Chemotherapy-based combination therapy is advocated for advanced non-small cell lung cancer, which can prolong survival and improve survival rates. However, although the efficacy achieved by chemotherapy has improved compared with the past, it has limited improvement in survival and is controversial in terms of pharmacoeconomics and limited symptom relief, and the efficacy of combined targeted therapy is under observation. Clinical oncologists should be properly informed and guided by evidence-based medicine to carry out standardized chemotherapy, while also focusing on individualized chemotherapy and looking forward to new breakthroughs in chemotherapy for advanced non-small cell lung cancer.
1.The general situation of advanced non-small cell lung cancer
The treatment of non-small cell lung cancer (NSCLC) is a worldwide challenge. About 80% of diagnosed NSCLC patients show progressive lesions, and there is almost no chance of cure for advanced NSCLC. The treatment mode for advanced non-small cell lung cancer is still multidisciplinary treatment, which means that the existing treatments are applied in a planned and rational manner according to the patient’s physical condition, pathological type, invasion scope and developmental trend, with the aim of significantly increasing the cure rate and improving the patient’s quality of life.
The vast majority of patients with advanced non-small cell lung cancer require chemotherapy-based combination therapy. The new drugs developed and applied in the past 20 years have been observed to be beneficial to survival, and what has been achieved so far is still only palliative efficacy.
2. Consensus and current status of chemotherapy for advanced non-small cell lung cancer
Chemotherapy for NSCLC has so far been dominated by platinum-based regimens. in the late 1980s, five new effective drugs were confirmed through clinical trials: vincristine, paclitaxel, doxorubicin, gemcitabine and irinotecan, combined with platinum to form a third-generation chemotherapy regimen, which is widely used in clinical practice for patients with behavioral status (PS) scores of 2 or less. Several randomized controlled trials have been conducted for these new agents, and the results of the studies confirm that third-generation regimens improve median survival and 1-year survival compared with best supportive care, and that symptoms improve in 60% to 70% of patients. There are no major differences in efficacy or side effects between third-generation chemotherapy regimens, and two-drug regimens are superior to single- or three-drug regimens.
There is little difference between platinum and non-platinum regimens, with non-platinum regimens appearing to be less toxic. The effective second-line chemotherapy agents are doxorubicin and pemetrexed. The combination of chemotherapy with targeted agents remains to be seen, and targeted agents alone are appropriate for patients with certain characteristics. The chemotherapy cycle needs to be considered in combination with efficacy, PS score and toxicity response, and is usually 4-6 cycles. Currently, meta-analysis has shown that survival of patients with advanced non-small cell lung cancer can be prolonged by combination chemotherapy, which improves median survival by 6 to 8 weeks and increases 1-year survival by 10% compared with best supportive care. However, this result is currently difficult to compare with the efficacy of chemotherapy for advanced colorectal cancer and breast cancer.
3. Confusion in chemotherapy for advanced non-small cell lung cancer
3.1 Comparison with second-generation platinum-containing regimens: Several randomized trials have confirmed that none of the third-generation regimens compared with the older regimens randomly observed lower survival rates with the newer drugs than with the older regimens . In 2000, Bonomi et al. reported a phase III clinical trial of a paclitaxel+cisplatin-controlled EP regimen enrolling 599 patients, with a median survival of 9.9 months vs. 7.6 months and a 1-year survival rate of 38.9% vs. 31.8%. Rosell reported a median survival of 8.7 months vs. 7.2 months in a phase III clinical trial of gemcitabine + cisplatin-controlled EP regimen enrolling 751 patients. As can be seen, there was no substantial improvement in median survival, or 1-year survival, compared to the second-generation platinum-containing regimen.
