Therapeutic drug monitoring (TDM) serves as a potent tool for adjusting drug concentration within a reasonable range. However, continuous monitoring of anticancer drugs in-vivo presents a significant ...challenge. Herein, we propose a needle-in-needle electrochemical sensor based on an acupuncture needle electrode, capable of monitoring the anticancer drug etoposide in the peritoneal cavity of living rats. The acupuncture needle was modified with Au nanoparticles and etoposide-templated molecularly imprinted polymer (MIP), resulting in high sensitivity and selectivity in the electrochemical detection of etoposide. The modified acupuncture needle (0.16 mm diameter) was anchored inside a syringe needle (1.40 mm diameter), allowing the outer syringe needle to protect the modified materials of the inner acupuncture needle during skin piercing. Due to the unique needle-in-needle design, high stability was obtained during in-vivo etoposide monitoring. Connecting to a smartphone-controlled portable electrochemical workstation, the needle-in-needle sensor offers great convenience in point-of-care TDM. Moreover, the electrode materials on the acupuncture needle were carefully characterized and optimized. Under the optimized conditions, low detection limits and wide linear range were achieved. This work provides new insights into acupuncture needle electrochemical sensors and further expands the feasibility for real-time and in-vivo detection.
Summary Background Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this ...study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. Methods The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov ( NCT00433563 ) and is currently in follow-up. Findings Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 95% CI 0·95–1·45; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% 95% CI −3·2% to 13·7%). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 74% of 266 patients in the twice-daily group vs 170 65% of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 49% vs 101 38%; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 19% of 254 patients in the twice-daily group vs 47 19% of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 3% of 254 vs 4 2% of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). Interpretation Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Funding Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).
BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for ...advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months.
The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group.
Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).
Cancer stem cells (CSCs) are known to contribute to tumor relapses by virtue of their chemoresistance. With the knowledge that nanoformulations can overcome drug resistance, we evaluated the efficacy ...and cytotoxicity of clinical-grade carboplatin (CPT)- and etoposide (ETP)-loaded lactoferrin nanoparticles (Lf-Nps) on total, CD133-enriched (non-CSC), and CD133-depleted (CSC) populations of retinoblastoma (Rb) Y79 cells.
Physicochemical properties of drug-loaded Lf-Nps were measured with transmission electron microscopy and attenuated total reflectance-Fourier transform infrared. The encapsulation efficiency, uptake, and release of drug-loaded Lf-Nps were measured using high-performance liquid chromatography and a UV-visible spectrophotometer. Cytotoxicity of the standard and drug-loaded Lf-Nps was evaluated by the MTT assay.
The mean (SD) size and encapsulation efficiency of Lf-CPT and Lf-ETP were 61.2 (3.94) nm, 60% and 45.15 (5.85) nm, 38%, respectively, and the drug release efficiency was highest at pH 6. The increased drug uptake and lower release of drug-loaded Lf-Nps were observed in CSC and non-CSC populations compared to their standard forms. The relative increase of drug uptake and sustained intracellular retention of the drug-loaded Lf-Nps compared to standard drugs showed an enhanced cytotoxicity up to 50%, especially in Rb Y79 CSCs (IC50: CPT, 230.3; Lf-CPT, 118.2; ETP, 198.1; and Lf-ETP, 129) compared to non-CSCs.
Our study documents an increase in drug uptake, retention, and cytotoxicity of Lf-CPT and Lf-ETP on Y79 CSCs and non-CSCs as compared to their standard drugs in vitro. The reversal of chemoresistance in the CSC population by nanoformulation appears promising with the potential to pave the way for improved targeted therapy and better clinical outcomes.
Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to ...chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03054896.
The aim of this study is to demonstrate the enhanced therapeutic efficacy of anticancer drugs on drug-resistant breast cancer using multicomponent microemulsions (ECG-MEs) as an oral delivery system. ...The etoposide-loaded ECG-MEs were composed of coix seed oil and ginsenoside Rh2 (G-Rh2), both of which possess not only the synergistic antitumor effect with etoposide, but also have excipient-like properties. Orally administrated ECG-MEs were demonstrated to be able to accumulate at the tumor site following crossing the intestines as intact vehicles into the blood circulation. The spatiotemporal controlled release characteristics of ECG-MEs brought about the efficient P-gp inhibition by the initially released G-Rh2 and the increased intracellular accumulation of the sequentially released etoposide. The combination antitumor activity of etoposide, G-Rh2 and coix seed oil using ECG-MEs was verified on the xenograft drug-resistant breast tumor mouse models. In addition, the safety evaluation studies indicated that treatment with ECG-MEs did not cause any significant toxicity in vivo. These findings suggest that ECG-MEs as an oral formulation may offer a promising strategy to treat the drug-resistant breast cancer.
