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Published on 1 November 2004

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Treatments for advanced colorectal cancer

teaser

Ada Henrike Braun
MD
Research Instructor
Gastrointestinal Cancer and Epithelial Cell Biology
Vanderbilt University Medical Center
Nashville, TN
USA
E:ada.h.braun@vanderbilt.edu

Colorectal cancer is a major cause of worldwide cancer morbidity and mortality, and is the second-leading cause of cancer-related deaths in the developed world.(1,2) About half of all colon cancer patients develop metastatic disease. For them, palliative systemic therapy may considerably improve disease control, survival and quality of life. This article reviews the clinical rationale of current systemic therapies and future perspectives in the treatment of patients with metastatic colorectal cancer.

Available anticancer agents
For more than three decades, therapeutic approaches have almost exclusively been based on 5-fluorouracil (5-FU), which remains the mainstay of treatment in colorectal cancer. Whereas single-agent bolus administration shows moderate antitumour activity, treatment outcome is improved significantly by protracted infusion, combination regimens and biochemical modulation using folinic acid (FA, Leucovorin, LV) or methotrexate (Biotrexate). Today, treatment options for advanced colorectal cancer have broadened considerably, with over half a dozen agents approved, including thymidylate synthase (TS) inhibitors, oral fluoropyrimidines (eg, tegafur–uracil [UFT] or capecitabine [Xeloda]),(3) the topoisomerase 1 interactive compound irinotecan (CPT-11, Campto),(4) the diaminocyclohexane (DACH)-platinum derivative oxaliplatin (Eloxatin),(5) and biologically targeted agents against the epidermal growth factor receptor (EGFR: cetuximab; Erbitux) or the vascular endothelial growth factor (VEGF: bevacizumab; Avastin).(6,7) Indeed, with improving understanding of cancer cell biology, novel molecular targeted therapeutics have emerged and have entered clinical evaluation. Compounds in advanced clinical development that are predicted to enter the market in the near future include the EGFR-directed antibodies panitumumab (ABX-EGF; Amgen),(8) EMD72000 (Merck KGaA)(9) and small-molecule inhibitors such as gefitinib (Iressa; AstraZeneca)(10) and erlotinib (Tarceva; OSI Pharmaceuticals/Genentech),(11) inhibitors of the EGFR tyrosine kinase, or PTK787/ZK222584 (Novartis/Schering AG), which inhibits VEGF receptor tyrosine kinases.

Approved colorectal cancer treatments

5-FU and biomodulators
5-FU is an antimetabolite that has been available in clinics since the 1950s. Combination therapy with the biomodulator LV improves 5-FU efficacy, albeit without providing survival advantage.(12) Similarly, continuous-infusion 5-FU–LV regimens are more effective than intravenous (IV) bolus regimens in terms of response,(13,14) progression-free survival or safety,(15–17) but they do not improve overall survival. Whereas infusional regimens are frequently employed in Europe, they require prior implantation of a Port-a-Cath system and portable infusion pumps. A major advance has been the generation of orally available 5-FU prodrugs.

Oral fluoropyrimidines
Oral 5-FU prodrugs such as UFT and capecitabine mimic protracted 5-FU infusion and facilitate drug administration. Moreover, there is strong evidence that high intratumoural levels of thymidine phosphorylase may selectively increase capecitabine-deduced fluoropyrimidine concentrations, resulting in enhanced efficacy and reduced systemic toxicity. Four large randomised phase III trials have implemented the therapeutic value of both oral fluoropyrimidines, which are convenient and meaningful alternatives to 5-FU–LV bolus regimens.(18–21) Currently, their activity is being compared with that of infusional 5-FU–LV in combination with either irinotecan or oxaliplatin. Although they are unlikely to improve clinical efficacy results, oral formulations may considerably improve a patient’s quality of life by circumventing possible nuisances of IV drug application, such as paravasation or infection.

Oxaliplatin
Oxaliplatin is a third-generation 1,2-DACH platinum compound, which differs from other platinum derivatives in clinical activity and toxicity profiles and is effective in the systemic treatment of advanced colon cancer, both as a single agent and in combination regimens with either 5-FU or irinotecan. While single-agent oxaliplatin achieved only moderate response rates and short progression-free survival in various phase II trials, considerable improvement was obtained in combinations with 5-FU–LV,(22–38) yielding improved overall response and median times to disease progression, as well as a trend towards improved survival. The combination of oxaliplatin with irinotecan achieved similar safety and efficacy results as the IFL bolus (irinotecan+5-FU–LV) protocol, and may be considered in cases of contraindications to 5-FU.(39–41)

Irinotecan
Irinotecan has demonstrated meaningful clinical efficacy and tolerability, both as a single agent(42–45) and in combination with either bolus(46–54) or infusional(55–64) 5-FU–LV, and in concomitant versus alternating schedules of administration.(65–68) Overall, the efficacy of the combined regimens significantly surpassed that of 5-FU–LV alone; two studies in particular yielded remarkable response rates of over 70% with six-times-weekly schedules of irinotecan and intermittent infusional 5-FU–LV.(64) Newer irinotecan combinations in phase II clinical assessments include oral fluoropyrimidines(69–72) and the direct TS inhibitor raltitrexed.(73–77) Additionally, an oral irinotecan formulation is currently being evaluated in clinics, which may provide substantial benefit for cancer patients.

