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Background: Vinca alkaloids are widely used in cancer treatment for their ability to target microtubule dynamics. While their efficacy in treating certain cancers is well-established, the full spectrum of their adverse event profiles remains an area of ongoing research., Methods: We analyzed AEs related to vinorelbine and vincristine using a retrospective case/non-case approach with data from the FDA Adverse Event Reporting System (FAERS). We applied various algorithms to detect AE signals: the reporting odds ratio (ROR) and proportional reporting ratio (PRR) measured disproportionality and association strength; the Bayesian confidence propagation neural network (BCPNN) calculated the Information Component (IC) for associations against background rates; and the multi-item gamma Poisson shrinker (MGPS) yielded empirical Bayes geometric mean (EBGM) values, accounting for reporting variability., Results: Both medications significantly involve the blood and lymphatic systems, with vinorelbine reporting 401 cases in this System Organ Class (SOC), exhibiting a ROR of 17.4, PRR of 12.4, IC of 3.63, and EBGM of 12.38. An intersection analysis of Preferred Terms (PTs) has uncovered previously unreported AEs shared by both drugs, including posterior reversible encephalopathy syndrome and inappropriate antidiuretic hormone secretion., Conclusions: This analysis highlights the need for ongoing research of the risks associated with vinorelbine and vincristine.

Adjuvant chemotherapy is underutilized in clinical practice, in part, because its anticipated survival benefit is limited. We evaluated the impact of AC on overall and recurrence-free survival among completely resected pN1 NSCLC patients enrolled in the North American Intergroup phase III (JBR10) trial. A post-hoc subgroup analysis of pN1 NSCLC patients was performed. Participants were randomized to cisplatin+vinorelbine (AC) (n = 118) or observation (n = 116) following complete resection. The primary endpoint was overall survival (OS). The secondary endpoint was recurrence free survival (RFS). Kaplan-Meier methods were used to compare OS and RFS between the two treatment groups. Cox regression was used to identify factors associated with OS and RFS endpoints. Both groups had similar baseline characteristics. AC patients had improved 5-year OS (AC 61.4% vs observation 41.0%, log-rank p = .008) and 5-year RFS (AC 56.2% vs observation 39.9%, log-rank p = .011) rates compared to observation. Cox regression analyses confirmed the OS (HR 0.583, 95% CI 0.402-0.846, p = .005) and RFS (HR 0.573, 95% CI 0.395-0.830, p = .003) benefit associated with AC. AC was associated with a lower risk (HR 0.648, 95% CI 0.435-0.965, p = .0326) and a lower cumulative incidence (Subdistribution Hazard Ratio [SHR], 0.67, 95% CI 0.449-0.999, p = .0498) of lung cancer deaths. In the JBR10 trial, treatment with AC conferred a significant OS and RFS advantage over observation for pN1 NSCLC patients. These data suggest that pN1 NSCLC patients may experience a disproportionately greater clinical benefit from AC than the 6% survival advantage estimated by the LACE meta-analysis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet., Objectives: Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms., Methods: Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion., Results: The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis., Conclusion: This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Importance: In spite of the effectiveness of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the first-line treatment for estrogen receptor (ER)-positive, erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2/neu])-negative (ER+/ERBB2-) metastatic breast cancer (MBC), patients eventually develop resistance, and eventually most will receive chemotherapy. The METEORA-II trial compared a metronomic all-oral treatment with intravenous (IV) chemotherapy., Objective: To compare the efficacy of the oral vinorelbine plus cyclophosphamide plus capecitabine (VEX) regimen vs weekly IV paclitaxel among patients with ER+/ERBB2- MBC who are candidates for chemotherapy., Design, Setting, and Participants: This phase 2 randomized clinical trial including 140 women 18 years and older (randomized 1:1) with ER+/ERBB2- MBC was carried out from September 13, 2017, to January 14, 2021 at 15 centers in Italy. Eligible patients could have received 1 prior line of chemotherapy for MBC and/or 2 lines of endocrine therapy (including CDK4/6 inhibitors)., Interventions: In 4-week cycles, patients received either metronomic oral VEX or weekly IV paclitaxel., Main Outcomes and Measures: The primary end point was investigator-assessed time to treatment failure (TTF) defined as the interval between the date of randomization to the end of treatment (because of disease progression or lack of tolerability or because further trial treatment was declined). Secondary end points included progression-free survival (PFS), overall survival (OS), and disease control rate (complete or partial response or stable disease lasting for at least 24 weeks)., Results: In total, 133 patients received either VEX (n = 70) or paclitaxel (n = 63) in 4-weekly cycles. The median age was 61 (range, 30-80) years. The VEX treatment significantly prolonged TTF vs paclitaxel (hazard ratio [HR], 0.61; 95% CI, 0.42-0.88; P = .008), median TTF was 8.3 (95% CI, 5.6-11.1) months for VEX vs 5.7 (95% CI, 4.1-6.1) months for paclitaxel, and the 12-month TTF was 34.3% for VEX vs 8.6% for paclitaxel. The median PFS was 11.1 (95% CI, 8.3-13.8) months vs 6.9 (95% CI, 5.4-10.1) months favoring VEX (HR, 0.67; 95% CI, 0.46-0.96, P = .03). The 12-month PFS was 43.5% for VEX vs 21.9% for paclitaxel. No difference in OS was found. The TF event for 55.6% of patients was progression of disease; for 23% it was AEs. More patients assigned to VEX had at least 1 grade 3 or 4 targeted adverse event (VEX, 42.9%; 95% CI, 31.1%-55.3% vs paclitaxel, 28.6%; 95% CI, 17.9%-41.3%), but essentially no alopecia., Conclusion and Relevance: This randomized clinical trial found significantly prolonged TTF and PFS for oral VEX but no improvement in OS compared with intravenous paclitaxel, despite increased but still manageable toxic effects. The VEX regimen may provide more prolonged disease control than weekly paclitaxel for ER+/ERBB2- MBC., Trial Registration: ClinicalTrials.gov Identifier: NCT02954055.

Background: This study evaluated the efficacy and safety between 8 spheres plus bronchial arterial infusion (BAI) cisplatin and intravenous vinorelbine plus cisplatin as third-line treatments in locally advanced non-small cell lung cancer (NSCLC) patients. Materials and Methods: Totally, 56 locally advanced NSCLC patients with second-line chemotherapy failure were recruited. Then, 28 patients received 8 spheres plus BAI cisplatin treatment, and another 28 patients received intravenous vinorelbine plus cisplatin treatment. Results: In general, 8 spheres plus BAI cisplatin increased objective response rate (57.2% vs. 17.8%, p  = 0.002) and disease control rate (78.6% vs. 42.8%, p  = 0.003) compared with intravenous vinorelbine plus cisplatin; meanwhile, it also elevated quality of life (QOL) score (46.7 ± 7.1 vs. 41.5 ± 5.2, p  = 0.003) compared with intravenous vinorelbine plus cisplatin. Furthermore, 8 spheres plus BAI cisplatin prolonged progression-free survival (PFS) (median [95% confidence interval, CI]: 7.9 [6.3-9.5] months vs. 4.3 [3.5-5.1] months, p  < 0.001) and overall survival (OS) (median [95% CI]: 14.6 [11.0-18.2] months vs. 10.5 [10.2-10.8] months, p  = 0.029) compared with intravenous vinorelbine plus cisplatin, which was further supported by multivariate Cox's regression analysis (PFS: p  < 0.001; OS: p  = 0.007). In addition, subgroup analyses revealed that 8 spheres plus BAI cisplatin markedly elevated treatment response, QOL, and survival compared with intravenous vinorelbine plus cisplatin in squamous cell carcinoma patients, but not in adenomatous carcinoma and adenosquamous carcinoma patients. Regarding safety, 8 spheres plus BAI cisplatin exhibited lower rates of gastrointestinal tract complication ( p  < 0.001) and myelosuppression ( p  < 0.001) than intravenous vinorelbine plus cisplatin. Conclusions: 8 spheres plus BAI cisplatin displays good efficacy and well-tolerated safety profiles in locally advanced NSCLC patients with second-line chemotherapy failure.

