I t is our pleasure to announce the publication of the following book: Metronomic Chemotherapy : Pharmacology and Clinical Applications

the editors are Guido Bocci and Giulio Francia

With 19 chapters covering all fields of metronmic chemotherapy from the birth of the concept to updated clinical reviews. This book coversall aspects of metronomic chemotherapy, describes the pharmacological bases of metronomic chemotherapy, presents and discusses the clinical results of all published studies on metronomic chemotherapy, in a wide range of tumors This book analyzes all aspects of metronomic chemotherapy, a new approach involving low-dose, long-term, and frequently administered therapy that has preclinical and clinical activity in various tumors. After an opening section on the pharmacological bases of metronomic chemotherapy, including its antiangiogenic effects and impact on immunity, preclinical studies on various classes of drug are discussed. Clinical applications of metronomic chemotherapy in a wide variety of tumors are then addressed in detail, with description of the results of all published studies. The clinical pharmacology of metronomic chemotherapy is also considered in depth, encompassing pharmacokinetics, pharmacogenetics, pharmacoenconomics, and adverse drug reactions. The book closes by describing the role of this therapy in the veterinarian clinic.

The book can be purchased here on the Springer website.

 Development and Evolution of the Concept of Metronomic Chemotherapy: A Personal Perspective Robert S. Kerbel PhD

Pages 3-21 The concept of metronomic dosing and scheduling of conventional chemotherapy drugs was first published in 2000, based on preclinical findings. Tentative validation for the treatment concept has now been obtained based on randomized phase III clinical trial testing. Most promising applications of metronomic chemotherapy may be in the maintenance treatment setting after induction therapy, using oral chemotherapeutic drugs, especially when combined with certain types of targeted agents such as VEGF pathway inhibiting antiangiogenic agents. A personal account of the historical development of the metronomic chemotherapy concept is summarized along with suggestions for improving its impact as a promising means of achieving better and less toxic cancer control, not only in patients in low and middle income countries, but also patients in highly developed high income countries as well.

 Mechanisms of Action of Low-Dose Metronomic Chemotherapy Ella Fremder, Yuval Shaked PhD

Pages 23-38 Evidence from a growing body of preclinical and clinical studies points to the efficacy of continuously administrating anticancer chemotherapeutic drugs in low doses. This relatively new treatment strategy concept is called low-dose metronomic (LDM) chemotherapy. The therapeutic efficacy of LDM has been assessed for reducing the tumor load during the acute phase and in delaying relapse during the maintenance phase. The major benefits found in using LDM include the lack of major toxicities or complications as compared to conventional chemotherapy regimens and improved quality of life. Traditional therapeutic modalities in oncology aim toward more specific tumor targets at the tumor microenvironment, whereas LDM chemotherapy acts on a broad spectrum of mechanisms, some of which are still not clear. We will discuss in this chapter several possible LDM chemotherapy anticancer mechanisms of action. Initially, LDM was considered an antiangiogenic treatment strategy; however, in the last decade additional preclinical studies uncovered other possible mechanisms including enhancing the antitumor immune response, substantially increasing the efficacy of targeted drugs by various mechanisms, targeting a subset of chemotherapy-resistant tumor cells, and blunting host response effects found following conventional therapy. While LDM chemotherapy is currently undergoing phase III clinical evaluation, its mechanisms of action are only partially understood. Elucidating LDM’s mechanisms of action will give physicians an additional major weapon to deploy in the comprehensive management of cancer.

