Symptom or faecal immunochemical test based referral criteria for colorectal cancer detection in symptomatic patients: a diagnostic tests study

The current study is a post hoc analysis performed within the COLONPREDICT study: a multicentre, cross-sectional, blinded study of diagnostic tests. The study aimed to create and validate a CRC prediction index based on available biomarkers, clinical and demographical data. We performed this post hoc analysis in the 1572 patients included in the derivation previously described [25].

The details of the study have been described extensively elsewhere and are summarized here [25, 26]. We used the Colonoscopy Research into Symptom Prediction questionnaire (CRISP) to record symptoms and demographic data [27]. Based on this questionnaire, they determined if patients met the CG27 referral criteria for CRC detection [3]. f-Hb concentration was assessed using the automated OC-SENSOR MICRO analyser (Eiken Chemical Co., Ltd., Tokyo, Japan). The faeces for the f-Hb determination were collected using the OC-Sensor probe. Moreover, we determined blood haemoglobin (b-Hb) and mean corpuscular volume with a Beckman Coulter Autoanalyzer (Beckman Coulter Inc., CA, USA). Colonoscopy was performed blind for the questionnaire and analytical results.

On the basis of the information obtained from the CRISP questionnaire and the analysis performed (f-Hb, b-Hb and mean corpuscular volume), we determined which of the 2017 NG12 criteria for CRC suspicion were met. Two researchers (JMH and JC) independently decided the equivalence between each NICE criteria and the information collected. Finally, they reached a consensus version. NG12 referral criteria are shown in Table 1 [13]. We considered a positive faecal occult blood test if the f-Hb concentration was ≥10 μg Hb/g faeces.

COLONPREDICT score is a CRC prediction model based on a multivariable logistic regression analysis [25]. The COLONPREDICT score is based in eleven variables and the mathematical formula is as follows: 0.789 x rectal bleeding + 0.536 x change in bowel habit + 2.694 x rectal mass − 1.283 x benign anorectal lesions + 2.831 x f-Hb ≥20 μg Hb/g faeces + 1.561 x b-Hb (< 10 g/dL) + 0.588 x b-Hb (10–12 g/dL) + 1.511 x CEA ≥3 ng/mL + 0.040 x age (years) + 0.813 x sex (male) -2.073 x previous colonoscopy (last 10 years) -0.849 x continuous treatment with aspirin. It shows a high diagnostic accuracy for CRC detection. Two thresholds have been defined with 90% and 99% sensitivity for CRC: 5.6 and 3.5.

FAST Score is a CRC prediction model based on a multivariable logistic regression analysis [26]. The FAST score is based on three variables and the mathematical formula is as follows: 0 x f-Hb (0) μg Hb/g faeces 0.684 x f-Hb (1, 19) + 2.824 x f-Hb [20, 200) μg Hb/g faeces + 4.184 x f-Hb ≥200 μg Hb/g faeces + 0.031 x age (years) + 0.479 x sex (male). Two thresholds have been defined with 90% and 99% sensitivity for CRC: 4.50 and 2.12.

The main outcome was CRC detection. According to previous studies evaluating FIT in symptomatic patients, [14‐21] we considered significant colonic lesion (SCL) detection as the secondary outcome. We defined SCL as CRC, advanced adenoma (≥10 mm, villous histology, high-grade dysplasia), polyposis (> 10 polyps of any histology, including serrated lesions), histologically confirmed colitis (any aetiology), polyps ≥10 mm, complicated diverticular disease (diverticulitis, bleeding), colonic ulcer and/or bleeding angiodysplasia.

First, we performed a descriptive analysis of the population included in the study. In order to determine differences in diagnostic accuracy between the NG12 referral criteria and the rest of diagnostic criteria, the CG27 referral criteria, the f-Hb concentration, the COLONPREDICT and the FAST score we performed two analysis. First, we determined the number of individuals with a positive result and the sensitivity and the specificity for CRC and SCL detection. We determined if the differences between the sensitivity and the specificity of the NG12 referral criteria and the rest of diagnostic criteria, CG27 referral criteria, the COLONPREDICT and the FAST scores at the pre-stablished thresholds and the f-Hb at a 10 and 20 μg Hb/g faeces concentration threshold, were statistically significant using the McNemar’s test. Finally, we also calculated the positive and negative predictive value (PPV, NPV), the positive and negative likelihood ratios (LR) and the diagnostic Odds Ratio (OR) of all the diagnostic tests. Diagnostic OR is defined as the odds of positivity in subjects with disease relative to the odds in subjects without disease.