3.2 Chemotherapy plus best supportive care (BSC) versus best supportive care: Spiro et al. reported the results of a randomized controlled study of 725 cases of NSCLC with a median survival of 8.0 months for chemotherapy patients and 5.7 months for non-chemotherapy patients, a difference of 9 weeks, but 5% of patients in the chemotherapy group had treatment-related deaths. It is believed that this efficacy hardly gives hope to the patients. When the physician explains the efficacy of chemotherapy to the patient, the patient is informed of the results and can only assume that “to treat or not to treat” is not significant, although the physician believes that there is a statistical difference. Therefore, it is important to fully respect the patient’s wishes and ideas before treatment.
3.3 The efficacy of third-generation chemotherapy has been reported differently: several collaborative groups have reported some differences in the efficacy of third-generation chemotherapy regimens for advanced non-small cell lung cancer, with SWOG 9509 [8] reporting an efficiency (RR) of 25%, median survival (MST) of 8.6 months, 1-year survival rate of 38%, and 2-year survival rate of 15% in 206 patients treated with paclitaxel + carboplatin, while 202 patients treated with vincristine + cisplatin RR was 28% , MST 8.1 months, 1-year survival rate 36% and 2-year survival rate 16%.ECOG1594 [9] reported that 303 patients applied paclitaxel + cisplatin RR was 21%, MST 7.8 months, 1-year survival rate 31% and 2-year survival rate 10%, 301 patients applied gemcitabine + cisplatin RR was 22%, MST 8.1 months 1-year survival rate of 36% and 1-year survival rate of 13%, 304 patients applied doxorubicin + cisplatin RR of 17%, MST 7.4 months, 1-year survival rate of 31% and 2-year survival rate of 11%, 299 patients applied paclitaxel + carboplatin RR of 17%, MST 8.2 months, 1-year survival rate of 35% and 2-year survival rate of 11%. tax326 reported 408 patients applied doxorubicin Paclitaxel + cisplatin RR 32%, MST 11.3 months.
The 1-year survival rate was 46% and 2-year survival rate was 21%, 406 patients applied doxorubicin + carboplatin RR24%, MST 9.1 months, 1-year survival rate was 38% and 2-year survival rate was 18%, 404 patients applied vincristine + cisplatin RR25%, MST 10.1 months, 1-year survival rate was 41% and 2-year survival rate was 14%. While Kubota et al. reported 145 patients applied paclitaxel + carboplatin RR21%, MST 7.8 months, 1-year survival rate 51%, 146 patients applied gemcitabine + cisplatin RR21%, MST 7.4 months, 1-year survival rate 60%. 145 patients applied vincristine + cisplatin RR17%, MST 7.8 months, 1-year survival rate 48%, 145 patients applied eretiken + cisplatin RR 15%, MST 8.1 months, 1-year survival rate 59%.
How can these differences in multicenter clinical observations be explained? On the one hand, there are indeed some differences in drug dose intensity and cycle interval in certain regimens; on the other hand, it indicates a large tumor heterogeneity in advanced non-small cell lung cancer. Therefore, it is worth considering whether comprehensive evaluation and some tests can be used to predict the indications and efficacy of chemotherapy before the implementation of chemotherapy, and to reasonably select patients in order to achieve individualized treatment.
3.4 Efficacy of second-line chemotherapy: Shepherd et al. applied doxorubicin to compare chemotherapy with BSC in patients who failed first-line platinum-containing regimens, and the results suggested that the 1-year survival rate was 29% vs. 12%, and the MST was 7 months vs. 4.6 months, and both doxorubicin groups were superior to the BSC group. Doxorubicin monotherapy for advanced NSCLC that has failed platinum-based chemotherapy was approved by the FDA in 1999 and is now considered the gold standard for second-line chemotherapy in NSCLC. Pemetrexed 500 mg/m2 and 288 patients were treated with doxorubicin 75 mg/m2 until disease progression or intolerable toxicity and request for withdrawal from the group.
