Conversion treatment for advanced intrahepatic cholangiocarcinoma: Opportunities and challenges

Abstract

The prevalence of intrahepatic cholangiocarcinoma (ICC) is increasing globally. Despite advancements in comprehending this intricate malignancy and formulating novel therapeutic approaches over the past few decades, the prognosis for ICC remains poor. Owing to the high degree of malignancy and insidious onset of ICC, numerous cases are detected at intermediate or advanced stages of the disease, hence eliminating the chance for surgical intervention. Moreover, because of the highly invasive characteristics of ICC, recurrence and metastasis postresection are prevalent, leading to a 5-year survival rate of only 20%-35% following surgery. In the past decade, different methods of treatment have been investigated, including transarterial chemoembolization, transarterial radioembolization, radiotherapy, systemic therapy, and combination therapies. For certain patients with advanced ICC, conversion treatment may be utilized to facilitate surgical resection and manage disease progression. This review summarizes the definition of downstaging conversion treatment and presents the clinical experience and evidence concerning conversion treatment for advanced ICC.

Key Words: Intrahepatic cholangiocarcinoma; Conversion treatment; Downstaging; Combination therapy; Chemotherapy; Immunotherapy; Locoregional therapies

Core Tip: The conversion treatment for unresectable intrahepatic cholangiocarcinoma (ICC) can reduce tumor burden and enhance the likelihood of surgical resection. Chemotherapy is still the base treatment for advanced ICC. However, locoregional therapies and systemic therapies are promising treatment strategies for advanced ICC, aiming to enhance tumor response and improve patient outcomes. Achieving an adequate future liver remnant is crucial to prevent posthepatectomy liver failure; techniques are being investigated to enhance future liver remnant and improve outcomes in patients with advanced ICC.

INTRODUCTION

Intrahepatic cholangiocarcinoma (ICC) ranks as the second most prevalent primary liver cancer after hepatocellular carcinoma (HCC), constituting approximately 10%-15% of primary liver cancers[1]. Chronic inflammation typically occurs when ICC develops, leading to cholestasis and subsequent cholangiocyte injury[2]. The numerous risk factors for ICC include bile duct cysts, cholangitis, Caroli’s disease, hepatolithiasis, cirrhosis, viral hepatitis, parasitic infection, digestive diseases, and metabolic and endocrine disorders, among others[3]. As the main risk factors for ICC have become more common over the past few decades, mortality from this disease has tended to grow in a number of areas across the world[4].

Surgical treatment is the most effective approach for achieving long-term survival in patients with cholangiocarcinoma. The patient should undergo surgery if radical resection of cholangiocarcinoma is feasible and if there are no distant metastases or other surgical contraindications[5]. However, cholangiocarcinoma is typically asymptomatic in the initial stages, leading to a diagnosis only when the disease has progressed significantly, severely limiting therapy options and resulting in a poor outcome[6,7]. Only 20%-30% of patients have resectable disease[8]. Even in cases where surgical resection is performed with the goal of curing the disease, the 5-year overall survival (OS) rate is only 20%-35%[2].

Nonsurgical therapy for ICC has advanced significantly in recent years. Chemotherapy, targeted therapy, immunotherapy, and their combination might yield favorable outcomes in the management of advanced or unresectable ICC; furthermore, localized interventions such as transarterial chemoembolization (TACE), hepatic arterial infusion (HAI) chemotherapy (HAIC), transarterial radioembolization (TARE), and radiotherapy are frequently utilized. Advancements in technology and pharmaceuticals, coupled with systemic therapies, not only yield superior outcomes in terms of tumor reduction but also increase patient survival. Conversion treatment is the process of transforming an unresectable ICC into a resectable ICC and then surgically excising the tumor. Several studies have shown that conversion treatment, which involves the use of systemic or local therapies, can increase the percentage of patients suitable for curative resection, hence considerably improving their long-term survival rates[9-13].

As methods of treatment improve, future research will focus mostly on identifying the most efficient conversion treatment procedures for advanced ICC, particularly to determine which patients are most likely to benefit from this strategy. A unified definition of conversion treatment and explicit criteria for patient selection are essential for the advancement of this therapeutic technique and the assurance of consistent clinical outcomes.

CONCEPT AND SIGNIFICANCE OF CONVERSION TREATMENT

The conversion treatment method is a novel approach for unresectable malignancies that was originally suggested for HCC patients and aims to reduce the tumor burden by applying combination therapy, thereby making patients appropriate for surgical resection[14,15]. In recent years, conversion treatment has received increasing interest in the field of ICC, as increasing amounts of data indicate that multimodal strategies for treatment can enhance resectability and patient outcomes. In contrast to HCC, where conversion treatment is well established, ICC has historically exhibited low conversion rates; however, advancements in systemic and locoregional therapies are progressively altering this approach. A study showed that patients with advanced ICC who undergo surgical resection following successful conversion treatment have a two-year survival rate of 88%, with a median survival of 46 months[16].

In certain instances, radical excision may be unfeasible because of the advanced stage of the tumor and its infiltration into hepatic blood vessels[13]. Nonetheless, some patients may have the chance to undergo radical resection via conversion treatment to achieve tumor downstaging. Given the rapid development of antitumor therapies, a combination therapy approach may lead to tumor downstaging in patients with unresectable ICC, increase the likelihood of radical surgical resection, and prolong patient survival. The optimal conversion treatment results in a high objective response rate (ORR), minimal harmful effects on patients, and the ability to achieve conversion as rapidly as possible. In addition to improving survival, conversion treatment can also offer symptomatic relief by diminishing the tumor burden, potentially alleviating biliary obstruction, discomfort, and other symptoms related to ICC. Thus, this may result in an increase in quality of life, even when complete resection is not possible.

Conversion treatment typically involves the application of active treatment modalities (such as targeted therapy, immunotherapy, etc.) to manage or reverse tumor proliferation, which has significant potential for a cure or prolonged response. In contrast, palliative care primarily aims to alleviate symptoms and enhance quality of life[17]. It includes interventions such as percutaneous transhepatic biliary drainage and biliary stenting. It is typically employed for individuals with advanced ICC and has poor treatment efficacy on the tumor itself.

