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Anastomotic leakage in rectal surgery after neoadjuvant therapy

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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 οοοοο οοοοο οοοοο οοοοο οοοοο 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.

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