Treatment of lung cancer.
(I) Treatment principles
The principle of combining multidisciplinary comprehensive treatment and individualized treatment should be adopted, i.e., the multidisciplinary comprehensive treatment mode should be adopted according to the patient’s organism condition, pathological histological type and molecular typing of tumor, invasion scope and development tendency, and surgery, chemotherapy, radiotherapy and molecular targeted therapy should be applied in a planned and reasonable manner, so as to maximize the patient’s survival time, improve survival rate, control tumor The aim is to maximize the survival time, improve the survival rate, control the tumor progression and improve the quality of life of patients.
(B) Surgical treatment
1. Principles of surgical treatment: anatomical pneumonectomy is the main treatment for early-stage lung cancer and is also an important method for clinical cure of lung cancer. Lung cancer surgery is divided into complete resection, incomplete resection and indeterminate resection. We should strive for complete resection to achieve complete removal of tumor, reduce metastasis and recurrence, and perform accurate pathological TNM staging and molecular pathological staging to guide comprehensive postoperative treatment. The following surgical principles should be observed for surgically resectable lung cancer.
(1) Comprehensive treatment planning and necessary imaging (clinical staging, especially accurate N-staging) should be completed prior to surgical treatment. Adequate evaluation determines the possibility of surgical resection and develops the surgical plan.
(2) Complete resection of the tumor and regional lymph nodes should be achieved whenever possible, while preserving as much functional normal lung tissue as possible.
(3) Video-assisted thoracoscopic surgery (VATS) is a well-established minimally invasive thoracic surgical technique in recent years, and VATS and other minimally invasive methods are recommended in the absence of contraindications to surgery.
(4) Anatomic pneumonectomy (lobectomy, bronchial and vascular sleeve lobectomy or total pneumonectomy) is feasible depending on the patient’s physical condition. If physical condition does not allow, sublobar resection is performed, of which anatomic lung segmental resection is preferred and wedge resection is also feasible.
(5) Indications for anatomic segmental lung resection or wedge lung resection are.
(i) Patients with advanced age or low lung function, or at major risk for lobectomy;
(2) CT findings of intrapulmonary peripheral lesions (defined as those located in the lateral 1/3 of the lung parenchyma) with a lesion diameter ≤2 cm and one of the following characteristics: pathologically confirmed adenocarcinoma; CT follow-up of more than 1 year with high suspicion of carcinoma; CT findings of a solid component ≤50% of the ground glass shadow.
(iii) Excision of lung tissue with a cut edge ≥ 2 cm from the lesion margin or with a cut edge distance ≥ lesion diameter and a negative cut edge on intraoperative rapid pathology;
④Systematic sampling of hilar and mediastinal lymph nodes should be performed before deciding on sublobectomy. At present, the sublobar resection for early-stage lung cancer is still in the clinical research stage, and participation in clinical research is encouraged, and it cannot be promoted as a standard procedure.
(6) 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 for complete resection (R0 surgery), and the locations should be marked for pathologic examination. At least 3 mediastinal drainage areas (N2 stations) should be cleared or sampled for lymph nodes, ensuring whole lymph node resection as much as possible. It is recommended that the lymph nodes in the right chest be removed in the following areas: 2R, 3a, 3p, 4R, 7-9 groups of lymph nodes and surrounding soft tissue, and the lymph nodes in the left chest be removed in the following areas: 4L, 5-9 groups of lymph nodes and surrounding soft tissue.
(7) Normally, the pulmonary veins and pulmonary arteries should be treated sequentially intraoperatively, and the bronchi should be treated last, or the order of treatment should be decided according to the actual intraoperative situation.
(8) Bronchial sleeve lobectomy is the extent of resection performed to preserve as much lung tissue and lung function as possible under the condition of intraoperative rapid pathological examination to ensure negative margins (including bronchial, pulmonary artery or venous dissection), and the postoperative quality of life is better than that of patients undergoing total pneumonectomy.
(9) For patients with recurrence or isolated lung metastasis 6 months after complete lung cancer resection, resection of the recurrent lateral residual lung or lung metastasis is feasible if the extra-pulmonary distant metastasis and cardiopulmonary function and other organic conditions allow.
