Accepted Article
Received Date : 02-Apr-2014 Accepted Date : 16-Apr-2014 Article type
: Systematic Review
National and international guidelines for rectal cancer
Liv Bjerre Juul Nielsen, M.D. Peer Wille-Jørgensen, M.D., Dr. Med. Sci
Digestive Disease Center - K Bispebjerg Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark
Correspondence to Liv Bjerre Juul Nielsen Bodenhoffs Plads, 10, 3. th, 1430 Copenhagen K [email protected]
A systematic review without meta-analysis.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/codi.12678 This article is protected by copyright. All rights reserved.
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Liv Bjerre Juul Nielsen contributed to the manuscript with study conception and design, acquisition of data, analysis and interpretation of data and writing manuscript. Peer Wille-Jørgensen contributed to the manuscript with study conception and design, analysis and interpretation of data and writing manuscript.
Abstract Aim: Rectal cancer is a common malignancy. Differences in daily practice may influence the morbidity and mortality and many national and international organizations have created guidelines for staging and treatment of rectal cancer. Even though consensus is reached within the individual guideline it might not be the case between the guidelines. No formal evaluation of the contrasting guidance has been reported. Method: A systematic search for national and international guidelines on rectal cancer was performed. Eleven guidelines were found for further analysis. Results: There was no consensus concerning the definition of rectal cancer. Ten out of 11 guidelines use the TNM staging system and there was general agreement regarding the recommendation of MRI and CT in rectal
cancer.
There
was
consensus
concerning
a
multidisciplinary
approach,
preoperative
chemoradiotherapy (CRT) and total mesorectal excision (TME). There were no consensus concerning local treatment of T1 tumours, adjuvant therapy and not all the guidelines included metastatic disease and recurrence. There was no consensus on the protocol for follow-up. The guidelines had different approaches to evidence. All referred to evidence but not all considered the level of evidence. Conclusion: The intention of the study was to provide an overview of international guidelines for rectal cancer based on the underlying evidence, but despite hard evidence it was very difficult to come to general conclusions. Despite much knowledge, there is no international consensus on guidelines on the staging and treatment of rectal cancer.
What does this paper add to the literature? The aim of this study was to determine whether there was international consensus on guidelines for the treatment of rectal cancer. This has not been previously described in the literature. The findings show no consensus.
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Introduction Rectal cancer is common in the western world with a high morbidity and mortality. In the European Union its incidence is estimated to 15-25/100000 per annum and the mortality from 4-10/100000 per annum. (1,2) During the last 15 years scientific and practical improvements based on important randomized studies have lead to an improvement in the treatment and overall survival. (3) Differences in daily practice may influence the morbidity and mortality; thus many national and international organizations have created guidelines for staging and treatment of rectal cancer based on that research to shape clinical practice and to develop future programmes and investigational protocols. Even though consensus is reached within the individual guideline it might not be between one guideline and another. No formal evaluation of contrasting guidance has hitherto been reported. Furthermore multidisciplinary management is now standard in most centres dealing with rectal cancer and may have resulted in improved local control, postoperative mortality and even overall survival, but the available studies are not conclusive in this respect. (1,2,3,4,5) The aim of this paper was to determine whether there was consensus internationally concerning guidelines for staging, treatment and follow up for rectal cancer. Thus we wanted to provide an overview of some of the guidelines available.
Method A systematic search for national and international guidelines on rectal cancer has been performed. PubMed have systematically been searched with the keywords “rectum” or “rectal and “cancer” and “guideline*” on October 10th 2013. Cross references, gastrointestinal and surgical society websites have been
searched for additional literature. Only guidelines with clear recommendations were included and only guidelines with a full text version in English or a Nordic language with a publication date within the past ten years were included. Eleven guidelines were found for further analysis in total. (Figure 1). We registered all recommendations and whetheror not these were evidence based and if possible the level of evidence. Results Guidelines In Table 1 an overview of the 11 guidelines and their definition of rectal cancer is presented. We immediately found discrepancies amongst the guidelines on anatomic description and method of assessment
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of the height of the rectal cancer. Four guidelines used 15 cm from the anal verge as a definition for the length of the rectum and two used 12 cm from the anal verge. Six guidelines used rigid proctoscopy to measure the distance and two guidelines measured height of the tumour by MRI.
Staging The guidelines mostly agreed concerning the system of pathological classification. (Table 2) Ten used the TNM (Tumor-Nodes-Metastasis) but not necessarily from the the same edition of the JCC, and some guidelines did not specify the edition. Two guidelines use Haggit’s classification for the small tumours. (6) In UK they used Dukes’ classification as a supplements to TNM and Japan had its own classification. There was general agreement on the imaging that was recommended for staging. All guidelines recommended magnetic resonance imaging (MRI) for T-staging. This provides information on the soft tissue and mesorectal fascia in the mesorectum and is useful in predicting the state of the circumferential margin (CRM) before surgery. (7,8) In ten guidelines endorectal ultrasonography (ERUS) was recommended for small tumours often as a supplement to other methods. ERUS is more specific in the evaluation of muscularis propria invasion and therefore local tumour invasion as in stages T1 and T2. (7) Two of the guidelines recommended computed tomography (CT) as an alternative or supplement to other methods. Nine guidelines recommended CT for disseminated disease (M-status) and one if thea chest x-ray is suspicious. CT should be performed with intravenous and oral contrast. Three guidelines recommended MRI as a supplement for liver lesions and two recommended proton emission tomography (PET) to confirm or exclude metastatic disease. One guideline accepted plain chest X-ray and liver ultrasound (US), as the option for first line staging.
