Gallbladder Cancer Shishir K. Maithel, MD FACS Emory University - PowerPoint PPT Presentation

Gallbladder Cancer Shishir K. Maithel, MD FACS Emory University International Society of Gastrointestinal Oncology Nov 1, 2018

Gallbladder Cancer Disclosures • None

Gallbladder Cancer Gallbladder Cancer Gallbladder 8,500 new cases in Cancer the US Incidental Per Primum GB Cancer GB Cancer • 70% • 30% • ~1 of every 150 • Most metastatic or cholecystectomy locally advanced at specimens diagnosis

Gallbladder Cancer Outline • T-stage • Residual disease • Operative strategy − Timing − Extent of operation • Adjuvant therapy • Future directions

Gallbladder Cancer Incidental Gallbladder Cancer Incidental GB Cancer Is simple cholecystectomy oncologically appropriate? YES NO No Re-resection Re-resection

Gallbladder Cancer Incidental Gallbladder Cancer • Better prognosis with re-resection than no re-resection Re-resection No re-resection p<0.0001

Gallbladder Cancer Incidental Gallbladder Cancer • Prognosis after re-resection is T-stage dependent T1 T2 T3 T4 p<0.0001

Gallbladder Cancer Incidental Gallbladder Cancer • Better prognosis with radical resection in T1b disease

Gallbladder Cancer Incidental Gallbladder Cancer • Better prognosis with re-resection for T2 disease than T3 T2 T3 Re-resection Re-resection No re-resection No re-resection

Gallbladder Cancer Incidental Gallbladder Cancer • Re-resection currently based on T-Stage alone HPB (Oxford). 2015 Jul; 17(8): 681-6 90.

Gallbladder Cancer Incidental Gallbladder Cancer • Re-resection currently based on T-Stage alone HPB (Oxford). 2015 Jul; 17(8): 681-6 90. Is T-Stage really the best patient selection tool?

Gallbladder Cancer Patient Selection • Better prognosis without residual disease than with No residual tumor Residual tumor p<0.0001

Gallbladder Cancer Patient Selection • Incidence of residual disease increases with T-stage

Gallbladder Cancer Patient Selection • Residual disease may be most important factor J Am Coll Surg. 2014 Sept; 219(3): 416-429.

Gallbladder Cancer Patient Selection • LVI and PNI predictive of survival in IHC HPB (Oxford). 2012 Aug; 14(8): 514-22.

Gallbladder Cancer Patient Selection • Grade predictive of survival in IGBC J Am Coll Surg. 2014 Sept; 219(3): 416-429.

Gallbladder Cancer Patient Selection • Grade predictive of disseminated disease at reoperation HPB (Oxford). 2011 Jul; 13(7): 463-472.

Gallbladder Cancer US EBMC • U.S. Extrahepatic Biliary Malignancy Consortium − 10 diverse, academic institutions across U.S. Emory University University of Louisville Johns Hopkins University University of Wisconsin New York University Vanderbilt University Stanford University Wake Forest University The Ohio State University Washington University, St. Louis • Retrospective chart review • All patients with hilar cholangiocarcinoma, distal cholagiocarcinoma, or gallbladder cancer who underwent surgery from 2000-2015 USEBMC (n=1,092) Hilar Cholangiocarcinoma Gallbladder Cancer Distal Cholangiocarcinoma (n=329, 30%) (n=449, 41%) (314, 29%)

