Gall Bladder Cancer (S+DT)

Incidence of Gallbladder Cancer

• India: 10-22 cases/100,000
• Asia: 5-8 cases/100,000
• Eastern Europe: 2-4 cases/100,000
• South America: 9-14 cases/100,000
• United States: 1-2 cases/100,000
  • 6th most common GI malignancy in the US
  • Most common biliary tract malignancy in the US

Risk Factors

• Gallstone Disease: Mechanical injury, bacterial colonization, chronic inflammation
  • 75-90% occur in setting of cholelithiasis
  • Stone size : ≥ 3cm
  • Incidence: 0.3-3%
  • Nature of stone is not a determinant.
• Polyps:
  • sessile polyp >1cm

  • 6mm in PSC

  • with stones
  • age > 50yr
  • Cholesterol polyp does not increase risk.
  • polyposis is not a risk factor
  • Adenomyomatosis is not a risk factor
  • Adenoma Carcinoma sequence = RARE
• Calcification = 10% ; Stippled > diffuse
• Geographic and Ethnic Variations:
  • Chile: High prevalence of gallstones (36% women, 16% men)
  • Hispanic and Native American populations: Higher risk in the US
• Obesity
• Multiparity
• Gender: 3x higher in women
• Socioeconomic Status: Low status linked to decreased healthcare access, less cholecystectomy
• Infections: Chronic Salmonella typhi, Helicobacter pylori
• Environmental Exposures: Pollutants, chemicals, smoking
• Japan: K-ras mutation, anomalous pancreaticobiliary junction, TP53 gene mutations.
• Chemical Risk Factors in Gallbladder Carcinogenesis
  • Methyldopa
  • Oral contraceptives
  • Isoniazid
  • Occupational exposure in the rubber industry
  • (Source: Blumgart 6th edition, page 787)

Prognostic Factors

• Disease Extent at Diagnosis: Most important predictor of survival
• Higher T-stage and Lymph Node Involvement: Associated with decreased overall survival
• (MCQ) Most important prognostic factor in survival of GB cancer = Lymph Nodes

MCQ: True Statements About the Etiology of Gallbladder Carcinoma Except

Question: Which of the following is not true regarding the etiology of gallbladder carcinoma?

Options: a) Gallstone present in 0.3-3% of patients with carcinoma

b) History of typhoid infection is a risk factor for gallbladder carcinoma

c) Women are 3 times more likely to develop gallbladder carcinoma

d) Cholesterol metabolism gene polymorphism associated with increased risk of cancer

Summary:

• Gallstones and Gallbladder Carcinoma: While 90% of gallbladder cancer specimens contain stones, the incidence of gallbladder cancer in patients with stones is 0.3% to 3%. This indicates a low incidence when considering stones as the sole risk factor.
• Typhoid Infection: A history of typhoid infection is a known risk factor, as it exposes the gallbladder mucosa to chronic inflammation, contributing to cancer risk.
• Gender Disparity: Women are approximately three times more likely to develop gallbladder cancer than men across all populations.
• Cholesterol Metabolism Gene Polymorphism: There is an association between cholesterol metabolism gene polymorphisms and an increased risk of both gallbladder cancer and stones.

Correct Answer: A) Gallstone present in 0.3-3% of patients with carcinoma

Lymphatic Spread of Gall bladder Cancer:

• Cystic ⇒ Choledochal ⇒ Posterior Superior Pancreatico Duodenal (station 13) ⇒either SMA / Celiac ⇒ Aortocaval
• PSPD LN are previously considered metastatic are now regional
• First echelon = 12c (cystic duct) , 12b (bile duct)
• Second echelon = 12a (CHA), 12p (periportal), 13a (PSPD)
• 3 group of lymph nodes are considered metastatic
  • Celiac group (9)
  • SMA group (14)
  • Aortocaval group (16)
• No of LN harvested = 6

TNM and AJCC staging of GB cancer:

