Application of anlotinib combined chemotherapy in preparation of drugs for neoadjuvant therapy of esophageal cancer

Abstract

The invention discloses application of anlotinib combined chemotherapy in preparation of a medicine for treating esophagus cancer in a new adjuvant therapy mode, experimental verification shows that the anlotinib combined chemotherapy has high clinical and pathological remission rate in the new adjuvant therapy of esophagus cancer patients, and meanwhile compared with chemotherapy combined radiotherapy, the operation difficulty can be reduced, the operation time can be shortened, and the esophagus cancer treatment efficiency can be improved. In addition, the occurrence rate of complications in the perioperative period is not increased, and assistance is provided for accelerating postoperative rehabilitation (ERAS). Therefore, in the neoadjuvant therapy of the esophageal cancer patient, the micromolecular multi-target angiogenesis inhibitor combined chemotherapy can improve the feasibility of the neoadjuvant therapy of the esophageal cancer and reduce the surgical technical threshold after the neoadjuvant therapy, so that the technology can be more widely popularized and applied; according to the application, the micromolecular multi-target angiogenesis inhibitor is used as a new selection mode for new adjuvant therapy of esophageal cancer patients.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical materials, and specifically relates to an application of anlotinib combined with chemotherapy in the preparation of a drug for the neoadjuvant treatment of esophageal cancer. Background Art

[0002] Esophageal carcinoma (EC) is one of the most common and lethal malignancies, posing a serious threat to people's health and safety. Comprehensive treatment, primarily surgery, has become the most widely adopted multidisciplinary approach to esophageal cancer treatment. However, most esophageal cancer patients present with advanced disease, and given the inherent technical difficulty of esophageal cancer surgery, this can result in incomplete resection of the primary lesion and regional lymph nodes, a major factor affecting prognosis in esophageal cancer patients.

[0003] With the application of neoadjuvant therapy for esophageal cancer, surgical resection rates have improved to a certain extent, but the expected results have not yet been achieved. In neoadjuvant therapy based on chemotherapy alone, treatment failure often occurs due to the low sensitivity of esophageal cancer cells to chemotherapeutic drugs and the poor tolerance of some patients to their toxic side effects. Therefore, studies have reported that combining chemotherapy with radiotherapy can improve the clinical and pathological remission rates of esophageal cancer, thereby improving patient survival. However, due to the damage to the normal structure of the esophagus and surrounding tissues caused by radiotherapy, it may increase the difficulty of surgery and the incidence of perioperative complications. At the same time, due to the limitations of radiotherapy instruments and equipment, its promotion is difficult. Therefore, the search for new treatment models that are safer, more effective, and easier to promote has become a hot topic in the field of neoadjuvant treatment of esophageal cancer.

[0004] In recent years, with the promotion and application of molecular targeted therapy in clinical practice, its efficacy has been confirmed. Angiogenesis inhibitors, among others, have proven their efficacy in treating advanced malignancies. While the safety and reliability of anlotinib in the treatment of esophageal cancer have been demonstrated, its use in the neoadjuvant setting has not yet been explored. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems in the related art to a certain extent. To this end, the main purpose of the present invention is to provide an application of anlotinib combined with chemotherapy in the preparation of a drug for the neoadjuvant treatment of esophageal cancer.

[0006] The purpose of the present invention is achieved through the following technical solutions: Application of anlotinib combined with chemotherapy in the preparation of neoadjuvant drugs for the treatment of esophageal cancer.

[0007] In certain embodiments, the chemotherapy drug is selected from paclitaxel, cisplatin, or a mixture thereof.

[0008] In certain embodiments, the drug is a combination of several separate formulations, which are administered simultaneously or sequentially.

[0009] In certain embodiments, the drug is in any pharmaceutically acceptable dosage form.

[0010] In certain embodiments, the drug contains an effective dose of anlotinib, a chemotherapy agent, and a pharmaceutically acceptable carrier.

[0011] Preferably, the drug further comprises a pharmaceutically acceptable carrier, such carriers including (but not limited to): diluents, buffers, suspensions, emulsions, granules, encapsulations, excipients, fillers, adhesives, sprays, transdermal absorbents, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavoring agents or adsorption carriers.

[0012] The drug of the present invention can be prepared into various dosage forms as needed, including but not limited to tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories.

[0013] The administration route of the drug of the present invention is not limited, as long as it can exert the desired therapeutic or preventive effect, including but not limited to oral administration, intravenous injection, intramuscular injection, subcutaneous injection, sublingual dissolution, rectal irrigation, nasal spray, oral spray, local skin or systemic transdermal administration.

[0014] The pharmaceutical composition of the present invention can also be used in combination with other drugs for neoadjuvant treatment of esophageal cancer. The combined use of multiple drugs can greatly improve the success rate of treatment.

[0015] Compared with the prior art, the present invention has at least the following advantages: The present invention provides the use of anlotinib combined with chemotherapy in the preparation of a drug for the neoadjuvant treatment of esophageal cancer. Experimental verification shows that anlotinib combined with chemotherapy has a high clinical and pathological response rate in the neoadjuvant treatment of esophageal cancer patients. Compared with chemotherapy combined with radiotherapy, anlotinib combined with chemotherapy can reduce the difficulty of surgery, shorten the operation time, and does not increase the incidence of perioperative complications, thus providing support for enhanced recovery after surgery (ERAS). Therefore, in the neoadjuvant treatment of esophageal cancer patients, the combination of small molecule multi-target angiogenesis inhibitors with chemotherapy can improve the feasibility of neoadjuvant treatment of esophageal cancer and lower the technical threshold for surgery after neoadjuvant treatment, enabling the technology to be more widely promoted and applied. This study proposes small molecule multi-target angiogenesis inhibitors as a new option for neoadjuvant treatment of esophageal cancer patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the specific embodiments of the present invention, the following briefly introduces the drawings required for the specific embodiments or the description of the prior art.

[0017] Figure 1 The figure is a flow chart of the neoadjuvant treatment mode of anlotinib combined with chemotherapy for advanced esophageal cancer in the present invention. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below with reference to the accompanying drawings and embodiments, but it should not be understood as limiting the scope of protection of the present invention. Any formal equivalent transformation based on the concept of the present invention should be considered as the scope of the present invention.

[0019] This document provides general and / or specific descriptions of the materials and experimental methods used in the experiments. Unless otherwise specified, all experimental or testing methods are conventional methods. All reagents and instruments used, unless the manufacturer is specified, are commercially available, conventional products and were prepared or used using conventional methods.

[0020] Example 1: Screening of subjects This application intends to enroll 112 patients with untreated stage III esophageal squamous cell carcinoma, who will be randomly assigned to either the experimental or control group in a 1:1 ratio. Unless the following circumstances occur, such as the subject withdrawing informed consent, intolerable drug side effects, or the investigator deeming the patient unsuitable for further study, the study treatment duration for each subject will continue until tumor progression is confirmed by imaging.

[0021] Table 1 Basic information of the subjects in the experimental group or the control group From the data in the table, it can be seen that there is no statistical difference in the basic clinical information of the two groups of patients.

[0022] Example 2: Establishment of a neoadjuvant treatment model of anlotinib combined with chemotherapy in advanced esophageal cancer This example provides an experimental method for the neoadjuvant treatment of advanced esophageal cancer with anlotinib combined with paclitaxel and cisplatin. The process is as follows: Figure 1 As shown in the present application, the subjects were randomly assigned to the experimental group or the control group in a 1:1 ratio. The experimental group received 2 cycles of TP regimen (paclitaxel 135 mg / m 2 iv, day 1, every 3 weeks, cisplatin 60-75 mg / m 2After treatment with 12 mg qd, d1-d14, q3w) combined with anlotinib (12 mg qd, d1-d14, q3w), the surgical indications were evaluated. If the patient was suitable for surgery, anlotinib combined with TP regimen was used for 4 cycles after surgery, and then anlotinib was used for maintenance treatment until disease progression. If there was no surgical indication, the original chemotherapy regimen was continued, and anlotinib was used for maintenance treatment.

[0023] The control group received neoadjuvant treatment with TP regimen combined with semi-quantitative radiotherapy, and then the surgical indications were evaluated. Patients with resectable disease were given TP regimen for 4 cycles after surgery and observed until disease progression; patients without surgical indications continued with the original regimen for 4 cycles.

[0024] The specific dosing regimen (the chemotherapy dose was adjusted according to the 2019 CSCO guidelines, and the dosing cycle was adjusted from 2 weeks to 3 weeks to match the dosing cycle of small molecule multi-target angiogenesis inhibitors) is as follows: Experimental group plan: ① Preoperative neoadjuvant therapy Small molecule multi-target angiogenesis inhibitor 12 mg qd, d1-d14, q3w Paclitaxel 135 mg / m 2 ,iv,d1,q3w,2 cycles Cisplatin 60–75 mg / m 2 ,iv,d1,q3w,2 cycles ② Postoperative adjuvant chemotherapy Small molecule multi-target angiogenesis inhibitor 12 mg qd, d1-d14, q3w, 4 cycles Paclitaxel 135 mg / m 2 ,iv,d1,q3w,4 cycles Cisplatin 60–75 mg / m 2 ,iv,d1,q3w,4 cycles ③ Maintenance treatment Small molecule multi-target angiogenesis inhibitor 12 mg qd, day 1-day 14, q3w until disease progression Control group plan: ① Preoperative conversion therapy Paclitaxel 135 mg / m 2 ,iv,d1,q3w,2 cycles Cisplatin 60–75 mg / m 2 ,iv,d1,q3w,2 cycles Semi-quantitative radiotherapy: 2 Gy / day, d1-d5, qw, 3 cycles ② Postoperative adjuvant chemotherapy Paclitaxel 135 mg / m 2 ,iv,d1,q3w,4 cycles Cisplatin 60–75 mg / m 2 ,iv,d1,q3w,4 cycles The drug administration cycles (6 chemotherapy cycles) are 2 cycles before surgery and 4 cycles after surgery; maintenance treatment continues until disease progression.

[0025] Example 3: Evaluation of the perioperative benefit of anlotinib combined with chemotherapy For the two groups of subjects in the experimental group and the control group set up in Example 2, patients who met the surgical indications underwent minimally invasive esophageal cancer radical resection, and the surgical R0 resection rate and the incidence of perioperative complications were monitored. The results are shown in Table 2; The effect of the conversion scheme on the incidence of perioperative complications was evaluated by comparing data such as resection rate (RR), R0 resection rate, operation time, postoperative complications, intraoperative blood loss, and lymph node dissection.

[0026] The surgical resection rate (RR) was used as the primary efficacy indicator, and the normal distribution approximation method was adopted. When the surgical resection rate of the experimental group was significantly higher than that of the control group (p < 0.05) and the increase was considered to be clinically significant, the experimental regimen was considered superior to the control regimen.

[0027] Table 2 Surgical results of subjects in the experimental group and the control group As shown in the table, among patients undergoing surgical treatment, the total operative time (203 ± 23.5 minutes) was significantly shorter in the small molecule multi-target angiogenesis inhibitor combined with chemotherapy group than in the chemotherapy plus radiotherapy group (264.0 ± 39 minutes). The difference in operative time between the two groups occurred primarily during the thoracoscopic procedure (67.2 ± 16.2 minutes vs. 110.0 ± 28.6 minutes). This difference is primarily attributed to the significantly lower thoracoscopic difficulty in the small molecule multi-target angiogenesis inhibitor group compared with the chemotherapy plus radiotherapy group. Radiotherapy can cause severe scarring of tumor tissue, obliterating the normal clearance between tumor tissue and surrounding organs and tissues, increasing the difficulty of surgical operation and raising the technical threshold. There was no difference in abdominal operative time between the two groups. Furthermore, a comparison of intraoperative blood loss between the two groups revealed that the small molecule multi-target angiogenesis inhibitor combined with chemotherapy group (54 ± 40.1 ml) was significantly less than the chemotherapy plus radiotherapy group (171 ± 122.7 ml).

