Gallbladder Cancer Awareness Month: Steady Progress in Optimizing Patient Care

Patrick Wagner, MD

Gallbladder cancer is a challenging condition that, though rare, is difficult to diagnose early and has poor survival outcomes for patients. Only a small percentage of gallbladder cancers can be treated with surgery when first found, according to the American Cancer Society.¹

“The resection options quickly start to go out the window when a gallbladder cancer progresses to the point where it causes symptoms,” Patrick Wagner, MD, a surgical oncologist with Allegheny Health Network (AHN), said during an interview with Targeted Oncology^TM.

Patients now have better systemic therapy options for biliary tract cancers (BTC) including the addition of immunotherapy to frontline chemotherapy. Additionally, there are more opportunities to discover candidates for targeted therapies through the use of molecular testing.

Surgeons like Wagner, director of complex general surgical oncology at AHN Cancer Institute, have high hopes that further exploration of neoadjuvant therapies can make resection a potentially curative option that would be available for more patients.

Targeted Oncology^TM: What recent clinical trials have been practice changing for patients with gallbladder cancer?

WAGNER: As far as gallbladder cancer goes, the trials examining immunotherapy for cholangiocarcinoma and other cancers—gallbladder cancer gets lumped in with cholangiocarcinoma—are where the advances have been the strongest. [The TOPAZ-1 trial (NCT03875235)] has led to FDA indications for the addition of durvalumab [Imfinzi] with gemcitabine and cisplatin for advanced BTC.² There are agnostic approvals for other immune checkpoint inhibitors in the setting of advanced disease, so those clinical trials are probably the most exciting to us, and not just for metastatic patients.^3,4 Coming at this from the point of view of a surgeon, it opens up opportunities for long-term disease control in patients we can operate on, or even concepts of conversion to resectability for patients who initially start out with advanced disease but can be downstaged with immunotherapy or targeted therapy.

How have investigators researched adjuvant or neoadjuvant therapy to improve the outcomes of surgical resection for these patients?

The concept of neoadjuvant treatment for advanced BTC is evolving. It was not traditionally an area in which neoadjuvant approaches were explored for a number of reasons, probably because the efficacy was low, and we didn't want to miss opportunities to resect patients. If there was a borderline case, we wanted to try to get to surgery before we lost our window.

These days, with improving efficacy and actionable targets, there has been more momentum for neoadjuvant strategies, both with conventional cytotoxic combinations like gemcitabine/cisplatin, and sometimes with radiation. Especially exciting would be the newer targeted therapies, including those directed at molecular biomarkers, or immunotherapy for MSI [microsatellite instability]-high patients, or with an agnostic approach for immunotherapy. As those directed and targeted therapies expand their utility, I think neoadjuvant strategies will evolve.

For advanced BTC, there is potentially a role for hepatic arterial infusion therapy as an approach to conversion to resectable disease, meaning patients who have advanced disease at presentation can be downstaged and converted to resectability using hepatic arterial infusion pump therapy.

What is the role of molecular testing in this setting?

Molecular testing is now essentially the standard of care, or the gold standard. Without it we lose out on a number of important options, including the immunotherapy approach with immune checkpoint inhibition, which sometimes relies on an assessment of tumor mutational burden or MSI information. Then there are a number of specific molecular biomarkers of relevance for targeted therapy, including FGFR fusions, IDH1 mutations, BRAF mutations, and NTRK gene fusions. These are all emerging targets for molecular therapies or directed therapies. We seldom, if ever, talk about a patient in our tumor boards without going through the molecular testing results to guide our systemic therapy options.

How are targeted therapies impacting this treatment landscape?

Like many targeted therapies, the population for which any targeted therapy is applicable are a minority. If you put all of those targeted options together, which is massive progress relative to a few years ago, you're still only talking about perhaps 10% to 20% of patients who have an actionable target; most patients are not going to have one.

There are [many] potential agents on the horizon. If you pick any target, there's someone developing a therapeutic strategy around it. We're catching up with the ones that we do have at our disposal, and often trying to figure out how they fit into preexisting algorithms for advanced BTC.

Outside of systemic therapy, what other improvements to treatment have been made for patients with gallbladder cancer and similar cancers?

