Adjuvant Therapy of Colon Cancer,
From Chemotherapy To Targeted Therapies

Aimery de Gramont, MD.
Service de Médecine Interne-Oncologie, GERCOR, INSERM U673, H?pital Saint-Antoine , 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Considerable progress has been made in improving disease-free survival in stage III colon cancer with use of adjuvant chemotherapy. In the absence of adjuvant therapy, 3-year disease-free survival (DFS) in stage III colorectal cancer (CRC) is approximately 44% to 52% [1,2] .
5-FU/Fluoropyrimidine Monotherapy
Use of various 5-FU regimens has improved 3-year DFS to 61% to 67% in patients with stage III disease. Studies of bolus 5-FU with leucovorin ( LV ) established 5-FU as standard adjuvant chemotherapy [3-7] . However, these studies did suggest some guidelines for monotherapy by showing that: 6 months was equivalent to 12 months [4,5] ; 36 weeks of treatment provided no significant benefit over 24 weeks of treatment [7] ; and low-dose LV was as effective as high-dose LV [6] . Subsequent trials have shown that regimens of continuous infusion (CI) 5-FU are better tolerated than bolus 5-FU regimens and result in comparable response and survival rates [7-10] . The oral fluoropyrimidine capecitabine was better tolerated than and had comparable efficacy to bolus 5-FU/LV (Mayo Clinic regimen) in patients with stage III CRC (3-year DFS, 64% vs 61%) [11,12] . Benefits of adjuvant 5-FU therapy in patients with stage II disease were suggested by the QUASAR trial [13] , which showed improved 5-year recurrence (22% vs 26%) and overall survival (80% vs 77%) rates for adjuvant therapy vs no adjuvant therapy.
Combination Therapy
5-FU/LV has been combined with irinotecan and oxaliplatin in adjuvant therapy. Combinations of 5-FU regimens with irinotecan generally have not yielded promising results. Regimens combining bolus 5-FU/LV with irinotecan are associated with significant toxicity [14] . The CALGB C89803 trial in 1264 patients showed that the IFL regimen of bolus 5-FU/LV plus irinotecan was associated with nonsignificantly inferior DFS compared with infusional 5-FU/LV alone ( Roswell Park regimen) [15] . The ACCORD 2 trial in 400 high-risk patients with stage III disease showed that infusional 5-FU/LV plus irinotecan was associated with nonsignificantly inferior 3-year DFS compared with infusional 5-FU/LV alone (51% vs 60%, P = 0.22) [16] . The more recently reported and larger PETACC 3 trial [17] showed that infusional 5-FU plus irinotecan (AIO regimen) produced a nonsignificant absolute 3% improvement in observed 3-year DFS (63.3% vs 60.3%) compared with infusional 5-FU/LV alone in 2094 patients with stage III disease; adjusted analysis showed a small but significant improvement in 3-year DFS with combined treatment (65.2% vs 60.4%, P =0.021).
The combination of oxaliplatin with bolus 5-FU/LV also is associated with significant toxicity [18] ; however, toxicity is reduced and efficacy is improved in combinations with infusional 5-FU/LV [19,20] . In the MOSAIC trial in 2246 patients with stage II (40%) or III disease, the combination of infusional LV5FU2 with oxaliplatin 85 mg/m 2 (FOLFOX4) [21, 22] improved 4-year DFS by an absolute 6.6% ( P <0.001) compared with 5-FU/LV alone. Although risk reduction was not significant in stage II disease overall (18% reduction) or among patients with high-risk stage II disease (24% reduction), the magnitudes of risk reduction were similar to that in stage III disease, suggesting a consistent treatment effect. Toxicities reported more frequently with FOLFOX4 included neutropenia, diarrhea, vomiting, and grade 3 neuropathy. However there was no increase in the number of therapy-related death. The NSABP C07 trial [23] in 2407 patients showed that the addition of oxaliplatin to 5-FU/LV (FLOX regimen) produced an absolute 4.9% improvement in 3-year DFS (76.5% vs 71.6%, P < 0.004) compared with 5-FU/LV alone (Roswell Park regimen). The FLOX regimen was associated with less grade 3 or 4 neutropenia (4%) than that observed with FOLFOX4 in the MOSAIC trial, but caused more grade 3 or 4 diarrhea (38%, compared with 11%). Results are awaited from a trial comparing the Mayo Clinic 5-FU/LV regimen with the XELOX regimen in 1800 patients with stage III disease (XELOX NO16968 trial).
