INTRODUCTION

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and aggressive primary liver malignancy, defined by the unequivocal histomorphological presence of both hepatocytic and cholangiocytic differentiation within a single tumor.^1,2 Although its reported incidence ranges from 0.4% to 14.2% of primary hepatic cancers, its clinical prognosis remains dismal. Outcomes for cHCC-CCA are frequently inferior to those of hepatocellular carcinoma (HCC) and often comparable to or even worse than those of intrahepatic cholangiocarcinoma (iCCA), with 5-year survival rates often failing to reach 30%.^1-3

Surgical resection with regional lymphadenectomy currently offers the only potential chance for a cure; however, long-term survival is frequently compromised by high rates of locoregional recurrence and distant metastasis, with more than 60% of patients experiencing disease relapse even after curative-intent hepatectomy. For patients with unresectable disease, the current standard of care, gemcitabine and cisplatin-based systemic chemotherapy, has reached a therapeutic plateau, providing limited survival benefit with median overall survival (OS) typically remaining under 1 year. Consequently, there is an urgent clinical imperative to optimize locoregional control strategies to improve clinical outcomes.

The selection of appropriate adjuvant treatment options for cHCC-CCA is uniquely complicated by its biphenotypic nature, exhibiting features resembling both HCC and cholangiocarcinoma (CCA). As patients with cHCC-CCA experiencing poor survival and a heightened likelihood of distant metastasis may stand to benefit from adjuvant therapies, an essential prerequisite is the accurate evaluation and prediction of survival outcomes specific to this subtype. Although external beam radiotherapy (EBRT) is not yet universally established in cHCC-CCA management guidelines, emerging evidence from iCCA underscores that high-dose ablative radiotherapy (RT) and particle therapies, such as proton or carbon-ion RT, can significantly enhance local control and OS.

Given the biological similarities between the biliary component of cHCC-CCA and iCCA, these radiotherapeutic modalities warrant careful investigation through the extrapolation of robust data from iCCA, which is a specific subtype of the broader biliary tract cancer category. This review synthesizes current evidence regarding the multifaceted role of RT in cHCC-CCA, ranging from adjuvant settings for high-risk resections to definitive ablative treatments for advanced disease, and proposes therapeutic strategies by leveraging advances in nodal mapping and dose-escalation to support individualized clinical decision-making.

THERAPEUTIC RATIONALE FOR RADIOTHERAPY

Overcoming the limitations of conventional locoregional therapies

Catheter-based locoregional therapies, including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), are established treatment options for advanced or recurrent HCC. However, the therapeutic efficacy of TACE and TARE might be constrained by the biological heterogeneity and variable vascularity of cHCC-CCA. Recent evidence indicates that the radiographic appearance and vascular profile of cHCC-CCA are largely determined by the predominant histological component.^2,4 While TACE demonstrates high response rates (approximately 85%) in hypervascular, HCC-dominant tumors, its efficacy drops precipitously to around 10% in hypovascular lesions, which typically exhibit CCA predominance or a dense fibrous stroma.⁵ Although TARE has emerged as a promising option for HCC and iCCA, as well as for cHCC-CCA, with response rates reported between 55% and 60%,^6,7 the lack of standardized treatment protocols and the reliance on arterial blood supply remain significant challenges. Consequently, the hypovascular or desmoplastic regions within cHCC-CCA frequently evade the ischemic and cytotoxic effects of chemoembolization, leading to incomplete therapeutic responses. In contrast, RT delivers ionizing radiation that induces DNA damage largely independent of the tumor's vascular architecture or embolic accessibility. This modality offers a distinct advantage by providing a potent cytocidal effect across both the hypervascular HCC and the relatively hypoperfused, desmoplastic CCA components, thereby addressing the intrinsic limitations of catheter-based therapies in these heterogeneous tumors.

Bridging the gap in microscopic disease control

The aggressive nature of the biliary component in cHCC-CCA manifests as a high propensity for microscopic infiltrative spread, which frequently eludes surgical clearance. Pathological hallmarks such as lymphovascular invasion (LVI) and perineural invasion are strong predictors of early locoregional failure and distant metastasis, with recent data identifying LVI as a predominant independent factor for poor survival.^8-10 This prognostic impact aligns with established evidence from iCCA, where vascular and perineural invasion are widely recognized as critical determinants of recurrence and survival.^11-15 Furthermore, the incidence of regional lymph node (LN) metastasis, reported to range from 20% to 40% in cHCC-CCA compared to less than 5% in pure HCC, suggests that subclinical microscopic disease is often present beyond the macroscopically resected area.^15,16 To address these microscopic risk factors, RT provides a targeted cytocidal effect to sterilize potential zones of subclinical disease, thereby compensating for the geographic limitations of surgical resection. Since regional LN involvement is an important predictor of short disease-free survival,^17,18 RT serves as a rational spatial intensifier. By targeting these zones of microscopic persistence in the liver parenchyma and regional lymphatic basins, RT addresses the spatial limitations of surgery and the systemic focus of chemotherapy.