Gallbladder Cancer Methods • Retrospective cohort study • All patients with incidental Gallbladder Cancer gallbladder cancer who (n=449) underwent reoperation from Not Incidentally Incidentally 2000-2015 Discovered Discovered (n=183, 41%) (n=266, 59%) • Had data regarding the presence of locoregional No info for residual or distant disease (n=4) residual and/or distant disease Reoperation (n=262, 58%) • Descriptive statistics were performed for the entire cohort Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Results Locoregional Disease Distant Disease Pathology Data n (%) p-value n (%) p-value AJCC T-Stage <0.001 0.005 Tis/T1a 0 (0) 0 (0) T1b 2 (17) 0 (0) T2 42 (40) 9 (8) T3/T4 60 (70) 19 (21) Grade 0.02 0.05 Well 7 (32) 1 (4) Moderate 53 (51) 13 (11) Poor/Undifferentiated 37 (65) 13 (22) Lymphovascular invasion 0.004 0.01 Negative 18 (33) 2 (3) Positive 31 (63) 10 (19) Perineural invasion 0.04 0.006 Negative 19 (40) 1 (2) Positive 37 (63) 12 (19) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Results Overall Survival T-STAGE GRADE T1b Proportion Surviving Proportion Surviving Well-diff T2 Mod-diff Poor-diff T3/T4 p<0.001 p=0.012 Time (months) Time (months) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Results Overall Survival PNI LVI Proportion Surviving Proportion Surviving Negative Negative Positive Positive p=0.007 p=0.008 Time (months) Time (months) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Predictive Risk Score Gallbladder Cancer Predictive Risk Score (GBRS) T-Stage Tis/T1a 0 T1b 1 T2 2 T3/T4 3 Grade G1 (Well-diff) 1 G2 (Mod-diff) 2 G3 (Poor-diff) 3 LVI Negative 1 Positive 2 PNI Negative 1 Positive 2 GBRS Group Totals Low 3 – 4 Intermediate 5 – 7 High 8 – 10 Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Predictive Risk Score • Predicts locoregional residual and distant disease Locoregional Distant Disease Disease n (%) p-value n (%) p-value GBRS Group 0.001 0.006 Low (3-4) 0 (0) 0 (0) Intermediate (5-7) 13 (35) 1 (3) High (8-10) 29 (71) 10 (24) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Predictive Risk Score • Predicts overall survival Low Risk MNR Proportion Surviving Intermediate Risk 67 months High Risk 16 months GBRS Group p = <0.001 Time (months) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Predictive Risk Score • Compared to T-stage alone, GBRS may better predict locoregional residual and distant disease Locoregional Disease Distant Disease OR (95% CI) p-value OR (95% CI) p-value GBRS 4.5 0.002 12.2 (1.5 – 100.0) 0.02 (1.7 – 11.6) High vs Intermediate T-stage 3.5 <0.001 3.0 0.01 (1.9 – 6.3) (1.3 – 7.0) T3/T4 vs T2 Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Predictive Risk Score • Compared to T-stage alone, GBRS may better predict overall survival Overall Survival HR (95% CI) p-value GBRS 4.6 <0.001 (2.0 – 10.3) High vs Intermediate T-stage 2.2 <0.001 (1.5 – 3.3) T3/T4 vs T2 Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Predictive Risk Score • Differences in overall survival within T-stage T2 Disease Intermediate GBRS Proportion Surviving 67 months High GBRS 26 months p=0.03 Time (months) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer Incidental Gallbladder Cancer HPB (Oxford). 2015 Jul; 17(8): 681-6 90.

Gallbladder Cancer Incidental Gallbladder Cancer HPB (Oxford). 2015 Jul; 17(8): 681-6 90. Timing of reoperation?

Gallbladder Cancer Timing of Reoperation • Timing of reoperation varies between 1 day and 2 years following initial cholecystectomy − Minimize inflammation and fibrosis in the operative field − Referral patterns and scheduling logistics • In benign setting, most surgeons elect to reoperate − Within first 7-10 days, before inflammation peaks − After approximately 4-6 weeks, after inflammation beings to subside • In malignancy, tumor biology plays an additional role when considering the optimal time for reoperation Butte et al. J Amer Coll Surg, 2014. Franko et al. Ann Thoracic Surg , 2016. Huntington et al. Ann Surg Oncol , 2016.

Gallbladder Cancer US EBMC • Patients were then separated into 3 groups according to their time-interval to reoperation: − Group A (< 4 weeks) − Group B (4 – 8 weeks) − Group C (>8 weeks) Gallbladder Cancer (n=449) Not Incidental (n=183) Incidentally-Discovered (n=266, 59%) No date for initial cholecystectomy (n=33) Reoperation (n=233, 53%) Group A Group B Group C <4 weeks 4-8 weeks >8 weeks (n=49, 21%) (n=91, 39%) (n=93, 40%)

Gallbladder Cancer Results Group A Group B Group C p-value Baseline/Preoperative Variables (<4 weeks) (4-8 weeks) (>8 weeks) Total n (%) 25 (12) 91 (44) 91 (44) Time to re-operation (wks), median (range) 2.9 (0.4-3.9) 5.9 (4.1-8.0) 11.4 (8.1-179.6) Age (yrs), mean + SD 65 + 9 64 + 11 66 + 12 0.75 Male gender, n (%) 10 (40) 34 (37) 33 (36) 0.94 BMI, mean + SD 28.7 + 6.5 29.0 + 6.9 30.3 + 7.0 0.40 Race, n (%) White 21 (88) 67 (77) 68 (76) African-American 0 (0) 11 (13) 12 (13) 0.81 Latino 2 (8) 5 (6) 6 (7) Asian 1 (4) 2 (2) 2 (2) Other 0 (0) 2 (2) 2 (2) ASA class, n (%) 1 0 (0) 1 (2) 1 (2) 2 13 (62) 19 (29) 25 (37) 0.22 3 8 (38) 44 (67) 39 (57) 4 0 (0) 2 (3) 3 (4) Comorbidities ± , n (%) 0 4 (17) 32 (37) 25 (28) 0.16 1 15 (65) 34 (39) 37 (42) >2 4 (17) 21 (24) 26 (30) Clinical Jaundice, n (%) 2 (8) 9 (11) 4 (5) 0.34 ± Includes hypertension, diabetes, prior cardiac event, end-stage renal disease Ethun, Maithel et al. JAMA Surg 2017