Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study

Young-Jun Ki; Hyo Jeong Kim; Mi-Sook Kim; Chan Mi Park; Min Jung Ko; Young Seok Seo; Sun Mi Moon; Jin A Choi

doi:10.4143/crt.2016.128

Articles

Page Path: HOME > Cancer Res Treat > Volume 49(1); 2017 > Article

Original Article Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study: Young-Jun Ki, MD¹, Hyo Jeong Kim, MPH², Mi-Sook Kim, MD, PhD^3,, Chan Mi Park, PhD^2,, Min Jung Ko, PhD², Young Seok Seo, MD³, Sun Mi Moon, MD, PhD¹, Jin A Choi, MPH²; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2017;49(1):29-36.
DOI: https://doi.org/10.4143/crt.2016.128
Published online: July 4, 2016

¹Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

²National Evidence-based Healthcare Collaborating Agency, Seoul, Korea

³Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

Correspondence: Mi-Sook Kim, MD, PhD Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
Tel: 82-2-970-1264 Fax: 82-2-970-2412 E-mail: mskim@kcch.re.kr

Co-Correspondence: Chan Mi Park, PhD National Evidence-based Healthcare Collaborating Agency, Namasan Square (Kukdong B/D) 7F 173 Toegye-ro, Jung-gu, Seoul 04554, Korea
Tel: 82-2-2174-2899 Fax: 82-2-747-4916 E-mail: chpark@neca.re.kr

*Young-Jun Ki and Hyo Jeong Kim contributed equally to this work.

• Received: March 24, 2016 • Accepted: June 11, 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

11,992 Views
307 Download
18 Web of Science
15 Crossref
20 Scopus

prev next

Full Article

Download PDF

Abstract

Purpose
Metformin is associated with an anticancer effect. However, the effects of metformin in rectal cancer are controversial. This study investigated the impact of metformin on the survival of patients with diabetes mellitus and nonmetastatic rectal cancer who underwent curative surgery.
Materials and Methods
The database was provided by the Korea Center Cancer Registry and National Health Insurance Service of the Republic of Korea. A cohort of patients with newly diagnosed rectal cancer between 2005 and 2011 was identified. Drug exposure was defined as receiving the oral hypoglycemic agent for at least 90 days over the period from 6 months before the initial diagnosis of rectal cancer to the last follow-up.
Results
A total of 4,503 patients were prescribed oral hypoglycemic agents and classified as the diabetic group, of which 3,694 patients received metformin for at least 90 days. Unadjusted analyses showed a significantly higher overall survival (hazard ratio, 0.596; 95% confidence interval, 0.506 to 0.702) and rectal cancer-specific survival (hazard ratio, 0.621; 95% confidence interval, 0.507 to 0.760) in the metformin group than in the nonmetformin group. The adjusted overall survival (hazard ratio, 0.631; 95% confidence interval, 0.527 to 0.755) and cancer-specific survival (hazard ratio, 0.598; 95% confidence interval, 0.479 to 0.746) in the group with a medication possession ratio of 80% or greater was significantly higher than in the group with a medication possession ratio of less than 80%.
Conclusion
Metformin use is associated with overall and cancer-specific survival in diabetic patients with a nonmetastatic rectal cancer treated with a curative resection.
Key words: Rectal neoplasms, Metformin, Diabetes mellitus, Colorectal surgery, Survival

Introduction

Colorectal cancer is the third most common cancer in Korea and worldwide, with a total of 73,759 cancer deaths occurring in Korea during 2012, accounting for 26.7% of all deaths [1,2]. According to the seventh edition of the American Joint Committee on Cancer, the 5-year relative survival rate for stage II and III rectal cancer is 61.6%-78.7% and 31.2%-85.1%, respectively [3].

Type II diabetes mellitus (DM) increases the risk of numerous cancer types, including colorectal cancer [4,5]. A large cohort study showed that the mortality rate of patients with diabetes is higher than that of patients without diabetes in several cancers [6]. In addition, type 2 DM is associated with a 40%-60% increased risk of colorectal cancer [7]. Metformin is the most common antidiabetic drug [8]. Recently, in addition to its antidiabetic effect, it has been shown to reduce the incidence of malignancy and cancer-related mortality [9,10]. Several meta-analyses and epidemiologic studies evaluated the effects of metformin on the of incidence cancer, and suggested that metformin is associated with a 20%-30% reduction in carcinogenesis including breast cancers and colorectal cancers [11,12]. Inhibition of the mammalian target of the rapamycin pathway has been considered as a mechanism to explain the antitumor effects of metformin [13]. In addition, decreasing the insulin levels in the blood by increasing the insulin sensitivity in patients with diabetes has been considered as a mechanism to explain the antitumor effect of metformin because insulin is considered a tumor growth factor. Although the molecular mechanism describing the antitumor effects of metformin has been elucidated for several years, the effects of metformin in human cancer is an ongoing area of research.

Many studies have shown that in colorectal cancer, metformin is associated with a tumor preventive effect as well as an anticancer effect, reducing mortality [14,15]. On the other hand, a few clinical studies reported conflicting results when describing the effects of metformin in colorectal cancer [16]. In the present study, it was hypothesized that the use of metformin might have survival benefits when a homogenous cancer cohort group is analyzed to minimize any selection bias. Although colon and rectal cancer have many similar clinical features, each cancer is treated using different protocols that combine surgery, radiation therapy, and chemotherapy. For rectal cancer, with the exception of early stage cases, the standard treatment is a total mesorectal excision after preoperative chemoradiotherapy [17]. Metformin is associated with a higher pathologic complete response as well as improved survival in patients with rectal cancer receiving preoperative radiotherapy [18]. In contrast, the standard method for colon cancer treatment includes a resection followed by chemotherapy [19]. A study using the Surveillance, Epidemiology, and End Results (SEER) database reported differences in survival between colon and rectal cancer [20]. Therefore, a study of the effects of metformin on the clinical outcomes in the present study cohort focused on patients with pre-existing DM and nonmetastatic rectal cancer treated with a curative resection.

Materials and Methods

1. Data source

The data were initially provided by the Korea Center Cancer Registry (KCCR) and subsequently linked to the national claims data from the National Health Insurance Service (NHIS) of the Republic of Korea, and death registration data from the Korea National Statistical Office, using the personal identification numbers for this study under the consent of the KCCR.

The KCCR data covers cancer cases nationwide from Korea with the inclusion of the date and site of the patients’ primary cancer diagnosis [1]. The NHIS covers 100% of the Korean population, and has comprehensive data sets of the diagnoses, treatments, procedures, surgical history, and prescription records for all insured patients. In addition, the insured population, and their dependents are all required to have periodic general health examinations.

As this study was based routinely on collected administrative data, participant consent was not specifically obtained. This study was approved by the Institutional Review Board of National Evidence-based Healthcare Collaborating Agency (NECA IRB 14-004).

2. Study subjects

A cohort of patients with newly diagnosed rectal cancer was identified from the KCCR between 2005 and 2011 (International Classification of Diseases, 10th revision, C20). Individuals aged 18 to 90 years were eligible if they had undergone surgery for rectal cancer with the NHIS. The participants were excluded if they did not undergo surgery for rectal cancer, as well as other criteria including cases of nonadenocarcinoma, SEER stage 7 (distant site[s]/node[s] involved), familial adenomatous polyposis, ulcerative colitis or Crohn disease, synchronous metastasis, death due to complications (death during hospital stay or death due to operative complication), or insulin prescriptions (in the outpatient clinic). Fig. 1 presents the inclusion criteria.

