Radial Margin Positivity as a Poor Prognostic Factor for Colon Cancer

Ramzi Amri,1,2 Liliana G Bordeianou,1,2 Patricia Sylla,1,2 David L Berger 1,2

1 Massachusetts General Hospital, Division of General and Gastrointestinal Surgery.2 Harvard Medical School, Department of Surgery.

95th Annual Meeting of the New England Surgical SocietySeptember 12 - 14, 2014, Stowe, Vermont

Introduction

• Radical resection is essential to prevent recurrence

• Radial Margin Positivity (RMP) is universally a poor prognostic factor 1

• Effects are well studied for rectal carcinoma 2,3

• Research on RMP in colon carcinomas is scarce

1 Hermanek P, Wittekind C. The pathologist and the residual tumor (R) classification. Pathol Res Pract. 1994;190(2):115–123. 2 Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol. 2008;26(2):303–3 3. Parfitt JR, Driman DK. The total mesorectal excision specimen for rectal cancer: a review of its pathological assessment. J Clin Pathol. 2007;60(8):849–855.

Radial Margin: definition

RMP in colon:•At the cut edge of mesenteric attachment points, in colonic segments (A)

•Extension through the wall in nonserosalized (retroperitoneal) segments (B)

Impact of RMP on colon cancer outcomes

B

Methods

Included: • Surgical colon cancer patients at MGH 2004-2011• With relevant data on surgical margins (n=1039)• Excluded: aborted, incomplete, palliative resections

Comparison:• RMP vs. radial margin-negative

Statistical analysis• Ordinal: χ2, continuous: Mann Whitney U• Multivariate: Cox & binary logistic regression

Results: baseline

RMP: 5.6%

•Demographics similar•Obesity rates lower•Lower polyposis rates•Lower screening rates

•More emergency diagnoses

Radial margin P

Negative Positive

N (%) 980 (94.4%) 59 (5.6%) Age (mean, SD) 66.9 ±14.0 64 ±13.7 0.14 Gender (% male) 51.9% 44.1% 0.24 Ethnicity (% nonwhite) 10.1% 13.6% 0.40 Ever smokers 52.6% 52.5% 0.99 Current smokers 11.3% 13.6% 0.60 Alcohol abuse 7.9% 11.9% 0.27 Obese (% BMI>30, mean, SD) 29.7% 12.3% 0.005 Weight loss >10% 9.3% 13.6% 0.28 Charlson score (mean, SD) 0.74 ±1.2 0.61 ±1.0 0.48 Previous CRC (%) 2.7% 1.7% 0.65 History of polyposis (%) 13.7% 3.4% 0.023 HNPCC (%) 1.9% 0% 0.28 Neoadjuvant chemo (%) 3.3% 3.4% 0.96 Screening diagnosis (%) 27.4% 3.4% <0.001 Emergency diagnosis (%) 9.1% 16.9% 0.046

Results: surgical outcomes

• Less laparoscopies, yet still more conversions

• Far higher rates of multivisceral resections• More right-sided resections• Longer admissions

Radial margin

RR (95%CI) P Negative Positive

Laparoscopic surgery (%) 26.0% 13.6% 0.52 (0.27-1.00) 0.052 Conversion (%) 12.7% 50.0% 3.93 (1.62-9.55) 0.003 Multivisceral resection (%) 12.3% 39.0% 3.15 (2.20-4.53) <0.001

Resection type

Right 52.6% 69.5% 1.32 (1.11-1.58) 0.002 Transverse 4.1% 1.7% 0.41 (0.06-2.97) 0.38 Left 11.2% 5.1% 0.46 (0.15-1.40) 0.17 Lower 24.7% 15.3% 0.61 (0.34-1.14) 0.12 Total/multiple 7.6% 8.5% 1.12 (0.47-2.67) 0.79

Duration of surgery (M, min) 126 ±103 114 ±105 - 0.55 Duration of admission (M, days) 5 ±4 6 ±6 - 0.001

