Capsule endoscopy compared with conventional colonoscopy for detection of colorectal neoplasms

Abstract

Colon capsule endoscopy (CCE) may be a means to overcome the low adherence to colorectal cancer screening. The device is an ingestible capsule with a video camera at both ends that can take photographs as it progresses through the gastrointestinal tract. PillCam colon (PCC1) may be used for structural evaluation of the large bowel following an adequate cleaning procedure. PCC1 measures 11 mm × 31 mm and has dual cameras that enable the device to acquire video images from both ends with a wide coverage area, automatic light control and a frame rate of four frames per second. The system includes a sensor array and data recorder connected to the patient during the procedure. The recorded data are downloaded to the Given Imaging Rapid workstation for review of the colon video. The second generation of PillCam Colon (PCC2) is similar to PCC1 and incorporates new developments. The angle of view has been increased to 172 degrees. It has an adaptive frame rate, alternating from 35 frames per second while in motion to 4 images when virtually stationary. The new RAPID^® software now includes a simple graphic interface tool for polyp size estimation. The procedure of bowel cleansing until capsule ingestion is similar to that used for traditional colonoscopy. However it is more rigorous as the bowel cleanliness for capsule colonoscopy has to be excellent or at least good to result in an adequate sensitivity of the method. Briefly, it consists of 3.5-4 L of split dose polyethylene glycol. Oral NaP boosters are administered after 1-2 h if the capsule has entered the small bowel. Sodium phosphate (NaP) seems to be a necessary adjunct to the regimen because the total transit time is doubled without NaP. The cleansing level was considered to be good to excellent in 72%-88% in studies with PCC1. The sensitivity for significant polyps (> 6 mm or more than 3 polyps >3 mm) ranged from 63%-88% with specificities between 64%-94%. PCC2 showed an improved sensitivity of 89% and a specificity of 76%. CCE seems to be a safe and effective method of visualizing the colonic mucosa through colon fluids without the need for sedation or insufflation of air. The sensitivity of CCE to detect polyps, advanced adenomas and cancer is lower compared to optical colonoscopy but improvements will be made in the near future. With an increased recording duration, even a panenteric examination of the whole gastrointestinal tract may be possible.

Key Words: Colon capsule endoscopy, Colorectal cancer, PillCam colon, Conventional colonoscopy

INTRODUCTION

Colorectal cancer is the second leading cause of cancer death in North America[1] and Western Europe. Screening colonoscopy was introduced in the National Cancer Prevention Program in Germany in 2002[2], even though results from randomised controlled studies on its effect on incidence and mortality of colorectal cancer were not yet available. A first evaluation of screening colonoscopy in Germany showed a detection rate of adenomas of 20%, advanced adenoma 6% and colorectal cancer 0.7%[3], similar to the detection rates in Poland[4]. However, the participation in colonoscopy screening is as low as 3%-4%[5]. In the US, a decrease in incidence and mortality of colorectal cancer may be attributed partly to an increased screening activity[1].

A means to overcome the low screening activity might be to introduce new convenient methods to reduce people’s resistance. One of these methods might be colon capsule endoscopy (CCE). Small bowel capsule endoscopy has been used successfully to visualize the upper gastrointestinal tract and small bowel. The instrument is an ingestible capsule with a video camera at one end that can take photographs as it progresses through the gastrointestinal tract. The main indication for use of the small bowel capsule is obscure gastrointestinal bleeding[6] and it has been shown to be feasible and cost saving as an outpatient procedure[7]. The newly developed PillCam colon (PCC1) may be used for structural evaluation of the large bowel following an adequate cleaning procedure.

