Ann Surg Oncol (2015) 22:741–746 DOI 10.1245/s10434-014-4342-x
CONTINUING EDUCATION – GLOBAL SURGERY: EDUCATIONAL REVIEW SERIES
Establishing Translational and Clinical Cancer Research Collaborations Between High- and Low-Income Countries T. Peter Kingham, MD1,2 and Olusegun I. Alatise, MD2,3 Department of Surgery/Hepatopancreatobiliary, Memorial Sloan Kettering Cancer Center, New York, NY; 2Surgeons OverSeas, New York, NY; 3Department of Surgery, Obafemi Awolowo University, Ile-Ife, Nigeria
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ABSTRACT Both infectious and noninfectious related malignancies are a growing problem in low- and middleincome countries (LMIC). It is difficult to extrapolate data and guidelines regarding cancer care from high-income countries (HIC) to cancer patients in LMIC. Due to the rise in noncommunicable cancer rates, there is a widening gap between the need for evidence-based treatments for cancer control plans and existing research capabilities. Surgeons frequently provide all surgical and medical oncology treatments for patients in LMIC for diseases, such as breast, gastric, cervical, and colorectal cancers. Surgical oncology clinical and translational research collaborations, however, are lacking. There are several successful consortiums that focus on HIV- and infectious-related malignancies. These collaborations can be used as an example for future surgical research efforts. The Memorial Sloan Kettering Cancer Center-Nigerian collaboration that is concentrating on colorectal cancer is used as an example of how to initiate a research collaboration that can build research infrastructure and provide the necessary data to generate realistic treatment guidelines. The need for expanded surgical oncology research and the growing population of patients with noninfectious-related malignancies in LMIC has created a unique opportunity for surgeons to initiate and lead clinical and translational research collaborations between HIC and LMIC.
Ó Society of Surgical Oncology 2015 First Received: 27 August 2014; Published Online: 9 January 2015 T. P. Kingham, MD e-mail:
[email protected]
Cancer care is a growing problem in low- and middleincome countries (LMIC). By 2020, up to 70 % of patients with cancer will live in LMIC.1 This increase in cancer diagnoses is contributing to a ‘‘double burden of disease’’ in LMIC, as infectious diseases remain common and incidence of noncommunicable diseases, such as cancer, rapidly increases.2 Improvements in the approach to oncology research are crucial to improving patient care in LMIC. Most global oncology policy discussions focus on prevention, screening, or medical therapy. These discussions frequently ignore the role of surgeons and the need for translational and clinical research. It often is a surgeon who will provide surgery and/or chemotherapy, as indicated, and a surgeon who will be the primary health care provider for most patients with solid tumors in LMIC.3 Despite the predominance of surgical involvement in caring for cancer patients, estimates suggest only 5 % of the annual global oncology research and development budget supports surgical research.4 There are global advocacy groups, such as the International Atomic Energy Agency (IAEA), that stress the importance of radiotherapy. Still, no such official, global organizations exist for surgical oncology. In high-income countries (HIC), there is a paradigm of cancer care that combines basic and translational science with clinical research (Fig. 1). Risk factors for common cancers have been identified and therapies have been tested by large cooperative groups with prospective, clinical trials and tissue banking. The results of these research endeavors are frequently used to generate national evidence-based guidelines, such as those provided by the National Comprehensive Cancer Network (NCCN) in the United States. Such large-scale collaborations and the data they generate are lacking in LMIC. It is impossible to have evidence-based cancer control policies without an understanding of disease biology, implementation science, and cost-effectiveness research to assess treatment options, and generation of regional capacity to perform clinical and translational research.
