Editor’s Note: Cholangiocarcinoma is characterized by its high malignancy, with the majority of patients presenting with unresectable disease at initial diagnosis. In recent years, conversion therapy—which utilizes systemic treatment to downsize tumors—has emerged as a pivotal, offering select patients a pathway to curative-intent resection. However, striking the right balance between therapeutic efficacy and overtreatment remains a significant clinical challenge. At APPLE 2026, Prof. Stephen L. Chan, from the Chinese University of Hong Kong (CUHK) Faculty of Medicine, offered an in-depth analysis of these issues during an exclusive interview with our journal. Prof. Chen advocates for earlier genomic testing for alterations such as FGFR2 and IDH1, and proposes a multidimensional assessment framework combining radiology with circulating biomarkers like ctDNA and MRD to precisely identify the optimal surgical window. Furthermore, he recommends a stratified postoperative strategy guided by pathological response (MPR/pCR) to maximize recurrence-free survival. Q1. How do you determine the timing of targeted agent intervention based on key driver alterations when selecting a conversion therapy regimen, beyond standard chemo-immunotherapy? How do you balance optimizing the ORR with preserving a safe window for subsequent surgery?
Prof. Chan: Regarding the choice of conversion therapy for cholangiocarcinoma, traditionally, we look at the radiological response rate—and the higher the radiological response rate, the more likely we believe the regimen will serve as a better conversion therapy for patients. But recently, we have also seen data suggesting that targeting genetic alterations such as FGFR2 may shrink tumors in a proportion of patients, thereby enabling conversion. Therefore, I think that in the future, we should look at a number of factors—not only the response rate, but also genetic alterations.
Regarding the timing of testing for these genetic alterations, conventionally, we test once patients become inoperable, when the disease is more advanced. But as I mentioned, more data suggest that we should test earlier, with the purpose of guiding treatment and pursuing conversion, rather than reserving testing for palliative purposes.
Q2. Traditional RECIST criteria have limitations in evaluating responses to immunotherapy and targeted agents. In clinical practice, which dynamic changes in tumor markers would you integrate to establish a more sensitive early-warning system for efficacy assessment?
Prof. Chan: I have to say, regarding endpoints for predicting which patients are about to convert—while radiological response is still crucial, as it determines the anatomical resectability—we also look at other parameters, like tumor markers. Traditionally, if we see CA19-9 or CEA trending downward, that correlates with benefits from systemic therapy. And looking forward, I think the work being done on circulating markers like ctDNA and MRD will be key to predicting, or at least correlating with, those patients who are about to achieve a response.
Q3. Following successful downstaging with conversion therapy, timing the surgical intervention is critical. What core indicators do you rely on to determine the optimal surgical window?
Prof. Chan: Typically, based on the clinical trial data we have, we see responses or significant tumor shrinkage within about two to three months. But of course, we know some patients might take longer to show an effect. So, it’s hard to give one exact cutoff. What’s crucial is monitoring the response using imaging, tumor markers, and the patient’s overall condition. We do this for two main reasons: one, to make sure we don’t miss the chance for surgery—the surgical window; and two, to switch treatments immediately if the disease starts progressing. And after surgery, we always look at the pathological response. That result can actually determine what kind of treatment the patient needs next.
Q4. Regarding postoperative adjuvant therapy, should we continue the conversion regimen or pivot to a new strategy, and what drives this decision?
Prof. Chan: That’s a very challenging question. We know these patients are prone to relapse, so even after a successful conversion, they need some form of postoperative or adjuvant treatment. Traditionally, if we see a major pathological response (MPR) or even a pathological complete response (pCR) in the surgical specimen, we tend to stick with the same regimen that achieved the conversion. How long? Well, we don’t have a definitive answer yet, but I think six months is typical—sometimes even longer, up to a year. However, if the patient fails to achieve a pathological response in the surgical sample, I believe it’s usually best to switch to an alternative therapy. Changing the regimen is perfectly acceptable to keep the patient in a recurrence-free state.