3. Exposure and follow-up

Drug exposure was categorized into metformin or nonmetformin, including sulfonylurea, thiazolidinedione, dipeptidyl peptidase 4 inhibitors, or other oral antidiabetic drugs. Drug exposure was defined as receiving oral hypoglycemic agents (OHA) for at least 90 days during a period 6 months before the initial diagnosis of rectal cancer to the last follow-up. The medication possession ratio (MPR) was defined as the total number of days the target medication had been prescribed divided by the total number of days between the prescriptions. An MPR greater than 80% was considered as acceptable adherence. The patient cohort entry dates were the dates when each patient underwent rectal cancer surgery, and the exit date (censoring date) was the earliest date among the date of death, date recording a clinical event, 5 years after cohort entry, or end of the study period (December 31, 2013).

4. End point

The primary outcome assessed was the overall survival. The rectal cancer-specific survival data was obtained from the National Population Registry of the Korea National Statistical Office until December 31, 2013, using the unique personal identification numbers.

5. Covariates

Information available from the KCCR included data on the patients’ cancer diagnosis and date of diagnosis. All other demographic and clinical information was obtained from the claims data or health examination data provided by the NHIS. The cancer-related treatment data, including surgery, radiotherapy, or chemotherapy, as well as the DM-related medications were determined from the NHIS data. Comorbidities occurring from 1 year prior to rectal cancer surgery until the date of surgery were determined from the NHIS claims data.

6. Statistical analysis

The main analysis compared the baseline characteristics and the use of OHA in patients with and without metformin treatment. The rates of overall and rectal cancer-specific survival during the follow-up period among the patients with and without metformin treatment were compared further using the cumulative probability curves derived from Kaplan-Meier estimates. The same analysis was then used to compare the groups based on their MPR. After the unadjusted analyses were initially performed, this study conducted adjusted analyses, including the potential confounders of age, sex, Charlson’s comorbidity index [21], SEER stage and adjuvant chemotherapy, anticancer therapy (radiotherapy, chemotherapy) before surgery, and anticancer therapy after surgery. All analyses were performed using SAS ver. 9.3 (SAS Institute Inc., Cary, NC).

Results

1. Characteristics of the study population

Among 58,124 patients with rectal cancer (C20), who were diagnosed between January 1, 2005, and December 31, 2011, 26,410 underwent surgery and met none of the exclusion criteria. Of those patients, 4,503 were prescribed OHAs and were classified as diabetic, with 3,694 receiving metformin for at least 90 days (Fig. 1). The median age of the metformin group was 65 years and that of the nonmetformin group was 67 years. The use of adjuvant chemotherapy was higher in the metformin group than in the nonmetformin group (30.4% vs. 26.7%) (Table 1).

2. Clinical outcome

Among the patients with diabetes during the follow-up period, the overall survival and rectal cancer-specific survival was significantly higher in the metformin group than in the nonmetformin group (Fig. 2). In unadjusted analyses, the metformin group showed a significantly higher overall survival (hazard ratio [HR], 0.596; 95% confidence interval [CI], 0.506 to 0.702) and rectal cancer-specific survival (HR, 0.621; 95% CI, 0.507 to 0.760) than the nonmetformin group. After multivariable analysis adjusting for the clinical covariates, the metformin group still had a significantly lower risk of events than the nonmetformin group (Table 2).

In the metformin group, the adjusted overall survival (HR, 0.631; 95% CI, 0.527 to 0.755) and rectal cancer-specific survival (HR, 0.598; 95% CI, 0.479 to 0.746) in patients with an MPR of 80% or greater, was significantly higher than in the patients with an MPR of less than 80% (Table 3, Fig. 3).

Discussion

Several studies have shown that DM increases the mortality of patients with colorectal cancer. Two population-based studies reported that DM is associated with reduced survival in patients with colorectal cancer [22,23]. Three meta-analyses reported that patients with diabetes have an increased incidence of mortality from colorectal cancer [24-26]. In addition, Caudle et al. [27] compared the neoadjuvant chemoradiotherapy responses in diabetic and nondiabetic patients with rectal cancer and reported that the complete pathologic response rate was significantly higher in patients without diabetes. In contrast, a case-control study showed no significant difference in survival between patients with colorectal cancer who had well-controlled diabetic diabetes (hemoglobin A1c < 7.5%) or who did not have diabetes [7].

