Transcript Sentinel node in colorectal cancer: role and controversial

Anastomotic leakage in rectal surgery
after neoadjuvant therapy
Montecatini Terme 28 maggio 2005
Dario Scala
INT Napoli
Anastomotic leakage in rectal surgery:
risk factors
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TME
Anastomosis
height
Protective stoma
Neoadjuvant
therapy
Extension and
tumor-related
obstruction
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Gender
Bowel preparation
Intraoperative blood
loss
Pelvic drainage
Co-morbidities
Adjuvant therapy and rectal cancer
Adjuvant Therapy for Patients with Colon and Rectum
Cancer. NIH Consensus Statement 1990
Is there effective adjuvant therapy for patients with rectal cancer?
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We recommend adjuvant therapy for stage II and III
rectal cancer
Combined post-operative chemotherapy and radiation
therapy improves local control and survival in stage II
and III rectal cancer
JAMA 1990
Postoperative RT
randomized trials
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GITSG
FISHER
DUTCH
DANISH
MRC III
EORTC
48 Gy
46.5 Gy
50 Gy
50 Gy SPLIT
40 Gy
46 Gy
Local control in 2 trial (p<0.005)
Toxicity
No influence on survival
Post-operative combined
radiotherapy and chemotherapy
•Adjuvant combined RT and CHT produce a benefit in terms
of local control and overall survival.
•Compared to surgery alone RT decreases LR
•With the addition of CHT
decreases local failure (-10%)
increases 5-years survival (+10/15%).
but
•increase in acute toxicity 25 to 50%
•only 50- 65% of patients completing the therapeutic plan.
Guidelines on colorectal cancer, ASSR, Roma 2002
Preoperative vs
postoperative RT
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Short Course
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25Gy in 5 days
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Rider
Stockholm I e II
RCG
ICRF
Rotterdam
Swedish
Advantages:
• irradiating tissue not
rendered hypoxic by
previous surgery
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•Enhancing sphincter
preservation by shrinking
large distal tumors
(standard RT only)
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•Decreasing likelihood of
radiation-induced injury
to small bowel trapped
in the pelvis by
adhesions
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•Lower acute and longterm toxicity
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Standard
45-50 Gy in 5
weeks
VASAG I e II
MSKCC
MRC I e II
EORTC
PUCC
Norway
MRC
Pre-operative high-dose short-term radiotherapy
The Dutch Trial
1718 pts with T1-T3 operable rectal tumors
Optimal surgery alone vs
pre-operative radiotherapy and immediate optimal surgery.
Local recurrence
Surgery alone
Pre-op. radiotherapy
and surgery
Upper rectum
3.5%
1.5%
Mid rectum
10.0%
1.0%
Lower rectum
10.0%
5.8%
The overall recurrence rate at 2 years fell from 8.4% to 2.4%.
E Kapitaijn et al. N Engl J Med 2001; 345:638-646
Pre-operative high-dose short-term radiotherapy
The Dutch Trial
Pre-operative radiotherapy had no impact on survival:
the distant recurrence rate was equivalent in the two arms (16%
vs 15%) with 15% of patients dead in each arm by two years.
E Kapitaijn et al. N Engl J Med 2001; 345:638-646
Pre-operative radiotherapy did not allow to achieve downstaging of the tumoral lesion. This treatment cannot be used to
facilitate either sphincter preservation or secondary resection of
initially unresectable tumors.
CAM Marijen et al. J Clin Oncol 2001; 19: 1976-1984
Neo-adjuvant chemo-radiotherapy and surgery
END POINTS
Chemotherapy is a radiation sensitizer
Down-staging
Local recurrence reduction
Improvement of overall survival
Increase in rates of sphincter-saving surgical procedures
Improvement of quality of life
Neoadjuvant concomitant
radiochemotherapy
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Bosset (EORTC)
Chari
Grann
Rich
Valentini
INT Napoli
5FU/LV
5FU-CDDP
5FU/LV
5FU PVI
5FU CI
Tom/FU/OXA
45 Gy
45 Gy
50.4 Gy
50.4 Gy
37.8 Gy
45 Gy
Increases complete pathological responses (10-30%)
Increases sphincter-saving procedures (60-85%)
Neoadjuvant therapy and
anastomotic leakage
Is neoadjuvant therapy in rectal cancer
a relevant risk factor
for anastomotic leakage?
