Systemic Therapy for Gallbladder Cancer: What Patients and Families Need to Know

Table of Contents

• Key Points
• Background: Why Gallbladder Cancer Is a Serious Problem
• How This Review Was Put Together
• Standard First-Line Chemotherapy
• Newer First-Line Combinations and Ongoing Trials
• Second-Line Chemotherapy: FOLFOX and Its Evidence
• Genetic Testing: Chinese and US Patients Differ
• HER2/neu: A Target That Already Helps Some Patients
• What Past Targeted Therapy Trials Showed
• Immunotherapy: Modest Alone, Promising in Combination
• What This Means for Patients and Families
• Limitations: What This Review Could Not Prove
• Practical Recommendations
• Conclusions From the Authors
• Frequently Asked Questions
• Source Information

Key Points

• For advanced gallbladder cancer, gemcitabine plus cisplatin is standard first-line chemotherapy, based on the ABC-02 trial where median overall survival was 11 months.
• FOLFOX is the recommended second-line treatment; in the ABC-06 trial it improved median overall survival to 6.2 months versus 5.3 months with supportive care alone.
• About 13% of gallbladder cancers overexpress HER2/neu; in a small study of 11 patients, HER2-directed antibodies trastuzumab and pertuzumab produced tumor shrinkage in some.
• Genetic testing shows gallbladder cancer differs from other biliary cancers and between Chinese and US patients, so a 'one size fits all' approach should be discouraged.
• Single-agent immunotherapy had a 6% response rate in one trial, but combinations like nivolumab with chemotherapy showed a 37% response rate in a phase I study.

Background: Why Gallbladder Cancer Is a Serious Problem

Gallbladder cancer is officially classified as a rare tumor. In practice, though, it causes a large number of deaths in Latin America and Asia, and it is the most common biliary cancer worldwide. Biliary cancers are cancers that start in the bile ducts or the gallbladder, the small organ that stores bile.

The numbers explain why doctors take this disease so seriously. Surgery is the only treatment that can cure gallbladder cancer. When patients are able to have surgery, 5-year overall survival (the percentage of patients still alive five years later) reaches up to 63.2%. That figure applies only to the minority who are diagnosed early.

Most patients are different. They learn they have gallbladder cancer only after the disease is already advanced and unresectable (meaning the cancer cannot be removed with surgery). For this group, prognosis is extremely poor. Reported 5-year overall survival is less than 5%, which means fewer than 1 in 20 patients is alive after five years. Across all biliary tract cancers, including gallbladder cancer, the estimated 5-year overall survival is under 20%.

Because surgery is not an option for most patients, systemic therapy (drug treatment that travels through the bloodstream to reach cancer anywhere in the body) becomes the main treatment. The authors reviewed what that treatment should be.

One important historical point shapes all the research described below. Gallbladder cancer patients have traditionally been enrolled in clinical trials alongside patients with other biliary tract cancers. For this reason, the chemotherapy options for gallbladder cancer closely mirror those for cholangiocarcinoma (cancer of the bile ducts).

Targeted drugs have already shown promise in biliary tract cancers. These include agents that block FGFR (fibroblast growth factor receptor), MEK, ERBB2, IDH1 (isocitrate dehydrogenase-1), and PARP1 (Poly ADP-ribose polymerase 1). Of these, ERBB2 — better known as HER2/neu — is the most relevant to gallbladder cancer specifically.

How This Review Was Put Together

This is a review article, not a new experiment. The three authors are cancer specialists from the MD Anderson Cancer Center in Houston, Peking Union Medical College Hospital in Beijing, and Memorial Sloan Kettering Cancer Center in New York. They gathered and interpreted already-published clinical trials, genetic studies, and case reports.

No new patients were enrolled for this paper, and no new laboratory work was performed. The authors also stated that they have no conflicts of interest to declare. That matters because it means the conclusions were not influenced by any drug company funding.

The evidence base they drew on included several landmark studies:

• The ABC-02 trial, a phase III randomized study that established the current first-line chemotherapy standard.
• A phase II trial of a three-drug regimen combining gemcitabine, cisplatin, and nab-paclitaxel.
• The ABC-06 trial, which tested second-line FOLFOX against supportive care alone.
• Next-generation sequencing (NGS) studies of 108 Chinese and 107 US patients with gallbladder cancer.
• HER2-directed therapy studies, including a case series of 187 patients and the MyPathway study.
• Immunotherapy trials, most notably KEYNOTE-158 with pembrolizumab.

Standard First-Line Chemotherapy

"First-line" means the first drug treatment a patient receives. For advanced or unresectable biliary tract cancers, including gallbladder cancer, that treatment is a combination of gemcitabine and cisplatin — two chemotherapy drugs given together.

The proof comes from the ABC-02 trial. Researchers enrolled 400 patients and compared gemcitabine plus cisplatin against gemcitabine alone. Of the 410 patients described across the trial reports, 36% had gallbladder cancer.

The combination worked, but modestly. Median progression-free survival (the time until the cancer started growing again) was 8 months. Median overall survival was 11 months. In plain terms, the average patient in this trial lived just under one year.

Gallbladder cancer patients did benefit specifically. About 149 enrolled patients had gallbladder cancer, and in a subset analysis the two-drug combination prolonged their overall survival compared with gemcitabine alone. The hazard ratio was 0.61 (range 0.41–0.89). A hazard ratio of 0.61 means patients on the combination had about a 39% lower risk of dying at any given point in time compared with those on gemcitabine alone.

This result established gemcitabine plus cisplatin as the standard of care for advanced, unresectable gallbladder cancer. The authors note that this first-line standard has limited effectiveness, with median overall survival under one year.

Other combinations have been tested in gallbladder cancer as alternatives:

• GEMOX (gemcitabine plus oxaliplatin)
• Gemcitabine plus capecitabine
• Gemcitabine plus S1

These regimens may have similar effectiveness to gemcitabine plus cisplatin when used first. None has clearly proven superior.

Newer First-Line Combinations and Ongoing Trials

A more recent phase II trial tested a three-drug combination: gemcitabine, cisplatin, and nab-paclitaxel (a protein-bound form of the chemotherapy drug paclitaxel). The drugs were given on day 1 and day 8 of each 21-day cycle. The trial included patients with biliary tract cancers, gallbladder cancer among them.

The results were encouraging. The primary endpoint was progression-free survival. Median follow-up was 12.2 months, and median progression-free survival was 11.8 months (95% confidence interval: 6.0–15.6 months).

Response rates were also notably high for this disease:

• Partial response (meaning tumors shrank measurably) in 43% of patients — roughly 2 in 5.
• Disease control (tumors shrank or stayed stable) in 84% of patients — more than 4 in 5.
• Median overall survival of 19.2 months (95% confidence interval: 13.2 months to "not estimable," meaning the upper limit could not yet be calculated).

Treatment effectiveness was not significantly affected by tumor type, so gallbladder cancer patients appeared to benefit alongside other biliary cancer patients. The most common side effect was neutropenia (a drop in the white blood cells that fight infection), affecting 32% of patients — about 1 in 3.

This three-drug regimen is now being tested in a phase III trial, the stage of research designed to confirm whether a treatment truly works. That trial is registered as ClinicalTrials.gov Identifier NCT03768414.

In the European Union, a different combination is under investigation. Researchers are comparing FOLFIRINOX (a regimen of 5-fluorouracil, irinotecan, and oxaliplatin) against gemcitabine plus cisplatin for advanced biliary tract cancers, including gallbladder cancer. The authors note these studies may refine the current first-line options.

Second-Line Chemotherapy: FOLFOX and Its Evidence

"Second-line" means treatment given after the first regimen stops working. Until recently, no second-line therapy had been established as a standard for biliary tract cancers.

Early evidence was weak. A systematic review of 20 studies found a weighted overall response rate of just 5.1% and a median progression-free survival of 4 months. In a separate study, median overall survival for biliary tract cancer patients measured from the start of second-line therapy was 11 months (95% confidence interval: 8.8–13.1 months). For the 24.8% of patients in that study who had gallbladder cancer, median overall survival was 9.4 months (95% confidence interval: 7.2–12.3 months).

