Signs and symptoms predictive of colorectal cancer
Systematic review evidence[edit source]
In symptomatic patients without a colorectal cancer diagnosis, what signs or symptoms (persistent changed bowel movements, persistent diarrhoea or constipation, unexplained rectal bleeding, general or localised abdominal pain, unexplained palpable abdominal or rectal mass, unexplained weight loss, iron deficient anaemia, tiredness, fatigue, or any combination) correlate best with a diagnosis of colorectal cancer? (SPT1-2a)
A systematic review of the predictive value of signs and symptoms of colorectal cancer was recently undertaken to inform the UK National Institute for Health and Care Excellence (NICE) guidelines. We updated the NICE systematic review to 31 August 2016, identifying two new relevant papers. The systematic reviews and meta-analyses focused on the positive predictive values of individual symptoms, signs and combinations of symptoms and, where possible, stratified these by age and sex. Some studies also included levels of haemoglobin and markers of iron deficiency from a full blood count.
Due to the nature of the research question, the studies included used mainly case-control and cohort designs and are therefore subject to several biases, including patient selection, non-consecutive patient sampling and missing data, especially in relation to specification of symptoms. All studies were conducted on Western populations, with the majority based on European populations, particularly in the UK. Only one study was conducted in Australia. However, the evidence is likely to be generalisable to the Australian average risk population presenting in primary care.
The NICE guidelines aimed to identify symptoms associated with a positive predictive value of at least 3% to inform selection for urgent referral for investigation of colorectal cancer. This threshold should be compared against the current positive predictive value of 3.5% for a positive immunochemical faecal occult blood test (iFOBT) in the Australian National Bowel Cancer Screening Program. For those patients with symptoms associated with a positive predictive value of below 3%, NICE developed a health economic model to test different diagnostic strategies in primary care. Specifically, they modelled the following tests in people aged 40 years and over with a change in bowel habit:
- faecal occult blood test using guaiac test
- faecal occult blood test using the immunochemical faecal occult blood test (iFOBT)
- barium enema
- flexible sigmoidoscopy
- CT colonography.
At a threshold of GBP20,000 (approximately $40,000) per quality-adjusted life year (QALY), iFOBT was the most cost-effective test in people aged 40 years and over with a change in bowel habit.
For details about this systematic review, please see the Technical report.
Evidence summary and recommendations[edit source]
|Rectal bleeding presenting in primary care was associated with a PPV for colorectal cancer of up to 4.8% (95% CI 3.3 to 6.8). This PPV tended to increase with age in both men and women.||II, III-2, III-3||, , , , , , , , , , , , , , |
|Abdominal pain presenting in primary care was associated with a PPV for colorectal cancer of up to 2.0% (95% CI 0.5 to 7.6). This PPV tended to increase with age in both men and women.||III-2, III-3||, , , |
|Anaemia* presenting in primary care was associated with a PPV for colorectal cancer of up to 5.8% (95% CI 2.6 to 12.0). This PPV tended to increase with age in both men and women.
Two new studies since the meta-analysis estimated the PPV for anaemia in referred populations as 10.2% (95% CI 4.6 to 17.3) and 12.0% (95% CI 8.0 to 16.0).
|II, III-2, III-3, IV||, , , , , , |
|Weight loss presenting in primary care was associated with a PPV for colorectal cancer of up to 3% (95% CI 0.3 to 22.9). This PPV tended to increase with age in both men and women.
One new study since the meta-analysis estimated the PPV for weight loss in a referred population as 5.2% (95% CI 2.5 to 9.2).
|II, III-2, III-3||, , |
|Dyspepsia presenting in primary care was associated with a PPV for colorectal cancer of up to 0.6% (95% CI 0.3 to 1.4).||III-2||, , |
* The available data did not allow clear distinction between iron-deficiency and non-iron deficiency anaemia. PPV: positive predictive value; CI: confidence interval
Individual studies[edit source]
|Constipation presenting in primary care in two studies was associated with a PPV for colorectal cancer of 0.4–2.5%. In one further small study in selected patients the estimated PPV was 15.7% (95% CI 10.2 to 23.2).||II, III-2, III-3||, , |
|Change in bowel habit presenting in primary care in two studies was associated with a PPV for colorectal cancer of 2.8–2.9%. This PPV tended to increase with age in both men and women. In one further small study in selected patients the estimated PPV was 14% (95% CI 6.7 to 23.3).||III-2||, , |
PPV: positive predictive value; CI: confidence interval
Combination of symptoms[edit source]
|Nine studies that examined the PPVs for rectal bleeding in combination with other symptoms reported wide-ranging estimates. Some studies reported other combinations of symptoms.
