The Hong Kong consensus statements on unresectable hepatocellular carcinoma: narrative review and update for 2021.

Background and Objective: Hong Kong, like many parts of Asia, faces a high burden of hepatocellular carcinoma (HCC) caused by high endemic rates of hepatitis B virus infection. Hong Kong clinicians have developed a high level of expertise in HCC treatment across surgical, transarterial, ablative, radiotherapeutic and systemic modalities. This publication summarizes the latest evidence-based recommendations on how these modalities should be used. Methods: In two meetings held in 2020, a multidisciplinary panel of surgeons, oncologists and interventional radiologists performed a narrative review of evidence on the management of HCC, with an emphasis on treatment of HCC not amenable to surgical resection. Close attention was paid to new evidence published since the previous version of these statements in 2018. Key Content and Findings: The expert panel has formulated 60 consensus statements to guide the staging and treatment of unresectable HCC. Since the previous version of these statements, considerable additions have been made to the recommendations on use of targeted therapies and immunotherapies because of the large volume of new evidence. Conclusions: Our consensus statements offer guidance on how to select HCC patients for surgical or non-surgical treatment and for choosing among non-surgical modalities for patients who are not candidates for resection. In particular, there is a need for more evidence to aid physicians in the selection of second-line systemic therapies, as currently most data are limited to patients with disease progression on first-line sorafenib.

Systemic Treatment of Advanced Unresectable Hepatocellular Carcinoma after First-Line Therapy: Expert Recommendations from Hong Kong, Singapore, and Taiwan.

Background: Asia has a high burden of hepatocellular carcinoma (HCC) due to the high rates of chronic hepatitis B infection and accounts for 70% of HCC cases globally. In the past 20 years, the systemic treatment landscape of advanced HCC has evolved substantially - from tyrosine kinase inhibitors to immune-oncology agents plus anti-vascular endothelial growth factor agents. The appropriate sequence of therapies has become critical in optimizing patient outcomes given the increase in systemic therapeutic options. This article evaluates the evidence and provides expert recommendations for the use of systemic therapies after first-line treatment in patients with advanced HCC. Summary: Based on three virtual meetings held in early 2021, a team of 17 experts comprising oncologists, a hepatologist, and a hepatobiliary surgeon from Hong Kong, Singapore, and Taiwan reviewed available data about systemic treatments for HCC after first line and formulated 28 statements. These statements aimed to provide expert guidance on selecting first and subsequent lines of therapies as well as recommending therapies in special circumstances, such as poor liver function, posttransplantation, recent gastrointestinal bleeding, or autoimmune diseases. Data supporting the statements were drawn from clinical trials and real-world studies. The 28 statements were then evaluated anonymously using a 5-point Likert scale, and 24 reached consensus, predefined as achieving 75% agreement. Statements generated covered the selection of first-line systemic therapy, considerations and goals of second-line systemic therapies, treatment selection following first-line therapy, and treatment recommendations following first-line tyrosine kinase inhibitors, immune-oncology monotherapy, or immune-oncology combination therapy. The authors also shared expert opinion on the use of second-line systemic therapy in patients with liver dysfunction, liver transplantation, and recent gastrointestinal or autoimmune disease. Key Messages: These expert statements summarize the latest data and expert opinion on selecting systemic treatment following first-line therapy in patients with unresectable advanced or metastatic HCC.

Prospective Study of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma on Waitlist for Liver Transplant.

BACKGROUND AND AIMS: There are no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for HCC. This study aimed to evaluate the efficacy and safety of SBRT as bridging therapy, with comparison with transarterial chemoembolization (TACE) and high-intensity focused ultrasound (HIFU). APPROACH AND RESULTS: Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015 and compared with a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1 year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity, and posttransplant survival. During the study period, 150 patients were evaluated (SBRT, n = 40; TACE, n = 59; HIFU, n = 51). The tumor control rate at 1 year was significantly higher after SBRT compared with TACE and HIFU (92.3%, 43.5%, and 33.3%, respectively; P = 0.02). With competing risk analysis, the cumulative incidence of dropout at 1 and 3 years after listing was lower after SBRT (15.1% and 23.3%) compared with TACE (28.9% and 45.8%; P = 0.034) and HIFU (33.3% and 45.1%; P = 0.032). Time-to-progression at 1 and 3 years was also superior after SBRT (10.8%, 18.5% in SBRT, 45%, 54.9% in TACE, and 47.6%, 62.8% in HIFU; P < 0.001). The periprocedural toxicity was similar, without any difference in perioperative complications and patient and recurrence-free survival rates after transplant. Pathological complete response was more frequent after SBRT compared with TACE and HIFU (48.1% vs. 25% vs. 17.9%, respectively; P = 0.037). In multivariable analysis, tumor size <3 cm, listing alpha-fetoprotein <200 ng/mL, Child A, and SBRT significantly reduced the risk of dropout. CONCLUSIONS: SBRT was safe, with a significantly higher tumor control rate, reduced the risk of waitlist dropout, and should be used as an alternative to conventional bridging therapies.