DEVICE DESCRIPTION OF THE COLON CAPSULE

PCC1

PCC1 capsule endoscope (Given Imaging Ltd., Yoqneam, Israel) was the first capsule with a battery life that enables visualization of the colon[8,9]. The capsule measures 11 mm × 31 mm and has dual cameras that enable the device to acquire video images from both ends with a wide coverage area, automatic light control and a frame rate of four frames per second. The operation time is approximately 10 h and after an initial image transmission of 3 min, the capsule enters a delay mode (of approximately 2 h), after which it spontaneously “wakes up” and restarts the transmission of images. The system includes a sensor array and data recorder connected to the patient during the procedure. The recorded data are downloaded to the Given Imaging Rapid workstation for review of the colon video. The localization display of the RAPID^® software enables the physician to identify the location of findings, i.e. right, transverse or left colon segments once the main anatomical landmarks (first cecal image, hepatic flexure, splenic flexure and exit of the capsule) have been selected. RAPID^® Access RT by Given Imaging allows real time visualization of capsule images. This allows localization of the device and consequently an intervention to optimize the procedure during the ongoing examination. One example is that the patient has to drink a small amount of sodium phosphate 2 h after ingestion of the capsule in order to push the capsule through the small bowel. However, he should only drink sodium phosphate if the capsule has passed the stomach because sodium phosphate may delay gastric emptying time.

PCC2

The second generation of PillCam Colon (PCC2), Given Imaging Ltd., Yoqneam, Israel, is similar to PCC1 and consists of an ingestible video capsule measuring 11.6 by 31.5 mm and has two imagers, one at each end of the capsule. The second-generation system incorporates new developments to the capsule, the data recorder and the RAPID^® software[10].

The angle of view has been increased to 172 degrees (from 156 in PCC1). In order to conserve battery energy, the capsule captures images at an adaptive frame rate, alternating from 35 frames per second while it is in motion (such as in the transverse colon) to 4 images when it is virtually stationary. After swallowing, the capsule works with a low frame rate of 14 per minute until it automatically identifies the small bowel.

The new data recorder also assists and guides the medical staff and patient through the procedure. It buzzes, vibrates and displays instruction numbers in order to alert the patient to take the laxative booster or that the procedure has terminated.

The new RAPID^® software now includes a simple graphic interface tool for polyp size estimation. After marking the distance from one side of the polyp to the other, the RAPID^® software calculates the distance and displays the polyp size in millimetres.

PROCEDURE AND CLEANLINESS

The procedure of bowel cleansing until capsule ingestion is similar to that used for traditional colonoscopy. However, it is more rigorous as the bowel cleanliness for capsule colonoscopy has to be excellent or at least good to result in an adequate sensitivity of the method. The reason for the rigorous procedure is that with a capsule, unlike a colonoscope, fluid cannot be aspirated. If the fluid is unclear, the bowel mucosa may not be seen by CCE.

The reason for the combination of PEG with laxatives is to maintain the colon cleanliness and facilitate progression of the capsule through the gastrointestinal tract.

Briefly, it consists of a clear liquid diet with/without a small breakfast on the day before capsule ingestion and 3.5-4 L of split dose polyethylene glycol (PEG). Oral NaP boosters are administered after 1-2 h if the capsule has entered the small bowel and again 2-3 h later, followed by the administration of a bisacodyl suppository two hours after the second boost if the capsule has not been excreted (Table 1). The procedures for PCC1[8,9,11,12] and for the newly developed PCC2[10] are similar.

Table 1 Procedure protocols and cleansing levels.

Authors	Eliakim 2006[8]	Schoofs 2006[9]	Sieg 2009[12]	Van Gossum 2009[11]	Eliakim 2009[10]	Spada 2010[13] (Standard/modifiedprocedure)
Device	PCC1	PCC1	PCC1	PCC1	PCC2	PCC1
Day 2	Low fibre diet	-	-	-	-	-
Day 1	7-8 pm	6-9 pm	1-6 pm	6-9 pm	evening	evening
	PEG 2 L	PEG 3 L	PEG 3 L	PEG 3 L	PEG 2 L	PEG 3 L
Day 0					morning	morning
6-7 am	PEG 1 L	PEG 1 L	PEG 0.5 L	PEG 1 L	PEG 2 L	PEG 1 L
8-9 am	Tegaserod 6 mg	Domperidone 20 mg	Domperidone 20 mg	Domperidone 20 mg		Domperidone 20 mg
	Capsule ingestion	Capsule ingestion	Capsule ingestion	Capsule ingestion	Capsule ingestion	Capsule ingestion
10:00 am	NaP 30 mL	NaP 45mL	NaP 22mL	NaP 45 mL		NaP 45 mL/0.5 L PEG
	+
12 am-1 pm	Tegaserod 6 mg		NaP 22 mL		1-2 h later NaP 45mL
02:00 pm	NaP 15 mL	NaP 30 mL		NaP 22 mL	2 h later NaP 22 mL	NaP 22 mL/0.5L PEG
04:30 pm	Bisacodyl supp 10 mg	Bisacodyl supp 10 mg	Bisacodyl supp 10 mg		Bisacodyl supp 10 mg	Bisacodyl supp 10 mg
Cleansing level Good and excellent (%)	84.4	88	72	72	78	35/53

PCC1: PillCam Colon 1 (Given Imaging Ltd, Yoqneam, Israel); PCC2: Second generation of PillCam Colon (Given Imaging Ltd, Yoqneam, Israel).

With this regimen 69%-84% of the capsules were excreted within 6-8 h[8-13] and 92.8% within 10 h[10]. If only conventional colonoscopy preparation was used, the excretion rates were as low as 20%. Sodium phosphate (NaP) seems to be a necessary adjunct to the regimen. In two studies, NaP was omitted from the regimen and replaced by PEG[12,13]. This resulted in a low excretion rate and the total transit time was doubled, without improvement of the colon cleanliness. The combination of PEG and NaP may cause problems in patients with advanced cardiovascular or renal disease as outlined below.

The cleansing level was considered to be good to excellent in 72%-88% in studies with PCC1[8,9,11,12] and 78% in a study with PCC2[10]. In one study from Italy, an adequate cleansing level was achieved in only 35% of the patients with the standard procedure containing NaP and in 53% of a modified procedure where NaP was replaced by PEG[13] with a similar regimen (Table 1). The cleansing level is significantly different in different segments of the colon[10,12] and the best results are achieved in the transverse and descending colon. The segment with the poorest cleansing level is the rectum. Future studies may improve the visibility of this part of the colon. A significant difference could not be confirmed in one study[13].

DETECTION OF LESIONS

The long-term objective of colon capsule endoscopy (CCE) is screening of the average population. In the first feasibility studies, the sensitivity for significant polyps (> 6 mm or more than 3 polyps >3 mm) was evaluated in patients with an indication for colonoscopy and ranged from 63%-88% with specificities between 64%-94%[8,9,11,13,15] (Table 2). In a small study under routine screening conditions from Switzerland, the sensitivity of significant findings was only 50% (95% CI: 19-81)[14] and in a study from France in patients at average and increased risk, the sensitivity was 39% (95% CI: 30-48)[16]. CCE was successfully used in an ambulatory practice of gastroenterology with a median transit time of 4.5 h[12]. In patients with short transit time, a panenteric examination of the upper, mid and lower gastrointestinal tract would be possible. In patients with excellent or good colon cleanliness, the sensitivity was significantly higher than in patients with poor cleanliness[11]. Meta-analyses on PCC1 with 626 patients[17] and 837 patients[18] found sensitivities for significant polyps of 69% and 76%, with specificities of 86% and 82% respectively.

Table 2 Sensitivity and specificity of colon capsule endoscopy for polyps 6 mm or larger performed with PCC1 and PCC2.

	Eliakim[8]	Schoofs[9]	Van Gossum[11]	Spada[13]	Pilz[14]	Gay[15]	Sacher-Huvelin[16]	Eliakim[10]
Year	2006	2006	2009	2010	2010	2010	2010	2009
Device	PCC1	PCC1	PCC1	PCC1	PCC1	PCC1	PCC1	PCC2
N	84	36	328	40	36	128	545	98
Sens (%)	63	76	64	63	50	88	39	89
Spec (%)	94	64	84	87	76	76	88	76

PCC1: PillCam Colon 1 (Given Imaging Ltd, Yoqneam, Israel); PCC2: Second generation of PillCam Colon; N: Patients with complete examination; Sens: Sensitivity; Spec: Specificity.

A second generation capsule (PCC2) showed an improved sensitivity of 89% and a specificity of 76% in 98 patients aged 18 to 57 years scheduled to undergo colonoscopy for suspected or known colonic disease[10]. The sensitivity described is higher than with any other CCE so far but still has to be established in further studies.

