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

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 http://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 http://links.lww.com/DCR/B185. (Traducción—Dr. Jorge Silva Velazco)

Effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer: a cohort study

“…Therefore, a new, less toxic agent needs to be identified that could enhance tumor regression in patients with rectal cancer. Recently, metformin with NCRT was examined in rectal cancer, and a good tumor response and cancer-specific survival rate, as well as a lower risk of cancer recurrence, was reported [ 45 ]. Herein, we used mistletoe extract, which has been approved by the Korean Food and Drug Administration, as an anti-malignant drug for NCRT in advanced rectal cancer to enhance the tumor response.…”

The effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer

“…It is needed a new agent to enhance tumor regression for the patient with rectal cancer with less toxicity. Recently, metformin was applied to NCRT together in rectal cancer, and a good tumor response rate and cancer-speci c survival as well as lower risk of cancer recurrence were reported [46]. We applied mistletoe extract approved by the Korean Food and Drug Administration (KFDA) as an anti-malignant drug to NCRT for advanced rectal cancer to enhance tumor response.…”

Metformin with neoadjuvant chemoradiation to improve pathologic response in rectal cancer: A pilot phase I/II trial

“…Metformin has thus been proposed as a novel radiation modifier [22,24]. In a recent retrospective study, metformin use was associated with improved tumor responses after neoadjuvant CRT in rectal cancer [25].…”