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Breast (Edinburgh, Scotland) Dec 2005We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a... (Review)
Review
We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a variety of preclinical models, including human breast cancer xenografts. The advantages of metronomic-maintenance-type chemotherapy regimens include significantly reduced host toxicity, potentially reduced costs, increased convenience for patients when oral chemotherapy drugs are used, and the possibility of adopting chronic combination therapies involving conventional chemotherapy drugs and cytostatic molecularly targeted therapies. However, a disadvantage is the empiricism associated with determining the optimal biologic dose (OBD). Recently, we have developed a surrogate biomarker approach involving measurement of circulating endothelial progenitor cells (CEPs) in peripheral blood to help determine the OBD of anti-angiogenic drugs or treatments, including metronomic chemotherapy. Using this approach we determined the OBD for different metronomic chemotherapy regimens and then tested the effect of such drugs for the treatment of established, advanced (high volume) and widespread human breast cancer metastases in immunodeficient mice. This treatment strategy, which was maintained for over 6 months, with no breaks, resulted in marked prolongation of survival and was devoid of overt toxicity. These results suggest the possibility of using metronomic chemotherapy regimens as an adjuvant therapy for early-stage disease, including breast cancer, as was demonstrated recently using long-term daily low-dose UFT for the treatment of early-stage resected non-small cell lung cancer or UFT in combination for early stage breast cancer combined with tamoxifen.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Mice; Mice, SCID; Xenograft Model Antitumor Assays
PubMed: 16199161
DOI: 10.1016/j.breast.2005.08.026 -
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 -
Indian Journal of Cancer 2020Worldwide, hospitals are facing problems in managing cancer patients during the ongoing COVID-19 pandemic. Given the immense cancer burden of oral cancer in India,...
Worldwide, hospitals are facing problems in managing cancer patients during the ongoing COVID-19 pandemic. Given the immense cancer burden of oral cancer in India, scheduling surgeries are becoming increasingly difficult. Upfront surgeries are recommended for curative treatment of oral cancers and postponing them raises the fear of progression. Metronomic chemotherapy can be considered during the waiting period given its potential oncological benefits and ease of administration without much toxicity.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; COVID-19; Coronavirus Infections; Humans; India; Mouth Neoplasms; Oral Surgical Procedures; Pandemics; Pneumonia, Viral
PubMed: 33078758
DOI: 10.4103/ijc.IJC_553_20 -
Journal of Cancer Research and... Jan 2012To assess the feasibility of metronomic chemotherapy in the palliative care setting.
CONTEXT
To assess the feasibility of metronomic chemotherapy in the palliative care setting.
AIMS
To study the toxicity profile and efficacy of metronomic chemotherapy for palliation in oral cavity cancers.
SETTINGS AND DESIGN
Retrospective analysis of prospectively collected data.
MATERIALS AND METHODS
Subjects receiving metronomic chemotherapy from August 2010 to January 2011 for palliation in oral cancers subjected to certain criteria were included. Metronomic chemotherapy offered was a combination of twice daily celecoxib 200 mg and weekly methotrexate 15 mg/m 2 .The chemotherapy was continued till disease progression, intolerable side effects or patients' desire to stop. The toxicity profile was reported in accordance with common terminology criteria for adverse events (CTCAE) version 4.02. The efficacy was noted in terms of symptom control, response rates, progression free survival (PFS) and overall survival (OS).
STATISTICAL ANALYSIS USED
SPSS version 16 has been utilized. Descriptive analysis has been presented. The Kaplan-Meier survival analysis was performed for estimation of the PFS and OS.
RESULTS
Eighteen patients with a median age of 50.5 years, 13 males and 5 females, participated in the study. Five patients had received no previous treatment while the rest had some form of previous treatment. ECOG performance status was 1 in 14 patients and 2 in 4 patients. Grade 3-4 mucositis was seen in one patient. Clinical benefit rate was 66.67%. The estimated median PFS and median OS were 5.2 months and not reached respectively.
CONCLUSIONS
Use of metronomic chemotherapy seems promising and well tolerated in this setting. Large trials are warranted to confirm these results.
Topics: Administration, Metronomic; Adolescent; Aged; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Methotrexate; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Palliative Care; Pyrazoles; Sulfonamides
PubMed: 22322727
DOI: 10.4103/0973-1482.92223 -
Bulletin Du Cancer Dec 2011Angiogenesis is crucial for the growth and metastasis of many cancers. A series of new inhibitors of angiogenesis are now in intensive development. Recent preclinical... (Review)
Review
Angiogenesis is crucial for the growth and metastasis of many cancers. A series of new inhibitors of angiogenesis are now in intensive development. Recent preclinical studies suggest that frequent administration of certain conventional cytotoxic agents at low doses increases their putative antiangiogenic activity. Moreover, many clinical trials confirm efficacy of this metronomic chemotherapy in terms of clinical benefice and survival prolongation. Combining metronomic chemotherapy with hormonotherapy, angiogenesis inhibitors and radiotherapy increases efficacy. Many biomarkers are used to predict optimal drugs and appropriate use of them. This review describes experimental and clinical studies published and discuss its potential uses and limits.
Topics: Age Factors; Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 22146261
DOI: 10.1684/bdc.2011.1493 -
Journal of the Formosan Medical... May 2021Stage II colorectal cancer has a relatively good prognosis. Adjuvant chemotherapy following surgery is the standard treatment for stage III colorectal cancer but is not...
BACKGROUND
Stage II colorectal cancer has a relatively good prognosis. Adjuvant chemotherapy following surgery is the standard treatment for stage III colorectal cancer but is not routinely recommended for all stage II colorectal cancer patients. We aimed to evaluate the clinical outcomes, treatment results, and prognostic factors in stage II colorectal cancer patients who underwent curative surgery with/without oral tegafur-uracil (UFT).
METHODS
We included stage II colorectal cancer patients who underwent curative surgery and were followed up for at least 5 years after surgery at the National Taiwan University Hospital between January 2008 and December 2012. Excluding patients receiving neoadjuvant therapy, adjuvant therapy other than UFT, and those lost follow-up, patients treated with UFT (UFT group) and those without adjuvant therapy (surgery alone group) were analyzed for their clinical outcomes and prognostic factors.
RESULTS
A total of 233 patients were recruited. Of these, 104 (44.64%) underwent only surgery while 129 (55.36%) received adjuvant chemotherapy with oral UFT following surgery. Recurrence or death occurred within 5 years in 60 patients (25.75%), with a significant difference between the surgery alone (36/104, 34.62%) and UFT groups (24/129, 18.61%) (p = 0.007). The UFT group demonstrated significantly superior 5-year disease-free (p = 0.003) and overall survival rates (p = 0.001), respectively. Patient age of ≤35.3 or ˃72.7 years, UFT duration of <486.8 days, 7.1 cm < tumor size ≤13.2 cm, number of harvested lymph nodes ≤13.5, and mucinous adenocarcinoma were associated with poorer 5-year overall survival.
CONCLUSION
The present data suggest that UFT following curative surgery may be associated with lower recurrence and improved survival in patients with stage II colorectal cancer.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Taiwan; Tegafur; Uracil
PubMed: 33023787
DOI: 10.1016/j.jfma.2020.09.014 -
JAMA Oncology Sep 2017Although oral metronomic chemotherapy is often used in progressive pediatric solid malignant tumors, a literature review reveals that only small single-arm retrospective... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Although oral metronomic chemotherapy is often used in progressive pediatric solid malignant tumors, a literature review reveals that only small single-arm retrospective or phase 1 and 2 studies have been performed. Skepticism abounds because of the lack of level 1 evidence.
OBJECTIVES
To compare the effect of metronomic chemotherapy on progression-free survival (PFS) with that of placebo in pediatric patients with primary extracranial, nonhematopoietic solid malignant tumors that progress after at least 2 lines of chemotherapy.
DESIGN, SETTING, AND PARTICIPANTS
A double-blinded, placebo-controlled randomized clinical trial was conducted from October 1, 2013, through December 31, 2015, at the cancer center at All India Institute of Medical Sciences in children aged 5 to 18 years with primary extracranial, nonhematopoietic solid malignant tumors that progressed after at least 2 lines of chemotherapy and had no further curative options.
INTERVENTIONS
One arm received a 4-drug oral metronomic regimen of daily celecoxib and thalidomide with alternating periods of etoposide and cyclophosphamide, whereas the other arm received placebo. Disease status was assessed at baseline, 9 weeks, 18 weeks, and 27 weeks or at clinical progression.
MAIN OUTCOMES AND MEASURES
The primary end point was PFS as defined by the proportion of patients without disease progression at 6 months, and PFS duration and overall survival (OS) were secondary end points.
RESULTS
A total of 108 of the 123 patients screened were enrolled, with 52 randomized to the placebo group (median age, 15 years; 40 male [76.9%]) and 56 to the metronomic chemotherapy group (median age, 13 years; 42 male [75.0%]). At a median follow-up of 2.9 months, 100% of the patients had disease progression by 6 months in the placebo group vs 96.4% in the metronomic chemotherapy group (P = .24). Median PFS and OS in the 2 groups was similar (hazard ratio [HR], 0.69; 95% CI, 0.47-1.03 [P = .07] for PFS; and HR, 0.74; 95% CI, 0.50-1.09 [P = .13] for OS). In post hoc subgroup analysis, cohorts receiving more than 3 cycles (HR for PFS, 0.46; 95% CI, 0.23-0.93; P = .03) and those without a bone sarcoma (ie, neither primitive neuroectodermal tumor nor osteosarcoma) (HR for PFS, 0.39; 95% CI, 0.18-0.81; P = .01) appeared to benefit from metronomic chemotherapy.
CONCLUSIONS AND RELEVANCE
Metronomic chemotherapy does not improve 6-month PFS, compared with placebo, among pediatric patients with extracranial progressive solid malignant tumors . However, patients without bone sarcoma and those able to tolerate therapy for more than 3 cycles (9 weeks) benefit.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01858571.
Topics: Administration, Metronomic; Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Celecoxib; Child; Child, Preschool; Cyclophosphamide; Disease Progression; Disease-Free Survival; Double-Blind Method; Etoposide; Female; Follow-Up Studies; Humans; Male; Neoplasms; Response Elements; Retreatment; Sarcoma, Ewing; Survival Rate; Thalidomide; Time Factors
PubMed: 28384657
DOI: 10.1001/jamaoncol.2017.0324 -
Cancer Research Jan 2007Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of...
Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Growth Processes; Cell Survival; DNA, Neoplasm; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Endothelial Cells; Female; Humans; Mice; Neovascularization, Pathologic; Ovarian Neoplasms; Purines; Taxoids
PubMed: 17210709
DOI: 10.1158/0008-5472.CAN-06-3282 -
Journal of Endocrinological... Mar 2013The potential benefit of further chemotherapy approaches in patients with adrenocortical carcinoma (ACC) showing progressive disease after 2 chemotherapy lines is... (Clinical Trial)
Clinical Trial
OBJECTIVE
The potential benefit of further chemotherapy approaches in patients with adrenocortical carcinoma (ACC) showing progressive disease after 2 chemotherapy lines is actually unknown. This study provides explorative information on the activity of metronomic chemotherapy in heavily pre-treated ACC patients.
DESIGN AND METHODS
We tested the activity of cytotoxic treatments administered on a metronomic schedule in metastatic ACC patients showing disease progression after treatment with gemcitabine and capecitabine scheme.
RESULTS
Eight patients out of 28 consecutively enrolled in that trial were treated with several metronomic cytotoxic regimens. Six of them showed disease progression, but 2 patients obtained a clear benefit. The first patient was treated with oral etoposide (50 mg daily) as the 6th-line therapy and obtained a partial response lasting 24 months, while the second patient obtained a partial response lasting 10 months with metronomic oral cyclophosphamide (50 mg daily) as the 5th chemotherapy line. Both patients had sex hormone secreting tumors and were bearing a rather indolent ACC.
CONCLUSIONS
The administration of several chemotherapy lines in advanced ACC patients cannot be routinely recommended outside prospective clinical trials. Few patients with indolent tumors, however, may benefit from this approach. According to our experience, oral cyclophosphamide and oral etoposide may be used in this setting.
Topics: Administration, Metronomic; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cyclophosphamide; Etoposide; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Treatment Outcome
PubMed: 22522572
DOI: 10.3275/8334 -
Drug Discovery Today Feb 2013Low-dose metronomic (LDM) chemotherapy represents an emerging concept in the treatment of cancer. Directed against tumor cells and other types of cells, such as... (Review)
Review
Low-dose metronomic (LDM) chemotherapy represents an emerging concept in the treatment of cancer. Directed against tumor cells and other types of cells, such as endothelial and immune cells, this treatment regimen alters the tumor microenvironment and suppresses innate features which support tumor growth. Ongoing Phase III clinical studies explore various applications of LDM chemotherapy, mostly combined with other anticancer agents, to act as complementary treatments to conventional maximum tolerated dose (MTD) chemotherapy. In this article we summarize preclinical and clinical experience with LDM chemotherapy, emphasizing the potential contribution of this new treatment modality to future paradigms in the systemic treatment of patients with cancer.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents; Humans; Immune System; Neoplasms
PubMed: 22868084
DOI: 10.1016/j.drudis.2012.07.015