Evolving role of radiation therapy in advanced/metastatic intrahepatic cholangiocarcinoma

Abstract

This review evaluates the role of stereotactic body radiation therapy (SBRT) in advanced/metastatic intrahepatic cholangiocarcinoma (iCCA), highlighting its efficacy, integration with systemic therapy, and potential for resection or transplantation. SBRT is emerging as a transformative, non-invasive treatment for iCCA, extending beyond palliation. SBRT with a biologically effective dose > 75 Gy improves survival in unresectable iCCA, with median overall survival (mOS) of 15-24 months, significantly surpassing lower-dose regimens. Advanced motion management techniques like fiducial tracking and gating achieve > 70% local control at 1 year. In metastatic iCCA, hypo-fractionated SBRT provides symptom relief with mOS of 6-9 months and reduced toxicity. Neoadjuvant SBRT increases R0 resection rates to 60%-75% in borderline resectable cases, compared to 30%-40% with chemotherapy alone. SBRT combined with systemic therapy expands eligibility for liver transplantation, achieving 3-year post-transplant survival > 65%. SBRT is a transformative therapy for iCCA, improving control, survival, and eligibility for curative treatments. Further research is needed to optimize protocols and patient selection.

Key Words: Intrahepatic cholangiocarcinoma; Stereotactic body radiation therapy; Radiation therapy; Advanced; Metastatic

Core Tip: This review explores the transformative role of radiation therapy, including stereotactic body radiation therapy (SBRT), in managing intrahepatic cholangiocarcinoma, an aggressive malignancy with limited treatment options. With advances in radiation delivery, motion management, and systemic therapy integration, SBRT is evolving beyond palliation to improve local control, survival outcomes, and potential synergy with transplantation strategies.

INTRODUCTION

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy, accounting for approximately 3% of all gastrointestinal cancers[1]. Surgery remains the cornerstone of treatment, offering a 5-year survival rate of 25%-40%[2,3].The standard treatment for patients with advanced/metastatic iCCA remains systemic therapy/targeted therapy[4,5]. Gemcitabine/cisplatin-based chemotherapy has shown an approximate median overall survival (mOS) of 11.5 months in patients with advanced CCA[6,7]. Additionally, Durvalumab to gemcitabine/cisplatin (TOPAZ-1 trial) was associated with improved mOS to 12.9 months[8]. However, limited studies have reported improved OS and reduced treatment-related liver failure with the addition of loco-regional liver-directed therapies to systemic therapy[9,10]. For instance, Yamashita et al[11] reported a median disease-specific survival of 17 months with chemotherapy alone vs 23 months with combined chemotherapy and radiation therapy. Moreover, liver failure-related mortality was 72% in the chemotherapy group compared to 41% in the radiation group.

Various locoregional therapies (LRT), including microwave ablation (MWA), radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), radiation therapy, and selective internal radiation therapy, that can be used in addition to systemic therapies, have resulted in improved OS and local control (LC)[12,13]. Furthermore, combining radiation with systemic therapy has led to tumor downstaging, enabling resection or liver transplantation (LT)[14]. This review explores the evolving role of radiation in improving outcomes for patients with advanced or metastatic iCCA.

SEARCH METHODOLOGY

For this literature review, a comprehensive search of PubMed, Web of Science, and EMBASE was conducted to identify peer-reviewed articles focused on the terms SBRT, Stereotactic Body Radiation therapy, intrahepatic cholangiocarcinoma, iCCA, hypofractionated radiation therapy, advanced iCCA, metastatic iCCA, locoregional treatments, liver cancer, chemotherapy, immunotherapy, etc. The findings were meticulously summarized from these sources to provide a thorough overview of the current research in this field.

Inclusion criteria

Peer-reviewed English-language articles discussing SBRT for advanced and metastatic iCCA, covering indications, contraindications, treatment outcomes, response assessment, and toxicity, were included. Comparative studies evaluating SBRT against other locoregional treatments (TACE, RFA, conventional radiotherapy, and Y-90 radioembolization) were also included. Clinical trials, meta-analyses, retrospective and prospective studies, and case reports were considered.

