Improving colon cancer Improving colon cancer prognosis using Index of prognosis using Index of

Metastasis:Metastasis:A SEER analysisA SEER analysis

George J. Chang, Chung-Yuan Hu, Miguel A. Rodriguez-Bigas, John M. Skibber

The University of Texas, M.D. Anderson Cancer CenterHouston, Texas

Abstract 4019

Disclosure Slide

Background

• Colon cancer affects approximately 107,000 new patients each year and is the second leading cause of cancer death among men and women.

• Survival and staging in localized colon cancer is related to the number of lymph nodes containing metastasis.• Related to the total number of lymph nodes evaluated.

• Fewer than one-half of cases of resected colon cancer have had an adequate LN evaluation based on a benchmark of 12 or more lymph nodes.

Limitations of AJCC 6th Edition• American Joint Committee on Cancer (AJCC)

TNM staging does not account for the cases with only few lymph nodes.

• Survival within an AJCC/TNM stage can range widely due to the heterogeneous nature of the sub-stage cohort and variations in surgical and pathologic quality.

Objective

To evaluate the predictive value of the Index of Metastasis (IM) for survival

among Stage III colon cancer patients and to define the boundaries of this

relationship.

Methods—Data Source and Patient Characteristics• Surveillance Epidemiology and End Results

(SEER 17) Program of the NCI• Patients diagnosed 1988 to 2005,

histologically confirmed invasive colon cancer.

• AJCC 6th edition stage III• EXCLUSIONS• Age <18, >90 years; >1 primary tumor;

missing data regarding lymph nodes.

Methods—Statistical Analysis• Patients were stratified by the total number of LN (totLN)

evaluated and by IM quartile within each T stage category (T1-2, T3, or T4).

• Stratified Kaplan-Meier analysis was performed to compare cancer specific survival (CSS).

• Log-rank cut-point analysis was performed to determine degree of sensitivity of AJCC sub-staging and IM staging to the total number of lymph nodes evaluated.

• Data were analyzed using STATA Intercooled v.10.0 (rel. 2007, College Station, TX).

totLN

LNposIMastasisIndexofMet

#)(

ResultsCHARACTERISTIC N (%)

Age (median yrs and IQR) 70 (59-78)

Sex Male

Female21,150 (47.1)23,840 (52.9)

Tumor StageIIIAIIIBIIIC

3,873 (8.6)26,158 (58.1)14,959 (33.3)

Tumor GradeWell DifferentiatedMod. DifferentiatedPoorly DifferentiatedUndifferentiatedUnknown

2,330 (5.2)28,554 (63.5)12,076 (26.8)

519 (1.1)1,511 (3.4)

CHARACTERISTIC N (%)

Tumor GradeLowHighUnknown

30,884 (68.7)12,595 (28.0)

1,511 (3.3)

EthnicityWhite (incl. Hispanic)Black Asian (incl. Pac Island)Unknown or others

36,217 (80.5)4,698 (10.5)3,968 (8.8)

107 (0.2)

Median positive LN (IQR) 2 (1-4)

Median total LN (IQR) 12 (8-18)

Median Index of Metastasis (IQR)

.22 (.11-.45)

Total N= 44,990

Distribution of cases by TN stage and IM quartile

T1-2(N=4,513)

IM T3(N=31,575)

IM T4(N=8,877)

IM

IM Q1 1,134 8,442 2268

IM Q2 1,135 0.091 7,699 0.111 2251 0.133

IM Q3 1,221 0.167 7,654 0.222 2146 0.286

IM Q4 1,023 0.333 7,780 0.429 2212 0.563

N1 3,873 21,059 5099

N2 640 10,516 3778

IM Quartile distribution specific to each T stage group

Survival by AJCC Stage varies widely within each stage group and is affected by the total number LN examined

GROUP

5-yr Cancer-Related Survival (%)Stratified by totLN quartile and N stage

T1-2 (N=4,513) T3 (31,575) T4 (N=8,877)

<7 All* >15 <9 All >18 <9 All >18

N1 82.9 85.0 89.3 61.4 68.3 76.7 41.7 50.2 60.7

N2 82.1 71.9 69.6 41.6 47.5 52.0 24.5 29.0 35.2

Median Total LN examined and IQR = 9 (6, 15) for T1-2, 12 (8, 18) for T3, and 12(8, 18) for T4 tumors.* Total LN examined quartile 1 (0-25th percentile) specific to each T stage group (1-2, 3, or 4). † Entire cohort of patient within T stage group.‡ Total LN examined quartile 4 (75th-100th percentile) specific to each T stage group (1-2, 3, or 4).