Mitigating mortality from tumor-related liver failure

While distant metastasis is a significant concern in cHCC-CCA, local progression remains a critical driver of mortality. Evidence from iCCA cohorts indicates that approximately 70% of patients with unresectable disease succumb to tumor-related liver failure (TRLF), caused by biliary obstruction, vascular invasion, or extensive parenchymal replacement, rather than extrahepatic tumor burden.^19-21 Consequently, liver-directed RT is hypothesized to provide a significant oncologic benefit by mitigating death due to TRLF.^22-24 Retrospective analyses have demonstrated a clear dose-response relationship in this setting; ablative RT, defined as a biologically effective dose (BED₁₀) >80.5 Gy, significantly prolongs median OS compared to conventional doses (23.7 vs. 12.8 months).²³ Importantly, the benefit of preventing TRLF extends even to patients with metastatic disease.²⁵ Propensity-matched analysis revealed that definitive liver RT significantly reduced the rate of death attributable to TRLF compared to chemotherapy alone (47% vs. 82%). This local control translated into a substantial survival advantage, with median OS increasing from 9 months to 21 months with the addition of RT. These findings suggest that controlling the dominant liver tumor is essential for altering the natural history of the disease, irrespective of metastatic status.

CURRENT GUIDELINES AND THE CLINICAL GAP IN cHCC-CCA MANAGEMENT

Current international guidelines, primarily established for biliary tract cancers, position RT as a critical option for specific high-risk clinical scenarios. In the adjuvant setting, while the American Society of Clinical Oncology (ASCO) guidelines recommend adjuvant capecitabine as the standard of care,²⁶ both the National Comprehensive Cancer Network (NCCN)²⁷ and the American Society for Radiation Oncology (ASTRO)²⁸ guidelines provide conditional recommendations to consider adjuvant chemoradiotherapy (CRT) specifically for patients with adverse features, such as microscopically positive margins (R1) or regional LN metastases, to enhance local control. In the definitive setting for unresectable disease, NCCN lists EBRT as a locoregional treatment option, and ASTRO strongly supports the use of high-dose or ablative RT (e.g., stereotactic body radiotherapy [SBRT]) for liver-confined disease, where technically feasible and safe for adjacent organs, noting its association with improved survival compared to conventional doses. However, due to the rarity of cHCC-CCA, high-level evidence specific to this histologic subtype remains virtually non-existent. A recent international multicenter survey²⁹ revealed that only 13% of expert centers have a specific treatment policy for cHCC-CCA, with most decisions relying on institutional preference. Consequently, therapeutic strategies for cHCC-CCA are currently extrapolated from the aforementioned iCCA guidelines, utilizing RT as a rational approach to address locoregional failure in both high-risk postoperative and unresectable settings.

ADJUVANT RADIOTHERAPY FOR RESECTABLE DISEASE

Survival benefit in high-risk populations

While specific data for cHCC-CCA are limited, large-scale population-based analyses of iCCA provide compelling evidence for the survival benefit of adjuvant strategies, often delivered as concurrent CRT (CCRT), which serves as a benchmark for cHCC-CCA management. A surveillance, epidemiology, and end results analysis³⁰ demonstrated that adjuvant RT significantly improved median OS compared to surgery alone (11 vs. 6 months, P=0.014). Regarding the optimal treatment modality, a nationwide analysis of 599 patients³¹ suggested that concurrent CCRT was associated with a reduced mortality risk compared to chemotherapy alone (hazard ratio [HR], 0.67; P=0.001), with the clinical benefit being most pronounced in patients with locally advanced disease or positive surgical margins.