There are currently no clear criteria for the indications for conversion treatment in ICC. Some patients with advanced ICC who are unsuitable for surgical resection due to inadequate residual liver volume, impaired liver function, and other factors might be included in conversion treatment. The following section outlines the significant breakthroughs in locoregional and systemic as well as combination therapies for the conversion treatment of ICC.

OPTIONS FOR ICC CONVERSION TREATMENT

Chemotherapy

In 2010, the ABC-02 study recommended the gemcitabine + cisplatin (GC) regimen as a first-line treatment option for advanced cholangiocarcinoma and reported an ORR of 26.1%[18]. In another phase III clinical study (KHBO1401-MITSUBA), the ORR for the GC regimen group in patients with advanced cholangiocarcinoma was 15%, with no instances of successful conversion treatment reported. In the GC + S-1 regimen, the ORR was 41.5%, with three patients successfully converted to surgical resection[19]. In addition to the GC regimen, the combination of gemcitabine and oxaliplatin (Gemox) is another therapy recommended by the National Comprehensive Cancer Network guidelines for advanced cholangiocarcinoma[20]. Despite the absence of a randomized trial evaluating the efficacy of the Gemox regimen against the GC regimen, Gemox was favored as a standard regimen in certain areas and was utilized as a reference regimen in multiple clinical trials for cholangiocarcinoma[21].

A retrospective study assessed the efficacy of neoadjuvant chemotherapy in managing initially unresectable ICC. Among the 74 advanced ICC patients, 39 (53%) successfully converted and underwent further resection following a median of six cycles of treatment[22]. The results revealed that individuals with locally advanced ICC who underwent surgical intervention after neoadjuvant chemotherapy presented comparable outcomes to those with initially resectable ICC who received surgery only[22]. A GC regimen combined with nab-paclitaxel was studied in a clinical trial. The survival results were encouraging, with a median OS of 19.2 months[23]. Twelve patients (20%) were successfully converted from unresectable to resectable and subsequently underwent surgery[23].

Radiotherapy

Owing to the different radiosensitivities of hepatic tissue and the limitations of radiotherapy technology, radiotherapy is infrequently utilized for the management of liver cancer. Nonetheless, advancements in imaging and radiation technologies, together with an enhanced comprehension of the radiation tolerance of normal liver tissue, have prompted an increasing number of researchers to use radiotherapy for the treatment of liver cancer[24,25]. The treatment effects observed in contemporary research exhibit considerable variability[26-28], potentially attributable to disparities in radiotherapy methods and study cohorts.

A retrospective analysis involved 79 patients with unresectable ICC, 70 of whom underwent systemic chemotherapy prior to radiation. The overall 3-year survival rate for the total group was 44%. Patients receiving a biologically equivalent radiation dose exceeding 80.5 Gy had a superior survival rate of 73% compared with 38%, and the local control (LC) rates were 78% and 45%, respectively[29]. Another phase II study evaluated the application of proton radiation in 92 patients with localized, unresectable ICC or HCC. Patients underwent 15 portions of proton treatment, culminating in a maximum cumulative dosage of 67.5 Gy equivalent. The ICC patients had a median tumor size of 6 cm, with 25% having more than one tumor and 30% having vascular thrombosis. The two-year LC and OS rates in the ICC group were 94% and 47%, respectively[30]. Data from preclinical and clinical studies have shown that radiation therapy enhances T cell infiltration, increases the quantity of lymphocytes that infiltrate tumors, and broadens the repertoire of T cell receptors[31]. This could serve as a potential method to augment the efficacy of immunotherapy, offering a combination therapy alternative for the conversion treatment of unresectable ICC.

TACE

TACE is a therapeutic approach for people with locally advanced malignancies that aims to administer locally high concentrations of chemotherapy to induce tumor ischemia[32,33]. TACE has been utilized in multiple liver malignancies, including ICC. In this method, the hepatic artery supplying blood to the tumor is accessible, typically through femoral artery access, and identified via conventional angiography[34]. TACE is performed by administering an emulsion containing chemotherapy drugs and an oily contrast medium such as lipiodol conventional TACE or special particles combined with chemotherapy drugs (drug-eluting bead-TACE). The chemotherapy drugs mixed with the oil-based contrast agent are injected into the hepatic artery during conventional TACE. The artery is subsequently embolized with embolic material, cutting off the tumor’s blood supply[35]. Common chemotherapy medications include cisplatin, mitomycin C, and doxorubicin[36]. However, the high liquidity of lipiodol leads to systemic toxicity. Consequently, alternative interventional embolic materials, including drug-eluting beads, have been studied to increase drug loading and release in TACE therapy, referred to as drug-eluting bead-TACE[37].

Compared with HCC, ICC has a limited arterial blood supply, making it challenging for TACE to achieve optimal embolization efficacy. The OS following TACE is limited, with considerable variation in patient selection, sample size, and research methodology across different studies. Overall, the median OS reported in various studies ranged from 6 to 21 months[37-43]. It has been reported that when combined with the GC regimen, the ORR of D-TACE can reach 68%, enabling the effective conversion of 25% of patients into operable patients. The median OS of the combined treatment group was 33.7 months[44].

TARE

The technique used in TARE parallels that utilized in TACE. This method uses microspheres tagged with the β-emitter yttrium-90 (Y-90) to direct radiation onto inoperable primary or metastatic liver cancers[45]. Owing to the preferential entrapment of Y-90 microspheres in tumor blood vessels, substantial doses of radiation can be delivered to the tumor while presenting acceptable radiation levels for adjacent normal liver tissue[46].

Mouli et al[47] reported that Y-90 radioembolization for unresectable ICC resulted in an overall objective tumor response in 98% of patients; the mean tumor shrinkage rate was 35%. According to the World Health Organization standards, 11 patients (25%) achieved a partial response, 33 patients (73%) demonstrated stable disease, and 1 patient (2%) experienced increasing disease. Five patients (11%) were downstaged to a resectable condition following treatment and successfully underwent R0 resection[47]. Similarly, in another study combining GC chemotherapy and Y-90 microspheres, 9 patients (22%) were able to be downstaged to surgery, and 8 of them (20%) successfully underwent R0 surgical resection, with a median OS of 46 months after surgery[16].

