Epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors are newly emerging targeted therapeutic agents with proven efficacy in solid tumors. The developmental studies are based on the idea that tumor development and metastasis are closely related to protein tyrosine kinases in cell signaling; the latter affects cell proliferation and differentiation mainly by catalyzing the phosphorylation of tyrosine kinase residues of many important proteins; and EGFR overexpression in most tumors is directly related to elevated tyrosine kinase activity. Therefore, the development of EGFR-targeted therapies targeting EGFR and its tyrosine kinases has become a new hot spot in antitumor research today. Recent basic and clinical studies have demonstrated the efficacy of EGFR-TK-targeted drugs in treating tumors. Currently, there are two major classes of EGFR-TK inhibitors: one is monoclonal antibodies (IMC-C225, ABX-EGF), which mainly act in the extracellular region of EGFR and inactivate the receptor by competitively inhibiting the binding of ligands to EGFR; the other is small molecule compounds (Iressa, OSI-774), which can enter the cell and act directly on the intracellular region of EGFR, interfering with ATP binding and inhibiting tyrosine activity. Although monoclonal antibodies and small-molecule compounds have different mechanisms of action, they have demonstrated significant antitumor activity in in vitro cells, in vivo animal tests, and in clinical trials. Among them, small-molecule tyrosine kinase inhibitors have attracted much attention due to the advantages of oral administration and direct intracellular access to inhibit the target enzyme. Although the clinical efficacy of EGFR-targeted drugs is encouraging, these drugs only inhibit but not kill tumors, and the clinical efficiency of single drugs is only about 15%. Therefore, it is hoped that the combination with chemotherapy can further improve the anti-tumor effect. Recent experimental studies have shown that the combination of EGFR-TK-targeted drugs IMC-C225, IRESSA and OSI-774 with chemotherapeutic drugs of different mechanisms of action can improve the antitumor effect to varying degrees. For this reason, clinical phase II and III studies of EGFR-TK-targeted therapy in combination with chemotherapy have also been conducted in different solid tumors [6-8]. As a result, IMC-C225 combined with chemotherapy to improve clinical outcomes has been reported more frequently. the efficiency (CR+PR) of Herbst et al. with IMC-C225+cisplatin for head and neck squamous carcinoma in which cisplatin-containing combination chemotherapy was ineffective (SD+PD) was above 20%. In a randomized phase III clinical study by the Eastern U.S. Oncology Collaborative Group, placebo+cisplatin was only 9.3% effective in head and neck cancer, compared to 22.6% effective in the IMC-C225+cisplatin group, but median TTP was not significantly prolonged. Gatzemeier et al. reported that IMC-C225 combined with cisplatin and nolvadex was 50% effective in the treatment of advanced non-small cell lung cancer, which was significantly more effective compared to 29% with cisplatin + nolvadex alone [12]. However, clinical reports of improved efficacy of IRESSA or OSI-774 in combination with chemotherapy are rare, and Fandi et al. showed no significant improvement in efficacy with IRESSA in combination with Tysodi for advanced non-small cell lung cancer compared with Tysodi alone. Since targeted therapy is a new therapeutic modality based on molecular biology theory, its mode of action is completely different from traditional chemotherapeutic drugs, and the mechanism of action and characteristics of various targeted drugs are not exactly the same. Therefore, whether the combination of different targeted drugs and chemotherapy can achieve synergistic or additive effects, the mechanism of their combined action, the optimal effect and the most suitable regimen should be determined by systematic studies before clinical trials. tumors with high EGFR expression are relatively sensitive to chemotherapy, while tumor resistance to chemotherapy is thought to be related to the reduction of its growth signal [14]. If targeted therapy is given concurrently or before chemotherapy, it may reduce the effectiveness of chemotherapy. Conversely, if induction of multi-cycle chemotherapy is given first, it may further increase the expression level of EGFR and make subsequent targeted drugs more targeted [15-16]. It is thus concluded that the combination of EGFR-TK-targeted drugs and chemotherapy may not be a simple addition of the effects of the two drugs. How to rationally arrange targeted therapy and chemotherapy to maximize their effects is an urgent clinical problem. The mechanism of action of EGFR-TK-targeted drugs is unique. The following mechanisms of action are known: inhibition of EGFR-TK; inhibition of damage repair in tumor cells; blocking cells in G1 phase; induction and maintenance of apoptosis; and anti-neovascular formation. Since tumors with high EGFR expression are relatively sensitive to chemotherapy; and tumor resistance to chemotherapy is related to the reduction of growth signals, the analysis of the combined effect with chemotherapy according to the mechanism of action of EGFR-TK-targeted drugs should be about the timing of administration and the order of administration. Simultaneous or prior administration of chemotherapy may affect its combined effect. This is because (1) if targeted therapy is given simultaneously or before chemotherapy, the effect of chemotherapy may be reduced due to the inhibition of EGFR signaling. If chemotherapy is given before targeted therapy, it may induce tumor EGFR expression and enhanced signaling, making the subsequent targeted therapy more targeted. (2) Since cells start DNA repair and division in the G2/M phase, subsequent targeted therapies that block cells in the