Several studies have provided evidence describing a survival relationship between metformin use and colorectal cancer. A single institution study in Korea reported that metformin reduced the overall mortality and colorectal cancer specific mortality in diabetic patients with colorectal cancer [15]. In addition, metformin was reported to have survival benefits compared to other anti-diabetic agents in diabetic patients with colorectal cancer [28]. One meta-analysis showed that patients with colorectal cancer taking metformin had a 34% improvement in the overall survival compared to nonmetformin users [29]. The only data examining the benefits of metformin focusing on rectal cancer was provided by Skinner et al. [18]. Through a single institute cohort study, the improvement in the pathological complete response rate as well as the outcomes in patients with locally advanced rectal cancer was shown. On the other hand, other studies did not show consistent results describing the beneficial effect of metformin [16]. An Irish study, which compared 207 metformin receiving and 108 nonmetformin receiving patients with stage I-III colorectal cancer and diabetes, reported that the metformin group did not demonstrate a significant difference in survival compared to the nonmetformin group [30].

This study was based on a nationwide population database, which included a large number of patients compared to single institute cohorts. In addition, the analyzed patients included only those with nonmetastatic rectal cancer treated by a curative resection, which is considered a relatively homogeneous population with a similar prognosis.

This study has several limitations. First, the patient adherence in taking metformin cannot be confirmed exactly because only the claim data was used. Second, this study could not provide information regarding the appropriate dose of metformin required to observe any anti-tumor effects. The MPR was analyzed for metformin and showed that a higher MPR was associated with improved survival. On the other hand, the optimal dose of metformin could not be provided because the individual dosage data was not available from the NHIS database. The last limitation is the concern that there might be unmeasured confounding factors due to the retrospective design of the study, despite examining a large population. Information on other tumor-related parameters besides tumor stage, such as tumor differentiation, the presence of lymphovascular invasion, or the status of microsatellite instability, was unavailable.

Conclusion

Metformin use was associated with the overall survival and cancer-specific survival in diabetic patients with nonmetastatic rectal cancer treated by a curative resection. These results could provide evidence for conducting future prospective randomized controlled trials.

NOTES

Conflict of interest relevant to this article was not reported.

Acknowledgements

This study was supported by the National Evidence-based Healthcare Collaborating Agency, Seoul, Korea (project number NECA-P-14-006).

Fig. 1.

Flowchart: study population. ICD-10, International Classification of Disease, 10th revision; SEER, Surveillance Epidemiology and End Result.

Fig. 2.

Survival curves comparing metformin and nonmetformin use in rectal cancer patients. (A) Overall survival. (B) Rectal cancer-specific survival. RMST, restricted mean survival time.

Fig. 3.

Survival curves comparing MPR levels for metformin in patients with rectal cancer. (A) Overall survival. (B) Rectal cancer-specific survival. MPR, medication possession ratio; RMST, restricted mean survival time.

Table 1.

Baseline characteristics of the rectal cancer patients with diabetes mellitus

Characteristic	Metformin group (n=3,694)	Nonmetformin group (n=809)	p-value
Sex
Male	2,397 (64.9)	520 (64.3)	0.741
Female	1,297 (35.1)	289 (35.7)
Age, median (interquartile range, yr)	65 (58-71)	67 (60-73)	< 0.001
SEER stage
Localized	1,393 (37.7)	304 (37.6)	0.980
Regional	2,016 (54.6)	444 (54.9)
Unknown	285 (7.7)	61 (7.5)
Radiotherapy	1,322 (35.8)	273 (33.7)	0.271
Before surgery	781 (21.1)	153 (18.9)	0.157
After surgery	541 (14.6)	120 (14.8)	0.891
Preoperative chemotherapy	697 (18.9)	137 (16.9)	0.200
Adjuvant chemotherapy	1123 (30.4)	216 (26.7)	0.037
Charlson comorbidity index score (interquartile range)	5 (4-7)	6 (4-7)
0-3	692 (18.7)	155 (19.2)	0.140
4-6	1,778 (48.1)	356 (44)
7-9	976 (26.4)	242 (29.9)
≥ 10	248 (6.7)	56 (6.9)

Values are presented as number (%) unless otherwise indicated. SEER, Surveillance Epidemiology and End Result.

