-
Frontiers in Pharmacology 2023Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a...
Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations. We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25-40 mg/m for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25-50 mg/m daily for 48 consecutive weeks. A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9-117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively. We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients.
PubMed: 37205905
DOI: 10.3389/fphar.2023.1132219 -
International Journal of Molecular... Jan 2024Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its...
Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models. In this study, mice bearing HCC tumors were treated with the vehicle, sorafenib (15 mg/kg), vinorelbine (3 mg/kg), and sorafenib-vinorelbine combination (Sora/Vino). Rigorous monitoring of the tumor growth and side effects coupled with comprehensive histological and molecular analyses was conducted. The overall survival (OS) of mice bearing HCC orthotopic tumors was also assessed. Our data showed a notable 86.4% response rate to Sora/Vino, surpassing rates of 31.8% for sorafenib and 9.1% for vinorelbine monotherapies. Sora/Vino significantly inhibited tumor growth, prolonged OS of mice bearing HCC orthotopic tumors ( < 0.01), attenuated tumor cell proliferation and angiogenesis, and enhanced necrosis and apoptosis. The combination therapy effectively suppressed the focal adhesion kinase (FAK) pathway, which is a pivotal player in cell proliferation, tumor angiogenesis, survival, and metastasis. The noteworthy antitumor activity in 22 HCC PDX models positions Sora/Vino as a promising candidate for early-phase clinical trials, leveraging the established use of sorafenib and vinorelbine in HCC and other cancers.
Topics: Humans; Animals; Mice; Sorafenib; Carcinoma, Hepatocellular; Vinorelbine; Liver Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Xenograft Model Antitumor Assays; Antineoplastic Agents
PubMed: 38338842
DOI: 10.3390/ijms25031563 -
The Oncologist Nov 2020This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference...
BACKGROUND
This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers.
MATERIALS AND METHODS
Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method.
RESULTS
Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine.
CONCLUSION
Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules.
IMPLICATIONS FOR PRACTICE
Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Neoplasm Recurrence, Local; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Sarcoma; Vinorelbine
PubMed: 32584482
DOI: 10.1634/theoncologist.2020-0352 -
Lung Cancer (Amsterdam, Netherlands) Jan 2021The PACIFIC trial demonstrated that durvalumab significantly improved progression-free and overall survival (PFS/OS), versus placebo, in patients with Stage III NSCLC... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The PACIFIC trial demonstrated that durvalumab significantly improved progression-free and overall survival (PFS/OS), versus placebo, in patients with Stage III NSCLC and stable or responding disease following concurrent, platinum-based chemoradiotherapy (CRT). A range of CT and RT regimens were permitted, and used, in the trial. We report post-hoc, exploratory analyses of clinical outcomes from PACIFIC according to CRT-related variables.
METHODS
Patients were randomized 2:1 (1-42 days post-CRT) to up to 12 months durvalumab (10 mg/kg intravenously every 2 weeks) or placebo. Efficacy and safety were analyzed in patient subgroups defined by the following baseline variables: platinum-based CT (cisplatin/carboplatin); vinorelbine, etoposide, or taxane-based CT (all yes/no); total RT dose (<60 Gy/60-66 Gy/>66 Gy); time from last RT dose to randomization (<14 days/≥14 days); and use of pre-CRT induction CT (yes/no). Treatment effects for time-to-event endpoints were estimated by hazard ratios (HRs) from unstratified Cox-proportional-hazards models.
RESULTS
Overall, 713 patients were randomized, of whom 709 received treatment in either the durvalumab (n/N = 473/476) or placebo arms (n/N = 236/237). Durvalumab improved PFS, versus placebo, across all subgroups (median follow up, 14.5 months; HR range, 0.34-0.63). Durvalumab improved OS across most subgroups (median follow up, 25.2 months; HR range, 0.35-0.86); however, the 95 % confidence interval (CI) of the estimated treatment effect crossed one for the subgroups of patients who received induction CT (HR, 0.78 [95 % CI, 0.51-1.20]); carboplatin (0.86 [0.60-1.23]); vinorelbine (0.79 [0.49-1.27]); and taxane-based CT (0.73 [0.51-1.04]); and patients who were randomized ≥14 days post-RT (0.81 [0.62-1.06]). Safety was broadly similar across the CRT subgroups.
