The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology are not only the standard for clinical decision making in the field of oncology in the United States, but have also become the most widely used guidelines in oncology clinical practice worldwide. Currently, the 2014 NCCN non-small cell lung cancer (NSCLC) treatment guidelines have been updated to the third edition (2014.V3), with more extensive updates than the 2013 guidelines, and through these updates it is also seen that the individualized treatment of NSCLC has become more standardized and improved. Li Tian, Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, China Now we invited Prof. Liu Xiaoqing and Dr. Guo Wanfeng, Deputy Chief Physician of PLA 307 Hospital, Prof. Chen Kernen, Prof. Zhu Guangying and Dr. Yu Huiming, Deputy Chief Physician of Peking University Cancer Hospital, Beijing, China, to analyze the main updates of the comprehensive diagnosis and medical treatment, surgical treatment and radiotherapy parts of the NSCLC guidelines, respectively. I. Diagnosis, follow-up updates and changes in presentation Molecular diagnosis The 2014 NCCN guidelines put more emphasis on molecular diagnosis. It is recommended that sufficient tissue be used for molecular subtype classification and, if possible, repeat biopsies be considered if necessary. For fewer tissue samples, especially in advanced NSCLC, immunohistochemical (IHC) testing should give way to molecular diagnosis. In most cases, detection of one marker for squamous carcinoma (p63) and one marker for adenocarcinoma [thyroid transcription factor 1 (TTF-1)] is sufficient. For adenocarcinoma, large cell carcinoma, or unclassified NSCLC, ALK testing is recommended for category 1. The population characteristic of ALK rearrangement has been removed from “tendency to be present in young and advanced NSCLC patients” and the test is not limited to lung adenocarcinoma. Epidermal growth factor receptor (EGFR) ± ALK is recommended as two targets for multiplex or next-generation sequencing in NSCLC, especially in patients with squamous and mixed histologic types who do not smoke or have small specimens (Figure 1). For patients with EGFR mutations and ALK rearrangement negativity, other mutation testing may be considered. As sensitive mutations for tyrosine kinase inhibitors (TKI), testing for the L861 mutation in EGFR exon 21 and the G719 mutation in exon 18 is recommended. metastasis, and epithelial mesenchymal transition (EMT) correlation. Figure 1 Identification of histologic subtypes of metastatic NSCLC Follow-up After 3-6 months of follow-up for non-solid or partially solid nodules larger than 10 mm with low-dose CT, the condition for consideration of surgical resection adds “increased solid component” in addition to increased size. For multiple pulmonary lesions, “small subsolid nodules with slow growth” was added to the list of observable symptomatic low-risk patients, and “accelerated growth of subsolid nodules or increased solid component or increased deoxyglucose (FDG) uptake” was added to the list of high-risk patients considered for treatment. “. Patients with stage I-IV NSCLC without clinical and imaging manifestations were monitored by history and physical examination and chest CT (enhanced or plain scan) every 6-12 months for 2 years, followed by annual monitoring by history and physical examination and chest CT plain scan, and this recommendation was changed from 2B to 2A category. The expression “supportive care” was changed to “integrate palliative care”. The expression “marginally resectable” was changed to “possibly resectable”. The 2014 NCCN guidelines for medical therapy place greater emphasis on the use of molecularly targeted therapeutics. The guidelines summarize the targeted agents for patients carrying genetic alterations (driving events) (Table 1). The treatment process for ALK-positive patients is refined, and recommendations are also categorized, especially for post-progression therapy. This fully demonstrates that individualized therapy guided by molecular markers is the direction of treatment for lung cancer. Table 1 Genetic alterations in lung cancer and their corresponding targeted agents First-line treatment For patients with EGFR-sensitive mutation positive in lung adenocarcinoma, large cell carcinoma or unclassified NSCLC, the guideline adds a class 1 recommendation for afatinib if EGFR gene mutation is found before first-line chemotherapy. If an EGFR mutation is identified during first-line chemotherapy, treatment is modified to “interrupt or complete the established chemotherapy regimen and initiate or add erlotinib or afatinib therapy (Class 2B)” (Figure 2). The guideline adds “Erlotinib