Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma

Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC

Characterization of response to atezolizumab + bevacizumab versus sorafenib for hepatocellular carcinoma: Results from the IMbrave150 trial

Background: IMbrave150 is a phase III trial that assessed atezolizumab + bevacizumab (ATEZO/BEV) versus sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (HCC) and demonstrated a significant improvement in clinical outcomes. Exploratory analyses characterized objective response rate (ORR), depth (DpR), and duration of response (DoR), and patients with a complete response (CR). Methods: Patients were randomized 2:1 to intravenous ATEZO (1200 mg) + BEV (15 mg/kg) every 3 weeks or oral SOR (400 mg) twice daily. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and HCC-modified RECIST (mRECIST). ORR by prior treatment and largest baseline liver lesion size, DoR, time to response (TTR), and complete response (TTCR) were analyzed. Results: For both criteria, responses favored ATEZO/BEV versus SOR regardless of prior treatment and in patients with lesions ≥3 cm. Median TTR was 2.8 months per RECIST 1.1 (range: 1.2-12.3 months) and 2.8 months per mRECIST (range: 1.1-12.3 months) with ATEZO/BEV. Patients receiving ATEZO/BEV had a greater DpR, per both criteria, across baseline liver lesion sizes. Characteristics of complete responders were similar to those of the intent-to-treat population. In complete responders receiving ATEZO/BEV per mRECIST versus RECIST 1.1, respectively, median TTCR was shorter (5.5 vs. 7.0 months), mean baseline sum of lesion diameter was longer (5.0 [SD, 5.1] vs. 2.6 [SD, 1.4] cm), and mean largest liver lesion size was larger (4.8 [SD, 4.2] vs. 2.3 [SD, 1.0] cm). Conclusions: These data highlight the improved ORR, DpR, and CR rates with ATEZO/BEV in unresectable HCC. Keywords: Response Evaluation Criteria in Solid Tumors; hepatocellular carcinoma; immunotherapy

Evolving strategies in the diagnosis of hepatocellular carcinoma

Background: Contrast-enhanced ultrasound (CE-US), con- trast CT scan and gadolinium dynamic MRI are recommended for the characterization of liver nodules detected during surveillance of patients with cirrhosis with US. Aim: To assess the sensitivity, specificity, diagnostic accuracy and economic impact of all possible sequential combinations of contrast imaging techniques in patients with cirrhosis with 1-2 cm liver nod- ules undergoing US surveillance. Methods: Sixty four patients with 67 de novo liver nodules (55 with a size of 1-2 cm) were consecutively examined by CE-US, CT, MRI, and a fine-needle biopsy (FNB) as a diagnostic standard. Undiagnosed nodules were re-biopsied; non-malignant nodules underwent enhanced imaging follow-up. The typical radiological feature of hepatocellular carcinoma (HCC) was arterial phase hypervascularisation followed by portal/venous phase washout. Results: HCC was diagnosed in 44 (66%) nodules (2, 2 cm). The sensitivity of CE-US, CT and MRI for 1-2 cm HCC was 26%, 44% and 44%, repectively, with 100% specific- ity; the typical vascular pattern of HCC being identified in 22 (65%) by a single technique versus 12 (35%) by at least two techniques car- ried out at the same time point (p = 0.028). Compared with the cheapest dual examination (CE-US + CT), the cheapest single tech- nique of stepwise imaging diagnosis of HCC was equally expensive (euro 26,440 versus euro 28,667) but led to a 23% reduction of FNB procedures (p = 0.031). Conclusions: In patients with cirrhosis with a 1-2 cm nodule detected during surveillance, a single imaging technique showing a typical contrast pattern confidently permits the diagnosis of HCC, thereby reducing the need for FNB examinations

mRECIST for HCC: Performance and novel refinements

Summary In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). We intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease (development of ascites, enlargement of lymph nodes, etc.). mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches (i.e. immunotherapy) and combination therapies there is a need to further refine and clarify some concepts around the performance of mRECIST. Similarly, changes in the landscape of standard of care at advanced stages of the disease are pointing towards progression-free survival as a potential primary endpoint in some phase III investigations, as effective therapies applied beyond progression might mask overall survival results. Strict recommendations for adopting this endpoint have been reported. Overall, we review the performance of mRECIST during the last decade, incorporating novel clarifications and refinements in light of emerging challenges in the study and management of HCC

Quality Improvement Guidelines for Radiofrequency Ablation of Liver Tumours

The development of image-guided percutaneous techniques for local tumour ablation has been one of the major advances in the treatment of liver malignancies. Among these methods, radiofrequency ablation (RFA) is currently established as the primary ablative modality at most institutions. RFA is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when liver transplantation or surgical resection are not suitable options [1, 2]. In addition, RFA is considered a viable alternate to surgery (1) for inoperable patients with limited hepatic metastatic disease, especially from colorectal cancer, and (2) for patients deemed ineligible for surgical resection because of extent and location of the disease or concurrent medical conditions [3]. These guidelines were written to be used in quality-improvement programs to assess RFA of HCC and liver metastases. The most important processes of care are (1) patient selection, (2) performing the procedure, and (3) monitoring the patient. The outcome measures or indicators for these processes are indications, success rates, and complication rates

Guidelines for the use of contrast-enhanced ultrasound in hepatocellular carcinoma

