In Western countries, although the incidence and mortality rate of lung cancer still rank first, the overall number of patients with the disease has decreased significantly, while China, on the contrary, not only has not decreased, but also continues to rise. According to the information from the Cancer Registry of the Health Planning Commission, the incidence of lung cancer in China is about 57/100,000 and the mortality rate is about 48/10,000, which means that there are more than 600,000 new lung cancer patients every year and more than 500,000 people die from lung cancer, so the situation is very serious. Considering that China’s smoking population accounts for 1/3 of the world (1/5 of the total population), the serious environmental pollution, especially air pollution, caused by rapid socio-economic development and the aging problem, this number will increase in the next 10 to 20 years.
The new revised staging scheme for lung cancer
This revision is more related to tumor size, redefines certain indicators of T, confirms the current criteria for defining N and some regarding the number of metastatic nodes, and divides the metastatic group into 3 groups and increases the staging, which allows a better estimation of patient prognosis. the T staging adjustments are mainly related to tumor size, involvement of main bronchi, pulmonary atelectasis/pneumonia, involvement of transverse membranes, and mediastinal pleura. Of these, tumor size was the most prominent factor influencing T-staging. However, the data of this staging were not specifically designed as a study of TNM staging, lacked detailed information, and did not register information on EGFR mutation status in patients with lung adenocarcinoma, for which molecular staging is important for current lung cancer diagnosis and treatment.
Early diagnosis of lung cancer: CT presentation of pulmonary ground glass nodules and clinical strategies
The report of GGO clinicopathological diagnosis study showed that the CT manifestation of GGN (ground glass nodules: nodules characterized by ground glass shadow (GGO)) correlated well with histopathological diagnosis, and GGN>5mm was an independent influencing factor for malignant lesions. It was found that GGN grows more slowly than solid nodules, but has a higher probability of malignancy; it is generally a non-metastatic lesion, but requires long-term follow-up (relying mainly on HRCT) for at least 3-5 years, and should be aggressively surgically removed once the diameter increases or new solid lesions appear.
Treatment options for early stage lung cancer: surgery or SABR?
The choice between surgery and SABR in the treatment of early-stage lung cancer has been debated. A randomized controlled study with a small clinical sample. The study selected patients with clinical stage cT1-2a (<4cm) N0M0 and histological or imaging/PET diagnosis of NSCLC, randomized to 3-year OS, RFS and major serious toxicities. The results showed that SABR was superior to surgery in both OS and RFS, 95% vs. 79% and 86% vs. 80%, respectively, indicating that SABR is a treatment option for operable stage I NSCLC. However, this study has some problems such as small sample size and short follow-up time, and more accurate conclusions need to be compared with more randomized controlled studies. Moreover, there are many concerns about SABR for early-stage lung cancer, such as a significant proportion of patients with clinical early-stage lung cancer have hilar or even mediastinal lymph node metastases even for cT1N0M0. SABR only irradiates the tumor locally, which makes some patients with lymph node metastases to lose the chance of cure. Therefore, for patients with early stage operable NSCLC, the current consensus is that surgical resection is still the first choice.
Advanced NSCLC: Challenges for precise treatment
Although the proportion of early diagnosis of NSCLC continues to increase, advanced NSCLC remains a priority in lung cancer treatment. Stereotactic radiotherapy has improved local control of tumors, and advances in surgery have led to a 5-year survival rate of 30.1% for stage IIIa/b NSCLC patients, which is close to that of concurrent radiotherapy, yet drug therapy remains the primary choice for most NSCLC patients. Current treatment strategies for advanced lung cancer are divided into those targeting tumor cells and tumor microenvironment, with the former including individualized chemotherapy and molecular targeted therapy, and the latter including anti-angiogenic therapy and immunotherapy. It was found that individualized chemotherapy options based on ERCC1 and RRM1 expression were not reliable; while molecular targeted therapy based on driver genes was effective but benefited fewer people and targeting resistance was inevitable. According to the theory of neovascularization or vascular normalization, anti-vascular therapy should be effective in most NSCLC, but clinical trial results show that less than 70% of patients benefit from the combination of anti-vascular and chemotherapy. Clinical trials targeting immune checkpoint (Checkmate017) have shown significantly better efficiency than chemotherapy in squamous lung cancer, but are still low at about 20%, and the role of PD-L1, a molecular marker predicting efficacy, is inconclusive. With the availability of NGS technology, we have obtained a dramatic increase in lung cancer-related data, but the interpretation of these data faces many challenges, and the use of this information to guide clinical practice has a long way to go.
