AHCC Completed Studies

Hepatocellular Carcinoma Registry in Asia (INSIGHT): Insight into Real World Practice of Management of HCC in Asia-Pacific (Clinicaltrials.gov Identifier: NCT03233360)​

Singapore 

Pierce Chow (National Cancer Centre), Dan Yock Young (National University Hospital), Brian Goh (Singapore General Hospital) ​

Australia

Edmund Tse (Royal Adelaide Hospital), Simone Strasser (Royal Prince Alfred Hospital)

China

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)

Hong Kong

Thomas Yau (Queen Mary Hospital)

Japan

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)

New Zealand

Adam Bartlett (Auckland City Hospital)

South Korea

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)

Taiwan

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)

Thailand

Rawisak Chanwat (National Cancer Institute), Supot Ninanong (Siriraj Hospital, Mahidol University)

​Pierce Chow

pierce.chow@duke-nus.edu.sgpierce.chow.k.h@singhealth.com.sg

Precision Medicine in Liver Cancer across an Asia-Pacific Network (The PLANet Study)

(Clinicaltrials.gov Identifier: NCT03267641)​

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world but the 2nd most important cause of cancer death. Due to its highly heterogeneous nature, the current approach to identifying druggable targets have not delivered efficacious therapies in HCC and is a main reason for the high case fatality. Even when surgical resection is potentially curative in early disease, tumor recurrence remains high and long term survival poor because of the absence of useful adjuvant therapy.

It is shown that through multi-region sampling of freshly resected HCC and phylogenetic analysis, that significant intra-tumoral heterogeneity exists and have identified the specific positions of known clonal drivers. Simultaneously we have analyzed the immune landscape of the tumor microenvironment with deep immune-phenotyping and found unique inter-patient immune landscapes predictive of clinical trajectory. Clinical trajectories are tracked and genomic and immunological studies are repeated when tumors recur, to confirm clonally dominant driver mutations and immunological processes that are targetable. Concurrently, representative pre-clinical models will be developed from the tissues sampled.

The study aims to combine these approaches to overcome the challenges posed by genomic and immunomics heterogeneity and to guide the development of therapeutics and precision medicine in HCC.

Publications:

1. Thng DKH, Hooi L, Toh CCM, Lim JJ, Rajagopalan D, Syariff IQC, Tan ZM, Rashid MBMA, Zhou L, Kow AWC, Bonney GK, Goh BKP, Kam JH, Jha S, Dan YY, Chow PKH, Toh TB, Chow EK (2023). Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer. Mol Oncol, https://doi.org/10.1002/1878-0261.13417 
2. Jeon AJ, Teo YY, Sekar K, Chong SL, Wu L, Chew SC, Chen J, Kendarsari RI, Lai H, Ling WH, Kaya NA, Lim JQ, Ramasamy A, Oguz G, …, Goh BKP, Tucker-Kellogg G, Foo RSY, Chow PKH. (2023) Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma. BMC Cancer, 23(1):118. https://doi.org/10.1186/s12885-022-10444-3 
3. Thng DKH, Toh TB, Pigini P, Hooi L, Dan YY, Chow PK, Bonney GK, Rashid MBMA, Guccione E, Wee DKB, Chow EK. (2022) Splice-switch oligonucleotide-based combinatorial platform prioritizes synthetic lethal targets CHK1 and BRD4 against MYC-driven hepatocellular carcinoma. Bioeng Transl Med, 8(1):e10363. https://doi.org/10.1002/btm2.10363  
4. Lee YH, Chuah S, Nguyen PHD, Lim CJ, Lai HLH, Wasser M, …, Chow PKH, Albani S, Liu H, Chew V (2022) IFNγ-IL-17+ CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma, Cancer Lett, 552:215977. https://doi.org/10.1016/j.canlet.2022.215977
5. Chan JJ, Zhang B, Chew XH, Salhi A, Kwok ZH, Lim CY, …, Chen L, Gao X, Chow PKH, Yang H, Tay Y. (2022) Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis. Nat. Cell Biol., https://doi.org/10.1038/s41556-022-00913-z
6.  Lim JTC, Kwang LG, Ho NCW, Toh CCM, Too DSH, Hooi L, Benoukraf T, Chow PKH, Dan YY, Chow EKH, Toh TB, Fong ELS. (2022) Hepatocellular carcinoma organoid co-cultures mimic angiocrine crosstalk to generate inflammatory tumor microenvironment. Biomaterials, 284:121527. https://doi.org/10.1016/j.biomaterials.2022.121527
7. Nguyen PHD, Wasser M, Tan CT, Lim CJ, Lai HLH, Seow JJW, DasGupta R, Phua CZJ, Ma S, … Zhai WW, Albani S, Chow PKH, Chew V. (2022) Trajectory of immune evasion and cancer progression in hepatocellular carcinoma. Nat Commun., 13(1):1441. https://doi.org/ 0.1038/s41467-022-29122-w
8. Suthen S, Lim CJ, Nguyen PHD, Dutertre CA, Lai HLH, Wasser M, Chua C, …, Zhai WW, Ginhoux F, Chow PKH, Albani S, Chew V. (2022) Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology, https://doi.org/ 10.1002/hep.32419
9. Tan SLW, Israeli E, Ericksen RE, Chow PKH, Han W. (2022) The altered lipidome of hepatocellular carcinoma. Semin Cancer Biol., S1044-579X(22)00025-6. https://doi.org/ 10.1016/j.semcancer.2022.02.004
10. Zhai WW, Lai H, Kaya NA, Chen J, Yang HC, Lu BX, …, Tam WL, Toh HC, Foo RSY, Chow PKH. Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in Hepatocellular Carcinoma: the PLANET study, Nat. Sci. Rev. https://doi.org/10.1093/nsr/nwab192
11. Nguyen PHD, Ma S, Phua CZJ, Kaya NA, Lai HLH, Lim CJ, Lim JQ, Wasser M, Lai L, Tam WL, Lim TKH, Wan WK, Loh T, Leow WQ, Pang YH, Chan CY, Lee SY, Cheow PC, Toh HC, Ginhoux F, Iyer S, Kow AWC, Young Dan Y, Chung A, Goh BKP, Albani S, Chow PKH, Zhai W, Chew V. (2021) Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat Commun., 12(1):227. https://doi.org/10.1038/s41467-020-20171-7. PMID: 33431814.
12. Chew SC, Choo SY, Chow PKH. (2021) A new perspective on the immune escape mechanism in HCC: onco-foetal reprogramming. Br. J. Cancer. https://doi.org/10.1038/s41416-021-01286-0.
13. Nguyen PHD, Ma S, Phua CZJ, Kaya NA, Lai HLH, Lim CJ, Lim JQ, Wasser M, Lai L, Tam WL, Lim TKH, Wan WK, Loh T, Leow WQ, Pang YH, Chan CY, Lee SY, Cheow PC, Toh HC, Ginhoux F, Iyer S, Kow AWC, Young Dan Y, Chung A, Goh BKP, Albani S, Chow PKH, Zhai W, Chew V. (2021) Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat Commun., 12(1):227. https://doi.org/10.1038/s41467-020-20171-7. PMID: 33431814.
14. Sharma A, Seow JJW, Dutertre CA, Pai R, Blériot C, Mishra A, Wong RMM, Singh GSN, Sudhagar S, Khalilnezhad S, Erdal S, Teo HM, Khalilnezhad A, Chakarov S, Lim TKH, Fui ACY, Chieh AKW, Chung CP, Bonney GK, Goh BK, Chan JKY, Chow PKH, Ginhoux F, DasGupta R. (2020) Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell, 183(2):377-394.e21. https://doi.org/10.1016/j.cell.2020.08.040. PMID: 32976798
15. Ding, Z., Ericksen, R, Escande-Beillard, N., Lee, Q.Y, Loh A., Denil, S., Steckel, M., Andrea Haegebarth, A., Ho, S.W., Chow, P.K., Toh, H.C., Reversade, B., Gruenewald, S., Han, W. (2020) Metabolic pathway analyses identify proline biosynthesis pathway as a promoter of liver tumorigenesis. J. Hepatol., 72(4):725-35, ISSN 0168-8278, https://doi.org/10.1016/j.jhep.2019.10.026
