( A ) Rationale of adjuvant chemotherapy
Most breast cancers are systemic diseases, which have been confirmed by numerous experimental studies and clinical observations. When breast cancer develops to a size larger than 1 cm and a lump can be palpated clinically, it is often a systemic disease and there may be distant micro-metastases, but they cannot be detected by current examination methods. The purpose of surgical treatment is to maximize the local control of the primary tumor and regional lymph nodes, reduce local recurrence and improve survival rate. However, after tumor removal, residual tumor cells are still present in the body. Based on the concept that breast cancer is a systemic disease at the time of diagnosis, the purpose of systemic chemotherapy is to eradicate the residual tumor cells in the body to improve the cure rate of surgical procedures.
(II) Postoperative adjuvant chemotherapy
Indications for postoperative adjuvant chemotherapy.
The basic principles of European St. Gallen consensus on the selection of adjuvant therapy for early-stage breast cancer proposed that firstly, the tumor responsiveness to endocrine therapy should be considered, which is divided into Endocrine responsive ( endocrine therapy responsive ), Endocrine nonresponsive ( endocrine therapy non-responsive ), Uncertain endocrine responsiveness ( endocrine therapy response uncertain ); then the risk of recurrence should be subdivided according to other factors as follows Low risk (low risk), moderate risk (intermediate risk) and high risk (high risk).
Definition of low risk: negative axillary lymph nodes with all of the following characteristics: pT ≤ 2 cm of the lesion, pathological grade 1, no invasion of the peripheral vessels of the tumor, HER-2(-), and age ≥ 35 years.
Intermediate risk was defined as.
① Negative axillary lymph nodes with at least one of the following features: pT > 2 cm, pathologic grading of grade 2-3, invasion of tumor peripheral vessels, HER-2 gene overexpression or amplification, and age < 35 years.
② Axillary LNM 1-3 (1-3 metastases in axillary lymph nodes) and HER-2( – ).
Definition of high risk.
① Axillary LNM 1-3 and HER-2 ( + ) ;
② Axillary LNM > 3.
Chemotherapy is not administered to low-risk patients, and chemotherapy is required for high-risk patients. Intermediate-risk patients with response to endocrine therapy can be treated with endocrine therapy alone without chemotherapy or with chemotherapy sequential endocrine therapy first, and chemotherapy is required for non-response to endocrine therapy, and chemotherapy sequential endocrine therapy is required for uncertain response to endocrine therapy.
In contrast, the indications for chemotherapy in the US NCCN guidelines differ from the St. Gallen consensus, and chemotherapy is administered to those with positive axillary lymph nodes. Chemotherapy is required for all axillary lymph node negative, tumor larger than 1 cm, ER negative or HER-2 positive, and considered for those who are ER positive and HER-2 negative. Axillary lymph node negative, tumor size of 0.6-1.0 cm, ER negative or HER-2 positive, or tumor is moderate or low differentiation, consider chemotherapy. Patients with negative axillary lymph nodes, tumor less than 0.5 cm, or tumor size of 0.6-1.0 cm with high differentiation and no adverse prognostic factors are not treated with chemotherapy. There are special criteria for ductal carcinoma or mucinous carcinoma with positive axillary lymph nodes or tumors larger than 3 cm, such as hormone receptor negative, chemotherapy, and hormone receptor positive, endocrine therapy. If the axillary lymph nodes are negative, such as tumor less than 1cm, no treatment, if the tumor is 1-3cm, hormone receptor positive, consider endocrine therapy, if hormone receptor negative, consider chemotherapy.
Choice of chemotherapy regimen.
Preferred regimen: ①Dose intensive chemotherapy AC×4 → T×4 ( AC sequential docetaxel dose intensive regimen ) with doxorubicin 75 mg/m2 IV d1 and cyclophosphamide 500 mg/m2 IV d1 for 14 days in 1 cycle for 4 cycles and sequential docetaxel 75 mg/m2 IV d1 for 14 days in 1 cycle for 4 cycles under G-CSF support. (ii) TC×4 with docetaxel 75 mg/m2 IV d1 and cyclophosphamide 600 mg/m2 IV d1 for 21 days for 1 cycle for 4 cycles.
(C) Preoperative adjuvant therapy (neoadjuvant therapy)
The significance of preoperative neoadjuvant chemotherapy.
The purpose is to shrink the tumor lesion and reduce the tumor stage, so that inoperable locally advanced patients can be surgically resected for more chances of breast-conserving surgery, and also play the role of in vivo drug sensitivity test, which can evaluate the effect of preoperative chemotherapy according to the resected tumor specimen and serve as a reference for choosing chemotherapy regimen after surgery or in case of recurrence.
