Cochrane Database Syst Rev. 2004;(2):CD002101. Curative surgery for obstruction from primary left colorectal carcinoma: primary or staged resection? De Salvo GL, Gava C, Pucciarelli S, Lise M REVIEWERS CONCLUSIONS: The limited number of identified trials together with their methodological weaknesses do not allow a reliable assessment of the role of either therapeutic strategy in the treatment of patients with bowel obstruction from colorectal carcinoma. It would appear advisable to conduct high quality large scale RCT to establish which treatment is more effective. However, it is doubtful whether they could be carried out in a timely and satisfactory way in this particular surgical context
Segmental resection vs Subtotal colectomy Scotia Study Group increased bowel (Br J Surg) 1995 frequency in subtotal group Torralba et al post operative (Dis Colon diarrhoea Rectum) 1994 in 31%
Extended right vs Segmental left Nyam et al Dis Colon Rectum 1996 no difference in bowel frequency no difference in complications
Mortality rates Scotia Gp (Br J Surg) 1995 12% Poon et al (Br J Surg) 1998 7% Alvarez et al (Dig Dis) 2005 11% Poon et al (Dis Col Rectum) 2005 11% McGillicuddy et al (Arch Surg) 2009 15%
Rationale – converting emergency into elective surgery Pre-operative correction and stabilisation of fluid and electrolyte balance Reduction of diaphragmatic splinting and pain with improvement in respiratory function Treatment of medical co-morbid disease Accurate pre-operative staging of the patient Referral to a specialist colorectal surgeon In a few patients with rapidly progressive (advanced) disease or unstable comorbid disease, major surgery may be avoided
CReST is funded by CRUK and was developed by the NCRI Colorectal Cancer CSGCReST
Stenting needs to be properly evaluated in arandomised controlled trial addressing two keyquestions: * Is there a worthwhile net benefit (in reduced operativemortality and morbidity, reduced stoma formation andbetter quality of life adjusted survival) from endoluminalstenting for patients presenting with an obstructingcolonic cancer? * If a benefit exists, is this identifiable in patientsundergoing attempted curative treatment, palliativetreatment, or both?
Eligibility criteria Left sided colorectal cancer Clinical or radiological evidence of obstruction Patient is fit for surgery Responsible doctor feels that there may be some benefit to the patient from stenting as a bridge to surgery
Emergency surgery ObstructingColorectal cancer R Insertion of Failed stenting endoluminal stent Palliative care Successful decompression Elective surgery
End PointsPrimary: 1. 30 day mortality 2. Length of hospital stay Secondary: a) Presence and duration of a stoma b) Stenting completion and complication rate c) Anastomosis rate d) Quality of life (EQ 5D and EORTC QLQ-CR 29) e) Overall survival f) Disease-free survival at three years (attempted curative surgery group only) g) Length of stay on ITU or HDU h) In-hospital morbidity i) Cost benefit analysis j) Rate of adjuvant chemotherapy (stage II and stage III cancer) and adherence to chosen chemotherapy protocols
NICE draft guidance Clinical question: For patients presenting with acute large bowel obstruction as a first presentation of colorectal cancer, what are the indications for stenting as a bridge to elective surgery? What are the indications for stenting patients and the optimal timing for stenting to occur? Clinical evidence There is very little evidence of any type with which to address this topic. There are no directly applicable studies and so in assessing the body of evidence, consideration was given to the possibility that relevant evidence may not be directly available and so studies which compared stenting as a bridge to surgery, stenting for palliative purposes or immediate emergency surgery were also reviewed to check whether these studies contained information relevant to the topic. Despite this consideration, very little evidence of relevance was found from these studies and what was available was of very poor quality.