Targeted therapy for squamous lung cancer: nivolumab delivers a surprise
Squamous lung cancer is a difficult area for targeted therapy. Current clinical trials targeting driver-related genes are mostly ineffective in squamous lung cancer. Analysis of gene expression mutation profiles in squamous lung cancer reveals that the spectrum of gene alterations in squamous cancer is very complex, and there are often copy increases or mutations in multiple genes (e.g., SOX2, PIK3CA, TP53, etc.), making single targeted therapies ineffective. In the past, it was thought that squamous carcinoma was not suitable for anti-angiogenesis inhibitors, but new data show that patients with squamous carcinoma are not at increased risk for anti-angiogenesis inhibitors and have improved remission rates, prolonged PFS, and an improving trend in OS, suggesting that not all patients with squamous carcinoma cannot be treated with anti-angiogenesis inhibitors. Data from a large phase IV clinical trial showed no significant difference in PFS, TTP and OS between adenocarcinoma and squamous carcinoma with recombinant human vascular endothelial inhibitor combined with chemotherapy. The monoclonal antibody nivolumab against the immune checkpoint PD-1 showed superior efficacy to docetaxel in squamous lung cancer with significantly improved OS. Prof. Cai-Cun Zhou believes that targeted therapy for squamous lung cancer requires more therapeutic targets, and the anti-immune checkpoint drug nivolumab offers new hope.
Questions and thoughts on anti-vascular targeted therapy
Regarding the current vascular targeted therapy for lung cancer, Prof. Baohui Han believes that two large samples of postoperative adjuvant therapy + anti-vascular targeted therapy studies (E1505 and CN115) both showed that adjuvant chemotherapy combined with anti-vascular targeted therapy did not significantly prolong overall survival and disease-free survival. Postoperative chemotherapy + anti-vascular targeting does not prevent recurrence and metastasis, but may be effective in some patients. Vascular growth factor is a key factor in tumor growth but far from a driver gene, and vascular-targeted TKI (multi-target) therapy has mostly failed in the first line. Evidence-based medical evidence suggests that vascular-targeted monotherapy-based treatment of NSCLC cannot achieve the same efficacy as driver gene inhibitors. Therefore, the role of anti-vascular targeted therapy is not a “blessing in disguise” but an “icing on the cake”. An analysis of the efficacy data of 272 cases of advanced NSCLC treated with first-line chemotherapy combined with recombinant human vascular endothelial inhibitor in a long cycle (maintenance therapy) showed that excluding the cases that did not continue with recombinant human vascular endothelial inhibitor combined with chemotherapy before 4 cycles due to progression, the median OS of <4 cycles vs >4 cycles (n=200) was 14 months for the former and 22.5 months for the latter. This indicates that vascular targeted therapy is not only about combination but also maintenance! For the choice of chemotherapy regimen in combination therapy, there is little difference between TC, PC, etc. Therefore, for vascular targeted therapy for lung cancer, screening the beneficiary population for precise treatment is the key!
Small cell lung cancer: the first light of immunotherapy
SCLC accounts for 15-20% of lung cancer, has a short course, poor prognosis, and is prone to multidrug resistance. Moreover, research on small cell lung cancer is relatively insufficient, and since the establishment of a comprehensive treatment model combining radiotherapy and chemotherapy in the 1990s, the progress of SCLC treatment has been slow. Over the years, most clinical trials of targeted therapies for small cell lung cancer have ended with bevacizumab, sorafenib and other anti-vascular and multi-targeted drugs. The high heterogeneity of small cell lung cancer and the complexity of its signaling pathways are important factors. Despite this, clinical trials of targeted agents Roniciclib (cell cycle blocker) and Veliparib (PARP inhibitor) in combination with chemotherapy for SCLC are ongoing, and the road to targeted therapy for small cell lung cancer will continue to be explored.
