Efficacy of Regorafenib in Metastatic Colorectal Cancer: A Multi-institutional Retrospective Study

Aljubran, Ali; Elshenawy, Mahmoud A; Kandil, Magdy; Zahir, Muhammed; Shaheen, Ahmed A.; Gad, Ahmed; Alshaer, Omar Rezk; Alzahrani, Ahmed; Eldali, Abdelmonem; Bazarbashi, Shouki

doi:10.1177/1179554918825447

Cited by 20 publications

(14 citation statements)

References 16 publications

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“…32 A similar finding has recently been published based on a multivariate analysis of overall survival in a cohort of 78 patients with mCRC. 34 In conclusion, the population PK model incorporating EHC described in this analysis adequately describes the PK profiles of…”

Section: Discussionmentioning

confidence: 78%

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake

Keunecke

Hoefman

Drenth

et al. 2020

Brit J Clinical Pharma

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Regorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M-2 and M-5 in solid tumours. Methods: The model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib. This was then applied to sparsely sampled data from four phase 3 studies in patients with advanced solid tumours. The need for exact food intake data to estimate individual drug exposure was evaluated. Results: By incorporating EHC, the model adequately described the PK profiles of regorafenib, M-2 and M-5 after single and multiple doses in patients from phase 1 studies. Individual exposure in phase 3 studies was adequately described based on assumptions on the time and frequency of food intake, although exact food intake data are recommended to improve the estimation. Covariate analysis identified sex and body mass index (BMI) as impacting exposure to regorafenib, and sex as strongly impacting exposure to M-2 and M-5 (also influenced by the BMI effect on parent regorafenib in the joint model developed); however, these factors accounted for a small portion of the overall variability in exposure. Conclusions: The adequate description of regorafenib PK after multiple dosing requires the incorporation of EHC. Neither single nor combined covariates predicted exposures that would warrant a priori regorafenib dose adjustment.

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Section: Discussionmentioning

confidence: 78%

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake

Keunecke

Hoefman

Drenth

et al. 2020

Brit J Clinical Pharma

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“…The replacement of FOLFOXIRI with other first-line treatment strategies is currently under development for the treatment of (metastatic) CRC. Treatment for stage IV CRC is proposed using various strategies such as (i) the combination of capecitabine and oxaliplatin [61], (ii) capecitabine, with or without a targeted drug (NCT00642603) [62,63], (iii) cetuximab (epidermal growth factor receptor inhibitor) [64] and (iv) regorafenib (multi-target kinase inhibitor) [65] or bevacizumab (Avastin ® ) [26,27,66].…”

Section: Discussionmentioning

confidence: 99%

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

et al. 2020

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The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies.

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“…FOLFIRI is a combination of 5-FU, folic acid, and irinotecan (topoisomerase inhibitor) 40 . Regorafenib is a multi-receptor tyrosine kinase inhibitor 41 .…”

Section: Relationships Between Collagen Fiber Organization and Architmentioning

confidence: 99%

Simulating the human colorectal cancer microenvironment in 3D tumor-stroma co-cultures in vitro and in vivo

Devarasetty

Dominijanni

Herberg

et al. 2020

Sci Rep

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The tumor microenvironment (TME) plays a significant role in cancer progression and thus modeling it will advance our understanding of cancer growth dynamics and response to therapies. Most in vitro models are not exposed to intact body physiology, and at the same time, fail to recapitulate the extensive features of the tumor stroma. conversely, animal models do not accurately capture the human tumor architecture. We address these deficiencies with biofabricated colorectal cancer (cRc) tissue equivalents, which are built to replicate architectural features of biopsied cRc tissue. our data shows that tumor-stroma co-cultures consisting of aligned extracellular matrix (ECM) fibers and ordered micro-architecture induced an epithelial phenotype in cRc cells while disordered ecM drove a mesenchymal phenotype, similar to well and poorly differentiated tumors, respectively. Importantly, co-cultures studied in vitro, and upon implantation in mice, revealed similar tumor growth dynamics and retention of architectural features for 28 days. Altogether, these results are the first demonstration of replicating human tumor ecM architecture in ex vivo and in vivo cultures. Tumors are products of their environment. They send signals that can have significant effects on local tissue, and they receive signals from nearby cells and extracellular matrix (ECM) that can alter their progression 1-3. Despite the importance of a tumor's environment, current strategies for prognostication of tumors are centered around analyses of the tumor cells in isolation, such as morphological assessment or proliferative index calculation 4,5. Although these metrics are correlated to tumor progression, they do not capture the dynamics between a tumor and its surrounding space leading to inaccuracies when attempting to predict tumor progression and chemotherapeutic response 6,7. New technologies that improve prognostication will have a significant effect on patient mortality and lead to development of novel therapeutics which target and control tumor cells specifically, sparing healthy tissue from the deleterious effects of contemporary chemotherapeutics 8,9. Recent studies have identified the tumor microenvironment (TME) as a major contributing factor to cancer development and growth. The combination of paracrine factors, stromal cells such as endothelial, macrophages and tumor associated fibroblasts (TAFs), ECM proteins, and tissue mechanics coalesce into the perfect environment for a cancer to thrive and evade treatment 2,3. Of particular interest to our research: a number of studies have shown that tissue biomechanics 10-12 and ECM architectures 13,14 can alter and guide cancer cell phenotype, as well as alter therapeutic response. These findings indicate the TME as a potential target for innovative anti-cancer cell, or cancer-modulating, therapies. To devise TME targeting therapies, in vitro models of the TME need to be developed and validated. Many groups, including ours, have used tissue engineering techniques to fabricate tumor constructs that ...

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Efficacy of Regorafenib in Metastatic Colorectal Cancer: A Multi-institutional Retrospective Study

Cited by 20 publications

References 16 publications

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

Simulating the human colorectal cancer microenvironment in 3D tumor-stroma co-cultures in vitro and in vivo

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