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Tumori Oct 2023Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic...
BACKGROUND
Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic advanced or progressive forms is recommended. Following promising results in adult patients, oral vinorelbine is investigated in young patients.
METHODS
A retrospective review of young patients (<25 years old) with advanced or progressive desmoid type fibromatosis treated with oral vinorelbine in eight large centers of the Société Française des Cancers de l'Enfant was performed. In addition to tumor assessment according to RECIST 1.1, pre-treatment and during-treatment imagery were reviewed centrally to assess tumor volume and estimate fibrosis score through the change in percentage in hypoT2 signal intensity.
RESULTS
From 2005 to 2020, 24 patients (median age 13.9 years [range, 1.0-23.0]) received oral vinorelbine. Median number of prior systemic lines of treatment was 1 (range, 0-2), mainly based on intravenous low dose methotrexate and vinblastine. Before vinorelbine initiation, all patients had a progressive disease: radiological for 19, radiological and clinical (pain) for three and only clinical for two. Oral vinorelbine was delivered for a median duration of 12 months (range, 1-42). The toxicity profile was favorable, with no grade 3-4 event. Overall response estimated on 23 evaluable patients according to RECIST 1.1 criteria was three partial responses (13%), 18 stabilization (78%) and two progressive disease (9%). Overall progression-free survival was 89.3% (95% confidential intervals 75.2-100) at 24 months. Four stable tumors according to standard RECIST criteria displayed a partial response with > 65% tumor volume reduction. Among 21 informative patients, the estimated fibrosis score decreased for 15 patients, was stable for four patients and increased for two patients.
CONCLUSION
Oral vinorelbine seems to be effective to control advanced or progressive desmoid type fibromatosis in young patients, with a well-tolerated profile. These results support testing this drug as first-line alone or in combination to improve response rate while preserving quality of life.
Topics: Adult; Child; Adolescent; Humans; Vinorelbine; Fibromatosis, Aggressive; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Vinblastine; Fibrosis; Treatment Outcome
PubMed: 37114926
DOI: 10.1177/03008916231169806 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2022Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies... (Review)
Review
Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies of most chemotherapeutics are lacking for the HD patient, and the small amount of evidence available comes mostly from case reports and small case series. In this review, we provide recommendations based on treatment experience of cHL patients on HD in the literature. HD patients undergoing chemotherapy are at risk of overdose and toxicities because many drugs are significantly eliminated by the kidneys, and at the same time, are at risk of undertreatment because many drugs are removed by HD. Therefore, dose modifications and timing of drug administration in relation to HD sessions must be carefully planned according to the distinct traits of each chemotherapeutic. We carried out an exhaustive literature review of reports of actual administrations of chemotherapeutics to cHL on HD, and also extrapolated data from reports of the same chemotherapeutics that were administered to HD patients with malignancies other than cHL. We summarized the information found in the literature, and provide practical and balanced recommendations concerning dose modifications and optimal timing of drug administration in relation to HD sessions for each chemotherapeutic. Chemotherapy regimens and individual chemotherapeutics studied in this review include ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), BEACOPP (bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisolone), MOPP (mechlorethamine + vincristine + procarbazine + prednisolone), gemcitabine, vinorelbine, brentuximab vedotin, and PD-1 inhibitors (nivolumab and pembrolizumab).
Topics: Humans; Hodgkin Disease; Vinblastine; Vincristine; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Brentuximab Vedotin; Mechlorethamine; Procarbazine; Vinorelbine; Nivolumab; Immune Checkpoint Inhibitors; Bleomycin; Dacarbazine; Doxorubicin; Cyclophosphamide; Prednisolone; Renal Dialysis
PubMed: 35948477
DOI: 10.1016/j.clml.2022.07.008 -
Journal of Neurochemistry Jan 2016Polysialic acid (PSA), a large, linear glycan composed of 8 to over 100 α2,8-linked sialic acid residues, modulates development of the nervous system by enhancing cell...