The effective rate of pemetrexed vs. doxorubicin was 9.1% vs. 8.8%, median survival was 8.3 months vs. 7.9 months, no statistical difference was seen, and median disease-free survival and 1-year survival rates were 2.9 months and 29.7%. In terms of toxic reactions, however, they were higher in the doxorubicin group. 2004 The US FDA approved pemetrexed for second-line chemotherapy in NSCLC. Second-line therapy is used in patients who have failed first-line platinum-containing regimens, and the effective rate is currently less than 10%, and most of the effective cases are those that were effective with first-line therapy. The median survival is around 8 months, while the median survival of first-line treatment is also around 8 months. The significance of second-line treatment to improve survival is questionable, and there is no controlled study of second-line chemotherapy with BSC in a large number of cases.
3.5 Limitations of chemotherapy combined with targeted therapy: The introduction of targeted therapy with gefitinib (Gefitinib) has encouraged the confidence of clinical practitioners. However, the findings of the ISEL trial confused people, the significance of the drug on survival improvement was largely negated, the subgroup observation was only beneficial for certain populations in the East, and this year the US FDA strictly limited the indications of the drug. The monotherapy findings for erlotinib (Erlotinib) appear to be better than those for gefitinib, but the combination chemotherapy remains suboptimal, with the TRIBUTE trial suggesting that the Erlotinib combined with paclitaxel + carboplatin regimen did not improve overall survival in patients with untreated progressive non-small cell lung cancer compared with paclitaxel + carboplatin alone.
The results of randomized controlled studies of Gefitinib or Erlotinib in combination with chemotherapy were negative, and no results were seen that the combination could increase efficacy, but whether the phenotype has EGFR mutations, gender, smoking, and the order of administration may affect the efficacy, pending future in-depth studies. rosell et al. evaluated the first-line treatment of vincristine + cisplatin in combination with cetuximab (Cetuximab) in EGFR-expressing NSCLC. 86 patients were enrolled, with 92% in stage IV. The efficacy rate was 31.7% higher than the control group at 20%, but not statistically significant, and no statistical difference was seen in the time to disease progression of 4.7 months vs. 4.2 months and median survival of 8.3 months vs. 7.0 months. With regard to toxic reactions, weakness and malaise were more common in the group with the addition of sitosterol, and the incidence of infection and acne-like rash was higher, while there was no significant difference in gastrointestinal toxicity or leukopenia.
This finding does not support a further phase III study of chemotherapy combined with cetuxol. Only the positive results of targeted therapy in combination with chemotherapy were reported at the 2005 ASCO annual meeting. Patients were enrolled with stage IIIB and IV NSCLC with non-squamous cancer and pleural effusion, and paclitaxel + carboplatin in combination with bevacizumab (trade name Avastin) was compared with the combination of carboplatin + paclitaxel alone. The results were statistically significant for efficiency in the combination Bevacizumab group, 27% vs 10%, progression-free survival and MST in the combination Bevacizumab group, 6.4 months vs 4.5 months and 12.5 months vs 10.2 months, respectively. Neutropenia and thrombosis were higher in the Bevacizumab group, but the incidence of bleeding and treatment-related mortality were higher in the Bevacizumab group, with a total of 5 deaths related to bleeding. This result was only significant for patients with non-squamous carcinoma, and patients with squamous carcinoma were excluded from the indication.
3.6 Symptom relief: There are fewer reports of symptom relief with chemotherapy for advanced non-small cell lung cancer, with improvement in about 60% to 70% of patients. Common symptoms of advanced non-small cell lung cancer include cough, hemoptysis, dyspnea, chest pain, and lung infection directly caused by the tumor. It also includes bone pain, dyspnea, and abdominal pain caused by metastatic lesions. Generally speaking, tumor control and symptoms are parallel. The efficacy of chemotherapy is unsatisfactory, and it remains to be seen whether the benefit of symptom relief can be obtained. The relief of symptoms associated with tumor-induced pulmonary atelectasis and pleural effusion is also a factor of the body’s own compensation and cannot be considered as an effect of chemotherapy.
