Causing and Controlling Cancer

by Ian Magrath

Golden lads and girls all must, As chimney-sweepers, come to dust.
William Shakespeare, Cymbeline. iv, 2.

Cancer control is a term used to refer to all attempts to reduce death and suffering caused by cancer. It includes prevention (primary and secondary), early detection, specific treatment and palliative care (see Figure 1).

Cancer Control Figure 1

Effective cancer control can only be based on science, although it involves a constituency that extends well beyond the health practitioner since it includes a major public health component. Because cancer encompasses many diseases, each of which may be more or less amenable to prevention or treatment, notions such as “a cure for cancer” are oversimplifications and tend to distract attention from the even more attractive goal of preventing cancer. Many patients with cancer can be cured— 50% or more in the affluent countries are alive at five years—and it is theoretically possible to prevent at least 50% of cancers in these countries—particularly those caused by tobacco and dietary factors (estimated to be two-thirds of all cancers in affluent nations). Unfortunately, more than 60% of patients with cancer live in developing countries and have poor access to therapy, so that a much lower fraction receive appropriate treatment, while the populations of these same countries are poorly informed about cancer, inadequately protected against environmental risks, and have limited access to screening programs that could prevent some cancers.

For each cancer, the optimal approach to its control depends upon available knowledge of its causal factors, its natural history and its response to current therapy. The risk posed by cancer-causing environmental factors can be reduced by primary preventive measures such as lifestyle changes (e.g., not smoking) or actions that limit or avoid exposure (e.g., to toxic chemicals, sunlight, radioactivity or certain infectious diseases). Many of the preventable cancers (e.g. lung cancer) are often poorly responsive to treatment unless detected in a very early stage. Diseases in which the early stages, including pre-malignant lesions, can be readily detected and removed by simple surgical methods, (e.g. cervical intraepithelial neoplasia, a precursor of cervical cancer), may be well controlled by screening appropriate target populations and ensuring appropriate treatment. The success of prevention programs at a public health level is dependent, of course, upon achieving good population coverage. Diseases in which the causal factors are not known or cannot be readily avoided, or in which preneoplastic lesions are not readily detected, may be effectively treated, sometimes, even when in advanced stages (e.g., most childhood cancers).

Given that cancer control must be disease-specific (although tobacco and diet are relevant to many cancers), systematic strategies directed towards controlling cancer must take into consideration the relative proportions of different types of cancer within the targeted geographic areas or population sub-groups, as well as existing resources for cancer control and their distribution within the regions in question. While primary cancer control is largely a public health problem, secondary cancer control and treatment rely upon primary care health practitioners and cancer specialists. Consequently, the successful establishment of systematic cancer control strategies is dependent upon a variety of cultural, social, economic and political factors, including the priority given to cancer by governments, the type of health care system and the diligence and knowledge of individual practitioners.

Figure 2

Figure 2 (above) shows the geographic variability in cancer incidence at a global level for the year 2000 (adjusted to an age-adjusted standard world population), based on cancer registry data and, where this is not available, estimated information. The variability in overall incidence shown here reflects an even greater variability in the incidence of each type of cancer throughout the world, and confirms the need for individualized cancer control plans at national or regional levels. It must also be recognized, however, that this map gives no indication of the constantly evolving patterns of cancer resulting from changes in population age-structure and lifestyles, and changes in the prevalence of, or exposure to causal factors. Although developing countries presently have a lower incidence of cancer, the fact that their populations are growing much faster than those of affluent nations, the increasing proportion of elderly in the population, and the rapid changes in lifestyles and environments are leading to both a higher incidence of cancer and a trend toward cancer patterns that increasingly resemble those of affluent nations. The progressive rise in the incidence of tobacco-related cancers is particularly worrisome and will impose a heavy burden of chronic disease on these countries, further challenging their healthcare systems. This implies an urgent need to focus more attention on cancer control in developing countries now, even though cancer incidence is relatively low.

Inevitably, the concepts and strategies of cancer control have evolved with our understanding of cancer itself. Prior to the modern era, cancer was only dimly perceived as a discrete set of diseases, although the existence of inexorably progressive swellings or tumors, or festering sores which eroded adjacent tissues, has been recognized since ancient times. Before pathological diagnosis became feasible, it was often impossible to distinguish between cancer and many chronic infectious or inflammatory diseases, but in the absence of effective therapy for any of these conditions this scarcely mattered. Treatment was sometimes attempted by the simple and obvious expedient of surgical removal or cautery, but since the available techniques were primitive, such attempts were rarely successful and achieved, at best, a temporary delay in the progression of the disease. Unfortunately, any such prolongation of life was bought, in the absence of anaesthesia and effective pain control, at the high price of the excruciating suffering of the patient, while the infectious complications that followed the primitive attempts at extirpation were likely to prove fatal. Doubtless, such treatments often shortened the life of the victim while managing to make it even more miserable, or, in Hobbesian terms, “nasty, brutish and short.”

