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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 -
Child's Nervous System : ChNS :... May 2024Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term...
Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term morbidities, particularly in younger patients. While historically chemotherapy was reserved for cases progressing after radiotherapy, evolving recommendations now advocate for its early use, particularly in younger age groups. The carboplatin and vincristine (CV) combination stands as a standard systemic therapy for PLGG, varying in dosage and administration between North America and Europe. Clinical trials have shown promising response rates, albeit with varying toxicity profiles. Vinblastine has emerged as another effective regimen with minimal toxicity. TPCV, a regimen combining thioguanine, procarbazine, lomustine, and vincristine, was compared to CV in a Children's Oncology Group trial, showing comparable outcomes, but more toxicity. Vinorelbine, temozolomide, and metronomic chemotherapy have also been explored, with varied success rates and toxicity profiles. Around 40-50% of PLGG patients require subsequent chemotherapy lines. Studies have shown varied efficacy in subsequent lines, with NF1 patients generally exhibiting better outcomes. The identification of molecular drivers like BRAF mutations has led to targeted therapies' development, showing promise in specific molecular subgroups. Trials comparing targeted therapy to conventional chemotherapy aim to delineate optimal treatment strategies based on molecular profiles. The landscape of chemotherapy in PLGG is evolving, with a growing focus on molecular subtyping and targeted therapies. Understanding the role of chemotherapy in conjunction with novel treatments is crucial for optimizing outcomes in pediatric patients with low-grade gliomas.
PubMed: 38819670
DOI: 10.1007/s00381-024-06458-w -
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 -
Clinical Breast Cancer Oct 2022The tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including...
INTRODUCTION
The tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including vinorelbine, an older anti-tubulin. Vinorelbine is commonly still used after eribulin, but potentially risks cross-resistance and its efficacy in this setting is unproven.
MATERIALS AND METHODS
A retrospective analysis of all patients who received vinorelbine after prior eribulin (VAE) 2011-2015 and a parallel cohort of consecutive patients who received vinorelbine without prior eribulin (VWE) for previously treated ABC between 2005 and 2011. Patient demographics, histopathological features, treatment duration and responses were recorded. The primary endpoint was progression-free survival from date of first vinorelbine for each cohort. Secondary endpoints included radiological response rate, and overall survival (OS).
RESULTS
Thirty-five VAE and 103 VWE patients were identified, all female, 71.4% and 78.6% were ER positive/HER2 negative, 8.6% and 6.8% HER2 positive, and 20.0% and 14.6% triple negative for VAE and VWE cohorts, respectively. The median number of lines of chemotherapy lines prior to vinorelbine was 4 (range 2-6) and 2 (range 0-4), respectively. Fifteen VAE patients (42.9%) received ≥1 line of chemotherapy between eribulin and vinorelbine. VAE and WWE Patients received a median of 3 cycles of vinorelbine (range 1-9 and 1-12, respectively). The median progression-free survival for VAE patients was 2.1 months and 2.0 months for VWE patients. No VAE patients were progression-free at 24 weeks, compared to 15.5% of VWE patients. Median OS from commencing vinorelbine was 4.3 months for VAE and 6.4 months for VWE patients.
CONCLUSION
Vinorelbine was of limited benefit after prior eribulin in our study, suggesting cross-resistance. Even without prior eribulin, only 15% of patients experienced clinical benefit from vinorelbine monotherapy.
Topics: Antineoplastic Agents; Breast Neoplasms; Female; Furans; Humans; Ketones; Retrospective Studies; Tubulin Modulators; Vinorelbine
PubMed: 35840514
DOI: 10.1016/j.clbc.2022.05.008 -
Musculoskeletal Surgery Mar 2023Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered... (Review)
Review
Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered in cases of disease progression. This systematic review aimed to evaluate the effectiveness and toxicity of each medical treatment by reviewing only the studies that included progressive disease as the inclusion criterion. We searched the EMBASE, PubMed, and CENTRAL databases to identify published studies for progressive DTs. The disease control rates of the medical treatments, such as low-dose chemotherapy with methotrexate plus vinblastine or vinorelbine, imatinib, sorafenib, pazopanib, nilotinib, anlotinib, doxorubicin-based agents, liposomal doxorubicin, hydroxyurea, and oral vinorelbine for progressive DTs were 71-100%, 78-92%, 67-96%, 84%, 88%, 86%, 89-100%, 90-100%, 75%, and 64%, respectively. Low-dose chemotherapy, sorafenib, pazopanib, nilotinib, anlotinib, and liposomal doxorubicin had similar toxicities. Sorafenib and pazopanib were less toxic than imatinib. Doxorubicin-based chemotherapy was associated with the highest toxicity. Hydroxyurea and oral vinorelbine exhibited the lowest toxicity. Stepwise therapy escalation from an initial, less toxic treatment to more toxic agents is recommended for progressive DTs. Sorafenib and pazopanib had limited on-treatment side effects but had the possibility to induce long-term treatment-related side effects. In contrast, low-dose chemotherapy has some on-treatment side effects and is known to have very low long-term toxicity. Thus, for progressive DTs following active surveillance, low-dose chemotherapy is recommended in young patients as long-term side effects are minor, whereas therapies such as sorafenib and pazopanib is recommended for older patients as early side effects are minor.
Topics: Humans; Vinorelbine; Sorafenib; Imatinib Mesylate; Hydroxyurea; Fibromatosis, Aggressive; Watchful Waiting; Methotrexate; Doxorubicin
PubMed: 35150408
DOI: 10.1007/s12306-022-00738-x -
Brain Sciences Oct 2023To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a...
