China is a country with a high incidence of lung cancer, and the incidence of lung cancer has been on a continuous rise in recent decades, and now occupies the first place in the incidence of all malignant tumors. The current situation of lung cancer in China is: on the one hand, the incidence rate of small cell lung cancer is increasing rapidly, and the proportion of lung cancer in the total lung cancer is increasing year by year. Early diagnosis of lung cancer is still very difficult, and 80% of patients are already in the middle and late stages when diagnosed, losing the chance of radical surgery. However, on the other hand, with the continuous improvement of treatment technology, the treatment of lung cancer has made more obvious progress and the efficacy has been significantly improved.
1. Overall treatment progress of lung cancer
Many patients, including a considerable number of primary care doctors, think that the outcome of lung cancer is similar whether they are treated or not. In fact, this view is incorrect. In the past 20 years, chemotherapy for lung cancer has been significantly improved. With the introduction of new effective anti-cancer drugs such as paclitaxel and pemetrexed, and the accumulation of clinical experience, chemotherapy regimens have been improved. Among the first-line chemotherapy regimens for lung cancer, those for small cell lung cancer have been focused on regimens such as CAV and EP, while those for non-small cell lung cancer have been focused on NP, GP, TP and DP.
In addition, the introduction of new targeted therapeutic agents has provided new options for chemotherapy for non-small cell lung cancer. The efficacy of chemotherapy for lung cancer has also been significantly improved, and the remission rate (RR) of combined chemotherapy for small cell lung cancer can reach over 90%, and the CR can reach 30%-40%. The sensitivity of chemotherapy for non-small cell lung cancer has also increased from 15% to 20% of the remission rate of combination chemotherapy in the 1970s to 20% to 40% at present. However, with the widespread use of antineoplastic drugs, drug resistance has become one of the most common and difficult to overcome problems of chemotherapy failure in clinical tumors.
According to general data, the median survival time after diagnosis of advanced lung cancer is 3-5 months without effective treatment. With aggressive chemotherapy and radiotherapy after diagnosis, the median survival time is generally 7 to 9 months. According to our recent data, the median survival time after diagnosis of advanced stage (clinical stage III and IV) lung cancer can be 11 to 12 months in small cell lung cancer and more than 15 months in non-small cell lung cancer if chemotherapy-based combination therapy is used.
This shows that the survival time is very different between treatment and no treatment. Therefore, we need to change the past concept. Instead of simply classifying lung cancer as a terminal disease and waiting negatively, lung cancer should be regarded as a chronic disease, and effective treatment can improve patients’ quality of life and control the progress of the disease to a certain extent.
2. Chemotherapy resistance of lung cancer
After lung cancer patients receive chemotherapy, some of them have good treatment, while others have unsatisfactory treatment, and some of them have chemotherapy resistance regardless of which chemotherapy regimen. Chemotherapy resistance in lung cancer can be divided into two types according to its occurrence. One type is primary drug resistance, also known as intrinsic drug resistance or natural drug resistance, which means that tumor cells are originally tolerant to the drugs and the efficacy of chemotherapy drugs is poor or ineffective, which is manifested as high tolerance to chemotherapy drugs from the beginning of treatment.
The other category is secondary drug resistance, also known as acquired drug resistance, which means that the initial treatment is effective, but after a period of treatment, the tumor cells become tolerant to the previously effective drugs, thus making the drug treatment fail again. Although both small cell lung cancer and non-small cell have primary and secondary drug resistance problems, chemotherapy resistance is more severe in non-small cell lung cancer.
Small cell lung cancer accounts for approximately 20% of lung cancers, and it is highly malignant and prone to distant metastases. Although in patients with extensive-stage small cell lung cancer, the median survival time from the start of chemoresistance to patient death remains unsatisfactory. However, small cell lung cancer is generally more sensitive to initial treatment and has a higher efficiency of chemotherapy, i.e., there is less primary chemoresistance in small cell lung cancer. And for small cell lung cancer that has been in clinical remission for more than six months, reuse of the initial treatment regimen remains effective when the disease progresses.
Non-small cell lung cancer accounts for approximately 80% of lung cancers and is the most common malignancy death. The current first-line chemotherapy regimens for non-small cell lung cancer mostly use a combination of platinum plus gemcitabine (GP), vincristine (NP), paclitaxel (TP) or docetaxel (DP). Whereas the overall effective rate of these regimens is generally 20% to 40%, the remission rate of any one regimen does not exceed 40%. This shows that most patients with non-small cell lung cancer have difficulty in achieving effective remission with chemotherapy.
