The Evolving Role of Radiation Therapy for CCA

The use of radiation therapy (RT) is controversial in cholangiocarcinoma (CCA). This may be partly attributable to poor data quality, which mainly come from single-institution retrospective reviews or large databases, such as Surveillance, Epidemiology, and End Results, with limited single patient details and a heterogenous mix of CCA subtypes (hilar, distal bile duct, and gallbladder cancers). At the 5th annual CCA Summit meeting, Jennifer Wo, MD, discussed the evolving role of RT in CCA.¹

The clinical benefit of adjuvant therapy for biliary tract cancers (BTCs) is presently unclear. A meta-analysis of studies that compared adjuvant therapy including chemotherapy (CT), RT, or chemotherapy plus RT (CRT) versus surgery alone indicated that patients receiving CT or CRT achieved statistically greater benefit compared with RT alone, with the greatest benefit observed in patients with lymph node–positive and resection margin–positive disease.²

In patients with intrahepatic CCA (iCCA), emerging evidence indicates that RT may result in long-term local control (LC), therefore providing a survival benefit.¹ Historically, liver RT was limited by techniques and concern for toxicity; however, these concerns are being mitigated by recent technical advancements, including liver stereotactic body radiation therapy (also known as stereotactic ablative body radiotherapy) and emerging radiation targeting and delivery approaches.¹ In a phase 2 multi-institutional study, high-dose hypofractionated proton beam therapy demonstrated high LC rates (94.1%) in patients with localized unresectable iCCA.³ In another study of stereotactic RT in patients with inoperable iCCA, RT dose was identified as an important prognostic factor, with higher overall survival (OS; 73% vs 38%; P =.017) and LC (78% vs 45%; P =04) benefit in the group that received biologic equivalent dose (BED) >80.5 Gy versus those who received BED <80.5 Gy.⁴

Liver-directed local therapy correlated with improved OS.¹ One study found that patients treated with CT developed liver failure at the time of death significantly more frequently than did patients treated with resection (P <.001) or radiation (P <.001); local therapy (resection or radiation) was a sole predictor of death without liver failure.⁵

Emerging evidence supports a role for radiation in combination with checkpoint inhibition in cancers.¹ Tumor regressions were reported in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation; it was proposed that radiation enhances the diversity of the T-cell receptor repertoire of intratumoral T cells in this setting.⁶ However, resistance was mediated by upregulation of PD-L1 on melanoma cells and was associated with T-cell exhaustion, providing rationale for combination of radiation plus anti-CTLA4 and anti–PD-L1 inhibition.⁶ A phase 2 study (NCT03482102) is evaluating dual checkpoint blockage and radiation in patients with metastatic BTC/hepatocellular carcinoma; among 12 patients who reached radiation, overall response rate was 25%.⁷

Dr Wo concluded that long-term survival benefit with RT in combination with CT and immunotherapy is feasible in some patients with unresected iCCA; high-dose radiation with ablative intent may be warranted to yield benefit.¹

Sources:

1. Wo J. Radiation therapy for cholangiocarcinoma: an evolving role. Presented at: 5th Annual CCA Summit Meeting, October 19-21, 2023; Scottsdale, AZ.
2. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30(16):1934-1940.
3. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016;34:460-468.
4. 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.
5. Yamashita S, Koay EJ, Passsot G, et al. Local therapy reduces the risk of liver failure and improves survival in patients with intrahepatic cholangiocarcinoma: a comprehensive analysis of 362 consecutive patients. Cancer. 2017;123(8):1354-1362.
6. Victor CT-S, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373-377.
7. Hong TS, Goyal L, Parikh AR, et al. A pilot study of durvalumab/tremelimumab (durva/treme) and radiation (XRT) for metastatic biliary tract cancer (mBTC): preliminary safety and efficacy. J Clin Oncol. 2020;38(4):547.