Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Abstract

Metronomic chemotherapy (mCHT), defined as continuous administration of low-dose chemotherapeutic agents with no or short regular treatment-free intervals, was first introduced to the clinic in international guidelines in 2017, and, since then, has become one of the available strategies for the treatment of advanced breast cancer (ABC). Despite recent successes, many unsolved practical and theoretical issues remain to be addressed. The present review aims to identify the “lights and shadows” of mCHT in preclinical and clinical settings. In the preclinical setting, several findings indicate that one of the most noticeable effects of mCHT is on the tumor microenvironment, which, over the last twenty years, has been demonstrated to be pivotal in supporting tumor cell survival and proliferation. On the other hand, the direct effects on tumor cells have been less well-defined. In addition, critical items to be addressed are the lack of definition of an optimal biological dose (OBD), the method of administration of metronomic schedules, and the recognition and validation of predictive biomarkers. In the clinical context—where mCHT has mainly been used in a metastatic setting—low toxicity is the most well-recognised light of mCHT, whereas the type of study design, the absence of randomised trials and uncertainty in terms of doses and drugs remain among the shadows. In conclusion, growing evidence indicates that mCHT is a suitable treatment option for selected metastatic breast cancer (MBC) patients. Moreover, given its multimodal mechanisms of action, its addition to immunological and targeted therapies might represent a promising new approach to the treatment of MBC. More preclinical data are needed in this regard, which can only be obtained through support for translational research as the key link between basic science and patient care.

Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation

“…Taken together with other published data, our results confirm the multimodality mechanism of action of mCHT and contribute to understanding of the cellular and molecular mechanisms underlying the effect observed in clinical trials in TNBC patients treated with mCHT therapy ( 69 ). Moreover, our findings support the rationale for its employment in TNBC patients, where the dual targeting of the tumor and its vasculature at the same time would result in better therapeutic outcomes.…”

Efficacy of Metronomic Oral Vinorelbine, Cyclophosphamide, and Capecitabine vs Weekly Intravenous Paclitaxel in Patients With Estrogen Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer

“…Metronomic VEX’s safety profile in METEORA-II was similar to that of other metronomic regimens in MBC and still manageable . Another important aspect is the cost of treatment.…”

A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2‐negative metastatic breast cancer

“…Low‐dose continuous administration of CAP is also safe and well‐tolerated 26,46–48 . The combination of oral VNR and CAP has been studied in several clinical trials 49–51 . A phase II clinical trial revealed that the metronomic combination regimen encompassing VNR, cyclophosphamide and CAP displayed remarkable activity and favorable tolerability in patients with HR‐positive MBC.…”

“…Another open‐label, international, multicenter, phase II study enrolled 40 MBC cases who were administered oral VNR at 60 mg/m (2) on days 1, 8 and 15, along with CAP at 1000 mg/m (2) bid from day 1 to day 14. The treatment cycles were 3 weeks, and the response rate was 23.5% in the 34 evaluable cases 50 . The VICTOR‐2 study examined the efficacy of the mNC regimen in patients with HER‐2‐negative MBC.…”