Metronomic Chemotherapy

Chapter 78


Metronomic Chemotherapy



Conventional cytotoxic chemotherapy agents have been the cornerstone of the medical oncologist’s treatment arsenal for many decades. However, in the emerging era of newer targeted drugs such as receptor tyrosine kinase inhibitors, traditional chemotherapy agents are being reexamined to determine whether particular efficacy and resistance patterns may be explained, at least in part, through a different mechanism than solely the killing of highly proliferative cancer cell populations.


The design of conventional chemotherapy treatment protocols is based largely on the principle of administration of the maximum tolerated dose (MTD), which requires an obligatory “break” period to allow for the recovery of normal cell populations. Despite the use of these chemotherapy protocols for the treatment and outright cure of certain cancers, some oncologists believe that we may be nearing the limit of what cytotoxic chemotherapy regimens can accomplish. A different approach based on more continuous exposure time, with reduction or elimination of the break period between each dose, has come to be known as metronomic chemotherapy delivery. Not surprisingly, to provide a more continuous treatment schedule, a reduction in drug dose is required. The reduced toxicity profile, ease of administration when oral drugs are used, and relatively low cost make metronomic chemotherapy protocols appealing in veterinary oncology; however, an understanding of the mechanisms of action and rigorous clinical evaluation in veterinary patients are still at an early stage.



Antitumor Mechanisms



Antiangiogenesis


Cytotoxic chemotherapeutics achieve at least a portion of their therapeutic efficacy by inhibition of tumor angiogenesis, which is the process of new blood vessel growth in tumors. The basis for this notion likely originated with the observation that tumor endothelial cell populations are much more proliferative than the quiescent endothelial cells elsewhere in the body. These rapidly dividing endothelial cells are targets of chemotherapy, and for this reason other proliferative cells, such as intestinal epithelia and bone marrow precursors, are also damaged. When the antiangiogenic effects of MTD chemotherapy were evaluated in preclinical models, it was revealed that repair and repopulation of endothelial cells occurs during the break period, just as it does for other cell populations. Therefore the key to maximizing the antiangiogenic potential of chemotherapeutic drugs was considered to be the reduction or elimination of the break period between doses.


Like many aspects of physiology, angiogenesis is regulated through the relative balance of endogenous promoters and inhibitors of this process. Experimental evidence has suggested that up-regulation of the endogenous angiogenesis inhibitor thrombospondin-1 in the tumor microenvironment occurs during metronomic treatment with cyclophosphamide (CYC), and possibly other agents, leading to an antiangiogenic effect. This indirect antiangiogenic mechanism may complement the direct cytotoxicity to endothelial cells provided by chemotherapy.


The process of tumor angiogenesis also may involve recruitment of circulating cells from the bone marrow that travel to the tumor site and incorporate into endothelial walls or support vessel growth indirectly through cytokine production. Circulating endothelial progenitor cells (CEPs) from the bone marrow are an example. These cells, if they play a significant role in the growth of tumor blood vessels, may be most influential after the acute damage that occurs in the early break period of MTD chemotherapy schedules. Preclinical models have demonstrated that CEPs immediately decrease with MTD treatment (similar to other bone marrow progenitor populations), only to rapidly rebound during the break period, and potentially contribute to endothelial cell repopulation. In contrast, metronomic chemotherapy does not appear to be associated with a CEP rebound, leading instead to a sustained antiangiogenic effect.



Immunomodulation


In addition to tumor blood vessels, other components of the tumor microenvironment may be the target of metronomic chemotherapy drugs. Immune effector cells such as lymphocytes and macrophages influence tumor biology and may be affected by chemotherapy treatment. For this reason, the potential immunomodulatory mechanisms of metronomic chemotherapy, particularly that associated with using the alkylating agent CYC, are receiving significant research interest. Low doses of CYC alter the T-lymphocyte subset population by decreasing levels of CD4+CD25+ regulatory T (Treg) cells. Treg cells inhibit the immune response and thereby suppress tumor immune surveillance. In dogs with various malignancies, circulating Treg cells in the blood have been quantified by flow cytometry and have been found to decrease in dogs with soft tissue sarcoma during treatment with metronomic CYC (Burton et al, 2011). Further effects of metronomic CYC on tumor immunology are under investigation, and possible immunomodulatory mechanisms for other antineoplastic agents delivered metronomically may be revealed in future studies.



