cancer: nineteenth century science — twentieth century technology

COMMUNITY HEALTH STUDIES VOLUME V, NUMBER 2, 1981

CANCER: NINETEENTH CENTURY SCIENCE - TWENTIETH CENTURY TECHNOLOGY

John D. Potter

CSIRO Division of Human Nutrition, Kintore Avenue, Adelaide, 5000.

Abstract Cancer is a major cause of death in western

societies. Overall, there has been no decline in the incidence and little improvement in survival for twenty years. Hundreds of millions of dollars are regularly spent on cancer research. It is argued that much r e sea rch effort i s misd i rec ted a s a consequence of a limited view of the nature of the cancer process and the influences on it. Preoccupation with a nineteenth century view of the genesis of cancer and a twentieth- c e n t u r y h igh- technology approach to t r ea tmen t h a s p reven ted the p rope r exploration of the determinants of cancer, and the development of different therapeutic modes. Several models of the cancer process are examined. A model which considers h u m a n popu la t ions , h u m a n behav iour (including social and economic factors) and the interactive nature of the biologic response of living organisms to- the environment is developed. Some of the implications of this model for research and therapy are discussed.

Introduction I t is now widely accepted that the decline of

infectious disease mortality in western industrialized societies is attributable to change in social, economic and environmental conditions rather than to advances in therapeutics.’ Understanding the mode of influence of these diverse and changing circumstances at the level of the individual has been particularly hampered by a preoccupation with specific aetiology, and by the consequent focus of t he rapeu t i c endeavour on the elimination of a specific agent .2,3

A great deal of research effort and time has

POTTER 133

been expended on developing antibiotics and antiparasitics, often barely one step ahead of the adaptations of the target organisms. A similar effort directed into the application of information we already have on the complex aetiology of infectious diseases - such as improving poor nutrition and housing and, more fundamentally perhaps, attempting to eliminate powerlessness in our social forms - would free much of the world’s population from a debilitating burden of disease.

In this paper it is argued that similar problems and a similar misdirection of research are to be found in relation to the aetiology and treatment of cancer.

Cancer Incidence, Survival, and Research Funding

Cancer now causes about 20 per cent of all deaths in Western societies.4 The incidence of cancer overall has been largely unchanged for two decades. United States figures suggest that it is now increasing in that country.5 Table 1 shows trends in 5-year relative survival rates [adjusted for age and other causes of death) for the leading cancer sites in whites in the United States of America. The most noticeable feature of these trends is that while there was an improvement in survival rates from the 1940s to the 1950s, the subsequent figures show little change.B,’ Table 2 shows the increases in cancer research funding over the last decade in the United States of America.8 These data taken together suggest that very large amounts of money have been spent on cancer research with little impact on the two criteria by which we can judge the final value of such research. Neither is incidence declining, nor i s survival more than marginally improving. The improvement in

COMMUNITY HEALTH STUDIES

TABLE 1.

5-Year Survival Rates for 7 Major Cancer Sites (US Whites) 1940-73

Primary Approx. % 1940-49 1950-59 1960-66 1967-73 Site of all

BreaPt 13 53 60 64 65

Colon 9 32 44 44 46 Lung 13 4 8 9 9

Prostate 7 37 47 53 59 Rectum 5 29 40 39 44 Bladder 5 42 55 58 63 Uterus 4 61 71 73 77

Source: Refs. 5,6

survival during the 1940s i s usually attr ibuted to a reduction in rperative mortality as techniques of surgery and anaesthesia were refined.

If oil exploration produced as poor results, it would be decided to look for it elsewhere. Before drilling in another spot we would probably review our theory of geologic markers - if dry wells had consistently occurred in places where oil was expected under present theory, then the theory itself would need reviewing.

The HenJe-Koch Hypothesis In the nineteenth century much painstaking

endeavour led to the formulation of the Henle- Koch postulates - a hierarchical series of statements which helped considerably in understanding the link between bacteria and infectious disease. The postulates, stated briefly, are: 1. The organism must be found in all cases

of the disease in question.

2.. It must be isolated from patients and grown in pure culture.

3. When the pure culture is inoculated into susceptible animals or man it must reproduce the disease.

This model had already been severely compromised by von Pettenkoffer who had consumed large cultures of bacteria without ill effects.8 This action, while not disproving that a particular bacterium is a necessary cause of a disease, certainly demolished the notion of bacteria a s sufficient cause. On that basis, the underlying (barely-stated) model of active organism/passive victim is also very much in trouble - a fact acknowledged by the adoption of a later model, much loved of c o n t e m p o r a r y i n f e c t i o u s d i s e a s e ep idemio log i s t s : t h a t of h o s t - a g e n t - environment interacting to establish a health- disease balance.10

The Passive Victim-Active Agent Model This inappropriate model - passive

TABLE 2

Funding for National Cancer Institute (US) 1971-1978

Fiscal year 1971 $181M. Fiscal year 1974 $580M. Fiscal year 1978 $873M.

Source: Ref. 8

POTTER 234 COMMUNITY HEALTH STUDIES

victim-active agent - underlies the current study of aetiology, therapy and prevention of cancer.

A recent review of breast cancer therapy begins with a discussion of the natural history of breast cancer.” However, “natural history” a s understood in this context merely means what happens after the cancer has been clinically detected. The review in question points out that surv iva l has plateaued since 1955, then devotes 27 pages and 313 references to recent advances in treatment.

