Analyses of Multiple Factors for Determination of "Selected Patients" Who Should Receive Rechallenge Treatment in Metastatic Colorectal Cancer: a Retrospective Study from Turkey

  • Ozaslan, Ersin (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Duran, Ayse Ocak (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Bozkurt, Oktay (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Inanc, Mevlude (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Ucar, Mahmut (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Berk, Veli (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Karaca, Halit (Department of Medical Oncology, Erciyes University Faculty of Medicine) ;
  • Elmali, Ferhan (Department of Biostatistics, Erciyes University Faculty of Medicine) ;
  • Ozkan, Metin (Department of Medical Oncology, Erciyes University Faculty of Medicine)
  • 발행 : 2015.04.14


Background: Repeating a prior chemotherapy (rechallenge therapy) is an option for selected patients with metastatic colorectal cancer, but there is very little evidence in the literature for this approach. Thus, we reviewed our registry to evaluate prognostic factors and survival of patients who received irinotecan and oxaliplatin-based regimens as rechallenge third and fourth-line therapy. Materials and Methods: Patients who received irinotecan-based or oxaliplatin-base regimen as first-line had been rechallenged with third-line or fourth-line therapy. These patients were selected from the database of Turkish mCRC registry archives between October 2006 and June 2013 and evaluated retrospectively for factors effecting progression free survival (PFS) and overall survival (OS) by the Kaplan-Meire and Cox-regression methods. Results: Thirty-nine patients were enrolled. The median duration of follow-up was 36 months (14-68 months). Thirty-one patients (76%) died during follow-up. In terms of rechallenge treatments, 29 patients had received third-line and 10 patients had received fourth-line. Response rate (RR) was found to be 12.9%, with stable disease in 19 (48.7%) patients. The median PFS was 6 months (95%CI=4.64-7.35 months) and the median OS was 11 months (95%CI=8.31-13.68 months). The factors effecting survival (PFS and OS) were only being PFS after first-line chemotherapy ${\geq}12months$ (p=0.007, 95% CI=1.75-35.22 and p=0.004, 95%CI=1.44-7.11), both in univariate and multivariate analyses. Conclusions: This study indicates that rechallenge treatment could be a good option as a third or later line therapy in patients who had ${\geq}12months$ PFS onreceiving first line therapy.


