Lung cancer-related deaths have surpassed the mortality rates of the next four malignancies combined. For many years, the treatment of lung cancer has been viewed with pessimism, but a growing number of advances and discoveries have brought the treatment of lung cancer, especially non-small cell lung cancer (NSCLC), into a new arena. -Diagnosis and Treatment of Lung Cancer. Here we have systematically analyzed and summarized the treatment of lung cancer as a topic. Yang Jibing, Department of Respiratory Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine
Treatment of Stage I and II NSCLC
For the treatment of stage I and II NSCLC, surgical resection is still the most basic treatment, but the management paradigm for this part of patients is undergoing very many changes. Due to the wider use of CT scanning technology, earlier stage lung cancer or even small ground glass nodules can be detected, and lung segmental resection techniques and stereotactic radiation techniques are gradually being applied to the treatment of early stage lung cancer.
For patients with clinically diagnosed stage I and II NSCLC, surgery is recommended first if there are no contraindications to surgery (Level of evidence: 1B); non-surgical treatment (e.g., radiofrequency ablation or stereotactic radiation therapy) may be considered after evaluation by a thoracic oncologist or a multidisciplinary team (Level of evidence: 2C).
Thoracoscopic minimally invasive resection may be preferable to open pneumonectomy in patients with clinically diagnosed stage I NSCLC (Level of Evidence: 2C). Systematic sampling and dissection of mediastinal lymph nodes during surgery is preferable to selective sampling or no sampling of lymph nodes in patients with either stage I or stage II NSCLC (Level of evidence: 1B), and further mediastinal lymph node dissection does not improve survival in patients with stage I NSCLC if intraoperative sampling of both hilar and mediastinal lymph nodes is not suggestive of metastasis (Level of evidence: 2A). However, systematic lymph node dissection should be chosen over simple lymph node sampling during open-heart surgery for patients with stage II NSCLC (Level of Evidence: 2B). Tumor lesions located at the hilum may be selected for sleeve resection if complete resection is possible, and total pneumonectomy is not mandatory (Level of Evidence: 2C).
When stage I or II NSCLC is clinically diagnosed and surgical resection is performed, lobectomy is recommended over lung segmental resection (Level of evidence: 1B). in patients with stage I NSCLC, sexual segmental resection is preferred over non-surgical treatment in cases where lobectomy is not tolerated due to poor lung function or comorbid other diseases (Level of evidence: 1B). In contrast, during lung segmental resection, for <2 cm masses, the cutting edge should be more than the maximum tumor diameter from the tumor focus, while for >2 cm masses, the cutting edge should be at least 2 cm from the tumor focus, thus minimizing the possibility of positive cutting edge and local recurrence (level of evidence: 1C). In cases where patients are at significantly increased risk of perioperative death, lung segmental resection should be performed rather than lobectomy (Level of evidence: 2C). Pulmonary segmental resection may also be considered for a clinical diagnosis of stage I with a ground glass nodular shadow of ≤2 cm (Level of evidence: 2C).
For patients with clinically diagnosed stage I NSCLC who cannot tolerate surgery, either stereotactic radiation therapy or wedge resection is preferable to no surgery (Level of evidence: 2C).
Patients with postoperative stage IA or IB NSCLC may be treated without postoperative adjuvant chemotherapy (Level of Evidence: 1B). Patients with postoperative stage IIA or IIB (N1) NSCLC with good PS scores require postoperative platinum-based combination chemotherapy (level of evidence: 1A).
Treatment of stage III NSCLC
Patients with stage III NSCLC are a heterogeneous group, presenting partly with resectable tumor lesions themselves but also with occult microscopic nodules, or with unresectable massive nodular lesions.
