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The Journal of Small Animal Practice Jan 2019To determine whether the addition of metronomic chemotherapy improved outcome for dogs with splenic haemangiosarcoma treated with splenectomy and adjuvant maximum...
OBJECTIVES
To determine whether the addition of metronomic chemotherapy improved outcome for dogs with splenic haemangiosarcoma treated with splenectomy and adjuvant maximum tolerated dose chemotherapy.
MATERIALS AND METHODS
Medical records were examined retrospectively for dogs with splenic haemangiosarcoma that had undergone splenectomy followed by anthracycline-based chemotherapy. Thirty-nine dogs underwent splenectomy followed by maximum tolerated dose chemotherapy with an anthracycline, cyclophosphamide, or both (Group 1). Twenty-two dogs underwent splenectomy followed by adjuvant maximum tolerated dose chemotherapy with an anthracycline, cyclophosphamide, or both, plus metronomic chemotherapy (Group 2). Dogs in both groups were further separated into those treated with either maximum tolerated dose anthracycline or maximum tolerated dose anthracycline and cyclophosphamide.
RESULTS
Median progression-free survival was 165 days and median overall survival time was 180 days in Group 1. Median progression-free survival was 185 days and median overall survival time was 212 days in Group 2. In both groups, the overall survival was shorter in dogs that had received maximum tolerated dose cyclophosphamide.
CLINICAL SIGNIFICANCE
The addition of metronomic to maximum tolerated dose chemotherapy protocols does not appear to improve outcome in dogs with splenic haemangiosarcoma treated with splenectomy and maximum tolerated dose chemotherapy.
Topics: Administration, Metronomic; Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cyclophosphamide; Dog Diseases; Dogs; Female; Hemangiosarcoma; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Retrospective Studies; Spleen; Treatment Outcome
PubMed: 30209807
DOI: 10.1111/jsap.12926 -
Nature Reviews. Cancer Jun 2004
Review
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 15170445
DOI: 10.1038/nrc1369 -
International Journal of Molecular... Oct 2017Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the... (Review)
Review
Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the potential to eliminate therapy-resistant cancer cells. However, their effectiveness may be limited either by the immunosuppressive tumor microenvironment, or by immune cell death induced by cytotoxic treatments. High-frequency low-dose (also known as metronomic) chemotherapy can help improve the activity of CTLs by providing sufficient stimulation for cytotoxic immune cells without excessive depletion. Additionally, therapy-induced removal of tumor cells that compete for shared nutrients may also facilitate tumor infiltration by CTLs, further improving prognosis. Metronomic chemotherapy can also decrease the number of immunosuppressive cells in the tumor microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Immune checkpoint inhibition can further augment anti-tumor immune responses by maintaining T cells in an activated state. Combining immune checkpoint inhibition with metronomic administration of chemotherapeutic drugs may create a synergistic effect that augments anti-tumor immune responses and clears metabolic competition. This would allow immune-mediated elimination of therapy-resistant cancer cells, an effect that may be unattainable by using either therapeutic modality alone.
Topics: Administration, Metronomic; Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Immunomodulation; Immunotherapy; Maximum Tolerated Dose; Molecular Targeted Therapy; Neoplasms; T-Lymphocyte Subsets; Treatment Outcome; Tumor Microenvironment
PubMed: 29027915
DOI: 10.3390/ijms18102134 -
The Lancet. Oncology Dec 2001Tumour endothelium is a new target for anticancer treatments. Proliferating endothelial cells from the tumour, even if qualitatively different from those of blood... (Review)
Review
Tumour endothelium is a new target for anticancer treatments. Proliferating endothelial cells from the tumour, even if qualitatively different from those of blood vessels in the normal tissue of origin, remain putatively normal and genetically stable cells. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses (a tenth to a third of the maximum tolerated dose), known as 'metronomic' chemotherapy, increases the antiangiogenic activity of the drugs. The effects of these metronomic schedules of cytotoxic agents may be further enhanced by concurrent administration of novel, selective, treatments that inhibit, at a molecular level, the processes of tumour formation and growth eg angiogenesis, growth factor pathways, and other signal transduction cascades. The need to treat patients for long periods also supports the use of metronomic scheduling for chemotherapy, to minimise toxicity and to target both proliferating tumour cells and endothelial cells. This review describes the experimental studies involving metronomic schedules of chemotherapy, alone and in combination with angiogenesis inhibitors, and suggests a new therapeutic anticancer paradigm for controlling cancer by long-term therapy, based on the development of combinations of metronomic cytotoxic agents with individually tailored compounds designed to target specific molecules.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Endothelium, Vascular; Forecasting; Humans; Neoplasms; Time Factors
PubMed: 11902515
DOI: 10.1016/S1470-2045(01)00587-3 -
Cancer Investigation 2006Pediatric cancer has a better outcome profile than adult cancers. However, refractory disease and the potential for long-term morbidity resulting from the use of... (Review)
Review
Pediatric cancer has a better outcome profile than adult cancers. However, refractory disease and the potential for long-term morbidity resulting from the use of conventional therapies necessitate the development of novel treatments for this population. Recent advances in oncology include the use of low dose metronomic (LDM) chemotherapy. The promise of this novel therapeutic approach includes reduced toxicity and the potential for efficacy predominantly through an antiangiogenic effect. The clinical benefit may be realized especially when combined with other antiangiogenic agents and/or conventional maximally tolerated doses of chemotherapy. In this article, we review the evidence for the use of LDM chemotherapy with a focus on pediatric cancer. Included are some of the possible risks attributable to this therapy in a pediatric setting and some of the hurdles to overcome in order to conduct good clinical research. Emphasis is placed on the development of proper surrogate markers to monitor antiangiogenic therapy in order to both optimize the dosing schedule for LDM chemotherapy and to provide a way of tracking therapeutic efficacy.
