The colorectal tumors that can be treated by endoscopic

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1 /STRU^NI RAD Endoscopic treatment for early stage colorectal tumors: The comparison between EMR with small incision, simplified ESD, and ESD using the standard Flush knife and the ball tipped Flush knife... T Toyonaga 1, M Man-i 2, R Chinzei 2, N Takada 3, Y Iwata 4, Y Morita 2, T Sanuki 2, M Yoshida 2, T Fujita 2, H Kutsumi 2, T Hayakumo 2, H Inokuchi 5, T Azuma 2 1 Department of Endoscopy, Kobe University Hospital 2 Department of Gastroenterology, Kobe University 3 Department of Surgery, Takaishi Kamo Hospital 4 Department of Gastroenterology, Takaishi Kamo Hospital 5 Department of Gastroenterology, Hyogo Cancer Center UDK / DOI: /ACI T BACKGROUND: Early stage colorectal tumors can be removed by endoscopic mucosal resection but larger such tumors (>20mm) may require piecemeal resection. Endoscopic submucosal dissection (ESD) using newly developed endo-knives has enabled en-block resection of lesions regardless of size and shape. However ESD for colorectal tumor is technically difficult. Therefore, we performed EMR with small incision (EMR with SI) for more reliable EMR, ESD with snaring (simplified ESD) and ESD using thestandard Flush knife and the novel ball tipped Flush knife (Flush knife BT) for easier and safer colorectal ESD. AIMS: The aims of our study were 1) to compare the treatment results of the following 3 methods (EMR with SI/si-mplified ESD/ ESD) for early stage colorectal tumors, and 2) to assess the performance of Flush kni-fe BT in colorectal ESD. METHODS: We treated 24/44/468 colorectal tumors and examined the clinicopathological features and treatment results such as tumor size, resected specimen size, procedure time, en-bloc resection rate, complication rate. We also treated 58 colorectal tumors (LST-NG:20, LST-G:36, other:2) using standard Flush knife and 80 colorectal tumors (LST-NG:32, LST- G:44, other:2) using Flush knife BT, and examined the clinicopathological features and treatment results mentioned above and also the procedure speed. RESU- LT: The median tumor size (mm) (EMR with SI/ simplified EMR/ESD) was 20/17/30 (EMR with SI vs. simplified ESD:p=n.s, simplified ESD vs. ESD:p< ). The median resected specimen size (mm) was 22.5/26 /41 (EMR with SI vs. simplified ESD: p=0.0018, simplified ESD vs. ESD: p<0.0001). The procedure time (min.) was 19/27/60 (EMR with SI vs. simplified ESD: p=n.s, simplified ESD vs. ESD: p< ) The en-block resection rate (%) was 83.3/90.9 /98.9. The complication rate (post-operative bleeding rate/perforation rate) was 0/0, 2.3/4.5, 1.5/1.5 (simplified ESD vs. ESD : rezime p=n.s). In the treatment results of ESD for LSTs by knives, there was no difference between standard Flush knife and Flush knife BT for clinicopathological features and treatment results (procedure time, complication rate and en bloc R0 resection rate). However, procedure speed (cm 2 /min.) of LST-G was significantly faster in the Flush knife BT than in standard Flush knife. (standard Flush knife: 0.21 vs. Flush knife BT: 0.27, p= 0.034). CONCLUSION: EMR with small incision (EMR with SI) and ESD with snaring (simplified ESD) are good option to fill the gap between EMR and ESD in the colorectum, and also considered to become the nice training for the introduction of ESD. Flush knife BT appears to improve procedure speed compared with standard Flush knife, especially for LST-G in colo-rectal ESD. Key words: Colorectal neoplasms, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), EMR with small incision, simplified ESD, Flush knife, Flush knife BT INTRODUCTION The colorectal tumors that can be treated by endoscopic resection range from small sessile, and (or) 0-IIc type lesions, to huge LSTs (lateral spreading tumors) which occupy almost whole round of the rectum. The treatment method of these lesions also diverge into many branches, such as hot biopsy, polypectomy, EMR (endoscopic mucosal resection), and ESD (endoscopic submucosal dissection). In the colorectum, the detailed preoperative diagnoses with the magnified endoscopy precisely have enabled to judge the lesions that must be removed by en-bloc resection from the lesions that are fully cured by piecemeal resection. Therefore, it is important to choose the treatment method for every lesion while considering the clinicopathological background and technical aspect.