Table 2.

Mortality risk based on metformin use in patients with rectal cancer

Outcome	Incidence		Unadjusted		Adjusted^a)
Outcome	Metformin group (n=3,694)	Nonmetformin group (n=809)	HR (95% CI)	p-value	HR (95% CI)	p-value
Overall mortality	541 (14.6)	196 (24.2)	0.596 (0.506-0.702)	< 0.001	0.653 (0.554-0.770)	< 0.001
RC-specific mortality	363 (9.8)	126 (15.6)	0.621 (0.507-0.760)	< 0.001	0.662 (0.540-0.812)	< 0.001

Values are presented as number (%). HR, hazard ratio; CI, confidence interval; RC, rectal cancer; SEER, Surveillance Epidemiology and End Result.

^a) Adjusted: sex, age, SEER stage, Charlson’s comorbidity index score, preoperative chemotherapy, adjuvant chemotherapy.

Table 3.

Mortality risk based on the MPR levels in the metformin group

Outcome	Incidence		Unadjusted		Adjusted^a)
Outcome	MPR ≥ 80% (n=1,702)	MPR < 80% (n=1,992)	HR (95% CI)	p-value	HR (95% CI)	p-value
Overall mortality	179 (10.5)	362 (18.2)	0.606 (0.506-0.724)	< 0.001	0.631 (0.527-0.755)	< 0.001
RC-specific mortality	116 (6.8)	247 (12.4)	0.573 (0.459-0.714)	< 0.001	0.598 (0.479-0.746)	< 0.001

Values are presented as number (%). MPR, medication possession ratio; HR, hazard ratio; CI, confidence interval; RC, rectal cancer; SEER, Surveillance Epidemiology and End Result.

^a) Adjusted: sex, age, SEER stage, Charlson’s comorbidity index score, preoperative chemotherapy, adjuvant chemotherapy.

