Staging and risk assessment

A complete medical history with comorbidities, weight loss, performance status (PS) and physical examination must be recorded. An exhaustive smoking habit assessment has to be included, indicating type, quantity and timing.

Laboratory

Standard tests including routine haematology, renal and hepatic function and bone biochemistry tests are required. The routine use of serum markers, such as carcinoembryonic antigen (CEA), is not recommended [IV, B] [71].

The neutrophil to lymphocyte ratio (NLR) is a widely available blood-based data point, validated in numerous oncological settings as a potential prognostic marker. NLR has been considered as a potential dynamic marker but further prospective validations are needed [IV, C] [72, 73].

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. Imaging of the central nervous system (CNS) is most relevant in those patients with neurological symptoms or signs [IV, A]; however, if available, imaging of the CNS with magnetic resonance imaging (MRI, preferably with gadolinium enhancement) or CT of the brain with iodinated contrast should  be  carried  out  at  diagnosis  [IV, B]. MRI is more sensitive than CT scan [III, B] [74].

Leptomeningeal disease (LMD) is a deadly complication of solid tumours and has a poor prognosis. Adenocarcinomas are the most common tumours to metastasise to the leptomeninges. In case of clinical suspicion, LMD diagnostic imaging should include the brain and the spinal cord, as LMD can impact the entire neuraxis. If metastatic disease has been determined by CT scan of the chest and upper abdomen or by brain imaging, other imaging is only necessary if it has an impact on treatment strategy. If bone metastases are clinically suspected, bone imaging is required [IV, B]. Bone scan or positron emission tomography (PET), ideally coupled with CT, can be used for detection of bone metastasis [IV, B]. PET-CT is the most sensitive modality in detecting bone metastasis [II, B] [75]. Fluorodeoxyglucose (FDG)-PET or PET-CT has higher sensitivity and specificity than bone scintigraphy [76]. FDG-PET-CT scan also has high sensitivity for the evaluation of solitary pulmonary nodules, intrathoracic pathological lymph nodes and distant metastatic disease [77]. However, the low sensitivity of this exam in small lesions, in lesions close to FDG-avid structures (overprojection) or in lesions that move extensively, such as those just above the diaphragm, should be considered. MRI may complement or improve the diagnostic staging accuracy of FDG-PET-CT imaging, particularly in assessing local chest wall, vascular or vertebra invasion and is also effective for identification of nodal and distant metastatic disease. NSCLC is staged according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) system (8th edition) and is grouped into the stage categories shown in Tables 2 and 3 [78, 79].

Table 2: Clinical classification UICC TNM 8 [79]

   
Primary tumour (T)
TX Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visual- ised by imaging or bronchoscopy
T0 No evidence of primary tumour
Tis Carcinoma in situa
T1 Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)b
T1mi Minimally invasive adenocarcinomac
T1a Tumour 1 cm or less in greatest dimensionb
T1b Tumour more than 1 cm but not more than 2 cm in greatest dimensionb
T1c Tumour more than 2 cm but not more than 3 cm in greatest dimensionb
T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following featuresd
-Involves main bronchus regardless of distance to the carina, but without involvement of the carina
-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
T3 Tumour more than 5 cm but not more than 7 cm in greatest dimension or one that directly 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
T4 Tumour more than 7 cm or of any size that invades any of the following: diaphragm, 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
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodules or malignant pleural or pericardial effusione
M1b Single extrathoracic metastasis in a single organf
M1c Multiple extrathoracic metastasis in a single or multiple organs
aTis includes adenocarcinoma in situ and squamous carcinoma in situ.
bThe uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a.
cSolitary adenocarcinoma (not more than 3 cm in greatest dimension), with a predominantly lepidic pattern and not more than 5 mm invasion in greatest dimension in any one focus.
dT2 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 but not larger than 5 cm.
eMost pleural (pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple microscopic 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 staging descriptor.
fThis includes involvement of a single non-regional node.  
TNM, tumour, node and metastasis; UICC, Union for International Cancer Control.
Reprinted from [79] with permission from John Wiley & Sons, Inc.

Table 3: Staging and stage grouping UICC TNM 8 [79]

       
Occult carcinoma TX N0 M0
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IA1 T1mi N0 M0
T1a N0 M0
Stage IA2 T1b N0 M0
Stage IA3 T1c N0 M0
Stage IB T2a N0 M0
Stage IIA T2b N0 M0
Stage IIB T1a-c T2a,b N1 M0
T3 N0 M0
Stage IIIA T1a-c T2a,b N2 M0
T3 N1 M0
T4 N0, N1 M0
Stage IIIB T1a-c T2a,b N3 M0
T3, T4 N2 M0
Stage IIIC T3, T4 N3 M0
Stage IV Any T Any N M1
Stage IVA Any T Any N M1a, M1b
Stage IVB Any T Any N M1c

TNM, tumour, node and metastasis; UICC, Union for International Cancer Control.

Reprinted from [79] with permission from John Wiley & Sons, Inc.

In the presence of a solitary metastatic lesion on imaging studies, including pleural and pericardial effusion, efforts should be made to obtain a cytological or histological confirmation of stage IV disease [IV, A].

Response evaluation is recommended after 2–3 cycles of chemotherapy (ChT) or immunotherapy, using the same initial radiographic investigation that demonstrated tumour lesions [IV, B]. 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 [IV, B]. Follow-up with PET is not routinely recommended, due to its high sensitivity and relatively low specificity [IV, C].

Measurement of lesions should follow Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 [IV, A] [80]. The adequacy of RECIST in evaluating response to EGFR or ALK TKIs in respective genetically driven NSCLC is still debatable even if this remains the standard method of evaluation for these patients [IV, B]. In these two subgroups of patients (and in other actionable oncogene alterations), treatment beyond RECIST progression is a common approach, pursuing clinical benefit more than morphological response. This approach differs from what was carried out historically with cytotoxic agents. The conventional radiological response criteria are unable to describe pseudoprogression (PsPD) and can result in underestimation of the therapeutic benefit of immune checkpoint blockade. Several radiological criteria have been developed specifically for immunotherapy, to better define the tumour response in this context. Two-dimensional immune-related response criteria (irRC) were proposed in 2009 and modified in 2013 with the immune-related RECIST (irRECIST) [81, 82]. More recently, the RECIST working group published a proposition of new criteria called immune-RECIST (iRECIST), to standardise response assessment among immunotherapy clinical trials [83]. A subsequent adaption of RECIST designed to better capture cancer immunotherapy responses has been published: immune-modified RECIST (imRECIST) [84]. More data are needed to compare the RECIST, iRECIST, imRECIST and irRECIST to quantify the differences in outcome estimation before using of them in clinical practice. Nonconventional responses and PsPD are very rarely observed in NSCLC, ranging generally under 5% of all cases, and RECIST v1.1 should still be used in routine practice [IV, B] [85–88].

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