Conversion treatment for advanced intrahepatic cholangiocarcinoma: Opportunities and challenges

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.

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.