16. Chong YC, Toh TB, Chan Z, Lin QXX, Thng DKH, Hooi L, Ding Z, Shuen T, Toh HC, Dan YY, Bonney GK, Zhou L, Chow P, Wang Y, Benoukraf T, Chow EK, Han W. (2020) Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression. Hepatol. Commun., 4(9):1362-81. https://doi.org/10.1002/hep4.1559.
17. Lim CJ, Chew V. (May 2020) Impact of Viral Etiologies on the Development of Novel Immunotherapy for Hepatocellular Carcinoma. Seminars in Liver Disease. 10.1055/s-0039-3399534
18. Samuel Chuah, Valerie Chew. (Feb 2020) High-dimensional immune-profiling in cancer: implications for immunotherapy. Journal for ImmunoTherapy of Cancer. 10.1136/jitc-2019-000363
19. Jin, Y., Wong, Y.S., Goh, B.K.P., Chan, C.Y., Cheow, P.C., Chow, P.K.H., Lim, T.K.H., Goh, G.B.B., Krishnamoorthy, T.L., Kumar, R., Ng, T.P., Chong, S.S., Tan, H.H., Chung, A.Y.F, Ooi, L.L., Chang, J.P.E., Tan, C.K., and Lee, C.G.L. (2019) Circulating microRNAs as potential diagnostic and prognostic biomarkers in hepatocellular carcinoma. Sci. Rep., 9(10464). https://doi.org/10.1038/s41598-019-46872-8
20. Jin, Y., Lee, W.Y., Toh, S.T., Tennakoon, C., Toh, H.C., Chow, P.K., Chung, A.Y., Chong, S.S, Ooi, L.L., Sung, W.K., and Lee., C.G. (2019) Comprehensive analysis of transcriptome profiles in hepatocellular carcinoma. J. Transl. Med. https://doi.org/10.1186/s12967-019-2025-x
21. Justin L Tan, Feng Li, Joanna Z Yeo, Kol Jia Yong, Mahmoud A Bassal, Guo Hao Ng, May Yin Lee, Chung Yan Leong, Hong Kee Tan, Chan-Shuo Wu, Bee Hui Liu, Tim H Chan, Zi Hui Tan, Yun Shen Chan, Siyu Wang, Zhi Han Lim, Tan Boon Toh, Lissa Hooi, Kia Ngee Low, Siming Ma, Nikki R Kong, Alicia J Stein, Yue Wu, Matan T Thangavelu, Atsushi Suzuki, Giridharan Periyasamy, John M Asara, Yock Young Dan, Glenn K Bonney, Edward K Chow, Guo-Dong Lu, Huck Hui Ng, Yoganathan Kanagasundaram, Siew Bee Ng, Wai Leong Tam, Daniel G Tenen, Li Chai. (Aug 2019) New High-Throughput Screening Identifies Compounds That Reduce Viability Specifically in Liver Cancer Cells. Gastroenterology. 10.1053/j.gastro.2019.08.022.
22. Tai D, Choo SP, Chew V. (Dec 2019) Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers. Cancers. 10.3390/cancers11121926.
23. Zhao, Y., Shuen, T.W.H., Toh, T.B., Chan, X.Y., Liu, M., Tan, S.Y., Fan, Y., Yang, H., Lyer, S.G., Bonney, G.K., Loh, E., Chang, K.T.E., Tan, T.C., Zhai, W., Chan, J.K.Y., Chow, E.K., Chee, C.E., Lee, G.H., Dan, Y.Y., Chow, P.K., Toh, H.C., Lim, S.G., and Chen, Q. (2018). Development of a New Patient-Derived Xenograft Humanised Mouse Model to Study Human-Specific Tumour Microenvironment and Immunotherapy. Gut. pii: gutjnl-2017-315201. https://doi.org/10.1136/gutjnl-2017-315201.
24. Lim, C.J., Lee, Y.H., Pan, L., Lai, L., Chua, C., Wasser, M., Lim, T.K.H., Yeong, J., Toh, H.C., Lee, S.Y., Chan, C.Y., Goh, B.K., Chung, A., Heikenwalder, M., Ng, I.O., Chow, P., Albani, S., and Chew, V. (2018). Multidimensional Analyses Reveal Distinct Immune Microenvironment in Hepatitis B Virus-Related Hepatocellular Carcinoma. Gut. https://doi.org/10.1136/gutjnl-2018-316510.
25. Chew, V., Lee, Y.H., Pan, L., Nasir, N.J.M., Lim, C.J., Chua, C., Lai, L., Hazirah, S.N., Lim, T.K.H., Goh, B.K.P., Chung, A., Lo, R.H.G., Ng, D., Filarca, R.L.F, Albani, S., and Chow, P.K.H. (2018). Immune Activation Underlies a Sustained Clinical Response to Yttrium-90 Radioembolisation in Hepatocellular Carcinoma. Gut. pii: gutjnl-2017-315485. https://doi.org/10.1136/gutjnl-2017-315485.
26. Fong ELS, Toh TB, Lin QXX, Liu Z, Hooi L, Mohd Abdul Rashid MB, Benoukraf T, Chow EK, Huynh TH, Yu H. (2018) Generation of Matched Patient-Derived Xenograft in Vitro-in Vivo Models Using 3d Macroporous Hydrogels for the Study of Liver Cancer. Biomaterials. 10.1016/j.biomaterials.2017.12.026
27. Zhai W, Lim TK, Zhang T, Phang ST, Tiang Z, Guan P, Ng MH, Lim JQ, Yao F, Li Z, Ng PY, Yan J, Goh BK, Chung AY, Choo SP, Khor CC, Soon WW, Sung KW, Foo RS, Chow PK (2017) The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat. Commun. 8:4565. https://doi.org/10.1038/ncomms14565
28. Chew V, Lai L, Pan L, Lim CJ, Li J, Ong R, Chua C, Leong JY, Lim KH, Toh HC, Lee SY, Chan CY, Goh BKP, Chung A, Chow PKH, Albani S. (2017). Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc. Natl. Acad. Sci., 114(29):5900-09. https://doi.org/10.1073/pnas.1706559114.