Exclusion criteria

Non-English articles, studies focusing solely on non-liver cancers, articles lacking specific SBRT-related data or outcomes, and review articles without original data or novel insights were excluded.

ROLE OF RADIATION IN ICCA

The selection of the LRT was dependent on various factors like size, number of lesions, location of tumor in relation to critical structures like bile duct, vessels, vascularity of tumor, and underlying liver functions[15,16]. LRT can be used as a curative modality, including a downstaging procedure, or as consolidative therapy post-systemic therapy, or with a palliative intent. SBRT is continuing to evolve and has been used as an LRT modality in managing advanced/metastatic iCCA.

DIFFERENT MODALITIES /FRACTIONATION IN ICCA

The two most common types of radiation beams in cancer treatment are photon therapy and charged particle therapy (proton therapy)[17]. Charged particle therapies, including proton-beam therapy (PBT) and carbon-ion RT, have distinct dosimetric characteristics compared with photon therapy due to the Bragg peak[18]. As charged particles traverse tissue, their rate of energy loss increases, resulting in maximum energy deposition at the end of their range, followed by a sharp fall-off; this is defined as the Bragg peak. Consequently, particle therapy delivers minimal or no exit dose, unlike photon therapy[19]. The reduced radiation spill allows for greater liver sparing and lower doses to surrounding organs at risk, such as the bowel, enabling dose escalation to primary tumors while decreasing the incidence of radiation-induced liver disease (RILD). Another approach for tumor dose escalation is the simultaneous integrated boost with simultaneous integrated protection (SIB-SIP) technique. In this method, a higher radiation dose is targeted to the hypoxic regions of the tumor, while adjacent areas near sensitive luminal structures, such as the bowel, receive a slightly reduced dose to minimize gastrointestinal toxicity[20].

External beam radiation therapy (EBRT) can be classified as conventional, hypo-fractionated, or SBRT based on dose per fraction and the total number of fractions. In conventional fractionated radiation therapy, treatment is delivered over several weeks at 1.8-2 Gy per fraction, whereas in hypo-fractionated radiation therapy, the dose rate is 2-5 Gy per fraction over 6-15 fractions. SBRT delivers a highly conformal ablative dose > 5 Gy per fraction to the tumor in 1-5 fractions over 1-2 weeks[21].

There is no consensus on radiation dose or fractionation, as it varies from 25 Gy to 50 Gy in 3-15 fractions depending on tumor size, number of lesions, location, size, remaining liver volume, and underlying liver function status. In patients with underlying cirrhosis and baseline Child-Pugh B status or those with a tumor in close proximity to the organ at risk, hypofractionated radiation therapy (30-50 Gy in 7-15 fractions) can be delivered to reduce toxicity[20,22].

Various studies have demonstrated better LC and OS with a biologically effective dose (BED) > 75 Gy. In a study by Tao et al[20], a median BED of 80.5 Gy (range 43.75-180 Gy) was associated with improved LC and OS. Three-year OS and LC rates were 73% and 78%, respectively, for patients receiving a high BED (> 80.5 Gy), compared with 38% and 45%, respectively for those receiving a BED ≤ 80.5 Gy[20]. Similarly, Zhang et al[23] demonstrated a better response rate (relative risk: 94.4% vs 44%, P = 0.001) and disease control rate (disease control rate: 100% vs 74%, P = 0.001) with BED > 70 Gy compared with those treated with BED ≤ 70 Gy. In contrast, studies by Jung et al[24] and Gkika et al[25] did not observe any significant improvement in LC with increased radiation dose.