Abstract Surveillance of patients at risk of developing hepatocellular carcinoma (HCC) relies on ultrasound (US) examinations performed at 6-month intervals. Early detection of HCC on a cirrhotic background is a challenging issue, since the US features of the different entities in the multi-step process of hepatocarcinogenesis – such as low-grade and high-grade dysplastic nodule – do overlap. Contrast-enhanced US allows reliable detection of arterial neo-angiogenesis associated with the malignant change. Several reports have shown that the ability of contrast-enhanced US to diagnose HCC currently approaches that of optimised multidetector computed tomography (CT) or dynamic magnetic resonance (MR) imaging protocols. The use of contrast-enhanced US to characterise nodular lesions in cirrhosis has recently been recommended by the clinical practice guidelines issued by the European Federation of Societies for Ultrasound in Medicine and Biology and the American Association for the Study of Liver Diseases. Contrast-enhanced US has also been successfully used to assess response of HCC to image-guided percutaneous ablation procedures. In this article, we discuss the advantages and limitations of contrast-enhanced US with respect to the other imaging modalities in the setting of HCC

Frequency of sexually transmitted diseases and main methodological implications

Background. High risk Human Papillomavirus (HR-HPV) persistence is the most important cervical cancer risk factor, while Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma hominis (MH), Mycoplasma genitalium(MG), Ureaplasma urealyticum (UU) and parvum (UP) are sexually transmitted diseases (STDs) causing infertility, pregnancy complication, lung problems in newborns. Methods. 135 urine, 135 urethral swabs, 553 cervical swabs, 110 seminal fluids and 1440 Thin Prep, were tested with culture methods, Real-Time PCR (RT-PCR) and multiplex SYBR Green PCR-endpoint to detect STDs. PCR- endpoint was performed to detect HPV. Results. Culture methods showed the lowest sensitivity: for MH it was only 24% (compared to RT-PCR). UP/UU were the most frequent pathogens (13% with culture, 29% with PCR-endpoint, 41,67% with RT-PCR). Turn Around Time was respectively: 48h, 6h and 2h. RT-PCR cervical frequencies for CT, MH, MG, UU, UP were: 5.42%, 11.03%, 1.81%, 11.21% and 35.08%. HPV positivity in primary and secondary screening was 17.33% and 51.14%. Highes t positivity age group was: 23-32 years for CT (17%), and 18-27 years for HPV (33%). Conclusions. RT-PCR is more sensitive, faster, less expensive than other molecular tests like PCR-endpoint and microarrays. It allows more efficient laboratory organization: pre-analytical phase is more automated and enable the implementation of further diagnostic tests for pathologies that need rapid identification, such as meningitidis and sepsis, with reduced human and instrumental resource. Regarding STDs screening, it should be performed in women: for CT at least up to 27 years; for HPV between 35-50 years, since persisting HR-HPV infection is responsible of high-grade lesions

User-centered design and development of TWIN-Acta: A novel control suite of the TWIN lower limb exoskeleton for the rehabilitation of persons post-stroke

Introduction: Difficulties faced while walking are common symptoms after stroke, significantly reducing the quality of life. Walking recovery is therefore one of the main priorities of rehabilitation. Wearable powered exoskeletons have been developed to provide lower limb assistance and enable training for persons with gait impairments by using typical physiological movement patterns. Exoskeletons were originally designed for individuals without any walking capacities, such as subjects with complete spinal cord injuries. Recent systematic reviews suggested that lower limb exoskeletons could be valid tools to restore independent walking in subjects with residual motor function, such as persons post-stroke. To ensure that devices meet end-user needs, it is important to understand and incorporate their perspectives. However, only a limited number of studies have followed such an approach in the post-stroke population. Methods: The aim of the study was to identify the end-users needs and to develop a user-centered-based control system for the TWIN lower limb exoskeleton to provide post-stroke rehabilitation. We thus describe the development and validation, by clinical experts, of TWIN-Acta: a novel control suite for TWIN, specifically designed for persons post-stroke. We detailed the conceived control strategy and developmental phases, and reported evaluation sessions performed on healthy clinical experts and people post-stroke to evaluate TWIN-Acta usability, acceptability, and barriers to usage. At each developmental stage, the clinical experts received a one-day training on the TWIN exoskeleton equipped with the TWIN-Acta control suite. Data on usability, acceptability, and limitations to system usage were collected through questionnaires and semi-structured interviews. Results: The system received overall good usability and acceptability ratings and resulted in a well-conceived and safe approach. All experts gave excellent ratings regarding the possibility of modulating the assistance provided by the exoskeleton during the movement execution and concluded that the TWIN-Acta would be useful in gait rehabilitation for persons post-stroke. The main limit was the low level of system learnability, attributable to the short-time of usage. This issue can be minimized with prolonged training and must be taken into consideration when planning rehabilitation. Discussion: This study showed the potential of the novel control suite TWIN-Acta for gait rehabilitation and efficacy studies are the next step in its evaluation process

Objective response by mRECIST as a predictor and potential surrogate end point of overall survival in advanced HCC

Background & Aims: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this endpoint as a potential surrogate of OS.Methods: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n = 334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point.Results: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4 months, p < 0.001). In addition, objective response had an independent prognostic value (HR = 0.48; 95% confidence interval [CI], 0.26-0.91, p = 0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R = -0.92; 95% CI, -1 to -0.73, p < 0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4 months).Conclusions: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding.Lay summary: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population.Clinical trial number: NCT00825955

Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P &lt; 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease