Grosshansdorf, Germany; 4Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden; 5Department of Cardiothoracic Surgery, Medical
University of Vienna, Vienna, Austria; 6Medical Oncology Service, Vall dHebron University Hospital, Barcelona, Spain

incidence and epidemiology
Non-small-cell lung cancer (NSCLC) accounts for 80%85% of
all lung cancer cases. Approximately 90% of lung cancers
among men and 80% among women are related to smoking.
The majority of patients present with advanced disease. The
incidence differs considerably across different countries in
Europe. The rates vary from 22 to 63 per 100 000 and from 5 to
33/100 000 per year in men and women, respectively. In most
European countries, the incidence continues to rise in women
but decreases in men. This trend seems to occur later in
Southern and Eastern Europe than in the Northern regions.
Five-year age- and area-adjusted relative survival of all lung
cancer patients in Europe continues to be low at 11%. Central
European countries show slightly higher survival compared with
other regions. Trends in lung cancer mortality in men have
tended to decrease in many European countries during the last
two decades, particularly in North and Western Europe. Among
women, mortality rates are still increasing in many countries.
The major histopathological subtypes are adenocarcinoma,
squamous cell carcinoma and large cell carcinoma. Again there
are variations across different regions mainly reflecting
different smoking behaviours. The proportion of
adenocarcinoma has been increasing over time possibly due to
the shift to low-tar filter cigarettes, which are inhaled more
deeply into the periphery of the lung and also contain a higher
amount of nitrosureas. On the other hand, the incidence of
squamous cell carcinoma is decreasing. A subset of NSCLC
tumour specimens are also categorized as NSCLC not otherwise
specified (NOS), either due to small specimen size or poorly
differentiated histology.
diagnosis
Pathological diagnosis should be made according to the WHO
classification. Histological or cytological specimens can be
obtained from the primary tumour, lymph node or distant
metastases or from a malignant effusion. In general, the least
invasive procedure should be used; however, quality and
quantity of the sampling should allow for distinction of
histological subtypes and for epidermal growth factor receptor
(EGFR) mutation analysis. Histological specimens are preferred.
Use of predictive markers for treatment
Activating EGFR mutations (Exons 19, 21) are predictive for
response and progression-free survival to the tyrosine kinase
inhibitors (TKIs) gefitinib and erlotinib based on several trials.
The incidence of EGFR mutations in a Caucasian population
is 10%. Higher rates are observed in never-smokers, in
East-Asians, in patients with adenocarcinoma subtype and in
women. Further prognostic and predictive molecular markers
have been described but not prospectively validated.
staging and risk assessment

*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: February 2002, last update
December 2009. This publication supercedes the previously published versionAnn
Oncol 2009; 20 (Suppl 4): iv68iv70.
Conflict of interest: Dr DAddario has reported no conflicts of interest; Dr Fruh has
reported that he is currently participating as an investigator on a phase III study
sponsored by Novartis; Dr Reck has reported that he is a member of the advisory board
of Lilly, Merck, Hoffmann-La Roche and Astra Zeneca and that he has received
honoraria from Lilly, Merck, Hoffmann-La Roche and Astra Zeneca; Dr Baumann,
Dr Klepetko and Dr Felip have reported no conflicts of interest.
 Complete history including smoking history, past medical
history including significant comorbidities, weight loss,
performance status and physical examination.
 Blood counts and standard serum chemistry including renal
function tests.
 CT scan of the chest and upper abdomen (including
i.v.-contrast examination of liver and adrenals).
 MRI of the brain in the case of abnormal neurological
findings (MRI preferred to CT scan due to higher sensitivity).
 Bone scan in the presence of bone pain, elevated serum
calcium or elevated alkaline phosphatase levels.

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Annals of Oncology clinical practice guidelines
 In the presence of a single metastatic lesion on imaging after interdisciplinary discussion, ideally at a tumour-board or
studies, biopsy of this lesion should be pursued to prove conference involving different specialists (medical and
metastatic disease if otherwise curable (does not apply to radiation oncologist, pneumologist, thoracic surgeon,
solitary brain metastases). radiologist and pathologist). Systemic treatment should be
 Pleural/pericardial effusions should be confirmed by guided by an experienced medical oncologist and selection of
a cytology or tissue specimen in patients otherwise curable. agents should take into account the patients situation, the
 In the case of a solitary metastasis in brain, lung or adrenal treatment goal and potential side-effects of the different
gland: brain imaging and PET should be performed followed treatments.
by further mediastinal staging if appropriate. In any stage of NSCLC, smoking cessation should be highly
 The staging system for lung cancer has recently been revised encouraged because smoking cessation may increase efficacy of
through the International Association for Study of Lung treatment and decrease the risk of complications.
