Screening
Screening for lung cancer in smokers using semi-annual cytological sputum analysis and/or a chest x-ray is not indicated.
Diagnostic Procedures
Patient History, Physical Examination, and Chest X-Ray
For all patients with indications of lung carcinoma, a patient history should be taken, a physical examination should be conducted and a chest x-ray should be made.
Laboratory Tests
For all patients with suspected lung carcinoma, a limited laboratory evaluation should be performed, including at least haemoglobin, calcium, albumin, sodium, lactate dehydrogenase and alkaline phosphatase. A more comprehensive laboratory evaluation is performed to assess organ function prior to treatment.
Bronchoscopy
In principle, all patients with indications of lung cancer should undergo bronchoscopy. Bronchoscopy is recommended for patients with a peripheral tumour <2 cm for staging purposes, rather than to diagnose a lesion.
Chest Computed Tomography (CT)-Scan
All patients with suspected or confirmed non-small cell lung cancer (NSCLC) should be considered for a CT scan of the chest and upper abdomen, unless surgery, radiotherapy or chemotherapy is not being considered. Performing the CT scan before bronchoscopy is recommended.
Transthoracic Lung Puncture
For patients with a lung lesion suspected of malignancy, transthoracic lung puncture should be performed if the results could affect further management.
Pleural Effusion
Aspiration of pleural effusion should occur in patients without distant metastases. Puncturing should be repeated no more than twice if the result is negative.
If the cytological assessment of the pleural effusion is negative, supplemental thoracoscopy and possibly guided biopsy can be performed, provided that the outcome may affect further management.
Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)
Patients with NSCLC who are deemed candidates for intentionally curative surgery should undergo FDG-PET scan after conventional evaluation for metastatic disease and before mediastinoscopy.
See also the recommendations for mediastinoscopy.
Mediastinoscopy
During cervical mediastinoscopy, sufficient biopsies should be taken from at least 4 of the 6 accessible lymph node stations, namely 2 ipsilateral stations, 1 contralateral station and node station 7.
Cervical mediastinoscopy should be performed in patients with (signs of) NSCLC in whom no extrathoracic metastases are found, and in whom CT and/or FDG-PET scans show evidence of lymph node involvement.
The imaging-based criteria that suggest (mediastinal) lymph node involvement are (a) at least one lymph node with a short-axis diameter >1 cm on the CT scan or (b) a focus of increased activity in the hilus or mediastinum on the FDG-PET scan.
In patients with a negative mediastinal FDG-PET scan, mediastinoscopy can be omitted provided that the following 4 criteria are met:
- There is clear uptake of FDG in the primary tumour
- There is no evidence of hilar metastases on the PET scan
- The tumour is not close to the mediastinum
- The short-axis diameters of the nodes visible on the CT scan are less than 1 cm
Endoscopic Ultrasound (EUS) with Needle Puncture
The value of EUS with fine-needle aspiration (FNA) lies mainly in detecting mediastinal lymph node metastases (particularly on the left side or in the lower mediastinum) and possibly in determining whether central tumours are unresectable (T4) (see the original guideline document for the tumor/node/metastasis [TNM] staging definitions).
Although the definitive role of EUS-FNA in lung carcinoma is under investigation, this procedure can be considered for:
- Analysis of PET-positive lesions that are suspected of N2 or N3 lymph node metastases
- Mediastinal restaging following chemotherapy
- Evidence of T4 mediastinum for central tumours on the left side
Treatment Criteria
Criteria for Medical (In)operability
Age
For patients aged 70 to 80 years, it appears that the increased surgical risk due to age is not a reason to withhold lung surgery. It is advised that these patients are evaluated for lung surgery in accordance with the recommendations listed below with extra attention given to comorbidity and general condition. Caution is warranted, however, when considering right-side pneumonectomy.
Resection should also be considered as a possible treatment modality for patients aged more than 80 years without relevant comorbidity and in good condition, provided that the doctor and patient find the surgical risk acceptable.
Cardiovascular Evaluation
Before surgery, cardiac disorders such as coronary disease, heart failure, valve disease and rhythm disorders should be detected through patient history, physical examination and ECG.
If lung surgery is planned for a patient with (signs of) heart disease, a cardiologist or an anaesthesiologist should assess the perioperative risk and advise on the perioperative protocol.
Lung Function
The surgical risk is not considered increased if the forced expiratory volume in one second (FEV1) and the diffusion capacity (TLCO) are both >80% and there is no unforeseen exertional dyspnoea.
If these criteria are not met, it is advised to calculate the predicted postoperative lung function using the calculation method (perfusion scan with left-right proportion and, for lobectomy, supplemented with the segment method).
If the operability of the patient is questioned based on the lung function assessment and/or the patient history (unforeseen exertional dyspnoea), an exertion test that includes determination of the maximum oxygen uptake (VO2max) is advisable.
Use of the flowchart in Figure 2.1 in the original guideline document is recommended for the evaluation of perioperative risk.
General
Before surgery, it should be determined what maximum degree of parenchymal resection is prudent.
For patients with an increased surgical risk, alternatives such as limited resection or chemotherapy and/or radiotherapy should be weighed against the increased risk of surgery in a multidisciplinary consultation.
Intraoperative Assessment of the Type of Resection and Resectability
For operable patients with NSCLC in whom tumour growth is limited to one lobe, lobectomy is the treatment of choice. Intentionally curative radiotherapy is a good alternative if the surgical risk is determined to be (too) high.
Patients in whom lung function is so limited that lobectomy is not possible may be considered for segment resection (preferred) or wedge excision if complete resection using this method is possible.
In principle, if the lung tumour has spread from one lobe to another, a lobectomy plus a wedge resection of the other lobe should be performed. For central tumours, bilobectomy or pneumonectomy may be an option.
If a conventional lobectomy is not possible due to tumour growth up to or past the level of the bronchial ostium, a sleeve lobectomy is advisable because complete resection is possible with this technique even when lung function precludes pneumonectomy.
A sleeve resection of the pulmonary artery should be performed only if the patient cannot tolerate pneumonectomy due to lung function.
If there is tumour growth in the direction of the thoracic wall and it is questionable whether the tumour has spread through the parietal pleura, one should immediately opt for including the affected thoracic wall en bloc.
If during surgery it appears that the tumour has spread to the intrapericardially positioned portion of the pulmonary artery, it is often possible to conduct a pneumonectomy.
If during surgery it appears that the tumour has spread to or into the main carina, which precludes a conventional pneumonectomy, a sleeve lobectomy may be attempted. If this is not possible, it should be immediately ascertained whether a sleeve pneumonectomy can be performed on the right side. On the left side, a sleeve pneumonectomy can occur in 2 phases. Referral to a treatment centre is indicated.
If during surgery it appears that the tumour is growing into the vena cava superior, the adventitia of the aortic wall, the pericardium or the diaphragm, primary resection should not be ruled out a priori.
If during surgery it appears that the tumour is growing into the spinal column or into the left atrium substantially, it is seldom resectable.
If during surgery it appears that the tumour is growing into the pulmonary trunk or through the entire aortic wall or has led to pleuritis carcinomatosa, it is unresectable. This likely holds true also for spread to the oesophagus.
If during surgery it appears that there are more tumours present in one lobe, lobectomy is performed. If multiple tumours are present in different lobes (M1), primary resection is an option.
Requirements for Intraoperative Staging
If before surgery there is no known tissue diagnosis, intraoperative frozen section assessment of the tumour is recommended before proceeding to lung resection.
Intraoperative frozen section assessment is recommended if macroscopic findings of lymph nodes provide reason for it (indications of extranodal growth or bulky disease). This is applicable if the result of the assessment can influence the surgical procedure (lung resection and/or mediastinal lymph node dissection).
For central tumours, intraoperative frozen section assessment of the bronchial resection field is recommended, unless a positive result would have no influence on the surgical procedure. Regardless of the location of the tumour, all intrapulmonary and hilar lymph nodes (N1 node stations 10, 11 and 12) should be removed en bloc with the resected section if possible.
Regardless of the location of the tumour, all intrapulmonary and hilar lymph nodes (N1 node stations 10, 11 and 12) should be removed en bloc with the resected section if possible.
To determine the status of mediastinal lymph nodes (N2 stations), at least the lymph node stations to which the tumour preferably drains should be systematically sampled during surgery.
