Since it was first defined at the turn of the century, metronomic chemotherapy (MC) has seen increasing use and acceptance in veterinary patients (Mutsaers, 2007) and involves the long-term use of low doses of chemotherapeutic agents to control the growth of cancer cells (Hanahan et al., 2000). It is an alternative to what has historically been the mainstay of cancer chemotherapy and treatment, which relies on giving high doses of cytotoxic medication using a maximum tolerated dose (MTD) concept. This method is undoubtably effective, but it is not without its dangers. While veterinary protocols seek to keep the doses tempered so that side effects are minimised, they are not reduced to zero, and such MTD-based regimes require treatment breaks to be incorporated to allow for the recovery of non-neoplastic, rapidly dividing cells that are inevitably damaged by these untargeted treatments.
Metronomic chemotherapy: the theory
As our understanding of tumour biology has improved, and continues to do so, our understanding of the mechanisms of action of MC and its potential for management of neoplastic disease has improved in parallel and it is currently the focus of much ongoing research.
Tumour cells do not exist in a vacuum but rather in an environment that is a complex milieu of pro- and anti-tumorigenic factors, both cellular and humoral, and while MC was initially thought to exert its effects by an anti-angiogenic mechanism, it is now understood to interact with the tumour micro-environment (TME) in multiple and diverse ways.
Perhaps the four most important mechanisms of MC are its effects on tumour neovascularisation, tumour immunity, cancer stem cells and the induction of tumour dormancy
Perhaps the four most important mechanisms of MC are its effects on tumour neovascularisation, tumour immunity, cancer stem cells and the induction of tumour dormancy.
Angiogenesis, the formation of new blood vessels from endothelial cells, is essential for tumour growth. It is a complex process that occurs in microscopic pre-invasive lesions as well as during the rapid growth phase of tumour growth.
MC acts firstly by direct action on endothelial cells (Mutsaers, 2009), causing selective apoptosis (programmed cell death), and by a direct selective inhibition of migration and proliferation of endothelial cells (Gaspar et al., 2017). Secondly, MC modulates pro- and anti-angiogenic factors, downregulating the former and upregulating the latter, creating an environment less favoured to endothelial proliferation (Mutsaers, 2009). MC is also known to block the mobilisation of marrow-derived circulating endothelial progenitor cells (Mutsaers, 2007) which are also responsible for tumour vascularisation. It seems that MC has both local and systemic effects on vascularisation.
The immune system
Tumours are highly antigenic but are able to assume a “cloak of invisibility” that protects them from the host immune system. This cloak is provided by immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Both are central in limiting inflammation in both physiologic and neoplastic conditions. They are present in high levels in oncology patients with active malignant disease (Biller, 2014). Tumours will induce Tregs by producing suppressive cytokines (IL-10, IL-35, transforming growth factor-b) and, accumulated within the tumour, they suppress the activity of both tumour-specific cytotoxic T cells and non-specific T effector cells, natural killer (NK) and NK T-cells. In addition, they prevent the maturation of dendritic antigen-presenting cells.
MC works by suppressing Treg function and number, thus removing the block on the immune system, both specific and non-specific, and allows for maturation and improved function of dendritic cells
MC works by suppressing Treg function and number, thus removing the block on the immune system, both specific and non-specific, and allows for maturation and improved function of dendritic cells.
Cancer stem cells
Cancer stem cells (CSCs) are a subpopulation of tumour cells that can act like normal stem cells. They have a self-regenerative and differentiation capacity and importantly have DNA repair capacity (Biller, 2014). They can produce high levels of vascular endothelial growth factor (VEGF), a major pro-angiogenic factor. They are thought to be the cause of resistance in conventional chemotherapy and radiation therapy. The assumption is that the lower dose rates of MC are not directly cytotoxic to neoplastic cells, but some authorities maintain that there is a direct drug-mediated effect on CSCs. It may also be that there is an effect on CSC survival because of the indirect effect on VEGF necessary for their survival. There is therefore a reduction in stem cell ability to act as such.
Tumour dormancy occurs during early-stage disease before the development of local conditions that support proliferation, and also during the later stages, post-treatment remission. It is a result of cell cycle arrest or a dynamic equilibrium between cellular proliferation and apoptosis and can be present in both primary and metastatic disease. Dormancy can be angiogenic, cellular or immune-mediated and, as can be seen from the foregoing, it is at least theoretically possible that by acting on all of these phases, MC could induce dormancy and long-term control of disease.
