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

• None

Disclosures

Gallbladder Cancer

Gallbladder Cancer Gallbladder Cancer Per Primum GB Cancer Incidental GB Cancer

8,500 new cases in the US

• 30%
• Most metastatic or

locally advanced at diagnosis

• 70%
• ~1 of every 150

cholecystectomy specimens

Gallbladder Cancer

• T-stage
• Residual disease
• Operative strategy

− Timing − Extent of operation

• Adjuvant therapy
• Future directions

Outline

Gallbladder Cancer

Incidental Gallbladder Cancer

Incidental GB Cancer

Is simple cholecystectomy oncologically appropriate? YES NO No Re-resection Re-resection

Gallbladder Cancer

• Better prognosis with re-resection than no re-resection

Incidental Gallbladder Cancer

Re-resection No re-resection p<0.0001

Gallbladder Cancer

• Prognosis after re-resection is T-stage dependent

Incidental Gallbladder Cancer

T1 T2 T3 T4 p<0.0001

Gallbladder Cancer

• Better prognosis with radical resection in T1b disease

Incidental Gallbladder Cancer

Gallbladder Cancer

• Better prognosis with re-resection for T2 disease than T3

Incidental Gallbladder Cancer

T2 T3

Re-resection No re-resection Re-resection No re-resection

Gallbladder Cancer

• Re-resection currently based on T-Stage alone

Incidental Gallbladder Cancer

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

Gallbladder Cancer

• Re-resection currently based on T-Stage alone

Incidental Gallbladder Cancer

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

Is T-Stage really the best patient selection tool?

Gallbladder Cancer

• Better prognosis without residual disease than with

Patient Selection

Residual tumor No residual tumor p<0.0001

Gallbladder Cancer

• Incidence of residual disease increases with T-stage

Patient Selection

Gallbladder Cancer

• Residual disease may be most important factor

Patient Selection

J Am Coll Surg. 2014 Sept; 219(3): 416-429.

Gallbladder Cancer

• LVI and PNI predictive of survival in IHC

Patient Selection

HPB (Oxford). 2012 Aug; 14(8): 514-22.

Gallbladder Cancer

• Grade predictive of survival in IGBC

Patient Selection

J Am Coll Surg. 2014 Sept; 219(3): 416-429.

Gallbladder Cancer

• Grade predictive of disseminated disease at reoperation

Patient Selection

HPB (Oxford). 2011 Jul; 13(7): 463-472.

Gallbladder Cancer

• 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

US EBMC

USEBMC

(n=1,092)

Hilar Cholangiocarcinoma

(n=329, 30%)

Gallbladder Cancer

(n=449, 41%)

Distal Cholangiocarcinoma

(314, 29%)

Gallbladder Cancer

• Retrospective cohort study
• All patients with incidental

gallbladder cancer who underwent reoperation from 2000-2015

• Had data regarding the

presence of locoregional residual and/or distant disease

• Descriptive statistics were

performed for the entire cohort

Methods

Gallbladder Cancer

(n=449)

Not Incidentally Discovered

(n=183, 41%)

Incidentally Discovered

(n=266, 59%)

Reoperation

(n=262, 58%)

No info for residual or distant disease (n=4)

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Results

Pathology Data

Locoregional Disease Distant Disease n (%) p-value n (%) p-value

AJCC T-Stage Tis/T1a T1b T2 T3/T4 0 (0) 2 (17) 42 (40) 60 (70) <0.001 0 (0) 0 (0) 9 (8) 19 (21) 0.005 Grade Well Moderate Poor/Undifferentiated 7 (32) 53 (51) 37 (65) 0.02 1 (4) 13 (11) 13 (22) 0.05 Lymphovascular invasion Negative Positive 18 (33) 31 (63) 0.004 2 (3) 10 (19) 0.01 Perineural invasion Negative Positive 19 (40) 37 (63) 0.04 1 (2) 12 (19) 0.006

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Results

GRADE

p=0.012

Well-diff Mod-diff Poor-diff

Proportion Surviving Time (months)

Overall Survival

T-STAGE

p<0.001

T1b T2 T3/T4

Proportion Surviving Time (months) Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Results

