Colorectal cancer

Optimal maximum time from referral to diagnosis and treatment

From Cancer Guidelines Wiki

Background[edit source]

Intuitively, it would be expected that diagnosing cancer quickly would be beneficial, as tumours grow and are more likely to metastasise with time. Indeed, perception of a ‘delayed diagnosis’ of cancer is a leading cause of medicolegal complaints in primary and ambulatory care, on the assumption that harm occurred as a result of late diagnosis.[1]

The diagnostic pathway[edit source]

So-called delays in cancer diagnosis can occur at various points along the diagnostic pathway.[2] Patients may take time appraising their symptoms before seeking healthcare, they may experience multiple visits to their GP about their symptoms before referral for specialist diagnostic tests,[3] and there may be long waiting times to access these diagnostic tests. This latter point along the diagnostic pathway, from GP referral to diagnosis, is the focus of this section.

Access to timely colonoscopy is an important contributor to the overall diagnostic interval for colorectal cancer (defined usually as the time a patient first presents to healthcare until the time of diagnosis).[4]

Methodological issues[edit source]

Proving that earlier detection of symptomatic cancer matters is epidemiologically challenging, the ‘waiting time paradox’ describes the phenomenon in which patients with late stage cancers present with severe symptoms and are therefore often diagnosed promptly, but have poorer outcomes.[5] This type of confounding by indication is an important source of bias in studies examining the effect of time to diagnosis on outcomes in symptomatic cancer populations. Many studies that have examined associations between the diagnostic interval and clinical outcomes have assumed a linear relationship between time to diagnosis and mortality. Their analyses, therefore, have not accounted for potential effects of the waiting time paradox. More recent studies have introduced the use of spline regression to allow for flexible associations between the diagnostic interval and clinical outcome.[6][7] These important methodological considerations must be taken into account when interpreting the evidence, which includes apparently inconsistent findings. When making recommendations, we applied greater weight to studies that attempted to account for the waiting time paradox.

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Systematic review evidence[edit source]

In symptomatic patients without a colorectal cancer diagnosis, what is the optimal maximum diagnostic interval that achieves better than or equivalent outcomes in terms of survival, mortality, and diagnosis of metastatic disease? (SPT1-2b)

Nine studies[8][9][10][7][6][11][12][13][14] examined the effect of the diagnostic interval on colorectal cancer related outcomes including mortality, cancer specific survival and mortality, and stage of tumour at diagnosis. Seven studies[8][9][10][6][7][11][12] had a moderate risk of bias and two had a high risk of bias.[13][14]

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

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Mortality[edit source]

A Canadian retrospective cohort study[10] found that diagnostic interval had no significant effect of diagnostic interval length on colorectal cancer mortality with 1–6 years follow-up.

Danish prospective population-based cohort studies in primary care,[7][11] a UK retrospective cohort study,[9] and a study that included one retrospective and two prospective primary care cohort studies conducted in Denmark and the UK[6] reported significantly higher 3- and 5-year mortality rates associated with shorter waiting periods (all < 1 month). These findings are consistent with the ‘waiting time paradox’ where patients with severe symptoms associated with later stage disease are diagnosed promptly.

Three Danish and UK primary care cohort studies[6] reported U-shaped associations between diagnostic interval and overall mortality (at 3 or 5 years) using spline regression analyses. Analysis of combined datasets found that higher 5-year mortality was associated with diagnostic intervals greater than 130 days (HR=1.28 95% CI 1.28-1.55).

A large US retrospective study of > 9,000 patients diagnosed with colorectal cancer between 1998 and 2005[8] found that, for patients with colon cancer only, diagnostic intervals of ≥ 8 months compared with 14–59 days showed a significant effect on overall mortality (OR 1.31, 95% CI 1.08 to 1.58). For local stage rectal cancer, mortality was higher for diagnostic intervals < 2 weeks and 2–4 months, compared with 14–59 days, consistent with the U-shaped associations demonstrated in UK and Danish populations.[6][7][11]

Colorectal cancer-specific mortality[edit source]

In an analysis of a large US dataset of medical records for adults aged ≥ 66 years with invasive colon or rectal cancer, colorectal cancer-specific mortality was reported separately for patients diagnosed with either colon cancer or rectal cancer.[8] For those diagnosed with colon cancer, in unadjusted analysis, higher mortality was reported for shorter diagnostic delay (< 2 weeks), compared with 14–59 days (OR 1.27, p < 0.05). Significantly higher mortality was reported when comparing short diagnostic interval (14–59 days) with longer diagnostic intervals of 4–8 months and ≥ 8 months (OR 0.76, p < 0.05, and OR 0.82, p < 0.05, respectively), thus failing to demonstrate any evidence of a U-shaped association between interval and colorectal cancer-specific mortality.