Patents:

1. A system and method for classifying cancer patients into appropriate cancer treatment groups and compounds for treating the patient (Valerie Chew, Pierce Chow, Albani Salvatore) (Application number: 10201709924T; Filing Date: 30/11/2017)
2. Cell-based biomarkers of immunotherapy in hepatocellular carcinoma (Ankur Sharma, Florent Ginhoux, Ramanuj Dasgupta, Pierce Chow) (Singapore Provisional Application number.: 10202007868Q; Filing Date: 17/08/2020)

Singapore

Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital)

Malaysia

Yoong Boon Koon (University Malaya Medical Center)

Philippines

Maria Vanessa H. de Villa (The Medical City)

Thailand

Rawisak Chanwat (National Cancer Institute)

United States of America

Sabino Zani Jr (Duke University School of Medicine)

​Theme 1: Genomic evolution in HCC and the discovery of novel drug targets

Theme PI: Zhai Weiwei (Senior Research Scientist, Genome Institute of Singapore)

Theme 2: Translational Immunomics: Immune-phenotyping, monitoring and discovery of novel immunotherapies

Theme PI: Salvatore Albani (Director, SingHealth Translational Immunology and Inflammation Centre)

Theme 3: Clinical Trajectory and Translational Therapeutics

Theme PI: Pierce Chow (Senior Consultant, National Cancer Centre)

​Pierce Chow

pierce.chow@duke-nus.edu.sgpierce.chow.k.h@singhealth.com.sg

Phase III Multi-Centre Open-Label Randomized Controlled Trial of Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB)
(Clinicaltrials.gov identifier: NCT01135056)

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.

Publications:

1. Chew XH, Sultana R, Mathew EN, Ng DCE, Lo RHG, Toh HC, Tai D, Choo SP, Goh BKP, Yan SX, Loke KSH, Thang SP, Gogna A, Venkatanarasimha NK, Tong AKT, Moe FNN, Chua JSS, Ang RWT, Ong AD, Ng AWY, Hoang MTQ, Too CW, Thng CH, Chan WY, Kee W, Chan JHM, Irani F, Leong S, Lim KH, Wang MLC, Chow PKH. (2021) Real-World Data on Clinical Outcomes of Patients with Liver Cancer: A Prospective Validation of the National Cancer Centre Singapore Consensus Guidelines for the Management of Hepatocellular Carcinoma. Liver Cancer. https://doi.org/10.1159/000514400
2. Pierce K.H. Chow, Mihir Gandhi, Say-Beng Tan, et al. (2018) SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients with Hepatocellular Carcinoma. J. Clin. Oncol., https://doi.org/10.1200/JCO.2017.76.0892.
3. Gebski V, Gibbs E, Gandhi M, Chatellier G, Dinut A, Pereira H, Chow PK, Vilgrain V (2017) VESPRO: An Individual Patient Data Prospective Meta-Analysis of Selective Internal Radiation Therapy Versus Sorafenib for Advanced, Locally Advanced, or Recurrent Hepatocellular Carcinoma of the SARAH and SIRveNIB Trials. JMIR Res. Protoc. 6(2):17. https://doi.org/1010.2196/resprot.7016.
4. Chow, P.K., Gandhi, M., and Gebski, V. (2017). The Sirvenib and Sarah Trials and the Role of Sir-Spheres(R) Y-90 Resin Microspheres in the Management of Hepatocellular Carcinoma. Future Oncol.,13:2213-16. https://doi.org/10.2217/fon-2017-0395.
5. Gandhi M, Choo SP, Thng CH, Tan SB, Low AS, Cheow PC, Goh AS, Tay KH, Lo RH, Goh BK, Wong JS, Ng DC, Soo KC, Liew WM, Chow PK (2016) Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial. BMC Cancer 16(1):856. https://doi.org/10.1186/s12885-016-2868-y.

Singapore 

Kenneth Mak (Khoo Teck Puat Hospital), Choo Su Pin (National Cancer Centre), Kieron Lim (National University Hospital), Cheow Peng Chung (Singapore General Hospital) 

Brunei

Kenneth Kok (The Brunei Cancer Centre)

Indonesia

L.A Lesmana (Cipto Mangunkusumo Hospital, University of Indonesia), Tjakra Wibawa Manuaba (Sanglah General Hospital, Denpasar)

Malaysia

Aloysius Raj (Penang Adventist Hospital), Nik Azim Bin Nik Abdullah (Sarawak General Hospital), Yoong Boon Koon (University Malaya Medical Center)

Mongolia

Ariunaa Khasbazar (National Cancer Center of Mongolia)

Myanmar

Khin Maung Win (Yangon GI & Liver Centre)

New Zealand

Adam Bartlett (Auckland City Hospital)

Philippines

Rolley Lobo (Davao Doctors Hospital), Catherine Teh (Makati Medical Center), Janus Ong (The Medical City), Ian Cua (St Luke’s Medical Center)

South Korea

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)

Taiwan

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)

Thailand

Chanisa Chotipanich (Chulabhorn Hospital)

​Pierce Chow

pierce.chow@duke-nus.edu.sgpierce.chow.k.h@singhealth.com.sg

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.

Publication:

1. Chow, P. K., Poon, D. Y., Khin, M. W., Singh, H., Han, H. S., Goh, A. S., Choo, S. P., Lai, H. K., Lo, R. H., Tay, K. H., Lim, T. G., Gandhi, M., Tan, S. B., and Soo, K. C. (2014) Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma. PLoS One, 9:90909. https://doi.org/10.1371/journal.pone.0090909. PMID: 24614178

Singapore

Alexander Chung (Singapore General Hospital), Choo Su Pin (National Cancer Centre)

South Korea

Han Ho Seong (Seoul National University Hospital)

Malaysia

Harjit Singh (Selayang Hospital)

Myanmar

Khin Maung Win (Yangon GI & Liver Centre)

Pierce Chow

pierce.chow@duke-nus.edu.sgpierce.chow.k.h@singhealth.com.sg

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.

• Tumour assessment, tumour calculation and measurement will be performed by an independent radiologist. CT scans from all participating sites will be sent in DICOM format to the designated radiologist for assessment.
• Safety assessment and grading of CTCAE will be performed by the same investigator for that same patient throughout the entire study period. There will be an interim analysis when all patients complete 24 weeks evaluating the safety profile and target tumour response of the patients.
• 32P BioSiliconTM will be prepared by designated personnel licensed to handle radioactive products and all radioactive waste will be handed and managed as per the institution's guidelines and in compliance with local regulatory requirements.