Treatment of Carcinoma Gallbladder:

• Incidental Gall bladder:

  • T1a = observation
    • Risk of Nodal disease = <3%
    • Cholecystectomy is sufficient
    • cures 85-100%
  • T1b =
    • tumor penetrates musclar layer
    • Risk of nodal disease is 10%
    • Radical Cholecystectomy is warranted
    • Port site excision not done

  

  -NO ROLE OF PORT SITE EXCISION FOR ANY STAGE OF GB CANCER -ROUTINE CBD EXCISION IS NOT WARRANTED BUT EXCISED IF CYSTIC DUCT MARGIN POSITIVE/ CHOLEDOCHAL CYST PRESENT

• Non Incidental GB cancer:

  

  • T1A = LAP CHOLECYSTECTOMY
  • T1B = EXTENDED CHOLECYSTECTOMY
    • Staging Lap is mandatory
    • Kocherization = sampling of aortocaval LN = if positive = abort surgery
    • excise liver
      • Wedge excision
      • formal segmentectomy of IVb and V
    • Lymphadenectomy = 12a , 12c, 12b, 12 p ,8, 13
    • Routine CBD excision not done unless
      • Cystic duct margin positive
      • Contiguous involvement
      • Choledochal cyst/ APBJ
      • Papillary variant ????
  • T2 OR HIGHER = RADICAL CHOLECYSTECTOMY

Contraindication for Radical resection in Ca Gallbladder:

• Metastases in any segment not contiguous with Gb mass = considered Distant Mets
• CHA Involvement
• Main Portal Vein involved
• Distant metastasis
• LN outside regional chain
  • Simultaneous Duodenal and Colonic involvement = we can operate
  • RHA and RPV involvement is not a contraindication = we can do Liver resection

Intraoperative Image of Radical Cholecystectomy

1. blue loop = PV
2. superior Red loop = Right Hepatic artery
3. Inferior Red loop = Bile duct

Intra op image of Ca gb resection:

• Kocherization of duodenum = exposing IVC and left renal vein origin and aorta for sampling of Aortocaval LN

MCQ: Not true about liver resection in carcinoma of the gallbladder?

A) Extent of hepatic resection does not improve survival

B) Wedge resection is similar to anatomical segmentectomy

C) Involvement of main portal vein implies right hepatectomy

D) Simple cholecystectomy with lymph node resection can be done in peritoneal side tumor

Correct Answer: D. Simple cholecystectomy with lymph node resection can be done in peritoneal side tumor

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Explanation:

• Simple cholecystectomy with lymph node resection is not adequate in the treatment of peritoneal side tumors in gallbladder carcinoma, as more extensive resection is often necessary.
• A) Extent of hepatic resection does not improve survival:
  • This is true. There is no significant improvement in survival with more extensive liver resections beyond what is necessary to achieve clear margins.
• B) Wedge resection is similar to anatomical segmentectomy:
  • This is true. Studies have shown that wedge resection can provide outcomes similar to anatomical segmentectomy in appropriate cases.
• C) Involvement of the main portal vein implies right hepatectomy:
  • This is true. If the tumor involves the main portal vein, a right hepatectomy may be required to achieve negative margins.
• D) Simple cholecystectomy with lymph node resection can be done in peritoneal side tumor:
  • This is false. Tumors on the peritoneal side often require more than a simple cholecystectomy; additional resection of adjacent liver tissue is typically needed to ensure clear margins.

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Conclusion: The correct answer is D, as simple cholecystectomy with lymph node resection is inadequate for tumors on the peritoneal side of the gallbladder.

MCQ: A 45-year-old female underwent laparoscopic cholecystectomy for gallstone disease. The HPR report revealed adenocarcinoma reaching up to the muscularis propria. She was planned for revision radical cholecystectomy. What is not true?

