Original Contributions: Colorectal Cancer

Survival Benefit for Metformin Through Better Tumor Response by Neoadjuvant Concurrent Chemoradiotherapy in Rectal Cancer

Kim, Jung Min M.D.¹; Park, Jung Won M.D.¹; Lee, Jin Ha M.D.¹; Park, Ye Hyun M.D.¹; Park, Soo Jung M.D., Ph.D.¹; Cheon, Jae Hee M.D., Ph.D.¹; Kim, Won Ho M.D., Ph.D.¹; Kim, Tae Il M.D., Ph.D.^1,2,3

Author Information

¹ Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

² Yonsei Cancer Prevention Center, Seoul, Republic of Korea

³ Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in HTML and PDF versions of this article on the journal’s Web site (www.dcrjournal.com).

Funding/Support: Supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1631020).

Financial Disclosures: None reported.

Poster presentation at the meeting of the International Meeting on Intestinal Diseases in Conjunction with the annual congress of Korean Association for the Study of Intestinal Diseases (IMKASID), Seoul, Korea, April 13 to 14, 2018, and at the meeting of United European Gastroenterology Week (UEGW), Vienna, Austria, October 20 to 24, 2018.

Correspondence: Tae Il Kim, M.D., Ph.D., Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. E-mail: [email protected]

Diseases of the Colon & Rectum 63(6):p 758-768, June 2020. | DOI: 10.1097/DCR.0000000000001624

Abstract

BACKGROUND:

Metformin may reduce cancer risk and mortality and improve radiotherapy responses in several malignancies.

OBJECTIVE:

This study aimed to compare tumor responses and prognoses of metformin and nonmetformin groups of diabetic patients receiving neoadjuvant concurrent chemoradiotherapy for rectal cancer.

DESIGN:

This is a retrospective study.

SETTING:

This study was conducted at a single institution in the Republic of Korea.

PATIENTS:

Between January 2000 and November 2017, 104 patients with rectal cancer who were taking diabetes medication and treated with neoadjuvant concurrent chemoradiotherapy followed by radical surgery were reviewed. Patients were divided into those taking (n = 62) and not taking metformin (n = 42). Tumor responses, survival, and other outcomes were analyzed.

MAIN OUTCOME MEASURES:

Tumor response, rectal cancer-specific survival, and disease-free survival rates were measured.

RESULTS:

Tumor regression grade (p = 0.002), pathological complete response (p = 0.037), and N downstaging (p < 0.001) after neoadjuvant concurrent chemoradiotherapy were significantly higher in the metformin group than in the nonmetformin group. In analysis of cancer-specific mortality, metformin use, differentiation (well, moderate vs poor), pathological Union for International Cancer Control stage (3 vs 1–2), ypN stage (1–2 vs 0), and N downstaging (HR, 0.256 (95% CI, 0.082–0.794), p = 0.018; HR, 0.147 (95% CI, 0.031–0.697), p = 0.016; HR, 3.693 (95% CI, 1.283–10.635), p = 0.015; HR, 3.181 (95% CI, 1.155–8.759), p = 0.025, and HR, 0.175 (95% CI, 0.040–0.769), p = 0.021) were significant factors related to mortality in diabetic patients with rectal cancer. In addition, in the multivariate analysis of cancer recurrence, the interaction between metformin use and lymph node downstaging was a significant predictive factor (HR, 0.222 (95% CI, 0.077–0.639); p = 0.005).

LIMITATIONS:

This was a small retrospective study conducted at a single institution.

CONCLUSIONS:

Metformin use was associated with better tumor responses and cancer-specific survival, as well as a lower risk of cancer recurrence, in patients with diabetes mellitus who had lymph node downstaging after neoadjuvant concurrent chemoradiotherapy in rectal cancer. See Video Abstract at https://links.lww.com/DCR/B185.

BENEFICIO EN SUPERVIVENCIA CON METFORMINA A TRAVÉS DE UNA MEJOR RESPUESTA TUMORAL CON QUIMIORRADIOTERAPIA CONCURRENTE NEOADYUVANTE EN CÁNCER RECTAL

ANTECEDENTES:

La metformina puede reducir el riesgo de cáncer y la mortalidad y mejorar las respuestas a la radioterapia en varios tumores malignos.

OBJETIVO:

Comparar las respuestas tumorales y los pronósticos de los grupos con metformina y sin metformina de pacientes diabéticos que reciben quimiorradioterapia concurrente neoadyuvante para cáncer de recto.

DISEÑO:

Estudio retrospectivo.

ESCENARIO:

Institución única en la República de Corea.

PACIENTES:

Se revisaron 104 pacientes entre enero de 2000 y noviembre de 2017, con cáncer rectal que tomaban medicamentos para diabetes y que fueron tratados con quimiorradioterapia concurrente neoadyuvante seguida de cirugía radical. Los pacientes se dividieron en aquellos que tomaban (n = 62) y los que no tomaban metformina (n = 42). Se analizaron las respuestas tumorales, la supervivencia y otros resultados.

PRINCIPALES MEDIDAS DE RESULTADO:

Se midieron las tasas de la respuesta tumoral, la supervivencia específica de cáncer rectal y de la supervivencia libre de enfermedad.

RESULTADOS:

El grado de regresión tumoral (p = 0.002), la remisión patológica completa (p = 0.037) y la reducción de la etapa N (p < 0.001) después de la quimiorradioterapia concurrente neoadyuvante fueron significativamente mayores en el grupo de metformina que en el grupo sin metformina. En el análisis de la mortalidad específica por cáncer, el uso de metformina, la diferenciación (bien, moderada vs pobre), el estadio patológico UICC (3 vs 1–2), el estadio ypN (1–2 vs 0) y la disminución de la etapa N (hazard ratios [intervalos de confianza 95%]: 0.256 [0.082–0.794], p = 0.018; 0.147 [0.031–0.697], p = 0.016; 3.693 [1.283–10.635], p = 0.015; 3.181 [1.155–8.759], p = 0.025 y 0.175 [0.040–0.769], p = 0.021, respectivamente) fueron factores significativos relacionados con la mortalidad en pacientes diabéticos con cáncer rectal. Adicionalmente, en el análisis multivariado de la recurrencia del cáncer, la interacción entre el uso de metformina y la disminución de la etapa ganglionar (N) fue un factor predictivo significativo (hazard ratios [intervalos de confianza del 95%]: 0.222 [0.077–0.639]; p = 0.005).

LIMITACIONES:

Este fue un estudio retrospectivo pequeño realizado en un solo instituto.

CONCLUSIONES:

El uso de metformina se asoció con mejores respuestas tumorales y supervivencia específica de cáncer, así como un menor riesgo de recurrencia del cáncer, en pacientes con disminución de la etapa ganglionar (N) después de quimiorradioterapia concurrente neoadyuvante en pacientes con cáncer rectal y diabetes. Consulte Video Resumen en https://links.lww.com/DCR/B185. (Traducción—Dr. Jorge Silva Velazco)