A cohort study comparing outcomes in patients with early and late diagnosis[14] reported significantly higher 5-year cancer-specific survival for a diagnostic interval ≥ 50 days compared with < 50 days when all participants were included in the analysis (94% versus 73%, respectively, p = 0.007).[14] No attempt was made to account for the waiting time paradox in this study.

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Tumour stage at diagnosis[edit source]

Four studies[12][13][14][10] examined associations between diagnostic intervals and tumour stage but only one[10] conducted analyses to account for a potential waiting time paradox.

A retrospective cohort study[12] compared stages for three interval cut-offs (> 41 days, > 60 days, > 90 days), assuming a linear effect of time. Shorter intervals were associated with more advanced stage disease.[12]

Another retrospective cohort study[13] reported shorter diagnostic intervals were associated with earlier stages of cancer, however this effect was non-significant.[13]

A cohort study comparing outcomes in patients with early and late diagnosis[14] reported greater rates of Dukes’ stage A cancer in participants with a diagnostic interval ≥ 50 days (57.1%) compared with < 50 days (15.2%, p = 0.006).[14]

A large Canadian retrospective cohort study[10] reported higher rates of stage III/IV colorectal cancer for participants with a diagnostic interval < 15 days compared with 51 to < 116 days or ≥ 116 days (OR 0.59, CI 0.39 to 0.89 and OR 0.50, CI 0.33 to 0.75, respectively) but not 15 to < 51 days, consistent with a U-shaped association between diagnostic interval and clinical outcome.[10]

Summary[edit source]

The studies that performed analyses to account for the waiting time paradox found potentially important U-shaped associations between diagnostic intervals and (1) overall mortality[6][7][11][8] and (2) late-stage disease at diagnosis,[10] but not colorectal cancer-specific mortality[8]

The following cut-off intervals for first presentation to healthcare to diagnosis were associated with poorer outcomes:

  • 130 days in the largest study combining three datasets from Danish and UK primary care cohorts[6]
  • 8 months (approximately 243 days) in a large US retrospective study[8]
  • 116 days in a Canadian retrospective study from population-based cancer registry and administrative database.[10]

In the Australian setting, the presentation–diagnosis interval would most commonly represent the time from GP consultation to diagnostic colonoscopy (or other diagnostic procedure) in specialist care.

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Evidence summary and recommendations[edit source]

Evidence summary Level References
Analyses of cohort data have reported U-shaped associations between diagnostic interval and (1) overall mortality and (2) late-stage disease at diagnosis, but not colorectal cancer-specific mortality. III-2 [11], [7], [6], [8], [10]
Diagnostic interval cut-off points associated with poorer outcomes range between 116 days and 8 months. III-2 [6], [8], [10]
Evidence-based recommendationQuestion mark transparent.png Grade
For patients with symptoms suggestive of colorectal cancer, the total time from first healthcare presentation to diagnostic colonoscopy should be no more than 120 days. Diagnostic intervals greater than 120 days are associated with poorer clinical outcomes.

First healthcare presentation is defined as the date of presentation in general practice with symptoms suggestive of colorectal cancer or positive iFOBT for screening.

Evidence-based recommendationQuestion mark transparent.png Grade
A diagnostic interval of 120 days should be the maximum time from first healthcare presentation to diagnostic colonoscopy for triage Categories 1 and 2, whether it is for a patient with symptoms or after a positive iFOBT used for colorectal cancer screening. Diagnostic intervals greater than 120 days are associated with poorer clinical outcomes.

First healthcare presentation is defined as the date of presentation in general practice with symptoms suggestive of colorectal cancer or positive iFOBT for screening.


Consensus-based recommendationQuestion mark transparent.png

Triage category 1 patients, whether due to symptoms or positive iFOBT, should continue to be considered most urgent and prioritised for diagnostic colonoscopy, in any model of care at any jurisdictional level.

Practice pointQuestion mark transparent.png

Colonoscopy for symptomatic patients should be performed as promptly as possible after referral from general practice, especially for those meeting triage Category 1 criteria. If cancer is present, there is no evidence that prognosis is worsened within 120 days from first presentation to diagnostic colonoscopy. However, performing colonoscopy as promptly as possible after referral from general practice is to minimise the risk of psychological harm in symptomatic or iFOBT-positive patients who are potentially anxious while awaiting investigation. Prompt scheduling will also help to ensure that any unexpected delays between general practice referral and colonoscopy triaging do not flow on to exceed the 120-day threshold after which prognosis can worsen if cancer is present.

