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Semi-automation in colorectal screening seems feasible with PET/CT. A focal colorectal
FDG accumulation with SUV
_max
?5 should automatically trigger a referral for colonoscopy leaving the cases with
SUV
_max
5 for individual interpretation. Even if the SUV
_max
varies with scanner type, the semi-automation approach seems robust; a possible scanner-related
shift of this threshold value will be compensated by subjective interpretation as
for any other focal colorectal uptake below the trigger threshold.

Normalisation to a priori known extrinsic factors

We found no correlation between the SUV
_max
and a priori known extrinsic factors that could bias the SUV
_max
measurements (Additional file 1: Table S1). This suggests that the SUV
_max
does not need to be further normalised for these a priori known extrinsic factors.
The lack of correlation between the SUV
_max
and the time to scan suggests that the SUV
_max
is independent of the time of scanning in the tested range 59–112 min (mean: 75 ± 14 min)
after injection. Further study is needed using dynamic PET to test intra-individually
at 30, 60, 90 and 120 min to ascertain which time interval between injection and imaging
is optimal for the detection of malignant colorectal uptakes. It has recently been
found that normalisation to the blood pool in the aorta provides a means of correcting
for scan time dependence 9]. This requires further verification. The lack of correlation between the SUV
_max
and activity in the tested range 94–395 MBq (mean: 329 ± 46 MBq) suggests that the
activity can be reduced, possibly independent of weight, to 200 MBq. This is of interest
in situations where PET/CT may be offered to asymptomatic individuals instead of screening
colonoscopy where endoscopy is contraindicated, refused or not possible to complete.

Benefit vs. radiation risk of PET/CT

To be justified, the benefit of PET/CT in early detection must compensate for its
radiation risk. With 200 MBq activity the total radiation exposure can be reduced
to less than two times natural background radiation (200 MBq × 6.7 mSv/350 MBq 10] + 0.8 mSv 11] = 4.6  2 × 2.4 = 4.8 mSv, assuming a linear relationship between MBq and mSv if
350 MBq results in 6.7 mSv 10]). The dose issue is especially significant if PET/CT is used for screening before
the onset of symptoms in healthy subjects. The purely hypothetical 12] and delayed radiation risk is compensated if PET/CT detects 3 % of the colorectal
cancers which occur in 0.9 % of cases (colonoscopic prevalence in a screening setting)
13] (x % sensitivity × 0.9 % prevalence 0.005 %/mSv 14] radiation risk × 4.8 mSv radiation exposure; with x % 3 %). In this calculation of the minimum required sensitivity (x %  3 %), the concurrent detection of extra-colonic cancer entities and advanced
adenomas, as well as other serious conditions such as cardiovascular disease, were
not taken into account thus underestimating the overall benefit of PET/CT. Furthermore,
there is a 10- to 40-year delay 15] between the hypothetical induction and development of radiation-induced cancer; the
natural history of a missed cancer, had PET/CT not been performed, is more severe
than the natural history of a hypothetical and delayed induced cancer, had PET/CT
been performed. Additionally, the benefit-to-risk ratio of PET/CT increases with age
due to the decreasing radiation risk and increasing incidence of cancer. This is in
contrast to colonoscopy, where the rate of complication increases with age, while
the prophylactic meaning of a polypectomy decreases. This is especially relevant as
colorectal screening is recommended for individuals up to 70 years of age 16].

Determination of the optimum SUV
_max
threshold

In our study, we found the minimum SUV
_max
in 54 colorectal carcinomas to be 5 thus determining the threshold. There are only
a few studies which showed an SUV
_max
lower than 5 for colorectal cancer. Sarikaya et al. 17] reported four carcinomas that were detected with SUV
_max
4.5, of which three were mucinous. Peng et al. 18] reported a range in SUV
_max
from 3.1 to 28 which included two mucinous carcinomas. The low cellularity of mucinous
carcinomas may explain the low SUV
_max
. A meta-analysis regarding the SUV
_max
of colorectal cancer is not possible because the SUV
_max
was not always listed for each carcinoma. When SUV
_max
is used as the sole trigger, and not in combination with other factors, an SUV
_max
threshold of 5 would cover 96 % (215/224) of FDG-positive colorectal cancers (Figs. 1, 2, 3, 4) 17]–31], leaving only 4 % of positive cases requiring individual interpretation.

