Guidelines Summary

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

According to the National Comprehensive Cancer Network (NCCN) guidelines, gallbladder cancer may be diagnosed as an incidental finding in patients who undergo laparoscopic cholecystectomy, either at surgery or on pathologic review. In such cases, the NCCN recommends postoperative imaging with multiphasic abdominal and pelvic computed tomography (CT) or magnetic resonance imaging (MRI) with intravenous contrast and chest CT with or without contrast. In cases that are an incidental finding on pathologic review, the NCCN also recommmends considering staging laparoscopy.^[30]

For cases that present as a mass on an imaging study, the recommended workup includes the following:

History and physical examination
Multiphasic abdominal/pelvic CT/MRI with IV contrast
Chest CT with or without contrast
Liver function tests (LFTs) and assessment of hepatic reserve
Surgical consultation
Consider carcinoembryonic antigen (CEA) and CA 19-9 testing

For patients who present with jaundice, the recommended workup includes the following:

History and physical examination
Liver function tests and assessment of hepatic reserve
Chest CT with or without contrast
Multiphasic abdominal/pelvic CT/MRI with IV contrast
Cholangiography (preferably magnetic resonance cholangiopancreatography [MRCP])
Surgical consultation
Consider CEA and CA 19-9 testing
Consider staging laparoscopy
Consider biliary drainage

The European Society for Medical Oncology clinical practice guidelines for biliary cancer published in 2016 recommend diagnosis on the basis of MRI with MRCP contrast-enhanced and diffusion-weighted imaging. CT was deemed less useful. Pathological diagnosis is required before any nonsurgical therapy, but is not critical in patients with characteristic findings of resectable tumors. Endoscopic retrograde cholangiopancreatography (ERCP)–guided biopsies are preferred to biliary brush cytology.^[36]

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^[37]:

Endoscopic ultrasound (EUS) or fine-needle aspiration (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.^[17]

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 resectable disease^[30]:

Simple cholecystectomy for T1a lesions (limited to the mucosa)
Staging laparoscopy, followed immediately (in the same session) by definitive resection; biopsy is not required
For patients with T1b or greater lesions, radical cholecystectomy and lymphadenectomy with or without bile duct excision; hepatic resection is performed to obtain clear margins, which usually consists of segments IV B and V but may need to be extended beyond that in some patients
For patients with suspicious mass on imaging or with jaundice, cholecystectomy plus en bloc hepatic resection and lymphadenectomy with or without bile duct excision
Jaundice that is not amenable to drainage is considered a relative contraindication to surgery; only a portion of those with node-negative disease potentially benefit from complete resection; surgery should only be performed with curative intent
Fluoropyrimidine-based chemoradiotherapy, or fluoropyrimidine or gemcitabine chemotherapy alone may be considered for adjuvant treatmen, except for individuals with resected T1a or T1b N0 tumors

The 2016 ESMO recommendations for resectable disease include the following^[36]:

Every T-stage above T1a and positivity of any mentioned parameters requires a reoperation and a segment IVb/V liver resection with a ligamentary lymphadenectomy
If the gallbladder was not removed with a bag during laparoscopic resection or the gallbladder perforated (an adverse prognostic factor), the port sites should also be resected
When patients present with jaundice, evaluation of potential resectability is needed
Advanced T-stage (including T4 tumors) is not a contraindication for resection provided they are located in the fundus; these tumors require major liver resection with potential resection of the transverse colon.
Achieving a curative resection of an advanced tumor located at the infundibulum requires the resection of the bile duct, the duodenal bulb and, potentially, the pancreatic head together with a major hepatectomy, especially if right-sided vessels (right hepatic artery, right portal vein) are involved

For management of patients with unresectable or metastatic disease, NCCN makes the following recommendations^[30]:

Gemcitabine/cisplatin combination therapy (category 1)
Fluoropyrimidine-based or other gemcitabine-based chemotherapy regimen
EBRT with concurrent fluoropyrimidine
Radiation therapy
Clinical trial
Best supportive care
Entrectinib or larotrectinib (only for NTRK gene fusion–positive tumors)
Pembrolizumab (only for tumors with high microsatellite instability or deficient mismatch repair)

Medication

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