Hepatocellular Carcinoma Registry in Asia (Clinicaltrials.gov Identifier:
Edmund Tse (Royal Adelaide Hospital), Simone Strasser (Royal Prince Alfred Hospital)
Li Lequn (Guangxi Medical University Cancer Center), Jiangtao Li (Second Affiliated Hospital Zhejiang University School of Medicine), Fan Jia (Zhongshan Hospital, Fudan University), Zhu Xu (Beijing Cancer Hospital), Yuxian Bai (Harbin Medical University Cancer Hospital), Qin Shu-Kui (Nanjing Bayi Hospital)
Thomas Yau (Queen Mary Hospital)
Masatoshi Kudo (Kindai University Hospital), Junji Furuse (Kyorin University School of Medicine), Kazuaki Shimada (National Cancer Centre), Kiyoshi Hasegawa, (University of Tokyo), Nobuyuki Takemura (National Center of Global Health and Medicine)
Adam Bartlett (Auckland City Hospital)
Pierce Chow (National Cancer Centre), Dan Yock Young (National University Hospital), Brian Goh (Singapore General Hospital)
Hyun-Ki Yoon (Asan Medical Centre), Kim Yun-Hwan (Korea University Anam Hospital), Joon-Hyeok Lee (Samsung Medical Centre), Ho-Seong Han (Seoul National University Hospital), Yang Jin-Mo (St Vincents Hospital), Choi Jong-Young (St. Mary’s Hospital), Hee-Jung Wang (Ajou University Hospital), Do-Young Kim (Severance Hospital, Yonsei University College of Medicine)
Peng-Cheng Yuan (China Medical University Hospital), Yee Chao (Taipei Veterans General Hospital), Tsung-Hui Hu (KS-Chang Gung Memorial Hospital), Pin-Nan Cheng (National Cheng Kung University Hospital), Chien-Hung Chen (National Taiwan University Hospital)
Rawisak Chanwat (National Cancer Institute), Supot Ninanong (Siriraj Hospital, Mahidol University)
Phase III Multi-Centre Open-Label Randomized Controlled Trial of Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB)
The optimal therapeutic regime for locally advanced hepatocellular carcinoma (HCC) with and without vascular invasion remains unclear. This study evaluates the efficacy of Selective Internal Radiation Therapy using SIR-Spheres yttrium-90 microspheres (Y90) versus sorafenib in Asian Barcelona Clinic Liver Cancer (BCLC) stage B and C patients without extra-hepatic metastasis.
This investigator-initiated multi-center trial randomized eligible patients with locally advanced inoperable HCC to single injection of Y90 or sorafenib till progressive disease or unacceptable toxicity. The sample size, assuming type I error (two-sided) of 0.05 and power of 90% was 360 patients. Final analysis was planned at 266 reported deaths.
The trial found that patients with locally advanced HCC treated with Y90 have statistically significant better tumour-response-rates (TRR) and fewer serious adverse events (SAE) when compared with those treated with sorafenib. There were no statistically significant differences in overall survival between Y90 and sorafenib.
SIRT with Y90 is a significantly less toxic therapy with less serious adverse events such as diarrhoea, alopecia, hypertension, fatigue and hand-foot skin reactions. This is also similar to the findings in the SARAH (a similar trial conducted in France). Both trials showed that SIRT with Y90 is a less toxic therapy (for Asians and Europeans) and this is important for patients as SIRT imparts better quality of life. It also provided strong scientific support for the use of SIRT as a less toxic therapy. In the study, SIRT regressed the tumors of a significantly larger numbers of patients than sorafenib.
The scientific data from the trial established the safety and efficacy of loco-regional therapy with yttrium-90 in locally advanced HCC and gave clinicians the confidence to use SIRT in a larger number of patients. SIRT-Y90 became standard-of-care for locally advanced HCC patients in NCCS and elsewhere. To date, Singhealth has treated more than 500 HCC patients with Y90. The results were published in Liver Cancer (impact factor: 9.72) in April 2021.
