Effect of type 2 diabetes mellitus on survival in metastatic pancreatic cancer

Abstract

Background/Aim: Many epidemiological studies describe a relationship between pancreatic cancer (PC) and Diabetes mellitus (DM). However, there are not enough studies investigating the effect of DM on survival of patients with metastatic PC. The purpose of this retrospective study was to investigate the effect of DM and its treatment on survival of patients with metastatic PC who received chemotherapy (CT) as first line treatment. Methods: Patients with metastatic PC who were followed up at the department of medical oncology between 2006 and 2018 were enrolled in this retrospective cohort study. Patients aged 18 years and over, who had metastatic disease at diagnosis and were treated with CT were analyzed. Patients with DM were stratified into two groups based on the history of medical treatments used for DM as follows: Oral antidiabetic (OAD) and OAD + insulin combination. Results: Following results were obtained after analyzing the medical records of 372 patients with metastatic PC, among which 125 (33.6%) had type II DM at the time diagnosis: The median age of the patients was 61 (range: 28-83) years. There were 136 (36.6%) female patients, and the median overall survival (OS) was 9.0 months in patients without DM, and 7.0 months (P=0.023) in those with DM. OS was 8.0 months in diabetic patients using OAD+insulin combination compared to 7.0 months in those receiving OAD (P=0.614) only. Multivariate analysis revealed that the presence of DM [Hazard ratio (HR), 1.43)], Eastern Cooperative Oncology Group Performance Status 3 (HR, 1.62), treatment with gemcitabine+Nab-paclitaxel (HR, 0.29) or folfirinox (HR, 0.46), and CA 19-9 level (HR, 1.01) were factors related to OS. Conclusion: In our study, we observed that the presence of DM adversely affected survival in metastatic PC patients who received CT as first line treatment; however, whether these patients used OAD or OAD+insulin combination did not affect survival.

Keywords

• Pancreas cancer
• Diabetes mellitus
• fasting plasma glucose
• Survival
• Prognosis

References

1. 1. Allen PJ, Kuk D, Castillo CF, Basturk O, Wolfgang CL, Cameron JL, et al. Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma. Ann Surg. 2017;265:185-91. doi: 10.1097/SLA.0000000000001763.
2. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34. doi: 10.3322/caac.21551.
3. 3. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxford). 2008;10:58-62. doi: 10.1080/13651820701883148.
4. 4. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605-17. doi: 10.1056/NEJMra0901557.
5. 5. Harris MI. Impaired glucose tolerance in the U.S. population. Diabetes Care. 1989;12:464-74. doi: 10.2337/diacare.12.7.464.
6. 6. Sullivan PW, Morrato EH, Ghushchyan V, Wyatt HR, Hill JO. Obesity, inactivity, and the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S., 2000-2002. Diabetes Care. 2005;28:1599-603. doi: 10.2337/diacare.28.7.1599.
7. 7. Batabyal P, Vander Hoorn S, Christophi C, Nikfarjam M. Association of diabetes mellitus and pancreatic adenocarcinoma: a meta-analysis of 88 studies. Ann Surg Oncol. 2014;21:2453-62. doi: 10.1245/s10434-014-3625-6.
8. 8. Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA. 2000;283:2552-8. doi: 10.1001/jama.283.19.2552.

