This article reviews the current state of cancer research around the world.
Cancer, the second leading cause of death globally, remains a significant challenge for societies, healthcare systems, and affected individuals worldwide. Adding to this challenge are complex disparities in access to and use of cancer care, basic and clinical research, and clinical trials, as well as disparities in cultural beliefs and genetics. To improve cancer treatment, it is essential that cancer investigators, cooperative groups, national research institutions, national governments, competent authorities, ethics committees, and pharmaceutical companies come together to strengthen global collaboration in cancer research. Once we reach this goal, the resulting data will be more broadly applicable to all patients. This article reviews the current state of cancer research around the world.
Cancer is a significant challenge for society, healthcare systems, and the growing number of affected patients and their families. In 2018, out of the 18 million cases of cancer worldwide, 9.5 million were in men and 8.5 million were in women. Cancer is the second leading cause of death globally, with an estimated 9.6 million deaths. The most common cancers are lung cancer (2.09 million), female breast cancer (2.09 million), prostate cancer (1.28 million), colorectal cancer (1.1 million), non-melanoma skin malignancies (1.04 million), and stomach cancer (1.03 million). Cancer-related deaths, from most to least frequent, are due to lung cancer (1.76 million), colorectal cancer (862,000), stomach cancer (783,000), and liver cancer (782,000). More than two-thirds of these cancer fatalities occur in low- and middle-income countries.
High body mass index, low fruit and vegetable consumption, lack of physical activity, tobacco use, and alcohol use are the five leading behavioral and dietary risk factors for cancer-related deaths. It is estimated that tobacco use alone is responsible for approximately 22% of cancer deaths. Some 25% of cancer cases in low- and middle-income countries stem from infections, such as hepatitis and human papillomavirus. Beyond the risk factors and common causes of cancer, the economic impact of the disease is significant, and it is increasing. More than 90% of high-income countries have cancer treatment services available compared with fewer than 30% of low-income countries. Only one in five low- and middle-income countries has the necessary data to drive cancer policy.[5,6]
No single country can successfully fight this global public health problem on its own. Science is collaborative in nature and international in scope. To effectively improve treatments and identify cures, it is essential to fund the most promising research from all corners of the globe. Translational cancer research covers the continuum of research, including basic, preclinical, early clinical, late clinical, and outcomes research. Basic/preclinical research serves as the foundation for early clinical research, bridging the gap between science and practice. A prime example comes in the form of progress made towards controlling the infectious diseases that are linked to certain malignancies, such as hepatocellular carcinoma, cervical cancer, and stomach cancer. Coordinated approaches in basic research, translational research, and clinical trials may be applied to fighting cancer worldwide. This article reviews the current state of cancer research around the globe.
While 85% of cancer patients are diagnosed and treated at local, community-based clinical practices, cancer-related clinical research and clinical trials have traditionally been conducted at well-established academic medical centers in the United States. For the last 4 decades, the National Cancer Institute (NCI) has acknowledged the importance of community-based oncology research through several initiatives and programs. The significance of this research was validated in 1982, when the NCI initiated the Community Clinical Oncology Program (CCOP). The CCOP was designed to disseminate and implement advances in cancer care by linking cancer investigators and academic centers to community-based practices, thus expanding access to clinical trials and promoting cancer treatment innovations within the community populations that otherwise might not have had access. This collaborative partnership between research institutions and community physicians helped to facilitate phase III cancer prevention, control, and treatment trials in the local practice setting. Despite these efforts, community-based cancer research continued to face challenges as a result of the era of emerging science, technology, genomics, and molecularly targeted therapy, as well as a rapidly changing healthcare environment.
In 2007, the NCI further expanded its community-based efforts by launching the NCI Community Cancer Centers Programs (NCCCP), a publicÃ¢€“private partnership with 21 community hospitals in 16 states. The goals of the NCCCP were to enhance access to, and improve the quality of, cancer care by expanding the infrastructure to support a platform for basic, clinical, and population-based research, as well as informatics, biospecimen collection, and cancer care disparities in community hospitals. Self-reported data from NCCCP sites between 2007 and 2010, supplemented with data from the NCI Cancer Therapy Evaluation Program, showed that the availability of phase III trials and patient accrual increased by 16% and 133%, respectively, at NCCCP sites, compared with 8% and 30% nationally. In addition, enrollment of racial and ethnic minorities in oncology trials increased by 82%, from 83 to 151 patients; the accrual of patients age 65 years or older in oncology trials also rose by 221%, from 200 to 641 patients at NCCCP sites. The exact changes in trial portfolios and accrual differed by sophistication of the site and by prior experience conducting clinical trials at the site.
In 2014, the NCI initiated a new community-based program, the NCI Community Oncology Research Program (NCORP), to align with and replace the CCOP and NCCCP programs. The goals of the NCORP are to support clinical trials on cancer control, prevention, treatment, and cancer screening in the community setting, as well as to expand the scope of research to include cancer care delivery. The NCORP initiative emerged around the same time as two other significant changes: 1) the transformation and condensing of nine longstanding NCI Cooperative Group Programs into four new groups under the National Clinical Trials Network (NCTN), and 2) the implementation of the NCI Central Institutional Review Board. Both of these changes helped to provide easier access to all NCI Cooperative Group clinical trials, with some reduced regulatory load.
The NCTN structure included five US Network groups and the Canadian Collaborating Clinical Trials Network (Figure). Membership in the individual NCTN groups is based on criteria that are specific to each group. Sites can belong to more than one group, and membership in at least one group allows a site to participate in the trials led by any NCTN group for which their investigators are qualified. Consequently, researchers from the Lead Academic Participating Sites, NCORP, other academic centers, community practices, and international members associated with the Network groups may all enroll patients onto NCTN trials. Clinical trials led by NCTN groups may receive support from the Imaging and Radiation Oncology Core Group, Clinical and Translational Science Awards, and tissue banks, according to the scientific needs of the trials.
The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) is the adult cooperative oncology group based in Canada committed to assessing all modalities of therapy across the spectrum of different types of cancer. The NCIC-CTG has been operational since 1980. The group's activities have included leadership of, and participation in, large randomized clinical trials conducted in the United States and Canada by both the NCIC-CTG and US-based cooperative groups. The mission of the NCIC-CTG is to develop and conduct clinical trials aimed at improving the treatment and prevention of cancer, with the ultimate goal of reducing morbidity and mortality from this disease. NCIC-CTG collaborates with the NCI's Cancer Therapy Evaluation Program and US-based groups through its NCTN Program to develop new intergroup trials under NCIC-CTG leadership and to ensure more rapid accrual to trials led by US-based groups, thereby enhancing the overall clinical research program for adults and children with cancer.
Pharmaceutical companies may run international trials on their own or in conjunction with established clinical trials cooperative groups. Untill the late 1990s, few pharmaceutical companies showed interest in oncology products. Most new anticancer drugs in development reached the cooperative group researchers through the NCI. Within the past 2 decades, however, a record number of pharmaceutical and biotechnology companies have come up with hundreds of novel agents, compelling cooperative group investigators to work directly with industry partners. Chronic underfunding of the cooperative groups by NCI, coupled with the opportunity to access novel compounds, inevitably led to the development of much closer relationships between the cooperative groups and the pharmaceutical industry. While some effective collaborations between industry and clinical trials groups have resulted in the successful completion of many important cancer trials, the potential conflict between the goals of government-funded cooperative groups vs pharmaceutical industry sponsors has raised concerns in some others. The primary objective of the pharmaceutical companies is to provide data appropriate for a licensing application, while the objective of the cooperative groups is to evaluate the additive benefit of that new agent to standard treatment. A trial addressing a question of great importance to oncologists and patients may be of no interest to the pharmaceutical industry. The cooperative groups may also want to combine or compare agents from two different companies, which may not serve the interests of industry. This is an ongoing challenge in the United States especially.
While representing less than 10% of the global population, one-quarter of all cancers occur in Europe. Due to an aging population, these numbers are expected to increase, with an estimated 3.9 million Europeans diagnosed with cancer and 2 million cancer-related deaths in 2018 alone. Progress from basic research to patient treatment has historically been a long and fragmented process in Europe. At the 2000 European Council meeting in Lisbon, member states of the European Union signed on to an ambitious program aimed at helping Europe to become the most competitive and dynamic knowledge-based economy in the world by 2010. The cornerstone of the Lisbon Agenda was the creation of a European Research Area. These activities led to the establishment of the European Research Council in 2007, which helped consolidate fragmented European research towards innovation.[13-15] A pivotal Sixth Framework Programme initiative, the EUROCAN+PLUS Project, was followed by the Seventh Framework Programme EurocanPlatform Network of Excellence in 2011, emphasizing the need to stimulate multisite translational cancer research policies.
A direct outcome of these projects was the formation of Cancer Core Europe (CCE) in 2014. The main goal of CCE is to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations. Cancer Core Europe is now a legal entity including seven large European cancer centers, most of which are Comprehensive Cancer Centers. They operate with a single portal system to engage in various research projects with partners. Motivated by the creation of CCE, the leaders of 10 research institutes with prominent cancer prevention programs in Europe (the International Agency for Research on Cancer in France, and institutes in the United Kingdom, Denmark, Netherlands, Germany, Sweden, and Italy) came together and established Cancer Prevention Europe (CPE).
CPE is a consortium of multidisciplinary centers focused on reducing cancer mortality and morbidity through development of prevention policies. These infrastructures are intended to serve as a hub to connect and interact with other centers across Europe and beyond, bringing innovative approaches to cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes. Presently, CCE and CPE are integrating therapeutics and prevention strategies to address worsening cancer burden as a central engine. In 2017, a goal of achieving long-term survival in 3 out of 4 cancer patients by 2030 was proposed as a mission. This was deemed to be possible through innovative prevention and treatment strategies in a virtual European cancer center/infrastructure. In June 2018, a press release from the European Commission concerning Horizon Europe stated that "Examples of missions could range from the fight against cancer, to clean transport or plastic free oceans."
Cancer is one of the leading causes of death in South Korea, Taiwan, Singapore, and Hong Kong, as well as in urban China. The incidence of cancer has increased significantly over the past several years in the Asia-Pacific region, becoming a major concern for many healthcare systems. During the 1980s and 1990s, impressive economic growth in the East and Southeast Asia countries and China has improved standards of living and healthcare systems, leading to fewer deaths from infectious diseases. The increase in cancer deaths has been attributed to the enormous economic successes, longer life spans, and a population that is expanding far more rapidly than those in Europe and the United States. Furthermore, the proportion of people older than 65 years of age has been increasing. Over the last 25 years, while the total population of China has increased by 31%, the number of people over age 65 years has increased by 81%.[19,20]
The number of cancer cases in Asia is expected to rise to 8.1 million by 2020 if the current management strategies are not changed. Much of the Asia-Pacific population has certain characteristics that increase their cancer risk. In men, the smoking rate is about twice that seen in Europe and the United States. Culprit infections are much more common in Southeast Asia, including Helicobacter pylori, which increases the risk of stomach cancer by 5 to 6 times, and hepatitis B, which increases the risk of liver cancer. Nasopharyngeal cancer is a very common disease in Asia, predominantly affecting people of southern Chinese descent. The global UV index for Asia is about twice that of the countries in the Northern Hemisphere, further increasing cancer risk in this population.
While cancer research is in great demand across the Asia-Pacific region, the infrastructure and resources to conduct clinical trials can be variable. Australia, Japan, South Korea, Hong Kong, Taiwan, and Singapore have adequate resources to conduct clinical trials efficiently. Countries such as China and India have built institutions that can provide infrastructure and access to clinical trials for large populations of cancer patients, which has been a good resource for industry clinical trials. With the advent of immuno-oncology and the number of new agents undergoing testing, a multitude of centers and studies have cropped up to meet demands in the region. Challenges to participation in clinical trials in the Asia-Pacific region include specific inclusion/exclusion criteria of these trials, unavailability or irrelevance of the standard care arm (if a trial has one), and the lack of genetic biomarker testing in these developing countries. Another challenge, which at times can be an advantage in the Asia-Pacific region, is the genetic makeup of this population, which may display a difference in the incidence of the mutation being studied.
Similar to the incidence of the most common cancers worldwide, breast cancer, lung cancer, colorectal cancer, and prostate cancer are the most frequent cancers in the Middle Eastern and North African countries. Bladder and stomach cancers, however, constitute the fifth and sixth most common cancers in this region. Cancer incidence rates vary widely within and between Arab populations. There are few population-based cancer registries in Arab countries, with only 2% to 5% of populations reporting high-quality incidence data. National and regional spending on research and development has been relatively modest. In 2013, the regional gross expenditure on research and development by all Arab states was $15.5 million, compared with $282 million and $427 million by the European Union and North America, respectively.
Conducting research in this region of the world has been more challenging due to language barriers and lack of research infrastructure for reliable and valid data collection, as well as too few researchers and too little networking among them. Furthermore, constant political instability in this part of the world has adversely affected the number of research publications in circulation.[25-28] Due to weak infrastructure, low research spending, and the cultural attitudes of physicians and patients towards clinical research, high-evidence analytical research studiesÃ¢€”such as randomized clinical trialsÃ¢€”have been very problematic to conduct.[29-31]
To reduce the incidence and impact of cancer in the Middle East, a regional initiative for cancer research and treatment, the Middle East Cancer Consortium (MECC), was established in 1996. MECC members include the United States, Cyprus, Egypt, Israel, Jordan, the Palestinian Authority, and Turkey.[32-34] The goal of MECC was to launch and sustain academic-based medical programs that bring together scientists, academics, and clinical professionals from its member countries. MECC has helped to establish a successful Middle Eastern Network of Cancer Registry Centers, and initiation of palliative programs in its member countries.
International networks for research collaboration are not new for Europe and North America. The European Organisation for the Research and Treatment of Cancer (EORTC) has been around since 1962, with its top 35 accruing institutions located in 11 European countries, as well as Turkey and Egypt. Likewise, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Children's Oncology Group have brought cancer researchers from Canada and the United States together for many years. The NCIC-CTG has worked closely with investigators in the United States, Europe, and Australia. Advantages of international collaboration include faster accrual for both common and uncommon tumors, broader applicability of research results, fewer duplicative trials, and rapid dissemination of innovations. Thus, the need for global partnership in cancer research is crucial to maximize resource utilization, permitting cancer researchers around the world to complete high-priority trials in a timely manner. There are, however, several challenges to this approach. Regulatory, logistical, and financial hurdles often hamper the conduct of clinical trials even at the individual country level. One can only imagine the hurdles that can be faced when international collaboration is sought. Disadvantages of international collaboration in cancer treatment trials include differing regulations among countries, disparate levels of clinical trial support infrastructure, contrasting processes and schedules for scientific review, longer lead time for concept and trial development, various licensing arrangements and distribution issues for specific drugs, and incongruent contractual issues with pharmaceutical companies in different countries. Despite these challenges, there have been some successful examples of effective international interchange between clinical trials groups. The Breast International Group and the International Breast Cancer Study Group bring together 41 member groups from Europe, Canada, Latin America, Australia/New Zealand, and Asia, in addition to those from North America. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, sponsored by the NCI, the Breast International Group, and GlaxoSmithKline, is an example of a worldwide trial made possible through international collaboration and industry partnership.
With the steady increase in global cancer burden and the unprecedented pace of discoveries in basic cancer science, it is clear that cancer investigators, cooperative groups, national research institutions, national governments, competent authorities, ethics committees, and pharmaceutical companies need to get together, now more than ever, to strengthen global collaboration in cancer research.
Integration of cancer investigators and cooperative groups in Latin America, Asia, Africa, the Middle East, and Europe into the existing cancer research networks is critical if research is to become more representative of the entire globe. Once we reach that goal, the resulting research will be more broadly applicable to all patients.
Financial Disclosure:Dr. Copur has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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