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Second-line therapy for advanced colorectal carcinoma

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Abstract

The past decade has witnessed considerable advances in the treatment of colorectal cancer (CRC). The emergence and integration into clinical practice of new cytotoxic agents, such as irinotecan and oxaliplatin, has had a significant impact on outcomes from advanced CRC with median survivals of 18 to 21 months now achievable. Improvements in survival as a consequence of using these drugs as salvage therapies ultimately led to demonstration of efficacy for both in the first-line treatment of CRC. As the importance of second-line therapy is increasingly recognized, key issues, such as optimal schedules, chemotherapy combinations, and sequential therapy, need to be addressed. The integration of newer biologic agents, such as cetuximab and bevacizumab, for which recent data have emerged, has further added to the complexities of delivering therapy to patients with advanced CRC, heralding a new treatment era for this disease.

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References and Recommended Reading

  1. Pizzolato JF, Saltz LB: The camptothecins. Lancet 2003, 361:2235–2242.

    Article  PubMed  CAS  Google Scholar 

  2. Atalay G, Cardoso F, Paesmans M, et al.: Second-line treatment in advanced colon cancer: Are multiple phase II trials informative enough to guide clinical practice? Anticancer Drugs 2003, 14:703–713.

    Article  PubMed  CAS  Google Scholar 

  3. Van Cutsem E, Cunningham D, Bokkel Huinink WW, et al.: Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer 1999, 35:54–599.

    Article  PubMed  Google Scholar 

  4. Rothenberg ML, Cox JV, DeVore RF, et al.: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 1999, 85:786–795.

    Article  PubMed  CAS  Google Scholar 

  5. Cunningham D, Pyrhonen S, James RD, et al.: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998, 352:1413–1418.

    Article  PubMed  CAS  Google Scholar 

  6. Rougier P, Van Cutsem E, Bajetta E, et al.: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998, 352:1407–1412.

    Article  PubMed  CAS  Google Scholar 

  7. Rouits E, Boisdron-Celle M, Dumont A, et al.: Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 2004, 10:5151–5159.

    Article  PubMed  CAS  Google Scholar 

  8. Saltz LB, Cox JV, Blanke C, et al.: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000, 343:905–914.

    Article  PubMed  CAS  Google Scholar 

  9. Douillard JY, Cunningham D, Roth AD, et al.: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised Trial. Lancet 2000, 355:1041–1047.

    Article  PubMed  CAS  Google Scholar 

  10. Fischel JL, Rostagno P, Formento P, et al.: Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines. Br J Cancer 2001, 84:579–585.

    Article  PubMed  CAS  Google Scholar 

  11. Grothey A, Goldberg RM: A review of oxaliplatin and its clinical use in colorectal cancer. Expert Opin Pharmacother 2004, 5:2159–2170.

    Article  PubMed  CAS  Google Scholar 

  12. Rothenberg ML, Oza AM, Bigelow RH, et al.: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and gluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003, 21:2059–2069.

    Article  PubMed  CAS  Google Scholar 

  13. Rothenberg ML, Oza AM, Burger B: Final results of a phase III trial of 5-FU/leucovorin versus oxaliplatin versus the combination in patients with metastatic colorectal cancer following irinotecan, 5-FU, and leucovorin [abstract]. Proc ASCO 2003, 22:1011.

    Google Scholar 

  14. Haller D, Rothenberg ML, Wong AO: Final results of a randomised phase III trial comparing irinotecan plus oxaliplatin (IROX) to irinotecan monotherapy in patients with metastatic colorectal cancer previously treated with fluoropyrimidines [abstract]. Ann Oncol 2004, 15:2630.

    Google Scholar 

  15. de Gramont A, Figer A, Seymour M, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000, 18:2938–2947.

    PubMed  Google Scholar 

  16. Giacchetti S, Perpoint B, Zidani R, et al.: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000, 18:136–147.

    PubMed  CAS  Google Scholar 

  17. Goldberg RM, Sargent DJ, Morton RF, et al.: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004, 22:23–30. A large trial demonstrating superiority for FOLFOX first line but also highlighting the potential value of second-line therapy with a different agent second line in prolonging survival.

    Article  PubMed  CAS  Google Scholar 

  18. Tournigand C, Andre T, Achille E, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004, 22:229–237. An important randomized trial addressing the issue of the optimal sequence of oxaliplatin and irinotecan as first- and second-line treatments in sequential therapy.

    Article  PubMed  CAS  Google Scholar 

  19. Grothey A, Sargent D, Goldberg RM, et al.: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004, 22:1209–1214. A review of seven trials concluding that exposure to all three active agents (5-FU, irinotecan, and oxaliplatin) during treatment is likely to be a key determinant of survival.

    Article  PubMed  CAS  Google Scholar 

  20. Marmor MD, Skaria KB, Yarden Y: Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys 2004, 58:903–913. A good review of the molecular processes underlying the EGFR pathway and implications for tumorigenesis.

    Article  PubMed  CAS  Google Scholar 

  21. Mayer A, Takimoto M, Fritz E, et al.: The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and Mdr gene expression in colorectal cancer. Cancer 1993, 71:2454–2460.

    Article  PubMed  CAS  Google Scholar 

  22. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003, 21:2787–2799. An excellent review of the biology, preclinical, and clinical development of cetuximab across tumor types.

    Article  PubMed  CAS  Google Scholar 

  23. Prewett MC, Hooper AT, Bassi R, et al.: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002, 8:994–1003.

    PubMed  CAS  Google Scholar 

  24. Rubin MS, Shin DM, Pasmantier M: Monoclonal antibody IMC-C225, an anti-epidermal growth factor receptor (EGFr) for patients with EGFr-positive tumours refractory to or in relapse from previous therapeutic regimens [abstract]. Proc ASCO 2000, 19:1860.