Combinations associated with higher estimated PPVs included:
Several of the estimates from these studies are likely to be artificially inflated due to small numbers of participants with specific combinations of symptoms.
|III-2, III-3, IV||, , , , , , , , |
PPV: positive predictive value; CI: confidence interval
Combinations of symptoms and baseline risk factors predicting prevalent cancer[edit source]
The QCancer colorectal cancer risk prediction model incorporates the following variables for men and women to calculate positive predictive values for combinations of multiple symptoms and baseline risk factors:
- Women: age, family history of gastrointestinal cancer, abdominal pain, appetite loss, rectal bleeding, weight loss, anaemia (< 11 g/dL).
- Men: age, family history of gastrointestinal cancer, alcohol consumption, abdominal pain, appetite loss, rectal bleeding, weight loss, anaemia (< 11 g/dL), change in bowel habit.
On internal validation the QCancer model showed good discrimination; the area under receiver operating curve (ROC) statistics were 0.89 for women and 0.91 for men. In an independent external validation study the ROC statistics were 0.92 for women and 0.91, and the risk prediction model explained 68% and 66% of the variation in women and men, respectively.
Consensus-based colonoscopy triage categories[edit source]
Table 10.1 presents triage categories to determine urgency and need for colonoscopy based on symptom profile, patient age and results from investigations available in primary care.
The guideline development group applied evidence about the predictive value of individual and combinations of symptoms, including allowance for patient age, to inform the development of colonoscopy triage categories. They build on Victorian draft guidelines for colonoscopy triage. The guideline development group discussed the use of additional investigations in primary care to support triage which had been informed by the NICE guidelines and had undergone extensive expert consultation.
In addition to its traditional use as a screening test in asymptomatic patients, iFOBT is potentially useful for assessing risk in symptomatic patients, especially those who have not recently participated in the NBCSP. In addition to the NICEmodelling study (see Systematic review evidence), we considered new evidence about the use of iFOBT and calprotectin in patients with bowel symptoms referred from primary care. This demonstrated that a negative iFOBT can be useful in ruling out significant bowel disease, including colorectal cancer. The study also showed that faecal calprotectin is a useful test in distinguishing patients with inflammatory bowel disease (IBD) and irritable bowel syndrome, consistent with international guidance on using this test to rule out IBD.
The guideline development group also discussed the role of CT colonography as an alternative investigation. CT colonography has high sensitivity for colorectal cancer and could potentially be used therefore to rule out this diagnosis in patients with bowel symptoms. CT colonography may be considered as an alternative diagnostic test, particularly in the following scenarios:
- Individuals with symptoms of colorectal cancer below the 3% CRC risk threshold.
- Individuals in areas with limited access to colonoscopy services but where there is access to CT.
- Individuals who have contra-indications to colonoscopy.
The New Zealand Society of Gastroenterology recommends CT colonography as an alternative to colonoscopy in: symptomatic patients over 80 years, individuals with an abdominal mass, and in those at higher risk of complications from colonoscopy. It should be noted that in the NICE modelling study of alternative testing strategies in individuals with symptoms of colorectal cancer below the 3% risk threshold, iFOBT was the most cost-effective investigation to support triage of referrals for colonoscopy. This modelling was set in a UK healthcare context and did not consider issues of differential access to colonoscopy and CT colonography.
Under current Medicare eligibility rules, GPs can only request CT colonography if a patient has had an incomplete colonoscopy in the previous 3 months or there is a contraindication to colonoscopy. This creates a significant barrier to its use in Australian primary care as an alternative test to colonoscopy in symptomatic individuals. It can be requested by a specialist ‘for exclusion of colorectal neoplasia in a symptomatic or high risk patient’, and therefore may have a potential role in triage for a colonoscopy triage setting.
