Relationship between fluorouracil systemic exposure and tumor response and patient survival.

1994 ◽  
Vol 12 (6) ◽  
pp. 1291-1295 ◽  
Author(s):  
G Milano ◽  
M C Etienne ◽  
N Renée ◽  
A Thyss ◽  
M Schneider ◽  
...  
Keyword(s):  
Tumor Response ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Tumor Stage ◽  
Continuous Variable ◽  
First Line ◽  
Dose Adaptation ◽  
Venous Infusion ◽  
Continuous Venous Infusion

PURPOSE The aim of this study was to analyze the link between fluorouracil (FU) systemic exposure and tumor response and overall survival. PATIENTS AND METHODS One hundred eighty-six patients (162 men, 24 women) with head and neck cancer were studied. All received cisplatin plus FU for three cycles as first-line chemotherapy. The treatment consisted of cisplatin (100 mg/m2 intravenously [IV]) followed by a 5-day continuous venous infusion of FU (1 g/m2/d). The median follow-up duration for the 104 patients alive was 24 months. For each cycle, we calculated the area under the curve over the duration of pharmacokinetic follow-up (AUC0-105 h) for plasma FU. For each patient, we analyzed the averaged AUC0-105 h and the averaged total dose for the three cycles. RESULTS The response rate was 30% complete responses (CRs), 22% partial responses (PRs) more than 75%, 25% PRs less than 75%, and 23% no response (NR). Medians for averaged AUC and dose per cycle were 27,906 ng/mL h (first through third quartile, 25,398 to 31,060) and 7,000 mg (first through third quartile, 6,200 to 7,833), respectively. The tumor response was significantly linked to tumor stage (P < .001) and to averaged AUC (P = .05), but not to averaged dose. Analysis of parameters (continuous variable) expressing FU treatment intensity showed that dose did not influence survival contrary to the AUC (P = .001). The AUC remains significant (P = .025) in a multivariate analysis including tumor stage, demonstrating that the greater the FU systemic exposure, the longer the survival. CONCLUSION These results strengthen the interest of individual FU dose adaptation based on pharmacokinetics.

Comparative Pharmacokinetic Study of Continuous Venous Infusion Fluorouracil and Oral Fluorouracil With Eniluracil in Patients With Advanced Solid Tumors

2002 ◽  
Vol 20 (6) ◽  
pp. 1683-1691 ◽  
Author(s):  
Alex A. Adjei ◽  
Joel M. Reid ◽  
Robert B Diasio ◽  
Jeff A. Sloan ◽  
Deborah A. Smith ◽  
...  
Keyword(s):  
Steady State ◽  
Oral Administration ◽  
Dihydropyrimidine Dehydrogenase ◽  
Area Under The Curve ◽  
Clinical Activity ◽  
Moderate Activity ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Venous Infusion ◽  
Continuous Venous Infusion

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α–fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (CP) and area under the curve (AUC)144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state CP and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.

Pembrolizumab as first-line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC): Phase 2 results from CARSKIN.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9547-9547 ◽  
Author(s):  
Eve Maubec ◽  
Marouane Boubaya ◽  
Peter Petrow ◽  
Nicole Basset-Seguin ◽  
Jean Jacques Grob ◽  
...  
Keyword(s):  
Tumor Response ◽  
Blocking Agent ◽  
Median Number ◽  
First Line ◽  
Stage Design ◽  
First Line Therapy ◽  
Independent Review ◽  
Line Setting ◽  
Ecog Ps

9547 Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556.

scholarly journals Outcomes of first-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥50%) metastatic NSCLC at US oncology practices

Immunotherapy ◽  
2019 ◽  
Vol 11 (18) ◽  
pp. 1541-1554 ◽  
Author(s):  
Vamsidhar Velcheti ◽  
Sheenu Chandwani ◽  
Xin Chen ◽  
M Catherine Pietanza ◽  
Bilal Piperdi ◽  
...  
Keyword(s):  
Real World ◽  
Tumor Response ◽  
Progression Free Survival ◽  
Small Cell Lung ◽  
First Line ◽  
Free Survival ◽  
Metastatic Nsclc ◽  
Kaplan Meier ◽  
Tumor Expression

