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Journal of Clinical Oncology : Official... Jul 2020To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA...
PURPOSE
To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m, day 1) plus cisplatin (75 mg/m, day 1) or vinorelbine (25 mg/m, days 1 and 8) plus cisplatin (80 mg/m, day 1) with stratification by sex, age, pathologic stage, mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients.
RESULT
Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had -sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% 0.3%, respectively), neutropenia (81.1% 22.7%, respectively), and anemia (9.3% 2.8%, respectively). One treatment-related death occurred in each arm.
CONCLUSION
Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pemetrexed; Vinorelbine; Young Adult
PubMed: 32407216
DOI: 10.1200/JCO.19.02674 -
JAMA Oncology Sep 2023In 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,... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of Metronomic Oral Vinorelbine, Cyclophosphamide, and Capecitabine vs Weekly Intravenous Paclitaxel in Patients With Estrogen Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: Final Results From the Phase 2 METEORA-II Randomized Clinical Trial.
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.
Topics: Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Paclitaxel; Receptor, ErbB-2; Receptors, Estrogen; Vinorelbine; Adult; Aged; Aged, 80 and over
PubMed: 37440239
DOI: 10.1001/jamaoncol.2023.2150 -
Gan To Kagaku Ryoho. Cancer &... Dec 2022Advanced medical care is a system that allows the use of off-label treatments in conjunction with insurance reimbursement, and is used for clinical trials to evaluate... (Randomized Controlled Trial)
Randomized Controlled Trial
Advanced medical care is a system that allows the use of off-label treatments in conjunction with insurance reimbursement, and is used for clinical trials to evaluate off-label treatments. Since pemetrexed has been not approved for patients with resected non-small cell lung cancer(NSCLC)in Japan, we conducted the randomized phase Ⅲ study(JIPANG)to evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as adjuvant chemotherapy in patients with stage Ⅱ-ⅢA nonsquamous NSCLC. This study needed 5-year registration period, and 5-year follow-up after registration of the last patient. The JIPANG study failed to show the superiority of pemetrexed plus cisplatin in terms of recurrence-free survival, as primary endpoint. In Japan, the challenges in conducting academia-led clinical trials of unapproved drugs and drugs for off-label use are the establishment of a system for conducting trials, the provision of drugs, and the procurement of funds.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Lung Neoplasms; Neoplasm Staging; Pemetrexed; Vinorelbine
PubMed: 36539239
DOI: No ID Found -
Oncology Research and Treatment 2022As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional... (Review)
Review
BACKGROUND
As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional chemotherapy (CCT) and targeted therapies.
SUMMARY
MCT, defined as continuous administration of low-dose chemotherapeutic agents, is accepted as a therapy that exerts its effects via immunomodulation, anti-angiogenesis and direct cytotoxic effects. Oral administration of MCT is safe, easy to handle, and allows for flexible drug dosing. Dose accumulations associated with non-tolerable side effects are rare, so the medication can be administered for longer periods of time. Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic disease resistant to endocrine-based therapy and not requiring rapid tumor response are generally suitable for MCT. However, MCT may also be promising in patients with triple-negative and HER2-positive tumors without aggressive disease who prefer a lower toxicity profile compared to CCT. The most commonly used agents are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE), and vinorelbine (VRL), whereby a combination of agents is frequently applied. Key Messages: Based on the growing body of evidence, MCT can be considered as a suitable treatment option in selected MBC patients. Nevertheless, there is an urgent need for randomized controlled trials comparing MCT with CCT, but also with best supportive care. Due to the multimodal mechanisms of action, the combination with targeted and immunological therapies may represent a new promising approach for the treatment of MBC.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Female; Humans; Quality of Life; Receptor, ErbB-2
PubMed: 34794154
DOI: 10.1159/000520236 -
Journal of Clinical Oncology : Official... Dec 2023JCO The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant... (Randomized Controlled Trial)
Randomized Controlled Trial
JCO The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Lung Neoplasms; Neoplasm Staging; Pemetrexed; Survival Analysis; Vinorelbine
PubMed: 37656928
DOI: 10.1200/JCO.23.00179 -
Cancers Apr 2020There is a need to improve the effectiveness of radiotherapy (RT) in hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to explore the efficacy and...