2 42 T. Toyanaga et al. ACI Vol. LVII TABLE 1 PATIENT AND LESION BASELINE DATA OF 3 METHODS EMR with SI (n=24) Simplified ESD (n=44) ESD (n=468) Tumor size <20 mm >20 mm Median tumor size 20*(13-34) 17(4-33) 30**(6-158) 17(6-20) 30(21-158) Median resected specimensize 22.5$(15-35) 26(13-45) 41$$(17-165) 30(17-72) 41(23-165) Median procedure time (min) 19#(3-35) 27(89-98) 60##(11-335) 42(11-260) 60(18-335) Histopatological diagnosis ade 19(79.2) 22(50.0) 161(34.4) 48(49.5) 113(30.5) m-cancer 5(20.8) 17(39.6) 227(48.5) 32(33.0) 195(52.6) sa-cancer 0(0) 5(11.4) 78(16.7) 17(17.5) 61(61.4) mp-cancer 0(0) 0(0) 2(0.4) 0(0) 2(0.5) *p=n.s(emr with SI vs Simplified ESD); **p< (Simplified ESD vs ESD);$p=0.018(EMR with SI vs Simplifiled ESD) $$p<0.0001(simplified ESD vs ESD); #p=n.s(e+mr with SI vs Simplifiled ESD); ##p<0.001(simplifiled ESD vs ESD) EMR:endoscopic mucosal resection, SI:small incision, ESD: endoscopic submucocal dissection, ade:adenoma, m-cancer:mucosal cancer, sm-cancer:submucosal cancer, mp-cancr: muscularis propria-invasive cancer TABLE 2 EN BLOCK RESECTION RATE OF 3 METHODS EMR with SI (n=24) Simplified ESD (n=44) ESD (n=468) Tumor size <20 mm >20 mm En block resection rate (%) 83.3* (20/24) 90.9#(40/44) 98.9(463/468) 100(97/97) 98.7(366/371) *p=0,0005(emr with SI vs ESD); #p=0.0044(simplified ESD vs ESD) TABLE 3 COMPLICATION RATE OF 3 METHODS EMR with SI (n=24) Simplified ESD (n=44) ESD (n=468) Tumor size <20 mm >20 mm Postopertive bleeding (%) 0 (0/24) 2.3(1/44) 1.5*(7/468) 1.0(1/97) 1.6(6/371) Perforation (%) 0(0/24) 4.5(2/44) 1.5#(7/468) 1.0(1/97) 1.6(6/371) *p=n.s(emr with SI vs ESD); #p=n.s(simplified ESD vs ESD) As for EMR, in the case that the sizes of lesions are larger than 2cm, the rates of piecemeal resection obviously increase. However, even though lesions are smaller than 2cm, there are these lesions which are difficult to be treated by EMR because of the location of lesions and the existences of the "non-lifting sign". The locations which make the EMR difficult are the backside of fold, the corner of flexure, the neighboring of diverticulum. The "nonlifting sign" indicates the severe fibrosis or massive invasion in the submucosal layer. ESD has enabled en-bloc resection regardless of size and shape. However, ESD is technically difficult, time consuming, and causes high risk of complication. The colorectum has narrow lumen and many folds and the thin luminal wall, so the risk of complication in the colorectum is much higher than that in the stomach. The introduction of ESD in colorectum should be carefully decided, and the new methods are needed to make EMR more reliably, and to ESD more easily, safely and speedily. To overcome these problems, we performed and assessed EMR with small incision (EMR with SI) and also ESD with snaring (simplified ESD) as new methods, also ESD using standard Flush knife and Flush knife BT as a new endo-knife.