A) Immediate surgery should be done due to the risk of further spread

B) Adjuvant capecitabine is given after surgery

C) Staging laparoscopy with PET CT is done in preoperative staging

D) Laparoscopic surgery can be done

Correct Answer: A. Immediate surgery should be done due to the risk of further spread

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Explanation:

• A) Immediate surgery should be done due to the risk of further spread:
  • This is false. Optimal timing for re-resection is 4-8 weeks after the initial cholecystectomy. Immediate surgery is not necessary, and waiting for a few weeks can improve prognosis and allow for better planning.
• B) Adjuvant capecitabine is given after surgery:
  • This is true. Capecitabine, a chemotherapy agent, is often used as adjuvant therapy following surgery for gallbladder cancer.
• C) Staging laparoscopy with PET CT is done in preoperative staging:
  • This is true. Staging laparoscopy along with PET CT helps in preoperative assessment to check for any metastatic disease or spread that might affect surgical planning.
• D) Laparoscopic surgery can be done:
  • This is false. Revision radical cholecystectomy for gallbladder cancer typically requires open surgery rather than laparoscopic surgery, due to the need for wide resections and lymph node dissection. BUT Laparoscopic staging needs to be done so consider option a as the single best answer.

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Conclusion: The correct answer is A, as immediate surgery is not required. The best timing for re-resection is typically 4-8 weeks post the initial surgery to allow for optimal outcomes.

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GB Cancer [Doctutorials]

Risk Factors and Associations with Ca Gallbladder (Ca GB)

1. Chronic Inflammation
   • Cholelithiasis: Associated with female gender, obesity, and multiparity.
2. Infections
   • Chronic Salmonella infection
   • H. pylori infection
3. Anomalous Pancreatobiliary Duct Junction (APBDJ)
4. Primary Sclerosing Cholangitis (PSC)
5. Genetic Mutations
   • K-ras mutation
   • TP53 mutation

Regional and Gender Associations

• Common in India:
  • Points 1-2 are more frequent.
  • Women > Men
• Common in Japan:
  • Points 3-5 are more frequent.
  • Women = Men

Processes that promote chronic gallbladder irritation and inflammation are also significant risk factors for gallbladder cancer:

• History of biliary disease
• Mirizzi syndrome
• Age (increasing age is a risk factor)
• Female gender
• Obesity
• High carbohydrate diet
• Ethanol abuse
• Tobacco abuse

These factors, especially those associated with calculous biliary disease, have been linked to a higher risk of developing gallbladder cancer.

(Source: Shackelford 8th edition, page 1323)

Summary: Management of Gallbladder Polyps

The management of gallbladder polyps is based on symptoms and the risk of occult malignancy.

Risk Factors for Malignancy:

• Primary sclerosing cholangitis
• Congenital polyposis syndromes
• Chronic hepatitis

Indications for Cholecystectomy:

• Symptomatic patients with gallbladder polyps.
• Suspicious polyps, characterized by:
  • Size >10 mm
  • Number <3
  • Sessile lesions
  • Sonographic evidence of mucosal invasion

In such cases, a cholecystectomy is recommended to mitigate the risk of malignancy.

(Source: Shackelford's Surgery of the Alimentary Tract, 8th Ed, Pg 1323)

Summary: Types and Characteristics of Gallbladder Tumors

Gallbladder cancers can be categorized based on their growth patterns and invasion characteristics:

• Papillary Tumors:
  • Grow in a polypoid fashion.
  • Tend to fill the lumen of the gallbladder with minimal wall invasion.
  • best prognosis
• Nodular Tumors:
  • Invade into adjacent pericholecystic structures early.
  • Unlike infiltrative cancers, they induce sharply defined borders, which can facilitate curative resection.
• Infiltrative Tumors:
  • The most common variety of gallbladder cancer.
  • Initially appear as indurated areas of gallbladder wall thickening.
  • These tumors spread into the subserosal plane, which is typically violated during routine cholecystectomy, making them more challenging to treat.