The picture changed with the ABC-06 trial. This trial randomized 162 patients — 81 in each treatment arm — to receive either FOLFOX (a combination of 5-fluorouracil, leucovorin, and oxaliplatin) or supportive care alone. Supportive care means treatment focused on symptoms and comfort rather than on attacking the cancer. Of the participants, 21% had gallbladder cancer.

After 150 overall survival events had occurred, the adjusted hazard ratio was 0.69 (P=0.031) in favor of FOLFOX. A P value of 0.031 means there is roughly a 3 in 100 chance that a difference this large would appear by random luck alone — a statistically significant result.

The survival gain was real but modest. Median overall survival was 6.2 months in the FOLFOX arm versus 5.3 months in the supportive-care-only arm. That is a difference of about one month.

Based on this, FOLFOX is now recommended as the standard second-line treatment for biliary tract cancer, producing a modest improvement in survival compared with supportive care alone. The authors add a caution: further details should be reviewed once the complete report is published, because those details may guide how broadly this recommendation should apply.

Importantly, there is still no clinical evidence that gallbladder cancer responds differently from other biliary tract cancers to chemotherapy. That is why the authors consider it reasonable, for now, to keep enrolling gallbladder cancer patients in chemotherapy trials together with other biliary tract cancer patients. They do, however, expect this bundling to be abandoned in the future.

Genetic Testing: Chinese and US Patients Differ

Here the authors make their most important argument: gallbladder cancer is not the same disease as cholangiocarcinoma at the genetic level, and treatment choices should reflect that.

Different biliary cancers carry different mutations (changes in the DNA of cancer cells). According to the review:

• IDH1/2 and BAP1 mutations and FGFR fusions are most likely in intrahepatic cholangiocarcinoma (cancer inside the liver).
• KRAS, p53, and SMAD4 mutations are more common in extrahepatic cholangiocarcinoma (cancer outside the liver).
• Gallbladder cancer stands out for its high frequency of ERBB2 amplifications (extra copies of the HER2/neu gene).

The authors also found that genetics differ by geography. Next-generation sequencing — a technique that reads many cancer genes at once — was studied in 108 Chinese and 107 US gallbladder cancer patients. The most frequent alterations in the Chinese cohort were:

• TP53: 69%
• CDKN2A/B: 26%
• ERBB2: 19%
• PIK3CA: 17%
• CCNE1: 13%

In the US cohort, the most frequent alterations were:

• TP53: 58%
• CDKN2A/B: 25%
• SMAD4: 17%
• ARID1A: 14%
• PIK3CA: 14%
• ERBB2: 13%

Looking at the top nine dysregulated genetic pathways in cancer, Chinese patients had more frequent mutations in the ERBB family of genes — 31% versus 19%, a statistically significant difference (P=0.04). The PI3K/mTOR pathway was altered at a high frequency in both groups: 37% in Chinese patients and 33% in US patients (P=0.5, meaning no significant difference between the groups).

Both groups also showed a relatively high tumor mutational burden (TMB), a measure of how many mutations a tumor carries. TMB above 10 mutations per megabase was seen in 17.6% of Chinese patients and 17.0% of US patients — about 1 in 6 in each group. High TMB sometimes makes tumors more responsive to immunotherapy.

This heterogeneity (variation) matters a great deal for treatment decisions. As the authors write, the "one size fits all" approach must be discouraged.

HER2/neu: A Target That Already Helps Some Patients

The HER2/neu gene drives cancer growth when it is overactive. Its overexpression — too much protein produced because of gene amplification — is already a critical treatment target in breast cancer and gastric cancer. The same principle applies in gallbladder cancer.

A Japanese and Chilean group studied HER2/neu expression in 187 cases of gallbladder cancer, the largest reported series to date using the widely accepted American Society of Clinical Oncology criteria. Of those patients, 13% had HER2/neu overexpression, measured as 3+ by immunohistochemistry (IHC) — a lab test that stains tissue to show how much protein is present. That is roughly 1 in 8 patients. Radiological partial responses, meaning tumors shrank on scans, were seen in patients treated with HER2-directed therapies.

