Debate on colorectal cancer screening by faecal occult blood.

We read with great interest the debate on colorectal cancer (CRC) screening in volume 13 issue 1 of the Annals of Oncology [1]. As opinions in the debate are controversial we would like to contribute to the discussion on the basis of our experience. The criticisms by the majority of the authors involved in the debate are based on the results of randomised trials that demonstrate the efficacy of guaiac-based faecal occult blood tests (FOBTs). Guaiac testing was the only available method at the time those trials started, approximately two decades ago. This kind of test can be affected by non-human haemoglobins and several plant foods. In order to minimise false positive results due to diet, the positivity threshold had been set at a high level. This explains the very low sensitivity of unhydrated guaiac FOBTs (Hemoccult-II). When rehydration was used, sensitivity increased with an important decrease in specificity. Since that time, new immunochemical FOBTs have been developed. Both immunochemical and guaiac FOBTs aim to detect bleeding, an indirect sign of the presence of cancer. Due to their specificity for human haemoglobin, immunochemical tests are more efficient than Hemocult-II because they are not influenced by diet. This allows a lower positivity threshold with minor effects on specificity due to non-neoplastic bleedings. The test that has been most commonly compared with Hemoccult-II is reversed passive hemagglutination (RPHA). This test has been compared with Hemoccult-II in several studies on patients with neoplasms or volunteers and in institutionor community-based screening programmes [2–5]. Whenever the two tests were compared, RPHA sensitivity for cancer was higher than Hemoccult-II (9–85%). In several studies, RPHA sensitivity for adenomas with diameter >1 cm was higher than Hemoccult-II [3, 5]. In a case–control study conducted in Japan comparing the efficacy of guaiac and immunochemical screening in reducing CRC mortality, a higher efficacy of immunochemical screening compared with Hemoccult-II was observed [6]. In the majority of the above-mentioned reports, RPHA proved to be more specific than Hemoccult-II [2–4]. In one study, Hemoccult II was more specific than RPHA (98% versus 95%) [5]; however, it should be noted that in this study, which recorded a positivity rate (PR) of 2.5% for Hemoccult-II, guaiac sensitivity was as low as 37% for cancer and 31% for adenomas >1 cm in diameter, whereas the corresponding values for RPHA were 69% and 67%, respectively. Therefore, RPHA showed the better balance between sensitivity and specificity. Guaiac tests with increased sensitivity have been proposed (HemoccultSensa). In one of the above-mentioned studies, HemoccultSensa proved to be more sensitive for cancer than RPHA (79% versus 68%), but corresponding specificity estimates were 87% and 94%, respectively [5]. In our population-based screening programme we have been comparing 3-day rehydrated Hemoccult-II and 1-day RPHA testing [7]. Our results confirm the higher sensitivity of RPHA compared with guaiac testing despite rehydration of the latter [7, 9]. Specificity was also higher for RPHA compared with rehydrated Hemoccult-II provided the higher positivity threshold was adopted. As a result, RPHA screening (whatever threshold of positivity was adopted) proved to be more cost-effective than rehydrated Hemoccult-II as far as costs per subject with detected cancer or adenoma(s) of >1 cm in diameter were concerned. The results of our cost-analysis are consistent with the cost-analysis conducted in Japan, confirming RPHA screening to be more costeffective compared with unhydrated Hemoccult-II [2]. The relative complexity of RPHA development procedure may be simplified by means of the partial automation of the dispensing and reading phases using the instruments supplied by the test manufacturer. This allows a shortening of the development time and an improved standardization of test results. To date in our screening programme, PR was ∼4.5% at first screening and ∼3.7% at repeat screening. It could be argued that, despite the partial automation of the development procedure, RPHA testing is rather complex and time consuming. In addition, the positivity threshold is fixed by the manufacturer and can be little modified by the laboratory technician. More recently we have been comparing RPHA with a Latex agglutination test. The latter is a quantitative test allowing the choice of the positivity cut-off point and the complete automation of the development procedure. Our results suggest that Latex performances are consistent with RPHA provided a positivity threshold of 100 ng haemoglobin per millilitre of sample solution is adopted [8]. For this reason, Latex agglutination testing has been introduced in our programme as an acceptable alternative to RPHA testing. In our opinion, despite the existing evidence of efficacy of guaiac testing in reducing CRC mortality, its inefficiency prevents a wide distribution of CRC screening. The information now available on immunochemical tests is enough to encourage the use of immunochemical FOBTs in order to improve screening performances and cost-effectiveness. In Tuscany, our Regional Government promoted a regional screening programme using 1-day immunochemical FOBTs, which aimed to cover the general population aged 50–70 years [9]. In the first 2 years almost 200000 subjects were invited and >80000 underwent screening (compliance 40.4%). Overall PR