LVI PNI

p=0.007 p=0.008

Negative Positive Negative Positive

Proportion Surviving Time (months) Proportion Surviving Time (months)

Overall Survival

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Predictive Risk Score

Gallbladder Cancer Predictive Risk Score (GBRS)

T-Stage Tis/T1a 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

Locoregional Disease Distant 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)

• Predicts locoregional residual and distant disease

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Predictive Risk Score

• Predicts overall survival

GBRS Group

Low Risk

MNR

High Risk

16 months

Intermediate Risk

67 months

p = <0.001

Proportion Surviving Time (months)

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Predictive Risk Score

Locoregional Disease Distant Disease

OR (95% CI) p-value OR (95% CI) p-value

GBRS

High vs Intermediate

4.5

(1.7 – 11.6)

0.002 12.2

(1.5 – 100.0) 0.02

T-stage

T3/T4 vs T2

3.5

(1.9 – 6.3)

<0.001 3.0

(1.3 – 7.0)

0.01

• Compared to T-stage alone, GBRS may better

predict locoregional residual and distant disease

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Predictive Risk Score

Overall Survival

HR (95% CI) p-value

GBRS

High vs Intermediate

4.6

(2.0 – 10.3)

<0.001 T-stage

T3/T4 vs T2

2.2

(1.5 – 3.3)

<0.001

• Compared to T-stage alone, GBRS may better

predict overall survival

Ethun, Maithel et al. Ann Surg Oncol 2017

Gallbladder Cancer

Predictive Risk Score

p=0.03 Intermediate GBRS

67 months

High GBRS

26 months

Proportion Surviving Time (months)

T2 Disease

• Differences in overall survival within T-stage

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 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

Timing of 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

• 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)

US EBMC

Gallbladder Cancer (n=449) Incidentally-Discovered (n=266, 59%) Reoperation (n=233, 53%) Group A <4 weeks (n=49, 21%) Group B 4-8 weeks (n=91, 39%) Group C >8 weeks (n=93, 40%)

Not Incidental (n=183) No date for initial cholecystectomy (n=33)

Gallbladder Cancer

Results

Baseline/Preoperative Variables Group A (<4 weeks) Group B (4-8 weeks) Group C (>8 weeks) p-value

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 African-American Latino Asian Other 21 (88) 0 (0) 2 (8) 1 (4) 0 (0) 67 (77) 11 (13) 5 (6) 2 (2) 2 (2) 68 (76) 12 (13) 6 (7) 2 (2) 2 (2) 0.81 ASA class, n (%) 1 2 3 4 0 (0) 13 (62) 8 (38) 0 (0) 1 (2) 19 (29) 44 (67) 2 (3) 1 (2) 25 (37) 39 (57) 3 (4) 0.22 Comorbidities±, n (%) 1 >2 4 (17) 15 (65) 4 (17) 32 (37) 34 (39) 21 (24) 25 (28) 37 (42) 26 (30) 0.16 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

Gallbladder Cancer

Results

Operative Variables Group A (<4 weeks) Group B (4-8 weeks) Group C (>8 weeks) p-value

Total n (%) 25 (12) 91 (44) 91 (44) Location of original cholecystectomy Participating institution 6 (24) 8 (9) 9 (10) 0.09 Locoregional residual disease, n (%) 14 (56) 42 (47) 42 (48) 0.71 Distant disease, n (%) 2 (8) 18 (20) 16 (18) 0.38 Attempted resection, n (%) 22 (88) 79 (87) 77 (85) 0.87 Completed resection, n (%) 22 (88) 74 (81) 72 (79) 0.60 Extent of resection, n (%) Radical cholecystectomy + Portal LN Major hepatectomy 21 (96) 1 (5) 66 (87) 10 (13) 69 (93) 5 (7) 0.29 Operative Approach Open Laparoscopic 23 (100) 0 (0) 84 (97) 3 (3) 85 (97) 3 (3) 0.67 Common bile duct resection, n (%) 9 (41) 29 (37) 23 (30) 0.54 EBL (mL), mean + SD 428 + 318 294 + 292 352 + 396 0.26 Major complication, n (%) 3 (13) 8 (9) 16 (18) 0.24 Ethun, Maithel et al. JAMA Surg 2017