What is the EBM report?
Neoadjuvant therapy and anastomotic
leakage: pathogenesis of the damage
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Fibrosis induced by radiotherapy is likelihood
to provide hypoxic tissues and anastomosis
Preoperative chemoradiotherapy for advanced
rectal cancer results in a significant
preoperative and postoperative immune
dysfunction as indicated by depression of
lymphocyte subpopulations, monocytes,
granulocytes, and proinflammatory cytokine
release Wichmann et al Dis Colon Rectum. 2003 Jul;46(7):875-87.
Neoadjuvant radiotherapy morbidity
randomized trials
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UKMRC 1b (1982)
UKMRC 1a (1984)
EORTC (1988)
UKMRC 2 (1996)
SRCT (1997)
No increase in
the dehiscence
of colorectal
anastomosis
Neoadjuvant therapy and
anastomotic leakage
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Stevens KR Jr, et al. Cancer 1978 May;41(5):2065-71.
higher incidence of anastomotic leakage in
preoperative irradiated patients
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Simunovic M, Heald RJ Br J Surg 2003 (90):999-1003
pre RT group
no RT group
11,4% anastomotic leakage
7,8% anastomotic leakage
Neoadjuvant therapy and
anastomotic leakage
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The Dutch trial N Engl J Med 2001; 345: 638-46
1861 pts randomly assigned to short RT followed by TME or
TME alone
no difference as concerns anastomotic leaks
more perineal wound infections after APR in the RT group
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German Rectal Cancer study group. N Engl J Med 2004;351:1731-40
823 pts randomly assigned to receive preop or post CT-RT
no difference in anastomotic leaks between preop (11%) e
postop (12%) treatment
Neoadjuvant therapy and
anastomotic leakage
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Norwegian Rectal Cancer Group Colorectal Dis. 2005 Jan;7(1):51-7.
1958 pts undergoing rectal surgery with anterior resection
overall rate of AL of 11,6%
risk significantly higher in pts receiving preop RT (O.R. 2.2)
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Morino M, Parini U et al 2003 Ann Surg 237:335-342.
100 pts undergoing laparoscopic anterior resection
overall rate of AL of 17%
higher incidence in pts with preop RT (21% vs 12,5%)
Neoadjuvant therapy and
anastomotic leakage
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Delgado S, Lacy AM et al. Surg Endosc 2004, 18:1457-1462.
220 pts undergoing laparoscopic assisted rectal surgery
130 pts (59%) receiving preop CT-RT
overall AL rate 7,3% (12/166)
7/12 leaks in pts treated with preop CT-RT
5/12 leaks in pts not treated before surgery
no difference between the two groups in AL rate
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Horie H et al. Surg Today 1999; 29(10):992-8.
29 pts undergoing preop CT-RT
48 pts undergoing surgery alone
no difference between the two groups in AL rate
Neoadjuvant therapy and
anastomotic leakage
…....I am so confused……….
What is the literature EBM response
about anastomotic leaks and
neoadjuvant therapy of rectal cancer?
Istituto Nazionale dei Tumori – Napoli
Colorectal Cancer Cooperative Team
Surgical Oncology “C”
V. Parisi, F. Cremona, F. Ruffolo,
Medical Oncology A R. Palaia, P. Delrio, D. Scala,
G. Comella, P. Comella V. Albino, M. Di Marzo, D.N. Idà
R. Casaretti, A. Avallone
Exp.Oncology
A. Budillon
E. Di Gennaro
Radiology
A. Siani, V. De Rosa,
G. Burgazzi, A. Petrillo
Pathology
G. Botti
F. Tatangelo
Radiotherapy
B. Morrica,
C. Guida, V. Ravo,
M. Elmo, B. Pecori
Nuclear Medicine
S. Lastoria
G.M. Cascini
Endoscopy
A.Tempesta
G.B. Rossi, M. De Bellis,
Exp. Oncology
Univ. Fed. II
P. Marone, F. Petrulio
S. Pepe
Treatment plane
Phase I-II clinical study
-1
45 Gy
1.8 Gy X 25
weeks
RT
1
2
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3
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Oxaliplatin 2 hrs
CT
Days
5
4
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Day 1
Raltitrexed 15 min.
