Abstract Advanced non-small cell lung cancer (NSCLC) is stage IIIB and IV with malignant pleural or pericardial effusion, and its treatment is based on systemic chemotherapy. Systemic chemotherapy has improved survival and quality of life in advanced NSCLC. Several new approaches have been identified for the treatment of NSCLC, including new cytotoxic agents, paclitaxel, gemcitabine, pemetrexed and the molecularly targeted drugs erlotinib , bevacizumab. Efforts to increase the effectiveness of first-line therapy have focused on adding new targeted agents to the platinum-based two-combination drugs. Bevacizumab, an antibody against vascular endothelial growth factor, was first shown to increase the efficacy of systemic chemotherapy in advanced NSCLC. Studies evaluating the role of maintenance therapy after four to six courses of combination chemotherapy are ongoing. Maintenance therapy can be administered with cytotoxic or targeted therapeutic agents. Of interest is the desired effect of maintenance therapy with paclitaxel after four cycles of carboplatin and paclitaxel treatment. Assessing the role of gemcitabine, pemetrexed and erlotinib as maintenance therapy in patients treated with four courses of combination chemotherapy in effective or stable patients is ongoing. The ability of this approach to increase survival in specific patients still needs to be evaluated. Current FDA-approved second-line agents for NSCLC include docetaxel, pemetrexed & erlotinib. Third-line therapy for advanced NSCLC is available with gefitinib, and erlotinib is superior to best supportive care.
Preface
Lung cancer is one of the most prevalent malignancies with the highest morbidity and mortality rates, and NSCLC accounts for approximately 85% of all lung cancer cases. Despite further standardization of lung cancer treatments in recent years, there has been no significant improvement in lung cancer survival rates, with a five-year survival rate of only 15% [1]. The lack of effective screening methods for early detection, smoking-related coexisting disease, and inherent molecular heterogeneity all hinder the improvement of prognosis for lung cancer patients.
The treatment of NSCLC is determined by the stage of the disease. Surgical treatment remains the mainstay of treatment for early and limited lesions, with standard multi-method treatment for locally advanced stages. In contrast, palliative chemotherapy is used for advanced and metastatic lung cancer, with its ability to prolong survival and improve quality of life. Systemic chemotherapy has also benefited patients with early stage lung cancer and is now one of the multiple treatment strategies for patients with stage II and III lung cancer [2, 3]. Therefore, the development of new systemic chemotherapeutic agents has become a focus of research in NSCLC. There is a view that the plateau of chemotherapy effectiveness has been reached using current agents, and therefore molecularly targeted agents have entered the therapeutic field in recent years [4,5]. Targeted agents targeting the epidermal growth factor receptor (EGFR) and vascular pathways have been shown to be effective in the treatment of NSCLC [4,5]. Several other molecularly targeted therapies are being evaluated as monotherapy or in combination with systemic chemotherapy.
Chemotherapy for advanced NSCLC
Approximately 40% of NSCLC patients are advanced at the time of detection, including patients with metastatic and malignant pleural and pericardial effusions. Treatment options are decided based on PS, as PS is an important determinant of prognosis. Combination chemotherapy is the standard of care for patients whose PS is 0 or 1. Platinum-based or non-platinum two-drug combinations have been shown to be effective first-line therapy for advanced NSCLC [6, 7, 8].
Patients with a PS score of 2 have a poor prognosis, with a median survival of 4 months [9]. Although monotherapy is widely used for patients with a PS score of 2 especially with coexisting disease, the appropriate treatment strategy needs to be further defined.
Platinum-based chemotherapeutic agents
The results of a randomized clinical trial of the superiority of platinum-based combination chemotherapy over best supportive care were initially reported in 1988. Subsequent evidence for the effectiveness of platinum-based chemotherapy was a meta-analysis of multiple randomized clinical trials [10], which showed that platinum-based chemotherapy improved one-year survival by 10% (hazard ratio, 0.73).
Based on the better effectiveness of single agents, paclitaxel, gemcitabine and vincristine were used in combination with platinum-based substances. Several randomized clinical trials evaluated cisplatin monotherapy or in combination with paclitaxel, gemcitabine, and vincristine [11, 12]. These studies provide further evidence to support the use of cisplatin-based first-line regimens for the treatment of NSCLC.