3 Br. 3 Endoscopic treatment for early stage colorectal tumors 43 TABLE 4 PATIENT END LESION BASELINE DATA USING FLUSH KNIFE AND FLUSH KNIFE BT Flush knife (n=58) Flush knife BT (n-80) p Median tumor size (mm) 32.0(8-100) 30.5(10-87) n.s Median resected specimen size (mm) 45(24-180) 41.5(22-90) n.s Macroscopic type n.s LST-G 36(62.1) 44(55.0) LST-NG 20(34.5) 32(40.0) Others 2(3.4) 4(5.0) Median procedure time (min) 66(12-660) 57(21-203) n.s Median procedure speed (cm2/min) 0.18( ) 0.20( ) n.s Histopathological diagnosis n.s adenoma 22(37.9) 22(27.5) mucosal cancer 32(55.2) 45(56.3) submucosal cancer 4(6.9) 13(16.2) En bloc resection rate 100(58/58) 100(80/80) n.s Postoperative bleeding (%) 0(0/58) 1.3(1/80) n.s Perforation rate (%) 1.7(1/58) 1.3(1/80) n.s LST-G:laterally spreading tumor-granular type; LST-NG:laterally spreading tumor-non granular PATIENTS/MATERIAL AND METHODS We treated 24 colorectal tumors by EMR with SI, 44 colorectal tumors by simplified ESD, and 468 colorectal tumors by ESD at the Kishiwada Tokushukai Hospital in Osaka between June 2002 and June 2007, or at the Kobe University Hospital in Kobe between July 2007 and December EMR with SI at both hospital and ESD (simplified ESD and ESD) at Kishiwada Tokushukai Hospital were performed by one skilled endoscopist (T.T). ESD (simplified ESD and ESD) at Kobe University Hospital was performed by T.T and another skilled endoscopist including the author and 3 endoscopists supervised by the experienced authors. EMR with small incision (EMR with SI): In the case that the lesions were located on the folds or close to the diverticulm and the snaring technique on conventional EMR are difficult, small mucosal incision by the tip of snare was carried out on the oral side of the lesion, and then the snaring was performed with the situation that the tip of snare was pushed lightly to the incision. Because of the fixed tip of snare, the appropriate snaring could be possible by sliding the tip of sheath to vertical or horizontal direction. EMR with SI was similar to the scratch-stick-method for EMR 1, but our method could more effectively fix the tip of snare because the tip was reliably fixed and the opening of snare was not interfered by the surrounding mucosa. In the cases that reliable snaring was impossible with EMR with SI, simplified ESD was tried as described below. ESD with snaring (simplified ESD): this was the method that lesions were resected by snaring after the circumferential incision and submucosal dissection to some extent. Sodium hyaluronate was used for the local injection solution. The tip of snare, Flex knife, and standard Flush knife were used for the devices for the mucosal incision. This method was considered to be a good for the lesions that were less than 3-4cm in size. The cases were classified as simplified ESD when the snaring was planned from the first, and the cases were classified as ESD when the snaring was difficult even after some extent of the submucosal dissection. ESD: As described in previous reports 2,3,4,5,6, Flex knife and standard Flush knife were used as endo-knives. Ancillary devices such as Needle knife, ST hood, and Hook knife were used additionally at the endoscopist s discretion. In this study, the 536 lesions were divided into 2 groups that one group was smaller than 2cm and the other was larger than 2cm in size. The cases resected by ESD included the cases that the treatment method had shifted from above 2 methods, and the cases with scar after EMR. We also treated 58 laterally spreading tumors (LSTs) by standard Flush knife and 80 LSTs by Flush knife BT at the Kobe University Hospital in Kobe between April 2009 and March The lesions were then divided into two subgroups based on endoscopic findings: LST- granular type (LST-G) which has even or uneven nodules or granules on the lesion surface

