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Journal of Cancer Research and Clinical... Aug 2021Chemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active...
Chemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active discussion among researchers. One of the proposed solutions is to shift the therapeutic paradigm from complete eradication of cancer to maintenance, i.e., to treat it as a chronic disease. A concept of metronomic therapy (low chemotherapy doses applied continuously) emerged in early 2000s and was henceforth shown to offer a number of benefits, including targeting endothelial cells and reducing acquired drug resistance. Using mathematical modeling and optimal control techniques, we investigate the hypothesis that lower doses of chemotherapy are beneficial for patients. Our analysis of a mathematical model of tumor growth under angiogenic signaling proposed by Hahnfeldt et al. adapted to heterogeneous tumors treated by combined anti-angiogenic agent and chemotherapy offers insights into the effects of metronomic therapy. Firstly, assuming constant long-term drug delivery, the model suggests that the longest survival time is achieved for intermediate drug doses. Secondly, by formalizing the notion of the therapeutic target being maintenance rather than eradication, we show that in the short term, optimal chemotherapy scheduling consists mainly of a drug applied at a low dose. In conclusion, we suggest that metronomic therapy is an attractive alternative to maximum tolerated dose therapies to be investigated in experimental settings and clinical trials.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Calibration; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Models, Theoretical; Neoplasms; Neovascularization, Pathologic; Survival Analysis; Time Factors
PubMed: 34050795
DOI: 10.1007/s00432-021-03657-9 -
Indian Journal of Cancer 2023Ovarian cancer is a leading cause of death from gynecological cancer in the world and in India. This study aims to evaluate the efficacy and toxicity profile of oral... (Observational Study)
Observational Study
BACKGROUND
Ovarian cancer is a leading cause of death from gynecological cancer in the world and in India. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of etoposide, cyclophosphamide, and tamoxifen in recurrent and metastatic ovarian cancer.
METHODS
This was a retrospective observational study that included those post-treatment patients who had the recurrent or metastatic disease after completion of treatment in 2018 at Regional Cancer Centre, Bikaner, Rajasthan. Forty patients who were unfit for further intensive intravenous chemotherapy were included. The oral MCT constituted etoposide, cyclophosphamide, and tamoxifen. Descriptive statistics and Kaplan-Meier analyses were performed. Progression-free survival (PFS) and overall survival (OS) were assessed.
RESULTS
Forty women with a median age of 62 (range: 35-80) years were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) was 0-1 in 28 patients and 2-3 in 12 patients. The best clinical response rate post-oral MCT was seen in the first 4 months. Objective response was observed in 24 (60%) of patients in the form of stable disease (19, 47.5%) and partial response (5, 12.5%). Disease progression was observed in 10 (25%) of patients. The median follow-up was 6.4 months (4.5-9.2 months). The median estimated OS was 6.5 months. The median estimated PFS was 3.7 months. Nineteen (47.5%) patients had grade-I/II mucositis. Grade-III/IV mucositis were observed in 9 (22.5%) patients. Thirty-seven (92.5%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (37.5%) patients.
CONCLUSION
Oral MCT was found to be an effective and well-tolerated regime with good symptomatic control and low-moderate toxicity profile in patients with relapsed and metastatic ovarian cancer. However, 22% of patients showed grade-III/IV thrombocytopenia.
Topics: Humans; Female; Adult; Middle Aged; Aged; Aged, 80 and over; Carcinoma, Ovarian Epithelial; Retrospective Studies; Etoposide; Mucositis; Administration, Metronomic; India; Cyclophosphamide; Ovarian Neoplasms; Tamoxifen; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37530237
DOI: 10.4103/ijc.IJC_143_20 -
Cancer Letters Nov 2023Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration.... (Review)
Review
Metronomic chemotherapy, dampening of immunosuppressive cells, antigen presenting cell activation, and T cells. A quartet against refractoriness and resistance to checkpoint inhibitors.
Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration. Preclinical and clinical studies summarized and discussed in the present review have demonstrated that maximum tolerable dosage (MTD) vs low-dosage, continuous (metronomic) administration of most chemotherapeutics have polarized effects on immune cells. In particular, metronomic schedules might be associated - among others effects - with activation of antigen presenting cells and generation of new T cell clones to enhance the activity of several types of immunotherapies. Ongoing and planned clinical trials in different types of cancer will confirm or dismiss this hypothesis and provide candidate biomarker data for the selection of patients who are likely to benefit from these combinatorial strategies.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; T-Lymphocytes; Neoplasms; Administration, Metronomic; Antigen-Presenting Cells
PubMed: 37806515
DOI: 10.1016/j.canlet.2023.216441 -
Journal of B.U.ON. : Official Journal... 2021The purpose of this study was to investigate the efficacy and safety of maintenance therapy of capecitabine metronomic chemotherapy combined with autologous...
