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

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Presentation on theme: "Anastomotic leakage in rectal surgery after neoadjuvant therapy Montecatini Terme 28 maggio 2005 Dario Scala INT Napoli."— Presentation transcript:

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 48 Gy FISHER46.5 Gy DUTCH50 Gy DANISH50 Gy SPLIT MRC III40 Gy EORTC46 Gy Local control in 2 trial (p<0.005) Toxicity No influence on survival

5 Post-operative combined radiotherapy and chemotherapy Guidelines on colorectal cancer, ASSR, Roma 2002 Adjuvant combined RT and CHT produce a benefit in termsAdjuvant combined RT and CHT produce a benefit in terms of local control and overall survival. Compared to surgery alone RT decreases LRCompared to surgery alone RT decreases LR With the addition of CHTWith the addition of CHT decreases local failure (-10%) increases 5-years survival (+10/15%). but increase in acute toxicity 25 to 50%increase in acute toxicity 25 to 50% only % of patients completing the therapeutic plan.only % of patients completing the therapeutic plan.

6 Preoperative vs postoperative RT Short Course 25Gy in 5 days Rider Stockholm I e II RCG ICRF Rotterdam Swedish Standard 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

7 Pre-operative high-dose short-term radiotherapy The Dutch Trial 1718 pts with T 1 -T 3 operable rectal tumors Optimal surgery alone vs pre-operative radiotherapy and immediate optimal surgery. Local recurrence Surgery alone Pre-op. radiotherapy and surgery Upper rectum3.5%1.5% Mid rectum10.0%1.0% Lower rectum10.0%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:

8 Pre-operative high-dose short-term radiotherapy 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. 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: E Kapitaijn et al. N Engl J Med 2001; 345: The Dutch Trial

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 45 Gy Chari 5FU-CDDP45 Gy Grann5FU/LV50.4 Gy Rich5FU PVI50.4 Gy Valentini5FU CI37.8 Gy INT NapoliTom/FU/OXA45 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 11,4% anastomotic leakage no RT group 7,8% anastomotic leakage

15 Neoadjuvant therapy and anastomotic leakage The Dutch trial N Engl J Med 2001; 345: 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: 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): 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 2003 Ann Surg 237: 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: 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): pts undergoing preop CT-RT 48 pts undergoing surgery alone no difference between the two groups in AL rate

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 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 Exp.Oncology A. Budillon E. Di Gennaro Pathology G. Botti F. Tatangelo Medical Oncology A G. Comella, P. Comella R. Casaretti, A. Avallone Endoscopy A.Tempesta G.B. Rossi, M. De Bellis, P. Marone, F. Petrulio Radiology A. Siani, V. De Rosa, G. Burgazzi, A. Petrillo Nuclear Medicine S. Lastoria G.M. Cascini Exp. Oncology Univ. Fed. II S. Pepe Colorectal Cancer Cooperative Team

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

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 -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 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 CT-RT Accrual

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

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

29 The Quality of the TME Specimen

30 The surgeon as prognostic factor Hermanek EJSO 96 Steele EJSO 96 Harmon Ann Surg 99 Temple DCR 99 van de Velde 00 Martling Lancet 00 Surgical volume recommended At least 4 rectal resection /month Non colorectal surgeons > LR > APR Surgical training50% reduction of LR

31 Effects of neo-adjuvant chemo-radiotherapy

32 OXATOM + FAFU + RT : phase II patients (n=30) ACCRUALfrom 2002 July to 2004 March No. Pts% Gender M1653 F1447 Age average (range)56 (30 – 74) PS (ECOG)

33 Activity No.Pts % DOWNSIZING Complete mesorectal excision Almost complete m. excision 1 3 R R1 2 7 pMRC > 1 mm pMRC < 1mm 2 7 pN+ ( 32 average N retrieved ) 5 ( 1 focal ;4N1;1N2) 17 TRG1/2-pN+ 1/21 5

34 Activity No.Patients % TRG TRG TRG 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. 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 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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