(10) Patients with stage I and II NSCLC whose cardiopulmonary function is assessed to be inoperable may choose radical radiation therapy, radiofrequency ablation therapy and drug therapy.
2. Indications for surgery: stage I, II and some stage IIIA (T1-2N2M0; T3N1-2M0; T4N0-1M0 completely resectable) NSCLC and stage I SCLC (T1-2N0M0). Some stage IV NSCLC with solitary contralateral lung metastasis and solitary brain or adrenal metastasis Intrapulmonary nodules with high clinical suspicion of lung cancer, which cannot be diagnosed qualitatively by various examinations, can be surgically explored.
3. Contraindications to surgery: those with poor general condition and important organ functions such as heart, lung, liver and kidney cannot tolerate surgery. Most of the stage IV, most of the stage IIIB and some of the stage IIIA NSCLC with clear diagnosis.
(C) Radiotherapy
Radiotherapy for lung cancer includes radical radiotherapy, palliative radiotherapy, adjuvant radiotherapy and prophylactic radiotherapy, etc.
1.Principles of radiotherapy.
(1) Radical radiotherapy is applicable to 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.
(2) Palliative radiotherapy is indicated for symptom reduction for both primary and metastatic foci of advanced lung cancer. For patients with surgically resected single brain metastases in NSCLC, postoperative whole brain radiotherapy and chest radiotherapy for extensive stage SCLC can be performed.
(3) Adjuvant radiotherapy is indicated for patients with preoperative radiotherapy, positive postoperative radiotherapy margins (R1 and R2); patients with inadequate surgical exploration or those with close surgical margins; and for patients with positive postoperative pN2, participation in clinical studies of postoperative radiotherapy is encouraged.
(4) The design of postoperative radiotherapy should refer to the patient’s surgical pathology report and surgical records.
(5) Prophylactic radiotherapy should be applied to whole brain radiotherapy for SCLC patients with effective systemic therapy.
(6) The scope of concurrent radiotherapy: for inoperable stage IIIA and IIIB patients, the recommended concurrent radiotherapy regimens are EP regimen (pegylated glycosides + cisplatin), NP regimen (vincristine + cisplatin) and paclitaxel-containing regimen. If the patient cannot tolerate, sequential radiotherapy can be administered.
(7) Patients receiving radiotherapy have increased potential side effects and should be informed prior to treatment. Radiation therapy should be designed and delivered with attention to the protection of the lung, heart, esophagus and spinal cord. Unplanned interruption of radiotherapy due to improper management of toxic side effects should be avoided as much as possible during treatment.
(8) Advanced radiotherapy techniques such as 3D conformal radiotherapy, intensity-modulated radiotherapy or image-guided radiotherapy should be used, and stereotacticbody radiation therapy (SBRT) is recommended under excellent radiophysical technology.
(9) Enhanced CT localization or PET-CT localization is recommended for radiotherapy target area outlining. The tumor target area can be outlined in the enhanced CT localization image by referring to the tumor bio-image of PET-CT.
(10) Patients who receive radiotherapy or radiochemotherapy should be given adequate monitoring and supportive treatment during the treatment break.
2. Indications for radiotherapy for NSCLC: Radiotherapy can be used for the radical treatment of early stage NSCLC patients who cannot be treated surgically due to medical reasons, preoperative and postoperative adjuvant treatment for operable patients, local treatment for patients with unresectable locally advanced lesions and important palliative treatment for patients with advanced incurable disease.
When patients with stage I NSCLC are medically unsuitable for surgery or refuse surgery, large fractionated radiation therapy is an effective radical treatment and SBRT is recommended. The tolerated dose of radiotherapy for organ-threatening tissues such as spinal cord, esophagus, trachea, heart, chest wall and brachial plexus nerve should be evaluated with due consideration and care.
For patients with surgically treated NSCLC with negative postoperative surgical margins and positive mediastinal lymph nodes (pN2 stage), in addition to the usual postoperative adjuvant chemotherapy, the addition of postoperative radiotherapy is recommended, with a suggested sequence of chemotherapy followed by sequential radiotherapy. For pN2 stage tumors with positive margins, postoperative concurrent chemotherapy is recommended if the patient is physically able to do so. For patients with positive margins, radiotherapy should be started as early as possible.
