Objective: AJCC Stage II colon cancer patients form a group where the choice to either undergo or forego adjuvant chemotherapy is far from evident and often remains controversial. This study analyzes several pathological characteristics in order to assess their predictive value for outcomes in stage II colon cancer. Design: Retrospective review of a prospectively maintained, IRB-approved data repository. Setting: Tertiary care center. Patients: A series of 313 consecutive stage II patients treated surgically for colon cancer at our center (2004-2011) were included. Main outcome measures: Mortality, disease-specific mortality and metastasis, including multivariable Cox regression adjusted for stage subdivisions (II-A/II-B/II-C) and potential confounders. Results: Colon cancer-specific mortality was substage-independently increased in patients with baseline carcinoembryonic antigen (CEA) >5ng/L (HR=2.97;P=0.041), large vessel invasion (HR=3.93; P=0.002) and perineural invasion (HR=3.67; P=0.004). Overall mortality adjusted for substage, age and comorbidity was also significantly higher in patients with high-grade disease (HR=2.73; P<0.001)><0.001).>5ng/L (HR=2.37; P=0.046), large vessel invasion (HR=2.80; P=0.002), perineural invasion (HR=2.57; P=0.010), and extramural vascular invasion (EMVI) (HR=2.83; P=0.002). The number of high-risk features (0,1,2-3,4+) was associated with a clearly incremental increase in disease-specific mortality (P=0.008) and recurrence (P<0.001).>5ng/L, large vessel invasion, perineural invasion and EMVI are all independent risk factors for recurrence and disease-specific mortality in Stage II colon cancer patients. The number of factors present form risk strata that should be weighed heavily in decisions regarding adjuvant treatment.

1. Risk Stratification in Stage II Colon
Cancer Patients
Ramzi Amri, MD, PhD; Liliana G Bordeianou, MD, MPH;
and David L Berger, MD
Massachusetts General Hospital, Division of General and Gastrointestinal Surgery.
Harvard Medical School, Department of Surgery.
96th
Annual Meeting of the New England Surgical Society
September 25 - 27, 2015, Newport, Rhode Island

2. Stage II colon cancer: definition
• Invasion at least through muscularis propria (=stage IIA T3 tumors)
• Higher substages:
– IIB for T4a tumors: invasion through the serosa
– IIC for T4b tumors: direct invasion into adjacent organs
• No lymph node involvement (stage III) or distant metastasis (stage IV)

3. Introduction
• Stage II colon cancer remains prognostically
heterogenous,1
despite introduction of:
– AJCC stage subdivisions
– ASCO2
/NCCN3
risk profiles (based on grade, lymph node yield
and margin status)
• Decisions regarding adjuvant therapy are difficult
• Risk of both under- and overtreatment
 We aim introduce a risk stratifying score based on
readily-available factors that can help in decisions
regarding adjuvant therapy
1. Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart AK. Revised TN categorization for colon cancer based on
national survival outcomes data. J. Clin Oncol. 2010;28(2):264–271.
2. Benson AB, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant
chemotherapy for stage II colon cancer. J. Clin. Oncol. 2004;22(16):3408–3419.
3. Engstrom PF, Arnoletti JP, Benson AB, et al. NCCN Clinical Practice Guidelines in Oncology: colon cancer. J Natl
Compr Canc Netw 2009;7(8):778–831.

4. Methods
Included:
• Surgical colon cancer patients at MGH 2004-2011
• 313 consecutive stage II patients
Association of Survival, DFS with 5 risk factors:
• High baseline CEA (>5ng/L)
• High grade disease (<50% well-differentiated)
• Large vessel invasion
• Perineural invasion
• Extramural Vascular Invasion (EMVI)
Assessment of factors individually, and as a
stratified cumulative score (0, 1, 2-3, 4+)
Adjusted for AJCC substage, adjuvant
chemotherapy status (Cox Regression)

5. Results: incidence and overlap
All
(n=313)
Stage IIA 75.1%
Stage IIB 17.6%
Stage IIC 6.7%
Baseline CEA >5ng/L
32.3%
(61/189)
High-grade disease 16.4%
Large vessel invasion
22.7%
(68/299)
Perineural invasion
22.7%
(50/302)
Extramural vascular
invasion (EMVI)
22.4%
• Majority IIA, high risk factors incidence range: 16-33%
• Substantial variations in rates within substages
• Limited overlap: strong correlation EMVI and large
vessel insvasion (r=0.59), other correlations r<0.25)
CEA
>5ng/L
High
grade
Large
vessel
Peri-
neural
EMVI
26.9% 14.9% 19.1% 12.8% 18.1%
54.5% 16.4% 40.7% 27.3% 38.2%
36.5% 33.3% 15.0% 30.0% 33.3%
4.8%NS
(9/189)
8.7%NS
(16/183)
3.7%NS
(11/298)
9.8%***
(18/184)
3.3% NS
(10/300)
6.4%**
(19/298)
9.5%NS
(18/189)
6.1%**
(19/311)
15.7%***
(47/299)
8.3%***
(25/302)
Stage-for-stage
rates
(% of any 2
simultaneously
present)

