1. Anastomotic leakage in rectal surgery after neoadjuvant therapy
Montecatini Terme 28 maggio 2005
Dario Scala
INT Napoli

2. Anastomotic leakage in rectal surgery: risk factors
TME
Anastomosis height
Protective stoma
Neoadjuvant therapy
Extension and tumor-related obstruction
Gender
Bowel preparation
Intraoperative blood loss
Pelvic drainage
Co-morbidities

3. 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?
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

4. Postoperative RT randomized trials
GITSG Gy
FISHER Gy
DUTCH 50 Gy
DANISH 50 Gy SPLIT
MRC III 40 Gy
EORTC 46 Gy
Local control in 2 trial (p<0.005)
Toxicity
No influence on survival

5. only 50- 65% of patients completing the therapeutic plan.
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 % of patients completing the therapeutic plan.
Guidelines on colorectal cancer, ASSR, Roma 2002

6. Preoperative vs postoperative RT
Advantages:
irradiating tissue not rendered hypoxic by previous surgery
Enhancing sphincter preservation by shrinking large distal tumors (standard RT only)
Decreasing likelihood of radiation-induced injury to small bowel trapped in the pelvis by adhesions
Lower acute and long-term toxicity
Short Course
25Gy in 5 days
Rider
Stockholm I e II
RCG
ICRF
Rotterdam
Swedish
Standard
45-50 Gy in 5 weeks
VASAG I e II
MSKCC
MRC I e II
EORTC
PUCC
Norway
MRC

7. 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
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:

8. 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:
Pre-operative radiotherapy did not allow to achieve down-staging 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:

9. 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

10. Neoadjuvant concomitant radiochemotherapy
Bosset (EORTC) 5FU/LV Gy
Chari 5FU-CDDP 45 Gy
Grann 5FU/LV Gy
Rich 5FU PVI Gy
Valentini 5FU CI Gy
INT Napoli Tom/FU/OXA 45 Gy
Increases complete pathological responses (10-30%)
Increases sphincter-saving procedures (60-85%)

11. Neoadjuvant therapy and anastomotic leakage
Is neoadjuvant therapy in rectal cancer
a relevant risk factor
for anastomotic leakage?
What is the EBM report?

12. Neoadjuvant therapy and anastomotic leakage: pathogenesis of the damage
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 Jul;46(7):

13. Neoadjuvant radiotherapy morbidity randomized trials
UKMRC 1b (1982)
UKMRC 1a (1984)
EORTC (1988)
UKMRC 2 (1996)
SRCT (1997)
No increase in the dehiscence of colorectal anastomosis

14. Neoadjuvant therapy and anastomotic leakage
Stevens KR Jr, et al. Cancer 1978 May;41(5):
higher incidence of anastomotic leakage in preoperative irradiated patients
Simunovic M, Heald RJ Br J Surg 2003 (90):
pre RT group ,4% anastomotic leakage
no RT group ,8% anastomotic leakage

15. Neoadjuvant therapy and anastomotic leakage
The Dutch trial N Engl J Med 2001; 345:
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
German Rectal Cancer study group. N Engl J Med 2004;351:
823 pts randomly assigned to receive preop or post CT-RT
no difference in anastomotic leaks between preop (11%) e postop (12%) treatment

16. Neoadjuvant therapy and anastomotic leakage
Norwegian Rectal Cancer Group Colorectal Dis 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)
Morino M, Parini U et al Ann Surg 237:
100 pts undergoing laparoscopic anterior resection
overall rate of AL of 17%
higher incidence in pts with preop RT (21% vs 12,5%)

17. Neoadjuvant therapy and anastomotic leakage
Delgado S, Lacy AM et al. Surg Endosc 2004, 18:
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
Horie H et al. Surg Today 1999; 29(10):992-8.
29 pts undergoing preop CT-RT
48 pts undergoing surgery alone

18. Neoadjuvant therapy and anastomotic leakage
…....I am so confused……….
What is the literature EBM response about anastomotic leaks and neoadjuvant therapy of rectal cancer?

19. Istituto Nazionale dei Tumori – Napoli
Colorectal Cancer Cooperative Team
Surgical Oncology “C”
V. Parisi, F. Cremona, F. Ruffolo,
R. Palaia, P. Delrio, D. Scala,
V. Albino, M. Di Marzo, D.N. Idà
Radiotherapy
B. Morrica,
C. Guida, V. Ravo,
M. Elmo, B. Pecori
Medical Oncology A
G. Comella, P. Comella
R. Casaretti, A. Avallone
Pathology
G. Botti
F. Tatangelo
Exp.Oncology
A. Budillon
E. Di Gennaro
Nuclear Medicine
S. Lastoria
G.M. Cascini
Endoscopy
A.Tempesta
G.B. Rossi, M. De Bellis,
P. Marone, F. Petrulio
Radiology
A. Siani, V. De Rosa,
G. Burgazzi, A. Petrillo
Exp. Oncology
Univ. Fed. II
S. Pepe

20. Phase I-II clinical study
Treatment plane
Phase I-II clinical study RT
weeks 1 2 3 4 5
- 1
45 Gy
1.8 Gy X 25
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Days CT **
1st course
2nd
course
3rd
Raltitrexed 15 min.
Day 1
LFA 2 hrs
5-FU bolus
Day 2
Oxaliplatin 2 hrs

21. 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.

22. Radiotherapy 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

23. 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 > /ml; total bilirub < 1,5 mg/dl; creat < 1,5 mg/dl

24. Short term radiotherapy
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.

25. 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

26. 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:
A mesorectal circumferential margin < 1mm can be accurately predicted by a 5 mm distance at MRI

27. Dynamic evaluation of response
PET scan (before and during CHT-RT)
DNA ploidy (before and during CHT-RT)

28. Surgery
8 weeks after the end of radiochemotherapy Low or ultralow anterior resection or APR according to restaging loop ileostomy

29. The Quality of the TME Specimen

30. 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

31. Effects of neo-adjuvant chemo-radiotherapy

32. OXATOM + FAFU + RT : phase II patients (n=30)
ACCRUAL from 2002 July to 2004 March
No. Pts %
Gender M F
Age
average (range) (30 – 74)
PS (ECOG)

33. Activity DOWNSIZING 30 100 Complete mesorectal excision 29 97
No.Pts %
DOWNSIZING
Complete mesorectal excision
Almost complete m. excision R R
pMRC > 1 mm
pMRC < 1mm
pN+ (32 average N retrieved) (1focal;4N1;1N2)
TRG1/2-pN /

34. Activity TRG1 12 40 TRG2 9 30 TRG3 6 23 TRG4 2 7 TRG5 0 0
No.Patients %
TRG
TRG
TRG
TRG
TRG
At a median follow up of 16 months (7-27)
all the 30 pts of phase II study are alive and disease free.

35. Neoadjuvant therapy for rectal cancer: Naples NCI experience
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)

36. Protective stoma
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

37. Morbidity and mortality
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%)

38. Anastomotic leakage
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

39. Anastomotic leakage: treatment
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

40. Crical data evaluation
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

41. Critical data evaluation
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%)

42. Conclusions
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

43. Conclusions
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 life-threatening complications, allows a quick discharge of pts and a outpatient care of the problem.