Is hepatopancreatoduodenectomy an acceptable operation for biliary cancer? Eung Chang Lee, Sung-Sik Han, Hyeong Min Park, Seung Duk Lee, Seong Hoon Kim, Sang-Jae Park Center for Liver Cancer National Cancer Center, Korea

Introduction HPD - first introduced In 1980 for locally advanced GB cancer After HPD was first introduced in 1980, recent studies have generally reported a mortality rate of (클릭) 0–20% , and 5-year survival rate of approximately (클릭) 10–65% in BD cancer and (클릭) 0-25% in GB cancer. J HEPATO-BIL-PAN SCI 2014

Introduction Safety? Survival benefit? Nevertheless, questions still persist concerning the safety and survival benefit of HPD.

Purpose To investigate surgical outcomes of BD and GB cancer after HPD So, the purpose of this study is to investigate the surgical outcomes of BD & GB cancer after HPD

Patients and Methods Jan 2004 – Dec 2013 22 patients Indication - BD cancer 14 - GB cancer 8 Indication BD cancer (n = 14 ) GB cancer (n = 8 ) Diffuse bile duct infiltration 11 (78.6%) - Common bile duct cancer with r/o GB cancer 3 (21.4%) LN#13 metastasis 6 (75.0%) LN#12 metastasis with intrapancreatic CBD invasion 1 (12.5%) Duodenal invasion From January 2004 to December 2013, a total of 22 patients were included in this study. In BD cancer, mostly diffuse bile duct infiltration, and In GB cancer, LN metastasis and Duodenal invasion were indicated for HPD The detailed indication of HPD are listed here, as you see. In BD cancer, diffuse bile duct infiltration and CBD cancer with suspicious concurrent GB cancer but the final pathologic report of these GB lesions were 2 xanthogranulomatous cholecystitis and 1 cystic duct cancer. And In GB cancer, The detailed indication are listed here, as you see. And In GB cancer, Retropancreas LN metastasis and, hepatoduodenal LN metastasis with intrapancreatic CBD invasion, Duodenal invasion were indicated for HPD

Patients and Methods Extent of surgery BD cancer (n = 14 ) GB cancer Extent of hepatectomy Major hepatectomy‡ Right hemiliver, S4b, S1 11 (78.6%) 2 (25.0%) Right hemiliver, S4b - Left hemiliver, S5 1†(12.5%) Minor hepatectomy Anatomic resection of S4b, S5 3*(21.4%) Wedge resection of the GB bed 1 (12.5%) Type of PD PD 2 (14.3%) 3 (37.5%) PPPD 12 (85.7%) 5 (62.5%) Portal vein resection and reconstruction 1 (7.1%) In BD & GB cancer, Almost 70% underwent major hepatectomy and 2 PV R&A was conducted. In BD cancer, 11 extended right hemihepatectomy and 3 minor hepatectomy with S4b,S5 for who were suspicious for concurrent CBD and GB cancer. Likewise, the Extent of HPD for GB caner are described here. (including the right hemiliver, S4b and S1) was performed in 11 (78.6%) patients, whereas in 3 (21.4%) patients who were suspicious for concurrent BD and GB cancer , only S4b, S5 were resected. Two PD, and 12 PPPD was done and one PV resection and reconstruction was performed Likewise, the Extent of HPD for GB caner are listed here. And, (가리키며) This patient who underwent Lt. Hemihepatectomy received neoadjuvant chemotherapy before HPD, and the final pathological report was Stage 0. *Bile duct cancer with R/O GB cancer 1