The Use of Cabozantinib in Advanced Hepatocellular Carcinoma in Hong Kong-A Territory-Wide Cohort Study.

(1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 in Hong Kong. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AE) were assessed. (3) Results: Overall, 42 patients were included. Approximately 83.3% had Child-Pugh A cirrhosis. About 64.3% received cabozantinib as a single agent, and the remaining 35.7% received cabozantinib as an add-on to immune checkpoint inhibitors (ICIs). For single-agent patients, the median follow-up was 6.7 months. The ORR was 3.7%, DCR was 44.4%, and the median OS was 8.28 months. About 74.1% of patients experienced any AEs with 7.4% having grade ≥3 AEs. Among patients who received prior ICIs (n = 16), the ORR was 6.3%, and the median OS was 8.28 months. An exploratory analysis of patients who received cabozantinib as an add-on to ICIs showed an ORR of 6.7% and a median OS of 15.1 months, with 73.3% having any AE and 13.3% having grade ≥3 AEs. (4) Conclusions: Cabozantinib had good anti-tumor activity, survival benefits, and acceptable tolerability in real-life aHCC patients.

Hong Kong Consensus Statements for the Management of Unresectable Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is highly prevalent in Hong Kong due to the high prevalence of chronic hepatitis B infection. Liver cancer is the fourth most common cancer and the third most common cause of cancer death. Due to the high case load, there is a high level of local expertise in treating HCC, and the full spectrum of treatment modalities is available. This document summarizes how these modalities should be used based on the latest evidence. SUMMARY: In 2 meetings held in early 2017, a multidisciplinary group of Hong Kong clinicians, including liver surgeons, interventional radiologists, clinical oncologists, and medical oncologists, met to update local consensus statements for management of HCC. These statements are based on the latest evidence and give detailed guidance on how to deploy these modalities, in particular for cases of HCC which are not suited to surgical resection. KEY MESSAGES: These statements give detailed information on how to decide if a patient is a candidate for resection, methods to improve candidacy for resection, and guidance for use of various nonsurgical interventions to manage patients ineligible for resection.

Consensus on Stereotactic Body Radiation Therapy for Small-Sized Hepatocellular Carcinoma at the 7th Asia-Pacific Primary Liver Cancer Expert Meeting.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an advanced technique of external beam radiation therapy that delivers large ablative doses of radiation. In the past decade, many cancer centers have adopted SBRT as one mode of radically treating small-sized hepatocellular carcinoma (HCC), based on encouraging clinical outcomes. SBRT thus seems reasonable as first-line treatment of inoperable HCC confined to the liver. However, most of the clinical studies to date have been retrospective in nature, with key issues still under investigation. SUMMARY: The above-mentioned publications were subjected to scrutiny, fueling discussions at the 7th Asia-Pacific Primary Liver Cancer Expert (APPLE 2016) Meeting on various clinical variables, such as indications for SBRT, therapeutic outcomes, treatment-related toxicities, doses prescribed, and specific techniques. The consensus reached should be of interest to all professionals active in the treatment of HCC, especially radiation oncologists. KEY MESSAGES: SBRT is a safe and effective therapeutic option for patients with small-sized HCC, offering substantial local control, improved overall survival, and low toxicity.

Prediction of occupational disability from psychological and neuropsychological evidence in forensic context.

