Rapid Recurrence 4 Months Post-Surgery and No Options Left? HAIC Combined with Immunotherapy Achieves a Breakthrough in Desperate Circumstances

Case Introduction

This case explores a patient with cholangiocarcinoma who developed liver metastasis with PD-L1 high expression shortly after surgery, who achieved disease control through hepatic arterial infusion chemotherapy (HAIC) combined with immunotherapy induction therapy, followed by ongoing immunological maintenance treatment. The core challenge lay in selecting an effective strategy to control liver metastatic lesions while managing a "mixed response" pattern during treatment — where some lesions shrank while new ones appeared simultaneously.

The multidisciplinary team (MDT) ultimately employed HAIC combined with immunotherapy, achieving effective disease control. This case suggests that for patients with PD-L1 high-expression cholangiocarcinoma developing post-operative liver metastasis as second-line treatment, HAIC combined with immunotherapy may represent a promising therapeutic approach worthy of exploration.

I. Case Overview: Baseline Status and Core Challenges

Baseline Status

Patient: Male, 58 years old.

October 2024: Underwent pancreaticoduodenectomy (Whipple procedure). Postoperative pathology confirmed: bile duct poorly differentiated adenocarcinoma, invading the full thickness of the bile duct wall, with perineural invasion. No lymph node involvement detected.

Pathological staging: T3N0M0 (Stage IIB).

Molecular/genetic profiling:

• PD-L1 expression: TPS 60%, CPS = 65 (very high)
• KRAS p.G12R mutation: variant allele frequency 7.30%
• ARID1A p.Q372Sfs*19 frameshift mutation: VAF 10.4%

Adjuvant chemotherapy: Gemcitabine + S-1 (tegafur/gimeracil/oteracil potassium), 3 cycles completed.

Disease-free survival (DFS): Only 4 months before progression was documented.

Core Challenge at Progression

After completing 3 cycles of adjuvant chemotherapy, imaging revealed:

• Intrahepatic and Glisson's capsule multiple metastases
• Metastases in the right anterior lobe of the liver and body/tail region of pancreas
• Suspected metastatic lymph nodes at the porta hepatis and retroperitoneal regions

Critical question: How to effectively control these metastatic lesions and provide precise individualized treatment for this patient with advanced biliary tract cancer?

II. Decision-Making: MDT Core Analysis and Strategy Deliberation

MDT Team Composition: Medical Oncology, Hepatobiliary Surgery, Interventional Radiology, Radiology, Pathology.

Following confirmation of disease progression, the MDT team deliberated on three potential pathways for managing rapid-onset liver metastasis from cholangiocarcinoma after first-line failure:

Pathway A: Locally-Dominant Treatment

Proposed stereotactic radiotherapy or ablation for intrahepatic multiple metastatic lesions. Advantages: Rapid local control, physical ablation overcoming the limited systemic efficacy typically seen in cholangiocarcinoma, with potential synergistic antigen release for subsequent immunotherapy. Limitations: The patient already had suspected extrahepatic metastases; local treatment cannot address systemic dissemination. Additionally, treating numerous intrahepatic lesions via irradiation or ablation poses significant hepatotoxicity risk that could compromise future systemic therapies. This pathway was considered too risky as a primary strategy and was not adopted.

Pathway B: Systemic Targeted Therapy for KRAS p.G12R Mutation

Genomic testing identified KRAS p.G12R as a clear driver mutation. While targeted agents against KRAS G12C have achieved clinical success and pan-RAS inhibitors show promise in early trials, data specifically for cholangiocarcinoma remains limited. Furthermore, no pan-RAS inhibitor clinical trials were available for enrollment in China at the time. Although KRAS G12R could potentially serve as a backup option, it was not pursued as the primary strategy due to lack of accessible targeted drugs.

Pathway C: Hepatic Arterial Infusion Chemotherapy (HAIC) + Immunotherapy

Based on the Korean NIFTY study, liposomal irinotecan (nal-IRI) combined with 5-fluorouracil (5-FU) and leucovorin (LV) has demonstrated efficacy as second-line therapy for advanced biliary tract cancer progressing after gemcitabine-based regimens. HAIC delivers higher concentrations of chemotherapeutic agents directly into the hepatic arterial system.