Treatment A multidisciplinary approach to rectal cancer as a preoperative decision-making was widely used, but there was a wide variation in the recommendations for treatment. (Table 3) All guidelines recommended chemoradiotherapy (CRT) as neoadjuvant treatment for some tumours but there was no consensus on the indication for this treatment and there is no consensus regarding short term or long term radiotherapy, dose and the type of chemotherapy.
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Seven guidelines recommend CRT postoperatively if it had not been given preoperatively and if the tumour was at a locoregionally advanced stage. Five guidelines recommended it for stage II and stage III or high risk stage II and stage III di8sease, two for T4 only, CRM positivity or tumour perforation. Three guidelines recommended only chemotherapy as adjuvant treatment. There was no consensus on chemotherapy regimen. All the guidelines agreed in recommending total mesorectal excision (TEM) (9) as the surgical approach for laparoscopic and open surgery. Six guidelines agreed that very low tumours should have abdominoperineal resection (APR) and five that tumours in the upper rectum should have a partial mesorectal excision (PME) with removal of mesorectum for a distance of 5tcm distal to the lower border of the tumour. Eight of the guidelines recommended local excision of small tumours either by endoscopic mucosal resection (EMR) (3) or transanal endoscopic microsurgery (TEM). Only the Japanese guideline recommended pelvic wall lymph node dissection and only in some circumstances. For the treatment of metastasis the guidelines recommended resection for resectable liver and lung metastasis if the primary tumour is resectable, but there was no agreement on the use or regimen of
adjuvant
radiotherapy or chemotherapy. Two guidelines recommended cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinosis, which was described as an effective treatment for peritoneal involvement in colorectal cancer. (10)
Not all the guidelines had a direction on the treatment of locoregional recurrence, but the six which included a recommendation recommended chemotherapy and resection if possible.
Follow up The guidelines did not agree on the protocol of follow up. (Table 3). The principal aim for a follow-up programme was to improve survival. This required that effective treatments are available for recurrent disease and that these should be superior when recurrence is detected at a preclinical stage. (11) Eleven of the guidelines included CT and colonoscopy in the follow up programme,
six included serum
carcinoembryonic antigen (CEA) measurement. There was considerable ariation between the number and the interval of assessments during follow up. Evidence The guidelines hd different approaches to evidence and level of evidence. European Society for Medical Oncology (ESMO) used Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the
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American Society of Clinical Oncology (12) in most of their recommendations. Level I was the highest level and was based on metanalysis or high power randomised trials, recommendation A was based on level 1 evidence or certain parts of levels II-IV. Statements without grading were considered justified standard clinical practice by expert authors and the ESMO faculty. In the guideline 41 recommendations were given a level of evidence. Nine recommendations had evidence level I, 9 level II, 12 level III, 10 level IV and one evidence level V. (13)
EURECA was a Consensus Conference organized with endorsement of the European Society of Medical Oncology, European Society of Surgical Oncology, and European Society of Therapeutic Radiation Oncology. At the conference it is stated whether or not evidence was taken into accounjt for the recommendations, but the level(s) of evidence was (were) not given. (3) The Spanish Society of Medical Oncology (SEOM) based their recommendation on various trials, but did not relate these directly to evidence or level of evidence. (1) Cancer Care Ontario had a programme based on evidence-based care. They referred to evidence in all recommendations and based them on other guidelines and the level of evidence in those guidelines. (14)
All recommendations of the National Comprehensive Cancer Network (NCCN) were category 2A unless otherwise noted. 2A was defined as based upon lower-level evidence, and consensus of the NCCN authors regarding the treatment. Recommendations for the choice of preoperative chemotherapy for T3N0 or TxN+ were category 1, defined as being based on high-level evidence, and consensus of the NCCN authors regarding the treatment. Radiotherapy for patients with limited liver or lung metastasis can be considered in highly selected cases. These recommendation are category 3, defined as being based upon any level of evidence, with no consensus of the NCCN authors regarding the treatment. (15)
The guidelines of the Association of Coloproctology of Great Britain and Ireland relate to level of evidence. They were arrived at using a system designed by the Health Services Research Unit, University of Aberdeen. (16) Every reference was graded as follows: Ia: evidence obtained from meta-analysis of randomised controlled trials. Ib: evidence obtained from at least one randomised controlled trial.
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IIa: evidence obtained from at least one well-designed controlled study without randomisation. IIb: evidence obtained from at least one other type of well-designed quasi-experimental study. III: evidence obtained from well-designed non-experimental descriptive studies such as comparative studies, correlation studies and case studies. IV: evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Recommendations were based on this system and were as follows: Grading A: levels Ia, Ib. Grading B: levels IIa, IIb, and III. Grading C: level IV. Every recommendation carried a grading mark according to this system. Some recommendations covered topics, which were not amenable to formal study, but represented good clinical practice. (16) Of 53 recommendations concerning colorectal cancer nine were level A, 25 level B, 14 level C and 5 represented good clinical practice.