Comparison of platinum-based combination therapy
Several effective drugs were obtained and compared in The four-arm randomized controlled clinical phase III study, the Eastern Collaborative Oncology Group (ECOG) 1594 trial, compared cisplatin plus gemcitabine, cisplatin plus doxorubicin, and carboplatin plus paclitaxel, with cisplatin plus paclitaxel as the reference [6]. These four groups did not differ in terms of efficiency, median survival time, or one-year survival rate. However, cisplatin plus gemcitabine had a longer disease progression-free period.
Gemcitabine was initially identified as first-line therapy in two randomized controlled trials. In a phase III randomized controlled clinical trial with 552 patients with advanced NSCLC, cisplatin combined with gemcitabine had higher survival and efficiency than cisplatin monotherapy [11]. In another randomized controlled trial comparing cisplatin plus gemcitabine as first-line therapy with cisplatin plus pedialyte [13], cisplatin plus gemcitabine had a higher efficiency rate and a tendency for longer survival. Based on these studies, cisplatin plus gemcitabine has become a common combination regimen for the treatment of advanced NSCLC.
Docetaxel, a semisynthetic paclitaxel, has been shown to be effective in combination with platinum-based therapy. In a randomized phase III clinical trial (n=1,218), cisplatin plus docetaxel was compared with cisplatin plus vincristine and carboplatin plus docetaxel [14]. Median survival and two-year survival rates were higher in the cisplatin plus docetaxel group. However, the effect of carboplatin plus docetaxel was similar to that of cisplatin plus vincristine. The docetaxel combination group had a higher quality of life compared with cisplatin combined with vincristine. Based on these results, the cisplatin plus docetaxel treatment regimen was licensed by the U.S. Food and Drug Administration.
In Japan, irinotecan combined with cisplatin has been extensively evaluated for the treatment of advanced NSCLC [15]. Four randomized controlled clinical trials compared irinotecan in combination with cisplatin, carboplatin in combination with paclitaxel, cisplatin in combination with vincristine, and cisplatin in combination with gemcitabine [16]. Similar to the ECOG1594 trial, this study confirmed the similar effectiveness of the four groups, and their very good tolerability. Therefore, cisplatin in combination with irinotecan is often used as a treatment for NSCLC in Japan.
Because of the similar effectiveness of several chemotherapy regimens for NSCLC, the choice of drug must take into account the method of administration, toxicity and cost. Efforts to individualize therapy based on molecular markers of tumor resistance are ongoing. overexpression of the ERCC1 gene has been associated with platinum resistance [17]. Therefore, treatment regimens can be determined based on tumor tissue ERCC1 mRNA levels, with low ERCC1 mRNA levels treated with cisplatin plus docetaxel and high ERCC1 mRNA levels treated with gemcitabine plus docetaxel. Cisplatin plus docetaxel was more effective in the low-ERCC1 level group. Similarly, the nucleotide reductase M1 (RRM1) gene was associated with gemcitabine resistance [18]. Randomized phase II clinical trials confirmed the feasibility of treatment selection based on RRM1 expression, suggesting that treatment selection based on drug genes has a high efficiency rate. Based on these results, phase III clinical trials are underway. In the near future this new individualized therapy will optimize treatment.
Comparison of carboplatin and cisplatin
Carboplatin-based drugs are easy to administer out-of-hospital and have lower non-hematologic toxicity compared to cisplatin. Several studies have compared carboplatin- or cisplatin-based therapy for advanced NSCLC [6,14,19]. Some studies suggest a slight benefit of cisplatin-based, and it is unclear whether this is offset by higher toxic effects. A meta-analysis comparing cisplatin and carboplatin-based drug therapy demonstrated longer survival with cisplatin combined with newer agents [20]. Overall, cisplatin-based had higher efficiency than carboplatin-based therapy. Because the main purpose of systemic chemotherapy is palliative, it still continues to be debated that the marginal merits of cisplatin-based drugs are the rationale for their routine use because of the associated side effects that may have an impact on the patient’s quality of life. In curable situations, such as the early stages of NSCLC (adjuvant chemotherapy), cisplatin-based agents may be superior to carboplatin-based agents. Cisplatin-based agents are frequently used in the United States, while Europe prefers carboplatin-based agents.
Comparison of platinum and non-platinum substances
Non-platinum substances have been extensively scrutinized for the purpose of improving NSCLC chemotherapy indices. The benefit of excluding platinum-based substances is that platinum-based substances have considerable toxicity. Randomized trials have directly compared platinum-based and non-platinum-based combinations and have demonstrated comparable effects. This observation was established by a recent meta-analysis comparing platinum-based and non-platinum substances and confirmed comparable one-year survival rates [21]. Although platinum-based are slightly more effective, they are also more toxic. Based on these, non-platinum-based agents are an optional first-line treatment option for advanced NSCLC and represent an alternative option for those who cannot tolerate platinum-based substances.