For infiltrating stage III NSCLC (N2, 3) with PS score 0-1, treatment needs to be selected with the aim of disease cure, and radiation therapy alone is not recommended (level of evidence: 1A), and a combination of platinum-based chemotherapy and radiation therapy (60-66 Gy) needs to be applied (level of evidence: 1A), and if the patient’s weight loss is not significant, simultaneous radiotherapy should be selected instead of radiotherapy sequential therapy (Level of Evidence: 1A). We do not recommend prophylactic cranial irradiation for infiltrating stage III NSCLC (N2, 3) that has achieved complete remission with concurrent radiotherapy treatment (Level of evidence: 2C).
For infiltrating stage III NSCLC (N2, 3) with a PS score of 2 and significant weight loss (>10% loss), concurrent radiotherapy may still be considered, but the pros and cons of concurrent radiotherapy need to be fully evaluated in patients (Level of Evidence: 2C). Palliative radiotherapy is recommended if the PS score is 3-4, or if there is coexisting disease, or if the disease itself is too severe to be treated with curative intent. The choice of radiation therapy dose and format should be based on the physician’s judgment and the patient’s needs (Level of evidence: 1C).
For patients with isolated N2 lymph node metastases and preoperative staging of IIIA, an integrated multidisciplinary team is recommended to develop the patient’s treatment plan (Level of evidence: 1C), and the choice of concurrent radiotherapy or induction chemotherapy combined with surgery is recommended over surgery or radiation therapy alone (Level of evidence: 1A), and the preference for surgery combined with postoperative adjuvant chemotherapy is generally not recommended (Level of evidence 1C).
For patients with stage III NSCLC who opt for surgical resection, systematic mediastinal lymph node sampling and dissection is required (Level of evidence: 1B). If latent N2 lymph node metastases are found intraoperatively, complete lymph node and primary tumor resection is still feasible, and the initiated pneumonectomy and lymph node dissection should be completed (Level of evidence: 2C). For resected NSCLC with latent N2 lymph node metastases (stage IIIA) and a good PS score, platinum-based combination adjuvant chemotherapy is recommended (Level of evidence: 1A). patients with R0 resected NSCLC found to have latent N2 lymph node metastases may be treated with sequential adjuvant radiation therapy if local recurrence is highly suspected (Level of evidence: 2C) Patients with intraoperative finding of latent N2 lymph node metastasis (IIIA) who fail to undergo complete resection (R1, 2) are recommended to undergo concurrent adjuvant radiotherapy postoperatively (Level of Evidence: 2C)
Treatment of stage IV NSCLC
It is estimated that approximately 40% of lung cancer patients are stage IV at the time of definitive diagnosis. As the results of new clinical trials continue to be published, the 2013 Guidelines make the following recommendations for the treatment of stage IV NSCLC.
The appropriate treatment regimen is selected based on the patient’s PS score and his or her histologic type. For stage IV NSCLC with a good PS score (0-1), platinum-based two-drug combination chemotherapy is recommended because it is superior to best supportive care in improving survival, prognosis, and quality of life (level of evidence: 1A), and early palliative treatment is recommended to improve quality of life and survival (level of evidence: 2 B), but the addition of a third cytotoxic chemotherapeutic agent is not recommended because it not only does not provide a survival benefit but may be harmful (Level of Evidence: 1A).
In stage IV non-squamous NSCLC, bevacizumab in combination with carboplatin and paclitaxel may improve survival if patients do not have hemoptysis and brain metastases and may be considered as a treatment option for these patients (Level of Evidence: 1A). If patients have brain metastases and their brain metastases are stable after treatment, first-line application of bevacizumab in combination with platinum-containing chemotherapy regimens is safe (Level of Evidence: 2B).
For stage IV non-squamous NSCLC, four cycles of pemetrexed in combination with platinum therapy for stable disease, pemetrexed maintenance therapy is recommended (Level of Evidence: 2B), and if four cycles of platinum-containing two-drug chemotherapy without pemetrexed and stable disease, pemetrexed maintenance therapy is still recommended (Level of Evidence: 2B). Erlotinib maintenance therapy is also recommended for those with stable disease at the end of a four-cycle platinum-containing two-drug chemotherapy regimen (Level of Evidence: 2B).