Gallbladder Cancer

Results

Pathology Variables Group A (<4 weeks) Group B (4-8 weeks) Group C (>8 weeks) p-value

Total n (%)◊ 25 (12) 91 (44) 91 (44) Final margin status, n (%) R0 R1 R2 19 (76) 3 (12) 3 (12) 72 (79) 1 (1) 18 (20) 69 (76) 3 (3) 19 (21) 0.10 Tumor size (mm), mean + SD 38.9 + 18.1 28.4 + 25.4 30.2 + 19.9 0.31 AJCC T-Stage, n (%) T1a/b T2 T3/4 1 (5) 11 (50) 10 (46) 5 (6) 50 (63) 24 (30) 10 (12) 35 (43) 36 (44) 0.11 Grade, n (%) Well/Moderate Poor/Undifferentiated 13 (62) 8 (38) 51 (71) 21 (29) 56 (76) 18 (24) 0.45 Lymphovascular invasion, n (%) 5 (46) 20 (50) 17 (41) 0.69 Perineural invasion, n (%) 8 (73) 19 (46) 25 (58) 0.25 Lymph node (LN) positive, n (%) 9 (39) 31 (47) 30 (40) 0.63 Total LN retrieved, mean + SD 5.8 + 5.5 5.2 + 5.4 4.7 + 4.9 0.63 Neoadjuvant chemotherapy, n (%) 0 (0) 0 (0) 7 (8) 0.01 Adjuvant chemotherapy, n (%) 8 (44) 41 (54) 40 (52) 0.77 Ethun, Maithel et al. JAMA Surg 2017

Gallbladder Cancer

Results

Group A (<4 wks) Median: 17 mos Group B (4-8 wks) Median: 40 mos Group C (>8 wks) Median: 22 mos p = 0.03

Overall Survival from Date of Reoperation (All Patients)

Ethun, Maithel et al. JAMA Surg 2017

Gallbladder Cancer

Results

Univariable Cox Regression Multivariable Cox Regression Variable HR (95% CI) p-value HR (95% CI) p-value

Time-Interval Group A (0-4 wks) Group B (4.1-8wks) Group C (>8wks) 1.94 (1.06 – 3.56) Reference 1.68 (1.08 – 2.59) 0.03 0.02 2.63 (1.25 – 5.54) Reference 2.07 (1.17 – 3.66) 0.01 0.01 Clinical Jaundice 1.69 (0.85 – 3.38) 0.14 Extent of resection Radical cholecystectomy + Portal LN Major hepatectomy Reference 1.35 (0.67 – 2.73) 0.40 – – Residual disease at reoperation 3.10 (2.01 – 4.76) <0.001 1.51 (0.90 – 2.54) 0.12 Final margin status R0 R1 R2 Reference 2.73 (0.98 – 7.59) 4.33 (2.77 – 6.77) 0.05 <0.001 Reference 1.19 (0.34 – 4.18) 2.69 (1.27 – 5.69) 0.79 0.009 AJCC T-stage T1a/b T2 T3/4 0.16 (0.02 – 1.18) Reference 2.16 (1.39 – 3.36) 0.07 0.001 0.28 (0.04 – 2.08) Reference 1.85 (1.11 – 3.08) 0.21 0.02 Grade Well/Moderate Poor/Undifferentiated Reference 1.40 (0.87 – 2.26) 0.16 – – Lymph node positive 1.72 (1.07 – 2.76) 0.03 1.56 (0.94 – 2.60) 0.09 Adjuvant chemotherapy 0.99 (0.62 – 1.59) 0.98 – –

Univariable and Multivariable Cox Regression Analyses for Overall Survival from Date of Reoperation

Ethun, Maithel et al. JAMA Surg 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.

Operative Strategy?