TREATMENT OF ADVANCED/ INOPERABLE ICCA

For patients with unresectable or locally advanced cholangiocarcinoma who are not candidates for surgery, definitive radiation therapy, sometimes combined with chemotherapy, offers a vital lifeline and a renewed sense of hope. Multiple retrospective and prospective studies have shown that even in the face of a challenging diagnosis, definitive chemoradiation can significantly improve cancer-specific survival and LC[26,27]. Notably, SEER database analyses and institutional series have reported mOS of 9.6-30 months, with higher radiation doses (BED > 80.5 Gy) associated with better outcomes[26]. Advances such as SBRT and dose-escalated external beam techniques have further improved patients' prospects, achieving 1-year LC rates as high as 94% and mOS of 11-35.5 months in selected cases[27,28]. Adding brachytherapy boosts may offer further LC, albeit with a careful balance to avoid increased toxicity[29]. Beyond survival statistics, definitive radiation therapy can provide meaningful symptom relief, improve biliary decompression, and, in rare but encouraging cases, enable long-term survival. These advances underscore the evolving and essential role of definitive radiation as a standard, non-surgical option that can restore hope and dignity to patients facing inoperable biliary tract cancers (BTC)[26].

Neoadjuvant radiation therapy

Surgical resection remains the only curative treatment for intrahepatic CCA. Limited studies, often with heterogeneous data, have explored neoadjuvant approaches including chemotherapy, radiation therapy, and chemoembolization, reporting R0 resection rates of 30%-80%[26-28]. The rationale for neoadjuvant therapy includes downstaging borderline or locally advanced disease, achieving tumor-free (R0) resection margins, initiating systemic treatment early to target micrometastases, assessing disease biology, facilitating proper patient selection, and evaluating the tumor’s response to chemotherapy[29-33].

Most studies have demonstrated the role of chemotherapy in the neoadjuvant setting, resulting in better LC and improved OS. With gemcitabine/cisplatin-based chemotherapy, the tumor was downstaged to resection in approximately 20%-35% of patients[34-36]. In another study, OS improved in patients who received neoadjuvant chemotherapy (29 months vs 12 months, P < 0.001)[14]. Neoadjuvant treatment with combined chemotherapy and chemoradiotherapy can also improve LC and OS. In a case report by Kato et al[34], neoadjuvant treatment with gemcitabine-based chemotherapy followed by radiation therapy was reported to have good downstaging and pathological response with disappearance of > 90% tumor cells. In a study by Sumiyoshi et al[37], neoadjuvant chemo-radiotherapy (NCRT) was given in 15 intrahepatic cholangiocarcinoma patients. Post NCRT, 11 (73.3%) were judged to have resectable cholangiocarcinoma after chemoradiotherapy, and received radical hepatectomy (R0 resection in 9 patients). The mOS in patients who underwent resection was 37 months, with 1-, 2-, and 5-year survival rates of 80.8%, 70.7% and 23.6%, respectively. Except for one patient who received segmentectomy, the surgical procedures were mainly lobectomy or trisegmentectomy.

Liver transplantation is generally not considered for patients with intrahepatic CCA, primarily due to the tumor’s aggressive behavior and poor biological characteristics. However, recent studies have demonstrated improved outcomes after LT, if such patients are considered for neoadjuvant chemotherapy, chemoradiotherapy, or SBRT[38]. Hong et al demonstrated an OS of 100% [95% confidence interval (CI): 100-100] at 1 year, 83.3% (27.3-97.5) at 3 years, and 83.3% (27.3-97.5) at 5 years. Three patients developed recurrent disease at a median of 7.6 months (interquartile range: 5.8-8.6) after transplantation, with 50% (95%CI: 11.1-80.4) recurrence-free survival at 1, 3, and 5 years[39]. Lunsford et al[40] showed that 50% patients underwent LT post-chemotherapy in patients with advanced iCCA. The authors also showed an OS of 100% (95%CI: 100-100) at 1 year and 83.3% (27.3-97.5) at 5 years with a recurrence-free survival of 50% (95%CI: 11.1-80.4) at 5 years post-transplantation[40]. Rayar et al[41] also demonstrated the combined use of chemotherapy with trans-arterial radio embolization (TARE) and EBRT for downstaging the tumor prior to LT. In a retrospective study of 30 patients with iCCA treated with neoadjuvant chemotherapy and SBRT followed by liver transplantation, the 5-year OS was reported as 100%[42] (Table 1).