4 44 T. Toyanaga et al. ACI Vol. LVII TABLE 5-1 TREATMENT RESULTS OF LST-G USING FLUSH KNIFE AND FLUSH KNIFE BT Flush knife (n=36) Flush knife BT (n=44) p Medial resected specimen size (mm) 48.5(31-180) 49.5(28-90) n.s Median procedure time (min) 80(21-660) 63(24-203) n.s Median procedure speed (cm2/min) 0.21( ) 0.27( ) En block R0 resection (%) 100(33/36) 100(44/44) n.s TABLE 5-2 TREATMENT RESULTS OF LST-G USING FLUSH KNIFE AND FLUSH KNIFE BT Flush knife (n=20) Flush knife BT (n=32) p Medial resected specimen size (mm) 38(25-52) 37(26-60) n.s Median procedure time (min) 63(12-145) 51(21-163) n.s Median procedure speed (cm2/min) 0.16( ) 0.16( ) En block R0 resection (%) 100(20/20) 100(32/32) n.s and LST-non granular type (LST- NG) which has a smooth surface without nodules or granules 7. EVALUATED PARAMETERS In comparison of 3 methods (EMR with SI, simplified ESD, ESD), the retrospectively evaluated data included tumor size, resected specimen size, procedure time, enbloc resection rate, complication rate (post operative bleeding rate and perforation rate). In the comparison of main endo-knife (standard Flush knife, Flush knife BT), the evaluated data mentioned above and procedure speed were evaluated. The procedure time was counted from the beginning of the local injection to the end of the procedure, and the procedure speed was calculated by dividing the procedure time into the area of the resected specimen (cm 2 /min.). We approximated the area of resected specimen to be an oval, and the area was calculated as follows: 3.14x0.25x long axis x minor axis. All procedures were recorded on videotape and parameters such as procedure time, perforation were noted for evaluation. STATISTICS Data were expressed as medians. Independent continuous variables were compared by Mann-Whitney U-test and categorical variables were compared by the X 2 test using Statview 5.0.All p-values were two- sided, and the p- value of =0.05 was considered significant. RESULTS The median tumor size was 20 mm (range:13-34) in EMR with SI, 17 mm (range:4-33) in simplified ESD and 30 mm (range:6-158) in ESD (EMR with SI vs. simplified ESD: p=not significant (n.s), simplified ESD vs. ESD: p<0.0001). The median resected specimen size was 22.5mm (range:15-35) in EMR with SI, 26mm (range:13-45) in simplified ESD and 41 mm (range:17-165) in ESD (EMR with SI vs. simplified ESD: p= simplified ESD vs. ESD: p<0.0001). The procedure time was 19 min (range:3-35) in EMR with SI, 27 min (range:8-98) in simplified ESD and 60 min.(range:11-335) in ESD (EMR with SI vs. simplified ESD: p=n.s simplified ESD vs. ESD: p<0.0001). There was no significant difference between EMR with SI and simplified ESD. The en-block resection rate was 83.3 % in EMR with SI, 90.9 % in simplified ESD and 98.9 % in ESD (Table2). The en-bloc resection rate of ESD was significantly higher than that of the other groups (EMR with SIvs.ESD:p=0.0005, simplified ESD vs. ESD:p=0.0044). The complication rate (postoperative bleeding rate / perforation rate) was 0/0 in EMR with SI, 2.3/4.5 in simplified ESD, and 1.5/1.5 in ESD (simplified ESD vs. ESD: p=n.s) (Table 3). The complication rates in simplified ESD tended to be higher than that in the other groups. There were 20 LST-NG and 36 LST-G resected using standard Flush knife and 32 LST-NG and 44 LST-G resected using Flush knife BT. The clinicopathological features (median tumor size, mac-