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FIG. 1 Translational and clinical research examples and infrastructure in low-, middle-, and high-income countries
WHAT ARE THE SURGICAL ONCOLOGY RESEARCH NEEDS IN LOW- AND MIDDLEINCOME COUNTRIES? It is challenging to identify the particular research needs that should be addressed first to begin improving cancer care in LMIC. There are general health care insufficiencies, such as a lack of equipment, financial resources, infrastructure, and personnel, which affect all aspects of providing medical care, including oncology care. While these obstacles may seem daunting, the same obstacles faced the public health community when HIV/AIDS was discovered in the 1980s. Years of large collaborative efforts have led to impressive results in both scientific discoveries related to HIV and vastly improved patient outcomes. Oncology research needs include building cancer registries, determining the biology of cancers in LMIC, evaluating cost-effective screening methods and therapies, and studying the implementation of tiered guidelines that can be applied across settings with differing resources. The temptation is to forgo undertaking large collaborative research projects in LMIC and instead use data and treatment paradigms from HIC to generate guidelines for oncology patients in LMIC. It is unclear, however, how relevant these data and the resultant guidelines can be. Patients in LMIC often present at a younger age, with advanced-stage disease, and with different mutation patterns, clinical presentations, and responses to chemotherapy.5,6 In addition, they present to systems with a wide range of resources and capabilities and are required to pay for any treatment they undergo. For example, colorectal cancer screening guidelines in HIC recommend screening begin at age 50 years with combinations of fecal occult blood testing, sigmoidoscopy, and colonoscopy at 1–10year intervals. This is not relevant in most LMIC where there are no screening programs and more than a third of
the patients are younger than 50 years, the utility of fecal occult blood testing in a population with high rates of dysentery and hemorrhoids is unclear, and access to quality colonoscopy is limited. Given differences, such as these for all cancers, it is difficult to assume HIC treatment guidelines are relevant in providing cancer care for LMIC oncology patients. This makes it challenging to develop national cancer control plans. HIV AND ONCOLOGY COLLABORATIONS EXIST AS MODELS FOR SURGICAL ONCOLOGY RESEARCH Global medical collaborations exist on individual, institutional, consortia, and multinational levels. There are collaborative efforts that focus on HIV and medical oncology that are examples of the type of translational and clinical research projects that are required for advancing surgical oncology care. Surgical oncology researchers can learn from them and potentially share infrastructure. A collaboration that demonstrates the capacity for long-term success in LMIC is the one between Harvard University and Universite´ Cheikh Anta Diop of Dakar, Senegal. Their work focusing on HIV/AIDS research began in 1985 and led to the longest prospective study of HIV in Africa. There is now an advanced AIDS research laboratory in Dakar. HIV-2 was discovered by this group, and they have published many seminal HIV manuscripts, including two manuscripts in Nature. An example from the oncology community is the International Network for Cancer Treatment and Research (INCTR) Burkitt Lymphoma study group with five hospitals in Nigeria, Kenya, Uganda, and Tanzania.7 INCTR researchers have prospectively studied new drug treatment guidelines for Burkitt lymphoma and reported impressive improvement in survival rates.
High- and Low-Income Countries Research Collaborations
There also are successful oncology-based partnerships that focus on infection- associated malignancies. The Fred Hutchinson Cancer Research Center, for example, has a program in Global Oncology that focuses on infectionrelated cancers. In 2004, they established collaboration with the Uganda Cancer Institute focusing on malignancies, such as Burkitt lymphoma and Kaposi sarcoma. They focus on training research leaders, research managers, and research implementers to build research infrastructure in Uganda. Training includes a 1-year certificate-earning training program at the Hutchinson Cancer Center and a 2-year Masters in Public Health program. Another example is the Gambia Hepatitis Intervention Study supported by The Gambian Government, the Medical Research Council UK, and the International Agency for Research on Cancer. Founded in the 1980s, this group has conducted, randomized vaccine trials of the HBV vaccine among 120,000 newborns.8 There are several collaborative groups focusing on noninfectious-associated cancers. Many of these efforts are young compared with the consortia that exist for infectious diseases and for hematologic malignancies. In addition, surgical involvement, while rare in these collaborations, is vital for both translational and clinical research particularly on solid tumors in LMIC. The field of medical oncology for solid tumors is new or nonexistent in many LMIC and radiation therapy often is not available. This provides a unique opportunity for surgeons to lead collaborative research and treatment efforts. The largest pan-African organization that focuses on oncology is the African Organization for Research and Training in Cancer (AORTIC). It was formed in 1983 and has sponsored nine international cancer conferences. The 2013 conference in Durban, South Africa, had almost 1,000 attendees. Translational and clinical research presentations on solid and liquid tumors were presented. The goals of the organization are to further research relating to cancer prevalence in Africa, support the management of training programs in oncology for healthcare workers, address the challenges of creating cancer control and prevention programs, and raise public awareness of cancer in Africa. AORTIC is a growing umbrella organization that fosters new research collaborations, similar to ASCO in the United States. MEMORIAL SLOAN KETTERING CANCER CENTER’S COLLABORATION IN NIGERIA Our collaboration on translational and clinical research projects grew out of a fellowship program (the Soudavar Fellowship) at Memorial Sloan Kettering Cancer Center (MSKCC) that hosts junior faculty from around the world