Introduction: An increasing body of evidence from clinical trials and real-world studies suggests that metronomic oral vinorelbine (VNR) is a promising treatment option for elderly and unfit advanced non-small cell lung cancer (NSCLC) patients. The aim of this multicenter study was to present real-world data about the experience in treatment of NSCLC with metronomic VNR in Portugal., Material and Methods: Retrospective data from NSCLC patients not eligible for conventional chemotherapy or tyrosine kinase inhibitors who received oral metronomic VNR irrespective of treatment line and dose was retrieved from 19 Portuguese Oncology Centers between 2016 and 2018., Results: A total of 293 patients were included, with a median of 76 (39 - 94) years; 71% were ≥70 years old. Patients had a median of 3 comorbidities and predominantly (61%) ECOG PS 2. Most (42%) received metronomic oral VNR as first-line treatment. Overall response rate was 18%, with 42 (18%) partial and no (0%) complete responses. A total of 54% of patients experienced stable disease and 28% of patients, disease progression. Disease control rate was 72%. Patients were a median of 4 (1 - 40) months on treatment. Treatment discontinuation was observed in 90%, mostly (67%) due to disease progression, followed by death (16%). Adverse events leading to treatment discontinuation were only reported in 5% of patients. Female gender (HR 0.601, 95% CI 0.434 - 0.832; p = 0.002) and ECOG PS 1 (HR 0.625, 95% CI [0.443 - 0.881]; p = 0.007) were significantly associated with a lower risk of metronomic oral VNR discontinuation. Overall, 21% of patients experienced G3/4 toxicity., Conclusion: The present real-world results agree with what has been previously reported by other international Centers and support the concept that metronomic scheduling is a relevant and safe approach to treat advanced NSCLC patients., (Copyright © 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: A phase Ia/Ib trial of metronomic oral vinorelbine (MOV) driven by a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Disease Control Rate, progression free survival, toxicity and PK/PD were the main endpoints., Methods: Best MOV scheduling was selected using a simplified phenomenological, semi-mechanistic model with a total weekly dose of 150-mg vinorelbine. Computation of individual PK parameters was performed using population approach., Results: The mathematical model proposed the following metronomic schedule for a 150-mg weekly dose of vinorelbine: 60 mg D1, 30 mg D2, 60 mg D4. A total of 37 heavily pre-treated patients (30 evaluable) were enrolled. Grade III/IV neutropenia was observed in 30% patients. Median PFS was 11 weeks. Disease Control Rate was 73% (i.e.; 13% partial response and 60% stable disease). A large variability in drug exposure (AUC 0-24 h : 53%) and PK parameters (Cl: 83%) were observed among patients. Simulated trough levels after D2 and D4 showed similarly 56-73% variability among patients. Drug exposure was not associated with efficacy, but neutropenia was more frequent in patients with AUC > 250 ng/ml.h. Tumor burden, performance status and neutrophils-to-lymphocyte ratio (NLR) were associated with PFS, suggesting that MOV would be indicated in selected patients. We built a composite score to predict efficacy, mixing baseline tumor size and NLR showing 84% selectivity and 75% specificity., Conclusions: MOV was characterized by important variability in drug exposure among patients. However, and despite being all heavily pre-treated, 73% of disease control rate and 11 weeks PFS were achieved with manageable toxicities. PK/PD relationships yielded conflicting results depending on the initial tumor burden and BSA, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker suggests immunomodulating features with MOV., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab., Methods: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m 2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed., Findings: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia)., Interpretation: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma., Funding: Bayer Healthcare Pharmaceuticals., Competing Interests: Declarations of interests HLK reports grants paid to the University of Chicago to support clinical trials for Aduro, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Harpoon, Inhibrx, MacroGenics, Merck, Polaris, Seattle Genetics, and Vivace; consulting fees from Bristol Myers Squibb, Deciphera, Inventiva, Novocure, and Seattle Genetics; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events for AstraZeneca; support for attending meetings, travel, or both from AstraZeneca and Inventiva; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Inventiva, and Seattle Genetics; and leadership or fiduciary role on board of directors for the International Mesothelioma Interest Group. SN reports personal payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Pfizer, Pharmamar, Roche, and Takeda; and personal fees for participation on a data safety monitoring board or advisory board from AstraZeneca, Bayer, Daiichi Sanko, Eli Lilly, Pfizer, Roche, Sanofi, and Takeda. AB reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Eli-Lilly, Pfizer, Roche, and Takeda; and support for attending meetings, travel, or both for Boehringer Ingelheim, Merck Sharp and Dohme, and Roche. GLC reports personal consulting fees for their advisory role for Novocure and Zai Lab; personal speaker engagements for Astellas, AstraZeneca, Merck Sharp and Dohme, Novocure, and Zai Lab; and support for attending meetings, travel, or both for Astellas, Novocure, and Merck Sharp and Dohme. JGJVA reports consulting fees for the advisory boards for Amphera, Bayer, Bristol Myers Squibb, Eli-Lilly, and Merck Sharp and Dohme; patents issued on allogenic tumour cell lysate and on combination immuno-oncology, owned by Erasmus MC Cancer Centre; participation on a data safety monitoring board or advisory board for Biocad; unpaid leadership role for the International Association for the Study of Lung Cancer; and stock or stock options for Amphera. JSp reports clinical trial reimbursement to Guy's & St Thomas’ NHS Foundation Trust from Bayer, BergenBio, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, IO Biotech, Lytix, Seattle Genetics, and Starpharma; consulting fees paid to King's College London from Apobec, AVACTA, Bristol Myers Squibb, IO Biotech, and Seattle Genetics; support for attending meetings, travel, or both from Amgen and Janssen; participation on a data safety monitoring board or advisory board for AstraZeneca and Merck; and stock or stock options (co-founder) for Epsilogen. PT reports fees for a symposium presentation from AstraZeneca; and a conference registration fee from AstraZeneca. KN reports personal fees for advisory boards from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Belgium, and Roche Belgium; personal fees for lectures from Roche Belgium; and support for attending meetings, travel, or both from AstraZeneca, Merck Sharpe and Dohme, and Pfizer. AG reports payment to Newcastle upon Tyne Hospitals NHS Foundation Trust for the care of patients on a study from Bayer (support for this manuscript). JAB reports institutional payment to the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital for support of investigator-initiated study from Merck Sharp and Dohme, consulting fees paid to the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital from Bristol Myers Squibb, and payment to the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital for participation on a data safety monitoring board or advisory board for Roche. AS reports consulting fees from ArQule and Sanofi; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Abbvie, Amgen, ArQule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Eli-Lilly, Gilead, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda; and participation on a data safety monitoring board or advisory board for Bayer, Bristol Myers Squibb, Eisai, Gilead, Merck Sharp and Dohme, Pfizer, and Servier. SC reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Merck Sharp and Dohme Oncology, and Pfizer; and support for attending meetings, travel, or both from Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Merck Sharp and Dohme Oncology, and Pfizer. JPVM reports consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Pfizer, and Roche; payment and reimbursement of expenses for services and consultancy from Amgen; registration fees from AstraZeneca, Merck Sharp and Dohme Belgium, Bristol Myers Squibb, GlaxoSmithKline, and Roche; and travel and accommodation support from AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme Belgium, and Roche. AKN reports personal fees for consulting for clinical trials, quality of life research, and tumour measurement from Bayer (support for this manuscript); grants or contracts to institution from AstraZeneca and Douglas Pharmaceuticals; consulting fees from Atara Biotherapeutics (personal), Pharmabcine (institutional), and Seagen (personal); personal payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Bristol Myers Squibb; travel support from AstraZeneca; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb (personal). GBJ reports personal grants or contracts from Adaptimmune, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Elelixis, Genentech, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, MedImmune, Merck, Novartis, Regeneron, Repertoire Immune Medicines, Roche, Tmunity Therapeutics, Torque, Verastem, and Xcovery; personal consulting fees for AbbVie, Adicet, Amgen, Ariad, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, Genentech, Gilead, Instil Bio, Janssen, Lilly, Maverick Therapeutics, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Viogin Biotech, and Xcovery; participation on a data safety monitoring board or advisory board for Maverick Therapeutics and Virogin Biotech (personal); and stock or stock options for Virogin Biotech. GBJ also has an immediate family member employed by Johnson and Johnson and Janssen. JSi is an employee of Bayer Healthcare Pharmaceuticals with ownership of stock; and reports unpaid leadership roles for the American Statistical Association, International Society for Clinical Biostatistics, and the Pharmaceutical Industry Working Group on Estimands in Oncology. LK is an external employee of Bayer Healthcare Pharmaceuticals. KK is an employee of Bayer AG Pharma with ownership of stock. AOW is an employee of Bayer AG Pharma. BHC and CE are employees of Bayer Healthcare Pharmaceuticals. RH reports institutional support for the conduct of this study via a Cooperative Research and Development Agreement (CRADA) between Bayer and the Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. He also has a CRADA with TCR(2) for conduct of clinical studies unrelated to this manuscript. DAF reports grants from Astex Therapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp and Dohme; personal fees from Aldeyra, Atara, Bristol Myers Squibb, Inventiva, Lab21, Roche, RS Oncology, and Targovax; and non-financial support from Bristol Myers Squibb, Clovis, Eli-Lilly, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study reports the treatment feasibility and efficacy of a novel multiagent intensive treatment program for young patients with desmoplastic small round cell tumor. This small series includes three patients and should be seen as a first suggestion of integration of the dose density and the maintenance chemotherapy concept. The IrIVA regimen (irinotecan, ifosfamide, vincristine, and actinomycin-D) is added-used at a short interval between chemotherapy administrations-at more classic intensive ifosfamide-based regimens. The vinorelbine and low-dose oral cyclophosphamide maintenance therapy is added at the end of conventional chemotherapy to achieve an antiangiogenic effect.

