DOI QR코드

DOI QR Code

Metformin Addition to Chemotherapy in Stage IV Non-Small Cell Lung Cancer: an Open Label Randomized Controlled Study

  • Sayed, Rana (Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University) ;
  • Saad, Amr S (Department of Clinical Oncology, Faculty of Medicine, Ain Shams University) ;
  • El Wakeel, Lamia (Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University) ;
  • Elkholy, Engi (Department of Clinical Oncology, Faculty of Medicine, Ain Shams University) ;
  • Badary, Osama (Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University)
  • 발행 : 2015.10.06

초록

Purpose: To evaluate effects of metformin on clinical outcome of non-diabetic patients with stage IV NSCLC. Materials and Methods: A prospective, randomized, open-label, controlled pilot study was conducted on patients with stage IV NSCLC with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2, excluding patients with diabetes and lactic acidosis. Thirty chemo-$na\ddot{i}ve$, non-diabetic patients with stage IV NSCLC were enrolled. Fifteen patients received intravenous gemcitabine/cisplatin regimen alone (arm B) while fifteen patients received the same regimen plus daily oral metformin 500mg (arm A). The effect of metformin on chemotherapy-response rates, survival, and adverse events in these patients was evaluated. Results: Objective response rate (ORR) and median overall survival (OS) in arms A and B were 46.7% versus 13.3% respectively, p=0.109 and 12 months versus 6.5 months, respectively, p=0.119. Median progression free survival (PFS) in arms A and B was 5.5 months versus 5 months, p=0.062. No significant increase in toxicity was observed in arm A versus arm B. Percentage of patients who experienced nausea was significantly lower in arm A versus arm B, at 26.7% versus 66.7% respectively, p=0.028. Conclusions: Metformin administration reduced occurrence of chemotherapy induced-nausea. Non-statistically significant improvements in the ORR or OS were observed. Metformin had no effect on PFS.

