Progress in Oncology
In 1943, Nathanson2 reviewed published rates about the curability and survival from cancer. He stated that:
“There is still a conviction among the laity and some of the medical profession that cancer cannot be cured or controlled. The pessimism exists in spite of extensive and convincing evidence to the contrary. It is a well-accepted fact that present-day treatment is effective in the early stages of the disease, before it has spread to distant organs or tissues that are essential to life. Moreover, the prognosis is far from hopeless even in more advanced cases. Unfortunately, however, a large proportion of the patients reporting for treatment are still in far-advanced stages.”
He continued that:
“…..powerful weapons are available that, if used judiciously and intelligently, will do much to control the disease. Naturally, all look forward to the discovery of an agent that will have a specific action or will enable the body to overwhelm the cancer cell, but even if such an agent is found, it is apparent that it cannot be expected to cure all the cases.”
Much of what he wrote is applicable today: cancer frequently considered a death sentence by the general population, despair at late presentation of disease, optimism of the oncological community and hope for the development of future therapies.
Table 1 contains the estimates of cancer curability from around the early 1940s. By modern standards, these curability rates make bleak and distressing reading. The dramatic improvement in prognosis seen for breast cancer and prostate cancer from the low curability rates [prostate cancer (8%) and breast cancer (22-28%)] owe much to earlier detention and improved therapies. Similarly for cancers of the colon and rectum. Testis cancer curability has improved dramatically due to the development of successful therapy. It is comforting that the situation is much improved today and highlights the progress which has been made.
Throughout the second half of the 20th Century until modern times, there has been a remarkable improvement in many aspects of Oncology from understanding the causes, both lifestyle and biological, and enormous progress in developing more effective treatments for many forms of cancer1. However, these improvements have not been available for all patients with cancer.
There are enormous differences in life expectancy between rich and poor countries, only part of which can be explained. There are many factors which influence this situation including economic factors, healthcare availability factors, poverty and lifestyle, although the individual contribution of each remains unquantified and unknown. Improving life expectancy, and particularly healthy life expectancy remains the number one priority of Public Health worldwide, particularly in those poorer communities where life expectancy is currently low. How best to do this is also a major unknown although it is clear that there are many potential ways to contribute to improving this situation.
It has been estimated that 54.5 million people die each year3. Deaths from cancer represent around one seventh of all deaths although there will be more people who will have died with cancer although it was not the direct cause of death. Mortality data provide important information but are restricted to giving insight into the absolute lack of health in a small proportion of any population. Cancer incidence data have the substantial advantage of providing a clearer picture of the cancer problem and have a key role to play in service planning and related activities. It is also clear, at least in qualitative terms, that the cancers which are common in certain parts of the world are not so common in others. It is essential to have estimates of the burden of cancer and its different types in different parts of the world.
Boyle and Levin4 estimated that for the year 2008, there were 12.4 million incident cases of cancer, 7.6 million deaths from cancer and 28 million persons alive with cancer within five years from initial diagnosis. IARC also estimated that just over half of incident cases and two thirds of cancer deaths arise in low- and medium-income countries. In 2013, the world population was estimated to be 7.2 billion and expected to rise to 8.3 billion by 20305. During this period the populations of high-income countries are expected to increase by 4% while the increase would be approximately 30% in low- and medium-income countries. Additionally, the proportion of the population in low- and medium-income countries aged over 65 is expected to increase by between 5% and 10%. In view of the strong association between cancer rates and age, these will combine to increase the cancer burden by 2030, with low- and medium-income countries most affected.
There are three clear scenarios under which the global cancer burden could increase over time. First of all, the increase in the world’s population anticipated from 6.1 billion in 2000 through 6.7 billion in 2008 to attain 8.3 billion by 2030 will lead to an increase in the cancer burden even if the age-specific rates remain constant. Secondly, given the very large increases in cancer risk with age, if the population size and the age-specific rates remain constant, then the burden will increase if the population ages. Figure 1 clearly shows that the world population will age considerably by 2030 as well as increasing significantly.