The authors include a detailed case. A 73-year-old woman had gallbladder cancer that had spread to a lymph node behind the peritoneum (the lining of the abdomen). A contrast-enhanced CT scan showed a 1.9-cm lymph node behind the left renal vein. After two months of treatment with trastuzumab and pertuzumab (two antibodies that block HER2), the lymph node shrank to 1.2 cm. The improvement was sustained over 5 months.

Additional evidence comes from the MyPathway study. Researchers combined trastuzumab and pertuzumab in 11 patients with HER2-positive biliary cancer — 8 with HER2 amplification or overexpression and 3 with HER2 mutations. At a median follow-up of 4.2 months (range 2.0–12.0 months), 4 patients had partial responses and 3 had stable disease lasting more than 4 months. These findings further support the value of targeting HER2/neu in gallbladder cancer.

Other targeted options, including drugs aimed at EGFR (epidermal growth factor receptor), are discussed in other publications cited by the authors.

What Past Targeted Therapy Trials Showed

Clinical trials of targeted therapies specifically in gallbladder cancer have lagged behind those in more common gastrointestinal cancers. Trials of EGFR, MEK, VEGFR, and PI3-kinase inhibitors have nevertheless been completed. The disappointing headline is that randomized phase II and phase III trials have failed to show that any targeted agent added to chemotherapy is superior to chemotherapy alone in biliary tract cancers.

The specific results, as summarized in the authors' Table 1, were:

• Gemcitabine plus cisplatin, with or without erlotinib (an EGFR inhibitor): progression-free survival 5.2 months with erlotinib versus 4.8 months without (P=0.80); overall survival 9.5 months versus 9.5 months (P=0.6).
• GEMOX with or without cetuximab (an EGFR inhibitor): progression-free survival 6.1 versus 5.5 months (not significant); overall survival 11 versus 12.4 months (not significant).
• GEMOX with or without panitumumab (an EGFR inhibitor): progression-free survival 5.3 versus 4.4 months (P=0.72); overall survival 9.9 versus 10.2 months (P=0.42).
• Gemcitabine plus cisplatin with or without cediranib (a VEGFR inhibitor): progression-free survival 8 versus 7.4 months (P=0.72); overall survival 14 versus 12 months (P=0.62).
• Gemcitabine with or without sorafenib (a multi-targeted tyrosine kinase inhibitor): progression-free survival 3 versus 4.9 months (P=0.859); overall survival 8.4 versus 11.2 months (P=0.775); not significant.

None of these differences was statistically meaningful. Despite this, the authors identify two areas of particular interest for gallbladder cancer: HER2/neu alterations and DNA repair gene alterations. Each occurs in roughly 10–15% of the gallbladder cancer population, which makes them realistic targets for specific drugs. Case series and case reports have already shown benefits from targeted agents in this group.

Immunotherapy: Modest Alone, Promising in Combination

Immunotherapy with checkpoint inhibitors works by releasing the brakes that cancer places on the immune system. These drugs are now being explored in biliary tract cancers. Preliminary data suggest only modest effectiveness when a single checkpoint inhibitor is used alone.

The largest study so far was KEYNOTE-158, which tested pembrolizumab. It enrolled 104 patients with biliary tract cancer, and 58% of them were PD-L1 positive (meaning their tumors carried a protein marker that can predict response to this type of drug). The response rate was 6% — about 1 in 17 patients. Disease stability occurred in 16%, and responses lasted between 6 and more than 16 months.

Combinations appear more promising than single drugs. Nivolumab was combined with gemcitabine and cisplatin in a phase I study of biliary tract cancers. That combination produced a 37% response rate and 15-month overall survival. Similar encouraging results have been reported in ongoing trials of pembrolizumab plus GM-CSF, and of lenvatinib plus pembrolizumab.

The authors are clear that randomized, controlled trials are needed before these results can change standard practice.

What This Means for Patients and Families

The practical message is that gallbladder cancer now has defined drug treatment options at two stages of the disease, and a third route — genetic targeting — is opening.

