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Cholangiocarcinoma News

Gallbladder Cancer: Novel Approaches to Therapy Are Needed

December 2020, Vol 1, No 3

The current standard of care for the systemic treatment of patients with advanced gallbladder cancer is the chemotherapy combination of gemcitabine and cisplatin, which is suboptimal, yielding only modest benefit, said Richard Kim, MD, Section Chief, Gastrointestinal Medical Oncology, Moffitt Cancer Center, Tampa, FL, at the 2020 Cholangiocarcinoma Summit.

The major pathogenic factor of gallbladder cancer is a chronic inflammatory state. The progression from normal epithelium to inflammation to metaplasia to dysplasia to invasive carcinoma occurs over approximately 15 years.

The TP53 mutations are present in approximately 50% of patients with gallbladder cancer, and inactivation of TP53 is an early genetic carcinogenic promoter. KRAS mutations can occur when the disease progresses to invasive carcinoma.

Gallbladder cancer, extrahepatic cholangiocarcinoma (CCA), and intrahepatic CCA have distinct molecular tumor profiles. A high frequency of ERBB2 amplification in patients with gallbladder cancer represents a potential therapeutic target.

Moving forward, targeting molecular alterations in gallbladder cancer will be the key to patient management, Dr Kim advised.

Advanced Disease

The analyses of systemic therapy in patients with advanced gallbladder cancer have included few patients or were conducted in heterogeneous populations of patients with intrahepatic CCA and those with extrahepatic CCA.

“Because of the rarity of GBC [gallbladder cancer], most studies have grouped all biliary tract cancer and gallbladder [cancer] together. There are very few GBC-specific studies in advanced disease,” said Dr Kim.

Combination Chemotherapy

In the only published randomized clinical trial in patients (N = 81) with gallbladder cancer, those with unresectable disease were randomized to receive best supportive care, weekly 5-fluorouracil (5-FU) bolus, or a modified regimen of gemcitabine and oxaliplatin. Compared with best supportive care, the response rate, overall survival (OS), and progression-free survival (PFS) favored the gemcitabine plus oxaliplatin arm. Bolus 5-FU had modest efficacy.

Standard chemotherapy for gallbladder cancer remains gemcitabine and cisplatin, based on a 2010 study that showed favorable results with the standard regimen.

Although no randomized clinical trial has compared chemotherapy in patients with gallbladder cancer versus CCA, a pooled analysis of more than 1000 patients using more than 100 chemotherapy regimens showed higher response rates in patients with gallbladder cancer than with CCA, Dr Kim said.

In a retrospective series of more than 400 patients, Japanese investigators assessed 5 systemic chemotherapy regimens and found similar response rates of approximately 10% in the patients with CCA and those with gallbladder cancer, with a trend toward better OS in the patients with CCA.

In a recent single-arm phase 2 clinical trial, adding nab-paclitaxel (Abraxane) to gemcitabine and cisplatin as first-line treatment induced partial responses in 45% of patients, with a median PFS of 11.8 months and a median OS of 19.2 months in patients with unresectable, locally advanced biliary tract cancer. Of the 60 patients enrolled, 13 had gallbladder cancer; the other patients had intrahepatic or extrahepatic CCA.

The response rate was 40% in the patients with gallbladder cancer, which was similar to patients with CCA. The median OS has not yet been reached in the intrahepatic CCA arm and was approximately 15 months in the gallbladder cancer cohort, Dr Kim said.

The randomized phase 3 ABC-06 trial compared second-line treatment with modified FOLFOX plus active symptom control versus active symptom control alone in 162 patients with locally advanced or metastatic biliary tract cancers, 34 (21%) of whom had gallbladder cancer. The median OS was 6.2 months with FOLFOX plus symptom control versus 5.3 months with symptom control alone.

“More important, 6 month OS and 12 month OS favored the arm of FOLFOX, which I think is more significant,” said Dr Kim. The efficacy was similar between the cohorts, regardless of the tumor site.

Palliative Care

Palliative care has an important role in the management of advanced gallbladder cancer, Dr Kim noted, and requires a multidisciplinary approach, with the goal of pain relief and treatment of jaundice by endoscopic biliary stenting or percutaneous transhepatic cholangiography.

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