Table 10.1. Colonoscopy triage categories[edit source]
|Category 1||Category 2||Category 3||No colonoscopy indicated|
|Positive immunochemical faecal occult blood test (iFOBT) (asymptomatic)|
|Anaemia and any one of:
||Anaemia and all of:
||Anaemia and all of:
||Anaemia and all of:
|Rectal bleeding < 12 months and any one of:
||Rectal bleeding < 12 months and all of:
||Rectal bleeding ≥ 12 months and all of:
||Rectal bleeding ≥ 12 months and all of:
|Altered bowel habit > 6/52 and any one of:
||Altered bowel habit > 6/52 and all of:
||Altered bowel habit > 6/52 and either:
|Unexplained abdominal pain and any one of:
||Unexplained abdominal pain and all of:
||Unexplained abdominal pain and either:
|A resolved episode of acute abdominal pain**
or Diverticulitis with typical CT features and no other GI symptoms
|Unexplained weight loss and any one of:
||Unexplained weight loss and all of:
||Unexplained weight loss and all of:
|Mass palpable on abdominal or rectal examination or on rigid sigmoidoscopy|
Source: Victorian Colonoscopy Categorisation Guidelines
GI: gastrointestinal; > 6/52: symptom present for more than 6 weeks per episode; CT: computed tomography NB. Faecal calprotectin is a useful test in distinguishing patients with inflammatory bowel disease and irritable bowel syndrome, but has no role in detecting colorectal cancer. There is currently no Medicare Benefits Scheme (MBS) rebate for calprotectin.
**Abdominal pain present for less than 5 weeks should be assessed and treated, with consideration of colonoscopy if no response.
In people with symptoms other than overt rectal bleeding, immunochemical faecal occult blood testing (iFOBT) can be used as part of the diagnostic assessment in primary care.
Benefits and harms[edit source]
The recommendations aim to support a rational process to determine the urgency of colonoscopies, particularly in the context of long waiting lists for colonoscopy in the public hospital system. It should be noted that no symptoms are strongly predictive of colorectal cancer, nor are there any symptoms which rule out cancer. Thus it remains possible that even patients in Category 3, who have ‘low risk but not no risk’ symptoms, may eventually be diagnosed with colorectal cancer. Those patients who do not meet criteria for colonoscopy should be reviewed by their GP and reconsider the need for investigation if new symptoms or signs have developed.
Health system implications[edit source]
Clinical practice[edit source]
The triage categories, while moderately complex, are designed for use by endoscopy units to assess the urgency of referrals for colonoscopy. GPs should apply this evidence to inform their use of simple investigations in primary care (full blood count, iron studies and iFOBT) as part of their assessment of patients with symptoms suggestive of colorectal cancer. It should also be noted which patients are identified in this guideline as not requiring referral for colonoscopy.
Health services and endoscopy units should consider implementing specific GP referral proformas designed to capture the information needed to apply the triage criteria.
Endoscopy units may need dedicated staff to apply the triage criteria consistently.
Barriers to implementation[edit source]
Primary Health Networks should support this implementation in general practice as part of the national Optimal Care Pathways for colorectal cancer.
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Unresolved issues[edit source]
Timely diagnosis of colorectal cancer is important for improving survival. The triage criteria are designed to improve the efficiency of the referral and triage processes for people with symptoms suggestive of colorectal cancer, but further evidence is required on the impacts of their implementation.
Studies currently underway[edit source]
The Victorian colonoscopy guidelines are currently being piloted to assess their feasibility of implementation.
Future research priorities[edit source]
Further research is needed to determine how best to reduce missed opportunities for colorectal cancer diagnosis in primary care, applying the evidence about symptoms as predictors of colorectal cancer risk.
The colonoscopy triage criteria are based on current best evidence. The following further research is needed to evaluate their implementation:
- prospective, comparative validation studies measuring clinical outcomes
- studies assessing the impact on waiting times, diagnostic intervals and colorectal cancer outcomes.
See also: Optimal maximum time from referral to diagnosis and treatment.
Next section: optimal max time from referral to diagnosis and treatment
- ↑ 1.0 1.1 1.2 1.3 National Institute for Health and Care Excellence. Suspected cancer: referral and recognition. National Collaborating Centre for Cancer; 2015 Available from: https://www.nice.org.uk/guidance/ng12.
- ↑ 2.0 2.1 Rodríguez-Alonso L, Rodríguez-Moranta F, Ruiz-Cerulla A, Lobatón T, Arajol C, Binefa G, et al. An urgent referral strategy for symptomatic patients with suspected colorectal cancer based on a quantitative immunochemical faecal occult blood test. Dig Liver Dis 2015 Sep;47(9):797-804 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26055489.