Moreover, some patients with non-small cell lung cancer have multidrug resistance and are not sensitive to various chemotherapy drugs. Moreover, unlike small cell lung cancer, patients with non-small cell lung cancer who have achieved remission after initial treatment are not well treated with the original regimen when the disease progresses again, even if the remission period is more than 6 months. Therefore, the primary and secondary drug resistance rates of non-small cell lung cancer are both high. Compared with small cell lung cancer, the impact of chemotherapy resistance on the efficacy and prognosis of non-small cell lung cancer is more prominent and more difficult to solve, which has become one of the major problems in lung cancer prevention and treatment.
3.Comprehensive treatment can improve chemotherapy sensitivity of lung cancer to a certain extent
The sensitivity of lung cancer patients to chemotherapy is the result of a combination of many factors, which is related to individual lung cancer cell heterogeneity, physical status and immune function of patients, as well as the intrinsic environmental factors such as age, gender, organ function, enzymes and endocrine. Therefore, when choosing a treatment plan, a comprehensive approach should be adopted according to the different tissue types, stages of the disease and the patient’s systemic condition of lung cancer.
Non-small cell lung cancer has not been highly sensitive to chemotherapy. Compared with 20 years ago, the sensitivity of gemcitabine, docetaxel and pemetrexed has improved, but the effective remission rate of single-agent chemotherapy is still not high, and all chemotherapeutic drugs have different degrees of adverse effects. The research and development of new drugs with “high efficiency and low toxicity” may be expected;
Under the existing conditions, it is desirable to use a combination of chemotherapeutic drugs with different mechanisms of action to increase sensitivity through synergistic effects, and this is a consensus in academic circles. However, in the clinical observation of non-small cell first-line chemotherapy regimens, it was found that the efficacy of three-drug combination was not increased compared with two-drug combination, but the toxicity was increased.
The immune function of the body is closely related to the occurrence and development of tumors, and the incidence of tumors is increased when the host immune function is low or suppressed. When the tumor grows progressively, the immune function of the patient is further suppressed. The immune system is often suppressed after repeated chemotherapy, and the disruption of the balance between various immune functions may also be another reason for this.
Some studies have also shown that administration of OK432 (sapropterin), high polyglucagon, interferon, interleukin, thymidine, and some immunomodulatory agents such as colony cell stimulating factor while receiving chemotherapy can improve immune recognition and immune response in lung cancer chemotherapy patients, and to a certain extent can relieve the immune resistance or immunosuppression state. The clinical efficacy of novel tumor vaccine trials has also been initially confirmed. Immunotherapy not only provides patients with an alternative treatment method, but also shows the effect of improving the efficacy of chemotherapy, which is a promising research direction.
In addition, TCM has gained certain efficacy in the treatment of non-small cell lung cancer, and has played a characteristic role in relieving symptoms and prolonging survival. Traditional Chinese medicine against cancer is based on its traditional deficiency tonic, detoxification and expectorant, and stasis removal, which has the efficacy of expelling cancer toxins, eliminating accumulation and pain, and softening and dispersing nodules. Modern research shows that herbal medicine mainly acts in S-phase, which is a cell cycle specific drug.
Ginsenoside, Ganoderma lucidum polysaccharide, Lycium barbarum polysaccharide, Shiitake mushroom polysaccharide and Yunzhi polysaccharide extracted from Chinese herbal medicine have the functions of inhibiting lung cancer cell proliferation, improving the sensitivity of chemotherapy drugs such as cisplatin and reversing lung cancer’s resistance to platinum, as well as elevating white blood cells and improving immune function, which can improve the quality of survival and prolong the survival period.
4.Individualized treatment is expected to improve the efficiency of chemotherapy
Drug resistance of lung cancer is related to the following factors: enhanced self-repair ability of lung cancer cells after injury, dense reinforcement of lung cancer extracellular surrounding matrix, enhanced activity of detoxifying substances in lung cancer cells, abnormal change of regulatory substances of drug-induced apoptosis in lung cancer cells, overexpression of ATP-dependent transporter protein in lung cancer cell membrane, abnormal cellular signal transduction, and many other factors.
However, for each lung cancer patient, the causes of chemoresistance vary, and the types of drugs tolerated also differ. Individuals who are platinum-resistant may be sensitive to gemcitabine, while those who are resistant to both gemcitabine and docetaxel may still be sensitive to gefitinib. The underlying reason for this individual variation may be due to differences in patients’ chemosensitivity-related gene profiles.
In lung cancer patients, there are individual differences in the mutation and expression of various cancer-related genes such as KRAS, TP53, BCL-2, EGFR, EMP-1, ERCC1, ERCC4, RRM1, as well as microtubulin and methylenetetrahydrofolate reductase, which are often associated with chemosensitivity in non-small cell lung cancer.