9. 9. Stolzenberg-Solomon RZ, Graubard BI, Chari S, Limburg P, Taylor PR, Virtamo J, et al. Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA. 2005;294:2872-8. doi: 10.1001/jama.294.22.2872.
10. 10. Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076-83. doi: 10.1038/sj.bjc.6602619.
11. 11. Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med. 2006;166:1871-7. doi: 10.1001/archinte.166.17.1871.
12. 12. Calle EE, Murphy TK, Rodriguez C, Thun MJ, Heath CW, Jr. Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults. Cancer Causes Control. 1998;9:403-10. doi: 10.1023/a:1008819701485.
13. 13. Aggarwal G, Kamada P, Chari ST. Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas. 2013;42:198-201. doi: 10.1097/MPA.0b013e3182592c96.
14. 14. Nakai Y, Isayama H, Sasaki T, Mizuno S, Sasahira N, Kogure H, et al. Clinical outcomes of chemotherapy for diabetic and nondiabetic patients with pancreatic cancer: better prognosis with statin use in diabetic patients. Pancreas. 2013;42:202-8. doi: 10.1097/MPA.0b013e31825de678.
15. 15. Choi Y, Kim TY, Oh DY, Lee KH, Han SW, Im SA, et al. The Impact of Diabetes Mellitus and Metformin Treatment on Survival of Patients with Advanced Pancreatic Cancer Undergoing Chemotherapy. Cancer Res Treat. 2016;48:171-9. doi: 10.4143/crt.2014.292.
16. 16. Iizumi S, Kuchiba A, Okusaka T, Ikeda M, Sakamoto Y, Kondo S, et al. Impact of the Duration of Diabetes Mellitus on the Outcome of Metastatic Pancreatic Cancer Treated with Gemcitabine: A Retrospective Study. Intern Med. 2019;58:2435-41. doi: 10.2169/internalmedicine.2539-18.
17. 17. Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology. 2008;134:981-7. doi: 10.1053/j.gastro.2008.01.039.
18. 18. Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012;18:2905-12. doi: 10.1158/1078-0432.CCR-11-2994.
19. 19. Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST. Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108:510-9; quiz 20. doi: 10.1038/ajg.2013.7.
20. 20. Lee W, Yoon YS, Han HS, Cho JY, Choi Y, Jang JY, et al. Prognostic relevance of preoperative diabetes mellitus and the degree of hyperglycemia on the outcomes of resected pancreatic ductal adenocarcinoma. J Surg Oncol. 2016;113:203-8. doi: 10.1002/jso.24133.
21. 21. Lee S, Hwang HK, Kang CM, Lee WJ. Adverse Oncologic Impact of New-Onset Diabetes Mellitus on Recurrence in Resected Pancreatic Ductal Adenocarcinoma: A Comparison With Long-standing and Non-Diabetes Mellitus Patients. Pancreas. 2018;47:816-22. doi: 10.1097/MPA.0000000000001099.
22. 22. Hank T, Sandini M, Qadan M, Weniger M, Ciprani D, Li A, et al. Diabetes mellitus is associated with unfavorable pathologic features, increased postoperative mortality, and worse long-term survival in resected pancreatic cancer. Pancreatology. 2020;20:125-31. doi: 10.1016/j.pan.2019.10.007.
23. 23. Ma J, Wang J, Ge L, Long B, Zhang J. The impact of diabetes mellitus on clinical outcomes following chemotherapy for the patients with pancreatic cancer: a meta-analysis. Acta Diabetol. 2019;56:1103-11. doi: 10.1007/s00592-019-01337-2.
24. 24. Mao Y, Tao M, Jia X, Xu H, Chen K, Tang H, et al. Effect of Diabetes Mellitus on Survival in Patients with Pancreatic Cancer: A Systematic Review and Meta-analysis. Sci Rep. 2015;5:17102. doi: 10.1038/srep17102.
25. 25. Chu CK, Mazo AE, Goodman M, Egnatashvili V, Sarmiento JM, Staley CA, et al. Preoperative diabetes mellitus and long-term survival after resection of pancreatic adenocarcinoma. Ann Surg Oncol. 2010;17:502-13. doi: 10.1245/s10434-009-0789-6.
26. 26. Balzano G, Dugnani E, Gandolfi A, Scavini M, Pasquale V, Aleotti F, et al. Effect of Diabetes on Survival after Resection of Pancreatic Adenocarcinoma. A Prospective, Observational Study. PLoS One. 2016;11:e0166008. doi: 10.1371/journal.pone.0166008.
27. 27. Li D, Mao Y, Chang P, Liu C, Hassan MM, Yeung SJ, et al. Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer. Am J Cancer Res. 2015;5:3260-9.