There is a need to improve the effectiveness of radiotherapy (RT) in hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to explore the efficacy and toxicity of the anti-microtubule agent Vinorelbine as a radiosensitizer in HCC. The radio sensitivity of 16 HCC patient-derived xenograft (PDX) models was determined by quantifying the survival fraction following irradiation in vitro, and Vinorelbine radio sensitization was determined by clonogenic assay. Ectopic HCC xenografts were treated with a single dose of 8 Gy irradiation and twice-weekly 3 mg/kg Vinorelbine. Tumor growth and changes in the proteins involved in DNA repair, angiogenesis, tumor cell proliferation, and survival were assessed, and the 3/16 (18.75%), 7/16 (43.75%), and 6/16 (37.5%) HCC lines were classified as sensitive, moderately sensitive, and resistant, respectively. The combination of RT and Vinorelbine significantly inhibited tumor growth, DNA repair proteins, angiogenesis, and cell proliferation, and promoted more apoptosis compared with RT or Vinorelbine treatment alone. Vinorelbine improved HCC tumor response to standard irradiation with no increase in toxicity. HCC is prevalent in less developed parts of the world and is mostly unresectable on presentation. Vinorelbine and conventional radiotherapy are cost-effective, well-established modalities of cancer treatment that are readily available. Therefore, this strategy can potentially address an unmet clinical need, warranting further investigation in early-phase clinical trials.
PubMed: 32260169
DOI: 10.3390/cancers12040872 -
Bioorganic & Medicinal Chemistry Sep 2023Vincamine is a naturally occurring indole alkaloid showing antioxidant activity and has been used clinically for the prevention and treatment of cerebrovascular... (Review)
Review
Vincamine is a naturally occurring indole alkaloid showing antioxidant activity and has been used clinically for the prevention and treatment of cerebrovascular disorders and insufficiencies. It has been well documented that antioxidants may contribute to cancer treatment, and thus, vincamine has been investigated recently for its potential antitumor activity. Vincamine was found to show cancer cell cytotoxicity and to modulate several important proteins involved in tumor growth, including acetylcholinesterase (AChE), mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and T-box 3 (TBX3). Several bisindole alkaloids, including vinblastine and vincristine and their synthetic derivatives, vindesine, vinflunine, and vinorelbine, have been used as clinically effective cancer chemotherapeutic agents. In the present review, the discovery and development of vincamine as a useful therapeutic agent and its antioxidant and antitumor activity are summarized, with its antioxidant-related mechanisms of anticancer potential being described. Also, discussed herein are the design of the potential vincamine-based oncolytic agents, which could contribute to the discovery of further new agents for cancer treatment.
Topics: Vincamine; Vasodilator Agents; Antioxidants; Acetylcholinesterase; Antineoplastic Agents
PubMed: 37579526
DOI: 10.1016/j.bmc.2023.117439 -
Journal of Immunology (Baltimore, Md. :... Jul 2023Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2)...
Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
Topics: Humans; Female; Animals; Epitopes; Vinorelbine; Receptor, ErbB-2; Breast Neoplasms; Immunotherapy; Mammary Neoplasms, Animal; Peptides; Dendritic Cells; Trastuzumab
PubMed: 37204246
DOI: 10.4049/jimmunol.2300077 -
Frontiers in Oncology 2020The only registered systemic treatment for malignant pleural mesothelioma (MPM) is platinum based chemotherapy combined with pemetrexed, with or without bevacizumab.... (Review)
Review
The only registered systemic treatment for malignant pleural mesothelioma (MPM) is platinum based chemotherapy combined with pemetrexed, with or without bevacizumab. Immunotherapy did seem active in small phase II trials. In this review, we will highlight the most important immunotherapy-based research performed and put a focus on the future of MPM. PD-(L)1 inhibitors show response rates between 10 and 29% in phase II trials, with a wide range in progression free (PFS) and overall survival (OS). However, single agent pembrolizumab was not superior to chemotherapy (gemcitabine or vinorelbine) in the recent published PROMISE-Meso trial in pre-treated patients. In small studies with CTLA-4 inhibitors there is evidence for response in some patients, but it fails to show a better PFS and OS compared to best supportive care in a randomized study. A combination of PD-(L)1 inhibitor with CTLA-4 inhibitor seem to have a similar response as PD-(L)1 monotherapy. The first results of combining durvalumab (PD-L1 blocking) with cisplatin-pemetrexed in the first line are promising. Another immune treatment is Dendritic Cell (DC) immunotherapy, which is recently tested in mesothelioma, shows remarkable anti-tumor activity in three clinical studies. The value of single agent checkpoint inhibitors is limited in MPM. There is an urgent need for biomarkers to select the optimal candidates for immunotherapy among MPM patients in terms of efficacy and tolerance. Results of combination checkpoint inhibitors with chemotherapy are awaiting.
PubMed: 32154179
DOI: 10.3389/fonc.2020.00187