Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy with a globally increasing incidence, accounting for approximately 15% of primary liver tumors and 10%-20% of biliary tract cancers^[1]. Most patients with iCCA have a poor prognosis due to the aggressive nature of the disease, its frequent presentation at advanced stages, and the limited efficacy of standard chemotherapy regimens^[1,2]. In early-stage disease, surgery combined with adjuvant chemotherapy remains the cornerstone of treatment^[3,4]. For advanced stages, systemic therapy represents the standard of care, with survival outcomes improving following the introduction of targeted therapies and immunotherapy^[5-7].

The majority of patients are diagnosed with unresectable disease^[1]. As observed in other liver tumors, in selected patients, systemic therapy may induce sufficient tumor shrinkage to allow conversion to secondary resectability. In hepatocellular carcinoma and colorectal liver metastases, conversion therapy followed by surgery has been associated with a significant survival advantage compared with palliative treatment alone^[8-11]. Preliminary findings suggest similar results in iCCA^[12], although available studies are heterogeneous in terms of therapeutic approach (systemic therapy, radioembolization, intra-arterial chemotherapy or radiotherapy), inclusion criteria, and conversion rates.

Conversely, liver resection with lymphadenectomy is recommended for all patients with technically resectable disease^[13-15]. Advances in liver surgery have enabled resection even in patients with extensive tumor burden or complex disease presentations^[16,17]. However, about 15%-20% of patients experience very early recurrence (≤ 6 months) and early cancer-related death, without deriving a meaningful survival benefit from surgery^[18-21]. Oncologic resectability, defined as resection associated with a survival benefit, does not necessarily coincide with technical resectability, and the former should guide multidisciplinary decision-making^[22-24]. Patients who are technically resectable but of uncertain oncologic resectability may undergo preoperative “selection” through neoadjuvant treatment^[25]. Theoretically, this approach may help identify patients with more favorable tumor biology while also reducing tumor size, facilitating safer resections, and improving R0 rates^[24,25]. In colorectal liver metastases, neoadjuvant therapy has become standard practice in most cases^[26]. Data regarding its use in iCCA remain preliminary, heterogeneous, and challenging to interpret when considered individually.

The present study aims to clarify the role of systemic therapies in conversion strategies for initially unresectable iCCA and in neoadjuvant settings for resectable disease through a systematic review and meta-analysis of the available literature.

The present review aimed to address the following key clinical questions regarding the use of systemic therapy as conversion or neoadjuvant treatment in patients with iCCA.

The first PICOTS concerns conversion therapy: Do patients who undergo resection after conversion therapy achieve a survival benefit compared with those treated with systemic therapy alone?

In details:P (Patients): Patients with unresectable iCCAI (Intervention): Conversion strategyC (Comparison): Systemic therapyO (Outcomes): overall survival (OS)T (Timing): Outcomes at 12, 36, and 60 monthsS (Study design): Systematic review of the available original articles and meta-analysis of results.

The second PICOTS concerns neoadjuvant therapy: Does neoadjuvant therapy followed by surgery provide any survival benefit compared with upfront surgery?

In details:P (Patients): Patients with resectable iCCAI (Intervention): Neoadjuvant therapyC (Comparison): Upfront surgeryO (Outcomes): OST (Timing): Outcomes at 12, 36, and 60 monthsS (Study design): Systematic review of the available original articles and meta-analysis of results.

In patients undergoing conversion therapy, the primary endpoints were to assess the secondary resectability rate of initially unresectable cases and their oncological outcomes after surgery compared with patients receiving palliative systemic therapy. In patients receiving neoadjuvant therapy, the primary endpoints were the dropout rate during preoperative systemic therapy and the oncological outcomes of resected patients after systemic therapy compared with those undergoing upfront surgery. In both groups, the secondary endpoints included the radiological and pathological response to systemic therapy, and the 90-day postoperative outcomes of liver resection in pretreated patients.

