The incidence of breast cancer is increasing year by year, but the mortality rate has not increased accordingly, due to the early diagnosis of breast cancer and the rational application of postoperative adjuvant therapy to prevent recurrence and metastasis. Among them, as the traditional treatment for breast cancer, adjuvant chemotherapy remains important as new drugs are not considered to be introduced. In this paper, we introduce the basic principles of adjuvant chemotherapy for breast cancer and discuss several hot issues facing the practice, combining clinical practice experience and information from the latest conferences.
1. Do all breast cancer patients need adjuvant chemotherapy?
Breast cancer is no longer a single disease. The 2007 St c.allen conference consensus classified breast cancer patients into low risk, intermediate risk and high risk based on factors such as axillary lymph nodes, hormone receptors, tumor size, pathological histological grading, age, HER-2 status and whether the tumor is infiltrated by peripheral vasculature. For low-risk patients, adjuvant chemotherapy was not recommended by the guidelines at that time; for intermediate-risk patients, chemotherapy may be considered depending on the hormone receptor status; and for high-risk patients, chemotherapy should be routinely given. The risk/benefit ratio of the patient needs to be considered when formulating a treatment plan for the patient. At that time, clinicopathological features such as axillary lymph node status remained the most important prognostic factor for recurrent metastases.
The 2013 StGallen Consensus allows for the classification of different subtypes based on genetic analysis or immunohistochemistry, and these subtypes have different biologic characteristics and different effects on local and systemic therapy. To facilitate clinical application, the consensus emphasizes subtype classification based on clinicopathology, combined with genetic analysis results. There are four major categories based on hormone receptor, HER-2 and Ki67 status: Luminal A type, Luminal B type, HER-2 positive type, and triple negative type.
LuminaIA type: estrogen receptor (ER) and progesterone receptor (PR) positive, HER-2 negative, Ki67<14%; Luminal B type is divided into Luminal B type (HER-2 negative): ER positive and HER-2 negative, and PR negative or Ki67≥15%, and Luminal B type (HER-2 positive): ER positive and HER-2 overexpressed, regardless of PR and Ki67 status; HER-2 positive type: HER-2 overexpressed and ER and PR negative; and triple negative type: ER and PR negative and HER-2 negative. In general, the subtype classification determines the systemic treatment strategy.
Luminal A breast cancer is usually endocrine dependent and has poor chemotherapy sensitivity; Luminal B, although ER positive, is less endocrine dependent and requires chemotherapy; triple negative breast cancer is not endocrine dependent and there is no clear effective molecular targeted therapy and requires chemotherapy more; HER-2 positive type is suitable for treatment with chemotherapy combined with trastuzumab. However, when deciding on postoperative adjuvant chemotherapy, it is important to emphasize the importance of clinicopathological staging, such as positive axillary lymph nodes, especially more than 3 positive lymph nodes, and factors such as risk of recurrence by 21- or 70-gene testing are still important factors in deciding chemotherapy.
2.The best time to start adjuvant chemotherapy
The optimal time to start adjuvant chemotherapy is uncertain, generally starting normal treatment a few weeks after surgery, but it is uncertain whether earlier treatment is better, and whether delayed treatment has a worse prognosis. The IBCSG trial, a retrospective study using CMF chemotherapy regimens, found a significant improvement in 10-year DFS in hormone receptor-negative, premenopausal patients who started treatment 21 days after surgery compared with delayed treatment (60% vs. 34%, p=0.0003). a prospective data from the Royal Marsden Hospital showed that more than 1,100 patients underwent adjuvant chemotherapy and approximately 60% A prospective data from the Royal Marsden Hospital showed that more than 1,100 patients received anthracyclines, showing no difference in DFS or OS between chemotherapy within 21 days and delayed chemotherapy. Therefore, the start of postoperative adjuvant therapy needs to be decided after weighing various factors such as the patient’s postoperative surgical incision recovery and general condition.
3.Course of chemotherapy
The EBCTG meta-analysis evaluated 5 CMF-based clinical trials and found no survival benefit for treatment beyond 6 months. 2 trials showed equivalence between 4 weeks of AC and 6 weeks of CMF. The first study was the NASBP B-15 trial in lymph node-positive TAM-resistant tumors, and the second study was the NASBP B-23 trial in lymph node-negative, ER-negative patients randomized to AC or CMF with or without TAM. other randomized clinical trials showed significantly improved OS and DFS with the same course of anthracycline regimens such as FAC and FEC compared to CMF. Whether FAC/FEC is significantly better than AC/EC or extended treatment cycles (6-8 cycles of FEC/FAC versus 4 cycles of AC) is not known, however, the FASC-OI trial showed that 6-week FEC50 was better than 3-week FEC 50 or 75 and that 6-week FEC 50 was better than 3-week FEC 50 in terms of OS.
4. Chemotherapy regimens and doses
The CMF regimen, which emerged in the 1970s, was the first effective adjuvant chemotherapy regimen and remained the primary adjuvant chemotherapy regimen for many years. An Oxford review analyzed 47 clinical trials of mostly CMF-based chemotherapy regimens and showed that adjuvant chemotherapy significantly reduced the risk of recurrence and death. Benefits were independent of axillary lymph node status, hormone receptors, and the use of TAM, but the degree of benefit was related to age and menopausal status. For lymph node-positive patients <50 years of age, chemotherapy significantly improved 10-year survival by 10% (53% vs 42%); for patients <50 10="">70 years of age there was little benefit, but this subgroup was smaller.
(1) Anthracyclines remain an irreplaceable cornerstone of breast cancer chemotherapy
The EBCTCC review showed a small but significant benefit of anthracyclines compared with conventional CMF regimens in terms of recurrence-free survival and OS. Other studies have also confirmed the benefits of anthracycline-based therapy. The National Cancer Institute of Canada MA.5 trial showed that 6-week FEC was superior to 6-week CMF, and the Southwest Oncology Organization 8897 clinical trial showed that FAC was superior to CMF. the UK NEAT study showed that E-CMF was superior to CMF alone. anthracycline-based adjuvant chemotherapy is the current standard of care, but the most effective drug combinations, doses, and regimens remain undefined, and different regimens Different regimens are being used in the clinic.
Doxorubicin and epirubicin are currently the two most prominent anthracyclines in clinical practice. In the Cancer and Leukemia Group B (CALGB) 9344 trial, patients with lymph node-positive breast cancer were randomized to 4 courses of AC chemotherapy ± 4 weeks of paclitaxel, and doxorubicin (adriamycin) was divided into 3 dose groups of 60, 75, or 90 mg/m2. The results showed that the standard dose of doxorubicin was 60 mg/m2, with no clear benefit above 60 mg/m2.
For the standard dose of epirubicin, patients with a poor prognosis of positive lymph nodes were randomized to 6 weeks of FEC 50 (epirubicin 50 mg/m2) or 6 weeks of FEC 100 (epirubicin 100 mg/m2) in the French Adjuvant Study Group (FASG-05) trial. OS (77.4% vs. 65.3%). However, there was a corresponding increase in toxicity such as decreased granulocytes, anemia, nausea/vomiting, stomatitis, hair loss and 3rd degree infection.
In the US Oncology 9735 clinical trial, a total of 1016 patients were randomized from June 1997 to December 1999 to receive 4 weeks of standard doses of AC (60 and 600 mg/m2, 510 patients) or TC (75 and 600 mg/m2, 506 patients). At a median follow-up of 7 years, DFS was 75% vs. 81%, HR=0.74, p=0.033, and OS was 82% and 87%, respectively (HR=0.69, p=0.032). TC was superior to AC at 7 years for both DFS and OS. The results of this trial do not overturn the status of anthracyclines, but provide an alternative to our adjuvant chemotherapy regimen, especially for older patients or those with a prior history of cardiac disease. The results of this trial do not overturn the status of anthracyclines, but provide us with another option for adjuvant chemotherapy, especially for elderly patients or those with a history of heart disease that contraindicates the use of anthracyclines.
(2) Significance of paclitaxel drugs
Current clinical trials with large samples have highlighted the potential importance of paclitaxel as an adjuvant therapy. The results of 4 important clinical trials evaluating the efficacy of adding paclitaxel to anthracyclines in patients with positive lymph nodes have been reported earlier.3 In the CALGB9344 trial, 3 1 2 1 patients randomized to receive 4 weeks of different doses of AC±4 weeks of paclitaxel, the addition of tight cedar showed a small but statistically significant difference in DFS (50% absolute, P=0.0023) and OS ( 3% absolute, P=0.0064) showed small but statistically significant differences.
The NSABP B-28 trial was a similarly designed trial with 3,000 patients randomized to 4-week AC sequential with 4-week paclitaxel versus 4-week AC alone. median follow-up was 64 months and there were 861 events. The paclitaxel group had a significant 4% improvement in DFS (72% vs 76%, p=0.008), but no difference in OS (85% vs 85%, p=0.46). The difference in effectiveness between these two trials may be due to differences in treatment regimens rather than to the addition of paclitaxel.