Purpose: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation., Patients and Methods: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m 2 on day 1) plus vinorelbine (25 mg/m 2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS)., Results: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively., Conclusion: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial., Competing Interests: Hirohito TadaHonoraria: Chugai Pharma Tetsuya MitsudomiHonoraria: AstraZeneca, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Taiho Pharmaceutical, Lilly, Novartis, MSD K.K., Kyowa Hakko Kirin, Amgen, Daiichi-Sankyo, Guardant Health, Ethicon, Thermofisher Scientific Biomarkers, Merck KGaA, Janssen Oncology, TakedaConsulting or Advisory Role: AstraZeneca, Pfizer, Boehringer Ingelheim, Chugai Pharma, Ono Pharmaceutical, MSD Oncology, Lilly, Novartis, Amgen, Daiichi Sankyo, Thermo Fisher ScientificResearch Funding: Boehringer Ingelheim (Inst), AstraZeneca (Inst), Pfizer (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Sanofi/Aventis (Inst), Daiichi Sankyo (Inst), MSD K.K. (Inst), Kyowa Hakko Kirin (Inst) Toshihiro MisumiSpeakers' Bureau: Chugai Pharma, AstraZeneca Kenji SugioHonoraria: AstraZeneca, Chugai PharmaResearch Funding: Covidien Japan, Lilly Japan Masahiro TsuboiHonoraria: AstraZeneca Japan, Chugai Pharma, Taiho Pharmaceutical, Teijin Pharma, Johnson & Johnson, Novartis, MSD K.K., Ono Pharmaceutical, Bristol Myers Squibb Japan, MedtronicResearch Funding: Boehringer Ingelheim (Inst), Merck (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai/Roche (Inst) Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Kyowa Kirin Shinji AtagiHonoraria: Chugai Pharma, MSD K.K., Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Lilly Japan, Pfizer, Bristol Myers Squibb Japan, Hisamitsu Pharmaceutical, Kyowa Hakko Kirin, Merck, Novartis, Thermo Fisher ScientificResearch Funding: MSD K.K. (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Lilly Japan (Inst), Pfizer (Inst), Bristol Myers Squibb Japan (Inst), Roche (Inst), Merck (Inst) Toshiaki TakahashiHonoraria: AstraZeneca KK, Chugai Pharma, Lilly Japan, Ono Pharmaceutical, MSD K.K., Pfizer, Boehringer Ingelheim, Roche, Takeda Pharmaceutical Co Ltd, Yakult HonshaResearch Funding: AstraZeneca KK (Inst), Lilly Japan (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), MSD K.K. (Inst), Pfizer (Inst), Amgen (Inst), Boehringer Ingelheim (Inst) Hidetoshi HayashiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, MSD, Novartis, Merck SeronoConsulting or Advisory Role: Lilly, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Pfizer, Merck Serono, Shanghai HaiHe Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca, AbbVie (Inst), AC Medical (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Lilly Japan (Inst), EPS Associates Co, Ltd (Inst), GlaxoSmithKline (Inst), Japan Clinical Research Operations (Inst), Kyowa Hakko Kirin (Inst), Merck Serono (Inst), Novartis (Inst), Otsuka (Inst), Parexel (Inst), Pfizer (Inst), PPD-SNBL (Inst), Quintiles Inc (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Yakult Honsha (Inst)Patents, Royalties, Other Intellectual Property: Sysmex Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (Inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Hiroshige YoshiokaHonoraria: Lilly, Chugai Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Novartis, Kyowa Kirin Co, Ltd, Daiichi Sankyo, Nippon Kayaku, Delta-Fly Pharma, PfizerConsulting or Advisory Role: Delta-Fly Pharma Kazuhisa TakahashiSpeakers' Bureau: AstraZeneca Ichiro YoshinoHonoraria: Johnson & Johnson, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Shionogi, Astra Zeneca, Intuitive Surgical, Daiichi Sankyo, Boehringer Ingelheim, Covidien/MedtronicConsulting or Advisory Role: Astra Zeneca, Intuitive Surgical, Covidien/MedtronicResearch Funding: Chugai Pharma (Inst), Taiho Pharmaceutical (Inst), Pfizer (Inst), Shionogi (Inst) Kazuhiko NakagawaHonoraria: AstraZeneca KK, Ono Pharmaceutical, Chugai Pharma, Nippon Boehringer Ingelheim, Lilly, Pfizer, Bristol Myers Squibb, Novartis, CareNet, Taiho Pharmaceutical, Yodosha, Nikkei Business Publications, Inc, Kyorin, Takeda, Medical Review Co, Ltd, MSD K.K., AbbVie, Merck, Roche Diagnostics, Bayer Yakuhin, Nippon Kayaku, Amgen, Kyowa Kirin Co, Ltd, Medical Mobile Communications Co, Ltd, 3H Clinical Trial, Astellas Pharma, Yomiuri Telecasting Corporation, Medicus Shuppan, publishers Co, Ltd, Thermo Fisher Scientific, Hisamitsu Pharmaceutical Co, Inc, Nichi-iko, Nanzando Co, Ltd, Daiichi Sankyo Co, LtdConsulting or Advisory Role: Pfizer, Kyorin Pharmaceutical Co, Ltd, Lilly Japan, Ono Pharmaceutical, Astellas Pharma, TakedaResearch Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Pfizer (Inst), Takeda (Inst), Nippon Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Lilly (Inst), Parexel International Corp. (Inst), A2 Healthcare (Inst), Novartis (Inst), IQvia (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca KK (Inst), Kissei Pharmaceutical (Inst), EPS Holdings (Inst), Bayer Yakuhin (Inst), MSD K.K. (Inst), Pfizer (Inst), Otsuka (Inst), Syneos Health (Inst), EPS International (Inst), PRA Health Sciences (Inst), PPD-SNBL (Inst), Covance (Inst), GlaxoSmithKline K.K. (Inst), Sysmex (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Japan Clinical Research Operations (Inst), Sanofi (Inst), Medical Research Support (Inst), ICON (Inst), CMIC (Inst), Kyowa Kirin Co, Ltd (Inst)No other potential conflicts of interest were reported.

