Did you mean: 'metronomic chemotherapy'
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JAMA Oncology Jan 2021Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable...
Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial.
IMPORTANCE
Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.
OBJECTIVE
To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.
INTERVENTIONS
Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.
MAIN OUTCOMES AND MEASURES
Primary outcomes were objective response rate (ORR) and progression-free survival (PFS).
RESULTS
Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).
CONCLUSIONS AND RELEVANCE
In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02853318.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cohort Studies; Cyclophosphamide; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Quality of Life; United States
PubMed: 33211063
DOI: 10.1001/jamaoncol.2020.5945 -
Journal of Clinical Oncology : Official... Mar 2020Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes.
METHODS
Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach.
RESULTS
There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes.
CONCLUSION
Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Breast Neoplasms; Cyclophosphamide; Dietary Supplements; Disease-Free Survival; Doxorubicin; Female; Humans; Middle Aged; Paclitaxel; Proportional Hazards Models; Vitamins
PubMed: 31855498
DOI: 10.1200/JCO.19.01203 -
Cancers May 2021Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs,... (Review)
Review
Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low -and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research.
PubMed: 34066606
DOI: 10.3390/cancers13092236 -
Nature Communications Apr 2023Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to...
Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1's role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Immune Checkpoint Inhibitors; Radioimmunotherapy; Myeloid Cells; Chemokine CXCL16; Tumor Microenvironment; STAT1 Transcription Factor
PubMed: 37055410
DOI: 10.1038/s41467-023-37727-y -
Annals of Oncology : Official Journal... Feb 2019Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved... (Review)
Review
BACKGROUND
Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors.
PATIENTS AND METHODS
This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy.
RESULTS
Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms.
CONCLUSION
Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Drug Therapy, Combination; Humans; Immunotherapy; Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 30608567
DOI: 10.1093/annonc/mdy551 -
Mathematical Biosciences and... Feb 2017This volume was inspired by the topics presented at the international conference "Micro and Macro Systems in Life Sciences" which was held on Jun 8-12, 2015 in Będlewo,...
This volume was inspired by the topics presented at the international conference "Micro and Macro Systems in Life Sciences" which was held on Jun 8-12, 2015 in Będlewo, Poland. System biology is an approach which tries to understand how micro systems, at the molecular and cellular levels, affect macro systems such as organs, tissue and populations. Thus it is not surprising that a major theme of this volume evolves around cancer and its treatment. Articles on this topic include models for tumor induced angiogenesis, without and with delays, metastatic niche of the bone marrow, drug resistance and metronomic chemotherapy, and virotherapy of glioma. Methods range from dynamical systems to optimal control. Another well represented topic of this volume is mathematical modeling in epidemiology. Mathematical approaches to modeling and control of more specific diseases like malaria, Ebola or human papillomavirus are discussed as well as a more general approaches to the SEIR, and even more general class of models in epidemiology, by using the tools of optimal control and optimization. The volume also brings up challenges in mathematical modeling of other diseases such as tuberculosis. Partial differential equations combined with numerical approaches are becoming important tools in modeling not only tumor growth and treatment, but also other diseases, such as fibrosis of the liver, and atherosclerosis and its associated blood flow dynamics, and our volume presents a state of the art approach on these topics. Understanding mathematics behind the cell motion, appearance of the special patterns in various cell populations, and age structured mutations are among topics addressed inour volume. A spatio-temporal models of synthetic genetic oscillators brings the analysis to the gene level which is the focus of much of current biological research. Mathematics can help biologists to explain the collective behavior of bacterial, a topic that is also presented here. Finally some more across the discipline topics are being addresses, which can appear as a challenge in studying problems in systems biology on all, macro, meso and micro levels. They include numerical approaches to stochastic wave equation arising in modeling Brownian motion, discrete velocity models, many particle approximations as well as very important aspect on the connection between discrete measurement and the construction of the models for various phenomena, particularly the one involving delays. With the variety of biological topics and their mathematical approaches we very much hope that the reader of the Mathematical Biosciences and Engineering will find this volume interesting and inspirational for their own research.
