Clinical Trial Illuminates Treatment Options for Bile Duct Cancers

gallbladder. These cancers are relatively rare: they represent approximately 3% of digestive cancers. They can remain asymptomatic for a long time. This is why patients generally present with advanced disease for which surgical resection is not an option.

Chemotherapy remains possible. It consists of gemcitabine and cisplatin, molecules used in several other types of cancer. However, the results of this dual therapy remain modest. And the addition of immune checkpoint inhibitors – aimed at removing the protection of cancer cells from the immune system – brings little benefit to patients. Thus, although rare, bile duct cancer has a poor prognosis, with an overall 5-year survival rate of only 10 to 40%, even after surgical resection of the tumor. It is therefore essential to find new, more effective treatment options.

Triple chemotherapy to increase survival time?

“ The two-drug approach has been the standard for more than 10 years, and it is not particularly effective. […] We need more and better options for all patients said Dr. Rachna Shroff, head of the division of hematology and oncology in the department of medicine at the University of Alberta in Tucson. Co-leader of the gastrointestinal clinical research team at the University of Arizona Cancer Center, she is interested in developing new therapies for pancreatic and hepatobiliary cancers.

Preclinical data suggests that stromal remodeling nanoparticles (the non-tumor tissue found within a tumor) improve the delivery and effectiveness of chemotherapeutic agents in certain tumors, such as pancreatic cancer and cholangiocarcinoma.

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Paclitaxel linked to an albumin nanoparticle (or nab-paclitaxel for nanoparticle albumin–bound paclitaxel) showed such effects. In 2019, a phase 2 clinical trial involving patients with advanced biliary tract cancer, showed that administration of nab-paclitaxel combined with gemcitabine-cisplatin resulted in a median progression-free survival of 11.8 months and overall median of 19.2 months. The partial response rate to treatment was 45% and the disease control rate was 84%.

Encouraged by these results, Shroff and colleagues designed a randomized phase 3 study to evaluate the benefit of triple therapy (gemcitabine, cisplatin and nab-paclitaxel) compared to standard dual therapy (gemcitabine and cisplatin), in the case of newly diagnosed locally advanced and metastatic bile duct cancers. Their results were published in the Journal of Clinical Oncology.

No significant difference between the two therapies

“ Triple chemotherapy has been shown to be relatively effective in the treatment of advanced and inoperable pancreatic and colorectal cancers. We wondered whether a similar approach to treating advanced, inoperable gallbladder and bile duct cancers might also lead to better outcomes. », Explains the researcher.

This is the first randomized phase 3 clinical trial conducted in the United States for patients with newly diagnosed advanced bile duct cancer. Tissue and blood samples collected during this trial created the largest repository of biliary cancer samples in the United States.

The study involved 441 patients, the majority (67%) of whom had intrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma and gallbladder carcinoma accounted for 17% and 16% of participants, respectively. These cancers were metastatic in 73% of cases.

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Patients were randomly assigned to dual or triple therapy. In terms of overall survival, the researchers observed no significant difference between the two approaches. Indeed, the median duration was 14 months with triple therapy compared to 13.6 months with dual therapy. The estimates of overall survival at 12 and 24 months were 56% and 25%, respectively, in the triple therapy group vs. 53% and 28% in the dual therapy group. Median progression-free survival was also similar between the two groups: 7.5 months vs. 6.3 months.

“ MDespite the promising efficacy signal from the phase 2 study, this phase 3 study did not confirm the benefit of cytotoxic triple therapy », concludes the team.

A potentially useful approach for specific cases

Not only does three-drug chemotherapy not improve patient survival, it increases treatment toxicity. More treatment-related severe adverse events occurred in patients receiving triple therapy. These included hematological disorders (which affected 60% of patients vs. 45% of patients in the other group).

The team also reports that seven deaths were attributed to triple therapy. The causes were cardiac arrest, three septicemias, superior vena cava syndrome, a thromboembolic event and an upper gastrointestinal hemorrhage. Only one participant in the dual therapy group died, following a progressive disease potentially favored by cisplatin.

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Triple therapy did not improve patient survival rates, but could nevertheless prove useful in certain specific cases. Indeed, subset analyzes revealed that the combination of all three drugs further improved progression-free survival time in patients with gallbladder cancer. Likewise, the survival benefits were greater in those whose cancer had not metastasized. However, the differences remained statistically insignificant.

The team is currently carrying out further analyzes to better identify subsets of patients likely to benefit from triple therapy. “ Bile duct cancer is relatively rare, but it is aggressive and spreads quickly. Our accumulation of over 450 patients in just over two years really shows that there is a need for new methods “, underlined Rachna Shroff.