Cholangiocarcinoma News

Keynote: Crossfire Debates on the Management of CCA

December 2022, Vol 3, No 4

Pictured left to right: Nilofer Azad, MD; Teresa Macarulla, MD, PhD; Mark Yarchoan, MD

Debate on Medical Therapy

Teresa Macarulla, MD, PhD, of the Vall d’Hebron University Hospital in Barcelona, Spain, and Mark Yarchoan, MD, from Johns Hopkins Medicine, debated the question, “Should immunotherapy be standard of care in cholangiocarcinoma (CCA)?” Dr. Macarulla discussed data in support of this topic, defending the use of gemcitabine/cisplatin (GemCis) and durvalumab as the new first-line standard of care. Since the results of ABC-02 were published,1 GemCis has been standard of care for all patients with biliary tract cancer (BTC). It has been hypothesized that immunotherapy may be effective in BTC based on studies that demonstrated expression of programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte–associated protein 4 in the BTC tumor microenvironment.2 Data from TOPAZ-1 showed clinical benefit with the addition of durvalumab to GemCis in patients with advanced BTC, regardless of PD-L1 status. The addition of durvalumab resulted in a median overall survival (OS) of 12.8 months versus 11.5 months with GemCis alone (hazard ratio [HR], 0.80; P = .021).3 Dr. Macarulla argued that progression-free survival (PFS) curves started to separate around 4 months,3 and with an additional 6.5 months of follow-up from the primary analysis, there was continued OS superiority with durvalumab (HR, 0.76).4 The phase 3 TOPAZ-1 clinical trial data led to the approval of durvalumab with GemCis for first-line treatment of patients with advanced BTC, establishing a new standard of care with immunotherapy as first-line treatment.

Dr. Yarchoan offered a counterargument by detailing 4 problems with the TOPAZ-1 study. First, he argued that the clinical trial design comparing durvalumab maintenance therapy with placebo maintenance therapy was unrealistic in clinical practice because placebo is not standard of care in this setting. He emphasized that the survival curves from TOPAZ-1 overlapped for the first 6 months, after which they started to separate when 1 group continued on placebo.3 Results from KEYNOTE-966, where GemCis will be continued as maintenance therapy instead of placebo, will be key in determining the benefit of immunotherapy versus chemotherapy.5 Next, he noted that GemCis plus paclitaxel has demonstrated better outcomes than GemCis plus durvalumab. GemCis plus paclitaxel had an objective response rate (ORR) of 45% in a phase 2 trial,6 which is almost double the 26.7% ORR seen with durvalumab plus GemCis in TOPAZ-1.3 Dr. Yarchoan emphasized the importance of results from SWOG1815, a phase 3 trial of GemCis plus nab-paclitaxel, in which outcomes have the potential to be practice changing. He also argued that cross-trial comparisons have shown that the benefit of a PD-L1 inhibitor plus chemotherapy was similar to immunotherapy monotherapy in second-line CCA, suggesting a rationale for saving immunotherapy for later treatment lines.7,8 Finally, he emphasized that the 1.3-month survival benefit seen with durvalumab plus GemCis in TOPAZ-13 may not be enough to be practice changing, especially after selecting out groups with high tumor mutational burdens and inflamed tumor microenvironments. Although TOPAZ-1 offered support for immunotherapy in CCA, there may be other appropriate first-line options, and results of ongoing trials will be important in understanding future standard-of-care treatments.

Pictured left to right: Flavio Rocha, MD, FACS, FSSP; Pashtoon Kasi, MD, MS; Ryan Fields, MD, FACS

Debate on Surgical Therapy

Pashtoon Kasi, MD, MS, from Weill Cornell Medicine, and Ryan Fields, MD, FACS from the Washington University School of Medicine, debated whether circulating tumor DNA (ctDNA) should be used to guide perioperative therapy for CCA. Dr. Kasi defended the use of ctDNA in the perioperative setting and emphasized the potential role in CCA to assess minimal residual disease (MRD) and treatment response and as a predictive biomarker for molecular determination.9 He acknowledged that, although data are lacking in CCA, the most important considerations for ctDNA utilization are the type of assay used, how it is used, and the clinical question at hand, regardless of tumor type. He emphasized the importance of tumor biology, noting that liver/bile duct cancers are “high shedders,” meaning they are among cancers with the highest ctDNA levels detected in blood,10 which typically benefit most from ctDNA technology. A study aimed at validating a cell-free DNA screening tool found that the sensitivity for cancer signal detection was 93.5% in liver/bile duct cancers, which was among the highest across all cancer types studied.11 ctDNA can be used as a promising prognostic biomarker, which was demonstrated in a study that aimed to quantify ctDNA in 276 patients with BTCs (62 CCAs).12 The study demonstrated that declining ctDNA positivity readings from baseline to during and after treatment correlated with lower MRD rates, which can allow for determination of response to therapy and identification of patients who are at increased risk for recurrence. Overall, Dr. Kasi argued that ctDNA in the perioperative setting in CCA can be used to stratify treatment decisions, assess therapeutic response and recurrence, and aid in molecular profiling.

Dr. Fields began his argument by acknowledging the potential for future success using ctDNA to guide treatment decisions and overcome resistance and recurrence with current therapies, but he emphasized the lack of data in BTC to support its routine use, describing the current progress as “putting the cart before the horse.” He went on to note that “a chance to cut is still the only chance to cure,” and resectable patients should not be spared of that opportunity because of ctDNA. Currently, ctDNA has poor sensitivity as a diagnostic test and does not offer an advantage over imaging when assessing tumor burden. In terms of treatment selection, Dr. Fields argued that there is currently no benefit beyond biopsy and standard genomic profiling with ctDNA. Promising areas for ctDNA may lie in prognosis post resection and monitoring for relapse or treatment efficacy, although there is currently no advantage over imaging and routine blood work. In addition, negative consequences may result from ctDNA use, including patient anxiety and lack of treatment consensus in patients with positive ctDNA levels who are healthy or have negative imaging. Cost is an additional negative factor, especially with widespread adoption based on limited data and industry marketing, which can have negative consequences in a test that does not have utility or efficacy. Overall, ctDNA is a promising development with potential for a variety of uses in clinical practice but should not be rushed to widespread use. He concluded that ctDNA should be further studied in clinical trials.

Pictured left to right: Shamar Young, MD; Riad Salem, MD, MBA; Milind Javle, MD

Debate on Locoregional Therapy

Riad Salem, MD, of Northwestern Medicine, and Milind Javle, MD, of MD Anderson Cancer Center, debated the role for upfront liver-directed therapy (LDT) in CCA. Dr. Salem argued in favor of the use of first-line local regional therapy (LRT) in inoperable CCA. A major advantage to LRTs compared with other treatments is that they are single, outpatient treatments usually performed once in a patient’s lifetime, typically using radioembolization or chemoembolization. He noted most people prefer radiotherapy with Yttrium-90 (Y90) because it is arguably the most efficient method of delivering radiotherapy if there is arterial blood supply to the tumor. Advantages to Y90 include no limitation by location or respiratory motion, confirmation of precise dose deposition with post-treatment imaging, and the ability to deposit much higher doses that allow for complete pathological necrosis using a threshold dose.13 Additionally, Y90 can be performed safely in patients with Child-Pugh class A score and does not cause hepatic decompensation, allowing for the use of subsequent systemic therapy.14 An important goal for upfront LDT is to be able to downstage patients to resection. A phase 2 study of patients who were chemotherapy-naïve with unresectable intrahepatic CCA (iCCA) demonstrated that selective internal radiotherapy in combination with chemotherapy resulted in a response rate of 41%, disease control rate of 98%, and 22% of patients were able to be downstaged to surgical intervention, with 8 of 9 patients achieving R0 resection.15 In addition, radiation lobectomy with Y90 is a unique concept that is able to induce hypertrophy in the future liver remnant while limiting tumor progression in the untreated lobe.16 Overall, Dr. Salem argued that there is nothing to lose by allowing interventional radiologists to try an effective local therapy that offers the opportunity for downstaging and a potential for cure.

