Low-dose Metronomic Chemotherapy Research Articles

Metronomic chemotherapy remodel cancer-associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice.

The present study aimed to evaluate whether capecitabine or 5-fluorouracil (5-Fu) chemotherapy with the metronomic pattern may cause significant chemoresistance compared with the traditional pattern, and whether CAFs are involved in drug resistance. SGC-7901 cells were subcutaneously injected into the nude mice, and the mice were divided into five groups: The control group, intraperitoneally injected with normal saline; the 5-Fu conventional dose group [5-Fu maximum tolerated dose (MTD) group], intraperitoneally injected with 50 mg/kg, twice per week for 2 weeks, with an 1-week discontinuation for 6 weeks; the capecitabine conventional dose group (capecitabine MTD group), intragastric 500 mg/kg, twice per week for 2 weeks, with a 1-week discontinuation for 6 weeks; the 5-Fu metronomic group [5-Fu low-dose metronomic (LDM) group], intraperitoneally injected with 15 mg/kg, twice a week for 6 weeks; and the capecitabine metronomic group (capecitabine LDM group), intragastric administration at 200 mg/kg, twice a week for 6 weeks. The chemotherapy resistance markers [glutathione transferase Pi (GSTP) and multidrug resistance protein 1 (MDR1)] were detected by immunohistochemical staining (IHC), and the association of the expression of these markers with the chemotherapy administration patterns was analyzed. Vascular endothelial growth factor (VEGF) and the cancer-associated fibroblast (CAF) marker α-smooth muscle actin were also examined by IHC to illustrate the possible mechanism of chemoresistance. The expression of GSTP and MDR1 in the MTD groups was significantly higher compared with those of the LDM groups (P<0.01). Furthermore, the number of CAFs and the level of VEGF in the MTD groups were significantly higher compared with those of the LDM groups (P<0.05). The low dose metronomic chemotherapy did not increase the risk of chemoresistance compared with the conventional dose traditional chemotherapy in terms of capecitabine or 5-Fu, the increasing amount of CAFs in the microenvironment of cancer cell following therapy may protect cell from capecitabine or 5-Fu via producing VEGF to increase vascularization.

Low-dose metronomic delivery of cyclophosphamide is less detrimental to granulosa cell viability, ovarian function, and fertility than maximum tolerated dose delivery in the mouse.

Chemotherapy can cause early menopause or infertility in women and have a profound negative impact on the quality of life of young female cancer survivors. Various factors are known to influence the risk of chemotherapy-induced ovarian failure, including the drug dose and treatment duration; however, the scheduling of dose administration has not yet been evaluated as an independent risk factor. We hypothesized that low-dose metronomic (LDM) chemotherapy scheduling would be less detrimental to ovarian function than the traditional maximum tolerated dose (MTD) strategy. In vitro, MTD cyclophosphamide exposure resulted in decreased proliferation and increased granulosa cell apoptosis, while cells treated with LDM cyclophosphamide were not different from untreated controls. Treatments of MTD cyclophosphamide induced high levels of follicle atresia and enhanced follicle recruitment in mice. In contrast, LDM delivery of an equivalent dose of cyclophosphamide reduced growing follicle numbers, but was not associated with higher levels of follicle atresia or recruitment. MTD cyclophosphamide induced significant vascular disruption and DNA damage in vivo, while LDM chemotherapy with equal cumulative amounts of cyclophosphamide was not different from controls. MTD chemotherapy also had a negative effect on mouse-fertility outcomes. Our findings suggest that LDM scheduling could potentially minimize the long-term effects of cyclophosphamide on female fertility by preventing follicle depletion from enhanced activation.

Synergistic antitumor effects of combination treatment with metronomic doxorubicin and VEGF-targeting RNAi nanoparticles

