Special section on Metronomic Chemotherapy, Guest Edited by Ravi Kumar and A.K. Sood from the Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX, USA and the Frank McGraw Memorial Chair in Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA has been published in Cancer Letters.

This special section is a collection 14 pieces that covers a wide variety topics related to the potential of metronomic therapy: ranging from potential use in a given disease (colon cancer, pancreatic cancer, esophageal and gastroesophageal cancer, breast cancer, head & neck cancer), mechanism of action (imunnity, resistance) and new emerging fields (mathematical modelization, nanotechnologies) and results from clinical trial (breast cancer) or preclinical work (S1 & colon cancer). It is great for the field of metronomic chemotherapy that a journal such as Cancer Letters initiate such an initiative. Nevertheless, not a single piece dedicated to low and middle income countries or children.... maybe next time ?

 The potential clinical promise of ‘multimodality’ metronomic chemotherapy revealed by preclinical studies of metastatic disease

Robert S. Kerbel, Yuval Shaked We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse models of cancer involving treatment of advanced metastatic disease. Historically, mouse cancer therapy models have been dominated by treating established primary tumors or early stage low volume microscopic disease. Treatment of primary tumors is also almost always the case when using genetically engineered mouse models (GEMMs) of cancer or patient-derived xenografts (PDXs). Studies using such models, and others including transplanted cell lines, often yield highly encouraging results which are seldom recapitulated in the clinic, especially when assessed in randomized phase III clinical trials. While there are likely many different reasons for this discrepancy, one is likely the failure to recapitulate treatment of advanced visceral metastatic disease in mice. With this gap in mind, we have developed a number of models of metastatic human tumor xenografts (and more recently, of mouse tumors in syngeneic immunocompetent mice). A pattern of response we have observed with various targeted agents, e.g. VEGF pathway targeting antiangiogenic drugs or trastuzumab, is effective when treating primary tumors in contrast to a complete or severely reduced lack of such efficacy when treating advanced metastatic disease. Interestingly, an exception to this pattern has been observed using various continuous low-dose metronomic chemotherapy regimens, where counterintuitively, superior responses are observed in the metastatic setting, as well as superiority or equivalence of metronomic chemotherapy over standard maximum tolerated dose (MTD) chemotherapy, with lesser toxicity. The basis for these encouraging results may be related to the multiple mechanisms responsible for the anti-tumor effects and longer duration of metronomic chemotherapy regimens made possible by lesser toxicity. These include antiangiogenesis, stimulation of the immune system, stromal cell targeting in tumors, and possibly direct tumor cell targeting, including targeting cancer stem cells (CSCs). In addition, metronomic chemotherapy regimens minimize or even eliminate the problem of chemotherapy-induced host responses that may actually secondarily promote tumor growth and malignancy after causing an initial and beneficial anti-tumor response. We suggest that future preclinical studies of metronomic chemotherapy should be concentrated in the following areas: i) further comparative assessment of anti-tumor efficacy in primary vs metastatic treatment settings; ii) rigorous comparative assessment of conventional MTD chemotherapy vs metronomic chemotherapy using the same agent; iii) assessment of potential predictive biomarkers for metronomic chemotherapy, and methods to determine optimal biologic dose and schedule; and iv) a further detailed assessment of the potential of different chemotherapy drugs administered using MTD or metronomic regimens on stimulating or suppressing components of the innate or adaptive immune systems.

 Metronomic chemotherapy: A potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation

Eirini Biziota, Leonidas Mavroeidis, Eleftheria Hatzimichael, Periklis Pappas Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor’s neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule.

 Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: A phase II trial

Emilia Montagna, Antonella Palazzo, Patrick Maisonneuve, Giuseppe Cancello, Monica Iorfida, Angela Sciandivasci, Angela Esposito, Anna Cardillo, Manuelita Mazza, Elisabetta Munzone, Antonella Lai, Aron Goldhirsch, Marco Colleoni In a phase II study we assessed the safety and efficacy of metronomic oral chemotherapy with vinorelbine, cyclophosphamide capecitabine in patients with metastatic breast cancer, either as first-line (naïve group) or second-line or greater therapy (pre-treated group). Eligible patients had histologically or cytologically proven, hormone-receptor positive metastatic breast cancer. The primary end point was median time to progression (TTP). A total of 43 patients in the naïve group and 65 in the pre-treated group were enrolled. The median TTP was 25.1 months in the naïve group and 11.2 months in the pre-treated group. The most frequently reported grade 2 treatment-related adverse events were leukopenia and hand and foot syndrome. Metronomic combination of cyclophosphamide, capecitabine and vinorelbine showed significant activity and good tolerability in patients hormonal receptor positive, metastatic breast cancer patients.

 Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model

Amr S. Abu Lila, Naoto Moriyoshi, Masakazu Fukushima, Cheng-Long Huang, Hiromi Wada, Tatsuhiro Ishida Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.

 Tackling pancreatic cancer with metronomic chemotherapy

Adriana Romiti, Rosa Falcone, Michela Roberto, Paolo Marchetti Pancreatic tumours, the majority of which arise from the exocrine pancreas, have recently shown an increasing incidence in western countries. Over the past few years more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to significant improvements. However, despite such advances in therapy, prognosis of pancreatic cancer remains disappointing. Metronomic chemotherapy (MCT), which consists in the administration of continuous, low-dose anticancer drugs, has demonstrated the ability to suppress tumour growth. Thus, it may provide an additional therapeutic opportunity for counteracting the progression of the tumour. Here we discuss evidence arising from preclinical and clinical studies regarding the use of MCT in pancreatic cancer. Good results have generally been achieved in preclinical studies, particularly when MCT was combined with standard dose chemotherapy or antinflammatory, antiangiogenic and immunostimolatory agents. The few available clinical experiences, which mainly refer to retrospective data, have reported good tolerability though mild activity of metronomic schedules. Further studies are therefore awaited to confirm both preclinical findings and the preliminary clinical data.

 Metronomic chemotherapy and immunotherapy in cancer treatment

Yu-Li Chen, Ming-Cheng Chang, Wen-Fang Cheng Systemic chemotherapy given at maximum tolerated doses (MTD) has been the mainstay of cancer treatment for more than half a century. In some chemosensitive diseases such as hematologic malignancies and solid tumors, MTD has led to complete remission and even cure. The combination of maintenance therapy and standard MTD also can generate good disease control; however, resistance to chemotherapy and disease metastasis still remain major obstacles to successful cancer treatment in the majority of advanced tumors. Metronomic chemotherapy, defined as frequent administration of chemotherapeutic agents at a non-toxic dose without extended rest periods, was originally designed to overcome drug resistance by shifting the therapeutic target from tumor cells to tumor endothelial cells. Metronomic chemotherapy also exerts anti-tumor effects on the immune system (immunomodulation) and tumor cells. The goal of immunotherapy is to enhance host anti-tumor immunities. Adding immunomodulators such as metronomic chemotherapy to immunotherapy can improve the clinical outcomes in a synergistic manner. Here, we review the anti-tumor mechanisms of metronomic chemotherapy and the preliminary research addressing the combination of immunotherapy and metronomic chemotherapy for cancer treatment in animal models and in clinical setting.

 Metronomic chemotherapy in metastatic colorectal cancer

In Sook Woo, Yun Hwa Jung Overall survival and quality of life of patients with metastatic colorectal cancer (mCRC) have improved due to the development of standard systemic treatment. However, many patients are still suffering from the eventual progression of cancer, treatment-related toxicities, and the economic burden of new drugs. Salvage or maintenance therapy, which consistently controls or stabilizes tumor progression without debilitating quality of life, is required. Recently, metronomic capecitabine maintenance therapy after disease control using conventional chemotherapy with maximal tolerated doses has demonstrated beneficial results in a phase III trial. Metronomic chemotherapy has been known to control tumors through antiangiogenesis and immunomodulation as well as a direct effect on tumor-initiating cells. It has the characteristics of being minimally toxic, inexpensive, and durable for maintaining disease stabilization. Therefore, patients with mCRC, who tend to be elderly and frail and have been previously treated, might be suitable for metronomic therapeutic strategies. Furthermore, antiangiogenic therapy has been an important component in treating mCRC, but the schedules and doses of metronomic chemotherapy have not yet been established. Here we review translational and clinical research on metronomic chemotherapy in colorectal cancer (CRC).

 Metronomics in the neoadjuvant and adjuvant treatment of breast cancer

Elisabetta Munzone, Marco Colleoni The concept of metronomic chemotherapy (MC) has evolved from a descriptive preclinical phenomenon encompassing inhibition of angiogenesis to a clinically validated treatment concept involving multiple potential mechanisms of action. Clinicians are progressively more incline to consider MC as a component of mainstream medical oncology practice in advanced breast cancer. However, more recently MC has been tested even in the adjuvant/neoadjuvant setting, taking the opportunity to obtain tumor specimens and blood samples, in order to identify tumor-specific or patient-specific biomarkers for personalizing treatments. In addition, the antiangiogenic and pro-immune nature of metronomic chemotherapy made triple negative breast cancer (TNBC) a good candidate for exploring low-dose maintenance treatment in the adjuvant setting or in combination with immunomodulatory drugs. The potential development of MC in breast cancer pass through the research to identify biomarkers and individual tumor characteristics that can better address the use of this treatment strategy in the future. Finally, the subjective attitude of patients represents one of the major factors that influence the choice and acceptance of a therapeutic program. Personal preference and considerations about quality of life should guide the treatment choice eventually prioritizing the use of MC. Nevertheless, more robust data from randomized phase III trials are needed in the future, in order to make clinicians more confident in using metronomic strategies.