CONCLUSION
Durvalumab prolonged PFS and OS irrespective of treatment variables related to prior CRT to which patients with Stage III NSCLC had previously stabilized or responded. Limited patient numbers and imbalances in baseline factors in each subgroup preclude robust conclusions.
Topics: Antibodies, Monoclonal; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Lung Neoplasms
PubMed: 33285469
DOI: 10.1016/j.lungcan.2020.11.024 -
Cancer Research Communications Sep 2022In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates...
UNLABELLED
In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates how different data sources can contribute to and assist phase I trial designs. Single-drug and drug combination toxicity and pharmacokinetic data were primarily reviewed from several databases. We focused on the MTD, dose-limiting toxicity (DLT), toxicity, and pharmacokinetic profiles. To demonstrate the feasibility and utility of these data sources in improving trial designs, phase I studies reported in ClincalTrials.gov from January 1, 2018 to December 31, 2018 were used as examples. We evaluated whether and how these studies could have been designed differently given toxicity and pharmacokinetic data. None of the existing pharmacokinetic and toxicity databases contain either MTD or DLT. Among 268 candidate trials, four drug combinations were studied in other phase I trials before 2018; 185 combinations had complete or partial information on drug interactions or overlapping toxicity, and 79 combinations did not have available information. Two drug combination trials were selected as case studies. The nivolumab-axitinib trial could have been designed as a dose deescalating study, and the vinorelbine-trastuzumab emtansine trial could have been designed with a lower dose of either drug. Public data sources contain significant knowledge of the drug combination phase I trial design. Some important data (MTD and DLT) are not available in existing databases but in the literature. Some phase I studies could have been designed more efficiently with additional preliminary data.
SIGNIFICANCE
Prior preclinical and clinical knowledge is critical for designing effective and efficient cancer drug combinatory trials. We reported results on the feasibility and utility of different informatics resources for contributing to and assisting phase I trial designs based on our designed classification approach. We also found that public data sources contained significant knowledge for drug combination phase I trial design, but some critical data elements (MTD and DLT) were missing.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Vinorelbine
PubMed: 36922938
DOI: 10.1158/2767-9764.CRC-22-0160 -
LC-MS-MS Determination of Cytostatic Drugs on Surfaces and in Urine to Assess Occupational Exposure.Journal of Analytical Toxicology Jan 2023The ever-increased usage of cytostatic drugs leads to high risk of exposure among healthcare workers. Moreover, workers are exposed to multiple compounds throughout...
The ever-increased usage of cytostatic drugs leads to high risk of exposure among healthcare workers. Moreover, workers are exposed to multiple compounds throughout their lives, leading to cumulative and chronic exposure. Therefore, multianalyte methods are the most suitable for exposure assessment, which minimizes the risks from handling cytostatic drugs and ensures adequate contamination containment. This study describes the development and full validation of two liquid chromatography-tandem mass spectrometry methods for the detection of gemcitabine, dacarbazine, methotrexate, irinotecan, cyclophosphamide, doxorubicinol, doxorubicin, epirubicin, etoposide, vinorelbine, docetaxel and paclitaxel in working surfaces and urine samples. The urine method is the first to measure vinorelbine and doxorubicinol. For surfaces, limits of detection (LOD) and limits of quantification (LOQ) were 5-100 pg/cm2, and linearity was achieved up to 500 pg/cm2. Inaccuracy was between -11.0 and 8.4%. Intra-day, inter-day and total imprecision were <20%, except for etoposide and irinotecan (<22.1%). In urine, LOD and LOQ were 5-250 pg/mL, with a linear range up to 1,000-5,000 pg/mL. Inaccuracy was between -3.8 and 14.9%. Imprecision was <12.4%. Matrix effect was from -58.3 to 1,268.9% and from -66.7 to 1,636% in surface and urine samples, respectively, and extraction efficiency from 10.8 to 75% and 47.1 to 130.4%, respectively. All the analytes showed autosampler (6°C/72 h), freezer (-22°C/2 months) and freeze/thaw (three cycles) stability. The feasibility of the methods was demonstrated by analyzing real working surfaces and patients' urine samples. Contamination with gemcitabine, irinotecan, cyclophosphamide, epirubicin and paclitaxel (5-4,641.9 pg/cm2) was found on biological safety cabinets and outpatients' bathrooms. Analysis of urine from patients under chemotherapy identified the infused drugs at concentrations higher than the upper LOQ. These validated methods will allow a comprehensive evaluation of both environmental and biological contamination in hospital settings and healthcare workers.
