Advances in the treatment of advanced unresectable intrahepatic cholangiocarcinoma

Authors: Li Qingze, Dong Guofei, Hao Qisheng, Li Xinyu, Gong Mingkai, Zha Lichao, Tian Lantian

Source: Chinese Journal of Hepatobiliary Surgery, 2024, 30(9)

summary

Intrahepatic cholangiocarcinoma is a highly malignant tumor with poor prognosis, and in the process of clinical diagnosis and treatment, only a few patients can receive timely surgical treatment, and most patients have local invasion or distant metastasis at the time of presentation, and can only prolong survival through adjuvant therapy. At present, the treatment methods for advanced intrahepatic cholangiocarcinoma include chemotherapy, targeted therapy and immunotherapy. This article reviews the progress of systemic therapy and some clinical trials in patients with advanced unresectable intrahepatic cholangiocarcinoma, so as to provide reference for the clinical diagnosis and treatment of intrahepatic cholangiocarcinoma.

The incidence of intrahepatic cholangiocarcinoma is on the rise worldwide [1]. Intrahepatic cholangiocarcinoma is a highly heterogeneous, aggressive, and prognostic malignancy, and is the second most common primary liver cancer after hepatocellular carcinoma [2, 3]. Intrahepatic bile duct stones, cirrhosis, hepatitis B virus, hepatitis C virus, etc., cause cholestasis and abnormal proliferation of bile duct endothelial cells, which in turn leads to intrahepatic cholangiocarcinoma [4]. Surgical resection is an important radical treatment for intrahepatic cholangiocarcinoma, but only patients diagnosed early have the opportunity to undergo surgery. The clinical manifestations of intrahepatic cholangiocarcinoma are non-specific, and only a few patients have symptoms such as discomfort and fatigue in the early stage of the disease course, which makes it difficult to diagnose in the early clinical stage, and most patients are found incidentally during health examination or other disease examinations. The early diagnosis rate of intrahepatic cholangiocarcinoma is less than 30%, and more than 70% of patients with intrahepatic cholangiocarcinoma are diagnosed when they have locally advanced symptoms or metastasis, and the opportunity for surgery is lost [5]. Chemotherapy is currently the main treatment for patients with intrahepatic cholangiocarcinoma who have multiple intrahepatic cholangiocarcinoma and lymph node or peritoneal metastases that are difficult to undergo surgery. The standard regimen of gemcitabine combined with cisplatin is mostly used for chemotherapy in patients with intrahepatic cholangiocarcinoma, but the objective response rate is only 20%, the median overall survival is 6~8 months, and the 5-year survival rate is less than 10% [6, 7, 8, 9]. Therefore, there is a clinical need to develop more accurate early diagnosis methods and comprehensive treatment strategies for patients with advanced intrahepatic cholangiocarcinoma. In recent years, scholars at home and abroad have carried out various studies and clinical attempts around the above issues, among which the research on targeted and immunotherapy for intrahepatic cholangiocarcinoma has made rapid progress. Therefore, this article reviews the progress of systemic therapy and the results of clinical trials in patients with newly diagnosed and unresectable intrahepatic cholangiocarcinoma, so as to provide reference for clinical diagnosis and treatment.

1. Targeted therapy

As more and more scholars recognize that gene mutations are an important feature of tumors, targeted therapy is becoming more and more important. Targeted therapy has gradually gained attention as an emerging treatment strategy. Targeted therapy can screen out patients with potential benefits and provide them with more targeted treatment options to improve treatment efficacy. Targeted therapy for breast cancer and lung cancer has made tremendous progress, and targeted drug therapy has significantly improved prognosis [10, 11]. With the in-depth study of the potential mechanism of intrahepatic cholangiocarcinoma and the rapid development of molecular sequencing technology, the gene mutation sites and potential therapeutic targets of intrahepatic cholangiocarcinoma have gradually become clear, making targeted therapy a promising treatment for patients with advanced inoperable intrahepatic cholangiocarcinoma. At present, commonly used targeted drugs include fibroblast growth factor receptor (FGFR)2 inhibitors, isocitrate dehydrogenase (IDH) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, etc.

1．FGFR：

FGFR is a group of tyrosine kinase receptors, which are mainly divided into 5 different isoforms FGFR1~5. Fibroblast growth factor (GF) plays a key role in cell proliferation, differentiation, apoptosis, and migration by signaling through receptor binding [12]. Genomic studies of intrahepatic cholangiocarcinoma have shown that approximately 23% of 72 patients with intrahepatic cholangiocarcinoma have FGFR2 gene fusions [13]. In a phase II clinical trial, FIGHT-202 (NCT02924376), in 107 patients with metastatic cholangiocarcinoma with FGFR-2 gene fusion or rearrangement, had an objective response rate of 35.5%, a disease control rate of 82.2%, and a median progression-free survival of 6.9 months and median overall survival of 21.1 months, respectively [14]. The results of FIGHT-302 (NCT03656536), a randomized, multicenter phase III clinical trial, compared pemitinib with gemcitabine in combination with cisplatin as the first-line treatment of patients with advanced intrahepatic cholangiocarcinoma with FGFR2 gene rearrangement [15]. In another Phase II clinical trial, FOENIX-CCA2 (NCT02052778), 103 previously treated patients with unresectable or metastatic FGFR2 gene fusion or rearrangement with intrahepatic cholangiocarcinoma had a significant tumor remission after treatment with futibatinib, with a median progression-free survival of 9.0 months and a median overall survival of 21.7 months [16]. In addition, a Phase III clinical trial evaluating the efficacy and safety of formitinib versus gemcitabine in combination with cisplatin chemotherapy as a first-line treatment for patients with advanced, metastatic or recurrent intrahepatic cholangiocarcinoma with FGFR2 gene rearrangement is underway (NCT04093362, NCT03656536). These drugs are approved by the United States Food and Drug Administration as treatment options for advanced FGFR2-mutated cholangiocarcinoma [17]. See Table 1.

Advances in the treatment of advanced unresectable intrahepatic cholangiocarcinoma

2．IDH：

IDH is an oxidoreductase enzyme in cellular metabolism, and mutations in the IDH-1 and IDH-2 genes are associated with the pathogenesis of intrahepatic cholangiocarcinoma [18]. In a phase III trial of 187 patients with IDH1 mutations in intrahepatic cholangiocarcinoma, the IDH1 inhibitor ivosidenib resulted in median progression-free survival of 2.7 months and median overall survival of 10.3 months, compared with 1.4 months and 7.5 months in the placebo group [19]. Ivosidenib is now approved by the United States Food and Drug Administration for the first-line treatment of intrahepatic cholangiocarcinoma progression [17].

3．EGFR：

EGFR is a transmembrane glycoprotein receptor that can bind to epidermal growth factor to activate intracellular signaling pathways, promote cell proliferation, angiogenesis, and inhibit apoptosis. Panitumumab is a humanized monoclonal antibody that targets EGFR and was originally used to treat metastatic colorectal cancer after chemotherapy failure. In a phase II clinical trial (NCT00948935) of 35 patients with unresectable advanced cholangiocarcinoma treated with a combination of panitumumab, gemcitabine, and irinotecan, the 5-month progression-free survival rate was 69%, the median progression-free survival was 9.7 months, and the median overall survival was 12.9 months [20]. With the continuous advancement of sequencing technology, gene sequencing for biliary tract malignancies has shown that EGFR mutations are present in more than 15% of biliary tract malignancies [18].

The genomic characteristics of intrahepatic cholangiocarcinoma can help patients to undergo specific treatments, predict treatment outcomes, and achieve more effective and personalized tumor management. Studies on intrahepatic cholangiocarcinoma have revealed the molecular mechanisms associated with the pathogenesis of intrahepatic cholangiocarcinoma and discovered many new therapeutic targets, but there is a certain gap between targeted therapy and significantly improving the 5-year overall survival rate of patients. More efficient sequencing methods and improved data analysis tools should be studied to facilitate comprehensive genetic testing of patients, identify potential molecular therapeutic targets, and guide patients in subsequent targeted therapy. It is believed that with the deepening of targeted therapy research, a steady stream of new therapeutic targets will emerge, making there a variety of options for the clinical treatment of intrahepatic cholangiocarcinoma.

2. Immunotherapy

Immunotherapy is playing a central role in cancer treatment and has received extensive attention as an emerging cancer treatment strategy. Normally, immune cells recognize and remove tumor cells from the body. However, tumor cells can interfere with the normal anti-tumor immune response through a variety of pathways, leading to immune dysregulation, which in turn leads to immune escape. Intrahepatic cholangiocarcinoma is often characterized by an inadequate blood supply to the extracellular matrix and interstitial that promotes connective tissue proliferation, and the matrix contains a mixture of many nonimmune and immune cells, such as tumor-associated fibroblasts and tumor-associated macrophages, which are prognostic disadvantages [21]. Tumor stroma can provide an environment conducive to tumor growth, metastasis, chemoresistance, and immune escape. The tumor microenvironment of intrahepatic cholangiocarcinoma has been analyzed based on stromal cell types and gene transcripts, and has been divided into four subtypes: immunodesert, immunogenic, myeloid, and mesenchymal [22]. These subtypes have different immune escape mechanisms, and tumor microenvironment typing can provide a reference for clinical trials to evaluate the effect of immunotherapy regimens in patients with intrahepatic cholangiocarcinoma and screen out immunotherapy regimens that are more suitable for patients.

Immunotherapy is developed on the basis of the study of tumor immune escape mechanisms, which can reactivate the anti-tumor immune response and block the pathways that lead to immune escape, thereby achieving the goal of radical cure or control of tumors. Compared with radiotherapy and chemotherapy, immunotherapy is more personalized and precise. At present, the main strategies of immunotherapy for intrahepatic cholangiocarcinoma include immune checkpoint inhibitors, adoptive cell therapy, cytokine therapy, tumor vaccines, and specific antibodies. Immune checkpoint inhibitors and adoptive T cell therapies are two classes of immunotherapies that have been extensively tested and clinically approved.

免疫检查点抑制剂是一组针对免疫检查点蛋白的抗体，用抗体来阻断免疫检查点，进而解除免疫细胞的抑制状态，从而清除肿瘤。免疫检查点抑制剂主要包括程序性死亡蛋白-1(programmed death-1, PD-1)，例如纳武利尤单抗、帕博利珠单抗，程序性死亡蛋白配体-1(programmed death-ligand 1, PD-L1)抑制剂，例如度伐利尤单抗、阿替利珠单抗。细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4, CTLA-4)抑制剂，例如伊匹木单抗、贝拉西普、阿巴西普等。

A total of 60 patients with biliary tract cancer were included in the study, and the median overall survival was 5.2 months and the median progression-free survival was 1.4 months for nivolumab alone. In contrast, in patients treated with nivolumab plus gemcitabine plus cisplatin chemotherapy, the median overall survival was 15.4 months and the median progression-free survival was 4.2 months, which showed that immune checkpoint inhibitors alone were less effective [23]. However, the combination of immune checkpoint inhibitors, such as durvalumab and pembrolizumab, on the basis of gemcitabine plus cisplatin, has shown better therapeutic efficacy, and patients have improved progression-free survival and overall survival [24]. In the latest United States National Comprehensive Cancer Network guidelines, durvalumab in combination with gemcitabine and cisplatin was adjusted as the preferred regimen for patients with advanced intrahepatic cholangiocarcinoma, becoming a milestone in the treatment and management of patients with advanced intrahepatic cholangiocarcinoma.

The TOPAZ-1 trial evaluated gemcitabine in combination with cisplatin in combination with durvalumab in patients with intrahepatic cholangiocarcinoma. Median progression-free survival was 7.2 months and a 2-year cumulative survival rate of 24.9 percent in the durvalumab arm compared with 5.7 months and a 2-year cumulative survival rate of 10.4 percent in the placebo arm. More importantly, Asian cholangiocarcinoma patients in this trial achieved better treatment outcomes [25]. At present, gemcitabine combined with cisplatin combined with durvalumab has been included in the first-line treatment of patients with intrahepatic cholangiocarcinoma in major domestic and international diagnosis and treatment guidelines [26, 27]. In another phase III clinical trial, KEYNOTE-966, gemcitabine plus cisplatin plus pembrolizumab was evaluated in patients with advanced and/or unresectable cholangiocarcinoma, with median overall survival of 12.7 months and median progression-free survival of 6.5 months in the control arm (gemcitabine plus cisplatin) and median progression-free survival of 5.6 months in the control arm (gemcitabine plus cisplatin) [28]. Pembrolizumab may be a new treatment option for patients with unresectable intrahepatic cholangiocarcinoma. In another phase II clinical study, nivolumab monotherapy was shown to be an objective response rate of 11 percent, median progression-free survival of 3.7 months, and median overall survival of 14.2 months in 46 patients with advanced intrahepatic cholangiocarcinoma [29].

Studies have shown that in patients with intrahepatic cholangiocarcinoma, the density of CTLA-4-positive lymphocytes in cancer tissues is higher than that in pericancerous liver tissues and patients with PD 1/PD-L1 and CTLA-4 signaling activation, which may provide a potential target for the treatment of patients with intrahepatic cholangiocarcinoma. The density of CTLA-4-positive lymphocytes and infiltrating tumor lymphocytes is an independent predictor of overall survival [30]. A study (NCT04634058) to evaluate the efficacy and safety of PD-L1 antibody in combination with CTLA-4 inhibitor in patients with advanced intrahepatic cholangiocarcinoma is underway and is expected to lead to new research advances. In addition, in a nonrandomized phase II clinical trial, nivolumab in combination with ipilimumab treated 39 patients with intrahepatic cholangiocarcinoma with an objective response rate of 23 percent, a disease control rate of 44 percent, a median progression-free survival of 2.9 months, and a median overall survival of 5.7 months [31]. In the early treatment of 30 patients with intrahepatic cholangiocarcinoma with PD-L1 inhibitors alone, the median overall survival was 5.2 months and the median progression-free survival was 1.4 months [23]. Therefore, the combination of CTLA-4 is more advantageous, and this combination may be the preferred immunotherapy regimen for biliary tract cancer.

In addition to immune checkpoint inhibitors, adoptive cell therapy is also commonly used. Adoptive cell therapy is to expand and modify the patient's immune cells in vitro to enhance their targeted killing function, and then infuse them back into the patient's body to destroy tumor cells, mainly including T cell receptor engineered T cell therapy and chimeric antigen receptor T cell therapy [32]. Adoptive immune cell therapy has made important progress in the treatment of hematologic tumors [33, 34, 35], but its therapeutic effect on solid tumors needs to be verified by more clinical trials. A phase I clinical trial explored the efficacy of chimeric antigen receptor T cells targeting EGFR in 17 patients with EGFR-positive (>50%) advanced cholangiocarcinoma, with 1 complete response and 10 stable disease with a median progression-free survival of 4 months [36]. In another clinical trial, a patient with multiple metastatic cholangiocarcinoma after chemotherapy was treated with T cells and 4 interleukin-2 treatments. At 7 months after treatment, the number of all tumor metastases was reduced by 30 percent, and after 13 months, tumor progression was observed only in lung metastases, while no progression was observed in liver metastases [37]. Adoptive cell immunotherapy is a promising treatment, but its efficacy and safety in intrahepatic cholangiocarcinoma still need to be confirmed by a large number of clinical trials.

Immunotherapy is booming and has become an important treatment to alleviate the pain of patients and prolong their survival. Immune checkpoint inhibitors (immune checkpoint inhibitors) are currently the most concerned and promising immunotherapy methods, and the combination of immune checkpoint inhibitors on the basis of chemotherapy has become an advantageous strategy for the first-line treatment of patients with intrahepatic cholangiocarcinoma [26]. There is still a lack of accurate biomarkers to screen suitable patients for immunotherapy, a lack of large-sample, multi-center clinical trials to verify the therapeutic effect of immunotherapy combined with chemotherapy, a lack of more detailed analysis of the tumor microenvironment of patients with intrahepatic cholangiocarcinoma, and a lack of exploration of immunotherapy combined with targeted therapy. We look forward to addressing the above issues one by one in the future and improving the prognosis of patients through immunotherapy.

3. Chemotherapy

Gemcitabine combined with cisplatin has been identified as the first-line standard chemotherapy regimen for cholangiocarcinoma patients [38, 39]. Based on the gemcitabine combined with cisplatin regimen, various clinical research centers at home and abroad are also constantly exploring. In a study of 354 patients with unresectable advanced cholangiocarcinoma who analyzed the efficacy of gemcitabine plus Tigio, the median overall survival was 15.1 months and the median progression-free survival was 6.8 months, compared with 13.4 months and 5.8 months [40]. However, the advantage of gemcitabine plus Tigio is that it does not require hydration and can be used as an alternative to standard of care for patients who are poorly tolerated with gemcitabine plus cisplatin.

Compared with the dual chemotherapy regimen, the triple chemotherapy regimen has a more significant clinical effect. The results of the phase III randomized controlled trial KHBO1401 gemcitabine combined with cisplatin combined with Tegio triple chemotherapy were 13.5 months, the median progression-free survival was 7.4 months, the 1-year survival rate was 59.4%, and the relative risk was 41.5%, and the gemcitabine combined with cisplatin was 12.6 months, 5.5 months, 53.7%, and 15.0%, respectively, with a statistically significant difference (P=0.046) [41].

A study enrolled 441 patients with cholangiocarcinoma, including 296 patients with intrahepatic cholangiocarcinoma, who had a median overall survival of 14 months and a median progression-free survival of 8.2 months after a combination of gemcitabine, cisplatin, and nab-paclitaxel, and approximately 24% of patients who discontinued the drug due to drug toxicity. The control group was treated with gemcitabine plus cisplatin with a median overall survival of 12.7 months, a median progression-free survival of 6.4 months, and 19 percent of patients who discontinued the drug due to toxicity [42]. In another study of oxaliplatin, irinotecan, and 5-fluorouracil, a total of 191 patients with advanced cholangiocarcinoma were treated with the triple regimen described above, and the six-month progression-free survival rate was 44.6 percent compared with cisplatin and gemcitabine [43]. It has been reported that 47 patients with advanced cholangiocarcinoma treated with oxaliplatin plus gemcitabine plus capecitabine had a median progression-free survival of 5.7 months and a median overall survival of 8.7 months. In addition, 49 patients with advanced cholangiocarcinoma were treated with gemcitabine plus cisplatin with a median progression-free survival of 7.3 months and a median overall survival of 12.0 months [44]. These studies have shown that the triple chemotherapy regimen is not satisfactory and is associated with more adverse effects, so more caution should be exercised in the choice of drugs in the triple regimen.

Second-line treatment for unresectable intrahepatic cholangiocarcinoma is less effective after first-line treatment failure. In the phase III randomized controlled trial ABC-06, the effect of active symptom control combined with FOLFOX chemotherapy regimens (leucovorin, fluorouracil and oxaliplatin) in advanced cholangiocarcinoma was analyzed. Median overall survival was 6.2 months in the active symptom control plus FOLFOX group compared with 5.3 months in the active symptom control group alone [45]. In a clinical study of 193 patients with advanced cholangiocarcinoma, the median progression-free survival of irinotecan with fluorouracil and leucovorin was 7.1 months, compared with 1.4 months in the fluorouracil and leucovorin alone groups, but the former had a higher rate of adverse events [46]. In the AIO-HEP-0116 clinical trial, which included 100 patients with advanced cholangiocarcinoma, including 64 patients with intrahepatic cholangiocarcinoma, the median progression-free survival was 2.76 months in the 5-fluorouracil and leucovorin plus irinotecan group, compared with 2.3 months in the 5-fluorouracil and leucovorin alone group, but the incidence of adverse events was higher [47]. Therefore, whether irinotecan combined with 5-fluorouracil combined with leucovorin can be used as a second-line regimen still needs to be confirmed by more clinical studies.

At present, the research progress of first-line chemotherapy drugs is slow, and although the clinical results of some triple chemotherapy regimens are more encouraging, the adverse reactions and real effectiveness of triple chemotherapy regimens still need to be confirmed by higher-quality clinical studies. With the breakthrough of theory and technology, the selectivity of targeted drugs and immune drugs used in clinical practice has gradually increased, and the combination therapy of multiple types of drugs has gradually shown advantages. At present, chemotherapy-based combination therapy is becoming the main adjuvant treatment option for intrahepatic cholangiocarcinoma in various countries. At present, clinical studies of chemotherapy-based combination therapy regimens such as NCT05924880, NCT05771480, and NCT05297903 are underway, and the results of these studies are expected.

4. Radiation therapy

With the increasing incidence of intrahepatic cholangiocarcinoma and the increasing number of patients with unresectable intrahepatic cholangiocarcinoma, research centers at home and abroad are exploring new treatments, such as stereotactic radiosurgery and particle implantation therapy.

The development of radiotherapy technology provides a potential treatment option for patients with intrahepatic cholangiocarcinoma, stereotactic radiosurgery is a highly precise treatment that can radiate the tumor in high doses without affecting the surrounding healthy organs, and can reduce the risk of liver disease induced by radiation compared to systemic radiotherapy. Modern radiotherapy techniques have been able to safely and effectively treat a wide range of liver tumors [48], and stereotactic radiosurgery is worth considering for patients with intrahepatic cholangiocarcinoma who are not candidates for surgical resection. In a retrospective study of 37 patients with advanced cholangiocarcinoma, the median overall survival was 14 months, the median progression-free survival was 9 months, and the one- and two-year survival rates were 57 and 25 percent, respectively [49]. Another clinical study investigated the efficacy and safety of stereotactic radiosurgery in patients with advanced intrahepatic cholangiocarcinoma in 34 patients with median overall survival of 17 months and median progression-free survival of 10 months [50]. These studies confirm that stereotactic radiosurgery can be a safe and effective local treatment option for patients with unresectable intrahepatic cholangiocarcinoma. In a phase II clinical trial, 37 patients with intrahepatic cholangiocarcinoma received 15 sessions of stereotactic radiosurgery with a maximum total dose of 67.5 Gy. The median overall survival was 22.5 months, with a two-year local control rate of 94 percent and a two-year cumulative survival rate of 47 percent [51].

Selective radiotherapy uses radionuclide 90Y microspheres loaded with β radiation as a radiation source and injected into the tumor tissue through the hepatic artery for continuous brachytherapy of the tumor. In a review of the prognostic data of 85 patients with unresectable and refractory intrahepatic cholangiocarcinoma, transarterial 90Y glass microsphere radioembolization showed a median overall survival of 21.4 months, with acceptable adverse effects compared with treatment response [52]. Selective internal radiation therapy of 90Y microspheres for liver malignant tumors has a history of more than 50 years, and the mainland has started slowly. At present, the mainland has issued an expert consensus on standardized operation [ 53 ], according to which selective internal radiation therapy will be actively promoted. The inclusion of internal radiation therapy in adjuvant therapy may further improve the prognosis of patients with advanced unresectable intrahepatic cholangiocarcinoma when other adjuvant therapies are difficult to administer.

Intrahepatic cholangiocarcinoma is a malignancy with a poor prognosis, and radiotherapy is a potential opportunity to improve local control and overall survival in addition to systemic therapy in patients with intrahepatic cholangiocarcinoma that has been resected but has lymph node involvement or positive margins, as well as unresectable intrahepatic cholangiocarcinoma. Unfortunately, the existing clinical studies are small in size, and higher quality clinical studies are needed to confirm the effectiveness of these treatment regimens and the optimal population. Studies on the combination of radiotherapy and chemotherapy in patients with advanced cholangiocarcinoma are ongoing (NCT03482102, NCT03898895), and it is expected that these findings will lead to more effective treatment options.

5. Summary and outlook

For patients with advanced intrahepatic cholangiocarcinoma who are difficult to undergo surgery, gemcitabine combined with cisplatin is still an indispensable part of adjuvant therapy. Treatment concepts such as molecular medicine and precision medicine have been continuously improved, and gemcitabine combined with cisplatin combined with immunotherapy has become a new first-line treatment option, which has further improved the prognosis of patients. The in-depth research of targeted therapy enables patients to receive personalized diagnosis and treatment plans, achieve precise treatment, and reduce unnecessary adverse reactions. At present, immune checkpoint inhibitors and molecularly targeted drug therapy have been included in the treatment guidelines for intrahepatic cholangiocarcinoma [26] and have become new treatment options. According to the overall data of the treatment of patients with advanced intrahepatic cholangiocarcinoma, the improvement of survival prognosis is still limited regardless of first-line or second-line treatment. At present, more large-sample and multi-center clinical studies are still needed to guide the exploration of more effective and safer treatment concepts and models, develop more effective treatment regimens, and further improve the prognosis of patients with advanced intrahepatic cholangiocarcinoma.