Primary lung cancer (hereinafter referred to as lung cancer) is one of the most common malignant tumors in China. In order to further standardize the diagnosis and treatment of lung cancer in China, the Medical Administration of the National Health and Family Planning Commission has entrusted the China Anti-Cancer Association Clinical Chemotherapy Committee to develop the 2015 version of the primary lung cancer diagnosis and treatment standard on the basis of the “Primary Lung Cancer Diagnosis and Treatment Standard (2011 Edition)” of the former Ministry of Health.
Diagnosis
1. Clinical manifestations
When the disease develops to a certain extent, the following symptoms often appear: irritating dry cough, blood in sputum or bloody sputum, chest pain, fever, shortness of breath. When lung cancer invades the surrounding tissues or metastases, corresponding symptoms of metastases may appear, such as hoarseness of voice when invading the laryngeal nerve, and the syndrome of superior vena cava obstruction such as facial and neck edema when invading the superior vena cava.
2. Physical examination
Most patients with early stage lung cancer do not have obvious positive signs. When the disease has progressed to a certain extent, extra-pulmonary signs of unknown causes and persistent treatment may appear, such as pestle and mortar finger (toe), non-wandering joint pain, male breast enlargement, skin darkening or dermatomyositis, ataxia and phlebitis.
3. Laboratory tests
Commonly recommended markers for primary lung cancer include carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1) and gastrin-releasing peptide precursor (ProGRP), and squamous epithelial cell carcinoma antigen (SCC).
NSE and ProGRP are ideal indicators for the diagnosis of small cell lung cancer (SCLC); elevated levels of CEA, SCC, and CYFRA21-1 contribute to the diagnosis of non-small cell lung cancer (NSCLC).
It is recommended that patients should have their tumor markers tested every 3 months for 1 to 3 years after the start of treatment, every 6 months for 3 to 5 years, and annually after 5 years. If tumor markers are found to be significantly elevated (more than 25%) during the follow-up, they should be retested within 1 month, and if they are still elevated, it indicates possible recurrence or metastasis.
4. Imaging examination
Chest X-ray is the basic imaging examination method before and after lung cancer treatment.
Low-dose spiral CT (LDCT) is 4 to 10 times more sensitive than conventional chest X-ray in detecting early lung cancer, and can detect early peripheral lung cancer, which is the most effective screening tool for lung cancer.
MRI is particularly suitable for determining whether there are metastases in the brain and spinal cord, and brain-enhanced MRI should be used as a routine preoperative staging examination for lung cancer.
PET-CT is the best method for lung cancer diagnosis, staging and re-staging, efficacy evaluation and prognosis assessment, and is recommended for those who have the conditions.
5. Endoscopic examination
Transbronchial lung biopsy (TBLB): suitable for the diagnosis of peripheral lung lesions (PPL) in the outer and outer 2/3 of the lung.
Mediastinoscopy: the current gold standard for clinical evaluation of the status of mediastinal lymph nodes in lung cancer.
Thoracoscopy: accurate diagnosis and staging of lung cancer, providing a reliable basis for the development of a comprehensive treatment plan and individualized treatment plan.
Combined application of bronchoscopy under direct vision, biopsy, needle aspiration and bronchial lavage to obtain cytological and histological diagnosis can improve the detection rate.
6. Other related tests
Sputum cytology, thoracentesis, pleural biopsy, biopsy of superficial lymph nodes and subcutaneous metastatic nodes.
Staging
1. NSCLC: The International Association for the Study of Lung Cancer 2009 7th edition staging criteria (IASLC 2009) were used.
2. SCLC: The American Legion Lung Cancer Association’s staging methods for limited and extensive stages were used for patients undergoing non-surgical treatment, and the IASLC 2009 7th edition staging criteria were used for patients with limited stage SCLC undergoing surgery.
Treatment
1. Surgical treatment
Indications
(1) Stage I, II and part of stage IIIA (T1~2N2M0; T3N1~2M0; T4N0~1M0 completely resectable) NSCLC and stage I SCLC (T1~2NOM0). (2) Some stage IV NSCLC with solitary contralateral lung metastasis, solitary brain or adrenal metastasis.
(3) Intrapulmonary nodules with high clinical suspicion of lung cancer, which cannot be diagnosed qualitatively by various examinations, may be surgically explored.
Contraindications
(1) Those with poor general condition, and those whose heart, lung, liver, kidney and other important organ functions cannot tolerate surgery.
(2) Most of the stage IV, most of the stage IIIB and some of the stage IIIA NSCLC with a clear diagnosis.
