Treatment Strategy for Non-curative Resection of Early Gastric Cancer. Jun Haneg Lee. Sungkyunkwan University, Samsung Medical Center, Seoul Korea

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1 Treatment Strategy for Non-curative Resection of Early Gastric Cancer Jun Haneg Lee. Sungkyunkwan University, Samsung Medical Center, Seoul Korea

2 Classic EMR/ESD data analysis style Endoscopic resection Conventional indication Expanded indication Beyond expanded indication Not including undifferentiated Including undifferentiated

3 Our EMR/ESD data analysis style Endoscopic resection Differentiated Undiffererentiated Curative resection Poorly differentiated Noncurative resection Signet ring cell carcinoma

4 Outcome after curative endoscopic resection of EGC Long-term follow-up data Comparison with surgery such as propensity score matched studies

5 Long-term Outcome after Curative ESD for Differentiated EGC (both absolute and expanded) Jun Haneg Lee. Sungkyunkwan University, Samsung Medical Center, Seoul Korea

6 Study population EGCs treated by ESD at Samsung Medical Center 1,838 patients with 1,889 differentiated-type EGCs November 2003 May 2011 Censoring date: May 2014 Differentiated-type EGC Well or moderately differentiated or papillary EGC According to the quantitatively predominant histologic type Differentiated-type EGC > 50% Min BH. Endoscopy 2015

7 1,838 patients with 1,889 differentiated-type EGCs 1151 patients with 1171 EGCs-absolute - Single lesion: Two lesions: patients with 331 EGCs-expanded - Single lesion: 325 -Two lesions: 3 18 patients with 37 EGCs including both EGC-absolute and EGC-expanded - Two lesions: 17 -Three lesions: patients with at least one lesion treated with non-curative resection - Single lesion: Two lesions: 7 - Three lesions: 1 - Op: 1 - Residual lesion: 2 - Synchronous lesion: 9 - Follow up < 1 year: Op: 21 - Residual lesion: 0 - Synchronous lesion: 4 - Follow up < 1 year: 44 - Op: 0 - Residual lesion: 0 - Synchronous lesion: 0 - Follow up < 1 year: 3 *1032 patients with 1049 EGCs-absolute *259 patients with 261 EGCs-expanded *15 patients with 31 EGCs including both EGC-absolute and EGC-expanded 1 LR - EGC: 1 38 MR - EGC: 36 - pt2 AGC: 2 1 EGR 0 LR 8 MR - EGC: 7 - pt2 AGC: 1 1 EGR 0 LR 1 MR - EGC: 1 0 EGR Op: 1 Op: 16 ER: 22 Op: 1 Op: 3 ER: 5 Palliative Op: 1 ER: 1 * A total of 1,306 patients with 1,341 EGCs were included in the outcome analysis.

8 About 79% of curatively resected cases were absolute indication cases Depth Histology M cancer SM cancer No ulceration Ulcerated SM1 SM2 20 mm > 20 mm 30 mm > 30 mm 30 mm Any size Differentiated A B B D B D Undifferentiated C D D D D D A absolute indication (n=1,032, 79.0%) B expanded indication, differentiated (n=274, 21.0%) C expanded indication, undifferentiated D surgery (gastrectomy + lymph node dissection) Min BH. Endoscopy 2015

9 Long-term outcome - 1,306 curative ESDs from December 2003 to May 2011 Median follow-up: 61 months (range ) Local recurrence: 0.08% (1/1,306) Metachronous recurrence: 3.6% (47/1,306) Definition of metachronous recurrence: at least 12 months after ER Extragastric recurrence: 0.15% (2/1,306) 5-year overall survival Absolute indication: 97.3% Expanded indication: 96.4% Min BH. Endoscopy 2015

10 2 extragastric recurrences (0.15%) Min BH. Endoscopy 2015

11 Overall-survival - 1,306 curative ESDs from December 2003 to May 2011 Min BH. Endoscopy 2015

12 Comparison with Surgery - A Propensity Matched Cohort Study Jun Haneg Lee. Sungkyunkwan University, Samsung Medical Center, Seoul Korea

13 Differentiated type EGC ( ) (n = 3595) EGC meeting indication treated with curative intent (n = 2563 ) Excluded 1) LNM on CT or EUS (n=6) 2) Previous gastric cancer (n=20) 3) Cancer of other origin (n=150) 4) Follow up < 2 years (n=856) Endoscopic resection (n = 1290) Surgery (n =1273) Propensity score matching Endoscopic resection (n = 611 ) Surgery (n = 611 ) Pyo JH. Am J Gastroenterol 2016

14 Baseline characteristics (1) Overall Propensity score matched Variables Endoscopic resection (n=1290) Surgery (n=1273) P-value* Endoscopic resection (n=611) Surgery (n=611) P -value* Age, median (IQR), years 61 (54-68) 59 (51-65) < (53-67) 60 (53-67) Sex, n(%) Male Female 1020 (79.1) 270 (20.9) 947 (74.4) 326 (25.6) (79.4) 126 (20.6) 487 (79.7) 124 (20.3) Performance (ECOG), n(%) or above 1270 (98.5) 5 (0.4) 15 (1.2) 1261 (99.1) 4 (0.3) 8 (0.6) (99.0) 1 (0.2) 5 (0.8) 604 (98.9) 2 (0.0) 5 (0.8) F/U duration, median (IQR), month 44 (32-60) 58 (38-72) < (32-61) 58 (38-73) Criteria of indication, n(%) Absolute criterion Expanded criterion I Expanded criterion II Expanded criterion III Beyond indication 895 (69.4) 178 (13.8) 7 (0.5) 100 (7.8) 110 (8.5) 536 (42.1) 460 (36.1) 36 (2.8) 130 (10.2) 111 (8.7) < (63.2) 127 (20.8) 5 (0.8) 44 (7.2) 49 (8.0) 362 (59.2) 123 (20.1) 16 (2.6) 84 (13.7) 26 (4.3) <0.001 Pyo JH. Am J Gastroenterol 2016

15 Baseline characteristics (2) Variables Endoscopic resection (n=1290) Overall Surgery (n=1273) P-value* Propensity score matched Endoscopic resection (n=611) Surgery (n=611) P -value* Tumor size, mean (SD), cm 1.4 (0.9) 2.6 (1.7) < (1.1) 1.7 (1.1) Morphology of tumor, n(%) Elevated Flat or depressed 770 (59.7) 520 (40.3) 192 (15.1) 1081 (84.9) < (21.4) 480 (78.6) 140 (22.9) 471 (77.1) Location of tumor, n(%) Upper third Middle third Lower third Histology of tumor, n(%) Well differentiated Moderately differentiated Depth of tumor invasion, n(%) Mucosa Submucosa Lymphovascular invasion Absent Present R0 resection No Yes 78 (6.1) 357 (27.7) 855 (66.3) 511 (39.6) 779 (60.4) 1076 (83.4) 214 (16.6) 1217 (94.3) 73 (5.7) 223 (17.3) 1067 (82.7) 89 (7.0) 331 (26.0) 853 (67.0) 429 (33.7) 844 (66.3) 1054 (82.8) 219 (17.2) 1226 (96.3) 47 (3.7) 46 (3.6) 1227 (96.4) (6.6) 180 (29.5) 391 (64.0) (37.5) 382 (62.5) (84.3) 96 (15.7) (94.4) 34 (5.6) < (17.8) 502 (82.2) 45 (7.4) 170 (27.8) 396 (64.8) 224 (36.7) 387 (63.3) 504 (82.5) 107 (17.5) 588 (96.2) 23 (3.8) 23 (3.8) 588 (96.2) <0.001 Pyo JH. Am J Gastroenterol 2016

16 Overall survival A. All samples B. Propensity matched samples Pyo JH. Am J Gastroenterol 2016

17 Overall survival Disease free survival Endoscopic resection Surgery Disease specific survival Recurrence free survival Pyo JH. Am J Gastroenterol 2016

18 Box summary Long-term outcome after curative endoscopic resection of early gastric cancer has been established in many types of studies. The remaining question is the long-term outcome after non-curative endoscopic resection.

19 Long-term outcome after non-curative resection for differentiated EGC Jun Haneg Lee. Sungkyunkwan University, Samsung Medical Center, Seoul Korea

20 Surgery for all non-curative ER? Low LN metastasis rate: 5.8% 8.2% Old age or other medical conditions Progression to metastatic disease Occurs in only limited case Substantial time is usually required. Kim ER. Br J Surg 2015

21 Study population 2,036 patients with 2,091 differentiated-type EGCs EMR or ESD April 2000 May 2011 Censoring date: May 2014 Differentiated-type EGC Well or moderately differentiated or papillary EGC EGC with histological heterogeneity According to the quantitatively predominant histologic type Differentiated-type EGC > 50% Kim ER. Br J Surg 2015

22 Noncurative resection 341 Lateral margin positive 67 (19.6%) Risk of lymph node metastasis 274 (80.4%) Surgery 194 (70.8%) Lymph node 11 (5.6%) Local residual 10 (5.2%) Observation 80 (29.2%) Patients refusal : 64 High surgical risk : 8 (severe comorbidities) Concomitant advanced cancer in other organs : 8

23 Observation Surgery (n = 80) (n = 194) P value Age (yrs) < Mean ± SD 67.6 ± ± 8.5 Median (range) 69.4 (42-86) 63.1 (44-84) Gender (%) Male Female Concomitant disease (%) Cancer Cardiovascular disease Respiratory disease Diabetes Charlson comorbidity index Mean ± SD 4.1 ± ± 1.3 Median (range) 4 (1-11) 3 (1-8) Procedure (%) Endoscopic submucosal dissection Endoscopic mucosal resection En bloc resection (%) En bloc Piecemeal Kim ER. Br J Surg 2015

24 Observation Surgery (n = 80) (n = 194) P value Tumour site (%) Antrum/Angle Body/Fundus/Cardia Tumour size (cm, Mean ± SD) 2.7 ± ± Tumour depth (%) Mucosa SM1* SM2 or SM Differentiation (%) Well differentiated Moderately differentiated Lateral resection margin (%) Negative Positive Unknown Vertical rsection margin (%) Negative Positive Unknown 0 0 Lymphovascular invasion (%) < Negative Positive Kim ER. Br J Surg 2015

25 Predictors of LN metastasis (5.7%) Kim ER. Br J Surg 2015

26 11 cases (5.7%) with LN (+) in additional surgery after ESD for EGC

27 Progression into advanced cancer Observation group Surgery group 5 cases (6.3%) (21 to 40 months) 1 case (0.5%) (22 months) (P = 0.013) Kim ER. Br J Surg 2015

28 Six cases with documented progression C a s e S e x A g e C C I Surgery Progression to AGC after ER (months) Location Size (cm) Diff SM invasion (μm) LVI RM Local r ecurren ce Distant mets Alive Further Treatment 1 F 80 6 No 21 Antrum 2.8 MD 2500 Pos Pos Yes No Alive Op 2 F 73 4 No 40 Angle 4.8 WD 200 Pos Neg Yes Peritonea l seeding Death F/U loss 3 M 71 5 No 28 Body 1.3 MD 1000 Pos Neg Yes Liver Death F/U loss 4 M 75 8 No 38 Antrum 2.8 MD 1500 Pos Neg Yes Peritonea l seeding Alive No Tx 5 M 59 2 No 36 Body 1.0 MD 1500 Pos Neg No Lung Alive Metastatecto my 6 M 63 3 Yes 22 Antrum 1.6 WD 300 Pos Pos No Liver Death ChemoRx Kim ER. Br J Surg 2015

29 Initial endoscopy for cases with cancer progression after non-curative ESD Recurrence after STG for noncurative resection

30 Overall survival - Median duration of follow-up after ER: 60.5 months (6-141) Kim ER. Br J Surg 2015

31 Overall survival - Median duration of follow-up after ER: 60.5 months (6-141) Kim ER. Br J Surg 2015

32 Surgery is the only an independent risk factor of survival Kim ER. Br J Surg 2015

33 Box summary Progression to advanced stage in patient not undergoing additional treatment: 6.3% (5/80) Additional surgery confer a survival benefit. Surgery was the only independent predictor of overall survival. Kim ER. Br J Surg 2015

34 Is surgery always required after noncurative resection with risk of LN mets? The 5 year survival rate is about 80% without surgery in non-curative resection patients with risk of lymph node metastasis. Kim ER. Br J Surg 2015

35 Selection of patients for surgery Jun Haeng Lee. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

36 Is surgery necessary in all patients who do not meet the curative criteria? 54% Hatta W, et al. J Gastroenterology 2016 (Epub)

37 Hatta W, et al. J Gastroenterology 2016 (Epub)

38 Overall survival 96% 84% Hatta W, et al. J Gastroenterology 2016 (Epub)

39 Disease-specific survival 99.4% 98.7% Hatta W, et al. J Gastroenterology 2016 (Epub)

40 Hatta W, et al. J Gastroenterology 2016 (Epub)

41 Conclusion from the Japanese multicenter trial Although radical surgical resection is currently indicated for these patients, we suggest that follow-up with no additional treatment after ESD may be an acceptable option for patients at low risk. Consequently, further risk stratification is needed for appropriate individualized treatment strategies. Hatta W, et al. J Gastroenterology 2016 (Epub)

42 ecura system - Scoring system using multivariate logistic regression analysis Criteria OR Points Tumor size > 30 mm Tumor depth SM2 or more Lymphatic invasion Positive Vascular invasion Positive Vertical margin Positive

43 Risk of lymph node metastasis based on the ecura system Risk category Total points Rate of LNM (%) Low Intermediate High

44 Conclusion Until now, the standard treatment after noncurative resection is surgery. Because the 5 year survival without surgery is about 80%, careful observation may be an option in patients with operational risk factors. Prediction model like ecura system seems to be promising.

45 Thank you for your attention.