Topics: Humans; Chromatography, Liquid; Cytostatic Agents; Epirubicin; Irinotecan; Etoposide; Tandem Mass Spectrometry; Vinorelbine; Cyclophosphamide; Gemcitabine; Paclitaxel; Occupational Exposure
PubMed: 36164930
DOI: 10.1093/jat/bkac073 -
International Journal of Nanomedicine 2020Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM)...
BACKGROUND
Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse.
PURPOSE
The objective of this study was to construct a novel CPP modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG-MAL and CPP-PVGLIG-PEG, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration.
METHODS AND RESULTS
The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency.
CONCLUSION
CPP modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.
Topics: A549 Cells; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Movement; Chickens; Endocytosis; Epithelial-Mesenchymal Transition; Humans; Hydrolysis; Liposomes; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neovascularization, Pathologic; Phosphatidylethanolamines; Polyethylene Glycols; Tumor Microenvironment; Vinorelbine
PubMed: 32922011
DOI: 10.2147/IJN.S258906 -
Frontiers in Veterinary Science 2021Chemotherapy overdoses (ODs) are severe complications that can occur following the use of antineoplastics. However, little is known about chemotherapy ODs in veterinary...
Chemotherapy overdoses (ODs) are severe complications that can occur following the use of antineoplastics. However, little is known about chemotherapy ODs in veterinary medicine. The goals of this retrospective study were to report the occurrence, type, and cause of known chemotherapy ODs in companion animal medicine. The American College of Veterinary Internal Medicine oncology and internal medicine listservs were solicited for chemotherapy OD cases in dogs and cats. An OD was defined as administration of a chemotherapy dose 10% higher than intended, or at a shorter interval than planned. Twelve non-anthracycline ODs in 11 dogs, and 3 cat ODs, were collected. Overdoses in dogs included carboplatin, cyclophosphamide, L-asparaginase, lomustine, mustargen, vincristine, and vinorelbine. The cat ODs included doxorubicin and vincristine. In dogs, the median OD was 2.1x (range: 1.2-10x) the intended dose. All dogs survived the OD and developed a variety of gastrointestinal and hematologic toxicities of varying grades. Both cats with a 2.4x vincristine OD died despite supportive care. The cat who received a 2x OD of doxorubicin survived the event, experiencing Veterinary Cooperative Oncology Group-common terminology criteria for adverse events (VCOG) grade I thrombocytopenia and anemia, and VCOG grade II neutropenia. Chemotherapy ODs appear to be rare in veterinary medicine and are typically 2-3xs the intended dose. Clinical effects include VCOG grade I and II gastrointestinal distress and VCOG grade III and IV hematologic effects. With appropriate supportive care, most patients will survive the event. Life-threatening events are more common in cats following vincristine ODs.
PubMed: 34631850
DOI: 10.3389/fvets.2021.718967 -
Prostate International Mar 2016In elderly patients affected by metastatic castration-resistant prostate cancer (mCRPC) chemotherapic treatment may be the choice if one considers not only the...
BACKGROUND
In elderly patients affected by metastatic castration-resistant prostate cancer (mCRPC) chemotherapic treatment may be the choice if one considers not only the chronological age, but also the clinical status, the functional reserve, and the vulnerability of patients. Several studies have confirmed the survival benefit of docetaxel and vinorelbine among every class of age. Most CRP elderly patients are defined as frail, maybe due to comorbidities: these patients, who are unable to be candidates for a standard treatment, should be candidates for a more tolerable treatment.