6. Results: outcomes per risk
factor
Baseline CEA >5ng/L * Yes (%) No (%) HR (95%CI) P
Overall mortality 31.1 16.4 1.78(0.93-3.40) 0.080
Colon cancer mortality 14.8 4.7 2.97(1.05-8.43) 0.041
Metastatic recurrence 18.0 8.6 2.37(1.02-5.50) 0.046
High-grade disease Yes (%) No (%) HR (95%CI) P
Overall mortality 45.1 22.7 2.73(1.63-4.59) <0.001
Colon cancer mortality 9.8 6.2 1.84(0.65-5.16) 0.249
Metastatic recurrence 15.7 11.5 1.62(0.73-3.56) 0.235
Large vessel invasion Yes (%) No (%) HR (95%CI) P
Overall mortality 32.4 24.5 1.43(0.86-2.38) 0.169
Colon cancer mortality 14.7 4.5 3.93(1.66-9.31) 0.002
Metastatic recurrence 22.1 9.4 2.80(1.45-5.41) 0.002
Perineural invasion Yes (%) No (%) HR (95%CI) P
Overall mortality 46.0 22.4 1.82(1.08-3.06) <0.001
Colon cancer mortality 12.0 5.7 2.31(0.87-6.15) 0.094
Metastatic recurrence 22.0 10.3 2.57(1.25-5.29) 0.010
EMVI Yes (%) No (%) HR (95%CI) P
Overall mortality 40.8 21.9 2.38(1.50-2.78) <0.001
Colon cancer mortality 15.5 4.1 3.67(1.52-8.83) 0.004
Metastatic recurrence 23.9 8.7 2.83(1.46-5.47) 0.002
HR: hazard ratio adjusted for stage II subdivision (stage IIA/IIB/IIC i.e. T3/T4a/T4b).
Overall survival also adjusted for age, Charlson comorbidity score.
Metastatic recurrence also adjusted for adjuvant chemotherapy status.
* Preoperative CEA known in 189/313 patients (60.4%)

7. Results: risk score and
outcomes
High–risk features 0 1 2-3 ≥4 P**
Number of patients:* 70 54 50 8
Lymph node yield >12 91.4 82.6 86.0 75.0 0.35
Adjuvant chemotherapy (%) 14.3 20.4 32.0 50.0 0.031
High–risk features 0 1 2-3 ≥4 P** mHR P
Metastatic recurrence (%) 7.1 7.4 28.0 62.5 <0.001 2.32(1.65-3.25) <0.001
Patients without
adjuvant chemotherapy
6.7 9.3 23.5 25.0 0.080 1.89(1.21-2.94) 0.005
Overall mortality (%) 10.0 16.7 36.0 50.0 0.001 2.31(1.69-3.16) <0.001
Patients without
adjuvant chemotherapy
11.7 18.6 38.2 50.0 0.10 2.29(1.57-3.33) <0.001
Colon cancer mortality (%) 2.9 3.7 16.0 25.0 0.008 2.71(1.66-4.42) <0.001
Patients without
adjuvant chemotherapy
3.3 4.7 11.8 0 0.35 2.04(0.88-4.69) 0.095
* Aggregate score calculated in patients with data on all 5 characteristics (n=182)
** Kruskal-Wallis H test
mHR: HR: hazard ratio adjusted for stage II subdivision (stage IIA/IIB/IIC i.e.
T3/T4a/T4b) and adjuvant chemotherapy status (metastatic recurrence only).

8. Summary of findings
 The number of high risk factors present form
strata incrementally associated with higher risks
of recurrence and mortality
• Independent of stage II subcategory
• Independent of adjuvant chemotherapy status
Inflection point at 2+ factors:
• One in 4 patients without adjuvant chemotherapy
develop recurrence
• Mortality rises to ~7% to >30%

9. Discussion
Limitations
•Predominance of stage IIA patients
•1 in 3 patients lacked baseline CEA, therefore
score could not be computed for all patients
Conclusion:
This score provides a readily-available
prognostic tool that helps in treatment decisions
after surgery in stage II colon cancer patients

10. Questions?
Disclosures: None.
Contact:
E: ramri@mgh.harvard.edu
W: hsph.me/ramri
Slides: bit.ly/AmriNESS2015