Cancer-specific survival by total number LN examined quartile

0.00

0.25

0.50

0.75

1.00

0 50 100 150 200analysis time

totLN Q1 totLN Q2totLN Q3 totLN Q4

Kaplan-Meier survival estimates AJCC IIIB

73.3

56.1

0.00

0.25

0.50

0.75

1.00

0 50 100 150 200analysis time

totLN Q1 totLN Q2totLN Q3 totLN Q4

Kaplan-Meier survival estimates AJCC IIIC

48.7

39.0

T-stage stratified IM accurately predicts survival

GROUP

5-yr Cancer-Related Survival (%)Stratified by Total Number LN Evaluated (totLN) and IM quartile

T1-2 (N=4,513) T3 (31,575) T4 (N=8,877)

totLN <7* All†

totLN >15‡

totLN <9

AlltotLN >18

totLN <9

AlltotLN>

18

IM Q1 -- 87.7 90.0 -- 76.0 77.4 58.0 60.0 62.0

IM Q2 84.7 85.1 82.0 69.0 68.5 67.0 44.3 46.4 46.1

IM Q3 84.5 83.8 82.2 61.8 58.2 54.4 41.8 36.6 33.0

IM Q4 80.9 77.5 59.6 46.6 42.6 29.9 26.1 21.7 13.2

Median Total LN examined and IQR = 9 (6, 15) for T1-2, 12 (8, 18) for T3, and 12(8, 18) for T4 tumors* Total LN examined quartile 1 (0-25th percentile) specific to each T stage group (1-2, 3, or 4). † Entire cohort of patient within T stage group.‡ Total LN examined quartile 4 (75th-100th percentile) specific to each T stage group (1-2, 3, or 4).

CSS among T3 patients by IM quartile

0.00

0.25

0.50

0.75

1.00

0 50 100 150 200analysis time

totLN Q1 totLN Q2totLN Q3 totLN Q4

Kaplan-Meier survival estimates T3 IM Q2

0.00

0.25

0.50

0.75

1.00

0 50 100 150 200analysis time

totLN Q1 totLN Q2totLN Q3 totLN Q4

Kaplan-Meier survival estimates T3 IM Q3

0.00

0.25

0.50

0.75

1.00

0 50 100 150 200analysis time

totLN Q1 totLN Q2totLN Q3 totLN Q4

Kaplan-Meier survival estimates T3 IM Q1

0.00

0.25

0.50

0.75

1.00

0 50 100 150 200analysis time

totLN Q1 totLN Q2totLN Q3 totLN Q4

Kaplan-Meier survival estimates T3 IM Q4

5 yr

AJCC6 IIIB

AJCC6 IIIC

25% of patients N156% of patients N1

Cut point analysis shows AJCC stage is highly sensitive to totLN

0

50

100

150

200

250

300

350

400

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Total Number of LN (>=n vs <n)

Lo

g R

ank

Ch

i-S

qu

are

Val

ue

Stage IIIA Stage IIIB Stage IIIC IMQ1 for T1-2 IMQ2 for T1-2

IMQ3 for T1-2 IMQ4 for T1-2 IMQ1 for T3 IMQ2 for T3 IMQ3 for T3

IMQ4 for T3 IMQ1 for T4 IMQ2 for T4 IMQ3 for T4 IMQ4 for T4

IIIB

IIIC

IM Q4 for T3

Summary of results

• 5-year CSS for each AJCC stage group was dependent upon the total number of LN examined.

• Range of 5-year CSS within a single TN stage group varies based on the total number of LN examined.

• AJCC staging incorrectly predicts prognosis when few LN are evaluated

Summary of results

• Cut point analysis demonstrated survival prognosis by AJCC stage is very sensitive to the total number of LN examined.

• IM reliably predicts CSS and is not sensitive to the total number of LN examined.

Conclusions

• AJCC 6th ed. staging poorly predicts prognosis in an individual patient due in part to variability in the total number of LN examined at resection.

• When stratified by T stage, index of metastasis more accurately predicts survival and except at the highest IM levels, is not influenced by the number of LN examined.