In a second step, we evaluated the discriminatory ability using receiver-operating characteristic (ROC) curves for CRC and SCL diagnosis, and we calculated the area under the curve (AUC). We determined whether there were statistically significant differences using the chi-square test of homogeneity of areas. Additionally, we determined if there were differences in the discriminatory ability of each of the diagnostic criteria according to the healthcare level referring the patient to colonoscopy. Primary healthcare referral was determined when a general practitioner was requesting the colonoscopy and secondary healthcare referral was determined when a specialist (gastroenterologist, surgeon..) was requesting the exploration.

Among the 1572 patients included in the derivation cohort of the COLONPREDICT, a CRC was detected in 214 (13.6%) patients and a SCL in 463 (29.5%) patients: advanced adenomas in 251 (16.0%), a polyp ≥10 mm with non-adenoma histology in 6 (0.4%), colitis in 36 (2.3%) and other SCLs in 6 (0.4%) patients. Direct referrals from primary care to endoscopic evaluation accounted for 22.9% of the patients included.

As we show in the Table 1, 1,479 out of the 1572 (94.1%) met at least one of the 2017 NG12 referral criteria. In contrast, 52.2% of the patients met any of the CG27 referral criteria, 38.7% had a f-Hb concentration ≥ 20 μg Hb/g faeces, 44.4% had a f-Hb concentration ≥ 10 μg Hb/g faeces, 30.9% had a COLONPREDICT Score ≥ 5.6, 60.5% had a COLONPREDICT Score ≥ 3.5, 37.1% had a FAST Score ≥ 4.50 and 88.0% had a FAST Score ≥ 2.12.

The sensitivity of the 2017 NG12 referral criteria for CRC detection reaches 100% at the expense of a low specificity (6.8%). As we show in the Table 2, the sensitivity of the 2017 NG12 referral criteria is superior to the sensitivity of the CG27 referral criteria, the f-Hb (≥20 μg Hb/g and ≥ 10 μg Hb/g faeces), the COLONPREDICT Score at a 5.6 threshold (p < 0.001) and the FAST Score at a 4.50 threshold. In contrast, the sensitivity is similar to the COLONPREDICT Score at a 3.2 threshold and the FAST Score at a 2.12 threshold (p = 1) and the specificity is inferior to any of the other criteria (p < 0.001). The rest of the diagnostic accuracy analysis is displayed in Table 2.

On the other hand, 2017 NG12 referral criteria allows the diagnosis of 98.9% of SCL. As in the diagnostic accuracy for CRC detection, the specificity is extremely low (7.9%). As we show in the Table 3, the sensitivity of the 2017 NG12 referral criteria is similar to the FAST Score at a 2.12 threshold (p = 1) and superior the rest of the evaluated criteria. In contrast, the specificity of the 2017 NG12 criteria is inferior to any of the additional criteria evaluated (p < 0.001). We show the PPV, NPV, positive and negative LR and the diagnostic OR in Table 2.

The analysis of the discriminatory ability for CRC detection of the NICE referral criteria, the f-Hb concentration, the COLONPREDICT and the FAST Score is shown in Fig. 1. The discriminatory ability of the 2017 NG12 referral criteria is inferior to any of the evaluated criteria in the Chi-square homogeneity test comparison of AUC. Additionally, we found no differences in the performance of each diagnostic test in the evaluation of the discriminatory ability according to the healthcare referring the patient to colonoscopy: 2017 NG12 referral criteria (primary = 0.53, 95% CI 0.46–0.60; secondary = 0.53, 95% CI 0.48–0.58; p = 0.1), CG27 referral criteria (primary = 0.60, 95% CI 0.54–0.66; secondary = 0.59, 95% CI 0.55–0.63; p = 0.7), f-Hb concentration (primary = 0.85, 95% CI 0.80–0.89; secondary = 0.86, 95% CI 0.83–0.89; p = 0.5), COLONPREDICT Score (primary = 0.90, 95% CI 0.86–0.94; secondary = 0.93, 95% CI 0.91–0.95; p = 0.1), FAST Score (primary = 0.84, 95% CI 0.79–0.89; secondary = 0.88, 95% CI 0.85–0.90; p = 0.1). Fig. 2 shows the discriminatory ability for SCL detection of the diagnostic tests evaluated. The discriminatory ability of the 2017 NG12 referral criteria is similar to the CG27 referral criteria and inferior to the rest of the evaluated criteria in the Chi-square homogeneity test comparison of AUC.