The ERCC1 gene is a highly conserved evolutionary gene, and its expression of ERCC1, a highly conserved protein, is required to maintain life activity. ERCC1 acts as a rate-limiting enzyme in nucleic acid exocytosis repair activity. In non-small cell lung cancer treated with platinum-based adjuvant chemotherapy after surgery, patients with low ERCC1 expression have a better prognosis. patients with negative ERCC1 protein benefit more significantly from adjuvant chemotherapy with platinum-containing regimens. Overexpression of RRM1, another key enzyme in cellular DNA synthesis and repair, was associated with both platinum and gemcitabine resistance.
Therefore, RRM1 and ERCC1 can be used as prognostic markers in patients with early-stage non-small cell lung cancer without chemotherapy, but in advanced non-small cell lung cancer, chemotherapy may lead to resistance to GP (or GC) regimens if administered, and patients with high RRM1 and ERCC1 expression are not suitable for chemotherapy with platinum and gemcitabine options. Patients with non-small cell lung cancer with high beta microtubulin III expression are more likely to benefit from NP chemotherapy regimens.
KRAS is a key regulatory molecule downstream of EGFR, and KRAS and EGFR-mutated NSCLC are mutually exclusive. EGFR mutations are mainly seen in nonsmokers, while KRAS mutations are more commonly seen in smoking-associated lung cancer. KRAS codon 12 and 13 mutations are present in approximately 15-30% of patients with NSCLC, leading to primary resistance to gefitinib and erlotinib.
EMP-1 has also been suggested to be a biomarker for both primary and acquired resistance to Gefitinib. Thus, while patients with non-small cell lung cancer who are potentially resistant to conventional platinum-containing regimens of chemotherapy may be treated with the small molecule inhibitors of EGFR, gefitinib and erlotinib, as monotherapy, this option may be futile in the presence of KRAS mutations and overexpression of EMP-1.
To date, at least 50 genes have been identified that are associated with chemotherapy sensitivity, and the expression of these genes can be used as biomarkers to predict the sensitivity of tumor chemotherapeutic agents. Before choosing chemotherapy regimens, if genomic or proteomic analysis can be performed on patients to determine chemotherapy regimens based on individual genomic and proteomic characteristics, it will undoubtedly be beneficial to reduce the blindness of chemotherapy, thus improving the sensitivity of chemotherapy and reducing the chance of chemotherapy resistance.
5.Gene therapy may be the fundamental solution for multidrug resistance in lung cancer
Multidrug resistance refers to the phenomenon that tumors are resistant to one chemotherapeutic drug and at the same time, they are cross-resistant to many other chemotherapeutic drugs with different structures and mechanisms of action. This is a unique phenomenon of broad-spectrum drug resistance. Although multidrug resistance in non-small cell lung cancer may be related to a combination of apoptosis inhibition and immune mechanisms, the underlying cause lies in the genetic characteristics of lung cancer cells.
The mechanism of multidrug resistance is currently considered to be a complex process with multifactorial effects and multiple genetic alterations. Telomerase and genes such as GST, survivin and bcl-2 are all involved in multidrug resistance in non-small cell lung cancer to some extent, but the most important cause may be the abnormal expression of MDR. The expression level of multidrug-resistant MDRl gene is proportional to the multidrug resistance of human cancer cells, and its copy number can be amplified tens or even hundreds of times. Multidrug resistance-related proteins (MRP) are all positively expressed in NSCLC and jointly mediate the involvement in the inherent multidrug resistance mechanism of NSCLC.
There is a lack of effective solutions for multidrug resistance in non-small cell lung cancer. Transfer inhibitors acting on P-glycoprotein, cyclophilin A, hormonal and anti-hormonal drugs, interferons, glutathione-depleting agents, and drug-protein cross-linking agents may have some transfer-resistant effects. However, none of these drugs can solve the problem at the root and have certain adverse effects. In terms of strategic analysis, the most promising approach to address multidrug resistance is gene therapy for non-small cell lung cancer.
There are various methods of gene therapy. For the high expression of multidrug resistance-related genes, genetic engineering technology can be used to produce antagonists of drug-resistant proteins, which can be used in combination with chemotherapy drugs to reverse the drug resistance phenomenon and make the original drug-resistant patients sensitive to chemotherapy again. Antisense oligonucleotide or SiRNA interference techniques can also be used to block the expression of abnormally high expression of drug resistance-related proteins and reduce the expression level of drug resistance-related proteins or factors in lung cancer tissues to relieve the chemoresistance of lung cancer cells.
In addition, abnormal gene structure and expression are molecular features of tumor cells, and tumor-associated genes with disordered structure and function are corrected in vitro and then introduced into lung cancer cells to restore their function to normal. Current experimental studies targeting mdrl, survivin, bcl-2, Tp53 and other base therapies have shown preliminary effects. If the gene therapy technology eventually achieves full success, it may even replace the current chemotherapy, which is one of the most promising approaches to overcome lung cancer.