Gallbladder cancer (GBC) is a highly lethal disease and the most common cancer of the biliary tract. Numerous patients are diagnosed at an advanced stage, limiting surgical options and necessitating local or systemic treatment. Despite advancements in cancer treatment, 5-year survival rates remain low. Various therapeutic methods are available for the treatment of advanced GBC, including local therapy, chemoradiotherapy, immunotherapy and targeted therapy. Although these treatments offer hope and broader prospects for patients, challenges persist. Through a systematic review of the literature from PubMed and Web of Science over the past decade, a summary and analysis of treatment trends, existing challenges and the latest research developments in advanced GBC were provided.
gallbladder cancerchemoradiotherapylocal therapyimmunotherapyKey Joint Project of Chongqing Health Commission and Science and Technology Bureau2024ZDXM007Medical Research Project of Daping HospitalZXAIZD003The present study was supported by the Key Joint Project of Chongqing Health Commission and Science and Technology Bureau (grant no. 2024ZDXM007) and the Key Medical Research Project of Daping Hospital (grant no. ZXAIZD003).Introduction
Gallbladder cancer (GBC) is a highly lethal disease and the most common malignancy of the biliary tract (1–3). The highest incidence rates are observed in Chile and India, followed by Eastern Europe, Pakistan and Japan (4). In the United States, >1,000 new cases of GBC are diagnosed annually, with a mean age at diagnosis of 71 years (5). Women account for ~70% of GBC cases, with a female-to-male ratio of 2.41:1 (6). GBC is characterized by aggressive behavior, including local invasion, early lymph node metastasis and frequent distant metastasis. The initial stages of GBC are asymptomatic, leading to diagnoses at advanced stages (1,7,8). The median survival time is <1 year and the overall survival (OS) rate ranges from 17.8 to 21.7% (9). Although notable advancements have been made in the treatment of advanced GBC in recent years, their impact on patient prognosis remains limited. The present study aims to provide a comprehensive review of the latest treatment strategies and research progress in the management of advanced GBC.
Local treatment
Local therapies have proven effectiveness in prolonging patient survival and enhancing quality of life in advanced GBC. Transarterial hepatic embolization, transarterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) have been well documented in the treatment of advanced GBC (10–12). These treatments selectively block the tumor arterial blood supply using various embolic agents, with or without local chemotherapeutic agents (13). In the literature, the most common adverse events of vascular interventional therapy included post-embolization syndrome, characterized by abdominal pain, fever and intestinal obstruction (14). Additionally, some cases of GBC were poorly responsive to treatment. A meta-analysis of different transarterial chemotherapy methods, such as TACE, HAIC and DEB-TACE, demonstrated an OS time of 15.7 months from the time of diagnosis. These findings suggest that transarterial chemotherapy-based treatment for cholangiocarcinoma (including GBC) is safe, well-tolerated and results in a survival benefit of 2–7 months compared with systemic treatments (15).
Other local treatment options for GBC include endoscopic radiofrequency ablation (RFA), radiotherapy (RT) and endoscopic photodynamic therapy (PDT) (16,17). RFA is increasingly being utilized for local tumor control (18). Biliary tract cancers (BTCs) (including GBC) may need higher doses in order to achieve better local control and maybe also a survival benefit, compared to other solid tumors. Concepts for safer dose escalation include the use of stereotactic body RT (SBRT), brachytherapy or proton beam RT (19–21). SBRT has been reported as a promising local treatment for cancer, providing effective local control (LC) and prolonging OS time. However, current guidelines recommend TACE as a primary treatment option for patients with early to intermediate-stage cancer, while SBRT is not included as a standard treatment (22). Compared with TACE, SBRT has demonstrated comparable OS time and improved LC across various stages of cancer, ranging from early to advanced stages, without causing serious adverse events. SBRT should be considered an effective treatment option for different stages of gallbladder cancer, as well as a comprehensive assessment of the patient's body. In one study, SBRT led to local control rates ranging from 65 to 100%, with OS time of 11–35.5 months (median, 15 months), in selected patients (23). RT is widely used to treat various cancer types, and while it can effectively control the local spread of GBC, it may not be sufficient on its own. To overcome the limitations of single-modality RT, combination chemotherapy is often administered concurrently.
PDT involves the intravenous injection of a photosensitive agent followed by irradiation with a specific wavelength of light to selectively target cancer cells and modulate the cancer microenvironment (24). However, the efficacy and safety of PDT for advanced GBC have not been fully evaluated. Further research is necessary to assess the role of PDT in combination with other therapies and its potential impact on the tumor microenvironment.
While there are various local treatment options for advanced GBC, each center may have different experiences and preferences with regard to selecting the most appropriate approach. Currently, there is no unified consensus on the optimal local treatment methods for advanced GBC.
Chemotherapy and radioembolization
GBC is known for its high rate of malignancy and multidrug resistance. Common chemical drugs used for the treatment of GBC include cisplatin (CDDP), gemcitabine (GEM), 5-fluorouracil (5-FU), epirubicin, oxaliplatin (OXA), S-1, capecitabine and irinotecan (25–28). The results of clinical trials showed that the response rates from combining these chemotherapy drug combinations were still low at 26.1, 15.5, 30.7, 14.3, and 29.8 for GEM + CDDP, GEM, GEM + OXA, 5-FU + folinic acid and GEM + S-1, respectively (29–31). The response rate of GEM + CDDP as a first-line chemotherapy regimen (26.1%) was 10.6% higher than that of GEM alone (15.5%) (29). Chemotherapy response remains suboptimal in patients with advanced GBC, often accompanied by high rates of chemotherapy resistance. Genetic testing of individual cancers that will be matched with known chemotherapy regimens or sensitizers will allow for individualized treatment based on the characteristics of specific tumor genes (32). A comprehensive list of clinical trials focusing on chemotherapy for patients with GBC was obtained from ClinicalTrials.gov and is detailed in Table I.
The GEM + CDDP regimen has served as the standard first-line treatment for GBC for over a decade, as demonstrated in the phase III clinical trial known as ABC-02 (29). However, owing to the risk of renal dysfunction associated with CDDP, CDDP has been gradually replaced by OXA. A single-arm phase II trial (SWOG S0809), conducted in the United States and published in 2015, enrolled 79 patients with extrahepatic cholangiocarcinoma and GBC. The trial demonstrated the efficacy of adjuvant GEM + capecitabine chemotherapy, followed by capecitabine + RT. The results showed that the 2-year survival rate was 65% (95% CI, 53–74%), with mortality rates of 67 and 60% for R0 and R1 patients, respectively. The median OS time was 35 months (R0, 34 months; R1, 35 months) (33).
Second-line or subsequent systemic therapy regimens for GBC are similar to those employed in other gastrointestinal malignancies, including regimens such as 5-FU + leucovorin + OXA (also known as FOLFOX), 5-FU + leucovorin + irinotecan (also known as FOLFIRI) and nanoliposomal irinotecan + 5-FU + leucovorin (1,34). The 2015 prospective case series reported by Dodagoudar et al (35) utilized second-line agents, including folic acid, 5-FU and oxaliplatin (FOLFOX), demonstrating promising responses. The response rate was 24.2% (16/66), the disease control rate was 59.1% (39/66), the median time to progression was 3.9 months (95% CI, 3.1–4.7) and the median OS was 7.6 months (95% CI, 6.8–8.2). RT has proven effective for patients with advanced GBC. A Phase 2 clinical trial involving 41 patients with intrahepatic cholangiocarcinoma with selective radiotherapy combined with chemotherapy (cisplatin and gemcitabine) showed a 39% increase in response rate, a median progression-free survival (PFS) of 14 months and a median OS of 22 months (36).
Radioembolization has emerged as a valuable and increasingly utilized treatment option for patients with advanced GBC. Although it is typically offered as a palliative treatment for liver tumors, ongoing advances are broadening the range of treatment options for patients with advanced GBC and offer a promising avenue for future research and clinical applications.
Targeted therapy and immunotherapy
Advanced sequencing technologies, such as next-generation sequencing (NGS), whole exome sequencing, RNA sequencing and single-cell analysis, have enabled the identification of genetic and epigenetic features, as well as key molecules that could serve as potential therapeutic targets for GBC (37–39). Kuipers et al (40) found that tumor protein p53 (TP53; ~57%), sonic hedgehog signaling molecule (~20%), E74-like ETS transcription factor 3 (~18.6%) and AT-rich interaction domain 1A (~14%) are among the most commonly mutated genes in GBC. Additionally, mothers against DPP homolog 4 (~13.1%), epidermal growth factor receptor (EGFR; also known as HER1/ERBB1; ~12%), erb-b2 receptor tyrosine kinase 2 (ERBB2; also known as HER2/NEU; ~10%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (~14.6%) and KRAS proto-oncogene GTPase (KRAS; ~10.3%) were also identified (41–44). Ongoing clinical trials investigating targeted therapies and immunotherapy options for patients with GBC are summarized in Table II (45–48).
TP53
Mutations in the TP53 tumor suppressor gene are present in ~50% of all human cancer cases. TP53 acts as a transcription factor that directly regulates the expression of ~500 genes and blocks their tumor suppressive functions by preventing them from binding to target DNA sequences. TP53 also upregulates genes involved in cellular processes, such as apoptosis, cell cycle arrest and senescence, which are key mechanisms that prevent tumorigenesis (49–51). The frequency of TP53 mutations varies notably across different tumor types. TP53 mutations are present in >90% of ovarian cancer cases, whereas <15% of cases of acute myeloid leukemia exhibit TP53 mutations. This disparity suggests the possibility of tissue-specific factors influencing the loss of wild-type TP53 function or the gain of function in mutated p53 (52). The expression and accumulation levels of p53 increase from precancerous lesions (dysplasia) to aggressive GBC (53–55). Detection of p53 protein upregulation can be a valuable diagnostic tool for accurate cancer identification. Stancu et al (56) found that p53 is upregulated in 30% of papillary regions, 30–50% of undifferentiated adenocarcinomas and 80–100% of highly differentiated adenocarcinomas, particularly in the context of chronic cholecystitis (56). In general, TP53 represents a promising therapeutic target, and with the advancement of p53-targeted therapies, personalized treatment plans based on specific p53 mutations are becoming increasingly feasible.
A phase IIa/IIb, open-label, single-arm, multicenter trial of brigimadlin (BI 907828) is currently ongoing in patients with locally advanced/metastatic, mouse double minute 2-amplified, TP53 wild-type biliary tract adenocarcinoma, pancreatic ductal adenocarcinoma and other selected solid tumors. The study aims to assess the efficacy of BI 907828 in treating cancers affecting the biliary tract, pancreas, lungs or bladder (57).
TP53 mutations have significant effects on several aspects of the immune system; they can promote immune evasion and cancer progression by regulating exosomes, growth factors, cytokines and chemokines (58). These mutations can alter the immune recognition of tumor cells and, through mechanisms such as reduced infiltration, decrease the cytotoxicity and activity of immune cells, thereby promoting the recruitment of immune-suppressive cells (59,60).
EGFR and vascular endothelial growth factor (VEGF) pathways
Both EGFR and VEGFR activate signaling pathways that regulate cell growth and proliferation (9,61). Additionally, the simultaneous inhibition of both EGFR and VEGFR may enhance antitumor effects (62). Studies on GBC have shown that overexpression of VEGF-A plays a crucial role in angiogenesis and serves as an independent prognostic factor associated with reduced survival (63). VEGF overexpression in GBC cells promotes angiogenesis, cell proliferation and metastasis (64,65). Up to 48% of patients with GBC exhibit elevated VEGF-A expression, potentially benefiting from anti-angiogenic drugs (63). Research has proved the efficacy of drugs targeting tumor angiogenesis via the VEGF/VEGFR pathway (66,67).
Bevacizumab is a humanized monoclonal antibody targeting VEGFA, while ramucirumab regulates VEGFR-2 specifically (68). Regorafenib, a novel oral multikinase inhibitor, blocks various vasogenic and stromal receptor tyrosine kinases (FGFR1, PDGFR-OMAN, TIE2, VEFR1, VEF2 and VVF3) and downstream cellular signaling pathways (RAS/LUR/MEK/ERK and PI3K/PTEN/AKT) (69–71). In a multi-center, open-label, single-arm phase 2 trial evaluating regorafenib efficacy in refractory BTC, 33 patients treated for at least 3 weeks. The results showed a median PFS time of 3.9 months and an OS time of 6.7 months. The target response rate was 9.1%, with a disease control rate of 63.6% (45).
ERBB2
The receptor tyrosine protein kinase ERBB2, also known as HER2, is a member of the receptor tyrosine kinase EGFR family. Heterodimerization of this receptor with other members of the EGFR family leads to the self-phosphorylation of tyrosine residues in the heterodimeric cytoplasmic domain and initiates multiple signaling pathways, leading to cell proliferation and tumorigenesis (72). ERBB2 upregulation has been observed in several solid tumors, such as breast cancer, gastroesophageal junction cancer and BTC (73–77). Nam et al (78) found that in patients with gallbladder cancer (N=21), the proportion of HER2-positive disease was 28.6%.
A phase 2 clinical trial, which was investigator-initiated, open-label, non-randomized and multi-institutional, evaluated the efficacy of treatment in patients aged ≥19 years with ERBB2-positive BTC (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and GBC) that had progressed despite GEM and CDDP chemotherapy (79). The trial reported an overall response rate of 29.4% (95% CI, 16.7–46.3) and a disease control rate of 79.4% (95% CI, 62.9–89.9). The median PFS time was 5.1 months (95% CI, 3.6–6.7), while the median OS time was 10.7 months (95% CI, 7.9-not reached) (46).
PI3K/AKT/mTOR pathway
The PI3K-AKT-mTOR signaling pathway is a critical pathway involved in drug resistance and malignant processes in patients with solid cancer, with dysregulation potentially leading to various human cancers (79–82). This pathway is increasingly being recognized as a promising target in cancer and related diseases, such as hepatocellular carcinoma and colon cancer (83). Abnormal activation of the PI3K-AKT -mTOR pathway has been observed in GBC and in other malignancies, such as prostate, breast and endometrial cancer (42). Activation of this pathway promotes increased cell proliferation and growth, and plays a key role in angiogenesis. The pathway is also involved in numerous cellular processes, including proliferation, invasion, migration, apoptosis and metabolism (84–86). Targeting the PI3K/AKT/mTOR pathway in combination with chemotherapy or other targeted therapies can help inhibit tumor progression (87).
In a phase I trial, a chemotherapy regimen combining everolimus, an mTOR inhibitor, with GEM and CDDP resulted in stable disease in 6 out of 10 patients with BTC, suggesting a potential therapeutic benefit (47).
KRAS
KRAS, a member of the RAS oncogene family, was first identified in the 1980's by Barbacid (88) in a human bladder cancer cell line. This gene, also known as HRAS, is a homolog located on chromosome 11 (11p15.1–11p15.3) (88). KRAS is the best-known oncogene, the most common driver of numerous cancer types, with relatively high mutation rates in various cancers, such as non-small cell lung cancer, colorectal cancer and pancreatic ductal adenocarcinoma (89,90). Numerous studies have demonstrated the biochemical heterogeneity of KRAS mutations across various aspects, including intrinsic GTPase activity and affinities for effectors and binding sites. For instance, alterations in codons 12, 13 and 61 typically result in impaired intrinsic GTPase activity in KRAS, unlike the mutations KRAS G12D, KRAS G12C and KRAS G13D (91,92). The simultaneous activation of KRAS and the typical Wnt pathway induces BTC (93). Initial clinical reports for KRASG12C-mutated BTC showed a limited clinical response to sotorasib and GDC-6036 (48), and secondary mutations in the KRAS gene conferred acquired resistance to KRASG12C inhibitors. A phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249) was begun to evaluate adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding non-small cell lung cancer and colorectal cancer). As of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). Among 57 patients with measurable disease at baseline, the median duration of response was 5.3 months (95% CI, 2.8–7.3) and the median PFS time was 7.4 months (95% CI, 5.3–8.6) (48). KRAS mutant tumors exhibit significant heterogeneity, highlighting the urgent need for selective inhibitors that target specific KRAS mutations. Notable progress has been made in targeting KRAS, particularly KRASG12C. New approaches, including NMR-based fragment screening, drug teaming and computational drug design, have been employed to discover novel compounds that bind directly to KRAS (92). However, achieving effective KRAS targeting is still a considerable challenge. Such treatments are essential to effectively inhibit the function of various KRAS mutants, aligning with the goals of precision oncology (92).
Immune checkpoint inhibitors
Chemotherapy primarily delays tumor growth by inhibiting DNA replication, blocking the cell cycle and interfering with cellular metabolism (94). Additionally, some cytotoxic chemotherapy agents, such as anthracyclines and OXA, can induce immunogenic cell death and stimulate antitumor immune responses (95,96). Therefore, for chemotherapy-based immunotherapy with antibodies targeting programmed cell death protein 1/programmed death ligand 1 (anti-PD-1/PD-L1) may serve as a suitable partner to enhance the ability of chemotherapy to control tumor growth (97).
Currently, the common immune checkpoints of GBC include PD-1/PD-L1 and cytotoxic T-lymphocyte protein 4 (CTLA-4), and monoclonal antibodies targeting these targets have also been tested in clinical trials (98–100). PD-1 serves as a well-known immunosuppressive checkpoint, whereas PD-L1 acts as its ligand (101). PD-L1 is a biomarker for patient prognosis and susceptibility to PD-1/PD-L1 inhibitors. PD-L1 is expressed mainly in tumor cells, tumor-infiltrating cells and antigen-presenting cells in a number of cancer types, such as breast and bone cancer (102). Numerous studies have affirmed the clinical importance of PD-1/PD-L1 antibodies in influencing the prognosis of human cancer (97,103–105). Based on the immense success of clinical trials, ten anti-PD-1 antibodies (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab and dostarlimab) and three anti-PD-L1 antibodies (atezolizumab, durvalumab and avelumab) have been approved for the treatment of various types of cancer, including pancreatic and gastric cancer (106).
A multicenter phase II study involving 54 patients assessed the effectiveness and safety of nivolumab monotherapy in patients with advanced cholangiocarcinoma who had undergone first to third-line treatment. The study found that PD-L1 upregulation was significantly associated with worse OS times (hazard ratio, 1.58; 95% CI, 1.30–1.92; P<0.001) (107). However, serious challenges remain, such as limited beneficiaries, high drug resistance, lack of predictive and prognostic biomarkers, and treatment-related adverse reactions (108). Moreover, few predictive biomarkers can identify the types of patients who will benefit from treatment (109). Nevertheless, PD-1/PD-L1 immune checkpoint inhibitors have wide application prospects and clinical value for the treatment of cancer in humans.
CTLA-4, a receptor found on activated T cells, has been the focus of numerous clinical trials on combination therapies. The use of both CTLA-4 and PD-1 inhibitors has shown effectiveness in enhancing the response rates and survival of patients with various cancer types, including pancreatic and gastric cancer (110,111). However, combination therapy may also increase the risk of adverse events (112). A recent phase I clinical trial (NCT01938612) revealed that treatment with durvalumab and tremelimumab in patients with BTC led to a median OS time of 10.1 months (95% CI, 6.5–11.6) compared with 8.1 months (95% CI, 5.6–10.1) in patients with durvalumab monotherapy (113).
Adoptive immunotherapy
Immunotherapy has recently revolutionized cancer treatment and constitutes the fourth cornerstone of cancer therapy following surgery, RT and chemotherapy. To date, >700 clinical trials of CAR-T therapy have been registered at clinicaltrials.gov, with a number focusing on solid tumors. CAR-T cell immunotherapy has achieved marked success in the treatment of hematological malignancies. However, only six chimeric antigen receptor T-cell (CAR-T) cell products approved by the US Food and Drug Administration (FDA) for the treatment of R/R B cell malignancies, including tisagenlecleucel (Kymriah; Novartis), axicabtagene ciloleucel (Yescarta; Gilead), brexucabtagene autoleucel (Tecartus; Gilead), lisocabtagene maraleucel (Breyanzi; Bristol Myers Squibb), idecabtagene vicleucel (Abecma; Bristol Myers Squibb and Bluebird Bio), and ciltacabtagene autoleucel (Carvykti; Legend and Janssen) (114). There are currently six commercial CAR-T products that have been FDA approved for diseases such as B-acute lymphoblastic leukemia, large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (115). In a single-arm, open-label, first-in-human phase I pilot study (NCT03159819), patients aged 18–70 years with confirmed CLDN18.2-positive advanced gastric or pancreatic cancer received one or more cycles of CAR-CLDN18.2 T cell infusion following lymphocyte pretreatment, until disease progression or the onset of intolerable toxicity. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month PFS rates were 69% (95% CI, 61–75) and 59% (95% CI, 51–66), respectively (116). Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed CAR T-cell therapy approved for relapsed/refractory MCL. Patients who underwent leukapheresis between August 1, 2020, and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month PFS rates were 69% (95% CI, 61–75) and 59% (95% CI, 51–66), respectively (117). However, due to the complexity of solid tumors and their unique anatomical locations, treating solid tumors with CAR-T cells presents numerous challenges, such as the lack of cancer-specific antigens, inefficient transport and migration of CAR-T cells to the tumor site. Consequently, the immunosuppressive tumor microenvironment (TME) and CAR-T therapy for solid tumors remain underdeveloped (114,118,119). As a result, CAR-T therapy for solid tumors is still in its developmental stages (120). However, clinical studies have demonstrated promising antitumor efficacy of CAR-T therapy, and the potential remains.
In recent years, various strategies have been developed to enhance the efficacy and safety of CAR-T cell therapies for solid tumors, primarily by addressing challenges posed by the unique characteristics of T cells and the TME. Companion diagnostics, such as immunohistochemistry and circulating tumor cell detection assays, can play a crucial role in improving the treatment of solid tumors with CAR-T cells (121).
Tumor vaccine
There are four types of cancer vaccines: Tumor- or immune cell-based vaccines, peptide-based vaccines, viral vector-based vaccines and nucleic acid-based vaccines (122). Vaccines based on nucleic acids (DNA or RNA) show great promise. mRNA cancer vaccines stand out due to their efficiency, safe management, rapid development potential and cost-effectiveness. Clinical trials have demonstrated positive results for over two dozen mRNA-based immunotherapies in treating solid tumors. Notably, a 3-year phase 1 follow-up from BioNTech's neoantigen individualized mRNA vaccine [autogene cevumeran (BNT122, RO7198457)] clinical study for patients after complete resection of pancreatic ductal adenocarcinoma has shown promising results (123).
Cancer vaccines are an effective treatment option as they stimulate a durable immune response that targets and eliminates tumor cells. However, the complexity of the immune system makes the development of effective cancer vaccines challenging. In particular, the heterogeneity of solid tumors may require different vaccinations. With the promising results from multiple clinical trials involving mRNA cancer vaccines against aggressive solid tumors, rapid advancements in mRNA vaccine technology can be anticipated for cancer immunotherapy in the near future (124).
Palliative treatment
The goal of palliative care for patients with GBC is to ensure unobstructed biliary drainage and provide nutritional support. Biliary drainage can be achieved using percutaneous catheterization or endoscopic biliary stenting to alleviate biliary obstruction, relieve liver cholestasis and enhance liver function. A multicenter retrospective analysis was performed of all cases of consecutive endoscopic ultraound-guided gallbladder drainage (EUS-GBD) with lumen-apposing metal stents (LAMSs) used as a rescue treatment for patients with distal malignant biliary obstruction (DMBO) in 14 Italian centers between June 2015 and June 2020. The study showed that EUS-GBD with LAMSs used as a rescue treatment for patients affected by DMBO represents a valuable option in terms of technical and clinical success rates, with an acceptable adverse event rate (5 patients; 10.4%) (125).
Tumors often compress the stomach or duodenum. In situations where the tumor compresses the stomach or duodenum, various interventions, such as nasoenteral nutrition tubes, gastrojejunal bypass therapy and peripheral nutrition support, can be employed to improve the patient's nutritional status (126). In addition to prolonging life, effective relief of symptoms is also of utmost importance for two reasons: i) Relief of physical suffering is desirable and can improve quality of life; and ii) effective symptom control translates into improved existential well-being (127). As advanced tumors often involve tumor spread or metastasis, a single treatment approach is often insufficient to achieve optimal treatment results. Therefore, palliative care also requires the collaboration of experts from multiple disciplinary fields to develop and implement individualized treatment programs aimed at improving patient outcomes and quality of life (128). At the same time, psychological intervention and symptomatic treatment should be carried out for patients. Psychosocial care for advanced cancer encompasses a wide range of interventions that help patients make life-changing decisions, relieve patient suffering, confront impending mortality and improve other patient outcomes (129). Cancer care guidelines also recommend distress screening for patients with cancer and the provision of psychological support when necessary, although a number of patients decline such support when offered.
Tondorf et al (130) conducted a prospective observational study to assess distress, the intention to utilize psycho-oncology support, and the acceptance of psycho-oncology services. Of the 333 patients assessed (mean age, 61 years; 55% male; 54% distress thermometer ≥5), 25% intended to use the psycho-oncology service (yes), 33% were ambivalent (maybe) and 42% reported no intention (no). Overall, 23% had attended the psycho-oncology service 4 months later.
Challenges and future prospects
The treatment of GBC, the most common malignancy of BTC, has progressed over the past 20 years. However, the treatment of advanced GBC remains challenging due to chemotherapy resistance and tumor heterogeneity due to mutations of genes such as KRAS and TP53. Given the improving understanding of the unique tumor biology of GBC, treatments for advanced GBC have changed markedly. The treatment options are no longer limited to single chemotherapy or local treatment, and the application of combination therapy can improve the prognosis of patients with advanced GBC. NGS of genes, related molecular genetic analysis and biomarker studies will aid the development of effective targets and drugs for GBC therapy, improve patient prognosis and improve therapeutic effectiveness.
Acknowledgements
Not applicable.
Availability of data and materials
Not applicable.