Gallbladder Cancer

• Extent of Resection

− Lymph node dissection − Liver resection − Bile duct resection − Port-Site Resection

Operative Strategy

Gallbladder Cancer

OPERATIVE STRATEGY

LYMPH NODE DISSECTION

Gallbladder Cancer

LN Involvement and T-Stage

• Rate of LN metastases increases with T stage

T1a: < 2.5% T1b: 12.5% T2: 31.3% T3: 45.5%

Pawlik et al. J Gastrointest Surg 2007 Pilgrim et al. Eur J Surg Oncol 2009

Gallbladder Cancer

Lymphadenectomy and Survival

• 2009 SEER study with 1,348 patients (T1b and T2)

Jensen et al. Surgery 2009

Radical Rsxn + LN Radical Rsxn, No LN Simple Rsxn, No LN

Gallbladder Cancer

Extent of Lymphadenectomy

• Is more better?

− Nodal disease beyond hepatoduodenal ligament is similar to metastatic disease

No mets Regional LN mets Distant LN mets or metastatic disease

Kondo and Nimura et al. Br J Surg 2000

Gallbladder Cancer

OPERATIVE STRATEGY

EXTENT OF LIVER RESECTION

Gallbladder Cancer

D’Angelica et al. Ann Surg Oncol 2009

• 1988 – 2003
• Decreased major

hepatectomy rates

• Not associated with

worse clinical or pathologic parameters

Similar Findings in Multiple Studies

Extent of Resection

Gallbladder Cancer

OPERATIVE STRATEGY

BILE DUCT RESECTION

Gallbladder Cancer

D’Angelica et al. Ann Surg Oncol 2009

Bile Duct Resection

Gallbladder Cancer

Shih and Talamini et al. Ann Surg 2007

Bile Duct Resection

Gallbladder Cancer

Bile Duct Resection

Pawlik et al. J Gastrointest Surg 2007

Repeatedly Shown NOT To Increase Lymph Node Yield

Gallbladder Cancer

Complete Resection is the Goal

Pawlik et al. J Gastrointest Surg 2007

Gallbladder Cancer

OPERATIVE STRATEGY

PORT-SITE RESECTION

Gallbladder Cancer

Operative Strategy

Ann Surg Oncol. 2012; 19: 409-417.

Gallbladder Cancer

Operative Strategy

J Visceral Surg. 2013; 219: 277-284.

Port-Site Excision No Port-Site Excision Port-Site Excision No Port-Site Excision

All patients R0 Only

Gallbladder Cancer

Operative Strategy

J Visceral Surg. 2013; 219: 277-284.

15% port-site incisional hernia rate

Gallbladder Cancer

• Retrospective cohort study
• All patients with incidental

gallbladder cancer who underwent a curative intent reoperative from 2000-2015

• Had data regarding port-site

resection

US EBMC

Gallbladder Cancer (n=449) Not Incidentally Discovered (n=183, 41%) Incidentally Discovered (n=266, 59%) Curative Intent Re-Resection (n=193, 73%)

Palliative/R2, No info for port-site resection (n=73)

No Port-Site Resection (n=146, 76%) Port-Site Resection (n=47, 24%)

Gallbladder Cancer

Results

Overall Survival (Residual Disease Only)

(+) Residual Disease

Port-site (n=16) Median: 31mos No Port-site (n=59) Median: 20mos

p=0.44

Ethun, Maithel et al. J Surg Onc 2017

Gallbladder Cancer

Results

Univariable Cox Regression Multivariable Cox Regression Variable HR (95% CI) p-value HR (95% CI) p-value

Port-site resection 0.60 (0.35 – 1.03) 0.07 0.64 (0.33 – 1.22) 0.18 AJCC T-Stage T1 T2 T3/T4 Ref 2.56 (0.79 – 8.32) 4.80 (1.47 – 15.7) 0.12 0.01 Ref 2.65 (0.62 – 11.3) 4.52 (1.04 – 19.6) 0.19 0.04 Grade Well/Moderate Poor Ref 1.92 (1.16 – 3.17) 0.01 Ref 1.84 (1.09 – 3.12) 0.02 Margin positive 3.20 (1.58 – 6.46) 0.001 2.54 (1.03 – 6.22) 0.04 Lymph node positive 1.51 (0.96 – 239) 0.08 – – Residual Disease 2.16 (1.40 – 3.34) 0.001 1.67 (0.97 – 2.89) 0.07

Ethun, Maithel et al. J Surg Onc 2017

Gallbladder Cancer

Results

20 40 60 80 100

2000-2004 (n=43) 2005-2009 (n=63) 2010-2014 (n=87)

% Patients

Incidence of Port-Site Resection over Time

Port-Site Resection No Port-Site Resection

33%

(n=14)

22%

(n=14)

22%

(n=19)

p=0.36

Ethun, Maithel et al. J Surg Onc 2017

Gallbladder Cancer

ADJUVANT THERAPY

Gallbladder Cancer

• Significant early disease recurrence

Incidental Gallbladder Cancer

J Am Coll Surg. 2014 Sept; 219(3): 416-429.