Summary
Treatment with dose‐adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA‐EPOCH‐R) has become the standard of care for primary ...mediastinal B‐cell lymphoma (PMBCL) at many institutions despite limited data in the multi‐centre setting. We report a large, multi‐centre retrospective analysis of children and adults with PMBCL treated with DA‐EPOCH‐R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA‐EPOCH‐R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA‐EPOCH‐R. Radiation therapy was administered in 14·9% of patients. With median follow‐up of 22·6 months, the estimated 3‐year event‐free survival (EFS) was 85·9% 95% confidence interval (CI) 80·3–91·5 and overall survival was 95·4% (95% CI 91·8–99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy‐five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG‐PET) scan at the completion of DA‐EPOCH‐R, defined as Deauville score 1–3. Negative FDG‐PET at end‐of‐therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA‐EPOCH‐R for the treatment of PMBCL in children and adults. Patients with a positive end‐of‐therapy FDG‐PET scan have an inferior outcome.
Background
Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo‐SCT) conditioning ...regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context.
Materials and methods
A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo‐SCT with TBI‐based myeloablative conditioning associated with cyclophosphamide (CY, 60 mg/kg/day × 2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment‐related mortality.
Results
Thirty‐five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval CI 1.145; 31.445, P = 0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI 0.071; 0.969, P = 0.04). No significant difference was highlighted between the two treatments for survival or for treatment‐related mortality.
Discussion
This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.
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Daam1 (Dishevelled-associated activator of morphogenesis 1) is a Wnt/PCP signaling protein that engages in cytoskeleton reorganization and is abnormally activated in certain tumors. ...Daam1 is closely related to cancer metastasis, which is expected to become a target for cancer treatment. However, the natural small molecules targeting Daam1 have not been identified.
We screened several natural small molecules that may bind to Daam1 by Sybyl molecular simulation docking technique. As a first-line drug for the treatment of small cell lung cancer, etoposide was chosen for further investigation. Next, we used Micro Scale Thermophoresis (MST) to verify the interaction of etoposide and Daam1. Small cell lung cancer H446 cells and breast cancer MCF-7 cells were treated with etoposide and subjected to Western blotting to measure the Daam1 expression. The effect of etoposide on cell proliferation was determined by CCK-8 assay in vitro and by a tumor-bearing mouse model in vivo. Wound healing assay and Boyden chamber assay were used to evaluate the role of etoposide in the migration and invasion ability of tumor cells. The effect of etoposide on the microfilament assembly was visualized by immunofluorescence staining with phalloidine. Finally, the possible mechanism of down-regulation of Daam1 expression after etoposide-induced small cell lung cancer cells was detected by a half-life experiment and immunofluorescence staining with lysosomal marker LAMP1.
Sybyl molecular modeling docking technique was performed to screen a natural chemical library for molecules that bound to the FH2 domain of Daam1 and found etoposide was virtually interacted with Daam1. MST validated etoposide directly bound to the FH2 domain of Daam1. Etoposide significantly down-regulated the expression of Daam1 in small cell lung cancer H446 cells and breast cancer MCF-7 cells. Moreover, 270 μmol/L etoposide largely inhibited the proliferation, migration, and invasion of H446 cells and MCF-7 cells. Immunofluorescence staining experiments revealed that etoposide induced the disassembly of microfilaments in H446 cells and MCF-7 cells, which were rescued by Daam1 overexpression. In nude mice transplanted with H446 cells, 5, 10, 20 mg/kg etoposide (drug/weight) injected via tail vein largely retarded the proliferation of subcutaneous tumors. Etoposide induced Daam1 to shorten its half-life and enter the lysosome degradation pathway, and eventually leading to the downregulation of Daam1 expression.
Etoposide is a novel natural small molecule targeting Daam1. Etoposide inhibits the proliferation, migration and invasion of small cell lung cancer cells and breast cancer cells, and also suppresses tumor proliferation of small cell lung cancer in vivo.
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It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating ...P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide’s solubility approximately 100 times (16 mg mL−1) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC0-∞ of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg−1), AUC0-∞ and Cmax were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg−1. A single oral dose of 20 mg kg−1 zosuquidar followed by 20 mg kg−1 oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.
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