PURPOSE
The purpose of this study was to investigate the efficacy and safety of maintenance therapy of capecitabine metronomic chemotherapy combined with autologous cytokine-induced killer (CIK) cell immunotherapy in patients with recurrent metastatic triple-negative breast cancer (mTNBC).
METHODS
The clinical data of 110 patients with recurrent mTNBC were retrospectively analyzed. Among, 55 were treated with maintenance therapy of capecitabine metronomic chemotherapy combined with autologous CIK cell immunotherapy (DC-CIK group), while the rest 55 were treated with simple metronomic chemotherapy (control group).
RESULTS
The ORR of patients in DC-CIK group and control group was 29.1% and 16.4%, and the DCR was 74.5% and 63.6%, respectively. After treatment, the proportions of CD3+ T lymphocytes, CD4+ T lymphocytes and NK cells as well as the CD4/CD8 cell ratio were notably higher in DC-CIK group than those in control group, while the proportion of CD8+ T lymphocytes was notably lower in DC-CIK group than that in control group. Compared with those before treatment, the scores of quality of life evaluated using the FACT-B-V4.0 scale were remarkably improved in both groups after treatment. The score of emotional status and total score were distinctly higher in DC-CIK group than those in control group. Moreover, the follow-up results together with log-rank test revealed that the PFS in DC-CIK group was notably superior to that in control group.
CONCLUSIONS
The maintenance therapy of capecitabine metronomic chemotherapy combined with DC-CIK cell immunotherapy is effective in the treatment of recurrent mTNBC, with tolerable adverse reactions. It can improve the patients' immune function, improve their quality of life, and prolong their PFS. Key words: capecitabine, metronomic chemotherapy, immunotherapy, breast cancer, recurrent and metastatic.
Topics: Administration, Metronomic; Adult; Antimetabolites, Antineoplastic; Capecitabine; Combined Modality Therapy; Cytokine-Induced Killer Cells; Female; Humans; Immunotherapy, Adoptive; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Treatment Outcome; Triple Negative Breast Neoplasms
PubMed: 34268928
DOI: No ID Found -
Drug News & Perspectives Mar 2010Angiogenesis is crucial for the growth of cancer. As such, it has become an established target to fight cancer. Metronomic chemotherapy-the chronic administration of... (Review)
Review
Angiogenesis is crucial for the growth of cancer. As such, it has become an established target to fight cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration, at close regular intervals, with no prolonged drug-free breaks-is a potential approach to control advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property to kill resistant cancer cells and/or to inhibit tumor growth while significantly reducing undesirable toxic side effects. Here, we will discuss potential mechanisms of action of metronomic chemotherapy and briefly review the data regarding the clinical experience with this kind of anticancer treatment. Based on recent insights in the various mechanisms of action, we will try to predict the potential new developments of metronomic chemotherapy in oncology.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Drug Administration Schedule; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 20369080
DOI: 10.1358/dnp.2010.23.2.1475913 -
Molecular Cancer Therapeutics Dec 2015There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique antiangiogenic effects, we tested the...
There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique antiangiogenic effects, we tested the efficacy of nab-paclitaxel, which stimulates thrombospondin-1, and topotecan, which inhibits hypoxia-inducible factor 1-α, at metronomic dosing for the treatment of ovarian carcinoma. In vitro and in vivo SKOV3ip1, HeyA8, and HeyA8-MDR (taxane-resistant) orthotopic models were used to examine the effects of metronomic nab-paclitaxel and metronomic topotecan. We examined cell proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (microvessel density, MVD) in tumors obtained at necropsy. In vivo therapy experiments demonstrated treatment with metronomic nab-paclitaxel alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight (62% in the SKOV3ip1 model, P < 0.01 and 96% in the HeyA8 model, P < 0.03) compared with vehicle (P < 0.01). In the HeyA8-MDR model, metronomic monotherapy with either cytotoxic agent had modest effects on tumor growth, but combination therapy decreased tumor burden by 61% compared with vehicle (P < 0.03). The greatest reduction in MVD (P < 0.05) and proliferation was seen in combination metronomic therapy groups. Combination metronomic therapy resulted in prolonged overall survival in vivo compared with other groups (P < 0.001). Tube formation was significantly inhibited in RF-24 endothelial cells exposed to media conditioned with metronomic nab-paclitaxel alone and media conditioned with combination metronomic nab-paclitaxel and metronomic topotecan. The combination of metronomic nab-paclitaxel and metronomic topotecan offers a novel, highly effective therapeutic approach for ovarian carcinoma that merits further clinical development.
Topics: Administration, Metronomic; Albumins; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Mice; Neovascularization, Pathologic; Ovarian Neoplasms; Paclitaxel; Topotecan; Xenograft Model Antitumor Assays
PubMed: 26516159
DOI: 10.1158/1535-7163.MCT-14-0630 -
PloS One 2020To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT)...
PURPOSE
To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT) in the 4T1 mammary tumor model of locally advanced breast cancer.
METHODS
Twelve Balb/c mice with metastatic breast cancer were divided into treated and untreated (control) groups. The treated group (n = 6) received five treatments of anti-metabolite agent 5-Fluorouracil (5FU) in the span of two weeks. dMRI and DCE-MRI were acquired for both treated and control groups before and after MCT. Immunohistochemically staining and measurements were performed after the post-MRI measurements for comparison.
RESULTS
The control mice had significantly (p<0.005) larger tumors than the MCT treated mice. The DCE-MRI analysis showed a decrease in contrast enhancement for the control group, whereas the MCT mice had a more stable enhancement between the pre-chemo and post-chemo time points. This confirms the antiangiogenic effects of 5FU treatment. Comparing amplitude of enhancement revealed a significantly (p<0.05) higher enhancement in the MCT tumors than in the controls. Moreover, the MCT uptake rate was significantly (p<0.001) slower than the controls. dMRI analysis showed the MCT ADC values were significantly larger than the control group at the post-scan time point.
CONCLUSION
dMRI and DCE-MRI can be used as potential biomarkers for assessing the treatment response of MCT. The MRI and pathology observations suggested that in addition to the cytotoxic effect of cell kills, the MCT with a cytotoxic drug, 5FU, induced changes in the tumor vasculature similar to the anti-angiogenic effect.
Topics: Administration, Metronomic; Animals; Antimetabolites, Antineoplastic; Case-Control Studies; Contrast Media; Diffusion Magnetic Resonance Imaging; Feasibility Studies; Female; Fluorouracil; Longitudinal Studies; Magnetic Resonance Imaging; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Treatment Outcome
PubMed: 33237905
DOI: 10.1371/journal.pone.0241916 -
Aging Apr 2016
Topics: Administration, Metronomic; Animals; Antineoplastic Agents; Female; Humans; Triple Negative Breast Neoplasms
PubMed: 27084985
DOI: 10.18632/aging.100947 -
Neoplasia (New York, N.Y.) Mar 2011Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic...
BACKGROUND
Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC).
METHODS
We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot.
RESULTS
Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib.
CONCLUSION
Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Drug Combinations; ErbB Receptors; Fluorouracil; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid; Piperidines; Quinazolines; Tegafur; Tumor Cells, Cultured
PubMed: 21390182
DOI: 10.1593/neo.101186 -
Journal of Feline Medicine and Surgery Jun 2021Although feline mammary carcinomas (FMCs) are highly metastatic, the literature and treatment options pertaining to advanced tumours are scarce. This study aimed to...
OBJECTIVES
Although feline mammary carcinomas (FMCs) are highly metastatic, the literature and treatment options pertaining to advanced tumours are scarce. This study aimed to investigate the clinical outcome of metastatic FMC with or without adjuvant treatment.
METHODS
The medical records of 73 cats with metastatic FMC (stage IV) were reviewed and included in this study. Metastatic disease was detected by distinct imaging techniques (radiography, ultrasound and CT) and confirmed by cytology and/or histopathology. Cats with adjuvant chemotherapy treatment (n = 34) were divided into three groups: group 1 (n = 9) cats receiving maximum tolerated dose chemotherapy; group 2 (n = 15) cats receiving metronomic chemotherapy; and group 3 (n = 10) cats treated with toceranib phosphate. The study endpoints were time to progression (TTP) and tumour-specific survival (TSS). Treatment-related toxicity was evaluated according to the Veterinary Co-operative Oncology Group's Common Terminology Criteria for Adverse Events version 1.1 (VCOG-CTCAE).
RESULTS
Overall mean TTP and TSS were 23 and 44 days, respectively. Cats with clinical signs at the time of diagnosis had a lower TSS (14 days) than asymptomatic cats (128 days; <0.001). Cats with pleural effusion had a lower TSS (16 days) than cats without ( <0.001). Median TSS was 58, 75 and 63 days in groups 1, 2 and 3, respectively ( = 0.197). Toxicity was observed in 66.7%, 20% and 30% of cats in groups 1, 2 and 3, respectively.
CONCLUSIONS AND RELEVANCE
To the best of our knowledge, this study includes the highest number of patients with metastatic FMC assessed. Despite the overall poor prognosis, some cats survived >6 months, indicating that adjuvant treatment may be an option to consider in metastatic disease. More studies are warranted for better understanding and management of stage IV patients.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cat Diseases; Cats; Chemotherapy, Adjuvant; Female; Prognosis; Retrospective Studies
PubMed: 33078692
DOI: 10.1177/1098612X20964416