Online search conducted in PubMed database identified 1,981 papers. Initial screening led to the exclusion of five duplicates and 1,925 articles based on title and abstract evaluation. The full texts of the remaining 51 papers were retrieved and analyzed, of which 21 were retained for the present analysis^[39-59]. The selection process is summarized in Figure 1.

The characteristics of the included papers are reported in Table 1. All studies except three were published since 2020, and six (29%) were multicenter. The papers included one randomized controlled trial (gemcitabine, cisplatin, and S-1 chemotherapy vs. gemcitabine and cisplatin in a conversion setting), two prospective series, and 18 retrospective analyses. Three studies, all comparing neoadjuvant therapy followed by surgery with upfront surgery, used propensity score matching analysis^[44,51,58].

Thirteen analyses addressed the outcomes of conversion therapy, while eight addressed the outcomes of neoadjuvant therapy. The distinction between conversion and neoadjuvant settings was based on the definition of iCCA as unresectable or resectable, the inclusion criteria that allowed classification of patients as resectable or unresectable, or the authors’ statements in the Methods section. Notably, one study combined the two groups (conversion and neoadjuvant) without reporting separate results. Because this study focused exclusively on resected patients and included a predominance of neoadjuvant over conversion cases, it was classified within the neoadjuvant group^[42].

The median number of included patients per study was 45 (IQR 23-77), and their characteristics are summarized in Table 2.

According to the NOS, the overall quality of comparative studies was low, with only two studies scoring 7 or higher [Supplementary Table 2].

The present study, by pooling available evidence through rigorous methodology, demonstrates that systemic therapy is central to a biology-driven approach in the management of patients with iCCA, without adversely affecting postoperative recovery. In selected patients with initially unresectable disease, systemic therapy can achieve conversion to resectability in approximately one-fourth of cases, resulting in excellent long-term survival rates approaching those of patients who are upfront resectable. In high-risk resectable patients, neoadjuvant treatment was associated with superior survival compared with upfront surgery when the treatment strategy was successfully completed, although a dropout rate exceeding 20% and potential biases in the available studies warrant careful consideration.

Understanding tumor biology is fundamental to a true precision-medicine approach. Surgical oncologists must shift their focus from technical to oncologic resectability, identifying which patients, and at what time, truly benefit from surgery^[22,25]. In this context, collaboration between surgical and medical oncologists within hepatobiliary multidisciplinary teams has intensified, driven by the increasing aggressiveness of surgical approaches and the growing effectiveness of modern systemic therapies^{[5-7,16,17,62,63]}. Conversion and neoadjuvant therapies are now routinely considered in the management of liver malignancies, although evidence supporting their specific benefits in iCCA remains limited.

Before discussing the outcomes of onco-surgical strategies, a preliminary comment is needed regarding the definitions of unresectable and high-risk iCCA. Despite ongoing efforts to reach a consensus, substantial heterogeneity persists in liver disease resectability criteria^[64]. Interestingly, some consistency emerged among the analyzed studies, with common criteria for unresectability including bilateral vascular and/or biliary involvement. Some authors more precisely defined the limit as the technical unreconstructability of hepatic vessels or bile ducts^{[43,46-48,52]}. Choi et al. specifically defined the limit for biliary reconstruction as bilateral tumor extension beyond the borders of the respective portal veins^[43]. Murakami et al. proposed a definition of unresectability as tumor extension more distal than 10 mm from both the U point (the inflection between the umbilical portion and transverse sections of the left portal vein) and the P point (the junction between the anterior and posterior branches of the right portal vein)^[52]. Another consistent criterion was an insufficient future liver remnant, although liver hypertrophy techniques may be applied to overcome this limitation^[65]. Some agreement was also observed regarding distant or extensive lymph node involvement and intrahepatic metastases, although for the latter, the distinction between multifocal and metastatic disease remains blurred. On the contrary, identifying high-risk patients within the technically resectable group, and thus defining appropriate indications for neoadjuvant therapy, remains far less well established. Only two of the eight studies provided explicit definitions^[42,50], highlighting substantial uncertainty, with N+ tumors and multifocal disease being the most commonly shared indications. However, when considering ongoing trials, such uncertainty appears to be more theoretical than practical. Indeed, current studies evaluating neoadjuvant systemic therapy for resectable iCCA adopt fairly homogeneous inclusion criteria [Table 4], based on risk factors for early postoperative recurrence and established prognostic factors^{[18-21,66,67]}. De facto, all studies included patients with a solitary tumor > 5 cm, multiple tumors, tumors with vascular invasion, or confirmed or suspected nodal involvement. Consequently, if these studies yield positive results, the indication for neoadjuvant therapy will be established. Debate remains regarding the assessment of satellite nodules, the CA 19-9 cutoff value, and the likelihood of achieving a complete resection. Although this latter criterion has been included in only one trial (NCT06037980), we consider R0 resection mandatory and believe that, when it cannot be reasonably ensured, this should constitute an indication for preoperative treatment.