- ↑ Chowdhury ATMD, Longcroft-Wheaton G, Davis A, Massey D, Goggin P. Role of faecal occult bloods in the diagnosis of iron deficiency anaemia. Frontline Gastroenterology 2014 Oct 1;5(4):231-36.
- ↑ 4.0 4.1 4.2 Mant, A. Bokey, E. L. Chapuis, P. H. Killingback, M. Hughes, W. Koorey, S. G. Cook, I. Goulston, K. J. Dent, O. F.. Rectal bleeding. Do other symptoms aid in diagnosis? Dis Colon Rectum 1989;32(3): 191-196.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Collins GS, Altman DG. Identifying patients with undetected colorectal cancer: an independent validation of QCancer (Colorectal). Br J Cancer 2012 Jul 10;107(2):260-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22699822.
- ↑ du Toit J, Hamilton W, Barraclough K. Risk in primary care of colorectal cancer from new onset rectal bleeding: 10 year prospective study. BMJ 2006 Jul 8;333(7558):69-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16790459.
- ↑ 7.0 7.1 Ellis BG, Thompson MR. Factors identifying higher risk rectal bleeding in general practice. Br J Gen Pract 2005 Dec;55(521):949-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16378565.
- ↑ 8.0 8.1 Fijten GH, Starmans R, Muris JW, Schouten HJ, Blijham GH, Knottnerus JA. Predictive value of signs and symptoms for colorectal cancer in patients with rectal bleeding in general practice. Fam Pract 1995 Sep;12(3):279-86 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8536830.
- ↑ Helfand M, Marton KI, Zimmer-Gembeck MJ, Sox HC Jr. History of visible rectal bleeding in a primary care population. Initial assessment and 10-year follow-up. JAMA 1997 Jan 1;277(1):44-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8980209.
- ↑ 10.0 10.1 10.2 10.3 10.4 Hippisley-Cox J, Coupland C. Identifying patients with suspected colorectal cancer in primary care: derivation and validation of an algorithm. Br J Gen Pract 2012 Jan;62(594):e29-37 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22520670.
- ↑ Jones R, Latinovic R, Charlton J, Gulliford MC. Alarm symptoms in early diagnosis of cancer in primary care: cohort study using General Practice Research Database. BMJ 2007 May 19;334(7602):1040 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17493982.
- ↑ 12.0 12.1 Metcalf JV, Smith J, Jones R, Record CO. Incidence and causes of rectal bleeding in general practice as detected by colonoscopy. Br J Gen Pract 1996 Mar;46(404):161-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8731622.
- ↑ 13.0 13.1 Norrelund N, Norrelund H. Colorectal cancer and polyps in patients aged 40 years and over who consult a GP with rectal bleeding. Fam Pract 1996 Apr;13(2):160-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8732328.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Panzuto, F. Chiriatti, A. Bevilacqua, S. Giovannetti, P. Russo, G. Impinna, S. Pistilli, F. Capurso, G. Annibale, B. Delle Fave, G.. Symptom-based approach to colorectal cancer: survey of primary care physicians in Italy. Dig Liver Dis 2003;35(12): 869-875.
- ↑ Parker C, Hippisley-Cox J, Coupland C, Vinogradova Y. Rectal and postmenopausal bleeding: consultation and referral of patients with and without severe mental health problems. Br J Gen Pract 2007 May;57(538):371-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17504587.
- ↑ 16.0 16.1 Robertson R, Campbell C, Weller DP, Elton R, Mant D, Primrose J, et al. Predicting colorectal cancer risk in patients with rectal bleeding. Br J Gen Pract 2006 Oct;56(531):763-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17007706.
- ↑ 17.0 17.1 Wauters H, Van Casteren V, Buntinx F. Rectal bleeding and colorectal cancer in general practice: diagnostic study. BMJ 2000 Oct 21;321(7267):998-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11039968.
- ↑ Heintze C, Matysiak-Klose D, Kröhn T, Wolf U, Brand A, Meisner C, et al. Diagnostic work-up of rectal bleeding in general practice. Br J Gen Pract 2005 Jan;55(510):14-9; discussion 18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15667760.
- ↑ Bellentani, S. Baldoni, P. Petrella, S. Tata, C. Armocida, C. Marchegiano, P. Saccoccio, G. Manenti, F.. A simple score for the identification of patients at high risk of organic diseases of the colon in the family doctor consulting room. The Local IBS Study Group. Fam Pract 1990;7(4): 307-312.
