For stage I and some stage II breast cancer patients, breast preserving surgery is adopted and radiotherapy and chemotherapy are given after surgery; for stage III breast cancer patients, neoadjuvant chemotherapy is given first, followed by surgery for better efficacy. Pan Huexing, Department of Glandular Surgery, Tangshan Workers’ Hospital Zhang Mei, Department of Two Glandular Surgeries, Qianfo Mountain Hospital, Shandong Province
Breast cancer is the most common malignant tumor among women, and the incidence of breast cancer is increasing year by year all over the world. However, epidemiological data in the United States show that the mortality rate of breast cancer is decreasing year by year, which is greatly related to the enhanced screening, significantly improving the detection rate of early breast cancer and systematic adjuvant treatment.
The study showed that about 1% to 5% of breast cancer cases are in the general population. The study showed that about 1% to 5% of breast cancer patients were found to have metastatic lesions at the time of consultation. The vast majority of patients need systemic medical treatment because of the possibility of systemic metastases in the early stages of breast cancer. Currently, this treatment modality is widely accepted, and breast-conserving surgery with adjuvant systemic therapy has been widely adopted for early-stage breast cancer.
The development of clinical chemotherapy regimens for breast cancer has gone through the course of single agent chemotherapy and combination chemotherapy. First-line therapeutic agents have evolved from cyclophosphamide (CTX), 5-fluorouracil (5-FU), and methotrexate to the use of anthracyclines (adriamycin, ADM, and epiamycin, EPI) in the 1980s. The use of paclitaxel-based drugs (Tysol, Tysodi) in the nineties led to a significant improvement in the prognosis of breast cancer. The newly developed some new antitumor drugs including gemcitabine (Gemcitabine, GEM) and capecitabine (Xeloda, Xeloda) have made effective remedial treatment available for patients with advanced breast cancer.
Commonly used chemotherapy drugs include CTX, ADM, Epi-ADM, MTX, 5-FU, Xeloda, Paclitaxel, Docetaxel, Gemcitabine, etc.
I. Adjuvant chemotherapy
Systemic adjuvant therapy has been widely accepted because most people believe that reducing tumor load is helpful to improve the efficacy of antitumor therapy. Most studies have proven this view. Adjuvant chemotherapy can effectively reduce the recurrence rate and mortality in early stage patients, therefore, adjuvant chemotherapy has become an important part of the comprehensive treatment of breast cancer.
Postoperative adjuvant chemotherapy
Postoperative adjuvant chemotherapy can reduce the recurrence rate and mortality of breast cancer patients, and adjuvant chemotherapy should be given to all patients with stage II or above. It was once thought that patients with negative axillary lymph nodes and primary tumors less than 1 cm did not need adjuvant chemotherapy, however, about 25% of patients with negative axillary lymph nodes have recurrence or metastasis later, therefore, it is now believed that adjuvant chemotherapy can be given to even early stage patients. For primary tumors <1 cm and negative lymph nodes, adjuvant chemotherapy should be individualized. Some breast cancers with small tumors, negative lymph nodes, and good histological types have been shown in retrospective studies to achieve long-term survival with local treatment and thus do not require chemotherapy. However, adjuvant chemotherapy should be given to those at high risk of recurrence even if they have negative axillary lymph nodes. High-risk groups include those who are estrogen receptor (ER) negative, breast cancer during lactation or pregnancy, those with a significant familial predisposition, pathology reports of thrombosis in blood vessels or lymphatic vessels or nerve involvement and/or patients under 35 years of age. In recent years, with the development of genetic testing, some gene expression status has also become an indicator to determine the risk level, such as Cerb-B2, P53, MVD, PCNA, etc.