[0028] There were no significant differences between the two groups in other surgery-related evaluation indicators, including R0 resection rate, lymph node dissection method, number of lymph node dissection, number of lymph node dissection stations, number of positive lymph nodes, proportion of positive lymph nodes, blood transfusion, and transfer rate.

[0029] Example 4: Anlotinib combined with chemotherapy for the relief of specific lesions For the subjects who were eligible for surgery in the experimental group and control group set in Example 2, pathological examination of the primary lesion and regional lymph nodes was performed after surgery to determine the pathological remission rate. The relevant data were compared with the control group to determine whether the relevant evaluation indicators were improved and enhanced compared with the control group. The results are shown in Table 3: The specific method for evaluating and analyzing the effectiveness of anlotinib combined with chemotherapy using REDX is: ①Effectiveness evaluation will be conducted every 6 weeks. All imaging data will be retained and submitted to an independent imaging evaluation committee for collective assessment of efficacy; ② If the subject discontinues the trial before PD, imaging examinations will be performed every 6 weeks to observe whether the tumor progresses. No other anti-tumor treatment should be performed before PD. ③ Detect the changes in peripheral blood circulating tumor cells at different time periods and systematically evaluate the changes in tumor cell characteristics during the treatment of esophageal cancer patients.

[0030] Table 3 Specific lesion relief in the experimental and control groups Note: pCR, pathological complete response (ypT0N0M0, equivalent to TRG 0); TRG: Tumor regression grade (TRG 0, pathological complete response of the primary tumor, showing no residual cancer cells; TRG 1, single or small clusters of cancer cells remaining; TRG 2, residual cancer cells interspersed with fibrosis; TRG 3, few or no tumor cells regress.) From the data in the table, it can be seen that there was no significant statistical difference in the postoperative pT stage, pN stage, M stage, degree of differentiation and tumor regression grade between the two groups of patients.

[0031] Example 5: Incidence of adverse events in anlotinib combined with chemotherapy Adverse events that did not resolve upon discontinuation of the study drug in this example should be tracked and a final evaluation made. All patients should be followed up for 28 days after the last dose to detect any new adverse events; the specific results are shown in Table 4: Table 4 Adverse events in the experimental and control groups From the data in the table, we can see that during the neoadjuvant treatment, no serious adverse events occurred in either group of patients, and there was no significant difference in the incidence of other adverse events between the two groups.

[0032] In summary, in the neoadjuvant treatment of esophageal cancer patients, small molecule multi-target angiogenesis inhibitors combined with chemotherapy can improve the feasibility of neoadjuvant treatment of esophageal cancer and lower the surgical technical threshold after neoadjuvant treatment, enabling this technology to be more widely promoted and applied. Small molecule multi-target angiogenesis inhibitors are a new option for neoadjuvant treatment of esophageal cancer patients.

[0033] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some or all of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and description of the present invention.

Claims

1. Application of anlotinib combined with chemotherapy in the preparation of neoadjuvant drugs for the treatment of esophageal cancer.

2. The use according to claim 1, characterized in that The chemotherapy drug is selected from paclitaxel, cisplatin or a mixture thereof.

3. The use according to claim 1 or 2, characterized in that The drug is a combination of several separate preparations, which are administered simultaneously or sequentially.

4. The use according to claim 3, characterized in that The drug is in any pharmaceutically acceptable dosage form.

5. The use according to claim 4, characterized in that The medicine contains an effective dose of anlotinib, a chemotherapy preparation and a pharmaceutically acceptable carrier.

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