Generic placeholder image

Reviews on Recent Clinical Trials


ISSN (Print): 1574-8871
ISSN (Online): 1876-1038

Mini-Review Article

Metformin: A Promising Radiosensitizer in Neoadjuvant Rectal Cancer Treatment

Author(s): Nikolaos S. Georgopoulos*, Maria Tolia, Davide Mauri, Konstantinos Kamposioras, Nikolaos Charalampakis, Nikolaos Tsoukalas and Areti Gkantaifi

Volume 18, Issue 3, 2023

Published on: 22 May, 2023

Page: [172 - 180] Pages: 9

DOI: 10.2174/1574887118666230428114349

Price: $65


Background: Neoadjuvant chemoradiotherapy (nCRT) decreases the risk of local recurrence after surgery in patients with locally advanced rectal cancer (LARC) and metformin is constantly gaining scientific interest due to its potentially radiosensitizing effect.

Objective: This review article aims to better clarify the role of metformin as a radiosensitizer in patients with LARC undergoing neoadjuvant concurrent chemoradiotherapy.

Methods: We used the PubMed database to retrieve journal articles and the inclusion criteria were all human studies that illustrated the effective role of metformin in the neoadjuvant setting of locally advanced rectal cancer.

Results: Our search resulted in 17 citations, of which 10 eventually fulfilled the inclusion criteria of our study. Promising results (improved tumor and nodal regression as well as higher pathologic complete response rate) have been occasionally documented with metformin use in some of the included studies. However, regarding survival and all-cause mortality, no significant difference has been found.

Conclusion: Metformin might constitute a highly promising radiosensitizer in neoadjuvant LARC treatment attracting much scientific interest. Due to the lack of studies with high evidence, further advanced research is required to enhance the existing knowledge about its potential value in this field.

Keywords: Colorectal cancer, LARC, metformin, radiosensitizer, neoadjuvant rectal cancer treatment, CRM.