Topics: Adult; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomarkers, Tumor; Child; Drug Administration Schedule; Humans; Maximum Tolerated Dose; Neoplasms; Neovascularization, Pathologic
PubMed: 16777697
DOI: 10.1080/07357900600705599 -
Cancer Chemotherapy and Pharmacology Oct 2016A metronomic schedule of chemotherapy (resulting in a greater frequency of drug delivery) has shown efficacy in head and neck cancer. Our aim was to investigate the...
PURPOSE
A metronomic schedule of chemotherapy (resulting in a greater frequency of drug delivery) has shown efficacy in head and neck cancer. Our aim was to investigate the overall survival in tongue cancer patients with metronomic neoadjuvant chemotherapy with bleomycin compared to those with surgery alone.
METHODS
In this retrospective study, 117 patients with stages I-II tongue cancer, who had undergone surgery, were divided into the "surgery group" or "metronomic neoadjuvant chemotherapy with bleomycin (15 mg × 6) group." The rate of overall survival was the primary outcome measure; the secondary outcome measures included the rates of distant metastasis, regional recurrence, and local recurrence.
RESULTS
Of these patients, 54 underwent surgery alone and 63 received neoadjuvant chemotherapy. Neoadjuvant chemotherapy increased overall survival (76 vs. 90 %, P = 0.039). The neoadjuvant chemotherapy group had a significantly lower rates of distant metastasis (0 vs. 13 %, P = 0.003). There was no chemotherapy-related death.
CONCLUSIONS
Metronomic neoadjuvant chemotherapy decreased the rates of distant metastasis and increased the overall survival of tongue tumor patients.
Topics: Administration, Metronomic; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Bleomycin; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Survival Analysis; Tongue Neoplasms; Young Adult
PubMed: 27577260
DOI: 10.1007/s00280-016-3141-4 -
Esophagus : Official Journal of the... Oct 2022Improving outcomes in locally advanced esophageal/GEJ squamous cell cancer (SCC) is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Improving outcomes in locally advanced esophageal/GEJ squamous cell cancer (SCC) is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC) following definitive chemoradiotherapy (CRT).
MATERIALS AND METHODS
This was a randomized open-label integrated phase II/III study in patients with SCC of esophagus/GEJ following definitive CRT who had no radiologic evidence of progression, and no endoscopically detected disease. Randomization was 1:1 to OMC (celecoxib 200 mg twice daily and methotrexate 15 mg/m weekly) for 12 months or observation. The primary endpoint for the phase II portion was progression-free survival (PFS); secondary endpoints were overall survival (OS) and toxicity. P ≤ 0.2 for PFS was required to proceed to phase III.
RESULTS
Between Jan 2016 and Dec 2019, we enrolled 151 patients for the phase II portion, 75 to OMC and 76 to observation. The tumor originated in the upper thoracic esophagus in 79% patients. Concurrent CRT consisted of median 63 Gy in a median of 35 fractions; concurrent chemotherapy was weekly paclitaxel + carboplatin in 91%. OMC was started at a median of 2.6 months (IQR 2.3-2.8) from CRT completion. Grade 3 or higher toxicities occurred in 18 patients (24%) in the OMC arm and 9 (12%) in the observation arm; P = 0.071. Median PFS was 25 months (95% CI, 17-58) in the OMC arm and was not attained [NA] (95% CI, 25-NA) in the observation arm; HR, 1.51, 95% CI, 1-2; P = 0.073. Median OS was 36 months (95% CI, 23-NA) in the OMC arm, and not attained (95% CI, NA-NA) in the observation arm; HR, 1.77; 95% CI, 1-2.9; P = 0.023.
CONCLUSION
Oral metronomic methotrexate and celecoxib in patients who have not progressed radiologically and have no endoscopic evidence of disease following radical CRT for locally advanced esophageal/GEJ SCC does not improve outcomes and may lower survival. [Funded by the TMC-Research Administration Council (TRAC); CHROME study (CHemoRadiotherapy followed by Oral Metronomic therapy in Esophageal cancer); ctri.nic.in number: CTRI/2015/09/006204].
TRIAL REGISTRATION NUMBER
CTRI/2015/09/006204.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Celecoxib; Chemoradiotherapy; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Methotrexate
PubMed: 35614161
DOI: 10.1007/s10388-022-00923-8 -
Clinical and Molecular Hepatology Jun 2017
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Phenylurea Compounds
PubMed: 28669140
DOI: 10.3350/cmh.2017.0107 -
JAMA Oncology Dec 2023Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
IMPORTANCE
Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
OBJECTIVE
To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).
DESIGN, SETTING, AND PARTICIPANTS
This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021.
INTERVENTIONS
Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine.
MAIN OUTCOMES AND MEASURES
The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety.
RESULTS
Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia.
CONCLUSIONS AND RELEVANCE
This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01356290.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Female; Medulloblastoma; Etoposide; Quality of Life; Administration, Metronomic; Brain Neoplasms; Cerebellar Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37883081
DOI: 10.1001/jamaoncol.2023.4437 -
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