Ageing is a major issue for the future cancer burden. Ageing has proceeded more gradually in more developed countries than in less developed countries, affording these nations time to adjust to this structural change. Japan is the major exception, doubling its percentage of population age 65 or older in just 26 years. Other countries in East and Southeast Asia (especially China, South Korea, Taiwan and Thailand) are on a similarly rapid trajectory, fuelled by dramatic and relatively recent drops in fertility. It took 115 years for the proportion of France aged 65 and over to double from 7% (1865) to 14% (1980). In Singapore it will take an estimated 19 years for the proportion of the population to double from 7% (2000) to 14% (2019)
In China, due to vast improvements in health over the past five decades, life expectancy at birth has increased by two thirds, from 40.8 to 71.5 years, between 1955 and 2005. The percent of elderly (over 65) in China is projected to triple from 8 percent to 24 percent between 2006 and 2050. Because chronic health problems become more common in old age, China’s population aging has led to increases in the country’s prevalence of chronic disease and disability6, 7.
The third element that can lead to an increase in the cancer burden, even when the population size remains constant and the age distribution remains unchanged, is an underlying increase in the incidence rates. Tobacco smoking prevalence is generally declining in high-income countries where it is estimated 32% of the male population 15 years of age or older. There is some variability with rates as low as 22% in Australia and Brazil and 25% in Canada8. The prevalence in men over 15 years is estimated to be 37% in upper-middle income countries and 39% in lower-middle income countries. In low-income countries the prevalence is 30% which represents a steep rise over the past decades. In terms of WHO regions, the smoking prevalence in men aged 15 and over is 51% in the Western Pacific Region (includes China) and 17% in African region. Given the gap of around 40 years from the big change in smoking habits until the big change in related disease is witnessed, there is every reason to believe that the risk of cancer in lower resource countries is rising and will continue to rise.
The growth and ageing of the world’s population and the continual increase in the underlying incidence rates in low- and middle-income countries will contribute to increases in the global cancer burden. The global cancer burden under a range of scenarios of percentage increases is presented in Table 2. It is clear that population growth and ageing contribute much more to the future cancer burden than an underlying increase in the incidence rates. Under the zero increase in cancer incidence scenario, the global burden will increase from 10.9 million in 2002 to nearly 20 million in 2030. Similar figures and conclusions are available for mortality data (Table 3).
By extrapolation of these data, taking into account demographic changes and factoring in a yearly increase in cancer incidence of 1%, it could be expected that by 2030 there will be approximately 26.4 million incident cases of cancer and 17.0 million cancer deaths a year (Table 2). The extrapolations made are likely to be produce conservative estimates of the cancer burden when the 1% annual increase in incidence rates is assumed.
Situation in Low-income and Lower-middle-income Countries
Evidently, the greatest effect of this increase will fall on low-resource and medium-resource countries where, in 2001, almost half of the disease burden was already from non-communicable disease9. Low-resource and medium-resource countries are, arguably, harder hit by cancer than the high-resource countries. The effects will be considerable in terms of the treatment needs and the costs of treatment especially in low- and medium-resource countries still faced with the burden of infectious disease and a low budget for health.
In lower-resource settings, cancer treatment facilities are not universally available, and life-extending treatment is often unavailable, generally for economic reasons. The increasing burden of cancer, and other chronic diseases could thus cause devastating damage to entire families in several circumstances including when the head of household and the only source of income for a frequently extended family succumbs to cancer, or when death of the mother results in girls stopping their education to look after the household.
Low-resource and medium-resource countries are, arguably, harder hit by cancer than the high-resource countries10. Low-income countries are those with annual gross national income per capita of less than $765. Such countries often have a limited health budget and a high background level of communicable disease. Cancer treatment facilities are not universally available, and life-extending therapies are often unavailable generally for economic reasons. Cancer and other chronic diseases, which are becoming more common, can cause devastating damage.
Middle-resource countries are those with an annual gross national income per capita of less than $9,300. Such countries risk being somewhat overlooked as high-income countries increasingly focus on (expensive) new technologies and drugs to treat cancer, and many seek to help provide basic diagnostic and treatment facilities in low-income countries.
Many middle-income countries have diagnostic and treatment structures in place but face severe economic pressure to upgrade equipment and to pay for the new drugs used to treat cancer. Many hospitals need to be upgraded to high-income country standards and there is a need to accelerate training and to increase in the complement of specialised oncologists, radiotherapists, oncology nurses and all other medical, paramedical and technical personnel necessary.
