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1 Triage Optimisation in Patients with Symptoms Suspicious of Colorectal … 19
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Fig. 1.1 Summary receiver operator characteristic curves for FIT at various f-Hb positivity
thresholds for CRC detection. Solid Lines represent summary receiver operator characteristic
cure. Full coloured points on solid lines represent summary estimate point. Area with dashed line
represent 95% confidence region. Washed out/lighter coloured point represent study cohorts. Size
of washed out/lighter coloured points is proportional to number of participants of each study
determine the urgency of diagnostic colonoscopy for patients with symptoms suspicious of CRC. Recent diagnostic accuracy studies and subsequent meta-analyses
have reported on the diagnostic performance of FIT at higher positivity thresholds
[89, 92, 93, 95, 96]. At the higher quantitative positivity threshold of 100 µg Hb/
g faeces and 150 µg Hb/g faeces, specificity for CRC is estimated to be 93.4%
and 95.1% respectively [89]. Where reported, positive predictive values were consistently above 20% with positive likelihood ratios consistently > 10 [89]. These
diagnostic performance parameters suggest that FIT is a good “rule-in” test and
FIT values that can be leveraged to determine the urgency of access to diagnostic
tests with limited availability.
Recent FIT data have also pointed to an attractive quality of FIT in view of the
limitations of symptoms as a predictor of CRC diagnosis. Booth and colleagues
concluded that there was no difference between high-risk and low-risk symptom
clusters with sensitivity of FIT for CRC detection unaffected by the definition of
symptomatic patients used in a detailed meta-analysis of the effect of presenting
symptoms on FIT performance [88]. This observation is also supported by other
research [89, 97, 98]. This characteristic of FIT liberates clinicians from pointless
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debates about the assumed importance of some symptoms over others. Triaging
based on quantitative FIT data is also a more straightforward clinical exercise
compared to navigating through complex symptoms-based referral criteria. (See
Table 1.1). Quantitative FIT f-Hb data has the potential be the new “lingua franca”
to objectively and effectively communicate the risk of undiagnosed CRC between
clinicians and potentially with patients also.
These observations have led to comparisons between FIT and the contemporary
methods of triaging patients with symptoms suspicious of CRC. Cubiella and colleagues compared the diagnostic performance of FIT alongside both NICE (CG27)
and SIGN [126] referral criteria for the detection of CRC among patients with
symptoms suspicious of CRC [18]. FIT at the positivity threshold equivalent to
20 µg Hb/g faeces had AUROC of 0.88 compared to AUROC of SIGN referral
criteria at 0.62 and NICE referral criteria at 0.63 [18]. Expressed in test sensitivity
terms, FIT at 20 µg Hb/g faeces had a sensitivity of 87.6% compared to SIGN
referral criteria at 82.5% and NICE referral criteria at 61.9% [18]. However, the
clear advantage of FIT was observed in test specificity terms, with specificity of
FITat20µg Hb/g faeces of 77.4% compared to SIGN referral criteria at 42.7%
and NICE referral criteria at 65.2% [18]. Herero and colleagues conducted similar
comparisons with updated NICE referral criteria and similarly concluded that the
discriminatory ability of any symptom based criteria is limited when compared
with a FIT f-Hb data based triaging approach [99].
Most clinicians instinctively understand that with any test, there is an inherent
trade-off between test sensitivity and test specificity. The more sensitive a test is,
the less specific it will be to the target disease. This trade-off is best captured in
a singular measure as the AUROC, with tests that have AUROC > 0.7 generally
accepted to be tests with good discriminatory ability. Nicholson and colleagues
reported AUROC of > 0.9 for FIT for detection of CRC across all ages when
reviewing a large retrospective cohort of over 14,000 symptomatic patients [100].
In fact, all the data on FIT f-Hb use among symptomatic patients has consistently
shown that the AUROC of FIT at low f-Hb positivity thresholds is consistently
above 0.7 for the detection of CRC [18, 62, 93, 95, 97, 99–101]. FIT demonstrated test characteristics that result in a completely different and superior ROC
shape compared to symptoms-based referral criteria, thereby offering superior test
sensitivity and test specificity concurrently [18, 99](SeeFig.1.2).