Timing of adjuvant chemotherapy: chemotherapy should be started as early as possible after surgery, with the main purpose of hoping to effectively control or eliminate micro-metastases. However, the most appropriate time for postoperative chemotherapy cannot be unified. The timing of the start of postoperative chemotherapy may be influenced by the recovery of the patient’s general condition, the histological type of the lesion, and other factors. Some experts believe that adjuvant chemotherapy should be started within 2 to 4 weeks after surgery, and Lohrisch et al. retrospectively analyzed 2594 breast cancer patients treated with postoperative adjuvant chemotherapy and showed that there was no meaningful difference between starting chemotherapy earlier or later than 12 weeks, but starting adjuvant chemotherapy more than 12 weeks after surgery was associated with a high rate of local recurrence and poorer overall survival. Therefore, it is considered that chemotherapy should be started within 12 weeks after surgery. The treatment cycle is usually 6 cycles. Increasing the chemotherapy cycle does not improve the treatment outcome but increases chemotherapy toxicity.
The main chemotherapy regimens are CMF (CTX+MTX+5-FU), CAF (CTX+ADM+5-FU), CEF (CTX+Epi-ADM+5-FU), TA (Taxcol+ADM/Epi-ADM), AC-T, AC-T (dose-density method), TAC, etc.
Third, neoadjuvant chemotherapy
The significance of neoadjuvant chemotherapy is to shrink the primary tumor and increase the success rate of breast-conserving surgery; to reduce the number of positive axillary lymph nodes; and to inhibit the activity of tumor cells to reduce distant metastasis. It can also discover the sensitivity of the tumor to the drug. There are many studies available on neoadjuvant chemotherapy regimens. Any regimen available for postoperative adjuvant chemotherapy can be used for neoadjuvant chemotherapy.
In 2004 Buzdar reported a neoadjuvant chemotherapy and endocrine therapy combination chemotherapy study with paclitaxel given every 3 weeks for 4 cycles followed by 4 cycles of fluorouracil + epi-amycin + cyclophosphamide, which affirmed the endocrine plus chemotherapy regimen before the study was completed, thus terminating the trial of chemotherapy alone as neoadjuvant therapy. They concluded that neoadjuvant therapy should be added to endocrine agents in Her2/neu-positive patients.
Evans et al. comparatively studied the efficacy of AC (adriamycin and cyclophosphamide) and AD (adriamycin and doxorubicin) regimens as neoadjuvant chemotherapy for breast cancer with large primary lesions or inoperable disease. There were no meaningful differences in terms of clinical efficiency, pathologic complete remission rate, breast conservation rate and post-surgical lymph node negativity rate.
Steger et al. studied the efficacy of adriamycin plus doxorubicin combined with G-CSF as neoadjuvant chemotherapy for operable breast cancer in different cycles. Comparing 3 consecutive cycles with 6 consecutive cycles, the latter was better than the former in terms of pathological complete remission rate and post-surgical lymph node negativity rate, and there was no difference in breast conservation rate.
IV. The question of dose intensity
Theoretically, the magnitude of dose intensity correlates with efficacy and long-term outcome. Generally speaking, a higher dose intensity can improve the efficacy of chemotherapy. However, for most anti-tumor drugs, the difference between the dose of tumor killing and the dose of normal tissue toxicity is very small. Meanwhile, high-dose chemotherapy is very damaging to human immune function, and it takes a long time for patients who have undergone high-dose intensity chemotherapy to fully recover their immune function. The general reactions of chemotherapy, such as nausea, vomiting, and bone marrow suppression have been more satisfactorily resolved due to the clinical application of 5-HT3 antagonists, hematopoietic factors such as granulocyte colony-stimulating factor, and hematopoietic stem cell transplantation. In contrast, organ damage and organism malfunction caused by chemotherapy are more difficult to recover in high-dose intensity chemotherapy, and it is more difficult to deal with these problems than bone marrow suppression.
In addition to the sensitivity of the tumor to chemotherapy, the functional status of the internal organs, and the physical status of the patient, other factors governing the administration of high-dose intensity chemotherapy, such as the recovery of the patient’s immune function after chemotherapy, and the recovery of the internal organ function and physical status, should also be taken into consideration in clinical practice.