REFERENCES

1. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015;47:127–41. Article PubMed PMC PDF
2. International Agency for Research on Cancer. Globocan 2013: cancer fact sheets for colorectal cancer. Lyon: International Agency for Research on Cancer; 2013.
3. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. New York: Springer-Verlag; 2010.
4. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121:856–62. Article PubMed
5. Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007;50:1365–74. Article PubMed
6. 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;159:1160–7. Article PubMed
7. Siddiqui AA, Spechler SJ, Huerta S, Dredar S, Little BB, Cryer B. Elevated HbA1c is an independent predictor of aggressive clinical behavior in patients with colorectal cancer: a case-control study. Dig Dis Sci. 2008;53:2486–94. Article PubMed
8. van Staa TP, Patel D, Gallagher AM, de Bruin ML. Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia. 2012;55:654–65. Article PubMed
9. Chowdhury TA. Diabetes and cancer. QJM. 2010;103:905–15. Article PubMed
10. Geraldine N, Marc A, Carla T, Chantal M, Stefaan B, Welcome W, et al. Relation between diabetes, metformin treatment and the occurrence of malignancies in a Belgian primary care setting. Diabetes Res Clin Pract. 2012;97:331–6. Article PubMed
11. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3:1451–61. Article PubMed
12. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012;7:e33411Article PubMed PMC
13. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67:10804–12. Article PubMed
14. Cardel M, Jensen SM, Pottegard A, Jorgensen TL, Hallas J. Long-term use of metformin and colorectal cancer risk in type II diabetics: a population-based case-control study. Cancer Med. 2014;3:1458–66. Article PubMed PMC
15. Lee JH, Kim TI, Jeon SM, Hong SP, Cheon JH, Kim WH. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer. 2012;131:752–9. Article PubMed
16. Cossor FI, Adams-Campbell LL, Chlebowski RT, Gunter MJ, Johnson K, Martell RE, et al. Diabetes, metformin use, and colorectal cancer survival in postmenopausal women. Cancer Epidemiol. 2013;37:742–9. Article PubMed PMC
17. National Comprehensive Cancer Network. NCCN guidelines for treatment of cancer by site: rectal cancer. v2. Fort Washington, PA: National Comprehensive Cancer Network; 2015.
18. Skinner HD, Crane CH, Garrett CR, Eng C, Chang GJ, Skibber JM, et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med. 2013;2:99–107. Article PubMed PMC
19. National Comprehensive Cancer Network. NCCN guidelines for treatment of cancer by site: colon cancer, ver. 2. Fort Washington, PA: National Comprehensive Cancer Network; 2015.
20. Lee YC, Lee YL, Chuang JP, Lee JC. Differences in survival between colon and rectal cancer from SEER data. PLoS One. 2013;8:e78709Article PubMed PMC
21. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83. Article PubMed
22. Gross CP, Guo Z, McAvay GJ, Allore HG, Young M, Tinetti ME. Multimorbidity and survival in older persons with colorectal cancer. J Am Geriatr Soc. 2006;54:1898–904. Article PubMed
23. Polednak AP. Comorbid diabetes mellitus and risk of death after diagnosis of colorectal cancer: a population-based study. Cancer Detect Prev. 2006;30:466–72. Article PubMed
24. Luo W, Cao Y, Liao C, Gao F. Diabetes mellitus and the incidence and mortality of colorectal cancer: a meta-analysis of 24 cohort studies. Colorectal Dis. 2012;14:1307–12. Article PubMed
25. Stein KB, Snyder CF, Barone BB, Yeh HC, Peairs KS, Derr RL, et al. Colorectal cancer outcomes, recurrence, and complications in persons with and without diabetes mellitus: a systematic review and meta-analysis. Dig Dis Sci. 2010;55:1839–51. Article PubMed PMC
26. Jiang Y, Ben Q, Shen H, Lu W, Zhang Y, Zhu J. Diabetes mellitus and incidence and mortality of colorectal cancer: a systematic review and meta-analysis of cohort studies. Eur J Epidemiol. 2011;26:863–76. Article PubMed
27. Caudle AS, Kim HJ, Tepper JE, O'Neil BH, Lange LA, Goldberg RM, et al. Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer. Ann Surg Oncol. 2008;15:1931–6. Article PubMed