Management of narrow or positive surgical margins

Achieving a wide negative margin (R0≥1 cm) is often challenging in cHCC-CCA due to the tumor’s anatomical proximity to major vascular structures. Retrospective and registry analyses consistently demonstrate that adjuvant RT mitigates the oncologic risks associated with incomplete resection. Adjuvant CRT has been reported to significantly improve survival compared to chemotherapy alone in margin-positive patients, regardless of stage (HR, 0.51-0.65).³¹ Similarly, National Cancer Database (NCDB) analyses found significant survival advantages for adjuvant therapy in R1/R2 resections, whereas no such benefit was observed in R0 cases with wide margins.^32,33 For technically negative but narrow margins (<1 cm), evidence indicates that adjuvant RT can improve 3-year survival to levels comparable with wide-margin resection (55% vs. 65%), whereas narrow-margin resection alone yields significantly poorer outcomes (20%).³⁴ These findings support the role of adjuvant RT in “sterilizing” the resection bed in margin-compromised cases.

Role in node-positive and adverse pathologic features

While regional LN involvement is a known driver of poor outcomes, adjuvant strategies have shown potential to alter this trajectory. A meta-analysis³⁵ of over 6,700 patients with biliary tract cancers concluded that adjuvant CRT offers a superior survival advantage over surgery alone, particularly for LN-positive and R1-resected populations. Supporting this, retrospective data³⁶ for node-positive disease indicate that adjuvant RT can nearly double the median OS compared to observation (19.1 vs. 9.5 months, P=0.011). Similarly, a large-scale analysis of the NCDB³⁷ identified positive LNs status as a key predictor for adjuvant treatment benefit. Furthermore, in a nationwide Taiwanese cohort, Lin et al.³¹ demonstrated that adjuvant CCRT significantly reduced mortality risk in patients with stage III/IV disease (often driven by nodal involvement), with an adjusted hazard ratio of 0.55 compared to chemotherapy alone.

Beyond nodal status, specific adverse pathologic features identified in the latest cHCC-CCA research warrant intensified adjuvant strategies. While Kim et al.³⁸ reported that adjuvant CRT significantly improved recurrence-free survival in R0-resected, node-positive patients (HR, 0.44; P=0.036), recent findings by Chun et al.⁸ extend this rationale to LVI. In their cohort, LVI-positive cHCC-CCA patients exhibited a strikingly lower 5-year OS of 35.8% compared to 93.3% in LVI-negative cases. These data suggest that LVI, alongside tumor necrosis and elevated postoperative carbohydrate antigen 19-9, serves as a critical indicator for adjuvant RT to eradicate microscopic residual disease and prevent early locoregional relapse.

DEFINITIVE AND ABLATIVE RADIOTHERAPY FOR UNRESECTABLE DISEASE

The dose-response relationship and ablative radiotherapy

Recent clinical evidence has established a definitive dose-response relationship in iCCA, introducing the concept of ablative RT (A-RT) as a standard for overcoming the intrinsic radioresistance of the biliary component, within safe dose limits for adjacent organs. A landmark retrospective analysis by Tao et al.³⁹ identified a BED₁₀ of >80.5 Gy as a critical threshold for durable local control. Delivering doses above this threshold achieved a 3-year OS of 73%, a substantial improvement compared to the 38% observed with conventional doses. These single-institution findings have been validated by large-scale registry data; in an analysis of the NCDB encompassing 1,112 patients, De et al.²³ demonstrated that A-RT (BED₁₀ ≥80.5 Gy) nearly doubled the median OS compared to conventional RT (23.7 vs. 12.8 months, P<0.001). Consistent with these findings, the multi-institutional KROG 20-02 study⁴⁰ substantiated that an equivalent dose in 2 Gy fractions (EQD2) of ≥60 Gy serves as a significant independent prognostic factor for improved OS. A recent meta-analysis⁴¹ also demonstrated that A-RT is associated with a superior OS compared to conventional-dose RT (HR, 0.53).

This dose-dependent efficacy, which is drawn primarily from CCA experience in the absence of robust cHCC-CCA data, is consistently observed across modern high-precision modalities such as particle therapy capable of delivering such intensive doses while sparing healthy liver parenchyma (Table 1). High-dose proton beam therapy (PBT) has reported 2-year local control rates as high as 94% (median, 58 GyRBE),⁴² while hypofractionated photon RT has yielded a 2-year local control (LC) of 93%.²² Specifically, among patients treated with PBT, reaching higher dose thresholds has been linked to superior clinical outcomes: a BED >70 GyE was associated with significantly higher 1-year LC rates (83.1% vs. 22.2%, P=0.002),^43,44 and an EQD210 ≥80 GyE led to nearly doubled 2-year OS rates (23.8% vs. 13.2%). The Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) reported that carbon-ion RT achieved a median survival of 14.8 months and a 1-year local control rate of 83% in unresectable iCCA patients, with a favorable toxicity profile. Similarly, a recent meta-analysis⁴⁵ underscored the superiority of particle therapy (proton/carbon) and SBRT over conventional approaches. The analysis revealed that particle therapy and SBRT achieved significantly higher 1-year survival rates (71.8% and 59.2%, respectively) compared to conventional 3D-conformal RT (47.2%, P=0.0004), positioning ablative strategies as the preferred definitive locoregional treatment for unresectable disease. While these benchmarks are primarily derived from iCCA cohorts, they provide a critical therapeutic framework for cHCC- CCA, where the cholangiocytic component often dictates the aggressive clinical course and relative resistance to non-ablative therapies.

Role in metastatic disease

The benefits of definitive liver RT extend even to patients with iCCA with extrahepatic metastases (M1), challenging the traditional dogma that local therapy is futile in the metastatic setting. Controlling the dominant intrahepatic tumor burden is critical because local progression is a primary driver of mortality in this population. De et al.²⁵ reported that definitive liver RT significantly reduced the incidence of death due to TRLF compared to chemotherapy alone (47% vs. 82%) and improved median OS from 9 to 21 months. This finding is corroborated by an NCDB analysis by Sebastian et al.,²⁰ which found that adding liver-directed therapy (surgery or RT≥45 Gy) to chemotherapy significantly improved OS compared to chemotherapy alone (HR, 0.57; P<0.001). Given that the biliary component of cHCC-CCA frequently leads to catastrophic complications such as obstructive jaundice or hepatic insufficiency, prioritizing intrahepatic control through RT is a rational strategy to prevent terminal liver failure, even in the presence of extrahepatic spread.

Downstaging and conversion to resectability

Beyond survival prolongation, integrating RT with systemic therapy serves as a strategic bridge to curative surgery for initially unresectable disease.⁴⁶ Specifically, Sumiyoshi et al.⁴⁷ reported that 71.4% of locally advanced iCCA patients achieved downstaging following CRT, with 80% of those reaching R0 resection status. Similarly, Cho et al.⁴⁸ observed successful conversion in 12.5% of patients after concurrent CRT. The KROG 22-02 study⁴⁰ recently substantiated the role of dose escalation in this setting. High-dose RT (EQD2≥60 Gy) combined with sequential gemcitabine-cisplatin significantly improved resectability, achieving a 28% conversion rate compared to 8.6% in the low-dose group and 0% with RT alone. Notably, patients who successfully underwent curative resection following conversion achieved a 3-year OS of 75%, illustrating that effective downstaging can fundamentally alter the clinical trajectory. Given that achieving an R0 margin represents the only definitive pathway to long-term survival for cHCC-CCA, these conversion strategies are particularly vital. High-dose RT can induce significant tumor regression in locally advanced disease, thereby expanding the eligibility for curative-intent surgery among patients initially considered for palliative management only.

FUTURE PERSPECTIVE

A fundamental challenge in standardizing treatment for cHCC-CCA is its evolving pathological definition across successive World Health Organization (WHO) classifications and its inherent biological ambiguity, which remains insufficiently understood as to whether it behaves more similarly to HCC, iCCA, or a distinct entity. Due to this biological complexity and the paucity of disease-specific data, standardizing target volumes for cHCC-CCA remains a significant clinical challenge.