Even in FIT positivity threshold were adjusted, there would still be less disproportionate trade-off between test sensitivity and test specificity. Given the problems
with current approaches outlined earlier, having a tool that retains test sensitivity
without losing significant test specificity is critical in any effort to further optimise
triage of patients with symptoms suspicious of CRC, as there is a need to maintain clinician and patient confidence in ability to detect CRC without excessive
investigation.
A key goal for any attempts to optimise triaging of patients with symptoms is
to more efficiently identify patients with highest probability of undiagnosed CRC
to undergo colonoscopy. This will maximise the utility of limited colonoscopy
resource. The number needed to colonoscope (NNS), represents the number of
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Fig. 1.2 Receiver operator characteristic curves for detection of CRC of FIT, NICE referral criteria and SIGN referral criteria
patients required to undergo colonoscopy to detect one CRC [102]. Similar to
the concept of Number Needed to Treat, the NNS, is a number that is understood by many clinicians and can be used to guide conversations with regarding
colonoscopy access. The NICE FIT study is an adequately powered, prospective,
multi-centre study on FIT use in symptomatic patients in the United Kingdom with
the single largest cohort to date of over 9800 patients [93]. The authors reported
a NNS of 6.2 for patients with FIT ≥ 10 µg Hb/g faeces and a NNS of 265.3
for patients with FIT < 10 µg Hb/g faeces [93]. With use of NICE symptomsbased referral criteria only, NNS would be 29.9 [89]. This finding is similarly
observed in subsequent meta-analysis that included other relevant cohorts [46, 89].
With such a large difference in NNS between positive FIT and negative FIT cases,
FIT appears to be a very good sieve to identify patients who are most likely to
have undiagnosed CRC and is more efficient than relying solely on symptomsbased referral criteria. Based on the available evidence, it seems appropriate for
patients with symptoms suspicious of CRC but very low FIT f-Hb results not to be
referred for specialist assessment or colonoscopy given the very low probability of
undiagnosed CRC [88, 89, 93, 97, 101].
When used as a triaging tool for patients with symptoms suspicious of CRC,
FIT may offer an opportunity to address the previously discussed issue of
younger (<50-year-old) symptomatic patients in a number of ways. Most recent
meta-analyses included studies involving adult patients (>18 years old) with no
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restriction on age of included patients [88, 89, 92] Several analyses assessed the
utility of FIT when used in symptomatic patients under 50 years old [103–105]
At a positivity threshold of 10 µg Hb/g faeces, sensitivity for CRC ranged from
81.3% to 100% with a narrow specificity range of 83.6–88.5% [103–105] Methodological issues around patient inclusion into such studies limits the interpretation
of these findings as most younger symptomatic patients are not considered to have
CRC hence may not have been referred or asked to complete a FIT. However,
the available evidence would suggest that FIT is equally valid as a triage tool for
patients under 50 presenting with symptoms [104, 105] A high FIT f-Hb value
may at least prompt clinicians to re-evaluate pre-conceived notions about likelihood of undiagnosed CRC even in younger patients given the high specificity
even at FIT positivity threshold of 10 µg Hb/g faeces. While there are likely to be
more false positives if CRC is the only target condition, a high proportion of these
younger patients with FIT ≥ 10 µg Hb/g faeces are likely to have other significant
bowel pathology that requires management [103, 105] If FIT is incorporated into
triaging of patients with symptoms suspicious of CRC, reductions in numbers of
colonoscopy needed for patients above 50 years old with very low FIT f-Hb values
may be redistributed for use in patients below 50 years old with a moderately high
FIT f-Hb values.
FIT is also a non-invasive test, hence it has zero associated procedural risk to
patients compared to colonoscopy or CTC. FIT can be completed in the privacy
of one’s own home with specimens delivered to the lab for processing, further
limiting the impact of various barriers to access healthcare. Furthermore, FIT is
also a relatively cheap test, typically attainable at less than 1% of the cost of a
colonoscopy. A number of studies on patient perception have also indicated that
FIT is a well-received and acceptable test for patients with symptoms [106–108].
In summary, FIT use provides a data-driven approach to triaging patients with
symptoms suspicious of CRC based on objective, reliably reproducible measures.
Existing FIT f-Hb data can be utilised in the development of optimal triaging
pathways and brings clarity and transparency in monitoring adherence. FIT f-Hb
positivity thresholds can also be adjusted to match the desired diagnostic accuracy or respond to evolving logistical realities [109–112]. With the demonstration
of FIT as a reliable and accessible technology, risk assessment based largely on
interpretation of subjective and variably defined symptoms now seems incongruent
in modern medical practice.
1.7 Implementing FIT—A Proposed Triaging Approach
There have been numerous recent publications on the application of FIT in the
context of assessing patients with symptoms suspicious of CRC. In late 2023 the
new NICE (DG56) guideline was published [113]. This provides an up-to-date
framework to discuss approaches to implementation of FIT as a triaging tool for
the assessment of symptomatic patients. Figure 1.3 is built on the NICE DG56
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Fig. 1.3 Flow diagram of recommended FIT use from NICE DG56. Note UG—Unclear recom-
mendations in DG56 guideline. Consider alternate diagnostic guidelines
guideline and demonstrates a proposed approach of using a singular FIT to triage
patients presenting with symptoms suspicious of CRC [113].
FIT appears to simplify referral pathways to structural exams or specialist care
for many symptoms that raise concern for undiagnosed CRC. There is certainly
room for further optimisation of this proposed approach with adjustment to meet
the triaging goals and resource availability of each health jurisdiction. Further
research is required in a number of areas to guide the development of a more
complete diagnostic and management pathway involving FIT.
Within the new NICE guidelines itself, some questions remain regarding the
supporting evidence for some recommendations. There is still some uncertainty
about the optimal approach for patients with rectal bleeding under 50 years of
age as these new guidelines require the addition of abdominal pain or weight
loss before recommending testing with FIT [113]. Some authors have proposed
that patients with rectal bleeding and a negative FIT may still need referral to
secondary care for proctoscopy or flexible sigmoidoscopy [114, 115]. Although
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rectal bleeding had not been shown to be an exceptionally good predictor of CRC,
there may be good reasons for referral as rectal bleeding often indicates significant
benign pathologies that require treatment. A pathway that included FIT in the rectal
bleeding group could identify patients who need a full colonoscopy rather than just
a proctoscopy or flexible sigmoidoscopy and office treatment.
A practical consideration beyond the remit of this chapter and not fully covered
by the proposed approach above is the fact that some patients with symptoms suspicious of CRC will have benign conditions that require treatment. These patients
will greatly benefit from having their diagnosis clarified and appropriate treatment
instituted. For some of these clinical scenarios, such as possible inflammatory
bowel disease or unexplained anaemia, there may be existing guidelines or pathways that clinicians can utilise if symptomatic patients have a low FIT f-Hb
value. It is also important to remember that symptoms such as abdominal pain,
unexplained weight loss and anaemia have broad differential diagnoses beyond
just CRC. Another practical consideration not directly addressed by the proposed
approach above is on management of patients with persistent symptoms and ongoing clinical concern for undiagnosed CRC despite low FIT f-Hb. This will be
discussed further in the subsequent section.
Beyond what is outlined and immediately visible in simple diagrams (Fig. 1.3)
are some important lessons from early adopter institutions that are likely to be
crucial for implementation of FIT in the context of symptomatic patients. First,
implementation of FIT is safe at the level of secondary care or primary care. This
is demonstrated through a number of analyses from studies conducted in primary
care demonstrating equivalent efficacy of FIT with no increased risk of undetected
CRC if used in primary care [48, 97]. Bailey and colleagues reported that the
median number of days from FIT to diagnosis of CRC in patients testing above
the f-Hb threshold was 34 days when FIT was implemented at primary care level
[117]. Although only a subset of symptoms underwent FIT, this finding hints at
the possibility of more rapid diagnosis of CRC when FIT is implemented earlier
in the complex sequence of events that often precedes diagnosis.
Although there is no concrete evidence to point to whether FIT should be implemented in primary or secondary care, there is a clear logistical advantage in its use
in primary care. This avoids unnecessary referral and empowers general practitioners. However, it is important to acknowledge that there may be scepticism and
initial resistance at primary care level to the paradigm shift of using FIT for assessment of symptomatic patients with symptoms stemming from perceived shifting of
risk and responsibility to primary care [118]. Hence another important overarching
tenet for implementation of FIT is the need to include primary care from inception in planning, education and ongoing support for clinicians. Comprehensive
programmes to introduce the concept of using FIT in assessment of symptomatic
patients with continuing education and support for primary care practitioners are
important for successful, appropriate implementation of FIT as a triaging tool [48,
103, 117, 119]. NHS Tayside proactively provided comprehensive education and
supporting information for primary care practitioners when FIT was first implemented for assessment of symptomatic patients [119]. Although some symptoms
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were excluded from FIT testing, 96% of incident CRC cases were detected with
a 6% increased yield for significant bowel disease detection despite reduction of
referral to secondary care services by 15.1% with this strategy [119]. It logically
follows then that a key principle in the early stages of FIT implementation includes
the need to ensure that any FIT incorporated diagnostic pathway permits the referral of patients with low FIT f-Hb or negative FIT, especially if there is persistent
clinical concern for undiagnosed CRC [48, 118, 119].
