Proton, Hypofractionated Radiation Shine in Nonoperative Cholangiocarcinoma

Ethan B. Ludmir, MD, an associate professor in the Department of Gastrointestinal Radiation Oncology at The University of Texas MD Anderson Cancer Center, spoke with CancerNetwork® ahead of the 2026 Chicago Cholangiocarcinoma Symposium about where modern radiation techniques, including hypofractionation, proton beam therapy, and MRI-guided stereotactic body radiation therapy (SBRT), fit in the management of cholangiocarcinoma.

Ludmir explained that preoperative doses, typically around 50 Gy in 25 fractions, are not ablative, in part because of concerns that higher doses may cause fibrosis that complicates surgery, and that his institution generally avoids protons in the neoadjuvant and adjuvant settings because of toxicity concerns. For the majority of patients who will not undergo surgery, however, he said that dose-escalated radiation has been associated with more durable disease control, citing a retrospective dose-response analysis from MD Anderson published in 2016, and that techniques such as proton therapy can help deliver high doses while sparing the uninvolved liver.

Transcript:

CancerNetwork: How are modern targeted radiation techniques, such as hypofractionated radiation or proton therapy, enabling the delivery of biologically effective or ablative doses safely in the preoperative setting without compromising subsequent surgical planes?

Ludmir: I’ll spin it a few ways. Number 1, in the preoperative setting, the doses we tend to use, something like 50 Gy in 25 fractions, I wouldn’t call gentle. Patients do feel [adverse] effects from this; it is not a benign intervention. We space out the radiation over 5 weeks, and the advanced radiation techniques that we have seen emerge over the last decade or 2 are not necessarily as meaningful or as impactful in that setting. Don’t get me wrong, they’re still valuable in their own way, but the doses we’re using are not typically ablative, and that’s for a few reasons. We tend to think that in the preoperative setting, if you use exceedingly high doses of radiation, you risk creating a fair bit of fibrosis for the surgeons later, even if you go to the operating room relatively quickly. Some surgeons don’t feel this way, and some do, so there’s a lot of heterogeneity.

Certainly, in the adjuvant setting, after a surgeon has done the procedure, based on everything that has to happen as a product of the surgery and the anastomoses being made, depending on what procedure is done, we typically don’t feel that hypofractionation. Proton beam radiation and many of these other tools in our toolbox are appropriate because there is increased biological effectiveness with those modalities, and we see higher risks of [adverse] effects for patients. For patients watching this, and this is very important, just because a center has access to certain advanced radiation techniques doesn’t always mean it’s the right tool for that situation. Prudence says, “What’s the right tool for the right situation?” Very often, I will not use protons for neoadjuvant or adjuvant radiation, not because there’s anything wrong with protons per se, but because we tend to believe that, biologically and biophysically, there are different properties to those particles. As an institution, we’ve tended to feel that the toxicity risks are higher if you use some of those techniques in the neoadjuvant or adjuvant setting.

Now, all that said, most patients are not going to the [operating room]. What do you do for them? In those settings, there’s hypofractionated radiation, proton beam therapy, and advanced SBRT techniques with MRI-based linear accelerators…. To be clear, no one tool is better than the other. You hear a lot of commercial words, like CyberKnife; patients hear this, and even oncologists hear this. Unless you’re knee-deep in doing liver-directed radiation all day long, the water can get muddy real fast.

Big picture, there are a few key elements here. Number 1, the data we have so far show that if radiation is your definitive local therapy, turning the dial up seems to help in terms of durable disease control. That was a seminal paper published about 10 years ago from our institution, and that work has only grown from there. Number 2, getting those doses in must be done very safely, especially for bigger tumors or for patients with underlying liver dysfunction, which happens quite often in patients with cholangiocarcinoma. As with any local therapy to the liver, you have to treat the cancer but don’t break the liver. That’s a balancing act. Proton beam therapy, especially for large tumors on the right side of the liver, allows you to dial the dose very high and, most importantly, spare the uninvolved liver. That doesn’t mean one modality is always right or wrong.

All that’s by way of saying these are neat techniques that each have their right moment. For the nonoperative patients, that’s when you see proton beam therapy, high-dose radiation, and hypofractionated techniques, where you can deliver very walloping doses of radiation over 1, 2, or 3 weeks to knock out these tumors. That’s where that stuff shines.

Reference

Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016;34(3):219-226. doi:10.1200/JCO.2015.61.3778