The NIHCE guidelines for the management of colorectal cancer

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1 The NIHCE guidelines for the management of colorectal cancer Graeme Poston Chair Colorectal Cancer Guideline Development Group and Colorectal Cancer Quality Standards Committee National Institute of Health and Clinical Excellence Professor of Surgery Aintree University Hospital, Liverpool UK

2 Overall survival for patients with mcrc treated at MD Anderson and Mayo clinics, by year of diagnosis Kopetz S, et al. J Clin Oncol 2009;27: patients from two highly specialized centers Overall su urvival (%) Time (months) Over the past decade, OS has improved substantially in patients with mcrc

3 A guideline Is derived by a group of relevant multi-disciplinary experts with patients/carers from a careful synthesis and graded evaluation of the peer reviewed published evidence Addresses areas of clinical uncertainty e.g. which rectal Addresses areas of clinical uncertainty e.g. which rectal cancer pts should receive pre-operative radiotherapy: - Netherlands 60% - Sweden 40% - Norway 10% - Denmark 5%

4 A guideline The questions of uncertainty are independently agreed by all identified stakeholders prior to guideline production The recommendations are reviewed by stakeholders pre-publication Is independently peer reviewed prior to publication It is NOT: - a consensus statement - financially/politically underpinned by a body with a vested interest in the recommendations

5 Guidelines for the management of colorectal cancer Have been produced in many countries by many organisations over the last two decades Many have been general guidelines about all aspects of diagnosis and management Many have focused on specific issues: Many have focused on specific issues: - suspicious symptoms - screening - diagnosis - staging - management of the primary tumour - adjuvant treatment - management of advanced disease

6 All very well, but do they improve outcomes? Evidence is limited and dated Grimshaw and Russell, Lancet 1993; 342: systematic review of 59 published evaluations of effect of clinical guidelines - 24 guidelines for specific clinical conditions - 27 studied preventive care - 8 studied prescribing or support services guidelines 55 of 59 (2 oncology) detected significant improvement in the process of care after introduction of guidelines 9 of 11 ( no oncology) studies that assessed the outcome of care reported significant improvements

7 All very well, but do they improve outcomes? Successful introduction of guidelines depends on: - clinical context and relevance of the guideline - methods of guideline development - credibility of guideline development group - methods of guideline dissemination - methods of guideline implementation Successful implementation requires political will by commissioners/payers to utilise guideline Evaluation of effect of guidelines: - requires identification and measurement of meaningful outcome data - internal and external audit/clinical effectiveness data

8 Guideline development Identify and refine subject area of guideline Convene and recruit Guideline Development Group Define members and roles within GDG Required skills: - literature searching and retrieval - epidemiology and biostatistics - health services research and health economics - clinical experts - group process experts - writing and editing - PATIENT AND CARER REPRESENTATION Agree the relevant questions with stakeholders

9 Guideline development Identify and assess the evidence (e.g. Delphi): - what sort of evidence? - where to look for the evidence? - collect all the evidence - assess the evidence for relevance - assess the evidence for susceptibility to bias - extract and summarise the evidence about benefits, costs, and harms Summarise the evidence Categorise and grade the evidence

10 Factors contributing to the process of deriving recommendations Nature of the evidence (e.g. susceptibility to bias) Applicability of the evidence to the population of interest (generalisability) Costs Knowledge and understanding of the healthcare system Beliefs and values of the panel

11 Guideline development: methods of categorising evidence Ia: evidence from meta-analysis of randomised controlled trials Ib: evidence from at least one randomised controlled trail IIa: evidence from at least one controlled study without randomisation IIb: evidence from at least one other type of quasiexperimental study III: evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case-control studies IV: expert/respected authority opinion (consensus)

12 Types of strength of recommendations A: Directly based on Category I evidence B: Directly based on category II evidence or extrapolated recommendation from Category I evidence C: Directly based on Category II evidence or extrapolated recommendation from Category I or II evidence D: Directly based on Category IV evidence or extrapolated recommendation from Category I, II or III evidence (consensus statement)