Gallbladder cancers may also present as combined nodular-infiltrative or combined papillary-infiltrative types, displaying characteristics of both categories.

(Source: Shackelford 8th edition, page 1324)

MCQ: Imaging features of Ca Gb

Question: Which of the following is not true regarding the imaging features of Ca Gallbladder (Ca GB)?

Options: a) Mass replacing Gallbladder (GB): 45-60%

b) Irregular wall thickening: 25-30%

c) Polypoidal mass: 15-25%

d) CEUS: Dotted intralesional vessel

Answer: d) CEUS: Dotted intralesional vessel

Explanation:

• Mass replacing Gallbladder (GB): The most common imaging feature of Ca GB, seen in 45-60% of cases.
• Irregular wall thickening: Observed in 25-30% of cases, indicating a malignancy that may be infiltrating the gallbladder wall.
• Polypoidal mass: Appears in 15-25% of cases, representing a growth projecting into the gallbladder lumen.
• CEUS (Contrast-Enhanced Ultrasound): The statement about a "dotted intralesional vessel" is not true for Ca GB. This feature is not a typical imaging characteristic of Ca GB but “linear intralesional vessel“ and therefore makes option D the correct answer for the question.

Imaging in Ca Gallbladder (Ca GB)

Key Predictors Using CEUS (Contrast-Enhanced Ultrasound)

1. Branched or Linear Intralesional Vessels:
   • Sensitivity: 74.8%
   • Specificity: 98%
2. Gallbladder Wall Destruction Adjacent to the Lesion:
   • Sensitivity: 78.4%
   • Specificity: 92.9%

These two factors are identified as the best predictors of gallbladder cancer using CEUS.

FDG-PET Scans Impact

• Stage and Treatment Change: In 23% of patients.
  • Reason: Identification of occult metastatic disease, which made operative exploration unnecessary.
  • Context: The majority of these patients had previously undergone multiple additional imaging studies before the FDG-PET scan revealed the metastatic disease.

MCQ : SCC of GB

Question: Which of the following is not true about Squamous Cell Carcinoma (SCC) of the Gallbladder (GB)?

Options: a) Less nodal metastasis

b) Higher T stage at presentation

c) Better prognosis than adenocarcinoma

d) More liver involvement

Answer: c) Better prognosis than adenocarcinoma

Explanation:

• Less nodal metastasis (Option A): Squamous cell carcinoma of the GB is generally associated with fewer nodal metastases compared to adenocarcinoma.
• Higher T stage at presentation (Option B): SCC of the GB often presents at a higher T stage, indicating more advanced disease at the time of diagnosis.
• Better prognosis than adenocarcinoma (Option C): This statement is not true. Squamous cell carcinoma typically has a worse prognosis compared to adenocarcinoma due to its aggressive nature.
• More liver involvement (Option D): SCC of the GB often involves more extensive liver infiltration, making it more challenging to treat.

MCQ: Commonest Site of Gallbladder Cancer

Question: What is the commonest site of gallbladder cancer?

Options: a) Body

b) Infundibulum

c) Fundus

d) Cystic duct

Answer: c) Fundus

Explanation:

• Fundus (Option C): The most common site of gallbladder cancer, accounting for 60% of cases.
• Body (Option A): The second most common site, with 30% of cases.
• Neck (including infundibulum, Option B): Less commonly involved, with 10% of cases.
• Cystic Duct (Option D): Rarely the primary site of gallbladder cancer.

Summary: AJCC 8th Edition Staging for Gallbladder Cancer

Tumor Stage (T Stage)

• Tis: Carcinoma in situ
• T1a: Tumor invades lamina propria.
• T1b: Tumor invades muscular layers.
• T2a: Tumor invades perimuscular connective tissue on the peritoneal side.
• T2b: Tumor invades perimuscular connective tissue on the hepatic side.
• T3: Tumor invades or perforates serosa and/or directly invades the liver and/or one adjacent organ.
• T4: Tumor invades the main portal vein or hepatic artery and/or invades two or more adjacent organs.

