Evaluation of Overall Survival by Restricted Mean Survival Time of Advanced Biliary Tract Cancer treated with Immunotherapy: A Systematic Review and Meta-Analysis.

BACKGROUND: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan-Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis. METHODS: A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed. RESULTS: A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49-1.93), p < 0.001, I2 = 0%]. CONCLUSIONS: Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment.

Risk of Treatment Failure and Death after Ablation in Hepatocellular Carcinoma Patients-A Multiparametric Prediction.

BACKGROUND: Ablation is a first-line treatment for Barcelona Clinic Liver Cancer (BCLC)-0/A hepatocellular carcinoma (HCC). However, there are scarce data about patients' outcomes after recurrence. The present study evaluates the impact of patient and tumor characteristics at baseline and at recurrence on the Clinical Decision-Making process. METHODS: We evaluated BCLC-0/A patients treated with percutaneous ablation from January 2010 to November 2018. Clinical and radiological data such as age, tumor location at ablation, pattern of recurrence/progression, and comorbidities during follow-up were registered. Tumor location was divided into 'suboptimal' vs. 'optimal' locations for ablation. The Clinical Decision-Making was based on tumor burden, liver dysfunction, or comorbidities. The statistical analysis included the time-to-recurrence/progression, censoring at time of death, date of last follow-up or liver transplantation, and time-to-event was estimated by the Kaplan-Meier method and Cox regression models to evaluate the risk of an event of death and change of treatment strategy. RESULTS: A total of 225 patients [39.1% BCLC-0 and 60.9% BCLC-A] were included, 190 had unifocal HCC and 82.6% were ≤3 cm. The complete response rate and median overall survival were 96% and 60.7 months. The HCC nodules number (Hazard Ratio-HR 3.1), Child-Pugh (HR 2.4), and Albumin-Bilirubin score (HR 3.2) were associated with increased risk of death during follow-up. HCC in 'suboptimal location' presented a shorter time to recurrence. When comorbidities prevented further loco-regional or systemic treatment, the risk of death was significantly increased (HR 2.0, p = 0.0369) in comparison to those who received treatment. CONCLUSIONS: These results expose the impact of non-liver comorbidities when considering treatment for recurrence after ablation in the real-world setting and in research trials. Ultimately, we identified an orphan population for which effective interventions are needed.

New Challenges in the Management of Cholangiocarcinoma: The Role of Liver Transplantation, Locoregional Therapies, and Systemic Therapy.

Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15-35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory.

Outcome of patients with HCC and liver dysfunction under immunotherapy: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Immunotherapy-based regimes have changed the management of HCC. However, evidence of efficacy in patients with impaired liver function is unknown. This systematic review and meta-analysis assesses survival of HCC patients and liver dysfunction treated with immunotherapy-based regimens. METHODS: Systematic review and meta-analysis of original articles or abstracts reporting survival of HCC patients treated with immunotherapy according to liver function between 2017 and 2022. Overal survival (OS) according to restricted mean survival time (RMST) and median OS, and hazard ratio (HR) of Child-Pugh B or B/C versus Child-Pugh A were assessed while considering the line of treatment. RESULTS: Of the 2218 articles considered, 15 articles recruiting 2311 patients were included. Of these, 639 (27.7%) were Child-Pugh B and 34 (1.5%) C. RMST was 8.36 (95% CI, 6.15-10.57; I2 =93%) months, estimated from 8 studies. The HR was reported in 8 studies for survival between Child-Pugh B versus Child-Pugh A and metanalysis disclosed a 1.65 HR (95% CI,1.45-1.84; I2 =0% heterogeneity; p = 0.45). Treatment line data were available for 47% of the patients and 3 studies included patients treated with atezolizumab-bevacizumab in the first line. CONCLUSIONS: The high heterogeneity across studies reflects the incapacity of the current evidence to support the indication of immunotherapy in HCC patients with relevant liver dysfunction. It is mandatory to report complementary information to Child-Pugh classification such as prior liver decompensation, use of concomitant medication to control ascites, or signs of clinically significant portal hypertension to allow better patient stratification in future studies.

Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules.