For patients who cannot have surgery, gemcitabine plus cisplatin remains the standard first-line treatment. This is based on a randomized trial that included about 149 gallbladder cancer patients and showed a meaningful survival advantage for the combination. A three-drug regimen adding nab-paclitaxel produced even better numbers in a phase II trial — 11.8-month progression-free survival and 19.2-month overall survival — but those results must be confirmed in the ongoing phase III trial before the regimen becomes standard.

After first-line treatment stops working, FOLFOX is now the recommended second-line option. It adds roughly one month of median overall survival compared with supportive care alone, and the benefit was statistically significant.

The genetic findings carry their own implication. Two patients with gallbladder cancer may have completely different driving mutations. Testing the tumor's genes can reveal whether HER2/neu, DNA repair genes, or the PI3-kinase pathway are involved. When HER2/neu is amplified — about 13% of patients, roughly 1 in 8 — HER2-directed antibodies such as trastuzumab and pertuzumab have produced tumor shrinkage that lasted months.

Limitations: What This Review Could Not Prove

This is a narrative review, not a new clinical trial. It summarizes existing evidence rather than generating new data, so its strength depends entirely on the quality of the studies it describes.

Several specific limitations stand out. Gallbladder cancer patients have historically been grouped with other biliary tract cancer patients in chemotherapy trials. As a result, gallbladder-specific data are often limited to subset analyses, such as the 149 gallbladder cancer patients within the ABC-02 trial. The authors expect this bundling practice to end in the future, but it has not ended yet.

The HER2 evidence rests on small numbers. The largest HER2 expression series included 187 cases, and the combination treatment study included only 11 patients. Those are promising signals, not proof.

The most convincing targeted therapy data so far are negative. Every randomized trial of a targeted agent added to chemotherapy failed to show superiority. Meanwhile, the positive signals — such as the three-drug chemotherapy regimen and the nivolumab combination — come from phase I and phase II studies, which are designed to test safety and early activity rather than to prove benefit.

The ABC-06 trial results reported here are preliminary. The authors note that further details should guide how the second-line FOLFOX recommendation is applied once the complete report is published.

Practical Recommendations

Based on this review, patients and their care teams can consider the following steps:

1. Ask about molecular profiling. Next-generation sequencing of the tumor can identify ERBB2 (HER2), DNA repair gene, and PI3-kinase alterations. These are the changes most likely to open a targeted treatment option.
2. Confirm HER2 status early. Because about 13% of gallbladder cancers overexpress HER2/neu, testing is worthwhile. If HER2 is amplified, HER2-directed antibodies such as trastuzumab and pertuzumab may be discussed.
3. Know the standard sequence. Gemcitabine plus cisplatin is the standard first-line chemotherapy; FOLFOX is the recommended second-line regimen.
4. Ask about clinical trials. Phase III trials of gemcitabine, cisplatin, and nab-paclitaxel (NCT03768414) and of FOLFIRINOX versus gemcitabine plus cisplatin in Europe are actively recruiting and may raise the current standard of care.
5. Do not assume all biliary cancers are the same. The authors explicitly discourage a "one size fits all" approach. Genetic heterogeneity between gallbladder cancer and other biliary tract cancers should guide treatment selection.
6. Consider combination immunotherapy only within a trial. Single-agent checkpoint inhibitors gave a response rate of about 6%, while combinations such as nivolumab with chemotherapy produced a 37% response rate. Randomized data are still needed.

Conclusions From the Authors

Systemic therapy for gallbladder cancer has evolved significantly over the past decade. There is now an accepted first-line chemotherapy regimen and an accepted second-line regimen. Including gallbladder cancer alongside other biliary tract cancers in chemotherapy trials remains reasonable at this time.

For targeted therapies and immunotherapies, however, the genetic differences between gallbladder cancer and other biliary tract cancers must be taken into account. Next-generation sequencing studies point to HER2/neu, DNA repair genes, and PI3-kinase alterations as the most promising areas for further investigation.

Ongoing first-line chemotherapy trials, targeted therapy trials, and immunotherapy trials may together produce a paradigm shift — a fundamental change in how this disease is treated.

Frequently Asked Questions

What is the standard first-line treatment for advanced gallbladder cancer?

For advanced or unresectable gallbladder cancer, the standard first-line treatment is gemcitabine plus cisplatin. In the ABC-02 trial, which included about 149 gallbladder cancer patients, this combination improved overall survival compared with gemcitabine alone. Median overall survival was 11 months, and median progression-free survival was 8 months. Other combinations have not clearly proven superior.

What is the recommended second-line treatment after first-line chemotherapy stops working?

FOLFOX is the recommended second-line treatment for biliary tract cancer, including gallbladder cancer. In the ABC-06 trial of 162 patients, FOLFOX improved median overall survival to 6.2 months versus 5.3 months with supportive care alone. This benefit was statistically significant. The authors note that further details should be reviewed once the complete report is published.

How common is HER2/neu overexpression in gallbladder cancer, and what does it mean for treatment?

In a series of 187 gallbladder cancer cases, about 13% had HER2/neu overexpression, roughly 1 in 8 patients. If HER2 is amplified, HER2-directed antibodies such as trastuzumab and pertuzumab may be discussed. In a small study of 11 patients with HER2-positive biliary cancer, some had tumor shrinkage. Testing HER2 status early is worthwhile.

What genetic differences exist between gallbladder cancer patients in China and the United States?

Next-generation sequencing of 108 Chinese and 107 US gallbladder cancer patients found different alteration patterns. In Chinese patients, common alterations included TP53 (69%), CDKN2A/B (26%), ERBB2 (19%), and PIK3CA (17%). In US patients, common alterations included TP53 (58%), CDKN2A/B (25%), SMAD4 (17%), and ARID1A (14%). These differences suggest that a 'one size fits all' approach should be discouraged.

What is the role of immunotherapy in gallbladder cancer?

Single-agent checkpoint inhibitors show modest effectiveness. In the KEYNOTE-158 trial of 104 biliary tract cancer patients, pembrolizumab produced a 6% response rate. Combinations appear more promising: nivolumab plus gemcitabine and cisplatin produced a 37% response rate and 15-month overall survival in a phase I study. Randomized trials are needed before these results change standard practice.

What is the three-drug regimen being studied for first-line treatment?

A phase II trial tested gemcitabine, cisplatin, and nab-paclitaxel in biliary tract cancers, including gallbladder cancer. Median progression-free survival was 11.8 months and median overall survival was 19.2 months. Partial response occurred in 43% and disease control in 84%. Neutropenia affected 32%. This regimen is now being tested in a phase III trial (NCT03768414) to confirm whether it truly works.

What should patients and families ask their care team about treatment?

Ask about molecular profiling of the tumor to identify ERBB2 (HER2), DNA repair gene, and PI3-kinase alterations. Confirm HER2 status early. Know that gemcitabine plus cisplatin is standard first-line and FOLFOX is recommended second-line. Ask about clinical trials, such as the phase III trial of gemcitabine, cisplatin, and nab-paclitaxel. Do not assume all biliary cancers are the same.

When should a patient with advanced gallbladder cancer seek a second opinion?

A second opinion is worth considering when the tumor cannot be removed with surgery and drug treatment is being planned. Gemcitabine plus cisplatin is the standard first-line chemotherapy, and FOLFOX is the recommended second-line regimen after it stops working. Because gallbladder cancer carries a distinct genetic fingerprint, including HER2/neu amplifications in about 13% of patients, molecular profiling can reveal whether HER2-directed antibodies or other targeted options apply. A second opinion can also clarify eligibility for ongoing phase III trials. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Systemic therapy for gallbladder cancer

Publication details: Chinese Clinical Oncology (Chin Clin Oncol), August 2019; volume 8, issue 4, article 44. DOI: 10.21037/cco.2019.08.14. Published in final edited form; available in PubMed Central from 2021 June 22.

Author contributions: All authors contributed to conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval. The authors declared no conflicts of interest. They also confirmed accountability for all aspects of the work.

Note: This patient-friendly article is based on peer-reviewed research. It is intended for education and should not replace discussion with a qualified medical team.