Dutch stent in 1 – Endoscopy 2008 21 pts with obstruction Palliative cases Premature closure of the trial 11 adverse events in stenting arm 6 perforations • 4 early • 2 late on chemotherapy
2nd Dutch Stenting trial – multicentre van Hooft Lancet Oncol 2011;12:344–52 Obstructing left sided Primary outcome measure QoL 98 cases randomised Increased 30 day morbidity in stent gp (absolute risk increase 0.19) Trial currently halted by DMEC
2nd Dutch Stenting trial – multicentre van Hooft Lancet Oncol 2011; 12: 344–52 No difference • QoL • Mortality • Stoma rates Stent group • Perforation 13% • Successfully placed in 70% (all relieved obstruction) • 31 pts bridge to surgery Primary anastomosis in 20 (25% leak rate) 3 silent perforations found histologically
The authors concluded that colonicstenting has no decisive clinicaladvantages compared to emergencysurgery. They suggested that it could beused as an alternative treatment in as yetundefined subsets of patients, althoughwith caution because of concerns abouttumour spread caused by perforations.
French stenting trial – multi centre – Pirlet et al Surg Endosc 2010 Obstructing left sided carcinoma Endoscopic or radiological 60 patients randomised 53% technical failure stenting arm No reduction in stoma rates • 43% stenting arm, 56% emergency surgery 2/30 perforations in stenting arm Trial stopped early
Thus the evidence provided by published randomised trials to date demonstrates no evidence of benefit from stenting and importantly describes increased morbidity associated with stenting. The key questions relating to the use of stents in obstructing colorectal cancer remain unanswered. These questions can only be answered by a large randomised trial. The current status of stenting in obstructing colorectal cancer is analogous to the status of laparoscopic surgery for colorectal cancer in 2000. People should only have laparoscopic surgery as part of a clinical trial. In view of all the above we feel most strongly that the planned NICE Colorectal Cancer guidelines should state that; in patients fit enough to undergo emergency surgery, stenting in obstructing colorectal cancer should be limited to clinical trials so that we can be clear about its benefit and risks.
Clinical question: For patients presenting with acute large bowelobstruction as a first presentation of colorectal cancer, what are the indications for stenting as a bridge to elective surgery? What are the indications for stenting patients and the optimal timing for stenting to occur? The guidance on Improving outcomes in colorectal cancer‘ (2004) recommended stent insertion instead of emergency surgery for patients with acute bowel obstruction. Consequently the question investigated by this guideline focused on the indications and optimal timing for stent insertion to occur. The evidence you cite relates to the issue of stent insertion vs emergency surgery and is therefore not relevant to the topic which was considered by the guideline.
“The failure to consider the directly randomised evidence on thequestion addressed is indefensible and does a disservice topatients and their medical carers. As this randomised evidencepoints to the potential for serious harm as a result of insertion ofSEMS in patients with obstructing colorectal cancer, the NICEGuidance’s recommendation that colorectal surgeons shouldconsider inserting a colonic stent in patients presenting with acutelarge bowel obstruction, without mention that randomised trialshave failed to establish superiority of SEMS over decompressionsurgery, is ”perverse”. The appropriate recommendation - and theconclusion of the authors of all three randomised trials (seebelow) - is that stenting as a bridge to surgery remains anexperimental procedure requiring further randomised evidence toestablish its clinical and cost-effectiveness. The newly publishedguidance on SEMS should be corrected or withdrawn”.