In previous studies on TARE, tumor size or load has typically not been regarded as an exclusion criterion. Several studies have included patients with tumors larger than 5 cm or exhibiting multifocal intrahepatic disease[48,49]. The inclusion of patients with significant tumor burdens indicates that TARE may serve as a feasible therapeutic alternative for conversion treatment in ICC. TARE may effectively reduce tumor size and enhance resectability, serving as a bridge to curative surgery for patients with originally unresectable ICC. Further research on TARE for the treatment of ICC can elucidate more patient tumor characteristics and identify more suitable treatment populations to improve treatment outcomes.

HAIC

Compared with systemic chemotherapy, HAIC aims to provide substantial quantities of chemotherapeutic agents into the hepatic circulation, resulting in a more prominent local cytotoxic effect[50]. In HAIC, frequently utilized chemotherapeutic agents include floxuridine, gemcitabine, oxaliplatin, cisplatin, and their combinations[51-54]. Tumor size is not a contraindication for HAIC treatment, and certain trials have incorporated patients with tumors exceeding 10 cm in diameter[53,55].

A phase II clinical trial assessed the efficacy of HAI of floxuridine in conjunction with systemic chemotherapy for the treatment of 38 patients with unresectable ICC. The 6-month progression free survival (PFS) rate was 84.1%, 22 patients (58%) achieved a partial response, 32 patients (84%) achieved disease control, and 4 patients were successfully converted to surgical resection, with one achieving complete response[53]. In another study of HAI with gemcitabine in conjunction with oxaliplatin for the treatment of locally advanced ICC, 2 out of 12 patients achieved a partial response and underwent R0 resection surgery[56]. A study evaluated the therapeutic efficacy of HAIC vs first-line systemic chemotherapy for ICC, revealing superior outcomes for patients in the HAIC cohort compared with those receiving systemic chemotherapy[57]. In the subgroup analysis, patients with single tumors appeared to benefit from the consideration of HAIC for OS and PFS. These findings indicate that HAIC may exhibit superior efficacy in patients with early unresectable ICC. Nonetheless, additional prospective and randomized investigations are needed to validate this conclusion.

Targeted therapy

Targeted therapy is a treatment approach that has developed dramatically over the past decade. The mechanism of action involves inhibiting the signal transduction pathway during tumor proliferation by binding to the specific targets via chemical compounds, thereby inducing apoptosis in tumor cells, ultimately facilitating tumor stage reduction, and increasing the likelihood of surgical resection. In targeted therapy, key oncogenic targets in ICC tumor cells have been identified, and drugs to inhibit these targets have been developed. Mutations in genetic targets can be detected in nearly 40% of cholangiocarcinoma patients[58]. Common mutations may vary depending on where the tumor occurs. Mutations in isocitrate dehydrogenase-1 (IDH1) and rearrangements of fibroblast growth factor receptor 2 (FGFR2) are predominantly associated with ICC, whereas mutations in TP53 and KRAS, together with ERBB2 amplifications, are more frequently observed in extrahepatic cholangiocarcinoma (ECC)[21,59]. Mutations in the BAP1 and neurotropic tyrosine kinase receptor (NTRK) genes are commonly observed in ICC, whereas ECC typically shows abnormalities in the ELF3 and ARID1B genes, along with fusions of PRKACA and PRKACB[60-62].

FGFR abnormalities (fusion, mutation, and amplification) are crucial in the development of ICC; however, the mutation rate is low in ECC and gallbladder carcinoma[63]. Mutations in FGFR can result in dysregulated FGFR signaling, which may promote cancer by increasing cell proliferation, invasion, and angiogenesis[64]. Therapeutics targeting FGFR2 and its gene family have demonstrated significant potential in the treatment of ICC[65]. Pemigatinib, an inhibitor of FGFR1-3, has obtained Food and Drug Administration approval for the management of advanced cholangiocarcinoma[66]. Among patients with advanced cholangiocarcinoma who had FGFR2 rearrangements and fusion mutations, pemigatinib had an ORR of 35.5% in the FIGHT-202 study; 98% of these patients had ICC. Furthermore, among 107 advanced cholangiocarcinoma patients, two individuals who experienced tumor downstaging underwent effective surgical intervention, with a conversion rate of 1.8% and an average survival duration of 17.8 months[67].

IDH1 mutations are prevalent in cholangiocarcinoma, and occur more commonly in ICC than in ECC[68]. IDH1 is a member of the IDH protein family. Mutant IDH enzymes exhibit neomorphic activity, catalyzing the conversion of the physiological metabolite α-ketoglutarate to 2-hydroxyglutarate. 2-hydroxyglutarate functions as an oncometabolite, and its accumulation induces multiple epigenetic alterations[69]. Ivosidenib, a targeted agent for IDH1 mutations, prolongs OS among patients with advanced cholangiocarcinoma with IDH1 mutations[70]. In the ClarIDHy trial, patients with advanced cholangiocarcinoma who received ivosidenib exhibited a median OS of 10.3 months[71]. The findings of the trial supported the approval of this drug for clinical use[71].

The overexpression of human epidermal growth factor receptor 2 (HER2) is more prevalent in ECC (19.9%) than in ICC (4.8%)[72]. The overexpression of HER2 proteins promotes the formation of homodimers or heterodimers. Consequently, development and proliferation are predominantly facilitated by the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways[73]. A phase II clinical trial (KCSG-HB19-14) demonstrated that trastuzumab in combination with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) chemotherapy resulted in an ORR of 29.4% in patients with HER2-positive advanced cholangiocarcinoma who had previously failed GC chemotherapy, with a median OS of 10.7 months and no reported cases of successful conversion[74].