Conventional cancer treatment strategies have been aimed at eradicating all cancer cells. To this end, standard chemotherapeutic approaches have relied on the maximum tolerated dose (MTD) of cytotoxic drugs with a long off-therapy interval, leading to heavy toxic side effects accompanied by drug resistance. To avoid the problems associated with the traditional MTD chemotherapy, metronomic chemotherapy with relatively low dose continuous treatments of cytotoxic drugs has been proposed as an alternative to the predominant paradigm of directly killing all cancer cells. Low-dose metronomic (LDM) chemotherapy is expected to have not only antitumor effects without toxicity and drug resistance, but also beneficial anti-angiogenic effects by causing selective apoptosis of tumor endothelial cells. In an attempt to keep the drug resistance under control and halt exponential tumor growth, herein, we combined LDM chemotherapy with a second anti-angiogenic strategy. The selective blockade of vascular endothelial growth factor (VEGF) in combination with metronomic doxorubicin (Dox) induced synergistic antitumor effects mainly through an antiangiogenic mechanism. For specific VEGF suppression, VEGF-targeting siRNA was delivered to tumor tissue using polymerized siRNA/thiolated glycol chitosan (poly-siVEGF/tGC) nanoparticles, leading to efficient VEGF gene knockdown in tumor tissue with a sequence-specific manner. Although the single treatment with metronomic Dox and poly-siVEGF/tGC nanoparticles alone showed some antitumor activity, notably, the combination of the two therapies resulted in superb tumor regression without causing systemic toxicity or drug resistance. Thus, these results suggest that the VEGF-targeted RNAi using poly-siRNA/tGC nanoparticles in combination with LDM chemotherapy could be a promising synergistic strategy for controlling tumor growth by enhancing the efficacy of anti-angiogenesis while minimizing toxicity and drug resistance.

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

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.

Low dose metronomic chemotherapy in patients of acute myeloid leukemia

Background: Standard aggressive treatment of AML is expensive, requires significant supportive care (blood and platelet support) and toxic with significant morbidity and mortality. The metronomic approach refers to repetitive low doses of chemotherapy drugs and serves as one of the options of treatment for the patients who are unable to arrange the supportive care and those who are ineligible for intensive chemotherapy. Material and Methods: This is a hospital based observational single arm pilot study in which newly diagnosed 36 patients of AML who were unable to take standard aggressive chemotherapy were started on low dose metronomic chemotherapy and its effects evaluated over a period of 12 months. Results: Observed overall response rate (OR) was 21.87% (6.25% CR and 15.62% PR), mean survival was 3.58 months. 43.75% patients had non-hematological drug toxicities, 40.62% patients developed hematological toxicity, 3.12% developed hepatotoxicity and 9.32% patients developed febrile illness. Out of expired patients at the end of 1 year duration 70% died at their home with cause of death unidentified however rest 30% died in hospital (23% from bleeding and 7% from infection). On FACT-L questionnaire overall improvements were elicited in well being along with 43% improvement in additional concerns (including night sweats, pains, weight loss, tiredness). Conclusion: Data from our small study suggests that oral PEM metronomic chemotherapy for patients of AML with treatment possible on OPD basis itself appears to be an effective regimen with acceptable toxicities.

Therapy-activated stromal cells can dictate tumor fate.

In this issue of JEM, Chan et al. describe a novel way by which an investigational form of chemotherapy known as low-dose metronomic chemotherapy can inhibit tumor growth, which also has therapeutic implications for targeting tumor-initiating cells (TICs), the tumor stroma, and chemokine receptors, as well as invasion and metastasis.

Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells.

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.

Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai.

The 5th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6th – 8th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

Evidence Implicating Immunological Host Effects in the Efficacy of Metronomic Low-Dose Chemotherapy.

Conventional chemotherapy drugs administered at a maximum tolerated dose (MTD) remains the backbone for treating most cancers. Low-dose metronomic (LDM) chemotherapy, which utilizes lower, less toxic, doses given on a close regular basis over prolonged periods, is an alternative and better tolerated potential strategy to improve chemotherapy. LDM chemotherapy has been evaluated preclinically and clinically and has shown therapeutic benefit, in both early and advanced stage metastatic disease, especially when used as a maintenance therapy. However, knowledge about the antitumor mechanisms by which LDM chemotherapy acts remain limited. Here we characterized the effects of LDM and MTD capecitabine therapy on tumor and host cells using high-throughput systems approaches involving mass spectrometry flow cytometry and automated cell imaging followed by in vivo analyses of such therapies. An increase in myeloid and T regulatory cells and a decrease in NK and T cytotoxic cells were found in MTD-capecitabine-treated tumors compared with LDM-capecitbine-treated tumors. Plasma from MTD capecitabine-treated mice induced a more tumorigenic and metastatic profile in both breast and colon carcinoma cells than plasma from mice treated with LDM capecitabine. These results correlated, in part, with in vivo studies using models of human or mouse advanced metastatic disease, where the therapeutic advantage of MTD capecitabine was limited despite a substantial initial antitumor activity found in the primary tumor setting. Overall these results implicate a possible contribution of immunologic host effects in accounting for the therapeutic limitations of MTD compared with LDM capecitabine. Cancer Res; 76(20); 5983-93. ©2016 AACR.

