Role of Metformin in the Management of Colorectal Cancer: A Systematic Review

Colorectal cancer (CRC) is the second-leading cause of mortality and morbidity worldwide with multiple standard therapies that failed to improve outcomes. Metformin, an old, repurposed medication with pleiotropic effect in many cancers, arises as a possible treatment for CRC. This review aimed to assess the effect of metformin in addition to the treatment plan of CRC patients. To identify relevant studies, Google Scholar, PubMed, Egyptian Knowledge Bank (EKB), and clinical trial.gov were systematically searched. Pre-defined search keywords were used as “Metformin”, “colorectal cancer”, “randomized controlled trials”, “interventional studies”, and “observational studies”. Only English-based trials that are in full text were included. A total of 19 studies with different therapeutic adjuvant treatment options were evaluated for metformin treatment effects in CRC. Randomized control trials and observational studies were the main interest of the review while preventive and pre-clinical studies including animals and cell lines were excluded. In conclusion , Most of the studies except a few showed promising results on overall survival (OS), disease-free survival, and relapse-free time for metformin use as treatment in CRC. Also, a reductive effect of metformin was shown in toxicities as oxaliplatin-induced peripheral neuropathy and poor prognostic features as vessel co-option vasculature in liver metastasis. Future clinical randomized controlled studies are essential to confirm these results.


Introduction
Colorectal cancer is the third-leading type of cancer with a high incidence rate accounting for almost 1.9 million new cases every year.Not only that, it ranks as the second deadliest cancer type with almost 930,000 cases per year worldwide [1].These high rates of CRC may be related to multiple factors including missed diagnosis, lack of early screening, and lifestyle habits [2].
Several risk factors are associated with the development of CRC.Lifestyle habits such as physical inactivity, obesity, westernized diet, alcohol intake, and smoking are the main stimulators for CRC initiation [3].Moreover, hereditary genetic mutations in family members such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC) may induce gene alterations or inhibit repair systems that promote colorectal cell growth, the transformation of polyp into malignant cell and progression [4].Also, longstanding colitis as in inflammatory bowel diseases; ulcerative colitis, and Crohn's disease, increases cell turnover and promotes CRC malignancy [5].
The complexity of CRC pathogenesis is the main factor for late diagnosis, as the time from induction of benign adenoma from hyperproliferative rapidly dividing cells till enlargement then transformation of adenoma to cancer via a series of alterations takes minimally from 10 up to 18 years [6].Furtherly, in advanced stages of cancer, some of these cancerous adenomas may even spread via blood or lymphatic system to other parts of the body and metastasize [7].The detection of such precarious development is laborious and requires early notification that can only be achieved through screening, especially in high-risk patients such as the elderly, patients with a family history, or comorbidities like diabetes.Frequently, noninvasive tools such as fecal occult blood test (FOBT) and fecal immuno-chemical test (FIT) are used to detect CRC presence.However, a confirmation of CRC pathological malignancy can only be achieved through invasive endoscopy with its different scopes [3,8].
The management of CRC varies from surgery either curative or palliative, radiation, systematic chemotherapies, and immunotherapies to innovative targeted therapy.Early stages like stages 0-II, are generally treated with curative surgical resection, unlike late stages which require systemic therapy alongside surgery [9].The choice of such therapies as systematic chemotherapies, immunotherapies, or targeted therapy is mainly based on the stage of CRC, resectability of cancer, and cost of therapy [10].
Multiple challenges are associated with immune and targeted therapies use, including high cost that isn't feasible for developing countries while systematic chemotherapies pose a high toxicity burden, increasing rates of resistance, and progressive treatment failure.Thus, a need for novel therapeutic options became an urgent necessity for CRC management [11].
Drug repurposing is one of the emerging strategies for developing new therapeutic options for an existing medication without the hassle of time consumption and cost wasting.These drugs not only offer known safety and tolerability but also may improve clinical outcomes and overcome resistance [12].Metformin, a guanide derivative, originally used as a first-line antidiabetic medication for type II diabetes mellitus, was found to have a pleiotropic effect in multiple comorbidities including cancer [13].The antineoplastic effect of metformin is related to its induction and inhibition of diverse pathways.For instance, metformin's stimulatory effect on 5adenosine monophosphate-activated protein kinase (AMPK), allows the regulation of the tumorigenesis process via inhibition of the mammalian target of rapamycin (mTOR).Also, metformin-AMPK activation leads to stimulation of liver kinase B1 (LKB1)/tuberin-sclerosis complex 2 (TSC2), which suppresses hyperproliferation of CRC cells [14].Another pathway is the metformin inhibitory effect on insulin-like growth factor (IGF-1) which is majorly responsible for CRC initiation, progression, metastasis, and survival via proliferative downstream pathways as phosphatidylinositol 3 kinases (PI3K)/Akt/mTOR and RAS/RAF/mitogen [15, 16].

