1. Dukes B, or not Dukes B… that is the question.
Ryash Vather
Kamran Zargar
Tarik Sammour
Patricia A. Metcalf
Andrew B. Connolly
Andrew G. Hill

2. Case Mr S 72 y/o man with RLQ mass Otherwise quite fit and healthy
CT and colonoscopy consistent with
caecal adenocarcinoma
Open R hemi with no complication
Returns to OPC for discussion of histology…

3. Dukes B

4. Introduction Recurrence in Dukes B said to be ~ 30% This is due to:
Inadequate node harvest
Inadequate node identification
Vascular / local invasion
Most Dukes Bs don’t get offered chemo
Node +ve cases (Dukes C) do.
Missing a positive node?
The most important determinant of survival in patients with suspected localised colon cancer is the presence or absence of metastases to regional LNs.
Of these, the top 3 may all lead to understaging because a positive node has been missed. A dukes C tumour may thus be mislabelled a Dukes B. The implication here is that pts with dukes c are routinely offered adjuvant chemo, but this is not as routine in those with node negative disease.
For patients with suspected localised colon cancer the most important determinant of survival is the presence or absence of metastases to regional LNs.
Understaging – inadequate lymph node harvest misses a positive node, mislabelling a Dukes C as Dukes B. This is important as Dukes C patients are routinely offered adjuvant chemotherapy in contrast to Dukes B, where this is not as routine.

5. Lymph nodes in Dukes B How many nodes are required for
accurate differentiation?
Controversial
“Ideal” number of nodes varies: 6 – 17.
12 nodes generally accepted
as optimum by consensus.
There is an expanding field of literature on this topic, with studies aiming to identify an ideal minimum number of lymph nodes to – give accurate prognostic information (meaning a dukes b has been correctly labelled and that there are no positive-nodes) and to minimise recurrence rates.
Regardless, a universal finding across all studies was that long –term outcome …..
to stage a cancer with reasonable accuracy is debated. Data varies considerably between different studies, ranging from 6-17, with 12 being generally accepted as optimum.
Regardless, an almost universal finding is that long-term outcome improves in direct relation to the number of lymph nodes retrieved and examined.
The participants in this study came from the catchment area of Middlemore Hospital – a large tertiary care institution which services a unique multi-ethnic population (European 41%, Pacific Islander 28%, Maori 15%, Other 16%). International guidelines may not be accurate in this context.
The aim of this study was to therefore determine the “ideal” number of lymph nodes that should be examined during attempted curative resection of Dukes B colon cancer in our population.

6. Does this apply to our population?
The participants in our study all came from the catchment area of MMore hosp, a large tertiary care centre with a unique multi-ethn pop (here is a graph to elucidate this). In this context, int guidelines may not apply. We thus wished to identify an ideal minimum number of nodes to be examined which would give accurate prognos. Info and minimise recurrence rates in our pop.
Ideal minimum number of nodes needed to give accurate prognostic information and minimise recurrence rates.

7. Method Retrospective review
All patients with Dukes B colon cancer between Jan Dec 2001
Surgery at Middlemore Hospital.
Pathological analysis at Middlemore Hospital.
5 year follow-up.
How did we do this? We cons a retrospec database of all patients who underwent resection for histopath….
A retrospective database was constructed of 328 consecutive patients who underwent major colorectal resection for histopathologically defined Dukes B cancer between January 1993 and December 2001 (inclusive). All surgery was performed and pathological specimens analysed at a single tertiary care facility, Middlemore Hospital.
Individual patient NHIs were then used to acquire information for the parameters:
Age (at the time of surgery).
Gender.
Procedure performed.
Acuity of Surgery i.e. acute or elective.
Number of lymph nodes examined.
Local or distant cancer recurrence within 5 years of index operation. Disease activity was determined by clinical examination, regular sigmoidoscopy, colonoscopy, CEA levels and radiology. There was no standard follow-up protocol in the time frame studied.
Mortality within 5 years of index operation. This was subsequently sub-classified as cancer or non-cancer related.

8. Method Data collected: Analysis: Multivariate and regression analysis
Age / Gender
Procedure / Acuity of Surgery
No. of nodes examined
Recurrence within 5 years
Mortality within 5 years
Analysis:
Multivariate and regression analysis
Patient NHIs were used to acquire info for a number of parameters including … with the last 2 both being our primary outcome measures.
Data was used to create multiv and reg analysis models and ROC curves
A retrospective database was constructed of 328 consecutive patients who underwent major colorectal resection for histopathologically defined Dukes B cancer between January 1993 and December 2001 (inclusive). All surgery was performed and pathological specimens analysed at a single tertiary care facility, Middlemore Hospital.
Individual patient NHIs were then used to acquire information for the parameters:
Age (at the time of surgery).
Gender.
Procedure performed.
Acuity of Surgery i.e. acute or elective.
Number of lymph nodes examined.
Local or distant cancer recurrence within 5 years of index operation. Disease activity was determined by clinical examination, regular sigmoidoscopy, colonoscopy, CEA levels and radiology. There was no standard follow-up protocol in the time frame studied.
Mortality within 5 years of index operation. This was subsequently sub-classified as cancer or non-cancer related.