5 Br. 3 Endoscopic treatment for early stage colorectal tumors 45 roscopic type and histopathological diagnosis) and treatment results (procedure time, procedure speed, en bloc R0 resection rate and complication rate) using Flush knife BT were similar to that using standard Flush knife between April 2009 and March 2010 (Table 4). However, by the subtypes of LSTs, the procedure speed in LST-G was 0.27 cm 2 /min.( ) using Flush knife BT and 0.21 cm 2 /min ( ) using standard Flush knife. In LST- G, the procedure speed using Flush knife BT was significantly faster than that using standard Flush knife. On the other hand, in LST-NG, the procedure time and procedure speed were similar in using Flush knife BT and standard Flush knife. In LST-G and LST-NG, en bloc R0 resection rate was 100% using either knife (Table5-1,5-2). DISCUSSION There is a great difference between EMR and ESD. The treatment results of ESD for the early stage colorectal tumors are overwhelmingly better than that of EMR. However, the degree of technical difficulty and complication rate in ESD are remarkably more severe than that in EMR 8,9. Therefore, only the limited institutions can routinely perform colorectal ESD at the present. Therefore the new methods are needed to fill the gap 10,11,12,13,14. In this study, the new methods EMR with small incision (EMR with SI), and ESD with snaring (simplified ESD) have been adapted to step by step. When conventional EMR was difficult to perform, EMR with SI was tried at first, and simplified ESD with circumferential mucosal incision tried next, and ESD tried at last. The treatment results of EMR with SI and simplified ESD were impossible to be evaluated exactly, because these 3 methods were performed successively. In this study, the treatment result of ESD surpassed others, and the complication rate of simplified ESD was not significantly lower than that of ESD. These suggested that ESD could be the gold standard treatment method for the lesions which required reliable enbloc resection. But there are the colorectal lesions that can be fully cured by piecemeal resection 15,16, and the lesions smaller than 3-4cm are often not suitable for ESD because it is difficult to get into the submucosal layer. EMR with SI and simplified ESD are expected to achieve better treatment results than conventional EMR, if these methods are adapted to the lesions mentioned above. Moreover, it seems that these methods become the nice training for the introduction of ESD. On the other hand, we should not persist in performing the endoscopic treatment. In the cases that the lesions are located in the colon, the laparoscopic surgery can be the better choice because the functional disturbance after the surgical treatment is thought to have no difference with that after the endoscopic treatment However, in the cases that the lesions are located in the rectum, the functional disturbance can be the problem after the surgical treatment, and ESD is suggested to be the best treatment method, even if the lesions extend in the anal canal. For the easier and safer ESD, we have also developed water-jet emitting short needle knife 3,4,5 with which more than 1000 cases have been treated, yielding good results 10,19,20. Takeuchi et al 19 has reported in a prospective randomized controlled trial that standard Flush knife has reduced the procedure time for colorectal ESD. However, standard Flush knife has some problems in the operability that the tip of short needle easily slips out of the mucosa and submucosal layer during the procedure. Therefore, we have developed a novel ball-tipped Flush knife (Flush knife BT) for the improvement of operability. The ball-shaped tip of Flush knife BT facilitated the scooping up of the incised and dissected tissue, as reported 21 In this study, the procedure speed in LST-G using Flush knife BT was significantly faster than that using standard Flush knife, although the procedure speed in LST- NG using Flush knife BT was similar to that using standard Flush knife. It was supposed to be caused by the less fibrosis of the submucosal layer in LST-G than that in LST-NG 22. The lesions with severe fibrosis could be dealt with standard Flush knife (1.0 and 1.5 needle lengths type). Flush knife BT is suggested to be the suitable endoknife for ESD of LST-G, because it enables the speedy procedure. CONCLUSION EMR with small incision (EMR with SI) and ESD with snaring (simplified ESD) are good option to fill