bladder cancer is the second most frequent cancer of the genitourinary system , the fourth most common cancer in men , and the seventh most common of all ( 1 ) .
hematuria is the most prevalent symptom that occurs in 80% - 90% of cases and is usually presented without other urinary symptoms ( called painless hematuria ) ( 2 ) .
after diagnosis , the disease is treated with surgery , chemotherapy , or radiotherapy based on the patient s particular condition , but recurrence is very common ( 3 - 5 ) .
many drugs have been used in recent decades to lower the recurrence rate , such as bacillus calmette - guerin ( bcg ) , mitomycin c , doxorubicin , and thiotepa .
about forty years ago , heuson indicated that there is a relationship between diabetes mellitus ( dm ) and cancer ( 6 ) , and other investigators claimed that disorders of intracellular signaling pathways , insulin resistance , and treatment with anti - diabetic drugs can affect cancer incidence and progression ( 7 - 10 ) .
metformin is a semi - synthetic agent that is derived from galegine and is administered to lower blood sugar .
today , this drug is used for the treatment of diabetes mellitus and the prevention of cardio - vascular disease and polycystic ovarian syndrome ( pcos ) ( 11 , 12 ) .
preliminary evidence shows that metformin can lower the incidence rate of some cancers ( including those of the breast , colon , liver , lung , prostate , and pancreas ) in type 2 diabetic patients ( 13 - 15 ) .
metformin activates protein kinases and decreases rapamycin signaling ( mtor ) which can then lower blood sugar ( 16 ) .
based on current evidence , cancer cell growth in bladder cancer requires activation of mtor ( 17 , 18 ) , so it seems that inhibition of this pathway could be an effective way to treat or prevent bladder cancer .
this study was designed for the assessment of metformin usage in the prevention of bladder cancer recurrence after the trans - urethral resection of a bladder tumor ( tur - t ) .
from april 2013 to september 2014 , all patients referred to baqiyatallah hospital with the diagnosis of a bladder tumor who underwent tur - t were included in this study .
there were 65 patients and they were divided into two groups : group 1 included 32 patients who were administered metformin as part of their treatment plan , and group 2 included 33 patients who did not take the drug .
data on sex , age , history of smoking , diagnosis of dm , size and number of tumors , histology of tumor cells , and grade and stage of resected tumors were collected before surgery .
metformin was administered in doses of 1000 mg per day ( 2 doses 500 mg ) for the 32 patients in group 1 .
all patients were followed up with ultrasonography and cystoscopy every 3 months for a 1 year period . for analyzing the data ,
then , a chi - square test and spearman s rank correlation coefficient were used to determine qualitative parameters , and an independent t - test was used for assessing the quantitative parameters . in all tests ,
from april 2013 to september 2014 , all patients referred to baqiyatallah hospital with the diagnosis of a bladder tumor who underwent tur - t were included in this study .
there were 65 patients and they were divided into two groups : group 1 included 32 patients who were administered metformin as part of their treatment plan , and group 2 included 33 patients who did not take the drug .
data on sex , age , history of smoking , diagnosis of dm , size and number of tumors , histology of tumor cells , and grade and stage of resected tumors were collected before surgery .
metformin was administered in doses of 1000 mg per day ( 2 doses 500 mg ) for the 32 patients in group 1 .
all patients were followed up with ultrasonography and cystoscopy every 3 months for a 1 year period .
then , a chi - square test and spearman s rank correlation coefficient were used to determine qualitative parameters , and an independent t - test was used for assessing the quantitative parameters . in all tests , a p value of less than 0.05 was considered significant .
group 1 ( metformin ) included 32 patients with an age range between 46 and 91 years and a mean age of 63.44  11.71 years . in this group ,
group 2 ( control ) included 33 patients with an age range between 23 - 83 years and a mean age of 62.06  14.88 years .
of these patients , 8 were female ( 24.2% ) and 25 were male ( 75.8% ) .
other demographic characteristics are shown in table 1 . according to this it it is evident
that smoking , dm , previous surgery on the genitourinary tracts , tumor histology , and stage and grade were not statistically different between the 2 groups , but the tumor pedicle type ( papillary or sessile ) was statistically different ( p value < 0.05 ) .
none of patients showed any side effects of metformin use , including abdominal or stomach discomfort , cough or hoarseness , decreased appetite , diarrhea , fast or shallow breathing , fever or chills , general feeling of discomfort , lower back or side pain , muscle pain or cramping , painful or difficult urination , or drowsiness . in group 1 ,
the tumor size was between 0.5 - 5 cm with a mean size of 1.90  1.13 , and in group 2 , it was 0.5 - 11 cm with a mean of 2.14  1.79 .
there was no statistical differences between the 2 groups ( p value = 0.535 ) .
it was revealed that 8 ( 25% ) patients in group 1 and 10 ( 30.3% ) in group 2 had tumor recurrences during the 1 year follow - up period , and this rate is not statistically different ( p value = 0.633 ) .
the time of recurrence ( as shown in figure 1 ) is longer in group 1 but the prevalence of the recurrence time is not different ( p value = 0.5430 ) .
the results of a correlation test between recurrence and demographic characteristics are shown in table 2 .
there was no correlation between sex , dm , and tumor grade with tumor recurrence , but age and tumor size had a weak positive correlation with recurrence in group 1 , and a weak negative correlation with recurrence in group 2 .
however , neither of these correlations were statistically significant ( p value > 0.05 ) .
group 1 ( metformin ) included 32 patients with an age range between 46 and 91 years and a mean age of 63.44  11.71 years . in this group ,
group 2 ( control ) included 33 patients with an age range between 23 - 83 years and a mean age of 62.06  14.88 years .