should not be used as first-line therapy for patients with negative or unknown EGFR mutations.” Figure 2 First- and second-line treatment for EGFR-sensitive mutation-positive nonsquamous or unclassified NSCLC Second-line treatment For patients with EGFR-sensitive mutations in adenocarcinoma, large cell carcinoma, and unclassified NSCLC, the guidelines add the option of second-line treatment with afatinib for asymptomatic progression, symptomatic isolated or multiple brain metastases, and systemic isolated lesion progression based on the results of the LUX-Lung1 study (Figure 2). options (Figure 2). According to the CALGB30406 study, erlotinib may be given for cancerous meningitis. In case of systemic multiple metastases, a platinum-containing two-drug regimen ± bevacizumab ± erlotinib may be given. For patients with NSCLC with functional status score (PS) 0 to 2 EGFR mutation and ALK-negative or unknown status, second-line therapy adds the option of gemcitabine. For patients with NSCLC with a PS score of 0 to 2 who have not had gemcitabine, third-line therapy increases the choice of this agent. The guidelines add that “docetaxel, pemetrexed (for nonsquamous NSCLC), and gemcitabine are recommended as Class 2B if the patient has not received erlotinib or crizotinib and the following drugs in first and second lines.” Maintenance therapy The new guidelines weaken the recommendation for maintenance therapy by removing the option to “continue current regimen until disease progression.” For patients with EGFR- and ALK-negative or unknown NSCLC, gemcitabine prodrug maintenance has been changed from a Class 2A to a Class 2B recommendation. Switching maintenance of pemetrexed or erlotinib in non-squamous NSCLC and docetaxel or erlotinib in squamous cancer was also recommended from Category 2A to Category 2B. III. Surgery and adjuvant therapy Evolution of the status of VATS The prototype of television-assisted thoracoscopic surgery (VATS) dates back to 1912, but the success of thoracoscopic anatomical lobectomy was only in 1992, only 20 years ago now. In this short 20-year period, VATS has not only become technically mature and widely used, but more importantly, a wealth of evidence has confirmed oncologically that VATS is as effective or better than open pneumonectomy for early-stage non-small cell lung cancer (NSCLC). The National Comprehensive Cancer Network (NCCN) guidelines first included VATS in the 2006 edition, stating that “VATS may be a viable surgical option for resectable lung cancer as long as it does not violate oncologic standards of care and principles of thoracic surgical resection. The tone of this statement is one of moderation and hesitation. This is because, although studies have shown that VATS has some advantages over open surgery, such as causing less acute and chronic postoperative chest pain, shorter hospital stays, lower postoperative complications and mortality, and less risk of intraoperative bleeding or local regional recurrence. In addition, VATS allows for a faster return to self-care after hospital discharge in elderly and high-risk patients, but there was still much dissent and debate. With the emergence of more evidence-based evidence in favor of VATS and the finding that patients are more likely to receive and complete an adequate amount of full adjuvant chemotherapy after VATS, the 2010 edition of the guidelines was revised to read “VATS for NSCLC is a reasonable and acceptable procedure if the patient has no anatomic or surgical contraindications, provided that it does not violate oncologic standards of care and principles of thoracic surgical resection. The 2010 edition of the guideline was revised as “VATS for NSCLC is a reasonable and acceptable procedure if the patient has no anatomical or surgical contraindications, provided that it does not violate the standards of tumor treatment and the principles of thoracic surgery. Back then, the treatment of early stage NSCLC was still mainly open surgery. The 2014 edition of the guideline was further updated as “VATS or other minimally invasive pneumonectomy is highly recommended for early-stage NSCLC if the patient has no anatomical or surgical contraindications, as long as it does not violate oncologic treatment criteria and principles of thoracic surgical resection”. It is easy to see that VATS has become the mainstream procedure for early-stage NSCLC due to the advancement and application of VATS technology and the increasing evidence of evidence-based medicine, and it is also easy to understand that the status of open surgery will further decline. Postoperative adjuvant therapy The evidence level for adjuvant chemotherapy was changed from category 2B to 2A for