The World Congress on Gastrointestinal Cancer consisted of an expert panel reflecting clinical experience in addition to evidence-based medicine, but the guidelines did not reflect level of evidence. (2) The Japanese Society for Cancer of the Colon and Rectum referred to the evidence and classified it as high-level evidence: meta-analyses of systematic reviews/randomized controlled trials (RCTs) and low-level evidence: case series studies, case studies, expert opinion and clinical experience. The guideline were based on evidence and by a classification of recommendation categories based on consensus reached by the Guideline Committee members. These were as follows: Category A: unanimous recommendations by the Guideline Committee based on high-level evidence, Category B: unanimous recommendations by the Guideline Committee based on lowlevel evidence, Category C: recommendations that were not agreed to completely by the members of the Guideline Committee, irrespective of the level of evidence, Category D: recommendations that were not agreed to by three or more members of the Guideline Committee. Category D recommendations were not included in these Guidelines. (17) In the guideline there were 20 clinical questions with recommendations; six with recommendation level A, 10 with level B and 4 with on level C. The Danish Colorectal Cancer Group (DCCG) related all recommendations to evidence and the level of evidence, (18) using the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grades of Recommendations. (19) DCCG included 124 recommendations in their guideline, 23
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being level A (including 1A, 1B or 1C), 61 level B (including evidence level 2A, 2B, 2C, 3A or 3B), 26 level C (evidence level 4) and 14 level D (evidence level 5). The Norwegian Gastrointestinal Cancer Group related all the recommendations in the guideline to evidence and level of evidence. They used the system designed by the Health Services Research Unit, University of Aberdeen. (16,20) Seven of 35 recommendations were grade A, four were grade B, 11 grade C and 13 grade D. The National Institute for Health and Care Excellence (NICE) quality standards are for use by the NHS (National Health Service) in England and do not have formal status in the social care sector. They ensure that any standard is relevant and evidence-based, but they do not relate standards to the level of evidence. (21) Discussion There is good evidence for some parts of rectal cancer treatments and low level or no evidence in others. The guidelines are partly based on the same evidence, but there is no international consensus when it comes to the treatment of rectal cancer. It is obviously important to use the same classification system for staging rectal cancer, when doctors world wide have to collaborate in the fields of research and development. Even though TNM is the most widely used classification system, there is still no international consensus. In the international literature, there is no consensus on the anatomical description of the rectum and a study has shown that only 50% of a group of US and non-US surgeons agreed on the same surgical definition of the rectum, that of 15 cm from the anal verge. (22). The results of the study show that this is also reflected in the various guideline statements. It should not be difficult to try to establish conformity regarding this essential definition. A consensus meeting of those responsible for the individual Guideline documents should be considered. This might result in much rationalisation of the present variance.
The purpose of locoregional staging of newly diagnosed rectal cancer is to allocate the patient to appropriate management including the use of neoadjuvant therapy and the type of operation. A British study has shown a 94% correlation between MRI assessment and pT-stage. (23) Another study reporting on lymph node staging has shown a sensitivity of up to 85% and a specificity of 97% using morphological criteria, but others have not been able to reproduce these results owing to inter-observer variation with little consistency. (24) Some guidelines recommend ERUS in addition to MRI for T1-T2 tumours, as an accurate method to assess tumour penetration of the rectal wall. It can be used for the selection of patients with an early tumour for local excision. ERUS required operator expertise and only institutions performing over 30 examinations per
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year will have sufficient accuracy. (7,25) CT is widely used for M-status, especially for the diagnosis of liver and lung metastases because of a higher sensitivity to ultrasound, and chest CT X-ray. (26,27) Preoperative radiotherapy has been shown to reduce the recurrence rate by about 50 percent, and there is also consensus on this in all the guidelines. (28,29,30) However, there is no consensus whether it should be given long or short-term, although there may be little difference between them. (31,32) An extensive review has shown that patients with distal or advanced cancers obtain the greatest benefit from long term CRT although there is more acute toxicit, patient convenience and cost. (33) There is no consensus on the choice of adjuvant chemotherapy, but most of guidelines recommend it to include 5-fluorouracil (5-FU).
A follow-up programme should discover recurrence when it is potentially resectable for cure and identify new metachronous neoplasms at a pre-invasive stage. (15) Up to 40 % of curative surgery patients receiving curative surgery get local or metastatic recurrence. 80% of the recurrences occur within the first 3 years with liver and lung as the most frequent localizations. (34) Meta-analyses have shown that an intensive follow-up programme increases survival compared with lowintensity programmes while other studies have shown it is not cost-effective. (35,36,37) Early diagnosis of relapse may be identified by CEA monitoring although there is varying evidence in favour or against its usefulness in improving survival. (38,39) Local pelvic recurrence is often detected by rectal examination, but by this time most are already locally advanced. Thus endoscopy is of limited value in this situation and several randomized studies have shown no convincing effect on survival in such cases, although colonoscopy detects metachronous tumours. (40)
Studies have shown that implementation of evidence based clinical practice in colorectal surgery is a process taking a long time.. (41) The guidelines in this paper are good examples. They all mention evidence, but not all mention level of evidence and grades of recommendation. Furthermore they do not agree on which evidence grading system to use. In some cases recommendations may be made without evidence. The different systems grading
the evidence make it difficult to compare the various guidelines and free
interpretation of evidence in some makes it even more difficult to compare the recommendations of a given guideline with others. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) group is trying to harmonize the grading systems by providing a system for “rating quality of evidence and strength of recommendations that is explicit, comprehensive, transparent, and pragmatic”. (42) Unfortunately many surgeons have little awareness of evidence, with Australian, French and international
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studies showing surgical practice was not governed by evidence for up to half of surgeons. despite hard evidence against their value (41,43,44)
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Table 1 Overview of the guidelines and the definition of rectal cancer
ESMO
EURECACC2
European Society for Medical Oncology 201013
2nd European Rectal Cancer Consensus Conference (EURECA-CC2)
SEOM
Ontario
NCCN
ACPGBI
Spanish society of medical oncology
Cancer care Ontario
National Comprehensive Cancer Network
The Association of Coloproctology of Great Britain and Ireland Guidelines 200716
2008-201214 20101
201215
World Congress on GI Cancer 20072
JSCCR
DCCG
NGICG
NICE - UK
Japanese Society for Cancer of the Colon and Rectum
Danish Coloretal Cancer Group
Norwegian Gastrointestinal Cancer Group.
