Maintenance therapy is not a new concept, originally derived from experience in the treatment of tuberculosis and subsequently applied in the treatment of leukemia. “Oncology maintenance therapy” refers to the further treatment of patients whose disease has not progressed after several courses of combination therapy, in order to consolidate the efficacy of the treatment. The classical model is to keep one of the drugs as maintenance therapy until disease progression, and the other way is to change the drug for maintenance. With the advancement of research and treatment, the World Health Organization proposed to treat malignancy as a chronic disease in 2003, and the International Breast Conference in San Antonio in 2011 further emphasized the concept of “chronic disease” in the treatment of advanced breast cancer. Therefore, the current treatment strategy for advanced breast cancer needs to be changed to long-term treatment and management as a “chronic disease”, which is in line with the treatment strategy of maintenance therapy. It can be said that there is now a consensus on the concept of maintenance therapy. However, more in-depth research is needed on how to implement maintenance therapy, including patient selection and protocol selection. What principles should be followed for maintenance therapy With the in-depth research on molecular oncology, it is now believed that breast cancer is no longer a single disease, but can be divided into different subtypes according to the results of genetic analysis or immunohistochemistry, and these subtypes have different biological characteristics and different treatment strategies. 2011, the expert group of St. Gallen International Breast Cancer Conference reached a consensus that according to breast cancer tissue estrogen receptor, HER2 and Ki-67 status into five categories: LuminalA, LuminalB, HER2-positive, triple-negative and other specific types. Therefore, the treatment of advanced recurrent metastatic breast cancer should follow the principle of classifying treatment according to molecular typing. ☆ For hormone receptor positive breast cancer patients, maintenance therapy after effective endocrine therapy is not supported by data, but it has become the empirical consensus of clinical experts. ☆ For HER2-positive breast cancer patients, trastuzumab monotherapy maintenance therapy can be used if intolerable chemotherapy adverse reactions occur after effective first-line treatment with trastuzumab combined with chemotherapy. This is a common clinical practice and has been proven to be effective in several clinical studies. ☆ Chemotherapy is preferred for patients with advanced breast cancer who are HER2 negative, hormone receptor negative or hormone receptor positive but have progressed after endocrine therapy. A frequent clinical scene is that of a hormone receptor-negative, HER2-negative breast cancer patient who develops recurrent metastases several years after surgery, at which point her doctor will tell her that she needs to receive chemotherapy, and the patient immediately asks, “Doctor, how long do I need to undergo chemotherapy?” Different doctors must have different answers to this question: some answer that they will first receive chemotherapy for 4-6 months and then stop the drug for observation until the disease progresses again, while others believe that it is impossible to determine the course of treatment at this time and depends on the efficacy and tolerability. Which of the two answers is right? Based on the concept of “chronic disease” and “maintenance treatment” for advanced breast cancer, some scholars propose a treatment model that is more consistent with the goal of “chronic disease” treatment, replacing the original In order to achieve the goal of “prolonged life”, we propose a treatment model that is more consistent with the goal of “chronic disease”, instead of the original treatment model of “stop chemotherapy and wait for recurrence”, and use the treatment strategy of “long flow of water”. This means that for advanced breast cancer patients who are suitable for chemotherapy, after 6-8 cycles of first-line chemotherapy are effective, effective maintenance therapy is adopted to delay the recurrence. After the concept of maintenance chemotherapy is established, the problem is how to choose the maintenance chemotherapy regimen. How to develop a maintenance regimen <<<< Anthracyclines In the era of anthracyclines as the main drug, Coates et al. investigators compared the efficacy of 3 cycles of doxorubicin + cyclophosphamide (AC) versus AC or cyclophosphamide + methotrexate + fluorouracil + o nisone (CMFP) chemotherapy to disease progression. The study enrolled 305 patients, and the time to disease progression was significantly longer in the long-course treatment group than in the 3-cycle group (6 months versus 3 months), but no advantage in overall