The incidence of NTRK gene fusion in cholangiocarcinoma is less than 1%, and it is not commonly used as a regular screening marker[75]. However, some clinical trials have shown positive outcomes. Entrectinib and larotrectinib are NTRK inhibitors that have demonstrated success in treating patients with advanced malignancies that are NTRK fusion positive. Among patients with systemic treatment-treated NTRK fusion-positive advanced malignancies, those treated with entrectinib had an ORR of 57%[76]. Another clinical trial of larotrectinib for the treatment of NTRK fusion-positive malignancies reported an ORR of 75%[77].

In addition to single-target inhibitors, multitarget inhibitors have also shown efficacy in the treatment of ICC. Lenvatinib is a multitarget inhibitor of tyrosine kinase receptors that targets FGFR1-4, vascular endothelial growth factor receptor 1-3, and platelet-derived growth factors receptor-α, among others[78]. A phase II clinical trial demonstrated that lenvatinib monotherapy as a second-line treatment for advanced cholangiocarcinoma can achieve an ORR of 11.5% and a median survival duration of 7.35 months[79]. In 2021, the American Society of Clinical Oncology Annual Meeting reported a phase II clinical trial (NCT03951597) assessing the treatment of advanced ICC with lenvatinib combined with toripalimab and Gemox chemotherapy. In patients who completed the follow-up, the ORR was 80%, and the disease control rate (DCR) was 93.3%. Three patients were successfully converted and received surgical therapy[80]. Given the high ORR of 80%, it is important to interpret these results with caution. The limitations of this investigation, including sample size, bias in patient selection, treatment regimen variability, and study design, should be noted. In summary, while the high ORR is encouraging, it is crucial to emphasize that further studies are needed to confirm these findings in a broader patient population and with more standardized treatment protocols. For patients with ICC, the use of targeted therapies has new potential for conversion treatment. Many targeted therapies are in basic or clinical research, with several demonstrating promising antitumor efficacy; however, additional multicenter clinical trials are necessary to provide more reliable clinical evidence.

Immunotherapy

Immunotherapy has been investigated for ICC as a significant treatment option, and positive outcomes have been reported. As research on tumor immunity has advanced, an increasing number of studies have focused on programmed cell death 1 (PD-1), its ligand (PD-L1) inhibitors, and adoptive cell therapy (ACT). Research indicates that PD-L1 expression is increased in ICC tumor tissues, suggesting that PD-1/PD-L1 inhibitors could function as effective immunotherapies for ICC patients.

A clinical study of nivolumab performed a subgroup analysis of PD-L1 expression levels to evaluate its impact on median PFS. The findings indicated that patients exhibiting PD-L1 positivity (characterized by ≥ 1% of tumor cells exhibiting PD-L1 expression) experienced prolonged PFS[81]. Compared with chemotherapy alone, the findings of the TOPAZ-1 study indicated that the combination of durvalumab with GC enhanced OS, PFS, and the ORR in patients with unresectable advanced cholangiocarcinoma. The median OS for patients receiving combination therapy was 12.9 months, whereas it was 11.3 months for those receiving chemotherapy[82]. In another clinical trial, KEYNOTE-966, which had a median follow-up duration of 36.6 months, the median OS for the pembrolizumab cohort was 12.7 months, whereas it was 10.9 months for the placebo cohort[83]. The TOPAZ-1 and KEYNOTE-966 clinical trials confirmed the efficacy of immune checkpoint inhibitors targeting PD-1 and PD-L1 when combined with chemotherapy for advanced cholangiocarcinoma treatment. However, the variability in treatment protocols across studies, including differences in drug doses, treatment durations, and combination regimens, can impact the comparability and reliability of these results.

Early clinical results have been encouraging for ACT, a treatment based on the engineering and isolation of living T cells along with other immune cells[84]. This form of therapy has been extensively utilized in melanoma[85]. Kverneland et al[86] utilized ACT to treat three patients with advanced cholangiocarcinoma; one of the patients achieved a partial response. Furthermore, several reports exist regarding chimeric antigen receptor-modified T cell therapy for cholangiocarcinoma. A study targeting epidermal growth factor receptor (EGFR) in advanced cholangiocarcinoma included 19 patients with unresectable biliary system malignancies exhibiting high EGFR positivity (> 50% of cancer cells expressed EGFR). The findings indicated that one patient achieved a complete response, whereas the disease remained stable in 10 patients, yielding a median PFS of 4 months[87]. In recent years, ACT has demonstrated efficacy in various tumor treatments through optimization and improvement. However, its potential pivotal role in ICC conversion treatment requires further fundamental and clinical investigation.

Conversion treatment for future liver remnant volume

Posthepatectomy liver failure (PHLF) following major liver resection is linked to a high mortality rate. An adequate future liver remnant (FLR) is a critical element in reducing the risk of PHLF[88]. The method of promoting an FLR increase prior to tumor resection is a prevalent approach for facilitating conversion treatment in patients with FLR deficiency. A study revealed that an FLR less than 25% triples the likelihood of postoperative hepatic dysfunction and serves as a predictor of morbidity and duration of hospitalization. Ninety percent of patients who underwent trisectionectomy with an FLR of 25% or less exhibited postoperative hepatic dysfunction, while none of those with an FLR over 25% did[89].

By encouraging FLR hypertrophy, causing shrinkage of the liver volume intended for resection, and refining patient selection, portal vein embolization (PVE) lowers the risk of major hepatectomy[90]. The duration necessary for the remnant liver to regenerate post-PVE is typically prolonged (approximately 4 to 6 weeks), and more than 20% of patients ultimately forfeit the opportunity to have surgery because of tumor advancement or inadequate FLR proliferation during the interim period[91,92]. Current treatment techniques for these patients include combined TACE, hepatic vein embolization, and other methods to increase FLR growth and control tumor development[93,94]. Presently, PVE is infrequently used in the management of cholangiocarcinoma[95,96], and additional clinical trials are needed to investigate its value in conversion treatment. Some experts suggest that PVE is particularly crucial when the FLR is projected to be less than 25% of the whole hepatic volume in a healthy liver, less than 30% in cases of chemotherapy-induced liver damage, or less than 40% in a liver weakened by underlying cirrhosis. However, PVE must be administered cautiously to patients with severe liver cirrhosis, older patients, and rapidly progressing tumors.

