scholarly journals An Algorithm to Define the Optimum Biological Dose of Metronomic Chemotherapy

2018 ◽  
Vol 55 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Atanu Bhattacharjee ◽  
Vijay M. Patil ◽  
Vanita Noronha ◽  
Amit Joshi ◽  
Kumar Prabhash
Keyword(s):  
Effective Dose ◽  
Dose Response ◽  
Metronomic Chemotherapy ◽  
Threshold Value ◽  
Maximum Tolerated Dose ◽  
Molecular Target ◽  
Simulation Studies ◽  
Operating Characteristics ◽  
Biological Dose ◽  
Target Agent

Summary The best effective dose of a chemotherapy is defined using the maximum tolerated dose (MTD) of toxicity. It is possible that the toxicity of a dose may increase when the dose-response curve is not monotonic. In the case of metronomic chemotherapy (MC) a 1/10th level of MC dose is considered as a targeted dose of therapy and is safer in terms of toxicity levels. The objective of this study is to develop an algorithm based on the dose response model of MC to evaluate the best effective dose based on the molecular target agent. The molecular target agent is defined as the optimal biological dose achieved by the best effective dose, as the lowest dose with the highest rate of safety and efficacy. The first proposed design is parametric and assumes a logistic dose-efficacy curve for dose determination, and the second design uses quadratic regression to identify the optimal biological dose. We conducted extensive simulation studies to investigate the operating characteristics of the proposed designs. Simulation studies provide a possible way to decide on the best effective dose of MC to be considered in further phases through the finding of the optimal biological dose. The proposed design is assumed, with the threshold value of optimum biological dose (OBD), to detect the best dose of MC. This consistent design with specific dose response models can be recommended for practice.

scholarly journals A modular framework for early-phase seamless oncology trials

2021 ◽  
pp. 174077452098193
Author(s):  
Philip S Boonstra ◽  
Thomas M Braun ◽  
Elizabeth C Chase
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Response ◽  
R Package ◽  
Maximum Tolerated Dose ◽  
Response Evaluation ◽  
Operating Characteristics ◽  
Multiple Primary ◽  
Quality Design ◽  
Modular Framework

Background: As our understanding of the etiology and mechanisms of cancer becomes more sophisticated and the number of therapeutic options increases, phase I oncology trials today have multiple primary objectives. Many such designs are now “seamless,” meaning that the trial estimates both the maximum tolerated dose and the efficacy at this dose level. Sponsors often proceed with further study only with this additional efficacy evidence. However, with this increasing complexity in trial design, it becomes challenging to articulate fundamental operating characteristics of these trials, such as (1) what is the probability that the design will identify an acceptable, that is., safe and efficacious, dose level? or (2) how many patients will be assigned to an acceptable dose level on average? Methods: In this manuscript, we propose a new modular framework for designing and evaluating seamless oncology trials. Each module is comprised of either a dose assignment step or a dose-response evaluation, and multiple such modules can be implemented sequentially. We develop modules from existing phase I/II designs as well as a novel module for evaluating dose-response using a Bayesian isotonic regression scheme. Results: We also demonstrate a freely available R package called seamlesssim to numerically estimate, by means of simulation, the operating characteristics of these modular trials. Conclusions: Together, this design framework and its accompanying simulator allow the clinical trialist to compare multiple different candidate designs, more rigorously assess performance, better justify sample sizes, and ultimately select a higher quality design.

scholarly journals Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

2019 ◽  
Vol 2019 ◽  
pp. 1-31 ◽  
Author(s):  
Cem Simsek ◽  
Ece Esin ◽  
Suayib Yalcin
Keyword(s):  
Clinical Studies ◽  
Lower Cost ◽  
Metronomic Chemotherapy ◽  
Maximum Tolerated Dose ◽  
Cancer Management ◽  
The Past ◽  
Promising Therapeutic Approach ◽  
Treatment Models ◽  
Dose Dense ◽  
Preclinical And Clinical Studies

Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.

Epidemiological studies of CT scans and cancer risk: the state of the science

2021 ◽  
Vol 94 (1126) ◽  
pp. 20210471 ◽  
Author(s):  
Amy Berrington de Gonzalez ◽  
Elisa Pasqual ◽  
Lene Veiga
Keyword(s):  
Brain Tumors ◽  
Effective Dose ◽  
Dose Response ◽  
Public Health Problem ◽  
Epidemiological Studies ◽  
Ct Scans ◽  
Medical Record Linkage ◽  
Cancer Risks ◽  
Organ Doses ◽  
Study Methodology

