I. Diagnosis.
1. Obtain sufficient tissue for histological diagnosis and molecular testing to determine an individualized treatment plan.
2. Pathological diagnosis is made according to WHO classification and IASLC/ATS/ERS adenocarcinoma classification.
Definition of NSCLC subtypes is necessary for treatment decision making, and subtypes should be defined whenever possible.
4. Immunohistochemistry (IHC) should be used to reduce the NSCLC-NOS rate to less than 10% of diagnosed cases.
5, Epidermal growth factor receptor (EGFR) mutation status in patients with non-squamous progressive NSCLC should be systematically analyzed [I, A]. The assay should cover relevant mutations.
6. (Molecular) testing is not recommended for patients with confirmed squamous cell carcinoma, unless they are non-smokers and former small smokers (less than 15 packs per year) [IV, A].
7, Patients with non-squamous progressive NSCLC should be systematically tested for mesenchymal lymphoma kinase (ALK) rearrangement [II, A].
8, Fluorescence in situ hybridization (FISH) for detection of ALK translocation remains the standard protocol, but IHC may be useful for screening negative cases.
9, If possible, parallel detection of molecular abnormalities is more appropriate. Sequential testing may delay treatment.
10. A repeat tissue biopsy should be considered in cases of disease progression.
II. Staging and risk assessment.
1. A complete history should include a history of smoking, comorbidities, weight loss, physical status (PS), and physical examination.
2. Laboratory tests: standard tests including routine blood, liver and kidney function, and bone biochemical tests are required. Routine serum markers such as carcinoembryonic antigen (CEA) are not recommended.
3. Enhanced CT scan of the chest and upper abdomen should be performed.
4. Patients with neurological symptoms or indications should undergo central nervous system (CNS) imaging.
5. MRI is more sensitive than CT scan.
6. Local bone imaging is required when clinically suspicious bone lesions are present and cannot be evaluated on CT scan. Bone scan helps to detect systemic bone metastases.
7. PET-CT scan has the highest sensitivity and is recommended for the evaluation of mediastinal lymph node metastases and distant metastases.
8. The staging categories summarized according to the AJCC/UICC system (7th edition) for NSCLC are shown in Tables 1 and 2. Focal measurements should follow the efficacy evaluation criteria for solid tumors (RECIST) version 1.1.
9. When a single metastasis is found on imaging, cytologic or histologic evidence of stage IV disease should be obtained as much as possible.
10. For solitary brain metastases, adrenal lesions, and oligometastases confined to the lungs, assessment of the appropriateness of surgery or radical radiotherapy for curative purposes should be performed: cardiopulmonary function assessment, brain imaging, PET, and mediastinal lymph node assessment if necessary to determine treatment options.
III. Treatment strategy.
1. Treatment strategy should take into account histology, molecular pathology, age, PS, comorbidities, and patient wishes.
2. The treatment plan should be discussed in a multidisciplinary oncology treatment (MDT) committee.
3. All stage IV patients with PS of 0-2 should receive systemic therapy [I, A].
4. Smoking cessation should be encouraged for patients with any stage of NSCLC because it improves survival outcomes [II, A].
IV. First-line treatment.
1, The standard first-line chemotherapy is platinum-based two-drug chemotherapy [I, A].
2. In patients with nonsquamous carcinoma who receive third-generation chemotherapy regimens including gemcitabine and paclitaxel, cisplatin is the treatment of choice [I, B].
3, In patients with non-squamous cancer, pemetrexed is superior to gemcitabine or docetaxel [II, A]. The use of pemetrexed in any line of therapy should be strictly limited to non-squamous NSCLC [I, A].
4, After excluding contraindications, bevacizumab combined with paclitaxel + carboplatin regimen can be used in non-squamous NSCLC patients with PS of 0 to 1 [I, A].
5, The combination of bevacizumab and other platinum-based chemotherapy can be considered for the treatment of patients with appropriate non-squamous NSCLC [I, A].