To prevent PHLF, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) have been implemented to promote hypertrophy of the FLR[97,98]. This novel approach was swiftly embraced by hepatobiliary surgery for managing advanced liver tumors owing to its extremely high R0 resection rate[99,100]. A propensity score matching analysis demonstrated a significantly greater OS for patients with locally advanced ICC in the ALPPS group than for those receiving palliative chemotherapy[101]. Similarly, to validate the use of ALLPS in conversion treatment, further research with a greater degree of evidence is necessary.

Other treatments

The immunogenic subtype of ICC is correlated with increased sensitivity to immune checkpoint inhibitors, indicating that antigen-presenting cells may play a role in T cell priming and activation[102]. A recent preclinical study revealed that CD40-mediated activation of antigen-presenting cells in ICC markedly improved the efficacy of anti-PD-1 therapy, offering a novel approach for combination immunotherapy[103]. Photodynamic therapy is an advanced treatment that involves the intravenous delivery of a photosensitizing chemical, which is then activated by light exposure at a certain wavelength, leading to ischemic necrosis[104]. Many researchers have investigated its ability to reshape the tumor environment and efficiently stimulate antitumor immunity[105,106]. Thymosin alpha 1 is endogenously present in the thymus and is essential for T cell maturation and differentiation[107]. Recent research has indicated that thymosin alpha 1 could markedly increase OS in HCC patients[108]. Its potential involvement in the conversion treatment of ICC warrants further investigation by researchers.

Endoluminal radiofrequency ablation (RFA) has emerged as a novel therapeutic in the past decade. A radiofrequency catheter is inserted into the bile duct during endoscopy. RFA can diminish the tumor burden by inducing localized tumor damage and may also contribute to the modulation of tumor immunity, hence offering survival advantages for patients who are ineligible for radical surgery[109]. Nonetheless, the impact of RFA on survival remains contentious[110]. In addition, studies have explored the role of microwave ablation in the treatment of advanced ICC[111,112]. To standardize therapy options and improve patient selection, more prospective trials are needed.

COMBINATION THERAPY: OPPORTUNITIES AND CHALLENGES

Combination therapy is an excellent approach that enhances efficacy, significantly surpassing that of monotherapy. The combination of many therapies can augment the immunogenicity of tumor cells and modify the tumor environment, yielding more promising outcomes. Researchers have recently assessed the safety and clinical efficacy of lenvatinib combined with durvalumab and FOLFOX-HAIC among individuals with unresectable ICC. The findings indicated that the ORR according to the mRECIST criteria was 65.2%, the median PFS was 11.9 months, and 3 patients (13%) demonstrated tumor reduction or downstaging posttreatment, ultimately undergoing radical tumor resection[113]. A retrospective real-world study demonstrated that a triple regimen of chemotherapy, lenvatinib, and an anti-PD-1 antibody yielded favorable outcomes. The PFS was 4.6 months for the chemotherapy-only group, 11.9 months for the chemotherapy combined with anti-PD-1 antibody dual-regimen group, and 23.4 months for the triple-regimen group. In the triple-regimen cohort, two patients had substantial posttreatment outcomes, allowing them to proceed with radical surgical operations[114]. More clinical studies on combination conversion treatment for advanced ICC are listed in Table 1.

Table 1 Summary of clinical studies on conversion treatment for advanced intrahepatic cholangiocarcinoma.