Knockdown of Hypoxia-Inducible Factor 1α Improved the Efficacy of Low-Dose Metronomic Chemotherapy of Paclitaxel in Human Colon Cancer Xenografts.

Low-dose metronomic chemotherapy represents a new strategy for solid tumor treatments with a strong antiangiogenic activity and few side effects. However, low-dose metronomic therapy alone is not always as effective as traditional chemotherapy on eradication of tumor. On the contrary, low-dose metronomic in some cases could stimulate tumor growth due to hypoxia of tumor cells induced during therapy. Our study aimed to investigate whether knockdown of hypoxia-inducible factor-1α expression in tumor cell could facilitate low-dose metronomic therapy with paclitaxel for human colon cancer. Human colon cancer cell line (HT-29) stably transfected with specific short hairpin RNAs silencing hypoxia-inducible factor-1α exhibited marked attenuation of hypoxia-induced expression of the target genes such as vascular endothelial growth factor, glucose transporter 1, and P-glycoprotein. Compared with HT-29-c xenograft tumor model established by subcutaneous injection of HT-29 cells stably transfected with scrambled control short hairpin RNA, HT-29-ih xenograft tumor model showed more significant and long-lasting antitumor responses of empirical metronomic paclitaxel regimens, accompanied by drastic angiogenesis decrease and neglectable toxicity. All these data indicated that the combination of paclitaxel low-dose metronomic therapy with hypoxia-inducible factor-1α knockdown might provide a potent battle against colon cancer.

Abstract 288: Low-dose cabazitaxel inhibits the growth of prostate cancer cells and enhances the anti-tumor properties of PEDF with greater efficacy than docetaxel

Abstract Despite recently approved novel agents, taxane-based chemotherapy remains the major therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC). Still mCRPC continues to be incurable. Furthermore, patients often experience severe side effects, prompting a re-evaluation of conventional regimen. Past studies have demonstrated promise for Low-Dose Metronomic (LDM) chemotherapy; schedule defined as the frequent administration of low doses of chemotherapeutic drugs with no prolonged drug-free breaks. Yet relative activities of LDM taxanes and combinations with known anti-neoplasic agents have to be investigated. Using CRPC cell lines (PC3, Du145 and the LNCaP-derivative CL1), we have shown that cabazitaxel-treated cells have a significantly lower EC50 compared to docetaxel, with Du145 cells presenting the greatest differences. In cell cycle analysis, both low-dose taxanes increased the sub-G1 cells population. However, the sub-G1 increase was significantly greater in cabazitaxel- than in docetaxel-treated Du145 cells, but not in PC3 and CL1. Accordingly, plasma membrane Annexin V elevation occurred in Du145 cells at lower doses of cabazitaxel than docetaxel validating a higher efficacy due to increased apoptosis. As other possible cell death mechanisms, autophagy and necrosis were investigated. Beclin1 expression levels remain unchanged in all three cell lines. In contrast, necrosis was stimulated in all the taxanes-treated cell lines in a dose dependent manner. In vivo, LDM cabazitaxel was significantly more efficient in delaying tumor growth than docetaxel. This effect was markedly increased when cabazitaxel was combined with the angio-inhibitor and anti-tumor Pigment Epithelium-Derived Factor (PEDF). Other results showed that PEDF and LDM chemotherapy combination induces more phagocytosis of CRPC cells when compared to single treatments. In conclusion, our data demonstrate a higher efficacy of cabazitaxel on CRPC both in vitro and in vivo, and suggest that LDM taxane chemotherapy/PEDF combination could be used as a novel therapeutic strategy for CRPC. Citation Format: Courtney L. Jarvis, Thomas Nelius, Dalia Martinez-Marin, Srirupa Cheerla, Stéphanie Filleur. Low-dose cabazitaxel inhibits the growth of prostate cancer cells and enhances the anti-tumor properties of PEDF with greater efficacy than docetaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 288.