Table 1 Summary of key studies on radiation as a neoadjuvant and adjuvant treatment modality in intrahepatic cholangiocarcinoma.

Therapy type	Study/protocol	Regimen (RT + chemo)	Patient population	Key outcomes
Neoadjuvant	NACRAC[48]	45 Gy EBRT + Gemcitabine	Borderline/Locally advanced hilar CCA	R0 resection 89.6%
	SBRT + LT[49]	30-45 Gy SBRT + Capecitabine	Unresectable iCCA, transplant cohort	Pathologic CR in 3/6, 83% 1-year survival
Adjuvant	NCDB analysis[47]	RT (dose varies)	GBC, extrahepatic CCA, N+/R1	OS improvement in high-risk groups
	RT for iCCA[43]	NA	Resected iCCA, high-risk	Median OS 11 months

SBRT: Stereotactic body radiation therapy; EBRT: External beam radiation therapy; GBC: Gall bladder cancer; iCCA: Intrahepatic cholangiocarcinoma; CR: Complete response; OS: Overall survival; LT: Liver transplantation; RT: Radiation therapy; NCDB: National Cancer Database; NACRAC: Neoadjuvant chemoradiation therapy.

Adjuvant radiation therapy

Adjuvant radiation therapy is generally indicated in patients with high-risk factors like margin-positive and node-positive disease. Shinohara et al[43] concluded that there was a significant advantage of using adjuvant radiation therapy compared with single modality alone. The mOS was 11 months in the combination arm compared with 7 months in the radiation arm and 6 months in the surgery alone arm. Jiang et al[44] reported an improved OS using adjuvant radiation therapy with lymph node metastasis. Similarly, Zheng et al[45] found improved outcomes in patients with adjuvant radiation in patients with narrow margins along major vessels. In another case series of 18 patients, seven received adjuvant radiation due to positive margins. The authors reported significant improvement in LC (LC: Not reached vs 5.6 months, P < 0.001) and progression-free survival (PFS: 8.3 months vs 5.6 months, P = 0.047) in the adjuvant chemo-radiation arm compared with the surgery only group[46]. In contrast, in another analysis from the NCDB database, the authors concluded that there was no survival benefit in patients with high-risk disease, such as margin or node-positive disease[47]. Therefore, more prospective phase III RCTs are required, especially in patients with high-risk disease.

Definitive radiation therapy

In patients with advanced, unresectable iCCA, systemic therapy is the preferred treatment modality. As per the results of the ABC-02 study, the mOS was 11.7 months in patients who received doublet chemotherapy with gemcitabine and cisplatin[6]. However, the median PFS was 8 months, and approximately 88% of the patients failed at the local site. Therefore, the concept of LRT emerged, including TACE, MWA, SBRT, etc.[48,49].

In a phase 1 study by Tse et al[50], ten patients with iCCA were treated to a dose of 36 Gy in six fractions. The treatment was well tolerated with a mOS of 15 months. Later, various studies demonstrated a mOS of 12 to 30 months and PFS of 6 to 30 months[50-55]. In another study, Chen et al[51] evaluated the effectiveness of radiation therapy in patients with advanced iCCA and reported a complete response and partial response in 8.6% and 28.5%, respectively. The mOS was 9.5 months vs 5.1 months in the radiation arm vs non-radiation arm (P = 0.003). In another multicenter study with 41 iCCA patients, the LC and OS were 89% and 63% at 1 year, respectively. The authors also concluded that a higher radiation dose was associated with improved OS and LC[52]. Similarly, a propensity-matched study concluded that with the addition of radiation, there was a significant reduction in death hazards [hazard ratio (HR) = 0.83, 95%CI: 0.71-0.97, P = 0.018][53] compared with the standard chemotherapy arm. Sebastian et al[53] compared SBRT to TARE and conventional chemoradiotherapy and showed statistically significant improved OS compared to CRT (HR = 0.22; 95%CI: 0.11-0.44; P < 0.0001) and TARE (HR = 0.58; 95%CI: 0.37-0.91; P = 0.019). Barney et al[54] also showed the role of SBRT in primary or recurrent iCCA. In this study, at the median follow-up of 14 months (range 2-26 months), the 1-year OS was 73%[54]. In a systematic review (6 studies) by Bisello et al[55], the authors demonstrated a mOS of 14 months (range 10-48 months) in patients with advanced CCA. A summary of key studies is summarized in Table 2. Figure 1 shows an example of treatment response after SBRT.