Results Mortality 4.5% (1/22) Morbidity 68.2% (15/22) Clavien-Dindo grade ≥3 36.4% (8/22) wound 4, sepsis 1, bleeding 1, pleural effusion 1, C-J leak 1 - No liver failure Pancreatic fistula 50.0% (11/22) Grade A 40.9% (n=9), B 9.1% (n=2) BD cancer (n = 14 ) GB cancer (n = 8 ) Number 5-year (%) Median (mo) P Overall complication 0.556 0.448 Absent 5 (35.7) 20.1 2 (25.0) 50.0 16.4 Present (total/C-D grade≥3) 9/5 (64.3/35.7) 22.2/NA 11.0/10.9 6/3 (75.0/37.5) 16.7/0 8.2/17.9 Pancreatic fistula 7 (50.0) 28.6 11.3 4 (50.0) 25.0 8.2 A 20.0 11.0 B 2 (14.3) NA 0 (0.0) Bile leakage 1 (7.1) 10.9 Intra-abdominal abscess 10.2 Intra-abdominal bleeding Pneumonia 3 (21.4) 1 (12.5) Wound infection Sepsis 1† (7.1) 0.2 The overall mortality rate was 4.5% (n=1), and the morbidity rate was 68.2% (n=15). And, the patients with Clavien-Dindo more than grade 3 was 36.4% (n=8). No patient had liver failure, while overall pancreatic fistula occurred in 50.0% (11): but, only 9.1% (2) of them was grade B. (클릭클릭!!) In BD cancer, one (7.1%) patient died on postoperative day 5 due to multi-organ failure secondary to sepsis, and morbidity occurred in 64%(9). In GB cancer, there was not mortality but morbidity in 75.0% (6)

Results Stage (0/I/II/III/IV) Preop. biliary drainage 63.6% (14/22) - BD cancer (0/3/6/3/2) GB cancer (1/0/0/7/0) Preop. biliary drainage 63.6% (14/22) BD cancer 92.9% (n=13), GB cancer 12.5% (n=1) Neoadjuvant Chemotherapy GB cancer 25% (n=2) R0 86.4% (19/22) - BD cancer 78.6% (n=11), GB cancer 100% (n=8) The stage of BD and GB cancer are described here. Which shows GB cancer patients had more advanced disease. Preoperative biliary drainage was performed in about 60%. Two (25.0%) GB cancer patients received neoadjuvant chemotherapy R0 resection was acheved in total 86.% (19/22) 2

Overall Survival 5-yr OS -GB cancer 25.0% -BD cancer 17.9% The 5-year overall survival rate was about 18% in BD cancer , and 25.0% in GB cancer and there is no meaningful differences. The median survival length was 13.0 months in BD cancer and 16.4 months in GB cancer (P = 0.768)

Analysis of Risk Factors BD cancer (n = 14 ) GB cancer (n = 8 ) Number 5-year (%) Median (mo) P Age (years) 0.115 0.290 <65 9 (64.3) 27.8 32.2 6 (75.0) 33.3 17.9 ≥65 5 (35.7) 13.0 2 (25.0) 8.2 Sex 0.520 0.353 Male 10 (71.4) 20.0 16.8 1 (12.5) Female 4 (28.6) NA 10.9 7 (87.5) 28.6 CEA (ng/mL) 0.444 0.554 <5.0 26.7 3 (37.5) 23.5 ≥5.0 11.3 5 (62.5) 16.4 CA19–9 (U/mL), [1] 0.315 0.841 <300 29.6 ≥300 6.4 TB (mg/dL) 0.351 <4.0 25.0 8 (100.0) ≥4.0 0 (0.0) Preoperative biliary drainage 0.706 0.822 Absent 1 (7.1) Present 13 (92.9) 20.5 PVE 0.168 10.3 Neoadjuvant chemotherapy 0.338 14 (100.0) 12.9 16.7 50.0 Operation time (hours) 0.036 0.366 <10 7 (50.0) 38.1 32.8 7.5 ≥10 Blood loss (mL) 0.589 0.654 <1000 ≥1000, <2000 20.1 ≥2000 6 (42.9) 11.0 In this Risk Factor analysis, we can see the survival difference of BD cancer according to (클릭) operation time. Besides that, the other perioperative variables in this page including age, sex, CEA, CA19-9, TB, peoperative biliary drainage, PVE, and neoadjuvant chemotherapy, blood loss showed no significant difference in overall survival in either BD or GB cancer.