Radiotherapy is an essential component of the treatment of cancer, and whether used for cure or palliation, radiotherapy has been shown to be cost effective. In high-income countries, over half of new cases receive one course of radiotherapy and up to one quarter of cancer patients may receive a second course. In low and middle-income countries the need for radiotherapy is much greater due to late-stage presentations and the types of cancer that predominate. Breast and cervical cancers, the two leading female cancers globally, are highly treatable when detected early, and radiotherapy plays a major role in treatment protocols. Cervical cancer is the commonest form of cancer in women in Africa, and radiotherapy is an undeniable necessity. Simultaneously, it is essential to alter the 70%:30% balance of palliation over cure that exists at present11.
Most low- and middle-income countries have limited access to radiotherapy, although over 30 African and Asian countries have no services at all. In Africa the actual supply of radiotherapy is 20% of needs, while in the Asia-Pacific Region, with over 3 million new cases of cancer each year and the need for 4000 radiotherapy machines, only 1200 or so machines exist12. Total global shortages in low and middle income countries are over 7000 radiotherapy machines, and it is clear that accessible, affordable, and suitable radiotherapy technologies are needed.
The continuing improvements in cancer prevention, early detection and treatment are still overshadowed by premature mortality as a result of cancer. In resource-rich countries, two out of every five people diagnosed with cancer will die prematurely. This can rise to nine out of ten people in resource-poor countries where late presentations and limited resources deliver poor survival rates and, frequently, deaths in atrocious circumstances.
There are wide variations in the availability and quality of supportive and palliative care around the world and within countries13,14. Such disparities are seen in resource-poor countries as well as many resource-rich countries15. For many countries across the world there is no evidence of any formalised supportive or palliative care16.
Beyond the clinical services, availability of basic medications for symptom control remains an enormous challenge. For many countries, the availability of opioids is limited or absent17-20. In much of Africa, central Asia and South America pain control is using only step one of the World Health Organisation analgesic ladder21. In the period 2000-2002, 29 countries in Africa reported NO opioid availability and for the 18 countries reporting use, there was a 100 fold difference in the average defined daily dose of morphine22. In central and eastern Europe (1994-98), five countries reported NO opioid availability. For the other 23 countries, there was a greater than 500-fold difference in the average population defined daily dose of morphine23.
Despite the lack of financial and human resources, there are several shining examples of outstanding developments in lower-income countries. It does not need to be all gloom-and-doom. There are outstanding Cancer centres in India, China and other countries in Asia. The Shaukat Khanum Memorial Cancer Hospital and Research Centre in Lahore, Pakistan was built and is funded by Imram Khan in memory of his mother24. The AMPATH Oncology programme in Eldoret (Kenya)25 is a fine example of what can be achieved by a sustainable academic link with United States Universities. The work of Hospice Africa Uganda26 in providing palliative, supporting and terminal care is admirable. There are other outstanding examples.
Variation in Cancer Outcome
Cancer outcomes vary enormously across the world, frequently for reasons which are unable to be explained (Table 4). Work conducted in Europe reveals that there is little variation in population-based survival on a stage-by-stage basis. However, there is remarkably little variation in health care levels and access across Europe particularly when compared to middle and lower income countries. In addition, and importantly, there is relatively little variation in cancer outcomes across Europe.
In gross terms, 80% of cancers in low-income countries presents at a stage when cure is impossible and palliation is the only possible treatment available. The Economist Intelligence Unit (2009) has provided some estimates of the variation in outcomes across different resource settings (Table 4). The case fatality rates (the ratio of the number of new cases to the number of deaths for a particular form of cancer in a defined period) for all types of cancer form a gradient across the four large groupings identified by the World Bank (high-income, upper middle-income, lower middle-income, low-income). For breast cancer, in high-income countries the case fatality rate is 23.9 but there is a strong gradient to the low-income group where the case fatality rate is 56.3. Even for an eminently curable cancer such as testicular cancer, the case fatality rate varies from 5.1 in high-income countries to 41.4 in low-income countries.