  1. Aslam MI, Kelkar A, Sharpe D, et al (2010). Ten years experience of managing the primary tumours in patients with stage IV colorectal cancers. Int J Surg, 8, 305-13.
  2. Atreya CE, Sangale Z, Xu N, et al (2013). PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival. Cancer Med, 2, 496-506.
  3. Chibaudel B, Tournigand C, Artru P, et al (2009). FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study. Ann Oncol, 20, 1383-6.
  4. Dirican A, Varol U, Kucukzeybek Y, et al (2014). Treatment of metastatic colorectal cancer with or without bevacizumab: can the neutrophil/lymphocyte ratio predict the efficiency of bevacizumab? Asian Pac J Cancer Prev, 15, 4781-6.
  5. Divitiis CD, Nasti G, Montano M, et al (2014). Prognostic and predictive response factors in colorectal cancer patients: between hope and reality. World J Gastroenterol, 20, 15049-59.
  6. Douillard JY, Siena S, Cassidy J, et al (2014). Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol, 25, 1346-55.
  7. Fuchs CS, Marshall J, Mitchell E, et al (2007). Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol, 25, 4779-86.
  8. Galizia G, Lieto E, Orditura M et al (2008). First-line chemotherapy vs bowel tumor resection plus chemotherapy for patients with unresectable synchronous colorectal hepatic metastases. Arch Surg, 143, 352-35.
  9. Graf W, Bergstrom R, Pahlman L et al (1994). Appraisal of a model for prediction of prognosis in advanced colorectal cancer. Eur J Cancer, 30, 453-7.
  10. Haggar FA, Boushey RP (2009). Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg, 22, 191-7.
  11. He WZ, Jiang C, Yin CX, et al (2014). Prognostic model built on blood-based biomarkers in patients with metastatic colorectal cancer. Asian Pac J Cancer Prev, 15, 7327-31.
  12. Heinemann V, von Weikersthal LF, Decker T, et al (2014). FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol, 15, 1065-75.
  13. Huh JW, Kim CH, Lim SW, et al (2013). Early recurrence in patients undergoing curative surgery for colorectal cancer: is it a predictor for poor overall survival? Int J Colorectal Dis, 28, 1143-9.
  14. Hurwitz H, Fehrenbacher L, Novotny W, et al (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 350, 2335-42.
  15. Jemal A, Siegel R, Xu J, et al (2010). Cancer statistics. CA Cancer J Clin, 60, 277-300.
  16. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al (2007). Cetuximab for the treatment of colorectal cancer. N Engl J Med, 357, 2040-8.
  17. Karaca H, Berk V, Inanc M, et al (2011). Epidemiologic evaluation of the patients admitted to department of medical oncology, erciyes university, medical faculty, between 2006 and 2009. J Hlth Sci, 20, 1-8.
  18. Katoh H, Yamashita K, Kokuba Y et al (2008). Surgical resection of stage IV colorectal cancer and prognosis. World J Surg, 32, 1130-7.
  19. Kemeny N, Braun DW (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.
  20. Kleespies A, Fuessl KE, Seeliger H et al (2009). Determinants of morbidity and survival after elective non-curative resection of stage IV colon and rectal cancer. Int J Colorectal Dis, 24, 1097-109.
  21. Kobayashi H, Sugihara K, Kotake K (2013). Prognostic scoring system for stage IV colorectal cancer: is the AJCC subclassification of stage IV colorectal cancer appropriate? Int J Clin Oncol, 18, 696-703.
  22. Kohne CH, Kretzschmar A, Wils J (1998). First-line chemotherapy for colorectal carcinoma-we are making progress. Onkologie, 21, 280-9.
  23. Levy M, Visokai V, Lipska L, et al (2008). Tumor markers in staging and prognosis of colorectal carcinoma. Neoplasma, 55, 138-42.
  24. Mitsuyama Y , Shiba H, Haruki K, et al (2012). Carcinoembryonic antigen and carbohydrate antigen 19-9 are prognostic predictors of colorectal cancer with unresectable liver metastasis. Oncol Lett, 3, 767-8.
  25. Nielsen DL, Palshof JA, Larsen FO, Jensen BV, Pfeifer P (2014). A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan +/- targeted therapy. Cancer Treat Rev, 40, 701-15.
  26. Peeters M, Price TJ, Cervantes A, et al (2010). Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol, 28, 4706-13.
  27. Schwartzberg LS, Rivera F, Karthaus M, et al (2014). PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated,unresectable, wildtype KRAS exon 2 metastatic colorectal cancer. J Clin Oncol, 20, 2240-7.
  28. Settmacher U, Dittmar Y, Knosel T, et al (2011). Predictors of long-term survival in patients with colorectal liver metastases: a single center study and review of the literature. Int J Colorectal Dis, 26, 967-81.
  29. Stelzner S, Hellmich G, Koch R et al (2005). Factors predicting survival in stage IV colorectal carcinoma patients after palliative treatment: a multivariate analysis. J Surg Oncol, 89, 211-7.
  30. Tebbutt NC, Norman AR, Cunningham D et al (2003). Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut, 52, 568-73.
  31. Tejpar S, Celik I, Schlichting M, et al (2012). Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol, 30, 3570-7.
  32. Tonini G, Imperatori M, Vincenzi B, Frezza AM, Santini D (2013). Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer. J Exp Clin Cancer Res, 18, 32-3.
  33. Tsai HL, Chu KS, Huang YH, et al (2009). Predictive factors of early relapse in UICC stage I-III colorectal cancer patients after curative resection. J Surg Oncol, 100, 736-43.
  34. Tuncel T, Ozgun A, Emirzeoglu L, et al (2014). Mean platelet volume as a prognostic marker in metastatic colorectal cancer patients treated with bevacizumabcombined chemotherapy. Asian Pac J Cancer Prev, 15, 6421-23.
  35. Van Cutsem E, Kohne CH, Hitre E, et al (2009). Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med, 360, 1408-17.
  36. Yokota T (2012). Are KRAS/BRAF mutations potent prognostic and/or predictive biomarkers in colorectal cancers? Anticancer Agents Med Chem, 12, 163-71.
  37. Yun HR, Lee WY, Lee WS et al (2007). The prognostic factors of stage IV colorectal cancer and assessment of proper treatment according to the patient's status. Int J Colorectal Dis, 22, 1301-10.
  38. Bokemeyer C, Van Cutsem E, Rougier P, et al (2012). Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer, 48, 1466-75.
  39. Bozkurt O, Inanc M, Turkmen E, et al (2014). Clinicopathological characteristics and prognosis of patients according to recurrence time after curative resection for colorectal cancer. Asian Pac J Cancer Prev, 15, 9277-81.
  40. Cetin B, Kaplan MA, Berk V, et al (2012). Prognostic factors for overall survival in patients with metastatic colorectal carcinoma treated with vascular endothelial growth factor-targeting agents. Asian Pac J Cancer Prev, 13, 1059-63.
  41. Bajwa A, Blunt N, Vyas S et al (2009). Primary tumour resection and survival in the palliative management of metastatic colorectal cancer. Eur J Surg Oncol, 35, 164-7.

피인용 문헌

  1. Diet and Colorectal Cancer Risk in Asia - a Systematic Review vol.16, pp.13, 2015,