Study design	Intervention	Patients, n	Conversion treatment rate (%)	Key findings	Ref.
Retrospective study	Lenvatinib + durvalumab + FOLFOX-HAIC	23	13	Lenvatinib + durvalumab + FOLFOX-HAIC showed high ORR (65.2% mRECIST, 39.1% RECIST 11), with a median OS of 17.9 months and PFS of 11.9 months, supporting its potential as a first-line option for unresectable ICC	Zhao et al[113], 2024
Retrospective study	GC chemotherapy vs GC chemotherapy + PD-1 inhibitors vs GC chemotherapy + lenvatinib + PD-1 inhibitors	22 vs 20 vs 53	0 vs 0 vs 3.8	The triple-regimen group had the longest OS (39.6 months), significantly exceeding the dual-regimen (OS = 20.8 months) and chemo-only groups (OS = 13.1 months). ORR was 18.2% (chemo), 55.5% (dual), and 54.7% (triple), indicating superior efficacy of combination therapy for advanced ICC	Dong et al[114], 2024
Retrospective study	Gemox-HAIC + Gem-SYS combined with lenvatinib and PD-1 inhibitor	21	19	Gemox-HAIC plus Gem-SYS with lenvatinib + PD-1 inhibitor achieved a median OS of 19.5 months in large unresectable ICC. ORR was 52.3%. The regimen was well tolerated, with no grade 5 AEs	Ni et all[128], 2024
Retrospective study	Systemic chemotherapy vs systemic chemotherapy + PD-L1 inhibitors vs HAIC + lenvatinib + PD-L1 inhibitors	50 vs 49 vs 42	0 vs 2 vs 9.5	ORR (50.0%) and DCR (88.1%) were highest in the HAIC + lenvatinib + PD-L1 inhibitor group, surpassing systemic chemotherapy alone (ORR = 6.0%, DCR = 52.0%) and systemic chemotherapy + PD-L1 inhibitor (ORR = 18.4%, DCR = 73.5%). Fewer grade 3-4 AEs were reported in the HAIC + lenvatinib + PD-L1 inhibitor group, supporting its superiority over systemic chemotherapy alone for unresectable ICC	Lin et al[129], 2024
Retrospective study	Chemotherapy vs chemotherapy + PD-1/L1	30 vs 51	0 vs 5.9	The chemotherapy + anti-PD-1/PD-L1 group had significantly longer OS (11 months vs 8 months) than chemotherapy alone. ORR (29.4%) and DCR (78.4%) were also higher compared to chemotherapy alone (ORR = 13.3%, DCR = 73.3%), supporting its superior efficacy	Madzikatire et al[130], 2024
Retrospective study	Radiotherapy vs EQD2 < 60 Gy + GC chemotherapy vs EQD2 ≥ 60 Gy + GC chemotherapy	21 vs 70 vs 25	0 vs 8.6 vs 28	Patients receiving EQD2 ≥ 60 Gy + chemotherapy had the highest curative resection rate (28%) and significantly better OS than those receiving lower-dose radiotherapy or radiotherapy alone. These findings suggest that high-dose radiotherapy combined with chemotherapy improves outcomes in locally advanced unresectable ICC	Im et al[131], 2024
Retrospective study	SIRT using yttrium-90	28	34.5	SIRT for localized and locally advanced ICCA achieved a radiologic response rate of 57.1%, with a median OS of 22.9 months. 34.5% of patients were successfully downstaged to surgery or transplant, leading to significantly longer OS, supporting SIRT as an effective treatment option for advanced ICC	Yu et al[48], 2024
Retrospective study	GC chemotherapy vs HAIP chemotherapy	76 vs 192	1.3 vs 6.8	HAIP chemotherapy significantly improved survival in liver-confined unresectable ICCA compared to systemic chemotherapy. Median OS was 27.7 months with HAIP vs 11.8 months with GC chemotherapy	Franssen et al[132], 2024
Retrospective study	PD-1 inhibitors + lenvatinib + Gemox chemotherapy	53	11.3	PD-1 inhibitor + lenvatinib + Gemox chemotherapy showed a median OS of 14.3 months in advanced ICC. ORR was 52.8% and DCR was 94.3%, demonstrating high anti-tumor activity. Tumor burden score, TNM stage, and PD-L1 expression were identified as independent prognostic factors for survival	Zhu et al[133], 2023
Phase 2 clinical trial	Toripalimab + lenvatinib + Gemox chemotherapy	30	10	Toripalimab + lenvatinib + Gemox achieved an ORR of 80% and a DCR of 93.3% in advanced ICC. Median OS was 22.5 months, and PFS was 10.2 months. Patients with PD-L1 positivity (≥ 1%) showed a trend toward improved response	Shi et al[134], 2023
Retrospective study	Yttrium-90 + gemcitabine, cisplatin, and capecitabine	13	53.8	Yttrium-90 TARE combined with gemcitabine, cisplatin, and capecitabine achieved a median OS of 29 months and PFS of 13 months in locally advanced ICC. 53.8% of patients were downstaged to surgery, leading to significantly improved OS. Complete and partial responses were observed in 38.5% and 46.2% of patients, respectively	Ahmed et al[135], 2023
Retrospective study	TACE + TKIs + anti-PD-1 vs HAIC + TKIs + anti-PD-1	19 vs 39	0 vs 15.4	The HAIC + TKIs + anti-PD-1 group achieved significantly higher ORR (RECIST: 48.7% vs 15.8%; mRECIST: 61.5% vs 21.1%) and DCR (82.1% vs 36.8%) compared to TACE + TKIs + anti-PD-1 in unresectable ICC	Zhang et al[136], 2022
Retrospective study	TACE + lenvatinib	44	63.6	TACE combined with lenvatinib successfully downstaged 63.6% of patients with initially unresectable ICC to surgical resection. Among them, 82.1% achieved R0 resection. Patients who underwent successful downstaging had significantly better OS	Yuan et al[137], 2022
Phase 2 clinical trial	Gem/Cis vs Gem/Cis-DEBIRI	22 vs 24	8 vs 25 (downsizing to resection/ablation)	The Gem/Cis + DEBIRI group had significantly higher ORR at 2, 4, and 6 months compared to Gem/Cis alone. Downsizing to resection/ablation was more frequent (25% vs 8%). Median OS (33.7 months vs 12.6 months) were significantly improved, supporting Gem/Cis + DEBIRI as a safe and effective treatment option for unresectable ICC	Martin et al[44], 2022
Retrospective study	Yttrium-90	136	8.1	Yttrium-90 radioembolization achieved a median OS of 14.2 months in unresectable ICC. 8.1% of patients were downstaged to resection, with 72.7% achieving R0 resection. Post-resection median OS was 39.9 months, supporting Y90 as an effective treatment with potential for downstaging and long-term survival benefits	Gupta et al[138], 2022
Retrospective study	Yttrium-90	81	3.7	Yttrium-90 transarterial radioembolization achieved a median OS of 14.5 months in unresectable ICC, with objective response and DCRs of 41.8% and 83.6%, respectively	Bargellini et al[139], 2020
Retrospective study	Yttrium-90	115	4	Yttrium-90 radioembolization in unresectable ICC resulted in a median OS of 29 months from diagnosis. 4% of patients were downstaged to curative-intent resection, supporting yttrium-90 as a potential option for tumor control and downstaging	Buettner et al[140], 2020
Phase 2 clinical trial	HAI floxuridine + systemic Gemox	38	11	HAI plus systemic Gemox achieved a median OS of 25.0 months and a median PFS of 11.8 months in unresectable ICC. 58% of patients achieved a partial response, and 4 patients (11%) were downstaged to resection, with 1 complete pathologic response. Patients with IDH1/2 mutations had significantly better two-year OS	Cercek et al[53], 2020
Phase 2 clinical trial	SIRT + chemotherapy	41	22	SIRT combined with cisplatin and gemcitabine achieved a 39% response rate (RECIST) and a 98% DCR in unresectable ICC. Median PFS was 14 months, and median OS was 22 months. 22% of patients were downstaged to surgery, with 20% achieving R0 resection. These findings support SIRT plus chemotherapy as an effective treatment with potential for surgical downstaging	Edeline et al[16], 2020
Retrospective study	HAI of gemcitabine plus oxaliplatin	12	16.7	HAI of gemcitabine + oxaliplatin for unresectable locally advanced ICC achieved a DCR of 91%. Median OS was 9.1 months, and time to progression was 20.3 months. Partial responses enabled R0 resection in 2 patients, supporting HAI as a promising and tolerable therapy for locally advanced ICC	Ghiringhelli et al[56], 2013
Retrospective study	Drug eluting bead-TACE	26	3.8	Drug-eluting bead transarterial chemoembolization achieved a median OS of 11.7 months and PFS of 3.9 months. Local tumor control was achieved in 66% of DEB-TACE patients, with one patient successfully downstaged to resection. These findings suggest DEB-TACE is a safe and effective alternative for ICC	Kuhlmann et al[141], 2012
Prospective multicenter study	Drug-eluting bead therapy loaded with irinotecan	24	12.5	Drug-eluting bead therapy achieved a median OS of 17.5 months, significantly longer than chemotherapy alone in unresectable ICC. One patient was successfully downstaged to resection. These findings suggest that drug-eluting bead therapy is a safe and effective adjunctive treatment for ICC, providing a survival advantage over chemotherapy alone	Schiffman et al[142], 2011

FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; HAIC: Hepatic arterial infusion chemotherapy; RECIST: Response evaluation criteria in solid tumors; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; ICC: Intrahepatic cholangiocarcinoma; GC: Gemcitabine plus cisplatin; PD-1: Programmed cell death protein 1; AEs: Adverse events; PD-L1: Programmed cell death-ligand 1; DCR: Disease control rate; Gemox: Gemcitabine and oxaliplatin; Gem-SYS: Systemic gemcitabine chemotherapy; EQD2: Equivalent radiotherapy dose in 2 Gy fractions; SIRT: Selective internal radiation therapy; ICCA: Intrahepatic cholangiocarcinoma; TNM: Tumor-node-metastasis; HAIP: Hepatic arterial infusion pump; TKIs: Tyrosine kinase inhibitors; TACE: Transarterial chemoembolization; DEBIRI: Irinotecan drug-eluting beads; HAI: Hepatic arterial infusion; IDH: Isocitrate dehydrogenase.

Advancements in different methods of treatment have increased hope in the management of ICC (Figure 1). Nonetheless, the optimal timing for surgical intervention following effective conversion treatment remains uncertain. Furthermore, considerations must include the duration required for the medicine to exhibit efficacy, potential adverse reactions, and the necessity for prior discontinuation of the medication. Some clinicians endorse prompt curative resection subsequent to successful conversion treatment. The degree of urgency is predicated on the potential risk of forfeiting surgical options should tumor reprogression occur. Nevertheless, in practical settings, many patients who achieve effective tumor control via conversion treatment are often reluctant to undergo surgery, preferring to sustain their current condition. This hesitance predominantly stems from apprehensions regarding surgical intervention and the possible disruption of the tumor microenvironment postoperatively, which may heighten the risk of tumor recurrence. The timing of surgery is predominantly contingent upon the physician’s experience. For patients with ICC, multidisciplinary teams (MDTs) may be helpful in determining the best time for surgery and conversion treatment. Owing to the essential contribution of MDTs in enhancing patient outcomes, the National Comprehensive Cancer Network and other authorities advocate the use of MDTs in the management of cholangiocarcinoma[20,115-117]. Future studies are needed to ascertain the optimal period for effective conversion treatment and to identify suitable biological markers for predicting treatment efficacy (Table 2).

Figure 1 Schematic presentation of multiple conversion treatment options for intrahepatic cholangiocarcinoma. TACE: Transarterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy; TARE: Transarterial radioembolization; PD-1: Programmed cell death 1; PD-L1: Programmed cell death-ligand 1; FGFR2: Fibroblast growth factor receptor 2; IDH1: Isocitrate dehydrogenase-1; HER2: Human epidermal growth factor receptor 2; NTRK: Neurotropic tyrosine kinase receptor; RET: Rearranged during transfection; Gem: Gemcitabine; Cis: Cisplatin; Gemox: Gemcitabine and oxaliplatin; FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy; PVE: Portal vein embolization.

Table 2 Ongoing clinical trials of combination therapy for advanced intrahepatic cholangiocarcinoma.

ClinicalTrials.gov reference	Study phase	Interventions	Primary endpoint	Status
NCT05400902	Phase 2	HAIC combined with tislelizumab and apatinib	ORR	Recruiting
NCT05535647	Phase 2	Regorafenib and HAIC	ORR	Not yet recruiting
		FOLFOX
NCT06239532	Phase 2	TAE + HAIC + tislelizumab + surufatinib	ORR	Recruiting
NCT05010668	Phase 2	Cryoablation combined with sintilimab plus lenvatinib	ORR	Recruiting
NCT04954781	Phase 2	TACE in combination with tislelizumab	ORR	Recruiting
NCT06298968	Phase 2	Combined therapy using GC, lenvatinib and adebrelimab	ORR	Recruiting
NCT04961970	Phase 3	HAIC with FOLFOX	OS	Recruiting
		Systemic chemotherapy with GP
NCT06335927	Phase 2	HAIC-Gemox + cadonilimab + regorafenib	ORR	Recruiting
NCT04238637	Phase 2	Y-90 SIRT + durvalumab	ORR	Recruiting
		Y-90 SIRT + durvalumab + tremelimumab
NCT05342194	Phase 3	Toripalimab, lenvatinib, and gemcitabine-based chemotherapy	OS	Not yet recruiting
		Toripalimab, oral placebo, and gemcitabine-based chemotherapy
		Intravenous placebo, oral placebo, and gemcitabine-based chemotherapy
NCT04299581	Phase 2	Cryoablation combined with anti-PD-1 antibody	ORR	Recruiting
NCT05781958	Phase 2	Cadonilimab combined with gemcitabine and cisplatin	ORR	Active, not recruiting
NCT05174650	Phase 2	Combined treatment with atezolizumab and derazantinib	ORR	Active, not recruiting
NCT05422690	Phase 2	Gemcitabine, cisplatin and durvalumab chemotherapy treatments with Y-90	ORR	Recruiting
NCT04454905	Phase 2	Camrelizumab in combination with apatinib	PFS	Recruiting
NCT06648525	Phase 2	Adebrelimab + irinotecan liposomes + 5-fluorouracil + calcium folinate + lenvatinib	PFS	Not yet recruiting
		Adebrelimab + irinotecan liposomes + 5-fluorouracil + calcium folinate
NCT05738057	Phase 2	Combined therapy using D-TACE, gemcitabine and cisplatin, and camrelizumab	Conversion rate	Recruiting
NCT05835245	Phase 2	Cryoablation combined with sintilimab plus lenvatinib	ORR	Recruiting
NCT06058663	Phase 1	Radioembolization with tremelimumab and durvalumab	Incidence of treatment-emergent adverse events	Recruiting
NCT05655949	Phase 2	Gemcitabine + cisplatin + durvalumab + Y-90 selective internal radiation therapy	PFS	Recruiting
			Incidence of grade 3 or higher treatment-related toxicity
NCT06567600	Phase 2	Low-dose gemcitabine and cisplatin and PD-1/PD-L1 antibody	ORR	Not yet recruiting
NCT04634058	Phase 2	PD-L1 antibody combined with CTLA-4 antibody	ORR	Recruiting
NCT01862315	Phase 2	Hepatic arterial infusion with floxuridine and dexamethasone combined with systemic Gemox	PFS	Active, not recruiting
NCT05348811	Phase 2	HAIC combined with donafenib and sintilimab	ORR	Recruiting
NCT06192797	Phase 2	Combined HAIC, lenvatinib and pucotenlimab	Number of patients amendable to curative surgical interventions	Recruiting
NCT06192784	Phase 2	Combined DEB-TACE, lenvatinib and pucotenlimab	Number of patients amendable to curative surgical interventions	Recruiting
NCT04834674	Phase 2	DEB-TACE combined with apatinib and PD-1 antibody	ORR	Recruiting
			PFS
NCT05913661	Phase 2	Pemigatinib combined with PD-1 inhibitor	ORR	Recruiting

