Thoughts on the rational choice of chemotherapy drugs for breast cancer patients with high risk of recurrence

*Only for medical professionals to read for reference.
The original research Docetaxel has experienced the test of time to help patients with high risk of recurrence of breast cancer achieve their treatment goals and help hospitals improve the quality of medical care
.

In recent years, the global incidence of breast cancer has increased year by year
.

Research data shows that the global annual incidence of breast cancer is 2.
3 million, and the annual incidence rate has surpassed that of lung cancer, ranking first among malignant tumors
.

Some types of breast cancer have a higher risk of recurrence and progression
.

"Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines" defined the characteristics of the population at high risk of recurrence including: axillary lymph nodes ≥ 4 positive; lymph nodes 1-3 positive with other risks of recurrence; triple negative breast cancer
.

The characteristics of the population at high risk of recurrence defined in the "Chinese Anti-Cancer Association Guidelines and Norms for the Diagnosis and Treatment of Breast Cancer (2019 Edition)" include: 1-3 positives, HER2 gene overexpression or amplification, or ER and PR missing; ≥4 positives
.

It can be seen that early breast cancer with positive lymph nodes has a higher risk of recurrence after surgery, and postoperative adjuvant chemotherapy is essential for removing small residual lesions and is a key stage of treatment
.

For breast cancer patients with a high risk of recurrence, the original research docetaxel has experienced the test of time.
Chemotherapy has been used in the adjuvant treatment of breast cancer with a high risk of recurrence.
A series of studies have been carried out.
After long-term and large-scale clinical research, it has a stable and accurate effect
.

▎BCIRG 001 study This study enrolled 1491 patients with lymph node-positive breast cancer, and they were randomly divided into TAC (original research docetaxel + doxorubicin + cyclophosphamide) chemotherapy regimen group, and FAC (fluorouracil + doxorubicin + Cyclophosphamide) chemotherapy regimen group
.

In the two groups of patients, the number of axillary lymph nodes involved 1-3 accounted for 62%, and the number of axillary lymph nodes involved ≥ 4 accounted for 38%
.

The results showed that the 10-year disease-free survival (DFS) rate of the original docetaxel group was 62%, which was significantly better than 55% in the control group
.

And the 10-year overall survival (OS) rate also has a significant advantage (76% vs 69%)
.

▎BCIRG 005 Study This study included 3298 patients with HER2-negative and lymph node-positive breast cancer who were randomized to receive AC→T (N=1649, AC sequential docetaxel) or TAC (N=1649) regimen
.

The results showed that the therapeutic benefits of the TAC and AC-T groups were equivalent in the overall population (10-year DFS rate: 66.
3% vs 66.
5%; 10-year OS rate: 78.
9% vs 79.
9%)
.

▎BCIRG 006 study This study included 3222 patients with HER2-positive, lymph node-positive, or high-recurrence-risk lymph node-negative early breast cancer patients who were randomly divided into AC-TH (N=1074, AC sequential original research docetaxel + trastuzan Anti-), TCH (N=1075, original research docetaxel + carboplatin + trastuzumab) regimen and AC-T (N=1073) regimen adjuvant treatment group, in each group of patients, the number of positive lymph nodes is 1 3 persons accounted for about 38%, 4-10 persons accounted for about 23%, and >10 persons accounted for about 10%
.

The results showed that the efficacy of TCbH and AC-TH regimen was equivalent (10-year DFS rate: 73% vs 74.
6%)
.

In summary, for breast cancer patients, the goal is to pursue disease-free survival (clinical cure) and disease control
.

For the hospital, its goal is to pursue the improvement of the 5-year and 10-year survival rate of breast cancer patients after treatment
.

The original research docetaxel has undergone 23 years of testing, helping breast cancer patients with high recurrence risk achieve their treatment goals and helping hospitals improve the quality of medical care
.

Pay attention to the phenomenon of unequal curative effects that may exist in the clinic.
The unequal curative effect refers to the variability of drugs with the same main ingredient, dosage form, dosage, and route of administration (including those that exhibit bioequivalence in vivo) under the same dosage and usage.
Equal clinical response
.