Polysialic acid (PSA), a large, linear glycan composed of 8 to over 100 α2,8-linked sialic acid residues, modulates development of the nervous system by enhancing cell migration, axon pathfinding, and synaptic targeting and by regulating differentiation of progenitor cells. PSA also functions in developing and adult immune systems and is a signature of many cancers. In this study we identified vinorelbine, a semi-synthetic third generation vinca alkaloid, and epirubicin, an anthracycline and 4'-epimer of doxorubicin, as PSA mimetics. Similar to PSA, vinorelbine and epirubicin bind to the PSA-specific monoclonal antibody 735 and compete with the bacterial analog of PSA, colominic acid in binding to monoclonal antibody 735. Vinorelbine and epirubicin stimulate neurite outgrowth of cerebellar neurons via the neural cell adhesion molecule, via myristoylated alanine-rich C kinase substrate, and via fibroblast growth factor receptor, signaling through Erk pathways. Furthermore, the two compounds enhance process formation of Schwann cells and migration of cerebellar neurons in culture, and reduce migration of astrocytes after injury. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds vinorelbine and epirubicin, thus raising the possibility to re-target drugs used in treatment of cancers to nervous system repair. Vinorelbine and epirubicin, identified as PSA mimetics, enhance, like PSA, neuronal migration, neuritogenesis, and formation of Schwann cell processes, and reduce astrocytic migration. Ablating NCAM, inhibiting fibroblast growth factor (FGFR) receptor, or adding the effector domain of myristoylated alanine-rich C kinase substrate (MARCKS) minimize the vinorelbine and epirubicin effects, indicating that they are true PSA mimetics triggering PSA-mediated functions.
Topics: Animals; Cell Movement; Cells, Cultured; Epirubicin; Female; Male; Mice, Inbred C57BL; Mice, Knockout; Neuroglia; Neurons; Protein Structure, Tertiary; Sialic Acids; Vinblastine; Vinorelbine
PubMed: 26443186
DOI: 10.1111/jnc.13383 -
European Journal of Cancer (Oxford,... May 2019The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic... (Clinical Trial)
Clinical Trial
INTRODUCTION
The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic breast cancer (MBC).
METHODS
This phase III open-label, randomised, parallel-group, multicentre clinical trial enrolled patients with locally recurrent or MBC who had had 2-5 prior chemotherapy regimens, including an anthracycline and taxane) from September 26, 2013, to May 19, 2015. Women were randomised 1:1 to receive eribulin (1.4 mg/m, intravenously, on day 1 and day 8) or vinorelbine (25 mg/m, intravenously, on day 1, day 8 and day 15) every 21 days. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response and overall survival (OS).
RESULTS
Five hundred thirty women were randomised to receive eribulin (n = 264) or vinorelbine (n = 266). Improvement in PFS was observed with eribulin compared with vinorelbine (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.65-0.98, P = 0.036); median PFS was 2.8 months in both treatment arms. The median OS was 13.4 months with eribulin and 12.5 months with vinorelbine (HR: 1.03, 95% CI: 0.80-1.31, P = 0.838). The ORR was 30.7% (95% CI: 25.2%-36.6%) with eribulin and 16.9% (95% CI: 12.6%-22.0%) with vinorelbine (P < 0.001). Treatment-emergent adverse events leading to treatment discontinuation were less frequent with eribulin (7.2%) than with vinorelbine (14.0%).
CONCLUSIONS
Eribulin achieved statistically significantly superior PFS (and response rate) compared with vinorelbine in previously treated women with locally recurrent or MBC. Eribulin appeared to be better tolerated than vinorelbine, with no new safety signals observed.
TRIAL REGISTRATION
National Institutes of Health ClinicalTrials.gov registry, NCT02225470. Registered 05 August 2014- Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02225470?term=NCT02225470&rank=1.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Treatment Outcome; Vinorelbine; Young Adult
PubMed: 30928806
DOI: 10.1016/j.ejca.2019.02.002 -
Anticancer Research Jun 2022Tumor vasculature is an important component of the tumor microenvironment and deeply affects anticancer immune response. Eribulin is a non-taxane inhibitor of the...
BACKGROUND/AIM
Tumor vasculature is an important component of the tumor microenvironment and deeply affects anticancer immune response. Eribulin is a non-taxane inhibitor of the mitotic spindle. However, off-target effects interfering with the tumor vasculature have been reported. The mechanisms responsible of this effect are still unclear.
MATERIALS AND METHODS
We designed an in vitro study to investigate the effect of eribulin, with or without TGF-β, on neo-angiogenesis, and on the expression of the adhesion molecules ICAM-1 and VCAM-1. We also investigated the effects of paclitaxel and vinorelbine under the same experimental conditions.
RESULTS
Eribulin up-regulated the epithelial markers VE-cadherin and CD-31 in HUVEC and inhibited tube formation in HUVEC cells cultured in Matrigel. The drug effectively arrested tube formation even in the presence of TGF-β and counteracted the TGF-β-induced change in cell shape from the endothelial cobblestone-like morphology to an elongated spindle-shaped morphology. We also observed that eribulin was able to upregulate ICAM-1 and to counteract its down-regulation induced by TGF-β.