METHODS
Twenty-six elderly, frail patients were evaluated. The patients were affected by mCRPC and were receiving chemotherapy with intravenous weekly docetaxel (12 patients) or oral metronomic vinorelbine (14 patients). Safety and efficacy were investigated evaluating clinical and objective response and tolerability. The level of patient satisfaction with treatment was assessed through a questionnaire.
RESULTS
No significant difference was found between groups in terms of 6-month progression-free survival: 57.1% for patients treated with oral metronomic vinorelbine versus 58.3% for patients treated with docetaxel. Median progression free survival was 8.6 months (95% confidence interval: 7.1-9.4 months), and 8.2 months (95% confidence interval: 6.9-9.3 months) for patients treated with oral metronomic vinorelbine and socetaxel, respectively. Oral metronomic vinorelbine was associated with increased patient satisfaction with respect to docetaxel administration. The most frequent side effect associated with oral metronomic vinorelbine was anemia and vomiting, with similar frequency compared to patients treated with docetaxel.
CONCLUSION
Weekly docetaxel and oral metronomic vinorelbine are equally effective and well tolerated in elderly unfit and frail patients affected by mCRPC. Metronomic vinorelbine treatment is associated with higher patient compliance and satisfaction.
PubMed: 27014659
DOI: 10.1016/j.prnil.2015.12.003 -
PharmacoEconomics - Open Sep 2019Eribulin is a recommended treatment option for locally advanced or metastatic breast cancer (LABC/MBC) in adults whose disease has progressed after at least... (Review)
Review
Eribulin for Treating Locally Advanced or Metastatic Breast Cancer After One Chemotherapy Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
Eribulin is a recommended treatment option for locally advanced or metastatic breast cancer (LABC/MBC) in adults whose disease has progressed after at least two chemotherapy regimens. The National Institute for Health and Care Excellence (NICE) invited the manufacturer of eribulin (Halaven; Eisai Ltd) to submit evidence for the clinical and cost effectiveness of eribulin for treating LABC/MBC after one chemotherapy regimen in accordance with the institute's Single Technology Appraisal (STA) process. This article presents a summary of the company's evidence, Evidence Review Group (ERG) review and resulting NICE guidance (TA515), issued 28 March 2018. Clinical evidence for eribulin versus capecitabine in LABC/MBC was derived from a subgroup of 392 patients with human epidermal growth factor receptor (HER2)-negative disease which had progressed after only one prior chemotherapy regimen for LABC/MBC in the phase III, randomised, controlled Study 301 (n = 1102). Overall survival (OS) but not progression-free survival (PFS) was improved for patients treated with eribulin versus capecitabine in this subgroup. Using the discounted patient access scheme price for eribulin, the company developed a de novo economic model. In the base case, the incremental cost-effectiveness ratio (ICER) for eribulin versus capecitabine was £36,244 per quality-adjusted life year (QALY) gained. However, the ERG identified several problematic issues relating to modelling OS and PFS, drug costing and utility values, and made ten revisions to the company model. The overall impact of all ten revisions was to increase the ICER per QALY gained by £46,499. The Appraisal Committee (AC) accepted all changes made by the ERG except for the change to utility values; the AC considered that the value should be mid-way between the company's and the ERG's preferred values. A modified model was submitted by the company that included this utility value, but maintained some elements of the base case that the AC had been critical of (differential PFS between treatment arms and application of treatment cap). The new model also included a 'blended' comparator (capecitabine and vinorelbine). The AC noted there was no evidence to support a 'blended' comparator, differential PFS between treatment arms or a treatment cap. The AC therefore concluded that the most plausible ICER was likely to be £69,843 per QALY gained (derived from an ERG sensitivity analysis using the AC's preferred utility value, no differential PFS and no treatment cap). Therefore, eribulin was not recommended for treating LABC/MBC in adults who have had only one chemotherapy regimen.
PubMed: 30742256
DOI: 10.1007/s41669-018-0114-z