Graphical Abstract
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49.
[] [PMID: 33538338]
Fokas E, Liersch T, Fietkau R, et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: Updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol 2014; 32(15): 1554-62.
[] [PMID: 24752056]
Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355(11): 1114-23.
[] [PMID: 16971718]
Dhadda AS, Dickinson P, Zaitoun AM, Gandhi N, Bessell EM. Prognostic importance of Mandard tumour regression grade following pre-operative chemo/radiotherapy for locally advanced rectal cancer. Eur J Cancer 2011; 47(8): 1138-45.
[] [PMID: 21220198]
Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 2012; 99(7): 918-28.
[] [PMID: 22362002]
Chua YJ. Pathological complete response: Still a relevant endpoint in rectal cancer? Lancet Oncol 2010; 11(9): 807-8.
[] [PMID: 20692871]
Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009; 27(31): 5124-30.
[] [PMID: 19770376]
Gavioli M, Luppi G, Losi L, et al. Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer. Dis Colon Rectum 2005; 48(10): 1851-7.
[] [PMID: 16132481]
Zannella VE, Dal Pra A, Muaddi H, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res 2013; 19(24): 6741-50.
[] [PMID: 24141625]
Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004; 159(12): 1160-7.
[] [PMID: 15191933]
Dehal AN, Newton CC, Jacobs EJ, Patel AV, Gapstur SM, Campbell PT. Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: The Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol 2012; 30(1): 53-9.
[] [PMID: 22124092]
Wouters BG, Weppler SA, Koritzinsky M, et al. Hypoxia as a target for combined modality treatments. Eur J Cancer 2002; 38(2): 240-57.
[] [PMID: 11803141]
Anderson BJ, Wahlquist AE, Hill EG, et al. The impact of metabolic syndrome on outcome and response to neoadjuvant chemoradiation in locally advanced rectal cancer patients. Int J Surg 2016; Pt A(Pt A): 8-12.
Caudle AS, Kim HJ, Tepper JE, et al. Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer. Ann Surg Oncol 2008; 15(7): 1931-6.
[] [PMID: 18418656]
Nasri H, Rafieian-Kopaei M. Metformin: Current knowledge. J Res Med Sci 2014; 19(7): 658-64.
[PMID: 25364368]
Rizos CV, Elisaf MS. Metformin and cancer. Eur J Pharmacol 2013; 705(1-3): 96-108.
[] [PMID: 23499688]
Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med 2014; 2(6): 57.
[PMID: 25333032]
Gong L, Zhang Y, Liu C, Zhang M, Han S. Application of radiosensitizers in cancer radiotherapy. Int J Nanomedicine 2021; 16: 1083-102.
[] [PMID: 33603370]
Sinukumar S, Patil P, Engineer R, Desouza A, Saklani A. Clinical outcome of patients with complete pathological response to neoadjuvant chemoradiotherapy for locally advanced rectal cancers: The Indian scenario. Gastroenterol Res Pract 2014; 2014: 1-6.
[] [PMID: 25610460]
Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012; 30(15): 1770-6.
[] [PMID: 22493423]
de Wilt J, Vermaas M, Ferenschild F, Verhoef C. Management of locally advanced primary and recurrent rectal cancer. Clin Colon Rectal Surg 2007; 20(3): 255-64.
[] [PMID: 20011207]
Clifford R, Govindarajah N, Parsons JL, Gollins S, West NP, Vimalachandran D. Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer. Br J Surg 2018; 105(12): 1553-72.
[] [PMID: 30311641]
Restivo A, Cocco IMF, Casula G, et al. Aspirin as a neoadjuvant agent during preoperative chemoradiation for rectal cancer. Br J Cancer 2015; 113(8): 1133-9.
[] [PMID: 26372700]
Zanders MMJ, van Herk-Sukel MPP, Vissers P A J, Herings RMC, Haak HR, van de Poll-Franse LV. Are metformin, statin and aspirin use still associated with overall mortality among colorectal cancer patients with diabetes if adjusted for one another? Br J Cancer 2015; 113(3): 403-10.
[] [PMID: 26180924]
Koyama FC, Lopes Ramos CM, Ledesma F, et al. Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer. Br J Surg 2018; 105(2): e192-203.
[] [PMID: 29341150]
Li M, Li X, Zhang H, Lu Y. Molecular mechanisms of metformin for diabetes and cancer treatment. Front Physiol 2018; 9: 1039.
[] [PMID: 30108523]
Perez RO, Fernandez LM, Ortega CD. Metformin use in patients with rectal cancer undergoing neoadjuvant chemoradiation: The new magic bullet? Dis Colon Rectum 2020; 63(6): 718-9.
[] [PMID: 32384400]
Fernandes JM, Jandrey EHF, Koyama FC, et al. Metformin as an alternative radiosensitizing agent to 5-fluorouracil during neoadjuvant treatment for rectal cancer. Dis Colon Rectum 2020; 63(7): 918-26.
[] [PMID: 32229782]
de Mey S, Jiang H, Wang H, et al. Potential of memory T cells in bridging preoperative chemoradiation and immunotherapy in rectal cancer. Radiother Oncol 2018; 127(3): 361-9.
[] [PMID: 29871814]
Costa B, Fernandez LM, Parés O, et al. Zebrafish Avatars of rectal cancer patients validate the radiosensitive effect of metformin. Front Oncol 2022; 12: 862889.
[] [PMID: 36249066]
Besic N, Povsic MK. Long term survival in 200 patients with advanced stage of colorectal carcinoma and diabetes mellitus - a single institution experience. Radiol Oncol 2019; 53(2): 238-44.
[] [PMID: 31104000]