The third trial, Breast Cancer International Research Group (BCIRG)001, compared docetaxel (Tysodi) with anthracyclines applied concurrently rather than sequentially. This trial of 1491 patients was randomized to either the standard 6-week FAC regimen or the 6-week TAC regimen. At the time of the 2nd intermediate analysis, with a median follow-up of 55 months and 399 events, the TAC group significantly improved DFS (75% vs 68%, p=0.001) and OS (87% vs 81%, p=0.008). Toxicity-related deaths were similar in both groups, but the incidence of granulocytopenic fever was higher in the TAC group (despite concomitant use of oral ciprofloxacin), with rates of 24.7% and 2.5% in the two groups, respectively.
The fourth trial, the French PACS01 trial, compared 3-week FEC with 3-week docetaxel 100 mg/m26 weeks of FEC l00 in lymph node-positive patients. 5-year DFS was 78.3% and 73.2% in the two groups (HR 0.83, p=0.012), with the sequential docetaxel group showing a significant advantage. There were similar results in terms of OS, with 5-year OS of 90.37% and 86.7% in the two groups, respectively (HR 0.77, P=0.014).
The granulocyte colony-stimulating factor-supported 2-week administration instead of 3-week, so-called dose-dense chemotherapy CALCB 9741 trial showed that the intensive treatment group (4-week intensive AC regimen sequenced with 4-week intensive paclitaxel) was significantly more effective than the conventional 3-week regimen in patients with axillary lymph node-positive breast cancer, with 4-year DFS of 82% and 75%, respectively. In addition, the incidence of granulocytopenic sepsis was lower in the intensive treatment group. Similarly, an Italian abstract-only trial showed that intensive treatment of 6-week FEC increased efficacy while reducing the incidence of granulocytopenic sepsis. Reducing the duration of adjuvant therapy with intensive therapy is more attractive to patients, while reducing granulocytopenic sepsis may save healthcare resources.
The efficacy of the two major paclitaxel analogues (paclitaxel and docetaxel) for adjuvant therapy has been demonstrated in numerous clinical studies, but few studies have directly compared the efficacy of each. In the 2008 Laurent II et al. meta-analysis, the paclitaxel-containing regimen had a slightly lower risk ratio (HR) for DFS than the docetaxel-containing regimen (0.80 vs. 0.86). There is still no more conclusive evidence to confirm which paclitaxel is more effective.
Several clinical studies published in 2008 compared the efficacy of paclitaxel-containing regimens in sequential or combination regimens.
In the NSABP B30 study, the AC→D (AC sequential docetaxel) sequential regimen had significantly better DFS and OS than the combination regimen AD (doxorubicin + docetaxel) and a significant advantage over the DAC (docetaxel + doxorubicin + cyclophosphamide) regimen in terms of DFS. In the paclitaxel-containing regimen of the BIG2-98 study, the DFS of A→T→CMF (doxorubicin followed by docetaxel and CMF) was significantly better than that of A→T→CMF (HR=0.83, P=0.047), which was not significantly better than that of the common anthracycline regimen AC→CMF.
(3) Role of capecitabine in adjuvant therapy
A total of 633 patients were enrolled in September 2001 and December 2006. 326 patients in the standard treatment group received oral [CMF (C100mg/m2 d1~d14 orally; M 40mg/m2 d1, d8; FU 600mg/m2 d1, d8) every 4 weeks x 6 weeks In the capecitabine group, there were 307 cases [X(2000mg/m2 d1~d14) every 3 weeks x 4 weeks], 61% of whom were older than 70 years, 54% had masses >50px, 69% had positive lymph nodes, and 66% had positive HR.
At a median follow-up of 2 years, there was more myelosuppression in the standard treatment group, a higher incidence of hand-foot syndrome in the capecitabine group, and 2 drug-related deaths in the capecitabine group. The final conclusion was that the capecitabine group was worse than the standard CMF or AC regimens in older patients, especially in those with negative HR.
Another larger study is the FinXX trial, a large, prospective, open, multicenter randomized phase I clinical trial conducted by the Finnish Breast Cancer Study Group (FBCG) comparing the T-CEF (docetaxel – cyclophosphamide + epirubicin + 5-fluorouracil) regimen with XT-CEX (which is capecitabine instead of 5-fluorouracil and in advance of docetaxel), with the following enrollment criteria Breast cancer patients with positive or larger diameter lymph nodes than those with concomitant progesterone receptor (PR) negativity, stratified by number of positive lymph nodes (3 or >3), HER-2 status (positive or negative) and trial center. The results of the initial analysis (median follow-up of 3 years) did show a lower recurrence rate in the capecitabine group, but at 59 months of follow-up, there was no difference in recurrence between the two groups. There was also no difference in overall survival (OS) rates.
Another phase III trial that added capecitabine to adjuvant chemotherapy was the USON01062 trial, which compared the efficacy of 4 cycles of AC (doxorubicin + cyclophosphamide) → 4 cycles of T (docetaxel) versus 4 cycles of AC → 4 cycles of TX (docetaxel + capecitabine) adjuvant chemotherapy. At a median follow-up of 5 years, the results showed no statistical difference in DFS between the two groups, with patients in the AC→TX group having a significantly better OS than the AC→T group (P=0.011).
(4) Role of gemcitabine in adjuvant therapy
Gemcitabine alone showed good activity in advanced breast cancer as well as some synergistic effects in combination with paclitaxel. The randomized phase III clinical trial tAnGo compared the role of EC-T and EC-GT in early-stage breast cancer. 3,152 patients were randomized to the EC-GT group (1,576 patients) and the EC-T group (1,576 patients) from August 2001 to November 2004.
The EC-GT group regimen was 4-week E 90mg/m2 iv d1 repeated every 3 weeks; C 600mg/m2 iv d1 repeated every 3 weeks; sequential 4-week T 175mg/m2 iv d1; G 1250mg/m2 iv d1, 8d, repeated every 3 weeks.The EC-T group regimen was 4-week E 90mg/m2 iv d1; C 600mg/m2iv d1, repeated every 3 weeks; sequential 4-week T 175mg/m2 iv d1; G 1250mg/m2 iv d1, 8d, repeated every 3 weeks. The EC-T group was 4-week E 90mg/m2 iv d1; C 600mg/m2iv d1, repeated every 3 weeks; and sequential 4-week T 175mg/m2 iv d1, repeated every 3 weeks. Of these patients, 77% had positive axillary lymph nodes, 55% were <50 years of age, 41% were ER negative, 37% were PgR negative, and 26% had HER2 overexpression (total of 909 patients tested). At a median follow-up of 35 months, DFS HR=1.0, 95% CI 0.8-1.2, P=0.96; OS HR=I.I, 95% CI 0.9-1.4, P=0.35, were not significantly different between the two groups. It was concluded that adding this dose of gemcitabine to this regimen did not observe any advantage.
The NSABP B-38 study compared the efficacy and safety of DDAC_TG with DDAC_T and the TAC regimen in the adjuvant treatment of 4894 patients with lymph node positive breast cancer. The median follow-up of 64 months showed that the three regimens differed in terms of toxicities, with 5-year disease-free survival (DFS) rates of 80.6% and 82.2% in the DD AC→TG and DD AC→T groups, respectively (P=0.27), and 80.6% and 80.1% in the DD AC→TG and TAC groups (docetaxel + AC), respectively (P=0.71); the DDAC→T and TAC regimens were more effective in terms of DFS. T and TAC regimens did not show differences in DFS and OS, and the addition of G to DDAC→T did not provide additional survival benefit.
5. Sequence of radiotherapy-endocrine therapy
The INTOIOI trial confirmed that sequential administration of endocrine therapy after chemotherapy was better than combined endocrine therapy with chemotherapy. There is no clear conclusion on the sequence of radiotherapy. The order of radiotherapy needs to take into account whether the patient’s main risk is systemic metastasis or local recurrence; if the risk of systemic metastasis is high, chemotherapy is preferred; if the risk of local recurrence is high, radiotherapy is preferred. Radiotherapy and endocrine therapy can be applied simultaneously.
Summary
Bonadonna’s clinical study of postoperative CMF adjuvant chemotherapy for breast cancer with 30-year follow-up still showed improvement in disease-free survival and overall survival, establishing the status of adjuvant chemotherapy for postoperative breast cancer. Further clinical studies have demonstrated the superiority of anthracycline-containing chemotherapy regimens over CMF regimens. The efficacy of sequential or concomitant paclitaxel in addition to anthracyclines is better.
The goal of adjuvant chemotherapy for early-stage breast cancer should be to achieve a cure, so the selection of regimens should emphasize following guidelines and standardizing treatment behavior.
1. Standard chemotherapy regimens include standard drugs, doses, treatment intervals and treatment courses.
2. Anthracycline-containing regimens commonly used are CAF and CEF regimens, or AC and CE regimens, and there is no strict comparison of which of the two regimens is better.
The therapeutic effect of sequential application of paclitaxel and doxorubicin after anthracycline is not much different, but the three-week regimen of doxorubicin and weekly regimen of paclitaxel have better efficacy than the three-week regimen of paclitaxel. Therefore, the sequential application of paclitaxel three-week regimen after anthracycline is no longer the standard recommended regimen.
4. The sequential application of anthracycline and paclitaxel in adjuvant therapy may be more effective than simultaneous use (A-T>AT), so AT combination is not the recommended regimen for adjuvant therapy.
5. There is no solid evidence on the status of gemcitabine and capecitabine in adjuvant therapy.