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Transcript of Anastomotic leakage in rectal surgery after neoadjuvant therapy Montecatini Terme 28 maggio 2005...
Anastomotic leakage in rectal surgery after neoadjuvant
therapyMontecatini Terme 28 maggio 2005
Dario ScalaINT Napoli
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
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
Postoperative RT randomized trials
GITSG 48 Gy FISHER 46.5 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
Post-operative combined radiotherapy and chemotherapy
Guidelines on colorectal cancer, ASSR, Roma 2002Guidelines on colorectal cancer, ASSR, Roma 2002
•Adjuvant Adjuvant combined RT and CHTcombined RT and CHT produce a benefit in terms produce a benefit in terms
of of local controllocal control and and overall survivaloverall survival..
•Compared to surgery alone RT decreases LR Compared to surgery alone RT decreases LR
•With the addition of CHT With the addition of CHT
decreases local failure (-10%) decreases local failure (-10%)
increases 5-years survival (+10/15%). increases 5-years survival (+10/15%).
butbut
•increase in acute increase in acute toxicitytoxicity 25 to 50% 25 to 50%•only 50- 65% of patients completing the therapeutic plan.only 50- 65% of patients completing the therapeutic plan.
Preoperative vs postoperative RT
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
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
Pre-operative high-dose short-term radiotherapyPre-operative high-dose short-term radiotherapy
The Dutch TrialThe Dutch Trial1718 pts with T1718 pts with T11-T-T33 operable rectal tumors operable rectal tumors
Optimal surgery alone vs Optimal surgery alone vs pre-operative radiotherapy and immediate optimal surgery.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%.The overall recurrence rate at 2 years fell from 8.4% to 2.4%.
E Kapitaijn et al. N Engl J Med 2001; 345:638-646E Kapitaijn et al. N Engl J Med 2001; 345:638-646
Pre-operative high-dose short-term Pre-operative high-dose short-term radiotherapyradiotherapy
Pre-operative radiotherapy Pre-operative radiotherapy had no impact on survivalhad no impact on survival::
the distant recurrence rate was equivalent in the two the distant recurrence rate was equivalent in the two
arms (16% vs 15%) with 15% of patients dead in each arms (16% vs 15%) with 15% of patients dead in each
arm by two years.arm by two years.
Pre-operative radiotherapy Pre-operative radiotherapy did not allow to achieve did not allow to achieve
down-stagingdown-staging of the tumoral lesion. This treatment of the tumoral lesion. This treatment
cannot be used to facilitate either sphincter cannot be used to facilitate either sphincter
preservation or secondary resection of initially preservation or secondary resection of initially
unresectable tumors.unresectable tumors.CAM Marijen et al. J Clin Oncol 2001; 19: 1976-1984CAM Marijen et al. J Clin Oncol 2001; 19: 1976-1984
E Kapitaijn et al. N Engl J Med 2001; 345:638-646E Kapitaijn et al. N Engl J Med 2001; 345:638-646
The Dutch TrialThe Dutch Trial
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
Bosset (EORTC) 5FU/LV 45 Gy Chari 5FU-CDDP 45 Gy Grann 5FU/LV 50.4 Gy Rich 5FU PVI 50.4 Gy Valentini 5FU CI 37.8 Gy INT Napoli Tom/FU/OXA 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
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
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
Stevens KR Jr, et al. Cancer 1978 May;41(5):2065-71.
higher incidence of anastomotic leakage in preoperative irradiated patients
Simunovic M, Heald RJ Br J Surg 2003 (90):999-1003
pre RT group 11,4% anastomotic leakageno RT group 7,8% anastomotic leakage
Neoadjuvant therapy and anastomotic leakage
The Dutch trial N Engl J Med 2001; 345: 638-46
1861 pts randomly assigned to short RT followed by TME or TME aloneno difference as concerns anastomotic leaksmore perineal wound infections after APR in the RT group
German Rectal Cancer study group. N Engl J Med 2004;351:1731-40
823 pts randomly assigned to receive preop or post CT-RTno difference in anastomotic leaks between preop (11%) e postop (12%) treatment
Neoadjuvant therapy and anastomotic leakage
Norwegian Rectal Cancer Group Colorectal Dis. 2005 Jan;7(1):51-7.
1958 pts undergoing rectal surgery with anterior resectionoverall rate of AL of 11,6%risk significantly higher in pts receiving preop RT (O.R. 2.2)
Morino M, Parini U et al 2003 Ann Surg 237:335-342.