National Institue for Health and Care Excellence
201220
201121
2010-1318 201217
20093
Rigid sigmoideoscopy with biopsy. Tumour < 15 cm of the anal verge.
Rigid proctoscopy. MRI.
Below peritoneal refluction, tumour 12 cm of the anal verge.
Tumour between the termination of the sigmoid colon, usually at the level of the sacral promontory, and the dentate line.
Tumour within 12 cm of the anal verge on rigid proctoscopy.
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Tumour within 15 cm of the anal verge on rigid proctoscopy. Always biopsy.
CT or MRI: Rectum defined as below the 1st or 2nd sacral vertebra.
NA
Tumour within 15 cm of the anal verge on rigid proctoscopy.
Tumour within 15 cm of the anal verge on rigid proctoscopy.
NA
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Table 2 Staging rectal cancer ESMO
Classificati on
TNM
EURECA
TNM 5th edition
SEOM
TNM 2009
Ontario
TNM
NCCN
TNM 7th edition
ACPGBI
TNM 5th edition Dukes
World congress TNM
T1: Haggit.
T-status
M-status
T1-T2: ERUS
T1-T2: ERUS
T1-T2: ERUS
ERUS
ERUS
ERUS if local excision being considered.
T1-T4: MRI
T1-T4: MRI
T1-T4: MRI
MRI
MRI
MRI
CT chest, abdomen, pelvis.
CT chest, abdomen
Chest: Xray/CT.
Liver/abdomen: CT/MRI/US
Small tumors: ERUS
JSCCR
Japanese Classification of Colorectal Carcinoma 6th edition.
DCCG
NGICG
TNM
TNM
TNM
UICC
Haggits
Dukes
T1: ERUS
T1-T2: ERUS
ERUS if amenable to local excision
T1-T4: MRI
T1-T4: MRI
CT chest, abdomen, as an alternative; liver: MRI or US
CT chest, abdomen, pelvis
MRI
T3: CT-16 slicespiral as alternative
Chest+abd: CT. If liver lesions: MRI.
NICE
MRI
CT
Chest: X-ray if suspect CT CT abdomen
CT. PET if conventional imaging is equivocal for the presence of metastatic disease.
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CT chest, abdomen. PET: rule out or confirm metastases
CT chest abdomen pelvis.
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Table 3 Treatment for rectal cancer
ESMO
EURECA
SEOM
Ontario
NCCN
ACPGBI
World congress
JSCCR
DCCG
NGICG
NICE
MDT conference
Yes
NA
NA
Yes
Yes
Yes
Yes
NA
Yes
Yes
Yes
Neoajuvan t treatment
T2 very low+T3+some T4: 25 Gy short term. T3CRM+ + T4: 50,4 Gy long term + 5FU. Old/comorbid patients: 5X5 Gy
Stage II+III: Short course RCT
T3-T4 or TxN+: RCT
T3-T4 or TxN+: Long term 45-50,4 Gy + 5FU)
T3-T4N0 + TxN1-2M0: Long term 4550 Gy + 5FU/leucovorin (Short-term RT may be an appropriate choice in some situations)
T3-T4N0 + TxN1-2: - Resectable: Short course 25 Gy 5 fractions in 1 week.
T3-T4 and/or N+: Full course RCT 50, 4 Gy. Distal T2N0 should also be considered
cSS/cA or deeper pr cNpositive
Mid-rectum: T4+#3CRM< 5mm. Low: T3+4
T4 or ≤ 2 mm to the mesorectal fascia: 2 Gy X 25 (for elderly 5 Gy X 5 as alternative) + Chemo (capecitabin or nordic FLv)
Threatened (3-T4: TME. T4 with unresectable infiltration: Total pelvic extraction. Upper rectum: PME extending 5 cm below tumor.
T1 colonoscopy and CT.
ACPGBI
Colonoscopy pre or postoperative
World congress
JSCCR
Colonoscopy pre or postoperative
DCCG
NGICG
NICE
Colonoscopy pre or postoperative
Colonoscopy pre or postoperative
Colonoscopy pre or postoperative
CT chest an abdomen after 1 and 3 years. Colonoscopy every 5 years.
CEA every 6 month the first 3 years then after 4, 4,5 and 5 years. CT of abdomen after 6 month and 5 years. CT of the lungs every year in 5 years. US of liver after 1 year and then every 6 month until 4 years after surgery. Colonoscopy after 5 year.
Clinical visit 4-6 weeks after. CEA at least every 6 month in the first 3 years. CT chest, abdomen, pelvis minimum two times in the first 3 years. Colonoscopy after 1 year and then after 5 years. Stop when the benefits no longer outweigh the risks of further tests or when the patient cannot tolerate further treatments.
Alternative CTcolonography or barium enema
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Clean colon every 5 years. CT chest and abdomen once in the 2 first postoperative years.
Clinical examination and CEA every 3-6 month in 3 years. CT of chest and abdomen every 6-12 month for 5 years. Colonoscopy after 1 and 3 years and then after 3-5 years.
Clinical examination and tumor marker every 3 month for 3 years and then every 6 month for 2 years. Digital rectal exam, CT of chest, abdomen and pelvis every 6 month for 3 years and then ones a year for stage III and every 6 month for stage I and II in 2 years. Colonoscopy every year for 3 years.
Accepted Artic
Figure 1. Flowchart.