HAIC: Hepatic arterial infusion chemotherapy; ORR: Objective response rate; FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; TAE: Transcatheter arterial embolization; GC: Gemcitabine plus cisplatin; GP: Gemcitabine and cisplatin; Gemox: Gemcitabine and oxaliplatin; Y-90: Yttrium-90; SIRT: Selective internal radiation therapy; OS: Overall survival; PD-1: Programmed cell death 1; PFS: Progression free survival; PD-L1: Programmed cell death-ligand 1; CTLA-4: Cytotoxic T-lymphocyte antigen-4; DEB-TACE: Drug-eluting bead transarterial chemoembolization.

BIOMARKERS FOR TREATMENT GUIDANCE AND RESPONSE PREDICTION

On the basis of extensive research on the pathogenesis of ICC, personalized precision therapy based on immune and targeted therapy has emerged as a new treatment approach that has transformed clinical practice in recent years. Additionally, a number of studies have investigated biomarkers in order to better achieve the goal of precision treatment. It is becoming increasingly recognized that biomarkers, as potent tools for predicting treatment effects and patient prognosis, can be used to guide clinical practice and optimize the benefits of patient conversion treatment.

As mentioned above, the identification of sensitive biomarkers, such as FGFR2 fusions and IDH1 mutations, has become an important step in selecting ICC patients for targeted therapy. Furthermore, more genes are under investigation as biomarkers. In a previous study, researchers discovered that ARID1A is downregulated in ICC, which was correlated with unfavorable clinicopathological characteristics and poor prognosis, indicating that ARID1A may function as a prognosis indicator for ICC patients[118]. BAP1 is also regarded as a putative tumor suppressor in ICC and may function as a significant prognostic indicator and potential therapeutic target. Reduced BAP1 expression is strongly associated with OS and recurrence-free survival after surgery[119].

PD-1/PD-L1 expression is frequently utilized as a biomarker for immune checkpoint inhibitors. In the setting of ICC, PD-L1 expression is strongly linked with tumor invasion, tumor-node-metastasis stage, and other markers[120,121]. The immune system may successfully resume its attack on tumor cells by blocking the interaction between PD-1/PD-L1, and this therapeutic approach has emerged as a significant advancement in cancer treatment today[122].

Microsatellite instability has been investigated as a biomarker for the treatment of ICC[123], but the infrequency of microsatellite instability in ICC has hindered the ability to draw definitive conclusions about its occurrence and prognostic significance[124]. Furthermore, research has demonstrated that tumor mutation burden is an independent marker for the prognosis of ICC patients[125]. In addition to the biomarkers mentioned above, other factors that are being investigated include circulating tumor DNA and interleukin-6[126,127]. The identification of ICC biomarkers offers a basis for the development of clinical treatment strategies. Consequently, it is crucial to focus on the identification and investigation of ICC molecular targets and immune checkpoints to facilitate conversion treatment for patients with advanced ICC.

CONCLUSION

ICC remains an aggressive cancer that is almost always fatal and is becoming more common. Liver resection is one treatment that can improve long-term survival for people with ICC; however, the overall prognosis for these patients remains poor. Through ongoing advancements in tumor therapy, the stage of ICC can be reduced via systemic or local treatments in conjunction with techniques such as PVE and ALPPS, hence improving the resectability of ICC.

Conversion treatment has emerged as a viable option for patients with initially unresectable ICC, aiming to reduce the tumor burden and increase the likelihood of successful surgical resection. Although this approach has potential, there are still several challenges. The interventions used for ICC differ markedly among studies regarding combinations of medicines, dosing protocols, and patient criteria, resulting in diversity in clinical outcomes. The purpose of most related clinical trials is to explore the efficacy of new treatment options, and a small number of patients have unexpected conversion resections obtained during palliative treatment. Consequently, the treatment methods that yielded favorable outcomes in the trial have limited applicability for ICC conversion treatment. In conclusion, while conversion treatment may serve as a revolutionary treatment approach for patients with locally advanced ICC, considerable efforts are needed to produce more solid data. Reliable recommendations for the clinical implementation of conversion treatment in ICC can be established only through these procedures.