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With the tumor's molecular and biological characteristics of in-depth understanding of its role in tumor progression pathway specificity of biological research and application of new drugs have been developed, such a treatment called "targeted therapy." These biological agents (including cell growth factor receptor-targeted drugs, angiogenesis inhibitors and signal transduction inhibitor) is applied to non-small cell lung cancer is in progress (Table 1). At first, because they believe these drugs alone will not lead to cancer have been alleviated, so these biological agents were initially described as "inhibition of tumor cell proliferation," to distinguish it from conventional treatment of cytotoxic drugs; study found, however, some of which drugs alone can make an objective tumor response (although these drugs are usually only 10% -20% can achieve this effect).
Can assume that the purpose of the current targeted therapy is that these apply to specific types of cancer drugs that act on the biological approach with surgery, conventional chemotherapy or radiation therapy combined with the treatment used in various tumors, including the maintenance treatment and chemoprophylaxis (Figure 2). The following focuses on targeted therapy in non-small cell lung cancer the choice of treatment.

Epidermal growth factor receptor inhibitor

Human tumor cells expressed high levels of growth factor and its receptor. Epidermal growth factor receptor (EGFR) or ErbB tyrosine kinase receptor, is the most in-depth study of one of the tumor growth factor receptor. EGFR family includes four kinds of receptor types, in a variety of tumors have overexpressed. The study of lung cancer found that 81% -93% of lung cancer patients have EGFR expression, 45% -70% of the patients had over-expression (more than 20% of the cell receptor staining) in squamous cell carcinoma patients (57% -92%) of the over-expression than non-squamous cell carcinoma patients (36% -58%) is more common [9-11]. Application of anti-EGFR monoclonal antibodies or tyrosine kinase inhibitors (EGFR signal transduction pathway essential component) to inhibit EGFR, can inhibit the progress of the cell cycle, inhibit angiogenesis, inhibit chemotherapy or radiotherapy in the post-DNA repair, while increasing tumor cell apoptosis.
Trastuzumab (Herceptin) is an ErbB-2 (also known as HER2/neu) monoclonal antibody inhibitors, has been approved for the treatment of advanced breast cancer overexpressing HER2/neu. Trastuzumab combined with cytotoxic drug treatment of non-small cell lung cancer small research proved to be effective [12], ECOG has been planned for Herceptin used in non-small cell lung cancer Phase III randomized study; ErbB-2, however, the over-expression in non-small cell lung cancer is not common, the study found 2 + / 3 + overexpression of only about 10% of patients, so the program can be implemented is questionable [12].
Cetuximab (IMC-C225) is the ErbB-1 monoclonal antibody, which combined with chemotherapy or radiotherapy used in over-expression of EGFR (ErbB-1) in non-small cell lung cancer cell lines has made remarkable efficacy, while combination therapy in the with advanced colon cancer, head and neck cancer and pancreatic cancer such as cancer treatment has also made remarkable efficacy. Cetuximab in combination with carboplatin / gemcitabine or carboplatin / paclitaxel as first-line therapy or combined with docetaxel as second-line treatment programs II clinical study.
ZD1839 (Iressa) and OSI-774 (Tarceva) is structurally similar quinazolines as EGFR tyrosine kinase inhibitors. In a number of ZD1839 in Phase I clinical studies found that, ZD1839 for multiple cases of non-small cell lung cancer effective [13-15]. About 1 / 3 of non-small cell lung cancer application of ZD1839 in patients with stable disease after at least 3 months; pre-treatment in patients with stable disease obviously can last more than a year [14]. Currently, there are two large samples of Phase III studies are under way, more than 1,000 the previous phase III did not receive chemotherapy / IV non-small cell lung cancer patients, use of two doses of ZD1839 or placebo at the same time combined with gemcitabine / cisplatin or carboplatin / paclitaxel.
Two randomized, double-blind Phase II study (IDEAL I and IDEAL II) compared to tumor progression after chemotherapy of non-small cell lung cancer patients a separate oral ZD1839 (250mg / day vs 500mg / day) efficacy. The results of Clinical Oncology in 2002, the United States conducted a presentation at the annual meeting [16-17]. Kris and other studies for individual or to accept both containing platinum and docetaxel chemotherapy for at least two kinds of treatment failure in patients with Phase II clinical study [16]. In these patients, 102 patients ZD1839 dosage of 250mg / day, 114 dosage of 500mg / day.
In this study, two groups of patients with remission rates were 11.8% (250mg / day group) and 8.8% (500mg / day group); sustained relief of 3 to 7 + months. 250mg / day group and 500mg / day group of patients with stable disease rates were 31% and 27%. Interestingly, in order to improve the symptoms of lung cancer to evaluate the standard remission rate of 40%. The two groups in median survival time of patients with no significant difference (250mg / day group and 500mg / day group were 6.1 months and 6.0 months). The main drug-related side effects of mild, 3 / 4 of the side effects rate was only 6.9% (250mg / day group) and 17.5% (500mg / day group). Two kinds of doses of ZD1839 also showed significant anti-tumor activity of the role of long-term use is well tolerated.
In another Phase II study (IDEAL I), Fukuoka and his colleagues evaluated 208 patients to evaluate ZD1839 treatment of non-small cell lung cancer patients the efficacy and safety of these cases have one or two chemotherapy treatment failure history ( At least one platinum-based chemotherapy drugs) [17]. 250mg / day group and 500mg / day group response rate (respectively 18.4% and 19%) or overall survival (respectively 7.6 months and 8.1 months) there was no significant difference, 40.3% of patients have symptoms improved. Drug-related adverse reactions are very mild reaction, 250mg / day group only a small proportion of patients with 3 / 4 adverse reactions. Concluded that the application of ZD1839 250mg / day and 500mg / day similar efficacy, but rare side effects, and to a lesser extent.
Perez-Soler, etc. carried out on the OSI-774 Phase II clinical study of 57 non-small cell lung cancer of platinum-based chemotherapy drugs received at least once after the chemotherapy, and disease progression or recurrence, immunohistochemical test requirements can be assessed cancer cells in patients with EGFR-positive rate of over 10% [18]. Patients with objective response rate was 12.3% (including one patient complete remission, 6 patients with partial remission), there were 15 patients (26.3%) stable disease. The median survival period was 37 weeks, one-year survival rate was 48%. Efficacy of all patients, previously on average after two cycles of chemotherapy (1-4 cycles), of which six patients with adenocarcinoma, 2 large cell carcinoma patient, all of these EGFR-positive patients were 2 + / 3 + (an average of 2.7 +). With ZD1839 similar, OSI-774 The most common side effects of acne-like dermatitis, in this study, 50% of patients (only 1 in patients with ≥ 3 level); all occurred in patients with different types of skin reactions. 32% of the patients in treatable diarrhea (≥ 3 in patients with only one level).
2 OSI-774 is currently a large sample, randomized, double-blind Phase III study. In the United States, 1050 first received chemotherapy III / IV non-small cell lung cancer patients were applied to OSI-774 or placebo in combination with carboplatin / paclitaxel chemotherapy. An international study of 330 previously at least one time (not more than 2 times) of treatment failure with advanced or metastatic non-small cell lung cancer patients with the application of the evaluation of OSI-774. In this study, patients were given OSI-774 or placebo, applied OSI-774 and application of placebo patients the ratio of 2:1.
 
Angiogenesis inhibitor

Angiogenesis, the growth of most solid tumor expansion is critical, some special cells in the product and factor can promote angiogenesis, inhibit tumor angiogenesis is to control the growth of an important targeted therapy. Matrix metalloproteinase (MMP) can degrade extracellular matrix, promoting tumor progression, angiogenesis and tumor metastasis. MMP inhibitors are the first class to be studied anti-angiogenic drugs, some drugs alone have proven solid tumor animal models and effective. However, an MMP inhibitor prinomastat Phase III study found that the initial chemotherapy of advanced non-small cell lung cancer patients with carboplatin / paclitaxel for patients with these drugs did not lead to greater benefits Pack [19].
Vascular endothelial growth factor (VEGF) in cancer patients is a more common expression of a vascular endothelial growth factor, VEGF inhibitors is most likely to inhibit angiogenesis drugs. Ligand recombinant human anti-VEGF monoclonal antibody (rhuMAb-VEGF) in non-small cell lung cancer, colon cancer and breast cancer carried out in Phase II studies demonstrated anti-tumor activity. In DeVore, etc. Phase II studies conducted in non-small cell lung cancer patients with carboplatin / paclitaxel combined with or without low-dose or high-dose rhuMAb-VEGF, control group patients if the disease progression, can be applied to rhuMAb-VEGF. Control group, patients with objective response rate was 19% (32 people), low-dose rhuMAb-VEGF group objective response rate was 28% (32), high-dose rhuMAb-VEGF group reached 31.5% (35 people), three groups of patients with median disease, time to progression were 4.2 months, 4.3 months and 7.4 months, median survival was 14.9 months, 11.6 months and 17.7 months [20].
However, the application of rhuMAb-VEGF in patients with 6 patients in pulmonary hemorrhage (5 man-made low-dose group), while the control group, there is no one cases occurred in patients with pulmonary hemorrhage. 4 pulmonary hemorrhage as a squamous cell carcinoma, squamous cell carcinoma patients because the tumors were close to the central government, so there is a tendency to bleed more easily lesion Department. For non-squamous cell carcinoma patients (control group of 25 persons, low-dose rhuMAb-VEGF group of 22 people, high-dose rhuMAb-VEGF group of 31 people) for prognostic analysis found that patients with objective response rates were 12%, 27% and 32%, The median time to progression were 4.1 months, 6.3 months and 7.2 months, the median survival time was 12.3 months, 14.2 months and 18 months, one year survival rates were 52%, 50% and 68 % [21]. ECOG has started a Phase III study to evaluate the initial chemotherapy IIIb / IV advanced non-squamous non-small cell lung cancer alone carboplatin / paclitaxel or the combination of high-dose rhuMAb-VEGF effect of the two programs.
 
Signal transduction inhibitor

Protein kinase C in cell growth, differentiation, secretion, extracellular secretion, immune cell function regulation, receptor down, and so the process of apoptosis plays an important physiological role. Protein kinase C has been found to have more than 10 kinds of isomers, in a variety of tumors have overexpressed. Non-specific protein kinase C receptor inhibitor manifestations of anti-tumor activity in pre-clinical studies have found that protein kinase C antisense oligonucleotide can inhibit the mRNA and inhibit protein synthesis, which showed anti-tumor activity. ISIS-3521 is an anti-protein kinase C-α antisense oligonucleotide. In an I / II study were [22], untreated non-small cell lung cancer patients with carboplatin / paclitaxel plus ISIS-3521 of the objective response rate of 46%; disease, time to progression of 6.3 months, median survival time was 15.9 months, one year survival rate was 55%. 3 and 4 neutropenia incidence rates were 26% and 43%, 3 and 4 The incidence of thrombocytopenia were 21% and 11%. In an ongoing Phase III study, 600 non-small cell lung cancer patients were randomly alone carboplatin / paclitaxel or the combination of ISIS-3521, to evaluate its efficacy and toxicity.
 
Conclusion

A large number of non-small cell lung cancer targeted therapy in randomized studies are under way or being planned; studies provide data to improve our understanding of the efficacy of these drugs, while allowing us to better grasp how to use these drugs approach. Although the biological agents in most cases need to combined with chemotherapy and in the form of a joint treatment, but eventually the drugs will be applied to each phase of cancer treatment and chemoprevention in the maintenance treatment and to play its due role. However, pre-clinical treatment modalities still need to emphasize further research and these new targeted therapies active application of the importance of alternative treatment options, regardless of clinical application of these drugs on how the auxiliary guide. Evaluation of efficacy for each patient the truth is also very important.
Because of tumor molecular characteristics of the complex nature of the treatment is based on the best characteristics of patients with cancer to develop individualized treatment programs. Will eventually be found, the application of biological agents (such as molecular targeted therapy drugs, anti-angiogenesis drugs, monoclonal antibodies) and cytotoxic drugs combination therapy to reach the best effect. These new targeted therapy program will be new hope for treatment of lung cancer.