Figure 1 Post stereotactic body radiation therapy response in a case of intrahepatic cholangiocarcinoma. A: Pre-stereotactic body radiation therapy (SBRT) positron emission tomography/computed tomography: Metabolically active ill-defined hypodense lesions with heterogeneous peripheral arterial enhancement and central necrotic changes involving segments VIII and V suggestive of intrahepatic cholangiocarcinoma; B: Stereotactic body radiation therapy colorwash; C: Positron emission tomography/computed tomography (post SBRT and three cycles of Gemcitabine /cisplatin base chemotherapy): There is significant interval reduction in metabolic activity of the primary lesion along with mild interval reduction in size of the lesion with appearance of central necrotic changes. SBRT: Stereotactic body radiation therapy.

Table 2 Summary of key studies on stereotactic body radiation therapy in intrahepatic cholangiocarcinoma.

Ref.	Unresectable/metastatic	No.	Follow up (months)	mOS (months)	mPFS (months)	Adverse effects
Tse et al[50], 2008	Unresectable	10	NA	15	NA	RILD: 0%
Tao et al[20], 2016	Unresectable	79	33	30	30	Biliary complication: 33%
Liu et al[56], 2017	Unresectable	12	29	12.6	NA	RILD: 0%
Chen et al[51], 2010	Unresectable	35	7	9.5	NA	Grade II transaminitis
Weiner et al[57], 2016	Unresectable	12	8.8	13.2	24.7	Grade 3/4 reaction: 16%
Zhang et al[23], 2023	Unresectable	43	15	12	6	RILD: 0%
Shen et al[58], 2017	Unresectable	28	16	15	11	RILD: 7.1%
Kozak et al[59], 2020	Unresectable	25	18	23	NA	NA
Sharma et al[60], 2025	Unresectable/metastatic	17	14	21	10	RILD: 0%

RILD: Radiation-induced liver disease; M1: Metastatic; mOS: Median overall survival; mPFS: Median progression-free survival; NA: Not available.

TREATMENT OF METASTATIC ICCA

There is limited evidence for loco-regional therapies in metastatic iCCA. De et al[9] reported a mOS of 21 months and a 1-year OS of 85%. In another retrospective study, Sharma et al[60] demonstrated a mOS of 21 months (95%CI: 14.5-27.4) from diagnosis, with 1-year OS of 90%. The 1-year PFS and LC was 35% and 92%, respectively. Similarly, Sebastian et al[61] observed an mOS of 16.7 months in metastatic iCCA patients treated with chemotherapy and loco-regional therapy. A population-based propensity score-matched study further demonstrated improved OS (adjusted HR = 0.8544, 95%CI: 0.7722-0.9453, P = 0.00228) and cancer-specific survival (adjusted HR = 0.8563, 95%CI: 0.7711-0.9509, P = 0.0037) in patients receiving palliative radiation therapy compared with those who did not.

