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Contemporary Clinical Trials 36 (2013) 682686

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Contemporary Clinical Trials

journal homepage: www.elsevier.com/locate/conclintrial

Conducting randomised controlled trials across countries with disparate levels of socio-economic development: The experience of the Asia-Pacic Hepatocellular Carcinoma Trials Group
Nicole H.Y. Kong a, Pierce K.H. Chow b, c,
a b c

Dept of General Surgery, Singapore General Hospital, Outram Road 169608, Singapore Ofce of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore Dept of Surgical Oncology, National Cancer Centre, Singapore

a r t i c l e

i n f o

a b s t r a c t
Hepatocellular carcinoma (HCC), which constitutes over 8590% of all primary liver cancers, is the most predominant type of liver cancer, and the third leading cause of cancer related deaths in the world. While the Asia-Pacific is a highly heterogeneous region in geography, ethnicity and in the level of socio-economic development, the main burden of HCC falls in this region and there are compelling reasons and advantages to conduct definitive clinical trials in HCC where it is endemic. The Asia-Pacific Hepatocellular Carcinoma (AHCC) Trials Group was established in 1997 and has faced and overcome challenges that are inherent in conducting clinical trials in a disparate region. Clinical trial infrastructure is rudimentary at many sites and requires significant effort to be expended on training and monitoring to ensure production of definitive data. The benefits of industrial support of Investigator-Initiated Trials are discussed in the context of the Asia-Pacific. The positive experience of the AHCC trials group would be valuable to any collaborative trials in countries with disparate levels of socio-economic development. 2013 Elsevier Inc. All rights reserved.

Article history: Received 25 October 2012 Received in revised form 18 February 2013 Accepted 18 March 2013 Available online 12 April 2013 Keywords: Hepatocellular carcinoma Randomised controlled trials Clinical trials

1. Introduction Hepatocellular carcinoma (HCC), which constitutes over 8590% of all primary liver cancers, is the most predominant type of liver cancer, and the third leading cause of cancer related deaths in the world [1]. It has been estimated that HCC results in 650,000 deaths yearly, of which two-thirds are from Asia [2].

Author Information: The author Nicole Kong is a member of the Secretariat of the AHCC trials group, and Professor Pierce Chow is the protocol chair of several AHCC trials, namely AHCC01, AHCC02, AHCC04, AHCC05 and the currently recruiting AHCC06. Corresponding author at: Ofce of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore. Tel.: + 65 63266450. E-mail addresses: nicole.kong.h.y@sgh.com.sg (N.H.Y. Kong), pierce.chow@duke-nus.edu.sg, gsupc@singnet.com.sg (P.K.H. Chow). 1551-7144/$ see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cct.2013.03.012

While HCC itself has been reported to be associated with many risk factors including dietary aflatoxin exposure [3], alcohol consumption [4], obesity [5] and diabetes [6], chronic viral hepatitis is most important risk factor [7]. The geographical prevalence of HCC in this region is attributed to the high incidences of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, the main etiological agents for HCC [811]. HBV and HCV account for 8090% of all HCC worldwide [12]. The resources and expertise required to conduct randomised controlled trials (RCT) were previously confined to economically more developed nations, mainly outside of the Asia-Pacific. There was a consequential paucity of randomised controlled trials in HCC in the endemic regions of the AsiaPacific and other developing nations. Clinicians in Asia however share a common goal of seeking efficacious treatment for a cancer epidemic in the region that