survival was obtained. Similar studies were conducted by Muss, Gregory, and Ejlertsen, all of whom randomized patients to the extended treatment and discontinuation groups after 6-8 cycles of anthracycline-based chemotherapy regimens and showed a lag in disease progression in the extended treatment group. Certainly, chemotherapy-related adverse effects were more pronounced with extended treatment compared with discontinued treatment. The above studies consistently show that prolonging chemotherapy improves time to disease progression. The early findings provide theoretical support for maintenance therapy. Paclitaxel, capecitabine With the progress of drug development, paclitaxel, capecitabine and other drugs with stronger antitumor activity and relatively lower toxicity are more favorable for prolonged application, and there have been some studies reported on what role they can play in maintenance therapy. The GEICAM 2001-01 study evaluated the efficacy of polyethylene glycol liposomal doxorubicin for the maintenance treatment of advanced breast cancer. The investigators used a sequential paclitaxel regimen of doxorubicin or epirubicin as first-line treatment, and then divided into maintenance and observation groups. The results showed that maintenance therapy significantly prolonged patients' median progression-free survival (PFS, 16.04 months versus 9.96 months). However, considering the route of administration, ease of use and price of polyethylene glycol liposomal doxorubicin, it is difficult to be widely used in the clinic. The MANTA1 study evaluated paclitaxel for maintenance treatment of advanced breast cancer. The study enrolled 459 patients with recurrent metastatic breast cancer, who were randomized into paclitaxel maintenance treatment and observation groups after 6-8 cycles of first-line chemotherapy with doxorubicin or epirubicin combined with paclitaxel. An interim analysis showed that the PFS in the paclitaxel maintenance group and the observation group were 8 and 9 months, respectively, indicating that no PFS and overall survival (OS) benefit was achieved with anthracycline combined with paclitaxel first-line chemotherapy followed by 8 cycles of paclitaxel maintenance therapy. From today's perspective, the MANTA1 study is flawed. The study used paclitaxel dosing every 3 weeks, which is not optimal when compared to weekly paclitaxel dosing. In addition, 60% of hormone receptor positive breast cancer patients in the study received endocrine therapy concurrently with chemotherapy, while there is evidence that chemotherapy combined with endocrine therapy may reduce efficacy. Meta-analysis The more compelling evidence for maintenance therapy comes from the Meta-analysis conducted by Gennari et al. This analysis included 11 randomized controlled clinical trials enrolling 2269 patients to analyze the effect of duration of first-line chemotherapy on PFS and OS in metastatic breast cancer. The control groups were all treated with a fixed number of courses, and the study groups were divided according to the regimen design: (i) the same chemotherapy regimen as the control group and extended until tumor progression; (ii) the same chemotherapy regimen as the control group and extended to a fixed number of courses; and (iii) the same regimen as the control group treated with a different maintenance regimen (combination or single agent). The results showed that extending the duration of first-line chemotherapy significantly improved patients' OS, reduced tumor-related mortality by 9%, and significantly improved PFS; there was no significant difference between the different regimen designs. What's new in the KCSGBR0702 study Recently, Korean scholars published the results of a prospective, multicenter phase III clinical study (KCSGBR0702), which adds new evidence for maintenance chemotherapy, but also has many controversial aspects. The study was designed to see whether the use of gemcitabine in combination with paclitaxel (PG) as maintenance therapy improved PFS compared with the observation group. 324 chemotherapy-naïve patients with metastatic breast cancer were enrolled in the study and were first treated with PG for 6 cycles; 231 patients who achieved complete remission (CR), partial remission (PR), and stable disease (SD) were randomized to the group that continued with PG. The 231 patients who achieved complete remission (CR), partial remission (PR) and stable disease (SD) were randomized to the maintenance group (until disease progression) and the observation group without PG. The results showed that PFS was 7.5 months and 3.8 months, and OS was 32.3 months and 23.5 months in the maintenance and observation groups, respectively, with statistically significant differences; more patients in the maintenance group showed 3rd/4th degree granulocytopenia. Subgroup analysis showed that patients who were premenopausal, ≤50 