The management of metastatic iCCA has significantly evolved in recent years, with systemic therapy remaining the cornerstone of treatment[62]. The current standard first-line regimen combines gemcitabine, cisplatin, and the PD-L1 inhibitor durvalumab, as established by the TOPAZ-1 trial, which demonstrated a significant improvement in OS compared with chemotherapy alone[63]. Gemcitabine plus cisplatin remains a practical option for patients not fit for immunotherapy, as supported by the ABC-02 trial. Upon progression, second-line therapies such as FOLFOX (fluoropyrimidine and oxaliplatin), validated by the ABC-06 trial, or fluoropyrimidine combined with Nano liposomal irinotecan (NIFTY trial), may be considered[64,65]. Molecular profiling is now essential for all patients with metastatic iCCA, as approximately 40% harbor actionable mutations. Targeted therapies have transformed outcomes for selected patients, with FGFR2 fusion-positive tumors responding to agents like pemigatinib and futibatinib, and IDH1-mutated cases benefiting from ivosidenib. Other actionable alterations, such as HER2 amplification, BRAF V600E, and NTRK fusions, can be addressed with appropriate targeted agents, often in the context of clinical trials[66]. Immunotherapy with checkpoint inhibitors such as pembrolizumab may also be considered for tumors with high microsatellite instability or mismatch repair deficiency, although these are rare in iCCA. LRT, including SBRT and transarterial chemoembolization or radioembolization, may provide LC or symptom relief in select patients with liver-dominant oligometastatic disease. Palliative care, focusing on biliary decompression, pain management, and nutritional support, remains vital for maintaining quality of life. Participation in clinical trials is strongly encouraged, as ongoing research expands therapeutic options and improves outcomes for patients with metastatic iCCA.

RECENT ADVANCES IN RADIATION THERAPY

Proton radiotherapy

Proton-based or particle-based radiation therapy produces more conformal radiation with minimum spillage to normal tissue. It works on the principle of Bragg's peak. Various retrospective/prospective studies have demonstrated improved OS and LC after proton therapy[18,19,67]. In a multicentric prospective study[59], patients with a median tumor diameter of 5.0 cm (range 2.0-15.2 cm) received PBT. Patients received a 60-76 Gy relative biological effectiveness (RBE) in 20-38 fractions. The entire cohort's mOS and progression-free survival was 21.7 months (95%CI: 14.8-34.4 months) and 7.5 months (95%CI: 6.1-11.3 months), respectively. On multivariable analyses, Child-Pugh class was significantly associated with OS and PFS. Four patients (6.8%) developed ≥ grade 3 late adverse events[68]. Okubo et al[69] evaluated the efficacy of respiratory-gated proton beam therapy in 24 patients with iCCA. All patients were treated to a dose of 48-83.6 (RBE) in 20-38 fractions and were treated with respiratory-gating. At a median follow-up of 18.5 (range, 2.0-74.0) months, the 2-year OS, PFS, and local tumor control rates were 51%, 26%, and 73% respectively[69].

Recent advances in radiotherapy for iCCA include proton therapy and SBRT combined with immunotherapy. By leveraging its precise dose distribution, proton therapy has yielded impressive results. For example, a phase II study reported a two-year LC rate of 94.1% and mOS of 21.9 months with minimal high-grade toxicity[26]. SBRT combined with immune checkpoint inhibitors is also emerging as a promising strategy. In the NCT04648319 trial, SBRT plus nivolumab and ipilimumab achieved a clinical benefit rate of 31% in advanced BTC, with some patients experiencing durable responses[70]. Additionally, novel targeted therapies such as FGFR2 and IDH1 inhibitors, alone or in combination with immunotherapy and radiotherapy, are showing encouraging activity in molecularly selected patients and may further improve outcomes[71]. Collectively, these approaches highlight the evolving role of multimodal therapy to enhance disease control and quality of life in advanced iCCA.

Photodynamic therapy

Emerging therapies are broadening the treatment landscape for BTC. Photo-dynamic therapy combined with biliary stenting, has been shown in randomized trials to significantly prolong survival and improve symptom control in unresectable cases[72,73].

Targeted therapy

Antibody-drug conjugates (ADCs), such as IBI343 targeting CLDN18.2 and HER2-directed agents, demonstrate promising efficacy and safety in early-phase studies[74,75]. Additionally, molecularly targeted therapies, including FGFR2, IDH1, and HER2 inhibitors, are now standard for patients with actionable mutations, offering improved outcomes and new hope for those with advanced disease[26]. These novel approaches collectively enhance both survival and quality of life in BTC.

