Lymphadenectomy and Extended Resections - Pancreatic Cancer ...

Evidence Based Medicine – Pancreas
Lymphadenectomy and
Extended Resections
Shailesh V. Shrikhande, MBBS, MS, MD
Associate Professor and Surgeon
GI and HPB Surgery
Tata Memorial Hospital
Mumbai, India
IHPBA World Congress, Buenos Aires, Argentina 2010

Lymph node stations
Anterior Pancreaticoduodenal
Posterior Pancreaticoduodenal
Common hepatic artery
Hepatoduodenal d ligament
Superior mesenteric artery

Japan Pancreas Society
Alexakis et al., Br J Surg 2004

Lymph Node Involvement
Fernandez-Cruz et al. Dig Surg 1999
Esposito I et al., Ann Surg Oncol 2008

Standard Lymphadenectomy:
What happens in the real world?
4005 patients (SEER database, 1988 – 2003)
Inadequate number of lymph nodes
evaluated
N0 patients with < 12 LN‘s are understaged
N1 patients: Ratio of metastatic to
examined LN‘s will better stratify prognoses
Slidell MB et al., Ann Surg Oncol 2008

Open Question
Quality of Histopathology
LN range 0-30
pTNM -status t
was
commonly without
LN count
Prognostic
significance?
Slidell MB et al., Ann Surg Oncol 2008

Extended Lymphadenectomy
RCT‘s
Pedrazzoli et al., Ann Surg 1998 (81 patients)
Henne-Bruns et al., Hepatogastroenterol 1998
Yeo et al., Ann Surg 2002 (294 patients)
Nimura et al., Pancreatology 2004 (101 patients)
Farnell et al. Surgery 2005 (79 patients)

What constitutes Extended
Lymphadenectomy?
1998
No. of lymph nodes in the extended
d
groups
20 (Pedrazolli)
29 (Yeo)
36 (Farnell)
2005
40 (Nimura)

Extended radical resection
RCT (40 vs. 41)
Lymph node positive patients
Standard
Extended
Survival
~ 11 months ~ 18 months
p < 0.05
(subgroup analysis)
Pedrazzoli et al., Ann Surg 1998

Standard vs Extended resection
Three continents
(Europe, America, Asia)
No benefit of extended
lymphadenectomy!

Standard vs. Extended Lymphadnectomy
Review:
Comparison:
Outcome:
LA in PDAC
01 Extended LA vs Standard LA
02 3 YSR
3-year survival
Study Extended LA Standard LA OR (random) Weight OR (random)
or sub-category n/N n/N 95% CI % 95% CI
Pedrazzoli 1998 9/41 9/40 14.71 0.97 [0.34, 2.76]
Yeo 2002 65/148 64/146 56.03 1.00 [0.63, 1.59]
Farnell 2005 16/39 10/40 17.28 2.09 [0.80, 5.44]
Nimura 2005 5/50 9/51 11.98 0.52 [0.16, 1.67]
Total (95% CI) 278 277 100.00 1.05 [0.69, 1.59]
Total events: 95 (Extended LA), 92 (Standard LA)
Test for heterogeneity: Chi² = 3.42, df = 3 (P = 0.33), I² = 12.4%
Test for overall effect: Z = 0.21 (P = 0.83)
Review:
Comparison:
Outcome:
LA in PDAC
01 Extended LA vs Standard LA
04 Overall Complications
0.1 0.2 0.5 1 2 5 10
Favours Extended LA Favours Standard LA
morbidity
Study Extended LA Standard LA OR (random) Weight OR (random)
or sub-category n/N n/N 95% CI % 95% CI
Pedrazzoli 1998 8/41 11/40 27.46 0.64 [0.23, 1.81]
Yeo 2002 79/148 36/146 31.3434 3.50 [2.13, 5.74]
Farnell 2005 39/39 25/40 13.37 48.02 [2.75, 838.36]
Nimura 2005 34/50 7/51 27.83 13.36 [4.94, 36.11]
Total (95% CI) 278 277 100.00 4.52 [1.16, 17.61]
Total events: 160 (Extended LA), 79 (Standard LA)
Test for heterogeneity: Chi² = 20.64, df = 3 (P = 0.0001), I² = 85.5%
Test for overall effect: Z = 2.17 (P = 0.03)
0.1 0.2 0.5 1 2 5 10
Favours Extended LA Favours Standard LA
Michalski CW et al., Br J Surg 2007

PPPD or Whipple Resection?
Survival
Favors pppd
Favors c Whipple
RCT’s 6
Equally radical operations
No difference in survival
No difference in morbidity / mortality
Similar QOL
Wenger et al., Chirurg 1999
Tran et al., Ann. Surg. 2004
Lin et al., Hepatogastroenterology 2005
Seiler et al., Br. J. Surg. 2005
Paquet et al., Chir. Gastroenterol. 1998
Bloechle et al., DGCh Forumband 1999
Diener M et al., Ann. Surg. 2007

MARGIN POSITIVE RESECTIONS
Short survival and early recurrence!
Author R1 /
R2
Millikan 1999
% pts Survival
Survival
+ ve -ve
R1 29% 8 mo 17 mo
Sohn 2000
R1/R2 30% 12 mo 19 mo
Benassai 2000
Neoptolemos
2001
Richter 2003
Takai 2003
Kuhlmann 2004
R1/R2 20% 9 mo 26 mo
R1 19% 11 mo 17 mo
R1/R2 37% NS
NS
R1/R2 68% 8 mo 23 mo
R1/R2 50% NS
NS
Varadhachary GR, Tamm EP et al. Ann Surg Oncol 2006;13:1035-46.
Katz MH, Pisters PW et al. J Am Coll Surg. 2008;206:833-46; discussion 846-8. 8.