For patients with stage II-III NSCLC who cannot undergo surgery due to medical reasons, conformal radiotherapy combined with concurrent chemotherapy should be given if physically possible. For patients with clinical promise, radiotherapy or concurrent radiotherapy should be administered with a more conformal radiotherapy plan and more aggressive supportive therapy to minimize interruptions in treatment duration or reduction in treatment dose.
For patients with stage IV NSCLC with extensive metastases, some patients may receive radiation therapy to both primary and metastatic sites for palliative reduction. When patients have significant benefit from systemic therapy, SBRT technique can be considered to treat residual primary and/or oligometastatic foci for potential curative effect.
3. Indications for radiotherapy for SCLC: Combined radiotherapy and chemotherapy is the standard treatment for limited-stage SCLC. Patients with limited-stage SCLC are recommended to undergo synchronized chemoradiotherapy with initial treatment or 2 cycles of induction chemotherapy followed by synchronized chemoradiotherapy. If the patient cannot tolerate it, sequential chemoradiotherapy is also available. If the disease allows, radiation therapy for limited stage SCLC should be started as early as possible and can be considered in conjunction with the first or second cycle of chemotherapy. If the risk of lung injury due to radiation therapy is too high due to the size of the lesion, concurrent radiation therapy with the 3rd cycle of chemotherapy may also be considered.
For patients with extensive SCLC, the addition of chest radiotherapy after the control of distant metastases by chemotherapy can also improve the tumor control rate and prolong the survival.
4. Prophylactic brain irradiation: For patients with limited-stage SCLC, prophylactic brain irradiation is recommended after complete remission of intrathoracic lesions, and for patients in partial remission. If chemotherapy is effective in extensive SCLC, prophylactic brain irradiation can also reduce the risk of brain metastasis in SCLC. The recommended time for prophylactic brain irradiation is approximately 3 weeks after all chemoradiotherapy, preceded by an enhanced brain MRI to rule out brain metastases, and a whole brain radiation dose of 25 Gy in 10 fractions over 2 weeks.
The decision of whole brain prophylactic irradiation for SCLC should be fully discussed by both doctors and patients, and the pros and cons should be weighed according to the situation of each patient.
5. Palliative radiotherapy for patients with advanced lung cancer: The main purpose of palliative radiotherapy for patients with advanced lung cancer is to address local compression symptoms due to primary foci or metastases, pain due to bone metastases, and neurological symptoms due to brain metastases. For such patients, hypo-segmentation irradiation technique can be considered to make it more convenient for patients to get treatment and at the same time can relieve symptoms more rapidly.
6.Effectiveness of treatment: The evaluation of the efficacy of radiation therapy is carried out according to the WHO Response Evaluation Criteria for Solid Tumors (RECIST).
7.Protection: Using conventional radiotherapy techniques, attention should be paid to the protection of the lung, heart, esophagus and spinal cord to avoid serious radiation damage to important organs of the body. Acute radiation lung injury should refer to the grading standard of acute radiation injury of the International Collaborative Group on Radiation Therapy for Oncology.
(IV) Drug treatment
Drug therapy for lung cancer includes chemotherapy and molecular targeted therapy. Chemotherapy is divided into palliative chemotherapy, adjuvant chemotherapy and neoadjuvant chemotherapy, which should be carried out under the leadership of medical oncologists with strict control over the indications for treatment. Chemotherapy should fully consider the patient’s condition and physical status, assess the patient’s possible benefit and ability to tolerate the treatment, evaluate the efficacy in a timely manner, closely monitor and effectively prevent and treat adverse reactions.
The indications for chemotherapy are: Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤2 and tolerability of chemotherapy in vital organ function, with a relaxation of PS score to 3 for SCLC. Patients are encouraged to participate in clinical trials.
1. Drug therapy for patients with advanced NSCLC.
(1) First-line drug therapy. The platinum-containing two-drug regimen is the standard first-line chemotherapy regimen, 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 select targeted drug therapy in a targeted manner. The currently available therapeutic agents are shown in Tables 2 and 3.
