Gallbladder Cancer: Progress and Hope for Future Breakthroughs

Gallbladder with stone. Care and treatment of gallstones, cholecystitis, surgical removal. modern digital medicine. hand holds a gallbladder on dark blue digital background: © Tom - stock.adobe.com

February is Gallbladder Cancer Awareness Month, and while it may be less common than other cancers, it's crucial to understand the latest advancements and future directions in diagnosis, treatment, and care.

According to father and son duo, Horacio J. Asbun, MD, and Domenech Asbun, MD, both of Baptist Health South Florida, among the biggest advancements have been more awareness that gallbladder cancer is one that needs to be fought.

“Gallbladder surgery is 1 of the most common surgeries in the United States [with an] estimated 700,000 procedures in the United States a year. Therefore, a good number of gallbladder cancers are found incidentally in centers that treat gastrointestinal disease. What to do has been more standardized when that is the situation,” explained Horacio Asbun, chief of hepatobiliary and pancreas surgery at Miami Cancer Institute, in an interview with Targeted Oncology^TM.

Advancements

Surgical Techniques and Treatments

According to Domenech Asbun, minimally invasive surgery, including techniques like laparoscopic and robotic surgeries, are being increasingly used for the treatment of patients with gallbladder cancer. This method offers reduced recovery time and potential benefits for the patient.

“In surgery, 1 of the biggest advances that we've seen is pushing the boundary with minimally invasive surgery, laparoscopic, most of the time, and robotic. But even in the hepatobiliary space and pancreatic surgical space where a lot of these surgeries used to be considered too difficult to do minimally invasively, now we are doing them laparoscopic or robotic,” Domenech Asbun, hepatobiliary and pancreatic surgeon at Miami Cancer Institute, told Targeted Oncology in an interview.

Domenech Asbun, MD

Surgeons are also increasingly using fluorescence imaging for precise cancer tissue removal and opting for targeted liver resections to preserve healthy tissue.

“With the minimally invasive approach, there are added technologies that are making the surgery even better for the surgeon. One of the big things that I like to use a lot is fluorescence imaging with ICG. ICG is an intravenous dye that will get excreted by the liver. It also has a handful of other uses in general surgery, head and neck surgery, and thoracic surgery, etc.”

From a surgical standpoint, Domenech Asbun explained that a heavier emphasis is being placed on lymph node dissection and exploration of new systemic therapies like immunotherapy alongside traditional chemotherapy.

Despite guidelines recommending removal of 6 lymph nodes during gallbladder cancer surgery, studies show many surgeons are not doing enough, according to Domenech Asbun.

“Lymph node dissection is something that has been advocated for a long time in the national guidelines, but a lot of recent studies are showing that surgeons do not often do enough of a lymph node dissection...There is a big emphasis now on making sure to take your time to do a proper lymph node dissection, and that can have an effect on survival, based on the studies,” explained Domenech Asbun.

This “proper lymph node dissection” is now emphasized for potentially improved patient survival, even though the liver has fewer lymph nodes compared with other organs.

Historically, experts would also take out segments of the liver and try to do an anatomic resection. Now, there is a shift away from extensive liver resections, where large sections were removed, allowing for more targeted procedures that preserve healthy tissue while potentially improving outcomes.

Systemic therapy options continue to be incorporated into practice with more patients getting immunotherapy or chemotherapy. Domenech Asbun notes that the problem with this is that the data are not “super strong.”

“Gallbladder cancer is still primarily something that we treat with surgery. Even though we have seen a lot of advances in the field of surgical oncology, gallbladder cancer has been difficult to know where we incorporate these new technologies and these new trends.”

Horacio J. Asbun, MD

Clinical

While no huge breakthrough has come about in the gallbladder space, progress is ongoing, and experts like Horacio Asbun believe there are several promising avenues under exploration.

“There are several clinical trials ongoing but there has not been 1 in particular that has been newsworthy from the point of view that made a significant change in the treatment of gallbladder cancer. [We are] pretty optimistic though that we will find something that is going to be a game changer within the next few years.”

One exciting shift is the increased focus on personalized medicine. Unlike one-size-fits-all treatments, this involves studying various factors, including tumor location and potential spread, to guide individual treatment plans.

