Gallbladder Cancer Guidelines

Guidelines Contributor:   Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Diagnosis

National Comprehensive Cancer Network (NCCN) guidelines offer different algorithms for the following presentations of gallbladder cancer ^[25] :

• Incidental finding of suspicious mass at surgery
• Incidental on pathologic review of cholecystectomy specimen
• Mass on imaging study
• Jaundice

When a suspicious gallbladder mass is an incidental finding during surgery and hepatobiliary surgery expertise is available, the NCCN recommends intraoperative staging with or without biopsy, and resection if possible. Postoperatively, imaging studies are performed for staging. If hepatobiliary surgery expertise is unavailable or the tumor is unresectable, the NCCN recommends biopsy and molecular testing. The postoperative workup in those cases and in cases that present as a mass on an imaging study should include the following:

• History and physical examination
• Multiphasic abdominal/pelvic CT/MRI with IV contrast and chest CT ± contrast
• Liver function tests (LFTs) and assessment of hepatic reserve
• Consideration of CEA and CA 19-9
• Surgical consultation

For  the recommended workup includes the following:

• History and physical examination
• Multiphasic abdominal/pelvic CT/MRI with IV contrast
• Chest CT with or without contrast
• LFTs and assessment of hepatic reserve
• Consider CEA and CA 19-9 testing
• Surgical consultation

For patients who present with jaundice, the recommended workup includes all of the above, as well as the following:

• Cholangiography (preferably magnetic resonance cholangiopancreatography [MRCP])
• Consider staging laparoscopy
• Consider biliary drainage

The European Society for Medical Oncology (ESMO) clinical practice guidelines for biliary cancer, updated in 2023, recommend the following diagnostic and staging investigations ^[26] :

• Perform LFTs and other blood tests to identify underlying liver or biliary tract disease (eg, hepatitis B and C, steatohepatitis, primary cholangitis)
• Obtain a core biopsy for diagnostic pathology and molecular profiling before providing any nonsurgical treatment.
• Depending on tumor location, endoscopic ultrasound (EUS)–guided fine needle aspiration (FNA) or biopsy may be an option to obtain biopsies of enlarged regional nodes and to obtain a tumor biopsy if endoscopic retrograde cholangiopancreatography (ERCP)–guided biopsies are negative or inconclusive.
• Perform CT of chest and abdomen ± pelvis for staging; positron emission tomography (PET/CT, if available, may allow identification of nodal metastases, distant metastases, and disease recurrence
• Molecular analysis is recommended in advanced disease considered suitable for systemic treatment.
• Elevated CA 19-9 is associated with poorer prognosis and can be useful for assessing response to treatment

In 2013, the American Society for Gastrointestinal Endoscopy (ASGE) released guidelines for the use of endoscopy in the evaluation of biliary neoplasia. The recommendations for gallbladder polyps included the following ^[41] :

• EUS or FNA if the results would change the management
• Cholecystectomy for symptomatic patients with gallbladder polyps, asymptomatic patients with gallbladder polyps > 10 mm, and any patient with gallbladder polyps and primary sclerosing cholangitis
• Asymptomatic patients with gallbladder polyps 6-10 mm but no other risk factors for gallbladder cancer should receive annual transabdominal ultrasound screening

Staging

Gallbladder cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) and is classified into four stages based on the depth of invasion into the gallbladder wall and the extent of spread to surrounding organs and lymph nodes. ^[20]

TNM groupings by stage are as follows:

• Stage 0- Tis N0 M0
• Stage I - T1 N0 M0
• Stage IIA - T2a N0 M0
• Stage IIB - T2b N0 M0
• Stage IIIA - T3 N0 M0
• Stage IIIB - T1-3 N1 M0
• Stage IVA - T4 N0-1 M0
• Stage IVB - Any T Any N M1

Treatment

The NCCN guidelines include the following recommendations for treatment of gallbladder cancer discovered as an incidental finding during surgery ^[25] :

• If hepatobiliary surgery expertise is available and there is convincing clinical evidence of cancer, a definitive resection can be performed. If the diagnosis is not clear, frozen section biopsies can be considered in selected cases before proceeding with definitive resection. If malignancy is suspected or confirmed after cholecystectomy has been initiated and expertise is available, then definitive resection should be undertaken.
• If malignancy is suspected before cholecystectomy has begun and there is a question of resectability (eg, locally advanced, possible metastatic disease), then definitive resection can be postponed, regardless of available expertise, until complete staging and evaluation has been performed. Consider biopsy if chemotherapy is anticipated.
•  Definitive resection consists of radical cholecystectomy including segments IV B and V and lymphadenectomy and extended hepatic or biliary resection as necessary to obtain a negative margin.

