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ILCA 2019 - September 19-22, 2019: Chicago -

ILCA 2019 - September 19-22, 2019: Chicago -. ILCA Symposium 2: Perihilar cholangiocarcinoma. - Patient selection and optimization for surgery -. Masato Nagino, MD Department of Surgery Nagoya University Graduate School of Medicine. ABC-02 study (N Engl J Med, 2010)

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ILCA 2019 - September 19-22, 2019: Chicago -

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  1. ILCA 2019 - September 19-22, 2019: Chicago- ILCA Symposium 2: Perihilar cholangiocarcinoma - Patient selection and optimization for surgery - Masato Nagino, MD Department of Surgery Nagoya University Graduate School of Medicine

  2. ABC-02 study (N Engl J Med, 2010) - GEM vs. GEM+ＣＤＤＰfor relapsed / unresectable biliary cancer - Hazard ratio for death 0.64 (95% CI 0.52-0.80) P<0.001 MST8.1m MST11.7m GEM + CDDP Overall survival (%) GEM Months since randomization No. at Risk GEM GEM + CDDP • 151 97 53 28 15 4 3 2 • 204 167 120 76 51 28 17 8 2

  3. ABC-02 study (N Engl J Med, 2010) - GEM vs. GEM+ＣＤＤＰfor relapsed / unresectable biliary cancer - Hazard ratio for death 0.64 (95% CI 0.52-0.80) P<0.001 MST8.1m MST11.7m GEM + CDDP Overall survival (%) effective ????? GEM Months since randomization No. at Risk GEM GEM + CDDP • 151 97 53 28 15 4 3 2 • 204 167 120 76 51 28 17 8 2

  4. Chemotherapy is much less effective; No patients cured.

  5. Review of our experience Mt. Fuji

  6. Numberofresectionofperihilarcholangiocarcinoma 1000 100 200 300 400 500 600 700 800 900 60 50 40 30 20 10 0 1980 1985 1990 1995 2000 2005 2010 2015 2019

  7. Numberofresectionofperihilarcholangiocarcinoma 1000 100 200 300 400 500 600 700 800 900 60 50 40 400 622 30 20 10 0 1980 1985 1990 1995 2000 2005 2010 2015 2019

  8. Perihilar cholangiocarcinoma - January 1977 ～ December 2015, Nagoya University - Total number of perihilar cholangiocarcinoma treated [n=1077] Laparotomy [n=912] Inoperable [n=165] Unresectable [n=81] Not resected [n=246, 23%] Resected [n=831, 77%] pM0 and R0 [n=575] pM0 and R1/2 [n=134] pM1 (=stage IVB) [n=122]

  9. Perihilar cholangiocarcinoma - January 1977 ～ December 2015, Nagoya University - 831 consecutive resections include Bismuth type I / II Bismuth type III Bismuth type IV = 133 (16.0%) = 307 (36.9%) = 391 (47.1%)

  10. Trend of surgical procedure More extended surgery Left trisectionectomy Portal vein resection Anatomic right trisectionectomy 4．Hepatic artery resection 5．Hepatopancreatoduodenectomy （Natsume S, et al. Ann Surg 2012） （Ebata T, et al. Ann Surg 2003; Nagino M, et al. Ann Surg 2010 ） （Nagino M, et al. Ann Surg 2006; Matsumoto N, et al. Br J Surg 2014） （Nagino M, et al. Ann Surg 2010） （Ebata T, et al. Ann Surg 2012）

  11. Surgical treatment of perihilar cholangiocarcinoma Type of hepatectomy(1977~2015, n=831) (%) 1% 7% 8% Without Hx. 100 2% 3% 2% Central Hx. 1% 6% 10% 18% Rt hemi Hx. 31% 80 32% 32% 34% 24% Rt trisectionectomy 11% 60 10% 2% 5% 10% 26% Lt hemi Hx. 26% 40 40% 30% 38% 20 30% Lt trisectionectomy 28% 17% 0 10% 1977-1990 (n=72) 1991-2000 (n=116) 2001-2005 (n=168) 2006-2010 (n=218) 2011-2015 (n=257) 4%

  12. Surgical treatment of perihilar cholangiocarcinoma Combined resection(1977~2015, n=831) (%) ～2000 (n=188) 40 2001～05 (n=168) 2006～10 (n=218) 2011～15 (n=257) 30 20 57 (30%) 58 (35%) 89 (41%) 87 (34%) 10 25 (15%) 46 (21%) 56 (22%) 22 (12%) 20 (12%) 32 (15%) 30 (12%) 5 (3%) 0 PD PV resection HA resection