2. Recruitment (up to 14th November 2011) Date recruitment started: 23-Apr-2009Proposed date for recruitment to end: Extended to August 2013 Total number to be recruited: 400 Number recruited to date: 123
First 100 patients 50 randomised to stenting 48 stent attempted Success rate 85% (7 failures) No perforations 38 surgery 10 no surgery • 7 palliative cases • 1 MI before surgery • 1 benign disease • 1 unknown
mean 23.2 (22.8) (s.d.)Time from stent median (IQR) 19.5 (4 , 35)to surgery min 0 max 103
SAEs in stented patients having surgery (38 patients) Intra-abdominal abscess 2 Wound infection 2 PE 2 Myocardial 1 Urinary 2 Chest infection 3 Constipation 1 No anastomotic leaks but no. primary anastomosis unknown
Summary Colorectal community in UK has accepted the need for a trial and is supporting it Recruitment is progressing at a satisfactory rate Safety data is reassuring Given concerns raised by stenting trials, CReST trial is important Current NICE guidance is disservice to patients
TREC Trial –Transanal Endoscopic Microsurgery (TEM) and Radiotherapy in Early Rectal Cancer Jim Hill Manchester Royal Infirmary
Phase II feasibility study comparingradical TME surgery versus SCPRTplus delayed local excision fortreatment of early rectal cancer (T1-T2)
Early Rectal Cancer 10,000 new cases rectal cancer per year in England & Wales 49 – 62% screen-detected rectal cancers are “early” (pT1-2N0M0) Standard of care: Total Mesorectal Excision (TME) High rates of cure (3-6% relapse) Significant high mortality (3-4%) & post-operative morbidity
Radical Resection vs Local ExcisionBalance of reduction inmorbidity and mortality vs risk of oncological disaster
Results of Local Excision Alone T-Stage Local recurrence %(range) T1 9.7 (0-24) T2 25 (0-50) T3 38 (0-100)
Radical Resection - morbidity & mortality Significant morbidity (up to 60%) and mortality (0-12%) Wound infections, wound and parastomal herniae, urinary /sexual dysfunction, anastomatic leakage, stoma issues, anterior resection syndrome, incontinence APR: Perineal wound and stoma- related physical, psychological and financial cost
Short Course Pre-operativeRadiotherapy Preoperative radiotherapy more effective than post-op RT Pre-op can reduce local recurrence following TME Can induce tumour shrinkage or even complete pathological response Interval between SCPRT and surgery key to downstaging Surgery follows 1 week after traditional schedules of SCPRT
50 patients randomised to stenting. 47 have a stent insertion date recorded. 3 don’t (1071, 1086, 1088) Reasons for not having a stent insertion date are as follows: 1 not eligible - small bowel tumour on review (1071) 1 small bowel obstruction/fistula – going straight to surgery (1086) 1 stent attempted but failed – missing date. Assumed to be = date of surgery = 1 day after rand. (1088)
Of the 48 with a stent date recorded: 38 have a surgery date 10 don’t. Good reasons for not having a surgery date are as follows: 7 palliative (1016, 1034, 1051, 1059, 1062, 1068, 1069) 1 died before surgery (1022) Bad reasons for not having a surgery date are as follows: (forms being chased) 1 possible non-cancer (1092) 1 unknown (1043)
CReST RecruitmentProposed date for recruitment to end: Oct-2012Total number to be recruited: 400Number recruited to date, 19-Nov-10: 65
Benign disease Small et al, Surg Endosc 2008 23 cases Clinical success 22/23 Major complications 38% 87% occurred after 7 days
Planned analyses Interval analysis after recruitment of 150 patients of post-operative complications, in hospital stay, stoma formation, 30 day mortality. A primary analysis of outcome will be made once all patients have 2 years of follow up. Statistical analyses will use standard methods, e.g. comparisons of proportions by Mantel-Haenszel or Fisher’s exact test, logrank analyses of time to event data and multi-level model with repeated measures analysis for quality of life scores.
Conclusions of randomised trials reported to date No proven benefit for all comers compared to emergency surgery May be useful in selected patients (? Which ones) Further studies needed to look at oncological outcomes
Exclusion criteria Patients with signs of peritonitis and/or perforation Patients with obstruction in the rectum, that may require neoadjuvant therapy (i.e. tumours in the mid or lower rectum) Patients who are unfit for surgical treatments or refuse surgical treatment. Patients who are unwilling to consent to participate Pregnant patients
Martinez-Santoz et al, Dis Colon Rectum 2002 Emergency surgery (n=29) Pre-operative stent and elective surgery (n=26) Stenting and elective surgery was associated • an increase in the primary anastomosis rate (84.6% vs 41.4%, p=0.0025) • a lower need for a colostomy (15.4% vs 58.6%) • a significantly reduced hospital stay (14.23 vs 18.52 days and intensive care unit stay (0.3 vs 2.9 days)
Statistical Power 400 patients will be randomized over three years from 40 centres in the UK and selected centres overseas The feasible study size would be adequate to detect a 50% reduction in 30-day mortality with stenting and elective surgery compared to emergency surgery (e.g. 13% vs 27% as reported in audit data) 90% power to detect a reduction in operative complications from 40% to 25% - Martinez- Santoz et al reported a reduction from 41% to 12% in their non-randomised study).
Statistical Power 90% power to detect a 0.35sd reduction in days in hospital equivalent to 1-2 days. It is not anticipated that there will be any significant loss to follow-up. 90% power to detect differences in survival of similar magnitude to those seen in Birmingham audit data (where survival at 6 months in the emergency patients was 73% vs 87% in the elective group) or those reported in a recent national audit (mortality of 15.7% following surgery for obstructing colorectal
Statistical Power Adequate to detect a 50% reduction in 30-day mortality with stenting and elective surgery compared to primary anastomosis 90% power to detect a reduction in operative complications from 40% to 25% - Martinez- Santoz et al reported a reduction from 41% to 12% in their non-randomised study).
Sebastian et al, Am J Gastroenterol 2004 Pooled analysis of 1,198 patients in 54 studies. Median technical and clinical success rates of 94% (i.q.r 90-100) and 91% (i.q.r 84-94). Clinical success when used as a bridge to surgery was 71.7%. Major complications perforation (3.7%), stent migration (11.8%). Stent related mortality 0.58%.
Statistical Power 400 patients 90% power to detect differences in mortality if similar to those reported in a recent national audit (mortality of 15.7% following surgery for obstructing colorectal cancer and 4% following elective surgery). 90% power to detect a 0.35sd reduction in days in hospital equivalent to 1-2 days. 90% power to detect a reduction in operative complications from 40% to 25% - Martinez- Santoz et al reported a reduction from 41% to 12% in their non-randomised study).
CReST to date 125 pts recruited 33 recruiting centres 50 sites open
Presentation and Outcome COLORECTAL CANCERMode of % of all In-hospital 5 yrpresentation patients mortality survivalElective surgery 60 5 50Emergency 25 20 25Non-operative 15 40
Stenting workshops Combined endoscopic/fluoroscopic technique recommended Double channel gastroscope No pre or post stent insertion dilatation allowed Stent of radiologists/endoscopists choice Confidence levels of radiologists high No specific colonic stent numbers
Systematic reviews Little high level evidence No data QoL and economic analysis Little long term/survival data
2007 UK National Bowel Cancer Audit Project reported an 11 per cent mortality after colonic stenting for obstructing cancers The authors commented that this was higher than in previously published reports and needed further study
Stenting vs open surgery Tilney et at Surg Endosc 2007 451 pts Lower mortality p<0.03 LOS shorter by 7.7 days Stenting did not affect survival
Watt et al Ann Surg 2007 88 articles, Mortality comparable Shorter LOS Lower colostomy rates Lower complications
Serious Adverse Events SAEs – fatal, life-threatening, require or prolong hospitalisation or aresignificantly or permanently disabling For purposes of trial, adverse events include, but aren’t limited to: - Failure to deploy the stent - Bowel perforation - Stent displacement All SAEs reported to BCTU within 24 hrs
QuestionIn the absence of any randomisedclinical trial showing a benefit ofstenting in patients with obstructingleft sided colorectal cancer andconcerns about stenting (sufficient tostop the trials) in the only threerandomised trials so far conducted,should stenting be offered outside arandomised trial?
Left colon-Staged resection Cahill et al (Annals RCSE) 1991 44% prefer Hartmann Wigmore et al (Br J Surg) 1995 32-60% never reanastomosed