Lung cancer is currently one of the most deadly tumors worldwide, and 80% of these patients have non-small cell lung cancer (NSCLC). Due to the development and application of chemotherapy and molecular targeted drugs, as well as the development of multidisciplinary integrated treatment model, the treatment effect of NSCLC has been improved, but the overall prognosis of patients is still poor. In recent years, with the in-depth research on the molecular biology of tumors, the treatment of NSCLC has become more and more individualized. Multidisciplinary treatment plays an increasingly important role.
Adjuvant chemotherapy for non-small cell lung cancer
The NSCLC Research Collaborative Group (1) published a meta-analysis of eight clinical trials in 1995, in which 1,394 patients received postoperative combination chemotherapy, and found that the overall risk ratio (HR) for platinum-containing regimens was 0.87 (P=0.08), i.e., a 13% reduction in the risk of death, and showed a 3% increase in 2-year survival (95% confidence limits: 0.5%-7%) for patients treated with chemotherapy. The results have led oncologists to question the importance of the use of chemotherapy in the treatment of patients with NB. These results generated interest among oncologists in adjuvant chemotherapy for NSCLC, and a series of clinical trials were subsequently conducted to evaluate the role of adjuvant chemotherapy. In a prospective randomized controlled adjuvant chemotherapy study of 979 stage I lung adenocarcinomas by the Lung Cancer Research Group(2) (LCRG) in Japan, the 5-year survival rates of the adjuvant and control groups of stage I B patients treated with oral UFT were 84.9% and 75.3%, respectively, with statistically significant differences, whereas the 5-year survival rates of the adjuvant chemotherapy group of stage I A patients were not significantly improved.
Starting in 2003, a series of large randomized phase III clinical studies confirmed the value of adjuvant platinum-containing regimens after complete resection of NSCLC. The IALT study(3) first demonstrated[w1] that postoperative second-generation two-drug platinum-containing regimens increased the 5-year survival rate of operated patients by 4.1%, followed by the JBR10(4) and ANITA(5) studies[w2] , respectively, for postoperative adjuvant chemotherapy with vincristine + cisplatin in patients with stage II-IIIA NSCLC improved their 5-year survival rate with statistical significance; however, no benefit was seen in patients with stage IB. The CALGB9633 study[w3] (6) improved the 4-year survival rate of patients with stage IB NSCLC by 12% with the help of paclitaxel + carboplatin regimen. The final result of survival at 5 years of study follow-up was negative though, with a 5-year survival rate of 59% in the adjuvant chemotherapy group and 57% in the surgery alone group (P=0.375), and a median survival time of 95 months versus 78 months (P=0.10). This is a blow to adjuvant chemotherapy for early-stage NSCLC, especially stage IB NSCLC. Is adjuvant chemotherapy needed for stage IB NSCLC? From the current evidence-based medical evidence, adjuvant chemotherapy should not be the standard of care for stage IB NSCLC. However, the CALGB9633 stratified study concluded that adjuvant chemotherapy is beneficial for stage IB NSCLC with primary tumors larger than 4 cm, but this is only a retrospective analysis in this clinical study, and no definite conclusion can be drawn yet.
A meta-analysis of five randomized controlled trials by Pignon et al. (7) showed that cisplatin-based adjuvant chemotherapy significantly prolonged the survival of patients, with the degree of benefit correlating with the stage of the tumor, with the greatest benefit in patients with stage II-IIIA, where the 5-year postoperative survival rate increased from 43.5% to 48.8%, while patients with stage IA did not benefit, and the efficacy did not correlate with the type of cisplatin combination. There was no correlation between the efficacy and the type of cisplatin combination. The meta-analysis also established for the first time the importance of the cisplatin dose, which must exceed 300 mg in total; the vincristine + cisplatin regimen is currently the most certain regimen for adjuvant chemotherapy in NSCLC.