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Received Date : 02-Apr-2014 Accepted Date : 16-Apr-2014 Article type
: Systematic Review
National and international guidelines for rectal cancer
Liv Bjerre Juul Nielsen, M.D. Peer Wille-Jørgensen, M.D., Dr. Med. Sci
Digestive Disease Center - K Bispebjerg Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark
Correspondence to Liv Bjerre Juul Nielsen Bodenhoffs Plads, 10, 3. th, 1430 Copenhagen K [email protected]
A systematic review without meta-analysis.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/codi.12678 This article is protected by copyright. All rights reserved.
Accepted Article
Liv Bjerre Juul Nielsen contributed to the manuscript with study conception and design, acquisition of data, analysis and interpretation of data and writing manuscript. Peer Wille-Jørgensen contributed to the manuscript with study conception and design, analysis and interpretation of data and writing manuscript.
Abstract Aim: Rectal cancer is a common malignancy. Differences in daily practice may influence the morbidity and mortality and many national and international organizations have created guidelines for staging and treatment of rectal cancer. Even though consensus is reached within the individual guideline it might not be the case between the guidelines. No formal evaluation of the contrasting guidance has been reported. Method: A systematic search for national and international guidelines on rectal cancer was performed. Eleven guidelines were found for further analysis. Results: There was no consensus concerning the definition of rectal cancer. Ten out of 11 guidelines use the TNM staging system and there was general agreement regarding the recommendation of MRI and CT in rectal
cancer.
There
was
consensus
concerning
a
multidisciplinary
approach,
preoperative
chemoradiotherapy (CRT) and total mesorectal excision (TME). There were no consensus concerning local treatment of T1 tumours, adjuvant therapy and not all the guidelines included metastatic disease and recurrence. There was no consensus on the protocol for follow-up. The guidelines had different approaches to evidence. All referred to evidence but not all considered the level of evidence. Conclusion: The intention of the study was to provide an overview of international guidelines for rectal cancer based on the underlying evidence, but despite hard evidence it was very difficult to come to general conclusions. Despite much knowledge, there is no international consensus on guidelines on the staging and treatment of rectal cancer.
What does this paper add to the literature? The aim of this study was to determine whether there was international consensus on guidelines for the treatment of rectal cancer. This has not been previously described in the literature. The findings show no consensus.
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Introduction Rectal cancer is common in the western world with a high morbidity and mortality. In the European Union its incidence is estimated to 15-25/100000 per annum and the mortality from 4-10/100000 per annum. (1,2) During the last 15 years scientific and practical improvements based on important randomized studies have lead to an improvement in the treatment and overall survival. (3) Differences in daily practice may influence the morbidity and mortality; thus many national and international organizations have created guidelines for staging and treatment of rectal cancer based on that research to shape clinical practice and to develop future programmes and investigational protocols. Even though consensus is reached within the individual guideline it might not be between one guideline and another. No formal evaluation of contrasting guidance has hitherto been reported. Furthermore multidisciplinary management is now standard in most centres dealing with rectal cancer and may have resulted in improved local control, postoperative mortality and even overall survival, but the available studies are not conclusive in this respect. (1,2,3,4,5) The aim of this paper was to determine whether there was consensus internationally concerning guidelines for staging, treatment and follow up for rectal cancer. Thus we wanted to provide an overview of some of the guidelines available.
Method A systematic search for national and international guidelines on rectal cancer has been performed. PubMed have systematically been searched with the keywords “rectum” or “rectal and “cancer” and “guideline*” on October 10th 2013. Cross references, gastrointestinal and surgical society websites have been
searched for additional literature. Only guidelines with clear recommendations were included and only guidelines with a full text version in English or a Nordic language with a publication date within the past ten years were included. Eleven guidelines were found for further analysis in total. (Figure 1). We registered all recommendations and whetheror not these were evidence based and if possible the level of evidence. Results Guidelines In Table 1 an overview of the 11 guidelines and their definition of rectal cancer is presented. We immediately found discrepancies amongst the guidelines on anatomic description and method of assessment
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of the height of the rectal cancer. Four guidelines used 15 cm from the anal verge as a definition for the length of the rectum and two used 12 cm from the anal verge. Six guidelines used rigid proctoscopy to measure the distance and two guidelines measured height of the tumour by MRI.
Staging The guidelines mostly agreed concerning the system of pathological classification. (Table 2) Ten used the TNM (Tumor-Nodes-Metastasis) but not necessarily from the the same edition of the JCC, and some guidelines did not specify the edition. Two guidelines use Haggit’s classification for the small tumours. (6) In UK they used Dukes’ classification as a supplements to TNM and Japan had its own classification. There was general agreement on the imaging that was recommended for staging. All guidelines recommended magnetic resonance imaging (MRI) for T-staging. This provides information on the soft tissue and mesorectal fascia in the mesorectum and is useful in predicting the state of the circumferential margin (CRM) before surgery. (7,8) In ten guidelines endorectal ultrasonography (ERUS) was recommended for small tumours often as a supplement to other methods. ERUS is more specific in the evaluation of muscularis propria invasion and therefore local tumour invasion as in stages T1 and T2. (7) Two of the guidelines recommended computed tomography (CT) as an alternative or supplement to other methods. Nine guidelines recommended CT for disseminated disease (M-status) and one if thea chest x-ray is suspicious. CT should be performed with intravenous and oral contrast. Three guidelines recommended MRI as a supplement for liver lesions and two recommended proton emission tomography (PET) to confirm or exclude metastatic disease. One guideline accepted plain chest X-ray and liver ultrasound (US), as the option for first line staging.
