Metronomic Chemotherapy: A Steady Tempo for Maintenance Therapy

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Early studies show that continual low-dose chemotherapy lessens toxicity.
Early studies show that continual low-dose chemotherapy lessens toxicity.

Students of music may be familiar with the methodical “tick tick tick” of a metronome placed just within ear-shot to help them maintain a certain tempo or speed while learning songs. The world of oncology also has certain rhythms or speeds at which chemotherapy is administered and the results are noteworthy.

Recently, studies have been conducted to learn more about a medicinal delivery method called metronomic chemotherapy (MC), an emerging alternative to conventional chemotherapy.

MC refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor, according to Harold J. Burstein, MD,  of Dana-Farber Cancer Institute in Boston, MA. Dr. Burstein has led early-stage trials of MC to treat breast cancer.1

Early Studies Show Efficacy

During the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting several studies were presented that showed efficacy of this therapy method for various cancer types. Rabab Mohamed Gaafar, MD, of the National Cancer Institute in Cairo, Egypt, presented the findings of a study that looked at the efficacy and toxicity of MC.2

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The 3-year study, which ended in 2011, included 50 patients who were previously pretreated for metastatic breast cancer. Patients received MC oral cyclophosphamide 50 mg/day and methotrexate 2.5 mg twice on day 1 and 2 every week. The primary end point was time to progression (TTP) and secondary end points were response rate, overall survival (OS), safety, and effect on vascular endothelial growth factor (VEGF).

The study concluded that MC is a less toxic way to administer chemotherapy compared with high-dose chemotherapy and that patients with good performance status (PS) fared especially well.

Vijay Maruti Patil, MD, of Malbar Cancer Center in Mumbai India, also presented at the 2014 ASCO Annual Meeting. Dr. Patil presented the findings of his team's phase II study comparing MC with single-agent cisplatin in patients with metastatic, relapsed, or inoperable squamous cell carcinoma of head and neck (HNSCC). Of the 110 patients who participated in the study, those who were given MC experienced longer progression-free survival (PFS) (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (P=0.014).

This somewhat new drug delivery method has garnered the interest of so many in the oncology field that there is now a meeting dedicated to it. Yuval Shaked, PhD, of the Israel Institute of Technology in Haifa, Israel was interviewed during the 4th Metronomic Chemotherapy Meeting earlier this year in Milan, Italy. His research team has been looking at pancreas cancer models to study MC in mice and they have found that a continued low dose may be used as a maintenance strategy for patients.

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“Instead of giving a 'drug holiday' we just continue with a low dose. To do this—and in order to reduce the toxicity—we didn't use the high, maximum tolerated dose, we used a reduced dose,” Dr. Shaked said. And so far the results have showed great promise in terms of antitumor activity.

One of the most exciting features of MC is that it currently does not require the development of new drugs in order to study it further, he added. 

“The basic idea of [MC] is that you can use old drugs, off-patent drugs, and you gain antitumor activity,” Dr. Shaked said. Using existing chemotherapy drugs may be especially helpful in developing nations where the cost of treatment can hinder patients' access to treatment.

Looking more broadly at past studies, a statistical literature analysis was published in 2013 that identified, MEDLINE, EMBASE, and CENTRAL data of 80 phase II studies that included nearly 3,700 patients who received MC for different cancer types. Most were pretreated patients with

advanced/metastatic breast cancer (26.25%) and prostate cancer (11.25%). The most commonly used drug was cyclophosphamide (43%). MC was frequently combined with other therapies (64.5%). The review showed that MC appears to be a safe practice and can be used across different patient populations.5

Further clinical exploration, particularly phase III studies, are needed to further prove MC's efficacy, but, at this time, MC appears to be promising for patients who may be running out of treatment options. 


  1. Carmen Phillips. A new “target” for chemotherapy? NCI Cancer Bulletin Accessed August 28,2014.
  2. Gaafar RM, Hussein MM, Allahlou NM, et al. Toxicity and prediction of survival benefit with metronomic chemotherapy in metastatic breast cancer.  J Clin Oncol. 32:5s, 2014 (suppl; abstr 1045).
  3. Patil VM, Noronha V, Banaval SD, et al. A phase II study comparing metronomic chemotherapy with chemotherapy (single-agent cisplatin), in patients with metastatic, relapsed, or inoperable squamous cell carcinoma of head and neck. J Clin Oncol. 32:5s, 2014 (suppl; abstr 6017) .
  4. Shaked Y. 4th Metronomic Chemotherapy Meeting/Continual low-dose metronomic chemotherapy as potentially preferable to aggressive strategies. eCancer Conferences. Published June 25th, 2014. Accessed August 28, 2014.
  5. Lien K, Georgsdottir S, Sivanathan L, et al. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer. 2013;49(16):3387-3395.

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