Nodal Stage (N Stage)

• N0: No regional lymph node involvement.
• N1: Metastasis to 1–3 regional lymph nodes.
• N2: Metastasis to ≥4 regional lymph nodes.

Metastasis Stage (M Stage)

• M0: No distant metastasis.
• M1: Distant metastasis present, including to the peritoneum, liver (beyond direct extension), lungs, pleura, periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes.

Combined Stage Grouping

• Stage 0: TisN0M0
• Stage I: T1(a-b)N0M0
• Stage IIa: T2aN0M0
• Stage IIb: T2bN0M0
• Stage IIIa: T3N0M0
• Stage IIIb: T1(a-b)N1M0, T2(a-b)N1M0, or T3N1M0 = N1 starts here
• Stage IVa: T4N0M0 or T4N1M0
• Stage IVb: T(any)N2M0 or T(any)N(any)M1

MCQ: Hepatic Side Involvement in Ca Gallbladder (Ca GB)

Question: Hepatic side involvement has more of the following in comparison to peritoneal side in Ca GB except:

Options: a) Late lymph node spread

b) Early hematogenous spread

c) Poor prognosis

d) This applies for T2 tumors

Answer: a) Late lymph node spread

Explanation:

• Early Hematogenous Spread (Option B): Hepatic side involvement tends to result in earlier spread through the bloodstream due to proximity to the liver’s vascular structures.
• Poor Prognosis (Option C): Tumors involving the hepatic side are associated with a poorer prognosis because of the increased likelihood of liver invasion and hematogenous dissemination.
• This Applies for T2 Tumors (Option D): The characteristics mentioned are specifically relevant for T2 tumors involving the hepatic side.
• Late Lymph Node Spread (Option A): This is not true for hepatic side involvement. In fact, lymph node spread may occur earlier due to the tumor's close proximity to hepatic lymphatics.

Stage	Modified Nevin	Japanese	AJCC/TNM (7th ed)
I	In situ carcinoma	Confined to gallbladder capsule	Invasion of lamina propria (T1a) or muscular layer (T1b), N0, M0
II	Mucosal or muscular invasion	N1 LN, minimal liver or bile duct invasion	Invasion of perimuscular connective tissue without extension beyond serosa (T2), N0, M0
III	Transmural direct liver invasion	N2 LN, marked liver or bile duct invasion	Tumor through serosa or into liver or adjacent organs (T3), N0, M0 [IIIA]; or T1-3 with N1 LN [IIIB]
IV	Lymph node metastasis	Distant metastases	Invasion of portal vein or hepatic artery, or two or more extrahepatic organs (T4), N0-1, M0 [IVA]; any N2 LN or metastases [IVB]
V	Distant metastases

Incidental Gallbladder Cancer

• Incidental Discovery:
  • Occurs in 0.2% to 3% of all cholecystectomy specimens.
  • Represents 27% to 70% of all gallbladder cancers discovered during cholecystectomy or on pathologic review.
  • Most cases are early-stage (T1 or T2), offering potential for cure.
• Re-Resection:
  • Increased Survival:
    • T2 tumors: 5-year OS improved from 0% to 62% with re-resection.
    • T3 tumors: 5-year OS improved from 0% to 19% with re-resection.
  • Residual Disease:
    • Higher T stage correlates with increased incidence of residual disease in liver and lymph nodes.
    • T1 tumors: 0% residual disease in liver, 12.5% lymph node metastasis.
    • T2 tumors: 10.4% residual disease in liver, 31.2% lymph node metastasis.
    • T3 tumors: 36.4% residual disease in liver, 45.5% lymph node metastasis.

