I. Preface
Lung cancer is a highly prevalent tumor and is the leading cause of death from cancer in many countries and regions. Seventy-five percent of them are non-small cell lung cancer (NSCLC). The five-year survival rate of NSCLC through comprehensive treatment is 67% for stage IA, 57% for stage IB, 55% for stage IIA, 39% for stage IIB, 23% for stage IIIA, 5% for stage IIIB, and 0% for stage IV. However, only 20-30% of NSCLC cases have indications for surgery at the time of diagnosis, and about 65-70% of cases are stage III and IV patients who are not suitable for surgery. the treatment of NSCLC increasingly emphasizes comprehensive treatment according to the stage of the disease, and the following is a brief description of the comprehensive treatment strategy for lung cancer according to the stage of lung cancer.
Early stage lung cancer (I, II, T3N1M0)
The standard surgical procedure is lobectomy plus lymph node dissection or sample biopsy. Some patients who cannot tolerate lobectomy can be treated by lobectomy or wedge resection. Lymphatic route metastasis of lung cancer is common in clinical practice and is closely related to prognosis. Opinions on the scope and mode of surgical lymph node contouring for lung cancer are not uniform. Ishida et al. reported 221 cases of peripheral lung cancer less than 3 cm in diameter, pathologically confirmed lymph node metastasis in a “jumping” pattern accounted for 28.6% of the cases, and the 5-year survival rate of the group with lymph node dissection was 51%. The 5-year survival rate of the group with lymph node contouring was 51%, while the 5-year survival rate of the non-contouring group was 33%.
The NCCN guidelines emphasize that lymph node dissection or biopsy should be performed during lung cancer surgery. , with a follow-up of more than 89 months. The results showed no significant differences in length of stay, operative mortality, or overall survival between the two groups, but PFS times of 60.2 months and 44.8 months and local recurrence rates of 12.5% and 45% in the sweep and biopsy groups, respectively, were significantly different.
The same group designed a larger trial (1999.7-2004.2) including 1111 patients with stage I-IIIA NSCLC, and preliminary results were published in Ann Thorac Surg in 2006, with no significant differences in complications or mortality from surgery, and the impact on survival is still under observation.
Postoperative adjuvant chemotherapy is suitable for patients with stage II or higher NSCLC, and postoperative adjuvant chemotherapy or observation can be chosen for stage IA combined with high-grade factors (hypofractionated cancer, involvement of blood vessels or presence of cancer emboli, wedge resection, tumor less than 2 cm from the break) and stage IB NSCLC. According to Fled report: 162 postoperative patients with T1N0M0, there were 43 recurrences, 65% of which were due to extra-thoracic metastatic lesions, including brain metastases; in another group of 196 patients with T2N0M0, 72.8% (59/81) of recurrent lesions were located outside the thoracic cavity.
The results of a meta-analysis of 52 randomized controlled studies (9387 cases) of adjuvant chemotherapy after surgery were reported in the British Medical Journal (BMJ) in 1995, where adjuvant chemotherapy with alkylating agents was not beneficial, but rather reduced 5-year survival by 5% and increased the risk of death by 15% (p=0.005); the data on adjuvant chemotherapy with cisplatin-containing chemotherapy Most of the data with cisplatin-containing adjuvant chemotherapy favored the chemotherapy group, increasing 5-year survival by 5% and decreasing the risk of death by 13%. The IALT, CALGB9633, JBR.10 and ANITA trials have since confirmed the efficacy of postoperative adjuvant therapy.
The effect of adjuvant chemotherapy after UFT was also reported by Tsuboi et al. In Japan, 979 patients with stage I (T1N0M0, T2N0M0) NSCLC (adenocarcinoma) after radical resection were randomized into two groups, one treated with the oral chemotherapeutic agent UFT 250 mg/m2/day for 2 years and the other without any treatment. The 5-year survival rate was significantly better in the treatment group than in the control group (87.9% versus 85.4%, respectively; P=0.036). Subgroup analysis showed that the survival benefit was mainly in patients with T2N0M0, whose 5-year survival rates were 84.9% and 73.5% in the treated and untreated groups, respectively (P=0.005), while there was no significant difference in 5-year survival rates between the two groups in patients with T1N0M0 (P=0.867).