Key advantages: Exceptional control over intrahepatic disease (the "main battlefield"), relatively lower systemic toxicity — making it ideal for patients whose dominant burden is hepatic. Critically, the massive tumor cell killing induced by HAIC releases abundant tumor antigens that produce powerful "synergistic immune activation" when combined with PD-1 inhibition — especially relevant given this patient's PD-L1 CPS of 65 (an absolute advantage population).

Multidisciplinary Perspective Convergence

Medical Oncology perspective: Must use HAIC to rapidly control high-burden intrahepatic disease and prevent impending hepatic failure, while leveraging the patient's exceptionally high PD-L1 expression to initiate immunotherapy for maximal benefit.

Hepatobiliary Surgery & Interventional Radiology perspective: HAIC achieves potent cytoreduction via locally concentrated chemotherapy that intravenous systemic delivery cannot match — the most direct technical means to stabilize the current critical situation.

Biological considerations: The KRAS G12R mutation represents a potential future treatment reserve. Imaging findings necessitate close monitoring of extrahepatic lesion dynamics throughout treatment.

Final MDT Decision

The MDT team recommended "Hepatic Arterial Infusion Chemotherapy combined with PD-1 inhibitor" as the treatment strategy. This decision was grounded in the pragmatic assessment of the patient's high intrahepatic tumor burden, rapid disease trajectory, and the definitive advantage conferred by extremely high PD-L1 expression. The core objective was to employ the most powerful local modality to swiftly control the dominant hepatic lesions while simultaneously initiating the most promising systemic immunotherapy — buying time and creating options for subsequent lines of treatment.

III. The Breakthrough: Treatment Course and Technical Highlights

Treatment Timeline

Phase	Treatment	Duration / Notes
Primary Surgery	Pancreaticoduodenectomy (Whipple)	Oct 2024
Adjuvant Chemo	Gemcitabine + S-1	3 cycles
Progression	Liver metastasis confirmed	DFS: 4 months
Second-Line (Induction)	HAIC (nal-IRI + 5-FU + LV) + Tislelizumab (anti-PD-1)	7 cycles
Maintenance (Ongoing)	Tislelizumab monotherapy	Continuing; PFS > 1 year

Key Technical Analysis

The cornerstone of this case lies in employing HAIC as a "precision strike" against hepatic metastasis. As a localized treatment modality, HAIC delivers chemotherapeutic agents precisely to the tumor site via the hepatic artery, achieving significantly higher local drug concentrations while reducing systemic exposure and associated toxicities. When combined with immunotherapy, this creates a genuine synergistic effect between HAIC and immune activation.

Navigating the "Mixed Response" Challenge

A critical turning point emerged after Cycle 5: The original hepatic metastatic lesions showed shrinkage compared to baseline, but a new nodule appeared in the right lobe of the liver — a classic "mixed response" scenario that became the decisive moment determining whether treatment should continue or be abandoned.

MDT Assessment Strategy for Mixed Response:

• When feasible, the MDT recommended active biopsy of newly appearing lesions to confirm pathological nature.
• The patient declined repeat biopsy. In its absence, the MDT team refused to rely solely on RECIST criteria ("appearance of new lesions = progressive disease") as grounds for discontinuation.
• Radiology provided crucial objective evidence: continued shrinkage of established intrahepatic lesions, resolution of intrahepatic bile duct dilation — both indicating overall tumor burden remained under control.
• MDT decision: Maintain original HAIC + immunotherapy regimen.

This nuanced evaluation proved correct: the newly apparent nodule resolved on imaging after 2 additional treatment cycles, confirming the mixed response did not represent true disease progression but rather an immunologic phenomenon consistent with effective treatment.

IV. Outcome Evaluation and Follow-Up Strategy

Following completion of the combined HAIC and immunotherapy induction phase, the patient transitioned to immunological maintenance monotherapy. Serial radiographic assessments demonstrate:

• Newly observed lesion (at cycle 5) no longer visible on follow-up imaging after 2 additional cycles — confirming treatment effectiveness
• Overall response: Stable Disease (SD)
• No definitively new lesions detected since

Survival outcome: From initial documentation of liver metastasis and initiation of treatment, through the most recent assessment, the patient's progression-free survival (PFS) has exceeded 1 year and continues to extend. The patient remains under active surveillance.

Quality of life: Overall performance status is good. Treatment tolerance is acceptable with no Grade 3 or higher adverse events recorded.