Staging Laparoscopy

• Purpose:
  • Identifies occult metastatic disease before re-resection.
  • Peritoneal dissemination: Occurs in 30% to 75% of patients.
• Yield and Recommendations:
  • NCCN Guidelines: Recommend considering staging laparoscopy for incidental gallbladder cancer of T stage 1b and greater.
  • Low Yield: Staging laparoscopy in incidental gallbladder cancer yields around 4.8% to 20% detection of occult disease.
• Indications for Staging Laparoscopy:
  • T3 tumors
  • Disruption of the gallbladder wall
  • Positive resection margin
  • Poorly differentiated tumors
  • Lymphovascular or perineural invasion

Indications for Major Hepatectomy

• Hepatic Resection:
  • Justified by achieving R0 resection and preventing local recurrence.
  • Surgical options include anatomic resection of segments IVb and V, nonanatomic wedge resection, or major hepatectomy.
• Studies and Findings:
  • Wedge resection has equivalent oncologic efficacy to anatomic segmental resection if an R0 resection is achieved.
  • Location of the tumor (hepatic-sided vs. peritoneal-sided) affects survival outcomes.
  • Major hepatectomy is warranted if needed to achieve negative margins.
• Timing of Re-Resection:
  • Best prognosis with definitive operation 4 to 8 weeks after initial cholecystectomy.

Bile Duct Resection

• NCCN Guidelines:
  • Recommend hepatic resection and lymphadenectomy with or without bile duct excision for malignant involvement.
  • Routine common bile duct excision not shown to improve survival.
• Indications:
  • Positive cystic stump margin mandates bile duct resection to ensure negative margins.
  • Indications for bile duct excision include positive cystic duct margins, direct tumor involvement, and challenging anatomy (such as obese and fibrosed hepatoduodenal ligament).
  • Jaundice: Major symptom with BD involvement = may delay surgery.

Question:

Which of the following is not true about bile duct excision in radical cholecystectomy?

a) Bile duct involvement indicates poor survival

b) Cystic duct margin positive, direct involvement, obese and fibrosed HDL are indications

c) Indicates unresectability

d) Not recommended routinely

Answer:

c) Indicates unresectability

Explanation:

• Option a: True. Bile duct involvement is associated with poor survival due to advanced disease.
• Option b: True. Indications for bile duct excision include positive cystic duct margins, direct tumor involvement, and challenging anatomy (such as obese and fibrosed hepatoduodenal ligament).
• Option c: False. Bile duct involvement does not inherently indicate unresectability. Resection can still be attempted to achieve negative margins.
• Option d: True. Routine bile duct excision is not recommended unless specific indications are present, such as positive margins or direct involvement.

Portal Lymph Node Dissection

• Lymph Node Metastasis:
  • T1b tumors: 12% lymph node involvement.
  • T2 tumors: 31% lymph node involvement.
  • T3 tumors: 45% lymph node involvement.
• Importance:
  • Lymph node dissection is associated with improved survival.
  • Optimal lymph node yield is debated, but resection of at least six lymph nodes is recommended.

Port Site Resection

• Incidence:
  • Port site metastases occur in approximately 10% of cases.
• Studies and Findings:
  • Port site resection is not associated with improved survival or recurrence-free survival (RFS).
  • NCCN Guidelines: Do not consider port site resection as standard care for all patients undergoing re-resection.
  • Port Site excision done only if it is symptomatic.

Question:

Which of the following is not true about port site metastases?

a) 10% incidence in incidental Ca Gb

b) Not routinely recommended for resection

c) Associated with poor survival and disseminated disease

d) Improves survival after excision

Answer:

d) Improves survival after excision

Explanation:

• Option a: True. The incidence of port site metastases in incidental gallbladder cancer is approximately 10%.
• Option b: True. Port site resection is not routinely recommended as part of the management.
• Option c: True. Port site metastases are associated with poor survival and often indicate disseminated disease.
• Option d: False. Excision of port site metastases does not significantly improve survival, and therefore, routine resection is not recommended.