At the 2007 ASCO meeting, Pechoux et al. re-analyzed randomized controlled clinical trials of adjuvant chemotherapy after surgery and radiotherapy, analyzing data from 2626 patients in 11 clinical trials, 12% of whom had incomplete surgery. 10 trials used sequential radiotherapy, 8 trials used DDP in combination with vincristine/VP16, 1 trial used DDP combined with tegafur, and 2 trials used other platinum-based regimens. The results showed a survival risk HR of 0.88 (95% CI 0.81-0.97, p=0.0062) for chemotherapy and an improved 5-year survival rate from 29% to 34%. The HR for relapse-free survival was 0.84 (95% CI 0.77-0.93, p=0.0006), for local relapse-free survival 0.79 (95% CI 0.67-0.94, p=0.0075), and for distant relapse-free survival 0.75 (95% CI 0.66-0.87, p=0.0001). There was no difference in efficacy between the various chemotherapy regimens and no significant correlation with patient age, gender and stage.
Postoperative adjuvant radiotherapy is suitable for N2 positive patients, and is not suitable for N0 patients. adjuvant radiotherapy is an option for N1 positive patients with adverse factors (tumor invasion of the lymph node envelope, extensive lymph node metastases, tumor less than 2 cm from the break, and no standardized lymph node dissection). lally et al. 2006 in J Clin Oncol retrospectively analyzed stage II-III The efficacy of postoperative adjuvant radiotherapy in NSCLC was analyzed in 7465 patients, including 3531 in the adjuvant radiotherapy group and 3934 in the observation group.
The overall population analysis showed that the 5-year survival rate of the postoperative radiotherapy group was significantly lower than that of the observation group, and the subgroup analysis showed that the 5-year survival rate of the postoperative radiotherapy group was significantly lower than that of the observation group in N0 and N1 patients, while the 5-year survival rate of the postoperative radiotherapy group was higher than that of the observation group in N2 group.
III. N2-positive IIIA NSCLC
Although surgical treatment can be used for operable patients with locally advanced stage IIIA NSCLC or metastases in the ipsilateral mediastinum or subserosal lymph nodes, it is difficult to completely remove the lymph nodes during surgery, which is less effective in prolonging the survival of patients. In 1981, Skarin Frei and colleagues first reported the feasibility and preliminary results of preoperative chemotherapy (Neoadjuvant therapy) for potentially operable patients with stage III disease. The implications of neoadjuvant therapy are.
1. Neoadjuvant therapy can reduce the tumor load of the primary tumor, making subsequent local (surgical) treatment more likely to be successful;
2. Neoadjuvant therapy can control lesions that cannot be controlled by local treatment;
3. By reducing the number of cancer cells before surgery, the number of drug-resistant cell lines can be reduced accordingly, and the incidence of blood-borne dissemination and local implantation during surgery can be reduced;
4. Animal experiments have confirmed that preoperative administration of systemic chemotherapy can greatly reduce the incidence of potential metastases after surgery;
5. The therapeutic effect of neoadjuvant therapy can be verified pathologically by surgery and can provide guiding indicators for subsequent treatment (such as staging, drug resistance, prognosis and other relevant indicators); 6. In cases where neoadjuvant therapy is effective, the principle of maximum preservation of normal lung tissue during surgery is facilitated by the ability to make the scope of surgery relatively smaller due to the reduction of the lesion.
According to the randomized controlled studies conducted by Rosell, Roth and Depierre, respectively, confirmed that the median survival in the surgery group was shorter than that in the neoadjuvant chemotherapy group, suggesting that neoadjuvant chemotherapy may play a beneficial role in controlling both local recurrence and distant metastases in stage III NSCLC. According to the neoadjuvant treatment study of 680 cases of stage III NSCLC with DDP-based MVP regimen in 14 foreign hospitals, the remission rate of chemotherapy was 40-69%, the surgery rate was 15-90%, the total resection rate was 29-53%, and the median survival rate was 29%.
The Sloan-Keltting Cancer Center, USA, treated 136 patients with stage III NSCLC with the MVP regimen, and 77% (105/136) achieved RR. 78% of the 105 patients in remission with chemotherapy had complete surgical resection, and 21% of these patients had complete histological remission (HCR) after surgery. The 5-year survival rate for patients in complete histologic remission was 61%.
However, Albain et al. first reported the results of the phase III clinical trial of synergistic chemoradiotherapy followed by surgery for stage IIIA NSCLC (RTOG9309). 392 patients with stage IIIA NSCLC were randomized into two groups A and B. 201 patients in group A received two cycles of EP regimen chemotherapy (cisplatin 50 mg/day days 1 and 8, etoposide 50 mg/day days 1 to 5 ) and 45 Gy of radiotherapy, followed by radical surgical resection; 191 patients in group B received the same combination of chemoradiotherapy followed by radiotherapy.