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.

Publication:

1. Goh, A. S., Chung, A. Y., Lo, R. H., Lau, T. N., Yu, S. W., Chng, M., Satchithanantham, S., Loong, S. L., Ng, D. C., Lim, B. C., Connor, S., and Chow, P. K. (2007) A novel approach to brachytherapy in hepatocellular carcinoma using a phosphorous32 (32P) brachytherapy delivery device--a first-in-man study. Int. J. Radiat. Oncol. Biol. Phys., 67:786-92. PMID: 17141975

Singapore

Pierce Chow (National Cancer Centre)

Pierce Chow

pierce.chow@duke-nus.edu.sgpierce.chow.k.h@singhealth.com.sg

Publication:

1. Chung, A. Y., Ooi, L. L., Machin, D., Tan, S. B., Goh, B. K., Wong, J. S., Chen, Y. M., Li, P. C., Gandhi, M., Thng, C. H., Yu, S. W., Tan, B. S., Lo, R. H., Htoo, A. M., Tay, K. H., Sundram, F. X., Goh, A. S., Chew, S. P., Liau, K. H., Chow, P. K., Tan, Y. M., Cheow, P. C., Ho, C. K., and Soo, K. C. (2013) Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J. Surg., 37:1356-61. PMID: 23463394

Singapore

Alexander Chung (Singapore General Hospital), Tay Khoon Hean (Changi General Hospital), Chew Soo Ping (Tan Tock Seng Hospital)

Alexander Chung 

alexander.chung.y.f@singhealth.com.sg

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.

Publication:

1. Chow, P. K., Machin, D., Chen, Y., Zhang, X., Win, K. M., Hoang, H. H., Nguyen, B. D., Jin, M. Y., Lobo, R., Findlay, M., Lim, C. H., Tan, S. B., Gandhi, M., and Soo, K. C. (2011) Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br. J. Cancer, 105:945-52.

Singapore

Soo Khee Chee (National Cancer Centre), Pierce Chow (Singapore General Hospital)

Myanmar

Khin Maung Win (Yangon GI & Liver Centre)

New Zealand

Michael Findlay (The University of Auckland)

Philippines

Rolley Rey Lobo (Davao Doctors’ Hospital)

South Korea

Yang Jin-Mo (St. Vincent’s Hospital)

Vietnam

Hoang Hoa Hai (Choray Hospital), Nguyen Ba Duc (National Cancer Institute K Hospital)

Pierce Chow

pierce.chow@duke-nus.edu.sgpierce.chow.k.h@singhealth.com.sg

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.

Publication:

1. Chow, P. K., Tai, B. C., Tan, C. K., Machin, D., Win, K. M., Johnson, P. J., and Soo, K. C. (2002) High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology, 36:1221-26. (DOI: 10.1053/jhep.200236824) PMID: 12395333
2. Chow, P. K. (2005) Tamoxifen does not improve overall survival in people with advanced-stage hepatocellular carcinoma. Cancer Treat. Rev., 31:491-95. 
3. Chow, P., Kiat, T. C., Choo, T. B., and Machin, D. (1998) Tamoxifen in hepatocellular carcinoma. Lancet, 352:819-20.
   

Singapore 

Soo Khee Chee (National Cancer Centre), Ng Han Seong (Singapore General Hospital), S.C. Chia (Tan Tock Seng Hospital)

Australia

Jonathan Cebon (Austin and Repatriation Medical Centre)

Hong Kong

Phillip Johnson (Prince of Wales Hospital, Chinese University of Hong Kong)

Indonesia

Tjakra Wibawa Manuaba (Sanglah General Hospital)

Malaysia

A Haron (Hospital Universiti Kebangsaan)

Myanmar

Khin Maung Win (Yangon GI & Liver Centre)

New Zealand

Michael Findlay (Auckland Hospital)

South Korea

Si-Hyun Bae (St. Vincent’s Hospital)

Thailand

Thiravud Khuhaprema (National Cancer Institute)

Pierce Chow

pierce.chow@duke-nus.edu.sg pierce.chow.k.h@singhealth.com.sg