20 years ago, 3 manuscripts describing doses and potential cancer risks from CT scans in children raised awareness of a growing public health problem. We reviewed the epidemiological studies that were initiated in response to these concerns that assessed cancer risks from CT scans using medical record linkage. We evaluated the study methodology and findings and provide recommendations for optimal study design for new efforts. We identified 17 eligible studies; 13 with published risk estimates, and 4 in progress. There was wide variability in the study methodology, however, which made comparison of findings challenging. Key differences included whether the study focused on childhood or adulthood exposure, radiosensitive outcomes (e.g. leukemia, brain tumors) or all cancers, the exposure metrics (e.g. organ doses, effective dose or number of CTs) and control for biases (e.g. latency and exclusion periods and confounding by indication). We were able to compare results for the subset of studies that evaluated leukemia or brain tumors. There were eight studies of leukemia risk in relation to red bone marrow (RBM) dose, effective dose or number of CTs; seven reported a positive dose–response, which was statistically significant (p < 0.05) in four studies. Six of the seven studies of brain tumors also found a positive dose–response and in five, this was statistically significant. Mean RBM dose ranged from 6 to 12 mGy and mean brain dose from 18 to 43 mGy. In a meta-analysis of the studies of childhood exposure the summary ERR/100 mGy was 1.78 (95%CI: 0.01–3.53) for leukemia/myelodisplastic syndrome (n = 5 studies) and 0.80 (95%CI: 0.48–1.12) for brain tumors (n = 4 studies) (p-heterogeneity >0.4). Confounding by cancer pre-disposing conditions was unlikely in these five studies of leukemia. The summary risk estimate for brain tumors could be over estimated, however, due to reverse causation. In conclusion, there is growing evidence from epidemiological data that CT scans can cause cancer. The absolute risks to individual patients are, however, likely to be small. Ongoing large multicenter cohorts and future pooling efforts will provide more precise risk quantification.

Determining an Optimum Biological Dose of A Metronomic Chemotherapy

2021 ◽  
Vol 15 (1) ◽  
pp. 77-94
Author(s):  
Atanu Bhattacharjee ◽  
Vijay M Patil
Keyword(s):  
Metronomic Chemotherapy ◽  
Biological Dose

scholarly journals Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 332 ◽  
Author(s):  
Maharjan ◽  
Pangeni ◽  
Jha ◽  
Choi ◽  
Chang ◽  
...  
Keyword(s):  
Cell Monolayer ◽  
Angiogenesis Inhibitor ◽  
Xenograft Model ◽  
Metronomic Chemotherapy ◽  
Fold Increase ◽  
Oral Formulation ◽  
Treated Group ◽  
Maximum Tolerated Dose ◽  
Oral Route ◽  
Angiogenic Effect

Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was first complexed ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as the permeation enhancer. This was followed by dispersion with poloxamer 188 and Labrasol to form the solid oral formulation of PMX (PMX/DCK-OP). PMX/DCK-OP exhibited a 10.6-fold increase in permeability across a Caco-2 cell monolayer compared to PMX alone. This resulted in a 70-fold increase in the oral bioavailability of PMX/DCK-OP in mice over oral PMX alone. In the A549 xenograft model, tumor volume was reduced by 51.1% in the PMX/DCK-OP treated group compared to only 32.8% in the maximum tolerated dose (MTD)-treated group. Furthermore, PMX/DCK-OP exhibited a significant anti-angiogenic effect on the A549 xenograft mice when compared to the MTD-treated group, as indicated by microvessel density quantification for CD-31. In addition, PMX/DCK-OP enhanced the release of an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), into both the blood circulation and the tumor microenvironment. Therefore, due to its oral route of administration, PMX/DCK-OP appears to be a better alternative to the conventional treatment of PMX.

Metastatic feline mammary cancer: prognostic factors, outcome and comparison of different treatment modalities – a retrospective multicentre study

2020 ◽  
pp. 1098612X2096441
Author(s):  
Gonçalo Petrucci ◽  
Joaquim Henriques ◽  
Hugo Gregório ◽  
Gonçalo Vicente ◽  
Justina Prada ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Adjuvant Treatment ◽  
Imaging Techniques ◽  
Treatment Options ◽  
Clinical Signs ◽  
Stage Iv ◽  
Metronomic Chemotherapy ◽  
Maximum Tolerated Dose ◽  
Treatment Modalities ◽  
Number Of Patients

Objectives Although feline mammary carcinomas (FMCs) are highly metastatic, the literature and treatment options pertaining to advanced tumours are scarce. This study aimed to investigate the clinical outcome of metastatic FMC with or without adjuvant treatment. Methods The medical records of 73 cats with metastatic FMC (stage 4) were reviewed and included in this study. Metastatic disease was detected by distinct imaging techniques (radiography, ultrasound and CT) and confirmed by cytology and/or histopathology. Cats with adjuvant chemotherapy treatment (n = 34) were divided into three groups: group 1 (n = 9) cats receiving maximum tolerated dose chemotherapy; group 2 (n = 15) cats receiving metronomic chemotherapy; and group 3 (n = 10) cats treated with toceranib phosphate. The study endpoints were time to progression (TTP) and tumour-specific survival (TSS). Treatment-related toxicity was evaluated according to the Veterinary Co-operative Oncology Group’s Common Terminology Criteria for Adverse Events version 1.1 (VCOG-CTCAE). Results Overall mean TTP and TSS were 23 and 44 days, respectively. Cats with clinical signs at the time of diagnosis had a lower TSS (14 days) than asymptomatic cats (120 days; P <0.001). Cats with pleural effusion had a lower TSS (16 days) than cats without ( P <0.001). Median TSS was 58, 75 and 63 in groups 1, 2 and 3, respectively ( P = 0.197). Toxicity was observed in 66.7%, 20% and 30% of cats in groups 1, 2 and 3, respectively. Conclusions and relevance To the best of our knowledge, this study includes the highest number of patients with metastatic FMC assessed. Despite the overall poor prognosis, some cats survived >6 months, indicating that adjuvant treatment may be an option to consider in metastatic disease. More studies are warranted for better understanding and management of stage IV patients.