**
1st
course
**
2nd
course
LFA 2 hrs
5-FU bolus
Day 2
**
3rd
course
OXALIPLATIN
Down-regulation of TS expression
Influence over 5-FU clearance
In preclinic studies: Sinergic action with 5-FU and Raltitrexed.
Toxicity profile different from 5-FU and Raltitrexed.
High response rate (~ 50%) with both 5-FU and Raltitrexed in
pts with metastatic colorectal cancer
Improves efficacy of 5-FU/FA in adjuvant therapy of colorectal
cancer
Radiation sensitizer as well as 5-FU e Raltitrexed.
Radiotherapy
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Tecnica personalizzata
Generalmente, 3 campi isocentrici PA e 2
LL con cunei
Limiti Campi AP-PA: Sup. 2cm sopra il
promontorio sacrale; Inf.: a 2cm dal
margine inferiore della neoplasia (valutata
endoscopicamente e/o radiologicamente);
Lat.: 1,5cm oltre i limiti laterali della pelvi
ossea
Campi laterali: Sup.e Inf.come i campi
AP-PA; Ant.: 2cm al davanti della neoplasia
e/o linfonodi locoregionali; Post.: 2cm al di
dietro della faccia anteriore del sacro
Fotoni X 6-20 MV
Dose tot.45 Gy (1.8 Gy/fr.)
Istogrammi dose/volume (DVH)
Fusione di immagini
CT-RT Accrual
-Diagnosis of rectal cancer below the peritoneal reflection
- stage II/III (in the second group of phase I and in the whole phase II
study only cT4; cT3 < 5cm anal verge; cN+; cMCR+)
- age > 18 years.
- ECOG performance status 2 or less
- No previous chemotherapy, immunotherapy or radiotherapy
granulocytes > 1500/ml;
PLT > 100000/ml;
total bilirub < 1,5 mg/dl;
creat < 1,5 mg/dl
Short term radiotherapy
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short-term RT (25 Gy in five days,
surgery after 2 week) has been
administered to patients with T3N0
CRM- disease or T2N0 CRM- with tumor
at less than 5 cm from the anal verge.
Pretreatment staging of rectal cancer
- clinical exam.
- CEA
- chest X-ray scan
- abdomen and pelvis CT scan
- abdomen and pelvis MRI
- Flexible colonoscopy and biopsy
- EUS
- PET scan
All the procedures are ripeated before surgery
Accuracy of magnetic resonance imaging in prediction
of tumour-free resection margin in rectal cancer surgery
Beets-Tan R.G.H., Beets G.L., Vliegen R.F.A., Kessels A.G.H., Van Boven H., De Bruine A.,
von Meyenfeldt M.F., Baeten C.G.M.I., van Engelshoven J.M.A.
The Lancet 357; 2001: 497-504
A mesorectal circumferential margin < 1mm can be accurately
predicted by a 5 mm distance at MRI
Dynamic evaluation of response
PET scan (before and during CHT-RT)
DNA ploidy (before and during CHT-RT)
Surgery
8 weeks after the end of radiochemotherapy
Low or ultralow anterior resection or APR
according to restaging
loop ileostomy
The Quality of the TME
Specimen
1
Poor surgery
little mesorectum
2
Average surgery with
incomplete removal of
mesorectum
3
Excellent surgery with
complete mesorectal
excision
The surgeon as prognostic factor
Non colorectal surgeons
> LR
> APR
Surgical training 50% reduction of LR
Surgical volume recommended
At least 4 rectal resection /month
Hermanek EJSO 96
Steele EJSO 96
Harmon Ann Surg 99
Temple DCR 99
van de Velde 00
Martling Lancet 00
Effects of neo-adjuvant chemo-radiotherapy
OXATOM + FAFU + RT : phase II
patients (n=30)
ACCRUAL
from 2002 July to 2004 March
No. Pts
%
M
16
53
F
14
47
56
(30 – 74)
0
15
50
1
2
13
2
43
7
Gender
Age
average (range)
PS (ECOG)
Activity
No.Pts
%
DOWNSIZING
30
100
Complete mesorectal excision
29
97
1
3
R0
28
93
R1
2
7
pMRC > 1 mm
28
93
pMRC < 1mm
2
7
pN+ (32 average N retrieved)
5 (1focal;4N1;1N2)
TRG1/2-pN+
1/21
Almost complete m. excision
17
5
Activity
No.Patients
%
TRG1
12
40
TRG2
9
30
TRG3
6
23
TRG4
2
7
TRG5
0
0
At a median follow up of 16 months (7-27)
all the 30 pts of phase II study are alive and disease free.