Treatment A multidisciplinary approach to rectal cancer as a preoperative decision-making was widely used, but there was a wide variation in the recommendations for treatment. (Table 3) All guidelines recommended chemoradiotherapy (CRT) as neoadjuvant treatment for some tumours but there was no consensus on the indication for this treatment and there is no consensus regarding short term or long term radiotherapy, dose and the type of chemotherapy.
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Seven guidelines recommend CRT postoperatively if it had not been given preoperatively and if the tumour was at a locoregionally advanced stage. Five guidelines recommended it for stage II and stage III or high risk stage II and stage III di8sease, two for T4 only, CRM positivity or tumour perforation. Three guidelines recommended only chemotherapy as adjuvant treatment. There was no consensus on chemotherapy regimen. All the guidelines agreed in recommending total mesorectal excision (TEM) (9) as the surgical approach for laparoscopic and open surgery. Six guidelines agreed that very low tumours should have abdominoperineal resection (APR) and five that tumours in the upper rectum should have a partial mesorectal excision (PME) with removal of mesorectum for a distance of 5tcm distal to the lower border of the tumour. Eight of the guidelines recommended local excision of small tumours either by endoscopic mucosal resection (EMR) (3) or transanal endoscopic microsurgery (TEM). Only the Japanese guideline recommended pelvic wall lymph node dissection and only in some circumstances. For the treatment of metastasis the guidelines recommended resection for resectable liver and lung metastasis if the primary tumour is resectable, but there was no agreement on the use or regimen of
adjuvant
radiotherapy or chemotherapy. Two guidelines recommended cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinosis, which was described as an effective treatment for peritoneal involvement in colorectal cancer. (10)
Not all the guidelines had a direction on the treatment of locoregional recurrence, but the six which included a recommendation recommended chemotherapy and resection if possible.
Follow up The guidelines did not agree on the protocol of follow up. (Table 3). The principal aim for a follow-up programme was to improve survival. This required that effective treatments are available for recurrent disease and that these should be superior when recurrence is detected at a preclinical stage. (11) Eleven of the guidelines included CT and colonoscopy in the follow up programme,
six included serum
carcinoembryonic antigen (CEA) measurement. There was considerable ariation between the number and the interval of assessments during follow up. Evidence The guidelines hd different approaches to evidence and level of evidence. European Society for Medical Oncology (ESMO) used Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the
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American Society of Clinical Oncology (12) in most of their recommendations. Level I was the highest level and was based on metanalysis or high power randomised trials, recommendation A was based on level 1 evidence or certain parts of levels II-IV. Statements without grading were considered justified standard clinical practice by expert authors and the ESMO faculty. In the guideline 41 recommendations were given a level of evidence. Nine recommendations had evidence level I, 9 level II, 12 level III, 10 level IV and one evidence level V. (13)
EURECA was a Consensus Conference organized with endorsement of the European Society of Medical Oncology, European Society of Surgical Oncology, and European Society of Therapeutic Radiation Oncology. At the conference it is stated whether or not evidence was taken into accounjt for the recommendations, but the level(s) of evidence was (were) not given. (3) The Spanish Society of Medical Oncology (SEOM) based their recommendation on various trials, but did not relate these directly to evidence or level of evidence. (1) Cancer Care Ontario had a programme based on evidence-based care. They referred to evidence in all recommendations and based them on other guidelines and the level of evidence in those guidelines. (14)
All recommendations of the National Comprehensive Cancer Network (NCCN) were category 2A unless otherwise noted. 2A was defined as based upon lower-level evidence, and consensus of the NCCN authors regarding the treatment. Recommendations for the choice of preoperative chemotherapy for T3N0 or TxN+ were category 1, defined as being based on high-level evidence, and consensus of the NCCN authors regarding the treatment. Radiotherapy for patients with limited liver or lung metastasis can be considered in highly selected cases. These recommendation are category 3, defined as being based upon any level of evidence, with no consensus of the NCCN authors regarding the treatment. (15)
The guidelines of the Association of Coloproctology of Great Britain and Ireland relate to level of evidence. They were arrived at using a system designed by the Health Services Research Unit, University of Aberdeen. (16) Every reference was graded as follows: Ia: evidence obtained from meta-analysis of randomised controlled trials. Ib: evidence obtained from at least one randomised controlled trial.
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IIa: evidence obtained from at least one well-designed controlled study without randomisation. IIb: evidence obtained from at least one other type of well-designed quasi-experimental study. III: evidence obtained from well-designed non-experimental descriptive studies such as comparative studies, correlation studies and case studies. IV: evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Recommendations were based on this system and were as follows: Grading A: levels Ia, Ib. Grading B: levels IIa, IIb, and III. Grading C: level IV. Every recommendation carried a grading mark according to this system. Some recommendations covered topics, which were not amenable to formal study, but represented good clinical practice. (16) Of 53 recommendations concerning colorectal cancer nine were level A, 25 level B, 14 level C and 5 represented good clinical practice.