Advances in minimally invasive surgical treatment of early-stage non-small cell lung cancer
Minimally invasive techniques in the surgical treatment of early stage lung cancer: Minimally invasive techniques are one of the hot spots in the development of surgery. In the surgical treatment of lung cancer, the conventional postero-lateral open incision needs to cut through the latissimus dorsi muscle and even the anterior serratus muscle, which is highly traumatic and patients suffer from pain after surgery and their quality of life is affected to different degrees. In the process of comprehensive lung cancer treatment, the principle of equal emphasis on survival rate and quality of life should always be followed. Minimally invasive techniques are developing rapidly in the treatment of early stage NSCLC, and successful minimally invasive treatment not only does not reduce the survival rate of patients, but also greatly improves their quality of life. Small incision open thoracotomy with preservation of chest wall muscles is a commonly used minimally invasive surgical method. According to the tumor site and cosmetic requirements, axillary vertical incision, anterior lateral incision, posterior lateral incision with preservation of anterior serratus muscle, etc. can be chosen (8), and the length of incision is about 10-15 cm. small incision thoracotomy is less traumatic to chest wall muscles, quicker healing of incision, faster recovery of respiratory function and upper limb motor function, shorter hospital stay, and not only meets cosmetic requirements, but also significantly reduces postoperative pain and other complications. The development direction of surgical procedures for lung cancer (9).
Since the 1990s, television thoracoscopic technology has developed rapidly, and its application is no longer limited to the treatment of benign intra-thoracic diseases and local excision of tumors, but also has some value in the surgical treatment of early lung cancer, especially stage I lung cancer. The thoracic incision of this surgery is further reduced, the chest wall muscles remain largely intact, and the ribs are protected from external pulling forces. Preliminary studies have shown (10) that television thoracoscopic lobectomy for stage I lung cancer is satisfactory, less invasive, and results in rapid patient recovery. For a standard thoracoscopic lobectomy should include complete lobectomy as well as separate ligation of the severed bronchi as well as blood vessels, as performed in an open-heart procedure (11). The indication for television-assisted thoracoscopic surgery (VATS) is stage I primary lung cancer, and Mckenna (11) suggests that elderly patients with lung cancer and poorer general condition tolerate VATS lobectomy better than conventional open thoracotomy. Typical contraindications to VATS include tumors larger than 6 cm, patients treated with preoperative adjuvant chemotherapy or preoperative adjuvant radiotherapy, pathologically confirmed hilar lymph node metastases, and central lung cancer. There is debate as to whether open-heart surgery is better or worse than VATS, with opponents of VATS arguing that it is an unsafe procedure that violates the no-tumor principle and does not provide more benefit than open-heart surgery. Proponents argue that VATS is a safe and effective treatment modality for lung cancer, and although data from randomized prospective clinical trials are lacking, there is sufficient evidence to suggest that the postoperative recovery process and time are equal to or better than open-heart surgery. . A randomized clinical study from Germany(13) showed a significant reduction in postoperative complications with VATS compared to conventional open chest. A Japanese study also concluded that the cost of VATS as well as postoperative pain was reduced compared with open-chest surgery(14). The Department of Thoracic Surgery at Shanghai Pulmonary Hospital, Tongji University, has gained more mature experience due to the early performance of VATS lobectomy, and they found in their recent report (15) that VATS has fewer complications and less hospital stay than conventional open thoracotomy. However, it is difficult to achieve systematic clearance of mediastinal lymph nodes in thoracoscopic surgery, and its long-term efficacy needs further study, and it cannot replace open chest surgery at present. Minimally invasive surgery for lung cancer requires a small operable area for the surgeon, difficult intraoperative anatomy and complication management, and solid operating skills for the operator; high requirements for surgical anesthesia, and good muscle relaxation for the patient during surgery; good hardware facilities and equipment are required, and the treatment cost is high, so the surgeon should choose according to the actual situation and should not apply blindly.
New advances in molecular targeted therapy
Molecular targeted therapy for lung cancer has developed rapidly in recent years, starting with the small molecule epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) gefitinib and erlotinib, followed by the large molecule vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, both of which have shown remarkable efficacy in advanced NSCLC.
Can traditional cytotoxic drugs and emerging targeted therapeutics be used synergistically in the adjuvant treatment of NSCLC to eliminate micrometastases and increase the effectiveness of surgery? Kris et al. (16) selected patients with stage I and II NSCLC who were operable and underwent tissue biopsy to detect EGFR exons 18-24, followed by oral gefitinib for at least 21 days before surgical resection. If preoperative treatment is effective or if the patient has an EGFR mutation, he or she will continue to receive gefitinib for 2 years after surgery. Twenty-three patients have been enrolled and the results are still being followed.
