Neoadjuvant Therapy for Advanced Cholangiocarcinoma

John L. Marshall, MD: Katie, in every other GI [gastrointestinal] cancer, there’s a shift to neoadjuvant treatment to get systemic therapy first to shrink the cancer or improve surgical outcomes. Should we be thinking about that in bile duct cancers?

R. Kate Kelley, MD: Great question. I’ll ask Milind to weigh in, too, because he’s an expert in this area, but my answer is that we are increasingly considering neoadjuvant therapy with combination regimens such as GEM [gemcitabine]/CIS [cisplatin]. Based on phase 2 data, we are also considering the combination of GEM/CIS/nab-paclitaxel in patients who have liver-limited or liver-only disease. We’re concerned about not achieving a negative margin, ie, with patients where too much liver will need resection, or it’s too close to a vital structure. We’re strongly concerned about positive margins in an aggressive attempt to have a curative approach.

Absent is not true neoadjuvant, though. If you look at the definition of the word neoadjuvant, it’s intentional therapy before surgery in a patient who is already resectable. I use it in patients who are in an ill-defined borderline realm where we think they could become resectable. If they’re perfectly resectable, do we still favor going straight to surgery? That’s where we need data. There are some trials in development or recently initiated that will look at this. I’d love to ask Milind for his perspective. He and our colleague Rachna Shroff led the phase 2 trial I alluded to, which showed that in some patients, it turned out to be a conversion therapy.

Milind Javle, MD: That’s right, Katie. Of the 60 patients, they had 15 where surgeons had turned down for a resection and underwent margin negative resection with the triplet GEM/CIS and nab-paclitaxel. Of those 15, 3 had complete pathologic response. Coming from an institute where neoadjuvant is used very liberally in pancreatic cancer, we have learned treatment of micrometastatic disease downstaging, etc, but you also end up identifying the disease trajectory that may be most suitable for an extensive resection.

We have a current trial with the triplet for high-risk resectable, such as multiple lesions in the same lobe, vascular abutment, etc. Borderline is not defined yet. These patients, most of them undergo surgical resection successfully. Whether that translates into eventual survival benefit if treatment is in the reverse sequence with surgery followed by adjuvant is not known. The community and surgeons are favoring it, so they’re going to want us to do it in unresectable, borderline resectable, and resectable cases.

John L. Marshall, MD: Do we do the same approach that we do in tricky liver cases in colon cancer, where we embolize or ligate to try and grow some liver? What’s the concern about the hemotoxicity on the liver? Is it the same basic rules?

Milind Javle, MD: Fortunately, the drugs for us are not like irinotecan and oxaliplatin. There are fewer dosage effects, and our duration of treatments has been generally shorter. We are far behind where you were in colon cancer, though, in terms of neoadjuvant followed by surgical resection as first liver adjuvant therapy. I’ll let Katie and Sameek weigh in. Before surgical resection, we don’t have much experience. Centers like Robert H. Lurie Comprehensive Cancer Center at Northwestern University have been doing it routinely. Doing radioembolization before surgical resection seems to be an effective strategy in some cases.

John L. Marshall, MD: We have these other tools that are getting folded in.

R. Kate Kelley, MD: The nature of bile duct tumors is that they’re often intimately connected to the ductal structures in micrometastasis. I have seen a higher rate of patients having strictures or biliary complications. If patients have had a stent or cholangitis, they’re more likely to get an abscess because their ductal system has been breached by GI bacteria. We need longer follow-up data to create these more mainstream therapies, and it needs to be done in a very expert center.

John L. Marshall, MD: I agree. Even in expert centers, we get into trouble, right?

R. Kate Kelley, MD: Exactly.

John L. Marshall, MD: We’re vulnerable to that, too.

Transcript Edited for Clarity