Prognostic Factors for Overall Survival in Patients With Metastatic Colorectal Carcinoma Treated With Vascular Endothelial Growth Factor-Targeting Agents

  • Cetin, Bulent (Department of internal Medicine, Gazi University Faculty of Medicine) ;
  • Kaplan, Mehmet Ali (Department of internal Medicine, Dicle University Faculty of Medicine) ;
  • Berk, Veli (Department of internal Medicine, Division of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Ozturk, Selcuk Cemil (Department of internal Medicine, Dicle University Faculty of Medicine) ;
  • Benekli, Mustafa (Department of internal Medicine, Gazi University Faculty of Medicine) ;
  • Isikdogan, Abdurrahman (Department of internal Medicine, Dicle University Faculty of Medicine) ;
  • Ozkan, Metin (Department of internal Medicine, Division of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Coskun, Ugur (Department of internal Medicine, Gazi University Faculty of Medicine) ;
  • Buyukberber, Suleyman (Department of internal Medicine, Gazi University Faculty of Medicine)
  • Published : 2012.03.31


Objective: Angiogenesis represents a key element in the pathogenesis of malignancy. There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor (VEGF)-targeted therapy. The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer. Methods: Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naive metastatic colorectal cancer were collected from three Turkey cancer centers. Cox proportional hazards regression was used to identify independent prognostic factors for OS. Results: The median OS for the whole cohort was 19 months (95% CI, 14.3 to 23.6 months). Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology (ASMO) were independent predictors of short survival: serum lactate dehydrogenase (LDH) greater than the upper limit of normal (ULN; p<0.001); neutrophils greater than the ULN (p<0.0014); and progression free survival (PFS) less than 6 months (p =0.001). Conclusion: Serum LDH and neutrophil levels were the main prognostic factors in predicting survival, followed by PFS. This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents.


  1. Burzykowski T, Molenberghs G, Buyse M (2001). Validation of surrogate endpoints in multiple randomized clinical trials with failure-time endpoints. J Roy Stat Soc C Appl Stat, 50, 405-22.
  2. Buyse M, Burzykowski T, Carroll K, et al (2007). Progressionfree survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol, 25, 5218-24.
  3. Burzykowski T, Buyse M, Piccart-Gebhart MJ, et al (2008). Evaluation of tumor response, disease control, progressionfree survival, and time to progression as potential surrogate endpoints in metastatic breast cancer. J Clin Oncol, 26, 1987-92.
  4. Coiffier B, Gisselbrecht C, Vose JM, et al (1991). Prognostic factors in aggressive malignant lymphomas. Description and validation of prognostic index that could identify patients requiring a more intensive therapy. J Clin Oncol, 9, 211-19.
  5. Collette L, Burzykowski T, Carroll KJ, et al (2005). Is prostatespecific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? J Clin Oncol, 23, 6139-48.
  6. de Gramont A, Figer A, Seymour M, et al (2000). Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer. J Clin Oncol, 18, 2938-47.
  7. Dimopoulos MA, Barlogie B, Smith TL, et al (1991). High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med, 115, 931-35.
  8. Donskov F, von der Maase H (2006). Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol, 24, 1997-05.
  9. Ferrara N, Hillan KJ, Gerber HP, et al (2004). Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov, 3, 391.
  10. Ferrara N (2004). Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev, 25, 581-?.
  11. Grothey A, Hedrick EE, Mass RD, et al (2008). Responseindependent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol, 26, 183-89.
  12. Hecht JR, Trarbach T, Jaeger E (2005). A randomized, doubleblind, placebo-controlled, phase III study in patients with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5- fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1). J Clin Oncol, 23, 16S (abstr LBA3).
  13. Heng DY, Xie W, Regan MM, et al (2009). Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factortargeted agents:results from a large, multicenter study. J Clin Oncol, 27, 5794-99.
  14. Hollen CW, Henthorn J, Koziol JA, et al (1992). Serum interleukin-6 levels in patients with thrombocytosis. Leuk Lymphoma, 8, 235-41.
  15. Kemeny N, Braun DW Jr (1983). Prognostic factors in advanced colorectal carcinoma. Importance of lactic dehydrogenase level, performance status, and white blood cell count. Am J Med, 74, 786-94.
  16. Kerbel RS, Kamen BA (2004). The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer, 4, 423-?.
  17. Mancuso P, Colleoni M, Calleri A, et al (2006). Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood, 108, 452-?.
  18. Nisman B, Barak V, Hubert A, et al (2003). Prognostic factors for survival in metastatic breast cancer during first line paclitaxel chemotherapy. Anticancer Res, 23, 1939-42.
  19. Saltz L, Cox JV, Blanke C, et al (2000). Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med, 343, 905-14.
  20. Suppiah R, Shaheen PE, Elson P, et al (2006). Thrombocytosis as a prognostic factor for survival in patients with metastatic renal cell carcinoma. Cancer, 107, 1793-00.
  21. Tas F, Aykan F, Alici S, et al (2001). Prognostic factors in pancreatic carcinoma: serum LDH levels predict survival in metastatic disease. Am J Clin Oncol, 24, 547-50.
  22. Tas F, Aydiner A, Demir C, et al (2001). Serum lactate dehydrogenase levels at presentation predict outcome of patients with limited-stage small-cell lung cancer. Am J Clin Oncol, 24, 376-78.
  23. Tournigand C, Andre T, Achille E, et al (2004). FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol, 22, 229-37.
  24. Tournigand C, Cervantes A, Figer A, et al (2006). OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer-a GERCOR study. J Clin Oncol, 24, 394-00.

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