For stage IV NSCLC with epidermal growth factor receptor (EGFR) mutation-positive disease, first-line administration of EGFR-TKI (gefitinib, erlotinib) is associated with a more favorable treatment response, PFS, and lower toxicities than first-line platinum-containing two-drug chemotherapy (Level of Evidence: 1A).
For patients with stage IV NSCLC, maintenance therapy with drug changes other than pemetrexed is not recommended, as drug changes do not prolong their OS (Level of Evidence: 1B). Cetuximab in combination with chemotherapy is not recommended except in clinical trials (Level of evidence: 2B).
For second- and third-line treatment of stage IV NSCLC with good PS score (0-2), erlotinib or docetaxel (or single-agent chemotherapy such as pemetrexed) is recommended for second-line treatment (level of evidence: 1A). Third-line treatment is recommended for erlotinib because its relative best supportive therapy improves patient survival (Level of Evidence: 1B).
For older (70-79 years old) stage IV NSCLC, two-drug combination chemotherapy (monthly application of carboplatin and weekly application of paclitaxel) is recommended if the patient has a good PS score and no significant comorbidities (level of evidence: 1A).
For patients with stage IV NSCLC with a PS score of 2 (due to tumor), a two-drug chemotherapy regimen is recommended (Level of Evidence: 2B). For patients with a score of 2 and above, bevacizumab combination chemotherapy is not recommended (Level of Evidence: 2B).
Special issues in the treatment of NSCLC
The guidelines discuss and make recommendations for some special conditions and types of NSCLC, such as supraglottic sulcus tumors (Pancoast tumors), double primary nodules, multiple nodules in the same lobe, nodules in different lobes of the same lung (T4), contralateral lung nodules (M1a), multiple foci in both lungs, and isolated brain or adrenal metastases.
Pancoast tumors
For Pancoast tumors, it is recommended that a histologic diagnosis be obtained prior to treatment initiation (level of evidence: 1C).
For Pancoast tumors considered for radical resection, thoracic inlet and brachial plexus MRI is recommended to exclude tumor invasion into unresectable vascular structures or epidural areas (Level of evidence: 1C). Extra-thoracic imaging, (cranial CT/MRI, whole body PET or abdominal CT, bone scan) is also performed to exclude extra-thoracic metastases (level of evidence: 1C). For patients for whom surgery is feasible, complete resection is recommended when possible (Level of evidence: 1B). And recommended lobectomy instead of wedge resection (Level of evidence: 2C).
Neoadjuvant chemotherapy before surgery is recommended for patients with Pancoast tumors with good PS scores who are indicated for surgical resection (Level of evidence: 2B). Adjuvant chemotherapy and radiotherapy are recommended for patients with postoperative Pancoast tumors without metastases (Level of evidence: 2C).? And palliative radiotherapy is recommended for Pancoast tumors that cannot achieve radical treatment (Level of evidence: 2B)
Invasion of the chest wall
For NSCLC invading the chest wall, extrathoracic evaluation is recommended when radical resection is considered (Level of evidence: 2C). Simultaneous chemoradiotherapy is recommended when tumor involvement of mediastinal lymph nodes and/or the presence of metastatic disease is a contraindication to surgical resection (Level of Evidence: 2C). When metastases are excluded and tumors invading the chest wall are resected, complete resection is recommended when possible (Level of evidence: 1B).
Stage T4N0~1M0 NSCLC
Extrathoracic evaluation is recommended for stage T4N0~1M0 NSCLC considered for radical resection (Level of evidence: 1C). Invasive mediastinal staging is recommended for those who are feasible for radical surgery excluding extrathoracic metastases, and involvement of mediastinal lymph nodes is a contraindication to radical surgery (level of evidence: 2C). Resection at a specialized center only is recommended (level of evidence: 2C).
Double primary nodes
For suspected or confirmed lung cancer with a satellite node in the same lobe, a combination of features including clinical presentation, imaging, and cytology or histology (if available) is recommended to determine the nature of the satellite node (Level of evidence: 2C).
