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Cancer Medicine Aug 2019Patients with Non-Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination... (Comparative Study)
Comparative Study
Patients with Non-Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP-16) alone and that of MCC using both VP-16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI-LY-10 and SU-DHL-6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low-dose VP-16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP-16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy-related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP-16 48 hours + RAD001 24 hours is the optimal method for treating NHL.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Autophagy-Related Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Etoposide; Everolimus; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Non-Hodgkin; Survival Analysis; Treatment Outcome
PubMed: 31218841
DOI: 10.1002/cam4.2364 -
Thoracic Cancer Aug 2023This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in...
A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2-negative metastatic breast cancer.
BACKGROUND
This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in women with HER2-negative metastatic breast cancer (MBC) in China.
METHODS
The mNC regimen was administered to the enrolled cases, including oral vinorelbine (VNR) 40 mg three times weekly (on days 1, 3 and 5 every week) and capecitabine (CAP) 500 mg three times a day, until disease progression or intolerable toxicity. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and treatment-related adverse events (TRAEs). Stratified factors included treatment lines and hormone receptor (HR) status.
RESULTS
Between June 2018 and March 2023, 29 patients were enrolled into the study. The median follow-up time was 25.4 months (range, 2.0-53.8). In the entire group, the 1-year PFS rate was 54.1%. ORR, DCR and CBR were 31.0%, 96.6% and 62.1%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). Subgroup analysis revealed that ORRs were 29.4% and 33.3% in first- and ≥second-line chemotherapy, respectively. ORRs were 29.2% (7/24) and 40.0% (2/5) for HR-positive MBC and metastatic triple-negative breast cancer (mTNBC), respectively. Grade 3/4 TRAEs were neutropenia (10.3%) and nausea/vomiting (6.9%).
CONCLUSIONS
The dual oral mNC regimen showed very good safety features and improved compliance without loss of efficacy in both first- and second-line treatments. The regimen also reached an excellent ORR in the mTNBC subgroup.
Topics: Humans; Female; Breast Neoplasms; Capecitabine; Vinorelbine; East Asian People; Prospective Studies; Vinblastine; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2; Triple Negative Breast Neoplasms; Neoplasm Metastasis; Treatment Outcome
PubMed: 37402471
DOI: 10.1111/1759-7714.15011 -
The Journal of Experimental Medicine Dec 2016Although 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...
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.
Topics: Administration, Metronomic; Breast Neoplasms; Female; Fibroblasts; Humans; MCF-7 Cells; NF-kappa B; Receptors, Interleukin-8B; STAT1 Transcription Factor; Stromal Cells; U937 Cells
PubMed: 27881732
DOI: 10.1084/jem.20151665 -
Cancer Letters Apr 2018Conventional cytotoxic cancer chemotherapy is often immunosuppressive and associated with drug resistance and tumor regrowth after a short period of tumor shrinkage or... (Review)
Review
Conventional cytotoxic cancer chemotherapy is often immunosuppressive and associated with drug resistance and tumor regrowth after a short period of tumor shrinkage or growth stasis. However, certain cytotoxic cancer chemotherapeutic drugs, including doxorubicin, mitoxantrone, and cyclophosphamide, can kill tumor cells by an immunogenic cell death pathway, which activates robust innate and adaptive anti-tumor immune responses and has the potential to greatly increase the efficacy of chemotherapy. Here, we review studies on chemotherapeutic drug-induced immunogenic cell death, focusing on how the choice of a conventional cytotoxic agent and its dose and schedule impact anti-tumor immune responses. We propose a strategy for effective immunogenic chemotherapy that employs a modified metronomic schedule for drug delivery, which we term medium-dose intermittent chemotherapy (MEDIC). Striking responses have been seen in preclinical cancer models using MEDIC, where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, and on a schedule compatible with activation of a sustained anti-tumor immune response, thereby maximizing anti-cancer activity. We also discuss strategies for combination chemo-immunotherapy, and we outline approaches to identify new immunogenic chemotherapeutic agents for drug development.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents; Cell Survival; Combined Modality Therapy; Dose-Response Relationship, Drug; Humans; Immunotherapy; Neoplasms; Xenograft Model Antitumor Assays
PubMed: 29414305
DOI: 10.1016/j.canlet.2018.01.050 -
Medicine Nov 2022The current studies on metronomic chemotherapy in mCRC are all aimed at patients after multi-line therapy failure, and only a few studies have focused on maintenance...
BACKGROUND
The current studies on metronomic chemotherapy in mCRC are all aimed at patients after multi-line therapy failure, and only a few studies have focused on maintenance treatment after successful first-line therapy.
METHODS
The PubMed, Embase, Cochrane Library, Wanfang, CNKI, and VIP were searched, and the relevant data was extracted, including media progression-free survival (mPFS), media overall survival (mOS), and grade 3/4 adverse events (AEs).
RESULTS
We included 4 randomized controlled trials (RCTs), 2 RCTs showed that metronomic maintenance chemotherapy could significantly improve mPFS compared to observation group; another RCT showed that metronomic maintenance chemotherapy group did not have low mPFS than the bevacizumab maintenance treatment (MT). The final RCT showed that dual-agent metronomic chemotherapy combined with bevacizumab MT did not improve mPFS compared with bevacizumab MT. The 3 RCTs showed that the metronomic maintenance therapy could not effectively improve mOS in mCRC compared to observation group or bevacizumab MT, while another RCT reported that the mOS in metronomic maintenance chemotherapy group was similar to bevacizumab MT. AEs was mostly mild and manageable. Grade ≥ 3 AEs are mostly nonhematological toxicity, and no deaths related to AEs were reported.
CONCLUSION
This systematic review indicates that metronomic chemotherapy for mCRC MT can improve mPFS in some patients and is relatively safe. However, improvements in OS in most RCTs are arguable. Therefore, we need further studies to verify its long-term efficacy.
Topics: Humans; Bevacizumab; Colorectal Neoplasms; Randomized Controlled Trials as Topic; Colonic Neoplasms; Rectal Neoplasms; Lymphoma, Follicular
PubMed: 36401426
DOI: 10.1097/MD.0000000000031659 -
Cancer Letters Mar 2015The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard... (Review)
Review
The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.
Topics: Administration, Metronomic; Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Endothelial Cells; Humans; Immune System; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 25541061
DOI: 10.1016/j.canlet.2014.12.039 -
Indian Journal of Cancer 2017Metronomic chemotherapy has shown promising results in selected patients of head and neck cancer in a small randomized study. This retrospective analysis was done to see...
BACKGROUND
Metronomic chemotherapy has shown promising results in selected patients of head and neck cancer in a small randomized study. This retrospective analysis was done to see whether the efficacy of metronomic chemotherapy in an unselected cohort of head and neck cancer patients is similar to that reported in the randomized study and the influence of the site and subsite of head and neck cancer on survival.
MATERIALS AND METHODS
This was a retrospective analysis of head and neck cancer patients who received palliative metronomic chemotherapy between January 2013 and February 2015. The data of these patients were collected from our palliative chemotherapy database maintained in medical oncology outpatient department. The overall survival (OS) was calculated in days from the date of start of chemotherapy to the date of death. Patients who had not expired at last follow-up were censored during estimation of OS by Kaplan-Meier method. Factors affecting OS were identified by COX regression analysis.
RESULTS
Over the stipulated time period, 340 patients received palliative metronomic chemotherapy. The median age of these patients was 48 years (22-90 years). The sites of tumor origin were oral cavity in 281 patients (82.6%), oropharynx in 33 patients (9.7%), larynx in seven patients (2.1%), hypopharynx in 12 patients (3.5%), and maxilla in seven patients (2.1%). Previous treatment was received by 286 patients (84.1%). The median time to failure was 3.5 months (interquartile range 2.0-6.0 months). The overall median survival was 155 days (95% confidence interval 140.2-169.8 days). Failure within 6 months of previous treatment was the most important factor influencing OS. There was a trend toward lower OS in patients with oral cancers (139 days vs. 210 days). Among the various oral cancer subsites, oral tongue primary had a lower OS.
CONCLUSION
Oral metronomic chemotherapy has promising results when used in a selected cohort of patients but has dismal results in patients who failed within 6 months of previous treatment.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Palliative Care; Retrospective Studies; Young Adult
PubMed: 29199656
DOI: 10.4103/ijc.IJC_161_17 -
Cancer Communications (London, England) Oct 2022
Topics: Administration, Metronomic; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Xenograft Model Antitumor Assays
PubMed: 35924896
DOI: 10.1002/cac2.12347 -
In Vivo (Athens, Greece) 2018The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy,...
BACKGROUND/AIM
The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC).
MATERIALS AND METHODS
Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated.
RESULTS
No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001).
CONCLUSION
The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages.
Topics: Administration, Metronomic; Angiogenesis Inhibitors; Animals; Chemotherapy, Adjuvant; Combined Modality Therapy; Dog Diseases; Dogs; Female; Humans; Mammary Neoplasms, Animal; Thalidomide
PubMed: 30348731
DOI: 10.21873/invivo.11429 -
Medicine Jun 2021Metronomic chemotherapy (MC) strategy has been used in breast cancer for more than a decade since it was first proposed. The purpose of this study is to systematically...
BACKGROUND
Metronomic chemotherapy (MC) strategy has been used in breast cancer for more than a decade since it was first proposed. The purpose of this study is to systematically evaluate its efficacy and safety for breast cancer patients at various stages, as well as to clarify the most effective medication strategy when applying MC and discover its most sensitive subpopulation in breast cancer patients.
METHOD
We will systematically retrieve random controlled trials evaluating the efficacy and safety of MC in breast cancer on PubMed, Cochrane Library, Embase, and web of science to perform this network meta-analysis. Markov chain Monte Carlo method based on Bayesian Theory will be used to conduct network meta-analysis and the efficacy and safety will be ranked by combining direct and indirect evidence in mixed treatment comparisons. We will assess the quality of literatures with the Cochrane Risk Bias Assessment Tool and assess the strength of the evidence using the GRADE methodology. Data analysis will be completed with the WinBUGS, R, Stata and RevMan softwares.
RESULTS AND CONCLUSION
Through the analysis, we can obtain the ranking of efficacy and safety in different MC strategy, and reveal the specific breast cancer groups that are more sensitive to MC. We access the effectiveness by disease free survival, progress free survival, time to progress, objective response rate, and overall survival, and measure the toxicity by dose-limiting toxicity. The result of our study could provide evidence for clinicians to make a better choice when they consider MC.
INPLASY REGISTRATION NUMBER
INPLASY202140142.
Topics: Administration, Metronomic; Adult; Bayes Theorem; Breast Neoplasms; Clinical Protocols; Drug Therapy; Female; Humans; Meta-Analysis as Topic; Systematic Reviews as Topic
PubMed: 34115017
DOI: 10.1097/MD.0000000000026255