  13. Surgical treatment of perihilar cholangiocarcinoma Time・blood loss （excluding patients without Hx.） Time (minutes) Blood loss (mL) Period 648±181 4450±3543 1979～1985 (n=25) 673±151 4394±2329 1986～1990 (n=41) 858±249 5367±3450 1991～1995 (n=42) 760±159 2782±2234 1996～2000 (n=66) 674±145 1902±1270 2001～2005 (n=165) 2006～2010 (n=216) 605±134 1768±1130 2011～2015 (n=243) 598±128 1273±893

  14. Surgical treatment of perihilar cholangiocarcinoma Mortality (including all deaths related to surgery) No. of resection 90-day mortality Period 1977～1985 29 4 (13.8%) 4 (9.3%) 43 1986～1990 4 (8.2%) 49 1991～1995 7 (10.4%) 67 1996～2000 5 (3.0%) 168 2001～2005 3 (1.4%) 218 2006～2010 5 (1.9%) 257 2011～2015 831 32 (3.9%) Total

  15. Surgical treatment of perihilar cholangiocarcinoma (%） 100 All resections (n = 831) 80 60 50% 36% 40 25% 20 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk 59 831 317 176

  16. Surgical treatment of perihilar cholangiocarcinoma (%） 100 All resections, according to time period (n = 831） A: 2008～2015 80 P < 0.001* B: 2001～2007 P < 0.001* C: 1977～2000 61% *, Logrank test 60 46% 47% 40 36% 36% 25% 20 23% 14% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 390 137 47 34 B: 253 112 87 C: 188 68 42 25

  17. Surgical treatment of perihilar cholangiocarcinoma (%） R0 / pN0 / pM0 patients, according to time period (n = 356） 100 A: 2008～2015 P = 0.224* B: 2001～2007 83% P < 0.001* C: 1977～2000 80 70% *, Logrank test 74% 66% 60 57% 50% 40 43% 26% 20 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 172 85 35 28 B: 105 75 66 C: 79 45 32 19

  18. Surgical treatment of perihilar cholangiocarcinoma (%） R0 / pN1 / pM0 patients, according to time period (n = 219） 100 80 A: 2008～2015 P = 0.026* B: 2001～2007 P = 0.904* 60 C: 1977～2000 48% *, Logrank test 37% 40 29% 32% 19% 20 11% 15% 10% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 109 28 9 5 B: 69 22 13 C: 41 15 6 4

  19. Surgical treatment of perihilar cholangiocarcinoma (%） R0 / pN1 / pM0 patients, according to time period (n = 219） 100 80 A: 2008～2015 P = 0.026* B: 2001～2007 P = 0.904* 60 C: 1977～2000 48% *, Logrank test 37% 40 29% 32% 19% 20 11% 15% 10% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 109 28 9 5 B: 69 22 13 C: 41 15 6 4

  20. Surgical treatment of perihilar cholangiocarcinoma (%） R0 / pN1 / pM0 patients, according to time period (n = 219） 100 80 A: 2008～2015 P = 0.026* B: 2001～2007 P = 0.904* 60 C: 1977～2000 48% *, Logrank test 37% 40 29% 32% 19% 20 11% Gem + CDDP in ABC-02 trial 15% 10% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 109 28 9 5 B: 69 22 13 C: 41 15 6 4

  21. Surgical treatment of perihilar cholangiocarcinoma (%） R1･2 / pM0, according to time period (n = 134） 100 80 A: 2008～2015 P = 0.484* P < 0.001* B: 2001～2007 P = 0.067* 60 C: 1977～2000 *, Logrank test 40% 40 32% 20 16% 13% 17% 15% 3% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 68 15 3 1 B: 37 12 6 C: 29 5 1

  22. Surgical treatment of perihilar cholangiocarcinoma (%） R1･2 / pM0, according to time period (n = 134） 100 80 A: 2008～2015 P = 0.484* P < 0.001* B: 2001～2007 P = 0.067* 60 C: 1977～2000 *, Logrank test 40% 40 32% 20 16% 13% Gem + CDDP in ABC-02 trial 17% 15% 3% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 68 15 3 1 B: 37 12 6 C: 29 5 1

  23. Surgical treatment of perihilar cholangiocarcinoma (%） pM1, according to time period (n = 122） 100 80 A: 2008～2015 P = 0.004* B: 2001～2007 P = 0.886* 60 C: 1977～2000 *, Logrank test 34% 40 20 8% 8% 0 0 1 2 3 4 5 6 7 8 9 10 術後年数 No at risk A: 41 9 B: 42 3 2 C: 39 3 3

  24. Surgical treatment of perihilar cholangiocarcinoma (%） pM1, according to time period (n = 122） 100 80 A: 2008～2015 P = 0.004* B: 2001～2007 P = 0.886* 60 C: 1977～2000 *, Logrank test 34% 40 20 8% Gem + CDDP in ABC-02 trial 8% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 41 9 B: 42 3 2 C: 39 3 3