100 pts undergoing laparoscopic anterior resectionoverall rate of AL of 17%higher incidence in pts with preop RT (21% vs 12,5%)
Neoadjuvant therapy and anastomotic leakage
Delgado S, Lacy AM et al. Surg Endosc 2004, 18:1457-1462.
220 pts undergoing laparoscopic assisted rectal surgery130 pts (59%) receiving preop CT-RToverall AL rate 7,3% (12/166)7/12 leaks in pts treated with preop CT-RT5/12 leaks in pts not treated before surgeryno 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 aloneno 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
Surgical Oncology “C”V. Parisi, F. Cremona, F. Ruffolo,
R. Palaia, P. Delrio, D. Scala,V. Albino, M. Di Marzo, D.N. Idà
RadiotherapyB. Morrica,
C. Guida, V. Ravo,
M. Elmo, B. Pecori
Exp.OncologyA. Budillon
E. Di Gennaro
PathologyG. Botti
F. Tatangelo
Medical Oncology AG. Comella, P. Comella
R. Casaretti, A. Avallone
EndoscopyA.Tempesta
G.B. Rossi, M. De Bellis,
P. Marone, F. Petrulio
RadiologyA. Siani, V. De Rosa,
G. Burgazzi, A. Petrillo
Nuclear MedicineS. Lastoria
G.M. Cascini
Exp. Oncology
Univ. Fed. IIS. Pepe
Colorectal Cancer Cooperative TeamColorectal Cancer Cooperative Team
Treatment planeTreatment planePhase I-II clinical studyPhase I-II clinical study
RTRT
weeksweeks1 22 33 44 55-- 11
45 Gy 1.8 Gy X 25
DaysDays
CTCT
** 1st
course
** 2nd
course
** 3rd course
Raltitrexed 15 Raltitrexed 15 min.min.
Day 1Day 1
LFA 2 hrsLFA 2 hrs5-FU bolus5-FU bolus Day 2Day 2
Oxaliplatin 2 Oxaliplatin 2 hrshrs
οοοοο οοοοο οοοοο οοοοο οοοοο
OXALIPLATINOXALIPLATIN
Down-regulation of TS expression Influence over 5-FU clearanceIn 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 cancerImproves efficacy of 5-FU/FA in adjuvant therapy of
colorectal cancerRadiation sensitizer as well as 5-FU e Raltitrexed.
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
-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
CT-RT AccrualCT-RT Accrual
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.
- clinical exam.
- CEA
- chest X-ray scan
- abdomen and pelvis CT scan
- abdomen and pelvis MRI
- Flexible colonoscopy and biopsy
- EUS
- PET scan
Pretreatment staging of rectal Pretreatment staging of rectal cancercancer
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 A mesorectal circumferential margin << 1mm can be 1mm can be accurately predicted by a 5 mm distance at MRIaccurately predicted by a 5 mm distance at MRI
DNA ploidy (before and during CHT-RT)
Dynamic evaluation of response
PET scan (before and during CHT-RT)
8 weeks after the end of 8 weeks after the end of radiochemotherapyradiochemotherapy
Low or ultralow anterior resection or APR Low or ultralow anterior resection or APR according to restagingaccording to restaging loop ileostomyloop ileostomy
Surgery
The Quality of the TME Specimen
Poor surgerylittle mesorectum
1Average surgery withincomplete removal ofmesorectum
2Excellent surgery withcomplete mesorectalexcision
3
The surgeon as prognostic factorThe surgeon as prognostic factor
Hermanek EJSO 96Steele EJSO 96Harmon Ann Surg 99Temple DCR 99van de Velde 00Martling Lancet 00
Surgical volume recommended
At least 4 rectal resection /month
Non colorectal surgeons > LR > APR
Surgical training 50% reduction of LR
Effects of neo-adjuvant chemo-radiotherapy
OXATOM + FAFU + RT : phase IIpatients (n=30)
ACCRUAL from 2002 July to 2004 March
No. Pts %
Gender
M 16 53
F 14 47
Age
average (range) 56 (30 – 74)
PS (ECOG)
0 15 50
1 13 43 2 2 7
Activity No.Pts %
DOWNSIZING 30 100
Complete mesorectal excision 29 97
Almost complete m. excision 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) 17
TRG1/2-pN+ 1/21 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) At a median follow up of 16 months (7-27) all the 30 pts of phase II study are alive and all the 30 pts of phase II study are alive and
disease freedisease free..
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)
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
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%)
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
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
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
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%)
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
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.