MC has historically been considered as a palliative treatment when other conventional treatments have become ineffective, but three possible clinical indications have been identified (Loven et al., 2013):
- First-line treatment in patients diagnosed with advanced or incurable disease, where conventional MTD therapy would risk life-limiting toxicity
- Consolidation following adjuvant or neoadjuvant MTD chemotherapy with the intent of prolonging the acquired clinical remission – so called chemo-switch when there is a change of medication between MTD and metronomic
- Maintenance therapy as a substitute for a high-dose MTD regime regardless of achieved response, with the aim of offering improved quality of life
MC has historically been considered as a palliative treatment when other conventional treatments have become ineffective, but three possible clinical indications have been identified
Metronomic chemotherapy has a number of advantages which make it an attractive option in veterinary patients (Mutsaers, 2009; Gaspar et al., 2017):
- Better tolerability and fewer adverse effects, reducing the need for other supportive treatments
- Increased convenience to the pet owner and reduced stress for the patient as they are treated at home
- Generally, a reduced cost
- Reduced chance of acquired resistance
- Possible combination with other orally administered targeted therapies
Agents used in MC
By far the most widely used is cyclophosphamide (CYC) which has been shown to have strong anti-angiogenic and immunomodulatory effects. It can be employed either as a sole agent, or more usually in combination with other drugs. Side effects are unusual, but they are generally gastrointestinal. The classic sterile haemorrhagic cystitis seen in MTD protocols may be a problem with chronic administration, but morning administration and encouraging the patient to drink can minimise this risk. If necessary, the judicious use of diuretic medication can be employed to increase the frequency of urination. The dose of CYC is not yet clear, but recent work has indicated a dose of 12.5mg/m2 is both anti-angiogenic and immunomodulatory (Romiti et al., 2013).
By far the most widely used is cyclophosphamide (CYC) which … can be employed either as a sole agent, or more usually in combination with other drugs. Side effects are unusual, but they are generally gastrointestinal
Other cytotoxic medications that have been used to good effect are chlorambucil at 4mg/m2 once daily (Leach et al., 2011) and lomustine at 2.8mg/m2 once daily (Tripp et al., 2011). Both appear to be well tolerated.
Other drugs used in combination with MC
MC is almost invariably combined with additional medications that may augment the action of the protocol (Mutsaers, 2009).
NSAIDs are widely administered alongside CYC. Inflammatory mediators play a central role in the initiation and maintenance of cancer cell survival and growth. COX-2 is induced by inflammatory cells and mediators in the TME and neovasculature, where it has both angiogenic and immunomodulatory effects. It is over-expressed in many cancers, and so the use of COX-2 antagonists is rational to modulate these effects. Piroxicam is generally the most widely used, but the COX-2 specific drug celecoxib has also been studied.
Thalidomide, initially introduced to the human pharmacy as a sedative hypnotic and later withdrawn because of the teratogenicity that became apparent, is known to possess immunomodulatory and anti-inflammatory effects, as well as being anti-angiogenic by inhibiting vascular endothelial growth factor (VEGF). Trials have shown it to be effective in dogs with surgically treated soft tissue sarcomas (Elmslie et al., 2008) and haemangiosarcomas (Finotello et al., 2016). However, there are conflicting reports which do not confirm a positive benefit (Alexander et al., 2018).
Small molecule inhibitor is the term given to a variety of drugs that inhibit tyrosine kinase receptors. In veterinary medicine these are masitinib and toceranib. Both are licensed for use in mast cell cancers, but have been widely used in a variety of other cancers. Many of these receptors that are the targets for these drugs are pro-angiogenic and pro-tumorigenic, so again their use in combination with other drugs is rational.
Problems with MC
Problems do exist with MC. The definition is vague and imprecise, and indications and dose rates are yet to be clearly determined. There is a lack of randomised trials that compare it to classic cytotoxic regimes, and this perhaps is the main reason for scepticism and lack of wider application
Problems do exist with MC. The definition is vague and imprecise, and indications and dose rates are yet to be clearly determined. There is a lack of randomised trials that compare it to classic cytotoxic regimes, and this perhaps is the main reason for scepticism and lack of wider application. There exists a problem of defining optimum doses as they are not defined by dose-limiting toxicities, and establishing what is a positive result in advanced disease using criteria that are defined for solid tumours is not straightforward. There is little understanding of the mechanisms of resistance to MC and no veterinary studies determine such mechanisms. It is important to note that further clinical trials with detailed survival statistics with the aim of producing guidelines and reliable algorithms are required to help guide optimum use.
The aim of oncological treatments is to provide an improved quality of life for patients through improved disease control. It may be that long-term improvements can occur and survival times are longer in patients on MC, but the aim of treatment is disease management and, in this context, perhaps MC could be regarded as a truly palliative medication. Certainly, the risks of its use appear to be low and its impacts on the patient are generally minimal and there are potential benefits; however, the evidence is not clear cut in many cancers (Gaspar et al., 2017). In this setting, MC ought to shift the focus away from the disease and more on to the patient, with a wider systemic approach to patient wellness where other factors impacting on patient welfare are also taken into consideration. It should be seen perhaps as only part of the spectrum of treatments employed to ensure a global patient wellness.