Revolutionary Ideas
Treatment, however unsuccessful, at least was conceivable before there was any grasp of the nature of cancer. In contrast, the primary prevention of cancer requires an understanding of its causes. Such understanding had to await the industrial revolution when the exposure of large numbers of workers (and, via pollution, others living in industrial regions) to a wide range of noxious substances, led both to a dramatic surge in a broad range of diseases, including cancer, and to the recognition of the potential role of environmental agents in their cause. The same advances in manufacturing capabilities led to the industrial production of cigarettes, and the consequent onset of tobacco-related diseases, including cancers, of epidemic proportions. Infectious diseases, whose pattern was dramatically modified by changes in the environment, the management of sewage, improved personal hygiene and, eventually, by the development of antibiotics, became less important both as diseases in their own right, and as causes of cancer. Finally, the increased affluence brought by the industrial revolution translated into increased consumption of all kinds and altered patterns of reproduction. After the deprivations induced by the World Wars and the rapid economic development of the major combatants in the second half of the 20th century, the ill effects of a diet increasingly rich in fats and poor in fruit and vegetables became apparent. Doll and Peto have estimated that diet is involved in the causation of as much as a third of cancers in affluent countries; a high lipid intake and obesity have been associated with the development of colon cancer, endometrial cancer, prostate cancer and probably breast cancer, while a number of cancers have been shown to have a lower incidence in populations with a high intake of fruits and vegetables. The high incidence of breast cancer in more affluent societies is also linked, at least in part, to decreased fertility and a reduction in breast feeding.

Chimney Sweepers Provide a Model for Cancer Prevention
The importance of the environment in the genesis of illness is by no means a new concept. Hippocrates himself stressed the influence of climate and geography, and sometimes of local features such as marshes, the water supply and the habits of the people, on prevalent patterns of disease. At a practical level, the toxic effects of certain minerals to which miners were exposed was recognized from the beginning of recorded medical history. Galen, however, who further developed Hippocrates’ theories, considered cancer to be due to an excess of black bile (melancholia)—hardly a basis on which rational preventive measures could be undertaken. Although many other theories were put forward over the next 2,000 years, none provided any real insights. Sir Percival Pott, a surgeon at St Bartholomew’s Hospital in London famous for his descriptions of tuberculosis of the spine and fractures around the ankle joint—he sustained one himself, narrowly avoiding amputation and greatly stimulating his interest in this particular fracture—is generally credited with making one of the first scientifically sound connections between cancer and an environmental agent. Pott recognized, in 1761, that men who had been chimney sweeps as children frequently developed scrotal cancer. He postulated that chimney-sweepers’ cancer was due to the “ lodgement of soot in the rugae of the scrotum.” Pott became a staunch advocate of legislation to deal with this problem. Unfortunately, the first bill passed to protect workers, the Chimney-Sweeper’s Act of 1788, required only that apprentices be at least eight years old, and that sweepers could have no more than six “apprentices”! In Denmark, the chimney sweeps’ guild approached the problem differently, urging its members to take daily baths. This simple, if revolutionary, measure effectively prevented the cancer, although it was not until 1892 that an article in the British Medical Journal, “Why Foreign Sweeps Do Not Suffer From Scrotal Cancer,” revealed the advantages of a bath to the British. While hardly a controlled trial, there was little doubt that a critically important principle relating to the prevention of cancer— avoidance of exposure to a carcinogen—had been identified.

Meanwhile, doctors had noted similar cancers among gas plant workers in Germany and oil shale workers in Scotland, and in the early 20th century certain constituents of tar, soot, and oils, known as polycyclic aromatic hydrocarbons, were found to cause cancer in laboratory animals, thus identifying the specific substances responsible for cancer among workers in these occupations. Fortunately, protective measures taken in affluent countries today have largely relegated occupational exposure to a minor overall role in cancer causation, although rapid industrialization in developing countries, and the widespread use of agricultural chemicals, frequently in the absence of adequate worker protection or advice, and of pollution controls, may result in such exposures causing relatively high rates of particular cancers in specific populations or communities.

The Dangers of Tobacco Smoke

“Currently two million deaths from smoking occur each year in developed countries and 1 million in lesser developed countries. By 2025, this ratio will alter to 3 million per year in developed countries and 7 million in lesser developed countries. Based on current trends, the death toll from smoking will rise to 10 million people per year by 2025.” - WHO

Oxidation is a risky business, as vouched for by the numerous cellular enzymes that exist to limit the potential damage to our genes caused by the production of dangerous oxidation products, such as cancer-promoting free radicals. Oxidation, in the form of the burning of fossil fuels, provided the energy needed to drive the industrial revolution, but the resultant pollution of body and soul had numerous ill effects, chimney-sweepers’ cancer being just one of them. Indeed, “soot-wart” was a minor public health problem compared to the 20th century blights brought about by the increasing availability of fatty foods for oxidation in corpore and the growing addiction to inhalation of the smoke of the dried leaves of the plant, Nicotiana tobacum. An astute thinker might have guessed, from a survey of the grim cities shrouded in soot, and the plethora of occupational diseases related to the dramatic increase in the use of carbon-based fuels, that inhaling tobacco smoke would be injurious to health. Some did, but the importance of smoking in the causation of cancer was not widely accepted until enough cigarettes had been smoked by enough people for long enough to produce a veritable epidemic of cancer.

Tobacco had been a valuable trading commodity ever since the colonists of the New World discovered it among the native peoples they encountered. By the 1700s it had become a major international industry and the smoking of pipes, cigarettes and cigars was widespread. But in spite of the many who opposed its use on moral, health and social grounds, centuries were to pass before the extent of its negative medical consequences was fully recognized. Samuel Thomas von Soemmering of Maine reported on cancers of the lip in pipe smokers in 1795, and Benjamin Rush, the most famous American physician of his day and a signatory to the Declaration of Independence, wrote of the medical and moral dangers of tobacco in 1798 (he was concerned primarily with its promotion of thirst and, consequently, drunkenness!). The first association of lung cancer with smoking was made in 1912, by Isaac Adler, although at that time the incidence of lung cancer was only approximately 0.6 per 100,000 per year in the USA. At its peak, around 1990, it had risen to 75 per 100,000 in males. The industrial manufacture of cigarettes began in the late 19th century but already, by 1900, annual sales had reached 4.4 billion. The First World War brought with it a dramatic increase in smoking, and a consequent increase in the incidence of tobacco-associated cancers. By the 1920s pathologists and physicians had begun to report a relationship between smoking and lung cancer as annual global cigarette sales reached 600 billion (1929). The Second World War gave an added stimulus to the smoking habit and the connection with cancer was established beyond any doubt in solid epidemiological studies conducted in both Great Britain and the USA. In 1950 Doll and Hill found that heavy smokers in Britain had a fifty-fold increase in the incidence of lung cancer while Wynder and Graham reported that 96.5% of lung cancer patients they interviewed in the USA were moderate to heavy smokers.

In spite of these findings, cigarette sales continued to climb, reaching more than 5000 billion between 1990 and 2000. Doll and Peto have estimated that tobacco accounts for approximately one-third of cancers in the affluent nations. It has also become clear that Rush’s concern, some 200 years ago, of the dual ills of tobacco and alcohol consumption was well-founded, since cancers of the upper digestive tract and liver are greatly increased by a combination of high alcohol intake and smoking.

The Challenge
Prior to the Industrial Revolution, the incidence of cancer was much lower, perhaps one-third of its present level in affluent nations. Infections were much more important causes of cancer, as they are today in developing countries where infections can account for 25% or more of all cancers. The social and medical changes that dramatically reduced the incidence of many infectious diseases in affluent societies, ought, then, to have led to a reduction of the incidence of cancer. Unfortunately, while infectious diseases today are a less important cause of cancer in the affluent nations (accounting for perhaps 15% of cancers), this advantage has been far outweighed by the increase in cancer relating to smoking and dietary excesses. As developing countries become increasingly industrialized, they are likely to witness a similar increase in cancer. But whereas the emergence of the “cancer epidemic” associated with the ready availability of manufactured cigarettes and the increased consumption of more affluent populations in the 20th century was largely unanticipated, today, the growth of science and technology has provided sufficient knowledge to be able to establish effective cancer control programs across the globe. The challenge, as highlighted recently by the Director of the National Cancer Institute of the USA, is to use that knowledge to markedly reduce mortality from cancer.

“In no one view, it is possible to contemplate the creature man in a more absurd and ridiculous light, than in his attachment to tobacco.” —Dr. Benjamin Rush, Essays Literal, Moral and Philosophical, 1798

The incidence of cancer caused by infections is likely to decrease in developing countries, perhaps dramatically, in the course of the next 20 to 30 years, both as a result of increasing socioeconomic development, and from the introduction of more effective anti-infection measures (e.g., vaccination against the Human Papilloma Virus, responsible for over 90% of cases of cervical cancer). Unfortunately, it is likely to prove much more difficult to curb the growth of smoking habits and to ensure healthy eating. The World Health Organization estimates that since 1950 at least 10 million people have died from smoking in developing countries, and in the next 20 years, there could be an additional 70 million deaths. But some countries are still in the early stages of the epidemic, e.g., many African and South Asian countries, where the incidence of lung cancer is still less than 10 per 100,000 and cigarette consumption is less than 500 per person per year (compared to over 2500 per year in the countries that consume the most cigarettes). In such countries, preventing more people from smoking would have an enormously beneficial impact. Meeting this challenge will require the combined will of individuals and governments, the active cooperation of industry and the transfer of knowledge and resources from richer to poorer countries. One might be forgiven, in the light of history, competing interests and the limited resources of developing countries, for believing it more likely that the prediction of the International Agency for Research on Cancer—that cancer incidence will have increased by at least 50% (based on predicted population growth alone) and probably more, by the year 2020—will be fulfilled.