Optimal maximum time from referral to diagnosis and treatment

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Background

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

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 GPA medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients. 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 GPA medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients. 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

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

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

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]

ColorectalReferring to the large bowel, comprising the colon and rectum. cancer-specific mortality

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

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

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 GPA medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients. consultation to diagnostic colonoscopy (or other diagnostic procedure) in specialist care.

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Evidence summary and recommendations

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 recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question 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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. for screening.

C
Evidence-based recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question 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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. 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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. for screening.

D
Consensus-based recommendationA recommendation formulated in the absence of quality evidence, after a systematic review of the evidence was conducted and failed to identify admissible evidence on the clinical question.Question mark transparent.png

Triage category 1 patients, whether due to symptoms or positive iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin., should continue to be considered most urgent and prioritised for diagnostic colonoscopy, in any model of care at any jurisdictional level.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

ColonoscopyAn examination of the large bowel using a camera on a flexible tube, which is passed through the anus. 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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin.-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

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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. 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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. 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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. or with symptoms suggestive of colorectal cancer should have a colonoscopy as promptly as possible.

iDate of first presentation is defined as the positive screening iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin..

Benefits and harms

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 iFOBTA test that can detect microscopic amounts of blood in stools. Types of FOBT include immunochemical FOBTs (iFOBTs), which directly detect haemoglobin using antibodies specific for the globin moiety of human haemoglobin, and guaiac FOBTs (gFOBTs), which detect peroxidase activity, an indirect method for identification of haemoglobin. for screening) for all patients meeting either Category 1 or Category 2 criteria.

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Health system implications

Clinical practice

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

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

These recommendations are made in the context of the roll-out of the NBCSPThe National Bowel Cancer Screening Program. An Australian screening program that aims to reduce illness and death from bowel cancer through early detection or prevention of the disease., 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 GPA medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients. referral proforma[18] (see Resourcing).

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Discussion

Unresolved issues

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

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

Future research priorities

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

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Appendices


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