The effect of metformin administration on cancer-specific survival, overall survival, progression-free survival, and disease progression in renal cell carcinoma patients; a systematic review and meta-analysis

: The results of this study indicated that metformin affects the improvement in cancer-specific survival (CSS) and progression-free survival (PFS) of the disease in patients with renal cell carcinoma (RCC). The usefulness of this drug was proved in this study. In contrast, no advantage or significant impact was observed in the disease progression and overall survival of cancer improvement. There were limited number of studies on this subject. In addition, in each of the reviewed studies, the effect of metformin on some of the following cases of CSS, overall survival, PFS, and disease progression was not mentioned, therefore, it is recommended further researchers on this aspect of metformin.


Introduction
Renal cell cancer (RCC) is the most common type of renal cancer, which includes about 85% of all renal cancers (1). The highly proliferative and metastatic renal tumor cells account for 3.8% of all new cancers (2). The incidence of this cancer in Europe and the US is significantly higher than in Asian countries and lower in Japan and India (3,4).
The incidence of RCC in men is more than in women (5). The other risk factors for this disease include smoking (6), obesity (7), and high blood pressure (8). Considering the death of about half of these patients within 5-years after diagnosis (9), the importance of investigating this subject has increased.
Metformin, a biguanide anti-hyperglycemic agent, can be effective in patients with type 2 diabetes (T2D) treatment for more than 30 years (10). Some studies have shown the anti-tumor effects of this drug in cancers, including breast, colorectal, lung, prostate, and endometrial (11,12). Although there is much evidence of the clinical use of metformin in other tumors, no published clinical study has been reported in the field on the effect of metformin on the results of renal cell carcinoma (RCC) patients systematically (13). This meta-analysis aims to survey the effect of metformin use on RCC.

Study design
In this study, the relationship between metformin and RCC in patients with T2D is to be investigated.

Search strategy
In this meta-analysis, Google Scholar web browser and Scopus, Cochrane, Web of Science, and PubMed databases were searched without time and language restrictions. The search strategy phase was performed using the standard keywords "cancer-specific survival, overall survival, progression-free survival, disease progression, metformin, renal cell carcinoma" and the search was updated to 10.10.2022. Keywords were searched using Boolean operators "AND" and "OR". Reference lists of all primary studies were screened in a manual search. For example, the search strategy in the PubMed database is

PICO components
Population: Patients with T2D, Intervention: Metformin, Comparison: Patients who do not use metformin, Outcomes; cancer-specific survival, overall survival, progression-free survival, and disease progression.

Inclusion criteria
Studies that investigated the relationship between metformin and RCC were included in the meta-analysis.

Exclusion criteria
Case-report studies; not having enough data for analysis; lack of full text of some studies; Low quality of studies based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE ) checklist; Studies that examined the effect of metformin and another drug at the same time.

Qualitative assessment
Two researchers independently evaluated the quality of the studies based on the standard STROBE checklist (14). This checklist has 22 parts that cover different parts of a report. If the total score is between 1 and 15, it is low quality, if it is between 16 and 30, it is medium quality, and if it is between 31 and 44, it is considered high quality. The cut-off point of the Strobe checklist in the current study was 15.

Data extraction
In the data extraction stage, two researchers separately extracted the data required for meta-analysis from the analyzed studies. For this purpose, the researchers designed a checklist that included author's name, number of men and women, year of publication, type of study, average age, country, sample size, OR (HR) between metformin use and RCC, etc. In order to resolve the difference between the data extracted by the two previous researchers, the third researcher evaluates the data impartially.

Statistical analysis
Odds ratio (OR) or hazard ratio (HR) was conducted to examine the relationship between metformin use and RCC. To combine the results of different studies, the logarithm of OR (HR) of each study was used. The heterogeneity of the studies was evaluated using the I 2 index and Cochrane's Q-test. Data were analyzed using STATA 14 software. The significance level of the tests was considered P<0.05.

Results
In the first stage, 301 articles were searched. After reviewing the titles of the studies, 134 duplicate studies were excluded. The abstracts of 167 articles were reviewed and 44 other articles were excluded in the full text review stage. The full text of 123 articles was evaluated and another 115 articles were excluded based on the exclusion criteria. Finally, 8 articles that had the desired quality entered the meta-analysis phase (Figure 1). Table 1 shows one case-control study and seven cohort studies out of eight published ones from 2013 to 2022. The total number of samples was 10 404 cases, which 7000 men and 3404 women were among them.

Discussion
In eight studies with a total of 10 404 people, we concluded that the use of metformin improves CSS and PFS in patients with RCC. The anticancer activity of metformin has two aspects. On the one hand, its direct effect on tumor cells and on the other hand, its indirect effect on the host based on the reduction of blood glucose and insulin and anti-inflammatory effects (22,23). Following, the metaanalyses published in the field of "the effect of metformin on urology field cancers" will be discussed and reviewed.  (25). Another study in the kidney cancer field indicated an effective impact on DP improvement (HR = 0:80; 95%    (27). There is a controversy in the published metaanalysis results on the impact of metformin on bladder cancer. Factors such as type of study, age group of patients, and duration of metformin use and its dosage are involved in this controversy.
In the meta-analysis of Xiao et al, the relationship between metformin administration and the prognosis of prostate cancer in 13 cohort studies with 177 490 patients was studied. The pooled HRs for OS and CSS were 0.79 (95% CI: 0.63-0.98) and 0.76 (95% CI: 0.57-1.02), respectively (28). The meta-analysis by He et al aimed to survey the relationship between metformin and prostate cancer, and 30 cohort studies including 1 660 795 patients were included in this study. Based on the results of metformin therapy, the improvements in OS (HR = 0.72, 95% CI: 0.59-0.88), CSS (HR = 0.78, 95% CI: 0.64-0.94), and recurrence-free survival (HR = 0.60, 95% CI: 0.42-0.87) in prostate cancer were observed compared to the non-metformin therapy. Furthermore, metformin use did not contribute to a decrease in the incidence of prostate cancer (HR = 0.86, 95% CI: 0.55-1.34) (29).
The results of the study by Yao et al, regarding metaanalysis of prostate cancer showed that the recurrence risk of patients who use metformin is lower and their diseasespecific survival and OS (HR = 0:74; 95% CI: 0.61-0.90), CSS (HR = 0:74; 95% CI: 0.61-0.91), and OS (HR = 0:76; 95% CI: 0.65-0.90) have been improved (26). Metformin could improve the OS rate of patients with prostate cancer. There is still a challenge in the field of the metformin effect on CSS and more studies are necessary.

Conclusion
The results of this study indicated that metformin affects the improvement in CSS and progression-free survival of the disease in patients with RCC. The usefulness of this drug was proved in this study. In contrast, no advantage or significant impact was observed in the disease progression and OS of cancer improvement. According to the limited number of studies and since, in each of the reviewed studies, the effect of metformin on some of the following cases of CSS, OS, progression-free survival, and disease progression was not mentioned, therefore, it is recommended further researchers on this aspect of metformin.

Limitations of the study
There was no information on the effect of metformin on RCC based on subgroups, including gender, age group, duration of metformin administration, and dose of this drug. No analysis was presented based on these subgroups in this study.