Cancer (IASLC) and will be adopted by the UICC. Patients
with NSCLC shall now be staged according to the UICC
system (7th edition) and be grouped into the stage categories
first-line treatment
shown in Tables 1 and 2.
 Platinum-based combination chemotherapy prolongs
survival, improves quality of life, and controls symptoms in
treatment of stage IV NSCLC patients with a good performance status (PS) [I, A].
Recommended third-generation agents include vinorelbine,
Decisions on the treatment strategy should take into account gemcitabine, taxanes, irinotecan and pemetrexed (non-
disease, histology, age, performance status, comorbidities and squamous histology only).
patients preferences. Generally, treatment should be initiated  Pemetrexed is preferred to gemcitabine in patients with non-
squamous histology according to a survival benefit
Table 1. TNM classification
demonstrated in a pre-planned subgroup analysis of one large
randomized clinical trial [II, B].
TX Positive cytology only  According to results of several meta-analyses, non-platinum-
T1 3 cm based combination chemotherapy of third-generation agents
T1a 2 cm can be considered if platinum therapy is contraindicated.
T1b >23 cm Most trials show lower response rates for non-platinum
T2 Main bronchus 2 cm from combinations but similar survival rates [I, A].
carina, invades visceral  Several meta-analyses showed higher response rates for
pleura, partial atelectasis
cisplatin combinations when compared with carboplatin
T2a >35 cm
combinations. Overall survival was significantly superior for
T2b >57 cm
cisplatin in the subgroup of non-squamous histologies treated
T3 >7 cm; chest wall, diaphragm,
with third-generation regimens in one meta-analysis [I, A].
pericardium, mediastinal
pleura, main bronchus
 According to two randomized clinical trials,
<2 cm from carina, total
bevacizumab may be added to a combination regimen of
atelectasis, separate paclitaxelcarboplatin or gemcitabinecisplatin in patients
nodule(s) in same lobe with tumours of non-squamous histology and PS01.
T4 Mediastinum, heart, great Prolongation of survival has only been demonstrated for the
vessels, carina, trachea,
Table 2. Stage grouping
oesophagus, vertebra;
separate tumour nodule(s)
in a different ipsilateral Stage grouping
lobe Occult carcinoma TX N0 M0
N1 Ipsilateral peribronchial, Stage 0 Tis N0 M0
ipsilateral hilar Stage IA T1a,b N0 M0
N2 Subcarinal, ipsilateral Stage IB T2a N0 M0
mediastinal Stage IIA T2b N0 M0
N3 Contralateral mediastinal T1a,b N1 M0
or hilar, scalene or T2a N1 M0
supraclavicular Stage IIB T2b N1 M0
M1 Distant metastasis T3 N0 M0
M1a Separate tumour nodule(s) in Stage IIIA T1a,b, T2a,b N2 M0
a contralateral lobe; pleural T3 N1, N2 M0
nodules or malignant T4 N0, N1 M0
pleural or pericardial Stage IIIB T4 N2 M0
effusion Any T N3 M0
M1b Distant metastasis Stage IV Any T Any N M1

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clinical practice guidelines
paclitaxelcarboplatin combination. Careful patient selection
in view of specific toxicities related to bevacizumab is
mandatory [II, C].
 One large randomized clinical trial showed a survival benefit
with the addition of cetuximab to a combination of
vinorelbinecisplatin in EGFR-protein-expressing patients
with PS02 independent of histology [II, B].
 First-line treatment with a TKI (erlotinib or gefitinib), is an
option in patients with tumours harbouring an activating
EGFR mutation in Exon 19 and/or 21 [III, B].
 To date, other molecular markers (except for activating
EGFR mutation for consideration of first-line use of
gefitinib and erlotinib) should not be used for treatment
decisions.