 Effects of Metronomic Chemotherapy on Immunity Mamoru Harada MD, PhD

Pages 39-51 Chemotherapeutic agents are widely used for cancer treatment. However, these agents have the potential to kill tumor cells as well as nontumor cells, including immune cells. Therefore, conventional and maximum-tolerated dose chemotherapy is inevitably associated with the risk of immunity deterioration. Metronomic chemotherapy is a unique protocol that administers chemotherapeutic agents at relatively low doses, without prolonged drug-free periods. Metronomic chemotherapy was primarily developed to target circulating endothelial progenitor cells to inhibit tumor angiogenesis. Alternatively, certain chemotherapeutic agents have immunostimulatory effects. Specifically, cyclophosphamide (CTX) and gemcitabine (GEM) administration can decrease two major immunosuppressive cells, regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), respectively, both of which increase in tumor-bearing hosts. However, administration protocols heavily influence the host’s immunity because chemotherapeutic agents potentially kill proliferating lymphocytes. To this end, we investigated the effects of a CTX administration protocol on the in vivo induction of antitumor T cells in a preclinical model. We found that CTX administration at 4-day intervals deteriorated antitumor T cell immunity. Given these findings, we further tested a combination chemotherapy protocol with CTX and GEM at 8-day intervals and found that without impairing immunological competence, this protocol elicited antitumor T cells by decreasing Treg cells and MDSCs. In this chapter, I outline the in vivo induction of antitumor T cell immunity after chemotherapy, review the effects of metronomic chemotherapy on immunity, and discuss its underlying mechanisms.

 Preclinical Activity of Metronomic Regimens with Alkylating Agents and Antimetabolites Marta Vives, Berta Laquente, Francesc Viñals

Pages 53-67 We know that the same drug, when administered at different doses, schedules, and moments, can produce completely different effects on tumor progression. For the last 10 years, research has been trying to unravel how metronomic chemotherapy antitumor effects arise. Numerous in vitro and in vivo studies have provided evidence that the main effects of metronomic chemotherapy are related not only to tumor angiogenesis but also to the cancer cells, tumor environment, and stromal component. Nevertheless, there remain large gaps in our knowledge of the molecular mechanisms by which these effects arise. This review summarizes part of the preclinical research, performed with those alkylating agents and antimetabolites most commonly used in the metronomic chemotherapy approach. Much of this report concerns cyclophosphamide, since, in this context, it is the most widely explored drug so far. The report also draws attention to the numerous cancer cell lines and the main murine models used.

 Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments Eddy Pasquier, Maria Kavallaris, Nicolas Andre

Pages 69-90 Microtubule-targeting agents (MTAs) are amongst the most successful chemotherapeutic drugs commonly used in the clinic for the treatment of human cancers. Although originally administered at or close to the maximum tolerated dose once every 3 weeks, the discovery of their potent antiangiogenic properties at the end of the 1990s has led to the re-evaluation of treatment protocols. Nowadays, MTAs are often administered at lower doses either weekly or even more frequently following a metronomic schedule, thus leading to increased efficacy and decreased toxicity. In this chapter, we present an overview of the in vitro and in vivo studies that have contributed to the development of MTA-based metronomic chemotherapy protocols and increased our understanding of their mechanisms of action. First, we discuss the complex cellular and molecular mechanisms involved in the antiangiogenic activity of MTAs. We also present their effects on the immune system, which may contribute to the antitumour efficacy of MTA-based metronomic chemotherapy. Then, we review the results obtained with this type of therapeutic approach in preclinical models of human cancer, focusing on the most promising combination treatments. Finally, we oversee the future developments in this field in terms of new MTAs and novel formulations currently in development with the aims to improve efficacy and bioavailability while increasing tumour targeting and specificity.

 Metronomic Chemotherapy in Breast Cancers Elisabetta Munzone, Francesco Bertolini, Marco Colleoni

