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 SocietySeptember 25 - 27, 2015, Newport, Rhode Island

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)

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.

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)

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)

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%)

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).

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%

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

Questions?

Disclosures: None.

Contact:E: ramri@mgh.harvard.eduW: hsph.me/ramriSlides: bit.ly/AmriNESS2015