13 NIHCE Guideline Methodology Key stakeholders (professional associations, patient groups etc.) invited to submit specific questions relating to uncertainty in current practice Questions then posted on NICE website Stakeholders invited to a one day conference to prioritise the top 20 questions Agreed top 20 questions posted on NICE website If then agreed, the guideline process commences Each key question converted into a PICO [Population, Intervention, Comparator(s), Outcome(s)]

14 NIHCE Guideline Development Group (GDG) Chair, Lead Clinician and members appointed at interview after national advertisement Represent all the professional groups involved directly in the treatment of the guideline disease Three patient/carer representatives Do NOT represent the views of specific associations/organisations Meets bi-monthly for 30 months, addressing two PICO s at each meeting

15 NICE Colorectal Cancer Guideline Development Each specific question developed into a PICO PICO, individual specific question looks at: - Population - Intervention - Comparator(s) - Outcome(s) GRADE methodology: - Grading of Recommendations, Assessment, Development and Evaluation

16 GRADE methodology Quality element Limitations Inconsistency Descriptions of quality elements of GRADE Limitations in the study design and implementation may bias the estimates of the treatment effect. Major limitations in studies decrease the confidence in the estimate of the effect. Inconsistency refers to an unexplained heterogeneity of results. Indirectness Indirectness refers to differences in study population, intervention, comparator or outcomes between the available evidence and the clinical question. Imprecision Results are imprecise when studies include relatively few patients and few events and thus have wide confidence intervals around the estimate of the effect relative to the Publication bias minimal important difference. Publication bias is a systematic underestimate or overestimate of the underlying beneficial or harmful effect due to the selective publication of studies. Each quality element assessed and scored

17 GRADE Methodology Overall quality of outcome evidence in GRADE Quality element D High Moderate Low Very low Further research is very unlikely to change our confidence in the estimate of effect. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any estimate of effect is very uncertain.

18 Guideline recommendations Investigations, diagnosis and staging Management of local disease Management of metastatic disease Ongoing care and support

19 Investigations, diagnosis and staging Diagnostic investigations: - colonoscopy + biopsy - CT colography Staging: - contrast enhanced CT chest, abdomen and pelvis - Rectal cancer: pelvic MRI - Rectal cancer: EUS if MRI suggests amenable to local excision or MRI contraindicated

20 Risk of local recurrence of rectal cancer as predicted by MRI Risk of local recurrence High Moderate Low Characteristics of rectal tumour predicted by MRI Threatened (<1mm)/breached resection margin or low tumour encroaching inter-sphincteric plane or levator involvement T3b or greater with threatened potential surgical margin, or suspicious lymph node not threatening surgical margin, or presence of extra-mural vascular invasion T1, T2 or T3a and no suspicion of lymph node involvement

21 Rectal tumour appears resectable at presentation Do not offer short course pre-operative radiotherapy (SCPRT) or chemoradiotherapy (PCRT) to patients with low risk operable rectal cancer unless as part of a clinical trial Consider SCPRT for patients with moderate risk tumours and PCRT for patients with borderline moderate-high risk tumours Offer PCRT to patients with high risk tumours

22 Patients whose primary Colon or rectal tumours appear unresectable/borderline resectable Do not offer PCRT to patients with rectal cancer solely to facilitate sphincter saving surgery Do not offer neoadjuvant (preoperative) chemotherapy alone to patients with either colon or rectal cancer unless as part of a clinical trial

23 Use of colonic stents in acute large bowel obstruction Only consider for acutely obstructing left side tumours If being considered then CT chest, abdomen, pelvis scan to confirm diagnosis, exclude colonic perforation and stage disease Do NOT use contrast enema studies as only imaging modality Decision to consider stent made in combination by consultant colorectal surgeon with endoscopist experienced in stent placement Do not use for low rectal tumours or evidence of perforation Do not dilate tumour before stent placement Place stent within 24 hours of presentation

24 Stage One colorectal cancer Consider further treatment for patients with locally excised pathologically confirmed stage one cancer, taking into account pathological characteristics, imaging results and previous treatments An early rectal cancer MDT should decide which (if any) treatment to offer

25 Adjuvant chemotherapy Consider for High-risk Stage 2 and all Stage 3 rectal cancer Consider for high-risk Stage 2 colon cancer Recommended for all Stage 3 colon cancers Recommended regimens: - capecitabine monotherapy - oxaliplatin in combination with 5-fluorouracil and folinic acid