Pages 93-110 Breast cancer is a common disease in women and its incidence is increasing. A proportion of breast cancer patients are metastatic at diagnosis or become metastatic during the follow-up period and need a personalized and/or target treatment approach. Metronomic chemotherapy can be regarded as a multi-targeted therapy for advanced disease, combining effects not only on tumor cells but also on their microenvironment by inhibiting tumor angiogenesis, stimulating anticancer immune response, and potentially inducing tumor dormancy. In the last 10 years, many phase I/II trials with metronomic chemotherapy in advanced breast cancer were published and will be described in details. Although this treatment approach was initially designed to maintain a stable disease as long as possible for metastatic patients that cannot be cured, as results become evident, researchers and clinicians started looking for new applications of this therapeutic strategy. Biomarkers are being developed to identify reliable surrogate markers of response and also to identify the proper patients to be treated. Nowadays, there are several ongoing trials to identify the optimal regimen and schedule of metronomic chemotherapy in the different settings of breast cancer patients. Most trials are aimed at patients with triple negative disease, because in this setting chemotherapy still represents one of the most reliable option. Finally, the potential development of metronomic chemotherapy in breast cancer is still a matter of research with particular attention to identify biomarkers and individual tumor characteristics that can better address the use of this treatment strategy in the future.

 Overview of Metronomic Chemotherapy in SWOG Breast Cancer Cooperative Group Clinical Trials Zeina A. Nahleh

Pages 111-118 Metronomic chemotherapy, defined as continuous or frequent treatment with low doses of anticancer drugs, has been observed to provide excellent safety profiles and has been tested in many tumors. SWOG, formerly the Southwest Oncology Group, has reported extensively on metronomic chemotherapy used in breast cancer. The earliest trials reported on a continuous, or “Cooper-” type, Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen in the setting of adjuvant chemotherapy for node-positive breast cancer, in which cyclophosphamide is administered orally on a daily basis and the 5-FU and methotrexate are given by weekly intravenous injection. Subsequently, other regimens have been evaluated. We will, hereby, provide an overview of the main SWOG trials evaluating metronomic chemotherapy in breast cancer.

 Clinical Trials of Low-Dose Metronomic Chemotherapy in Castration-Resistant Prostate Cancer Keemo Delos Santos, Lavarnan Sivanathan, Kelly Lien, Urban Emmenegger

Pages 119-134 Low-dose metronomic (LDM) chemotherapy is the continuous or near-continuous use of conventional chemotherapeutic agents at doses that do not necessitate cyclic treatment interruptions. Recently, LDM chemotherapy has gained traction for the treatment of castration-resistant prostate cancer (CRPC). Its excellent safety profile and relatively low rate of severe (i.e., grade 3/4) toxicities make it an enviable treatment, especially for elderly and frail CRPC patients. By searching the MEDLINE, EMBASE, and CENTRAL databases, we identified fifteen published prostate cancer LDM chemotherapy trials comprising 471 patients. The trials were stratified and analyzed according to three common types of LDM regimens: (1) cyclophosphamide monotherapy, (2) cyclophosphamide plus corticosteroid, and (3) complex combination regimens. Oral cyclophosphamide was part of all LDM regimens. Collectively, LDM chemotherapy was found to be beneficial in almost 60 % of patients (mean clinical benefit rate of 58.08 ± 20.30). Severe treatment-associated side effects were rarely seen, with anemia being the most commonly reported. One comparative single-center study showed a superior safety profile and comparable benefit of LDM cyclophosphamide therapy compared to conventional, maximum tolerated dose (MTD) docetaxel chemotherapy. Another study highlights that prior LDM chemotherapy does not negatively impact on the subsequent use of MTD docetaxel chemotherapy. In addition, five studies document the benefit of LDM chemotherapy in CRPC patients that have undergone MTD docetaxel chemotherapy. Randomized phase III trials will be needed to allow definitive conclusions as to the clinical utility of the LDM approach in CRPC. Unfortunately, the metronomic use of off-patent drugs such as cyclophosphamide faces unique commercial and regulatory hurdles that are slowing down the clinical development of LDM chemotherapy in prostate cancer and other malignancies.

 The Role of Metronomic Chemotherapy in the Treatment of Metastatic Colorectal Cancer Patients Lisa Salvatore, Federica Zoratto, Fotios Loupakis, Alfredo Falcone

Pages 135-142 Neoangiogenesis is a crucial therapeutic target for metastatic colorectal cancer as demonstrated by the effectiveness of biologic drugs with exclusive or partial antiangiogenic activity such as bevacizumab, aflibercept, and regorafenib. Metronomic chemotherapy may be an alternative strategy for targeting tumor angiogenesis and several clinical studies suggested its promising activity and its extremely favorable toxicity profile in the treatment of metastatic colorectal cancer patients.

