Dose-Dense Chemotherapy in Metastatic Breast Cancer: Shortening the Time Interval for a Better Therapeutic Index

Abstract

factor receptor 2 (HER2)-positive advanced breast cancer. Still, despite these advances in targeted therapies, cytotoxic chemotherapy remains a cornerstone in the treatment of advanced disease.Clearly, chemotherapy has an essential role in rapidly progressive life-threatening disease. In these situations, it is sometimes prudent to sacrifice toxicity for improved efficacy leading to rapid responses which in turn should improve the quality of life of the patient.This goal can be achieved by combining chemotherapy with targeted agents like bevacicumab [2] and trastuzumab [3]. Another possibility to achieve a fast response is to combine several chemotherapeutic agents. Even though this approach does not lead to improved survival compared to sequential single-agent chemotherapy, it is sometimes necessary for prompt symptom control. In a meta-analysis of 12 trials with 2,317 patients randomized to combination chemotherapy compared to the same drugs used sequentially, the authors showed that combination chemotherapy led to a higher risk ratio (RR) of 1.13 (95% confidence interval (CI) 1.03-1.24; p = 0.008) at the cost of a higher rate of febrile neutropenia (RR 1.32, 95% CI 1.06-1.65; p = 0.01). Despite the higher response rate, there was no difference in overall survival (OS) between these treatment strategies (hazard ratio (HR) 1.04, 95% CI 0.93-1.16; p = 0.45). Furthermore, combination chemotherapy led to a higher risk of progression (HR 1.16, 95% CI 1.03-1.31; p = 0.01). This high-level evidence further supports the recommendations to use sequential monotherapy unless there is rapid disease progression [4].However, it is in this very situation that the concept of dose density can come into play, including in advanced and metastatic breast cancer. Dose-Dense ChemotherapyIn an attempt to increase the efficacy of anthracycline-and taxane-containing regimens originally used in the adjuvant treatment Keywords Dose-dense · Metastatic · Breast cancer · Weekly · Metronomic Summary Despite the advancement of targeted therapies in metastatic breast cancer, chemotherapy is still of pivotal importance. The concept of dose density is known to increase the efficacy of chemotherapy. In metastatic disease, preservation of the quality of life is equally important. Because of this, weekly regimens are a cornerstone in metastatic disease. Taxanes like paclitaxel or nab-paclitaxel as well as antracyclines are often used in palliative treatment. Further advances to increase dose density have led to the concept of daily metronomic schedules with oral chemotherapeutic drugs like cyclophosphamide, capecitabine, or vinorelbine. Metronomic chemotherapy affects tumor angiogenesis and also weakens immunosuppressive regulatory T cells, promoting better control of tumor progression. Weekly or daily dose-dense regimens are a reasonable compromise between efficacy and toxicity to improve the therapeutic index. This is most important for the treatment of chronic disease where palliation and preservation of quality of life are vital.

Dose-dense regimen versus conventional three-weekly paclitaxel combination with carboplatin chemotherapy in first-line ovarian cancer treatment: a systematic review and meta-analysis

“…Emerging evidence had demonstrated that exposure time was a pivotal determinant of paclitaxel cytotoxic activity, and sufficient cytotoxicity could be exerted under relatively low blood concentration if exposure time were extended [ 13 , 24 , 25 ]. Second, dose-dense therapy delivered chemotherapy drugs weekly, which could shorten the interval time and increase the density of drug delivery [ 26 ]. Besides, the valley of paclitaxel blood concentration was higher than that of three-weekly therapy [ 27 ], and the cumulative dose of paclitaxel for dose-dense therapy was more than that of conventional three-weekly therapy (240 mg VS 175 mg) [ 25 ].…”

Therapeutic Advances in Oncology

“…FDA approved chemotherapy drugs for breast cancer include taxanes, anthracyclines, and platinum. Compared to the standard schedule of treatment (every three-weeks), combination of doxorubicin, cyclophosphamide, and paclitaxel administered every two weeks with high density has slowed cancer growth and extended survival without introducing additional adverse side effects [ 35 ].…”

Investigations on anticancer activity of Eu3+ doped hydroxyapatite nanocomposites against MCF7 and 4T1 breast cancer cell lines: A structural and luminescence Perspective

“…This is supported by existing literature [ 6 ]. The efficacy of medication may be compromised if the administered doses, whether orally or intravenously, do not adequately reach the intended sites, as per sources [ 7 , 8 ]. Targeted therapies and immunotherapies represent a novel and auspicious approach to managing breast cancer [ 9 , 10 ].…”