26 Patients presenting with stage 4 disease Prioritise treatment to control symptoms if at any time primary tumour is symptomatic If both primary tumour and metastases are considered resectable/potentially resectable, anatomical site- specific MDTs should consider initial systemic treatment followed by sequenced or simultaneous surgery agreed by all MDTs If the CT scan shows metastatic disease confined to the liver, and there is no contraindication to further treatment, then a specialised Hepatobiliary MDT should determine which further imaging is necessary and what further treatment to be offered

27 Patients presenting with stage 4 disease Offer chest, abdomen, pelvis CT to assess stage If intra-cranial disease is clinically suspected then offer contrast-enhanced MRI of brain Do not routinely image head, neck and limbs unless clinically indicated Review all images by appropriate anatomical sitespecific MDT If CT shows potentially resectable extra-hepatic disease, the appropriate anatomical site-specific MDT should decide if a whole body PET-CT is appropriate If CT is inconclusive then offer repeat imaging at an agreed interval

28 Chemotherapy for advanced colorectal cancer Consider the following sequences of chemotherapy unless contraindicated: - FOLFOX, followed by single agent irinotecan - FOLFOX, followed by FOLFIRI - XELOX, followed by FOLFIRI Consider raltitrexed for patients who are intolerant of 5- FU with folinic acid Capecitabine or tegafur with uracil (+folinic acid) can be considered but only administered by oncologists who specialise in colorectal cancer Cetuximab (together with FOLFOX or FOLFIRI) can be given in 1 st line to patients with inoperable kras wildtype liver limited disease

29 Ongoing care and support Follow-up should commence 4-6 weeks after discharge from hospital and continue until such time that the patient and physician agree that the likely benefits no longer outweigh the risks of further tests, or the patient cannot tolerate further treatment Minimum of 2 chest, abdomen, pelvis CT scans in the first 3 years and regular serum CEA estimations (minimum 6 monthly) during the first 3 years Reinvestigate if there is any clinical, radiological or biochemical suspicion of recurrence Offer full verbal and written information before surgery and thereafter on the impact of treatment on bowel function

30 but do they improve outcomes? And if so, how do we measure it? Guideline development Improving outcomes

31 UK NCIN National Cancer Intelligence Network Collects data from: - cancer registries - hospital episode statistics (HES) based on HRGs and activity (OPCS) - NCRI badged clinical trial data Eight regional cancer registries in England looking at eight common cancers (lung, bladder, colorectal, oesophagogastric, gynaecological, skin, breast, prostate) Northern and Yorkshire registry (NYCRS) tasked with examining colorectal cancer

32 NCIN data on colorectal cancer in England Commenced from 1996 Data on 390,000 patients with CRC Identified at individual patient level by Identified at individual patient level by - unique NHS registration number - demographics - GMC licence number of consultants responsible for diagnosis and treatment - interventions received - stage of disease at diagnosis - outcome

33 Survival probability Five-year survival of English colorectal cancer patients first diagnosed (n=114,155) Morris EJA, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, Cottier B, Poston G. Brit J Surg 2010; 97: All Stage 4 All stage 4 resected n=3116 All stage 3 All patients Years Patients with resected liver metastases All patients without resected metastases Dukes C Dukes D

34 Survival of CRC patients after liver resection in England Morris EJA et al. Brit J Surg 2010; 97: Survival stratified by year of surgery ( ) Cumulative Survival N = censored 1998-censored 2000-censored 2001-censored 2002-censored 2003-censored 2004-censored 2005-censored Survival Time days 4000

35 Variation in use of hepatic resection for colorectal cancer metastases across English hospitals Percentage of patients receiving a liver resection wi ithin three years of resection of their colorectal primary Morris EJA et al. Brit J Surg 2010; 97: % difference between best and worst performing hospitals! 0.0 Trusts

36 Quality Standards A quality standard is a set of specific, concise statements that: act as markers of high-quality, cost-effective patient care across a pathway / clinical area; are derived from the best available evidence such as NICE guidance or other accredited sources are produced collaboratively along with partners, service users and carers

37 What is the purpose of a Quality Standard? To make it clear what high quality care is by providing definitions of clinical and costeffective care To support benchmarking of performance To provide information to patients and the public about the quality of care they can expect To directly measure the benefit of approved guideline introduction

38 Overview of Quality standards development Topic Evidence Source NICE or other NHS evidence accredited source Requires Generates Guidance Recommendations Distilled into Quality Statements Produce Quality Measures

39 How will quality standards be used? At present Are aspirational but achievable Used to drive up the quality of health care For use by: Patients, carers and the public Health and social care professionals plus public health practitioners Commissioners/payers of healthcare Service providers

40 Mersey and Cheshire Cancer Network patients already survived resection of primary CRC Patients treated with palliative chemotherapy for metastatic CRC Jan Dec 2009 n=110 Jones RP, et al. Br J Surg 2012 Discussed at liver MDT n=37 Not discussed at liver MDT n=73 Radiology reports and imaging requested Liver-only metastatic CRC n=55 Multi-site metastatic CRC n=18

41 Imaging reviewed by 7 liver surgeons at 5 centres Jones RP, et al. Br J Surg 2012; Graeme Poston, Hassan Malik, Steve Fenwick - Aintree Dave Berry - Cardiff Merv Rees - Basingstoke René Adam - Hôpital Paul Brousse, Villejuif Nic Vauthey - M D Anderson, Houston Each patient scored* 1.Easily resectable 2.Complex resectable 3.Borderline resectable 4. Irresectable 5.Unable to comment on scan *Results expressed as waterfall plots

42 100% Non-experts opinions on resectability Jones RP, et al. Br J Surg 2012; Bar plot to illustrate management decisions for each patient Non-resectable 0% Resectable/ potentially resectable All non-experts agreed non-resectable 100% Non-resectable

43 Experts opinions on resectability Jones RP, et al. Br J Surg % Bar plot to illustrate reviewer decisions for each patient Non-resectable Resectable 2 stage resectable Borderline, for downstaging chemotherapy Non-resectable 0% Resectable 100% 55% change in decision from non-resectable to resectable/borderline Kappa score = 0.577

44 Quality Standards for colorectal cancer People with suspected colorectal cancer without major comorbidity are offered colonoscopy to confirm the diagnosis unless contraindicated* People with colon cancer are offered contrast- enhanced CT of the chest, abdomen and pelvis to determine the stage of the disease* People with rectal cancer are offered contrastenhanced CT of the chest, abdomen and pelvis and pelvic MRI to determine the stage of the disease* * Denotes easily measurable metric

45 Quality Standards for colorectal cancer People with rectal cancer are offered a preoperative treatment strategy appropriate to their risk of local disease recurrence* People with locally excised, pathologically confirmed stage I colorectal cancer whose tumour had involved resection margins (less than 1 mm) are offered further active treatment* People with a CT scan suggesting liver metastatic colorectal cancer have their scans reviewed by a surgical member of the hepatobiliary multidisciplinary team [to decide whether further imaging is needed to confirm suitability for surgery or other interventions]* * Denotes easily measurable metric

46 Quality Standards for colorectal cancer People with locally advanced or metastatic colorectal cancer whose disease progresses after first-line systemic anti-cancer therapy are offered second-line systemic anti-cancer therapy if they are able to tolerate it* People free from disease after treatment for colorectal cancer are offered regular surveillance* * Denotes easily measurable metric

47 Conclusions Guidelines are presently aspirational, but in future will be linked to commissioner/purchaser expectations Successful future guidelines identify agreed areas of uncertainty To be of use, guidelines for the management of colorectal cancer need to identify metrics against which their implementation will be judged It is imperative on providers/commissioners of healthcare to: - actively collaborate in/sponsor guideline development - collect measurable outcome data that examine the impact of guideline implementation

48 Conclusions continued Guidelines can be used as a basis of implementing quality standards into healthcare commissioning Purchasers of healthcare (both government and private) can use the metrics of these quality standards to inform contracting of healthcare Failure to achieve these quality standards will lead to the imposition of financial penalties upon the institutions offering such healthcare interventions