Abstract ES4-2: Tailoring chemotherapy

Abstract Numerous advances have been made in the management of advanced breast cancer over the last decade. Many of these have focused on the development of targeted agents, capitalising on our increased understanding of the molecular pathways involved in breast cancer biology. Nonetheless for many patients the backbone of treatment remains cytotoxic chemotherapy, either as a sole therapy (in those with cancer phenotypes where additional targeted therapy is not indicated) or combined with targeted therapy. Whilst most of the chemotherapy agents indicated in the treatment of advanced breast cancer have been available in the clinic for many years there remain controversies and variations in practice around the use of these standard agents. This presentation will discuss the indications and factors which should be taken into account in making the choice between combinations as compared sequential single agent chemotherapy. The clinical trial evidence will be overviewed with examples from clinical practice. The continuation of chemotherapy beyond maximal response and the advantages and disadvantages of maintenance chemotherapy will then be discussed. This will lead on to a discussion of whether there is a population of patients in whom metronomic low-dose chemotherapy might be indicated. In the final part of the presentation whether choice of chemotherapy should be influenced by tumour phenotype as defined by estrogen receptor status, HER2 status and the patient's germline BRCA mutation status will be discussed. At the conclusion of this educational session it is anticipated that the attendees will have a good understanding of the evidence underlying these areas, as well as practical knowledge which will help in clinical practice. It is hoped that better understanding of the optimal use of chemotherapy will maximise the benefit of these agents for our patients: gaining longest possible control of disease with best possible quality of life. Citation Format: Ring A. Tailoring chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES4-2.

Abstract P2-11-12: Novel protocol combining metronomic nant-paclitaxel with HER2-targeted natural killer cells (innate immunotherapy) for HER2-positive metastatic breast cancer

Abstract Background. Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Phase 1 clinical trials in patients with advanced cancers demonstrated the safety of unmodified, activated NK-92 cells (aNK), with no evidence of cytokine storm from 18 infusions delivered over 6 months; clinical responses were observed in a subset of patients. Like T cells, NK cells can be engineered to express chimeric antigen receptors (CARs) to enhance their antitumor activity. A stable clonal HER2-specific NK-92 cell line (HER2.taNK) mediated selective and sequential killing of HER2-expressing MDA-MB-453 cells in vitro (Schönfeld. MolTher. 2015;23:330-338). In addition, HER2.taNK cells were enriched in MDA-MB-453/EGFP xenografts and reduced the number of pulmonary metastasis in a renal cell carcinoma model, suggesting that HER2.taNK cells are a promising clinical candidate for use in adoptive cancer immunotherapy. Metronomic (low-dose, continuous) chemotherapy can be more effective than high-dose therapy in patients with advanced breast cancer (Montagna. Canc. Treat. Rev. 2014;40:922-950). Here we evaluate HER2.taNK cells in combination with metronomic nant-paclitaxel (lyophilized polymeric micellar formulation of paclitaxel) in a mouse model of HER2-positive breast cancer to determine the feasibility of a human clinical trial of HER2.taNK in combination with metronomic nant-paclitaxel. Methods. HER2.taNK cells were generated as described previously (Schönfeld. MolTher. 2015;23:330-338). MDA-MB-453 cells were implanted into the mammary fat pads of female nude mice. When tumors reached 100 mm3, mice were divided into 6 groups of 5 mice and dosed (IV) with saline (10 mL/kg, qd x 15), nant-paclitaxel (2.5-4 mg/kg q2d x 15), γ-irradiated (5 Gy) HER2.taNK cells (1 x 107 cells, days 1, 3, 5, and 8), or nant-paclitaxel + γ-irradiated (5 Gy) HER2.taNK cells–γ-irradiation is a potential safety measure for clinical application and prevents HER2.taNK cell replication while preserving antitumor activity. Tumor size and animal weights were measured every other day post-implantation. Results: Results obtained 20 days post-treatment are shown in the table. Nant-paclitaxel alone and HER2.taNK alone significantly inhibited tumor growth. The combination of nant-paclitaxel + HER2.taNK led to significant tumor regressions (p&amp;lt;0.05). Treatment Dose T/C (%) P-ValueSalinenant-paclitaxel5 mg/kg-26.7 P &amp;lt; 0.05 (vs saline) HER2.taNK1 x 107 cells-22.2 P &amp;lt; 0.05 (vs saline)nant-paclitaxel +5 mg/kg +-60.0P &amp;lt; 0.05 (vs nant-paclitaxel)HER2.taNK1 x 107 cellsP &amp;lt; 0.05 (vs HER2.taNK) Conclusions: Single agent nant-paclitaxel and HER2.taNK were similarly effective at inhibiting tumor growth in this mouse model of HER2+ breast cancer. The combination of nant-paclitaxel + HER2.taNK appeared to be synergistic resulting in tumor regressions and significantly better efficacy vs each agent alone. This study illustrates the potential for combining metronomic low-dose chemotherapy with NK-based immunotherapy in a clinical trial of patients with metastatic breast cancer. Citation Format: Rabizadeh S, Simon B, Klingemann H, Sims D, Weiss R, Soon-Shiong P. Novel protocol combining metronomic nant-paclitaxel with HER2-targeted natural killer cells (innate immunotherapy) for HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-12.