Cetuximab
Combination of the anti-EGFR antibody cetuximab with irinotecan yielded 23% overall response and six months’ median response duration for patients with EGFR-positive therapy-refractory tumours.(78) In a similar population, cetuximab alone yielded only 11% overall response rate.(79,80) The most frequent adverse effect observed with EGFR-targeted agents is acneiform skin rash, the occurrence of which has been associated with tumour response. Three-drug regimens with cetuximab, irinotecan and infusional or bolus 5-FU–LV yielded remarkable overall response rates of 70% and 44% in early clinical trials.(81,82)

Bevacizumab
Bevacizumab is the first anti-VEGF antibody out of a large panel of angiogenesis-targeted agents to improve overall survival in patients with colorectal cancer; it has recently been licensed in Europe and the USA. Angiogenesis, the formation of new blood vessels, is an essential mechanism for tumour growth, invasion and metastatic spread. Combination of bevacizumab with bolus 5-FU–LV yielded increased response rates, time to progression and median survival compared with 5-FU–LV alone.(83,84) Its safety profile, however, warrants further assessment, as hypertension, thromboembolic events and bleeding have been reported.

Towards a standard therapy for advanced colorectal cancer
Tangible advances have been achieved for metastatic colorectal cancer patients over the past few years, with more treatment options available than ever, and a median survival now approaching 21 months. So far, serial schedules of infusional 5-FU–LV-based combinations with irinotecan or oxaliplatin in either sequence have reliably demonstrated survival benefit for patients with good performance status (WHO<2) and favourable prognostic factors (eg, low serum lactic dehydrogenase, alkaline phosphatase, normal complete blood count, limited number of tumour sites).(41,85–87) These and similar regimens containing oral 5-FU prodrugs continue to be evaluated in the clinic with or without sequential or concomitant biologically targeted therapeutics.(8,88–91) To date, there is no consensus standard schedule, sequence or duration of treatment for advanced colorectal cancer patients, but every option should be considered in an individualised multimodal therapeutic approach. Two recently published meta-analyses highlighted the importance of remission induction within the first-line treatment for patient outcome.(92,93) Importantly, patients with formerly unresectable metastases may potentially be rendered amenable for surgery with curative intent after effective neoadjuvant chemotherapy.(94,95) Recent results further indicate clinical benefit with continued treatment until disease progression, when compared with treatment suspension in cases of response or stable disease and same reinduction therapy upon disease progression.(96)

The future is likely to see more and more tailored systemic therapy options arising with our increasing understanding of cancer biology, but there will be a price to pay. So far, novel therapies have been added to existing treatment regimens, rather than replacing them, and we will have to face the additional economic impact in a time where healthcare costs are steadily spiralling upwards.