Authors' contributions
GC conceived and designed the study, SRZ carried out the data collection and BZ wrote the manuscript. All authors contributed to the revision of the manuscript and have read and approved the final version. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
ReferencesRoaJCGarcíaPKapoorVKMaithelSKJavleMKoshiolJGallbladder cancerNat Rev Dis Primers869202210.1038/s41572-022-00408-z36302789SongXHuYLiYShaoRLiuFLiuYOverview of current targeted therapy in gallbladder cancerSignal Transduct Target Ther5230202010.1038/s41392-020-00324-233028805ZhaoYYangMFengJWangXLiuYAdvances in immunotherapy for biliary tract cancersChin Med J (Engl)137524532202410.1097/CM9.000000000000275937646139SchmidtMAMarcano-BonillaLRobertsLRGallbladder cancer: Epidemiology and genetic risk associationsChin Clin Oncol831201931484487LauCSMZywotAMahendrarajKChamberlainRSGallbladder carcinoma in the United States: A population based clinical outcomes study involving 22,343 patients from the surveillance, epidemiology, and end result database (1973–2013)HPB Surg20171532835201710.1155/2017/153283528638176HickmanLContrerasCGallbladder cancer: Diagnosis, surgical management, and adjuvant therapiesSurg Clin North Am99337355201910.1016/j.suc.2018.12.00830846038FeoCFGinesuGCFancelluAPerraTNinniriCDeianaGScanuAMPorcuACurrent management of incidental gallbladder cancer: A reviewInt J Surg98106234202210.1016/j.ijsu.2022.10623435074510WangJRenMYuJHuMWangXMaWJiangXCuiJSingle-cell RNA sequencing highlights the functional role of human endogenous retroviruses in gallbladder cancerEBioMedicine85104319202210.1016/j.ebiom.2022.10431936374772ShenHHeMLinRZhanMXuSHuangXXuCChenWYaoYMohanMWangJPLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathwayJ Exp Clin Cancer Res38247201910.1186/s13046-019-1250-831182136WackerFDewaldCLocal and locoregional treatment of intrahepatic cholangiocarcinomaRadiologe622472522022(In German)10.1007/s00117-021-00946-934981129ScottAWongPMelstromLGSurgery and hepatic artery infusion therapy for intrahepatic cholangiocarcinomaSurgery174113115202310.1016/j.surg.2023.01.01936906437EdelineJLamarcaAMcNamaraMGJacobsTHubnerRAPalmerDGroot KoerkampBJohnsonPGuiuBValleJWLocoregional therapies in patients with intrahepatic cholangiocarcinoma: A systematic review and pooled analysisCancer Treat Rev99102258202110.1016/j.ctrv.2021.10225834252720MondacaSYarmohammadiHKemenyNERegional Chemotherapy for Biliary Tract Tumors and Hepatocellular CarcinomaSurg Oncol Clin N Am28717729201910.1016/j.soc.2019.06.00831472915ChangYJeongSWYoung JangJJae KimYRecent updates of transarterial chemoembolilzation in hepatocellular carcinomaInt J Mol Sci218165202010.3390/ijms2121816533142892RayCEJrEdwardsASmithMTLeongSKondoKGipsonMRochonPJGuptaRMessersmithWPurcellTDurhamJMetaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy inpatients with unresectable intrahepatic cholangiocarcinomaJ Vasc Interv Radiol2412181226201310.1016/j.jvir.2013.03.01923725793LarghiARimbasMTringaliABoškoskiIRizzattiGCostamagnaGEndoscopic radiofrequency biliary ablation treatment: A comprehensive reviewDig Endosc31245255201910.1111/den.1329830444547DeufelCLFurutaniKMDahlRAGramsMPMcLemoreLBHallemeierCLNeben-WittichMMartensonJAHaddockMGTechnique for the administration of high-dose-rate brachytherapy to the bile duct using a nasobiliary catheterBrachytherapy17718725201810.1016/j.brachy.2018.03.00629776892YinZJinHMaTZhouYYuMJianZA meta-analysis of long-term survival outcomes between Surgical resection and radiofrequency ablation in patients with a single hepatocellular carcinoma <2 cm (BCLC very early stage)Int J Surg566167201810.1016/j.ijsu.2018.04.04829723677GkikaEHawkinsMAGrosuALBrunnerTBThe evolving role of radiation therapy in the treatment of biliary tract cancerFront Oncol10604387202010.3389/fonc.2020.60438733381458FranzeseCBonuMLComitoTClericiELoiMNavarriaPFranceschiniDPressianiTRimassaLScorsettiMStereotactic body radiotherapy in the management of oligometastatic and recurrent biliary tract cancer: Single-institution analysis of outcome and toxicityJ Cancer Res Clin Oncol14622892297202010.1007/s00432-020-03285-932524292BiselloSBuwengeMPalloniAAutorinoRCelliniFMacchiaGDeodatoFCillaSBrandiGTagliaferriLRadiotherapy or chemoradiation in unresectable biliary cancer: A retrospective studyAnticancer Res3930953100201910.21873/anticanres.1344531177154KomiyamaSTakedaATateishiYTsurugaiYEriguchiTHoritaNComparison of stereotactic body radiotherapy and transcatheter arterial chemoembolization for hepatocellular carcinoma: Systematic review and meta-analysisRadiother Oncol202110614202510.1016/j.radonc.2024.11061439515381GkikaEHallauerLKirsteSAdebahrSBartlNNeeffHPFritschRBrassVNestleUGrosuALBrunnerTBStereotactic body radiotherapy (SBRT) for locally advanced intrahepatic and extrahepatic cholangiocarcinomaBMC Cancer17781201710.1186/s12885-017-3788-129162055SalgadoSMGaidhaneMKahalehMEndoscopic palliation of malignant biliary stricturesWorld J Gastrointest Oncol8240247201610.4251/wjgo.v8.i3.24026989459SasakiTTakedaTOkamotoTOzakaMSasahiraNChemotherapy for biliary tract cancer in 2021J Clin Med1031083122202110.3390/jcm1014310834300274YangLWangHGuoMHeMZhangWZhanMLiuYELF3 promotes gemcitabine resistance through PKMYT1/CDK1 signaling pathway in gallbladder cancerCell Oncol (Dordr)4610851095202310.1007/s13402-023-00799-536988891ChoiISKimKHLeeJHSuhKJKimJWParkJHKimYJKimJSKimJHKimJWA randomised phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapyEur J Cancer154288295202110.1016/j.ejca.2021.06.01934303267SharmaAKalyan MohantiBPal ChaudharySSreenivasVKumar SahooRKumar ShuklaNThulkarSPalSDeoSVPathySModified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: Results of a phase III randomised controlled trialEur J Cancer123162170201910.1016/j.ejca.2019.10.00431707181ValleJWasanHPalmerDHCunninghamDAnthoneyAMaraveyasAMadhusudanSIvesonTHughesSPereiraSPCisplatin plus gemcitabine versus gemcitabine for biliary tract cancerN Engl J Med36212731281201010.1056/NEJMoa090872120375404MorizaneCOkusakaTMizusawaJKatayamaHUenoMIkedaMOzakaMOkanoNSugimoriKFukutomiACombination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) randomized phase III clinical trialAnn Oncol3019501958201910.1093/annonc/mdz40231566666SharmaADwaryADMohantiBKDeoSVPalSSreenivasVRainaVShuklaNKThulkarSGargPChaudharySPBest supportive care compared with chemotherapy for unresectable gallbladder cancer: A randomized controlled studyJ Clin Oncol2845814586201010.1200/JCO.2010.29.360520855823LaiJYangSLinZHuangWLiXLiRTanJWangWUpdate on chemoresistance mechanisms to first-line chemotherapy for gallbladder cancer and potential reversal strategiesAm J Clin Oncol46131141202310.1097/COC.000000000000098936867653Ben-JosefEGuthrieKAEl-KhoueiryABCorlessCLZalupskiMMLowyAMThomasCRJrAlbertsSRDawsonLAMicetichKCSWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinomaJ Clin Oncol3326172622201510.1200/JCO.2014.60.221925964250LamarcaAPalmerDHWasanHSRossPJMaYTAroraAFalkSGillmoreRWadsleyJPatelKSecond-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): A phase 3, open-label, randomized, controlled trialLancet Oncol22690701202110.1016/S1470-2045(21)00027-933798493DodagoudarCDovalDCMahantaAGoelVUpadhyayAGoyalPTalwarVSinghSJohnMCTiwariSPatnaikNFOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patientsJpn J Clin Oncol465762201610.1093/jjco/hyv14826603355EdelineJTouchefeuYGuiuBFargeOTougeronDBaumgaertnerIAyavACampillo-GimenezBBeuzitLPrachtMRadioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: A phase 2 clinical trialJAMA Oncol65159202010.1001/jamaoncol.2019.370231670746ZhouYYuanKYangYJiZZhouDOuyangJWangZWangFLiuCLiQGallbladder cancer: Current and future treatment optionsFront Pharmacol141183619202310.3389/fphar.2023.118361937251319SchmidSJochumWPadbergBDemmerIMertzKDJoergerMBritschgiCMatterMSRothschildSIOmlinAHow to read a next-generation sequencing report-what oncologists need to knowESMO Open7100570202210.1016/j.esmoop.2022.10057036183443McCombieWRMcPhersonJDMardisERNext-generation sequencing technologiesCold Spring Harb Perspect Med9a036798201910.1101/cshperspect.a03679830478097KuipersHde Bitter Tjjde BoerMTvan der PostRSNijkampMWde ReuverPRFehrmannRSNHoogwaterFJHGallbladder cancer: Current insights in genetic alterations and their possible therapeutic implicationsCancers (Basel)135257202110.3390/cancers1321525734771420JavleMBekaii-SaabTJainAWangYKelleyRKWangKKangHCCatenacciDAliSKrishnanSBiliary cancer: Utility of next-generation sequencing for clinical managementCancer12238383847201610.1002/cncr.3025427622582RoaIGarciaHGameAde ToroGde AretxabalaXJavleMSomatic mutations of PI3K in early and advanced gallbladder cancer: Additional options for an orphan cancerJ Mol Diagn18388394201610.1016/j.jmoldx.2015.12.00326947513DixitRPandeyMTripathiSKDwivediANShuklaVKComparative analysis of mutational profile of sonic hedgehog gene in gallbladder cancerDig Dis Sci62708714201710.1007/s10620-016-4438-128058596YangPJavleMPangFZhaoWAbdel-WahabRChenXMeric-BernstamFChenHBoradMJLiuYSomatic genetic aberrations in gallbladder cancer: Comparison between Chinese and US patientsHepatobiliary Surg Nutr8604614201910.21037/hbsn.2019.04.1131929987KimRDSanoffHKPoklepovicASSoaresHKimJLyuJLiuYNixonABKimDWA multi-institutional phase 2 trial of regorafenib in refractory advanced biliary tract cancerCancer12634643470202010.1002/cncr.3296432453456LeeCKChonHJCheonJLeeMAImHSJangJSKimMHParkSKangBHongMTrastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14)Lancet Gastroenterol Hepatol85665202310.1016/S2468-1253(22)00335-136328033CostelloBABoradMJQiYKimGPNorthfeltDWErlichmanCAlbertsSRPhase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. InvestigNew Drugs32710716201410.1007/s10637-014-0096-3Bekaii-SaabTSYaegerRSpiraAIPelsterMSSabariJKHafezNBarveMVelasteguiKYanXShettyAAdagrasib in advanced solid tumors harboring a KRASG12C mutationJ Clin Oncol4140974106202310.1200/JCO.23.0043437099736KastenhuberERLoweSWPutting p53 in ContextCell17010621078201710.1016/j.cell.2017.08.02828886379VousdenKHLaneDPp53 in health and diseaseNat Rev Mol Cell Biol8275283200710.1038/nrm214717380161LevineAJp53: 800 million years of evolution and 40 years of discoveryNat Rev Cancer20471480202010.1038/s41568-020-0262-132404993KennedyMCLoweSWMutant p53: It's not all one and the sameCell Death Differ29983987202210.1038/s41418-022-00989-y35361963AjikiTOnoyamaHYamamotoMAsakaKFujimoriTMaedaSSaitohYp53 protein expression and prognosis in gallbladder carcinoma and premalignant lesionsHepatogastroenterology4352152619968799388ZhaoCYangZYZhangJLiOLiuSLCaiCShuYJPanLJGongWDongPInhibition of XPO1 with KPT-330 induces autophagy-dependent apoptosis in gallbladder cancer by activating the p53/mTOR pathwayJ Transl Med20434202210.1186/s12967-022-03635-w36180918NepalCZhuBO'RourkeCJBhattDKLeeDSongLWangDVan DykeALChoo-WosobaHLiuZIntegrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypesJ Hepatol7411321144202110.1016/j.jhep.2020.11.03333276026StancuMCaruntuIDSajinMGiuşcaSBadescuADobrescuGImmunohistochemical markers in the study of gallbladder premalignant lesions and cancerRev Med Chir Soc Med Nat Iasi111734743200718293709National Library of MedicineBrightline-2: A Study to Test Whether Brigimadlin (BI 907828) Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladderhttps://ClinicalTrials.gov/show/NCT05512377PilleySRodriguezTAVousdenKHMutant p53 in cell-cell interactionsGenes Dev35433448202110.1101/gad.347542.12033861719AgupitanADNeesonPWilliamsSHowittJHauptSHauptYp53: A guardian of immunity becomes its saboteur through mutationInt J Mol Sci213452202010.3390/ijms2110345232414156EfeGRustgiAKPrivesCp53 at the crossroads of tumor immunityNat Cancer5983995202410.1038/s43018-024-00796-z39009816GuoXFZhangYYKangJDouQHZhuXFA bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacyJ Drug Target30302312202210.1080/1061186X.2021.196179134319822HungMSChenICLinPYLungJHLiYCLinYCYangCTTsaiYHEpidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancerOncol Lett1245984604201610.3892/ol.2016.528728101216SinghPJainSLSakhujaPAgarwalAExpression of VEGF-A, HER2/neu, and KRAS in gall bladder carcinoma and their correlation with clinico-pathological parametersIndian J Pathol Microbiol64687692202110.4103/IJPM.IJPM_248_2034673587XuDLiJJiangFCaiKRenGThe effect and mechanism of vascular endothelial growth factor (VEGF) on tumor angiogenesis in gallbladder carcinomaIran J Public Health48713721201931110982De LorenzoSGarajovaIStefaniniBTovoliFTargeted therapies for gallbladder cancer: An overview of agents in preclinical and clinical developmentExpert Opin Investig Drugs30759772202110.1080/13543784.2021.192863633966562MabetaPSteenkampVThe VEGF/VEGFR axis revisited: Implications for cancer therapyInt J Mol Sci2315585202210.3390/ijms23241558536555234PatelSANilssonMBLeXCasconeTJainRKHeymachJVMolecular mechanisms and future implications of VEGF/VEGFR in cancer therapyClin Cancer Res293039202310.1158/1078-0432.CCR-22-136635969170AhamedASamantaAAlamSSMMirSAJamilZAliSHoqueMNonsynonymous mutations in VEGF receptor binding domain alter the efficacy of bevacizumab treatmentJ Cell Biochem125e30515202410.1002/jcb.3051538213080PapadimitriouMPapadimitriouCAAntiangiogenic tyrosine kinase inhibitors in metastatic colorectal cancer: Focusing on regorafenibAnticancer Res41567582202110.21873/anticanres.1480933517262YanHWuWHuYLiJXuJChenXXuZYangXYangBHeQLuoPRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axisNat Commun142756202310.1038/s41467-023-38430-837179400SahinIHTanEKimRRegorafenib, an investigational agent for the treatment of cholangiocarcinomaExpert Opin Investig Drugs30333341202110.1080/13543784.2021.186753733378249YardenYSliwkowskiMXUntangling the ErbB signaling networkNat Rev Mol Cell Biol2127137200110.1038/3505207311252954LiMLiuFZhangFZhouWJiangXYangYQuKWangYMaQWangTGenomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: A whole-exome sequencing analysisGut6810241033201910.1136/gutjnl-2018-31603929954840AugustinJESoussanPBassAJTargeting the complexity of ERBB2 biology in gastroesophageal carcinomaAnn Oncol3311341148202210.1016/j.annonc.2022.08.00135963482FernandezAILiuMBellizziABrockJFadareOHanleyKHarigopalMJornsJMKubaMGLyAExamination of Low ERBB2 Protein Expression in Breast Cancer TissueJAMA Oncol814202210.1001/jamaoncol.2021.723935113160KamAEMasoodAShroffRTCurrent and emerging therapies for advanced biliary tract cancersLancet Gastroenterol Hepatol6956969202110.1016/S2468-1253(21)00171-034626563MertersJLamarcaAIntegrating cytotoxic, targeted and immune therapies for cholangiocarcinomaJ Hepatol78652657202310.1016/j.jhep.2022.11.00536400328NamARKimJWChaYHaHParkJEBangJHJinMHLeeKHKimTYHanSWTherapeutic implication of HER2 in advanced biliary tract cancerOncotarget75800758021201610.18632/oncotarget.1115727517322National Library of MedicineTrastuzumab-pkrb Combined With Modified FOLFOX-6 in Biliary Tract Cancer Patients Progressed on First Line Therapyhttps://ClinicalTrials.gov/show/NCT04722133PengYWangYZhouCMeiWZengCPI3K/Akt/mTOR pathway and its role in cancer therapeutics: Are we making headway?Front Oncol12819128202210.3389/fonc.2022.81912835402264LavacchiDCalimanERossiGButtittaEBotteriCFancelliSPellegriniERovielloGPillozziSAntonuzzoLIvosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directionsPharmacol Ther237108170202210.1016/j.pharmthera.2022.10817035296436WangJJiangWLiuSShiKZhangYChenYShanJWangYXuXLiCLiXExosome-derived miR-182-5p promoted cholangiocarcinoma progression and vasculogenesis by regulating ADK/SEMA5a/PI3K pathwayLiver Int44370388202410.1111/liv.1577337950359NarayanankuttyAPI3K/akt/mTOR pathway as a therapeutic target for colorectal cancer: A review of preclinical and clinical evidence CurrDrug Targets2012171226201910.2174/138945012066619061812384631215384RosenbergLYoonCHSharmaGBertagnolliMMChoNLSorafenib inhibits proliferation and invasion in desmoid-derived cells by targeting Ras/MEK/ERK and PI3K/Akt/mTOR pathwaysCarcinogenesis39681688201810.1093/carcin/bgy03829538717CaiCDangWLiuSHuangLLiYLiGYanSJiangCSongXHuYGuJAnthrax toxin receptor 1/tumor endothelial marker 8 promotes gastric cancer progression through activation of the PI3K/AKT/mTOR signaling pathwayCancer Sci11111321145202010.1111/cas.1432631977138LiuHLiuCWangMSunDZhuPZhangPTanXShiGTanshinone IIA affects the malignant growth of Cholangiocarcinoma cells by inhibiting the PI3K-Akt-mTOR pathwaySci Rep1119268202110.1038/s41598-021-98948-z34588580ZhongLLiYXiongLWangWWuMYuanTYangWTianCMiaoZWangTYangSSmall molecules in targeted cancer therapy: Advances, challenges, and future perspectivesSignal Transduct Target Ther6201202110.1038/s41392-021-00572-w34054126BarbacidMras genesAnnu Rev Biochem56779827198710.1146/annurev.bi.56.070187.0040233304147HallinJBowcutVCalinisanABriereDMHargisLEngstromLDLaguerJMedwidJVanderpoolDLifsetEAnti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitorNat Med821712182202210.1038/s41591-022-02007-736216931ZhuCGuanXZhangXLuanXSongZChengXZhangWQinJJTargeting KRAS mutant cancers: From druggable therapy to drug resistanceMol Cancer21159202210.1186/s12943-022-01629-235922812HunterJCManandharACarrascoMAGurbaniDGondiSWestoverKDBiochemical and structural analysis of common cancer-associated KRAS mutationsMol Cancer Res1313251335201510.1158/1541-7786.MCR-15-020326037647HuangLGuoZWangFFuLKRAS mutation: From undruggable to druggable in cancerSignal Transduct Target Ther6386202110.1038/s41392-021-00780-434776511NagaoMFukudaAOmatsuMNamikawaMSonoMFukunagaYMasudaTArakiOYoshikawaTOgawaSConcurrent activation of Kras and canonical Wnt signaling induces premalignant lesions that progress to extrahepatic biliary cancer in miceCancer Res8218031817202210.1158/0008-5472.CAN-21-217635247892GotwalsPCameronSCipollettaDCremascoVCrystalAHewesBMuellerBQuaratinoSSabatos-PeytonCPetruzzelliLProspects for combining targeted and conventional cancer therapy with immunotherapyNat Rev Cancer17286301201710.1038/nrc.2017.1728338065ObeidMTesniereAGhiringhelliFFimiaGMApetohLPerfettiniJLCastedoMMignotGPanaretakisTCasaresNCalreticulin exposure dictates the immunogenicity of cancer cell deathNat Med135461200710.1038/nm152317187072ZhuHShanYGeKLuJKongWJiaCOxaliplatin induces immunogenic cell death in hepatocellular carcinoma cells and synergizes with immune checkpoint blockade therapyCell Oncol (Dordr)4312031214202010.1007/s13402-020-00552-232797385YiMZhengXNiuMZhuSGeHWuKCombination strategies with PD-1/PD-L1 blockade: current advances and future directionsMol Cancer2128202210.1186/s12943-021-01489-235062949WangLTangKLiXLuWAnti-PD-1-based immunotherapy plus lenvatinib to treat advanced gallbladder cancer in the elderly: A case series and review of current literatureJ Cancer Res Clin Oncol149941950202310.1007/s00432-022-04126-735759010PatelSPGuadarramaEChaeYKDennisMJPowersBCLiaoCYFerriWAJrGeorgeTJSharonERyanCWSWOG 1609 cohort 48: Anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancerCancer13029182927202410.1002/cncr.3524338358334ZhengQWuCYeHXuZJiYRaoJLuLZhuYChengFAnalysis of the efficacy and prognostic factors of PD-1 inhibitors in advanced gallbladder cancerAnn Transl Med91568202110.21037/atm-21-474734790774Jalili-NikMSoltaniAMashkaniBRafatpanahHHashemySIPD-1 and PD-L1 inhibitors foster the progression of adult T-cell Leukemia/LymphomaInt Immunopharmacol98107870202110.1016/j.intimp.2021.10787034153661ZuoHWanYInhibition of myeloid PD-L1 suppresses osteoclastogenesis and cancer bone metastasisCancer Gene Ther2913421354202210.1038/s41417-022-00446-535256753LukeJJRutkowskiPQueiroloPDel VecchioMMackiewiczJChiarion-SileniVde la Cruz MerinoLKhattakMASchadendorfDLongGVPembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): A randomized, double-blind, phase 3 trialLancet39917181729202210.1016/S0140-6736(22)00562-135367007WuMHuangQXieYWuXMaHZhangYXiaYImprovement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulationJ Hematol Oncol1524202210.1186/s13045-022-01242-235279217ChuXTianWWangZZhangJZhouRCo-inhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: Mechanisms and clinical trialsMol Cancer2293202310.1186/s12943-023-01800-337291608TangQChenYLiXLongSShiYYuYWuWHanLWangSThe role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancersFront Immunol13964442202210.3389/fimmu.2022.96444236177034XieQWangLZhengSPrognostic and clinicopathological significance of PD-L1 in patients with cholangiocarcinoma: A meta-analysisDis Markers20201817931202010.1155/2020/181793132724483XiaLLiuYWangYPD-1/PD-L1 blockade therapy in advanced non-small cell lung cancer: Current status and future directionsOncologist24(Suppl 1)S31S41201910.1634/theoncologist.2019-IO-S1-s0530819829AguiarPNJrDe MelloRAHallPTadokoroHLima LopesGPD-L1 expression as a predictive biomarker in advanced non-small cell lung cancer: Updated survival dataImmunotherapy9499506201710.2217/imt-2016-015028472902ZhangHDaiZWuWWangZZhangNZhangLZengWJLiuZChengQRegulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancerJ Exp Clin Cancer Res40184202110.1186/s13046-021-01987-734088360SznolMMeleroIRevisiting anti-CTLA-4 antibodies in combination with PD-1 blockade for cancer immunotherapyAnn Oncol32295297202110.1016/j.annonc.2020.11.01833307201RotteACombination of CTLA-4 and PD-1 blockers for treatment of cancerJ Exp Clin Cancer Res38255201910.1186/s13046-019-1259-z31196207DokiYUenoMHsuCHOhDYParkKYamamotoNIokaTHaraHHayamaMNiiMTolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancerCancer Med1125502560202210.1002/cam4.459335611499ZhangXZhuLZhangHChenSXiaoYCAR-T cell therapy in hematological malignancies: Current opportunities and challengesFront Immunol13927153202210.3389/fimmu.2022.92715335757715Goyco VeraDWaghelaHNuhMPanJLullaPApproved CAR-T therapies have reproducible efficacy and safety in clinical practiceHum Vaccin Immunother202378543202410.1080/21645515.2024.237854339104200National Library of MedicineClinical Study of CAR-CLD18 T Cells in Patients With Advanced Gastric Adenocarcinoma and Pancreatic Adenocarcinomahttps://ClinicalTrials.gov/show/NCT03159819WangYJainPLockeFLMaurerMJFrankMJMunozJLDahiyaSBeitinjanehAMJacobsMTMcguirkJPBrexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US lymphoma CAR T consortiumJ Clin Oncol4125942606202310.1200/JCO.22.0179736753699DepilSDuchateauPGruppSAMuftiGPoirotL‘Off-the-shelf’ allogeneic CAR T cells: Development and challengesNat Rev Drug Discov19185199202010.1038/s41573-019-0051-231900462SternerRCSternerRMCAR-T cell therapy: Current limitations and potential strategiesBlood Cancer J1169202110.1038/s41408-021-00459-733824268PanKFarrukhHChittepuVCSRXuHPanCXZhuZCAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapyJ Exp Clin Cancer Res41119202210.1186/s13046-022-02327-z35361234MaSLiXWangXChengLLiZZhangCYeZQianQCurrent progress in CAR-T cell therapy for solid tumorsInt J Biol Sci1525482560201910.7150/ijbs.3421331754328FaghfuriEPourfarziFFaghfouriAHAbdoli ShadbadMHajiasgharzadehKBaradaranBRecent developments of RNA-based vaccines in cancer immunotherapyExpert Opin Biol Ther21201218202010.1080/14712598.2020.181570432842798MalacopolATHolstPJCancer vaccines: Recent insights and future directionsInt J Mol Sci2511256202410.3390/ijms25201125639457036MiaoLZhangYHuangLmRNA vaccine for cancer immunotherapyMol Cancer2041202110.1186/s12943-021-01335-533632261BindaCAnderloniAFugazzaAAmatoAde NucciGRedaelliADi MitriRCugiaLPollinoVMacchiarelliREUS-guided gallbladder drainage using a lumen-apposing metal stent as rescue treatment for malignant distal biliary obstruction: A large multicenter experienceGastrointest Endosc98765773202310.1016/j.gie.2023.06.05437392954BensonABD'AngelicaMIAbbottDEAnayaDAAndersRAreCBachiniMBoradMBrownDBurgoyneAHepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncologyJ Natl Compr Canc Netw19541565202110.6004/jnccn.2021.001234030131StrangPPalliative oncology and palliative careMol Oncol1633993409202210.1002/1878-0261.1327835762045BeasleyAMBakitasMAIvankovaNShireyMREvolution and conceptual foundations of nonhospice palliative careWest J Nurs Res4113471369201910.1177/019394591985316231170893KozlovENiknejadBReidMCPalliative care gaps in providing psychological treatment: A review of the current state of research in multidisciplinary palliative careAm J Hosp Palliat Care35505510201810.1177/104990911772386028783958TondorfTGrossertARothschildSIKollerMTRochlitzCKissASchaefertRMeinlschmidtGHunzikerSZwahlenDFocusing on cancer patients' intentions to use psychooncological support: A longitudinal, mixed-methods studyPsychooncology2716561663201810.1002/pon.473529656415
Clinical trials of chemotherapy including GBC obtained from ClinicalTrials.gov.