Specifically, this implies for tumours of the
- Right upper and middle lobe: node stations 2R, 4R and 7
- Right lower lobe: node stations 4R, 7, 8 and 9
- Left upper lobe: node stations 5, 6 and 7
- Left lower lobe: node stations 7, 8 and 9
Requirements for Surgical Documentation
Following an operation for NSCLC, the surgical documentation should contain:
- Surgical approach (thoracotomy, sternotomy, etc)
- Tumour location, size, extent and distance from the main carina
- Presence or absence of satellite lesions and metastases in other lobes
- Lymph node stations (extranodal growth) and surgical technique used to evaluate mediastinal lymph nodes
- Presence and characteristics of pleural effusion; pleural lavage (duration and method), if applicable
- Result of frozen section assessment, if performed
- Distance between the tumour and the resection field, particularly the bronchial resection field
- Radicality of the resection (R0, R1 or R2)
- Placement of clips to demarcate the resection field, if applicable
- Perioperative consultation with other specialists
- Complications, if applicable
- Conclusion: procedure performed and intraoperative staging
Requirements for Pathological Documentation
The pathology report should include at least all evidence that allows for indisputable conclusions regarding staging (pTNM stage) and the completeness of resection.
The recommendation for pathological reporting calls for the use of a checklist (see appendix 17 in the original guideline document ).
Removed lymph nodes should be assessed using hematoxylin and eosin (HE) staining and immunohistochemical techniques.
Treatment
Resectable NSCLC
Postoperative radiotherapy is recommended if pathological assessment reveals involvement of the resection field. Postoperative radiotherapy should be considered for unexpected pN2 (possibly also pN3). The chance of improved local control should be weighed against the risk of radiotherapy-associated morbidity.
Postoperative radiotherapy is not indicated for pN0-1 nodes with R0 resection.
Locally Advanced NSCLC
Patients with locally advanced NSCLC (clinical stage III, based on cT4 and/or cN2-3) should be treated with combination therapy with curative intent. Exceptions include patients with World Health Organization (WHO) performance status 2, pleuritis carcinomatosa, extensive tumour invasion (requiring a radiotherapy field that would be too large with respect to lung function) or contralateral supraclavicular lymph node involvement.
Standard combination therapy consists of chemotherapy and radiotherapy. The value of surgery in this setting, particularly for stage IIIA N2 disease, has not yet been confirmed.
Radiotherapy is given at a biological equivalent of at least 60 Gy over 6 weeks.
At this time, chemotherapy is preferably given sequentially before radiotherapy. In accordance with the recommendations for advanced NSCLC, induction chemotherapy consists of 2 to 4 cycles of cis- or carboplatin in combination with a third generation cytostatic agent.
Chemotherapy can be given concomitantly with radiotherapy in selected patients provided that the associated increased risk of toxicity appears acceptable. For concomitant chemoradiotherapy, the chemotherapy regimen used is preferably one that has been used in published studies, such as cisplatin-containing chemotherapy in combination with vinca alkaloids, with or without mitomycin.
Superior Sulcus Tumors
For patients with locally advanced superior sulcus NSCLC and a WHO performance status 0-1, standard treatment consists of a multimodality approach using chemoradiotherapy and/or surgery. On the one hand, superior sulcus tumours can be considered the same as any other NSCLC. On the other hand, a more aggressive approach is justified, given the location and symptoms that are often difficult to treat if local control is not achieved.
For patients with a superior sulcus tumour that does not appear to be primarily resectable (stage cIII), sequential or concurrent chemoradiotherapy is advisable, in accordance with the recommendation for other NSCLC patients with stage III disease. If it is later determined that the tumour is in fact small enough to be resected, surgery can be considered for selected patients.
Treatment of patients with a superior sulcus tumour should occur in a specialised treatment centre.
Stage IIIB/IV
Chemotherapy Versus Supportive Care
For patients with stage IIIB/IV NSCLC and a WHO performance status 0-1, treatment should consist preferably of best supportive care and chemotherapy.
Choice of Chemotherapy
For patients with stage IIIB/IV NSCLC and WHO performance status 0-1, best supportive care and chemotherapy, consisting of cisplatin or carboplatin in combination with a third generation cytostatic agent, is preferred.
Age >70 Years
For patients aged more than 70 years with stage IIIB/IV NSCLC and WHO performance status 0-1, chemotherapy is preferred; comorbidity should be taken into account.