 Clinical Activity of Metronomic Chemotherapy in Central Nervous System Cancers Doo-Sik Kong MD, PhD, Do-Hyun Nam MD, PhD

Pages 143-155 Despite recent advances glioblastoma (GBM), which is the most frequent malignant central nervous system (CNS) tumor, remains a lethal disease. One of characteristics in malignant gliomas is the robust and aberrant vasculature within the tumor which could be the target for the frequent administration of low-dose metronomic chemotherapy. This chapter will mainly focus on determining current status and recent trends of metronomic treatment for CNS tumor by review of published literatures. Indeed, many preclinical evidences support the metronomic use of camptothecins and temozolomide in glioblastoma models and numerous clinical applications of metronomic regimens (e.g. etoposide, temozolomide) for adult patients with tumors of CNS have been described. Moreover, metronomic treatment may serve as a useful platform for combination strategies in certain CNS tumors.

 Metronomic Chemotherapy in Pediatric Malignancies Narges Baluch MD, Sushil Kumar, Reza Mokhtari, Sylvain Baruchel MD

Pages 157-172 Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is an emerging alternative to conventional chemotherapy. Several pediatric preclinical solid tumor models are supporting the clinical development of this new therapeutic modality in pediatric cancer. Maintenance low dose chemotherapy has proven its benefits in increasing overall survival in several pediatric cancer. This chapter is reviewing the current knowledge of pediatric metronomic chemotherapy and potential for future development as cytotoxic agents or in combination with targeted therapy including its potential application in emerging countries.

 Metronomic Chemotherapy in Hematological Malignancies Pannee Praditsuktavorn MD, Jia Ruan MD, PhD

Pages 173-188 Targeting tumor microenvironment and angiogenesis is a novel therapeutic strategy in hematological malignancies. The antiangiogenic effects of chemotherapeutic agents can be optimized when administered metronomically, by providing low doses of chemotherapeutic drugs on a continuous schedule without extended drug-free intervals. Metronomic chemotherapy preferentially targets endothelial cells of the growing tumor neovasculature instead of tumor cells themselves and therefore can be particularly effective against multidrug-resistant tumors. Metronomic therapy may further enhance immune response by modulating antitumor NK/T-cell functions. The past decade saw an increasing appreciation of the pathogenic roles that tumor angiogenesis plays in hematological malignancies including leukemias, lymphomas, and multiple myeloma. Experimentation with a variety of antiangiogenesis modalities has shown encouraging efficacy with metronomic chemotherapy in these disease categories, with generally low toxicity and cost. With the growing availability of the target-specific biological agents, some of which are specific for antiangiogenesis, it is conceivable that metronomic chemotherapy, either alone or in combination with biologics, has therapeutic potential in frontline and maintenance setting, in addition to its traditional role of salvage option for relapsed diseases in hematological malignancies.

 Clinical Activity of Metronomic Chemotherapy in Liver Cancers Yu-Yun Shao, Ann-Lii Cheng, Chih-Hung Hsu

Pages 189-202 Treating advanced hepatocellular carcinoma (HCC) remains challenging in clinical practice. Although sorafenib, an antiangiogenic targeted compound, has demonstrated survival benefits as a first-line therapy, the response rate and time to progression are not optimal. Metronomic chemotherapy has demonstrated antiangiogenic effects, and its reduced potential for toxicity renders it more tolerable to most advanced HCC patients. Clinical trials and retrospective studies have examined the use of metronomic chemotherapy, either alone or in combination with other antiangiogenic therapies, for treating advanced HCC. These studies have confirmed the feasibility and safety of metronomic therapy in patients with advanced HCC. Although objective responses were achieved using metronomic chemotherapy alone, it is difficult to discern the actual clinical benefits because of the small sample sizes of these studies. Nevertheless, metronomic chemotherapy can serve as a treatment option for advanced HCC patients who have progressed on or are intolerable to the standard therapy, sorafenib. In single-arm phase II clinical trials, combining metronomic chemotherapy with antiangiogenic targeted therapy has demonstrated improved efficacy for treating advanced HCC without increasing toxicities. Further research is warranted to confirm the benefits of combining metronomic chemotherapy with antiangiogenic targeted therapy for treating advanced HCC.