patients with stage IB~IIA NSCLC with negative surgical margins (R0) and high risk factors (tumor hypodifferentiation, >100px, dirty pleural invasion and incomplete lymph node sampling). In stage II to IIIA patients with positive surgical margins, adjuvant therapy for R1 (positive microscopic margins) and R2 (positive sarcoid tumor margins) was originally described in a footnote and is now specifically distinguished in the flow chart in the guidelines. Stage II R1 patients are recommended for re-excision + chemotherapy or (sequential or concurrent) radiotherapy, and R2 patients are recommended for re-excision + chemotherapy or concurrent radiotherapy. Stage IIIA R0 patients with explicit adjuvant chemotherapy were recommended as category 1, with sequential radiotherapy recommended for N2 patients; sequential or synchronous radiotherapy recommended for R1 patients; and synchronous radiotherapy recommended for R2 patients (Figure 3). Figure 3 Postoperative adjuvant therapy for stage I~IIIA NSCLC IV. Radiotherapy Whether to do prophylactic irradiation RTOG9311 trial was conducted to study the target area of radiotherapy for NSCLC, which proved that not doing prophylactic irradiation did not reduce the efficacy, the recurrence rate in the field was slightly higher, irradiation of only positive lesions helped to increase the irradiation dose, reduce toxicity, and thus improve the long-term survival rate, and induction chemotherapy could reduce the tumor volume to a certain extent and create conditions for dose boosting conditions. For stage I NSCLC, radical surgery ± adjuvant chemotherapy is still the standard treatment modality, and the new version of the guidelines has not made too many changes, with the following major updates: surgery is the preferred treatment for stage IA NSCLC, and for those who cannot or refuse surgery for medical reasons, radical radiotherapy, including stereotactic radiotherapy (SABRT), is feasible, with a recommended biological dose greater than 100 Gy. For patients with stage IB or II inoperable for medical reasons, lymph node status is added to the treatment recommendations, with radical radiotherapy including SABRT recommended for those with N0, followed by adjuvant chemotherapy for those at high risk (category 2B); radical chemoradiotherapy is recommended for those with N1 (Figure 4). The results of clinical trials have confirmed that radiotherapy is superior to radiotherapy alone for inoperable early-stage NSCLC patients, and concurrent radiotherapy is superior to sequential radiotherapy. Figure 4 Initial treatment for stage I-II NSCLC Radiotherapy for locally progressive and advanced NSCLC The standard treatment for stage III inoperable patients is radical concurrent radiotherapy. The RTOG0617 study compared standard-dose (60 Gy) radiotherapy with high-dose (74 Gy) radiotherapy in 464 patients with stage III NSCLC who also received paclitaxel and carboplatin chemotherapy, and the results showed that standard-dose radiotherapy better controlled tumor progression and spread and even improved overall survival, with patients in the high-dose group having a 56% increased risk of death and a 37% increased risk of local tumor progression. Possible reasons for the poorer outcome in the high-dose group are increased radiation to the heart or the causing of toxic reactions that have not been reported. The proportion of reported side effects was similar between the two doses of radiotherapy, but the incidence of esophagitis was higher in patients in the high-dose group (21% versus 7%). This study confirms that the standard dose of radiation for concurrent radiotherapy in stage III NSCLC remains 60 Gy. A meta-analysis confirms that hyperfractionated radiotherapy regimens improve survival, and a randomized study (RTOG1106) is evaluating individualized dose increases for hyperfractionated radiotherapy. The new guidelines differentiate treatment recommendations for those with recurrent mediastinal lymph nodes based on whether they have received prior radiotherapy, and add recommendations for systemic chemotherapy for patients who have received prior radiotherapy. The description of radical concurrent radiotherapy has been changed to “If full dose chemotherapy is not given concurrently with radiotherapy at the time of initial treatment, add an additional 2 cycles of full dose chemotherapy (note: previously 4 cycles).” The recommendation for weekly paclitaxel+carboplatin regimen was changed from Category 2B to Category 2A in the chemotherapy regimen followed by concurrent radiotherapy. Patients with stage IV M1b isolated site metastases, T1~2N0~1 or T3N0 patients were added the option of SABRT to the lung lesion after chemotherapy.