Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists

Rey, Jean‐Baptiste; Launay-Vacher, Vincent; Tournigand, Christophe

doi:10.1007/s11523-014-0333-x

Cited by 52 publications

(35 citation statements)

References 32 publications

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“…Proliferation and migration of colon cancer cells were analyzed in the presence or absence of regorafenib (2.5, 5, 10, and 20 μM) in real‐time by using Incucyte Zoom. Compared with control cells, proliferation and migration of all the tumor cell lines were inhibited by clinically effective concentrations of regorafenib (5–8 μM) irrespective of their KRAS and BRAF mutation status (Fig. ).…”

Section: Resultsmentioning

confidence: 98%

Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma

et al. 2016

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Interaction between tumor cells and stromal cells plays an important role in the growth and metastasis of colon cancer. We previously found that carcinoma‐associated fibroblasts (CAFs) expressed platelet‐derived growth factor receptor‐β (PDGFR‐β) and that PDGFR targeted therapy using imatinib or nilotinib inhibited stromal reaction. Bone marrow‐derived mesenchymal stem cells (MSCs) migrate to tumor stroma and differentiate into CAFs. A novel oral multikinase inhibitor regorafenib inhibits receptor tyrosine kinases expressed on stromal cells (vascular endothelial growth factor receptor 1–3, TIE2, PDGFR‐β, and fibroblast growth factors) and tumor cells (c‐KIT, RET, and BRAF). These molecules are involved in tumor growth, angiogenesis, lymphangiogenesis, and stromal activation. Therefore, we examined whether regorafenib impaired the tumor‐promoting effect of CAFs/MSCs. KM12SM human colon cancer cells alone or KM12SM cells with MSCs were transplanted into the cecal wall of nude mice. Co‐implantation of KM12SM cells with MSCs into the cecal wall of nude mice produced tumors with abundant stromal component and promoted tumor growth and lymph node metastasis. Single treatment with regorafenib inhibited tumor growth and metastasis by inhibiting both tumor cells and stromal reaction. This tumor‐inhibitory effect of regorafenib was more obvious in tumors developed by co‐implanting KM12SM cells with MSCs. Our data suggested that targeting of the tumor microenvironment with regorafenib affected tumor cell–MSC interaction, which in turn inhibited the growth and metastasis of colon cancer.

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Section: Resultsmentioning

confidence: 98%

Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma

et al. 2016

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“…The first question related to the optimal treatment choice and sequence at the refractory mCRC setting. Treatment options for refractory mCRC include: (1) the oral multikinase inhibitor regorafenib, which blocks the activity of protein kinases involved in tumor angiogenesis (including VEGF receptors 1–3), oncogenesis (including BRAF V600E and RAF‐1) and the tumor microenvironment (including platelet‐derived growth factor receptor and fibroblast growth factor receptor); (2) the oral combination drug TAS‐102, which contains the cytotoxic thymidine‐based nucleic acid analogue trifluridine and a thymidine phosphorylase inhibitor, tipiracil hydrochloride; and (3) “rechallenge” with prior chemotherapy and/or targeted therapy . To our knowledge, no randomized clinical trial has directly compared these options or different sequences for their use.…”

Section: Introductionmentioning

confidence: 99%

Real‐world treatment patterns and outcomes in refractory metastatic colorectal cancer

Chiang

Choi

Lam

et al. 2019

Asia-Pac J Clncl Oncology

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Aim To investigate treatment patterns and outcomes of metastatic colorectal cancer (mCRC) patients beyond second progression (PD2) since regorafenib and TAS‐102 became available in Hong Kong. Methods The clinical records of consecutive mCRC patients who were treated beyond PD2 at Department of Clinical Oncology, Queen Mary Hospital between June 2013 and February 2018, were retrospectively reviewed. Results Of 176 PD2 patients (76.7% Eastern Cooperative Oncology Group performance status 0/1 and a median follow‐up time of 6.6 [range, 0.4–37.2] months), 104 (59%) underwent palliative care only and 72 (41%) received active third‐line (3L) treatment: regorafenib (n = 22), TAS‐102 (n = 6), chemotherapy + antiepidermal growth factor receptor (n = 12), chemotherapy + antivascular endothelial growth factor (n = 28) or clinical trials (n = 4). Patients on active 3L treatment had significantly longer OS than those on palliative care only: 11.7 versus 5.5 months (adjusted hazard ratio = 0.41, 95% confidence interval: 0.28–0.61, P < 0.001). For those on active treatment, OS was significantly associated with the time from diagnosis of metastasis to PD2 (P < 0.001) and post‐3L treatments (P = 0.009). When analyzing treatment eligibility according to trial criteria, half of the eligible patients (54/109) did not receive active treatment, but both eligible and ineligible patients achieved better OS when receiving active 3L treatment versus palliative care only (P < 0.001 and P = 0.002). No unexpected toxicity was reported. Conclusion Active 3L and beyond treatment significantly prolonged OS versus palliative care, even in selected “trial ineligible” patients. Given a high rate of palliation only care in eligible patients, improved patient access to medicine and counseling may be needed to maximize outcomes.

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“…The area under the curve of regorafenib treatment varied for intake of the same dose, depending on the individual. Regorafenib was metabolized to M-2 and M-5, which act through CYP3A4 (6). UGT1A9 is associated with the inactivation of these products through glucuronate conjugation (6).…”

Section: Discussionmentioning

confidence: 99%

“…Regorafenib was metabolized to M-2 and M-5, which act through CYP3A4 (6). UGT1A9 is associated with the inactivation of these products through glucuronate conjugation (6). Therefore, the UGT1A9 gene polymorphism may be associated with the toxicity of regorafenib.…”

Section: Discussionmentioning

confidence: 99%

Pseudocirrhosis caused by regorafenib in an advanced rectal cancer patient with multiple liver metastases

Kumamoto

Endo

Isohata

et al. 2016

Molecular and Clinical Oncology

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Abstract.A 70-year-old man who was diagnosed with unresectable advanced rectal cancer with multiple liver metastases, received oxaliplatin-based treatment with bevacizumab as first-line chemotherapy and irinotecan-based treatment with bevacizumab as second-line chemotherapy for a total of 17 months. The patient was treated with regorafenib (160 mg/day for 3 weeks) as third-line chemotherapy. Following completion of one course of regorafenib treatment, the patient complained of abdominal distension. Computed tomography (CT) examination identified liver atrophy and massive ascites, while no such symptoms were observed prior to the regorafenib treatment. Blood testing revealed increases in the aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels. The patient was admitted to the Aizu Medical Center (Aizuwakamatsu, Japan). Approximately 2,000 ml of ascitic fluid were aspirated daily for 1 week by abdominal puncture. The patient was administered oral diuretics, including 20 mg/day of furosemide and 25 mg/day of spironolactone. Albumin was administered to correct the albumin deficit. The levels of AST, ALT and ALP were decreased from the peak value reported on admission and the patient was discharged from our hospital 16 days following treatment initiation. The CT examination after 1 month revealed that the volume of the liver had been restored and the ascites had disappeared. Furthermore, almost all the liver metastases were reduced in size. The carcinoembryonic antigen level, which was elevated prior to regorafenib treatment, also decreased to normal.

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Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists

Cited by 52 publications

References 32 publications

Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma

Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma

Real‐world treatment patterns and outcomes in refractory metastatic colorectal cancer

Pseudocirrhosis caused by regorafenib in an advanced rectal cancer patient with multiple liver metastases

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