Results: RMP per stage

RMP ranges 0 – 25.5%

•Already present in T3 and N0 tumors (AJCC IIA)•Quadruples from N1 to N2•Increases per AJCC stage

n RMP % P

T-stage

Tis 36 0%

<0.001 T1 162 0% T2 127 0% T3 468 4.7% T4 246 15.0%

N-stage N0 617 1.1%

<0.001 N1 252 5.2% N2 170 22.9%

M-stage M0 945 3.7% <0.001

M1 94 25.5%

AJCC stage

0 37 0%

<0.001

I 253 0%

IIA 237 0.8%

IIB 76 6.6%

IIIA 29 0% IIIB 194 3.6%

IIIC 119 17.6%

IV 94 25.5%

Results: pathology

Significantly higher prevalence of all poor prognostic pathological characteristics

Radial margin

RR (95% CI) P Negative Positive

T-stage 4 21.3% 62.7% 2.94 (2.34-3.70) <0.001

N-stage≥1 37.8% 88.1% 2.33 (2.06-2.64) <0.001

M-stage 1 7.1% 40.7% 5.69 (3.89-8.34) <0.001

High grade tumor 18.3% 43.1% 2.35 (1.70-3.26) <0.001

Small vessel invasion 40.4% 76.3% 1.89 (1.60-2.22) <0.001

Large vessel invasion 30.0% 69.5% 2.31 (1.90-2.82) <0.001

Extramural vascular invasion 28.1% 78.0% 2.78 (2.35-3.29) <0.001

Perineural disease 23.6% 66.6% 2.82 (2.26-3.51) <0.001

Infiltrating tumor border 69.7% 96.6% 1.38 (1.30-1.48) <0.001

No lymphocytic response 73.5% 82.5% 1.11 (0.98-1.27) 0.086

Results: long-term outcomes

Radial margin RR (95%CI) P

Negative Positive All time metastatic disease 24.5% 83.1% 3.39 (2.89-3.98) <0.001 Local recurrence (%) 1.4% 1.7% 1.18 (0.16-8.87) 0.87

Nonmet. Presentation: 1.5% 5% 3.31 (0.46-24.2) 0.15 Distant recurrence (%) 12.7% 16.9% 1.34 (0.74-2.41) 0.43

Nonmet. presentation: 14.2% 50.0% 3.53 (2.21-5.64) <0.001 Liver 7.3% 30.0% 4.10 (2.02-8.35) <0.001 Peritoneal 2.8% 20.0% 7.15 (2.73-18.7) <0.001

Overall death (%) 32.8% 86.4% 2.64 (2.31-3.02) <0.001 Colon cancer death (%) 16.4% 67.8% 4.13 (3.29-5.17) <0.001

Binary logistic regression

Univariate OR (95%CI)

P Covariates Multivariate OR(95%CI)

P

Death 13.1 (6.14-27.91) <0.001 T, N, M, G, EMVI 4.09 (1.79-9.32) 0.001

Colon cancer death

10.7 (6.05-18.97) <0.001 T, N, M, G, EMVI 2.24 (1.10-4.54) 0.026

Metastatic disease 15.11 (7.54-30.3) <0.001 T, N, M, G, EMVI 3.45 (1.46-7.16) 0.005

Distant recurrence 1.41 (0.70-2.85) 0.34 AJCC 0.72 (0.35-1.51) 0.39 Non-met. presentation 6.07 (2.47-14.9) <0.001 AJCC 2.75 (1.05-7.20) 0.04

Local recurrence 1.19 (0.16-9.21) 0.87 AJCC 0.96 (0.12-8.10) 0.96

Conclusions

• Stage-independent effect on outcomes• 60% of RMP patients present without baseline

metastasis.

• Tripling of distant metastasis rates• Leading to quadrupling of odds of death• Tripling of local recurrence in RMP patients

(NS)

• Theoretically ideal candidate for radiation therapy

• Anatomically difficult to achieve

Conclusions (cont’d)

• Despite a relatively low occurrence, RMP has profound clinical consequences.

• Marked association with poor pathology, outcomes

• These effects remain prominent in patients who present without baseline metastasis

• Should weigh heavily in any decision regarding adjuvant treatment

Questions?

Disclosures: None.

Contact:E: ramri@mgh.harvard.eduW: hsph.me/ramri