We have evaluated the diagnostic accuracy of the 2017 NG12 referral criteria for suspected CRC. As we clearly show, these updated criteria are more sensitive than CG27 version. However, they produce a marked increase in the number of patients meeting them and a reduction in the specificity. Furthermore, we had the opportunity to compare them with the f-Hb concentration and two f-Hb based prediction model. As we clearly show, both diagnostic tools have a higher discriminatory ability than the NICE referral criteria.

We have used a wide cohort of consecutive patients referred to colonoscopy due to gastrointestinal symptoms. Patients were evaluated homogenously using a symptom questionnaire and several analytics, including a FIT, were performed before colonoscopy. This questionnaire allowed us to gather all the details regarding type of symptoms, duration and evolution. Thus, we could evaluate the 2017 NG12 referral criteria for suspected CRC for the first time. Furthermore, we have been able to evaluate the use of FIT, with the 10 μg Hb/g faeces, as recommended in the DG30 [23]. On the other hand, our study has several limitations that must be taken in consideration. We cannot exclude a risk of bias of selection, as long as the symptomatic patients included in the study were previously selected for colonoscopy evaluation. However, we have included all consecutive patients referred both from primary and secondary healthcare to colonoscopy.

The update of the NICE referral criteria is based on reducing the PPV threshold required to refer patients from primary care using a suspected cancer pathway referral. The guideline development group agreed to use a threshold value of 3% PPV to underpin their recommendations [13]. So, those patients with symptoms (i.e ≥ 40 years with unexplained weight loss) with a PPV > 3% for CRC should be referred for further testing. Our results clearly demonstrate that this strategy increases the sensitivity for CRC detection in comparison with previous criteria. However, these criteria certainly introduce a risk of over investigation. In fact, what our analysis confirms is that the discriminatory ability of any group of symptoms for CRC detection is suboptimal [6].

An additional innovation of the 2017 NG12 referral criteria is the inclusion of the faecal occult blood test in the evaluation of symptomatic patients. However, its use is only limited to patients without rectal bleeding and with unexplained symptoms that do not meet the criteria for a suspected cancer pathway referral [13]. Our results confirm the data previously published: the f-Hb concentration measured with a FIT shows a higher discriminatory ability for CRC detection than the NICE referral criteria [14‐19]. So, probably, the strategy for the evaluation of the risk of CRC detection in symptomatic patients should be based on the f-Hb concentration irrespective of symptoms. Actually, in the COLONPREDICT Score, patients with a f-Hb concentration ≥ 20 μg Hb/g faeces have 17.0 times more risk of CRC detection. In contrast, patients with rectal bleeding or a change in bowel habit have 2.2 and 1.7 times more risk of CRC detection, respectively [25].

Recently, an article has evaluated the diagnostic accuracy of the 2017 NG12 referral criteria for CRC and SCL detection and compared these criteria with the f-Hb concentration [24]. This study used the database of three diagnostic tests studies evaluating FIT in symptomatic patients [15, 17, 19]. and shows that the discriminatory ability of the 2017 NG12 referral criteria are inferior to the f-Hb concentration. This cohort has significant differences with ours: the prevalence of symptoms related to CRC diagnosis, rectal bleeding, changes in bowel habit, iron-deficiency anaemia or rectal mass, is inferior as well as the prevalence of CRC or SCL. Probably, these differences are responsible for the differences in the number of patients that meet 2017 NG12 referral criteria and in the inferior discriminatory ability documented in our study. However, are results are consistent in the comparison of the 2017 NG12 referral criteria with the f-Hb concentration.

One of the main lessons learned in these years from the CRC screening programs is that lack of symptoms or the presence of non-specific symptoms do not exclude a CRC in adult population. Up to 20% of the incident CRC are detected in asymptomatic patients within a CRC screening program based in a guaiac faecal occult blood test [4]. So, the strategies for CRC detection in symptomatic patients should determine which patients require urgent referral, which require a normal referral and, finally, in what situations no additional evaluation is required. The NICE referral criteria only determine the scenarios where an urgent referral is required. Due to the increased discriminatory ability of the FIT for CRC, either the f-Hb concentration alone or a f-Hb based prediction model can allow to establish these three risk groups with different diagnostic strategies. As we have recently proposed, at least 90% of CRC should be detected in a high-risk group, requiring a fast-track referral to colonoscopy. In contrast, in a low-risk group, where no additional explorations are required, the probability of a missing CRC should be well below 1%, so that the risk of CRC is balanced with the risk of colonoscopy complications, mainly perforation [28].