Invasive mediastinal staging and extrathoracic evaluation are recommended for concurrent double primary NSCLC considered for radical resection, with involvement of mediastinal lymph nodes and/or the presence of metastatic disease as contraindications to surgical resection (Level of Evidence: 1B).
Resection of both carcinomas is recommended for those with no preoperative suspicion and a second carcinoma found intraoperatively on another lobe, if sufficient lung tissue remains and no N2 lymph nodes are involved (level of evidence: 2C).
Multiple nodules in the same lobe
For suspected or confirmed lung cancer with two nodes in the same lobe, extrathoracic evaluation of the primary node and staging of the mediastinal lymph nodes without compromising staging because of the other node are recommended (Level of evidence: 1C).
In patients with confirmed NSCLC, lobectomy is recommended for the presence of another nodule in the same lobe without mediastinal or distant metastases (Level of Evidence: 1B).
Nodule in a different lung lobe on the same side (T4)
For patients with suspected or confirmed lung cancer and nodules in different lobes of the same side, a multidisciplinary team of experts is recommended to combine clinical, imaging and or histologic features (if available) to determine whether the nodule in the other lobe is a benign lesion or a synchronous primary (level of evidence: 1C).
Extrathoracic evaluation is recommended for patients presenting with nodules in different lobes of the same side of the lung (level of evidence: 2C). Invasive mediastinal staging is also recommended (Level of evidence: 2C) If there are no mediastinal or distant metastases and the patient has adequate lung function storage, simultaneous resection of both nodes is recommended (Level of evidence: 1B).
Contralateral pulmonary nodule (M1a)
Invasive mediastinal staging as well as extrathoracic evaluation is recommended for patients with nodules in the contralateral lung (Level of Evidence: 2C). Simultaneous resection of nodules in both lungs is recommended if there are no mediastinal or distant metastases and the patient has adequate lung function storage (Level of evidence: 2C).
Multiple lesions in both lungs
In patients with multiple lesions in both lungs that are ground glass lesions and suspected to be malignant, it is recommended that these lesions be classified as multiple lung cancers. Radical treatment is recommended for both suspected and confirmed multifocal lung cancer (level of evidence: 2C). Lobectomy is recommended, and if lung function permits, resection of all lesions is recommended (Level of Evidence: 2C).
Isolated brain metastases
For those with isolated brain metastases arising from NSCLC, invasive mediastinal staging and extrathoracic evaluation are recommended when radical resection of the primary site is being considered, and the presence of metastatic disease is a contraindication to surgical resection (Level of evidence: 2C).
For resectable stage N0-1 primary NSCLC without metastases from other sites, resection of the primary lung lesion and surgical resection or radiosurgical ablation of isolated metastases in the brain are recommended (Level of evidence: 1C).
Surgical resection or radiosurgical ablation of isolated metastases in the brain is recommended for non-contemporaneous primary NSCLC without other metastases and with complete resection of the primary lung lesion (Level of Evidence: 1C).
Adjuvant whole-brain radiotherapy is recommended for those who have undergone radical resection of isolated metastases in the brain (Level of Evidence: 2B). Adjuvant chemotherapy may be considered for those who have undergone radical resection of the primary lung site and isolated metastases in the brain (Level of Evidence: 2B).
Isolated adrenal metastases
Invasive mediastinal staging and extrathoracic evaluation are recommended for those with isolated adrenal metastases arising from NSCLC when radical resection is considered (Level of evidence: 1C).
For resectable stage N0 to 1 concurrent primary NSCLC without metastases from other sites, resection of the primary lung focus and isolated adrenal metastases is recommended (Level of evidence: 1C).
Resection of isolated adrenal metastases is recommended for non-concurrent primary NSCLC without metastases from other sites and with complete resection of the primary lung lesion (Level of evidence: 1C).
Adjuvant chemotherapy is recommended for patients who have undergone complete resection of adrenal metastases (Level of evidence: 2B).
