research priority

CARISA’s research prioritisation and resource allocation is determined by predominant cancers as pointed to by cancer registries and epidemiological data. Cancer is a global health problem. It presents itself as a highly complex, ubiquitous and devastating disease causing 10 million new diagnoses world wide per annum. The World Health Organisation (WHO) estimates that these will be 16 million new cases every year by 2020.

A report on Chronic Diseases of Lifestyle in South Africa: 1995 – 2005, indicates that cancer has been ranked as the 4th leading cause of death for all persons. Among persons older than 60 years, cancer ranked as the 2nd highest cause of death next to cardio vascular disease. Studies indicate that evidence-based and cost-effective interventions throughout the cancer continuum (prevention, early detection, treatment, palliative care) through a integrated research programme is the most effective way to tackle the cancer problem and reduce the suffering caused to patients and their families.

Strategic priorities
The CARISA Cancer Strategic Priorities, as identified by the CARISA Steering Committee and in alignment with the strategic workshop held on the 23rd of August 2006 are:

• Mechanisms of carcinogenesis
  This priority will focus on the basic mechanisms involved in cellular transformation. This will cover a wide variety of aspects from environmental to genetic factors and will also include anticancer activity in dietary components. There will be a strong focus on molecular mechanisms in order to understand the processes leading to cellular transformation and the prevention of these processes. Carcinogenesis can be induced by exposure to exogenous agents or it can occur spontaneously without external intervention by aberrant metabolism. Carcinogenesis can be actively induced by chemicals, radiation, agents, or genetic susceptibility. Carcinogenic agents act at one of three specific levels; initiation, promotion or progression. As some cells are fortuitously initiated by uncontrolled variables such as irradiation and through changes in normal processes, the stimulation of growth and altered genetic expression by nongenotoxic agents may result indirectly in cancer development. The final stage of carcinogenesis, progression, can occur spontaneously, enhanced by formation and propagation of genetic errors due to increased cellular proliferation associated with the promotion stage. In addition, chemical and viral agents that lack the capacity for initiation and promotion may actively convert cells in the stage of promotion to the stage of progression.
• Molecular epidemiology
  General epidemiology represents the process by which health problems are detected, investigated and analyzed. Without epidemiology, it would be impossible to design effective strategies to prevent the occurrence of disease among individuals or to improve public health on a population basis. The identification of risk factors is crucial in our understanding of disease processes such as cancer. Molecular epidemiology is one of the most exciting and important areas of research leading into the 21st century. It represents a critical link between the Human Genome Project and medicine / public health. Without well-designed population-based molecular-epidemiology studies, it will be impossible to interpret the risk of disease associated with the presence of newly identified susceptibility genes. As a result, molecular epidemiology is essential for the development of medical diagnostics, public health prevention strategies and discussions of the ethical, legal and social issues related to the Human Genome Project.
  
  Molecular epidemiology is based on general epidemiology and utilises the same designs (i.e., case control and cohort studies) as those employed by general epidemiology. However, molecular epidemiology utilises molecular biology to define the distribution of disease in a population (i.e., descriptive epidemiology) and identify its potential etiological determinants (i.e., analytical epidemiology). In contrast to general epidemiology, molecular epidemiology enhances our understanding of the pathogenesis of disease by identifying specific pathways, molecules and genes that influence the risk of developing disease. For example, genetic markers rather than surrogate information (i.e., positive family history) are employed to characterise host susceptibility.
  