Suspected Gallbladder Cancer (Ca GB) Not Obvious on Imaging

• Criteria for Suspected Gallbladder Cancer:
  • Thick-walled gallbladder > 3 mm.
  • Irregular wall thickening.
  • GB polyp > 1 cm.
• Lucknow Approach:
  • Staging Laparoscopy:
    • Conduct a staging laparoscopy for patients meeting the above criteria.
    • If feasible, proceed with laparoscopic surgery:
      • Remove 1-2 cm wedge of liver along with the gallbladder.
      • Extract the gallbladder using a specimen bag.
    • Alternatively, perform an open cholecystectomy:
      • Remove the wedge of liver and gallbladder.
      • Send both specimens for frozen section analysis.
• Frozen Section Results:
  • If positive:
    • Proceed with lymph node dissection.
  • If negative:
    • Complete the procedure without further intervention.

Nonincidental Gallbladder Cancer

• Presentation and Prognosis:
  • Represents a minority of gallbladder cancer diagnoses.
  • Often presents with advanced disease symptoms such as jaundice and weight loss.
  • Worse outcomes compared to incidentally diagnosed gallbladder cancer.
• Clinicopathologic Differences:
  • Higher T-stage tumors and nodal metastases are more common.
  • Vascular, perineural, and lymphatic invasion are more likely.
  • Poorly differentiated tumors are more frequent.
  • Less likely to undergo resection due to advanced disease at presentation.
• Demographic and Clinical Factors:
  • Patients often have a lower BMI.
  • More common in non-Hispanic White race.
  • Higher likelihood of presenting with jaundice.
  • Associated with distant disease at exploration and higher rates of R1 or R2 resections.

• Surgical and Diagnostic Recommendations:

  • Intraoperative core needle biopsy with immediate frozen-section analysis is recommended if there's no preoperative tissue diagnosis.
  • Staging laparoscopy is recommended for all cases of suspected gallbladder cancer before laparotomy.

  

Adjuvant Therapy in Gallbladder Cancer

• High Recurrence Rates:
  • 70% of patients will develop recurrence postoperatively.
  • Majority of recurrences are distant (72%), followed by local (17%) and regional (11%).
• Systematic Review and Meta-Analysis:
  • Horgan et al. reviewed studies from 1960-2010.
  • Adjuvant therapy was associated with improved OS when large SEER database studies were excluded.
  • Chemotherapy: P < .001.
  • Chemoradiotherapy: P = .049.
  • Radiotherapy alone showed no survival benefit.
• Phase III Trial (Takada et al.):
  • Patients receiving adjuvant chemotherapy had a 5-year OS of 26.0% compared to 14.4% in surgery alone (P = .0367).
  • Improved DFS at 5 years: 20.3% vs 11.6% (P = .0210).

Key Randomized Controlled Trials (RCTs) Post-2010

• ABC-02 Trial (Valle et al.):
  • Cisplatin + Gemcitabine vs Gemcitabine alone.
  • Improved OS: 11.7 vs 8.1 months (P < .001).
  • Improved PFS: 8 vs 5 months (P < .001).
• PRODIGE-12/ACCORD-18 Trial (Edeline et al.):
  • Adjuvant GEMOX vs Best Supportive Care.
  • No significant difference in RFS, OS
• BCAT Trial (Ebata et al.):
  • Adjuvant Gemcitabine vs Best Supportive Care.
  • No significant difference in OS or RFS
• BILCAP Trial (Primrose et al.):
  • Adjuvant Capecitabine vs Best Supportive Care.
  • Improved OS
  • Improved RFS in first 24 months
  • Currently, adjuvant capecitabine for 6 months is a recommended strategy.
• SWOG0809 Trial (Ben-Josef et al.):
  • Adjuvant Capecitabine + Gemcitabine followed by radiotherapy.
  • OS: 67% in R0 group, 60% in R1 group.
  • The trial met the OS goals but lacked a control arm, limiting its applicability.