  25. Surgical treatment of perihilar cholangiocarcinoma (%） pM1, according to time period (n = 122） 100 80 A: 2008～2015 P = 0.004* B: 2001～2007 P = 0.886* 60 C: 1977～2000 *, Logrank test 34% 40 20 8% Gem + CDDP in ABC-02 trial 8% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 41 9 B: 42 3 2 C: 39 3 3

  26. Surgical treatment of perihilar cholangiocarcinoma (%） pM1 , according to site of distant metastasis (n = 122） 100 80 A: Liver metastasis or dissemination 60 48% 40 20 Gem + CDDP in ABC-02 trial 6% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 53 23 2

  27. Surgical treatment of perihilar cholangiocarcinoma (%） pM1 , according to the site of distant metastasis (n = 122） 100 80 61% A: Liver metastasis or dissemination 60 P = 0.002* B: Distant node metastasis alone *, Logrank test 48% 40 22% 20 11% Gem + CDDP in ABC-02 trial 6% 0 0 1 2 3 4 5 6 7 8 9 10 Years after surgery No at risk A: 53 23 2 5 B: 69 41 13

  28. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 1 1. Extended resection based strategy 96% of patients underwent major Hx. with caudate lobectomy. 40% of patients underwent combined PV resection. 21% of patients underwent combined HA resection. 13% of patients underwent combined pancreatoduodenectomy. 2. Blood loss and mortality decreased year by year For the most recent 10 years, Blood loss was 1506 mL on the average, and 90-day mortality was 1.7% (=8/475).

  29. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 2 3. Survival after resection was improved year by year 5-year survival 1977 - 2000 2001 - 2007 2008 - 2015 All patients 23% 36% 47% N0R0M0 43% 66% 70% N1R0M0 15% 19% 25% R1/2M0 3% 16% 15%

  30. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 2 3. Survival after resection was improved year by year 5-year survival 1977 - 2000 2001 - 2007 2008 - 2015 All patients 23% 36% 47% N0R0M0 43% 66% 70% N1R0M0 15% 19% 25% R1/2M0 3% 16% 15%

  31. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 2 3. Survival after resection was improved year by year 5-year survival 1977 - 2000 2001 - 2007 2008 - 2015 All patients 23% 36% 47% N0R0M0 43% 66% 70% N1R0M0 15% 19% 25% R1/2M0 3% 16% 15% Resection should be indicated even in patients with node metastasis

  32. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 2 3. Survival after resection was improved year by year 5-year survival 1977 - 2000 2001 - 2007 2008 - 2015 All patients 23% 36% 47% N0R0M0 43% 66% 70% N1R0M0 15% 19% 25% R1/2M0 3% 16% 15% Resection is somewhat beneficial even in R1/2 resection

  33. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 3 4. Distant node metastasis may be a candidate of resection Survival of pts. with liver metastasis and/or dissemination was dismal even after Resection. However, survival of pts. with distant node metastasis alone was unexpectedly better with 11% at 5 years.

  34. Surgical treatment of perihilar cholangiocarcinoma Summaryofourdata 3 4. Distant node metastasis may be a candidate of resection Survival of pts. with liver metastasis and/or dissemination was dismal even after resection. However, survival of pts. with distant node metastasis alone was unexpectedly better with 11% at 5 years. When distant node is preoperative PET positive ➔　inoperable. When distant node is preoperative PET negative but frozen positive ➔ resection

  35. Chemotherapy is much less effective; No patients cured. Strategy is to “pursue resectability with never give up spirit”

  36. Patientselectionfrom a view point of liver function Mｔ. Fuji

  37. How to evaluate functional reserve Liver volume Liver function FLR (%) ICGK

  38. How to evaluate functional reserve Liver volume X Liver function FLR (%) ICGK “ICGK-F” Nagino et al, 1995 Hepatology; Nagino et al, 2006 Ann Surg; Yokoyama et al, 2010 Br J Surg

  39. How to evaluate functional reserve Liver volume X Liver function FLR (%) ICGK “ICGK-F” 0.05 or more is safe criteria of Hx. Nagino et al, 1995 Hepatology; Nagino et al, 2006 Ann Surg; Yokoyama et al, 2010 Br J Surg

  40. How to evaluate functional reserve Biliary drainage PVE Liver volume X Liver function FLR (%) ICGK “ICGK-F” 0.05 or more is safe criteria of Hx. Nagino et al, 1995 Hepatology; Nagino et al, 2006 Ann Surg; Yokoyama et al, 2010 Br J Surg