Measuring the phenomenon of variations in cancer outcomes is not straightforward particularly in low-income and lower middle-income countries where medically certified schemes of recording causes of death do not exist. Neither the number of new cases of cancer nor the number of deaths caused by cancer is available from many parts of the world — in 2000, less than 20% of the world’s population was covered by Cancer Registration and 35% by vital statistics schemes based on medically-certified cause of death. Furthermore, this coverage was not spread equally over the globe: in Africa less than 13% of the population was covered by such schemes; in Asia about 9% was covered; by contrast, 95% of the population of Latin America was covered. The corresponding figures for cancer incidence statistics was 8% for Africa, 7% for Asia and 13% in Latin America4 These regions share a common factor in having a large portion of low-income and lower middle-income countries.
Calculation of population-based cancer survival is not a valid way to examine variations between regions nor, especially, temporal trends in survival over periods of time. Changes in survival correlate with changes in incidence and have no association with changes in cancer death rates27.
It is essential to have good quality quantitative data to investigate cancer outcomes in different regions of the world and to investigate the underlying reasons for such variation. It is also essential to have these data as well as complementary data regarding the availability of resources within national health care systems to identify the key parameters which influence cancer outcomes. These are vital and urgently needed data to help determine what are the key parameters which need to be put in place to provide the elements of a Health Care System to cope with the rapid increases which will take place in cancer burden especially in lower resource settings.
Luengo-Fernandez and colleagues28 provide important economic information regarding the economic coats of cancer in the European Union. Over three million people are diagnosed annually with cancer in the 27 countries of the European Union, and 1.75 million people die of it each year. Cancer costs the European Union €126 billion annually, with healthcare accounting for €51 billion (40%). Averaged across the European Union population, cancer represented an annual healthcare cost of €102 per EU citizen, with costs varying ten-fold between the lowest spender, Lithuania (€18 per person) and Luxembourg, the highest spender (€184). Productivity losses and informal care represented 41% and 18% of cancer costs, respectively. By cancer type, lung cancer accounted for 15% (€19 million) of overall cancer costs, followed by breast cancer (12%, €15 billion), colorectal cancer (10%, €13 billion) and prostate cancer (7%, €8 billion).
It is essential to develop a deeper knowledge of cancer and other chronic diseases worldwide but especially in lower-resource regions of the world. The knowledge required should:
- Aid understanding of key elements needed in an optimal health care system for treating cancer in lower income countries;
- Advance understanding of the reasons underlying variation in outcome within and between countries including those which are not related to treatment;
- Examine the variations in mutation profiles in different populations within and between countries on cancer course and impact on outcome;
- Understand at a practical level the clinical relevance of known and novel molecular markers whose introduction in clinical practice should improve diagnosis and outcome to a broadly-based community;
- Create a resource capable of testing new cancer biomarkers and targets.
The studies required to achieve these goals should be crafted such that they are not merely academic research studies but have a number of key policy objectives which could be achieved. Such studies should:
- Allow the development of a new paradigm of cancer management consistent with 21st Century demands;
- Aim to gain better understanding of cancers benchmarked internationally which will further improve clinical outcomes;
- Develop a understanding of the molecular map of cancer across social economic and geographic boundaries will transform the dynamics of the cancer system.
Conclusions and Summary
In July 2013, the world population will reach an estimated 7.2 billion, 648 million more than in 2005 or an average gain of 81 million persons annually. Even assuming that fertility levels will continue to decline, the world population is still expected to reach 9.6 billion in 2050 and 10.9 billion in 2100, according to the medium-variant projection8. The population is not only growing but is also ageing rapidly. Over one billion people do not have access to clean drinking water and two billion do not have access to sanitation. One billion people are under-nourished and one billion people are hungry today. There is a population movement from the countryside to cities and one third of city dwellers currently live in a slum. In the race to find ways to feed and supply clean water and sanitation to the rapidly growing population, Climate Change will present a major challenge.
Cancer is only part of the growing burden of disease which is taking place worldwide and is set to continue to do so for as long into the future that projections can be made with some degree of confidence. The global cancer burden is set to grow and the dominant contributions for the next fifty years will be from India, China and Nigeria. The United Nations also estimates that the current global population of 7.2 billion will reach 9.6 billion by 2050 and that India and China will both have a similar population by 20288 and at that point, both nations will number 1.45 billion people each. Subsequently India’s population will continue to grow until the middle of the century, while China’s slowly declines. Best estimates are that by 2050, the population of Nigeria will have overtaken that of the United States (Figure 3). The combined population of India, China and Nigeria will be 3.4 billion, approximately one-third of the global population in 2050.
