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Stage III Colon Cancer Treatment

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    Chemotherapy regimens prior to 2000

    Prior to 2000, 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Many of the early randomized studies of 5-FU in the adjuvant setting failed to show a significant improvement in survival for patients.[6,7,8,9] These trials employed 5-FU alone or 5-FU-semustine (methyl-CCNU).

    Evidence (5-FU alone and 5-FU-semustine):

    1. The NCCTG conducted a randomized trial comparing surgical resection alone with postoperative levamisole or 5-FU-levamisole.[10][Level of evidence: 1iiA]
      • A significant improvement in disease-free survival (DFS) was observed for patients with stage III colon cancer who received 5-FU-levamisole, but OS benefits were of borderline statistical significance.
      • An absolute survival benefit of approximately 12% (49% vs. 37%) was seen in patients with stage III disease treated with 5-FU-levamisole.
    2. In a large confirmatory intergroup trial, 5-FU-levamisole prolonged DFS and OS in patients with stage III colon cancer compared with patients who received no treatment after surgery.[11][Level of evidence: 1iiA] Levamisole alone did not confer these benefits.
    3. Subsequent studies tested the combination of 5-FU-leucovorin in the adjuvant treatment of patients with resected carcinoma of the colon.
      • Results of multiple randomized trials that have enrolled more than 4,000 patients comparing adjuvant chemotherapy with 5-FU-leucovorin to surgery or 5-FU-semustine-vincristine demonstrate a relative reduction in mortality of between 22% and 33% (3-year OS of 71%–78% increased to 75%–84%).[12,13,14]
    4. The completed Intergroup trial 0089 (INT-0089) randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of the following four treatment arms:[15]
      • The Mayo Clinic regimen administered for a total of six cycles.
      • The Roswell Park regimen administered for a total of four cycles.
      • The Mayo Clinic regimen administered with levamisole for six cycles.
      • The Levamisole regimen administered for a total of 1 year.

      Results:

      • Five-year OS ranged from 49% for the Mayo Clinic regimen with levamisole to 60% for the Mayo Clinic regimen, and there were no statistically significant differences among treatment arms.[15][Level of evidence: 1iiA]
      • A preliminary report in November 1997 demonstrated a statistically significant advantage for OS for the Mayo Clinic regimen with levamisole compared with the Levamisole regimen. This difference became insignificant with longer follow-up.
      • Overall, grade 3 or greater toxicity occurred more frequently for the Mayo Clinic regimen and the Mayo Clinic regimen with levamisole. In addition, the Mayo Clinic regimen was significantly more toxic with levamisole than without levamisole.
      • The death rate for all four regimens ranged from 0.5% to 1%.
      • Because of its ease of use and its good toxicity profile, the Roswell Park regimen became the preferred adjuvant regimen used in the United States and was often the control arm in subsequent randomized studies.
    5. In addition to INT-0089, multiple studies have refined the use of 5-FU-leucovorin in the adjuvant setting and can be summarized as follows:
      • Levamisole is unnecessary when using leucovorin.[15]
      • Treatment that includes 6 to 8 months of 5-FU-leucovorin is equivalent to 12 months of therapy.[16,17,18]
      • Treatment that includes 24 weeks of adjuvant 5-FU-leucovorin is equivalent to 36 weeks of therapy.[19]
      • High-dose leucovorin is equivalent to low-dose leucovorin.[20]
      • A meta-analysis of seven trials revealed no significant difference in efficacy or toxicity among patients 70 years or younger compared with patients older than 70 years.[21]
      • An infusional deGramont LV5FU2 schedule is safer than a bolus modified Mayo Clinic schedule of 5-FU-leucovorin.[19]
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