Purpose: We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550)., Methods: Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m 2 IV, days 1 and 8), vinorelbine (20 mg/m 2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m 2 , days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT., Results: Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months)., Conclusion: Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT., Competing Interests: Alison J. MoskowitzHonoraria: Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, Takeda, Imbrium Therapeutics, Merck, Janpix, Kyowa Kirin International, miRagen, ADC Therapeutics, Bristol Myers SquibbResearch Funding: Incyte, Seattle Genetics, Merck, Bristol Myers Squibb, miRagen, ADC Therapeutics, BeiGene Gunjan ShahResearch Funding: Janssen, Amgen Anita KumarStock and Other Ownership Interests: BridgebioConsulting or Advisory Role: Celgene, Kite, a Gilead company, AstraZeneca/MedImmuneResearch Funding: AbbVie/Genentech, Adaptive Biotechnologies, Celgene, Seattle Genetics, AstraZeneca/MedImmune, Pharmacyclics Oscar LahoudConsulting or Advisory Role: MorphoSysTravel, Accommodations, Expenses: MorphoSysOpen Payments Link: https://openpaymentsdata.cms.gov/physician/225358/summary Connie L. BatleviStock and Other Ownership Interests: Moderna Therapeutics, Novavax, Pfizer, Bristol Myers Squibb, Regeneron, ViatrisHonoraria: DAVAOncologyConsulting or Advisory Role: Lifesci Capital, GLG, Juno Therapeutics, Celgene, Seattle Genetics, Kite, a Gilead company, TG Therapeutics, Karyopharm TherapeuticsResearch Funding: Janssen Biotech, Novartis, Epizyme, Xynomic Pharma, Bayer, Roche, AutolusOpen Payments Link: https://openpaymentsdata.cms.gov/physician/2778694 Paul HamlinConsulting or Advisory Role: Juno Therapeutics, Karyopharm Therapeutics, Celgene, Sandoz, AstraZeneca/MerckResearch Funding: Spectrum Pharmaceuticals, Seattle Genetics, Janssen, Portola Pharmaceuticals, GlaxoSmithKline, Molecular Templates, Incyte David J. StrausConsulting or Advisory Role: Takeda, Seagen, EpizymeResearch Funding: Takeda Ildefonso Rodriguez-RiveraStock and Other Ownership Interests: Pfizer Philip CaronStock and Other Ownership Interests: AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson/Janssen, Novartis, Pfizer, Teva Steven M. HorwitzConsulting or Advisory Role: Celgene, Millennium, Kyowa Hakko Kirin, Seattle Genetics, ADC Therapeutics, Verastem, Takeda, Astex Pharmaceuticals, Kura Oncology, Acrotech Biopharma, C4 Therapeutics, Janssen Oncology, Trillium Therapeutics, Vividion Therapeutics, Myeloid Therapeutics, Ono Pharmaceutical, Secura Bio, Shoreline Biosciences Inc, TubulisResearch Funding: Celgene, Seattle Genetics, Takeda, Kyowa Hakko Kirin, Aileron Therapeutics, ADC Therapeutics, Verastem, 47, Trillium Therapeutics, Daiichi Sankyo, Affimed Therapeutics, Secura Bio Lorenzo FalchiConsulting or Advisory Role: GenmabResearch Funding: Roche, Genmab Erel JoffeConsulting or Advisory Role: AstraZeneca, Epizyme Christina LeeHonoraria: WebMDConsulting or Advisory Role: Intellisphere LLC M. Lia PalombaStock and Other Ownership Interests: Seres TherapeuticsHonoraria: Flagship Biosciences, Evelo Therapeutics, Jazz Pharmaceuticals, Therakos, Amgen, Merck, Seres TherapeuticsConsulting or Advisory Role: Flagship Biosciences, Novartis, Evelo Therapeutics, Jazz Pharmaceuticals, Therakos, Amgen, Merck, Seres Therapeutics, Kite, a Gilead company, Novartis, BeiGeneResearch Funding: Seres TherapeuticsPatents, Royalties, Other Intellectual Property: Intellectual Property Rights, Juno intellectual property rights Ariela NoyConsulting or Advisory Role: MorphoSys, Janssen Biotech, Prime OncologyResearch Funding: Pharmacyclics, Rafael PharmaceuticalsTravel, Accommodations, Expenses: Pharmacyclics, Janssen Oncology Matthew J. MatasarStock and Other Ownership Interests: MerckHonoraria: Genentech, Roche, Bayer, Pharmacyclics, Seattle Genetics, Takeda, Immunovaccine, ADC Therapeutics, Karyopharm TherapeuticsConsulting or Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, TakedaResearch Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, Immunovaccine, IGM BiosciencesTravel, Accommodations, Expenses: Genentech, Roche, Seattle Genetics, Bayer Georgios PongasHonoraria: Atara Biotherapeutics, Curio Science, OncLive/MJH Life SciencesTravel, Accommodations, Expenses: Atara Biotherapeutics Gilles SallesHonoraria: Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSysConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, BMS, BeiGene, Incyte, Miltenyi Biotec, Ipsen Santosha VardhanaHonoraria: AgiosConsulting or Advisory Role: Immunai, ADC Therapeutics Gottfried von KeudelllHonoraria: PharmacyclicsConsulting or Advisory Role: Pharmacyclics, Merck, Incyte Ahmet DoganConsulting or Advisory Role: Seattle Genetics, Takeda, EUSA Pharma, AbbVie, Peerview, Physicans' Education ResourceResearch Funding: Roche/Genentech Andrew D. ZelenetzHonoraria: NCCN, Clinical Care Options, Oncology Information Group, PER, PlexusConsulting or Advisory Role: Gilead Sciences, Amgen, Genentech/Roche, Celgene, AstraZeneca, DAVAOncology, MorphoSys, BeiGene, MEI Pharma, Vaniam Group, Verastem, Pharmacyclics, Karyopharm Therapeutics, Debiopharm Group, Seattle Genetics, Quant Health Ltd, Kite, a Gilead company, Curis, Coherus Biosciences, Juno/Celgene/Bristol Myers Squibb, Curio ScienceResearch Funding: Genentech/Roche, Gilead Sciences, MEI Pharma, BeiGene Craig H. MoskowitzConsulting or Advisory Role: Merck Sharp & Dohme, Molecular Templates, Takeda, AstraZeneca, IncyteResearch Funding: AstraZeneca, Merck Sharp & DohmeNo other potential conflicts of interest were reported.

The aim of our study was to investigate the effects of metronomic vinorelbine (mVNR) in a tumor model of Lewis Lung (LL) cancer in immunocompetent C57BL/6 mice, looking at the plasma levels of interleukin-2 (IL-2) and interleukin-8 (IL-8). mVNR caused a concentration-dependent antiproliferative effect in vitro on LL/2 cells. The in vivo experiment showed the significant antitumor effects of mVNR at the dose of 4 mg/Kg and 5 mg/Kg, 3 times/week, and the significant dose-dependent decrease of IL-2 concentrations in plasma samples. Conversely, such an effect was not observed for IL-8. A significant decrease in microvessel density was also found at both the active mVNR doses. In conclusion, our study confirmed the activity of mVNR in an immunocompetent model of lung carcinoma and suggest multiple mechanisms of action, including the modulation of IL-2 levels.

Background: The current standard postoperative treatment for stage II-IIIA non-small cell lung cancer (NSCLC) is a regimen of platinum doublet adjuvant chemotherapy. These regimens, which are the same as for solid NSCLC tumors, often cause severe adverse reactions in the treated patients. Therefore, an effective treatment regimen with fewer side effects is needed., Methods/design: The purpose of this study is to evaluate the effectiveness and safety of S-1 monotherapy (80 mg/m 2 orally administrated twice daily, at day 1-14, 16 cycles) and cisplatin with vinorelbine combination therapy (cisplatin 80 mg/m 2 at day 1,vinorelbine 25 mg/m 2 at day 1, 8, 4 cycles) in patients with II/IIIA stage non-small-cell lung cancer who underwent a total resection. In addition, we will also evaluate the level of treatment side effects by assessing quality of life (QOL), work productivity and activity performance. The primary endpoint is a 2-year relapse free survival (RFS) and the second primary endpoints are 2-year overall survival (OS), rate of treatment completion, safety, work productivity and activity, and quality of adjusted life years (QALY). At the same time, we aim to obtain precise information required to perform future phase 3 randomized controlled trials. The study is designed to estimate the primary endpoint with accuracy determined as the width of its 95% confidence interval to be less than 20%. Recruitment started in May 2017 and is ongoing., Discussion: This study has been conceived to establish a superior regimen for completely resected NSCLC based on efficacy, safety and QOL., Trial Registration: Registry number: UMIN000027435 . Registered May 22, 2017.