The World Congress on Gastrointestinal Cancer consisted of an expert panel reflecting clinical experience in addition to evidence-based medicine, but the guidelines did not reflect level of evidence. (2) The Japanese Society for Cancer of the Colon and Rectum referred to the evidence and classified it as high-level evidence: meta-analyses of systematic reviews/randomized controlled trials (RCTs) and low-level evidence: case series studies, case studies, expert opinion and clinical experience. The guideline were based on evidence and by a classification of recommendation categories based on consensus reached by the Guideline Committee members. These were as follows: Category A: unanimous recommendations by the Guideline Committee based on high-level evidence, Category B: unanimous recommendations by the Guideline Committee based on lowlevel evidence, Category C: recommendations that were not agreed to completely by the members of the Guideline Committee, irrespective of the level of evidence, Category D: recommendations that were not agreed to by three or more members of the Guideline Committee. Category D recommendations were not included in these Guidelines. (17) In the guideline there were 20 clinical questions with recommendations; six with recommendation level A, 10 with level B and 4 with on level C. The Danish Colorectal Cancer Group (DCCG) related all recommendations to evidence and the level of evidence, (18) using the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grades of Recommendations. (19) DCCG included 124 recommendations in their guideline, 23
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being level A (including 1A, 1B or 1C), 61 level B (including evidence level 2A, 2B, 2C, 3A or 3B), 26 level C (evidence level 4) and 14 level D (evidence level 5). The Norwegian Gastrointestinal Cancer Group related all the recommendations in the guideline to evidence and level of evidence. They used the system designed by the Health Services Research Unit, University of Aberdeen. (16,20) Seven of 35 recommendations were grade A, four were grade B, 11 grade C and 13 grade D. The National Institute for Health and Care Excellence (NICE) quality standards are for use by the NHS (National Health Service) in England and do not have formal status in the social care sector. They ensure that any standard is relevant and evidence-based, but they do not relate standards to the level of evidence. (21) Discussion There is good evidence for some parts of rectal cancer treatments and low level or no evidence in others. The guidelines are partly based on the same evidence, but there is no international consensus when it comes to the treatment of rectal cancer. It is obviously important to use the same classification system for staging rectal cancer, when doctors world wide have to collaborate in the fields of research and development. Even though TNM is the most widely used classification system, there is still no international consensus. In the international literature, there is no consensus on the anatomical description of the rectum and a study has shown that only 50% of a group of US and non-US surgeons agreed on the same surgical definition of the rectum, that of 15 cm from the anal verge. (22). The results of the study show that this is also reflected in the various guideline statements. It should not be difficult to try to establish conformity regarding this essential definition. A consensus meeting of those responsible for the individual Guideline documents should be considered. This might result in much rationalisation of the present variance.
The purpose of locoregional staging of newly diagnosed rectal cancer is to allocate the patient to appropriate management including the use of neoadjuvant therapy and the type of operation. A British study has shown a 94% correlation between MRI assessment and pT-stage. (23) Another study reporting on lymph node staging has shown a sensitivity of up to 85% and a specificity of 97% using morphological criteria, but others have not been able to reproduce these results owing to inter-observer variation with little consistency. (24) Some guidelines recommend ERUS in addition to MRI for T1-T2 tumours, as an accurate method to assess tumour penetration of the rectal wall. It can be used for the selection of patients with an early tumour for local excision. ERUS required operator expertise and only institutions performing over 30 examinations per
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Accepted Article
year will have sufficient accuracy. (7,25) CT is widely used for M-status, especially for the diagnosis of liver and lung metastases because of a higher sensitivity to ultrasound, and chest CT X-ray. (26,27) Preoperative radiotherapy has been shown to reduce the recurrence rate by about 50 percent, and there is also consensus on this in all the guidelines. (28,29,30) However, there is no consensus whether it should be given long or short-term, although there may be little difference between them. (31,32) An extensive review has shown that patients with distal or advanced cancers obtain the greatest benefit from long term CRT although there is more acute toxicit, patient convenience and cost. (33) There is no consensus on the choice of adjuvant chemotherapy, but most of guidelines recommend it to include 5-fluorouracil (5-FU).
A follow-up programme should discover recurrence when it is potentially resectable for cure and identify new metachronous neoplasms at a pre-invasive stage. (15) Up to 40 % of curative surgery patients receiving curative surgery get local or metastatic recurrence. 80% of the recurrences occur within the first 3 years with liver and lung as the most frequent localizations. (34) Meta-analyses have shown that an intensive follow-up programme increases survival compared with lowintensity programmes while other studies have shown it is not cost-effective. (35,36,37) Early diagnosis of relapse may be identified by CEA monitoring although there is varying evidence in favour or against its usefulness in improving survival. (38,39) Local pelvic recurrence is often detected by rectal examination, but by this time most are already locally advanced. Thus endoscopy is of limited value in this situation and several randomized studies have shown no convincing effect on survival in such cases, although colonoscopy detects metachronous tumours. (40)
Studies have shown that implementation of evidence based clinical practice in colorectal surgery is a process taking a long time.. (41) The guidelines in this paper are good examples. They all mention evidence, but not all mention level of evidence and grades of recommendation. Furthermore they do not agree on which evidence grading system to use. In some cases recommendations may be made without evidence. The different systems grading
the evidence make it difficult to compare the various guidelines and free
interpretation of evidence in some makes it even more difficult to compare the recommendations of a given guideline with others. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) group is trying to harmonize the grading systems by providing a system for “rating quality of evidence and strength of recommendations that is explicit, comprehensive, transparent, and pragmatic”. (42) Unfortunately many surgeons have little awareness of evidence, with Australian, French and international
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studies showing surgical practice was not governed by evidence for up to half of surgeons. despite hard evidence against their value (41,43,44)
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and
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Table 1 Overview of the guidelines and the definition of rectal cancer
ESMO
EURECACC2
European Society for Medical Oncology 201013
2nd European Rectal Cancer Consensus Conference (EURECA-CC2)
SEOM
Ontario
NCCN
ACPGBI
Spanish society of medical oncology
Cancer care Ontario
National Comprehensive Cancer Network
The Association of Coloproctology of Great Britain and Ireland Guidelines 200716
2008-201214 20101
201215
World Congress on GI Cancer 20072
JSCCR
DCCG
NGICG
NICE - UK
Japanese Society for Cancer of the Colon and Rectum
Danish Coloretal Cancer Group
Norwegian Gastrointestinal Cancer Group.
