Cancer, Gallbladder

Article Author:
Alejandro Recio-Boiles
Article Editor:
Hani Babiker
Updated:
10/27/2018 12:31:36 PM
PubMed Link:
Cancer, Gallbladder

Introduction

Gallbladder cancer (GC) is a rare malignancy but represents almost 50% of all biliary tract cancer. Biliary cancers are highly fatal malignancies with a 5-year survival rate of 17.6% (2007-2013). The prognosis of GC is poor due to the aggressive tumor biology, late presentation, complicated anatomic position, and advanced stage at diagnosis. Locally advanced and metastatic disease is treated with palliative chemotherapy. Conversely, early stage is potentially curative with surgical resection followed by adjuvant therapy.

Etiology

Chronic inflammation is the most important risk of GC. The strongest correlation to develop GC is a history of gallstones (cholelithiasis), and the risk increases with gallstone size, chronicity, and burden of symptoms. Porcelain gallbladder, a calcification of the gallbladder, is often related to chronic cholelithiasis. This is usually found incidentally on imaging and often leads to cholecystectomy. The other risk factors include gallbladder polyps, congenital biliary cysts, and abnormal pancreaticobiliary anatomy which all lead to chronic inflammation culminating to GC. Endemic areas with salmonella typhi and helicobacter report a link with chronic asymptomatic carriers and an elevated risk for GC. Moreover, carcinogens causing GC have been reported and include (e.g., methyldopa, isoniazid) work exposure (e.g., methylcellulose, radon) and lifestyle (e.g., cigarette smokers, obesity, high carbohydrate intake). Chronic primary sclerosing cholangitis and inflammatory bowel disease can also lead to GC.

Epidemiology

The incidence of GC is high in certain populations outside of the United States (e.g., South America, India, Pakistan, Japan, and Korea) due to the high prevalence of gallstones and chronic gallbladder infections in those areas. The American Cancer Society estimates 11,740 new cases of GC and 3,830 deaths in the USA with a female preponderance in 2017. The overall incidence of GC decreased in patients older than 50 years but increased in the younger population. GC is more common in Whites, Southwestern Native Americans, and Mexican Americans and less common in African Americans.

Pathophysiology

The current hypothesis establishes that chronic inflammation of the bile duct tissue accumulates successive genomic mutations that lead to malignant transformation. The most common mutations described are the oncogenes K-ras and tumor suppressors beta-catenin (CTNNB1). No hereditary familial risk has been described. Most the histopathology in GC is adenocarcinomas (90%), which progresses from pre-neoplastic dysplasia to a carcinoma in situ and ultimately to invasive cancer, following roughly 15 years of inflammation. Squamous cell carcinoma is rare in the gallbladder.

History and Physical

GC is detected more frequently as an incidental finding on imaging or after a surgical procedure. Early stage GC commonly is discovered after cholecystectomy and review of the surgical pathology specimen. 

GC patients are often asymptomatic at presentation or describe vague symptoms such as abdominal pain, nausea or vomiting, indigestion, weakness, anorexia, loss of appetite, weight loss, and can present with jaundice which can easily be confused as cholecystitis. Biliary obstruction by cancer leads to jaundice, clay-colored stools, cola-colored urine, and skin pruritus. In addition, Mirizzi syndrome (common hepatic duct obstruction by an impacted stone in the gallbladder neck due to an extrinsic compression) has been associated with GC and carries a poor prognosis due to unresectability at presentation. Others unspecific symptoms of advanced malignancy such as weight loss and general malaise may also be present.

Physical examination may demonstrate jaundice, right upper quadrant pain or Courvoisier sign (non-tender palpable gallbladder with jaundice) which is most likely to develop due to chronic progressive malignant obstruction rather than an intermittent gallstone obstruction. Hepatomegaly, abdominal palpable mass, ascites and bowel obstruction on physical examination are presentations indicating advanced metastatic stage.

Evaluation

Patients, particularly those with obstructive jaundice, will require complete blood count, basic chemistry panel, and a liver function test. Results may reveal an unspecific cholestatic pattern caused by bile obstruction requiring decompression. Ultrasonography (US) and computed tomography (CT) are usually ordered as initial imaging studies. Endoscopic ultrasonography (EUS) is considered more accurate than US (76%) and useful in differential diagnosis to correctly detect histological neoplasia (97%). EUS will provide valuable tumor stage description with invasion depth and local lymphadenopathy. CT has limitations in discriminating benign from malignant, but dynamic magnetic resonance (MR) and MR cholangiopancreatography (MRCP) can help assess disease extent more accurately and properly identify unresectable candidates with hepatoduodenal ligament invasion, vasculature encasement and /or lymph node involvement. Most GCs are 18F-fluorodeoxyglucose avid by positron emission tomography/computed tomography (PET/CT); hence the technique is able to identify occult and advanced stage disease, which helps avoid unnecessary surgery. Tumor markers, such as carcinoembryonic antigen and carbohydrate antigen19-9, are frequently elevated but considered non-diagnostic due lack of specificity (CA 19-9 92.7% versus 79.2% CEA) and sensitivity (CA 19-9 50% vs 79.4% CEA). CEA and CA 19-9 baseline tests are useful for monitoring response to therapy. The preferred staging system is TNM of the American Joint Committee on Cancer 2010 divided GC from stage 0 to IV correlating strongly with a 5-year overall survival 81%, 50%, 29%, 7-8%, and 2-3%, respectively.