The 3-year survival rate, 3-year progression-free survival rate, and 3-year progression-free survival were 38%, 29%, and 14 months in group A and 33%, 19.6%, and 11.7 months in group B, respectively; the number of deaths during treatment was more in group A, 14 and 3, respectively. Comparison of the efficacy of the two groups showed that the 3-year survival rate and disease-free survival rate of those who underwent surgical resection after chemoradiotherapy induction therapy were higher than those who underwent chemotherapy and radiotherapy alone, and the 3-year disease-free survival was significantly longer (P=0.02), and the survival rate of those with non-PD was higher (P=0.003).
However, at the same time, treatment-related mortality was significantly higher in those treated with surgery than in those treated with chemotherapy or radiation alone (P=0.04), resulting in the same overall survival rate for patients treated with chemoradiotherapy plus surgery as for those treated with chemotherapy or radiation alone (median survival 22.1 months:21.7 months, P=0.51).
The results of several trials of neoadjuvant therapy were published in ASCO 2007.Nicolson et al. conducted a clinical study of neoadjuvant therapy in Europe (MRCLU22/NVALT/EORTC08012 trial), enrolling 519 patients with staging including 17% Ia, 45% Ib, 3% IIa, 29% IIb and 7% IIIa, with chemotherapy regimens including
The results showed that 49% of patients achieved PR after neoadjuvant chemotherapy and only 2% of patients had disease progression without affecting the surgical approach or postoperative complications. However, PFS HR was 0.98 (95% CI 0.77-1.23) and OS HR was 1.04 (95% CI 0.81-1.35), and the results suggest that platinum-based neoadjuvant chemotherapy does not improve survival.
Pisters et al. reported the follow-up results of neoadjuvant chemotherapy trial S9900 in patients staged T2N0, T1-2N1, and T3N0-1 (excluding supraglottic sulcus), who received Taxol/CBP chemotherapy + surgery or surgery alone in both groups. 600 patients were planned to be enrolled in the trial, but it was terminated early in July 2004 because adjuvant therapy was becoming the standard of care. A total of 354 patients were enrolled, 180 in the chemotherapy+surgery group and 174 in the surgery-only group. The results showed that PFS was 33 and 21 months with an HR of 0.79 (p=0.098) and OS was 50 and 47 months with an HR of 0.83 (p=0.24) in the two groups, respectively. The investigators concluded that further phase III controlled studies with neoadjuvant and adjuvant chemotherapy should be conducted.
Milleron et al. designed a phase III clinical trial (IFCT0002 trial) to evaluate the efficacy of preoperative and perioperative chemotherapy. A total of 528 patients were enrolled and divided into 4 groups: group A GP2 cycle + GP2 cycle (objectively effective patients) + surgery; group B GP2 cycle + surgery + GP2 cycle (objectively effective patients); group C TC2 cycle + TC2 cycle (objectively effective patients) + surgery; and group D TC2 cycle + surgery + TC2 cycle (objectively effective patients). Preliminary results showed that the efficiency of the first 2 cycles of chemotherapy was 50.6%, 50.9%, 52.2% and 49.2% in the 4 groups, respectively; the percentage of effective patients receiving the 3rd/4th cycles of chemotherapy was 90.4%, 75.2%, 79.1% and 86.0%, respectively. Follow-up results of survival and PFS are still awaited.
IV. Locally advanced unsuitable for surgery
A Meta-analysis of a group including a total of 3033 patients from 22 clinical trials showed that combined chemoradiotherapy resulted in a 10% (P=0.0006) reduction in the risk associated with death compared with radiotherapy alone, and a 3% and 2% reduction in the absolute value of death at 2 and 5 years, respectively. There are four main modes of combined chemoradiotherapy treatment.
(1) Induction chemotherapy → radiotherapy → adjuvant chemotherapy;
(2) Simultaneous radiotherapy → adjuvant chemotherapy;
(3) induction chemotherapy → synchronous radiotherapy → adjuvant chemotherapy;
(4) Synchronized radiotherapy → surgery. A growing number of studies have shown that patients treated with synchronous radiotherapy have better overall survival than sequential radiotherapy, but also have the most severe toxicity and side effects, especially radiation esophagitis and pneumonia.