[Speaking] as a surgeon, we have to continue to develop minimally invasive techniques for the surgical management of gallbladder cancer. Our standard practice at our institution for gallbladder cancer would be to do a robotic resection of the gallbladder, the associated liver parenchyma, [with] a wide margin into the central liver. Then [comes] a thorough lymphadenectomy as a robotic, minimally invasive procedure that generally has a short recovery and a quick turnaround time to any need for adjuvant therapies. A lot of times we find out about a gallbladder cancer after the gallbladder has already been removed, and it's an incidental finding. In those scenarios, the surgical approach is the same, but we just resect the liver fossa—the area of the liver that the gallbladder was attached to.

There is an ongoing uptake of minimally invasive techniques. It's certainly not universal, far from it. Advanced centers do robotic surgery for these types of cancers. Most facilities are still doing open surgery. That is still an area of evolution in surgical management.

The biggest advances in radiation for BTC have been in the use of stereotactic body radiation therapy to treat hepatic lesions, either metastatic lesions or primary lesions depending on the size and the amount of parenchyma involved, as well as utilization of MRI-LINAC [MRI-guided linear accelerator] techniques to better guide radiation planning. We also have an active protocol for using functional imaging of the liver using a ferumoxytol [Feraheme] MRI technique to perform functional liver imaging to guide therapy, not just for advanced BTCs, but for any liver lesions, metastatic or primary.

What advice do you have for community oncologists who have patients with gallbladder cancer?

If state-of-the-art immunotherapy and targeted therapy protocols are not a part of your practice in the community, then [I recommend] referral to a specialty center, at least at the outset of care, to get advice on any clinical trials or molecular guided therapy. If it applies to a given patient, that is great, and if it doesn't, you have done due diligence to avail the patient of any options they might have.

Surgical second opinions are important, particularly when it comes to judging resectability of liver lesions. The answer that is given in community centers or even in larger centers may be different depending on the degree of expertise of the surgeon. Sometimes, it helps to have a specialty surgical team evaluate a case to verify that [a patient’s disease] is or is not resectable. I think that merits specialty discussion, regardless of where the patient is.

Palliative care is often important in these patients because they often have very advanced disease and the impact of progressive biliary tract malignancy and hepatic insufficiency, and failure brings up a lot of high intensity palliative care needs. If you have a patient with advanced disease who’s not curable, engaging palliative care early in the process is probably worthwhile. A lot of symptoms come with hepatic obstruction and failure that are difficult to manage towards the end of life. It is good to have palliative care specialists on board if you can.

Have there been any improvements in earlier diagnosis of this disease?

There's a lot of energy in the field of liquid biopsies and liquid biomarkers as diagnostic tests for many cancers. Gallbladder cancer being one of many, we lump gallbladder with BTC because it's one part of the anatomic biliary system. I think it will ride the wave as we develop better molecular testing, whether it's circulating tumor DNA or epigenetic circulating biomarkers that help us delineate the presence of a cancer. If a patient has a positive blood test, finding out that the disease is in the gallbladder and not somewhere else will still be very challenging.

What avenues of research has the AHN Cancer Institute been focused on that have the most potential in this setting?

Our institution has been working on developing injectable immunotherapy agents and oncolytic viruses, not specific to gallbladder cancer, but to abdominal malignancies in the metastatic setting. Because BTCs are often metastatic, I think it will be pertinent. I'd like to see our institution driving clinical trials for patients who have metastatic disease, especially peritoneal metastases, which often happen with gallbladder and BTCs.

BTCs are so aggressive that cytoreduction is usually not a favorable risk-benefit equation for patients. But if we were able to swing the odds with some sort of regional immunotherapy or an oncolytic viral therapy, we can make a big difference for a lot of patients. That's where our energy is focused. I would put gallbladder cancer in the category of abdominal cancers where carcinomatosis becomes a big concern in our strategies. While [our current strategies] may be good in patients with more indolent disease types, gallbladder and other hepatobiliary cancers are so aggressive that our hands are largely tied.

It is an exciting era, especially with all the new energy in immunotherapy and targeted therapy. There has been more movement in the past 5 years than in the previous decades put together, so hopefully in a few years there will be even more to talk about.

_References:

_{1. Surgery for Gallbladder Cancer. American Cancer Society. Accessed February 7, 2023. https://bit.ly/40zvNeG}

_{2. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. FDA. September 2, 2022. Accessed February 7, 2023. https://bit.ly/3YcJOgS}

_{3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 30, 2017. Accessed February 7, 2023. https://bit.ly/2lDQSG0}

_{4. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. August 17, 2021. Updated February 1, 2022. Accessed February 7, 2023. https://bit.ly/3HKobgI}