Strategies to improve the effectiveness of systemic chemotherapy
Randomized controlled trials comparing various platinum-based available agents have clearly demonstrated that a plateau in the effectiveness of chemotherapy for the treatment of advanced NSCLC has been reached. Accordingly, several new approaches have been evaluated to improve patient prognosis. One approach compares three-drug combination chemotherapy with standard two-drug chemotherapy [22]. The addition of a third cytotoxic agent made no difference in terms of effectiveness and was more toxic. This approach was then abandoned. Comparison of platinum-based two-drug combination therapy with monotherapy demonstrated high survival and efficiency of combination therapy [23]. Thus, two-drug combinations form the basis of systemic therapy for NSCLC.
Recent efforts have focused on adding molecularly targeted agents to the standard platinum-based combination therapy. combination therapy with EGFR inhibitors and chemotherapy has been extensively studied. Although preliminary clinical data support combination therapy, phase III studies could not confirm that combining EGFR tyrosine kinase inhibitors prolonged survival [24, 25, 26]. Other targeted agents that have been tested in combination with chemotherapy, such as matrix metalloproteinase inhibitors, farnesyltransferases, and protein kinase C-α inhibitors, have shown higher effectiveness than chemotherapy.
More recently, bevacizumab, a monoclonal antibody against vascular endothelial growth factor, showed long survival when given in combination with chemotherapy [5]. The important ECOG4599 phase III clinical study treated advanced non-squamous NSCLC with carboplatin combined with paclitaxel alone or in combination with bevacizumab. patients with histological squamous cell type, hemoptysis, brain metastases, uncontrolled hypertension and taking therapeutic doses of anticoagulants were excluded because of the high bleeding risk of bevacizumab. After six cycles of treatment, patients in the experimental group those who were effective and stable patients were given bevacizumab maintenance therapy until the onset of disease progression and unacceptable toxic effects. There was a high incidence of leukopenia, hypertension, proteinuria and treatment-related mortality with the three-drug treatment. Despite this, there was a longer survival time (12.3 vs 10.3 m) for bevacizumab added to carboplatin and vincristine. Based on this study, bevacizumab has been approved by the US FDA as first-line therapy in combination with carboplatin plus vincristine for the treatment of advanced non-squamous NSCLC.
Maintenance therapy
Maintenance chemotherapy is based on the hypothesis that early use of non-cross-resistance drugs increases the likelihood of killing cancer cells before they become resistant to the drug. Maintenance chemotherapy is additional chemotherapy given after a defined initial cycle of chemotherapy and after a maximal tumor response has been achieved. Maintenance chemotherapy is feasible in patients who are partially or fully effective after initial chemotherapy (also known as post-induction chemotherapy). In the absence of significant toxicity, maintenance therapy is continued for a period of time or until disease progression. The drug composition of maintenance chemotherapy can be either the same drug as the initial treatment or a low dose of a non-cross-resistant drug.
With the use of bevacizumab as maintenance therapy for disease that was effective or stable in the ECOG4599 trial, it is now used as maintenance therapy for advanced NSCLC. This has led to an important debate about the role of maintenance therapy in advanced NSCLC. Until now, there has been no evidence of the usefulness of maintenance therapy, as randomized clinical trials have demonstrated no survival advantage for continuous dosing outside of 3-6 cycles of systemic chemotherapy [27, 28, 29, 30]. However, there are several limitations in the available literature that challenge the rejection of maintenance therapy for NSCLC.
Smith et al [27] conducted a randomized trial comparing a three-cycle and six-cycle approach to the administration of mitomycin, vincristine, and cisplatin for the treatment of advanced NSCLC. 72% of patients were randomized to the three-cycle group and 31% of patients were randomized to the six-cycle group. The median survival time and one-year survival rates were similar in both groups. Moreover, quality of life parameters were higher in the three-cycle group. This study concluded that there was no benefit to continued chemotherapy outside of the three-cycle group. In a similar study, Socinski et al [28] studied the treatment of advanced NSCLC using carboplatin and vincristine, randomized to four cycles of chemotherapy or continuous chemotherapy until disease progression or unacceptable toxic effects. There was no difference in efficiency or overall survival time between the two groups. The results of these two randomized phase III clinical trials yielded the view that maintenance therapy is ineffective in advanced NSCLC. An important limitation is that most patients randomized to long-cycle chemotherapy did not reach the planned cycle. The reasons for treatment discontinuation were toxicity and disease progression. Therefore, the only conclusion that can be drawn is that continuous combination therapy outside of three or four cycles is not feasible, but effective monotherapy that is well tolerated without additional toxicity cannot be ruled out.