With this approach, experts can find better-suited therapies for each individual patient, maximizing their chances of success.

“[Treatment depends] on the location of the tumor in relation to the walls that are attached or not attached to the liver and the presence of suspicious lymphadenopathy or not. What is notable now is that guidelines overall have become more rigorous in terms of the development,” explained Horacio Asbun.

The field of gallbladder cancer research is not relying on guesswork. Today, stricter guidelines ensure clinical trials and studies adhere to robust methodologies, leading to more reliable and impactful results. This paves the way for truly groundbreaking discoveries in the near future.

In addition, and as noted by Domenech and Horacio Asbun, surgery remains the mainstay of treatment. However, minimally invasive techniques like magnetic resonance (MR) ablation therapy offer less disruptive options for certain cases.

“There are also reports of success using other local regional treatments, for example, ablation, irreversible electroporation, transarterial chemoembolization, or transarterial radioembolization, and even external beam radiation. They are starting to have a bit of a role in the management of these cancers, usually when they are unresectable or when they recur, but they are still enforcing our data to say that they are a part of the treatment algorithm,” explained Domenech Asbun.

“MR ablation therapy may play a role, depending on the extent of the disease once the gallbladder is out. There are also other types of therapy, like universal electroporation, that could play a role. All those decisions are made as a multidisciplinary team,” added Horacio Asbun.

Novel therapies continue to be explored in this space, hoping for the potential to combat this disease. Multidisciplinary teams also are of great importance when managing patients with gallbladder cancer. Surgeons, oncologists, and other specialists work together, ensuring each patient receives the most appropriate and advanced care available.

Notable Trials

While advancements in diagnosis and treatment are encouraging, several challenges remain in the gallbladder space. One challenge lies in personalizing treatment based on each tumors unique characteristics, as this field is still in its early stages.

According to Domenech Asbun, 2 trials have come out which represent potential breakthroughs in the treatment of patients with biliary tract cancers (BTC).

“We are trying to figure out what are the details of that 1 patient's specific tumor. How can we attack them? Especially in gallbladder cancer, [it is] in its infancy, and we do not have a lot of tools to work with yet. But recently in the field of immunotherapy, a landmark trial came out called the TOPAZ-1 trial [NCT03875235],” explained Domenech Asbun.

The phase 3 TOPAZ-1 trial1 was practice changing for patients with unresectable BTC, including cholangiocarcinoma, because it supported the addition of durvalumab (Imfinzi) to the prior preferred primary therapy of combination chemotherapy cisplatin plus gemcitabine.

The durvalumab-containing therapy significantly improved overall survival (OS), reaching the primary end point of the study. At a median follow up of 16.8 months (95% CI, 14.8–17.7) in the durvalumab arm and 15.9 months (95% CI, 14.9–16.9) in the placebo arm, the median OS was 12.8 months (95% CI, 11.1–14.0) compared with 11.5 months (95% CI, 10.1–12.5), resulting in a 0.70 hazard ratio (HR) for the decrease in the risk of death with added durvalumab.

Notably, at 12 months, 18 months, and 24 months, survival in the durvalumab/chemotherapy arm was 54.1% (95% CI, 48.4%–59.4%), 35.1% (95% CI, 29.%1–41.2%), and24.9% (95% CI, 17.9%–32.5%) vs 48.0% (95% CI, 42.4%–53.4%) 25.6% (95% CI, 19.9%–31.7%), and 10.4% (95% CI, 4.7%–18.8%) with placebo and chemotherapy. Another interesting point was that those treated with durvalumab had an overall response rate of 36.7% vs 18.7% in the placebo arm (odds ratio, 1.60; 95% CI, 1.11–2.31).

“We need more studies to corroborate this effect, but it does seem that immunotherapy is going to have a more established role in treatment of gallbladder cancer,” added Domenech Asbun.

A similar study, KEYNOTE-966 (NCT04003636), showed a significant improvement in OS when pembrolizumab (Keytruda) was added to standard-of-care (SoC) chemotherapy vs SoC chemotherapy alone in patients with locally advanced, unresectable, or metastatic BTC who received treatment in the first line.²

“The KEYNOTE-966 study was looking at the use of pembrolizumab, which acts similarly, and it is also immunotherapy. That was given with gemcitabine and cisplatin. It was modest, but there was a survival benefit for the patients that got the pembrolizumab,” explained Domenech Asbun.

Specifically, the combination of gemcitabine, cisplatin, and pembrolizumab led to a 17% reduction in the risk of death as first-line treatment for patients with locally advanced, unresectable, or metastatic BTC vs gemcitabine and cisplatin alone (HR, 0.83; 95% CI, 0.72–0.95; P =.0034) at a median follow-up of 25.6 months (range, 18.3–38.4). The median OS seen among patients given the pembrolizumab combination was 12.7 months (95% CI, 11.5–13.6) vs 10.9 months (95% CI, 9.9–11.6) for those given SoC chemotherapy alone.

At 1-year, the group treated with pembrolizumab to gemcitabine and cisplatin had an OS rate of 52% vs 44% among those given gemcitabine and cisplatin only. The OS rates at 2 years among those given the triplet vs doublet arm were 24.9% vs 8.1%, respectively, and overall, the OS benefit seen with pembrolizumab, gemcitabine, and cisplatin in the overall population was consistent in the subgroup population evaluated.

In November 2023, the FDA approved the combination for this intent-to-treat population.³

Unmet Needs

In addition to more data needed on personalized medicine, experts note that early diagnosis remains crucial for better outcomes among their patients. Early detection is crucial for improving patient outcomes and Domenech and Horacio Asbun underscore the need for better diagnostic tools. However, they note that vague symptoms observed in patients often lead to delays.

“Gallbladder cancer, just like so many cancers, is difficult to diagnose sometimes because the symptoms are very nonspecific. One might get a patient with jaundice, and that is a more alarming acute symptom, but a lot of times it's abdominal pain, maybe a little bit of weight loss, maybe nothing. A lot are incidentally found cancers. The important thing is to know what risk factors your patients have,” explained Domenech Asbun.

“Early diagnosis and molecular studies of the tumor and populations [hold the most potential for future breakthroughs] because this is a cancer that is clearly different depending on the population. If we can get some type of molecular identification that leads us towards populations of risks, we can be much more aggressive in screening those patients,” added Horacio Asbun.

Furthermore, the lack of a single, standout chemotherapy or immunotherapy option underscores the need for more effective treatments.

"Unfortunately, in this space, there are a lot of unmet needs…There are different regimes, but there is not 1 that has been touted as the best by far. Different tumors react differently,” said Horacio Asbun.

Finally, access to specialized care poses a significant barrier, as not all centers have the expertise and resources required to manage complex cases. It is important for community oncologists to understand the capacity their environments have for treating complex patients.

Studies show patients with complex conditions fare better when treated at specialized centers with high patient volume and extensive resources. These centers offer experienced surgeons, multidisciplinary teams, and access to complex treatments like chemotherapy regimens.

Not everyone has access to such centers; thus healthcare professionals should be aware of their existence and utilize them for second opinions or referrals, especially for those that are complex cases.

“[Community oncologists] need to be proactive from the moment that the patient has received a diagnosis, because the timing of re-exploration for surgery, or timing of receiving different treatments and the order of the treatments, varies. That is better done in centers that are specialized on this type of pathology, rather than on a setup that is not seen often enough, emphasizing that that does not mean that those physicians are less qualified,” explained Horacio Asbun.

“It is a team sport. Even for people who are specialized in something, you still have to rely on other specialists, even within the same field. Get different ideas, get different opinions,” added Domenech Asbun.

Addressing these challenges through continued research, improved awareness, and increased access to specialized care paves the way for a brighter future for those battling this disease.

REFERENCES:

1. Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evidence. Published online June 1, 2022. doi: 10.1056/EVIDoa2200015

2. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2023 Sep 16;402(10406):964]. Lancet. 2023;401(10391):1853-1865. doi:10.1016/S0140-6736(23)00727-4

3. FDA approves Merck's Keytruda (pembrolizumab) plus gemcitabine and cisplatin as treatment for patients with locally advanced unresectable or metastatic biliary tract cancer. News release. November 1, 2023. Accessed February 5, 2024. https://tinyurl.com/55xswd8f