    Google Scholar 

  25. Saltz LB, Rubin MS, Hochster H: Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFR) [abstract]. Proc ASCO 2001, 20:7.

    Google Scholar 

  26. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al.: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004, 22:1201–1208.

    Article  PubMed  CAS  Google Scholar 

  27. Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med 2004, 351:337–345. The pivotal randomized phase II study of 218 patients indicating the reversal of chemo-resistance in irinotecan-refractory patients treated with the combination of irinotecan and cetuximab and showing higher response rates and time to progression with second-line combination therapy as compared with cetuximab alone.

    Article  PubMed  CAS  Google Scholar 

  28. Lenz HJ, Mayer RJ, Gold PJ: Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin [abstract]. Proc ASCO 2004, 23:3510.

    Google Scholar 

  29. Gustafson NF, Saltz LB, Cunningham D: Safety profile of cetuximab in patients with metastatic colorectal cancer [abstract]. Proc ASCO 2004, 23:237.

    Google Scholar 

  30. Badarinath S, Mitchell P, Jennis A: Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): preliminary safety analysis of a randomised phase III trial [abstract]. Proc ASCO 2004, 23:3531.

    Google Scholar 

  31. Folkman J: Tumour angiogenesis: therapeutic implication. N Engl J Med 1971, 285:1182–1186.

    Article  PubMed  CAS  Google Scholar 

  32. Takebayashi Y, Aklyama S, Yamada K, et al.: Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer 1996, 78:226–231.

    Article  PubMed  CAS  Google Scholar 

  33. Choi HJ, Hyun MS, Jung GJ, et al.: Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and recurrence. Oncology 1998, 55:575–581.

    Article  PubMed  CAS  Google Scholar 

  34. Millauer B, Longhi MP, Plate KH, et al.: Dominant-negative inhibition of Flk-suppresses the growth of many tumor types in vivo. Cancer Res 1996, 56:1615–1620.

    PubMed  CAS  Google Scholar 

  35. Warren RS, Yuan H, Matli MR, et al.: Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995, 95:1789–1797.

    Article  PubMed  CAS  Google Scholar 

  36. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342. The pivotal randomized phase III study that led to regulatory approval for first-line bevacizumab in combination with intravenous 5-FU.

    Article  PubMed  CAS  Google Scholar 

  37. Novotny WF, Holmgren E, Nelson B: Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) does not increase the incidence of venous thromboembolism when added to first-line chemotherapy to treat metastatic colorectal cancer [abstract]. Proc ASCO 2004, 23:3529.

    Google Scholar 

  38. Hambleton J, Novotny W, Hurwitz H: Bevacizumab does not increase bleeding in patients with metastatic colorectal cancer receiving concurrent anti-coagulation [abstract]. Proc ASCO 2004, 23:3528.

    Google Scholar 

  39. Mass RD, Fyfe G, Hambleton J: Bevacizumab in combination with 5-FU/leucovorin improves survival in patients with metastatic colorectal cancer: a combined analysis [abstract]. Proc ASCO 2004, 23:3616.

    Google Scholar 

  40. Hedrick EE, Hurwitz H, Sarkar S: Post-progression therapy effect on survival in AVF2107: a phase III trial of bevacizumab in first-line treatment of metastatic colorectal cancer [abstract]. Proc ASCO 2004, 23:3517.

    Google Scholar 

  41. Mitchell EP, Alberts SR, Schwartz MA, et al.: High dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200 [abstract]. Proc GI Symposium 2005, 24:169a.

    Google Scholar 

  42. Saltz L, Lenz H, Kindler H, et al.: Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan versus cetuximab/bevacizumab in irinotecan-refractory colorectal cancer. Proc GI Symposium 2005, 24:169b.

    Google Scholar 

  43. Ciardiello F, Bianco R, Damiano V, et al.: Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 2000, 6:3739–3747.

    PubMed  CAS  Google Scholar 

  44. Wood JM, Bold G, Buchdunger E, et al.: PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000, 60:2178–2189.

    PubMed  CAS  Google Scholar 

  45. Bold G, Altmann KH, Frei J, et al.: New amilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumordriven angiogenesis. J Med Chem 2000, 43:3200.

    Article  PubMed  CAS  Google Scholar 

  46. Drevs J, Hofmann I, Hugenschmidt H, et al.: Effects of PTK787/ ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 2000, 60:4819–4824.

    PubMed  CAS  Google Scholar 

  47. Morgan B, Thomas AL, Drevs J, et al.: Dynamic contrastenhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 2003, 21:3955–3964.

    Article  PubMed  CAS  Google Scholar 

  48. Schleucher N, Trarbach T, Junker U: Phase I/II study of PTK787/ZK 222854 (PTK/ZK), a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer [abstract]. Proc ASCO 2004, 23:3558.

    Google Scholar 

  49. Steward WP, Thomas A, Morgan B: Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first line treatment for patients with metastatic colorectal cancer [abstract]. Proc ASCO 2004, 23:3556.

    Google Scholar 

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Authors and Affiliations

  1. Gastrointestinal and Lymphoma Units, Royal Marsden Hospital, Downs Road, SM2 5PT, Sutton, Surrey, UK

    Naureen Starling MRCP & David Cunningham MD, FRCP

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  1. Naureen Starling MRCP
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  2. David Cunningham MD, FRCP
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Starling, N., Cunningham, D. Second-line therapy for advanced colorectal carcinoma. Curr Oncol Rep 7, 173–180 (2005). https://doi.org/10.1007/s11912-005-0070-5

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  • DOI: https://doi.org/10.1007/s11912-005-0070-5

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