It usually occurs when replacing the same drug from different pharmaceutical companies or different batches of drugs from the same pharmaceutical company
.

That is, although the drug is pharmacologically equivalent and bioequivalent, it does not mean that it is therapeutically equivalent
.

Such unequal clinical reactions include weakening of curative effect and unexpected adverse reactions or increased intensity and frequency of adverse reactions, which affect the treatment of the disease and delay the condition
.

In addition, it may cause waste of people, materials, and financial resources
.

The FDA's adverse event reporting system monitors treatment inequalities and takes corresponding measures for this evaluation
.

This shows that there are real clinical phenomena such as pharmacy equivalence, bioequivalence and unequal curative effects, and it has attracted the attention of regulatory agencies
.

Especially for high-risk/extremely high-risk patients, patients with complex conditions, and patients undergoing major operations (such as organ transplantation, heart surgery, etc.
), special attention should be paid to the impact of dressing changes on the efficacy
.

Taking into account the completion of tasks with high volume and the rational drug demand of breast cancer patients with high risk of recurrence, the purchasing of drugs with volume is a major measure of medical reform
.

Bulk procurement can significantly reduce the price of medicines.
By the fifth round of the fourth batch, the average drop in drug prices was 52%, and the highest drop was even as high as 96%.
This greatly improved the availability of medicines, both for patients and hospitals.
It is of great significance
.

For low-risk breast cancer patients, the risk of disease recurrence or progression is low, and generic products purchased in quantities can be given priority.
For new formulations of drugs that have no clinical experience, it is also necessary to actively observe the efficacy and safety and accumulate evidence-based medicine.
And real world data
.

For breast cancer patients with high risk of recurrence with positive or negative lymph nodes and other high-risk factors, in order to reduce the risk of unequal curative effects that will cause the overall treatment effect to decline, priority can be given to the use of drugs that have been clinically proven for a long time
.

Therefore, it is necessary to ensure the accessibility of the original research drugs in the clinic, so as to ensure the rational use of drugs for patients with high risk of recurrence of breast cancer
.

In summary, through reasonable patient hierarchical management and at the same time ensuring the availability of purchased products in quantities and original research products, it is possible to effectively balance the completion of tasks in quantities and the rational use of drugs for breast cancer patients with a high risk of recurrence
.

>>>> Extended reading: The original docetaxel keeps improving on the raw materials and adopts the trihydrate crystallization technology ▎1.
The drug instructions are based on public information such as product instructions.
The active ingredient of the original docetaxel is a trihydrate compound, and there are many imitations.
The active substances of sitoxetin injection are anhydrous compounds.
The crystalline form of docetaxel trihydrate is different from that of docetaxel anhydrous compound, and the crystalline form of docetaxel trihydrate exists in terms of stability.
Obvious advantage
.

▎2.
The European Pharmacopoeia stipulates that docetaxel trihydrate and docetaxel are two different active drugs*, and separate evaluation criteria have been established (Figure 1)
.

At present, the Chinese Pharmacopoeia has no relevant standards
.

Figure 1 Docetaxel trihydrate and docetaxel anhydrous compound, source of European Pharmacopoeia* Docetaxel: white or almost white, crystalline, hygroscopic powder Docetaxel Trihydrate: white or almost white, crystalline, powder▎3, invention patent basis " According to the contents of the "Public Specification of Invention Patent Application of the People's Republic of China" (Figure 2), the differences between docetaxel trihydrate and docetaxel anhydrous compound are as follows: 1.
Differences in synthetic route: docetaxel trihydrate and docetaxel The preparation route of the anhydrous compound is different, and the preparation route of the docetaxel trihydrate has patent protection
.

2.
Differences in crystallization methods: With the help of X-ray diffraction, it is found that the crystalline form of docetaxel anhydrous compound is different from that of docetaxel trihydrate under the same conditions
.