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had few available therapeutic options. This impetus marked the beginning of the AHCC trials group. Subsequently other groups in the region similarly embarked on multi-centre cancer trials namely the Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers (ASCOLT) trial [13] and the Nimotuzumab and Cisplatin/Radiotherapy for locally Advanced Head and Neck Squamous Cell Cancer trial [14]. 2. History of the trials group The Asia Pacific Hepatocellular (AHCC) Trials Group was created in 1997 when its first randomised controlled trial in hepatocellular carcinoma (HCC) was initiated by the Singapore General Hospital, and the NMRC Clinical Trials and Epidemiology Research Unit (CTERU), Singapore [15]. This started as a single centre prospective HCC clinical trial at the Singapore General Hospital. Within a year this expanded to a multi-centre trial in the AsiaPacific region when centres from leading universities and hospitals from Hong Kong, Bali, Malaysia, Myanmar, Thailand, Australia, Korea and New Zealand joined the trial. The enterprise evolved into the first collaborative oncology trials group in the region. Collectively the group believes that definitive clinical trials on HCC should be carried out where the disease is endemic, and that they should benefit patients who would otherwise not have access to cutting-edge therapies. The main objectives of the group are to conduct preventive and therapeutic trials in HCC, to carry out basic and translational research in this field, and to develop training and educational programs in HCC [16]. After 15 years of conducting multicentre, multinational clinical trials, the AHCC network has morphed into a wellestablished platform for high-quality clinical studies. More than 30 centres from 14 countries have taken part in clinical trials of the AHCC trials group (Table 1). The group has launched 6 multicentre HCC clinical trials, the latest being the AHCC 06 (SIRveNIB) trial which commenced in 2010 (Table 2). 3. Paradigm shift: conducting clinical trials in the developing nations of Asia-Pacic The AHCC trials group was formed at a time when there was very little interest from the pharmaceutical industry to conduct or support randomised controlled trials in the Asia-Pacific in HCC or other diseases [17,18]. This has changed in the last decade. This paradigm shift was fuelled by mainly economic factors including the rapid expansion of the pharmaceutical industry, the significant potential of new markets, and cost-effectiveness mostly due to relatively cheaper costs of conducting clinical trials in the region. In addition, there has been improving quality of medical infrastructure, and considerably reduced amount of regulatory barriers required for drug approval in the region [17,19]. However while the advantages of conducting clinical trials in Asia are economically apparent, there are also social and scientific imperatives. The Asia Pacific is a highly diverse geographical region comprising of countries with vastly disparate levels of socio-economic development [20,21] and different ethnic populations. A commonly overlooked but relevant advantage of conducting RCTs in Asia-Pacific is that the heterogeneity of this region reflects the clinical reality of the disease on the ground. The large number of potential

research participants in this region permits ample opportunities for RCTs to achieve definitive outcomes because of the high disease incidence rates and availability of epidemiological data from a highly representative population. Well-conducted clinical trials based on sound scientific premises offer opportunities for patients to have access to promising new therapies. Conducting RCTs in the Asia-Pacific thus directly benefit patients in many developing countries who otherwise would have no access to new therapies, and this potentially brings about better patient outcomes in economically disadvantaged nations. HCC trials in this region also provide opportunities to characterise this disease through the elucidation of prognostic biomarkers, and the varied genetic and environmental influences that affect pathology and treatment responses across different ethnicity and populations. Clinical trials in such a diverse region are however also accompanied by significant challenges.

4. Meeting the challenges From the inception of the first AHCC Trial in 1997, the trials group faced novel and significant logistical challenges. These challenges remain similar today, and the lessons learnt are widely applicable. There were evident gaps in experience with local or multinational trials in some of the member sites of the AHCC trials group. Many centres were from countries that were challenged in socio-economic development and hence also largely rudimentary in medical facilities, infrastructure, and even indemnity assurance. At the other end of the spectrum, countries in the region that are ranked top globally for Gross Domestic Product (GDP) per capita, including Singapore, Korea, and New Zealand [21] were better prepared for clinical trials. When the first multi-centre trial was launched, there was general anxiety on the feasibility of conducting good GCPstandard clinical trials although there were also compelling pluses that performing RCTs in the Asia-Pacific would bring. Ensuring that Good Clinical Practise Guidelines (GCP) were in place was of paramount importance. Differences in the standard of care and cultural practices could also potentially affect implementation of the study protocol [22]. The heterogeneity of different sites required site management that was tailored to the economic status, culture, religion, language, medical infrastructure, and amount of RCT experience that each country possessed. The AHCC trials were successfully conducted with strict adherence to GCP guidelines, through repeated informative audits and frequent inspections and monitoring of trial sites. For example, 100% audit for the AHCC02 trial was adopted and such audits were highly educative for site personnel. Sites which were new to such guidelines required significant investment in staff training to efficiently conduct the trials in a GCP-compliant manner. An example would be a significant amount of time spent in training inexperienced but enormously valuable sites in Mongolia and Bali on fundamental trial procedures, e.g. setting up Institutional Review Board (IRB)s, reporting of adverse-events etc. Some of these sites require the approval of multiple institutional boards.

