Metronomic topotecan for colorectal cancer: a promising new option

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality and the fourth most common malignant neoplasm in the USA. Depending on the stage at diagnosis, liver and lung metastases occur in about 20e70% and 10e20% of patients, respectively. Unfortunately, distant metastases are the major cause of death for patients with advanced CRC. Despite use of standard therapies for metastatic CRC, treatment has only minimally improved survival, resulting in a medium survival of w2 years. As current chemotherapeutic drugs are used at maximum tolerated doses or high dose in standard therapies, toxicity remains a major issue for patients. Therefore, if the standard therapies could have prolonged breaks between successive cycles of drug administration, this could allow for recovery from toxic side effects. To solve this problem, Dr. Timothy Browder at Harvard Medical School first proposed metronomic chemotherapy to minimise toxicity by targeting the tumour-associated endothelium via frequent use of chemotherapeutic drugs at low doses over a longer period of time. Although the definition of metronomic chemotherapy varies, it now generally refers to the continuous administration of traditional chemotherapy, sometimes on a daily basis, at relatively low, minimally toxic doses, for longer periods. This emerging approach has been extensively evaluated in clinical trials and animal models. 1 Hackl et al 2 report for the first time that metronomic oral topotecan therapy in adjuvant and metastatic settings prolongs survival and reduces liver metastasis in mouse models of metastatic CRC. Their findings provide a rational for clinical trials of metronomic oral topotecan in CRC at stage III and metastatic CRC as well.It has been well established that the metastatic spread of carcinoma cells is a complex process that involves multiple steps ranging from the detachment of carcinoma cells from the surrounding matrix and neighbouring neoplasm to establishment of growth at a secondary site. The process requires cancer cells to migrate through the primary tumour mass, to intravasate into and survive in the blood and lymphatic vascular system, to extravasate from the vascular system into a secondary organ, and to re-establish growth. Therefore, cancer metastasis is regulated by cross-talk between the tumour cells and their microenvironment. The tumour microenvironment is a heterogeneous, complex milieu with features including elements of angiogenesis, inflammation and hypoxia. A growing body of evidence suggests that the high efficiency of metronomic chemotherapy is due to not only targeting tumour-associated angiogenesis and immune response but also induction of tumour cell dormancy. 1 As recent attempts to improve standard adjuvant therapy by adding either bevacizumab (the AVANT and NSABP C-08 trials) 3 or cetuximab (the NCCTG N0147 trial) have failed, there is a grave need for other potential drugs and/or approaches to be tested. Irinotecan is a topoisomerase I inhibitor and is used to treat patients with metastatic CRC in...

Optimization of liposomal topotecan for use in treating neuroblastoma

“…Enhanced exposure times can be achieved using a number of approaches including continuous drug infusions , more frequent dosing (i.e. metronomic dosing ), PEGylation of camptothecin derivatives and through use of nano‐scale drug delivery systems such as the liposomal formulations described here. Furthermore, topotecan's activity depends on maintaining an intact lactone ring and the liposomal formulations of topotecan will help maintain the drug in the lactone form for extended time periods following administration.…”

Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer

“…While the mechanisms are not clear, the clinical benefits of METRO have been demonstrated with several other drugs in a variety cancers, including mCRPC, with varying degrees of success ( Gebbia et al, 2011 ; Jellvert et al, 2011 ). Furthermore, low dose oral TOPO has been shown to be potent against several cancers, with its greatest efficacy for patients with ovarian cancer ( Merritt et al, 2009 ; Wang et al, 2013 ; Jedeszko et al, 2015 ).…”