the gap between EMR and ESD in the colorectum, and also considered to become the nice training for the introduction of ESD. On the other hand, the simplification of ESD by the development of endo-knife such as Flush knife BT and so on is required, because ESD can be the best treatment method for the early stage colorectal tumors. SUMMARY ENDOSKOPSKI TRETMAN RANOG STADIJUMA KOL- OREKTALNIH TUMORA: POREDENJE EMR SA MALOM INCIZIJOM, SIMPLIFIKOVANOG ESD I ESD, KORIŠ]ENJEM FLUSH NO@A I FLUSH NO@A SA KUGLICOM NA VRHU Uvod: Kolorektalni tumori ranog stadijuma mogu biti otklonjeni endoskopskom mukozalnom resekcijom, ali voluminizniji tumori (20mm) mogu zahtevati resekciju ve}eg komada. Endoskopska submukozalna disekcija (ESD) koriš}enjem novorazvijenih endo-no eva je omogu}ila resekciju lezija u bloku, bez obzira na veli~inu i oblik. Uprkos tome, ESD za kolorektalne tumore ostaje tehni~ki zahtevna. Iz tog razloga smo izveli EMR sa malom incizijom (EMR sa SI) zbog sigurnije EMR, ESD sa zaom~avanjem (simplifikovani ESD) i ESD sa koriš}enjem standardnog Flush no a i novitetet-flush no sa kuglicom na vrhu (Flush knife BT) za lak{u i sigurniju kolorektalnu ESD. Cilj: Ciljevi naše studije bili su: 1) poredjenje rezultata slede}e 3 metode (EMR sa SI/simplifikovana ESD/ ESD) za rani stadijum kolorektalnih tumo-ra i 2) ocenjivanje performansi Flush no a sa BT u kolo-rektalnoj ESD. Metode: Tretirali smo 24/44/468 kolorektanih tumora i ispitali klini~kopatološke odlike i rezultate tretmana, kao što su veli~ina tumora, odgovaraju}a veli~ina preparata, vreme za obaljanje procedure, stopu en-block resekcija, u~estalost komplikacija. Takodje smo tretirali 58 kolorektalnih tumora (LST-NG: 20, LST-G:36, ostalo:2) koriš}enjem standardnog Flush no a i 80 kolorektalnih tu-

6 46 T. Toyanaga et al. ACI Vol. LVII mora (LST-NG: 32, LST- G:44, ostalo: 2) koriste}i Flush no BT, analizirali klini~kopatološke odlike i rezultate tretmana pomenutih tehnika, kao i vreme za obavljanje istih. (LST-lateral spreading tumor-tumor sa leteralnim širenjem) Rezultati: srednja veli~ina tumora (mm) (EMR sa SI/simplifikovana EMR/ESD) bila je 20/17/30 (EMR sa SI vs. simplifikovana ESD: p=n.s, simplifikovana ESD vs. ESD: p<0.0001). Srednja veli~ina reseciranog preparata (mm) bila je 22.5/26/41 (EMR sa SI vs. simplifikovana ESD: p=0.0018, simplifikovana ESD vs. ESD:p< ). Vreme za obavljanje procedure (min) iznosilo je 19/27/60 (EMR sa SI vs. simplifikovana ESD: p=n.s, simplifikovana ESD vs. ESD: p<0.0001). Uspešnost en block resekcija (%) bila je 83.3/90.9/98.9. Incidenca komplikacija (postoperativno krvarenje/perforacije) je iznosila 0/0, 2.3/4.5, 1.5/1.5 (simplifikovana ESD vs. ESD:p=n.s.). Što se ti~e ESD sa LST no evima, nije bilo razlike izme-dju standardnog Flush no a i Flush no a sa BT u klini~-kopatološkim odlikama i rezultatima tretmana (vreme za izvodjenje procedure broj komplikacija i broj R0 en block resekcija). Medjutim, vreme za izvodjenje procedure (cm 2 /min) kod LST-G je bilo zna~ajno kra}e kod Flush no a BT nego kod standardnog Flush no a (standardni Flush no :0.21 vs. Flush no BT:0.27, p=0.034). Zaklju~ak: EMR sa malom incizijom (EMR sa SI) i ESD sa zaom~avanjem (simplifikovana ESD) su dobre opcije za popunjavanje praznina izmedju EMR i ESD, a smatraju se dobrim treningom za prelazak na ESD. Flush no BT je napredniji što se brzine procedure ti~e, u poredjenju sa sa standardnim Flush no em, posebno kod LST-G kod kolorektalnih ESD. Klju~ne re~i: kolorektalna neoplazma, endoskopska mukozna resekcija (EMR), endoskopska submukozna disekcija (ESD), EMR sa malom incizijom, simplifikovana ESD, Flush no, Flush no BT REFERRENCE 1. 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Endoscopy 2010 (in press) Funding: No funding was received for this study. Conflicts of Interest: Dr. Toyonaga invented the Flushknife in conjunction with Fujifilm Inc., Tokyo, Japan and receives royalties from its