False negatives (FN) (carcinomas)

Besides the 4 % of PET-positive colorectal cancer cases that fall below the threshold,
some cancer cases are completely PET negative. The rate of PET-negative cancer cases may be at least 5 % as suggested by studies looking at all patients who underwent
PET/CT followed by colonoscopy within a short period of time 25], 30], 32]. On the other hand, the miss-rate of optical colonoscopy can be estimated at a worst
case of 2.9 %, assuming that all 2.9 % of the so-called interval cancers occurring
within 5 years of a negative colonoscopy were missed and not newly developed 33].

The issue of false negatives must be viewed in context. The vast majority of the German
population currently does not come forward for screening due in large part to the
invasive nature of colonoscopy. Between 2002 and 2008, 2,821,392 screening colonoscopies
were performed across Germany which represents 15.5 and 17.2 % of all eligible men
and women, respectively, from the age group 55–74 years 13]. Thus, approximately 80 % of the target group did not take advantage of the colonoscopy
screening programme during this 6-year screening interval. Although the acceptance
rate is higher in some other countries, such as the US, there is a widespread reluctance
on the part of the population to come forward for colonoscopy-based screening. Shortcomings
in alternative screening techniques must be balanced against the significant number
of tumours which progress to a more advanced stage due to this very low acceptance
of colonoscopy screening. PET/CT should not replace colonoscopy screening in the minority
of individuals who assent, but provide an attractive alternative for the majority
who refuse. Thus, if colonoscopy is refused, PET/CT needs to be compared with faecal
occult blood test (FOBT) and not with colonoscopy.

False positives (FP)

FDG-enriched stool in the caecum is the most common cause of false-positive FDG accumulation
11]. FDG excretion into the small bowel and accumulation in the caecum during the 60-min
interval between injection and imaging may explain this observation. The typical location
in the caecum in conjunction with centric distribution and air-typical CT values,
which indicate air inclusions, helps to differentiate FDG-enriched stool from a wall-adherent
eccentric mass. Although Van Heoij et al. 31] recently found that the SUV
_max
in 404 focal colorectal uptakes was significantly higher for cancer (p  0.001) than for all other types of lesions (advanced adenoma, non-advanced adenoma
and benign lesions), Keyzer et al. 34] showed that the SUV
_max
alone does not differentiate true- from false-positive colorectal FDG foci. The metabolic
volume also failed to differentiate TP from FP 34], 35].

As the SUV
_max
in premalignant/malignant and physiological/benign colorectal FDG accumulation is
indistinct, the clear separation (cut-off) between TP and FP seems to be unattainable
with SUV
_max
alone. We therefore defined the trigger as automating the decision above a threshold
only (semi-automated analysis). Given the relatively low prevalence of focal colorectal
uptakes (3.6 %) but the relatively high risk of these being malignant or premalignant
(68 %) 36], the benefit of maximising the sensitivity with semi-automated analysis seems to
justify a lower specificity with more FPs. If colonoscopy is the worst consequence
of an FP, these patients would not be disadvantaged compared to their outcome had
they taken up the current screening programme 16], 37]. In comparison to colonoscopy, the 1.5 % rate of FP in PET/CT 36] with consecutive colonoscopy is far lower than the 26.5 % rate of false-positive
polypectomies, several polypectomies per person not counted 13].

