Metronomic chemotherapy is a low-dose, short-interval form of chemotherapy that allows drugs in the bloodstream to be maintained at a certain anti-tumor concentration for a longer period of time to prolong disease control while greatly reducing toxic side effects.
There have been several studies of beat chemotherapy in metastatic breast cancer that have shown some efficacy and a good safety profile. This article introduces you to this particular mode of chemotherapy.
What are the advantages of beat chemotherapy?
Breast cancer is relatively sensitive to chemotherapy, but conventional chemotherapy has the following shortcomings.
- Conventional doses of chemotherapy drugs can kill the tumor while also producing a series of adverse effects on the patient’s organism, with heavy adverse reactions, and some patients are even unable to tolerate the treatment and are forced to discontinue it.
- There is usually a long interval between cycles of conventional chemotherapy, which allows some of the actively growing tumor cells to come back, and the tumor cells that are growing again will be stronger than before and harder to destroy.
In 2000,
the concept of “beat chemotherapy” was introduced when scientists discovered in mice that small, continuous or high frequency doses could effectively inhibit the proliferation of endothelial cells in tumor blood vessels and thus exert anti-tumor effects.
There are some differences between beat chemotherapy and conventional chemotherapy (Table), and in theory, this approach has the potential to avoid the problems of “adverse effects of high-dose chemotherapy” and “tumor cell recovery between chemotherapy sessions.
| The difference between beat chemotherapy and conventional chemotherapy | ||
|---|---|---|
| Category | Conventional chemotherapy | Beat chemotherapy |
| Dosing | Maximum Tolerated Dose | 1/10 to 1/3 of the conventional dose |
| Dosing interval | Every 2 week period usually 3 to 4 weeks apart | High-frequency, continuous dosing |
| Mechanism of action | Attacks tumor cells, but may also damage normal human tissue | Anti-angiogenesis, immunomodulation, etc. |
| Application level | A wide range of applications | Progressive |
Our scholars compared conventional chemotherapy (capecitabine) with beat chemotherapy (continuous, low-dose capecitabine) in a mouse model and found that beat chemotherapy inhibited neovascularization and adjusted the ratio of immune cells, thereby inhibiting tumor formation.
While there was no difference in tumor volume between the two groups at the end of treatment, mice in the beat chemotherapy group had significantly higher white blood cell counts than those in the conventional chemotherapy group, meaning that beat chemotherapy reduced the adverse effects of chemotherapy.
Single-drug beat chemotherapy: exerting efficacy and reducing adverse effects
Researchers have conducted many explorations of beat chemotherapy with different drugs, and the main chemotherapy drugs include cyclophosphamide, methotrexate, capecitabine, and vincristine.
Vincristine
Thirty-two elderly patients with metastatic breast cancer who received beat chemotherapy with oral 1 doses of vincristine every 2 days had clinical benefit in 50% with no adverse effects above moderate.
Another 34 older adults with metastatic breast cancer, also treated with oral vincristine beat chemotherapy, achieved complete remission and partial remission in 6% and 32%, respectively, with median progression-free survival and median overall survival of 7.7 months and 15.9 months, respectively. Patients tolerated well during treatment.
Capecitabine
A phase II clinical study enrolled 60 patients with advanced breast cancer who had previously received other treatments and were subsequently given daily low-dose capecitabine beat chemotherapy to complete at least 2 courses (28 days for 1 course), with a clinical benefit rate of 62.0%, with median progression-free survival and median overall survival of 7 months and 17 months, respectively. For those 13 patients previously treated with capecitabine in intermittent dosing mode, there were still 2 cases who achieved partial remission and 7 cases with stable disease. Grade 3 to 4 adverse reactions and hematologic toxicity were uncommon during treatment .
Domestic investigators explored beat chemotherapy in 56 elderly patients with metastatic breast cancer who received capecitabine beat chemotherapy (2 small oral doses daily) or conventional chemotherapy, respectively. As a result, there was no significant difference in survival between the two forms of chemotherapy, but patients on beat chemotherapy had a significantly lower incidence of adverse effects such as hand-foot syndrome, myelosuppression, and gastrointestinal reactions, and a significantly better quality of life.
The phase III clinical trial of capecitabine beat chemotherapy, the CAMELLIA study, is ongoing, a national multicenter study led by the team of Professor Xu Binghe at the Cancer Hospital of the Chinese Academy of Medical Sciences, and is currently in patient recruitment.
The CAMELLIA study is comparing the efficacy and adverse effects of sequential capecitabine beat-to-beat or intermittent maintenance therapy in patients with HER-2 negative metastatic breast cancer who received capecitabine + docetaxel after the end of first-line combination chemotherapy. This large national multicenter study will provide additional evidence for the use of beat chemotherapy.
Studies in breast cancer have shown successively that single-agent beat chemotherapy can play a role in controlling breast cancer progression and is better tolerated by patients, with a lower incidence of adverse events than conventional chemotherapy .
Beat chemotherapy in combination with other treatments: more flexible options
Beat chemotherapy can also be used in combination with other breast cancer treatment options.
For metastatic breast cancer that is resistant to anthracycline and paclitaxel chemotherapy, consider the option of beat chemotherapy in combination with bevacizumab. Patients were treated with cyclophosphamide + methotrexate in beat chemotherapy, and trastuzumab was added for those who were HER-2 positive. The results showed that 31.8% of the 22 patients achieved partial remission, and 63.6% had clinical benefit. The patients had a median progression-free survival of 7.5 months and an overall survival of 13.6 months. The adverse reactions that occurred during the study were mild.
Studies of beat chemotherapy combined with anti-angiogenic or endocrine drugs are also in the pipeline, and we look forward to more exploration to provide us with good news.
How do you see the role of beat chemotherapy?
Beat chemotherapy is an emerging form of chemotherapy that has fewer side effects than traditional treatments, can overcome drug resistance to some extent, and is applied in a flexible form that allows physicians to give individualized treatment plans depending on the patient.
In terms of efficacy, the benefit of conventional chemotherapy in patients with advanced breast cancer is limited, and the clinical benefit of single-agent beat chemotherapy of more than 50% in small studies is very attractive.
Safety-wise, patients maintained good tolerability even with combination triple-agent beat chemotherapy, and for the triple-agent combination of vincristine + cyclophosphamide + capecitabine beat chemotherapy, the incidence of hand-foot syndrome, elevated transaminases, and neutropenia was low.
The benefits of beat chemotherapy, which is administered in a novel way with small doses and short intervals, is gradually being recognized for its antitumor effects through anti-tumor angiogenesis and immunomodulation, as well as for its low incidence of adverse effects and good treatment tolerability.
In the third edition of the ESO-ESMO International Consensus on Advanced Breast Cancer (ABC3), published in 2017 nearly 90% of experts favored beat chemotherapy as a reasonable option for patients who do not need rapid symptomatic relief. However, it is still important to compare beat chemotherapy with standard regimens and analyze the pros and cons before making a choice .
Summary
Beat chemotherapy in breast cancer has been studied predominantly in metastatic breast cancer, and small studies have found moderate efficacy and fewer adverse effects.
There is still a lack of support from large clinical studies for beat chemotherapy, and patients may consider trying it with the advice of their physicians.