Dr. Javle countered by arguing that despite technical abilities and feats, the biology of the disease is the most important factor when considering upfront LDT in CCA because it may not be appropriate for all patients. He argued that very few patients with unresectable CCA become resectable, and the majority of patients with iCCA will develop systemic disease after surgery and die of metastatic spread.17 Ultimately, very few patients have liver-limited disease, as seen in a post hoc analysis of the ABC clinical trials; of 534 patients with advanced BTC, approximately 10% of patients had liver-limited iCCA, with the remainder having metastatic disease.18 The OS in patients with liver-only, unresectable iCCA from this analysis was 16.7 months but increased to 18.9 months in patients who received 6 months of chemotherapy,18 suggesting that applying local therapy after chemotherapy in patients who still have stable disease may allow for an incremental effect rather than treating all patients with LDT up front. Dr. Javle argued a similar concept could be applied to transarterial Y90 radioembolization (TARE). A meta-analysis of 921 patients with unresectable iCCA treated with TARE had a disease control rate of 82%, PFS of 7.8 months from time of TARE, and OS of 12.7 months19; he suggested that this type of therapy may be better reserved for after 6 months of disease control with systemic chemotherapy. Another important consideration is the long-term toxicity of LDT, particularly portal hypertension, splenomegaly, and ascites, which can lead to death from liver failure. Finally, consensus from recently published guidelines using data from 93 studies and 3990 patients indicated that low-level evidence exists for LRT that does not support its use in patients with iCCA.20 Overall, Dr. Javle concluded that systemic therapy remains the mainstay for unresectable CCA and only a minority of patients may qualify for LDT. Additional clinical trials will be important in determining the role of consolidation radiation therapy after chemotherapy.


  1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281.
  2. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003-1010.
  3. Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evidence. 2022;1(8).
  4. Oh D, He AR, Qin S, et al. Updated overall survival (OS) from the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in patients (pts) with advanced biliary tract cancer (BTC). Ann Oncol. 2022;33(suppl 7):S19-S26.
  5. US National Library of Medicine. Pembrolizumab (MK-3475) Plus Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable Biliary Tract Carcinoma (BTC) (MK-3475-966/KEYNOTE-966) (KEYNOTE-966). NCT04003636. Accessed November 20, 2022.
  6. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5(6):824-830.
  7. US National Library of Medicine. A Phase I, Open-Label, Multicentre Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MEDI4736 in Patients with Advanced Solid Tumours. NCT01938612. Accessed November 20, 2022.
  8. Ueno M, Ikeda M, Morizane C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(8):611-621.
  9. Kasi PM. ctDNA Assays: Exploring Their Clinical Use in Oncology Care. ASCO Daily News. Accessed November 20, 2022.
  10. Zill OA, Banks KC, Fairclough SR, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin Cancer Res. 2018;24(15):3528-3538.
  11. Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. 2021;32(9):1167-1177.
  12. Kasi PM, Budde G, Dayyani F, et al. Tumor-informed assessment of circulating tumor DNA and its incorporation into practice for patients with hepatobiliary cancers. J Clin Oncol. 2021;39(suppl 15):4103-4103.
  13. Singh P, Anil G. Yttrium-90 radioembolization of liver tumors: what do the images tell us? Cancer Imaging. 2014;13(4):645-657.
  14. Memon K, Lewandowski RJ, Kulik L, et al. Radioembolization for primary and metastatic liver cancer. Semin Radiat Oncol. 2011;21(4):294-302.
  15. Edeline J, Touchefeu Y, Guiu B, et al. Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2020;6(1):51-59.
  16. Vouche M, Lewandowski RJ, Atassi R, et al. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol. 2013;59(5):1029-1036.
  17. Doussot A, Gonen M, Wiggers JK, et al. Recurrence patterns and disease-free survival after resection of intrahepatic cholangiocarcinoma: preoperative and postoperative prognostic models. J Am Coll Surg. 2016;223(3):493-505.e2.
  18. Lamarca A, Ross P, Wassan HS, et al. Advanced intrahepatic cholangiocarcinoma: post hoc analysis of the ABC-01, -02, and -03 clinical trials. J Natl Cancer Inst. 2020;112(2):200-210.
  19. Schartz DA, Porter M, SchartzE, et al. Transarterial Yttrium-90 radioembolization for unresectable intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Vasc Interv Radiol. 2022;33(6):679-686.
  20. Edeline J, Lamarca A, McNamara MG, et al. Locoregional therapies in patients with intrahepatic cholangiocarcinoma: a systematic review and pooled analysis. Cancer Treat Rev. 2021;99:102258.

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Milind Javle, MD, of the MD Anderson Cancer Center, led off the roundtable dialogue on emerging therapies in biliary tract cancers (BTCs) with a discussion around methylthioadenosine phosphorylase (MTAP) loss in cholangiocarcinoma (CCA). MTAP is located on the 9p21 chromosome, where CDKN2A/B is also located.
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