Table 3.

Landmark adjuvant trials in early stage colon cancer

Study (Reference)	Study population	Patients (n)	Experimental arm	Control arm	Study result/Conclusion
Intergroup (INT) 0035[64]	Stage II and III	1296	5-FU bolus + Levamisole for 1 yr.	Observation.	Stage III: 5-FU/Levamisole reduced recurrence rate by 41% (P < 0.0001) and the death rate by 33% (P = 0.006). Stage II- No survival benefit with 5-FU/Levamisole. One year of 5-FU based adjuvant chemotherapy became the standard for stage III patients.
NSABP C-03[66]	Duke stage B and C	1081	Bolus 5-FU plus LV for 1 yr.	MOF for 1 year.	5-yr DFS rates- 54% vs 66% in favor of 5-FU/LV, P = 0.0004. 5-yr OS rates - 66% vs 76% in favor of 5-FU/LV, P = 0.003.
IMPACT B2[77]	Stage II	1016	Bolus 5-FU/LV for 6 mo.	Observation.	Pooled analysis of B2 CC in 5 randomized trials. No significant improvement in survival with the adjuvant chemotherapy. The 5-yr EFS: 73% for controls and 76% for 5-FU + LV (HR, 0.83; 90%CI: 0.72-1.07). The 5-yr OS: 80% for controls and 82% for 5-FU + LV (HR, 0.86; 90%CI: 0.68-1.07).
Intergroup (INT) 0089[63]	High-risk stage II and stage III	3794	(1) Low-dose LV plus 5-FU (Mayo Clinic regimen); (2) High-dose LV plus 5-FU (Roswell Park regimen); and (3) Low-dose LV plus Levamisole plus 5-FU. Each for 30-32 wk.	Bolus 5-FU plus levamisole for 1 year.	None among the 4 arms was statistically superior in terms of DFS or OS. Roswell park regimen was better tolerated than Mayo Clinic regimen in terms of diarrhea. 6 mo of 5-FU/LV replaced 12 mo of 5-FU/Levamisole as standard of care.
GERCOR C96.1[85,86]	Stage II and stage III	905	Semimonthly infusional 5-FU/LV (de Gramont regimen). Duration- 24 vs 36 wk.	Monthly bolus 5-FU /LV (Mayo Clinic regimen). Duration- 24 vs 36 wk.	DFS and OS were not statistically different between treatment groups and treatment durations. Semimonthly infusional 5-FU/LV regimen had better toxicity profile and was adopted as the standard arm for the MOSAIC trial.
QUASAR[75]	Stage I-III	3239 (Colon stage II = 2291)	5-FU/LV monthly bolus (Mayo clinic regimen) for 6 mo.	Observation.	3.6% (95%CI: 1.0–6.0) absolute improvement in 5-year OS with adjuvant chemotherapy in stage II CC patients.
X-ACT trial[92]	Stage III	1987	Capecitabine- 6 mo.	5-FU/LV (Mayo Clinic regimen)- 6 mo.	5-yr OS rates 71.4% with capecitabine vs 68.4% with 5-FU/LV (P = 0.06). Capecitabine was at least equivalent to 5-FU/LV in terms of OS and DFS.
MOSAIC[53,76]	High-risk Stage II and stage III	2246	FOLFOX4 for 6 mo.	de Gramont regimen (infusional 5-FU/LV) for 6 mo.	10-year OS rates for stage III - 67.1% vs 59.0 % (HR, 0.80; P = 0.016) in favor of FOLFOX. 10-year OS rates for stage II - 78.4% vs 79.5% (HR, 1.00; P = 0.980). FOLFOX replaced 5-FU/LV as the standard adjuvant therapy in resected stage III CC.
NSABP C-07[17,90]	Stage II and stage III	2407	FLOX for 6 mo.	Bolus 5-FU/LV (Roswell Park) for 6 mo.	5-yr DFS 69.4 vs 64.2% favoring FLOX (HR, 0.82; 95%CI, 0.72–0.93; P = 0.002) corresponding to an 18% relative reduction in the risk of a DFS event. 5-yr OS was similar between treatment groups.
NO169968/ XELOXA[16]	Stage III	1886	CAPOX- 6 mo.	bolus 5-FU/LV (Mayo Clinic or Roswell Park regimen) for 6 mo.	7-yr DFS rates 63% versus 56% in favor of CAPOX (HR, 0.80; 95%CI, 0.69–0.93; P = 0.004). 7-year OS rates 73% vs 67% in favor of CAPOX (HR, 0.83; 95%CI, 0.70–0.99; P = 0.04).
IDEA meta-analysis[54]	Stage III	12834	FOLFOX or CAPOX for 3 mo.	FOLFOX or CAPOX for 6 mo.	Noninferiority of 3 mo versus 6 mo treatment was not confirmed in the overall study population. Among the patients with low-risk tumors (T1-T3, N1), 3 mo of therapy with CAPOX was noninferior to 6 mo, with a 3-year rate of disease-free survival of 85.0% versus 83.1% (hazard ratio, 0.85; 95%CI, 0.71-1.01).

CC: Colon cancer; 5-FU: 5 Fluorouracil; LV: Leucovorin; MOF: Lomustine + vincristine + 5-FU; NS: Not significant; DFS: Disease free survival; EFS: Event free survival; OS: Overall survival; HR: Hazard ratio; CAPOX: Capecitabine and oxaliplatin.