 In elderly patients and PS2 patients, single-agent
chemotherapy is the preferred option. Selected elderly
patients with good PS, or PS2 patients may be
offered combination chemotherapy. According to
subgroup analyses of large randomized trials, selected elderly
patients have the same overall survival benefit from platinum
doublets as younger patients at the cost of increased toxicity
[II, B].
 Timing and duration of palliative first-line treatment:
chemotherapy should be initiated while the patient is in
a good performance status. In most patients three or
four cycles should be administered. In responding
patients, a maximum of six cycles should not be exceeded
[II, B].
 The role of maintenance treatments [tested agents are
docetaxel, pemetrexed (non-squamous histologies), erlotinib]
is not definitively established; treatment decisions have to be
made on an individual basis. Survival benefits were observed
in phase III trials for pemetrexed and erlotinib in patients
with response or stable disease to first-line therapy; the
superiority of immediate maintenance therapy versus delayed
therapy is not proven.
 Poor performance status (PS34) patients should be offered
best supportive care [II, B]. In PS3 patients with EGFR-
mutated NSCLC TKI treatment (erlotinib or gefitinib) may
be justified [V, D].
second-line/third-line therapies
Second-line treatment improves disease-related symptoms
and survival in patients with PS02 [docetaxel, pemetrexed
(non-squamous histology only), gefitinib]; the same is
true for erlotinib in second-line patients who cannot
tolerate chemotherapy and third-line patients with PS03
[I, A].
Second-line combination regimens have demonstrated
higher response and progression-free survival but no
improvement of overall survival compared with single-agent
treatments in a recent meta-analysis [I, A].
response evaluation
Response evaluation is recommended after two to three cycles
of chemotherapy by repetition of the initial radiographic tests
showing tumour lesions.
v118 | DAddario et al.
Annals of Oncology
role of surgery and endoscopy
In certain situations surgery and endoscopic techniques should
be considered with palliative intention. These situations include:
 recurrent pleural effusions where talc pleurodesis represents
the standard of care; other sclerosing agents, e.g. bleomycin
or tetracycline, are less effective [II, B];
 uncontrolled intrapulmonary infection which precludes the
application of systemic antitumour therapy;
 significant local problems of a tumour (or metastasis) in
a particular location (i.e. spinal cord compression, pathologic
bone fracture);
 major airway stenosis with dyspnea or post-obstructive
infection, where endoscopic debulking by Nd-YAG laser,
cryotherapy or stent placement may be helpful;
 resection of a single metastasis in selected fit patients.
role of radiotherapy
Radiotherapy can provide rapid symptom control. Indications
are:
 pain due to chest mass, bone metastases or neural
compression;
 haemoptysis;
 cough and dyspnoea due to local obstruction of airways;
 superior vena cava syndrome;
 spinal cord compression;
 pathologic bone fractures (or risk of bone fractures) should
be considered for postoperative radiotherapy after stabilizing.
patients with solitary metastases
(brain, adrenal, lung)
solitary brain metastasis
 Resection or stereotactic radiosurgery (SRS) are the primary
alternatives.
 The addition of whole brain radiotherapy (WBRT) to surgery
or SRS improves local control but not overall survival.
Therefore an individual assessment should be applied.
 If the primary tumour is resectable (i.e. T13 N01): surgery
with or without chemotherapy is an option in highly selected,
fit patients. Alternatively, radiotherapy or chemoradiation is
an option in selected patients with localized thoracic disease.
In other patients chemotherapy is recommended [III, C].
isolated adrenal metastasis
Systemic chemotherapy is recommended. In selected fit
patients adrenalectomy can be considered, if lung disease is
resectable as well.
lung
Solitary lesions in the contralateral lung should be considered
as secondary primary and treated with curative intention if
both tumours are potentially curable.
Volume 21 | Supplement 5 | May 2010
Annals of Oncology clinical practice guidelines
follow-up
The optimal approach to post-treatment management of
patients with NSCLC, including the role of radiological
evaluation, is controversial. Due to the often aggressive nature
of the disease, generally close follow-up is advised. Modalities,
i.e. radiographic evaluations, should also depend on individual
retreatment options.
note
Levels of Evidence [IV] and Grades of Recommendation [A
D] as used by the American Society of Clinical Oncology are
given in square brackets. Statements without grading were
considered justified standard clinical practice by the expert
authors and the ESMO faculty.
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