CONCLUSION
Eribulin exerts different off-label effects: increases vascular remodeling, counteracts the endothelial-to-mesenchymal transition (EndMT) mediated by TGF-β and promotes tumor infiltration by immune cells via increasing the expression of ICAM-1 and transcription of CD31 and VE-cadherin. Moreover, eribulin was able to inhibit vasculature remodeling and the induction of EndMT mediated by TGF-β better than vinorelbine and paclitaxel. The effects observed in this study might have important therapeutic consequence if the drug is combined with immunotherapy.
Topics: Furans; Humans; Intercellular Adhesion Molecule-1; Ketones; Neoplasms; Paclitaxel; Transforming Growth Factor beta; Tumor Microenvironment; Vinorelbine
PubMed: 35641280
DOI: 10.21873/anticanres.15767 -
Future Oncology (London, England) Feb 2016Metronomic chemotherapy (mCT), a frequent administration of low-dose chemotherapy, allows prolonged treatment duration and minimizes the toxicity of standard-dose... (Review)
Review
Metronomic chemotherapy (mCT), a frequent administration of low-dose chemotherapy, allows prolonged treatment duration and minimizes the toxicity of standard-dose chemotherapy. mCT has multiple actions against cancer cells including inhibition of angiogenesis and modulation of the immune system. A number of studies lend support to the clinical efficacy of mCT in advanced breast cancer and non-small-cell lung cancer. However, further evidence is necessary to describe the optimal use of mCT and to identify suitable patients. Oral vinorelbine has emerged as a promising metronomic treatment in patients with metastatic breast cancer and non-small-cell lung cancer and is the only orally available microtubule-targeting agent. This paper reviews current evidence on metronomic oral vinorelbine, discusses its management and defines a suitable patient profile on the basis of a workshop of Italian experts.
Topics: Administration, Metronomic; Administration, Oral; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neoplasm Staging; Vinblastine; Vinorelbine
PubMed: 26584409
DOI: 10.2217/fon.15.306 -
Journal of Molecular Medicine (Berlin,... Apr 2023Neuroblastoma is the most common malignant tumor in childhood, and metastases occur in more than 30% patients. Recurrent metastasis is the main cause of poor prognosis...
Neuroblastoma is the most common malignant tumor in childhood, and metastases occur in more than 30% patients. Recurrent metastasis is the main cause of poor prognosis and high mortality in neuroblastoma. In this regard, there is still a lack of sufficient biomarkers and effective therapies. Therefore, we performed a multi-omics analysis of neuroblastoma patients from Therapeutically Applicable Research To Generate Effective Treatments (TARGET). With clinical relapse site information, tumor samples derived from the primary site were divided into recurrent metastasis and primary tumor groups. The initial gene signature was obtained by comparing RNA-Seq and copy number variation differences. Survival data was used to further filter prognosis-related genes. This 18-gene signature consists of three clusters: tumor suppression, cell proliferation, and immunity. A super enhancer is involved in the enhanced expression of NCAPG in cluster2 together with IRF3. Based on the gene signature expression in primary neuroblastoma, it is possible to predict tumor metastasis before it occurs. According to the anticancer drug dataset of Genomics of Drug Sensitivity in Cancer (GDSC), vinorelbine and docetaxel were predicted to have high sensitivity against recurrent metastatic neuroblastoma. In conclusion, our study offers a novel metastasis biomarker and helps understand the mechanisms of tumor recurrent metastasis. KEY MESSAGES: We identified a novel eighteen-gene signature of recurrent metastasis neuroblastoma and build risk and classification models. We dissected the regulatory role of NCAPG in signatures. We found immune exhaustion and immunosuppression in recurrent metastasis neuroblastoma. Vinorelbine and docetaxel were predicted to have high sensitivity against recurrent metastatic neuroblastoma.
Topics: Humans; Gene Expression Profiling; Docetaxel; Vinorelbine; DNA Copy Number Variations; Neoplasm Recurrence, Local; Neuroblastoma; Chronic Disease
PubMed: 36856811
DOI: 10.1007/s00109-023-02299-3 -
Lung Cancer (Amsterdam, Netherlands) Apr 2023To evaluate the safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage IV non-small-cell lung cancer.
Safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination in stage IV non-small-cell lung cancer: An open-label phase II trial (VinMetAtezo).
OBJECTIVE
To evaluate the safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage IV non-small-cell lung cancer.
METHODS
This was a multicenter, open-label, single-arm Phase II study performed in patients with advanced NSCLC without activating EGFR mutation or ALK rearrangement who progressed after first-line platinum-doublet chemotherapy. Combination treatment was atezolizumab (1200 mg IV day 1, every 3 weeks) and oral vinorelbine (40 mg, 3 times by week). The primary outcome was progression-free survival (PFS) during the 4-month follow-up from the first dose of treatment. Statistical analysis was based on the exact single-stage Phase II design defined by A'Hern. Based on literature data, the Phase III trial threshold was set at 36 successes in 71 patients.