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Table 1 Countries that have participated previously or are participants of AHCC trials, their respective sites, Principal investigators and trials participated [5,6]. Country Australia Brunei Hong Kong Indonesia Malaysia Site Austin and Repatriation Medical Centre Raja Isteri Pengiran Anak Saleha Hospital Prince of Wales Hospital Queen Mary Hospital Cipto Mangunkusumo Hospital Rumah Sakit Sanglah Hospital Universiti Kebangsaan Penang Adventist Hospital Selayang Hospital National Cancer Center of Mongolia Yangon General Hospital Auckland Hospital Davao Doctors Hospital Makati Medical Center St Luke's Medical Centre The Medical City Changi General Hospital Khoo Teck Puat Hospital Mount Elizabeth Hospital National Cancer Centre Principal investigator Jonathan Cebon Kenneth Kok Philip Johnson Ronnie Poon Laurentius Lesmana Tjakra Manuaba A. Haron Aloysius Raj Harjit Singh Ariunaa Khasbazar Khin-Maung Win Michael Findlay Paul Thompson Rolley Lobo Catherine Teh Ian Chua Janus Ong Jessica Tan Khoon-Hean Tay Jude Lee, Tzu Zen Tan Richard Guan Donald Poon Khee-Chee Soo Kian-Fong Foo, Susan Loong London Ooi Su-Pin Choo Stephan Chang Alexander Chung Anthony Goh Khee-Chee Soo Peng-Chung Cheow Kui-Hin Liau S. C. Chia Soo Ping Chew Mo-Yang Jin Si-Hyun Bae Hyun-Ki Yoon Yun-Hwan Kim Ho-Seong Han Si-Hyun Bae Jong-Yun Won Chien-Fu Hung Cheng-Yuan Peng Chao-Long Chen Po-Chin Liang Rhuen-Chuan Lee Thiravud Khuhaprema Ba-Duc Nguyen Hoa-Hai Hoang, Van-Viet Truong AHCC trial 01 06 01 06 06 02, 06 01 06 05 06 01, 02, 05, 06 01 02 02 06 06 06 06 02, 03 06 04 05 01,02 04 03 06 06 05 04 01, 02 06 04 01 03 02, 06 01 06 06 05, 06 06 06 06 06 06 06 06 02 02 02, 04 02

Mongolia Myanmar New Zealand Philippines

Singapore

National University Hospital Singapore General Hospital

Tan Tock Seng Hospital

South Korea

St. Vincent's Hospital Asan Medical Center Korea University Anam Hospital Seoul National University Bundang Hospital St. Mary's Hospital Yonsei University Severance Hospital Chang Gung Memorial Hospital China Medical University Hospital Kaohsiung Chang Gung Memorial Hospital National Taiwan University Hospital Taipei Veterans General Hospital Ramathibodi Hospital, Bangkok National Cancer Institute, Hanoi Cho Ray Hospital

Taiwan

Thailand Vietnam

Some of the sites in developing nations do not possess specifically required medical equipment for the trials, and accordingly would require outsourcing as an alternative. During the AHCC06 trial, CT scan imaging to specific criteria was used as recruitment criteria and this was outsourced to privately run institutions outside of the trial centres in some of these centres. Amongst the many similar challenges that the trial groups faced include ensuring drug accessibility in countries that have unusually stringent regulations for the import of drugs, and also the prevention of drug misallocation. Cultural differences in the region would require special attention and sensitivity for resolution. In some cultures

patients and clinicians may bear negative perceptions towards certain drugs or therapies while favouring others that may be more frequently used or accepted in the country's medical history. This situation if not handled properly may affect the recruitment or randomisation of patients at those sites or lead to high incidence of drop-outs when patients are randomised to a culturally unfavourable arm. An example would be the increasing number of patients and clinicians in Singapore who prefer therapies that they deem most suitable although there is absence of definitive data e.g. a preference for Yttrium-90 over sorafenib in the treatment of locally advanced hepatocellular carcinoma. While some patients may choose enrolment in clinical trials as a treatment option when equipoise exist

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N.H.Y. Kong, P.K.H. Chow / Contemporary Clinical Trials 36 (2013) 682686 Table 2 Study titles and identifiers of AHCC 01AHCC 06 trials [6]. AHCC trial ClinicalTrial.gov Study title identifier Randomised controlled trial of high-dose tamoxifen in inoperable HCC Randomised controlled trial of megestrol acetate in inoperable HCC Randomised controlled trial of adjuvant radioactive therapy after curative surgery in HCC Phase II dose escalation trial of intra-tumoral Brachysil in inoperable HCC Phase I/II trial of SIR-spheres plus Sorafenib in patients with non-resectable HCC Randomised Controlled Trial of SIR-Sphere versus Sorafenib in locally advanced inoperable HCC Protocol chair Pierce Chow Pierce Chow London Ooi Pierce Chow Pierce Chow 685

AHCC01 NCT00003424

AHCC02 NCT00041275

AHCC03 NCT00027768

AHCC04 NCT00247260

establish an experienced and wide network of Principal Investigators (PI)s at trial sites that have previously shown good collaboratory dynamics, and through this to conduct collaborative trials in future to investigate new therapies for HCC [15]. The establishment of such a network will allow industry to access of PIs from different countries in the region, who possess the experience and expertise having previously been involved in multinational trials. This facilitates support and broadens collaboration between members and other experts within and beyond participating institutions, and most importantly foster positive relationships among clinician investigators globally, which increase the opportunity for scientific breakthrough in future collaborations.

