HAIP Chemotherapy or Resection for Multifocal Bile Duct Cancer?

Hepatic arterial infusion pump (HAIP) floxuridine chemotherapy may represent an effective alternative to curative-intent resection in patients with multifocal intrahepatic cholangiocarcinoma who are at risk for surgical complications or who have more advanced disease, an international cohort study suggested.

In the analysis of more than 300 cases over the past three decades, median overall survival (OS) was 20.3 months with HAIP chemotherapy, which was not significantly different than the 18.9 months with resection, reported Bas Groot Koerkamp, MD, PhD, of Erasmus MC Cancer Institute in Rotterdam, The Netherlands, and colleagues.

As described in JAMA Surgery, patients with two or three lesions saw 5-year OS rates of 23.7% with HAIP chemotherapy and 25.7% with surgical resection. In those with four or more lesions, these rates were 5.0% and 6.8%, respectively.

Adjustment for risk factors significantly associated with survival — tumor diameter, lesion number, and nodal disease — revealed a non-significant trend toward improved OS with HAIP chemotherapy (HR 0.75, 95% CI 0.55-1.03, P=0.07).

“A minor liver resection or even a major resection in a patient with a good performance score may be justified in select patients with multifocal iCCA [intrahepatic cholangiocarcinoma], particularly those with only two or three lesions,” concluded Koerkamp and coauthors.

“Hepatic arterial infusion pump chemotherapy may be considered for patients with an increased surgical risk or more advanced disease, as reflected by the tumor diameter, number of tumors (four or more), and nodal disease,” the group continued. “Resection can be considered after HAIP chemotherapy in patients with a good response and a good performance score.”

But resection is not without its risks, the authors cautioned. Postoperative mortality in the analysis was significantly higher in the resection group compared to the HAIP group (6.2% vs 0.8% at 30 days, P=0.01). They suggested shared decision-making as a means of balancing these risks with the potential for long-term benefit.

Multifocal intrahepatic cholangiocarcinoma carries a poor prognosis, with most guidelines recommending palliative chemotherapy rather than surgery, explained Koerkamp and coauthors. In the ABC trials, patients with multifocal intrahepatic cholangiocarcinoma treated with gemcitabine-cisplatin had a median OS of 16.7 months, though none survived beyond 2.5 years.

Multifocal intrahepatic cholangiocarcinoma is a “controversial disease,” noted Clifford Cho, MD, of the University of Michigan Medical School in Ann Arbor, writing in an accompanying editorial.

“The controversy relates to the unresolved question of whether this disease is a manifestation of colocated primary tumors or of intrahepatic metastasis,” he wrote. “The possibility of a cure, which is modest but extant after resection of solitary tumors, drops precipitously with multiple tumors — motivating interest in transarterial therapies for this disease.”

HAIP allows for high-dose chemotherapy to be delivered directly to the liver while minimizing toxicities associated with systemic treatment. Intratumoral drug levels of floxuridine — the most effective agent, according to the study authors — reach levels nearly 200-fold higher than what can be achieved via systemic therapy.

But Cho argued that aside from patients “who barely meet the definition of multifocality,” prolongation of life rather than an attempt at cure may be more appropriate.

“Considering the selection biases inherent in any decision to offer HAIP floxuridine chemotherapy vs systemic gemcitabine with cisplatin alone, it becomes difficult to argue against the proposition that, aside from select cases of healthy patients with two tumors, nonoperative chemotherapy remains the standard of care for multifocal intrahepatic cholangiocarcinoma,” he wrote.

For their study, Koerkamp’s group examined 319 patients with multifocal intrahepatic cholangiocarcinoma: 141 consecutive patients with unresectable disease who underwent HAIP chemotherapy from 2001 to 2018 at Memorial Sloan Kettering Cancer Center in New York City; and 178 consecutive patients who underwent surgical resection at 12 hepatobiliary institutions across the U.S., Europe, Asia, and Australia from 1990 to 2017.

Patients were excluded from the analysis if they had stage IV disease, had undergone a resection prior to HAIP, or if they had received a liver transplant.

The HAIP group tended to be older (median 62 vs 60 years for the resection group), and included more women (56.0% vs 49.9%). These patients also had larger tumors (median 8.4 vs 7.0 cm, respectively), and were more likely to have four or more lesions (66.7% vs 24.2%), regional nodal disease (51.1% vs 24.7%), and bilobar disease (88.0% vs 34.3%).

In the resection group, 7.9% received neoadjuvant and 41.6% received adjuvant chemotherapy. For the HAIP group, 32.6% had chemotherapy prior to and 77.3% during HAIP.

Among the limitations cited by the study authors is the fact that HAIP is only offered at 30 centers worldwide.