NCCN recommendations for gallbladder cancer discovered as an incidental finding on pathologic review include the following ^[25] :

• Consider pathologic re-review by a hepatobiliary pathology expert and/or speak to surgeon to check for completeness of cholecystectomy, signs of disseminated disease, location of tumor, and any other pertinent information. Review the pathology report for T stage, cystic duct margin status, and other margins.
• Diagnostic laparoscopy can be performed but is of relatively low yield. Higher yields may be seen in patients with T3 or higher tumors, poorly differentiated tumors, or with a margin-positive cholecystectomy. Diagnostic laparoscopy should also be considered in patients with any suspicion of metastatic disease on imaging that is not amenable to percutaneous biopsy.
• Repeat cross-sectional imaging of the chest, abdomen, and pelvis should be performed prior to definitive resection.
• Initial exploration should rule out distant lymph node metastases in the celiac axis or aorto-caval groove, as these contraindicate further resection.
• Hepatic resection should be performed to obtain clear margins, which usually consists of segments IV B and V. Extended resections beyond segments IV B and V may be needed in some patients to obtain negative margins.
• Lymphadenectomy should be performed to clear all lymph nodes in the porta hepatis.
• Routine resection of the bile duct for lymphadenectomy is not recommended, as it increases morbidity and may not improve survival, but in some cases resection may be needed to obtain negative margins.
• Port site resection has not been shown to improve outcome, as the presence of implanted disease at a port site is a surrogate marker of underlying disseminated disease.

NCCN recommendations for gallbladder cancer discovered as an incidental finding on an imaging study include the following ^[25] :

• Biopsy is not necessary
• Diagnostic laparoscopy is recommended prior to definitive resection.
• In selected cases where the diagnosis is not clear, a reasonable approach may be to perform a cholecystectomy (including intraoperative frozen section) followed by definitive resection during the same setting if pathology confirms cancer.
• Definitive resection consists of radical cholecystectomy including segments IV B and V and lymphadenectomy and extended hepatic or biliary resection as necessary to obtain a negative margin.

The NCCN notes that the presence of jaundice in gallbladder cancer usually portends a poor prognosis, and curative-intent resection is usualy contraindicated. However, in selected patients with resectable disease curative-intent resection can be attempted in centers with expertise.

For management of patients with unresectable or metastatic disease, NCCN makes the following category 1 recommendations ^[25] :

• Durvalumab plus gemcitabine plus cisplatin (preferred)
• Gemcitabine plus cisplatin

For targeted therapy in unresectable or metastatic disease NCCN recommendations are as follows ^[25] :

• NTRK gene fusion–positive tumors: Entrectinib, larotrectinib
• High microsatellite instability/deficient mismatch repair (MSI-H/dMMR) tumors: Pembrolizumab
• High tumor metastatic burden (TMB-H) tumors: Nivolumab plus ipilimumab
• RET gene fusion–positive tumors: Pralsetinib
• BRAF V600Emutated tumors: Dabrafenib plus trametinib (subsequent-line therapy for progressive disease)

NCCN recommendations for second-line therapy in unresectable or metastatic disease are as follows ^[25] :

European Society for Medical Oncology

ESMO recommendations for local and locoregional disease include the following ^[26] :

• Radical surgery, which includes lymphadenectomy, is the only curative-intent treatment. The exact nature and extent of surgery will depend on tumor subtype and location and should be determined by a specialist hepatobiliary multidisciplinary tumor board.

• Radiologic imaging should be carried out before ERCP or percutaneous transhepatic cholangiography in patients with jaundice.

• Consideration of non-tumor-related factors (eg, performance status [PS], comorbidities) is important, as resection carries a significant risk of mortality.

• In incidentally diagnosed gallbladder (after cholecystectomy), re-operation with radical intent should be offered to sufficiently fit patients with stage ≥T1b disease, provided there is no metastatic spread. Resection of some or all of segment IVb/V of the liver is carried out together with a lymphadenectomy of the hepatoduodenal ligament.

• If the gallbladder was not removed with a bag during laparoscopic resection or the gallbladder was perforated, resection of the port sites may also be considered.

• Adjuvant chemotherapy with capecitabine should be considered following resection.

• Radiation therapy, after completion of adjuvant capecitabine, might be considered in selected patients (eg, R1 resection).

• In case of response following locoregional or systemic treatment of locally advanced tumors, patients should be re-assessed by the multidisciplinary team to discuss surgery.

• Curative-intent resection of tumors located at the infundibulum requires resection of the bile duct, the duodenal bulb and, potentially, the pancreatic head.

ESMO recommendations for management of advanced and metastatic disease are as follows ^[26] :

• Cisplatin–gemcitabine is recommended as the first-line standard of care for patients with a PS of 0-1
• The combination of cisplatin–gemcitabine with durvalumab should be considered as first-line treatment.
• Oxaliplatin may be substituted for cisplatin when kidney function is of concern.
• Gemcitabine monotherapy may be used in patients with a PS of 2.
• FOLFOX is the standard of care in the second-line setting after cisplatin–gemcitabine.
• FGFR inhibitors are recommended for the treatment of patients with FGFR2 fusions whose disease has progressed after ≥1 prior line of systemic therapy.
• Pembrolizumab is recommended in patients with MSI-H/dMMR disease that has progressed on or are intolerant to prior treatment.
• Dabrafenib–trametinib is recommended for the treatment of patients with BRAF V600E mutations whose disease has progressed after ≥1 prior line of systemic therapy.
• Patients with BRCA1/2 or PALB2 mutations responding to platinum-based therapy can be considered for treatment with PARP inhibitors.
• NTRK inhibitors are recommended in patients with NTRK fusions who have progressed on or are intolerant to prior treatment.
• HER2-directed therapies can be considered in patients with the respective genetic alterations who have progressed on or are intolerant to prior treatment.
• During systemic and locoregional therapy for advanced disease, conduct follow-up every 8-12 weeks. In addition to imaging with CT or MRI, CA 19-9 or CEA levels may be used to monitor the course of the disease if one or both are known to be secreted.