References

  1. Cancer Facts and Figures 2003. American Cancer Society; 2003:5008.03.
  2. CA Cancer J Clin 2003;53:5-26.
  3. Oncologist 2002;7:288-323.
  4. Ann Oncol 2003;14 Suppl 2: ii17-23.
  5. Curr Treat Options Oncol 2003;4:405-11.
  6. Curr Opin Oncol 2004;16:385-90.
  7. Eur J Cancer 2004;40:1292-301.
  8. Proc Am Soc Clin Oncol 2004;23: Abs 3511.
  9. J Clin Oncol 2004;22:175-84.
  10. Proc Am Soc Clin Oncol 2004;23: Abs 3572.
  11. Proc Am Soc Clin Oncol 2003;22:196 (Abs 785).
  12. J Clin Oncol 1992;10:896-903.
  13. Proc Am Soc Clin Oncol 2001;20:125a (Abs 497).
  14. Ann Oncol 1998;9:727-31.
  15. J Clin Oncol 2001;19:2413-21.
  16. J Clin Oncol 1997;15:808-15.
  17. Proc Am Soc Clin Oncol 2000;19:241a (Abs 935).
  18. J Clin Oncol 2002;20:3605-16.
  19. J Clin Oncol 2001;19:2282-92.
  20. J Clin Oncol 2001;19:4097-106.
  21. Eur J Cancer 2002;38 Suppl 2:15-20.
  22. Ann Oncol 1998;9:105-8.
  23. J Clin Oncol 1998;16:2739-44.
  24. Eur J Cancer 2001;37:1006-13.
  25. Proc Am Soc Clin Oncol 1999;18:255a (Abs 979).
  26. Proc Am Soc Clin Oncol 2000;19:271a (Abs 1055).
  27. J Clin Oncol 2002;20:2545-50.
  28. Proc Am Soc Clin Oncol 2001;20:138a (Abs 548).
  29. Proc Am Soc Clin Oncol 2002;21:136b (Abs 2356).
  30. Proc Am Soc Clin Oncol 2002;21:108b (Abs 2244).
  31. Proc Am Soc Clin Oncol 2000;19:300a (Abs 1177).
  32. Proc Am Soc Clin Oncol 2000;19:302a (Abs 1189).
  33. Proc Am Soc Clin Oncol 2001;20:145a (Abs 578).
  34. Proc Am Soc Clin Oncol 2002;21:145b (Abs 2393).
  35. Cancer 1992;69:893-900.
  36. Cancer 1999;85:2532-40.
  37. J Clin Oncol 1996;14:2950-8.
  38. Proc Am Soc Clin Oncol 2001;20:143a (Abs 569).
  39. J Clin Oncol 2001;19:4195-201.
  40. Proc Am Soc Clin Oncol 2001;20: Abs 566.
  41. Proc Am Soc Clin Oncol 1999;18: Abs 913.
  42. J Clin Oncol 1997;15:251-60.
  43. Cancer 2001;91:704-11.
  44. J Clin Oncol 1997;15:2910-9.
  45. J Clin Oncol 1996;14:709-15.
  46. Eur J Cancer 1999;35 Suppl 4:S70 (Abs 213).
  47. Proc Am Soc Clin Oncol 2001;20:111b (Abs 2196).
  48. 48. Proc Am Soc Clin Oncol 2002;21:123b (Abs 2307).
  49. Proc Am Soc Clin Oncol 2000;19:280a (Abs 1091).
  50. Ann Oncol 1998;9:1199-204.
  51. Ann Oncol 2000;11 Suppl 4:46 (Abs 197P).
  52. Proc Am Soc Clin Oncol 1997;16:266a (Abs 944).
  53. Proc Am Soc Clin Oncol 2003;22 (Abs 1123).
  54. Ann Oncol 2000;11:1323-33.
  55. Eur J Cancer 2001;37 Suppl 6:S295 (Abs 1091).
  56. Proc Am Soc Clin Oncol 2000;19:324a (Abs 1280A).
  57. Proc Am Soc Clin Oncol 2002;21:116b (Abs 2276).
  58. Proc Am Soc Clin Oncol 1999;18:257a (Abs 989).
  59. Proc Am Soc Clin Oncol 2001;20:108b (Abs 2183).
  60. Proc Am Soc Clin Oncol 2002;21:129b (Abs 2329).
  61. Proc Am Soc Clin Oncol 2001;20:115b (Abs 2210).
  62. Proc Am Soc Clin Oncol 2001;20:108b (Abs 2182).
  63. Proc Am Soc Clin Oncol 2002;21:107b (Abs 2241).
  64. Proc Am Soc Clin Oncol 2000;19:287a (Abs 1123).
  65. Ann Oncol 2000;11:1045-51.
  66. Proc Am Soc Clin Oncol 2001;20:135a (Abs 535).
  67. Proc Am Soc Clin Oncol 2001;20:135a (Abs 536).
  68. Proc Am Soc Clin Oncol  2001;20:112b (Abs 2199).
  69. Eur J Cancer 2001;37 Suppl 6:S293 (Abs 1082).
  70. Proc Am Soc Clin Oncol 2003;22 (Abs 1022).
  71. Eur J Cancer 2001;37 Suppl 6:S295 (Abs 1090).
  72. Proc Am Soc Clin Oncol 2002;21:106b (Abs 2238).
  73. Proc Am Soc Clin Oncol 2000;19:307a (Abs 1211).
  74. Proc Am Soc Clin Oncol 2000;19:309a (Abs 1220).
  75. Proc Am Soc Clin Oncol 2001;20:120b (Abs 2230).
  76. Proc Am Soc Clin Oncol 2002;21:102b (Abs 2220).
  77. Proc Am Soc Clin Oncol 2002;21:172a (Abs 685).
  78. Proc Am Soc Clin Oncol 2001;20:3a (Abs 7).
  79. Proc Am Soc Clin Oncol 2002;21:127a (Abs 504).
  80. N Engl J Med 2004;351:337-45.
  81. Proc Am Soc Clin Oncol 2002;21:135a (Abs 536).
  82. Proc Am Soc Clin Oncol 2002;21:159a (Abs 633).
  83. J Clin Oncol 2003;21:60-5.
  84. Proc Am Soc Clin Oncol 2003;22: Abs 3646.
  85. J Clin Oncol 2004;22:229-37.
  86. Proc Am Soc Clin Oncol 2003;22:252 (Abs 1009).
  87. Ann Oncol 2002;13:308-17.
  88. Proc Am Soc Clin Oncol 2004;23: Abs 3514.
  89. Proc Am Soc Clin Oncol 2004;23: Abs 3510.
  90. Proc Am Soc Clin Oncol 2004;23: Abs 3512.
  91. Proc Am Soc Clin Oncol 2004;23: Abs 3513.
  92. Lancet 2000;356:373-8.
  93. Cancer 2001;91:2033-8.
  94. Ann Oncol 1999;10:663-9.
  95. Br Med Bull 2002;64:127-40.
  96. Lancet 2003;361:457-64.

Resources
US National Cancer Institute
W:www.nci.nih.gov/cancertopics/types/colon-and-rectal
Clinical trials for colorectal cancer and other malignancies
W:www.clinicaltrials.gov
Colon Cancer Alliance
W:www.ccalliance.org



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