Structural Barriers to Diagnosis and Treatment of Cancer in Low- and Middle-Income Countries: The Urgent Need for Scaling Up.

Noncommunicable diseases are now recognized by the United Nations and WHO as a major public health crisis. Cancer is a main part of this problem, and health care systems are facing a great challenge to improve cancer care, control costs, and increase systems efficiency. The disparity in access to care and outcomes between high-income countries and low- and middle-income countries is staggering. The reasons for this disparity include cost, access to care, manpower and training deficits, and a lack of awareness in the lay and medical communities. Diagnosis and treatment play an important role in this complex environment. In different regions and countries of the world, a variety of health care systems are in place, but most of them are fragmented or poorly coordinated. The need to scale up cancer care in the low- and middle-income countries is urgent, and this article reviews many of the structural mechanisms of the problem, describes the current situation, and proposes ways for improvement. The organization of cancer services is also included in the analysis.

The international cancer expert corps: a unique approach for sustainable cancer care in low and lower-middle income countries.

The growing burden of non-communicable diseases including cancer in low- and lower-middle income countries (LMICs) and in geographic-access limited settings within resource-rich countries requires effective and sustainable solutions. The International Cancer Expert Corps (ICEC) is pioneering a novel global mentorship-partnership model to address workforce capability and capacity within cancer disparities regions built on the requirement for local investment in personnel and infrastructure. Radiation oncology will be a key component given its efficacy for cure even for the advanced stages of disease often encountered and for palliation. The goal for an ICEC Center within these health disparities settings is to develop and retain a high-quality sustainable workforce who can provide the best possible cancer care, conduct research, and become a regional center of excellence. The ICEC Center can also serve as a focal point for economic, social, and healthcare system improvement. ICEC is establishing teams of Experts with expertise to mentor in the broad range of subjects required to establish and sustain cancer care programs. The Hubs are cancer centers or other groups and professional societies in resource-rich settings that will comprise the global infrastructure coordinated by ICEC Central. A transformational tenet of ICEC is that altruistic, human-service activity should be an integral part of a healthcare career. To achieve a critical mass of mentors ICEC is working with three groups: academia, private practice, and senior mentors/retirees. While in-kind support will be important, ICEC seeks support for the career time dedicated to this activity through grants, government support, industry, and philanthropy. Providing care for people with cancer in LMICs has been a recalcitrant problem. The alarming increase in the global burden of cancer in LMICs underscores the urgency and makes this an opportune time fornovel and sustainable solutions to transform cancer care globally.

Cancer in adolescents and young adults in countries with limited resources.

Cancer in adolescents and young adults (AYA) represents a higher fraction of all cancer in countries that are still undergoing a demographic transition. Such countries tend to have much younger populations, and therefore unless they have a particularly low incidence of cancer in this age group, will have a higher burden of cancer (absolute number of cases with cancer) in AYA. Cancers in AYA are comprised of the tail end of the incidence curve of cancers that have their peak incidence, or occur almost exclusively in childhood, the beginning of the incidence curve of cancers that primarily affect the elderly, and a third set of cancers that have their peak incidence (or are at least common) in the AYA age group (e.g., testicular cancer, sarcomas, melanoma, thyroid cancer). Many, but not all, of these cancers require radiation or cancer surgery, but the poorest countries do not have a sufficient number of radiation therapy units and surgical oncologists, or indeed medical and pediatric oncologists, to deal with the burden of cancer they face. The AYA age group is particularly important, both with regard to their contribution to the economy now and in the future (the majority are in the "working" age-group defined as 15-64 years), as well as their important role in caring for their families. Moreover, some of these cancers are eminently curable with chemotherapy alone, and more could be cured by simply improving the efficiency of existing health services and providing education and training to both the public as well as oncologists and other specialists required for the care of AYA (although such individuals will not necessarily be exclusively concerned with this age group). Of particular importance is the detection and diagnosis of cancer patients at the earliest possible time in the course of their disease. Avoiding delays in initiating therapy, which are partly due to the poverty and lack of education of the public as well as to a failure on the part of primary health care providers to recognize the possibility of cancer, would lead not only to improved survival and less toxicity, but is likely to reduce the need for radiation as well as the cost of treatment. There are few good quality clinical trials that take place in the LMIC (in relationship to the extent of the existing cancer burden), and research training should be an integral component of capacity building. Research on the efficacy and toxicity of standardized treatment approaches that are either based on principles established in the HIC, or adapted from treatment protocols used in the HIC, would be a good place to begin, but health policy and multisectoral collaboration are essential if improved survival rates are to be achieved. Decisions will also need to be made regarding the treatment of diseases in which radiation or cancer surgery are important elements, when one or both of the latter are unavailable. Late effects are important in this young population in HIC, and protocol adaptations or design in LMIC should take into consideration the significant fraction of cured patients with late effects who were treated in HIC in an era where improving response and survival rates was the paramount consideration-the situation that applies today in less developed countries. Special adolescent units which better deal with psychological issues of young cancer patients are rare in LMIC and the psychosocial issues faced by adolescents are much less studied. Although survival is the first consideration, attention to psychosocial and financial issues may reduce existing delays in initiating therapy and also the fraction of patients that abandon therapy.

Paediatric cancer in low-income and middle-income countries.

Patterns of cancer incidence across the world have undergone substantial changes as a result of industrialisation and economic development. However, the economies of most countries remain at an early or intermediate stage of development-these stages are characterised by poverty, too few health-care providers, weak health systems, and poor access to education, modern technology, and health care because of scattered rural populations. Low-income and middle-income countries also have younger populations and therefore a larger proportion of children with cancer than high-income countries. Most of these children die from the disease. Chronic infections, which remain the most common causes of disease-related death in all except high-income countries, can also be major risk factors for childhood cancer in poorer regions. We discuss childhood cancer in relation to global development and propose strategies that could result in improved survival. Education of the public, more and better-trained health professionals, strengthened cancer services, locally relevant research, regional hospital networks, international collaboration, and health insurance are all essential components of an enhanced model of care.

New policies to address the global burden of childhood cancers.

Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers.

Treatment of Burkitt lymphoma in equatorial Africa using a simple three-drug combination followed by a salvage regimen for patients with persistent or recurrent disease.

Prior to the introduction of the International Network for Cancer Treatment and Research (INCTR) protocol INCTR 03-06, survival of patients with Burkitt lymphoma at four tertiary care centres in equatorial Africa was probably no more than 10-20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non-cross resistant second-line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first-line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid (CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first- and second-line therapy, but verification will require a further clinical study.

Towards curative therapy in burkitt lymphoma: the role of early african studies in demonstrating the value of combination therapy and CNS prophylaxis.

This paper describes the treatment of Burkitt lymphoma (BL) from the time of its discovery in Africa up to the present. Pioneer investigators explored the value of chemotherapy since surgery and radiation were not effective modalities. Complete response was observed with many drugs used as single agents, but Ziegler and colleagues showed that patients resistant to one drug could achieve cure and potentially long-term survival with other drugs. Subsequently, a combination of cyclophosphamide (CTX), vincristine (VCR), and methotrexate (MTX) was shown to be active, but a survival advantage compared to CTX alone could not be demonstrated because effective CNS prophylactic therapy, in the form of intrathecal therapy, was not given. A recent re-evaluation of this regimen in Africa with multiple doses of intrathecal therapy compares favourably with recent studies of single agent CTX, and other drugs have been shown to be non-cross resistant. Optimal results for patients with extensive disease probably require 5 or 6 effective drugs along with intrathecal therapy, using MTX and Ara-C. In Africa, doses must be lower, because of limitations in supportive care, but in technically advanced countries cure rates in excess of 90% can be obtained. Rituximab may improve the results in some patient groups and allow less intensive therapy without a reduction in survival in others.

Epidemiology: clues to the pathogenesis of Burkitt lymphoma.

The two major epidemiological clues to the pathogenesis of Burkitt lymphoma (BL) are the geographical association with malaria--BL incidence relates to the malaria transmission rate--and early infection by Epstein-Barr virus (EBV). Both agents cause B cell hyperplasia, which is almost certainly an essential component of lymphomagenesis in BL. The critical event in lymphomagenesis is the creation of a MYC translocation, bringing the MYC gene into juxtaposition with immunoglobulin genes and causing its ectopic expression, thereby driving the proliferation of BL cells. It is highly likely that such translocations are mediated by the activation-induced cytidine deaminase (AID) gene, which is responsible for hypervariable region mutations as well as class switching. Stimulation of the Toll-like receptor 9 by malaria-associated agonists induces AID, providing a mechanism whereby malaria could directly influence BL pathogenesis. EBV-containing cells must reach the memory cell compartment in order to survive throughout the life of the individual, which probably requires traversal of the germinal centre. Normally, cells that do not produce high affinity antibodies do not survive this passage, and are induced to undergo apoptosis. EBV, however, prevents this, and in doing so may also enhance the likelihood of survival of rare translocation-containing cells.

Diagnosis of Burkitt lymphoma using an algorithmic approach--applicable in both resource-poor and resource-rich countries.

Distinguishing Burkitt lymphoma (BL) from B cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL (DLBCL/BL), and DLBCL is challenging. We propose an immunohistochemistry and fluorescent in situ hybridization (FISH) based scoring system that is employed in three phases - Phase 1 (morphology with CD10 and BCL2 immunostains), Phase 2 (CD38, CD44 and Ki-67 immunostains) and Phase 3 (FISH on paraffin sections for MYC, BCL2, BCL6 and immunoglobulin family genes). The system was evaluated on 252 aggressive B-cell lymphomas from Europe and from sub-Saharan Africa. Using the algorithm, we determined a specific diagnosis of BL or not-BL in 82%, 92% and 95% cases at Phases 1, 2 and 3, respectively. In 3·4% cases, the algorithm was not completely applicable due to technical reasons. Overall, this approach led to a specific diagnosis of BL in 122 cases and to a specific diagnosis of either DLBCL or DLBCL/BL in 94% of cases that were not diagnosed as BL. We also evaluated the scoring system on 27 cases of BL confirmed on gene expression/microRNA expression profiling. Phase 1 of our scoring system led to a diagnosis of BL in 100% of these cases.

Lymphomas in sub-Saharan Africa--what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research?

Approximately 30 000 cases of non-Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub-Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub-Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub-Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B-cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T-cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub-Saharan Africa for fostering high-quality translational research.

Epidemiology and management of lymphoma in low-income countries.

Our current knowledge of the epidemiology and treatment outcome of lymphoma in low-income countries is very limited. In the poorest countries only a small proportion of patients have access to treatment while clinical research is almost non-existent. In order to address these problems and discuss potential solutions a Workshop on 'Epidemiology and Management of Lymphoma in Developing Countries: Challenges and Opportunities for International Collaborations' was held during the 10th International Conference on Malignant lymphoma in Lugano, Switzerland in June 2008 under the sponsorship of UICC, ESMO and ESO. We report here a summary of the discussed issues with some reflections on this workshop.

Pattern of relapse in childhood ALL: challenges and lessons from a uniform treatment protocol.

This retrospective analysis of 254 children less than 15 years of age treated with MCP-841 protocol from June 1992 to June 2002 was undertaken to identify the pattern of relapse and determine management lacunae. Two hundred twenty-three (87.8%) children achieved a complete remission of whom 40 (17.9%) relapsed. The mean age of relapsed patients was 6.5 years. The male/female ratio was 9:1. There were 23 (57.5%) isolated bone marrow (BM), 7 (17.5%) isolated central nervous system (CNS), 2 (5%) isolated testicular, 5 (12.5%) BM+testes and 1 each of BM+CNS, CNS+testes, and isolated bone relapses. Twenty-seven children (67.5%) relapsed on-therapy whereas 13 (32.5%) relapsed posttherapy. All 9 CNS relapses occurred on-therapy whereas 5/8 (62.5%) of testicular relapses occurred posttherapy. Lymphadenopathy was the only significant predictor for relapse. High-risk features such as age less than 1 year and greater than 10 years (P=0.047) and white cell count greater than 50.0 x 10(9)/L (P=0.044) were significantly more frequent in patients with early on-therapy relapse than in patients with off-therapy relapse. The overall survival in the entire study cohort was 67+/-3.5%. Modest survival outcome, relapse while on chemotherapy and the higher incidence of CNS and testicular relapse indicate the need for reappraisal of our treatment protocol. There is a need of identifying risk factors and high-risk groups in our set of patients and risk-stratified intensification of chemotherapy in them.

Organization of population-based cancer control programs: Europe and the world.

As cancer is to a large extent avoidable and treatable, a cancer control program should be able to reduce mortality and morbidity and improve the quality of life of cancer patients and their families. However, the extent to which the goals of a cancer control program can be achieved will depend on the resource constraints a country faces. Such population-based cancer control plans should prioritize effective interventions and programs that are beneficial to the largest part of the population, and should include activities devoted to prevention, screening and early detection, treatment, palliation and end-of-life care, and rehabilitation. In order to develop a successful cancer control program, leadership and the relevant stakeholders, including patient organizations, need to be identified early on in the process so that all partners can take ownership and responsibility for the program. Various tools have been developed to aid them in the planning and implementation process. However, countries developing a national cancer control program would benefit from a discussion of different models for planning and delivery of population-based cancer control in settings with differing levels of resource commitment, in order to determine how best to proceed given their current level of commitment, political engagement and resources. As the priority assigned to different components of cancer control will differ depending on available resources and the burden and pattern of cancer, it is important to consider the relative roles of prevention, early detection, diagnosis, treatment, rehabilitation and palliative care in a cancer control program, as well as how to align available resources to meet prioritized needs. Experiences from countries with differing levels of resources are presented and serve to illustrate the difficulties in developing and implementing cancer control programs, as well as the innovative strategies that are being used to maximize available resources and enhance the quality of care provided to cancer patients around the world.