Aim: To determine real-world outcomes with first-line pembrolizumab monotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor expression ≥50%. Methods: This retrospective study included adults with ECOG 0–1 initiating first-line pembrolizumab monotherapy on/after 24 October 2016 (EHR cohort) or from 1 December 2016 through 30 November 2017 (spotlight cohort) with ≥6-month follow-up. We estimated Kaplan–Meier overall survival (OS, both cohorts), and, for spotlight, real-world progression-free survival (rwPFS) by Kaplan–Meier and real-world tumor response (rwTR). Results: For 423 patients in the EHR cohort and 188 in spotlight, median OS was 18.9 months (95% CI: 14.9–25.5) and 19.1 months (12.6-not reached), respectively. For spotlight, median rwPFS was 6.8 months (5.3–8.1); rwTR of complete/partial response was 48% (41–56%). Conclusion: Observed OS, rwPFS and rwTR were consistent with clinical trial findings.

scholarly journals CD276-Positive Circulating Endothelial Cells Do Not Predict Response to Systemic Therapy in Advanced Colorectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 124 ◽  
Author(s):  
Elske C. Gootjes ◽  
Jaco Kraan ◽  
Tineke E. Buffart ◽  
Lotte Bakkerus ◽  
Barbara M. Zonderhuis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Systemic Therapy ◽  
Progressive Disease ◽  
Area Under The Curve ◽  
Poor Response ◽  
Circulating Endothelial Cells ◽  
First Line ◽  
Response Area

CD276 can discriminate between tumor derived and normal CECs (circulating endothelial cells). We evaluated whether CD276+CEC is a clinically relevant biomarker to predict response to palliative systemic therapy in patients with metastatic colorectal cancer (mCRC). Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial (NCT01792934). At baseline and after three cycles of 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, CECs were measured by flowcytometry (CD34+CD45negCD146+DNA+; and CD276+). A clinically relevant cut-off value of (CD276+)CECs was determined as 100% sensitivity (and 80% specificity in 95% confidence interval) identifying patients with progressive disease within 6 months. There were 182 baseline samples and 133 follow up samples available for analysis. CEC and CD276+CEC counts significantly increased during treatment from 48 to 90 CEC/4 mL (p = 0.00) and from 14 to 33 CD276+CEC/4 mL (p = 0.00) at baseline and at first evaluation, respectively. CEC and CD276+CEC counts were not predictive for poor response (area under the curve (AUC) 0.53 for CEC and AUC 0.52 for CD276+CEC). Despite numerical changes during therapy, CEC and CD276+CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC.

scholarly journals Serum urate and cardiovascular events in the DCCT/EDIC study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alicia J. Jenkins ◽  
Barbara H. Braffett ◽  
Arpita Basu ◽  
Ionut Bebu ◽  
Samuel Dagogo-Jack ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Serum Urate ◽  
Continuous Variable ◽  
Major Adverse Cardiovascular Events ◽  
Normal Range ◽  
The Metabolic Syndrome ◽  
Routine Measurement

AbstractIn type 2 diabetes, hyperuricemia is associated with cardiovascular disease (CVD) and the metabolic syndrome (MetS), but associations in type 1 diabetes (T1D) have not been well-defined. This study examined the relationships between serum urate (SU) concentrations, clinical and biochemical factors, and subsequent cardiovascular events in a well-characterized cohort of adults with T1D. In 973 participants with T1D in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), associations were defined between SU, measured once in blood collected 1997–2000, and (a) concurrent MetS and (b) incident ‘any CVD’ and major adverse cardiovascular events (MACE) through 2013. SU was higher in men than women [mean (SD): 4.47 (0.99) vs. 3.39 (0.97) mg/dl, respectively, p < 0.0001], and was associated with MetS features in both (men: p = 0.0016; women: p < 0.0001). During follow-up, 110 participants (11%) experienced “any CVD”, and 53 (5%) a MACE. Analyzed by quartiles, SU was not associated with subsequent CVD or MACE. In women, SU as a continuous variable was associated with MACE (unadjusted HR: 1.52; 95% CI 1.07–2.16; p = 0.0211) even after adjustment for age and HbA1c (HR: 1.47; 95% CI 1.01–2.14; p = 0.0467). Predominantly normal range serum urate concentrations in T1D were higher in men than women and were associated with features of the MetS. In some analyses of women only, SU was associated with subsequent MACE. Routine measurement of SU to assess cardiovascular risk in T1D is not merited.Trial registration clinicaltrials.gov NCT00360815 and NCT00360893.

scholarly journals Efficacy of two-week therapy with doxycycline-based quadruple regimen versus levofloxacin concomitant regimen for helicobacter pylori infection: a prospective single-center randomized controlled trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marouf Alhalabi ◽  
Mohammed Waleed Alassi ◽  
Kamal Alaa Eddin ◽  
Khaled Cheha
Keyword(s):  
Clinical Trial ◽  
Helicobacter Pylori ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Controlled Trial ◽  
Helicobacter Pylori Infection ◽  
First Line ◽  
Link Type ◽  
Syrian Population