To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy. To determine feasibility and assess toxicity rates, all children underwent clinical and hematological evaluation both during and after the treatment. To assess efficacy, all children performed contrast-enhanced MRI almost quarterly after the end of the treatment. In all children, following any treatment course, neurological improvement (>80%) was associated with a radiological response (41.7-46%). The longest overall survival (24 months) was observed in the child who underwent three courses of radiotherapy, without experiencing significant side effects. Even though it goes beyond the understanding of conventional radiobiology, first and second reirradiation in pediatric patients with progressive DIPG may represent a feasible and safe approach, capable of increasing overall survival and disease-free survival in selected patients and improving their quality of life.
PubMed: 37891817
DOI: 10.3390/brainsci13101449 -
British Journal of Haematology Feb 2024Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA...
Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA (ctDNA) profiling has emerged as a powerful predictive and prognostic tool in several haemopoietic and non-haemopoietic malignancies and may guide rational treatment choices in r/r cHL. To assess the predictive and prognostic value of ctDNA, we performed a retrospective analysis on 55 r/r cHL patients treated with the bendamustine, gemcitabine and vinorelbine (BEGEV) regimen and additionally evaluated the potential utility of integrating ctDNA with interim [ F]-FDG positron emission tomography (iPET). Baseline ctDNA genotyping in r/r cHL mirrored gene mutations and pathways involved in newly diagnosed cHL. We found that baseline ctDNA quantification and serial ctDNA monitoring have prognostic value in r/r cHL receiving salvage chemotherapy. Lastly, integrating ctDNA quantification with iPET evaluation may improve the early identification of patients at high risk of failing standard salvage therapy, who may benefit from an early switch to immunotherapeutic agents. Collectively, our results support the implementation of non-invasive methods to detect minimal residual disease in recurrent cHL and justify its prospective evaluation in appropriately designed clinical trials.
Topics: Humans; Hodgkin Disease; Circulating Tumor DNA; Retrospective Studies; Neoplasm Recurrence, Local; Prognosis; Positron-Emission Tomography; Fluorodeoxyglucose F18; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37853658
DOI: 10.1111/bjh.19162 -
Biomedicine & Pharmacotherapy =... Jun 2023Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary...
Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary to find drugs that could improve immune function and synergistically enhance the anti-tumor effect of vinorelbine. Thymosin is reported to inhibit tumor growth as an immunomodulator. Herein, to study the synergistic anti-cancer and attenuation effects of thymosin on vinorelbine, human lung cancer A549 cells that were labeled with CM-DiI were transplanted into zebrafish to establish the lung cancer xenotransplanted model. After treatment of vinorelbine and different concentrations of thymosin, the fluorescence intensity of CM-DiI-labeled A549 cells and the number of apoptotic muscle cells in the tumor-bearing zebrafish were detected. Besides, effects of thymosin on vinorelbine-reduced macrophages and T cells were identified in the transgenic zebrafish (Tg:zlyz-EGFP and Tg:rag2-DsRed). Then, the qRT-PCR was used to determine the alterations of the immune-related factors at the transcription level. Thymosin showed a marked synergistic anti-cancer effect with vinorelbine for the xenograft human lung cancer A549 cells, and the synergistic effect enhanced in a dose-dependent manner. Moreover, thymosin alleviated vinorelbine-induced muscle cell apoptosis, macrophage reduction, and T cell suppression. Compared with the vinorelbine group, co-administration with thymosin raised the mRNA levels of TNF-α, TNF-β, INF-γ, and GM-CSF. Thus, thymosin possesses synergistic anti-cancer effect on vinorelbine, and has protective effect on vinorelbine-induced immunosuppression. Thymosin, as an adjuvant immunomodulatory therapy, has great potential in enhancing the clinical application of vinorelbine.
Topics: Animals; Humans; Vinorelbine; Zebrafish; Thymosin; Cell Line, Tumor; Lung Neoplasms
PubMed: 37018994
DOI: 10.1016/j.biopha.2023.114633 -
Biomedicine & Pharmacotherapy =... Feb 2021Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients...
Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutation. However, some lung cancer patients fail to respond and eventually develop drug resistance. Therefore, new therapeutic strategies are needed to improve the outcomes for substantial clinical benefit. Here we aimed to explore the combination of vinorelbine with the second EGFR-TKI afatinib in NSCLC cells with or without EGFR mutation. The three cells of H1975, HCC827, and H460 were assessed for the combination of vinorelbine and afatinib. Vinorelbine combined with afatinib synergistically inhibited the three lung cancer cells growth without aggravating adverse effect on the normal lung cells. The combination of low doses of vinorelbine and afatinib suppressed the cancer cell proliferation by cell colony formation assay and significantly induced cell apoptosis. The anti-apoptotic proteins Bcl-xL and Bcl-2 showed significant reduction after the drug combination treatment, while the pro-apoptotic protein Bax as well as apoptosis indicators cytochrome C and cleaved PARP were observed a notable increasing. EGFR downstream pathways including AKT, ERK, JNK, and p38 were highly active and p53 was inactive in the three lung cancer cells, favoring tumor growth. The low doses of vinorelbine plus afatinib blocked the phosphorylation of AKT, ERK, JNK, and p38, but restored the expression of p53. Our findings suggested that the combination of vinorelbine and afatinib could be recommended as a therapeutic regimen for treatment of NSCLC with or without EGFR mutation.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Vinorelbine
PubMed: 33360044
DOI: 10.1016/j.biopha.2020.111144