6, Non-platinum-based combination chemotherapy containing third-generation therapeutic agents should be considered only when platinum-based therapy is contraindicated [I, A].
7. Chemotherapy should be started when the patient has good PS. Four cycles of chemotherapy are recommended for most patients, with a maximum of six cycles [II, B].
8. Chemotherapy prolongs survival and may improve quality of life (QoL) in NSCLC patients with PS of 2 compared with best supportive care (BSC) [I, B]. Single-agent chemotherapy with gemcitabine, vincristine, and paclitaxel may be an option [I, B].
9, Patients with an appropriate PS of 2 should be considered for a carboplatin-based combination chemotherapy regimen [II, A].
10, Patients without EGFR-activating (or sensitive) mutant tumors and with poor PS (3 to 4) should receive BSC [II, B].
11, Appropriate patients aged 70-89 years with PS of 0-2 and good organ function have seen a survival benefit with the application of carboplatin-based chemotherapy [I, B].
12, For other patients with progressive NSCLC without clinical screening, single chemotherapy remains the standard regimen for first-line treatment [I, B].
? The use of tyrosine kinase inhibitors (TKIs).
13, TKI (erlotinib, gefitinib, afatinib) is preferred as first-line treatment for patients with EGFR-activating (or sensitive) mutant tumors [I, A].
14, Patients with EGFR mutations and PS of 3 to 4 can also receive EGFR TKI [II, A].
15, EGFR TKI is not recommended as first-line treatment in EGFR wild-type patients, and its efficacy is secondary to chemotherapy [I, A].
16, Patients with NSCLC in the presence of ALK fusion should be treated with crizotinib during the course of the disease [I, A].
V. Maintenance therapy.
1, Maintenance chemotherapy is only used for patients with PS of 0~1 after first-line chemotherapy.
2, In patients with non-squamous carcinoma and PS of 0~1, 4 cycles of pemetrexed-converted maintenance therapy after platinum-based chemotherapy improves progression-free survival (PFS) and overall survival (OS) compared with placebo.
3, In all histologic subtypes, erlotinib conversion maintenance had PFS and OS benefit, with the greatest benefit in patients with stable disease (SD) after first-line treatment [I, B].
4, The decision to maintain therapy requires consideration of histology, efficacy of platinum doublet chemotherapy, residual toxicity after first-line chemotherapy, PS, and patient preference [I, B].
5, Continuation of pemetrexed therapy after 4 cycles of first-line cisplatin plus pemetrexed chemotherapy is recommended for patients with non-squamous cancer [I, B].
VI. Second-line treatment.
1, Patients with clinical or imaging progression after first-line chemotherapy and PS of 0-2 should receive second-line chemotherapy.
2. In second-line therapy, regimens containing pemetrexed (for non-squamous cancers only) or docetaxel (efficacy) are similar [I, B]. Erlotinib may be an additional option for patients with unknown EGFR status or EGFR wild type and PS 0-2.
3. Any patient with EGFR-activating (or sensitive) mutations in tumors that have not previously received an EGFR TKI should be treated as second-line therapy [I, A].
4. Any patient with NSCLC with ALK fusion who has not previously received crizotinib should be treated as second-line therapy [I, A].
5. If the disease is controlled and the toxicity is tolerable, the treatment can be extended [II, B].
VII. Follow-up therapy.
1, Patients with unknown EGFR status or EGFR wild-type not receiving EGFR TKI and PS of 0 to 3 can be treated with erlotinib [II, B].
2. Any patient with EGFR mutation-activated (or sensitive) tumors who has not previously received an EGFR TKI should be treated as such [I, A]. Similarly, any patient with NSCLC with ALK fusion who has not previously received crizotinib should be treated as such [I, A].
VIII. Treatment of oligometastatic focal NSCLC.
1, Patients with stage IV NSCLC with oligometastases in the brain: see the recommended approach for treatment of brain metastases.
2. Stage IV patients with 1 to 3 concurrent metastases may achieve long-term disease-free survival (DFS) after systemic therapy and local radical treatment (high-dose radiotherapy or surgery) [II, B]. Since there are only one non-randomized phase II trial results, priority (recommended patients) should be entered into clinical studies.
3. A small number of stage IV patients with non-concurrent metastases may receive local eradication therapy and achieve long-term DFS [III, B]. However, this is based on retrospective data only.
4. In most cases, a single lesion in the contralateral lung should be considered a concurrent second primary tumor and, if possible, treated with eradication [IV, B].
IX. Treatment of brain metastases.
1. Patients with RPA grade I (age <65 years, KI ≥70%, no other additional cranial metastases, and controlled primary tumor) or grade II are treated with stereotactic radiosurgery (SRS) when 2 to 3 metastases are present; SRS or resection is used when 1 brain metastasis is diagnosed [II, B]. Whole brain radiotherapy (WBRT) is recommended when more than 3 brain metastases are diagnosed [I, A].
2. Patients with RPA grade III (KI < 70%) should not be treated due to poor prognosis [I, B].
3. Asymptomatic brain metastases should not be given radiotherapy: delayed irradiation at progressive stage is an option [II, B].
4. Systemic therapy is a reasonable choice for patients with asymptomatic or relatively mildly symptomatic brain metastases; radiotherapy intervention can be given as early as possible during treatment if symptoms develop or worsen [II, B].
5. In most patients with symptomatic brain metastases and/or significant cerebral edema, dexamethasone (4 mg/d) or another corticosteroid at the same dose is recommended and tapered as early as possible after radiotherapy [II, A].
X. Interventional treatment of stage IV NSCLC.
1, Endoscopic laser reduction, cryotherapy or stent placement may be helpful in patients with symptomatic main airway obstruction or post-obstruction infection [III, C].
2, Endoscopy is helpful in the diagnosis and treatment of hemoptysis (endobronchial or by guided endovascular embolization) [III, C].
3. Vascular stenting is useful for superior vena cava compression associated with NSCLC [II, B].
XI. Palliative procedures for stage IV NSCLC.
1, Recurrent pleural effusion can be managed by pleural fixation.
2, The preferred sclerosing agent is talcum powder, which is more effective than bleomycin and tetracycline [II, B]. Thoracoscopic talc powder blow-in method is more effective than talc suspension for sclerosis [II, B].
XII. Radiotherapy.
1, Radiotherapy plays an important role in symptom control in cases of bone and brain metastases, and is also effective in treating pain associated with chest wall, soft tissue, or nerve invasion.
2, Neurological symptoms caused by spinal cord compression can be relieved by early radiotherapy.
3. Radiotherapy may be used after hemoptysis, symptomatic airway compression or obstruction, and CNS surgery and (in rare cases) bone surgery [II, B].
XIII. Drugs for the treatment of bone metastases.
1, Zoledronic acid to reduce bone-related events (SRE) (pathological fractures, bone radiotherapy/bone surgery, spinal cord compression) is recommended for stage IV bone metastatic disease [II, B].
2. Denosumab is non-inferior to zoledronic acid for SRE prevention in lung cancer and shows a trend toward superiority [II, B].
XIV. Early intervention in palliative care.
1. Early palliative care intervention is recommended in parallel with standard oncologic therapy [II, A].
XV. Efficacy assessment and follow-up.
1. Efficacy evaluation is recommended after 2-3 cycles of chemotherapy and should be performed using the same radiological imaging as the initial description of the tumor lesion.
2. Measurement and efficacy reporting should follow RECIST (version 1.1). However, the appropriateness of RECIST to assess EGFR or ALK TKI from the perspective of respective gene driven NSCLC is controversial.
3. Close follow-up, at least every 6 weeks after first-line therapy is recommended, but should depend on individual retreatment choices [III, B].
4, Imaging follow-up is considered every 6 to 12 weeks for early initiation of second-line therapy.
5. Despite the high sensitivity but relatively low specificity, PET follow-up is not routinely recommended.