With this population growth, it is also expected that the population of these three countries will experience an increase in life-expectancy and a growth in the numbers of the elderly in the population. Consequently, there will be dramatic increases in the cancer burden in India, China and Nigeria and these demographic increases, coupled with increases in cancer risk through the increasing population acquisition of western lifestyle habits, will drive the numbers of cases of cancer diagnosed in these countries. Increases in these countries, plus the large increases also expected in countries such as Indonesia, Pakistan, Bangladesh and Vietnam where rapid change is also taking place, will be the driving force of the changes expected in the global burden of cancer as well as other chronic diseases.
The benefits of reducing cancer incidence and death, as well as that from other chronic disease, is not only for the Health and life expectancy of the population but it also has economic consequences. The so-called Next 11 countries, have been identified as those economies which will drive the global economy in the second half of this century. This grouping comprises Bangladesh, Egypt, Indonesia, Iran, Korea, Mexico, Nigeria, Pakistan, Philippines, Turkey and Vietnam. It is clear in Figure 4, that there is a strong correlation between the evolution of increased wealth (GDP per capita) and life expectancy in those countries.
There is an urgent need for action. The current model is broken and will have no impact on limiting in any way the growth in the numbers of new cases of cancer nor the deaths which shall be caused. There is a simple menu which should be a charter of the rights of every population worldwide, and adapted according to their needs and means.
First of all, steps must be taken to prevent those cancers with have been determined to be preventable. The silo mentality of Cancer Prevention, Diabetes Prevention and Cardiovascular Disease prevention is an old and failed model. These common chronic diseases, and others such as osteoporosis, have many lifestyle habits in common and the model should be changed to consider their prevention as a single, unified action. This, of course, will be of major benefit in lower-resource regions where qualified staff are limited at present. All efforts from Governments and authorities should be taken to limit or avoid consumption of tobacco in any form and to avoid excess consumption of alcohol. Populations should be encouraged to avoid weight gain, overweight and obesity and to increase their physical activity levels. Specifically for cancer prevention, steps should be taken to avoid sunbeds and sunlight (in populations where this is necessary advice) and to eliminate occupational exposure to carcinogens. Participation in organised screening programmes and relevant vaccination programmes (e.g. against Hepatitis B and HPV) would also be beneficial.
Secondly, treatment resources should be available everywhere to diagnose and treat all cancers which develop. The stigma of cancer which exists still in many countries needs to be eliminated in order that more patients seek medical attention and increasingly at a stage where treatment is possible. Diagnosis and treatment extends to include appropriate imaging equipment, radiotherapy equipment, surgery, laboratory and pathology services as well as the necessary cancer drugs. Today the great majority of cancers have some positive degree of response to appropriate treatment. When looked at in a historical context, recent progress has been remarkable in developing effective therapies which frequently prolong life and substantially improve the quality of the remaining life. This comes from a variety of factors including the rapid increase in knowledge of what constitutes malignant disease and the biological processes which cancer involves. Cancer treatments have improved substantially. Surgery is less mutilating; Radiotherapy is more effective; Chemotherapy is also more effective; Nutrition of patients is improving. However, many patients around the world do not have access to these modern therapy regimes for a variety of reasons which encourage this disparity. Every cancer patient, no matter the situation, has a right to the best cancer treatments for their condition.
Thirdly, it is vital to have the resources in place to provide curative therapy for those cancers which are curable. There are many cancer patients now living longer and longer even with advanced stage disease and who maintain a good quality of life. Previously defining cure to be five-year survival is not appropriate today when life expectancy has increased substantially in many countries. Cure means much more than five-year survival and should be taken to mean that a treated patient has a life expectancy similar to the population of the same age. While there are some outstanding examples of cures, curative therapies have proven elusive for many common forms of cancer. Recent developments in understanding of cancer’s biological mechanisms have started to produce drugs targeted at specific biological or genetic features of certain cancers with some highly encouraging success. This provides substantial hope for the near future. However, there are many hurdles which will limit the introduction of such therapies into all but the highest resource settings: in many settings there is a lack of the number of good laboratories and trained staff capable of performing the companion diagnostic assay, lack of biobanks to better understand the mutational profiles of populations and major financial issues to overcome. This is a major challenge for Governments in lower-income countries and one which will be of increasing importance if the results of personalised medicine come about as anticipated. If these curative therapies do not become available in lower-income regions at the same time as in higher-income regions, then the gap between rich and poor will widen even further.
