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.