Another important lesson that can be learned is that implementation of FIT
may lower the clinical threshold for testing patients and fundamentally change the
nature of the cohort of patients being assessed. It is logical to hypothesise that as a
non-invasive and highly accessible test, clinicians may have a different risk–benefit calculations when deciding to use FIT or when deciding to refer a symptomatic
patient for a colonoscopy. Such subtle but important shifts can have significant
implications for the implementation of FIT but are not always observable in the
evidence base that is predominantly based on diagnostic accuracy studies rather
than service evaluations. Nottingham University Hospitals NHS Trust saw a 33%
rise in overall referral after implementation of FIT [120]. Positively, this still
resulted in a significant improvement in yield of CRCs detected despite specific
symptoms being excluded from FIT testing [120]. Due to the way the pathway
was designed and implemented as an early adopter institution, FIT implementation
resulted in significant reduction in colonoscopy request but significant increases in
CTC and flexible sigmoidoscopy use [120]. Such data appear to suggest that a
broader population of patients are being selected for FIT testing. FIT, as a good
discriminator for CRC, becomes even more advantageous as it more appropriately selects patients at truly increased risk of undiagnosed CRC. This allows for
efficient utilisation of limited structural examination resources. If the detection of
more CRC is the ultimate goal, such observations also again highlight the importance of continuously increasing or maintaining capacity for structural exams and
address the underlying resource limitation that created the need for triaging in the
first place.
1.8 Further Questions
Many questions remain about the application of FIT in the context of triaging
patients with symptoms suspicious of CRC. To the best of our knowledge, the
available evidence to support the use of FIT in the context of patients with symptoms suspicious of CRC is level III evidence at best. There are no randomised
controlled trials or long-term data on the use of FIT in this context. The impact of
higher level evidence (e.g. randomised control trial) in changing clinical practice
in this context is uncertain. Recent large diagnostic study cohorts may be followed
up to determine long term outcomes such as effect on CRC related survival, possible stage shift effect and reduction in late stage emergency presentations etcetera.
There are also concerns about the transferability of meta-analysis findings to other
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populations given the evidence base is dominated by cohorts from Europe, specifically the UK [89, 116]. Equity concerns about the impact of implementation of FIT
on subsections of the population such as minority ethnic groups and socioeconomically deprived patients have also been raised [117, 118]. These concerns are likely
to be better addressed by local, context specific pilot studies prior to population
level application, akin to the way FIT based CRC screening is introduced.
There will undoubtedly be concerns among some clinicians about FIT when
used as a “rule-out” test in triaging patients with symptoms suspicious of CRC.
No test is perfect. Current triaging approaches are fundamentally problematic and
not 100% sensitive [18, 119]. Even CTC and operator dependent colonoscopy
are not 100% sensitive at detection of CRC [18, 119]. Apart from other reported
advantages, FIT sensitivity for CRC actually approaches 91% at most commonly
reported low f-Hb positivity threshold of 10 µg Hb/g faeces and is even higher
at the lower limit of f-Hb detection with reported sensitivity that approaches 95%
[46]. While technically beyond the remit of this chapter, there are also concerns
that FIT is not as promising at excluding other important organic bowel disease
beyond CRC, particularly given some patients with symptoms suspicious of CRC
are likely to have alternate diagnoses such as inflammatory bowel disease that
necessitates treatment [89]. It is important to re-emphasise that triaging would not
be necessary if relative scarcity of resource is absent. Publication of landmark
documents such as the joint guideline from the Association of Coloproctology of
Great Britain and Ireland and the British Society of Gastroenterology are helpful in
increasing the clinical acceptability and awareness of the utility of FIT for assessment of patients with symptoms suspicious of CRC [46]. Ultimately a mature
discussion involving all stakeholders of a particular healthcare jurisdiction about
trade-offs and triaging priorities is required to achieve context specific consensus
on application of FIT for triaging patients with symptoms suspicious of CRC.