National Institue for Health and Care Excellence
201220
201121
2010-1318 201217
20093
Rigid sigmoideoscopy with biopsy. Tumour < 15 cm of the anal verge.
Rigid proctoscopy. MRI.
Below peritoneal refluction, tumour 12 cm of the anal verge.
Tumour between the termination of the sigmoid colon, usually at the level of the sacral promontory, and the dentate line.
Tumour within 12 cm of the anal verge on rigid proctoscopy.
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Tumour within 15 cm of the anal verge on rigid proctoscopy. Always biopsy.
CT or MRI: Rectum defined as below the 1st or 2nd sacral vertebra.
NA
Tumour within 15 cm of the anal verge on rigid proctoscopy.
Tumour within 15 cm of the anal verge on rigid proctoscopy.
NA
Accepted Arti
Table 2 Staging rectal cancer ESMO
Classificati on
TNM
EURECA
TNM 5th edition
SEOM
TNM 2009
Ontario
TNM
NCCN
TNM 7th edition
ACPGBI
TNM 5th edition Dukes
World congress TNM
T1: Haggit.
T-status
M-status
T1-T2: ERUS
T1-T2: ERUS
T1-T2: ERUS
ERUS
ERUS
ERUS if local excision being considered.
T1-T4: MRI
T1-T4: MRI
T1-T4: MRI
MRI
MRI
MRI
CT chest, abdomen, pelvis.
CT chest, abdomen
Chest: Xray/CT.
Liver/abdomen: CT/MRI/US
Small tumors: ERUS
JSCCR
Japanese Classification of Colorectal Carcinoma 6th edition.
DCCG
NGICG
TNM
TNM
TNM
UICC
Haggits
Dukes
T1: ERUS
T1-T2: ERUS
ERUS if amenable to local excision
T1-T4: MRI
T1-T4: MRI
CT chest, abdomen, as an alternative; liver: MRI or US
CT chest, abdomen, pelvis
MRI
T3: CT-16 slicespiral as alternative
Chest+abd: CT. If liver lesions: MRI.
NICE
MRI
CT
Chest: X-ray if suspect CT CT abdomen
CT. PET if conventional imaging is equivocal for the presence of metastatic disease.
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CT chest, abdomen. PET: rule out or confirm metastases
CT chest abdomen pelvis.
Accepted Articl
Table 3 Treatment for rectal cancer
ESMO
EURECA
SEOM
Ontario
NCCN
ACPGBI
World congress
JSCCR
DCCG
NGICG
NICE
MDT conference
Yes
NA
NA
Yes
Yes
Yes
Yes
NA
Yes
Yes
Yes
Neoajuvan t treatment
T2 very low+T3+some T4: 25 Gy short term. T3CRM+ + T4: 50,4 Gy long term + 5FU. Old/comorbid patients: 5X5 Gy
Stage II+III: Short course RCT
T3-T4 or TxN+: RCT
T3-T4 or TxN+: Long term 45-50,4 Gy + 5FU)
T3-T4N0 + TxN1-2M0: Long term 4550 Gy + 5FU/leucovorin (Short-term RT may be an appropriate choice in some situations)
T3-T4N0 + TxN1-2: - Resectable: Short course 25 Gy 5 fractions in 1 week.
T3-T4 and/or N+: Full course RCT 50, 4 Gy. Distal T2N0 should also be considered
cSS/cA or deeper pr cNpositive
Mid-rectum: T4+#3CRM< 5mm. Low: T3+4
T4 or ≤ 2 mm to the mesorectal fascia: 2 Gy X 25 (for elderly 5 Gy X 5 as alternative) + Chemo (capecitabin or nordic FLv)
Threatened (3-T4: TME. T4 with unresectable infiltration: Total pelvic extraction. Upper rectum: PME extending 5 cm below tumor.
T1 colonoscopy and CT.
ACPGBI
Colonoscopy pre or postoperative
World congress
JSCCR
Colonoscopy pre or postoperative
DCCG
NGICG
NICE
Colonoscopy pre or postoperative
Colonoscopy pre or postoperative
Colonoscopy pre or postoperative
CT chest an abdomen after 1 and 3 years. Colonoscopy every 5 years.
CEA every 6 month the first 3 years then after 4, 4,5 and 5 years. CT of abdomen after 6 month and 5 years. CT of the lungs every year in 5 years. US of liver after 1 year and then every 6 month until 4 years after surgery. Colonoscopy after 5 year.
Clinical visit 4-6 weeks after. CEA at least every 6 month in the first 3 years. CT chest, abdomen, pelvis minimum two times in the first 3 years. Colonoscopy after 1 year and then after 5 years. Stop when the benefits no longer outweigh the risks of further tests or when the patient cannot tolerate further treatments.
Alternative CTcolonography or barium enema
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Clean colon every 5 years. CT chest and abdomen once in the 2 first postoperative years.
Clinical examination and CEA every 3-6 month in 3 years. CT of chest and abdomen every 6-12 month for 5 years. Colonoscopy after 1 and 3 years and then after 3-5 years.
Clinical examination and tumor marker every 3 month for 3 years and then every 6 month for 2 years. Digital rectal exam, CT of chest, abdomen and pelvis every 6 month for 3 years and then ones a year for stage III and every 6 month for stage I and II in 2 years. Colonoscopy every year for 3 years.
Accepted Artic
Figure 1. Flowchart.
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