Preoperative CCRT for rectal cancer is an important treatment for inducing good tumor response and ultimately achieving pCR. However, 5-FU based chemotherapy can cause side effects related to toxicity. Several randomized control trials (RCTs) have demonstrated that the chemo-related toxicity increases in patients receiving preoperative CCRT rather than single radiation therapy in the preoperative treatment setting for rectal cancer 14–16. If a patient fails to achieve an adequate tumor response due to chemo-related toxicity, the patient's prognosis may be poor. Therefore, studies to find alternatives or adjuvants that can reduce chemo-related toxicity and induce better tumor response are attracting attention.
Some studies have reported the effectiveness of metformin as an anticancer therapy and anticancer adjuvant for various cancers 5,6. Several recent studies show that metformin improves tumor response after preoperative CCRT for rectal cancer 9,10. Retrospective studies have suggested that metformin use is associated with N-downstaging, pCR, and good TRG 9,10,17. Several researchers have conducted studies on metformin, but there are no clinical studies on the timing and dose of metformin for tumor response of preoperative CCRT. This study proved that the timing of metformin administration for CCRT was related to the tumor response. Indeed, a study has shown that the formation of aberrant crypt foci (ACF) in the rectum is inhibited in patients receiving metformin for 1 month 18. Additionally, Zhao et al. reported that when metformin was administered at 1500mg/day, the number of ACFs significantly reduced in the patient group taking metformin for 6 months compared to when metformin was administered for 3 months 19. In our study, patients who took metformin before the initiation of CCRT showed better tumor response than those who took metformin from the initiation of CCRT. In several studies, the rate of stage reduction due to metformin was 45-70% 9,10. In our study, the rates of T-downstaging, N-downstaging, and good TRG in the underlying metformin usage group were higher than in the other groups (80%, 40%, 66.7%, respectively). In particular, the rates of T-downstaging and good TRG increased significantly in the underlying metformin usage group (p = 0.02, p = 0.008, respectively). In other studies, the pCR rate was 20-25% 9,10, but in this study, the pCR rate of 33.3% was observed in patients who took metformin before the initiation of CCRT. In a multivariate analysis to identify predictors of tumor responses, metformin administration before the initiation of CCRT was found to be a significant predictor for predicting T-downstaging and good TRG. These results suggest that neoadjuvant metformin administration can have an intensive effect in addition to CRT.
The importance of the Akt phosphorylation and consequent activation in conferring resistance to radiation therapy has been shown, which explains the molecular mechanisms that determine poor response to radiation therapy 20. Metformin interferes with the mitochondrial respiratory complex 1 and decreases the effectiveness of intracellular ATP. Reduction of ATP indirectly increases the activity of AMPK, an inhibitor of the PI3K/Akt/mTOR pathway, resulting in an overall decrease in the mTOR pathway 21,22. In the cell line treated with metformin for more than 24 hours, AMPK was significantly increased, but within 2 hours, AMPK was not increased 23. In addition, phosphorylation of Akt did not decrease at 2 hours after metformin treatment, but it was removed after 24 hours 23. Treatment with metformin inhibits the PI3K/Akt/mTOR pathway, inhibiting protein synthesis and cell growth, resulting in anticancer activity. The above results may suggest that the timing of metformin administration affects the treatment response, as shown in our study.
One study shows that metformin increases survival rates in patients with colorectal cancer 9. However, in the ECR-PHARMO cohort, it was reported that the benefit of overall survival in colorectal cancer was not associated with metformin 24. Although this study showed a trend of increased survival rate in the good TRG group, it is likely that the patient's overall sample size and death events were not enough to derive significant results.
There are several limitations to this study. First, there are limitations of retrospective studies and small sample sizes. Second, since preoperative staging was based on imaging studies, it is inevitable to limit the accuracy of tumor response. However, to our knowledge, this study is the first clinical study on the neoadjuvant effect of metformin for tumor response of preoperative CCRT. A synergistic effect between the neoadjuvant metformin and CCRT can be expected based on this study. In addition, the potential effects of neoadjuvant metformin may affect the choice of a short course or long course radiation therapy. In the future, long-term, large-scale, well-designed randomized controlled trials are needed in the setting of patients with the adjustment for detailed relevant clinical and molecular factors.
In conclusion, in patients with rectal cancer who underwent preoperative CCRT and curative surgery, underlying metformin usage was significantly associated with good tumor response and tumor downstaging. This study suggests that neoadjuvant metformin improves response to radiation therapy in patients with rectal cancer. This study is of value in developing therapeutic strategies to improve tumor response in patients with rectal cancer.