Most iCCA patients are unresectable at diagnosis, and systemic therapy represents their only potential treatment^[1]; surgery can be considered secondarily if sufficient tumor shrinkage or downstaging occurs. The concept of conversion therapy in hepatic tumors, initially introduced by Bismuth et al. in 1996 for colorectal liver metastases^[68], has become a cornerstone in liver oncology, shifting secondary resectability from an occasional outcome to a defined treatment goal. Several conversion strategies for iCCA have been explored, often including radioembolization or intra-arterial treatments^[69-71]. The present analysis focused exclusively on systemic therapies and confirmed that, in selected patient cohorts, secondary resectability can be achieved in approximately one-fourth of cases (even up to one-third of cases in studies that explicitly detailed resectability criteria), with excellent R0 resection rates, exceeding 80%. Even if conversion rates varied across studies, patients who achieved secondary resection consistently showed excellent survival outcomes, with 5-year survival rates approaching those of upfront resectable patients and markedly exceeding those of unresected cases. With the advent of modern systemic treatments, including immunotherapy and targeted agents^[5-7], response rates are expected to improve further increasing the number of converted patients.

The present meta-analysis highlighted several relevant points. The main finding favored neoadjuvant therapy: patients who completed the full treatment sequence (preoperative therapy followed by surgery) achieved higher OS from diagnosis than those undergoing upfront surgery (44% vs. 37% at five years), corresponding to an expected survival gain of approximately 3.6 months. Additionally, Wehrle et al. reported a lower number of positive lymph nodes in patients receiving preoperative treatment^[58]. However, these positive outcomes should be interpreted with caution for at least two reasons. First, neoadjuvant therapy did not result in higher OS or RFS from surgery, nor in increased R0 resection rates. Second, all comparative studies analyzing OS from diagnosis included only resected patients, excluding those who dropped out from the neoadjuvant arm, thereby introducing a potential immortal time bias. Radiological disease progression occurred in approximately 10% of patients, consistent with rates generally reported and accepted for colorectal liver metastases^[72]. However, the overall dropout rate reported by the only available intention-to-treat study exceeded 20% (7/29)^[50]. Such a high dropout rate suggests that the survival benefit observed in the neoadjuvant group compared with upfront surgery could be substantially attenuated in an intention-to-treat perspective and raises concerns about the potential loss of a curative opportunity in patients who were initially resectable. Ongoing trials will answer these questions, but some considerations can already be made. The high dropout risk could be perceived differently when evaluated in the light of the previously mentioned 15%-20% risk of futile surgery after upfront resection due to very-early recurrence, a risk that may be even higher in patients with negative prognostic factors selected for neoadjuvant strategies^[18-21]. Would neoadjuvant therapy be considered a failure if it achieves survival similar to upfront surgery, given that it would spare a futile resection in approximately one-fifth of patients? Furthermore, the dropout risk is expected to decrease with the adoption of immune checkpoint inhibitors and targeted therapies, which are associated with higher response rates compared with standard chemotherapy^[5-7].

A further point of interest is the potential negative impact of preoperative therapy on postoperative outcomes. Early reports in patients with colorectal liver metastases undergoing hepatectomy after systemic therapy indicated higher blood loss, increased risk of liver failure, and even higher mortality compared with untreated patients^[73,74]. However, surgeons have learned to manage chemotherapy-related parenchymal injuries by adopting an adequate chemotherapy-to-surgery interval and by setting a higher cut-off value for the minimal volume of the future liver remnant^[75]. The experience accumulated in metastatic patients has been valuable for iCCA. Indeed, the present study confirmed low mortality rates and acceptable rates of severe morbidity after surgery in patients receiving preoperative chemotherapy, with minimal impact. Initially unresectable patients experienced slightly higher severe morbidity rates, but this is more likely attributable to the complexity of surgery rather than systemic treatment. Some concerns remain regarding increased blood loss, which warrant further investigation. In patients with colorectal liver metastases, chemotherapy has been associated with fragile livers, which may lead to increased intraoperative complexity and a higher bleeding risk^[75]. In iCCA patients, the scenario may be even more critical, as chemotherapy-related liver injury can be associated with pre-existing underlying fibrosis or cirrhosis, and tumors often present as large, deep-located lesions.

The present analysis is clinically relevant because it addresses several open questions. First, it highlights the importance of defining oncological resectability in iCCA, which is crucial for optimizing outcomes beyond purely technical considerations. Despite the heterogeneity of the literature, a relatively consistent definition of unresectability emerged, along with concordant characteristics of candidates for neoadjuvant therapy. Second, it clarifies the outcomes of standard systemic chemotherapy, highlighting both established evidence and existing knowledge gaps. Although no data are currently available for immunotherapy and targeted therapies, this should not be considered a major limitation, as not all ongoing neoadjuvant trials include immunotherapy and targeted therapies are still considered second-line options. The results reported here provide an essential reference for comparisons with future treatment strategies. Third, the favorable results observed in the conversion setting - both in terms of conversion rate and post-resection survival - support the development of a systematic approach aimed at achieving secondary resectability. Finally, the benefits of neoadjuvant treatment in resectable patients, together with the absence of any negative impact on postoperative outcomes, support this strategy whenever the advantage of upfront surgery is highly uncertain.

Some limitations should be acknowledged. First, most of the included studies were retrospective and had major limitations in design. Among conversion analyses, most were exploratory and did not include a well-designed comparison with other populations; in the neoadjuvant setting, only one had an intention-to-treat design, limiting a comprehensive assessment of the true impact of systemic therapy. No study explored the predictive factors of dropout, which could be valuable when scheduling a neoadjuvant therapy. Second, inclusion criteria were heterogeneous or, in some cases, not clearly defined, making direct comparisons challenging and pooled data difficult to interpret. Even the definitions of resectability and high-risk patients are not universally standardized, further complicating consistent classification of results. Finally, although most studies were recent, modern immunotherapies and targeted agents were rarely included. While a greater effect and benefit from preoperative treatment can be hypothesized, new specific evidence is needed.

In conclusion, secondary resectability should be the primary goal of systemic therapy in initially unresectable patients. Indications for neoadjuvant therapy should still be considered with caution, and its benefits require further validation through additional data; however, a short preoperative treatment may be considered in resectable patients with aggressive disease features or at high risk of incomplete surgery, acknowledging a non-negligible dropout rate (approximately 20%). If ongoing neoadjuvant trials yield positive results, based on their homogeneous inclusion criteria, indications will likely be rapidly extended to all patients with a solitary tumor > 5 cm, multiple lesions, N+ disease, or vascular invasion. The findings of the present review should guide multidisciplinary decision-making while awaiting conclusive evidence.