Ongoing management: The patient continues immunological maintenance treatment with comprehensive reassessment every 2–3 months, including tumor marker panels and imaging studies (with particular emphasis on monitoring hepatic metastasis dynamics). Should unequivocal disease progression be documented during follow-up, the MDT will reconvene immediately. Subsequent therapeutic strategies will be selected based on progression pattern, performance status, and updated molecular profiling results.

V. Key Insights from This Case

Insight 1: HAIC as a Precision Chemotherapy Platform

HAIC represents an optimized chemotherapy delivery platform capable of achieving precision targeting: direct drug delivery to the lesion site, reduced adverse effects from systemic exposure, and enhanced local drug concentration. Its efficacy is well-established across multiple indications. When combined with immunotherapy, the overall regimen demonstrates favorable safety and tolerability profiles.

Insight 2: Mixed Response Is Not Necessarily Treatment Endpoint

A "mixed response" does not automatically signal treatment failure requiring immediate switch. It demands refined evaluation integrating non-target lesion improvement and other objective evidence. Where possible, re-biopsy of emerging lesions can clarify whether they represent true progression or pseudo-progression/immune-related phenomena. This case demonstrates that carefully selected patients can derive continued benefit from maintaining treatment despite mixed response patterns — accurate identification of such patients requires the MDT framework.

Insight 3: Individualized Strategies Within the MDT Framework

This case exemplifies how advanced malignancies require individualized strategies formulated within a robust MDT framework — integrating molecular biomarker data, treatment sequencing logic, and dynamic response assessment rather than algorithmic protocol adherence alone.

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Expert Commentary

Prof. Bai Li

Department of Medical Oncology, PLA General Hospital (Chinese People's Liberation Army General Hospital, Beijing)

For cholangiocarcinoma regardless of primary site, once postoperative recurrence/metastasis occurs or the disease presents at an unresectable advanced stage, the response to chemotherapy is generally poor — particularly upon entering later-line treatments.

The landmark ABC-06 study established FOLFOX as the standard second-line chemotherapy recommendation for advanced biliary tract cancer, yet the objective response rate (ORR) reached only 5% with a median overall survival (mOS) of merely 6.2 months. The LEAP-005 study evaluated lenvatinib plus pembrolizumab, achieving an ORR of only 10% and mOS of 8.6 months. These figures underscore the reality that later-line treatment options remain limited, and median overall survival without actionable targets does not exceed 9 months.

HAIC originated primarily from the management of locally advanced or perioperative hepatocellular carcinoma (HCC). At ESMO 2025, Professor Zeng Yongyi from Fujian Medical University's Mengchao Hepatobiliary Hospital presented data on "Camrelizumab combined with apatinib plus TACE ± HAIC as first-line treatment for unresectable HCC", demonstrating that the HAIC cohort achieved an ORR of 46.5% and DCR of 93% — substantially outperforming the TACE-alone group (27.1% ORR, 91.5% DCR). Similar results have been reported across multiple studies. However, such evidence has rarely been demonstrated in cholangiocarcinoma.

This case innovatively extrapolates findings from HCC research to cholangiocarcinoma, leveraging the hepatic arterial first-pass effect to achieve intensive chemotherapy delivery while simultaneously combining immunotherapy — capitalizing on HAIC-induced improvements in the tumor immune microenvironment within hepatic metastatic deposits. The synergy between these modalities represents an optimized therapeutic strategy enabling prolonged survival.

Several distinctions between cholangiocarcinoma and HCC are particularly noteworthy:

1. Vascular supply differences: Cholangiocarcinoma lesions are predominantly hypovascular, which disfavors embolic approaches like conventional TACE.
2. Chemotherapy sensitivity: Cholangiocarcinoma relies more heavily on cytotoxic chemotherapy than HCC, where immunotherapy produces more pronounced tumor shrinkage. Moreover, the chemotherapy dose delivered via conventional TACE is markedly lower than that achievable with HAIC, resulting in weaker direct cytotoxic effects.
3. Systemic coverage: Despite being delivered via hepatic arterial catheterization, HAIC still provides equivalent systemic exposure to intravenous chemotherapy for any extrahepatic metastatic sites — an important advantage over purely locoregional embolic techniques.

Through HAIC-chemotherapy intercalated or sequential combination with immunotherapy (with or without antiangiogenic agents), the above disadvantages are meaningfully addressed. The preliminary outcomes from this case provide valuable reference and experience for treating other solid tumors where liver-dominant metastasis constitutes the principal pattern of spread — extending well beyond the traditional HCC indication.

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