Fourthly, the provision of palliative, supportive and terminal care is an essential which is missing in many of the poorer regions of the world. There have been major improvements in all aspects of Palliative, Supportive and Terminal care in the past decades although it has been surprisingly slow to be rolled out in every high-resource country. It is also disquieting that the little that is known about the quality-of-life of cancer patients comes from a remarkably small number of randomised trials. Palliation is needed not only for pain control in the final moments of life, but should be available at every part of the cancer pathway: at the time of surgery, radiotherapy and during chemotherapy. In Africa the situation is frankly appalling and there are very few trained in palliative care. There are around 30 countries without a single radiotherapy machine (which is useful for pain control) and the same number of countries where the importation of opioid medication is forbidden. Where opioids are available, the dose used can vary by several hundred-fold. Paracetomol is not an effective medication for the control of severe cancer pain, but that is all that is available in too many countries. This will require strong action coupled with significant training programmes. There are many countries which have neither a Radiotherapy machine nor morphine available for pain control. This situation needs urgent remedying. This is not only a problem for cancer patients but is frequently necessary for patients dying from other conditions such as AIDS.
Populations and cancer patients have certain rights in modern society. These can be achieved by implementing and adhering to the Four Pillars of Oncology (Table 5). Progress has been made in each of these Pillars although, tragically, disparities exist at many levels of society and not every cancer patient has access to these modern advances. While progress in Oncology has been remarkable in the recent decades, and the future looks very encouraging, not every cancer patient is benefitting from the advances made in treating their disease. This is true even in the high-resource countries where there are substantial differences in outcome according to the individual’s deprivation status. The contrast in diagnosis, treatment and its outcome between the high-resource and low-resource countries is dramatic.
This is a particularly important issue since the pattern of cancer globally in the foreseeable future will be heavily dependent on what happens in China, India and Africa, where one half of the world’s population currently live and the populations of each are ageing quickly and have developed lifestyle habits conducive to increasing cancer risk. India has a long tradition in Cancer Care but faces the challenge of extending that care to their growing population. China faces similar challenges to India and has been making solid investment in training and infrastructure to cope with the huge problem the country is facing. Life expectancy has increased from 55 fifty years ago to reach 75 at the present time and with it has come a rapidly increasing burden of cancer and other chronic diseases linked to ageing. Africa presents the biggest challenge with population growth and life expectancy increasing in many countries as the toll of AIDS declines. However, there has been little investment in capacity of any sort to deal with the current cancer problem never mind the rapid increased in incidence which is underway. This is a critical area for investment and not only of a purely financial nature.
It is bad to have cancer and worse to have cancer if you are poor. The gap between rich and poor, highly educated and little educated and the North-South divide is substantial and continuing to grow. Radical solutions are urgently needed: the status quo is not an appropriate response to the current situation. Recognising that no single source of philanthropy has the means to solve this problem, new models are needed to cope with and improve this situation. It is impossible to avoid the conclusion that there is a need for a major Public-Private partnership, involving a number of sources from different areas, to make the necessary progress with the briefest delay. The partnership needs the commitment of the Pharmaceutical industry and the wide span of industries involved in the technology for diagnosis and treatment. It needs the commitment of Governments and Non-Governmental Organisations to be effective. Effective will be measured against the Right of every patient with cancer to have the most appropriate treatment and care for their disease.
Working to improve health must cease to be viewed as a competition. Public and Private organisations have an underlying suspicion of each other that must be overcome in the interests of improving cancer care and outcome worldwide. The situation as portrayed in the State of Oncology Report 20131 is dramatic and urgent and it behoves all parties to put this frequently deep-rooted suspicion behind them and develop an effective collaboration to improve this key aspect of Public Health throughout the world.