In 2004, Mobus et al. reported the efficacy of increasing the intensity of chemotherapy in patients with operable breast cancer with four or more positive axillary lymph nodes. The results showed increased myelosuppression compared to the standard treatment dose regimen despite the combination of granulocyte colony-stimulating factor or/and erythropoietin. Patients had increased disease-free survival but did not show an increase in overall survival. And an earlier study by Citron and his colleagues showed that enhanced dose intensity increases efficacy over standard therapeutic dosing regimens, but also increases the toxic effects of chemotherapy. Recent studies have shown that high-dose chemotherapy using stem cell transplantation techniques still does not improve breast cancer outcomes. There is no conclusive evidence that increasing the intensity of chemotherapy doses is more effective than conventional doses of combination chemotherapy regimens.
V. Introduction of new chemotherapy regimens
AC-T or AC-D: Adriamycin 60mg/M2IVD1q21d×4.
Cyclophosphamide 600mg/M2IVD1q21d×4.
4 cycles followed by Tysol 175mg/M2 or Tysoldi 75mg/M2IV3hD1q21d×4
It was found that with the AC regimen, increasing the ADM dose did not increase survival. Sequencing with AC-T reduced recurrence and mortality. the benefit was greater in ER-negative patients, while the effect of tyso was overwhelmed by triptans in the latter 4 cycles in ER-positive patients. Therefore, AC-T is a good option for ER-negative, well-off patients. The regimen with the addition of Tysodi increases the clinical and pathological remission rate, and the outcome of survival remains to be further observed.
AC-T dose density method: Adriamycin 60mg/M2IVD1q14d×4.
cyclophosphamide 600mg/M2IVD1q14d×4.
After 4 cycles followed by Tysol 175mg/M2IV3hD1q14d×4
G-CSF support was used during the course of the treatment.
The results of a study published in JClinOncil 2003 showed that increasing the dosing intensity of high-dose chemotherapy, even with bone marrow or peripheral blood stem cell transplantation techniques, did not improve the efficacy of breast cancer. Increasing the dose density increases the efficacy and the use of G-CSF support reduces the toxic side effects caused by increasing the dose density.
TAC: Tysodi 75mg/M2IVD1q21d×6.
Adriamycin 50mg/M2IVD1q21d×6
Cyclophosphamide 500mg/M2IVD1q21d×6
In the International Breast Cancer Study Group study, it was confirmed that the TAC regimen has significant advantages over the standard FAC regimen. The disease-free survival and recurrence rates showed superiority. Regardless of negative or positive ER status, the TAC regimen was better than the FAC regimen. However, III to IV degree decline was heavier in the TAC regimen. It is recommended that weekly dosing with Tysodi in TAC (30-35 mg/M2IV, D1, 8) may reduce myelosuppression. Other non-hematologic toxicity FAC is higher than TAC. therefore, TAC regimen is an emerging better chemotherapy regimen for postoperative adjuvant chemotherapy in lymph node positive breast cancer in recent years.
PA: Tysol 175mg/M2IVD1q21d×6
Adriamycin 60mg/M2IVD1q21d×6
DA: Tysodi 75mg/M2IVD1q21d×6 or 35mg/M2IVD1,8,15q28d×6
Adriamycin 50mg/M2IVD1q21d×6 or q28d×6
DA, like PA, has good efficacy in breast cancer, with an efficiency rate of 74% to 81%. It is a very good option for patients with poor prognostic factors. Because of the high incidence of myelosuppression, a weekly dose approach with only a slightly longer duration of chemotherapy is recommended for Tysodi.
Xeloda: Xeloda 1275 mg/M2?d, PO, Bid, D1 to 14, q21d, continued until disease progression.
The efficacy of Xeloda alone was observed in a study of patients with advanced, metastatic breast cancer. 100% of the study patients had received tylosin and 91% had received anthracyclines, with an efficiency rate of up to 20% and a stabilization rate of 43% with Herodar alone. The efficiency rate for resistance to tamsulosin and anthracyclines was also 29%. It is a good palliative chemotherapy drug for patients with difficulties in choosing combination chemotherapy regimens in advanced stages. Its side effects are manageable and do not significantly affect the patient’s quality of life.