Overall study results showed that preoperative neoadjuvant chemotherapy did not improve survival compared to postoperative adjuvant chemotherapy. However, patients treated with neoadjuvant chemotherapy were more likely to undergo breast-conserving surgery. Patients who achieved pathologic complete remission (pCR) with neoadjuvant therapy had a longer survival than those who did not achieve pCR.
Indications for neoadjuvant therapy are locally advanced breast cancer (T3 and or N2 or higher) not suitable for surgery, some patients with stage T2 (primary tumor 3-5 cm) who have a desire for breast conservation, and early axillary node-negative patients with a primary tumor less than 3 cm who are treated with neoadjuvant therapy only at the time of clinical study.
The pathological diagnosis and stage should be clarified before treatment, and a coarse needle aspiration biopsy of the primary focus should be performed to determine the ER, PR and Her-2 status of the tumor tissue before treatment.
Patients with positive axillary lymph nodes on clinical examination should undergo puncture biopsy to clarify the diagnosis; if the puncture is negative, or patients with negative clinical examination should undergo sentinel lymph node biopsy before neoadjuvant therapy.
Neoadjuvant chemotherapy regimens containing anthracyclines and paclitaxel are recommended, either in combination or in sequence. Neoadjuvant endocrine therapy can be considered for elderly patients who are ER and/or PR positive and whose general condition is not suitable for chemotherapy.
Herceptin-containing regimens may be considered for HER-2-positive patients.
The number of cycles of neoadjuvant therapy depends on the different stages of disease and the purpose of treatment. A rigorous efficacy evaluation is important to decide on follow-up therapy. It is generally considered that each cycle should be examined for tumor size changes, imaging (ultrasound and X-ray) after 2 cycles to evaluate clinical efficacy, and 3-4 cycles to decide the next treatment based on efficacy evaluation and, if necessary, by puncture to understand pathological changes. Patients with clinical CR or PR should continue the original regimen for up to 6 cycles; patients with poor outcomes should consider changing the treatment regimen, such as changing the drug regimen, abandoning breast conservation for radical surgery or local radiotherapy. After effective neoadjuvant therapy for locally advanced patients, (modified) radical surgery is usually chosen; breast preservation is possible after neoadjuvant therapy, but patients with large primary tumors or positive axillary nodes before treatment should be cautious in choosing breast-conserving surgery.
Post-operative adjuvant therapy after neoadjuvant therapy, it should be noted that the patient’s staging has changed at the time of surgery, so the decision of adjuvant radiotherapy should be based on the staging before neoadjuvant therapy. Adjuvant therapy for hormone-responsive patients is based on endocrine therapy. In contrast, adjuvant therapy for patients who have not reached pCR after neoadjuvant therapy should be considered on an individual basis.
Nowadays, preoperative neoadjuvant therapy for breast cancer is being carried out more and more widely, but there are still many issues to be solved in neoadjuvant therapy, such as the optimal drug regimen and dosing cycle, reasonable means of efficacy evaluation and accurate timing of surgery, postoperative treatment for patients with different efficacy, etc. Future research will focus on better determining which patients can really benefit the most from neoadjuvant therapy.
(IV) Side effects of chemotherapy and their management
The main side effects of chemotherapy for breast cancer are.
1. Chemotherapy drugs can affect the stomach or the vomiting center of the brain to cause nausea and vomiting.
2. Adriamycin can cause hair loss and heart damage.
3.Chemotherapy can inhibit the ability of bone marrow to produce red blood cells, making patients feel weak, fatigue, dizziness or shortness of breath.
4.Anti-cancer drugs affect the hematopoietic function of bone marrow and make the white blood cells drop, meanwhile, it is easy to cause infections in various parts of the body, such as mouth, skin, lung and intestine.
5.Some chemotherapy drugs can affect intestinal mucous membrane cells causing diarrhea.
6, chemotherapy can directly cause constipation, which may also be caused by the reduced activity of patients after chemotherapy and unreasonable diet structure.
7.Cyclophosphamide can stimulate the bladder causing painful urination, urgency, frequency, fever and other symptoms.
Treatment.
When the white blood cell is too low, granulocyte colony-stimulating factor can be injected to enhance the number of white blood cells, anti-vomiting agents can be injected before and after chemotherapy to prevent and treat nausea and vomiting reactions, the application of adrenocorticotropic hormones can prevent and treat allergic reactions, and at the same time can appropriately reduce the toxic reactions of the heart, liver and kidneys, generally there is no need to be concerned about hair loss, wigs can be worn during treatment, and most of them can gradually grow out about 3 months after the end of chemotherapy.
In addition, during chemotherapy, patients should strengthen nutrition appropriately including protein, energy and vitamins, pay attention to rest, ensure sleep, appropriate physical exercise, lift the psychological burden, maintain a happy mood and family harmony is also particularly important.