Topics: Humans; Models, Theoretical; Neoplasms; Systems Biology
PubMed: 27879115
DOI: 10.3934/mbe.201701i -
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 -
Journal of Clinical Medicine May 2022Despite the significant expansion of the therapeutic armamentarium associated with the introduction of novel endocrine therapies, cytotoxic agents, radiopharmaceuticals,... (Review)
Review
Despite the significant expansion of the therapeutic armamentarium associated with the introduction of novel endocrine therapies, cytotoxic agents, radiopharmaceuticals, and PARP inhibitors, progression of metastatic castration-resistant prostate cancer (mCRPC) beyond treatment options remains the leading cause of death in advanced prostate cancer patients. Metronomic chemotherapy (MC) is an old concept of wise utilization of cytotoxic agents administered continuously and at low doses. The metronomic is unique due to its multidimensional mechanisms of action involving: (i) inhibition of cancer cell proliferation, (ii) inhibition of angiogenesis, (iii) mitigation of tumor-related immunosuppression, (iv) impairment of cancer stem cell functions, and (v) modulation of tumor and host microbiome. MC has been extensively studied in advanced prostate cancer before the advent of novel therapies, and its actual activity in contemporary, heavily pretreated mCRPC patients is unknown. We have conducted a prospective analysis of consecutive cases of mCRPC patients who failed all available standard therapies to find the optimal MC regimen for phase II studies. The metronomic combination of weekly paclitaxel 60 mg/m i.v. with capecitabine 1500 mg/d p.o. and cyclophosphamide 50 mg/d p.o. was selected as the preferred regimen for a planned phase II study in heavily pretreated mCRPC patients.
PubMed: 35628979
DOI: 10.3390/jcm11102853 -
Journal For Immunotherapy of Cancer Jan 2021Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged...
BACKGROUND
Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored.
METHODS
Colon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or mice bred into PARP-1 or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon cancer, respectively. Syngeneic MC-38 cell-based (microsatellite instability, MSI) or CT-26 cell-based (microsatellite stable, MSS) tumor models were used to assess the effects of PARP inhibition on host responses and synergy with anti-Programmed cell Death protein (PD)-1 immunotherapy.
RESULTS
Partial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/ -mediated intestinal tumorigenesis and -associated cachexia, while extensive inhibition, via gene knockout or a high dose of olaparib, was ineffective or aggravating. A sub-IC50-olaparib dose or PARP-1 heterozygosity was sufficient to block tumorigenesis in a syngeneic colon cancer model by modulating the suppressive function, but not intratumoral migration or differentiation, of MDSCs, with concomitant increases in intratumoral T cell function and cytotoxicity, as assessed by granzyme-B/interferon-γ levels. Adoptive transfer of WT-BM-MDSCs abolished the protective effects of PARP-1 heterozygosity. The mechanism of MDSC modulation involved a reduction in arginase-1/inducible nitric oxide synthase/cyclo-oxygenase-2, but independent of PARP-1 trapping on chromatin. Although a high-concentration olaparib or the high-trapping PARP inhibitor, talazoparib, activated stimulator of interferon gene (STING) in BRCA-proficient cells and induced DNA damage, sub-IC50 concentrations of either drug failed to induce activation of the dsDNA break sensor. STING expression appeared dispensable for MDSC suppressive function and was not strictly required for olaparib-mediated effects. Ironically, STING activation blocked human and mouse MDSC function with no additive effects with olaparib. A metronomic dose of olaparib was highly synergistic with anti-PD-1-based immunotherapy, leading to eradication of MSI or reduction of MSS tumors in mice.
CONCLUSIONS
These results support a paradigm-shifting concept that expands the utility of PARP inhibitor and encourage testing metronomic dosing of PARP inhibitor to enhance the efficacy of checkpoint inhibitor-based immunotherapies in cancer.
Topics: Administration, Metronomic; Animals; Azoxymethane; Cell Line, Tumor; Colitis; Colonic Neoplasms; Dextran Sulfate; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Mice; Myeloid-Derived Suppressor Cells; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Xenograft Model Antitumor Assays
PubMed: 33495297
DOI: 10.1136/jitc-2020-001643 -
Oncology Research and Treatment 2022As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional... (Review)
Review
BACKGROUND
As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional chemotherapy (CCT) and targeted therapies.
SUMMARY
MCT, defined as continuous administration of low-dose chemotherapeutic agents, is accepted as a therapy that exerts its effects via immunomodulation, anti-angiogenesis and direct cytotoxic effects. Oral administration of MCT is safe, easy to handle, and allows for flexible drug dosing. Dose accumulations associated with non-tolerable side effects are rare, so the medication can be administered for longer periods of time. Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic disease resistant to endocrine-based therapy and not requiring rapid tumor response are generally suitable for MCT. However, MCT may also be promising in patients with triple-negative and HER2-positive tumors without aggressive disease who prefer a lower toxicity profile compared to CCT. The most commonly used agents are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE), and vinorelbine (VRL), whereby a combination of agents is frequently applied. Key Messages: Based on the growing body of evidence, MCT can be considered as a suitable treatment option in selected MBC patients. Nevertheless, there is an urgent need for randomized controlled trials comparing MCT with CCT, but also with best supportive care. Due to the multimodal mechanisms of action, the combination with targeted and immunological therapies may represent a new promising approach for the treatment of MBC.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Female; Humans; Quality of Life; Receptor, ErbB-2
PubMed: 34794154
DOI: 10.1159/000520236