Periprostoneol therapy as maintenance treatment
Belani et al [31] conducted a randomized phase II clinical trial to evaluate weekly administration of paclitaxel plus carboplatin for advanced NSCLC. patients were randomized to three different paclitaxel regimens. After four courses of treatment, those patients who were effective and stable were randomized to weekly paclitaxel treatment or observation only. Of the 401 patients enrolled, 130 patients entered maintenance therapy. Overall, the median survival time was 75 weeks for those patients who received maintenance therapy compared to 58 weeks for those who did not. Moreover, weekly paclitaxel maintenance therapy was well tolerated. Because the purpose of these studies was not to determine the effectiveness of maintenance therapy, the results of these analyses will have to be further confirmed, but suggest the feasibility of giving a single drug with low toxicity as maintenance therapy for advanced NSCLC.
Another docetaxel is the only first- and second-line agent approved for the treatment of advanced NSCLC, and studies are underway to evaluate the potential role of docetaxel as maintenance therapy.
Docetaxel as maintenance therapy
Docetaxel is the only first- and second-line agent approved for the treatment of advanced NSCLC. A recent study conducted by Fidias et al [32] confirmed the potential role of docetaxel as maintenance therapy. In this study, patients with advanced NSCLC were treated with four cycles of carboplatin plus gemcitabine. Those patients who were effective and stable were randomized to docetaxel as maintenance therapy (early) or as remedial therapy in case of disease progression (late). 566 patients were enrolled in this study, 398 completed the GC regimen chemotherapy, and 309 were randomly assigned to two groups of docetaxel (early or late) therapy with a median disease-free progression (PFS) of 5.7m vs. 2.7m in the early and late groups, respectively, P =Median overall survival was 12.7m in the early and 9.7m in the late docetaxel group, respectively, but the difference was not statistically significant, P=0.0653. There was no increase in toxic effects and no decrease in quality of life.
Gemcitabine as maintenance therapy
The good tolerability of gemcitabine makes it an ideal drug for the evaluation of maintenance therapy.Brodowicz et al [33] conducted a phase III clinical study to evaluate the role of gemcitabine as maintenance therapy. Four cycles of advanced NSCLC were treated with cisplatin in combination with gemcitabine. Those patients who were effective and stable were subsequently randomized to either gemcitabine maintenance therapy or best supportive care (BSC). 352 patients were enrolled in the study, and 206 patients were randomly assigned 2:1 to either gemcitabine maintenance therapy or best supportive care. During the maintenance phase, the median time to progression was 3.6 months in the gemcitabine group and 2 months in the BSC (p < 0.01). Overall survival also supported the maintenance treatment group (13 months vs. 11 months, p=0.195). A mean of three cycles of gemcitabine maintenance therapy was given. Approximately 18% of patients had a definite effect during the maintenance phase of treatment. A limitation of the study was that 42 patients who were initially effective or stable could not enter the maintenance phase for various reasons. Also, 22% of patients who entered gemcitabine maintenance therapy had treatment delays. Despite these limitations, the study documented feasibility and useful evidence to support gemcitabine as maintenance therapy. For further evaluation, a randomized clinical trial is underway in the United States with four courses of carboplatin plus gemcitabine for advanced NSCLC. After this induction phase, those patients who are effective and stable will be randomized to gemcitabine maintenance therapy or given BSC only. the study has an estimated sample size of 600 patients and enrollment is nearing completion.
Pemetrexed as maintenance therapy
Pemetrexed is a multi-targeted anti-folate complex that has been approved as a second-line regimen for the treatment of NSCLC. Approval was based on a comparison of pemetrexed and docetaxel in the treatment of advanced NSCLC that had progressed after prior platinum-based chemotherapy [34]. The results of the effectiveness of the two substances were similar, but pemetrexed had a lower incidence of leukopenia, febrile leukopenia and thrombocytopenia, and a lower rate of hospitalization. Tolerability of pemetrexed was further improved by vitamin B12 and folic acid supplementation. Based on this study, pemetrexed has been frequently used as a second-line agent for the treatment of NSCLC. pemetrexed effectiveness is being evaluated as a number of regimens for the treatment of advanced NSCLC (in combination with platinum-based substances) and for the treatment of locally advanced NSCLC (in combination with platinum-based substances and external radiotherapy).