AHCC05 NCT00712790

6. Working with industry

Pierce Chow

AHCC06 NCT01135056

between different treatment options, other may prefer a specific therapy and decline to be randomised into clinical trials. Language differences require translation of study protocol, contracts, informed consent and all relevant documents according to ICH GCP guidelines [23]. In the first 2 randomised controlled trials conducted by the trials group, the European Organisation for Research and Treatment of Cancer (EORTC), was the source of Health Related Quality of Life (HRQOL) instrument used to assess the impact of the study therapeutics on global quality of life [24]. This instrument was not available for all ethnic languages required for the trials and new authorised translations into the respective native languages were required for some sites. The ultimate challenge necessitating the greatest effort to overcome is the standardization of all the above differences to eventually produce clinical data that is definitive and of quality. This challenge can be overcome by investing significant amounts of time and resources to maintain continuous efforts to train, update, and familiarise the staff involved with the study protocol and GCP guidelines, whilst maintaining a continued emphasis on thorough GCP training and GCP quality [25]. 5. The strategic advantage of a collaborative trials network There is rapidly growing competition globally in the clinical trial industry with an increasing number of Contract Research Organisations (CRO)s, Site Management organisations (SMO)s, academic medical centres, and independent non-academic sites. Consequently, more academic medical centres have started to form research networks [26,27]. A collaborative trials group is highly valuable, yet continually undervalued. The AHCC trials group is the first of its kind in the Asia-Pacific. Individual trials are governed by a steering committee, and managed by an Academic Research Organisation (ARO), network executives, and the protocol chair. The data centre of the AHCC Trials Group is at the Singapore Clinical Research Institute, a not-for-profit academic organisation at the Biopolis [28] in Singapore. The vision of the group is to

Although pharmaceutical-industry-initiated prospective trials are better funded compared to Investigator-Initiated Trials, increasing uncertainties are raised regarding the values, ethics, and accountability of such trials, and the degree of scientific independence from the pharmaceutical industry [2930]. Objectively, both industry-initiated and investigatorinitiated trials have deficiencies in clinical trials management [31]. While industry-initiated trials are entirely supported by the pharmaceutical industry, investigator-initiated trials receive funds directly from the government, National Institutes of Health, and non-commercial sources although such trials may also be supported by industry [16,30]. Examples of trials that are supported both by government and industry are the AHCC05 and AHCC06 trials of the AHCC trials group (Table 2). In addition, collaborative engagements with an ARO instead of a CRO in Investigator-Initiated Trials can make a significant difference. While CROs provide mainly the infrastructure for trial execution including site monitoring and data management, AROs are also engaged in the pursuit of academic objectives [32]. The collaboration of an ARO with InvestigatorInitiated Trials and their participation in trial groups like the AHCC safeguards the vision of the group and ensures that the objectives are synchronised and scientifically aligned. This minimises conflicts of interest between industrial investors, academic or governmental sponsors, principal investigators, and the ARO itself. The supporting role of an ARO impacts all processes of trials including important areas like statistical analysis and bioinformatics, educational development of internal and site staff, clinical trial management, and research methodology [15]. The AHCC would not have been able to meet the challenges of conducting pioneer multi-centre trials in the Asia-Pacific without the immense support and assistance provided by the Singapore Clinical Research Institute (SCRI). AROs like SCRI are harmonised with academic values [30,33]. The perception that commercial CROs are highly dependent on the industry may potentially affect trial processes such as recruitment of trial sites to join the Trials Groups, as well as patient recruitment. Indeed a recently published study in the New England Journal of Medicine showed that independent of trial quality, industry sponsorship can negatively influence the physician's perception of the credibility of trial findings, and reduce their willingness to prescribe the drugs and therapies studied [34].

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686 N.H.Y. Kong, P.K.H. Chow / Contemporary Clinical Trials 36 (2013) 682686 [8] Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet 1981;ii:112933. [9] Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma. Hepatology 2009;49(S5):S5660. [10] Sherlock S, Fox R, Niazi S, Scheuer P. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;i:12437. [11] Yuen M-F, Hou J-L, Chutaputti A. Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol 2009;24(3):34653. [12] Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2005;9(2):191211. [13] Aspirin for Dukes C, High Risk Dukes B colorectal Cancers (ASCOLT). ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/ NCT00565708 [Accessed: 3rd October 2012]. [14] Study of Nimotuzumab and Cisplatin/Radiotherapy for Locally Advanced Head and Neck Squamous Cell Cancer. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT00702481 [Accessed: 3rd October 2012]. [15] Singapore Clinical Research Institute. The Asia-Pacific Hepatocellular Carcinoma Trials Group [online]. Available at: http://www.scri.edu.sg/ index.php/about-ahcc [Accessed: 3rd October 2012]. [16] ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ [Accessed 1 October 2012]. [17] Choi HY, Ko JW. Facilitating large-scale clinical trials: in Asia. Urol Oncol Semin Orig Investig 2010;28(6):6912. [18] Hauser SL, Johnston SC. Global clinical trials: challenges ahead. Ann Neurol 2011;70(4):A89. [19] Glickman SW, McHutchison JG, Peterson ED, Cairns CB, Harrington RA, Califf RM, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med 2009;360(8):81623. [20] United Nations Economic and Social Commission for Asia and the Pacific (ESCAP). Economic and Social Survey of Asia and the Pacific 2011[online]. Available at: http://www.unescap.org/pdd/publications/survey2011/ download/Econimic-and-Social-Survey-2011.pdf [Accessed: 5th October 2012]. [21] United Nations Development Programme (UNDP). Human Development Index Trends, 19802011 [online]. Human Development Report. Available at: http://hdr.undp.org/en/media/HDR_2011_EN_Table2.pdf [Accessed 4th October 2012]. [22] Minisman G, Bhanushali M, Conwit R, Wolfe GI, Aban I, Kaminski HJ, et al. Implementing clinical trials on an international platform: challenges and perspectives. J Neurol Sci 2012;313(12):16. [23] ICH GCP. Good Clinical Practice [online]. Available at: http://ichgcpnet/; 2012 . [Accessed 6th October 2012]. [24] European Organisation for Research, Treatment of Cancer (EORTC). Quality of Life [online]. Available at: http://wwweortcorg/patients/ quality-life; 2012 . [Accessed: 6th October 2012]. [25] Chow PKH, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial. Hepatology 2002;36(5 II):12216. [26] Getz KA. AMCs rekindling clinical research partnerships with industry. Boston: Centerwatch; 1999. [27] Academic medical centers: slowly turning the tide. Centerwatch 1997;4(6):18. [28] Biopolis, Singapore. Agency for Science, Technology and Research [online]. Available at: http://www.a-star.edu.sg/ [Accessed: 8th October]. [29] Angell M. Is academic medicine for sale? N Engl J Med 2000;342(20): 15168. [30] Wadmad M. The quiet rise of the clinical contractor. Nature 2006;441(7089):223. [31] Shuchman M. Commercializing clinical trials - risks and benefits of the CRO boom. N Engl J Med 2007;357(14):13658. [32] Goldenberg NA, Spyropoulos AC, Halperin JL, Kessler CM, Schulman S, Turpie AGG, et al. Improving academic leadership and oversight in large industry-sponsored clinical trials: the ARO-CRO model. Blood 2011;117(7):208992. [33] Bodenheimer T. Uneasy alliance - clinical investigators and the pharmaceutical industry. N Engl J Med 2000;342(20):153944. [34] Kesselheim A. A randomized study of how physicians interpret research funding disclosures. N Engl J Med 2012;367(12):111927.

The AHCC has a good history of collaboration with industry [15,16] and here the presence of AROs as intermediaries can result in powerful and efficient partnerships [33]. The AHCC 05 trial was a prototypical collaboration between an academic medical centre, the Singapore General Hospital (SGH); an ARO, SCRI; and industry namely Bayer Healthcare Pharmaceuticals Inc./Bayer Schering Pharma and Sirtex Medical [16]. Such partnerships are efficient and are focused on answering scientific questions. This counters the notion that the industry is purely economically-motivated and unlikely to fund scientifically and clinically important studies that may potentially impact negatively on sales. 7. Conclusion The extreme diversity and poor social-economic development in many sites make conducting randomised controlled trials across the Asia Pacific demanding. The experience of the Asia-Pacific Hepatocellular Carcinoma Trials Group has demonstrated that, producing reliable and definitive data is achievable through reinforcing mechanisms that ensure high ethical, regulatory, and training standards. The benefits reaped from conducting trials in this region far outweigh the difficulties. Such endeavours also contribute towards establishing academic centres of excellence that in turn advances the science and contribute to the advancement of patient care. Acknowledgement The authors would like to thank the AHCC trials group for providing the information regarding the history of the trials group. References
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