Treatment of SCLC
Small cell lung cancer (smallcelllungcancer), also known as small cell undifferentiated carcinoma, is a highly malignant form of lung cancer with early and widespread metastasis. Since the ACCP guidelines published in 2007 had few modifications to the diagnosis and staging of SCLC and no subsequent modifications to improve treatment and survival, the third edition of the ACCP guidelines interpreted the diagnosis and staging of SCLC and treatment.
SCLC staging
The staging of SCLC has been following the two-stage staging method developed by the U.S. Veterans Administration Lung Cancer Study Group (VALSG), which divides patients into limited stage and extensive stage. the third edition of ACCP guidelines mainly discusses the role of staging evaluation items and PET on the initial staging, improved treatment plan, re-staging after treatment and prognosis of SCLC patients, and recommends that: the staging evaluation of SCLC should include medical history, physical examination, CBC and liver and kidney function tests, enhanced CT of the chest and abdomen or CT of the chest with liver and adrenal glands, MRI or CT of the brain, and bone scan (level of evidence: 1B), and for patients with limited clinical diagnosis, PET examination is recommended (level of evidence: 2C), and staging of SCLC patients in combination with VALSG staging and TMN staging is recommended.
Surgical treatment
Previous studies have shown that the benefit of radiation therapy for SCLC leads to premature abandonment of surgery, but analysis based on two major population databases has shown that SCLC patients who undergo surgery have a better prognosis than those who do not and that postoperative survival is strongly related to T and N staging, especially lymph node status. The guidelines state that preoperative traumatic mediastinal staging and extra-thoracic imaging (head MRI/CT and PET or abdominal CT + bone scan) are necessary for patients with stage I SCLC being considered for curative surgical resection (Level of Evidence: 1B), and that surgical resection is preferable to non-surgical treatment for patients with clinical stage I SCLC after accurate staging (Level of Evidence: 2C). In patients with stage I SCLC who have undergone surgical resection, postoperative administration of platinum-based adjuvant chemotherapy is recommended (Level of evidence: 2C).
Radiation therapy
The third edition of the APCC guideline focuses on the comparison of the efficacy of thoracic radiotherapy with placebo, chemotherapy and chemotherapy + thoracic radiotherapy in SCLC, and also discusses the optimal timing and dose of thoracic radiotherapy, the efficacy of thoracic radiotherapy in patients with extensive SCLC, and the role of prophylactic whole brain irradiation in patients with limited and extensive SCLC. Radiotherapy combined with platinum-based chemotherapy is feasible (level of evidence: 1B). Prophylactic whole-brain radiation therapy is recommended for patients with limited- or extensive-stage SCLC who are in complete or partial remission with initial treatment (Level of evidence: 1B). A course of consolidating thoracic radiotherapy is required for patients with extensive SCLC who have completed chemotherapy and are in complete remission of extrapulmonary lesions or partial remission of intrapulmonary lesions (Level of Evidence: 2C).
Chemotherapy and specific therapies
There are numerous chemotherapy regimens for small cell lung cancer, but several studies have shown that EP (platinum + etoposide) is as effective as alkylating agent-based regimens with less toxicity.EP or EC regimens remain the standard chemotherapy regimen for both limited and extensive SCLC.
Saridomide, an anti-angiogenic agent, has been found to be ineffective in both limited and extensive SCLC patients and to increase the risk of deep vein thrombosis and pulmonary embolism in patients with extensive SCLC. Phase 2 clinical trials have shown response rates of 64%-84% with median survival of 10.9, 11.7, and 12.1 months after bevacizumab in combination with EP, IP, and IC, respectively, and follow-up trials are ongoing. The third edition of the ACCP guidelines recommends that 4-6 courses of cisplatin or carboplatin in combination with etoposide or irinotecan are superior to other chemotherapy regimens in both limited- and extensive-stage SCLC patients (Level of evidence: 1A).