BACKGROUND & AIMS: Recognition of non-characterized liver nodules (NCLN) prior to direct-acting antivirals (DAAs) is associated with increased hepatocellular carcinoma (HCC) risk in patients with HCV. The risk of HCC has not been defined in F3/F4 patients in whom NCLN have been ruled-out before starting DAAs and at sustained virological response (SVR). This study aimed to estimate HCC incidence in this population. METHODS: We performed a prospective study including HCV-infected patients with F3/F4 fibrosis, without a history of HCC, and who achieved SVR after DAAs. Patients were only included if they had undergone ultrasound imaging that excluded the presence of HCC/NCLN within 30 days after SVR. All patients were evaluated every 6 months until developing primary liver cancer, death or withdrawal of informed consent. HCC incidence was expressed per 100 patient-years (/100PY). Adherence to screening program was calculated every 6 months for the first 48 months. RESULTS: A total of 185 patients (63/122, F3/F4) were included. Among those with cirrhosis, 92% were Child-Pugh A and 42.7% had clinically significant portal hypertension (CSPH). Albumin-bilirubin score was 1 in 84.9% and 2 in 15.1% of patients, respectively. The median clinical and radiologic follow-up was 52.4 months and 48 months, respectively. Ten patients developed HCC: HCC incidence was 1.46/100PY (95% CI 0.79-2.71) in the whole cohort, 2.24/100PY (95% CI 1.21-4.17) in F4 only and 3.63/100PY (95% CI 1.95-6.74) in patients with CSPH. No HCC was registered in patients with F3. Median time between SVR and HCC occurrence was 28.1 months; 12 non-primary liver cancers were also identified. CONCLUSIONS: Patients with cirrhosis without NCLN at SVR remain at risk of HCC development. The absence of HCC in patients with F3 reinforces their marginal cancer risk, but prospective studies are needed to exclude them from screening programs. LAY SUMMARY: Patients with HCV-related cirrhosis, without non-characterized liver nodules at sustained virologic response, remain at risk of hepatocellular carcinoma despite viral cure. However, the cancer risk after successful direct-acting antiviral treatment is marginal in patients with F3 fibrosis without non-characterized liver nodules. If confirmed in larger prospective studies, current screening recommendations may need to be revisited in this group of patients.

Current pharmacological treatment of hepatocellular carcinoma.

The landscape of hepatocellular carcinoma (HCC) has changed since the incorporation of sorafenib in 2007 as the first pharmacological treatment for HCC. The combination of atezolizumab plus bevacizumab is currently the first-line treatment for HCC patients, and there are several second-line options approved for patients who had received sorafenib as the first-line treatment. The advantage of having multiple options of pharmacological treatment for HCC patients is associated to the need to redefine the clinical decision-making approach and considering new endpoints for the clinical trials design. The aim of this review was to share the Barcelona Clinic Liver Cancer approach and to summarize the ongoing clinical trials, which are testing pharmacological treatments.

Early diarrhoea under sorafenib as a marker to consider the early migration to second-line drugs.

BACKGROUND: Despite atezolizumab and bevacizumab (A + B) is currently the first-line treatment for hepatocellular carcinoma (HCC) patients, some patients will not be adequate for this combination. In the setting of sorafenib some adverse events have been proposed as prognostic factors. OBJECTIVE: To characterize the early diarrhoea development as prognostic factor in 344 HCC patients. METHODS: The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first 60 days of treatment (e-diarrhoea) and 3-grouping variables were analysed: Patients with e-diarrhoea, patients who developed diarrhoea after the first 60 days of treatment (L-diarrhoea) and patients that never developed diarrhoea (never diarrhoea). RESULTS: The median overall survival in sorafenib treated patients was significantly different across groups (6.8 months for e-diarrhoea, 26.7 months for L-diarrhoea and 13.3 months for never-diarrhoea). The emergence of e-diarrhoea was associated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15-2.95]), while there was no increased/decreased risk of dismal evolution in patients with L-diarrhoea (HR 0.66 [95%CI 0.42-1.03]). CONCLUSION: The emergence of e-diarrhoea in HCC patients treated with sorafenib is an early predictor of dismal evolution under this therapy. Thus, prompt identification of these non-responders may be useful for an early switch to second-line therapies.

Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma.

Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1+ cells express activation markers, T DNAM-1+ cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells.

Pancreatic Insufficiency in Patients Under Sorafenib Treatment for Hepatocellular Carcinoma.

GOALS: To describe the occurrence of malabsorption (MA) in hepatocellular carcinoma (HCC) patients under sorafenib, the potential relationship with pancreatic insufficiency (PI), and the role of pancreatic enzymes supplementation. BACKGROUND: With the increasing options of second-line systemic therapies for HCC, the recognition of drug intolerance using practical tools is crucial. It has been proposed that a MA syndrome could be due to sorafenib-induced pancreatic dysfunction. STUDY: All sorafenib-treated patients with suspicion of MA (defined as decreased stool consistency lasting >4 wk or presenting ≥10% body weight loss without HCC progression) were prospectively evaluated by serum markers, endoscopy, and imaging techniques. RESULTS: We evaluated 81 sorafenib-treated patients and 21 developed MA suspicion (85.7% male, 81.5% Child-Pugh A, 52.4% BCLC-B, and 47.6% BCLC-C) within a median 5.9 months after starting sorafenib. The median treatment duration, follow-up, and overall survival after MA suspicion were 5.9, 20.3, and 20.3 months, respectively. Nine of them (42.9%) presented hyperparathyroidism secondary to vitamin D deficiency and 8 with PI. A gradual decrease in pancreatic volume of up to 19% was observed among patients with PI. Six of the 8 patients with PI received pancreatic enzymes, with complete recovery from MA symptoms and stabilization of pancreatic volume. CONCLUSIONS: We validated the association between MA and PI in 10% of sorafenib-treated patients. Pancreatic enzymes supplementation successfully led to symptomatic recovery. Awareness of this adverse event can help in the management of sorafenib irrespective of cancer type and likely, of other tyrosine kinase inhibitors for HCC patients.

Pharmacokinetics and pharmacogenetics of sorafenib in patients with hepatocellular carcinoma: Implications for combination trials.

BACKGROUND & AIMS: Sorafenib and lenvatinib are the first-line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. METHODS: We assessed the pharmacokinetics of sorafenib and its N-oxide metabolite at day-0, day-7, day-30, day-60, day-90, day-120, day-150 and day-180 and nine single-nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. RESULTS: We prospectively included 49 patients (96% cirrhotic, 37% hepatitis-C, 82% Child-Pugh-A and 59% BCLC-C). Pharmacokinetic values peaked at day-7 and progressively declined until day-60. In the 16 patients without further dose modifications after day-60, pharmacokinetic values remained stable through day-180 (sorafenib P = .90; N-oxide P = .93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N-oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972. CONCLUSIONS: Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors.

Systematic review with meta-analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib.

BACKGROUND: The positive results of the REFLECT trial in terms of survival (sorafenib vs lenvatinib) offer a new first-line option for hepatocellular carcinoma. Additionally, the expected results of immunotherapy could change the first-line treatment in hepatocellular carcinoma or the clinical trial design in first and second-line. AIMS: To evaluate the impact of dermatologic adverse events under sorafenib in hepatocellular carcinoma patients as a clinical marker to predict prognosis and critically evaluate outcomes within trials. METHODS: A systematic search of original articles published until October 2018 was performed using PubMed/MEDLINE and a meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of 393 studies were identified and 13 articles with 2035 patients (79.5% Child-Pugh-A, 73.2% BCLC-C) were selected for qualitative and quantitative analysis. The main type of dermatologic adverse events was hand-foot skin reaction (47.7%) but other dermatologic adverse events were reported in 31.7% of the cases. Presence of dermatologic adverse events was associated with a lower mortality when compared with those patients without them (pooled Hazard Ratio for the univariate analysis 0.45 (95% CI: 0.38-0.53) and there was no heterogeneity for the analysis (P = 0.511; I2  = 0.0%). Refuting this association would require the future report of 1370 negative studies. CONCLUSIONS: This meta-analysis shows a clinically meaningful association between dermatologic adverse events and a higher probability of longer survival. These data support the use of dermatologic adverse events in the clinical decision-making when informing the prognosis and when systemic treatment is decided.