Conversion therapy for advanced hepatocellular carcinoma in the era of precision medicine: Current status, challenges and opportunities.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Long-term oncological results of percutaneous radiofrequency ablation for intrahepatic cholangiocarcinoma.

INTRODUCTION: The effectiveness of percutaneous radiofrequency ablation (RFA) in intrahepatic cholangiocarcinomas (iCCA) remains insufficiently studied. METHODS: We conducted a retrospective study including patients with histologically proven iCCA within Milan criteria treated by percutaneous RFA from 2000 to 2022. The primary outcome was overall survival in treatment-naive patients and secondary outcomes included ablation completeness, adverse events, local and distant recurrence. A total of 494 patients with hepatocellular carcinoma (HCC) on cirrhosis treated by RFA were included as a comparison group. Oncological events were analysed using Kaplan-Meier, log-rank and univariate/multivariate Cox models. RESULTS: The main population included 71 patients, mostly cirrhotic (80%) with solitary tumours (66%) of a median size of 24 mm. Local recurrence was 45% at 5 years, lower in multibipolar versus monopolar RFA (22% vs. 55%, p = .007). In treatment-naive patients (n = 45), median overall and recurrence-free survivals were 26 and 11 months, respectively. Tumour size (p = .01) and Child-Pugh B (p = .001) were associated with death. The rate of distant recurrence was 59% at 5 years significantly lower for single tumours of less than 2 (p = .002) or 3 cm (p = .02). In cirrhotic patients naïve of previous treatment (n = 40), overall survival was shorter than in HCC (26 vs 68 months, p < .0001), with more local recurrences (p < .0001). Among distant recurrences, 50% were extrahepatic metastases compared to 12% in HCC (p < .001). CONCLUSION: Multibipolar RFA provides better results in terms of tumour recurrence than monopolar RFA and could be used to treat small iCCA (<3 cm). Adjuvant chemotherapy should be discussed due to the frequent extra-hepatic metastasis at recurrence.

Newly established borderline resectable 1 (BR1) category is one of the favorable candidates for selecting the use of multidisciplinary combination therapy in patients with advanced hepatocellular carcinoma treated with systemic therapy.

BACKGROUND: The aim of this study was to evaluate the newly established oncological criteria of resectability of hepatocellular carcinoma (HCC) for selecting suitable candidates for systemic and combination therapy. METHODS: The data of 156 consecutive HCC patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The patients were classified into three groups according to the novel oncological criteria for resectability (R, resectable; BR1, borderline resectable 1; and BR2, borderline resectable 2). The prognostic ability and clinical utility for selecting this population to receive combined use of multiple systemic sequential and locoregional therapy was then evaluated. Combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while systemic sequential therapy only and repeated locoregional treatment was defined as a single treatment procedure (STP). RESULTS: Patients classified as R and BR1 had significantly better overall survival (OS) compared with BR2 (R vs. BR2, p = 0.012; BR1 vs. BR2, p = 0.004). However, there was no significant difference between R and BR1 (p = 1.000), in spite of significantly worse oncological status in the BR1 patients. Following a R0 resection and MCT, the BR1 patients had significantly better OS compared with those receiving STP or no additional treatment (median OS, not reached vs. 25.2 months and 20.1 vs. 11.3 months, respectively; p = 0.034). CONCLUSIONS: In patients with advanced HCC with intrahepatic target nodules the BR1 category is one of the favorable candidates for selecting those to be treated with MCT strategies.

Locoregional treatment of primary tumor in synchronous metastatic head and neck squamous cell carcinomas.

