Systematic Review With Meta-analysis

Volatile Organic Compound Analysis to Improve Faecal Immunochemical Testing in the Detection of Colorectal Cancer

Subashini Chandrapalan; Sofie Bosch; Joaquín Cubiella; Jordi Guardiola; Peter Kimani; Chris Mulder; Krishna Persaud; Tim G. J. de Meij; Donato F. Altomare; Herman Brenner; Nanne K. H. de Boer; Luigi Ricciardiello; Ramesh P. Arasaradnam


Aliment Pharmacol Ther. 2021;54(1):14-23. 

In This Article

Abstract and Introduction


Background: Faecal immunochemical test (FIT) is emerging as a valid test to rule-out the presence of colorectal cancer (CRC). However, the accuracy of FIT is dependent on the cut-off applied. An additional low-cost test could improve further detection of CRC.

Aims: To evaluate the efficacy of combined FIT and volatile organic compounds (VOC) in the detection of CRC within symptomatic populations.

Methods: Systematic reviews on the diagnostic accuracy of FIT and VOC, for the detection of CRC, were updated. Meta-analyses were performed adopting a bivariate model for sensitivity and specificity. Clinical utility of combined FIT and VOC was estimated using Fagan's nomogram. Post-test probability of FIT negatives was used as a pre-test probability for VOC.

Results: The pooled sensitivity and specificity of FIT at 10 μg/g faeces, for the detection of CRC, were 0.914 (95% confidence interval [CI] = 0.894–0.936) and 0.783 (CI = 0.850–0.696), respectively. For VOC, the sensitivity was 0.837 (CI = 0.781–0.881) and the specificity was 0.803 (CI = 0.870–0.712). The area under the curve for FIT and VOC were 0.926 and 0.885, respectively. In a population with 5% CRC prevalence, the estimated probability of having CRC following a negative FIT was 0.5% and following both negative FIT and VOC was 0.1%.

Conclusions: In a FIT-negative symptomatic population, VOC can be a good test to rule-out the presence of CRC. The estimated probability reduction by 0.4% when both tests being negative offers adequate safety netting in primary care for the exclusion of CRC. The number needed to colonoscope to identify one CRC is eight if either FIT or VOC positive. Cost-effectiveness and clinical accuracy of this approach will need further evaluation.


Faecal immunochemical test (FIT) is presently used as a triage tool in the UK in symptomatic patients who are referred through the suspected cancer pathway (National Institute of Care and Excellence NG12) criteria.[1] The overall pooled sensitivity and specificity of FIT for the detection of CRC were 0.90 and 0.87, respectively.[2] Although FIT is being used in the symptomatic population as a "rule-out" test for colorectal cancer (CRC) at lower thresholds, there is still a miss rate of 1 in 10. A study, which looked at symptomatic patients referred on a 2-week referral pathway, showed that the false-negative rate of FIT—at the cut-off of 10 μg/g faeces—was 14%.[3] In screening populations, this could vary up to 66% depending on the cut-off values applied.[4–6] A false-negative FIT result can delay the diagnosis of CRC and could give false reassurance to patients. This will invariably have serious consequences not only for patients but also on the healthcare systems.

Several studies have attempted to analyse factors affecting false-negative rates of FIT. A recent systematic review and meta-analysis had identified male sex, having a family history of CRC, history of smoking, high blood glucose levels and hypertension as being significantly associated with high false-negative results.[7] Interestingly, a study by Ibañez-Sanz et al[5] concerning the diagnostic accuracy of FIT in a screening population showed that 94% of false-negative FIT values were below the limit of detection (below 4 μg/g faeces). This suggests that lowering the FIT cut-off below 10 μg/g faeces may not reduce false-negative rates significantly. Another quite recent study concluded that the sensitivity of FIT for stage I CRC was only 68% and, for stage III and IV cancers 82%-89%.[8] According to a recent systematic review and meta-analysis, sensitivity is even as low as 40% for T1 colorectal cancers.[9] In this context, introducing another test, as an adjunct to FIT, might help in improving the false-negative rates and reduce the number of cancers missed.

The detection of volatile organic compounds (VOC) emanating from bodily fluids has been shown to have a good diagnostic performance for CRC.[10–13] A recent meta-analysis by Zhou et al[14] showed that VOC had an overall sensitivity of 0.82 and specificity of 0.79 for the detection of CRC. This suggests that VOC has potential to be used as a complementary test to FIT, in particular in, the FIT-negative group.

The aim of our article was to critically assess the clinical utility of VOC in the FIT-negative symptomatic population for the detection of CRC, utilising results from two meta-analyses. This study also evaluates different scenarios (lowering FIT threshold vs adding a second test) in order to combat FIT-negative CRC. This is a collaborative effort from major centres across EU and the UK—"VOC(F)IT working group."