 Metronomic Chemotherapy in Gynecological Cancers Victoria A. Forte MD, Agustin A. Garcia MD Ovarian cancer is the 5th leading cause of cancer mortality in the United States, and despite major advances in cytoreductive surgery and the use of chemotherapy with a platinum and a taxane in the first-line setting, recurrence is still a common problem. Efforts to improve the efficacy of conventional chemotherapy have been resulted in general in limited benefit. Metronomic chemotherapy represents an alternate schedule of chemotherapy administration. Preclinical and clinical data attest to the efficacy of metronomic chemotherapy as a treatment modality in ovarian cancer. Further research, including phase III clinical studies, is required to determine the role of this promising therapeutic approach in the management of ovarian cancer.

 Metronomic Chemotherapy in Non-Small-Cell Lung Cancer Athanasios Kotsakis, Nikolaos Kentepozidis, Vassilis Georgoulias MD, PhD

Pages 217-226 Metronomic chemotherapy is an alternative approach for the administration of systemic chemotherapy that consists of the administration of low doses of a cytotoxic regimen without any interruptions. Endothelial cells of the tumor blood vessels are rapidly proliferating cells that could be affected with the metronomic use of chemotherapy. Indeed, it is strongly believed that this strategy inhibits vascular angiogenesis and subsequently tumor growth mainly through modulating the cancer microenvironment with favorable toxicity profile. In addition, immune suppression is a reality among the vast majority of cancer patients. T regulatory cells (Tregs) are the main representative of suppressive cells, and their increased expression in cancer has been associated with worse prognosis and tumor progression. Low doses of chemotherapeutic agents have been proven capable to restore the normal immune system function through the elimination of immune suppressive cells. Numerous studies have investigated the efficacy of metronomic strategy in NSCLC patients with very promising results. Several chemotherapeutic agents, such as vinorelbine, gemcitabine, cyclophosphamide, and docetaxel, have been tested as monotherapy or in combination with other drugs. Whether other mechanisms, such as tumor dormancy, are also involved in the effectiveness of metronomic administration of chemotherapy or if it is superior to conventional chemotherapy remains questionable, and further investigation is required.

 Pharmacokinetics and Pharmacogenetics of Metronomic Chemotherapy Guido Bocci MD, PhD, Giulio Francia PhD

Pages 229-246 Despite the numerous preclinical and clinical studies that have been conducted on metronomic chemotherapy in the past 10 years, few pharmacokinetic and pharmacogenetics data on this dosing regimen are available. Indeed, only the pharmacokinetics of metronomically administered drugs, such as irinotecan, UFT, and vinorelbine, have been described in patients, but no data are available on the most widely explored agents in such an approach like cyclophosphamide or capecitabine. Methodological issues and the neglected importance of the relationship between plasma concentrations of metronomically administered chemotherapeutic drugs (and their active metabolites) contributed to the absence of data on the commonly used 50 mg/day cyclophosphamide schedule. Moreover, few data are available on the pharmacogenetics of metronomic chemotherapy, and, although some objective responses have been obtained in various tumors, it remains largely unknown which genetic backgrounds could affect or predict the clinical response of patients. Trials integrating pharmacokinetic and pharmacogenetics research are necessary to better evaluate the clinical benefit of metronomic chemotherapy.