PURPOSE: Patients with synchronous metastatic head and neck squamous cell carcinomas (mHNSCC) are at risk of locoregional progression associated with significant morbidity and mortality. The aim of this study is to assess whether the addition of aggressive locoregional treatment to systemic therapy could be associated with an improved overall survival (OS) compared to systemic therapy alone in upfront mHNSCC patients. MATERIAL AND METHODS: This retrospective study included patients presenting with previously untreated mHNSCC who underwent first-line systemic therapy at a single institution between 1998 and 2018. Locoregional treatment was defined as either exclusive locoregional radiotherapy (RT) or surgery with or without adjuvant RT. RESULTS: One hundred forty-eight patients were included. Eighty patients were treated with systemic therapy alone and 68 patients were treated with a combination of locoregional treatment and systemic therapy. Median overall survival (OS) was 13 months [10.7-15] and median progression free survival (PFS) was 7.7 month [6.5-8.9]. The addition of a locoregional treatment to systemic therapy compared to systemic therapy alone was associated with improved survival (1-year OS, 65.8% vs. 41.1%, p < .001, and 1-year PFS, 42.5% vs. 18.5%, p < .001). Moreover, RT dose equal to 70 Gy was associated with even longer OS compared to a RT dose below 70 Gy and to no locoregional treatment (23.4 vs. 12.7 vs 7.5 months respectively). In a subgroup analysis on 75 patients presenting with a responding or stable metastatic disease after first-line systemic therapy, oropharyngeal primary tumor site and the addition of a locoregional treatment, especially a high radiation dose of 70 Gy, were evidenced as independent prognostic factors for improved OS. CONCLUSION: The addition of a high-dose RT locoregional treatment to systemic therapy is associated with prolonged OS in patients with synchronous mHNSCC and should be discussed for patients who respond to or have a stable disease after first-line systemic therapy.

MRI-based radiomics model and nomogram for predicting the outcome of locoregional treatment in patients with hepatocellular carcinoma.

BACKGROUND: Prediction of locoregional treatment response is important for further therapeutic strategy in patients with hepatocellular carcinoma. This study aimed to investigate the role of MRI-based radiomics and nomogram for predicting the outcome of locoregional treatment in patients with hepatocellular carcinoma. METHODS: The initial postoperative MRI after locoregional treatment in 100 patients with hepatocellular carcinoma was retrospectively analysed. The outcome was evaluated according to mRECIST at 6 months. We delineated the tumour volume of interest on arterial phase, portal venous phase and T2WI. The radiomics features were selected by using the independent sample t test or nonparametric Mann‒Whitney U test and the least absolute shrinkage and selection operator. The clinical variables were selected by using univariate analysis and multivariate analysis. The radiomics model and combined model were constructed via multivariate logistic regression analysis. A nomogram was constructed that incorporated the Rad score and selected clinical variables. RESULTS: Fifty patients had an objective response, and fifty patients had a nonresponse. Nine radiomics features in the arterial phase were selected, but none of the portal venous phase or T2WI radiomics features were predictive of the treatment response. The best radiomics model showed an AUC of 0.833. Two clinical variables (hCRP and therapy method) were selected. The AUC of the combined model was 0.867. There was no significant difference in the AUC between the combined model and the best radiomics model (P = 0.573). Decision curve analysis demonstrated the nomogram has satisfactory predictive value. CONCLUSIONS: MRI-based radiomics analysis may serve as a promising and noninvasive tool to predict outcome of locoregional treatment in HCC patients, which will facilitate the individualized follow-up and further therapeutic strategies guidance.

The Synergistic Effect of Interventional Locoregional Treatments and Immunotherapy for the Treatment of Hepatocellular Carcinoma.

Immunotherapy has remarkably revolutionized the management of advanced HCC and prompted clinical trials, with therapeutic agents being used to selectively target immune cells rather than cancer cells. Currently, there is great interest in the possibility of combining locoregional treatments with immunotherapy for HCC, as this combination is emerging as an effective and synergistic tool for enhancing immunity. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of locoregional treatments, improving patients' outcomes and reducing recurrence rates. On the other hand, locoregional therapies have been shown to positively alter the tumor immune microenvironment and could therefore enhance the efficacy of immunotherapy. Despite the encouraging results, many unanswered questions still remain, including which immunotherapy and locoregional treatment can guarantee the best survival and clinical outcomes; the most effective timing and sequence to obtain the most effective therapeutic response; and which biological and/or genetic biomarkers can be used to identify patients likely to benefit from this combined approach. Based on the current reported evidence and ongoing trials, the present review summarizes the current application of immunotherapy in combination with locoregional therapies for the treatment of HCC, and provides a critical evaluation of the current status and future directions.

Incorporation of Ancillary MRI Features Into the LI-RADS Treatment Response Algorithm: Impact on Diagnostic Performance After Locoregional Treatment of Hepatocellular Carcinoma.