Borderline resectable tumors

SMV /
PV Resection
16 cohorts
> 640 patients with venous resection
Mortality and morbidity not increased
No higher N+ and R1 resection rates
rather a problem of tumor location than of
aggressive biology
Hartel et al., Eur J Surg 2002, Fuhrman et al., Ann Surg 1996,
Harrison et al., Ann Surg 1996

BORDERLINE RESECTABLE TUMORS:
The Contradictions…
Standard PD
VR
181 patients 26.5 months
110 patients 23.4 months
VR must be offered and results are superior
to historical “Locally advanced disease”
BUT
If vein positive, artery also positive!
Tseng JF, Raut CP et al. J Gastrointest Surg 2004:8;935-4949

Borderline Resectable
Pancreatic Cancer with
Vein Resection
SMV – PV involved but SMA free!
GDA involved but HA free!
Large head mass but neck free!

Correlated with depth of invasion
Poor outcomes
Fukuda S, Ossoultzoglou E et al. Arch Surg 2007:142;172-79
79

Venous Resection (SMV / PV)
Fair evidence for resection
However the caveat is -
Judicious patient selection
Experienced surgeon / surgical team
R0 resection
Weitz et al., J Am Coll Surg 2007
Tseng et al., Best Pract Res Clin Gastroenterol t 2006
Capussotti et al. Arch Surg 2003
Bachellier et al. Am J Surg 2001
Roder et al. Am J Surg 2004
Siriwardana HP, et al. Br J Surg 2006

Multivisceral Resections
Pancreatic Cancer
with enbloc
Splenectomy and
Colectomy
Transverse Colon
Stapled Pancreas

A randomized multicenter trial comparing
resection and radiochemotherapy for
resectable locally invasive pancreatic cancer
Imamura et al., Surgery 2004 and *Surgery 2008
Resection
Radiochemotherapy
Patients 20 22
1-year survival 62% 32% p17 months 11 months p

Multivisceral Resections
Kleeff J et al., Ann Surg 2007

Multivisceral Resections
Technically feasible under elective conditions
Higher surgical morbidity and mortality
Longer ICU and hospital stay
No real data concerning
oncological outcomes
No follow-up studies
Sasson et al., J Gastrointest Surg 2002
Shoup et al., J Gastrointest Surg 2003
Nikfarjam et al. J Gastrointest Surg 2009

Pancreatic resection for M1 cancer
Aortocaval LN metastasis
Pancreaticoduodenectomy
Liver metastasis
Shrikhande SV, Kleeff J et al., Ann. Surg. Oncol. 2006

Pancreatic resection for M1 cancer
100
l distribution
function
Surviva
80
60
40
20
California Cancer Registry 1994-2000
1-year survival rate: 61.5%
Median survival : 13.8 months
0
0 6 12 18 24
Months after resection
30
Shrikhande SV, Kleeff J et al., Ann. Surg. Oncol. 2006

Pancreatic resection for M1 cancer
%
100
l distribution
function
Surviva
80
60
40
20
0
P-value aue= 0.1445
Liver metastases
(n = 11)
Lymph node metastases (n = 9)
(aortocaval lymph nodes)
Peritoneal / other metastases
(n = 9)
0 6 12 18 24 30
Months after resection
Shrikhande SV, Kleeff J et al., Ann. Surg. Oncol. 2006

Conclusions..
No difference in morbidity and mortality
“Median survival of 27 months after
interaortocaval lymph node dissection i is no
different from that of other lymph nodes…”
“..may be an option for intra-operatively
discovered metastatic but locally
resectable pancreatic cancer …”
Shrikhande SV, Kleeff J et al., Ann. Surg. Oncol. 2006

Michalski CW et al. Dig Surg 2008

Summary...
Conventional lymphadenectomy (I)
Improve LN yield by better surgery /
pathology
PPPD appears popular but cWhipple is not
inferior (I)
SMV / PV resection (R0) is justified in
expert hands (III) – to generate evidence
is difficult. Does it improve survival?

Summary...
Neoadjuvant approach in BR tumors
will aided extended pancreatectomy
Multivisceral resections – feasible but more
data needs to be generated
Resection in M1 disease – not justified
currently, but RCT’s should be done (III)
Evaluate outcomes of inter-aortocaval
node resection

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