 Metronomics: Potential Social Impact and New Business Models to Improve Availability of Cancer Treatments Yuliya Snihur, Eddy Pasquier, Graciela Scharovsky, Nicolas Andre

Pages 247-261 Over the last 15 years, metronomic chemotherapy (MC) alone or combined with drug repositioning (DR) has gradually gained interest from cancer researchers and clinicians. Metronomics, the combination of MC and DR, can provide inexpensive, easy to administer and non-toxic treatments for cancer patients, while introducing innovative mechanisms of anti-tumour action.In this article, we explore how the use of metronomics can deliver important social gain by allowing to treat patients for whom therapeutic options would be otherwise limited or absent. Thus, patients living in low- and middle-income countries (LMICs) can benefit from metronomics to the same extent as patients living in high-income countries (HICs). In both settings, frail patients can also take advantage of the low toxicity associated with metronomics. Here, we focus on new business models that could help in bridging the gap between LMICs and HICs with regard to anticancer treatments through the use of metronomics. In particular, we analyse the principles explaining how business model innovation can make cancer therapies available and affordable to patients with limited resources. Overall, we argue that new business models are essential to the optimal development of metronomics and the combination of business model innovation with metronomics can help fight cancer in LMICs.

 Adverse Side Effects Associated with the Use of Low-Dose Metronomic Chemotherapy Keemo Delos Santos, Kelly Lien, Soley Georgsdottir, Lavarnan Sivanathan…

Pages 263-279 The benefit of cancer therapies can be characterized by the therapeutic index incorporating the balance between antitumor activities and treatment-associated toxicities. Low-dose metronomic (LDM) chemotherapy is a novel treatment strategy that was developed to overcome resistance to maximum-tolerated dose (MTD) chemotherapy, while using conventional chemotherapeutics. Published findings suggest that the therapeutic index of LDM chemotherapy is particularly beneficial given the combination of excellent antitumor activity with a toxicity profile that is considered to be superior to MTD chemotherapy. In fact, a systematic analysis of 66 published phase I/II clinical LDM chemotherapy trials providing detailed toxicity data confirms the excellent safety profile of LDM chemotherapy. Severe (grade 3 or 4) side effects were rare, and the toxicity profiles seemed to be associated with the type of LDM regimen studied. Overall, incidences of any severe adverse effects were limited to less than 10 % of patients. Severe lymphopenia and neutropenia were the most frequent side effects reported, occurring in 6.44 % and 5.71 % of patients. Furthermore, three comparative studies reporting the rates of adverse events associated with LDM versus MTD regimens indicate superior tolerance and safety of LDM chemotherapy, while still displaying comparable antitumor effects. By making treatments more tolerable and thus accessible to a broader range of cancer patients, LDM chemotherapy is an example that less can sometimes be more. However, in the absence of validated predictive or pharmacodynamic markers of LDM chemotherapy, additional clinical studies are warranted to further improve the therapeutic index of LDM chemotherapy.

 Clinical Studies of Metronomic Chemotherapy in Dogs Veronica Marchetti, Mario Giorgi Pages

Pages 283-295 In the last decade metronomic chemotherapy has received increased interest in veterinary oncology. Indeed, low-dose metronomic chemotherapy has been shown an important stabilizing effect on cancer growth, conferring both prolonged clinical benefits and positive effects on the quality of life of patients. A number of studies have been performed in dogs on the efficacy of metronomic dosing of various chemotherapeutic drugs. Metronomic chemotherapy is offered as the treatment of choice for all pets with malignant tumors where owners are reluctant to embark on an aggressive therapy protocol. It is indicated in patients with organ failure in which the toxicity of chemotherapy may be fatal as well as in patients with an aggressive nature that would require sedation for each parenteral administration. Metronomic therapy induces minimal impact on the animal; it is a low-cost alternative and it is easy to administer. Moreover, it has been recently recognized that dogs affected by natural cancer serve as unique animal model for human tumors. For this reason, the metronomic chemotherapy experience in dogs could lead to innovative and unexplored schedules for humans. It may be used as a more accurate model than rodents with induced cancers for the extrapolation of dose, efficacy and safety profiles to humans.