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with an interest in surgical oncology for a 3-month observership at MSKCC. One of the authors (OIA) spent 3 months at MSKCC as a Soudavar Fellow. The relationships forged during this fellowship led to the first reciprocal trip to Nigeria. It was obvious to the Nigerian and American surgeons that Nigerian patients with colorectal cancer did not fit the patterns of patients with colorectal cancer in HIC. The patients’ age, presenting symptoms, metastatic pattern, and response to chemotherapy all appeared different. In addition, incidence in Nigeria appears to be rising, but with no proven etiology. A retrospective review of patients with colorectal cancer in Nigeria in comparison to those at MSKCC was published.5 The findings were sufficiently disparate to generate a more formal collaboration between Obafemi Awolowo University (OAU) and MSKCC, with the two authors as coPrincipal Investigators on several protocols. What started as a clinical exchange program with opportunities for training has now blossomed into an NCI recognized consortium—the African Colorectal Cancer Group (ARGO)— with MSKCC in the United States and Obafemi Awolowo University Hospital, Ladoke Akintola University Teaching Hospital, University of Ilorin, and Federal Medical Center Owo in Nigeria. We plan to expand this consortium to other leading teaching hospitals in Nigeria and other African countries. The NCI has a brief application that requires the rationale for the consortium, an overview of the research interest, the research aims, the organizational structure, data sharing plans, and a roster of consortium members. This mechanism also provides an avenue for funding that supports consortium meetings and to support consortium communications. To meet the locally identified needs for registry data, biologic studies, and screening evaluations of patients with colorectal cancer, ARGO initiated two prospective protocols. The first is the creation of a database of demographic and clinical data combined with storage of tissue, blood, and radiologic images. With a target enrollment of 200 patients, this protocol will provide the necessary data to design therapeutic trials. In addition, the tissue and blood samples are being used for mutational and epigenetic studies to compare the biology of colorectal cancer in Nigeria to that in the United States, because these data are lacking. The second prospective protocol is enrolling patients older than 45 years that present with rectal bleeding. These patients are surveyed with a colonoscopic examination; if a cancer is found the cost of their treatment is subsidized by the study. With a target enrollment of 100 patients, this protocol will be used to create a multi-institutional surveillance program of high-risk patients to identify colorectal cancer at an earlier stage. The data from both of these studies will be used to generate practice
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guidelines. Their implementation will be evaluated with both patient outcome and cost effectiveness as endpoints. LESSONS LEARNED FROM MSKCC’S COLLABORATION IN NIGERIA For LMIC–HIC collaborations, it is vital for each party to contribute both skills and ideas (Fig. 2). The model in which the LMIC participates solely by providing tissue for analysis that is done solely in a HIC is one that will not build long-term infrastructure or research capacity in LMIC. An academic surgical career is challenging in all settings. In LMIC, access to traditional resources (funding, online journal access, and academic infrastructure) that are available in HIC often are lacking. HIC institutions can offer: (a) Access to grants to help finance research. (b) Research infrastructure that can be useful as a model/ resource. (c) Model of academic surgery. LMIC institutions can offer: FIG. 2 Developing a global translational and clinical cancer collaboration
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(a) Knowledge of disease processes in their region. (b) Expansion of research ideas that have been limited by resources or time. (c) Access to grants not available to U.S.-based physicians. (d) Experienced public health workers with expertise from HIV and other infectious disease research projects. (e) New indications for oncology medications. (f) Cost-effective regimens that can aid in reducing health costs in HIC. The Nigerian collaborators have benefited in several ways. Through clinical exposure at MSKCC, the quality of surgical resections and perioperative management of patient with colorectal cancer have changed in their hospital. There also is development of multidisciplinary team reviewing and designing treatment protocol for patients with colorectal cancer, which is similar to that obtained at MSKCC. There also are now several grants that have been awarded with Nigerian surgeons as co-Principal Investigators. This has allowed Nigerian surgeons to build the research infrastructure required to perform research to answer their clinically relevant ideas. In addition, with equipment from MSKCC,
High- and Low-Income Countries Research Collaborations
clinical practice has expanded simultaneously with research efforts. MSKCC collaborators have benefited by gaining access to Nigerian colleagues with similar research interests and unique research questions. In addition, it is an opportunity for training surgical oncology fellows in a setting that is quite different than MSKCC. Despite the great enthusiasm among researchers in academic institutions in LMIC for involvement in international collaborations, the infrastructures available are very limited and may be obstacles. Limited infrastructure has been apparent in the collaboration between MSKCC and Nigeria. In order to prospectively gather data regarding colorectal cancer patients in Nigeria, an Access database was created at MSKCC. The consortium hired a Nigerian junior doctor, research nurse, and research coordinator to gather and enter data, and a secure shared website was established on the MSKCC server to host the database and comply with patient confidentiality requirements. Still, there have been many obstacles throughout this process. Data collection, meetings, and the research infrastructure have all been affected by differing versions of computer programs, corrupt databases due to use of pirated software, unreliable power supplies for data computers, difficult internet access, lengthy hospital strikes, transportation and treatment costs that limit patients’ abilities to follow treatment plans, and the global public health crisis surrounding Ebola. These challenges have underscored several important lessons. With multiple users in different countries using different systems, databases must be streamlined, strict data quality assessment needs to be performed to ensure high-quality data with minimal missing fields, and there has to be consistent communication of data to ensure safe storage in multiple locations. The Research Electronic Data Capture (REDCap) secure web-based data collection system sponsored by the NIH is available for use with research collaborations with LMIC. Also, it is useful to involve HIV and other public health researchers with regional experience for advice on building local research infrastructure. Communication within the consortium has been relatively easy using phone and conference calls. In addition, mobile phones now allow accurate follow-up with patients and their family members once they are enrolled in studies. Specimen sharing also is possible, because it is now easy to use formalin-fixed, paraffinembedded blocks for most tissue analysis, and these can be shipped via global carriers. In the instances when fresh tissue or blood are required, dry ice shipments are feasible. GOALS FOR FUTURE ARGO RESEARCH COLLABORATIONS The goal of ARGO researchers is eventually to create an oncology research infrastructure that is not organ-specific
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and can be used for general oncology prospective data collection and therapeutic trials. Success will require generation of funding independent of the HIC collaborator. This requires grant writing expertise and an institutional infrastructure that can receive and maintain grant funds. Another long-term goal is to have some tissue-based work performed locally. These goals are compatible with other efforts, such as The Human Heredity and Health (H3) Africa Initiative and programs funded by the Fogarty International Center and the NCI’s new Center for Global Health to bolster research capacity in LMIC. Another consortium goal is to increase exchanges between the institutions, as exposure to multidisciplinary treatment teams, databases, and research relationships at a HIC institution can help physicians from LMIC improve their ability to design successful infrastructure. This will include formal research training, such as a Masters in Public Health or Clinical Research. A formal degree program requires commitment from senior leadership to allow for protected time and can serve as a stimulus for academic recognition. In addition, this training helps researchers overcome potential technical barriers and develop into research mentors. CONCLUSIONS Global political and health policy organizations are calling for an increase in cancer research and treatment efforts in LMIC due to the steep increase in cancer incidence in these countries. The data used to develop treatment guidelines in HIC often do not apply to patients in LMIC. This has created a large void that offers surgeons in LMIC and HIC an opportunity to generate data and treatment guidelines for many cancer types in LMIC. Mutually beneficial collaborations are vital for long-term success. There are opportunities at clinical, translational, and basic science levels for research. Research on the differences in mutations, epigenomics, and the microbiome may all yield striking findings that can enhance our general understanding of oncogenesis and affect treatments and trials in both LMIC and HIC. Surgeons need to take the lead at the forefront of global oncology care. ACKNOWLEDGMENT Funding was provided by the NCI Center for Global Health Award for Pilot Collaborations in LMIC and Memorial Sloan Kettering Cancer Center Survivorship, Outcomes, and Risk Program Interdisciplinary Population Science Research Award.
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