Aim: This study aimed to compare the incidence of infusion site reactions (ISRs) induced by intravenous administration of brand-name and generic vinorelbine (VNR) for treating non-small cell lung cancer., Method: This single-centre retrospective cohort study was conducted by medical chart review of VNR infusions. ISRs were defined as symptoms around the infusion site, including pain, redness and swelling. ISRs requiring treatment were defined as ISRs requiring treatments including steroid ointments, vein repuncture and local steroid injections., Results: In all, 1973 VNR infusions were administered to 340 patients (brand-name 141 patients, generic 199 patients). ISRs and ISRs requiring treatment were observed in 161 and 100 patients, respectively. The ISR incidence per patient and per injection was significantly higher in generic VNR-treated patients than in brand-name VNR-treated patients (53.3% vs 39.0%, P = 0.0112 and 15.0% vs 9.9%, P = 0.0008, respectively). The frequency of ISRs requiring treatment was also significantly higher in the generic group (per patient 36.7% vs 19.2%, P = 0.0005; per injection 11.3% vs 5.5%, P < 0.0001). Multivariate analysis revealed that generic VNR was significantly associated with an increased risk of ISRs (per patient adjusted odds ratio [AOR] 1.775, P = 0.0155; per injection AOR 1.672, P = 0.004) and ISRs requiring treatment (per patient AOR 2.422, P = 0.0012; per injection AOR 2.286, P = 0.001)., Conclusion: Intravenous infusion of generic VNR was associated with an increased risk of ISRs. Further research is needed to elucidate the mechanism underlying the increased incidence of ISRs with generic VNR., (© 2020 The British Pharmacological Society.)

Purpose: ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor ( EGFR ) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results., Methods: From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and EGFR -activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data., Results: Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% ( P = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP ( P = .316) and 5y DFS rates were 22. 6% and 23.2% ( P = .928), respectively., Conclusion: Adjuvant therapy with gefitinib in patients with early-stage NSCLC and EGFR mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.

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.

Purpose: Peripheral T cell lymphomas (PTCLs) have an overall poor prognosis. Indeed, registry data in elderly patients show that the median progression-free survival (mPFS) following first- and second-line therapies are only 6.7 and 3.1 months, respectively. The aim of the study is to show the activity of metronomic chemotherapy, a regular administration of low chemotherapeutic drug doses allowing a favourable toxicity profile, on elderly PTCL patients., Methods: We report a series of 17 PTCL patients, treated with the all-oral metronomic schedule DEVEC (prednisolone-etoposide-vinorelbine-cyclophosphamide) in four Italian centres. Patients 5/17 (29.4%) were treatment-naïve (naïve) and 12/17 (70.6%) were relapsed-refractory (RR), respectively. The median age was 83 years (range 71-87) and 71.5 years (range 56-85) for naïve and RR, respectively. In vitro activity of metronomic vinorelbine (VNR), etoposide (ETO) and their concomitant combination on HH, a PTCL cell line, was also assessed., Results: Histology: PTCL-not-otherwise-specified = 12; angioimmunoblastic = 2; NK/T nasal type = 1; adult-type leukaemia lymphoma = 1, transformed Mycosis Fungoides = 1. The overall response rate was 80 and 58% in naïve and RR, respectively; whereas the PFS was 20 in naïve (95% CI 0-43) and 11 months (95% CI 4.2-17.8) in RR. The occurrence of relevant adverse events was 23.5%, which was managed with ETO dose reduction. In vitro experiments showed that both metronomic VNR and ETO caused a significant inhibitory activity on HH cells and a strong synergism when administered concomitantly., Conclusion: All-oral DEVEC showed an encouraging activity and acceptable toxicity. This schedule deserves further studies in elderly PTCL also for assessing combinations with targeted drugs.

Purpose: Patients with relapsed/refractory primary mediastinal B-cell lymphoma (rrPMBCL) represent a particularly challenging population to treat, with few life-saving treatment options in the context of a dismal prognosis., Patients and Methods: In this open-label, single-arm, phase II study, the safety and efficacy of combined regimen of chemotherapy consisting of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) plus anti-PD-1 antibody camrelizumab was assessed in rrPMBCL. Patients received chemo-immunotherapy every 3 weeks until the second confirmed complete response (CR) or up to 12 cycles, followed by camrelizumab monotherapy for up to 1 year. The primary endpoints were objective response rate (ORR) and safety., Results: Twenty-seven response evaluable patients were enrolled, who received a median of three first-line therapies, 59% with bulky disease. The ORR was 74%, including 56% with a CR. A median time of 1.7 months to response was observed, with 78% exhibiting tumor shrinkage at the first evaluation. After 24.8 months median follow-up, the median duration of response was not reached, with a 65% 2-year estimated response rate. Thirteen responders remained in sustained complete remission. Estimated 24-month progression-free survival and overall survival rates were 48.2% and 81.5%, respectively. Any grade and grade 3 treatment-related adverse events (AE) occurred in 93% and 33% of patients, respectively; with no grade 4 or 5 AEs. Baseline levels of IL10, IFNγ, and soluble Fas were associated with objective response., Conclusions: Camrelizumab plus GVD chemotherapy offers a potent option as life-saving chemo-immunotherapy with promising efficacy and a manageable safety profile for patients with rrPMBCL, especially with bulky aggressive disease., (©2020 American Association for Cancer Research.)

Purpose: To evaluate the efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with stage IIIB/IV and advanced non-small cell lung cancer (NSCLC)., Methods: The PubMed, Embase, Cochrane library, Wanfang, and CNKI databases were searched for relevant studies. The overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of severe adverse events (grade ≥ 3 adverse events; grade 3/4 AEs) were calculated using the methods of merging ratios and means. Merged ratios and means and their 95% confidence intervals (CIs) were used to descriptively analyze the efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with stage IIIB/IV and advanced NSCLC., Results: The ORR and DCR achieved with metronomic oral vinorelbine monotherapy were 12% (95% CI 5-20) and 48% (95% CI 38-59), respectively. Median PFS and OS were 3.46 months (95% CI 2.49-4.43) and 8.22 months (95% CI 7.21-9.24), respectively. The incidence of grade 3/4 AEs was 16% (95% CI 10-22). The more common grade 3/4 AEs were neutropenia 9% (95% CI 2-20) and leukopenia 8% (95% CI 1-19)., Conclusion: Metronomic oral vinorelbine monotherapy has a certain effect on patients with stage IIIB/IV and advanced NSCLC, especially for untreated elderly patients. It offers the advantages of convenience, lower cost and acceptable incidence of severe adverse events.