Material and methods
These systematic review findings were reported using the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines (http://www.prisma-statement.org).
(https://clinicaltrials.gov/).These electronic databases were accessed from the 3 rd of September to the 5 th of October 2023.Clinical trials till October 2023 were analyzed.Search terms used were "metformin treatment in colorectal cancer", "metformin and colorectal cancer: randomized controlled studies", "metformin treatment in colorectal observational studies ", and "metformin treatment and CRC".

Study screening and selection
Original English-written full-text trials were selected for inclusion in this review.Basic information such as the name of the main author, year of publication, study design, sample size, patient population, intervention, and control used, outcomes, and conclusions were reviewed for randomized control trials and observational studies used in this review.

Eligibility criteria
Inclusion criteria were randomized control trials (RCT), non-randomized clinical trials, and observational studies using metformin available in full-text version conducted on any stage of CRC.Preventive CRC studies, pre-clinical studies either in vitro or in vivo, and abstractonly clinical trials were excluded.

Results
The flow chart of study selection is demonstrated in Fig. 1.A total of 58761 studies were found during the investigational scholarly search.We eliminated 208 duplicate studies, 31,200 pre-clinical in vivo and in vitro studies, 27,200 preventive studies, 77 systematic review articles, and meta-analyses.The remaining qualified full text were 19 studies that evaluated the effect of metformin treatment in different stages of CRC.

Discussion
Throughout the years, the effect of metformin and its possible beneficial antineoplastic effects when added to CRC treatment plan have been explored.A single-arm study by Miranda et  Since diabetes poses a high risk for CRC, most of the observational studies either cohorts or retrospective compared the effect of metformin in diabetic CRC patients that use metformin versus non-metformin users.For instance, the Lee et al. cohort study on 219 stage II/III diabetic CRC assessed the effect between metformin users and non-metformin users on OS, time to recurrence, and relapse-free time.The metformin users were found to have better OS with a hazard ratio (HR) of 0.18, better time to recurrence, and relapsefree time with HR of 0.55 and 0.44, respectively [20].Also, Lee et al after a follow-up of 41 months for 595 stage III CRC patients, reported a decrease in mortality rate (HR 0.66) and percent mortality (27.5%) in the metformin user group versus (40.4%) in the non-metformin users.In addition, in specific CRC death, metformin users showed reduced rates of 21.3% vs. 30.9% in nonmetformin users Moreover, the retrospective study on 585 CRC patients by Zhu et al reported an association between metformin use and better OS compared to non-metformin users [22].Also, in the Kaltemeier et al cohort study, 270 CRC patients with liver metastasis who underwent hepatic resection were analyzed from January 2012 till December 2019 to determine the effect of metformin treatment on OS and recurrence-free survival.The patients on metformin showed longer OS in comparison to the non-metformin user group (72 months vs. 60 months, respectively) with an HR of 0.44.Also, a longer recurrence-free survival was reported in the metformin group (HR 0.44) at 49 months vs.33 months in the non-metformin users' group [23].In addition, a retrospective study by Chu et al, conducted on 6222 type II diabetic CRC patients who underwent surgery from 2000 to 2012, assessed the effect of metformin on OS and liver metastasis risk.In this study, it was shown that metformin was able to improve the 5-year OS significantly following surgery (HR 0.33) in comparison to non-metformin users.Also, an inverse association between metformin and liver metastasis risk was found (HR 0.79) [24].
On the other hand, some studies reported non-significant differences in either cancerspecific mortality or OS or relapse-free survival with metformin use in comparison to nonmetformin users.In type II diabetic patients, all studies analyzed the effect of metformin against other anti-diabetic medications.For instance, Garret et al assessed OS in type II diabetic CRC patients and reported an improvement in OS rate by 30% (56.9 months) versus (76.9 months) with other oral anti-diabetic medication users [27].Also, a cohort study by Spillane et

Conclusion
Although studies about the effect of metformin treatment in CRC were controversial, the major sum of studies with their impactful data was indicative of the beneficial effect of metformin therapy as anti-neoplastic in CRC.Longer follow-up periods, more randomized control trials, and extensive subjects especially non-diabetic CRC are needed to further confirm the therapeutic effectiveness of metformin.

Fig. 1 .
Fig. 1.The Flow chart of the study.
For instance, Mcmenamin U et al retrospective cohort study on 1917 diabetic CRC patients from 1998-2009 regarding cancerspecific mortality [25].Also, a sub-study of TOSCA randomized control study by Vernieri et al on high-risk stage II/III CRC receiving fluoropyrimidine-based therapies showed no significant effect of metformin on OS (HR 1.51) or relapsefree survival (HR 1.56) compared to nonmetformin users [26].

Table 1 :
Summary of included studies.
[35], the Rada et al study in 108 liver mCRC patients has shown a decrease in mortality rates and better prognosis in the metformin group than in non-diabetic and other anti-diabetic medication users.They related such metformin benefits to the ability of metformin to decrease co-option vasculature in liver metastasis, a strong indicative of poor prognosis[34].On the contrary, the observational study by Cossor et al analyzed 2066 post-menopausal diabetic CRC women for a median follow-up period of 4.1 years and showed no significant difference in CRC-specific survival in the metformin group in comparison to non-diabetics and other oral anti-diabetic medication groups[35].