Treatment / Management

Neoadjuvant therapy often is not an option due to the advanced disease at diagnosis and is not considered a standard of care in resectable cases. Referral for early clinical trials should be considered.

Surgery is the only curative treatment for patients with Stage II or less and no contraindications (see evaluation). Surgical resection of GC will include cholecystectomy with a marginal hepatectomy with regional lymphadenectomy or common bile duct resection (extended organs may be removed). For GC incidentally found on cholecystectomy pathological specimen with stage T2 or higher, it is recommended to return for further exploration and re-resection.

Postoperative chemotherapy should be offered within 8 to 12 weeks and requires baseline laboratory and imaging to re-stage disease prior to therapy initiation. Adjuvant therapy should be offered to patients with a resected pathological specimen report of T2 or higher, node positive and margin positive preferably for six months adjuvant chemotherapy (ACT) or alternative four months with concurrent adjuvant chemoradiation (ACRT). 

The National Comprehensive Cancer Network (NCCN) consensus-based guidelines suggest the following:

  1. Chemotherapy alone for six months with gemcitabine [1000 mg/weekly for three of every four weeks] or 5-FU (fluoropyrimidine) [leucovorin 20 mg/m followed by FU 425 mg/m intravenous [IV] bolus days 1 through 5 every 28 days] published in the ESPAC-3 Trial with median overall survival for CT 43.1 months versus 35.2 months in the observation group without statistical significance (data extrapolated from pancreaticobiliary malignancies).
  2. In addition to the aforementioned, another regimen includes four cycles of Capecitabine (Cap) [1,500 mg/m per day on days 1 to 14] plus Gemcitabine (Gem) [1,000 mg/intravenously on days 1 and 8] every 21 days followed by CRT [Cap 1330 mg/per day divided into two daily doses and RT 45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed] published in a single arm SWOG-S0809 trial with expected medical outcomes (mOS) of 35 months without a comparison group.  
  3. Lastly, 5-FU [225 mg/m daily]-based ACRT from other gastrointestinal malignancy extrapolation data. At ASCO 2017, BILCAP study was presented as first phase 3 randomized adjuvant therapy for patients with no post-surgical complications and Eastern Cooperative Oncological Group of two or less (ECOG < 2), 447 patients were randomized 1:1 Cap N 223[1250mg/m D1-14 every 21 days, for 8 cycles] or observation (Obs) N224 from 44 UK sites between 2006-2014, it included 18% GC, and results showed a mOS for Cap 53mo when compared to Obs 36mo (HR 0.75 p0.028). Hence, Cap soon will be adopted as the new standard of care.

Surveillance by NCCN recommendations includes imaging every six months for two years, if clinically indicated, then annually up to five years. Oncologists may monitor patients closely with liver function test and tumor markers (CEA and CA19-9) every three to four months for two years, then every six months up to five years. All other investigations can be performed when clinically indicated. 

Unresectable locally advanced and metastatic GCs are considered for palliative goals/chemotherapy. Locally advanced may be managed with external beam radiation therapy and usually involves a radiosensitizer, such as 5-FU, but this modality rarely will achieve tumor control. Patients who are fit (ECOG 0-1) for chemotherapy could consider a first line option of Gem [1,000 mg/m] plus Cisplatin (cis) [25 mg/m] on days 1 and 8 every 3 weeks with acceptable toxicity as published in ABC-02 randomized trial which included 148 patients with GC and had a mOS of 11.7 months in the combination arm when compared to 8.3 months of Gem alone (HR, 0.70; p0.002). Other first line gem-based combinations are not a randomized comparison, and single-arm studies have reported a mOS for GemCap 12.7 months, Gem with Oxaliplatin 14.3 months both on selected population or alternative 5-FU-based combination plus Cis 11.5 months or Cap 11.3 months. Poor performance patients may receive a more tolerable less toxic single oral agent Cap with a reported mOS of 9.9 months when compared to the best supportive care of 4.5 months. All patients with the advanced, unresectable disease should be offered to participate in clinical trials.