Multidisciplinary comprehensive treatment of stage III non-small cell lung cancer
I. Chemoradiotherapy for locally advanced NSCLC
In the past 15 years, there are two consensus opinions on the treatment of locally advanced NSCLC, namely, combined chemoradiotherapy is better than radiotherapy alone, and concurrent chemoradiotherapy is better than sequential chemoradiotherapy. The LAMP study (17), based on weekly paclitaxel + carboplatin/radiotherapy, compared the effects of induction chemotherapy followed by concurrent chemoradiotherapy, concurrent chemoradiotherapy followed by consolidation chemotherapy, and sequential chemoradiotherapy alone. In the SWOG9504 study [w5] (18), the median survival time was 26 months and the 5-year survival rate was 29% when the patients were treated with docetaxel after concurrent chemoradiotherapy with a full dose of etoposide + cisplatin (EP regimen), which was superior to the SWOG9019 study, which was a historical control with EP regimen for consolidation.
However, two phase III randomized controlled studies did not reach the same conclusion. CALGB 39801 (19) compared [w6] the efficacy of concurrent chemoradiotherapy with paclitaxel + carboplatin with concurrent chemoradiotherapy after paclitaxel + carboplatin induction chemotherapy and showed no significant difference in median survival between the two groups. carter et al. (20) reported a worse outcome in those with consolidation compared to those without consolidation, with a median survival of 26.7 months versus 16.1 months and a 3-year survival rate of 34 The median survival was 26.7 months versus 16.1 months, and the 3-year survival rate was 34% versus 23%. Therefore, the status of induction and consolidation chemotherapy in the treatment of locally advanced NSCLC is yet to be verified in more clinical trials.
The role of surgery in the treatment of stage IIIA-N2 NSCLC
Surgery was once considered as an important treatment in stage IIIA-N2 NSCLC, but the 5-year survival rate of patients after surgery is not satisfactory. Survival varies widely among patients with stage N2 NSCLC, with multiple groups of patients with massive N2 having a 5-year survival rate of only 5% to 8%, and patients with imaging single-station or microscopic N2 close to 35%. Patients who undergo total pneumonectomy have a high rate of postoperative complications and a high mortality rate. In recent years, since several studies have shown that patients with stage N2 who are staged down to N1 or N0 after preoperative induction therapy can achieve long-term survival, and that patients with inoperable locally advanced NSCLC have significantly improved outcomes with the combination of chemotherapy and radiotherapy, there is a need to reconceptualize the status of surgery in the treatment of stage IIIA-N2 NSCLC.
In the INT0139 (RT-OG9309) study [w7] (21), 429 patients with stage IIIA-N2 NSCLC were given 2 cycles of EP chemotherapy combined with concurrent radiotherapy up to 45 Gy. Those with stable disease were randomly divided into surgery and radiotherapy groups, and the radiotherapy group continued to complete radiotherapy up to 61 Gy, after which both groups received 2 cycles of EP regimen for consolidation of chemotherapy. Follow-up results showed that surgery after chemoradiotherapy improved progression-free survival compared with chemoradiotherapy in patients with stage IIIA-N2 (11.7% versus 22.4%, P=0.017), but not 5-year survival (20.3% versus 27.2%, P=0.10). In-depth analysis of the study revealed that the survival benefit population included those with down-staged lymph nodes and those who underwent lobectomy. 46% of patients in the surgery group had down-staged to N0 after chemoradiotherapy, and their 5-year survival rate was 40%, which was significantly higher than that of patients who had not down-staged (24%, P=0.0001). The median survival of those who underwent lobectomy after chemoradiotherapy and those who continued radiotherapy were 34 and 22 months, respectively, with 5-year survival rates of 36% and 18%, respectively, with statistically significant differences (P=0.002). This treatment modality is not suitable for total pneumonectomy patients.
In the EORTC08941 study [w8] (22), which differed from the INT0139 study, 572 patients with stage IIIA-N2 NSCLC who were judged by thoracic surgeons to be inoperable were first treated with 3 cycles of platinum-containing regimens for induction chemotherapy, and 333 patients who achieved remission were then randomized to the surgical and radiotherapy groups. The results showed that patients with stage IIIA-N2 NSCLC treated with induction chemotherapy did not improve either progression-free survival or overall survival with surgery compared with radiation therapy. Similar to the INT0139 study, EORTC08941 showed that patients who underwent total pneumonectomy had a poor prognosis, with median and 5-year survival rates only half those of patients who underwent lobectomy (13.4 and 25.4 months; 12% and 27%, respectively; P=0.009). Therefore, the European Organization for Research and Treatment of Cancer (EORTC) recommends that a combined chemoradiotherapy modality with nonsurgical treatment should be preferred for stage IIIA-N2 NSCLC that is not surgically resectable or has a high tumor load.
Based on the above research evidence, experts reached the following consensus: radical lobectomy after induction therapy is safe and effective, and total pneumonectomy should be avoided. Currently, it is advocated that the treatment plan for stage IIIA-N2 NSCLC should be decided according to the individual patient’s tumor load. For microscopic or single small N2, direct surgery or surgery after induction therapy can be performed; for multiple groups of sarcoid N2 and giant N2, induction therapy is recommended first, and those who are ineffective or progressive continue to complete curative chemoradiotherapy, while those with significantly down-staged N2 and meet the criteria for lobectomy can also choose Radical surgery is also an option for those with significantly reduced N2 and meeting the criteria for lobectomy.
Advances in the treatment of advanced non-small cell lung cancer
In the past decade, two-drug platinum-containing chemotherapy has become the standard first-line treatment for advanced NSCLC, especially for patients with good physical status (PS) scores, which can prolong survival and improve quality of life. However, the efficacy of conventional chemotherapy has reached a plateau, and several phase III randomized clinical trials, important collaborative group studies and meta-analyses have shown that the efficacy of different new platinum-containing regimens is similar.
To further improve the treatment of advanced NSCLC, several randomized controlled clinical trials have evaluated the efficacy and safety of molecularly targeted drugs in combination with chemotherapy in the first-line treatment of advanced NSCLC.
Four randomized controlled studies of the EGFR-TKI gefitinib or erlotinib in combination with chemotherapy had negative results and did not confirm that chemotherapy in combination with EGFR-TKI improved survival. Bevacizumab, an anti-VEGF monoclonal antibody, was used in combination with chemotherapy with encouraging results. In the ECOG4599 study [w9] (23), first-line treatment of nonsquamous NSCLC with bevacizumab in combination with paclitaxel + carboplatin significantly improved objective remission rates (27% vs. 10%, P<0.0001) and progression-free survival (6.4 vs. 4.5 months, P<0.0001) compared with paclitaxel + carboplatin chemotherapy alone, and also significantly prolonged patient survival, The median survival was 12.5 months and 10.2 months, respectively (P=0.007). Therefore, the Eastern Cooperative Oncology Group (ECOG) recommends paclitaxel + carboplatin in combination with bevacizumab as a reference regimen for first-line treatment of advanced non-squamous NSCLC without contraindications (history of bleeding and brain metastases).
Dowlati published the results of the prognostic factor analysis of the ECOG4599 study (23)[w10] , suggesting that intercellular adhesion molecules (ICAM) have a significant impact on prognosis. Patients with low basal ICAM values before treatment had a better prognosis than those with high basal values, with disease remission rates of 29% and 13%, respectively (P=0.03), and 1-year survival rates of 65% and 25%, respectively (P=0.04). This study suggests that patients with low ICAM basal values benefit more from bevacizumab in combination with chemotherapy.
For NSCLC with primary treatment failure, the US FDA recommends docetaxel or pemetrexed as the standard of care in second-line treatment, with similar efficacy but less toxic effects of pemetrexed.
Phase II clinical studies showed that both the EGFR-TKI gefitinib and erlotinib had good remission rates and prolonged survival as second-line agents, but phase III clinical studies comparing them with placebo had different results. that erlotinib prolonged survival in all patients. Gefitinib was launched in China in 2005, and registered clinical studies demonstrated an objective remission rate of 27%, a disease control rate of 54.1%, and a 1-year survival rate of 44% with a median survival of 10 months.
Is gefitinib first- and second-line treatment superior to currently reported chemotherapy for advanced NSCLC in Eastern populations? The results suggest that gefitinib monotherapy is comparable to chemotherapy in first-line treatment in non-selective small sample trials in Eastern populations, while its efficacy is better than chemotherapy in selective small sample trials, with an efficacy rate of 54.5%-61.6%. The SIGN study, which enrolled mainly Western patients, showed that second-line use of gefitinib was similar to docetaxel in efficacy and had a better safety profile (25). 2006 ASCO annual meeting, Japanese scholars reported a retrospective study comparing the efficacy of gefitinib with docetaxel in second-line treatment of nonsmoking NSCLC patients [w11] (26). The objective efficacy rate was 36% in the gefitinib group (69 cases) and 10% in the docetaxel group (39 cases), and the tumor progression-free survival time was 148 days in the gefitinib group and 43 days in the docetaxel group (P=0.002), suggesting a therapeutic advantage of gefitinib over docetaxel in nonsmoking NSCLC patients. These findings need to be confirmed in a large randomized controlled phase III trial.