Chemotherapy Dose Optimization
Conventional chemotherapy regimens are typically calibrated to deliver the maximum tolerable dose of cytotoxic drugs (Baszkowsky 2012; Galmarini 2012). Combination chemotherapy regimens are used more often than single agents, but the decision to use a combination or single agent depends on the cancer type (Cosman 2014; Peters 2000; Mihlon 2010; Galmarini 2012). In combination chemotherapy, drugs that are active against the tumor and have different toxicity profiles and mechanisms of action are used; the goal is to circumvent chemoresistance by using multiple drugs with different anticancer mechanisms (Doroshow 2017). The drugs are administered in repeated cycles at regular intervals (Chabner 2013a).
Most chemotherapy drugs show a steep dose-response curve, meaning even a small reduction in dose may lead to a significant reduction in tumor cell killing (Honkoop 1995; Lyman 2009; Lyman 2012). However, the side effects of chemotherapy are also dose-dependent, making it important to find the maximum tolerable dose (Remesh 2013; Galmarini 2012). A patient who does not suffer significant adverse reactions from chemotherapy may be better able to complete an entire course of treatment, and therefore have a better overall outcome (Remesh 2013; Baszkowsky 2012; Doroshow 2017).
Oral chemotherapy creates mild drug concentrations in the blood for an extended time, which allows for prolonged exposure of cancer cells to the chemotherapy agent (Feng 2011; Molina-Garrido 2014). Oral chemotherapy provides the convenience of home use (rather than clinic visits for intravenous infusions), and can allow complex dosing schedules, which may vary day-to-day or even within a single day (Held 2013; Neuss 2013; Bedell 2003).
Oral chemotherapy is becoming a more common method of treating cancer, and it is often as effective as other forms of chemotherapy (Neuss 2013; ACS 2014). Some classic cytotoxic drugs, such as cyclophosphamide (Cytoxan) and methotrexate (Trexall), have been used in oral treatment for over 50 years. Since 1998, the Food and Drug Administration (FDA) has approved more than 30 cancer drugs for oral administration, including newer, targeted, small molecules such as imatinib (Gleevec). It is estimated that over 25% of all cancer drugs under development are planned as oral agents (Segal 2014; Weingart 2008). Unfortunately, many important chemotherapy drugs (eg, taxanes including paclitaxel [Taxol] and docetaxel [Taxotere, Docefrez]) exhibit poor oral bioavailability and are therefore not currently candidates for oral administration (DeMario 1998; Hendrikx 2013; Attili-Qadri 2013; Torne 2010).
Metronomic Chemotherapy: An Emerging Chemotherapy Dosing Paradigm
Conventional high-dose chemotherapy regimens often cause significant side effects and require cyclical dosing, with breaks in treatment to allow healthy cells to recover from toxicity. However, these breaks also permit the recovery of cancer cells and the expansion of drug-resistant cancer cell populations (Scharovsky 2009).
In an effort to overcome these problems, lower-dose chemotherapy with more frequent administration has been tested in several studies. This approach is called low-dose metronomic chemotherapy (Lien 2013). Metronomic chemotherapy uses doses of chemotherapy that range from about one-tenth to one-third of standard doses, but is given more often than traditional chemotherapy. Since lower doses cause less toxicity, fewer rest periods are required (Kerbel 2004; Maiti 2014). Early evidence suggests metronomic chemotherapy may be more effective in some cases and less likely to induce drug resistance than conventional dosing (Maiti 2014; Scharovsky 2009; Pasquier 2010). Metronomic chemotherapy is generally administered via the oral route (Maiti 2014). Some studies have investigated intravenous metronomic chemotherapy, though research in this area is sparse (Mross 2012).
Metronomic chemotherapy is effective because of an often-overlooked action of certain conventional chemotherapy drugs: they inhibit the production of new blood vessels (Maiti 2014; Scharovsky 2009; Kerbel 2004). Under normal circumstances, tumors promote the growth of new blood vessels to ensure they get the resources they need to grow and survive. This process is called angiogenesis (Maiti 2014; Scharovsky 2009; Kerbel 2004; Pasquier 2010).
Angiogenesis—the formation of new blood vessels—relies on activation of endothelial cells, which line the inside of blood vessels. Some chemotherapeutic drugs exert toxic effects against activated endothelial cells, thus inhibiting angiogenesis. The anti-angiogenic effect of chemotherapy agents are apparent at lower blood concentrations than those needed to kill proliferating tumor cells. Furthermore, unlike cyclical high-dose chemotherapy, metronomic chemotherapy induces a sustained concentration of chemotherapy in the blood over an extended period, which may be more effective at preventing angiogenesis and reducing the efficiency of the tumor’s acquisition of new resources (Maiti 2014; Scharovsky 2009; Kerbel 2004).
Inhibiting angiogenesis may be a key mechanism by which metronomic chemotherapy undermines cancer, but other factors also appear to contribute. For example, metronomic chemotherapy may reduce populations of immune cells called regulatory T cells. Reducing regulatory T cells may promote a more robust anticancer immune response (Maiti 2014; Scharovsky 2009). Another potential effect of metronomic chemotherapy is induction of senescence in tumor cells. Cellular senescence is the gradual degradation of a cell’s capacity for division (Rodier 2011; Maiti 2014). Apoptosis, in which cells undergo self-destruction, is also thought to occur with this type of chemotherapy regimen (Maiti 2014; Bahl 2012).
Several small trials have investigated low-dose metronomic chemotherapy in patients with breast, prostate, ovarian, neuroendocrine, and non-small cell lung cancers; as well as those with lymphoma, multiple myeloma, pediatric solid tumors, and melanoma. Overall, these studies have found this approach to be effective and well tolerated. Cyclophosphamide is the chemotherapy drug most frequently used in a metronomic dosing regimen. Larger randomized controlled trials and detailed mechanistic studies are needed to firmly establish the potential utility of metronomic chemotherapy before it is more widely accepted into practice (Maiti 2014; Lien 2013; Scharovsky 2009).