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 advancement of research on molecular oncology, it is now believed that breast cancer is no longer a single disease and can be divided into different subtypes based on the results of genetic analysis or immunohistochemistry, which have different biological characteristics and different treatment strategies.
In 2011, the expert group of the St. Gallen International Breast Cancer Conference reached a consensus to classify breast cancer tissues into five categories according to their estrogen receptor, HER2 and Ki-67 status: Luminal A, Luminal B, 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 may be used for maintenance treatment after effective first-line treatment with trastuzumab in combination with chemotherapy if there are intolerable chemotherapy adverse effects. 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 the physician will tell her that she needs to receive chemotherapy, and the patient immediately asks, “Doctor, how long do I need to have 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; 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 Some scholars propose a treatment model that is more consistent with the goal of “chronic disease”, replacing the original “stop chemotherapy and wait for recurrence” treatment model, and using a “long-term” treatment strategy to achieve the goal of “prolonging life”. 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 treatment regimen
Anthracyclines In the era of anthracycline-based drugs, Coates et al. investigators compared the efficacy of 3 cycles of doxorubicin + cyclophosphamide (AC) with 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 some studies have been reported on the 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.
MANTA1 study
To evaluate 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. The 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.
With 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
More convincing evidence for maintenance therapy comes from a 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 protocol design into.
(i) the same chemotherapy regimen as the control group with an extended course of treatment until tumor progression;
②The same chemotherapy regimen as the control group, extended to a fixed number of courses;
(iii) the same regimen as the control group followed by a change to 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 different regimen designs.
What is the treatment experience in China
Due to the heterogeneity of tumor 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 treatment 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 4-6 cycles of combination therapy without progression received capecitabine monotherapy for maintenance treatment with a median PFS of 4.4 months.
A 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.