3.
Difference in hygroscopicity/stability: in an atmosphere of 4℃, 25℃, 35℃ and 90% relative humidity, the docetaxel trihydrate compound is stable for up to 18 months, and the crystal shape does not occur during this period.
Any changes
.

Under the same conditions, the anhydrous docetaxel slowly transforms into the trihydrate form
.

Figure 2.
Docetaxel trihydrate patent information ▎4.
Technical route The original research docetaxel keeps improving the API and adopts trihydrate crystallization technology.
The crystallization technology route is relatively complicated, as follows: Technical route 1: Protect from light Add 303 g of compound II (docetaxel anhydrous compound) with a concentration of 92.
4% (0.
314 mol) and 2.
875 kg of absolute ethanol (d=0.
79) into the reactor
.

The mixture was heated at 40°C until the compound II was completely dissolved, and ethanol was distilled under a pressure of about 12 KPa until a syrup that was difficult to stir was obtained
.

0.
983 kg of ethanol was added to the syrup and distilled again under the same conditions
.

To the obtained slurry, 1.
257 kg of ethanol was added and heated at 50°C until completely dissolved
.

The mixture was filtered hot, and then 4.
39 kg of pure water was added to the filtrate for 1 hour while the temperature was maintained at 50°C
.

After seeding, the mixture was cooled to 0°C within 4 hours
.

The crystals were separated by filtration, washed with 0.
909 kg and then 0.
606 kg of ethanol-water mixture (1-2 weight), and dried under reduced pressure (5.
07 KPa) at 38°C and 80% relative humidity for 48 hours
.

266.
5g of compound I (docetaxel trihydrate) was obtained, and the analysis result of high performance liquid chromatography showed that its concentration was 98.
7% (dry weight) and the water content was 6.
15%
.

Technical route 2: Dissolve 110.
0g of compound II with a concentration of 92.
5% and 0.
2224g of ascorbic acid in 1340cm3 of ethanol at about 35°C
.

At about 20°C under reduced pressure (8KPa), about 70% of the introduced ethanol was evaporated
.

The mixture was heated at 50°C and then filtered
.

Wash the filtrate 3 times with 70.
5cm3 of ethanol, and then add 860.
5cm3 of 50°C pure water within 15 minutes
.

Several crystals of compound I were used to inoculate seed crystals, followed by stirring for 30 minutes
.

Add 860.
5cm3 of 50°C pure water within 3 hours and cool down within 3 hours until the temperature is about 0°C
.

Filter the slurry
.

The filter cake was washed with 330g water-ethanol mixture (2-1 weight) followed by 220g of the same mixture, and dried under reduced pressure (5KPa) at 38°C under an atmosphere with a relative humidity of 80%
.

In this way, 110.
2 g of Compound I was obtained with a yield of 98%
.

Reviewer Professor Rao Yuefeng, Ph.
D.
from Zhejiang University First Hospital, Chief Pharmacist, Doctoral Supervisor, Zhejiang Provincial Medical Innovation Discipline-Clinical Pharmacotherapy Reserve Discipline Leader, National Natural Science Foundation Review Expert, Zhejiang Provincial Grade Hospital Review Expert, Journal of Biomedicine & pharmacotherapy Vice editing
.

Presided over more than 10 various scientific research projects such as the National Natural Science Foundation and the Provincial Natural Science Foundation, published more than 50 papers as the first and corresponding author, participated in the editing of 11 books, and authorized 7 patents
.

Won 1 second prize for scientific and technological progress in Zhejiang Province, 1 first prize for scientific research achievements in provincial institutions of higher learning, 2 second prizes for scientific and technological progress in provincial medicine and health, and pharmacy award from the Youth Hospital of China Pharmaceutical Association, Zhejiang Excellent Hospital Pharmacist Award, etc.
Honor
.

Main social part-time job: Teacher in the clinical pharmacist training base of the National Health Commission.
Member of the Chronic Disease Safety Drug Management Branch of the Chinese Pharmacological Society's Drug-induced Diseases Committee Member of the Zhejiang Pharmacological Society Council Approval Number: MAT-CN-2123127-v1.
0 -09/2021*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform