Neoadjuvant and Adjuvant Therapy for Intrahepatic Cholangiocarcinoma

Neoadjuvant therapy refers to treatment aimed at reducing the size of the tumor before the main therapy (usually surgical resection), with the goal of decreasing postoperative recurrence and prolonging postoperative survival. It is primarily applicable to patients with resectable tumors who have high-risk factors for postoperative recurrence, which mainly include non-R0 resection, higher tumor stages (T2 and above), and lymph node metastasis. Mason et al. [9] showed that in ICC patients with T2/T3 stage or lymph node involvement, neoadjuvant therapy combined with surgery improved the 5-year survival rate compared to surgery alone (29.9% vs. 37.2%, P<0.001).

1.1 Neoadjuvant Chemotherapy:

Choi et al. [10] reported on the safety of neoadjuvant chemotherapy, and their study results indicated that neoadjuvant chemotherapy does not increase the incidence of complications within 30 days post-surgery for ICC patients, nor does it extend hospital stays. Currently, there are few studies on the efficacy of pure neoadjuvant chemotherapy, most of which are small retrospective studies. A previous multicenter retrospective study included 1,057 ICC patients undergoing surgical resection, of which 62 received neoadjuvant chemotherapy (18 received hepatic artery chemotherapy, and 44 received systemic chemotherapy). After propensity score matching, it was found that while the median survival time of the chemotherapy group showed some improvement compared to the non-chemotherapy group, the difference was not statistically significant (46.9 months vs. 29.4 months, P=0.136), which may be due to the low proportion of neoadjuvant chemotherapy patients and the overall utilization rate of neoadjuvant chemotherapy being low [11].

Sutton et al. [12] conducted a retrospective analysis of 52 ICC patients who underwent liver resection, of which 10 received gemcitabine combined with platinum-based therapy preoperatively. The results showed that this chemotherapy regimen could improve long-term survival post-surgery [hazard ratio (HR)=0.16, P=0.010]. To explore the beneficiary population and indications for neoadjuvant chemotherapy, many related studies are actively underway. A phase II randomized controlled trial (NCT04523402) is expected to enroll 100 ICC patients at high risk of lymph node metastasis, comparing the progression-free survival and overall survival outcomes between patients receiving preoperative gemcitabine with oxaliplatin (GEMOX) combined with surgery and those undergoing surgery alone. Another study (NCT03673072) will evaluate the survival time after preoperative gemcitabine combined with cisplatin treatment followed by surgery, discussing the feasibility of this chemotherapy regimen.

1.2 Neoadjuvant Combination Therapy:

Neoadjuvant chemotherapy combined with radiotherapy can improve postoperative survival in cholangiocarcinoma patients while maintaining good safety [13,14]. A retrospective study included 106 cholangiocarcinoma patients undergoing surgical resection (27 received neoadjuvant chemoradiotherapy), and the results indicated that the neoadjuvant chemoradiotherapy group had a higher 3-year recurrence-free survival rate (78% vs. 58%, P=0.026). After reducing treatment selection bias using propensity score inverse probability weighting, neoadjuvant therapy was found to improve patient survival (HR=0.35, P=0.002) [13].

The immune response rate in ICC is low, and the efficacy of immune checkpoint inhibitors as a monotherapy still has room for improvement. Thoroughly studying the mechanisms of tumor-immune interactions in ICC is an important entry point to address existing immunotherapy challenges. Lin et al. [15] analyzed the genomic and immune phenotypes of 45 tumor regions from 207 ICC samples and found that there is significant intratumoral heterogeneity in immune infiltration in ICC, with varying degrees of immune infiltration affecting the tumor microenvironment characteristics: tumors in areas of high immune infiltration had higher levels of neoantigen load and chemokine expression, while those in areas of low immune infiltration had significantly upregulated signaling pathways such as cell cycle and oxidative phosphorylation. This suggests that immunotherapy requires more precise treatment strategies to achieve better therapeutic effects. To explore the feasibility of immunotherapy in neoadjuvant treatment for ICC, a randomized controlled study (NCT05672537) aims to evaluate the effects of preoperative durvalumab combined with traditional chemotherapy in high-recurrence-risk ICC patients, with the primary endpoint being the 1-year recurrence-free survival rate.

The development of molecular biology and genomics has led to significant advances in targeted therapy research. Pemigatinib and futibatinib are FGFR inhibitors approved by the U.S. Food and Drug Administration for the treatment of cholangiocarcinoma, and previous studies have confirmed their therapeutic efficacy in unresectable ICC patients with FGFR fusions [16,17]. However, there have been no reports of FGFR inhibitors being used as adjuvant treatment. A phase II study (NCT05514912) will evaluate the clinical benefits of preoperative FGFR inhibitor (infigratinib) combined with chemotherapy in resectable ICC patients with FGFR fusions. Notably, ICC patients with FGFR2 alterations (fusions and mutations) have lower neoantigen loads and levels of immune infiltration, while FGFR2 inhibitors can drive immune changes, thereby enhancing the sensitivity of FGFR2-altered ICC patients to immunotherapy, indicating that a combination of immunotherapy and FGFR2 inhibitors may achieve better clinical outcomes in this patient population [15]. An ongoing phase II-III randomized controlled trial (NCT04669496) includes ICC patients with high recurrence risk and assesses the feasibility of combining immunotherapy (toripalimab) with targeted therapy (lenvatinib).

To further improve postoperative survival in ICC patients, adjuvant therapy has been widely used globally in recent years. A multicenter retrospective study included 412 patients, of which 77 received postoperative adjuvant therapy (32 received hepatic artery chemotherapy embolization, 21 received systemic chemotherapy, 10 received radiotherapy, and 14 received chemoradiotherapy). Compared to the surgery-only group, the adjuvant therapy group had a longer median survival time (43 months vs. 21 months, P=0.015), and this advantage remained statistically significant after propensity score matching analysis [18].

2.1 Systemic Therapy:

Previous studies have shown that adjuvant chemotherapy has a limited impact on survival in cholangiocarcinoma post-surgery. Factors such as the choice and dosage of chemotherapy drugs, as well as the prolonged interval from surgery to the start of chemotherapy or decreased tolerance to chemotherapy post-surgery, may contribute to this [19,20]. Nevertheless, both the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend adjuvant chemotherapy for cholangiocarcinoma patients. The BILCAP phase III study is the first large-sample study supporting the benefit of adjuvant chemotherapy for cholangiocarcinoma patients, enrolling 447 ICC patients, of which 223 received postoperative capecitabine treatment. Compared to the postoperative observation group, the capecitabine group had a longer median survival time (51.1 months vs. 36.4 months, P=0.028) [21].

There is still no consensus on which patients can benefit from adjuvant chemotherapy. It is generally believed that patients with high-risk factors for postoperative recurrence need to receive adjuvant chemotherapy. Endo et al. [22] analyzed data from 726 ICC patients to establish a preoperative risk prediction model to assess patient prognosis and the necessity of postoperative adjuvant chemotherapy. Factors strongly correlated with patient prognosis include tumor T stage (HR=1.73), lymph node status (HR=3.80), tumor antigen 19-9 level (HR=1.17), and morphological subtype (HR=2.19). Compared to ICC patients with earlier tumor stages, those with later stages (T2 and above) are more likely to benefit from adjuvant chemotherapy, leading to a clinical preference for using adjuvant chemotherapy in such patients. Reames et al. [23] found that among patients with later tumor stages, the 5-year survival rate of the non-adjuvant chemotherapy group was 30%, while that of the adjuvant chemotherapy group was 37%, with a statistically significant difference (P=0.006). A retrospective study involving 148 T1N0M0 ICC patients showed that the median survival time for the non-chemotherapy group was 34 months, while the adjuvant chemotherapy group did not reach the median survival time by the end of follow-up (P=0.005) [24], indicating that even patients with earlier pathological stages of ICC may benefit from adjuvant chemotherapy, although further large-sample data verification is needed.

Patients with lymph node-positive ICC have a higher rate of local or distant recurrence post-surgery, significantly impacting their prognosis, and whether postoperative adjuvant chemotherapy is beneficial for lymph node-positive cholangiocarcinoma patients remains controversial. A retrospective study showed that neither postoperative adjuvant chemotherapy nor radiotherapy had a significant impact on postoperative survival in lymph node-positive ICC patients [25]. In contrast, a multicenter study involving 1,154 ICC patients (347 received adjuvant chemotherapy) indicated in subgroup analysis that postoperative adjuvant chemotherapy is a protective factor for postoperative survival in N1 stage ICC patients (5-year survival rates: 18.3% vs. 12%, P=0.050). Notably, patients who did not undergo local lymph node resection during surgery, leading to an inability to assess lymph node status (Nx stage), were less likely to receive adjuvant chemotherapy than those with N0 stage [odds ratio (OR)=0.47, P<0.001], resulting in missed treatment opportunities [23]. Although lymphadenectomy for ICC has gradually gained attention in recent years, the lymphadenectomy rate for ICC patients in China is still below 50%, although it has shown an upward trend in recent years [26]. Considering the role of appropriate lymph node staging in prognosis and treatment, routine regional lymphadenectomy should be included as part of surgical treatment for ICC.

Additionally, if there are other high-risk recurrence factors, such as non-R0 resection or neurovascular invasion, adjuvant chemotherapy is necessary [27]. There is currently no industry-recognized standard for adjuvant chemotherapy regimens. Gemcitabine combined with platinum drugs is the first-line chemotherapy regimen for advanced ICC. A small sample prospective study used it as an adjuvant chemotherapy method for ICC, with a median survival time of 36.9 months [28]. Another retrospective study used a combination of gemcitabine, cisplatin, and low-dose 5-fluorouracil as a triplet adjuvant chemotherapy regimen, showing that patients who underwent surgery with this regimen had a 3-year survival rate superior to that of patients undergoing surgery alone (61.9% vs. 8.8%, P<0.001) [29]. Actively exploring various possibilities for adjuvant chemotherapy regimens will contribute to the implementation of more precise individualized treatment in the future.

Previous studies have shown that combined immunotherapy and chemotherapy can improve overall survival in advanced ICC patients [30], and research on this combination as adjuvant therapy for ICC is also actively underway, such as the triplet therapy of durvalumab and tremelimumab combined with capecitabine (NCT05239169), and the combination of toripalimab and capecitabine (NCT04782804). Additionally, anti-angiogenesis drugs can complement immunotherapy and chemotherapy, thereby improving postoperative survival in advanced ICC patients [31]. Research exploring the combined effects of anti-angiogenesis drugs with immunotherapy and chemotherapy in the field of adjuvant therapy will also be conducted (NCT05620498).

2.2 Local Treatment:

Interventional therapy is an important method for local treatment of ICC. Compared to postoperative systemic chemotherapy, adjuvant transcatheter arterial chemoembolization (TACE) can block the tumor’s blood supply, increase the local concentration of chemotherapy drugs, and reduce overall patient exposure, leading to better clinical outcomes [18,32]. A nomogram established based on carcinoembryonic antigen levels, tumor antigen 19-9 levels, vascular invasion, lymph node metastasis, local invasion, and tumor size and number can reasonably predict postoperative survival in ICC patients (C-index of 0.71), thus guiding the application of postoperative TACE: this nomogram divides patients into high, medium, and low-risk categories. For high-risk patients, the 1-year (61.3% vs. 33.8%, P=0.001), 3-year (28.3% vs. 7%, P=0.001), and 5-year (21.3% vs. 6.2%, P=0.001) survival rates in the TACE group were all higher than those in the non-TACE group; however, for low-risk and medium-risk patients, whether or not to undergo TACE post-surgery did not significantly impact patient prognosis [33]. In a cohort of ICC patients with TNM stage I who underwent R0 resection, the median survival time of patients who did not undergo TACE (234 patients) was 66.8 months, while the median survival time of TACE group patients (35 patients) was 59.9 months, with no statistical significance between the two groups (P=0.707), indicating that adjuvant TACE is not suitable for early-stage ICC patients who can be completely resected [34].

Yu et al. [35] conducted a retrospective analysis of 72 postoperative recurrent ICC patients and found that 46 recurrences occurred in high-risk lymphatic drainage areas (lymph nodes stations 8, 9, 12, 13, 14, 16), which should be included in the areas affected by adjuvant radiotherapy. For non-R0 resection or lymph node-positive ICC patients, adjuvant radiotherapy may provide survival benefits [20,36]. Jiang et al. [37] retrospectively analyzed data from 90 ICC patients with lymph node metastasis and found that adjuvant radiotherapy could improve postoperative survival in these patients (median survival time: 19.1 months vs. 9.5 months, P=0.011). Zheng et al. [3] included 70 ICC patients in their study, grouping them based on surgical margins and whether adjuvant radiotherapy was combined. Multivariate analysis showed that compared to narrow-margin (margin <1 cm) liver resection alone, narrow-margin resection combined with adjuvant radiotherapy could improve the 3-year survival rate (55% vs. 20%, P=0.011) and the 3-year disease-free survival rate (44% vs. 10%, P=0.031), and could achieve similar 3-year overall survival rates (55% vs. 65%, P=0.685) and 3-year disease-free survival rates (44% vs. 33%, P=0.583) compared to wide-margin resections.

2.3 Systemic Combined Local Treatment:

Kim et al. [38] conducted a retrospective analysis of 18 ICC patients after R1 resection, showing that the median local recurrence-free survival period for patients not receiving any treatment or only chemotherapy was 5.6 months, while the adjuvant chemoradiotherapy group did not reach the median local recurrence-free survival period (P<0.001). However, both groups had prolonged progression-free survival (5.6 months vs. 8.3 months, P=0.047). A retrospective study confirmed that R0 resection (P<0.001) and the American Joint Committee on Cancer pathological staging (P<0.001) are independent factors affecting prognosis, and that adjuvant synchronous chemoradiotherapy can improve postoperative survival in ICC patients with early pathological non-R0 resection and advanced pathology (HR=0.67, P=0.001), thus when assessing whether to conduct adjuvant chemoradiotherapy in ICC patients post-surgery, both margin status and pathological staging should be considered [39].

ICC has a poor prognosis, and radical surgical resection is currently the only potential cure for ICC. However, more than half of patients experience recurrence within 1-2 years post-surgery, significantly impacting their survival prognosis. Previous studies have shown that neoadjuvant and adjuvant therapies provide certain benefits for ICC patients with high-risk factors for postoperative recurrence. However, due to the low incidence of ICC, most current studies are small retrospective analyses, thus lacking strong evidence to support their efficacy. The rise of research in neoadjuvant and adjuvant therapy in recent years has brought new hope, but many issues remain to be resolved. On one hand, the timing, dosage, duration, and combinations of treatment strategies for neoadjuvant and adjuvant therapies need to be optimized; on the other hand, there are still many underlying mechanisms worth exploring regarding the interactions between tumors and chemotherapy, radiotherapy, immunotherapy, and targeted therapy. With the rapid development of artificial intelligence and molecular biology, it is believed that in the near future, ICC patients with high-risk factors for postoperative recurrence will receive more standardized and refined treatments.