Considerations in making these recommendations[edit source]

These recommendations are based on the consensus of the guideline development group and interpretation of the best available evidence. There will of course never be Level I evidence to inform these recommendations as RCTs of different diagnostic intervals would be deemed unethical. A maximum diagnostic interval of 120 days from first presentation to healthcare (first healthcare presentation is defined as the date of presentation in general practice with symptoms suggestive of colorectal cancer or positive iFOBT for screening) to diagnosis should be the target to prevent poorer outcomes in those with colorectal cancer. We noted the current recommendation in the Optimal care pathway[15] for colorectal cancer of a maximum of four weeks from referral to colonoscopy for people with symptoms suggestive of colorectal cancer. Recognising that there will be a small proportion of people with colorectal cancer in triage Category 2 (approximately 1-2%), we recommend that all Category 1 and Category 2 colonoscopies (screen positive iFOBT or symptomatic patients) should be performed no later than 120 days from first presentationi to healthcare. Ideally colonoscopy should be performed sooner than this to reduce the risk of psychological harm to patients.[16][17]

The Working Party and subcommittee members had robust discussion regarding the maximum optimal time from first healthcare presentation to diagnostic colonoscopy and treatment. Although the group was in agreement about the interpretation of the systematic review evidence, there was concern about de-emphasising the need for prompt evaluation. The Working Party acknowledges that the guideline may be read with the expectation that it will assist in triage of colonoscopy patients. The authors resolved it was appropriate to maintain the evidence-based recommendations, acknowledging the grade and limitations of the available evidence, but also add the practice point about the ideal interval for symptomatic patients. Given the unavoidable delays along the pathway, all people with a positive iFOBT or with symptoms suggestive of colorectal cancer should have a colonoscopy as promptly as possible.

i Date of first presentation is defined as the positive screening iFOBT.

Benefits and harms[edit source]

There is evidence to suggest that a greater proportion of the diagnostic interval occurs from the point of referral to colonoscopy, rather than in primary care, especially where there is poorer access to colonoscopy. While recognising the current challenges of meeting demand in public health endoscopy services, the guideline development group recommended a target diagnostic interval of a maximum of 120 days from first presentation to healthcare (first healthcare presentation is defined as the date of presentation in general practice with symptoms suggestive of colorectal cancer or positive iFOBT for screening) for all patients meeting either Category 1 or Category 2 criteria.

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Health system implications[edit source]

Clinical practice[edit source]

GPs will need to remain alert to the possibility of colorectal cancer as a possible cause of a patient’s symptoms and investigate and refer promptly based on the evidence summarised in the previous section.

Resourcing[edit source]

Endoscopy services will need to establish clear diagnostic pathways for patients with suspected colorectal cancer and establish systems to apply the triage criteria and organise timely colonoscopy. Meeting a 120 day target from first presentation for all Category 1 and Category 2 will have significant resource implications for some public hospital endoscopy services.

Barriers to implementation[edit source]

These recommendations are made in the context of the roll-out of the NBCSP, due to be fully implemented by 2020 which will place additional demand for colonoscopy. We acknowledge the challenges of measuring this target given that the evidence is based on the diagnostic interval commencing at the time of first presentation to healthcare. In order to monitor the 120 day diagnostic interval target, referrals will need to record the date of first presentation to healthcare with symptoms suggestive of colorectal cancer. We recognise that this may be logistically challenging to collect and recommend that this information is collected within the standardised GP referral proforma[18] (see Resourcing).

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Discussion[edit source]

Unresolved issues[edit source]

Timely diagnosis of colorectal cancer is important for improving survival. While there are inevitable limitations in defining the optimal maximum time to diagnose someone with suspected colorectal cancer, we have applied the current best evidence to make our recommendations. The triage criteria and associated maximum intervals for colonoscopy in Category 1 and 2 patients are designed to improve the efficiency of the referral and triage processes for people with symptoms suggestive of colorectal cancer.

Studies currently underway[edit source]

The authors are not aware of any studies underway that may provide more information on this topic.

Future research priorities[edit source]

Further well-designed research, which accounts for the waiting time paradox, is needed to confirm the estimates of minimum diagnostic intervals associated with poorer colorectal cancer outcomes. In addition, studies should monitor the impact of the implementation of colonoscopy triage categories on waiting times, diagnostic intervals and colorectal cancer outcomes.