28. Garrett CR, Hassabo HM, Bhadkamkar NA, Wen S, Baladandayuthapani V, Kee BK, et al. Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br J Cancer. 2012;106:1374–8. Article PubMed PMC
29. Mei ZB, Zhang ZJ, Liu CY, Liu Y, Cui A, Liang ZL, et al. Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and meta-analysis. PLoS One. 2014;9:e91818Article PubMed PMC
30. Spillane S, Bennett K, Sharp L, Barron TI. A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2013;22:1364–73. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Metformin Does not Affect Outcomes in Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Therapy and Resection
Swati Sonal, Chloe Boudreau, Hiroko Kunitake, Robert N. Goldstone, Grace C. Lee, Christy E. Cauley, Liliana G. Bordeianou, Todd D. Francone, Rocco Ricciardi, David L. Berger
The American Surgeon™.2024; 90(4): 858. CrossRef
View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences
Guglielmina Froldi
Pharmaceuticals.2024; 17(4): 478. CrossRef
Type II diabetes and metformin use does not affect colorectal cancer prognosis
Mehrnoosh Shahrivar, Caroline E. Dietrich, Bengt Glimelius, Deborah Saraste, Anna Martling, Christian Buchli, Caroline Nordenvall
International Journal of Cancer.2024;[Epub] CrossRef
Survival benefit of metformin use according to cancer diagnosis in diabetic patients with metabolic syndrome
Ji Soo Park, Soo Jin Moon, Hyung Seok Park, Sang-Hoon Cho
Preventive Medicine Reports.2024; 48: 102928. CrossRef
Metformin combined with local irradiation provokes abscopal effects in a murine rectal cancer model
Mineyuki Tojo, Hideyo Miyato, Koji Koinuma, Hisanaga Horie, Hidenori Tsukui, Yuki Kimura, Yuki Kaneko, Hideyuki Ohzawa, Hironori Yamaguchi, Kotaro Yoshimura, Alan Kawarai Lefor, Naohiro Sata, Joji Kitayama
Scientific Reports.2022;[Epub] CrossRef
Clinicopathological Characteristics and Overall 5-Year Survival of Colorectal Cancer: A Retrospective Study
Rahaf Almuhanna, Fatma Al-Thoubaity, Khadijah Almalki, Nada Algarni, Renad Hamad, Toleen Makhtoum
Medical Sciences.2022; 10(3): 42. CrossRef
Prognostic value of metformin in cancers: An updated meta-analysis based on 80 cohort studies
Jing Yang, Hang Yang, Ling Cao, Yuzhen Yin, Ying Shen, Wei Zhu
Medicine.2022; 101(49): e31799. CrossRef
Potential intrinsic subtype dependence on the association between metformin use and survival in surgically resected breast cancer: a Korean national population-based study
Byoung Hyuck Kim, Moon-June Cho, Jeanny Kwon
International Journal of Clinical Oncology.2021; 26(11): 2004. CrossRef
Suppressive effects of metformin on colorectal adenoma incidence and malignant progression
Min Deng, Siqin Lei, Dongdong Huang, Hui Wang, Shuli Xia, Enping Xu, Yihua Wu, Honghe Zhang
Pathology - Research and Practice.2020; 216(2): 152775. CrossRef
Effect of metformin on the mortality of colorectal cancer patients with T2DM: meta-analysis of sex differences
Yunzi Wang, Jingping Xiao, Yuanyu Zhao, Shijuan Du, Jiang Du
International Journal of Colorectal Disease.2020; 35(5): 827. CrossRef
Postdiagnostic metformin use and survival of patients with colorectal cancer: A Nationwide cohort study
Wen‐Kuan Huang, Shu‐Hao Chang, Hung‐Chih Hsu, Wen‐Chi Chou, Tsai‐Sheng Yang, Jen‐Shi Chen, John Wen‐Cheng Chang, Yung‐Chang Lin, Chang‐Fu Kuo, Lai‐Chu See
International Journal of Cancer.2020; 147(7): 1904. CrossRef
Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression
Cheng-Ann Winston Ng, Amy Aimei Jiang, Emma Min Shuen Toh, Cheng Han Ng, Zhi Hao Ong, Siyu Peng, Hui Yu Tham, Raghav Sundar, Choon Seng Chong, Chin Meng Khoo
International Journal of Colorectal Disease.2020; 35(8): 1501. CrossRef
Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus
Akira Saito, Joji Kitayama, Hisanaga Horie, Koji Koinuma, Hideyuki Ohzawa, Hironori Yamaguchi, Hiroshi Kawahira, Toshiki Mimura, Alan Kawarai Lefor, Naohiro Sata
Cancer Science.2020; 111(11): 4012. CrossRef
Patterns of Rectal Cancer Radiotherapy Adopting Evidence-Based Medicine: An Analysis of the National Database from 2005 to 2016
Hae Jin Park, Sanghyun Cho, Yoon Kim
Cancer Research and Treatment.2018; 50(3): 975. CrossRef
UEG Week 2018 Poster Presentations