G1 phase after chemotherapy-induced cell damage can further interfere with the repair of damaged cells. (3) Previous basic studies have shown that the combination of EGFR-TK-targeted therapy with chemotherapy can further enhance apoptosis. Our previous study found that EGFR-TK-targeted drugs could maintain chemotherapy-induced apoptosis. (4) It was shown that EGFR-TK-targeted therapy can affect the expression and secretion of TGFα, VEGF, interleukin-8 and bFGF, thus reducing neovascularization. However, this effect may be apparent for the initial formation of tumor microvessels after effective chemotherapy, while it is difficult to be effective for larger vessels in advanced tumors. Therefore, theoretically, the combination of EGFR-TK-targeted drugs with chemotherapy should be considered in terms of how to rationally group the drugs, the most appropriate timing of administration and the best order of administration. Since Herceptin, the monoclonal anti-Her-2/neu, combined with paclitaxel or adriamycin, has been shown to significantly improve the clinical efficacy and prolong the survival of advanced breast cancer, clinical studies of EGFR-TK inhibitors have basically copied the dosing idea of Herceptin combined with chemotherapy, without fully understanding the different mechanisms of action and properties of different targeting drugs and without fully consider the effect of combining different target drugs with different chemotherapeutic drugs, nor fully evaluate the best timing and order of administration of the combination of two types of drugs, but simply adopt the order of simultaneous administration of two types of drugs or target drugs → chemotherapy from clinical considerations, which may affect the anti-tumor effect of their combination, resulting in a single clinical research model of combining EGFR-TK target drugs with chemotherapy. This has led to mixed results in several clinical studies of the combination of targeted agents with chemotherapy. Some of these clinical studies have shown encouraging results, but others have shown that the combination of targeted therapy with chemotherapy did not increase clinical benefit. Researchers from Hospital 307 of the Academy of Military Medical Sciences, together with researchers from NCI, Italy, explored the mechanism of IRESSA in combination with different chemotherapeutic agents from the perspective of molecular pharmacology, and systematically investigated the effects of the targeted drug IRESSA, chemotherapeutic agents, and different combination regimens on the antitumor effect, intracellular drug concentration, and regulation of signal transduction molecules [18-19]. It was found that the combination effect of IRESSA with chemotherapeutic agents such as platinum oxalate, irinotecan or 5-fluorouracil in colorectal cancer was regimen-dependent. The theory of the existence of an optimal dosing regimen and timing for the combination effect of IRESSA with chemotherapeutic agents was proposed for the first time. Our study showed that IRESSA inhibits the repair of chemotherapy-induced DNA damage; IRESSA not only induces apoptosis, but the greater effect lies in the maintenance of chemotherapy-induced apoptosis. Further studies revealed that this effect is based on the ability of IRESSA to maintain the intracellular concentration of chemotherapeutic drugs and to regulate the phenotypic activity of EGFR and its downstream molecular expression. It was also found that there exists not only an optimal sequence of administration of IRESSA in combination with chemotherapy, but also an optimal dose ratio [. Although we have traditionally advocated the principle of “no change in formula if effective, change if ineffective” in sequential chemotherapy [20], we propose that the optimal mode of IRESSA-chemotherapy combination, based on the clarification of the molecular mechanism of IRESSA-chemotherapy combination, should be to stop chemotherapy after the induction of the effect of chemotherapy and to give IRESSA sequentially and continuously. It is assumed that this sequential mode of administration has the potential to sustain tumor growth inhibition. The benefits of abruptly discontinuing chemotherapy are (1) to stop the toxic side effects of chemotherapy and allow the patient to fully recover, and (2) to observe the efficacy of IRESSA alone. If the tumor lesions continue to shrink or even disappear, they can be applied for a long time to consolidate the efficacy; even if the lesions do not shrink, as long as they are stable and unchanged, they can be administered for a long time for the clinical benefit of SD ≥ 6 months, and it is believed that their survival can be similar to that of CR and PR patients; (3) once IRESSA fails, because its plasma half-life is about 24 hours, and our in vitro study shows that IRESSA’s effect on cell division and proliferation is restored within a few hours after its washout removal, therefore, the tumor may still be sensitive to the original effective chemotherapy regimen and a restart of chemotherapy can be considered after a few days of IRESSA discontinuation. In the current clinical studies conducted with IRESSA for advanced non-small cell lung cancer and head and neck squamous carcinoma, we used this modality and the results initially showed the advantages of sequential dosing. One of the patients with advanced non-small cell lung cancer had multiple predominant lesions in both lungs and multiple bone metastases, lymph node metastases, and predominant pelvic lesions were found. Six cycles of multiple courses of chemotherapy including Kenzyme + cisplatin, paclitaxel + platinum oxalate, Tysodex + carboplatin, and Tysodex + novobiocin and radiotherapy of some lesions had been administered within 7 months in an outside hospital. Although most of the chemotherapy regimens could see results, the remission period of each cycle of chemotherapy