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). 

Comparative clinical performance - gFOBT and iFOBT

Many studies comparing iFOBT and gFOBT have been performed in the last 8 years, and several systematic reviews of the literature have been undertaken more recently. 

In 2007 Kerr published a systematic review by the Health Technology Assessment (NZHTA) of New Zealand which had the aim of identifying the international evidence for the clinical and cost effecttiveness of screening tests for colorectal cancer (Kerr et al. 2007). This review included all primary research published as full original reports and secondary research, systematic reviews and meta-analyses published since November 2004. It also included seven eligible primary research papers (Rozen, Knaani & Samuel 1997; Rozen, Knaani & Samuel 2000; Saito et al. 2000; Zappa et al. 2001; Cheng et al. 2002; Cole et al. 2003; Ko, Dominitz & Nguyen 2003) and five eligible secondary research papers; Australian Health Technology Advisory Committee (AHTAC) (1997), Conseil d'Évaluation des Technologies de la Santé du Quebec (2000), Canada, Craven UK (Craven 2001), Young World Health Organization and World Organization for Digestive Endoscopy (Young et al. 2002), Piper Blue Cross Blue Shield Association Technology Evaluation Center US

The review concluded that “there is limited definitive evidence regarding superior immunochemical FOBT performance over the guaiac tests. However, evidence from cross-sectional studies suggests that the immunochemical test HemeSelect, Beckman Coulter Inc. Fullerton, CA, USA… is comparable, or superior, to guaiac testing… The conclusions on this topic should be revisited if further reliable evidence on the comparative performance of screening FOBTs becomes available”.

A similar conclusion was reached in a systematic review commissioned by the UK NHS and undertaken by the Centre for Reviews and Dissemination of the University of York in 2007 (Burch et al. 2007) which examined the literature until 2004. The review included 59 studies 39 evaluated gFOBTs, 35 evaluated iFOBTs and one evaluated sequential FOBTs. It concluded that there was no clear evidence from direct or indirect comparisons to suggest that guaiac or immunochemical FOBTs performed better. However amongst iFOBTs, Immudia-HemSP (now Hem-SP) appeared to be the most sensitive and specific. 

In the four years since 2004, six studies comparing the performance of gFOBT and iFOBT have been published (Levi et al. 2006; Smith et al. 2006; Allison et al. 2007; Guittet et al. 2007; Dancourt et al. 2008; van Rossum et al. 2008). Some further studies have investigated the accuracy of iFOBTs which, although without a direct comparison with gFOBTs, confirmed the performance of iFOBTs which was reported in the following studies 

In Australia, Smith et al. (2006) performed a paired comparison of an iFOBT (InSure) with a sensitive gFOBT (Hemoccult SENSA); 2351 asymptomatic and 161 symptomatic subjects were requested to perform both FOBTs. iFOBT returned a true-positive result significantly more often in cancer (n = 24; 87.5% vs. 54.2%) and in significant adenomas (n = 61; 42.6% vs. 23.0%) while the false-positive rate for any neoplasia was marginally higher with the iFOBT than the gFOBT (3.4% vs. 2.5%; 95% CI of difference, 0–1.8%): the PPV for cancer and significant adenomas was slightly better for iFOBT (41.9% vs 40.4%).