Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions

Table 1 Role of surgery and adjuvant chemotherapy in early stage colon cancer (American Joint Committee on cancer stages I to III)

	Stage I	Stage II	Stage III
Definition	The tumor has grown through the colonic mucosa and has invaded the muscular layer of the colon	The tumor has grown through the wall of the colon or invaded adjacent organ, but has not involved the regional lymph nodes	The tumor has spread to the regional lymph nodes, but not to the distant organs
Contribution of surgery	5-yr DFS rate of 95% with surgery alone[6]	5-yr DFS rate of 82% to 88% with surgery alone[6,14]	5-yr DFS rate of 45%-50% with surgery alone[14,15]
Contribution of adjuvant chemotherapy	Adjuvant chemotherapy not recommended	Only offered to “high-risk” group-magnitude of benefit is uncertain	Recommended for all patients. Absolute improvement of 5-yr DFS rate is about 20% because of adjuvant chemotherapy[5,16,17]

DFS: Disease free survival.

Table 2 Prognostic features of malignant polyps

Features consistent with low risk of lymph node metastases (Low risk/favorable features)[26]	Features consistent with high risk of lymph node metastases (Poor prognostic features)[26]
Margins with no dysplasia or malignancy	Poorly differentiated
Well or moderately differentiated	Mucin/mucinous
No angiolymphatic invasion	Signet ring or cribriform histology
Superficial invasion into submucosa (≤ 2 mm)	Tumor budding
	Lymphovascular invasion
	Deeper invasion into submucosa (> 2 mm)

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.

Table 4 Evolving tools and biomarkers which may help precise patient selection for adjuvant therapy and therapy personalization in early stage colon cancer

Biomarker/tool	Clinical significance	Potential use and relevance	Ref.
ctDNA	Prognostic	ctDNA detection in the bloodstream after surgical resection and adjuvant chemotherapy provides direct evidence of residual micro-metastatic disease and correlates with a very high risk of cancer recurrence in resected stage II and III patients. Sensitivity, specificity, positive and negative predictive values are 48%, 100%, 100% and 91%, respectively. Reported studies suggest that ctDNA can potentially serve as a real time marker of adjuvant therapy efficacy in stage II and III patients.	[110-115]
Immunoscore	Prognostic	High immunoscore is associated with favorable prognosis in both stage II and III patients independent of patient T stage, N stage and microsatellite instability. High-risk stage II patients with high Immunoscore had similar time to recurrence compared with average risk stage II patients in a recent report.	[118-122]
dMMR	Prognostic and predictive	Associated with favorable prognosis in stage II and possibly low-risk (IDEA defined) stage III patients. Predicts lack of benefit and possibly harm with 5-FU based adjuvant chemotherapy in both stage II and III patients.	[124-137]
KRAS and BRAFV600E mutation	Prognostic	KRAS and BRAFV600E mutations have been reported to be associated with a worse prognosis in several large retrospective studies, in both stage II and III patients. dMMR status attenuates adverse prognostic impact of BRAFV600E mutation, possibly except in IDEA defined high-risk stage III CC.	[133,137 -141]
Genomic profiling (Oncotype Dx Colon Cancer®)	Prognostic	Prognostic discrimination capacity is insufficient to guide therapy in routine clinical practice.	[142-147]
PIK3CA mutations	Predictive	Retrospective analysis suggests an association between the use of aspirin and improved survival among the patients with mutated-PIK3CA colorectal cancer including stage I-III patients.	[152]
CDX2 expression	Prognostic and predictive	Retrospective analysis suggested lack of CDX2 expression was associated with worse outcome in stage II and III CC. Lack of CDX2 expression appears to be predictive of benefit from adjuvant chemotherapy in stage II patients.	[153]
CMS	Prognostic	CMS1 tumors have a good prognosis, the CMS4 tumors have a poor prognosis, and the CMS2 and CMS3 types have an intermediate prognosis. Not validated to guide therapy in routine clinical practice.	[148-151]

ctDNA: Circulating tumor DNA; dMMR: Deficient mismatch repair status; CC: Colon cancer; CMS: Consensus molecular subtypes.