Low-Dose Metronomic Chemotherapy in Metastatic Breast Cancer: A Retrospective Analysis of 40 Patients

Purpose: Low-dose metronomic chemotherapy is an emergent treatment schedule in which low doses of cytotoxic agents are given orally continuously, with no or short drug-free intervals. In general, it provides better tolerance, especially in patients who have been previously exposed to other oncologic treatments, with a favorable cost-effectiveness profile. It is well known that all these low-dose schedules have a favorable safety profile and may provide an adequate tumor control in patients with metastatic breast cancer. However, there are no data in literature reporting the patient’s tolerance and response to subsequent lines of chemotherapy after receiving metronomic regimens. Methods: We retrospectively analyzed 40 patients with metastatic breast cancer treated with low doses of Cyclophosphamide and/or Methotrexate and/or Capecitabine in a single center from June 2009 to April 2014. The following data were collected: age, hormone and epidermal growth factor receptor 2 (HER-2) status, number of lines of chemotherapy prior to and after low-dose metronomic treatment, duration of metronomic treatment, toxicity reason for treatment discontinuation. Duration of low-dose metronomic chemotherapy was also correlated with the variables analyzed and treatment outcomes. Results: The median time on metronomic chemotherapy was 5.4 months. The most frequent drugs administered were cyclophosphamide, methotrexate and capecitabine alone. Asthenia, myelotoxicity, gastrintestinal symptoms and handfoot syndrome were the most commonly recorded treatment related toxicity. Twenty six (65%) patients had the opportunity to receive a classic chemotherapy regimen following metronomic regimen interruption. Although patients who developed toxicity to low-dose metronomic chemotherapy remained less time (s that the use of prolonged metronomic treatment does not affect a patient’s ability to tolerate subsequent therapy.

Clinical efficacy of metronomic chemotherapy after cool-tip radiofrequency ablation in the treatment of hepatocellular carcinoma

Purpose: Anti-angiogenic agents have shown promise for treating advanced hepatocellular carcinoma (HCC), and the primary mechanism of low-dose metronomic chemotherapy using traditional cytotoxic drugs is anti-angiogenic. This study evaluated the efficacy of metronomic capecitabine and thalidomide after cool-tip radiofrequency ablation (RFA), relative to RFA alone, for treating patients with HCC. Methods and materials: Patients with HCC were randomly apportioned to a test group (n = 22) receiving metronomic chemotherapy with capecitabine and thalidomide after RFA, or a control group (n = 28) receiving RFA only. Serum circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured in all patients before and 1 month after RFA treatment. Enhanced computed tomography or ultrasound imaging was performed to evaluate efficacy during 12 months of follow-up. The treatment groups were further stratified as HCC within or outside the Milan criteria for transplantation. Results: One month post-treatment, the tumour response rate (TRR), including complete response and partial response rate, of the test and control groups was statistically similar. At 12 months, the TRR of the test group (68.2%) was significantly higher than that of the control group (35.7%). In the test group, the TRR of patients whose tumour burdens were outside the Milan criteria was significantly higher than that of the control group. One month post-treatment, CECs and VEGF levels of the test group were significantly lower than baseline, while those of the control group were significantly higher. At the end of the 12-month follow-up, there was a progression-free survival (PFS) benefit of 2 months in the test group. Conclusion: Metronomic capecitabine and thalidomide after RFA significantly reduced recurrence of HCC and extended PFS, especially for HCC outside the Milan criteria, perhaps via reduction of serum CECs and VEGF levels and inhibition of tumour angiogenesis.

Clinical overview of metronomic chemotherapy in breast cancer.