Morris ZS, Saha S, Magnuson WJ, et al. Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Cancer 2016; 122(16): 2487-95.
[] [PMID: 27203227]
Huang WS, Lin CT, Chen CN, Chang SF, Chang HI, Lee KC. Metformin increases the cytotoxicity of oxaliplatin in human DLD‐1 colorectal cancer cells through down‐regulating HMGB1 expression. J Cell Biochem 2018; 119(8): 6943-52.
[] [PMID: 29737584]
Skinner HD, Crane CH, Garrett CR, et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med 2013; 2(1): 99-107.
[] [PMID: 24133632]
Oh BY, Park YA, Huh JW, et al. Metformin enhances the response to radiotherapy in diabetic patients with rectal cancer. J Cancer Res Clin Oncol 2016; 142(6): 1377-85.
[] [PMID: 27011019]
Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG. Potentiating the effects of radiotherapy in rectal cancer: The role of aspirin, statins and metformin as adjuncts to therapy. Br J Cancer 2017; 117(2): 210-9.
[] [PMID: 28641310]
Clifford RE, Gerrard AD, Fok M, Vimalachandran D. Metformin as a radiosensitiser for pelvic malignancy: A systematic review of the literature. Eur J Surg Oncol 2021; 47(6): 1252-7.
[] [PMID: 33358075]
Fransgaard T, Hallas J, Thygesen LC, Gögenur I. Association between diabetes and oncological outcomes in patients undergoing neoadjuvant chemo-radiotherapy for rectal cancer. Surg Oncol 2019; 28: 62-6.
[] [PMID: 30851913]
Kim JM, Park JW, Lee JH, et al. Survival benefit for metformin through better tumor response by neoadjuvant concurrent chemoradiotherapy in rectal cancer. Dis Colon Rectum 2020; 63(6): 758-68.
[] [PMID: 32384406]
Wong CS, Chu W, Ashamalla S, et al. Metformin with neoadjuvant chemoradiation to improve pathologic response in rectal cancer: A pilot phase I/II trial. Clin Transl Radiat Oncol 2021; 30: 60-4.
[] [PMID: 34401534]
Planellas P, Cornejo L, Rodríguez-Hermosa JI, et al. Is metformin associated with improved response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer? J Surg Res 2021; 268: 465-73.
[] [PMID: 34418650]
Han J, Kim JH, Lee JW, Han SH, Kim H. Neoadjuvant therapy of metformin is associated with good tumor response after preoperative concurrent chemoradiotherapy for rectal cancer. Sci Rep 2022; 12(1): 3716.
[] [PMID: 35260687]
Sakamoto K, Okabayashi K, Matsui S, Seishima R, Shigeta K, Kitagawa Y. Association of tumor pathological response with the use of metformin during neoadjuvant chemoradiotherapy in rectal and esophageal/gastroesophageal cancer patients: A systematic review and meta-analysis. J Gastrointest Surg 2022; 26(10): 2227-36.
[] [PMID: 35829868]
van de Poll-Franse LV, Haak HR, Coebergh JWW, Janssen-Heijnen MLG, Lemmens VEPP. Disease-specific mortality among stage I-III colorectal cancer patients with diabetes: A large population-based analysis. Diabetologia 2012; 55(8): 2163-72.
[] [PMID: 22526616]
Milosevic M, Warde P, Ménard C, et al. Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res 2012; 18(7): 2108-14.
[] [PMID: 22465832]
Dodd MS, Sousa Fialho ML, Montes Aparicio CN, et al. Fatty acids prevent hypoxia-inducible factor-1α signaling through decreased succinate in diabetes. JACC Basic Transl Sci 2018; 3(4): 485-98.
[] [PMID: 30175272]
Catrina SB, Zheng X. Hypoxia and hypoxia-inducible factors in diabetes and its complications. Diabetologia 2021; 64(4): 709-16.
[] [PMID: 33496820]
Gunton JE. Hypoxia-inducible factors and diabetes. J Clin Invest 2020; 130(10): 5063-73.
[] [PMID: 32809974]
Koritzinsky M. Metformin: A novel biological modifier of tumor response to radiation therapy. Int J Radiat Oncol Biol Phys 2015; 93(2): 454-64.
[] [PMID: 26383681]
Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330(7503): 1304-5.
[] [PMID: 15849206]
Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27(20): 3297-302.
[] [PMID: 19487376]
Rêgo DF, Pavan LMC, Elias ST, De Luca Canto G, Guerra ENS. Effects of metformin on head and neck cancer: A systematic review. Oral Oncol 2015; 51(5): 416-22.
[] [PMID: 25636350]
Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: A systematic review and meta-analysis. Ann Oncol 2016; 27(12): 2184-95.
[] [PMID: 27681864]
Zaharenko L. Pharmacogenetics of Efficiency and Tolerance of the Peroral Antidiabetic Drug Metformin PhD thesis. Riga: University of Latvia. 2015.
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995; 333(9): 550-4.
[] [PMID: 7623903]
Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res 2012; 2012: 1-13.
[] [PMID: 22194737]
Whitburn J, Edwards CM, Sooriakumaran P. Metformin and prostate cancer: A new role for an old drug. Curr Urol Rep 2017; 18(6): 46.
[] [PMID: 28444639]
Mace AG, Pai RK, Stocchi L, Kalady MF. American joint committee on cancer and college of american pathologists regression grade: A new prognostic factor in rectal cancer. Dis Colon Rectum 2015; 58(1): 32-44.
[] [PMID: 25489692]
Symvoulakis EK, Zaravinos A, Panutsopulos D, et al. Highly conserved sequence of exon 15 BRAF gene and KRAS codon 12 mutation among Greek patients with colorectal cancer. Int J Biol Markers 2007; 22(1): 12-8.
[] [PMID: 17393356]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy