A periadjuvant, or perioperative, approach to the treatment of biliary tract cancers, including cholangiocarcinoma (CCA), has several potential advantages that may offer an opportunity to improve outcomes in these diseases, said James Harding, MD, Regional Director, Early Drug Development, Memorial Sloan Kettering Cancer Center, New York, NY, at the 2020 Annual Cholangiocarcinoma Summit.
Periadjuvant treatment is “elevating the idea of systemic therapy in the treatment of patients with biliary tract cancers,” said Dr Harding. “Surgery is the curative modality here. However, we often see a metastatic failure, and thus the application of systemic therapies at earlier times in the disease and around surgery may become critically important.”
With standard approaches, including adjuvant treatment after tumor resection, disease recurrence and death from cancer still remains high at 5 years.
“The idea of a perioperative approach is to treat patients earlier,” Dr Harding said. “There are several pros to this. First, we may be able to apply a systemic therapy to downstage the disease, which would hopefully improve outcome. We could more rapidly treat micrometastatic disease, which we know is critical in failure for many of these patients, particularly with intrahepatic cholangiocarcinoma.”
“You also have patients who have a better performance status presurgically, and they may be able to tolerate more aggressive therapy. It’s also possible that would prevent surgeries in those with poor biologies,” Dr Harding suggested.
The drawbacks to a periadjuvant approach to therapy are that the window of opportunity for surgery may close while systemic therapy is being administered, because patients may have disease refractory to the proposed systemic therapy, and overtreatment is a possibility.
Hypothesis-generating data suggest that administering treatment upfront may improve outcomes, according to Dr Harding.
A propensity score matched analysis by Yadav and colleagues indicated that neoadjuvant chemotherapy led to a higher probability of survival compared with adjuvant chemotherapy in patients with stage I, stage II, or stage III biliary tract cancers.1 Possible selection bias would necessitate prospective evaluation of the periadjuvant approach.
The application of perioperative chemotherapy versus adjuvant therapy in patients with resectable intrahepatic CCAs is being assessed in a randomized phase 2 clinical trial. The primary outcome is event-free survival at 24 months, Dr Harding said. The study objective is to determine the intrahepatic CCA genotype, using next-generation sequencing in tumor specimens and in tumor-derived cell-free DNA; the study will also define the concordance between tumor and cell-free DNA genotype. In addition, cell-free DNA as a potential marker of minimal residual disease is also being assessed.2
Investigational periadjuvant approaches to CCA include combination chemotherapies and locoregional therapy, precision medicine, and immunotherapeutics. A recent study showed that combination cytotoxic therapies induced an overall response rate of 60%, a median progression-free survival of 11.8 months, and median overall survival of 19.2 months in the locally advanced or metastatic setting.3
The feasibility of the combination of gemcitabine, cisplatin, and nab-paclitaxel is also being explored as neoadjuvant therapy for patients with locally advanced intrahepatic CCA.
Another potential approach is hepatic arterial infusion pump therapy. A small, 2-center, phase 2 clinical trial demonstrated “excellent disease control” with this approach,4 said Dr Harding.
Regional therapies under investigation in patients with locally advanced intrahepatic CCA include the combination of chemotherapy with Y-90, which demonstrated an objective response rate of 41% along with median overall survival of 22 months, in a recent phase 2 clinical trial by Edeline and colleagues.5
“When we think about the regional therapeutics in an operative candidate, one question that comes up is the potential for toxicities and potential delay in operation,” he said.
Damage to the biliary tree is possible with hepatic arterial infusion pump therapy, and abnormalities in liver function tests have been reported with Y-90.
Biliary tract cancers have several potentially actionable gene targets, suggesting a role for precision medicine, Dr Harding said. This suggests a “potential way to specifically link patients in a perioperative or periadjuvant approach to potentially enhance response and decrease the risk of recurrence,” he noted. Pemigatinib (Pemazyre) received FDA approval for the treatment of patients with unresectable CCA and FGFR2 rearrangement or fusion based on phase 2 clinical trial data.
Considerations for precision medicine include the difficulty in identifying low-frequency mutations in a rare disease, because 1 in 4 patients do not have enough tissue on a fine-needle aspiration or core biopsy to identify adequately a genomic mutation, and genomic alterations are present in only approximately 40% of patients with biliary tract cancers. In addition, polyclonal resistance often occurs, complicating patient selection for precision medicine.
According to Dr Harding, thus far, immunotherapy has disappointed in the setting of biliary tract cancers. “We clearly see that single-agent anti–PD-1 therapy in a nonselected patient population appears to have limited activity,” Dr Harding said.
“Perhaps by looking at PD-1 or PD-L1 expression in the tumor, we can slightly enrich antitumor activity, and certainly, we see it in the microsatellite instability-high subset. For the majority of patients, we need to have more. The majority of patients on genotyping seem to have cold tumors. Thus, novel combinations are going to need to be explored,” Dr Harding added.
The combination of chemotherapy and immunotherapy is an intriguing possibility.
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