  Given the international cancer trends and the South African mortality statistics, it follows that the prerequisite for early treatment is early detection. Detecting and diagnosing tumours early in the disease process, before the tumour invades surrounding tissue, can dramatically improve the patient’s odds for successful treatment and survival. Since cancer therapies are more effective for treatment of localised rather than metastatic disease, it is important to develop strategies for detection and treatment of early stage disease. This is particularly true for detection of pre-invasive or in-situ neoplastic lesions at a high risk of progression, as early treatment of such lesions has been shown to provide optimal outcomes as has been observed in the case of skin, breast, cervix, endometrium, testis, colon and rectum, and prostate. At present, the most important risk factor for invasive cervical cancer is the absence of Pap smear. In contrast, most lung, ovarian, oesophageal and pancreatic cancers are generally detected when invasive metastatic disease has already developed and is difficult to treat. Not surprisingly, five-year survival is extremely poor for these types of cancers. Evidence also suggests that 90% or more of colorectal cancer deaths could be prevented if precancerous polyps were detected with routine screening and removed at an early stage. Other factors critical for increased survival include; accurate staging of the disease; early prediction of incipient chemoresistence; and early detection and treatment of recurrent disease. Traditionally, cancer screening, as well as assessment of the extent or recurrence of disease, has been based on the morphologic assessment of relevant cells. While morphology-based screening and assessment of cancer is suitable for those cancers at easily accessible sites, morphologic evaluation of cells is impractical for many cancers such as lung, pancreas, and ovary; therefore, the development of cancer biomarkers is of great public health importance. Molecular biomarkers predicting high risk for cancer are also of interest, both to identify individuals who need close monitoring, and in some cases, for the treatment of high risk lesions. The impact of such markers on cancer prevention has been demonstrated in women who carry the BRCA ½ gene where prophylactic surgery has been shown to decrease development of cancers. Lastly, cancer biomarkers that predict the likelihood of progression to malignancy and patient susceptibility to specific therapies will play an increasingly central role in planning cancer therapy.
  
  An emphasis on improved and locally applicable diagnostic techniques focuses on recognition by patients and health workers on early signs and symptoms of cancer in an effort to reduce the rate of progression to advanced disease. Currently, a number of laboratory and imaging cancer diagnostic procedures are available, but the specificity and sensitivity of many of these tests are barely acceptable, and the diagnosis of cancer is usually made in combination with other parameters – biopsy being the most definitive. Most importantly, the diagnostic markers in many of these cancer tests may not have anything to do with cancer biology or etiology. The best and well known example is the prostate specific antigen (PSA) test for prostate cancer that measures PSA production (and hence its serum level) which is elevated in individuals with large prostate, enlarged prostate, or enlarging or inflamed prostate (by injury, infection, cancer, etc.). Although patients with prostate cancer usually have elevated PSA levels, a majority of people with abnormally high serum PSA levels do not have prostate cancer.
  
  Hence this theme is considered a core component with the CARISA Strategy and is focused on the development of better diagnostic tests for cancer. These include:
  • Development of tests for the identification of precancerous lesions for early treatment;
  • Improving the assessment of cancer prognosis by refining tumour classification and staging;
  • Predicting tumour progression and metastatic capacity;
  • Assessing the influence of gem line or somatic genetic mutations on disease prognosis;
  • Detecting recurrence or predicting response of the tumour to various treatments;
  • Improving existing in-vitro diagnostic technology to detect changes that indicate the remission, emergence or growth of tumours; and
  • Translational research from the laboratory to the clinic.
• Drug / vaccine development
  It stands to reason that the burden of cancer can be reduced by prevention and cure. Both approaches are valid and from a cost benefit perspective, prevention is more significant. While prevention, early detection and lifestyle changes are being implemented, many people will continue to contract cancer every year and there will be increased demand for the development of better medicines.
  
  South Africa is both a developing country and an emerging economy. In the case of basic therapeutic cancer research, South Africa has initiated a reasonably sophisticated platform for anti-cancer drug development ranging from organic synthesis using platinum and gold compounds, polymers and derivatives of existing chemotherapeutic agents, to indigenous medicinal plants and sea organisms. This is most probably the largest specific cancer research group in South Africa at present. The development of local vaccines, as described in the research priority for risk factors, is also to be promoted since South Africa, as a developing country, cannot afford the cost of vaccines that have been developed in the developed world.
  
  A drug discovery platform involving goal-directed research (e.g., searching for low toxicity and high efficacy molecules) and niche molecules are essential. This requires state of the art tissue culture facilities with a bank of different cancer cell lines and their “normal” counterparts for comparison purposes.
  
  Facilities required area state of the art microscopy, modern FACS equipment and animal facilities for the use of athymic nu/nu mouse breeding colony for testing anticancer drugs in vivo. Access to a cyclotron together with a PET/CT and micro PET/CT gamma cameras are essential to monitor drug distribution and drug effects in tumour bearing athymic nu/nu mice.
• Risk factors
  Prevention of cancer is the best way of controlling this disease. However, to implement prevention strategies, research has to be done to understand the disease and to determine what interventions would be successful. Primary cancer prevention strategies include the identification of risk factors and the reduction of exposure to carcinogenic substances, vaccination against cancer causing infectious agents and life style modification including exercise and diet. One third of cancers of the developing world could be prevented by targeting tobacco use, alcohol consumption, obesity ad inactivity (Mackay et al, 2006). Alcohol consumption is associated with increased risk of cancer of oral cavity, pharynx, larynx, oesophagus, liver and breast cancer. Fresh fruit and vegetables in the diet decrease the risk of oral cavity, oesophageal, gastric and colorectal cancer. Obesity increases the risk of oesophageal, colorectal, breast in post-menopausal women, endometrial and kidney cancer. The link between UV light and various types of skin cancer is well documented.
  