Direct Cancer Cell Targeting


Metronomic chemotherapy treatment likely retains a certain degree of direct cytotoxicity to cancer cells. Susceptible cancer cells still may sustain toxic damage at drug doses considerably lower than the MTD. Because of this, prolonged drug exposure protocols have merit for some agents, particularly those that display cell cycle phase–specific toxicity, and this type of schedule could be considered metronomic. Direct killing of cancer cells also has an indirect antiangiogenic effect, given that many potent proangiogenic growth factors, such as vascular endothelial growth factor (VEGF), are produced by tumor cells. Decreased VEGF levels in the tumor microenvironment may be accomplished through a reduction in tumor cell mass as a result of direct cancer cell killing by chemotherapy. This explains why the antiangiogenic actions of metronomic chemotherapy may be enhanced when there is concomitant direct tumor cell kill; however, in theory, blood vessel targeting by chemotherapeutic drugs does not require drug sensitivity of the tumor cell population.



Clinical Application


Small retrospective and phase II metronomic chemotherapy trials involving a variety of drugs and drug combinations have been reported recently in the veterinary oncology literature. Most clinical trial evaluations to date have paired conventional chemotherapy drugs with noncytotoxic drugs that are meant to target angiogenesis directly or indirectly. This approach was based on preclinical experiments demonstrating that such combinations resulted in superior outcomes, likely because of more complete neutralization of induced prosurvival factors such as VEGF in the tumor endothelium. As a result of this approach, most clinical trials have evaluated combination protocols without necessarily having any clear prior documentation of single-agent clinical activity for each drug. Bevacizumab, the antibody targeting human VEGF, has been a popular choice to pair with human metronomic chemotherapy schedules and has been approved by the U.S. Food and Drug Administration for the treatment of multiple cancers; however, other, more readily available “targeted” drugs shown to have at least indirect antiangiogenic effects also are commonly used. Examples are cyclooxygenase (COX) inhibitors, tetracyclines, thalidomide, and glitazones.



Veterinary Trials of Alkylating Agents



Cyclophosphamide


CYC has been the drug most commonly studied in low-dose metronomic treatment protocols in both human and veterinary oncology. A protocol of low-dose CYC 15 mg per sq meter q24h (dogs), alternating after 21 days with etoposide and paired with continuous piroxicam (0.3 mg/kg q24h PO) was evaluated for adjuvant treatment of splenic hemangiosarcoma in dogs (Lana et al, 2007). The survival time of 9 dogs treated with this regimen was no different from that of a historical control group of 24 dogs treated with doxorubicin alone. The metronomic protocol was well tolerated over a 6-month period. Pharmacokinetic analysis of etoposide in three dogs revealed detectable drug levels, although this drug may have low and variable oral bioavailability in the dog.


A low-dose continuous CYC and piroxicam protocol also was evaluated for adjuvant treatment of incompletely resected soft tissue sarcoma in dogs (Elmslie et al, 2008). Unlike in the hemangiosarcoma study, in this trial the dosage of CYC was 10 mg/m2 q24h or q48h PO. The disease-free interval was significantly longer in the treated group of 30 dogs than in an age-, site-, and grade-matched contemporary control group of 55 dogs treated with surgery alone. Again the protocol was well tolerated, although 40% of dogs experienced mild toxicity at some point in the treatment and one dog experienced grade 4 sterile hemorrhagic cystitis. The every-other-day dosing regimen was better tolerated than daily CYC dosing.


The use of metronomic CYC treatment also has been reported recently by Marchetti and colleagues (2012) for first-line therapy of metastatic canine tumors of varying histologic types. Fifteen dogs were treated with CYC at 25 mg/m2 q24h PO combined with the COX-2 inhibitor celecoxib at 2 mg/kg q24h PO. One dog showed a complete response and five dogs had stable disease with a treatment protocol that was devoid of toxicity. All dogs were reported to have improved quality-of-life scores. Most of the tumors treated were carcinomas, and as in many other trials, what the relative contribution of each drug may have been to the overall response rate was not apparent because single-agent responses to COX inhibitors have been documented in cancer-bearing dogs.


CYC has become a popular drug choice for metronomic scheduling, but it is associated with the potential for sterile hemorrhagic cystitis. Currently it is not known whether cystitis occurs more frequently in metronomic administration protocols, but close urinary monitoring is recommended strongly for these patients.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Metronomic Chemotherapy

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