Hepatocellular carcinoma (HCC) is one of the most common leading causes of cancer death worldwide. As most patients are diagnosed with advanced disease, systemic therapy remains the backbone of treatment. In recent years, we have witnessed the transformation of advanced HCC treatment landscapes from single-agent targeted therapies to immunotherapy combinations, with atezolizumab plus bevacizumab becoming the new first-line standard of care with an increase in overall survival, progression-free survival, and objective response rate compared to sorafenib, and a positive impact on quality of life. Although the efficacy and safety of this combination have been confirmed regardless of ethnicity, age, and etiology, only a subgroup of patients seems to benefit the most from this treatment. Currently, predictive serum and tissue biomarkers to select patients who are most likely to respond to atezolizumab plus bevacizumab are lacking. Moreover, the optimal subsequent therapy for patients who progress on first-line atezolizumab plus bevacizumab remains unknown, clinical trials are ongoing, and real-world data are needed to determine the most effective treatment sequence. Importantly, careful evaluation of bleeding risk and preservation of adequate liver function are fundamental to improve patients’ prognosis, especially when subsequent treatments are administered.

Aim: Breast cancer patients over the age of 65 are more likely to suffer chemotherapy side effects, with premature discontinuation, which negatively affects survival. Methods: We conducted a retros... Lay abstract Breast cancer patients over the age of 65 are more likely to suffer chemotherapy side effects, which negatively affect survival. We conducted a retrospective study of 128 elderly breas...

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients’ stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.

Immunotherapy with atezolizumab and bevacizumab (a + b) has improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the outcome for individual patients is highly variable. This study aimed to (i) develop and validate a prognostic prediction model to estimate individual prognosis and (ii) compare it with established models. In this multicenter retrospective study, patients with HCC undergoing first-line immunotherapy with a + b from 24 centers (Europe, USA) were included. Statistical analysis and reporting followed the TRIPOD guidelines. The primary objective was overall survival (OS). A Cox model was developed and externally validated. In total, 683 patients were included (training: 526, validation: 157). The C-reactive protein, albumin, bilirubin, lymphocytes, ECOG performance status, and extrahepatic spread (CABLE score) remained significantly associated with OS in Cox regression analysis. In the training set, the CABLE score had a higher discriminatory accuracy relative to ALBI, EZ-ALBI, mALBI, CRAFITY, PNI, NLR, PLR, and GPS (time-dependent AUC 0.79 and C-index 0.75 (95% CI 0.71–0.78) at 12 months). In the external validation set, the discriminatory performance of the CABLE score was comparable to ALBI, EZ-ALBI, and mALBI, but on average higher than PNI, CRAFITY, NLR, PLR, and GPS. In patients with Child-Pugh A, the CABLE score outperformed ALBI, EZ-ALBI, and mALBI in the first 9 months. We provide a web-based calculator for the CABLE score to allow estimation of individual prognosis for these patients (http://shiny.imbei.uni-mainz.de:3838/CABLE_Score/). The CABLE score shows good discriminatory performance in assessing the individual prognosis of patients undergoing first-line immunotherapy with a + b. Further validation studies are needed to investigate its performance compared with the ALBI score, in particular in subgroup analysis. The CABLE score allows estimation of the prognosis of patients with unresectable hepatocellular carcinoma undergoing first-line immunotherapy with atezolizumab and bevacizumab at an individual level using our web-based calculator. This feature, as well as the evaluation of the score’s added benefit through an extensive comparison with other established scores, can inform clinicians on their significance and may guide clinical decision-making in the context of a malignant disease where the prognosis has become highly variable. Further large validation studies are needed to investigate the incremental value of the CABLE score compared with the ALBI score, in particular in subgroups such as patients designated as Child-Pugh A.

Advanced hepatocellular carcinoma (HCC) management has become more complex as novel therapies have been proven effective. After sorafenib, the approval of other multikinase inhibitors (MKIs) and immune checkpoints inhibitors (ICIs) has considerably increased the number of systemic therapies available. Therefore, careful assessment and monitoring of response to systemic treatment are essential to identify surrogate endpoints of overall survival (OS) in clinical trials and reliable tools to gauge treatment benefit in clinical practice. Progression-free survival (PFS) and objective response rate (ORR) are early informative parameters of efficacy that are not influenced by further lines of therapy. However, none of them has shown sufficient surrogacy to be recommended in place of OS in phase 3 trials. With such a wealth of therapeutic options, the prime intent of tumor assessments is no longer limited to identifying progressive disease to spare ineffective treatments to non-responders. Indeed, the early detection of responders could also help tailor treatment sequencing. Tumor assessment relies on the Response Evaluation Criteria for Solid Tumors (RECIST), which are easy to interpret – being based on dimensional principles – but could misread the activity of targeted agents. The HCC-specific modified RECIST (mRECIST), considering both the MKI-induced biological modifications and some of the cirrhosis-induced liver changes, better capture tumor response. Yet, mRECIST could not be considered a standard in advanced HCC. Further prognosticators including progression patterns, baseline and on-treatment liver function deterioration, and baseline alpha-fetoprotein (AFP) levels and AFP response have been extensively evaluated for MKIs. However, limited information is available for patients receiving ICIs and regarding their predictive role. Finally, there is increasing interest in incorporating novel imaging techniques which go beyond sizes and novel serum biomarkers in the advanced HCC framework. Hopefully, multiparametric models grouping dimensional and functional radiological parameters with biochemical markers will most precisely reflect treatment response.