Analysis of Risk Factors BD cancer (n = 14 ) GB cancer (n = 8 ) Number 5-year (%) Median (mo) P Tumor size (cm) 0.030 0.700 <4.0 8 (57.1) 31.3 32.2 5 (62.5) 40.0 16.4 ≥4.0 6 (42.9) 10.9 3 (37.5) 17.9 Histological type 0.592 0.203 WD 3 (21.4) 16.8 0 (0.0) NA MD 5 (35.7) 20.0 PD 33.3 11.0 1 (12.5) 7.5 UD 8.2 Others 1† (12.5) 100 115.6 Microvascular invasion 0.693 0.221 Absent 9 (64.3) 4 (50.0) 50.0 Present 13.0 Lymphatic invasion 0.829 0.209 4 (28.6) 10 (71.4) 15.0 7 (87.5) 14.3 Perineural invasion 0.206 2 (14.3) 17.8 12 (85.7) 12.5 11.3 Portal vein invasion 0.022 0.822 13 (92.9) 19.2 28.6 1 (7.1) 6.4 23.5 In addition, (클릭) tumor size ,(클릭) PV invasion,

Analysis of Risk Factors BD cancer (n = 14 ) GB cancer (n = 8 ) Number 5-year (%) Median (mo) P T stage <0.001 0.343 Tis 0 (0.0) NA 1† (12.5) 100 115.6 1 1 (7.1) 2 5 (35.7) 30.0 32.2 2 (25.0) 0.50 5.0 3 6 (42.9) 11.3 5 (62.5) 16.4 4 2 (14.3) 0.2 N stage 0.248 0.209 7 (50.0) 28.6 20.1 7 (87.5) 14.3 Multiple LN metastasis‡ 0.020 0 or 1 10 (71.4) 25.0 ≥2 4 (28.6) 10.2 AJCC 7th Stage 0.001 I 3 (21.4) II 16.7 13.0 III 11.0 IV R0 resection 0.399 Yes 11 (78.6) 24.2 16.8 8 (100.0) No (클릭) T stage .(클릭) multiple LN metastasis ,(클릭) cancer Stage. But, In GB cancer, there were no variables affecting overall survival.

Analysis of Risk Factors BD cancer (n = 14 ) GB cancer (n = 8 ) Number 5-year (%) Median (mo) P Adjuvant Chemotherapy 0.081 0.841 Absent 7 (50.0) NA 10.9 3 (37.5) 33.3 8.2 Present 19.0 32.2 5 (62.5) 20.0 17.9 Radiotherapy 0.506 0.187 6 (75.0) 14.3 20.1 2 (25.0) 7.5 Length of hospital stay (weeks) 0.526 0.353 < 4 6 (42.9) 16.7 7 (87.5) 28.6 ≥ 4 8 (57.1) 11.0 1 (12.5) Overall complication 0.556 0.448 5 (35.7) 50.0 16.4 (total/C-D grade≥3) 9/5 (64.3/35.7) 22.2/NA 11.0/10.9 6/3 (75.0/37.5) 16.7/0 8.2/17.9 Pancreatic fistula 11.3 4 (50.0) 25.0 A B 2 (14.3) 0 (0.0) Bile leakage 1 (7.1) Intra-abdominal abscess 10.2 Intra-abdominal bleeding Pneumonia 3 (21.4) Wound infection Sepsis 1† (7.1) 0.2 And, Post-operative variables listed this page did not affect the overall survival of biliary cancer

Risk Factors for Survival of BD cancer Tumor size Portal vein invasion Multiple LN mets Operation time So, In this study, we found that besides the TNM stage, (클릭) tumor size, (클릭) PV invasion, (클릭) multiple LN metastasis, and (클릭) operative time significantly affected the overall survival of BD cancer. Furthermore, (클릭) we can see here that overall survival was noticeably better when there is no risk factor in comparison to when there are more than one risk factors (P = 0.002).

Summary & Conclusions Acceptable mortality 4.5% High morbidity 68.2% - but, Clavien-Dindo grade ≥ 3 36.4% GB cancer - comparable 5-yr OS(25.0%) against BD(17.9%) cancer after HPD BD cancer long-term survival when poor prognostic factors (-)  HPD can be considered in some selected cases to expect long-term survival In summary, First, (클릭) HPD can be done with acceptable mortality. Second, (클릭) HPD has high morbidity, about 70%. But considering complication rate with more than Clavien-Dindo grade 3 was about half of them, it can be considered acceptable. Third, (클릭) although in our data, the stage of GB cancer was more advanced in comparison to BD cancer, the overall survival of GB cancer after HPD were comparable. And, finally, (클릭) in BD cancer, a better overall survival can be predicted when there is no poor prognositic factor. So, (클릭) our conclusion is that HPD can be considered in some selected cases to expect long-term survival.

Thank you for listening