Second-line treatment
Most limited-stage and almost all extensive-stage SCLC will relapse. Patients with relapsed SCLC can be divided into two categories: recalcitrant/resistant (progression or relapse within 3 months of initial treatment) and relapsed/sensitive (relapse after 3 months of initial treatment). The survival time of relapsed patients remains short even with subsequent drugs, so the proposal of new treatment options is particularly important. The guidelines state that single-agent chemotherapy is recommended as a second-line treatment regimen for patients with relapsed or recalcitrant SCLC (level of evidence: 1B), and that reuse of first-line chemotherapy regimens is only for patients who relapse 6 months after completion of initial chemotherapy and are encouraged to join clinical trials.
Treatment of SCLC in the elderly
Approximately 43% of patients with diagnosed SCLC are less than 70 years of age and 10% are less than 80 years of age, and fewer clinical studies have been conducted because fewer clinical trials have enrolled older patients and many clinical trials have not grouped older patients with poor PS scores. The guidelines suggest that platinum-based combination chemotherapy + chest radiotherapy should be given to elderly patients with limited-stage SCLC (PS score 0-2) and closely monitored for treatment-related toxicities (level of evidence: 2B). Carboplatin-based combination chemotherapy is recommended for elderly patients with extensive-stage SCLC (PS score 0-2) (Level of evidence: 2A). For elderly SCLC patients with poor PS scores, chemotherapy is still recommended if the patient’s poorer PS score is caused by the SCLC disease itself (Level of evidence: 2C).
Complementary and integrative therapies
Integrative oncology refers to the study and use of new treatment concepts of complementary therapies that are not a traditional part of modern Western medical practice, but can be used as adjunctive therapies to mainstream medicine to manage tumors and the associated symptoms caused by oncologic treatments. This section is also a supplement to the ACCP guidelines following the second edition, which makes the following recommendations.
All lung cancer patients should be asked about their interest in and use of complementary therapies, and counseling on the advantages and disadvantages of these treatments is recommended (Level of Evidence: 2C).
The mind-body model is recommended as a multidisciplinary general practice treatment to reduce patient anxiety, mood swings sleep disturbances and improve quality of life (Level of Evidence: 2B); to reduce acute and chronic pain in patients (Level of Evidence: 2B); to reduce nausea and vomiting from prophylactic chemotherapy (Level of Evidence: 2B); and to reduce fatigue, sleep infections and improve patient mood (Level of Evidence: 2B).
For anxiety or pain that cannot be relieved by general care, massage therapy by a professionally trained massage therapist is recommended (Level of Evidence: 2B).
Patients with suspected lung cancer and impaired lung function awaiting surgical resection are recommended to have supervised pulmonary rehabilitation exercises to improve cardiopulmonary function (Level of Evidence: 2B).
Patients presenting with impaired lung function after surgery are recommended to have supervised pulmonary rehabilitation exercises to improve cardiopulmonary function (Level of Evidence: 2C).
Patients with advanced (no timing of surgery) lung cancer receiving palliative antineoplastic therapy presenting with impaired lung function are recommended to have supervised pulmonary rehabilitation exercises to improve cardiorespiratory function (Level of Evidence: 2C).
When patients present with nausea and vomiting due to chemotherapy or radiation therapy, acupuncture or other relevant methods are recommended as adjuvant therapy (Level of Evidence: 2B).
When patients present with tumor-related pain and peripheral neuropathy, acupuncture is recommended as an adjunctive therapy for symptom control (Level of Evidence: 2C).
A diet rich in non-starchy vegetables and fruits is recommended for people at risk for lung cancer to reduce the risk of developing lung cancer (Level of evidence: 2C).
It is recommended that people at risk for lung cancer limit their intake of red and processed meats, and that reducing meat intake may reduce the risk of lung cancer (Level of Evidence: 2C).
Increased intake of high-calorie and protein foods is recommended as nutritional therapy to maintain weight stability in patients undergoing treatment who are experiencing weight loss (Level of Evidence: 2C).
Oral n-3 fatty acid supplementation is recommended to improve the nutritional status of patients with lung cancer who develop muscle wasting disorder (Level of Evidence: 2C).