Following the 2013 CA184-041 clinical trial Ipilimumab in combination with paclitaxel/carboplatin showing benefit in immunotherapy for small cell lung cancer, the KEYNOTE-028 clinical study found that Pembrolizumab (anti-PD-1 high affinity antibody) had excellent anti-tumor activity in 20 evaluable PD-L1 positive patients with an objective efficacy of 35%, disease control of 33.3%, and durable remission in effective patients. Another immunotherapy clinical study (CheckMate032) found that the combination of nivolumab and ipilimumab was effective in treating patients with non-small cell lung cancer after failure of second-line therapy, with an objective efficacy rate of 32.6%. These clinical trials have greatly encouraged small cell lung cancer research and also provided new directions for the treatment of small cell lung cancer.
Real-world data and real-world evidence
With regard to clinical research on lung cancer in China, Prof. Yilong Wu believes that we have acquired an international perspective and achieved the initial transformation from spectator to practitioner, while the huge patient resources are the basis of our success and a number of young and middle-aged scholars have emerged, but influential studies are still scarce. Professor Yilong Wu also specifically raised the issue of the transformation from real-world data (data from non-randomized controlled trials used to support decision making) to real-world evidence (tissue-processed data that provide the basis for drawing conclusions or judgments), summarizing the insights brought to us by ICAN: ① The results of clinical studies are derived from highly selected populations, and the same conclusions are not necessarily drawn in non-selected clinical practice (2) when the benefit in clinical trials is very small, the application in clinical practice should be more cautious. Prof. Yilong Wu also emphasized that: China still lacks a real-world research environment, and RCTs are still the most important method to obtain evidence.
Clinical trials in lung cancer: China’s contribution
More than 210 conference submissions were received, and 31 excellent papers were selected for conference presentation and exchange, covering basic lung cancer research, surgery, chemotherapy, targeted therapy, radiotherapy, adjuvant and neoadjuvant, and other fields, and were brilliantly reviewed by renowned experts in the field of lung cancer.
Chemotherapy
The Fourth Hospital of Hebei Medical University published a study of pemetrexed combined with cisplatin first-line chemotherapy followed by pemetrexed maintenance therapy for EGFR mutation-positive advanced non-small cell adenocarcinoma. The study not only analyzed the efficacy of pemetrexed maintenance therapy in patients with EGFR mutation-positive advanced non-small cell adenocarcinoma, but also analyzed the effect of different mutation sites (19 deletion, 21 point mutation) on prognosis and the effect of different The effect of different mutation sites (19 deletion, 21 mutation) on the prognosis and the effect of different factors on the efficacy of chemotherapy was analyzed. The study enrolled 24 patients with an ORR (overall remission rate) of 16.7%, a DCR (disease control rate) of 100%, and a progression-free survival of 6.0 months. And subgroup analysis of different mutation types showed that patients with advanced lung adenocarcinoma with exon 21 mutation had better PFS than those with exon 19 deletion (8.0 months vs. 4.6 months, P=0.016). In addition, smoking status, age, and gender had no effect on the efficacy of maintenance therapy with pemetrexed.
The Cancer Hospital of Sun Yat-sen University reported the results of a phase I clinical study evaluating the tolerability, safety and efficacy of continuous intravenous enduro (recombinant human platelet inhibitor) combined with pemetrexed + carboplatin treatment in patients with advanced NSCLC, which initially enrolled 19 patients in three experimental groups of 7.5 mg, 15 mg and 30 mg for initial mapping and did continuous intravenous drip The pharmacokinetic results of Endo in humans. 20 new cases were expanded in the phase Ib trial to compare the efficacy of the 7.5mg/m2/d and 15mg/m2/d dose groups, and the results showed that continuous intravenous pumping of combination chemotherapy was feasible and effective in both dose groups and was expected to further improve tumor remission rates, while the 15mg/m2/d dose group may achieve better efficacy. The investigators look forward to further follow-up results.
Immunotherapy
In the excellent paper exchange session on immunotherapy in the afternoon of the 17th, Professor Chengping Hu from Xiangya Hospital of Central South University gave an excellent review of the studies from Shanghai Chest Hospital, Jilin Cancer Hospital and Fujian Medical University.