The 10th International Lung Cancer Congress reported on the LAMP study, which included 3 groups, Group A: 2 cycles of Tysol (T: 200 mg/m2) + carboplatin (C: AUC=6) followed by 63 Gy of chest radiotherapy; Group B: 63 Gy of radiotherapy with weekly Tysol (45 mg/m2) + carboplatin (AUC=2); and Group C: 2 cycles of TC chemotherapy followed by synchronous radiotherapy. The median survival of the three groups was 13.1, 12.7, and 16.1 months, respectively, but the incidence of more than 3rd degree esophagitis was also the highest in group C (P=0.0001). Therefore, the investigators concluded that simultaneous radiotherapy should be the main treatment option in the future, and new radiotherapy techniques such as three-dimensional conformal radiotherapy (3DCRT) should also be used to reduce side effects.
The results of the RTOG9410 trial were reported at the 2003 ASCO meeting, where patients were randomized to sequential radiotherapy (Cisplatin/Vinblastine 60 Gy RT D50), concurrent radiotherapy (Cisplstin/Vinb x 2/60 Gy RT D1) and chemotherapy combined with hyperfractionated radiotherapy (Cis/Oral?x 2 Vokes reported the results of the CALGB 39801 trial at the 2004 ASCO meeting, comparing induction chemotherapy (paclitaxel in combination with carboplatin) followed by concurrent radiotherapy with the incidence of 3rd/4th degree esophagitis.) Vokes reported the results of the CALGB 39801 trial at the 2004 ASCO meeting, comparing the efficacy of induction chemotherapy (paclitaxel combined with carboplatin) followed by concurrent radiotherapy with radiotherapy alone.
Huber’s 2006 article in J Clin Oncol also compared the efficacy of induction chemotherapy followed by concurrent radiotherapy with that of radiotherapy alone, enrolling 303 patients in stage III, 219 of whom were randomized. patients, 219 of whom were randomized. The results showed that the median survival was 18.7 months (95% CI 14.1-23.3) and 14.1 months (95% CI 11.8-16.3) for the two groups, respectively (p=0.09); however, for patients who achieved pr/cr after induction chemotherapy the median survival was 32.6 (95% CI 21.4-43.9) and 16.6 months (95% CI 12.5-20.6) for the two groups, respectively. 12.5-20.6) (p=0.04).
Albain reported the results of the INT 0139 trial at ASCO 2005, comparing the efficacy of simultaneous radiotherapy (Cis/Etoposide/45Gy RT D1) followed by continued radiotherapy to 61Gy and surgery, with 191 and 201 cases in the two groups, respectively, with median survival of 22 and 24 months, and 5-year survival rates of 20% and 27%, respectively. Logrank P = 0.24 (HR 0.87 (CI, 0.7, 1.10)); the analysis revealed a high mortality rate within 30 days after surgery in the surgical group, mainly in patients requiring total pneumonectomy, with a median survival of 34 months and a 5-year survival rate of 36% for patients requiring lobectomy. Therefore, simultaneous radiotherapy is preferred for patients who are not suitable for direct surgery in locally advanced stages, and patients who can be treated radically by lobectomy after radiotherapy can undergo surgery.
The single-branch trial of SWOG suggested that the administration of polyene paclitaxel after concurrent radiotherapy could prolong survival, and the administration of gefitinib after polyene paclitaxel consolidation could not further prolong survival. 2007 ASCO meeting Kelly et al. updated the latest follow-up results of the SWOG0023 trial, which enrolled patients with locally advanced NSCLC. In May 2005, the analysis of 243 patients enrolled (118 in the gefitinib group and 125 in the placebo group) suggested that gefitinib did not improve survival and the trial was prematurely stop enrolling patients.
The current median follow-up time reached 27 months, and the results showed that OS in the gefitinib and placebo groups were 23 and 35 months, respectively (p=0.013), with few adverse events of degree 3 or higher in both groups, suggesting that survival was decreased in the gefitinib group and was not associated with adverse events. Meanwhile, Hanna et al. designed a phase III clinical trial (HOG LUN 01-24/USO-023) to validate the role of consolidation chemotherapy. Patients with locally advanced NSCLC received concurrent radiotherapy (VP16 50mg/m2, days1-5 29-33, DDP 50mg/m2 days1, 8, 29, 36; total radiotherapy dose was 5940cGy) and patients with progression-free disease were randomized to receive 3 cycles of polyene paclitaxel 75mg/m2 day1 consolidation therapy or observation. Results A total of 203 patients were enrolled and 147 patients were randomized, including 73 patients in the consolidation treatment group and 74 patients in the observation group.
The PFS was 12.3 and 12.9 months (p=0.9412) and OS was 21.6 and 24.2 months (p=0.9402) in both groups, respectively. The decrease in febrile neutrophils of degree 3/4 was 10.9%, pneumonia 8.2%, hospitalization 28.8% and death 5.5% in the consolidation treatment group, all of which were significantly higher than in the observation group. Therefore, consolidation therapy does not improve survival, but increases adverse effects.