Purpose: Overall prognosis of advanced sarcoma remains poor, optimization of systemic treatment is urgently needed in this setting. Materials and methods: We systematically reviewed fully published English-speaking literature about maintenance therapy and drug holiday in sarcoma patients management. Results: We found that switch maintenance therapy with cyclophosphamide/vinorelbine improves the outcome of localized high-risk rhabdomyosarcoma. There is no other maintenance therapy recommended in sarcoma patients. After classical chemotherapy, maintenance therapy with immune-stimulating agents for localized osteosarcoma, bevacizumab for advanced angiosarcoma or pediatric advanced sarcoma, or mTOR inhibitors for metastatic sarcoma does not improve the outcome. Drug holiday has been assessed for metastatic gastrointestinal stromal tumor treated with imatinib as the first-line therapy or for metastatic soft-tissue sarcoma treated with trabectedin. Drug holiday has been found to lead to rapid disease progression and should be avoided. Conclusions: Data about both maintenance and drug holiday are spare in sarcoma management.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most significant neurologic complications of chemotherapy, impacting patient's behavior and quality of life. CIPN is mostly sensory, with rare incidences of autonomic dysfunction and other neuropathy., Methods: We conducted a single-center sub-group analysis of patients with metastatic breast cancer enrolled in a phase III study (NCT02225470) set up to compare eribulin mesylate (1.4 mg/m 2 on days 1 and 8 every 21 days) with vinorelbine (25 mg/m 2 on days 1, 8, and 15 every 21 days). The analysis investigated incidence of peripheral neuropathy, time to onset of neuropathy, and safety., Results: Our analysis included 110 women with a mean age of 50.7 (SD = 10.9). The median accumulated dose of eribulin was 11.2 mg/m 2 and 125.0 mg/m 2 for vinorelbine. Among patients in the eribulin group, a performance status (ECOG PS) of 2 was correlated with peripheral sensory neuropathy (p = 0.015), and accumulated eribulin dose (≥ 10 mg/m 2 ) was associated with all neuropathy and peripheral sensory neuropathy (p = 0.003 and p = 0.007, respectively). In the vinorelbine group, patient age (≥ 65 years) was positively associated with all neuropathy (p = 0.043). The time to onset of neuropathy appeared to be longer for eribulin versus vinorelbine (35.3 vs. 34.6 weeks; p = 0.046), with a significantly higher incidence of autonomic neuropathy at weeks 2 and 10 observed among patients receiving vinorelbine (p = 0.008 and p = 0.043, respectively)., Conclusion: Vinorelbine is associated with a higher incidence of autonomic neuropathy than eribulin in patients with metastatic breast cancer. Furthermore, the onset of neurotoxicity appears to occur earlier with vinorelbine than eribulin.

The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the role of vinorelbine-based chemotherapy in chemonaive locally advanced unresectable or metastatic NSCLC patients, according to real-world treatment patterns, has still not been widely explored. Eighty-one patients treated at a single institution were retrospectively analyzed. Thirty-seven received standard first-line single-agent vinorelbine, and 44 received vinorelbine plus platinum drugs, based on physician's choice; 61.7% were older than 70 years, and 60.5% were affected by ≥2 comorbidities. Sixty-three patients were evaluable for objective response: 22% achieved partial response and 41% stable disease. Median progression-free survival (PFS) was 5.4 months. A benefit in PFS was observed in patients treated with combinations vs. single-agent vinorelbine (6.7 vs. 3.5 months, p  = 0.043). Median overall survival (OS) was 10.4 months without a statistically significant difference between treatments (12.4 vs. 7.5 months). In 55 stage IV patients, OS was positively correlated with combination regimens, M1a stage, or ≤2 metastatic lesions. Grade 3-4 toxicity occurred in 33% of patients, and dose reduction in 11%. A statistically significant higher incidence of toxicity was observed in patients receiving combinations, in women, in patients younger than 75 years, or patients with metastases. In this real-word analysis, we confirmed the efficacy and tolerability of vinorelbine as a single agent or combined with platinums in patients usually underrepresented in controlled clinical trials. Single-agent vinorelbine may represent a suitable option in elderly or unfit NSCLC patients and warrants investigation as a potential drug candidate for immunochemotherapy combination regimens.

Background: The emergence of new molecular targeted drugs provides new prospects for the treatment of advanced breast cancer; the future therapeutic trend includes chemotherapy combined with molecular targeted therapy. Apatinib mesylate, a novel, small anti-angiogenic agent, highly selectively inhibits the activity of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib mesylate also blocks the signaling of vascular endothelial growth factor binding to its receptor, thereby strongly inhibiting tumor angiogenesis and exerting an anti-tumor effect. However, there have been no reports of a randomized controlled clinical trial of apatinib combined with vinorelbine for the treatment of triple-negative breast cancer (TNBC). We will compare the therapeutic effect of vinorelbine alone or in combination with apatinib mesylate, in patients with recurrent or metastatic TNBC in North China who have received at least two drug treatments, including anthracyclines and taxanes., Methods/analysis: This study is a triple-blind, randomized, placebo-controlled, parallel-group clinical trial. We plan to include 238 female patients with locally recurrent or metastatic TNBC, admitted to the Liaoning Cancer Hospital & Institute, Northeast China. All enrolled patients will be randomized to oral vinorelbine alone (40 mg, thrice a week (Mondays, Wednesdays, and Fridays) in each 3-week cycle), or in combination with oral apatinib mesylate (500 mg, once daily in each 3-week cycle). Radiographic assessment will be performed every 6 weeks for 36 weeks and every 9 weeks thereafter. The primary outcome is progression-free survival and secondary outcomes include overall survival, disease control rate, objective response rate, and incidence of adverse events at grades 3 and 4, as defined by the National Cancer Institute Common Toxicity Criteria Version 4.0. Outcome measures will be evaluated at baseline (< 2 weeks before starting treatment), every 6 weeks during treatment, and at 4 weeks and every 3 months after treatment discontinuation., Discussion: Based on the data from this trial, we hope to identify a treatment plan that is suitable for female patients with TNBC, who have been treated with anthracyclines and taxanes, in Northeast China., Trial Registration: ClinicalTrials.gov: NCT03932526. Registered on 30 April 2019.

Background: Elderly patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, but they are still underrepresented in clinical trials. In particular, data regarding efficacy and safety in frail or elderly patients with respect to immunotherapy are lacking. Importantly, immunosenescence in elderly patients might interfere with activities of immune-modulating drugs such as PD-1/PD-L1 inhibitors. Thus, there is an urgent need to assess safety and efficacy of such inhibitors in this group., Methods/design: This prospective, open label, treatment stratified, randomized phase II study will enroll 200 patients with stage IV NSCLC amenable at least to single-agent chemotherapy (CT). Eligible patients must be aged 70 years or older and/or "frail" (Charlson Comorbidity Index > 1) or have a restricted performance status (Eastern Cooperative Oncology Group, ECOG > 1). Patients are stratified according to modified Cancer and Age Research Group (CARG) score: "fit" patients are allocated to combination CT (carboplatin/nab-paclitaxel) and "less fit" patients receive single-agent CT (gemcitabine or vinorelbine). After allocation to strata, patients are randomized 1:1 to receive either four cycles of CT or two cycles of CT followed by two cycles of durvalumab and subsequent maintenance treatment with durvalumab every 4 weeks. The primary endpoint is the rate of treatment-related grade III/IV adverse events (Common Terminology Criteria for Adverse Events (CTCAE) V4.03). As secondary endpoints, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, response rate (RR), overall survival (OS), descriptive subgroup analyses according to PD-L1 expression, and quality of life are addressed. Geriatric screening assessments and functional tests will be performed to complete the phenotyping of a potential "frail" and "elderly" patient cohort. The trial is accompanied by a biomaterial repository to explore potential biomarkers., Discussion: The DURATION trial will prospectively investigate the safety and tolerability of anti-PD-L1 treatment with durvalumab after chemotherapy in elderly and frail patients and thereby provide new insights into the effect of PD-L1 blockade and the impact of immunosenescence in this cohort of patients., Trial Registration: ClinicalTrials.gov, NCT03345810; initially registered on 17 November 2017. Eudra-CT, 2016-003963-20; initially registered on 3 January 2017.