United European Gastroenterology Journal.2018;[Epub] CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study

Cancer Res Treat. 2017;49(1):29-36. Published online July 4, 2016

DOI: https://doi.org/10.4143/crt.2016.128

XML Download

Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study

Fig. 1. Flowchart: study population. ICD-10, International Classification of Disease, 10th revision; SEER, Surveillance Epidemiology and End Result.

Fig. 2. Survival curves comparing metformin and nonmetformin use in rectal cancer patients. (A) Overall survival. (B) Rectal cancer-specific survival. RMST, restricted mean survival time.

Fig. 3. Survival curves comparing MPR levels for metformin in patients with rectal cancer. (A) Overall survival. (B) Rectal cancer-specific survival. MPR, medication possession ratio; RMST, restricted mean survival time.

Fig. 1.

Fig. 2.

Fig. 3.

Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study

Characteristic	Metformin group (n=3,694)	Nonmetformin group (n=809)	p-value
Sex
Male	2,397 (64.9)	520 (64.3)	0.741
Female	1,297 (35.1)	289 (35.7)
Age, median (interquartile range, yr)	65 (58-71)	67 (60-73)	< 0.001
SEER stage
Localized	1,393 (37.7)	304 (37.6)	0.980
Regional	2,016 (54.6)	444 (54.9)
Unknown	285 (7.7)	61 (7.5)
Radiotherapy	1,322 (35.8)	273 (33.7)	0.271
Before surgery	781 (21.1)	153 (18.9)	0.157
After surgery	541 (14.6)	120 (14.8)	0.891
Preoperative chemotherapy	697 (18.9)	137 (16.9)	0.200
Adjuvant chemotherapy	1123 (30.4)	216 (26.7)	0.037
Charlson comorbidity index score (interquartile range)	5 (4-7)	6 (4-7)
0-3	692 (18.7)	155 (19.2)	0.140
4-6	1,778 (48.1)	356 (44)
7-9	976 (26.4)	242 (29.9)
≥ 10	248 (6.7)	56 (6.9)

Outcome	Incidence		Unadjusted		Adjusted^a)
Outcome	Metformin group (n=3,694)	Nonmetformin group (n=809)	HR (95% CI)	p-value	HR (95% CI)	p-value
Overall mortality	541 (14.6)	196 (24.2)	0.596 (0.506-0.702)	< 0.001	0.653 (0.554-0.770)	< 0.001
RC-specific mortality	363 (9.8)	126 (15.6)	0.621 (0.507-0.760)	< 0.001	0.662 (0.540-0.812)	< 0.001

Outcome	Incidence		Unadjusted		Adjusted^a)
Outcome	MPR ≥ 80% (n=1,702)	MPR < 80% (n=1,992)	HR (95% CI)	p-value	HR (95% CI)	p-value
Overall mortality	179 (10.5)	362 (18.2)	0.606 (0.506-0.724)	< 0.001	0.631 (0.527-0.755)	< 0.001
RC-specific mortality	116 (6.8)	247 (12.4)	0.573 (0.459-0.714)	< 0.001	0.598 (0.479-0.746)	< 0.001

Table 1. Baseline characteristics of the rectal cancer patients with diabetes mellitus

Values are presented as number (%) unless otherwise indicated. SEER, Surveillance Epidemiology and End Result.

Table 2. Mortality risk based on metformin use in patients with rectal cancer

Values are presented as number (%). HR, hazard ratio; CI, confidence interval; RC, rectal cancer; SEER, Surveillance Epidemiology and End Result.

Adjusted: sex, age, SEER stage, Charlson’s comorbidity index score, preoperative chemotherapy, adjuvant chemotherapy.

Table 3. Mortality risk based on the MPR levels in the metformin group

Values are presented as number (%). MPR, medication possession ratio; HR, hazard ratio; CI, confidence interval; RC, rectal cancer; SEER, Surveillance Epidemiology and End Result.

Adjusted: sex, age, SEER stage, Charlson’s comorbidity index score, preoperative chemotherapy, adjuvant chemotherapy.