  It is estimated that infectious agents are responsible for 1.9 million cases of cancer – 18% of the cancers globally and 27% of cancers in the developing world. Vaccination against the responsible agents is the best way to control these cancers. There are good examples of successful vaccination strategies to prevent cancer. Once it was proven that the hepatitis B virus (HBV) was causally associated with hepatocellular carcinoma, a vaccine could be developed to prevent infection with HBV and the associated disease. In Taiwan, 15-20% of the population were carriers of HBV in the 1980s. Introduction of vaccination significantly reduced the incidence of hepatocellular carcinoma in children. When HBV vaccination was introduced, the transmission from highly infectious mothers to their infants was reduced from 86-96% to 12-14%. If universal vaccination continues, by 2010 the carrier rate will be reduced to under 0.1%. However, HBV is only one of the viruses responsible for increasing the risk of liver cancer. A vaccine against the other virus, hepatitis C, is yet to be established. Specific types of human papillomavirus are causally involved in cervical cancer. Recently the phase 3 trials of an HPV vaccine designed to prevent infection with HPV types 16, 18, 6 and 11 have been completed and this vaccine is now available. This vaccine could have significant impact on cervical cancer and is implemented into the countries that do not have adequate screening programmes – South Africa is one of those countries. An important infectious agent that has been found to play an important role in increasing the risk gastric cancers is Helicobacter pylori. People infected with HIV are more likely to get Kaposi’s sarcoma caused by Human herpesvirus 8.
  
  For the individual, there are emerging prevention strategies that target biomarkers of disease. These can be specific genes that increase susceptibility to disease or identification of proteins that allow early diagnosis of disease. An example of this is the BRCA1 genes that substantially increase the risk of breast cancer to 56-80% lifetime risk. Options for individual with this risk include prophylactic mastectomy. In South Africa, there has been success at identifying genetic markers of colorectal cancer to target family members at high risk of developing disease for regular screening. Chemoprevention of cancers is also a prevention strategy.
• Treatment and palliation
  Cancer treatment options could include surgery, chemotherapy, biotherapy, radiation therapy, and hormonal therapy, or a combination of any of these, depending on the type and stage of the cancer. With some tumours, surgical removal of all or as much tumour as possible is considered the best treatment depending on the size and location of the tumour and whether the cancer cells have spread to other parts of the body, referred to as metastasis. If there is evidence that tumour cells have spread or if some of the tumour could not be removed during surgery, then one or more of the other available therapies may be used.
  
  Surgery plays an important role in the diagnosis, staging and treatment of local tumours. Surgery can contribute through the removal of tumour masses, palliation and treatment of some complications. It requires the support of other specialities and its cost effectiveness varies according to the stage of the disease being treated and, in some patients, the availability of alternative treatments. Accurate staging is required to limit unnecessary surgery in patients and this requires reliable diagnostics equipment.
  
  Chemotherapy or the use of chemical agents to destroy cancer cells, is a mainstay in the treatment of malignancies. The goal of treatment with chemotherapy has evolved from relief of symptoms to cure. A major advantage of chemotherapy has evolved from relief of symptoms to cure. A major advantage of chemotherapy is its ability to treat widespread or metastatic cancer, whereas surgery and radiation therapies are limited to treating cancers that are confined to specific areas.
  
  Biotherapy helps the immune system to function better by using substances that occur naturally in your body. The therapy may stimulate your body to make more of the substance, or the therapy may be a man made version of that natural substance itself. Other types of therapies use cells from the patient’s body, which are then altered in a laboratory and given back to the patient. Alternative names for biologic therapies include biologic agents, biologicals, biological response modifiers (BRMs), or immunotherapy.
  
  Radiation therapy specifically acts against cells that are reproducing rapidly. Normal cells are programmed to stop reproducing (or dividing) when they come into contact with other cells. In the case of a tumour, this stop mechanism is missing, causing cells to continue to divide. Radiation therapy uses high energy x-rays to damage the DNA of cells, thereby killing the cancer cells, but because normal cells are growing more slowly, they are better able to repair this radiation damage than are cancer cells. In order to give normal cells time to heal and to reduce a patient’s side effects, radiation treatments are typically given in small daily doses, five days a week, over a six or seven week period.
  
  Hormonal therapy is most often used to treat breast and prostate cancer, where its role is well established through numerous clinical trials. Research is ongoing to study the potential efficacy of hormonal manipulation in treating other cancer types.
  
  Despite an overall 5-year survival rate of nearly 50% in developed countries, the majority of cancer patients will need palliative care sooner or later in developing countries. The proportion requiring palliative care is at least 80%. According to the WHO, worldwide, most cancers are diagnosed when already advanced and incurable. The incidence and mortality of cancer and other non-communicable diseases will increase in the next 20 years. The fundamental responsibility of the health profession is to ease the suffering of patients. This cannot be fulfilled unless palliative care has priority status in public health and disease control programmes – it is not an optional extra. In countries with limited resources, it is not logical to provide extremely expensive therapies that may benefit a few patients, while the majority of patients presenting with advanced disease and urgently in need of symptom control must suffer without relief.
• Social and public health research
  Cancer is associated with lifestyle and is seen as a disease affecting older populations. Health service delivery in the previous dispensation focussed on curative services, and as such, hospitals were developed and maintained for curing the sick. Health service provision for the poor was limited. Economic wellbeing of the affluent population also contributed to the health wellbeing as this group also had easier access to private health services and medical aids. The early detection methods for certain cancers are all associated with sophisticated technology that is expensive and is covered by medical aids. This could be associated with the higher number of people being diagnosed earlier with cancers such as breast, prostate and colon.
  
  As the political climate changed the access to private health services increased and the services within the state sector deteriorated. With the onset of the new democratic dispensation, the health focus for South Africa changed from curative to prevention, focussing on equality and equity of health services for all. The Health Department developed a National Cancer Control Programme (NCCP) in 1998. The main focus of this programme is cervical screening and has lead to the development of a cervical screening policy. This in itself has had a significant impact on the number of women being diagnosed with cervical cancer as there is a direct correlation between health awareness and screening for secondary prevention. Tobacco control, a primary prevention strategy, received also priority attention on the NCCP and lead to the Tobacco Control Act of 1993. To date, it is mainly the Department of Health on a national and provincial basis, as well as CANSA (Cancer Association of South Africa) a non-governmental organisation that focus mainly on creating cancer awareness.
  
  For any cancer control plan to be effective, it is key that social and public health research including cancer control, behaviour studies, community studies, the economic burden of cancer, cancer prevention, and cultural aspects of cancer pathogenesis, treatment and prevention are conducted. Health-seeking behaviour and methods of data collection are included in this category.
• Data management and surveillance
  Considering the limited resources and the cancer position on national priority setting, it is important to explore and develop an innovative strategy that will enhance cancer research through access to information in order to limit costs and / or devise a more cost-effective and time saving approach. Data management is a broad field that encompasses decisions of all interested parties on the type of data to be collected, data sources and collection systems, computer systems, surveillance systems, management and analysis. A consistent management strategy for cancer data in South Africa has not been established. The purpose of establishing a management strategy for cancer data is to identify ad hoc cancer databases (electronic and paper) and other epidemiological databases that exist throughout the country that are built for a multitude of purposes and explore how these could be collated and / or used efficiently to inform cancer control and enhance cancer control research.
  
  There is unanimous agreement among South African cancer researchers that cancer surveillance through cancer registries should be in the centre and inform all the components of a national cancer control programme that is , prevention, early diagnosis, treatment and palliative care. Data from cancer registries can be used in a wide variety of cancer control ranging from etiological and epidemiological research, through primary and secondary prevention to health care planning, patient care and monitoring, so benefiting both the individual and society. Cancer registries possess the potential for developing and supporting important research programmes using the information they collect. Following this belief, and as a starting point for cancer data management, the proposal is that a strategy to improve existing cancer surveillance systems and how these data could be used to enhance cancer control research in South Africa.

Medical Research Council of South Africa

Cancer Association of South Africa