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Frontiers in Immunology 2023Neuroblastoma (NB) is a childhood tumor that originates in the peripheral sympathetic nervous system and is responsible for 15% of cancer-related deaths in the pediatric... (Review)
Review
Neuroblastoma (NB) is a childhood tumor that originates in the peripheral sympathetic nervous system and is responsible for 15% of cancer-related deaths in the pediatric population. Despite intensive multimodal treatment, many patients with high-risk NB relapse and develop a therapy-resistant tumor. One of the phenomena related to therapeutic resistance is intratumor heterogeneity resulting from the adaptation of tumor cells in response to different selective environmental pressures. The transcriptional and epigenetic profiling of NB tissue has recently revealed the existence of two distinct cellular identities in the NB, termed adrenergic (ADRN) and mesenchymal (MES), which can spontaneously interconvert through epigenetic regulation. This phenomenon, known as tumor plasticity, has a major impact on cancer pathogenesis. The aim of this review is to describe the peculiarities of these two cell states, and how their plasticity affects the response to current therapeutic treatments, with special focus on the immunogenic potential of MES cells. Furthermore, we will discuss the opportunity to combine immunotherapy with chemotherapy to counteract NB phenotypic interconversion.
Topics: Child; Humans; Epigenesis, Genetic; Neoplasm Recurrence, Local; Neuroblastoma; Immunotherapy
PubMed: 37849756
DOI: 10.3389/fimmu.2023.1268645 -
Cancer Research Communications Nov 2022The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current...
UNLABELLED
The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making. We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 "Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer." The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value. The variant allele frequency (VAF) of and mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS. Comparison via concordance index demonstrated or VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach.
SIGNIFICANCE
We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.
Topics: Humans; Irinotecan; Cisplatin; Deoxycytidine; Cell-Free Nucleic Acids; CA-19-9 Antigen; Pilot Projects; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Capecitabine
PubMed: 36970054
DOI: 10.1158/2767-9764.CRC-22-0343 -
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 -
The Lancet Regional Health. Southeast... May 2023Locally advanced head and neck cancers treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to...
BACKGROUND
Locally advanced head and neck cancers treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. Limited evidence suggests that it may do so in an adjuvant setting. Hence this randomized study was conducted.
METHODS
Patients of head and neck (HN) cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were randomized 1:1 to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Trial registration- Clinical Trials Registry- India (CTRI): CTRI/2016/09/007315 [Registered on: 28/09/2016] Trial Registered Prospectively.
FINDINGS
137 patients were recruited and an interim analysis was done. The 3 year PFS was 68.7% (95% CI 55.1-79.0) versus 60.8% (95% CI 47.9-71.4) in the observation and metronomic arm respectively (P value = 0.230). The hazard ratio was 1.42 (95% CI 0.80-2.51; P value = 0.231). The 3 year OS was 79.4% (95% CI 66.3-87.9) versus 62.4% (95% CI 49.5-72.8) in the observation and metronomic arm respectively (P value = 0.047). The hazard ratio was 1.83 (95% CI 1.0-3.36; P value = 0.051).
INTERPRETATION
In this phase 3 randomized study, oral metronomic combinations of weekly methotrexate and daily celecoxib failed to improve the PFS or OS. Hence observation post-complete response post radical chemoradiation remains the standard of care.
FUNDING
ICON funded this study.
PubMed: 37384061
DOI: 10.1016/j.lansea.2023.100162 -
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 -
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 -
Frontiers in Veterinary Science 2022The aim of this study was to evaluate the efficacy of metronomic chemotherapy in the palliative treatment of various malignant oral tumors in dogs. Our focus was to...
The aim of this study was to evaluate the efficacy of metronomic chemotherapy in the palliative treatment of various malignant oral tumors in dogs. Our focus was to determine the effect of treatment on local disease control and to assess the tolerability and safety of the treatment in dogs with various oral malignancies. Metronomic chemotherapy with cyclophosphamide was used to treat 12 dogs and was combined with non-steroidal anti-inflammatory drugs in 6/12 (50%) of dogs. A clinical benefit was observed in 6/12 (50%) patients 1 month and in 4/12 (33%) 3 months after treatment initiation. The median survival time of the dogs was 155 days (range 21-529 days). At the end of the observation period, the disease had progressed in 10/12 (83.3%) of the patients. Sterile hemorrhagic cystitis was the most commonly reported side effect of treatment, occurring in 4/12 (33.3%) dogs. The results of our study suggest that metronomic chemotherapy with cyclophosphamide can be, in a subset of dogs, beneficial in the palliation of malignant oral tumors.
PubMed: 35433894
DOI: 10.3389/fvets.2022.856399 -
Cancer Letters Jun 2024Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting... (Review)
Review
Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.
Topics: Humans; Administration, Metronomic; Hematologic Neoplasms; Antineoplastic Agents; Animals; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38636896
DOI: 10.1016/j.canlet.2024.216900 -
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 -
Cancer Letters Nov 2023Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration.... (Review)
Review
Metronomic chemotherapy, dampening of immunosuppressive cells, antigen presenting cell activation, and T cells. A quartet against refractoriness and resistance to checkpoint inhibitors.
Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration. Preclinical and clinical studies summarized and discussed in the present review have demonstrated that maximum tolerable dosage (MTD) vs low-dosage, continuous (metronomic) administration of most chemotherapeutics have polarized effects on immune cells. In particular, metronomic schedules might be associated - among others effects - with activation of antigen presenting cells and generation of new T cell clones to enhance the activity of several types of immunotherapies. Ongoing and planned clinical trials in different types of cancer will confirm or dismiss this hypothesis and provide candidate biomarker data for the selection of patients who are likely to benefit from these combinatorial strategies.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; T-Lymphocytes; Neoplasms; Administration, Metronomic; Antigen-Presenting Cells
PubMed: 37806515
DOI: 10.1016/j.canlet.2023.216441