 Metronomic chemotherapy for advanced breast cancer patients

Marina Elena Cazzaniga, Maria Rita Dionisio, Francesca Riva Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. This schedule seems to have not only a direct cytotoxicity on cancer cells but also an effect on the tumor microenvironment by inhibiting tumor angiogenesis and modulating immune response. Metronomic chemotherapy was widely investigated in patients with breast cancer. The results of these studies showed that this strategy is not only effective but has a low toxicity profile too, proposing as a promising strategy for breast cancer patients. In this review we summarize the results of Phase II and III studies evaluating metronomic therapy in metastatic breast cancer.

 Potential role of metronomic chemotherapy in the treatment of esophageal and gastroesophageal cancer

Vanita Noronha, Vijay M. Patil, Amit Joshi, Anuradha Chougule, Shripad Banavali, Kumar Prabhash Patients with esophagogastric cancer have poor prognoses in spite of the best available therapies. Patients are debilitated and may not tolerate, or may progress, on standard cytotoxic chemotherapy regimens. Metronomic chemotherapy is an attractive treatment option due to its very low reported toxicity, modest efficacy, low cost and ease of administration. Capecitabine is the most common drug used in metronomic scheduling; other drugs include cyclophosphamide and paclitaxel. Dosing of capecitabine can range from 1000 mg orally daily for 4 weeks on and 1 week off to a continuous dosing schedule of 1500 mg orally daily. Reported toxicities, including neutropenia, mucositis and hand-foot syndrome, occur in <10% of patients. As there is a lack of well-conducted, randomized clinical trials evaluating the role of metronomic chemotherapy in esophagogastric cancer, it cannot be recommended as the standard of care; however, it can be considered to be a therapeutic option, especially in elderly patients with relapsed disease for whom other therapeutic options are limited.

 Metronomic chemotherapy in head and neck cancer

Francesca De Felice, Ilaria Benevento, Angela Musella, Daniela Musio, Vincenzo Tombolini Head neck cancer (HNC) is generally treated with a multimodality approach. Loco-regional-distant control is often worst, due to the advantage stage disease at diagnosis and the optimal treatment option remains an unresolved issue. Metronomic chemotherapy (MCHT) is an emerging therapeutic option in clinical oncology and it may prove useful in HNC patients.

 Application of mathematical models to metronomic chemotherapy: What can be inferred from minimal parameterized models?

Urszula Ledzewicz, Heinz Schättler Metronomic chemotherapy refers to the frequent administration of chemotherapy at relatively low, minimally toxic doses without prolonged treatment interruptions. Different from conventional or maximum-tolerated-dose chemotherapy which aims at an eradication of all malignant cells, in a metronomic dosing the goal often lies in the long-term management of the disease when eradication proves elusive. Mathematical modeling and subsequent analysis (theoretical as well as numerical) have become an increasingly more valuable tool (in silico) both for determining conditions under which specific treatment strategies should be preferred and for numerically optimizing treatment regimens. While elaborate, computationally-driven patient specific schemes that would optimize the timing and drug dose levels are still a part of the future, such procedures may become instrumental in making chemotherapy effective in situations where it currently fails. Ideally, mathematical modeling and analysis will develop into an additional decision making tool in the complicated process that is the determination of efficient chemotherapy regimens. In this article, we review some of the results that have been obtained about metronomic chemotherapy from mathematical models and what they infer about the structure of optimal treatment regimens.

 Metronomic chemotherapy and nanocarrier platforms

Amr S. Abu Lila, Tatsuhiro Ishida The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods –known as “metronomic chemotherapy”– is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic “metronomic” therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed.

 Resistance to metronomic chemotherapy and ways to overcome it

Maria Riesco-Martinez, Karla Parra, Ronak Saluja, Giulio Francia, Urban Emmenegger Therapeutic resistance is amongst the major determinants of cancer mortality. Contrary to initial expectations, antivascular therapies are equally prone to inherent or acquired resistance as other cancer treatment modalities. However, studies into resistance to vascular endothelial growth factor pathway inhibitors revealed distinct mechanisms of resistance compared to conventional cytotoxic therapy. While some of these novel mechanisms of resistance also appear to be functional regarding metronomic chemotherapy, herein we summarize available evidence for mechanisms of resistance specifically described in the context of metronomic chemotherapy. Numerous preclinically identified molecular targets and pathways represent promising avenues to overcome resistance and enhance the benefits achieved with metronomic chemotherapy eventually. However, there are considerable challenges to clinically translate the preclinical findings.