Usefulness of plateletcrit in the prediction of major adverse cardiac and cerebrovascular events in patients with carotid artery stenosis

Vascular ◽  
2019 ◽  
Vol 27 (5) ◽  
pp. 479-486 ◽  
Author(s):  
Serkan Aslan ◽  
Ali Rıza Demir ◽  
Yusuf Demir ◽  
Ömer Taşbulak ◽  
Mehmet Altunova ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Carotid Stenosis ◽  
Complete Information ◽  
Threshold Value ◽  
Multivariate Regression Analysis ◽  
Adverse Outcomes ◽  
Operating Characteristics ◽  
Cerebrovascular Events ◽  
Long Term Mortality

Objectives Platelets play an important role in the pathogenesis of atherosclerosis and the physiopathology of cardiovascular events. Plateletcrit provides complete information on total platelet mass. The relationship between plateletcrit values and long-term outcomes in patients with carotid stenosis is not known. The purpose of the present study is to evaluate the reliability of plateletcrit for predicting major adverse cardiac and cerebrovascular events (MACCE) in patients with carotid stenosis. Methods A total of 230 patients with more than 50% stenosis of the carotid artery were retrospectively included in this study. All cases were divided into two groups according to the calculated threshold value of plateletcrit with receiver operating characteristics curve and baseline parameters and clinical outcomes were compared. Univariate and multivariate analyses were used to evaluate the association between the plateletcrit and MACCE. Results The cut-off value for plateletcrit was found to be 0.233 for predicting MACCE, with 56.2% sensitivity and 68.0% specificity. High plateletcrit levels were demonstrated to be statistically higher in patients with MACCE (0.247 in the MACCE (+) group vs. 0.213 in the MACCE (–) group, p < 0.001). In the Kaplan–Meier survival analysis, the long-term mortality rate was higher in the high plateletcrit group ( p = 0.006). Multivariate regression analysis showed that plateletcrit was independently associated with MACCE (OR: 2.196, CI: 1.200–4.018; p = 0.011). Conclusions Our data suggest that plateletcrit has an independently predictive value for long-term mortality and MACCE, and it can be used as a marker to predict the long-term adverse outcomes in patients with carotid stenosis.

Concentration-dependent interaction of theophylline with d-tubocurarine

1987 ◽  
Vol 62 (5) ◽  
pp. 1970-1974 ◽  
Author(s):  
N. Fuke ◽  
J. Martyn ◽  
C. S. Kim ◽  
S. Basta
Keyword(s):  
Steady State ◽  
Effective Dose ◽  
Dose Response ◽  
Postoperative Period ◽  
Statistical Significance ◽  
Surgical Patients ◽  
Response Curves ◽  
Dose Response Curves ◽  
Toxic Concentrations ◽  
Dependent Interaction

The interaction of theophylline with d-tubocurarine chloride (dTC) was examined in rabbits. After steady-state subtherapeutic (less than 10 mg/l), therapeutic (10–20 mg/l), and toxic (greater than 20 mg/l) concentrations of theophylline, dose-response curves for dTC were determined and compared with controls that received no theophylline. At therapeutic concentrations of theophylline the effective dose for 50% inhibition of twitch (ED50) for dTC (mean +/- SE, 0.115 +/- 0.016 mg/kg) was significantly shifted to the left in comparison with the control (0.165 +/-0.008 mg/kg). The ED50 of dTC for the subtherapeutic group was 0.143 +/- 0.011 mg/kg, which was less than the control but not of statistical significance (P = 0.1). The ED50 for the toxic theophylline group was 0.168 +/- 0.003 mg/kg, which was not significantly different from controls but significantly different from the theophylline therapeutic and subtherapeutic groups. Thus, toxic concentrations of theophylline reversed the potentiating effects of therapeutic and subtherapeutic concentrations of dTC dose-response curves. Therefore, depending on concentration, theophylline exhibits a biphasic interaction with dTC. Surgical patients on theophylline may require less dTC intraoperatively. More importantly, the use of theophylline in the postoperative period to reverse anesthetic effects may result in recurarization.

Sequential or combined designs for Phase I/II clinical trials? A simulation study

2019 ◽  
Vol 16 (6) ◽  
pp. 635-644 ◽  
Author(s):  
Caroline Rossoni ◽  
Aurélie Bardet ◽  
Birgit Geoerger ◽  
Xavier Paoletti
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Correct Decision ◽  
Operating Characteristics ◽  
In Series ◽  
Expansion Cohort

Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy–toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. Methods: In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy–toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. Results: For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy–toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Conclusion: As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.

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