Number of Chemotherapy Cycles
For patients with stage IIIB/IV NSCLC and WHO performance status 0-1, 3 to 4 cycles of chemotherapy is preferred; fewer may be given in the event of disease progression or severe toxicity.
Second-Line Treatment
For patients with stage IIIB/IV NSCLC and WHO performance status 0-1 with progression following first-line chemotherapy, best supportive care is preferred; additionally, patients may be considered for second-line chemotherapy.
Follow-Up
Routine follow-up after treatment for patients with NSCLC should consist of patient history, physical examination and possibly chest x-ray.
More intensive follow-up (additional imaging, tumour marker assessment, bronchoscopy) should occur only in the context of a study protocol or in a training or academic setting.
The study group recommends the following with regard to the frequency of follow-up (alternating though different clinicians if desired):
- For the first year: every 3 months
- For the second year: every 6 months
- After the second year: annually for a minimum of 5 years
Diagnosis of Metastases
Patients with clinical stage III NSCLC must undergo skeletal scintigraphy (unless PET scan was performed and was negative) and CT or magnetic resonance imaging (MRI) of the brain to avoid unnecessary combination therapy.
Organisation of Care
Maximum Acceptable Waiting Time
The study group recommends the following maximum acceptable waiting times:
- General practitioner: 80% within 2 working days, maximal 3 working days
- Pulmonologist: 80% within 5 working days for evidence of a lung tumour or abnormal chest image
- Diagnosis (CT scan, bronchoscopy with pathological anatomy (PA), PET, mediastinoscopy): 80% with 3 weeks
- PA: the result of the PA test should be known within 1 week unless hindered by special processing
- Curative therapy: 80% within 2 weeks after the diagnosis is made
- Palliative therapy: 80% within 1 week
Eighty percent of patients should be through the diagnostic trajectory within 3 weeks. Within 5 weeks is acceptable if mediastinoscopy is conducted.
If indicated, 80% of patients should undergo surgery and/or (the preparation for) radiotherapy and/or start chemotherapy within 2 weeks after the completion of the diagnostic trajectory.
Treatment Consultation and Reporting
All new patients should be discussed during a multidisciplinary (lung) oncology review.
Referral
A lung surgery centre should meet the requirements set for academic institutions for lung surgery as described in the report of the Interdisciplinary Committee on Lung Surgery (Interdisciplinaire Commissie Longchirurgie).
A treatment centre should be consulted in the following situations:
- cT3 or cT4 disease
- Increased pulmonary of cardiac comorbidity
- Use of combined treatment modalities
As a minimum, a treatment centre should provide the support of pulmonologists, radiation oncologists, (thoracic) surgeons, clinical pathologists, radiologists and specialised nurses, in accordance with the requirements set by the relevant professional societies.
A treatment centre should have a minimum of two specialists in each discipline to ensure continuity.
A treatment centre should offer consultation to clinicians in other hospitals.
Psychosocial Care
Prevalence
Based on the prevalence of psychosocial problems in patients with lung cancer, the care providers involved should inquire about anxiety and depression in every patient with lung cancer.
Interventions
From the beginning and throughout all phases of diagnosis and treatment, medical specialists, general practitioners and/or (oncology) nurses should be educated to inquire about and treat physical symptoms because prompt medical and/or behavioural therapy for these symptoms may promote psychosocial functioning and quality of life.
From the beginning and throughout all phases of diagnosis and treatment, medical specialists, general practitioners and/or (oncology) nurses should inquire about psychosocial stress factors and psychological symptoms because prompt treatment may promote improved psychosocial functioning and quality of life.
An (oncology) nurse should be involved in the process of care because he or she is an integral link in the chain of treatment, care and early signalling of somatic and psychological symptoms.
Care providers should pay attention to psychosocial problems in family members and/or others close to the patient.
Organisation
General practitioners, medical specialists and (oncology) nurses should be aware that basic psychosocial care must be offered from the initial phases of diagnosis and treatment for NSCLC. This care consists of customised education, adequate handling and temporary admission if necessary.
Good psychosocial care requires the availability of adequate referral options to care providers who are trained to address the psychosocial needs of cancer patients, such as nursing specialists, social workers (associated with the hospital), psychologists, psychiatrists and/or specific patient programmes (discussion groups, relaxation groups, rehabilitation programmes, patient associations).