Perhaps a universal practical concern in implementation of FIT as a triaging tool
in patients with symptoms suspicious of CRC is about the management of symptomatic patients with very low or undetectable f-Hb (i.e. negative FIT). Depending
on the positivity rate at selected FIT f-Hb positivity thresholds, most studies indicate that about 60–80% of currently referred patients may not need to be referred
for a colonoscopy at all [89]. It is difficult to ignore such a significantly large proportion of patients since many clinicians are accustomed to having a colonoscopy
report as an important milestone in managing such symptomatic patients. Authors
publishing in this area have often discussed the importance of safety netting for
these patients. While this mainly stems from the concern that FIT is not 100%
sensitive for the detection of CRC, it is also impractical to discharge a patient
with symptoms with no concrete management pathway, especially if the symptoms persist. The availability of appropriate evidence to inform the design and
implementation of a safety netting approach is however very limited at present
[46, 89]. A potential strategy that has been explored is to repeat FIT testing over
a period of weeks but data in this area remains limited [120–122]. Based on available findings, repeat FIT would still leave big gaps in suggested management of
a large proportion of symptomatic patients as many will still have very low or
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undetectable f-Hb on repeat testing [120–122]. The most concrete safety netting
advice many authors espouse is that if a clinician remains persistently concerned
about symptoms despite very low or undetectable FIT f-Hb values, then patients
should still be accepted for specialist assessment or a structural investigation [46,
89, 100, 123, 124]. A UK study of 3272 symptomatic primary care patients with
a specific subset of symptoms whose f-Hb < 10 µg Hb/g faeces and had follow
up 12 months later had reassuring results [125]. There were eight patients (0.2%)
with CRC identified, with a median time to diagnosis of 57 days after FIT testing
and the majority had been referred for lower GI assessment [125]. This is a very
important area for further research if FIT is to achieve widespread adoption as a
triaging tool for symptomatic patients.
Looking to the future, collecting and reporting outcome data from different
health settings after the introduction FIT testing would further clarify the strengths
and limitations of a FIT f-Hb based triaging approach. The earliest institutions to
adopt FIT as a routine part of triaging patients in this way will have rich real-world
data to share [80, 94, 120, 124, 126–128]. These will clarify the impact of a FIT
based triaging approach and inform ways to improve the investigation pathway for
these patients [80, 94, 120, 124, 126–128]. Different ways of using FIT, such as use
to determine urgency of colonoscopy, use of FIT to guide selection of diagnostic
test such as CTC and use of f-Hb data as part of a multivariable risk assessment
tool will also inform us on the optimal triaging method. Rapid developments in
the field of artificial intelligence may offer new methods to utilise existing data
in conjunction with FIT to optimise triaging. Advancements in FIT technology
for detection of molecular biomarkers beyond f-Hb alone and efforts to combine
multiple types of stool testing technology also hold promise.
1.9 Conclusions
Although the commonest presentation of CRC is following investigation of symptoms suggestive of CRC, the specificity of symptoms in predicting the presence of
CRC is very low. The primary investigations (colonoscopy and CTC) are invasive,
resource intensive and associated with complications and patient discomfort. In
the majority of symptomatic patients, these investigations do not identify significant pathology. With health systems worldwide struggling to meet the increasing
demand for colonoscopy, a triaging system that is more sensitive and specific than
symptoms alone is required. Combinations of symptoms and addition of other tests
such as haemoglobin or ferritin have shown some promise but have not received
widespread acceptance. Multiple studies have demonstrated a high sensitivity and
specificity for FIT testing in patients with symptoms suggestive of CRC. This
offers the possibility of effectively ruling out CRC in patients with very low FIT fHb levels and escalation of urgent colonoscopy in those with very high levels. The
issues that are still unanswered include the best method to identify those patients
who should be referred directly for colonoscopy without FIT testing (particularly
those with suspected inflammatory bowel disease) and the optimal safety-netting
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process to follow up those with very low f-Hb levels. As these issues continue to
be resolved there is a strong clinical case for introducing FIT testing in the setting
of symptoms suggestive of CRC.
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