Neoadjuvant therapy for rectal
cancer: Naples NCI experience
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From December 2000 to May 2005
65 pts with LARC submitted to CT-RT
23 pts with T3N0 CRM- and T2N0 CRM- below 5 cm submitted
to short-term RT
71 AR with TME (64 low or ultralow anastomosis, 7 Hartmann’s
procedures)
17 APR
56 side to end anastomosis by triple stapler technique
8 coloanal manual anastomosis (J pouch in 4)
Pelvic suction drainage in all (removed on day 2 to 5)
Protective stoma
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59 protective stoma performed out of 64
colorectal or coloanal anastomosis
5 pts refusing even a temporary stoma
(being aware about the risk for anastomotic
dehiscence)
55 loop ileostomy with a skin bridge
4 loop colostomy in elderly pts
Stoma closure 1-2 months after primary
surgery and after endoscopic control of
anastomosis
Morbidity and mortality
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1 death in the short RT group occurred the day after
surgery for heart failure (1,1%)
3 perineal wound infections out of 17 APR (17,6%)
8 abdominal wound infections (9,1%)
2 bowel obstructions requiring a reoperation (2,2%)
4 delayed bladder catheter removal (4,4%)
2 postoperative temporary anastomotic bleeding (2,2%)
Anastomotic leakage
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Clinical evidence: fever, neutrophylia, perineal
pain, anal discharge, pelvic infection at CT scan
5/64 anastomotic leakage (7,8%)
2 rectovaginal fistulas (1 radiological finding at
1st follow up, 1 in a patient reoperated on for
small bowel obstruction due to ileostomy loop
torsion, in which ileostomy was closed)
1 pelvic abscess after Hartmann’s procedure,
with dehiscence of rectal stump and anal
discharge
Anastomotic leakage:
treatment
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Conservative treatment by pelvic drainage and
washing in 4 pts (the patient with Hartmann
procedure and 3 pts with anastomotic dehiscence
and protective stoma)
Reoperation in 3 pts (1 rectovaginal fistula clinically
evident treated by temporary colostomy, 2 temporary
colostomy in pts with anastomotic leakage and no
protective stoma)
No treatment in the patient with rectovaginal fistula
radiologically but not clinically evident
Crical data evaluation
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Gender: all the anastomotic leaks and the
rectal stump dehiscence occurred in male
patients
Anastomosis: all leaks occurred after
mechanical side to end anastomosis by
means of TA 30, EEA 31, TA 60
Comorbidity: 3/8 pts were suffering from
Chronical pulmonary disease; 3/8 were
suffering from diabetes
Critical data evaluation
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Protective stoma: 2/5 pts (40%) without a
protective stoma suffered from anastomotic
leakage (3/6 if we consider also the female pt
reoperated for loop ileostomy torsion with
closure of the ileostomy and reoperated once
more for rectovaginal fistula clinically evident)
Short RT: 3/23 dehiscences (13%)
CT-RT: 5/65 complications (7,7%)
Conclusions
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Overall number of reoperations: 5 (2 for loop
ileostomy torsion, 2 for anastomotic leakage in non
protected pts, 1 for rectovaginal fistula after first
closure of ileostomy)
Average of hospital stay: 12 days for complicated pts
vs 7 days for non complicated pts
Transanal or perineal drainage removed after 2 to 4
days
Outpatient care of the problem by transanal washing
2 to 3 time a week
100% of spontaneous healing of anastomotic leakage
Delay in stoma closure of 2 months
Conclusions
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Literature reports don’t show a clear likelihood of
neoadjuvant therapy for anastomotic dehiscence in rectal
cancer surgery
Our data show a correlation between anastomotic
leakage and male gender, mechanical anastomosis,
chronical co-morbidities
Short RT more than CT-RT seems to have more likelihood
with anastomotic complications
We strongly recommend to perform a protective stoma in
all pts with LARC
The protective stoma avoids more important and lifethreatening complications, allows a quick discharge of pts
and a outpatient care of the problem.