SBRT with immunotherapy

The concurrent use of radiation therapy with immune checkpoint inhibitors has resulted in a synergistic effect. This effect is attributed to the release of tumor-associated antigen after SBRT, which, in the presence of cytokines and chemokines, results in dendritic cell activation and further priming of CD8⁺ T cells, and their recruitment to the tumor microenvironment (TME)[76]. In this way, SBRT can convert a “cold” TME into a “hot” tumor. In addition, radiation results in increased PD-1 and CTLA-4 expression on immune cells and PDL-1 expression on tumor cells[77] (Figure 2). Liu et al[56] reported combining immunotherapy (anti-PD-1) with SBRT in metastatic iCCA. The combination of ICI with radiation therapy (liver and lung) resulted in a complete response to the primary liver tumor along with the lymph nodes and other metastatic sites, with an OS of 26 months[78]. In another study by Zhao et al[79], SBRT was used along with a PD-1 inhibitor (Nivolumab), and one lesion became resectable, resulting in reasonable disease control in all patients.

Figure 2 Immunomodulatory effects of stereotactic body radiation therapy. TNF: Tumor necrosis factor; DC: Dendritic cells; TAA: Tumor-associated antigen; PD-1: Programmed cell death-1 receptor; CTLs: Cytotoxic T lymphocytes.

INTEGRATION OF BIOMARKER-GUIDED STRATEGIES

Recent advances in circulating tumor DNA (ctDNA) profiling have significantly enhanced the precision of molecular characterization and disease monitoring in BTC. ctDNA analysis demonstrates high concordance with tissue-based next-generation sequencing, with sensitivity and positive predictive value exceeding 80% for detecting actionable alterations such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplifications. Importantly, ctDNA can identify novel or emerging mutations not captured in archival tissue, thereby expanding opportunities for targeted therapy, especially in advanced BTC, where tissue samples may be limited[80,81]. Beyond baseline profiling, longitudinal ctDNA monitoring offers powerful prognostic and predictive value. In patients with resected extrahepatic cholangiocarcinoma, persistent ctDNA positivity before or during adjuvant therapy is strongly associated with increased risk of recurrence and inferior recurrence-free survival, often identifying molecular relapse several months before radiologic evidence of disease[82]. Conversely, clearance of ctDNA following treatment correlates with improved outcomes. These findings support the integration of ctDNA profiling and serial monitoring into multidisciplinary management pathways, enabling more refined patient selection, early detection of minimal residual disease, and timely adaptation of adjuvant or salvage therapies in BTC.

HOST/TUMOR BIOLOGY AND EMERGING BIOMARKERS IN BTC

Growing evidence highlights the interplay between host immune-microbiome axis dysregulation and BTC outcomes, with important implications for radiosensitivity and the design of combination therapies. Recent Mendelian randomization studies provide causal insights into these relationships. For example, a comprehensive bidirectional Mendelian randomization analysis identified specific gut microbiota, such as Ruminococcaceae UCG-002 [odds ratio (OR) = 0.70, P = 0.026] and Bacteroides (OR = 1.28, P = 0.046), as being causally linked to BTC risk, suggesting that alterations in gut microbial composition may modulate carcinogenesis through bile acid metabolism and chronic inflammation pathways[83]. Concurrently, another Mendelian randomization analysis of 731 immune cell phenotypes revealed that regulatory T cells (Tregs; CD25+CD127-, OR = 1.21, P = 0.003) and myeloid dendritic cells (HLA DR+ %DC, OR = 0.83, P = 0.012) are key mediators of BTC susceptibility, further supporting the role of the immune landscape in disease progression[84]. These findings align with preclinical data showing that Treg infiltration can promote radiotherapy resistance via TGF-β signaling, while activated dendritic cells may enhance antigen presentation following SBRT. The convergence of microbiota-derived metabolites and immune checkpoint expression (e.g., PD-L1/CTLA-4) may further influence the efficacy of SBRT-immunotherapy combinations. These studies highlight microbiota modulation (such as probiotics targeting Ruminococcaceae) and Treg/dendritic cell-focused strategies as promising avenues to optimize radiation-immune synergy in BTC[83,84].