Current Recommendations

• Currently Adjuvant therapy is recommended for T2 or above, node positive cases and R1 Resections.
• Adjuvant Capecitabine for 6 months is recommended based on BILCAP trial results.
• Gemcitabine + Cisplatin regimens are still frequently used in clinical practice.
• For patients with microscopically positive margins (R1), adjuvant chemoradiotherapy may be considered after a course of adjuvant chemotherapy, as per ASCO guidelines.

Neoadjuvant Therapy in Gallbladder Cancer

• Role and Rationale:
  • Not well defined; currently, no level I evidence guiding decisions.
  • Rationale includes:
    • Downstaging of the primary tumor.
    • In vivo test of chemosensitivity.
    • Immediate treatment of micrometastatic disease.
    • Optimizing patient selection for re-resection.
    • Potentially sparing patients from radical resection if the disease proves particularly aggressive.
• Risks and Considerations:
  • Risk of progression during therapy.
  • Decreased functional status due to toxicity, affecting surgical candidacy.
• NCCN Guidelines:
  • Consideration of neoadjuvant therapy after incidental gallbladder cancer finding if there is evidence of locoregional advanced disease (e.g., large mass invading liver, nodal disease).
  • Goal is to rule out rapid progression and avoid futile surgery.
  • Acknowledgment of limited data to define a standard regimen or definitive benefit.

Targeted Therapy in Gallbladder Cancer

• Genetic Alterations:
  • Tp53 mutation: Most common, occurring in approximately 55% of gallbladder cancers.
  • CDKN2A mutation: Present in 26%.
  • HER2/neu mutation: Found in 15%.
  • ERBB2 mutation: Detected in 12%.
  • Other genes involved include Kras, ARID1A, PBRM1, PIK3CA, BAP1, and SMAD4.
• Current Status:
  • Targeted therapy is not yet standard practice for gallbladder cancer.
  • Efficacy has been shown in smaller studies, and it is being investigated in multiple ongoing RCTs.
• Examples of Targeted Therapy:
  • HER2/neu-directed therapy:
    • Javle et al.: Retrospective review of patients with advanced gallbladder cancer and cholangiocarcinoma.
    • Patients received trastuzumab, lapatinib, or pertuzumab.
    • Outcomes in gallbladder cancer patients: 3 had disease stability, 4 had partial response, and 1 had complete response.
  • ERBB2/ERBB3 Mutations:
    • Li et al.: Whole genome sequencing on 157 patients and functional experiments on gallbladder cancer cell lines.
    • Sapitinib, an ERBB3 tyrosine kinase inhibitor, showed significant inhibition of tumor growth in cells with mutant ERBB2/ERBB3.
    • PD-1 upregulation in cancers with these mutations.
    • Combination therapy with anti-PDL1 and anti-ERBB showed enhanced reduction in cell viability (70%) compared to single-agent therapy.
  • EGFR and ERBB2 Interaction:
    • Iyer et al.: Co-immunoprecipitation studies in gallbladder cancer cell lines.
    • Findings suggest that ERBB2 requires EGFR for activation.
    • Downregulation of EGFR may suppress ERBB2 functionality, offering a potential therapeutic target.
    • Kras mutation (especially on codon 12) may confer resistance to anti-EGFR therapy, similar to findings in colon cancer.

Surveillance After Radical Resection for Gallbladder Cancer

• Lack of Specific Data:
  • There are no definitive data to support a specific surveillance schedule following radical resection for gallbladder cancer.
  • High rates of recurrence, especially distant recurrence, underscore the need for surveillance.
• NCCN Guidelines:
  • Recommend following the surveillance schedule from the BILCAP trial:
    • Imaging of chest, abdomen, and pelvis every 3 to 6 months for the first 2 years.
    • Then, every 6 to 12 months for up to 5 years.
    • Surveillance may be adjusted based on clinical indications.