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Annals of Oncology : Official Journal... Sep 2013Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended rest periods....
BACKGROUND
Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended rest periods. Herein, we investigated the therapeutic efficacy of metronomic cyclophosphamide (Cy) combined with doxorubicin (Dox) in two mouse mammary adenocarcinoma models.
MATERIALS AND METHODS
Mice were s.c. challenged with M-234p or M-406 mammary tumors, and when the tumors reached ∼150 mm(3), they were treated with: (I) no treatment (controls); (II) Cy in the drinking water (30 mg/kg body weight/day); (III) Dox (0.5 mg/kg body weight i.p. three times/week); (IV) treated as (II) + (III). Mice challenged i.v. with M-234p or M-406 tumor cells received, on day 3, the same treatments.
RESULTS
We found that MCT with Cy plus Dox inhibited tumor growth, decreased lung metastases, and increased the median survival time, while having low toxic effect. Combined MCT was more effective than each monotherapy causing decrease in VEGF serum concentration and tumor proliferation rate plus increase in tumor apoptosis.
CONCLUSION(S)
The therapeutic benefits of combined MCT with Cy and Dox on mammary adenocarcinomas together with its low toxic effect profile suggest the possibility of future translation into the clinic.
Topics: Adenocarcinoma; Administration, Metronomic; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Cyclophosphamide; Disease Models, Animal; Doxorubicin; Female; Ki-67 Antigen; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; Survival; Vascular Endothelial Growth Factor A
PubMed: 23666914
DOI: 10.1093/annonc/mdt164 -
Breast (Edinburgh, Scotland) Oct 2011Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used... (Comparative Study)
Comparative Study Review
Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed.
Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Indoles; Mastectomy; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Pyrroles; Sunitinib; Survival Analysis; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 22015294
DOI: 10.1016/S0960-9776(11)70295-8 -
Ecancermedicalscience 2016The 5 Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6 - 8 May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians...
The 5 Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6 - 8 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.
PubMed: 27994645
DOI: 10.3332/ecancer.2016.689 -
The Lancet. Global Health Sep 2020Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%)... (Randomized Controlled Trial)
Randomized Controlled Trial
Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.
BACKGROUND
Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings.
METHODS
We did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed.
FINDINGS
Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-to-treat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15·73 months, median overall survival in the intention-to-treat analysis population was 7·5 months (IQR 4·6-12·6) in the oral metronomic chemotherapy group compared with 6·1 months (3·2-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·773 [95% CI 0·615-0·97, p=0·026]). In the per-protocol analysis population, median overall survival was 7·5 months (4·7-12·8) in the oral metronomic chemotherapy group and 6·1 months (3·4-9·6) in the intravenous cisplatin group (unadjusted HR for death 0·775 [95% CI 0·616-0·974, p=0·029]). Grade 3 or higher adverse events were observed in 37 (19%) of 196 patients in the oral metronomic chemotherapy group versus 61 (30%) of 202 patients in the intravenous cisplatin group (p=0·01).
INTERPRETATION
Oral metronomic chemotherapy is non-inferior to intravenous cisplatin with respect to overall survival in head and neck cancer in the palliative setting, and is associated with fewer adverse events. It therefore represents a new alternative standard of care if current NCCN-approved options for palliative therapy are not feasible.
FUNDING
Tata Memorial Center Research Administration Council.
TRANSLATIONS
For the Hindi, Marathi, Gujarati, Kannada, Malayalam, Telugu, Oriya, Bengali, and Punjabi translations of the abstract see Supplementary Materials section.
Topics: Administration, Intravenous; Administration, Metronomic; Administration, Oral; Adolescent; Adult; Aged; Cisplatin; Costs and Cost Analysis; Female; Head and Neck Neoplasms; Humans; India; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Treatment Outcome; Young Adult
PubMed: 32827483
DOI: 10.1016/S2214-109X(20)30275-8 -
World Journal of Clinical Oncology Jun 2021The development of breast cancer is a complex process that involves the participation of different factors. Several authors have demonstrated the overexpression of... (Review)
Review
The development of breast cancer is a complex process that involves the participation of different factors. Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors (mAChRs) in different tumor tissues and their role in the modulation of tumor biology, positioning them as therapeutic targets in cancer. The conventional treatment for breast cancer involves surgery, radiotherapy, and/or chemotherapy. The latter presents disadvantages such as limited specificity, the appearance of resistance to treatment and other side effects. To prevent these side effects, several schedules of drug administration, like metronomic therapy, have been developed. Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively. Recently, two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs. The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment, since this combination not only reduces tumor cell survival without affecting normal cells, but also decreases pathological neo-angiogenesis, the expression of drug extrusion proteins and the cancer stem cell fraction. In this review, we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule.