RESULTS
71 patients were analyzed (median age, 64 years; male, 66.2%; ex-smokers/active smokers, 85.9%; ECOG performance status 0-1, 90.2%; non-squamous NSCLC, 83.1%; PD-L1 ≥ 50%, 4.4%). After a median follow-up of 8.1 months from treatment initiation, 4-month PFS rate was 32% (95% CI, 22-44), i.e. 23 successes out 71 patients. OS rate was 73.2% at 4 months and 24.3% at 24 months. Median PFS and OS were 2.2 (95% CI, 1.5-3.0) months and 7.9 (95% CI, 4.8-11.4) months, respectively. Overall response rate and disease control rate at 4 months were 11% (95% CI, 5-21) and 32% (95% CI, 22-44), respectively. No safety signal was evidenced.
CONCLUSION
Metronomic oral vinorelbine-atezolizumab in the second-line setting did not achieve the predefined PFS threshold. No new safety signal was reported for vinorelbine-atezolizumab combination.
Topics: Humans; Male; Middle Aged; Carcinoma, Non-Small-Cell Lung; Vinorelbine; Lung Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36868180
DOI: 10.1016/j.lungcan.2023.02.020 -
Expert Review of Anticancer Therapy Jan 2021Metronomic chemotherapy (MCT) is based on frequent dosing of the drug. . This leads to pharmacologically active but low plasma concentrations that reduce toxicity. MCT... (Review)
Review
INTRODUCTION
Metronomic chemotherapy (MCT) is based on frequent dosing of the drug. . This leads to pharmacologically active but low plasma concentrations that reduce toxicity. MCT seems to work primarily via indirect effects on tumor cells and their microenvironment, rather than direct antitumor effects. Oral vinorelbine is one of the most widely studied MCT approaches in both advanced breast cancer and non-small cell lung cancer.
EXPERT OPINION
MCT with vinorelbine has proven efficacy, tolerability and quality of life benefits both as monotherapy and in combination with other MCTs or targeted agents, in first-line therapy and in previously treated patients. Key populations are emerging who may be particularly well suited to metronomic vinorelbine, including those with indolent disease, older individuals, and those with multiple comorbidities and/or bone metastases. Ongoing trials should help to further delineate these target groups. Additional work is needed to better understand the optimal vinorelbine regimen, particularly when used in combination or in non-Caucasian patients. Markers are also required to help identify individuals who are most likely to respond. Nonetheless, the efficacy and tolerability of MCT, allied to improved patient convenience, reduced need for medical engagement and lower cost, make it an appealing option - particular in resource-constrained healthcare environments.
Topics: Administration, Metronomic; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Quality of Life; Tumor Microenvironment; Vinorelbine
PubMed: 33054438
DOI: 10.1080/14737140.2021.1835478 -
Pharmacological Research Aug 2020Anaplastic thyroid cancer (ATC) is a rare neoplasia with a poor prognosis. Proliferation and apoptosis assays were performed on ATC cell lines (8305C, 8505C) exposed to...
Anaplastic thyroid cancer (ATC) is a rare neoplasia with a poor prognosis. Proliferation and apoptosis assays were performed on ATC cell lines (8305C, 8505C) exposed to vinorelbine, lenvatinib, as well as to concomitant combinations. ABCB1, ABCG2 and CSF-1 mRNA expression was evaluated by real time PCR. The relative levels of pospho Akt were investigated as part of a human phospho-kinase array analysis, and CSF-1 and VEGFR-2 protein levels were measured by ELISA. The intracellular concentration of lenvatinib in ATC cells was measured by combined reversed-phase liquid chromatography-tandem mass spectrometry. An ATC subcutaneous xenograft tumor model in nude mice was treated with vinorelbine, lenvatinib, or vinorelbine plus lenvatinib. After treatment with vinorelbine, lenvatinib, a significant antiproliferative effect in ATC cell lines was observed. The concomitant treatment of vinorelbine and lenvatinib revealed synergism for all the fractions of affected cells. A decrease in ABCB1 expression was reported in both ATC cell lines treated with the lenvatinib plus vinorelbine combination, as was an increase in the intracellular concentration of lenvatinib. The combination caused a decrease in Akt, GSK3α/β, PRAS40 and Src phosphorylation, and in both CSF-1 mRNA and protein levels. In the subcutaneous tumor model, the combination reduced the tumor volume during the treatment period. Our results establish the synergistic ATC antitumor activity of a vinorelbine and lenvatinib combination.
Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Mice, Transgenic; Phenylurea Compounds; Quinolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Vinorelbine
PubMed: 32461187
DOI: 10.1016/j.phrs.2020.104920