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References[edit source]

  1. Wallace, E. Lowry, J. Smith, S. M. Fahey, T.. The epidemiology of malpractice claims in primary care: a systematic review. BMJ Open 2013;3(7).
  2. Walter F, Webster A, Scott S, Emery J. The Andersen Model of Total Patient Delay: a systematic review of its application in cancer diagnosis. J Health Serv Res Policy 2012 Apr;17(2):110-8 Available from:
  3. Lyratzopoulos G, Neal RD, Barbiere JM, Rubin GP, Abel GA. Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. Lancet Oncol 2012 Apr;13(4):353-65 Available from:
  4. Weller D, Vedsted P, Rubin G, Walter FM, Emery J, Scott S, et al. The Aarhus statement: improving design and reporting of studies on early cancer diagnosis. Br J Cancer 2012 Mar 27;106(7):1262-7 Available from:
  5. Neal RD, Tharmanathan P, France B, Din NU, Cotton S, Fallon-Ferguson J, et al. Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review. Br J Cancer 2015 Mar 31;112 Suppl 1:S92-107 Available from:
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Tørring ML, Frydenberg M, Hamilton W, Hansen RP, Lautrup MD, Vedsted P. Diagnostic interval and mortality in colorectal cancer: U-shaped association demonstrated for three different datasets. J Clin Epidemiol 2012 Jun;65(6):669-78 Available from:
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Tørring ML, Frydenberg M, Hansen RP, Olesen F, Hamilton W, Vedsted P. Time to diagnosis and mortality in colorectal cancer: a cohort study in primary care. Br J Cancer 2011 Mar 15;104(6):934-40 Available from:
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 Pruitt SL, Harzke AJ, Davidson NO, Schootman M. Do diagnostic and treatment delays for colorectal cancer increase risk of death? Cancer Causes Control 2013 May;24(5):961-77 Available from:
  9. 9.0 9.1 9.2 Redaniel MT, Martin RM, Ridd MJ, Wade J, Jeffreys M. Diagnostic intervals and its association with breast, prostate, lung and colorectal cancer survival in England: historical cohort study using the Clinical Practice Research Datalink. PLoS One 2015;10(5):e0126608 Available from:
  10. 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 Singh H, Shu E, Demers A, Bernstein CN, Griffith J, Fradette K. Trends in time to diagnosis of colon cancer and impact on clinical outcomes. Can J Gastroenterol 2012 Dec;26(12):877-80 Available from:
  11. 11.0 11.1 11.2 11.3 11.4 11.5 Tørring ML, Frydenberg M, Hansen RP, Olesen F, Vedsted P. Evidence of increasing mortality with longer diagnostic intervals for five common cancers: a cohort study in primary care. Eur J Cancer 2013 Jun;49(9):2187-98 Available from:
  12. 12.0 12.1 12.2 12.3 12.4 Wattacheril J, Kramer JR, Richardson P, Havemann BD, Green LK, Le A, et al. Lagtimes in diagnosis and treatment of colorectal cancer: determinants and association with cancer stage and survival. Aliment Pharmacol Ther 2008 Nov 1;28(9):1166-74 Available from:
  13. 13.0 13.1 13.2 13.3 13.4 Gómez-Domínguez E, Trapero-Marugán M, del Pozo AJ, Cantero J, Gisbert JP, Maté J. The colorectal carcinoma prognosis factors. Significance of diagnosis delay. Rev Esp Enferm Dig 2006 May;98(5):322-9 Available from:
  14. 14.0 14.1 14.2 14.3 14.4 14.5 14.6 Rupassara KS, Ponnusamy S, Withanage N, Milewski PJ. A paradox explained? Patients with delayed diagnosis of symptomatic colorectal cancer have good prognosis. Colorectal Dis 2006 Jun;8(5):423-9 Available from:
  15. Cancer Council Victoria. Optimal care pathway for people with colorectal cancer.; 2014 Available from:
  16. Lindholm E, Berglund B, Kewenter J, Haglind E. Worry associated with screening for colorectal carcinomas. Scand J Gastroenterol 1997 Mar;32(3):238-45 Available from:
  17. Parker MA, Robinson MH, Scholefield JH, Hardcastle JD. Psychiatric morbidity and screening for colorectal cancer. J Med Screen 2002;9(1):7-10 Available from:
  18. 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:

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Appendices[edit source]

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