Maintenance therapy is an option for patients who have achieved disease control (complete remission, partial remission and stable) with first-line therapy. Currently, the drugs with evidence-based maintenance therapy include pemetrexed (non-squamous) and gemcitabine; the drugs with evidence-based maintenance therapy with drug replacement include pemetrexed (non-squamous), and for patients with EGFR-sensitive mutations, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). tyrosinekinase inhibitor (EGFR-TKI) for maintenance therapy.
(2) Second-line drug therapy. Patients with EGFR-sensitive mutations who are not treated with EGFR-TKI in first-line and maintenance therapy should be treated with EGFR-TKI as a priority in second-line therapy; for patients with negative EGFR-sensitive mutations, chemotherapy should be considered as a priority (Table 4).
(3) Third-line drug therapy. EGFR-TKI can be chosen or participate in clinical trials.
2. Physical therapy for patients with locally advanced NSCLC that cannot be surgically resected: combination of radiotherapy and chemotherapy is recommended, and synchronous or sequential chemoradiotherapy can be chosen according to the specific situation.
3, postoperative adjuvant therapy: 4 cycles of postoperative adjuvant chemotherapy is recommended for patients with completely resected stage II-III NSCLC with a platinum-containing two-drug regimen. Stage lB patients with high risk factors can be considered for selective adjuvant chemotherapy. High-risk factors include poor differentiation, neuroendocrine, (except well-differentiated neuroendocrine carcinoma), vascular invasion, wedge resection, tumor diameter >4 cm, dirty pleural involvement, and inadequate lymph node dissection. Adjuvant chemotherapy is usually started 3 to 4 weeks after surgery, and the patient’s physical condition should be basically normalized after surgery.
4. Neoadjuvant chemotherapy: For resectable stage III NSCLC patients, 2 cycles of platinum-containing two-drug regimen can be selected for preoperative short-course neoadjuvant chemotherapy. Surgery is usually performed 2-4 weeks after the completion of chemotherapy.
5. Drug therapy for SCLC patients: Chemotherapy, surgery and radiotherapy are recommended as the main combination therapy for patients with limited stage SCLC. The first-line chemotherapy regimen is EP regimen or EC regimen (pegylated glycosides + carboplatin). Chemotherapy-based combination therapy is recommended for patients with extensive SCLC. First-line chemotherapy regimens are EP, EC or lP (cisplatin + irinotecan) or IC (carboplatin + irinotecan).
Patients with relapsed progressive disease within 3 months are recommended to enter clinical trials, and those with relapsed disease within 3-6 months are recommended to be treated with topotecan, irinotecan, gemcitabine or paclitaxel. The commonly used chemotherapy regimens for SCLC are shown in Table 5.
6. Principles of chemotherapy.
(1) Chemotherapy is contraindicated in patients with a Karnofsky functional status score <60 ecog="">2.
(2) Patients with leukocytes <3.0×109/L, neutrophils <1.5×109/L, platelets <6×109/L, erythrocytes <2×1012/L, and hemoglobin <8.0 g/dl should not be treated with chemotherapy in principle.
(3) Patients with abnormal liver and kidney function, laboratory indexes exceeding two times the upper limit of normal value, or those with serious complications and infections, fever, or bleeding tendency should not be treated with chemotherapy.
(4) In the course of chemotherapy, if the following conditions occur, discontinuation or change of regimen should be considered: if the lesion progresses after 2 cycles of treatment, or if the disease deteriorates during the rest period of the chemotherapy cycle, the original regimen should be discontinued and other chemotherapy regimens or treatment modalities should be selected as appropriate; if there is an adverse reaction of grade ≥3 of the National Cancer Institute’s Common Adverse Events Evaluation Criteria (version 4.0), which poses a significant threat to the patient’s life, the drug should be discontinued and the patient should be treated. In the event of an adverse reaction of grade 3 or higher on the National Cancer Institute’s Common Adverse Event Criteria (version 4.0), the drug should be discontinued and replaced with another regimen at the next treatment.
(5) The standardization and individualization of treatment protocols must be emphasized. The basic principles and requirements of chemotherapy must be followed.
(6) The efficacy of chemotherapy should be evaluated according to RECIST criteria.