Kenneth Kok (The Brunei Cancer Centre)
L.A Lesmana (Cipto Mangunkusumo Hospital, University of Indonesia), Tjakra Wibawa Manuaba (Sanglah General Hospital, Denpasar)
Aloysius Raj (Penang Adventist Hospital), Nik Azim Bin Nik Abdullah (Sarawak General Hospital), Yoong Boon Koon (University Malaya Medical Center)
Ariunaa Khasbazar (National Cancer Center of Mongolia)
Khin Maung Win (Yangon GI & Liver Centre)
Adam Bartlett (Auckland City Hospital)
Rolley Lobo (Davao Doctors Hospital), Catherine Teh (Makati Medical Center), Janus Ong (The Medical City), Ian Cua (St Luke’s Medical Center)
Kenneth Mak (Khoo Teck Puat Hospital), David Tai (National Cancer Centre), Dan Yock Young (National University Hospital), Cheow Peng Chung (Singapore General Hospital)
Hyun-Ki Yoon (Asan Medical Center), Yun-Hwan Kim (Korea University Anam Hospital), Ho-Seong Han (Seoul National University Bundang Hospital) Si-Hyun Bae (Seoul St Mary’s Hospital), Jong Yun Won (Severance Hospital, Yonsei University), Jin-Mo Yang (St Vincent’s Hospital)
Chien-Fu Hung (Chang Gung Memorial Hospital), Chao-Long Chen (Chang Gung Memorial Hospital, Kaohsiung), Cheng-Yuan Peng (China Medical University Hospital), Po-Chin Liang (National Taiwan University Hospital), Rheun-Chuan Lee (Taipei Veterans General Hospital)
Chanisa Chotipanich (Chulabhorn Hospital)
The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279) was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC) not amenable to curative therapies.
Sorafenib was initiated 14 days post-radioembolization with yttrium-90 (90Y) resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR) using RECIST v1.0. Secondary endpoints included: disease control rate (complete [CR] plus partial responses [PR] and stable disease [SD]) and overall survival (OS).
Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC) stage B (38%) or C (62%) HCC received a median of 3.0 GBq (interquartile range, 1.0) 90Y-microspheres followed by sorafenib (median dose/day, 600.0 mg; median duration, 4.1 months). Twenty-eight patients experienced $1 toxicity; 15 (52%) grade $3. Best ORR was 25%, including 2 (7%) CR and 5 (18%) PR, and 15 (54%) SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7%) had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively. This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib.
Pierce Chow (Singapore General Hospital), Anthony Goh (Singapore General Hospital), Alexander Chung (Singapore General Hospital), Soo Khee Chee (National Cancer Centre), Lai Hee Kit (Singapore General Hospital), Tay Kiang Hiong (Singapore General Hospital), Richard Lo Hoau Gong (Singapore General Hospital), Donald Poon Yee Hee (National Cancer Centre), Choo Su Pin (National Cancer Centre)
Han Ho Seong (Seoul National University Hospital)
Harjit Singh (Selayang Hospital)
Khin Maung Win (Yangon GI & Liver Centre)
Hoang Hoa Hai (Choray Hospital)
Brachytherapy is a recent technique used in the treatment of tumours and involves the use of radioactive sources brought into close contact with the target tissues. One of the principal benefits of brachytherapy is that high radiation doses can be localised within the tumour with the consequence of minimal side effects. 32P is a radionuclide ideal for brachytherapy as it has high energy beta emitting properties, typically a maximum tissue range of about 8 mm and a half-life of 14.3 days. 32P BioSiliconTM is an active implantable medical device encapsulating 32P within the internal microcrystalline structure of highly pure inert silicon and acts as a sealed source for the provision of 32 phosphorous.
Tumours targeted with 32P BioSiliconTM are hypothesized to show a reduction in volume with a low incidence of side effects associated with the treatment. Prolongation of survival and improved quality of life would be favourable outcomes of the investigational product.
Patients will be enrolled sequentially into the three groups, starting with Group 1 which will investigate the lower radioactivity level and then progress to a higher radioactivity level in Group 2 and then Group 3. The approval to enroll patients into the next group will be assessed and determined by a Data Monitoring Board. All patients will be followed up to 52 weeks from the start date of primary implantations.