Anatomical pneumonectomy
It is the main treatment for early stage lung cancer. Lung cancer surgery is divided into complete resection, incomplete resection and indeterminate resection. Complete resection of the tumor and regional lymph nodes is achieved as much as possible, while preserving as much functional normal lung tissue as possible. In the absence of contraindications to surgery, television-assisted thoracoscopic surgery (VATS) and other minimally invasive means are recommended.
Indications for anatomic segmental lung resection or pulmonary wedge resection.
(1) Patients with advanced age or low lung function, or at major risk for lobectomy.
(2) CT suggestive of an intrapulmonary peripheral lesion (defined as a lesion located in the outer third of the lung parenchyma and ≤ 2 cm in diameter with one of the following features: pathologically confirmed adenocarcinoma; CT follow-up of more than 1 year with high suspicion of cancer; CT suggestive of a solid component ≤ 50% in a ground glass shadow.
(3) Excision of lung tissue with a cut edge ≥ 2 cm from the lesion margin or a cut edge distance ≥ lesion diameter, with a negative cut edge on intraoperative rapid pathology.
(4) Systematic sampling of hilar and mediastinal lymph nodes should be performed before deciding on sublobar resection.
Complete resection (R0 surgery)
In addition to complete resection of the primary lesion, systematic resection of all groups of hilar and mediastinal lymph nodes (N1 and N2 lymph nodes) should be routinely performed.
It is recommended that the right thoracic lymph nodes be removed from 2R, 3a, 3p, 4R, 7-9 groups of lymph nodes and surrounding soft tissue, and the left thoracic lymph nodes be removed from 4L, 5-9 groups of lymph nodes and surrounding soft tissue.
2. Radiation therapy
Indications
Radical radiotherapy: for patients with Karnofsky functional status score ≥ 70, including early-stage NSCLC, unresectable locally advanced NSCLC and limited-stage SCLC that are inoperable due to medical or (and) personal factors.
Palliative radiotherapy: indicated for symptom reduction for both primary and metastatic foci of advanced lung cancer. Postoperative whole-brain radiotherapy is available for patients with surgically resected solitary brain metastases from NSCLC, and chest radiotherapy for extensive stage SCLC.
Adjuvant radiotherapy: Indicated for patients with preoperative radiotherapy, positive postoperative radiotherapy margins (R1 and R2); patients with inadequate surgical exploration or close surgical margins; for patients with positive postoperative pN2, participation in clinical studies of postoperative radiotherapy is encouraged.
Prophylactic radiotherapy: Applicable to whole brain radiotherapy for SCLC patients with effective systemic therapy.
For patients with inoperable stage IIIA and IIIB disease, EP (pegylated glycosides + cisplatin), NP (vincristine + cisplatin) and paclitaxel-containing regimens are recommended. If the patient cannot tolerate the treatment, sequential radiotherapy can be administered.
Radiotherapy for NSCLC
When patients with stage I NSCLC are medically unsuitable for surgery or refuse surgery, large fractionated radiation therapy is an effective radical treatment and stereotactic body radiation therapy (SBRT) is recommended. The principle of fractionation should be high dose, few fractions, and short treatment course.
For NSCLC patients who undergo surgery, if the postoperative pathology is negative for surgical margins but positive for mediastinal lymph nodes (pN2 stage), it is recommended to add postoperative radiotherapy in addition to conventional postoperative adjuvant chemotherapy, and if the patient is physically able, it is recommended to use simultaneous postoperative radiotherapy.
For patients with stage II-III NSCLC who cannot undergo surgery for medical reasons, conformal radiotherapy combined with concurrent chemotherapy should be given if physically possible.
For patients with stage IV NSCLC with extensive metastases, some patients can receive radiation therapy for both primary and metastatic foci for palliative reduction. SBRT may be considered for the treatment of residual primary and/or oligometastases for potential curative effect when there is significant benefit from systemic therapy.
Radiotherapy for SCLC
A combination of radiotherapy and chemotherapy is the standard of care for limited-stage SCLC. Patients with limited-stage SCLC are recommended to undergo concurrent chemoradiotherapy with initial treatment or 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy. Prophylactic brain irradiation is recommended after complete remission of intrathoracic lesions, as well as for patients who have achieved partial remission.
In patients with extensive SCLC, the addition of thoracic radiotherapy after control of distant metastases with chemotherapy can also improve tumor control rate and prolong survival. Prophylactic brain irradiation can also reduce the risk of brain metastasis in SCLC when chemotherapy is effective.
The recommended time for prophylactic brain irradiation is about 3 weeks after the completion of all chemoradiotherapy and should be preceded by an enhanced brain MRI to exclude brain metastases.
3. Drug treatment
(1) Indications for chemotherapy: Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 2, and vital organ function can tolerate chemotherapy, for SCLC chemotherapy, PS score can be relaxed to 3.