Over 15 years ago, low-dose metronomic chemotherapy was shown to induce disease control in patients with advanced-stage breast cancer with a lower incidence of adverse events compared with conventional maximum tolerated dose chemotherapy. Good response rates have been seen in heavily pre-treated patients for whom limited treatment options are available. Most patients prefer oral therapy and metronomic chemotherapy is a convenient alternative in patients with advanced-stage disease in which minimal toxicity and good tumour control are the overall aims of treatment. The addition of metronomic protocols to standard neoadjuvant chemotherapy regimens has produced promising pathological complete response rates. Ongoing trials including the SYSUCC-001 trial in patients with triple-negative breast cancer and the IBCSG 22-00 trial that is assessing a cyclophosphamide-methotrexate maintenance regimen after standard adjuvant therapy in hormone receptor-negative disease, will clarify the value of adding this approach to conventional therapies. The low cost associated with metronomic chemotherapy represents an opportunity for the utilization of this treatment option, especially in developing countries, and poses a challenge for the launch of large trials sponsored by industry. Using breast cancer as the principal example, we discuss the key clinical advances in this area, including new trial design, appropriate patient and end point selection, as well as the evolving rationale for metronomic chemotherapy combinations.

Anakoinosis: Communicative Reprogramming of Tumor Systems - for Rescuing from Chemorefractory Neoplasia.

Disruptive technologies, such as communicative reprogramming (anakoinosis) with cellular therapies in situ for treating refractory metastatic cancer allow patient care to accelerate along a totally new trajectory and highlight what may well become the next sea change in the care of patients with many types of advanced neoplasia. Cellular therapy in situ consisted of repurposed drugs, pioglitazone plus all-trans retinoic acid or dexamethasone or interferon-alpha (dual transcriptional modulation) combined with metronomic low-dose chemotherapy or low-dose 5-azacytidine, plus/minus classic targeted therapy. The novel therapeutic tools for specifically designing communication processes within tumor diseases focus on redirecting (1) rationalizations of cancer hallmarks (constitution of single cancer hallmarks), (2) modular events, (3) the ‘metabolism’ of evolutionary processes (the sum of therapeutically and intrinsically inducible evolutionary processes) and (4) the holistic communicative context, which determines validity and denotation of tumor promoting communication lines. Published data on cellular therapies in situ (6 histologic tumor types, 144 patients, age 0.9–83 years) in castration-resistant prostate cancer, pretreated renal clear cell carcinoma, chemorefractory acute myelocytic leukemia, multiple myeloma > second-line, chemorefractory Hodgkin lymphoma or multivisceral Langerhans cell histiocytosis, outline the possibility for treating refractory metastatic cancer with the hope that this type of reprogrammed communication will be scalable with minimal toxicity. Accessibility to anakoinosis is a tumor inherent feature, and cellular therapy in situ addresses extrinsic and intrinsic drug resistance, by redirecting convergent organized communication tools, while been supported by quite different pattern of (molecular-)genetic aberrations.

Dynamical properties of a minimally parameterized mathematical model for metronomic chemotherapy.

A minimally parameterized mathematical model for low-dose metronomic chemotherapy is formulated that takes into account angiogenic signaling between the tumor and its vasculature and tumor inhibiting effects of tumor-immune system interactions. The dynamical equations combine a model for tumor development under angiogenic signaling formulated by Hahnfeldt et al. with a model for tumor-immune system interactions by Stepanova. The dynamical properties of the model are analyzed. Depending on the parameter values, the system encompasses a variety of medically realistic scenarios that range from cases when (i) low-dose metronomic chemotherapy is able to eradicate the tumor (all trajectories converge to a tumor-free equilibrium point) to situations when (ii) tumor dormancy is induced (a unique, globally asymptotically stable benign equilibrium point exists) to (iii) multi-stable situations that have both persistent benign and malignant behaviors separated by the stable manifold of an unstable equilibrium point and finally to (iv) situations when tumor growth cannot be overcome by low-dose metronomic chemotherapy. The model forms a basis for a more general study of chemotherapy when the main components of a tumor's microenvironment are taken into account.

Low-dose metronomic chemotherapy in metastatic breast cancer: A retrospective analysis of 40 patients.

e11567 Background: Low-dose metronomic chemotherapy is an emergent treatment schedule in which low doses of cytotoxic agents are given orally continuously, with no or short drug-free intervals. In ...

A new perspective in cancer treatment: Low dose metronomic chemotherapy with old known drugs in advanced breast cancer patients—Phase II clinical trial.

e13500 Background: The oral administration of Cyclophosphamide (Cy) and Celecoxib (Cel) encourage the use of low-dose metronomic chemotherapy (MC) to treat heavily pretreated, multidrug resistant, ...