3.7 Pharmacoeconomics: The current third-generation chemotherapeutic agents for the treatment of non-small cell lung cancer are costly, often tens of thousands of dollars per cycle, but the efficacy is unsatisfactory and the pharmacoeconomic aspects have to be considered. The 2005 ASCO meeting reported the results of a randomized comparison of 445 primary NSCLC cases with the non-platinum regimen of tamsulosin + gemcitabine versus the platinum-containing regimen of gemcitabine + carboplatin, with an RR of 31.5% vs 28.5%, a 1-year survival rate of 43% vs 41%, and a median survival of 10 months vs 10.5 months. Non-platinum regimens with lower toxic responses, i.e., luxury combinations, need to be more cautious and focus on pharmacoeconomic principles.
4. Outlook
4.1 Evidence-based medicine guided standardized treatment
Evidence-based medicine emphasizes the combination of evidence, experience, and patients. Reference and application of the best current evidence-based medicine evidence is rational for first-, second- or third-line chemotherapy for advanced non-small cell lung cancer with the clear purpose of prolonging survival, relieving symptoms and improving quality of life. In particular, arbitrary extension of chemotherapy cycles is not recommended for patients with advanced NSCLC and should be considered in the context of medical history, efficacy, organ function, PS score and toxic effects. 2003 Sorenson reported a multicenter, randomized, prospective study comparing the effects of 3 and 6 cycles of carboplatin + vincristine on overall survival and quality of life in patients who received 6 cycles of chemotherapy in 2 to 3 degrees of myelosuppression were significantly higher than the control group, but the 1-year survival rate was the same in both groups, at 25%, and the median survival was 28 and 32 months for 3 and 6 cycles of chemotherapy, respectively, which can be for identification.
4.2 Individualized treatment
Individualized treatment tends to be individualized with reference to evidence-based medicine. As knowledge accumulates, clinicians will have access to the molecular biology of each patient’s tumor. With this information, clinicians will be able to make screening and provide individualized, more rational and less toxic treatment to patients before receiving treatment. It is also feasible to select some patients for chemotherapy with the aim of protecting body function and prolonging survival and improving quality of life, while the PS score greater than 2 and elderly patients cannot be uniformly excluded from chemotherapy.
An Italian multicenter randomized clinical study showed that the use of single-agent vincristine compared with best supportive care in patients older than 70 years of age improved 1-year survival approximately 3-fold, with a significant improvement in MST (28 weeks vs. 21 weeks) and a significant improvement in quality of life, providing a basis for individualized treatment. However, how to screen this group of patients and from which level is also a hot topic for future research.
4.3 The emergence of new drugs and new targets of new non-cross-resistant cytotoxic drugs is expected to have the potential for meaningful milestone progress. Therapeutic studies on 3 aspects of anti-angiogenesis, anti-tumor proliferation pathway, and increasing apoptosis are currently underway, such as Jansen C111577 and SCH66336, inhibitors of farnesyl transferase, Ad-p53, an apoptosis enhancer, and UCN-01, an inhibitor of protein kinase C. More targets are expected to emerge and early clinical trials will be conducted.
4.4 Utilize the advantages of TCM and combined Chinese and Western medicine treatment
TCM emphasizes holistic concept, evidence-based treatment, and quality of life. For patients with advanced non-small cell lung cancer that is currently incurable, this concept of focusing on quality of life and individualized diagnosis and treatment is particularly important. The combination of Chinese medicine and traditional Chinese and Western medicine is unique in improving patients’ quality of life, surviving with tumor, and relieving advanced symptoms, and the administration of Chinese medicine during chemotherapy can reduce toxicity and increase effectiveness, protect the body’s immune function, and enable patients to undergo chemotherapy successfully. There are still shortcomings in Chinese medicine treatment such as non-standardized and unified efficacy evaluation criteria, poor reproducibility, and unreasonable trial design, which also need to be gradually improved and explored in the future.
At the 36th American Society of Clinical Oncology (ASCO) in 2000, Dr. Bailes pointed out that decades of research results have shown that tumor treatment has been transformed from relatively non-specific cytotoxic therapy to more targeted therapy, usually not to eradicate the disease but to control its development in the long term. There is still a long way to go.