Refining radiotherapy target volumes for cHCC-CCA

A risk-adapted framework is proposed here, integrating anatomical recurrence patterns with the disease’s unique biphenotypic biology to move toward a hybrid targeting strategy (Fig. 1). Regarding the extent of the target volume, particularly in the adjuvant setting, evidence from recent nodal mapping, most notably by Yang et al.,⁴⁹ suggests that elective nodal irradiation should prioritize the common hepatic artery (station 8) and the hepatoduodenal ligament (station 12), where recurrence rates frequently exceed 30%. However, the clinical benefit of elective nodal irradiation remains a hypothesis-driven strategy. Given that the survival benefit of LN dissection is still a matter of controversy even within the iCCA literature, the necessity and impact of regional nodal coverage in cHCC-CCA, both in postoperative and locally advanced settings, require further prospective validation. Regarding the specific margins of the target volume, in contrast to the focal margins utilized in HCC, a more expansive clinical target volume (CTV) is recommended, analogous to biliary cancer atlases.⁵⁰ to address the infiltrative nature of the biliary component. This volume should be further individualized based on tumor laterality;⁵¹ left-sided tumors may exhibit a higher propensity for spread toward the celiac axis and lesser curvature stations. For definitive cases, a multifaceted approach is suggested: delivering ablative doses to the primary tumor to overcome intrinsic radioresistance, leveraging the dose-response relationship, while extending the CTV to include regional lymphatic echelons. This represents a strategic departure from the gross tumor volume-only approach common in HCC SBRT. Given the high prevalence of underlying cirrhosis in cHCC-CCA patients, this intensification must be balanced against the risk of radiation-induced liver disease. Consequently, advanced modalities such as PBT or carbon-ion RT may be uniquely suited to navigate this narrow therapeutic window, preserving functional liver reserve and host immunity while achieving robust locoregional control.

Synergistic potential of immuno-radiotherapy in cHCC-CCA

While the systemic therapeutic landscape for cHCC-CCA remains limited, the integration of RT with immune checkpoint inhibitors (ICIs) is being explored as a potential strategy to overcome treatment resistance. Although large-scale prospective evidence is currently lacking, preliminary case series^52-54 have noted instances where SBRT combined with programmed cell death protein-1 inhibition facilitated complete remission or enabled conversion surgery for unresectable disease. Interestingly, these responses have been observed even in tumor mutational burden-low or programmed cell death-ligand 1-negative cases, suggesting a possible role for RT in sensitizing immune-cold microenvironments. Mechanistically, it is hypothesized that RT may induce immunogenic priming by reprogramming the immune landscape and enhancing antigen presentation, thereby potentially increasing sensitivity to ICIs.^2,3 Results from ongoing trials investigating novel agents like camrelizumab are anticipated to clarify this paradigm.⁴⁶ However, since the synergy of immuno-radiotherapy is still under evaluation even in pure HCC and iCCA, its application in cHCC-CCA, harboring both components, involves even greater clinical uncertainty. Identifying the optimal systemic backbone remains a significant knowledge gap, emphasizing the need for prospective trials to resolve these complexities.

CONCLUSION

In conclusion, cHCC-CCA is a rare hybrid malignancy for which no established standard treatment currently exists. Due to the lack of prospective evidence and standardized protocols, clinical decisions regarding RT must be largely extrapolated from the management strategies of HCC and iCCA. As summarized in Table 2, RT remains a viable therapeutic option across the clinical spectrum: it can be utilized as an adjuvant treatment for high-risk surgical cases with features such as LVI or positive margins, as a definitive modality for unresectable disease unfeasible for surgery or transplantation, and as a palliative or curative-intent tool in metastatic settings. Moving forward, prospective trials are essential to establish high-level evidence and refine tailored dose-fractionation schemes based on specific tumor biology. Furthermore, the investigation of RT in combination with immunotherapy and advanced particle therapies represents a promising future direction for achieving personalized and optimized care for patients with cHCC-CCA.

Article information

Conflicts of Interest

The authors have no conflicts of interests to declare.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2025-16072367).

Data Availability

Not applicable.

Author Contributions

Conception: SHC, IJL

Manuscript preparation: SHC

Critical revision: WSK, IJL

Writing - review & editing: SHC, WSK, IJL

Approval of final manuscript: SHC, WSK, IJL

Figure 1.

Proposed radiotherapy target volume strategies for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The framework integrates biphenotypic biology by tailoring target volumes to anatomical recurrence patterns. In the adjuvant setting, the proposed framework suggests an expansive clinical target volume (CTV) that may optionally incorporate elective nodal irradiation (ENI) to address the infiltrative biliary component. This strategy targets high-risk nodal stations (e.g., stations 8 and 12) based on potential recurrence patterns, with laterality-based individualization, such as the celiac axis for left-sided tumors. For definitive cases, the strategy combines ablative-dose delivery to the primary tumor (HCC-like) with extended CTV for regional lymphatics (CCA-like). High-precision modalities (SBRT, PBT, and carbon- ion RT) are essential to maximize the therapeutic ratio by achieving robust locoregional control while preserving functional liver reserve. HCC, hepatocellular carcinoma; CCA, cholangiocarcinoma; SBRT, stereotactic body radiotherapy; PBT, proton beam therapy; RT, radiotherapy.

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