Molecular Targeted Agents
In studies in first- or second-line therapy for advanced CRC, the vascular endothelial growth factor inhibitor bevacizumab and the epidermal growth factor receptor inhibitor cetuximab have been found to improve efficacy of a number of combination regimens involving 5-FU/LV and oxaliplatin or irinotecan. In general, the benefits have occurred without marked increases in severe side effects. For example, the addition of bevacizumab has not been associated with any increase in neutropenia, diarrhea, allergy, or rash, but has produced increases in thrombosis (2% to 3%), hypertension (6%), and bowel perforation (1% to 2%); the addition of cetuximab has been associated with increases in diarrhea (15%), allergy (1%), and rash (9%), but no increases in neutropenia, thrombosis, hypertension, or perforation. Several ongoing trials are examining the potential role of bevacizumab and cetuximab in adjuvant regimens in CRC.
Bevacizumab
In the NSABP C08 trial, approximately 2700 patients with stage II or III disease are receiving modified FOLFOX6 with or without bevacizumab for 24 weeks, with the bevacizumab arm then receiving bevacizumab for an additional 24 weeks. The primary end point is DFS, and secondary end points include safety and overall survival. In the AVANT trial, a target of 3450 patients with stage II or III (target n = 2880) colon cancer are receiving: (1) FOLFOX4 for 24 weeks followed by observation for 24 weeks; (2) FOLFOX4 plus bevacizumab 5 mg/kg every 2 weeks for 24 weeks followed by bevacizumab 7.5 mg/kg every 3 weeks for 24 weeks; or (3) XELOX plus bevacizumab 7.5 mg/kg every 3 weeks for 24 weeks followed by bevacizumab at the same dose for 24 weeks. The primary end point is 3-year DFS for stage III disease; secondary endpoints include safety, overall survival, pharmacoeconomics, and convenience. In the ECOG E5202 trial patients with high-risk stage II disease with microsatellite stability and loss of heterozygosity at chromosome 18 are being randomized to FOLFOX or FOLFOX plus bevacizumab; this trial is the first phase III trial to assess targeted therapy based on the presence of biologic tumor markers. The Intergroup Rectal Adjuvant trial is comparing FOLFOX6 or FOLFOX6 plus bevacizumab for 24 weeks in a target of 2100 patients who have received neoadjuvant therapy with radiation therapy, infusional 5-FU/LV or capecitabine.
Cetuximab
The modified Intergroup N0147 trial is comparing modified FOLFOX6 for 24 weeks with modified FOLFOX6 plus cetuximab for 24 weeks in patients with stage III disease; the primary end point is DFS. The PETACC 8 trial is comparing FOLFOX4 for 24 weeks with FOLFOX4 plus cetuximab for 24 weeks, with the primary end point being DFS.
The Future
A number of additional issues in adjuvant therapy should be examined in clinical trials. A comparison of 6 vs 12 cycles of FOLFOX would help to determine if FOLFOX-associated neuropathy can be reduced without compromising efficacy. Additional comparisons of XELOX regimens vs FOLFOX regimens should be performed to determine whether oral capecitabine can replace 5-FU in standard adjuvant treatment. A direct comparison of regimens containing 6 months of bevacizumab vs those containing 12 months would be useful in helping to determine optimal duration of bevacizumab therapy. Trials are also needed to ascertain the potential benefits of combining cytotoxic chemotherapy with both vascular endothelial growth factor inhibition and epithelial growth factor receptor inhibition. Finally, much more work needs to be done in assessing pharmacogenomic strategies in designing and providing optimal adjuvant therapy for patients with colorectal cancer.

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