9. 254 patients with Dukes B colon cancer
Results
254 patients with Dukes B colon cancer
Exclusions
Incomplete data
Peri-operative death / mets 19
Previous colorectal cancer
216 patients for analysis
Patients with rectal cancer were excluded from this study because the method of invasion, spread and management varies from colonic neoplasms.
Both analyses carried out using the SAS program.
Categorical variables – Chi squared test
Continuous variables – Student’s t test
2 Multivariate regression models built – 2 outcomes: 1. mortality 2. recurrence. Placing both in the same model erroneously lowered statistical significance.
[ ROC curve plots sensitivity (Y) vs. 1-specificity (X). Inverse relationship between sensitivity and specificity)

10. Baseline Characteristics
Number of Patients
216
Mean age (years) 70
(range )
Male : Female
99 : 117
Acuity of Surgery
Acute 51
Elective
165
Procedure
R. hemicolectomy
133
L. hemicolectomy 74
Total colectomy 3
Hartmann’s procedure 6
Quite an elderly pop, with a male to female ratio which was roughly comparable. Most of the cases performed on an elective basis with the most common procedures being r and l hemis.

11. Recurrence & Mortality at 5 years
Recurrence of Cancer
44 (20%)
Mortality (all cause)
71 (33%)
Related to Cancer Recurrence
35 (16%)
Not related to Cancer Recurrence
36 (17%)
Looking at primary outcome measures. 44 patients evidence of recurrence in 5 years following op. likewise, 71 patients deaths in this follow up period, with 35 related to recurrence and 36 dying of unrelated causes.

12. Median no. of nodes = 14 Range = 2 - 48 Number of Patients
Graph showing number of pts for a given no. of LNs. Note early peak with bulk of the pts lying between the 5-25 LN mark. On further analysis, median….

13. Factors influencing no. of lymph nodes
Age
p=0.0018
Gender
N.S.
Acuity of Surgery
Age was the only factor which significantly influenced the no. of LNs examined, with an increas age being assoc with a reduc no. of LNs examined. Gender and Acuity were found to have NS effect

14. No. of nodes examined Recurrence No Recurrence
Mean number of nodes examined
11.8
17.1
( p= )
Death
Survival
Mean number of nodes examined
12.8
17.5
Mean number of nodes examined in pts with evidence of recurrence was 11.8 compared to 17.1 in those who survived. This difference found to be statis. Significant. Similarly for mortality, mean no. of pts….
( p= )

15. Here we have a graph of % of pts with cancer recurrence as broken down by lymph node strata. You can see that the recurrence rate is quite high in the earlier strata but drops off towards the end. Focussing now on the start, we see that the recurrence rate is 46.2% in the 1-4 node group. This is misleading because the number of patients in this group was relatively small. Moving on, we can see that in the 5-6, 9-12 and groups, the recurrence rate is around 25-30% which is what we would expect for a Dukes B tumour. However, after the 16 node mark, recurrence rate drops off sharply to 6.5%, and remains at this level for the remaining strata. This is important because this recurrence rate mimics that of Dukes A tumours. Further analysis of this drop reveals a statistically sign difference in recurrence rate between the 2 groups.
<16 nodes gives recurrence rates similar to that expected in Dukes B cases (25-30%).
>16 nodes, recurrence rates drop off sharply, approaching those of Dukes A.
Thus, >16 nodes is the ideal minimum in our pop.
Drop from to is significant (p=0.0368)
Drop <16 to >16 is significant (p=0.0001)
Accurate prognostic information means you remove a tumour with all negative nodes  how confident can you be that this is ACTUALLY a Dukes B and has not already metastasised?? The graph here shows recurrence within 5 years of patients who were thought to be Dukes B – this may mean a number of things including poor surgical technique with incomplete resection of the tumour, vascular invasion and spread, or most importantly, missing a positive node. The ROC curve has shown the latter is a predictor of recurrence, and we can see here that the recurrence rate drops off as the nodal strata increases indicating that this is likely to be involved in determining recurrence.
Thus back to the original point – the ideal minimum number is 16 nodes as after this number recurrence rate is small, indicating accurate prognostic information.
In the conventional sense a Dukes B has a mortality of 30%. However, this is a poor descriptor of what is actually going on – a person with 1 negative node will obviously have a much larger risk of recurrence and mortality than someone with 20 negative nodes. This means a ‘generalised’ mortality rate is inappropriate because it clumps people together from all ends of the spectrum. By breaking people down into these strata we are able to give 1. more accurate information on recurrence rates (e.g. a person with 14 nodes has a much higher rate than someone with 18 nodes) and are 2. able to say that people with >16 nodes are much more likely to have node-negative disease than person with <16 nodes. and hence 2. more accurate prognostic information. Thus the “ideal minimum” is a number above which recurrence rate falls dramatically.
p=0.0001

16. Conclusions
Dukes B patients with > 16 nodes on histology had a significant reduction in recurrence.
Aids patient counselling.
Should we be using this to determine chemo referral?