V. Late stage lung cancer
We can see that only some patients will benefit from chemotherapy, so how to choose patients and chemotherapy regimen? Hoang et al. of the University of Wisconsin School of Medicine made a clinical prediction model based on two large randomized controlled studies ECOG1954 and ECOG5592 of the Eastern U.S. Oncology Collaborative Group. 1436 patients with NSCLC receiving 3rd generation chemotherapy regimens entered the study and a total of 6 independent prognostic factors were screened: subcutaneous metastasis (relative risk ratio (HR) of 1.88), behavioral status score was poor (HR 1.46), decreased appetite (HR 1.62), liver metastases (HR 1.32), more than 4 metastatic sites (HR 1.20) and no previous surgical history (HR 1.16).
A clinical prediction model for 1- to 2-year survival in primary NSCLC was developed based on these six factors. According to the clinical prediction model if a patient has a low 1~2 year survival rate, that patient may not need aggressive anti-tumor therapy and supportive therapy may be the best option. Several oncogenes and proteins have been found to predict the efficacy of chemotherapy, including ERCC1 expression associated with platinum resistance, polymorphisms of RRM1 associated with gemcitabine resistance, βtublinIII expression associated with paclitaxel efficacy, and multidrug resistance gene MDR-1 associated with adriamycin and paclitaxel resistance.
At the ASCO 2005, Rosell reported the first prospective clinical randomized controlled study on the selection of chemotherapy regimens based on molecular marker typing, and the ERCC1 low expression group achieved 56.6% efficiency for the two-drug combination regimen containing cisplatin, but the ERCC1 high expression group achieved 37.7% efficiency for the platinum-free regimen, which was lower than the desired efficacy.
(I) First-line treatment of advanced NSCLC
The effectiveness of first-line chemotherapy for advanced NSCLC has now reached a therapeutic plateau, and a two-drug regimen based on platinum combined with 3rd-generation chemotherapeutic agents is recommended for 3 to 4 cycles according to NCCN guidelines. The efficacy of the regimens was similar, with objective effective rates ranging from 20-30%, median survival of 8-9 months, and 1-year survival rates of 37-39%, while the time to disease progression was slightly superior with the gemcitabine combined with platinum regimen.
The differences between the regimens were mainly in terms of side effects, with paclitaxel combined with carboplatin regimen having more pronounced neurotoxicity, allergic reactions and joint and muscle pain; gemcitabine combined with platinum regimen having more pronounced hematologic toxicity, especially platelet decline; doxorubicin combined with cisplatin regimen having more pronounced alopecia and neutrophil decline; and vincristine combined with cisplatin regimen having more pronounced neutrophil decline, vascular toxicity and weakness The TAX326 trial was a randomized controlled comparison.
The TAX326 trial randomized a controlled comparison of doxorubicin combined with platinum and vincristine combined with cisplatin, enrolling 1218 patients. The results showed that both doxorubicin combined with cisplatin regimens were superior to vincristine combined with cisplatin regimens, with median survival of 11.3 and 10.1 months (P=0.044) and objective effective rates of 31.6% and 24.5% (P=0.029) in the two groups, respectively.
Moreover, the doxorubicin combined with cisplatin regimen had lower anemia, gastrointestinal toxicity, peripheral neurotoxicity and decreased KPS score than the vincristine combined with cisplatin regimen. 2007 ASCO meeting Gronberg et al. studied pemetrexed combined with carboplatin (PEME 500 mg/m2 day1; CBP AUC=5 day1; 21 days per cycle for 4 cycles) in first-line treatment of The efficacy and adverse effects of NSCLC, the control group was the gemcitabine combined with carboplatin treatment group (GEM 1000mg/m2 day1, 8;; CBP AUC=5 day1; 21 days per cycle for 4 cycles), and a total of 446 patients were randomly enrolled. The results showed similar efficacy in both groups, while a 3/4 degree platelet decline and neutrophil decline were more common in the gemcitabine combined with carboplatin treatment group.
Avastin is a monoclonal antibody to VEGF, and the efficacy of Avastin and placebo combined with paclitaxel 200m/m2 plus carboplatin (AUC=6) in first-line treatment of stage IIIb and IV non-squamous NSCLC was compared in the ECOG4599 trial, with patients randomized to Avastin (15mg/m2) or placebo groups with 420 and The number of cases in the two groups was 420 and 427, respectively. The objective efficacy rate was 27.2% and 10.0% in the two groups.