키워드

참고문헌

  1. Aljada A, Mousa SA (2012). Metformin and neoplasia: implications and indications. Pharmacol Ther, 133, 108-15. https://doi.org/10.1016/j.pharmthera.2011.09.004
  2. Ashinuma H, Takiguchi Y, Kitazono S, et al (2012). Antiproliferative action of metformin in human lung cancer cell lines. Oncol Rep, 28, 8-14.
  3. Bolen S, Feldman L, Vassy J, et al (2007). Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med, 147, 386-99. https://doi.org/10.7326/0003-4819-147-6-200709180-00178
  4. Bost F, Sahra IB, Le Marchand-Brustel Y, et al (2012). Metformin and cancer therapy. Curr Opin Oncol, 24, 103-8. https://doi.org/10.1097/CCO.0b013e32834d8155
  5. Bradford SA, Khan A (2013). Individualizing chemotherapy using the anti-diabetic drug, metformin, as an "adjuvant": an exploratory study. J Cancer Sci Ther, 5, 6.
  6. Ceresoli GL, Cappuzzo F, Gregorc V, et al (2004). Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol, 15, 1042-7. https://doi.org/10.1093/annonc/mdh276
  7. Chakraborty A, Chowdhury S, Bhattacharyya M (2011). Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract, 93, 56-62. https://doi.org/10.1016/j.diabres.2010.11.030
  8. Di Maio M, Bria E, Rossi A, et al (2008). Progression-free survival as primary end point in advanced non-small-cell lung cancer: does the size matter? Ann Oncol, 19, 402-3. https://doi.org/10.1093/annonc/mdm586
  9. Evans JM, Donnelly LA, Emslie-Smith AM, et al (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ, 330, 1304-5. https://doi.org/10.1136/bmj.38415.708634.F7
  10. Forbes S, Clements J, Dawson E, et al (2006). COSMIC 2005. Br J Cancer, 94, 318-22. https://doi.org/10.1038/sj.bjc.6602928
  11. Han D, Li SJ, Zhu YT, et al (2013). LKB1/AMPK/mTOR signaling pathway in non-small-cell lung cancer. Asian Pac J Cancer Prev, 14, 4033-9. https://doi.org/10.7314/APJCP.2013.14.7.4033
  12. Janjetovic K, Vucicevic L, Misirkic M, et al (2011). Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur J Pharmacol, 651, 41-50. https://doi.org/10.1016/j.ejphar.2010.11.005
  13. Jiralerspong S, Palla SL, Giordano SH, et al (2009). Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol, 27, 3297-302. https://doi.org/10.1200/JCO.2009.19.6410
  14. Klastersky J, Awada A (2012). Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC). Crit Rev Oncol Hematol, 81, 49-57.
  15. Ma Y, Guo FC, Wang W, et al (2013). Kras gene mutation as a predictor of cancer cell responsiveness to metformin. Mol Med Rep, 8, 763-8.
  16. Mazzone PJ, Rai H, Beukemann M, et al (2012). The effect of metformin and thiazolidinedione use on lung cancer in diabetics. BMC Cancer, 12, 410. https://doi.org/10.1186/1471-2407-12-410
  17. Memmott RM, Mercado JR, Maier CR, et al (2010). Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res (Phila), 3, 1066-76. https://doi.org/10.1158/1940-6207.CAPR-10-0055
  18. Micic D, Cvijovic G, Trajkovic V, et al (2011). Metformin: its emerging role in oncology. Hormones (Athens), 10, 5-15. https://doi.org/10.14310/horm.2002.1288
  19. Na, II, Choe du H, Kim CH, et al (2010). Age at diagnosis predicts outcomes in gefitinib-treated female patients with non-small-cell lung cancer. Lung Cancer, 68, 295-8. https://doi.org/10.1016/j.lungcan.2009.06.005
  20. Nie SP, Chen H, Zhuang MQ, et al (2014). Anti-diabetic medications do not influence risk of lung cancer in patients with diabetes mellitus: a systematic review and metaanalysis. Asian Pac J Cancer Prev, 15, 6863-9. https://doi.org/10.7314/APJCP.2014.15.16.6863
  21. Okamoto T, Maruyama R, Shoji F, et al (2005). Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer, 47, 85-91. https://doi.org/10.1016/j.lungcan.2004.06.006
  22. Paesmans M, Sculier JP, Libert P, et al (1995). Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. The European lung cancer working party. J Clin Oncol, 13, 1221-30.
  23. Tan BX, Yao WX, Ge J, et al (2011). Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer, 117, 5103-11. https://doi.org/10.1002/cncr.26151
  24. Tan HK, Moad AI, Tan ML (2014). The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals. Asian Pac J Cancer Prev, 15, 6463-75. https://doi.org/10.7314/APJCP.2014.15.16.6463
  25. Tang T, Lord JM, Norman RJ, et al (2012). Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiroinositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev, 5, 3053.
  26. Wang SY, Chuang CS, Muo CH, et al (2013). Metformin and the incidence of cancer in patients with diabetes: a nested case-control study. Diabetes Care, 36, 155-6.
  27. Witters LA (2001). The blooming of the French lilac. J Clin Invest, 108, 1105-7. https://doi.org/10.1172/JCI14178
  28. Xiao YY, Zhan P, Yuan DM, et al (2013). Chemotherapy plus Vandetanib or chemotherapy alone in advanced non-small cell lung cancer: a meta-analysis of four randomised controlled trials. Clin Oncol (R Coll Radiol), 25, 7-15. https://doi.org/10.1016/j.clon.2012.09.005
  29. Yin M, Zhou J, Gorak EJ, et al (2013). Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncol, 18, 1248-55. https://doi.org/10.1634/theoncologist.2013-0111
  30. Zhang ZJ, Li S (2014). The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes Metab, [Epub ahead of print].

피인용 문헌

  1. The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development vol.11, pp.4, 2016, https://doi.org/10.1007/s11523-016-0423-z
  2. Metformin and Prostate Cancer: a New Role for an Old Drug vol.18, pp.6, 2017, https://doi.org/10.1007/s11934-017-0693-8
  3. Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity? vol.40, pp.3, 2017, https://doi.org/10.1007/s40264-016-0485-y
  4. The effect of metformin on survival of patients with pancreatic cancer: a meta-analysis vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-06207-x
  5. Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies vol.9, pp.5, 2017, https://doi.org/10.3390/cancers9050045
  6. Survival benefit associated with metformin use in inoperable non-small cell lung cancer patients with diabetes: A population-based retrospective cohort study vol.13, pp.1, 2018, https://doi.org/10.1371/journal.pone.0191129
  7. Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression vol.37, pp.22, 2018, https://doi.org/10.1038/s41388-018-0172-9
  8. Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead pp.02694727, 2019, https://doi.org/10.1111/jcpt.12759
  9. Drug Repurposing of Metabolic Agents in Malignant Glioma vol.19, pp.9, 2018, https://doi.org/10.3390/ijms19092768