- ↑ Droogendijk J, Beukers R, Berendes PB, Tax MG, Sonneveld P, Levin MD. Screening for gastrointestinal malignancy in patients with iron deficiency anemia by general practitioners: an observational study. Scand J Gastroenterol 2011 Sep;46(9):1105-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21726115.
- ↑ Farrus Palou, M. Perez Ocana, A. Mayer Pujadas, M. A. Piquer Gibert, M. Mundet Tuduri, X. Iglesias Rodal, M.. Anemia in primary care: etiology and morphological characteristics. Aten Primaria 2000;25(4): 230-235.
- ↑ Lucas CA, Logan EC, Logan RF. Audit of the investigation and outcome of iron-deficiency anaemia in one health district. J R Coll Physicians Lond 1996 Jan;30(1):33-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8745360.
- ↑ Stellon AJ, Kenwright SE. Iron deficiency anaemia in general practice: presentations and investigations. Br J Clin Pract 1997 Mar;51(2):78-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9158249.
- ↑ Yates JM, Logan EC, Stewart RM. Iron deficiency anaemia in general practice: clinical outcomes over three years and factors influencing diagnostic investigations. Postgrad Med J 2004 Jul;80(945):405-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15254305.
- ↑ Hallissey MT, Allum WH, Jewkes AJ, Ellis DJ, Fielding JW. Early detection of gastric cancer. BMJ 1990 Sep 15;301(6751):513-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2207416.
- ↑ Heikkinen M, Pikkarainen P, Takala J, Räsänen H, Julkunen R. Etiology of dyspepsia: four hundred unselected consecutive patients in general practice. Scand J Gastroenterol 1995 Jun;30(6):519-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7569757.
- ↑ 27.0 27.1 Meineche-Schmidt V, Jørgensen T. 'Alarm symptoms' in patients with dyspepsia: a three-year prospective study from general practice. Scand J Gastroenterol 2002 Sep;37(9):999-1007 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12374244.
- ↑ 28.0 28.1 Hamilton W, Round A, Sharp D, Peters TJ. Clinical features of colorectal cancer before diagnosis: a population-based case-control study. Br J Cancer 2005 Aug 22;93(4):399-405 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16106247.
- ↑ Mowat C, Digby J, Strachan JA, Wilson R, Carey FA, Fraser CG, et al. Faecal haemoglobin and faecal calprotectin as indicators of bowel disease in patients presenting to primary care with bowel symptoms. Gut 2016 Sep;65(9):1463-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26294695.
- ↑ National Institute for Health and Care Excellence. Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel. UK: NICE; 2013 Available from: https://www.nice.org.uk/guidance/dg11.
- ↑ Johnson CD, Chen MH, Toledano AY, Heiken JP, Dachman A, Kuo MD, et al. Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med 2008 Sep 18;359(12):1207-17 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18799557.
- ↑ de Haan MC, Pickhardt PJ, Stoker J. CT colonography: accuracy, acceptance, safety and position in organised population screening. Gut 2015 Feb;64(2):342-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25468258.
- ↑ Halligan S, Altman DG, Taylor SA, Mallett S, Deeks JJ, Bartram CI, et al. CT colonography in the detection of colorectal polyps and cancer: systematic review, meta-analysis, and proposed minimum data set for study level reporting. Radiology 2005 Dec;237(3):893-904 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16304111.
- ↑ New Zealand Society of Gastroenterology. NZSG recommendations for the use of Computerised Tomographic Colonography (CTC) and Colonoscopy in investigations of GI disease.; 2015 Available from: http://www.nzsg.org.nz/cms2/uploads/Position%20Statement%20on%20CTC.pdf.
- ↑ Victorian Department of Health and Human Services. Victorian colonoscopy categorisation guidelines.; 2016.
- ↑ Akbari A, Mayhew A, Al-Alawi MA, Grimshaw J, Winkens R, Glidewell E, et al. Interventions to improve outpatient referrals from primary care to secondary care. Cochrane Database Syst Rev 2008 Oct 8;(4):CD005471 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18843691.
- ↑ Cancer Council Victoria. Optimal care pathway for people with colorectal cancer.; 2014 Available from: www.cancer.org.au/ocp.