Within the fields of psychiatry, psychology, and neuropsychology, medical examiners are often tasked with providing an opinion about an injured individual's health prognosis and likelihood of returning to work. Traditionally, examiners have conducted such assessments by employing clinical intuition, expert knowledge, and judgment. More recently, however, an accumulation of research on factors predictive of disability has allowed examiners to provide prognostications using specific empirically supported evidence. This paper integrates current evidence for four common clinical issues encountered in forensic assessments-musculoskeletal pain, depression, Posttraumatic Stress Disorder, and traumatic brain injury. It discusses an evidence-informed, cross-diagnostic and multifactorial model of predicting disability that is emerging from the literature synthesis, along with recommendations for best forensic assessment practice.

Limitation of radiological T3 subclassification of rectal cancer due to paucity of mesorectal fat in Chinese patients.

OBJECTIVES: To describe the thickness of mesorectal fat in local Chinese population and its impact on rectal cancer staging. DESIGN: Case series. SETTING: Two local regional hospitals in Hong Kong. PATIENTS: Consecutive patients referred for multidisciplinary board meetings from January to October 2012 were selected. MAIN OUTCOME MEASURES: Reports of cases that had undergone staging magnetic resonance imaging for histologically proven rectal cancer were retrospectively retrieved and reviewed by two radiologists. All magnetic resonance imaging examinations were acquired with 1.5T magnetic resonance imaging. Measurements were made by agreement between the two radiologists. The distance in mm was obtained in the axial plane at levels of 5 cm, 7.5 cm, and 10 cm from the anal verge. Four readings were obtained at each level, namely, anterior, left lateral, posterior, and right lateral positions. RESULTS: A total of 25 patients (16 males, 9 females) with a median age of 69 (range, 38-84) years were included in the study. Mean thickness of the mesorectal fat at 5 cm, 7.5 cm, and 10 cm from the anal verge was 3.1 mm (standard deviation, 3.0 mm), 9.8 mm (5.3 mm), and 11.8 mm (4.2 mm), respectively. The proportions of patients with mean mesorectal fat thickness of <15 mm were 100%, 84%, and 75% at 5 cm, 7.5 cm, and 10 cm from the anal verge, respectively. The thickness of mesorectal fat was the least anteriorly, and <15 mm at all three arbitrary levels (P<0.001). CONCLUSION: The thickness of mesorectal fat was <15 mm in the majority of patients and in most positions. Tumours invading 10 mm beyond the serosa on magnetic resonance imaging may paradoxically threaten the circumferential resection margin in Chinese patients. Use of T3 subclassification of rectal cancer in Chinese patients may be limited.

Development of reading-related skills in Chinese and English among Hong Kong Chinese children with and without dyslexia.

This 2-year longitudinal study sought to identify a developmental pattern of Chinese and English reading skills in children with and without dyslexia from 6 to 8years of age. Three groups of 15 children each-those with dyslexia, age-matched (AM) controls, and reading-matched (RM) controls-participated. Dyslexia was diagnosed at 8years of age. All children were tested on phonological awareness, rapid automatized naming (RAN), morphological awareness, word reading, and vocabulary knowledge in both Chinese and English and also speed of processing skill. AM controls outperformed the group with dyslexia on all measures except for phonological awareness, English word reading, and vocabulary. However, those with dyslexia and AM controls developed at a similar rate across all reading-related skills from 6 to 8years of age. Compared with the RM controls, the group with dyslexia scored higher in phonological awareness, morphological awareness, and vocabulary knowledge in both Chinese and English and also in English word reading but scored similarly in RAN. Children with dyslexia, thus, manifested clear difficulties in Chinese vocabulary knowledge, morphological awareness, and RAN as well as general speed of processing, representing a developmental lag in cognitive skills. Among these, RAN deficits are likely to be the most severe deficits in Chinese children with dyslexia.

Treatment of primary liver cancer using highly-conformal radiotherapy with kV-image guidance and respiratory control.