PubMed: 34189066
DOI: 10.5306/wjco.v12.i6.404 -
Journal of Hepatology Oct 2013Hepatocellular carcinoma (HCC) is the most common liver malignancy, representing the third and fifth leading cause of death from cancer worldwide in men and women,... (Review)
Review
Hepatocellular carcinoma (HCC) is the most common liver malignancy, representing the third and fifth leading cause of death from cancer worldwide in men and women, respectively. The main risk factor for the development of HCC is the hepatitis B and C virus (HBV and HCV) infection; non-viral causes (e.g., alcoholism and aflatoxin) are additional risk factors. HCC prognosis is generally poor because of the low effectiveness of available treatments and the overall 5-year survival rate is approximately 5-6%. In this framework, immunotherapeutic interventions, including cancer vaccines, may represent a novel and effective therapeutic tool. However, only few immunotherapy trials for HCC have been conducted so far with contrasting results, suggesting that improvements in several aspects of the immunotherapy approaches need to be implemented. In particular, identification of novel specific tumor antigens and evaluation of most advanced combinatorial strategies could result in unprecedented clinical outcomes with great beneficial effect for HCC patients. The state of the art in immunotherapy strategies for HCC and future perspectives are reported in the present review.
Topics: Antigens, Neoplasm; Cancer Vaccines; Carcinoma, Hepatocellular; Combined Modality Therapy; Female; Humans; Liver Neoplasms; Male; Molecular Targeted Therapy; Tumor Microenvironment; Vaccination
PubMed: 23714157
DOI: 10.1016/j.jhep.2013.05.031 -
EMBO Molecular Medicine Sep 2020Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically...
Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
Topics: Breast Neoplasms; Female; Humans; Lung Neoplasms; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 32686360
DOI: 10.15252/emmm.201911416 -
Oncology Research Sep 2021This study evaluated the survival effects of metronomic maintenance therapy with oral fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to...
Prognostic Value of EGFR Expression for Patients With Stage III Colorectal Cancer Receiving Fluoropyrimidine Metronomic Maintenance Therapy After Radical Resection and Adjuvant Oxaliplatin-Based Chemotherapy.
This study evaluated the survival effects of metronomic maintenance therapy with oral fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy with oral capecitabine (daily dose of 850 mg/m², twice daily, on days 114 every 3 weeks for 6 months) on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockout of the gene, we analyzed the capacities of cell proliferation and migration. Relapse and survival were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent associated factor of relapse and survival as well as a prognostic factor of disease-free survival and overall survival. Significant intergroup differences in survival were only observed in patients with positive EGFR expression. Thus, our findings suggest EGFR expression is a prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. Analysis of EGFR expression in these patients helps identify potential candidates who may receive the optimal survival benefit from metronomic maintenance therapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Caco-2 Cells; Capecitabine; Cell Proliferation; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Female; Fluorouracil; Gene Expression; Genes, erbB-1; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Analysis
PubMed: 32859280
DOI: 10.3727/096504020X15986099915822 -
Clinical and Experimental Medicine Feb 2021Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a...
Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/m i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include inhibition of angiogenesis, direct cytotoxic effects on cancer cells, and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above-noted clinical trial. Our results show that pre-treatment plasma-level cutoffs of interferon gamma (> 12.84 pg/ml), sCD40L (< 2168 pg/ml), interferon alpha 2 (> 55.11 pg/ml), and IL-17a (< 15.1 pg/ml) were predictive markers for those patients with better progression-free survival (p < .05 for each cytokine). After 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and IL-6 (< 130 pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon gamma and sCD40L after 56 days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28 days (and 56 days) after treatment started (p < 0.05). Our results indicate that a selective cytokine elevation involves IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and the cytokine profiling we describe may guide future selection of gastrointestinal cancer patients for UFT/CTX/celecoxib combination metronomic chemotherapy.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytokines; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Prognosis; Survival Rate
PubMed: 33048259
DOI: 10.1007/s10238-020-00666-9 -
Future Oncology (London, England) Mar 2013Metronomic chemotherapy (MCT), the chronic administration, at regular intervals, of low doses of chemotherapeutic drugs without extended rest periods, allows chronic...
Metronomic chemotherapy (MCT), the chronic administration, at regular intervals, of low doses of chemotherapeutic drugs without extended rest periods, allows chronic treatment with therapeutic efficacy and low toxicity. Our preclinical results suggested that combined MCT with cyclophosphamide and celecoxib could inhibit breast cancer growth. The aim of this study was to determine the toxicity, safety and efficacy of oral MCT with cyclophosphamide 50 mg per orem daily and celecoxib 400 mg (200 mg per orem two-times a day) in advanced breast cancer patients. During the first stage of the study, the therapeutic response consisted of prolonged stable disease for ≥24 weeks in six out of 15 (40%) patients with a median duration of 37.5 weeks and a partial response in one out of 15 (response rate: 6.7%) patients lasting 6 weeks. The overall clinical benefit rate was 46.7%. The median time to progression was 14 weeks. Progression-free survival at 24 weeks was 40% and the 1-year overall survival rate was 46.7%. The adverse events were mild (gastric, grade 1; and hematologic, grade 1 or 2). No grade 3 or 4 toxicities were associated with the treatment. Evaluation of patients' quality of life showed no changes during the response period. MCT with cyclophosphamide plus celecoxib is safe and shows a therapeutic effect in advanced breast cancer patients.
Topics: Administration, Metronomic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Celecoxib; Cyclophosphamide; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplastic Cells, Circulating; Pyrazoles; Quality of Life; Sulfonamides; Surveys and Questionnaires; Treatment Outcome
PubMed: 23469980
DOI: 10.2217/fon.12.196