To date, conventional colonoscopy is the gold standard for detection of colorectal neoplasia, offering the ability to remove detected polyps and obtain biopsy samples with one examination in contrast to all diagnostic procedures. However, standard colonoscopy only detects about 90% of polyps 10 mm or larger[19-26]. Some studies also suggested that colonoscopy may be protective only for cancers[27] and advanced adenomas[28] in the distal but not proximal colon. The effectiveness of all screening programs depends on the quality of colonoscopy because colonoscopy is used to evaluate positive screening tests in all programs. A highly qualified colonoscopy with an adequate withdrawal time[29] is a prerequisite for all screening programs.

SAFETY

No capsule or laxatives-related adverse effects occurred during the first feasibility studies[8-10] and only mild to moderate adverse effects were reported in a multicenter trial[11]. Only 4 of 582 patients (0.7%) were unable to swallow the capsule[8-12].

COST EFFECTIVENESS

Cost-effectiveness of CCE was evaluated in a recent paper based on a mathematical Markov model[30]. With equal compliance rates, colonoscopy was more cost-effective than CCE. With a 30% increase in compliance, CCE becomes more cost-effective than colonoscopy. Moreover, future generations of capsules may improve the detection rate of polyps and thereby increase the cost-effectiveness. When both procedures are offered, patients prefer colonoscopy because of the higher sensitivity and that there is no need for a second test[31].

CONCLUSION

CCE seems to be a safe and effective method of visualizing the colonic mucosa through colon fluids without the need for sedation or insufflation of air. Colon cleanliness significantly influences the sensitivity for polyps and cancer. The sensitivity of CCE to detect polyps, advanced adenomas and cancer is lower when compared to optical colonoscopy. Improvements in capsule technology increased the sensitivity for colorectal neoplasms in PCC2 and, with the new generation of capsules, a similar sensitivity of CCE and colonoscopy may be accessible in the future. Currently, a large study on a standard screening population is not yet available. The future range of CCE in CRC screening will depend not only on sensitivity, but also on these issues: 1) Bowel preparation: The bowel preparation for CCE is more extensive than for colonoscopy as only clear liquids are allowed inside the colon. In contrast, during colonoscopy the rinse and suction techniques can be used to remove turbid fluids. The rigorous bowel cleansing required for CCE with 4 L PEG and laxatives restricts its application to healthy people. Persons with severe cardiovascular disease in whom colonoscopy may be too dangerous are not able to drink so much fluid. In some patients, especially with impairment of renal function, NaP may be not indicated because it is associated with clinically relevant electrolyte abnormalities related to the absorption of phosphate. Bowel preparation will set limits to a mass screening with CCE; 2) Reading time: The reading time of colon capsule endoscopy usually ranges between 30 and 60 min. This is a time-consuming procedure that lasts longer than a colonoscopy. Future developments may shorten the reading time by an automatic detection of neoplasms and/or a pre-reading by trained technicians; and 3) Costs: The actual costs of a colon capsule endoscopy in Germany exceed the costs for colonoscopy by about 6 times. CCE is not yet reimbursed by most of the insurance companies. The high price of CCE represents an obstacle to mass screening.

Nevertheless, a non-invasive method for CRC screening may be of interest for those reluctant to undergo colonoscopy because of its perceived inconvenience, discomfort or embarrassment as CCE seems to be an adequate alternative. The examination can even be performed in the privacy of a patient’s home at the weekend, avoiding the need to take time off work. I believe that CCE will have a place as an additional screening tool for CRC in a selected and limited population.

As CCE has still some limitations (cannot insufflate air, clean or take biopsies), future capsule prototypes seem to be necessary. An increase of frame rate, angle of view and duration of the procedure seem likely[32]. With an increased recording duration, even a panenteric examination of the whole gastrointestinal tract may be possible. Improvement of visualization of the small bowel by a computed color enhancement system (FICE)[33] is under evaluation and possibly could be applied to CCE. A smart capsule with motion control and 360 degree view (Capsovision, Saratoga CA) is also under evaluation. Remote control movement will improve with the use of magnets or electrostimulation. Even an active endoscopic robot seems to be possible according to animal experiments[34].