of these patients , 8 were female ( 24.2% ) and 25 were male ( 75.8% ) .
other demographic characteristics are shown in table 1 . according to this it it is evident
that smoking , dm , previous surgery on the genitourinary tracts , tumor histology , and stage and grade were not statistically different between the 2 groups , but the tumor pedicle type ( papillary or sessile ) was statistically different ( p value < 0.05 ) .
none of patients showed any side effects of metformin use , including abdominal or stomach discomfort , cough or hoarseness , decreased appetite , diarrhea , fast or shallow breathing , fever or chills , general feeling of discomfort , lower back or side pain , muscle pain or cramping , painful or difficult urination , or drowsiness .
in group 1 , the tumor size was between 0.5 - 5 cm with a mean size of 1.90  1.13 , and in group 2 , it was 0.5 - 11 cm with a mean of 2.14  1.79 .
there was no statistical differences between the 2 groups ( p value = 0.535 ) .
it was revealed that 8 ( 25% ) patients in group 1 and 10 ( 30.3% ) in group 2 had tumor recurrences during the 1 year follow - up period , and this rate is not statistically different ( p value = 0.633 ) .
the time of recurrence ( as shown in figure 1 ) is longer in group 1 but the prevalence of the recurrence time is not different ( p value = 0.5430 ) .
the results of a correlation test between recurrence and demographic characteristics are shown in table 2 .
there was no correlation between sex , dm , and tumor grade with tumor recurrence , but age and tumor size had a weak positive correlation with recurrence in group 1 , and a weak negative correlation with recurrence in group 2 .
however , neither of these correlations were statistically significant ( p value > 0.05 ) .
to our knowledge , the present study is the first one to evaluate the efficacy of metformin on bladder tumor recurrence after tur - t .
our results show that metformin can not reduce bladder tumor recurrence , but it can prolong the time to recurrence , although such intervals are not statistically significant .
this result is in contrast to those of many other studies ( 13 , 19 - 22 ) .
currie in 2009 claimed that in diabetic patients using insulin and metformin , the incidence of colorectal and pancreatic cancer was lower than the corresponding rates among the normal population ( 13 ) . in similar studies , the survival rates of diabetic patients who were treated for colorectal or pancreatic cancer were 30% higher than those of diabetic patients who received other anti - diabetic agents ( 19 - 21 ) .
furthermore , wright and colleagues found in their study on caucasian men that metformin can reduce the risk of prostate cancer by up to 44% ( 22 ) .
this discrepancy between our results and other studies may be due to our small sample size or the relatively short time of metformin administration and follow up ( 13 , 19 - 22 ) . in 2010 , patel studied diabetic patients who had undergone radical prostatectomy and claimed that there is no association between metformin usage and the recurrence of prostate cancer ; indeed , the recurrence rate was 55% higher in diabetic patients ( 23 ) .
these differences in the results may be due to the various risk factors that can affect incidence , progression , and recurrence of cancers , such as age , sex , obesity , smoking , genetics , and the environment .
for example , it has been shown that smoking can increase the risk of developing bladder cancers by 3.89% and 4.65% in men and women , respectively ( 24 ) , but this correlation was not shown in our study .
the precise effects of metformin on cancer are unclear , but some suggestions include the following : ( 1 ) it might stop the mtor signaling pathway through amp - activated protein kinase ( ampk ) ( 25 - 27 ) ; and ( 2 ) it might decrease the insulin level by way of reducing the insulin - like growth factor-1 ( igf-1 ) ( 26 , 28 ) .
furthermore , it is clear that metformin can increase poly ( adp - ribose ) polymerase ( parp)-dependent cell death and caspase - dependent apoptosis in breast cancer .
metformin has also been shown to decrease the activity and expression of her2 in cancer cells , which is dose dependent and can be seen in higher administered doses of metformin ( 29 - 31 ) .
it seems that metformin can prolong the recurrence interval of bladder cancer , but the recurrence rate itself is not affected .
this may be due to the small sample size and the short time of both administration and follow up in our study .
therefore , more studies with a greater sample size and longer administration and follow up times are needed .
it seems that metformin can prolong the recurrence interval of bladder cancer , but the recurrence rate itself is not affected .
this may be due to the small sample size and the short time of both administration and follow up in our study .
therefore , more studies with a greater sample size and longer administration and follow up times are needed .
 backgroundmany methods have been used for preventing and reducing recurrences of bladder cancers . in recent years 
 , some investigators have examined the use of metformin for this purpose . 
 first lines of evidence have shown that metformin inhibits cancer cell growth and prevents cancer occurrence in patients with type 2 diabetes.objectivesthis study is designed to assess metformin usage in the prevention of bladder cancer recurrence after the trans - urethral resection of a bladder tumor ( tur - t).patients and methodsin the present study , metformin was administered in the treatment of 32 patients with a history of bladder cancer , and their results were compared with those of 33 patients with bladder cancer recurrence ( placebo group ) . 
 patients in the metformin group received 1000 mg metformin ( 2 tablets 500 mg ) for 1 year . 
 frequency of tumor recurrence was calculated and compared with the placebo group.resultsthere was no statistical difference between the 2 groups with respect to the recurrence rate ( p > 0.05 ) . 
 although the recurrence interval was longer for the metformin group , this increase was not statistical significant ( p > 0.05 ) . 
 furthermore , tumor recurrence had no correlation with sex or the grade of the tumors.conclusionsaccording to our findings , it seems that metformin has no considerable inhibitory effect on the recurrence rate of bladder cancer , but that it can delay tumor recurrence . 