BACKGROUND. The LI-RADS treatment response algorithm may lack sufficient sensitivity for viable tumor after locoregional treatment (LRT) for hepatocellular carcinoma (HCC). OBJECTIVE. The purpose of our study was to evaluate the impact of incorporation of ancillary MRI features on the diagnostic performance of the LI-RADS treatment response algorithm after LRT for HCC. METHODS. This retrospective study included 141 patients (114 men, 27 women; median age, 56 years) who underwent gadoxetic acid-enhanced MRI after LRT for HCC between October 2005 and January 2020 and subsequent liver surgery. Two readers assessed lesions for LI-RADS features of viability for ancillary MRI features (transitional phase [TP] hypointensity, hepatobiliary phase [HBP] hypointensity, DWI hyperintensity or low ADC, and mild-to-moderate T2 hyperintensity). Interobserver agreement was assessed before reaching consensus. Significant ancillary features were identified using random forest analysis. The impact of incorporation of significant ancillary features on diagnostic performance for incomplete pathologic necrosis (IPN; pathologically viable tumor > 0 mm) was assessed using McNemar tests. RESULTS. Complete pathologic necrosis (CPN) was observed in 88 of 181 (48.6%) lesions. Interreader agreement was almost perfect for LI-RADS features of viability (κ = 0.92-0.97) and was substantial to almost perfect for ancillary features (κ = 0.73-0.94). Random forest analysis identified TP hypointensity (present in 8.0%, 25.0%, and 75.3% of lesions with CPN, viable tumor < 10 mm, and viable tumor ≥ 10 mm, respectively) and HBP hypointensity (9.2%, 25.0%, and 74.0%, respectively) as significant ancillary features. For detecting IPN, LR-TR (treatment response) Viable or LR-TR Equivocal had higher sensitivity than LR-TR Viable (71.0% vs 57.0%, respectively; p = .001) but had lower specificity (86.4% vs 94.3%, p = .02). However, LR-TR Viable or LR-TR Equivocal and TP hypointensity showed higher sensitivity than LR-TR Viable (64.5% vs 57.0%, p = .02) without a significantly different specificity (90.9% vs 94.3%, p = .25). LR-TR Viable or LR-TR Equivocal and HBP hypointensity also showed higher sensitivity than LR-TR Viable (65.6% vs 57.0%, p = .01) without a significantly different specificity (90.8% vs 94.3%, p = .25). CONCLUSION. TP hypointensity and HBP hypointensity increase the sensitivity of LI-RADS treatment response algorithm for viable tumor without lowering specificity. CLINICAL IMPACT. The two identified ancillary features may improve tumor viability assessment and planning of additional therapies after LRT for HCC.

Pathologic response translates to improved patient survival after locoregional treatment for hepatocellular carcinoma: the importance of minimally invasive microwave ablation.

BACKGROUND: Hepatectomy or transplantation can serve as curative treatment for early-stage hepatocellular carcinoma (HCC). Unfortunately, as progression remains a reality, locoregional therapies (LRT) for curative or bridging intent have become common. Efficacy on viability, outcomes, and accuracy of imaging should be defined to guide treatment. METHODS: Patients with HCC who underwent minimally invasive (MIS) microwave ablation (MWA), transarterial chemoembolization (TACE), or both (MIS-MWA-TACE) prior to hepatectomy or transplantation were identified. Tumor response and preoperative computed tomography (CT) accuracy were assessed and compared to pathology. Clinical and oncologic outcomes were compared between MIS-MWA, TACE, and MIS-MWA-TACE. RESULTS: Ninety-one patients, with tumors from all stages of the Barcelona Clinic Liver Cancer (BCLC) staging, were identified who underwent LRT prior to resection or transplant. Fourteen patients underwent MIS-MWA, 46 underwent TACE, and 31 underwent both neoadjuvantly. TACE population was older; otherwise, there were no differences in demographics. Fifty-seven percent of MIS-MWA patients had no viable tumor on pathology whereas only 13% of TACE patients and 29% of MIS-MWA-TACE patients had complete destruction (p = 0.004). The amount of remaining viable tumor in the explant was also significantly different between groups (MIS-MWA: 17.2%, TACE: 48.7%, MIS-MWA-TACE: 18.6%; p ≤ 0.0001). Compared with TACE, the MIS-MWA and MIS-MWA-TACE groups had significantly improved overall survival (MIS-MWA: 99.94 months, TACE: 75.35 months, MIS-MWA-TACE: 140 months; p = 0.017). This survival remained significant with stratification by tumor size. CT accuracy was found to be 50% sensitive and 86% specific for MIS-MWA. For TACE, CT had an 82% sensitivity and 33% specificity and for MIS-MWA-TACE, there was a 42% sensitivity and 78% specificity. CONCLUSION: The impact of locoregional treatments on tumor viability is distinct and superior with MIS-MWA alone and MIS-MWA-TACE offering significant advantage over TACE alone. The extent of this effect may be implicated in the improved overall survival.

Proposed Definition for Oligometastatic Recurrence in Biliary Tract Cancer Based on Results of Locoregional Treatment: A Propensity-Score-Stratified Analysis.

BACKGROUND: Oligometastatic recurrence involves relapsed tumors for which locoregional treatment (LT) may yield a survival benefit. However, there are no clear criteria for selecting patients for LT or determining the effects of LT in recurrent biliary tract cancer (BTC). The aim of this retrospective study is to assess the effects of LT on survival outcomes and to identify potential criteria for selecting LT in recurrent BTC. PATIENTS AND METHODS: In the present work, 232 consecutive patients with recurrent BTC who initially underwent curative surgery between 1996 and 2015 were evaluated. The primary outcome was length of survival after recurrence (SAR). Propensity score stratification with various tumor-related factors was used to identify patients who would likely benefit from LT. RESULTS: Among the cohort, 60 (25.9%) patients underwent LT, whereas 172 (74.1%) patients did not. The multivariate Cox model identified carbohydrate antigen 19-9 levels of > 50 U/mL, multiorgan recurrence, tumor number > 3, tumor size > 30 mm, and early recurrence (≤ 1 year) as independent predictors of poor SAR (P < 0.001 for each factor). In the propensity-score-stratified analysis, LT was associated with survival benefits for patients representing single-organ recurrence with at most three tumors and late-onset recurrence (> 1 year) (median SAR: 48.6 vs. 14.2 months, n = 33 vs. n = 34, hazard ratio: 0.10, 95% confidence interval: 0.04-0.20, P < 0.001). CONCLUSIONS: Patients with recurrent BTC may benefit from LT if they have single-organ recurrence with at most three tumors and late-onset recurrence. We propose that these patients may have clinically relevant "oligometastatic recurrence" of BTC.

Locoregional treatments before liver transplantation for hepatocellular carcinoma: a study from the European Liver Transplant Registry.

Locoregional treatment while on the waiting list for liver transplantation (Ltx) for hepatocellular carcinoma (HCC) has been shown to improve survival. However, the effect of treatment type has not been investigated. We investigate the effect of locoregional treatment type on survival after Ltx for HCC. We investigated patients registered in the European Liver Transplant Registry database using multivariate Cox regression survival analysis. Information on locoregional therapy was registered for 4978 of 23 124 patients and was associated with improved overall survival [hazard ratio (HR) 0.84 (0.73-0.96)] and HCC-specific survival [HR 0.76 (0.59-0.98)]. Radiofrequency ablation (RFA) was the one monotherapy associated with improved overall survival [HR 0.51 (0.40-0.65)]. In addition, the combination of RFA and transarterial chemoembolization also improved survival [HR 0.74 (0.55-0.99)]. Adjusting for factors related to prognosis, disease severity, and tumor aggressiveness, RFA was highly beneficial for overall and HCC-specific survival. The effect may represent a selection of patients with favorable tumor biology; however, the treatment may be effective per se by halting tumor progression. Clinicaltrials.gov number: NCT02995096.

Impact of remnant vital tissue after locoregional treatment and liver transplant in hepatocellular cancer patients, a multicentre cohort study.

The role of pathological findings after locoregional treatments as predictors of hepatocellular cancer recurrence after liver transplantation has been poorly addressed. The aim of the study was to identify the role of remnant vital tissue (RVT) of the target lesion in predicting hepatocellular cancer recurrence. Two hundred and seventy-six patients firstly undergoing locoregional treatment and then transplanted between January 2010 and December 2015 in four European Transplant Centres (i.e. Rome Tor Vergata, Birmingham, Brussels and Ancona) were enrolled in the study to investigate the role of pathological response at upfront locoregional treatment. At multivariable Cox regression analysis, RVT ≥2 cm was a strong independent risk factor for post-LT recurrence (HR = 5.6; P < 0.0001). Five-year disease-free survival rates were 60.8%, 80.9% and 95.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. When only Milan Criteria-IN patients were analysed, similar results were reported, with 5-year disease-free survival rates of 58.1%, 79.0% and 94.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. RVT is an important determinant of tumour recurrence after liver transplantation performed for hepatocellular cancer. Its discriminative power looks to be evident also in a Milan-IN setting, suggesting to more liberally use locoregional treatments also in these patients.

The prognosis and treatment outcomes of patients with recurrent hepatocellular carcinoma after liver transplantation.

Liver transplantation (LT) is performed in patients with hepatocellular carcinoma (HCC), but recurrent HCC after LT remains a problem. We retrospectively reviewed the data from 63 patients with recurrent HCC who underwent LT at a single institution between September 1996 and March 2011 to determine the prognosis of patients with recurrent HCC after LT. A survival analysis was performed with the preoperative data, histological findings, patterns of recurrence, and treatment methods. Univariate and multivariate analyses were performed to determine the factors associated with early (<1 yr) cancer-related death. The independent prognostic factors, according to the multivariate analysis, were recurrence within six months (hazards ratio [HR] = 4.557, p = 0.021) and initial multiple-organ involvement (HR = 5.494, p = 0.015). The survival rates of patients differed according to the treatment type. The combined treatment with local and systemic treatment resulted in increased survival even in patients with HCC recurrences involving multiple organs.

The Long-Term Results of Electrochemotherapy in the Treatment of Patients with Locoregionally Advanced, Unresectable Melanoma.

Background/Objectives: Despite observing progress in recent years in the treatment of patients with advanced melanoma, the optimal management of locoregional recurrence has not been determined. Various methods are used to treat this group of patients. One of these methods is electrochemotherapy. The present study presents the distant results in treating patients with the locoregional recurrence of melanoma, using the technique of electrochemotherapy. Methods: This study includes a retrospective analysis of 88 patients' data with locoregional melanoma recurrence, treated with electrochemotherapy (ECT) between 2010 and 2023, in two reference centers. Results: Approximately 80% of patients responded to the ECT treatment, achieving partial or complete remission. In a multivariate analysis, statistically significant longer overall survival was found in the group of patients who achieved complete remission after ECT and were treated with immunotherapy. Discussion: The results may suggest the existence of synergy between ECT and immunotherapy. However, confirmation of this fact requires further prospective studies that will also establish the role of ECT in the combination treatment of patients with locoregional recurrence of melanoma.

Immunotherapy as a Complement to Surgical Management of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor in adults, and the fourth leading cause of cancer-related deaths worldwide. While surgical and ablative therapies remain the standard of care in early localized disease, late presentation with advanced stages of disease, impaired hepatic function, or local recurrence following surgical resection preclude operative management as the sole treatment modality in a subgroup of patients. As such, systemic therapies, namely immunotherapy, have become an integral part of the HCC treatment algorithm over the past decade. While agents, such as atezolizumab/bevacizumab, have well-established roles as first-line systemic therapy in intermediate- and advanced-stage HCC, the role of immunotherapy in disease amenable to surgical management continues to evolve. In this review, we will discuss the current evidence and aggregate impact of immunotherapy in the context of HCC amenable to surgical management, including its application in the neoadjuvant and adjuvant settings.

The immune response of hepatocellular carcinoma after locoregional and systemic therapies: The available combination option for immunotherapy.

Hepatocellular carcinoma (HCC) is associated with a highly heterogeneous immune environment that produces an immune response to various locoregional treatments (LRTs), which in turn affects the effectiveness of immunotherapy. Although LRTs still dominate HCC therapies, 50-60% of patients will ultimately be treated with systemic therapies and might receive those treatments for the rest of their life. TACE, SIRT, and thermal ablation can dramatically increase the immunosuppressive state of HCC, a condition that can be addressed by combination with immunotherapy to restore the activity of lymphocytes and the secretion of cellular immune factors. Immune treatment with locoregional and systemic treatments has dramatically changed the management of HCC. In this review, we examine the research on the changes in the immune microenvironment after locoregional or systemic treatment. We also summarize the regulation of various immune cells and immune factors in the tumor microenvironment and discuss the different infiltration degrees of immune cells and factors on the prognosis of HCC to better compare the efficacy between different treatment methods from the perspective of the tumor microenvironment. This information can be used to help develop treatment options for the upcoming new era of HCC treatment in the future.

Recurrent Versus Metastatic Head and Neck Cancer: An Evolving Landscape and the Role of Immunotherapy.

Squamous cell carcinoma of the head and neck (SCCHN) is among the ten most common cancers worldwide, with advanced SCCHN presenting with a 5-year survival of 34% in the case of nodal involvement and 8% in the case of metastatic disease. Disease-free survival at 2 years is 67% for stage II and 33% for stage III tumors, whereas 12-30% of patients undergo distant failures after curative treatment. Previous treatments often hinder the success of salvage surgery and/or reirradiation, while the standard of care for the majority of metastatic SCCHN remains palliative chemo- and immuno-therapy, with few patients eligible for locoregional treatments. The aim of this paper is to review the characteristics of recurrent SCCHN, based on different recurrence sites, and metastatic disease; we will also explore the possibilities not only of salvage surgery and reirradiation but also systemic therapy choices and locoregional treatment for metastatic SCCHN.

Interventional Radiology Locoregional Therapies for Intrahepatic Cholangiocarcinoma.

Surgical resection remains the cornerstone of curative treatment for intrahepatic cholangiocarcinoma (iCCA), but this option is only available to a small percentage of patients. For patients with unresectable iCCA, systemic therapy with gemcitabine and platinum-based agents represents the mainstay of treatment; however, the armamentarium has grown to include targeted molecular therapies (e.g., FGFR2 inhibitors), use of adjuvant therapy, liver transplantation in select cases, immunotherapy, and locoregional liver-directed therapies. Despite advances, iCCA remains a challenge due to the advanced stage of many patients at diagnosis. Furthermore, given the improving options for systemic therapy and the fact that the majority of iCCA patients succumb to disease progression in the liver, the role of locoregional therapies has increased. This review will focus on the expanding role of interventional radiology and liver-directed therapies in the treatment of iCCA.

Locoregional treatment improves overall survival for liver cancer during second-line regorafenib or immune checkpoint inhibitor.

For advanced hepatocellular carcinoma (HCC), the best second-line treatment after first-line treatment with sorafenib is unclear. This study aimed to compared the efficacy of second-line regorafenib (a tyrosine kinase inhibitor) and immune checkpoint inhibitors (ICIs) in patients with advanced HCC after sorafenib therapy. This retrospective study included 89 patients with HCC treated with sorafenib, and then regorafenib (n = 58) or an ICI (n = 31). Treatment response, overall survival (OS) and progression-free survival (PFS) of the 2 groups were compared, and factors associated with post-treatment mortality or disease progression were evaluated. During follow-up period, compared to regorafenib, treatment with an ICI results in a slight increase in a 20% decrease of AFP (35.7% vs. 31.8%), complete response rate (6.5% vs. 0%), objective response rate (16.1% vs. 6.9%), median overall survival (13.3 vs. 5 months), and median PFS (3.0 vs. 2.6 months). Combined locoregional treatment (LRT) (hazard ratio [HR] = 0.40, 95% confidence interval [CI]: 0.15-0.99) during second-line treatment was associated with a decreased risk of post-treatment mortality. After propensity scoring matching, combined LRT during second-line treatment had longer post-treatment OS than patients without combined LRT. A 20% decrease of AFP (HR = 0.54, 95% CI: 0.31-0.94) was associated with a decreased risk of post-treatment disease progression. In conclusions, second-line treatment with regorafenib or ICI prolongs OS in patients with advanced HCC treated with sorafenib. Combined LRT during second-line treatment is associated with decreased post-treatment mortality. A 20% decrease of AFP level may be predictive of a lower rate of disease progression.

Combining Immune Checkpoint Inhibitors with Loco-Regional Treatments in Hepatocellular Carcinoma: Ready for Prime Time?

Hepatocellular carcinoma (HCC) is a disease with a poor prognosis, often diagnosed at an advanced stage. Therapeutic options have developed considerably in recent years, particularly with trans-arterial treatments. Systemic treatments have also evolved significantly, with the rise of immune checkpoint inhibitors (ICI) as first-line treatment for advanced HCC. The combination of loco-regional treatments and ICI is opening up new prospects and is the subject of numerous clinical trials. Recently, two global phase 3 trials investigating ICI-based adjuvant combinations have demonstrated improvements in recurrence-free survival or progression-free survival in patients treated with resection, ablation, or trans-arterial chemoembolization. However, mature data and overall survival results are still awaited but will be difficult to interpret. We are at the start of a new era of combinations of loco-regional treatments and immunotherapy. The identification of the best therapeutic strategies and predictive biomarkers is a crucial issue for future standards in clinical practice.