years old, had CR/PR, visceral metastases, hormone receptor negative, and heavy lesion loading benefited more from maintenance therapy; the median duration of maintenance therapy was 6 cycles at more than 85% of the standard dose, with no deterioration in quality of life and tolerable and manageable toxicity in the maintenance group. This study confirms the role of maintenance therapy, but its results have been questioned in a number of ways. The first question is whether the use of gemcitabine in combination with paclitaxel is appropriate for maintenance therapy. The combination of two chemotherapeutic agents for long-term treatment obviously brings more serious adverse effects than single agents. In fact, either of the drugs in the PG regimen has antitumor activity, which brings up the question of whether the choice of control group in the study could be more reasonable. Is the choice of a blank control group ethical? If a single drug is chosen as the control group, can the combination regimen still show advantages in maintenance treatment? The study subgroup analysis provides a basis for clinicians to select appropriate patients for maintenance therapy. What is the treatment experience in China Because of the heterogeneity of oncology patients, this is not only reflected in the response to antitumor therapy, but also in the difference of adverse effects. Therefore, how to select the right patients and choose the right regimen for maintenance therapy should be the focus of future research. A retrospective analysis of the oral chemotherapy drug capecitabine as a maintenance drug in treated patients was conducted in the authors' center. The analysis showed that among 64 patients with recurrent metastatic breast cancer treated with doxorubicin + capecitabine or vincristine + capecitabine, those who completed 4 to 6 cycles of combination therapy without progression received capecitabine monotherapy for maintenance treatment with a median PFS of 4.4 months. The national multicenter clinical study of subsequent capecitabine monotherapy maintenance treatment in metastatic breast cancer with non-disease progression after capecitabine-containing regimens of first-line chemotherapy, initiated by the authors and Professor Binghe Xu at the Cancer Hospital of the Chinese Academy of Medical Sciences, enrolled a total of nearly 2,000 patients with a PFS of 12.8 months on single-agent capecitabine maintenance therapy. These studies have demonstrated the possible advantages of maintenance therapy with the oral agent capecitabine. Conclusion The current conceptual strategies regarding maintenance therapy for advanced recurrent metastatic breast cancer have been endorsed by national and international consensus and guidelines. Maintenance therapy for patients with non-progressive first-line chemotherapy in advanced breast cancer is a reasonable strategy. The choice of maintenance regimens should in principle be effective, low-toxic, easy to use, and weigh time, cost, and efficacy. The study of more low-toxicity maintenance treatment strategies, such as the application of easily tolerated targeted drugs is the development direction of maintenance therapy. However, there are still many unanswered clinical questions. For example, how to optimize maintenance therapy regimens? Since not all patients with advanced disease require maintenance therapy, how to select the right patients who need maintenance therapy? What is the best time point to start maintenance therapy? What is the role of new targeted drugs in maintenance therapy? More clinical studies are needed to answer these questions. Based on the concept of "chronic disease" and "maintenance therapy" for advanced breast cancer, some scholars have proposed the "advanced breast cancer management model", which is more consistent with the goal of "chronic disease" treatment. This includes choosing the best first-line treatment for recurrent metastatic breast cancer, which can be endocrine therapy, chemotherapy and molecular targeting, and considering reasonable maintenance therapy for effective patients. For HER2 receptor positive patients, there is a consensus to use trastuzumab-based therapy until progression; hormone receptor [ER and/or PR] positive patients with slow disease progression, no visceral metastases or asymptomatic visceral metastases can be preferred to endocrine therapy until progression; hormone receptor negative, hormone receptor positive with symptomatic visceral metastases, hormone receptor positive but with rapid disease progression or to Chemotherapy should be considered first for patients who are ineffective in endocrine therapy. For patients with advanced breast cancer who are suitable for chemotherapy, after 6-8 cycles of first-line chemotherapy, appropriate maintenance therapy should be given to delay recurrence and achieve the goal of "prolonging life".