PURPOSE: To implement a reliable, practical and reproducible treatment procedure, based on in-room kV-image guidance and respiratory control, for liver cancer patients treated with high dose conformal radiotherapy using a commercially available treatment system. MATERIALS AND METHODS: CT stimulation was conducted under voluntary breath hold or gating using the Varian Real-time Position Management™ (RPM) System. Treatments were delivered daily under kV image guidance to verify the diaphragmatic or lipiodol-defined tumor position. RESULTS: Thirty-three patients with liver confined hepatocellular carcinoma were treated between May 2006 and Dec 2009. After a median follow-up period of 16.5 months (range: 3.5-40.7), all but 2 patients demonstrated radiological tumor regression. Eight patients (24%) achieved complete remission. The median tumor shrinkage was 42% (27-100%). Subsequent in-field tumor progression was observed in only three patients (10%). For the 23 patients with abnormal alpha fetoprotein level, 22 of them showed biochemical response with a median AFP level drop of 78%. The treatment was well tolerated: Grade 3 toxicities occurred in 5 patients (1 leucopenia, 1 elevated liver enzyme and 3 elevated bilirubin level) but there was no grade 4 toxicity or treatment related death. The 1 year overall survival rate is 71.7% and median survival time is 17.2 months (3.5-40.7 months). CONCLUSIONS: Excellent treatment results with minimal toxicities could be achieved in a clinical environment with a commercially available highly sophisticated radiotherapy system.

Adjuvant chemoradiation for resected gastric cancer: a 10-year experience.

BACKGROUND: The Intergroup 0116 study demonstrated that concurrent chemoradiation improved overall survival (OS) in resected gastric cancer. However, there are few reports focusing on late toxicity and factors governing prognosis. This study aimed to determine these two important aspects for employing this regimen. METHODS: Patients with resected gastric cancer stage IB to IV (M0) disease, treated between July 1998 and December 2007, were analyzed. The majority of the patients were treated using 5 cycles of 5-fluorouracil (5FU)/leucovorin chemotherapy with 45 Gy/25 fractions radiotherapy concurrent with cycles 2 and 3, as per the Intergroup 0116 study. RESULTS: We treated 120 patients (107 standard protocol, 13 with concurrent 5FU alone), and 14% had a close or positive margin. Median age was 59 years (35-79 years). Acute toxicity ≥ grade 3 was seen in 66% of all patients (hematological 61%, stomatitis 3%, diarrhea 6%, vomiting 2%). Median follow-up was 33 months (range 6-125 months). Five-year OS and relapse-free survival were 51 and 54%, respectively. On multivariate analysis, surgical margin status, stage of the disease, and radiotherapy with computed tomography (CT) planning were important prognostic factors. Anemia and gastritis were the two most frequently occurring late complications, though they were usually mild and asymptomatic. Clinically significant renal impairment was uncommon. Other rare complications included intestinal obstruction, malabsorption, hypertension, and secondary malignancy. CONCLUSIONS: Postoperative chemoradiation is safe and late toxicity is usually mild in extent. Results were comparable to the Intergroup 0116 study. R0 resection is of utmost importance and radiotherapy should best be delivered by conformal techniques.

Screening for family members of patients with nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is well known for its peculiarly skewed distribution with highest incidence in Southern Chinese population. Familial aggregation is evident, hence screening for early detection is offered by oncology centers in Hong Kong to first-degree relatives of patients with NPC. During the period 1994-2001, 929 family members were screened in our center. The screenees were advised to attend an annual examination that includes serological test against Epstein Barr Virus (EBV), physical examination to exclude cervical lymphadenopathy and cranial nerve palsy, and endoscopic examination of the nasopharyngeal region. Two different methods were used for the serology test: indirect immuno-fluorescent (IF) test for IgA against viral capsid antigen; and starting in 1997 enzyme-linked immunosorbent assay (ELIZA) against nuclear antigen and viral capsid antigen. Twelve cases of nasopharyngeal carcinoma were diagnosed, giving a detection rate of 5/1,155 (433/100,000) person-year for male and 7/1,404 (499/100,000) person-year for female participants observed. The corresponding average annual incidence in Hong Kong during this period was 24.1 and 9.6 per 100,000, respectively. Forty-one percent of these detected cases had Stage I disease, whereas only 2% of patients referred to the department for primary treatment presented with such early disease. Six cases were detected at first visit, and all were EBV-positive. Another 78 screenees with positive serology at first visit were followed up for 204 person years, and thus far NPC was detected in 3 after an interval of 6-32 months. Of the 845 initially EBV-negative screenees followed up for 2,337 person-years, NPC was detected in 3 after an interval of 12-45 months. One showed sero-conversion at the time of diagnosis. We conclude that family members of known patients do show a substantially higher risk of developing NPC, and regular screening by current method improves the chance of early detection.