(2) Treatment of NSCLC: platinum-containing two-drug regimens are the standard first-line chemotherapy regimens, which can be combined with vascular endothelial inhibitors on top of chemotherapy; patients with EGFR gene-sensitive mutations or ALK fusion gene-positive patients can be targeted with targeted drug therapy (see Tables 1 and 2).
Table 1 Common first-line chemotherapy regimens for non-small cell lung cancer
Chemotherapy regimen
Dose (mg/m2)
Dosing time
Duration and cycle
NP: Vincristine
25
d1,d8
q21d*4-6
Cisplatin
75-80
d1
TP: Paclitaxel
135-175
d1
q21d*4-6
Cisplatin
75
or 25
d1
d1-3
or carboplatin
AUC = 5-6
d1
GP: Gemcitabine
1000-1250
d1,d8
q21d*4-6
Cisplatin
75
or 25
d1
d1-3
or carboplatin
AUC = 5-6
d1
DP: Docetaxel
75
d1
q21d*4-6
Cisplatin
75
or 25
d1
d1-3
or carboplatin
AUC = 5-6
d1
AP: Pemetrexed (non-squamous carcinoma)
500
d1
q21d*4-6
Cisplatin
75
or 25
d1
d1-3
or carboplatin
AUC = 5-6
d1
Table 2 Anti-angiogenic drugs and targeted therapeutics commonly used in non-small cell lung cancer
Anti-angiogenic drugs
Dose
Duration of drug administration
Time
Vascular endothelial inhibitor
15 mg
d1-14
q21d
Targeted drug
Dose
Dosing time
Gefitinib
250 mg
qd
Erlotinib
150 mg
qd
Ectatinib
125 mg
tid
Crizotinib
250 mg
bid
(3) Treatment of SCLC: A combination of chemotherapy, surgery and radiotherapy is recommended for patients with limited stage SCLC. The first-line chemotherapy regimen is EP or EC (pegylated glycosides + carboplatin).
Chemotherapy-based combination therapy is recommended for patients with extensive SCLC. First-line chemotherapy regimens are EP, EC, or IP (cisplatin + irinotecan) or IC (carboplatin + irinotecan) (see Table 3).
Table 3 Common chemotherapy regimens for small cell lung cancer
Chemotherapy regimen
Dose (mg/m2)
Duration of dosing
Duration and period
EP: Podophyllin
100
d1-3
q21d*4-6
Cisplatin
75-80
d1
EC: Podophyllin
100
d1-3
q21d*4-6
Carboplatin
AUC = 5-6
d1
IP: Irinotecan
60
d1,d8,d15
q21d*4-6
Cisplatin
IP: Irinotecan
60
65
d1
d1,d8
q21d*4-6
q28d*4-6
Cisplatin
30
d1,d8
IC: Irinotecan
Carboplatin
50
AUC = 5
d1,d8,d15
4. Palliative care
All lung cancer patients should receive symptom screening, evaluation and treatment in palliative medicine throughout.
The symptoms to be screened include both common physical symptoms such as pain, dyspnea and fatigue, and also psychological problems such as sleep disturbance and anxiety and depression. Pain and dyspnea are the most common symptoms that affect the quality of life of lung cancer patients.
(1) Pain: The patient’s complaints are the gold standard for pain assessment, and the numerical pain grading method is preferred; children or elderly people with cognitive impairment can use the face method. Pain intensity is divided into 3 categories, i.e. mild, moderate and severe pain.
The WHO three-step pain relief principle is still the most basic principle of cancer pain treatment, which includes the following five main aspects: ① Preferred oral administration. ①Preferred oral administration (3) Timely administration of medication. ④Individualized treatment. ⑤ Pay attention to details.
(2) Dyspnea: The patient’s complaint is the gold standard for diagnosis. To get rid of reversible etiology as much as possible, anti-tumor and anti-infection treatment can be given in a targeted manner; bronchodilators and glucocorticoids are given for chronic obstructive pulmonary disease. Morphine is the drug of choice, and it is recommended to start with small doses, administered on time, slowly increasing the dose, closely observing and preventing side effects.
Monitoring and follow-up
For new lung cancer patients, a complete medical case and related data file should be established, and regular follow-up and corresponding examination should be conducted after diagnosis and treatment. Specific examination methods include medical history, physical examination, blood biochemistry and blood tumor marker examination, imaging examination and endoscopy, etc., aiming at monitoring disease recurrence or treatment-related adverse reactions and assessing quality of life.
The frequency of follow-up for postoperative patients was every 3-6 months for 2 years, every 6 months for 2-5 years, and every year after 5 years.