Patients will receive intratumoural implantations of 32P BioSiliconTM under imaging guidance and local anaesthesia by designated interventional radiologists, using the SIMPL needle or conventional needles depending on the size and location of the tumour as assessed by the designated interventional radiologists. There are only a designated number of sites that will perform the implantation procedure although there are multiple sites recruiting and following up with patients.
Implantations were successfully carried out in 8 patients (13–74 MBq, mean 40 MBq per tumor) awake and under local anesthesia. Six of the 8 patients reported 19 adverse events, but no serious events were attributable to the study device. Changes in hematology and clinical chemistry were similarly minimal and reflected progressive underlying hepatic disease. All targeted tumors were responding at 12 weeks, with complete response (100% regression) in three lesions. At the end of the study, there were two complete responses, two partial responses, three stable diseases, and one progressive disease.
Percutaneous implantation of this novel 32P brachytherapy device into hepatocellular carcinoma is safe and well tolerated. A significant degree of antitumor efficacy was demonstrated at this low dose that warrants further investigation.
Pierce Chow (Singapore General Hospital), Anthony Goh (Singapore General Hospital), Richard Guan (Mt Elizabeth Hospital), Foo Kian Fong (National Cancer Centre), Susan Loong (National Cancer Centre), Liau Kui Hin (Tan Tock Seng Hospital)
Pierce Chow (Singapore General Hospital), Lucien Ooi (National Cancer Centre), Tay Khoon Hean (Changi General Hospital), Chew Soo Ping (Tan Tock Seng Hospital)
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. We tested megestrol acetate (MA) against placebo in the treatment of advanced HCC.
From 2002 through 2007, this randomised double-blind trial enrolled 204 patients with treatment-naive advanced HCC (Eastern Cooperative Oncology Group (ECOG) performance rating of 0-3) from specialist care centres in six Asia-Pacific nations. Patients received placebo or MA (320 mg day1). End points were overall survival (OS) and quality of life.
An adverse but not statistically significant difference in OS was found for MA vs placebo: median values 1.88 and 2.14 months, respectively (hazard ratio (HR)¼1.25, 95% CI¼0.92–1.71, P¼0.16). However, OS was similar among patients of good functional status (Child-Pugh A and ECOG 0, 1 or 2) (44.3%) in both treatment groups, with the adverse effect of MA confined to those of poor status. Megestrol acetate patients had a worse global health status (not statistically significant) but reduced levels of appetite loss and nausea/ vomiting. Megestrol acetate has no role in prolonging OS in advanced treatment-naive HCC. Overall survival with placebo differed markedly from that in similar trials conducted elsewhere, suggesting therapeutic outcomes may be strongly dependent on ECOG status and Child-Pugh score.
Soo Khee Chee (National Cancer Centre), Pierce Chow (Singapore General Hospital)
M Findlay (Cancer Trials New Zealand)
Rolley Rey Lobo (Davao Doctors’ Hospital)
Yang Jin-Mo (St. Vincents Hospital)
Hoang Hoa Hai (Choray Hospital), Nguyen Ba Duc (National Cancer Institute K Hospital)
329 patients were recruited. Reported adverse drug reaction was 3% and 8 patients were lost to follow-up. The 3-month survival rates for P, TMX60 and TMX 120 were 44%, 41% and 35% respectively with significant trend difference in crude survival rates across the 3 treatment regimens (p=0.011). There is a significantly higher risk of death in TMX120 as compared with P (HR:1.39;95% CI of HR: 1.07 to 1.81). In conclusion, TMX does not prolong survival in inoperable HCC and has a negative impact with increasing dose. Changed international clinical practice with respect to the treatment of inoperable HCC. The practice of treating such patients with tamoxifen was found to be detrimental.
Jonathan Cebon (Austin Health)
Phillip Johnson (Prince of Wales Hospital, Chinese University of Hong Kong)
T Manuaba (Sanglah General Hospital)
A Haron (Hospital Universiti Kebangsaan)
M Findlay (Cancer Trials New Zealand)
Soo Khee Chee (National Cancer Centre), Tan Chee Kiat (Singapore General Hospital)
Si-Hyun Bae (St. Mary’s Hospital)
Thiravud Khuhaprema (National Cancer Institute)
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