Partial volume effects: a drawback of digitisation

Averaging within a volume pixel (voxel) of a finite edge length is a drawback of digitisation.
Smaller lesions in the range of only view voxels might not be visible due to spatial
and temporal averaging within one voxel (partial volume artefacts) 38]. The resultant blurring might reduce the overall contrast so that the lesion is not
delineated. However, a very high uptake—the so-called hot spot phenomenon, as known
from melanoma—might compensate for a larger voxel size and even depict lesions within
the range of the voxel resolution [currently: 95 mm
³
(=0.095 ml) based on 400 × 400 matrix reconstruction]. However, this potential inferiority
in voxel resolution compared to optical colonoscopy might be compensated by a shorter
screening interval (e.g. 5 years as for CT colonography 37]). This may be completely unnecessary when the long lead time of 10 years in the adenoma-to-carcinoma
sequence is taken into account 39]–42] and the fact that therapy in asymptomatic (lower stage) colorectal cancer is mostly
curative. Furthermore, it must be emphasised that lower voxel resolution can easily
be compensated for by a shorter screening interval, in contrast to a lower screening
acceptance rate which cannot be compensated for.

Extrapolation to advanced adenoma

There is some evidence that PET/CT failed to detect around half of cases with advanced adenoma43]. The study was performed between 2000 and 2009 using now outdated PET and PET/CT
technology. Since then, the spatial resolution has improved from 4.5 mm to almost
2 mm today, for example. In an interval screening programme, it is the accuracy of
the programme and not of the single test which matters. Furthermore, the consequence
of a missed tiny adenoma is unclear if the cancer can still be curatively resected
at the consecutive screening, if indeed the adenoma develops to cancer at all. The
mismatch in prevalence between advanced adenoma (6.4 %) and colorectal cancer (0.9 %)
13] suggests that not all advanced adenomas proceed to cancer. It is assumed that a patient
with advanced adenoma at age 55–65 has a greater than 50 % chance of developing colon
cancer 44]. The potential lack in screening sensitivity may be compensated by reducing the interval
between examinations (for example from 10 to 5 years as proposed for CT colonography
37]), but a low screening acceptance rate cannot be compensated.

To date, we have neither included advanced adenoma nor correlated the FDG uptake with
the KI 67 index as markers for proliferation. We measured FDG uptake versus TNM stage,
however, and found no correlation (Fig. 4). Pending further study, we might extrapolate that the trigger SUV
_max
?5 is also valid for advanced adenoma, depending on the growth rate. The hypothesis
that the SUV
_max
correlates with the growth rate seems correct; glucose provides the energy for proliferation
and is supported by the relationship between pre-operative
¹⁸
FDG uptake and epidermal growth factor receptor 45]. Also,
¹⁸
FDG-PET detects all cancers in patients with familial adenomatous polyposis 46]. This is still speculative, however, pending a larger study. Recently, Na et al.
47] proposed an SUV
_max
 = 5.8 as optimal cut-off to identify a malignancy or high-grade dysplasia but warned
that colonoscopy should be performed above an SUV
_max
 = 2.5 to avoid missing a malignancy or high-grade dysplasia. This is in line with
the semi-automation we propose: an SUV
_max
?5 should automatically trigger a referral for colonoscopy leaving the cases with
SUV
_max
5 for individual interpretation.

Case for PET/CT screening

A great deal of expertise and resources are currently invested in establishing, testing
and improving mono-organ screening methods. Screening programmes are currently in place for the early detection
of oncological, cardiovascular and metabolic diseases including prostate, lung, colorectal,
ovarian 48] and breast cancer, as well as arteriosclerosis, aortic aneurysm and osteoporosis.
PET/CT offers the possibility of replacing most mono-organ screening methods with a single multi-organ screening exam. A single PET/CT screening appointment lasting around 1 h promises
to be more accepted, efficient, effective and safe than the combined organ-specific
screening techniques currently in use.

In addition, PET/CT is a promising candidate for semi-automated analysis as it acquires
digital data, in vivo, at the molecular level. In the context of colorectal cancer,
this cannot be said of the subjective optical interpretation at the macroscopic level
required for colonoscopy. Although laxative-free CT colonography 49] and PET/CT are both non-invasive and require no bowel preparation, PET/CT seems superior
for multi-organ screening and semi- or potentially full automation of the analysis,
as we have discussed.