CHALLENGES AND LIMITATIONS OF SBRT IN ICCA

While SBRT is an effective LRT for iCCA, several challenges limit its widespread application.

a. Tumor motion and targeting: Liver tumors move with respiration, increasing the risk of geographical miss. Techniques like respiratory gating, fiducial markers, and motion tracking improve accuracy but add complexity.

b. Tumor size and proximity to critical structures: SBRT is most effective for small, well-defined tumors, but large or multifocal iCCA may require dose modifications. Tumors near the bile ducts, bowel, or major vessels pose a risk of strictures, ulceration, or vascular injury, necessitating careful dose planning.

c. Radiation-induced toxicity: Patients with underlying liver dysfunction (Child-Pugh B/C) face a higher risk of RILD. Biliary toxicity is another concern, especially in perihilar tumors, as bile ducts have limited regenerative capacity.

d. Dose standardization and patient selection: Unlike HCC, SBRT dose-fractionation for iCCA lacks standardization. Patient selection remains critical, as those with poor liver function or extensive disease may benefit more from alternative treatments like TARE or proton therapy.

FUTURE DIRECTIONS AND ONGOING CLINICAL TRIALS

SBRT's role in iCCA is expanding, with trials evaluating its synergy with ICIs and targeted therapies. SBRT-induced tumor cell death may enhance antigen presentation, modulating the TME to overcome immunotherapy resistance. PBT offers superior dose conformality and reduced toxicity, particularly in patients with limited hepatic reserve. AI-driven adaptive radiotherapy and radiomics may enable real-time dose adjustments based on tumor response. Future research should refine dose-fractionation schedules, identify predictive biomarkers, and optimize radiosensitizer integration to enhance efficacy while minimizing toxicity.

PATIENT SELECTION AND MULTIDISCIPLINARY APPROACH

Optimal SBRT selection requires a multidisciplinary approach involving radiation oncologists, medical oncologists, interventional radiologists, and hepatobiliary surgeons. Key factors include tumor burden, vascular invasion, hepatic function (Child-Pugh score, ALBI grade), and prior treatments. SBRT may serve as a definitive, consolidative, or neoadjuvant therapy to enable resection or LT. Tumor board discussions ensure integration with locoregional modalities like TARE, optimizing treatment sequencing and outcomes. Standardized patient selection and response assessment criteria will be essential to defining SBRT’s role in iCCA management.

CONCLUSION

Radiation therapy, especially SBRT, is reshaping the advanced and metastatic iCCA treatment landscape. High-dose regimens have improved LC and survival, while integration with systemic and neoadjuvant therapies can enable resection or LT. Emerging technologies like proton therapy and MRI-guided radiation are enhancing precision and reducing toxicity. As evidence grows, SBRT is poised to become a key component of personalized iCCA management, though further research is needed to refine patient selection and optimize treatment protocols.

Radiation therapy in particular is reshaping the treatment landscape for advanced and metastatic iCCA. High-dose regimens have demonstrated improved LC and survival, while integration with systemic therapies (e.g., gemcitabine/cisplatin + durvalumab) and neoadjuvant strategies enables curative resection or LT in select cases. Emerging technologies such as proton therapy and MRI-guided radiation enhance precision, reduce toxicity, and expand therapeutic possibilities. Biomarker-driven approaches, including ctDNA monitoring and molecular profiling, refine patient selection and personalize therapy. Despite these advances, further research is needed to optimize treatment protocols, validate combination strategies (e.g., SBRT + immunotherapy), and define biomarkers for radiosensitivity. Multidisciplinary collaboration and clinical trial participation remain pivotal to advancing personalized iCCA management. This revised conclusion integrates the transformative role of SBRT with emerging modalities, biomarker integration, and future directions, aligning with the manuscript’s focus on technical and translational advances in BTC care.