According to Prof. Hu, there are three main aspects of tumor cellular immunotherapy: tumor immune targets, tumor vaccines and peripatetic cellular immunotherapy. The immune targets currently under investigation are CTLA4 (cytotoxic T-cell antigen 4) and PD-1 (programmed cell death factor). Among them, PD-1 was a deserved big hit at ASCO and WCLC (World Conference on Lung Cancer) in 2015, with its role in negatively regulating T-cell function and preliminary clinical data showing its considerable potential efficacy in a variety of cancer types. Data from Shanghai Chest Hospital showed that on tumor cells from 356 Chinese non-small cell lung cancer patient samples, PDL-1 was expressed in 47.9% of squamous carcinomas and 34% of adenocarcinomas; PDL-1 expression in tumor-infiltrating immune cells was 53.5% vs. 21.7%. As a possible tumor screening biomarker, the study of PDL-1 expression in Chinese patients with non-small cell lung cancer provides some data support for individualized therapy and immunotherapy combined with chemotherapy.
The effect and significance of autologous tumor vaccine on postoperative immune function in lung cancer patients was studied at Jilin Cancer Hospital Cancer Hospital. After stimulating dendritic lymphocytes from peripheral blood of lung cancer patients to make tumor vaccine by co-culture with lung cancer cells heat shock protein 70 back into the patients, it was found that the number of CD3, CD4 and NK cells increased and the activity of NK cells as well as CTL was enhanced. In addition, Prof. Hu presented the results of a foreign phase II clinical study of tumor antigen-induced dendritic cell vaccine for advanced NSCLC, in which 22 patients received autologous DC vaccine induced by heterologous melanoma lysis products, and the number of treatments increased equivalently with the OS of patients, and the OS was 1783 days after 35 vaccine injections. Therefore, it is reasonable to believe that autologous DC tumor vaccine can help postoperative lung cancer patients restore their immune function and improve the anti-tumor activity of the body.
Targeted therapy
EGFR-TKI is the standard first-line treatment for EGFR mutation-sensitive individuals, yet its efficacy in advanced squamous lung cancer is not as definitive as that in lung adenocarcinoma. West China Hospital of Sichuan University reported the results of a multicenter retrospective study and a combined analysis of published literature on the efficacy of EGFR-TKI therapy in patients with EGFR mutation-sensitive advanced squamous lung cancer. A total of 63 patients with advanced squamous lung cancer treated with EGFR-TKI were included in the survival analysis. The results showed that the ORR, DCR, PFS and OS of EGFR mutation-sensitive squamous lung cancer patients treated with EGFR-TKI were 43.7%, 72.8%, 5.6 months and 21.7 months, respectively, which were better than chemotherapy but not as good as those of lung adenocarcinoma patients when compared with historical data. This study suggests that patients with EGFR mutation-sensitive lung squamous carcinoma may still benefit from EGFR-TKI, and the treatment and prognosis of this group of patients deserve further analysis.
There is no doubt that patients with EGFR-mutated NSCLC can benefit from EGFR-TKI, but for patients without access to tissue specimens, the detection of EGFR mutation genes has become a new “roadblock. Researchers have been trying to find new markers to replace tissue specimens for EGFR mutation testing, such as blood specimens, cell specimens and pleural fluid specimens. A more interesting study was done at Xiangya Hospital of Central South University to find the possibility of alternative tissue specimens for EGFR mutation gene detection by comparing tissue specimens, pleural fluid cell specimens and pleural fluid free DNA specimens from lung adenocarcinoma patients. In this study, 46 lung adenocarcinoma patients with combined malignant pleural fluid in Xiangya Hospital were paired with tumor tissue specimens, pleural fluid cell specimens and pleural fluid free DNA specimens by liquid phase microarray. It was found that there was good agreement between the EGFR mutation status of pleural fluid free DNA, pleural fluid cancer cells and tumor tissues (90.5% and 95.5% true positive rates for pleural fluid free DNA vs. tumor tissue and pleural fluid cells vs. tumor tissue, respectively), and the use of pleural fluid specimens for EGFR gene mutation detection can be considered instead when the patients’ tissues are difficult to obtain.