The good tolerability of pemetrexed allows it to be evaluated in the context of maintenance therapy. Randomized clinical trials are underway in which patients with platinum-based stable or effective advanced NSCLC after four courses are randomized 2:1 to pemetrexed and placebo as maintenance therapy. Maintenance therapy was continued until disease progression and unacceptable toxic effects. All patients received vitamin B12 and folic acid supplementation. The estimated sample size was 660 patients. Because the study was conducted with survival as the primary endpoint of the study, it is expected to be used as a new standard of care for advanced NSCLC.
EGFR inhibitors as maintenance therapy
Erlotinib is an EGFR tyrosine kinase inhibitor. It was approved by the FDA for the treatment of advanced NSCLC after one or two prior chemotherapies.The approval was based on a phase III study that demonstrated a higher survival rate in the erlotinib group compared to the placebo group [4]. Gefitinib, another EGFR tyrosine kinase inhibitor, had an efficiency rate of about 10% in advanced NSCLC, but the phase III study could not confirm any survival benefit. Both erlotinib and gefitinib have been studied as combination regimens for the first-line treatment of chemotherapy in advanced NSCLC, but the results have been disappointing [24, 25, 26]. There was no survival advantage over chemotherapy alone. In these randomized studies, EGFR tyrosine kinase inhibitors were used as a stand-alone treatment after six cycles of combination therapy. During the maintenance phase of treatment, both erlotinib and gefitinib showed long survival [26]. Based on these observations, a randomized study is utilizing erlotinib as a maintenance therapy after platinum-based chemotherapy. Patients (n=850) who are effective or stable after four cycles of combination chemotherapy will be randomized to the erlotinib or placebo arm. The primary endpoint is progression-free survival.
Second-line chemotherapy for advanced non-small cell lung cancer
The prognosis of patients with advanced non-small cell lung cancer is usually poor once tumor progression occurs after first-line treatment. Erlotinib as second-line treatment for advanced non-small cell lung cancer. The current FDA-approved second-line agents for NSCLC include docetaxel, pemetrexed and erlotinib.
Two randomized clinical studies completed and published in 2000 demonstrated that docetaxel was more effective as second-line chemotherapy than best supportive care or vincristine monotherapy in advanced NSCLC. regimen versus best supportive care for advanced non-small cell lung cancer. The results showed that docetaxel not only prolonged patient survival (7 months: 4.6 months), but also significantly improved quality of life. Another study designed to compare the efficacy of vincristine with docetaxel as second-line chemotherapy for non-small cell lung cancer [36] (TAX320) randomized enrolled patients to a single 3-week regimen of docetaxel (75 mg/m2) or a two-drug regimen of vincristine combined with isocyclophosphamide. Although the results of this trial showed that the median survival of patients after both treatments was 5 to 6 months without significant difference, the 1-year survival rate was 32% for patients receiving docetaxel, which was significantly higher than the 19% who received vincristine with isocyclophosphamide (P=0.025).
Pemetrexed is a new pyrrolopyrimidine anti-folate cytotoxic agent whose metabolites exert their cytotoxic effects by inhibiting key nucleic acid-dependent enzymes.A randomized phase III clinical trial designed to compare pemetrexed with docetaxel as second-line chemotherapy for non-small cell lung cancer was completed and published in 2004 [37]. The results of the trial showed similar efficacy of both treatments as second-line chemotherapy for non-small cell lung cancer.
Erlotinib, a small molecule tyrosine kinase inhibitor of the epidermal growth factor receptor, was published in the New England Journal of Medicine in 2005 in a multicenter phase III trial (BR.21 trial) from Canada [38], which demonstrated the efficacy of erlotinib in advanced non-small cell lung cancer. The results of this large randomized clinical trial showed that patients randomized to erlotinib had a treatment efficacy rate of 8.9%, which was significantly higher than that of those receiving placebo (1%); the overall survival rates at 1 year were 30% and 20% in the two groups; the disease progression-free time was 2.2 months and 1.8 months, respectively; and the median survival was 6.7 months and 4.7 months, respectively, which was superior in the erlotinib-treated group.