Abstract Background Antibiotic-resistance reduces the efficacy of conventional triple therapy for Helicobacter Pylori infections worldwide, which necessitates using various treatment protocols. We used two protocols, doxycycline-based quadruple regimen and concomitant levofloxacin regimen. The aim was to assess the effectiveness of doxycycline-based quadruple regimen for treating Helicobacter Pylori infections compared with levofloxacin concomitant regimen as empirical first-line therapy based on intention-to-treat (ITT) and per-protocol analyses (PPA) in Syrian population. Settings and design An open-label, randomised, parallel, superiority clinical trial. Methods We randomly assigned 78 naïve patients who tested positive for Helicobacter Pylori gastric infection, with a 1:1 ratio to (D-group) which received (bismuth subsalicylate 524 mg four times daily, doxycycline 100 mg, tinidazole 500 mg, and esomeprazole 20 mg, each twice per day for 2 weeks), or (L-group) which received (levofloxacin 500 mg daily, tinidazole 500 mg, amoxicillin 1000 mg, and esomeprazole 20 mg each twice per day for two weeks). We confirmed Helicobacter Pylori eradication by stool antigen test 8 weeks after completing the treatment. Results Thirty-nine patients were allocated in each group. In the D-group, 38 patients completed the follow-up, 30 patients were cured. While in the L-group, 39 completed the follow-up, 32patients were cured. According to ITT, the eradication rates were 76.92%, and 82.05%, for the D-group and L-group respectively. Odds ratio with 95% confidence interval was 1.371 [0.454–4.146]. According to PPA, the eradication rates were 78.9%, and 82.05% for the D-group and L-group respectively. The odds ratio with 95% confidence interval was 1.219 [0.394–3.774]. We didn’t report serious adverse effects. Conclusions Levofloxacin concomitant therapy wasn’t superior to doxycycline based quadruple therapy. Further researches are required to identify the optimal first-line treatment for Helicobacter-Pylori Infection in the Syrian population. Trial registration We registered this study as a standard randomized clinical trial (Clinicaltrial.gov, identifier-NCT04348786, date:29-January-2020).

scholarly journals Using advanced analysis of multifocal visual-evoked potentials to evaluate the risk of clinical progression in patients with radiologically isolated syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. M. Miguel ◽  
M. Roldán ◽  
C. Pérez-Rico ◽  
M. Ortiz ◽  
L. Boquete ◽  
...  
Keyword(s):  
Evoked Potentials ◽  
Visual Evoked Potentials ◽  
Area Under The Curve ◽  
Multifocal Visual Evoked Potentials ◽  
Radiologically Isolated Syndrome ◽  
Advanced Analysis ◽  
The Time Domain ◽  
Visual Evoked

AbstractThis study aimed to assess the role of multifocal visual-evoked potentials (mfVEPs) as a guiding factor for clinical conversion of radiologically isolated syndrome (RIS). We longitudinally followed a cohort of 15 patients diagnosed with RIS. All subjects underwent thorough ophthalmological, neurological and imaging examinations. The mfVEP signals were analysed to obtain features in the time domain (SNRmin: amplitude, Latmax: monocular latency) and in the continuous wavelet transform (CWT) domain (bmax: instant in which the CWT function maximum appears, Nmax: number of CWT function maximums). The best features were used as inputs to a RUSBoost boosting-based sampling algorithm to improve the mfVEP diagnostic performance. Five of the 15 patients developed an objective clinical symptom consistent with an inflammatory demyelinating central nervous system syndrome during follow-up (mean time: 13.40 months). The (SNRmin) variable decreased significantly in the group that converted (2.74 ± 0.92 vs. 4.07 ± 0.95, p = 0.01). Similarly, the (bmax) feature increased significantly in RIS patients who converted (169.44 ± 24.81 vs. 139.03 ± 11.95 (ms), p = 0.02). The area under the curve analysis produced SNRmin and bmax values of 0.92 and 0.88, respectively. These results provide a set of new mfVEP features that can be potentially useful for predicting prognosis in RIS patients.

scholarly journals Saliva RNA biomarkers predict concussion duration and detect symptom recovery: a comparison with balance and cognitive testing

2021 ◽  
Author(s):  
Gregory Fedorchak ◽  
Aakanksha Rangnekar ◽  
Cayce Onks ◽  
Andrea C. Loeffert ◽  
Jayson Loeffert ◽  
...  
Keyword(s):  
Test Performance ◽  
Area Under The Curve ◽  
Prediction Rule ◽  
Cognitive Testing ◽  
Cognitive Test ◽  
Clinical Tool ◽  
Post Injury ◽  
Symptom Recovery ◽  
Cognitive Test Performance

Abstract Objective The goals of this study were to assess the ability of salivary non-coding RNA (ncRNA) levels to predict post-concussion symptoms lasting ≥ 21 days, and to examine the ability of ncRNAs to identify recovery compared to cognition and balance. Methods RNA sequencing was performed on 505 saliva samples obtained longitudinally from 112 individuals (8–24-years-old) with mild traumatic brain injury (mTBI). Initial samples were obtained ≤ 14 days post-injury, and follow-up samples were obtained ≥ 21 days post-injury. Computerized balance and cognitive test performance were assessed at initial and follow-up time-points. Machine learning was used to define: (1) a model employing initial ncRNA levels to predict persistent post-concussion symptoms (PPCS) ≥ 21 days post-injury; and (2) a model employing follow-up ncRNA levels to identify symptom recovery. Performance of the models was compared against a validated clinical prediction rule, and balance/cognitive test performance, respectively. Results An algorithm using age and 16 ncRNAs predicted PPCS with greater accuracy than the validated clinical tool and demonstrated additive combined utility (area under the curve (AUC) 0.86; 95% CI 0.84–0.88). Initial balance and cognitive test performance did not differ between PPCS and non-PPCS groups (p > 0.05). Follow-up balance and cognitive test performance identified symptom recovery with similar accuracy to a model using 11 ncRNAs and age. A combined model (ncRNAs, balance, cognition) most accurately identified recovery (AUC 0.86; 95% CI 0.83–0.89). Conclusions ncRNA biomarkers show promise for tracking recovery from mTBI, and for predicting who will have prolonged symptoms. They could provide accurate expectations for recovery, stratify need for intervention, and guide safe return-to-activities.

scholarly journals Metformin use and long-term risk of benign prostatic hyperplasia: a population-based cohort study

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e041875
Author(s):  
Mette Nørgaard ◽  
Bianka Darvalics ◽  
Reimar Wernich Thomsen
Keyword(s):  
Cohort Study ◽  
Benign Prostatic Hyperplasia ◽  
Cox Regression ◽  
Population Based ◽  
Prostatic Hyperplasia ◽  
Haemoglobin A1c ◽  
First Line ◽  
Intention To Treat ◽  
Lowering Drug

ObjectiveTo assess whether metformin use affects risk of benign prostatic hyperplasia (BPH) by comparing the risk of BPH in men with type 2 diabetes who initiated first-line treatment with either metformin or sulfonylurea monotherapy between 2000 or 2006 in Northern Denmark. In this period, sulfonylurea and metformin were both frequently used as first-line glucose-lowering drug (GLD) treatment.DesignA population-based cohort study.SettingNorthern Denmark.ParticipantsAll men who filled at least two prescriptions for metformin or for sulfonylurea, respectively, during their first 6 months of GLD treatment. Follow-up started 6 months after treatment start.Primary outcome measuresRates of subsequent BPH, identified based on community prescriptions for BPH-related treatment or hospital BPH diagnoses, and rates of transurethral resection of the prostate (TURP). Rates in metformin and sulfonylurea users were compared overall and stratified by 6-month haemoglobin A1c (HbA1c) using Cox regression and an intention-to-treat (ITT) approach and an as-treated analysis.ResultsDuring follow-up, less than five persons were lost to follow-up due to emigration. In 3953 metformin initiators with a median follow-up of 10 years, the 10-year cumulative BPH incidence was 25.7% (95% CI 24.2 to 27.1). Compared with 5958 sulfonylurea users (median follow-up 8 years, 10-year cumulative incidence 27.4% (95% CI 26.2 to 28.6)), the crude HR for BPH was 0.83 (95% CI 0.77 to 0.89) and adjusted HR in the ITT analyses was 0.97 (95% CI 0.88 to 1.06). For TURP, the adjusted HR was 0.96 (95% CI 0.63 to 1.46). In the as-treated analysis, adjusted HR for BPH was 0.91 (95% CI 0.81 to 1.02).ConclusionsCompared with sulfonylurea, metformin did not substantially reduce the incidence of BPH in men with diabetes.

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