  41. Patients with perihilar cholangiocarcinoma (666 patients between 2006 and 2015) Candidates of right trisectionectomy N=65 No-PVE due to FLR>40% , n=6 (These 6 pts underwent resection) With PVE N=59 Progressive disease, n=3 Assessment of FLR N=56 Poor liver function, n=5 Laparotomy N=51 Unresectable, n=9 Combined resections PV n=25 HA n=1 PD n=3 Right trisectionectomy N=42

  42. Patients with perihilar cholangiocarcinoma (666 patients between 2006 and 2015) Candidates of right trisectionectomy N=65 No-PVE due to FLR>40% , n=6 (These 6 pts underwent resection) With PVE N=59 Progressive disease, n=3 Assessment of FLR N=56 Poor liver function, n=5 Laparotomy N=51 Unresectable, n=9 Combined resections PV n=25 HA n=1 PD n=3 Right trisectionectomy N=42

  43. Patients with perihilar cholangiocarcinoma (666 patients between 2006 and 2015) Candidates of right trisectionectomy N=65 No-PVE due to FLR>40% , n=6 (These 6 pts underwent resection) With PVE N=59 Progressive disease, n=3 Assessment of FLR N=56 Poor liver function, n=5 Laparotomy N=51 Unresectable, n=9 Combined resections PV n=25 HA n=1 PD n=3 Right trisectionectomy N=42

  44. Patients with perihilar cholangiocarcinoma (666 patients between 2006 and 2015) Candidates of right trisectionectomy N=65 No-PVE due to FLR>40% , n=6 (These 6 pts underwent resection) With PVE N=59 Progressive disease, n=3 Assessment of FLR N=56 Poor liver function, n=5 Laparotomy N=51 Unresectable, n=9 Combined resections PV n=25 HA n=1 PD n=3 Right trisectionectomy N=42

  45. Patients with perihilar cholangiocarcinoma (666 patients between 2006 and 2015) Candidates of right trisectionectomy N=65 No-PVE due to FLR>40% , n=6 (These 6 pts underwent resection) With PVE N=59 Progressive disease, n=3 Assessment of FLR N=56 Poor liver function, n=5 Laparotomy N=51 Unresectable, n=9 Combined resections PV n=25 HA n=1 PD n=3 Right trisectionectomy N=42

  46. Patients with perihilar cholangiocarcinoma (666 patients between 2006 and 2015) Candidates of right trisectionectomy N=65 No-PVE due to FLR>40% , n=6 (These 6 pts underwent resection) With PVE N=59 Progressive disease, n=3 Assessment of FLR N=56 Poor liver function, n=5 Laparotomy N=51 Unresectable, n=9 Combined resections PV n=25 HA n=1 PD n=3 Right trisectionectomy N=42

  47. Baseline characteristics of 56 study patients who received PVE prior to surgery Age (yrs) 67 (48-80) Gender men 35; women 21 Bismuth type IV 47; III 7; II 2 ICGK 0.164 (0.100 – 0.225) FLR (mL) 287 (141 – 642) FLR (%) 25 (14 – 41) ICGK-F 0.037 (0.021 – 0.068) Distribution of %FLR Distribution of ICGK-F 15 10 10 5 5 0 0 10% 20% 30% 40% 0.02 0.03 0.04 0.05 0.06 0.07

  48. Pre-PVE characteristics of 56 study patients who received PVE prior to surgery Age (years) 67 (48-80) Gender men 35; women 21 Bismuth type IV 47; III 7; II 2 ICGK* 0.164 (0.100 – 0.225) FLR (mL) 287 (141 – 642) FLR (%) 25 (14 – 41) ICGK-F* 0.037 (0.021 – 0.068) Distribution of %FLR Distribution of ICGK-F 15 10 10 5 FLR≤25% n=29 (52%) ICGK-F≤0.04 n=27 (48%) 5 0 0 10% 20% 30% 40% 0.02 0.03 0.04 0.05 0.06 0.07

  49. Details of PVE performed(n=56) Type of PVE Right + P4 (n=41,73%) ; Right alone (n=15, 27%) Embolic materials Ethanol (n=40) or gelatin sponge (n=16) + steel coils Operating time 2.1 hours (0.9 – 4.0 hours) Complications* 7 (13%) Re-canalization 9 (16%) Re-PVE 5 (9%) Mortality 0 *, biloma (n=2), hepatic artery injury (n=2), intraabdominal bleeding (n=1), PV thrombus (n=1), and peeled guidewire (n=1), with overlaps.

  50. Changes in volume after PVE: Righttrisegment(R3) PVE vs. Right (R2) PVE Volume of left medial segment Volume of left lateral segment R2PVE R2PVE R3PVE R3PVE Nagino M, et al., Surgery 2000.

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