European guidelines for quality assurance in colorectal cancer screening and diagnosis

Comparative clinical performance - gFOBT and iFOBT

In the USA, Allison et al. (2007) prospectively compared two types of FOBTs, a sensitive gFOBT (Hemoccult SENSA) and a manual iFOBT (Flexsure). A large number of patients (7394 subjects were eligible for the study) were requested to perform both tests. All patients positive for either FOBTs were invited to have a total colonoscopy, whereas all patients negative to FOBT were advised to have a sigmoidoscopy. All cancers occurring during the two years following the test were identified, so that it was possible to estimate the absolute sensitivity and specificity for detecting advanced neoplasms in the left colon within two years after the FOBT screening for the two tests administered separately and in combination. The sensitivity for detecting cancer was 81.8% (95% CI = 47.8% to 96.8%) for the iFOBT and 64.3% (95% CI = 35.6% to 86.0%) for the gFOBT. The sensitivity for detecting distal advanced adenomas was higher for gFOBT than for iFOBT 41.3% (95% CI = 32.7% to 50.4%) vs 29.5% (95% CI = 21.4% to 38.9%). PPV was much higher for iFOBT than for gFOBT for distal cancer (5.2% and 1.5% for iFOBT and gFOBT respectively) and for advanced adenomas (19.1 and 8.9% for iFOBT and gFOBT respectively). The authors concluded that iFOBT has high sensitivity and specificity for detecting left-sided colorectal cancer and that it may be a useful replacement for the gFOBT.

The study by Dancourt et al. (2008) compared the performance of a 3-day gFOBT and 2-day iFOBT in 17 215 subjects. For 1205 subjects who participated and had colonoscopy, the PPV for the guaiac and immunochemical test was respectively 5.9% v 5.2% for cancer and 27.2% and 17.5% for adenoma.  

The study by van Rossum et al. (2008) represents a milestone in the comparison of gFOBT with iFOBT, being the first randomised trial in a population based screening setting. A large number of people (20 623) aged 50–75 years were randomised to either gFOBT (Hemoccult II, Beckman Coulter Inc. Fullerton, CA, USA) or iFOBT (OC-Sensor). For iFOBT, the standard cut-off of 100 ng/mL was used. iFOBTs showed higher compliance than did gFOBTs (56.9% vs 46.9% respectively p<.01). The positivity rate was significantly higher in iFOBTs compared to gFOBTs (5.0% vs. 2.4% respectively, p<0.01). Cancer or advanced adenomas were found, respectively, in 11 and 46 of gFOBTs and in 24 and 121 of iFOBTs. The detection rate per 1000 examinations for cancer was 71% higher in iFOBT compared to gFOBT; the detection rate per 1000 examinations for advanced adenomas was 106% higher in iFOBT as compared to gFOBT. The number-to-scope to find 1 cancer or 1 adenoma was comparable between the tests, with the PPV not statistically different. In conclusion, iFOBT compared to gFOBT demonstrated a higher detection rate with a similar PPV.

The results of these five studies are consistent with data from the first European screening programmes. The UK Pilot study adopted Hema-screen, a conventional non-rehydrating gFOBT, using duplicate samples on 3 consecutive stools extended to 2 further sets of 3 stools if indicated. This UK pilot study gave a positivity rate during the first round of 1.9%. The Detection Rates (DR) for cancer and neoplasia (cancer and advanced or non-advanced adenoma) were 1.62 in 1000 and 6.91 in 1000 respectively. The PPV for neoplasia was 46.9% in England and 47.3% in Scotland (UK Colorectal Cancer Screening Pilot Group 2004). 

In Italy, a 1-day single sample iFOBT biennial test with positivity cut-off at 100 ng/mL is used in the regional colorectal cancer programmes. The paper by Zorzi that described Italian screening programmes showed a quite different outcome to the UK Pilot study (Zorzi et al. 2008). The positivity rate was relatively high, 5.3% during the first round, the DR for cancer was 3.1 in 1000 (almost two times the UK figure) and the DR for adenoma was 24.7 in 1000 (more than three times the UK result). The PPV for neoplasia was slightly higher than that observed in UK pilot study (54% vs 46.9%) (UK Colorectal Cancer Screening Pilot Group 2004). The Italian programme had adopted a more sensitive (but less specific) strategy compared to the UK. 

Hol et al. (2009) recently reported a randomised comparison of gFOBT (Hemoccult II) and iFOBT (OCSensor) in a population-based trial in the southwest Netherlands (age 50–74 years). For gFOBT, any 1 of 6 windows collected from 3 stools was designated positive and for iFOBT a single result above a cut-off concentration of 50 ng/mL was designated positive. Test kits were all distributed and returned by mail. Participants with positive results received colonoscopy. gFOBT positivity was 2.8%, and iFOBT positivity was 8.1% at a cut-off of 50 ng/mL, 5.7% at 75 ng/mL, 4.8% at 100 ng/mL and 4.0% at 150 ng/mL. At an iFOBT cut-off concentration of 75 ng/mL, the detection rate for advanced neoplasia was 2x higher than that by gFOBT and was considered to be the optimum cut-off and balance between detection rate and positivity.