The Aidi injection contains multiple active ingredients, including astragaloside (Re, Rb1, and Rg1), ginsenoside, cantharidin, elentheroside E, and syringin, and it is administered with vinorelbine and cisplatin (NP) to treat non-small-cell lung carcinoma (NSCLC). In this study, we performed a systematic review and meta-analysis to determine the clinical efficacy and safety of the Aidi injection with NP, and the optimal threshold and treatment regimen to produce the desired responses. We collected all studies regarding the Aidi injection with NP for NSCLC from Chinese and English databases (up to April 2019). Risk of methodological bias was evaluated for each study. Data for analysis were extracted using a standard data extraction form. Evidence quality was assessed following the Grading of Recommendations Assessment, Development and Evaluation approach. We included 54 trials containing 4,053 patients for analysis. Combining the Aidi injection with NP significantly increased the objective response rate (odds ratio [OR], 1.32; confidence interval [CI], 1.23, 1.42), disease control rate (OR, 1.14; CI, 1.11, 1.18), and quality of life (OR, 1.80; CI, 1.61, 1.98), with decreased risks of myelosuppression, neutropenia, thrombocytopenia, anemia, gastrointestinal reaction, and liver dysfunction. For patients with a Karnofsky Performance Status score of ≥60, the Aidi injection (50 mL/day, two weeks/cycle, with two to three cycles) treatment with vinorelbine (25 mg/m 2 ) and cisplatin (30-35 mg/m 2 or 40-50 mg/m 2 ) might be the optimal regimen for producing the desired tumor response and achieving a good safety level. Most results were robust, and their quality was moderate. The results suggest that administration of the Aidi injection and concomitant NP is beneficial to NSCLC, and provide evidence for the optimal threshold and treatment regimen that may improve tumor response with a good safety level., Competing Interests: Declaration of Competing Interest None of the authors of this manuscript have any financial interest related to this meta-analysis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterised by a combination of headache, encephalopathy, seizures and visual disturbances, associated with high-intensity abnormalities on T2-weighted images affecting subcortical white and grey matter of the occipital and parietal lobes. Among other causes, PRES has been associated with the use of several medications including chemotherapeutic agents. Here we report a case of a 65-year-old patient with squamous cell carcinoma of the lung treated with cisplatin/vinorelbine. Following the second administration of vinorelbine, she was admitted to the hospital for a generalised seizure. Blood pressure was just slightly elevated and, except for drowsiness, she had a near-normal neurological examination. MRI corroborated the diagnosis. Vinorelbine-induced PRES has been reported only once in the literature, also in association with cisplatin. Our case underlines the role of vinorelbine and suggests that its association with cisplatin in this setting may enhance the risk of PRES., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC)., Methods: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety., Results: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C., Conclusion: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases., Trial Registration: EudraCT Number: 2013-003894-87; registered 09-September-2013.

Background: For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma., Methods: RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m 2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m 2 , on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing., Findings: Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved., Interpretation: Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials., Funding: Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed., Methods: Postmenopausal women with untreated stage I-III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures., Results: Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1-2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (- 73.2%) was superior to both monotherapy arms combined (- 49.9%; p = 0.001) and mVNB (- 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (- 73.2%) was numerically higher compared to LTZ (- 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases., Conclusions: Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted., Trial Registration: NCT02802748 , registered 16 June 2016.

Introduction: Several non-comparative phase II studies have evaluated metronomic oral vinorelbine (MOV) in metastatic non-small cell lung cancer (NSCLC) but the small size of each study limits their conclusions., Purpose: To perform an individual patient-data metaanalysis of studies evaluating MOV in metastatic NSCLC in order to measure survival and safety of treatment with this regimen., Methods: Studies were selected if (1) administration of oral vinorelbine thrice a week; (2) fixed daily dose comprised between 30 and 50 mg, and; (3) being published before October 4th 2018. Database encompassed 8 variables characterizing disease and demography, 3 informing therapy, and 12 describing survival and toxicity., Results: Nine studies encompassing 418 patients fulfilled the selection criteria, 80% of them having frailty characteristics. Median overall survival (OS) was 8.7 months (95%CI: 7.6-9.5). OSrates at 6 months, one year and at two years after starting vinorelbine were 64%, 30.3% and 8.9%, respectively. In the Cox model, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 2, and anemia of any grade were significant determinants of shorter OS. Median progression-free survival(PFS) was 4.2 months (95%CI: 3.9-5). At 6 months and at one-year, PFS rates were 35% and 11.9% respectively. In the Cox model stratified for the variable "study", PS = 2and stage IV were significant determinants of shorter PFS. No toxicity was reported for 40% of patients, and 66 (15.8%) patients experienced a grade 3-4 toxicity. The most frequent toxicity was anemia of any grade (35.8%) that was higher with the 50 mg dosage., Conclusion: MOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients., Competing Interests: This work was supported by a grant from Pierre Fabre Oncology (Boulogne, France). This commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients.

Background: Vinorelbine has demonstrated anticancer activity and is primarily metabolized in the liver. This single-institution, phase I pilot study describes the safety and pharmacokinetics of vinorelbine in patients with varying degrees of hepatic impairment., Materials and Methods: Patients with treatment-refractory solid tumors were enrolled into treatment arms based on vinorelbine dose (weekly infusions of 7.5-30 mg/m 2 ) and liver function (normal liver function, mild, moderate, or severe liver dysfunction). Vinorelbine pharmacokinetics were evaluated to describe its relationship with liver function. Indocyanine green (ICG) clearance was assessed for correlation with pharmacokinetics., Results: Forty-seven patients were enrolled, and a total of 108 grade 3-4 treatment-related adverse events (AEs) occurred. Of these, grade 3-4 myelosuppression was the most common (34.3%). Thirty-three (30.6%), 22 (20.4%), and 9 (8.3%) grade 3-4 AEs were observed in the vinorelbine 20 mg/m 2 /severe, 15 mg/m 2 /moderate, and 7.5 mg/m 2 /severe liver dysfunction groups, respectively, with the majority being nonhematologic toxicities. ICG clearance decreased as liver function worsened. Vinorelbine pharmacokinetics were not correlated with ICG elimination or the degree of liver dysfunction., Conclusion: For patients with severe liver dysfunction (bilirubin >3.0 mg/dL), vinorelbine doses ≥7.5 mg/m 2 are poorly tolerated. The high incidence of grade 3-4 AEs with 15 mg/m 2 vinorelbine in moderate liver dysfunction (bilirubin 1.5-3.0 mg/dL) raises concerns for its safety in this population. Vinorelbine pharmacokinetics are not affected by liver dysfunction; however, levels of the active metabolite 4-O-deacetylvinorelbine were not measured and may be higher in patients with liver dysfunction if its elimination is impacted by liver impairment to a greater degree than the parent drug., Implications for Practice: Vinorelbine remains widely prescribed in advanced malignancies and is under development in immunotherapy combinations. Given vinorelbine is primarily hepatically metabolized, understanding its safety and pharmacokinetics in liver dysfunction remains paramount. In this phase I pilot study, weekly vinorelbine at doses ≥7.5 mg/m 2 is poorly tolerated in those with severe liver dysfunction. Furthermore, a high incidence of grade 3-4 toxicities was observed with vinorelbine at 15 mg/m 2 in those with moderate liver dysfunction. Vinorelbine pharmacokinetics do not appear affected by degree of liver dysfunction. Further evaluation of levels of the free drug and active metabolites in relationship to liver function are warranted., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Purpose: Metastatic breast cancer is regarded as an incurable entity. In heavily pretreated patients with increasingly limited options for palliative management, ensuring proper quality of life continues is to be an elusive issue. With this in mind, the authors evaluated the efficacy and safety of the Vinorelbine/Capecitabine doublet (VINOCAP)., Patients and Methods: The investigators retrospectively analyzed a cohort of 67 women with HER2 negative MBC treated at a large breast cancer practice and a local cancer center with Vinorelbine 22.5 mg/m2 IV on days 1 and 8 combined with Capecitabine 1 g PO BID for 14 consecutive days of 21 day cycles. Patients had been treated with an average of 4 prior lines of chemotherapy. Patient characteristics and outcomes were evaluated., Results: A total of 67 patients received VINOCAP, and an additional 2 underwent repeat exposure yielding a cohort of 69. Clinical benefit rate, defined as complete response (CR), partial response (PR) or stable disease ≥ 6 months (SD), was 55.07%. Complete response was seen in 4.34%, PR in 18.8% and SD ≥ 6 months in 31.9%. Median progression-free survival was 6.2 months and overall survival 35.47 months after VINOCAP exposure. The most common grade 3-4 toxicity was neutropenia in 10% of cases. Dose had to be reduced in 18% of cases due to toxicity of any type. The regimen was well tolerated, and serious side effects were uncommon., Conclusion: Vinorelbine/Capecitabine appears to be an active and well-tolerated regimen in women with MBC. In particular, encouraging was the efficacy of VINOCAP as fourth or greater line of chemotherapy.

