الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Colorectal cancer (CRC) is a common gastrointestinal malignancy which predominantly contributes to the majority of cancer-related mortalities secondary to distant metastasis. Early detection of CRC cases with high risk of developing metastasis is crucial for early treatment to improve patient outcomes and save treatment costs. Therefore, drugging metastasis pathways represents a potential new therapeutic opportunity. Our study aimed at investigating the anti-tumor activity and safety of mebendazole in patients with metastatic colorectal cancer (mCRC). In a prospective, randomized double blind placebo-controlled study, 40 patients with mCRC were recruited from Clinical Oncology Department, Tanta University Hospital and Damanhour Oncology Center, Egypt through the period from September 2017 to November 2019. The enrolled patients were randomized into two groups: the control group (n = 20) which received 6 cycles of bevacizumab with FOLFOX4 plus placebo tablets BID and mebendazole group (n = 20) which received 6 cycles of bevacizumab with FOLFOX4 plus mebendazole 500 mg orally BID for three months. Serum levels of chromosome segregation 1 like /cellular apoptosis susceptibility protein (CSE1L/CAS), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and carcinoembryonic antigen (CEA) were assessed at baseline and 3 months after treatment. Also, serum VEGF/PLTs and serum MMP-2/PLTs were calculated for correction of variation in PLTs. Assessment of liver, renal and hematological parameters were carried out at baseline and after 3 months to record the undesired adverse effects. Moreover, chest, abdominal and pelvic CT scanning was performed at baseline and 3 months after treatment to determine overall response rate (ORR) and disease control rate (DCR). ORR and DCR were determined after median treatment duration of 12 months (4-14 months). One-year overall survival (OS) and progression free survival (PFS) were also determined. Our study results showed that, mebendazole was well tolerated and its addition to bevacizumab and FOLFOX4 resulted in enhancement of tumor response to treatment translated by significant improvement of ORR and DCR three months after treatment and significant elevation of PFS. There was non-significant variation in ORR and DCR after median treatment duration of 12 months (4-14 months) and in 1- year OS. Furthermore, mebendazole produced significant decline in serum levels of CSE1L/CAS, VEGF, MMP-2 with non-significant variation in CEA, liver, renal and hematological parameters. Furthermore, mebendazole significantly decreased serum VEGF/PLTs and MMP-2/PLTs ratios. Correlation results postulated that, VEGF showed significant positive correlations with MMP-2, PLT count and CT scan results in mebendazole group after 3 months. Additionally, after 3 months, MMP-2 showed a significant positive correlation with CSEIL/CAS in mebendazole group. In conclusion, mebendazole may represent an attractive candidate for drug repositioning against mCRC secondary to its safety and efficacy in enhancing tumor response to treatment. Therefore, mebendazole is regarded a promising adjuvant therapy to chemotherapy and targeted therapy with low cost. Despite our promising results, we recommend further large scale studies with implication of higher doses of mebendazole to make a more comprehensive decision about the role of mebendazole in mCRC.