Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study

PLOS ONE, Nov 2019

Background Regorafenib has been demonstrated as effective in refractory metastatic colorectal cancer. Combination use with chemotherapy has not been reported. We examined the efficacy and safety of adding chemotherapy to Regorafenib for the treatment of metastatic colorectal cancer(mCRC) patients. Methods We recruited mCRC patients at our institute who received either regorafenib monotherapy or regorafenib in combination with other chemotherapies. All patients had received chemo and target therapies and presented with disease progression before regorafenib treatment. The primary end point was overall survival. Findings Between September1, 2015 and May 31, 2017, 100 mCRC patients at our institute received regorafenib treatment. 39 patients were excluded due to poor performance, lack of timely treatment, or inadequate clinical data. A total of 34 patients received regorafenib combined with other chemotherapies, and 27 patients received regorafenib alone. Median follow up time was 10.4 and 6.1 months, respectively. The primary end point of median OS was higher in the combination group than in the single use group (20.9m vs 10.3m, p = 0.015). The most frequent adverse events were hand-foot skin reactions(16[47.1%]vs 12[44.4%]), fatigue(6[17.6%] vs 7[25.9%]), gastrointestinal discomfort (7[20.6%] vs 6[22.2%]), neutropenia (4[11.8%] vs 1[3.7%]), diarrhea(4[11.8%] vs 1[3.7%]), and mucositis(5[14.7%] vs 1[3.7%]). Conclusion The present study showed the efficacy and side effects of regorafenib combination treatment. Superiority in median OS and median PFS was noted in the combination group. The sampling difference between the study and observation groups effects justifies the comparison. Further clinical evidence of combination therapy efficacy is pending future studies.

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Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study

January Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study Chun-Yu Lin 0 1 2 Tseng-Hsi Lin 0 1 Chou-Chen Chen 0 1 2 Ming-Cheng Chen 0 1 2 Chou- Pin Chen 0 1 2 0 Editor: Ramon Andrade De Mello, Universidade do Algarve Departamento de Ciencias Biomedicas e Medicina , PORTUGAL 1 Current address: Department of Colorectal Surgery, Taichung Veterans General Hospital , Taichung, Taiwan, ROC 2 Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital , Taichung, Taichung, Taiwan , 2 Division of Hematology, Department of Internal Medicine, Taichung Veterans General Hospital , Taichung , Taiwan - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Background Methods Findings Between September1, 2015 and May 31, 2017, 100 mCRC patients at our institute received regorafenib treatment. 39 patients were excluded due to poor performance, lack of timely treatment, or inadequate clinical data. A total of 34 patients received regorafenib combined with other chemotherapies, and 27 patients received regorafenib alone. Median follow up time was 10.4 and 6.1 months, respectively. The primary end point of median OS was higher in the combination group than in the single use group (20.9m vs 10.3m, p = 0.015). The most frequent adverse events were hand-foot skin reactions(16[47.1%]vs 12[44.4%]), fatigue(6[17.6%] vs 7[25.9%]), gastrointestinal discomfort (7[20.6%] vs 6[22.2%]), neutropenia (4[11.8%] vs 1[3.7%]), diarrhea(4[11.8%] vs 1[3.7%]), and mucositis(5[14.7%] vs 1 [3.7%]). Conclusion The present study showed the efficacy and side effects of regorafenib combination treatment. Superiority in median OS and median PFS was noted in the combination group. The sampling difference between the study and observation groups effects justifies the comparison. Further clinical evidence of combination therapy efficacy is pending future studies. Introduction During the past few decades, the incidence of colorectal cancer has increased worldwide[1]. There were 1,363,000 newly diagnosed cases worldwide, which led to 693,900 deaths in 2012 [ 2,3 ]. The colorectal incidence in Taiwan(44.32/100000) is high. There were 15,140 newly diagnosed cases leading to 5,265 deaths in 2013[4]. Approximately 25% of patients with colorectal cancer have metastatic disease with a clinically significant detrimental effect on prognosis[ 5,6 ]. With the administration of chemotherapy and target therapy, the median overall survival time of metastatic colorectal cancer(mCRC) has improved from 12 to 33 months(in KRAS wildtype patients)[ 7,8 ].However, the response rate of chemotherapy apparently decreased in the further therapies[9±12]. The identification of a chemotherapy with a higher response rate has attracted increasing attention and is addressed in the present study. Regorafenib is an orally available, small-molecule multikinase inhibitor that targets signaling pathways implicated in tumor angiogenesis(VEGF receptors 1±3 and TIE2), oncogenesis (KIT, RET, RAF1, and BRAF), and the tumor microenvironment (platelet-derived growth factor receptor and fibroblast growth factor receptor)[ 12 ]. Evidence of activity of regorafenib in metastatic colorectal cancer was demonstrated in two international randomized Phase III trials(CORRECT and CONCUR)[ 13,14 ]. These trials indicated that regorafenib monotherapy improved overall survival compared with the placebo dose (6.4 months vs 5.0 months, hazard ratio[HR] 0.77, 95% CI 0.64±0.94; p = 0.0052 in CORRECT and 8.8 months vs 6.3 months, [HR] 0.55, 95% CI 0.40±0.77; p = 0.00016 in CONCUR). However, adverse events (AE) of regorafenib were apparent, which were most likely observed as hand-foot skin reaction(HFS), diarrhea, fatigue, and elevated liver function. Adverse events are more frequent observed in Asians, and tolerance was lower[15].Currently, clinical practice use a dose-escalation protocol at certain institutes[16,17].which may increase drug compliance and with relatively the same effect. Regorafenib was approved for the treatment of mCRC by the US Food and Drug adminis tration in September 2012[ 18 ], and approved in mCRC treatment by the Taiwan National Health Insurance Scheme (NHI) since September 2015[19]. The superiority of combination use of target therapy with chemotherapy was demonstrated in Cetuximab in 2004[ 20 ]. The effect of regorafenib combination use remains unknown. We collected mCRC patients from our institute who had received regorafenib combined with chemotherapy and compared these individuals with patients who received only reforafenib to observe differences in the therapeutic effects and side effects between these groups. Methods Study design and patien (...truncated)


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Chun-Yu Lin, Tseng-Hsi Lin, Chou-Chen Chen, Ming-Cheng Chen, Chou-Pin Chen. Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study, PLOS ONE, 2018, Volume 13, Issue 1, DOI: 10.1371/journal.pone.0190497