Serpentine supravenous hyperpigmentation (SSH) is a unique type of chemotherapy-associated drug eruption, characterized by hyperpigmentation along the superficial venous network. Histopathology reveals an increase in melanin production without destruction of basal cells of the epidermis or dermal inflammatory infiltrate. Herein, we describe a patient who developed SSH after repeated intravenous infusions with carboplatin and vinorelbine; two medications that have been uncommonly reported in association with SSH previously., (© 2019 Wiley Periodicals, Inc.)

The aim of this paper was to evaluate the activity and tolerability of oral vinorelbine in patients with advanced castration resistant prostate cancer (CRPC) who progressed after a minimum of three lines including: abiraterone acetate, docetaxel, cabazitaxel, and enzalutamide.Treatment consisted of weekly oral vinorelbine 60 mg/m. Chemotherapy was administered until disease progression or unacceptable toxicity.Twenty-six patients received vinorelbine: their median age was 74 years (range 58-84 years). Twenty-four (92.3%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in 2 patients (7.7%). Among the subjects who were symptomatic at baseline, pain was reduced in 3 patients (13.6%) with a significant decrease in analgesic use. Median progression-free survival was 9 weeks (95% CI: 7 to 11) and median overall survival was 17 weeks (95% CI: 12 to 22). Treatment was well tolerated, and no grade 4 toxicities were observed.Our findings do not suggest the use of oral vinorelbine on a weekly schedule, in CRPC heavily pre-treated.

Purpose: To evaluate the efficacy and safety of oral weekly vinorelbine 60 mg/m 2 for metastatic breast cancer (MBC) in patients previously treated with anthracyclines or taxanes in routine clinical practice., Materials and Methods: Fifty-five patients were enrolled in a prospective multicentre study conducted in Spain. Women ≥ 18 years of age with locally advanced breast cancer who were not candidates for surgical treatment with a radical intention or patients with stage IV disease, and who had received a prior taxane or anthracycline regimen were eligible for participation., Results: Median age was 67 years. Median progression-free survival was 3.7 months (95% CI 2.5-4.9), median overall survival 10 months (95% CI 6.6-13.5), and overall response rate and clinical benefit rate were 29.1% and 49.1%, respectively. Main grade 3 and 4 toxicities were neutropenia 9.1%, febrile neutropenia 3.6% and constipation 3.6%. In total, 86% of the patients received complete treatment without delays or dose reduction. Moreover, HER2-positive patients who received oral vinorelbine concomitantly with trastuzumab showed better response (complete response: HER2-positive 14.3% vs. HER2-negative 0%; partial response: HER2-positive 42.9% vs. HER2-negative 25.6%; p = 0.008), better disease control rate (HER2-positive 100% vs. HER2-negative 46.2%; p = 0.011), and better values for the remaining analysed variables than HER2-negative patients., Conclusion: Our study provides real-world data on the use of oral weekly vinorelbine, which proves an effective and well-tolerated regimen for MBC patients previously treated with taxanes or anthracyclines. Patients with HER2-positive disease could also benefit from this treatment in combination with trastuzumab.

Purpose: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms., Methods: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints., Results: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r 2  = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r 2  = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms., Conclusions: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.

Background: Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early non-small cell lung cancer. However, few validated alternatives exist when cisplatin is not indicated or tolerated. Carboplatin is frequently used in this setting. We evaluated the 5-year overall survival, progression-free survival and toxicity in patients treated for stage IB to IIIB resected non-small cell lung cancer receiving adjuvant carboplatin-based chemotherapy compared to cisplatin in association with vinorelbine., Methods: Single-center retrospective study of patients having received adjuvant chemotherapy between January 2004 and December 2013 at the oncology clinic at Institut Universitaire de Cardiologie et de Pneumologie de Québec (Canada). Three sub-groups, cisplatin/vinorelbine, carboplatin/vinorelbine and the substitution of cisplatin/vinorelbine for carboplatin/vinorelbine (cisplatin/vinorelbine/carboplatin/vinorelbine), were studied during treatment., Results: One hundred twenty-seven patients were included in this study. The median PFS was not significantly different, with 50.4 months for cisplatin/vinorelbine, 57.3 months for cisplatin/vinorelbine/carboplatin/vinorelbine and not yet achieved for the carboplatin/vinorelbine group ( p = 0.80). Overall survival also did not differ significantly between the three groups. The 5-year overall survival rates were 66% in cisplatin/vinorelbine group, 55% in carboplatin/vinorelbine group and 70% in cisplatin/vinorelbine/carboplatin/vinorelbine group ( p = 0, 95). No differences were noted between groups concerning high-grade hematologic toxicity., Conclusions: Although the effectiveness and hematologic toxicity are comparable between cisplat in and carboplatin in the adjuvant treatment of resected non-small cell lung cancer, the results obtained corroborate the practice used at our oncology clinic. Nevertheless, more prospective studies would be needed to confirm these results.

Background: High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present a comparison of mobilisation outcomes using these regimens., Patients and Methods: Vino-Cy patients received Vinorelbine 25 mg/m 2 on day 1, cyclophosphamide 1500 mg/m 2 on day 2, and pegylated GCSF on day 4 or GCSF 10 mcg/kg/day from day 4 onwards. Cy patients were given cyclophosphamide 4000 mg/m 2 on day 1 and GCSF10 mcg/kg/day from day 5 onwards. The target CD34 + SC collection was 5 × 10 6  per kg/BW., Results: 149 patients were included. SC collection was lower in the Vino-Cy group (8.20 × 10 6 /Kg BW) compared to the Cy group (11.43 × 10 6 /Kg BW), with adjusted geometric mean ratio of 0.59 (95% CI 0.41 to 0.86, p = 0.006). Time taken to achieve an adequate PB SC count was shorter for Vino-Cy (9 ± 1 day compared to 12 ± 2 days for Cy, adjusted absolute mean difference -3.95, 95% CI -4.85 to -3.06, P < .001). Mobilisation related toxicities (in particular, neutropaenic fever) were greater for Cy., Conclusion: Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity., (Copyright © 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this phase II study was to evaluate the activity and safety of the combination of cisplatin and vinorelbine with thoracic radiotherapy in unresectable locally advanced stage III non-small cell lung cancer (NSCLC). The primary endpoint was the objective response rate (ORR). Secondary objectives included toxicity profile, progression-free survival (PFS), and overall survival (OS)., Materials and Methods: A total of 48 NSCLC patients were enrolled (median age 60 years, 52% stage IIIA and 48% stage IIIB, 52% adenocarcinoma). Patients received three cycles of chemotherapy every 21 days [intravenous cisplatin 80 mg/m 2 and intravenous vinorelbine 25 mg/m 2 on day 1 and oral vinorelbine on day 8 (60 mg/m 2 )] concurrent with radiotherapy (66 Gy, administered at 1.8 Gy per day, five consecutive days per week)., Results: ORR was 79.2% (72.9% showing partial response and 6.3% showing complete response). With a median follow-up of 20.7 months, median PFS was 12 months and median OS was 36 months. Grade 3/4 toxicities were: neutropenia (14.5%), anaemia (6.2%), vomiting (2%), and oesophagitis (4.2%). No toxic deaths were reported., Conclusion: This combined regimen shows efficacy and a manageable safety profile. PFS and OS outcomes are encouraging and warrant further research.

Background: Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC., Methods: In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m 2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m 2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175., Findings: Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8-43·1). 2-year disease-free survival was 81·4% (95% CI 69·6-93·1) in the erlotinib group and 44·6% (26·9-62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194-2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5-58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported., Interpretation: Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC., Funding: National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar)., Methods: Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments., Results: We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects., Conclusion: These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.