Subset Analysis of a Multicenter, Randomized Controlled Trial to Compare Magnifying Chromoendoscopy with Endoscopic Ultrasonography for Stage Diagnosis of Early Stage Colorectal Cancer

Background Our recent prospective study found equivalent accuracy of magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) for diagnosing the invasion depth of colorectal cancer (CRC); however, whether these tools show diagnostic differences in categories such as tumor size and morphology remains unclear. Hence, we conducted detailed subset analysis of the prospective data. Methods In this multicenter, prospective, comparative trial, a total of 70 patients with early, flat CRC were enrolled from February 2011 to December 2012, and the results of 66 lesions were finally analyzed. Patients were randomly allocated to primary MC followed by EUS or to primary EUS followed by MC. Diagnoses of invasion depth by each tool were divided into intramucosal to slight submucosal invasion (invasion depth <1000 μm) and deep submucosal invasion (invasion depth ≥1000 μm), and then compared with the final pathological diagnosis by an independent pathologist blinded to clinical data. To standardize diagnoses among examiners, this trial was started after achievement of a mean κ value of ≥0.6 which was calculated from the average of κ values between each pair of participating endoscopists. Results Both MC and EUS showed similar diagnostic outcomes, with no significant differences in prediction of invasion depth in subset analyses according to tumor size, location, and morphology. Lesions that were consistently diagnosed as Tis/T1-SMS or ≥T1-SMD with both tools revealed accuracy of 76–78%. Accuracy was low in borderline lesions with irregular pit pattern in MC and distorted findings of the third layer in EUS (MC, 58.5%; EUS, 50.0%). Conclusions MC and EUS showed the same limited accuracy for predicting invasion depth in all categories of early CRC. Since the irregular pit pattern in MC, distorted findings to the third layer in EUS and inconsistent diagnosis between both tools were associated with low accuracy, further refinements or even novel methods are still needed for such lesions. Trial Registration University hospital Medical Information Network Clinical Trials Registry UMIN 000005085


Background
Early stage CRC is colorectal caner within mucosal and submucosal invasion that is categorized into stage Tis and T1 according to theTNM classification. Intramucosal CRC (M) is a good indication for endoscopic resection because there is no probability of lymph node metastasis (LNM) (1). On the other hand, surgical resection is generally recommended for submucosal CRC because of about a 13% possibility of LNM (2). However, surgical resection for all submucosal CRCs would result in oversurgery because there are some submucosal CRCs with quite low risk of LNM. As a recent Japanese study has reported no LNM in submucosal cancer with slight submucosal invasion (invasion depth <1000 µm, SMS) (3), M/SMs has been currently considered an indication for endoscopic resection (4). Therefore, diagnosis of invasion depth before treatment is the most important for choosing the therapeutic strategy of early CRC. Both EUS and MC are considered as useful methods for the pre-diagnosis of invasion depth of early CRC. Tumor can be generally described as low echoic lesion by EUS and its spread to the 3 rd layer are diagnosed as submucosal CRC with deep submucosal invasion (invasion depth ≥1000 µm, SMD). Previous reports have shown 66-88% accuracy with EUS for diagnosis of invasion depth for early CRC (5-7). Although EUS for early CRC has been widely spread in Japanese clinical setting, performance of EUS is somewhat complicated because EUS requires distilled water injection and changing body position during procedure. Meanwhile, MC enables diagnosis of invasion depth of CRC by morphological evaluation of surface crypts on the tumor, which is called the pit pattern. MC can be quickly performed after standard endoscopic observation. The pit pattern is roughly divided into 5 patterns, and type V, which shows a fairly irregular and non-structural pit pattern, is a match for cancer. The classification of type V pit pattern was complex, but type V pit patterns with severe irregularity and a non-structural appearance are reported as cancer with SMD at the consensus symposium in 2004. Based on these diagnostic criteria, MC has reportedly shown 79-98.8% accuracy for diagnosis of invasion depth for early CRC (8-10). However, real efficacy of each tool remained unclear because these results of EUS and MC were reported as single arm study from special institution for each method. There have been two prospective studies to compare MC with EUS for the prediction of invasion depth of CRC so far. Both studies showed that EUS was consistently superior to MC with a higher accuracy for diagnosis of invasion depth (91.8% vs. 63.3%, P=0.0013 (11); 93% vs. 53%, P<0.0001 (12)). However, results of these trials were based on the previous definition before standardization of MC pit pattern, and the comparison of EUS and MC under the current pit pattern classification have been unknown. The latest retrospective study showed a better tendency of MC compared to EUS (MC: EUS, 87% vs. 75%, P=0.0985) although it was not significant (13).
From these previous results, standard diagnostic method for invasion depth of early CRC is still inconclusive and its usage depends on a choice of each institution and endoscopist. We thus planed this trial to prove the speriority of MC to EUS.

Study aim
To prospectively compare MC with EUS for preoperative diagnosis of invasion depth in early colorectal cancer (CRC) Primary endpoint: accuracy of invasion depth Secondary endpoint: Sensitivity and specificity for deep submucosal invasion, Observation time, Accuracy rate between MC in A group and EUS in B group, Accuracy rate in each group between MC and EUS M/SMS: A hypoechoic area limited to the 1 st /2 nd layers or with slight irregularity on the surface of the 3 rd layer ≥SMD：A hypoechoic area that clearly invades and penetrates into the 3 rd layer

Accuracy rate between MC in A group and EUS in B group：
Accuracy rate of the primary diagnostic method in each group

Accuracy rate in A and B group between MC and EUS：
Accuracy rate in each group between MC and EUS

Adverse events and safety insurance for the trial 12-1 Definition of adverse events
All harmful events during the trial, regardless of the presence or absence of causual relationship 12-2 Assessment ・Assessment using the following NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0) as toxicity grading criteria ・Record in a patient's case record when adverse events are observed.

12-3
Assessment and report of severe adverse events Definition of severe adverse events ① Fatality ② Life crisis ③ Need of hospitalization for treatment ④ Permanent or serious functional damage ⑤ Other serious medical event and reaction ・ All adverse events within 30 minutes after the trial should be reported.
However, events after 30 minute should be reported when relationship to the trial is suspicious. ・A managing investigator in each institution sends the detailed documentation of severe adverse events to the central office. ・A managing investigator in each institution has to report severe adverse events to the director of each hospital.