was too short and the tumor progressed again in less than a month. After continuous radiotherapy and chemotherapy, the patient and family completely lost confidence in the treatment because the toxic side effects were too great and the tumor was developing too fast. We treated the tumor with VP-16+platinum oxalate+isocyclophosphamide chemotherapy for one cycle, the tumor regressed significantly, and the lesion shrank further after two cycles, however, the patient’s physical condition also decreased significantly. In this case, we abruptly discontinued chemotherapy and gave IRESSA sequentially, which was evaluated as SD on review after one month. the patient has now been on IRESSA for about 2.5 months and the lesion has still not progressed. Recently, the results of two phase III clinical trials of IRESSA in combination with chemotherapy for advanced non-small cell lung cancer, which have been of great interest to the international oncology community, conducted simultaneously in the UK and the US, were disappointing. The results showed that the combination of IRESSA with paclitaxel + carboplatin, and with Kenzyme + cisplatin, did not improve patient survival compared with chemotherapy alone [10,22]. This clinical result disproves the conclusions of our study and the proposed idea of future clinical application of IRESSA. Numerous studies have shown that the sensitivity of chemotherapy is related to the proliferative activity of the tumor, that is, tumors with low proliferative activity are more resistant to chemotherapy. We note that the clinical design of these two studies was in the mode of simultaneous administration. The result may be that IRESSA inhibits the proliferative growth of tumors and reduces the efficacy of chemotherapy, so that drug combinations do not achieve synergistic or additive effects. Therefore, we believe that it is necessary to design more reasonable clinical trials to evaluate the optimal combination of IRESSA and chemotherapy. Foreign scholars have recognized the effectiveness of EGFR-TK-targeted drugs such as IRESSA in treating tumors. However, there is still confusion about how to rationalize targeted therapy and chemotherapy. Whether to combine with chemotherapy and how to combine, the current situation is like the initial use of endocrine drug triamcinolone acetonide in the treatment of breast cancer. The status of triamcinolone acetonide and chemotherapy and the rationalization of these two different treatments can only be determined through rigorous preclinical studies and rigorous randomized controlled clinical studies. We discussed the above mentioned ideas about IRESSA and chemotherapy sequencing at the 1st International Conference on Targeted Cancer Therapy held in Philadelphia, USA at the end of 2002 and at the 29th Conference of the Italian Cancer Society held in Genoa at the beginning of 2003, with mixed results. Most of the colleagues agreed with this idea, however, there are still a few clinicians who believe that there are moral issues such as sacrificing the patient’s interests by terminating the effective chemotherapy and switching to targeted oncology. We know that the current clinical application of targeted therapy is mainly for advanced non-small cell lung cancer, head and neck cancer and other tumors that are difficult to be cured by chemotherapy. Taking advanced non-small cell lung cancer as an example, even the most effective chemotherapy regimens recognized today, such as paclitaxel + carboplatin, or Kenzyme + cisplatin, have an efficiency rate of only 30-40% for primary patients, and the complete remission rate is even below 5%. In our clinical experience, if a chemotherapy regimen is effective, it should often be confirmed after 2-3 cycles. Once chemotherapy has taken effect, even after repeating the same regimen of chemotherapy for up to 6 cycles, it is rare to see cases where the good is added to the effective. Most literature reports a median TTP of only 4-6 months for 6 cycles of first-line treatment of advanced non-small cell lung cancer with combination regimens such as paclitaxel + carboplatin, or Kenzyme + cisplatin, and an even shorter TTP for second- or third-line treatment. Therefore, the subsequent cycles of chemotherapy may serve no more than a consolidation role. And many tumors may progress after 2-3 cycles of chemotherapy due to the development of drug resistance. Therefore, instead of continuing to repeat unnecessary and toxic chemotherapy, it is better to terminate it decisively and follow closely with targeted therapy for a long time to maintain or expand the efficacy until progression. EGFR-TK-targeted drugs will soon enter the Chinese market, and a few hospitals in China are currently participating in the ongoing international clinical registry trial of IRESSA for advanced non-small cell lung cancer and head and neck squamous carcinoma. However, before applying targeted drugs, we must fully understand the action characteristics of these drugs and do not over-expect that these drugs can achieve the effect of existing combination chemotherapy; the idea of using targeted drugs must also be clear, do not think that targeted drugs only play an inhibitory role on tumor and the objective clinical efficiency is not high, so we have less confidence in their clinical use and superimpose them with chemotherapy unnecessarily. In conclusion, the combination with chemotherapy is the future direction of clinical application of EGFR-TK targeted drugs. However, how to reasonably arrange these two therapeutic means and give full play to their respective advantages should be determined through rigorous preclinical studies based on the mechanism of action and characteristics of different targeted drugs and chemotherapy to determine the reasonable combination scheme, the most appropriate timing of drug administration and the best order of drug administration.