~40% 1-yr recurrence

Gallbladder Cancer

Incidental Gallbladder Cancer

• NEJM. 2010 Apr; 362(14): 1273-1281.

Gallbladder Cancer

PRODIGE 12

J Clin Oncol 35, 2017 (suppl 4S; abstract 225)

Julien Edeline, Franck Bonnetain, Jean Marc Phelip, Jérôme Watelet, Pascal Hammel, Jean-Paul Joly, Meher Ben Abdelghani, Olivier Rosmorduc, Karine Bouhier-Leporrier, Jean-Louis Jouve, Roger Faroux, Véronique Guerin Meyer, Eric Assenat, Jean Francois Seitz, David Malka, Christophe Louvet, Aurelie Bertaut, Beata Juzyna, Trevor Stanbury, Eveline Boucher

• Randomized, phase III trial

− Adjuvant Gemcitabine + Oxaliplatin (n=94) − Observation (n=99)

• All biliary tract cancers

− Intrahepatic (n=86), Hilar (n=15), Extrahepatic (n=54) − Gallbladder (n=38)

• Median relapse-free survival

− GEMOX: 30.4 months − Observation: 22.0 months − p=0.31

• Negative trial

Trend persisted among gallbladder cancer cohort

Gallbladder Cancer

BILCAP

• Randomized, phase III trial

− Adjuvant Capecitabine (n=223) − Observation (n=224)

• All biliary tract cancers

− Intrahepatic (19%), Hilar (28%), Extrahepatic (35%) − Gallbladder (18%)

• Median Survival

Intention-to-Treat OS − Cape: 51 months − Observation: 36 months − p=0.097

• Positive trial

Per Protocol OS − Cape: 53 months − Observation: 36 months − p=0.028 Intention-to-Treat RFS − Cape: 25 months − Observation: 18 months − p=0.036

Gallbladder Cancer

FUTURE DIRECTIONS

NEOADJUVANT THERAPY

Gallbladder Cancer

• To determine whether preoperative Gem/Cis

(treatment arm) given prior to reoperation for IGBC and postoperative capecitabine is associated with

− Improved overall survival at 3 years (primary endpoint) − Improved recurrence-free survival at 1 year (secondary endpoint) − Higher resectability (secondary endpoint)

compared to upfront surgery followed by postoperative capecitabine (control arm)

Specific Aims

Gallbladder Cancer

Study Design

132 randomized to surgery alone 132 randomized to perioperative chemotherapy

Gallbladder Cancer

• Phase III International RCT

− Treatment Arm: Preoperative Gem/Cis – Surgery – Postoperative Capecitabine − Control Arm: Surgery – Postoperative Capecitabine

• Inclusion criteria

− Gallbladder cancer discovered incidentally following cholecystectomy − T1b, T2, T3 disease − Resectable disease at the time of enrollment

• Exclusion criteria

− Tis, T1a, or T4 disease − Unresectable disease at the time of enrollment

Study Design

Gallbladder Cancer

• High-Volume, Academic, U.S. Centers

− 5-10 patients with IGBC undergo reoperation per year

• International collaboration, cooperation, and

participation

− UK, India, Chile, USA − 36-month recruitment period − Focused primary outcome (3-year OS)

• Gemcitabine and Cisplatin

− Currently standard of care for advanced biliary cancers − Uniformly reimbursed by third-party payers in U.S.

Feasibility

Gallbladder Cancer

Shishir K. Maithel, MD FACS Emory University

International Society of Gastrointestinal Oncology Nov 1, 2018

Gallbladder Cancer