It is no part of my argument to belittle advances that mean a reduction of pain and mutilation associated with breast cancer therapy, but this is a weaker sense of the word “advance” than would be associated with improvements in survival. While it is clear that knowing the antecendents of breast cancer in any given individual is not likely, at present, to influence specific therapy, knowing the pattern of antecedents for breast cancer in general might reasonably be expected to inform decisions regarding priorities for prevention, detection and therapy of this particular neoplasm.

Some passages selected from widely used textbooks in medicine, and quotations from current journals, further emphasize the preoccupation with a passive victim of the cancer process and a truncated view of “natural history” [emphases added]:

I ‘ . . . The interplay of a number of f a c t o r s i s r e s p o n s i b l e f o r t h e development of malignant disease. These include genetic, viral, chemical and physical factors, a s well a s the response of the host.”lZ

‘Carcinoma of the colon and rectum causes more deaths than any other form of cancer. The only known predisposing causes are familial multiple polyposis, chronic ulcerative colitis, chronic lymphogranuloma venereum. chronic granuloma inguinale, and perhaps adenoma“.13

“It has been estimated that one woman in 25 will develop (breast) malignancy. Only by detecting the disease in the earliest stages can cure be guaran teed”.l4

“The importance of genetic and environmental factors in the etiology of bronchogenic carcinoma is not known.

POTTER 135

However the disease is relatively rare in non-smo kers”.13

“Despite continuous advances in both diagnosis and operative technique, only 40 per cent of patients with oesophageal cancer can tolerate surgical treatment. Therefore, the urgent need for early diagnosis must be stressed’’.’s

“Although the therapy of carcinoma of the colon has been investigated, little progress has been made in prolonging the survival. For this reason a major effort in clinical research has been directed toward surgical adjuvant therapy”.le

It seems that a predominant assumption in medicine is that the organism is liable or not to develop cancer and that little will influence that development. Further, only medical high-technology services can then influence favourably the subsequent behaviour of the m a l i g n a n c y . T h i s pe rcep t ion i s t h e consequence of regarding the natural history of a particular disorder as only beginning at the time of professional consultation and persisting with a one cause-one disease-one cure model - a model which not only preoccupies many laboratory-based research workers but finds its way into popular expositions on cancer.17

I t is perhaps not surprising that in text books and journals primarily concerned with a clinical approach to cancer such statements as those above should appear. After all once a p a t i e n t p r e s e n t s w i t h c a n c e r t h e clinical/technologic approach i s surely appropriate. There is a reply to this objection which I will pursue later. At present it is sufficient to admit that the problemis not that such passages appear in text books and clinical journals, in which they may be appropriate, but that such passages dominate nearly all writing on cancer, its antecedents and consequences. The preoccupation with the clinical at the expense of the causal also underlies the problems in the way of the introduction of a more comprehensive model of cancer. If the majority of persons making decisions about the direction of research are commit ted to a res t r ic ted model of carcinogenesis then research programs which call for a different basis will not be conceived or will be rejected on peer review. One does not need to postulate conspiracy, merely conservatism.


ENVIRONMENTAL

Cell /

Malignant cell Eliminate

Figure I. A Passive Mode1 of Carcinogenesis (“Rx” means treatment)

If the model we use to understand cancer is the nineteenth century view of infectious disease, namely, tha t external factors (including living organisms] are responsible for malignancies in a passive human system, then the appropriate response is, of course, to identify these factors - meanwhile excising malignant t issue wi th surgery, radio- therapy, etcetera.

Indeed, resources have been concentrated on the pursuit of external agents, including viruses, and on the manipulation of these a t the isolated cellular level (Figure 1). I t is not suggested that this work has no value: it is suggested that it is appropriate only if other aspects of a more useful model of the cancer process are also taken into account. Models are not right or wrong in any absolute sense - models are constructs prepared in order to make the w o r l d unde r s t andab le a n d predictable. If a model ceases to be useful we discard it in favour of one which explains and predicts with greater accuracy. At the moment the limited mechanistic model is not doing very well.

The Minimally Reactive Model I have argued elsewhere that it is

inappropriate to regard the human or ‘any living organism as a passive recipient of environmental insults.18 Living organisms have large series of interlocking and hierarchical mechanisms for the maintenance of the internal milieu within very narrow limits, despite wide variation in the external env i ronmen t . An example of such a mechanism is the capacity for regulation of body t em p era t ur e .

Within the biologic model our health

depends on large numbers of such processes, known and unknown, including endocrine (control of blood sugar], nervous (body t empera tu re ) , immunologic (p ro tec t ion aga ins t mic roorgan i sms] a n d gas t ro - intestinal systems (hepatic detoxification mechanisms]. The recognition of this has led in part to an appreciation that the organism is not entirely passive and that, for instance. the immunologic system might be part of the body’s capacity to resist malignant change in i ts constituent cells (Figure 2).

This reactive model is similar to the host- environment-agent model of infectious disease, but the host is usually thought of as hav ing only l imi ted r e sponses when considering i he biological behaviour c?f cancer.

These two models with their passive and minimally reactive views of human health have shaped the way in which research money is spent. Figure 3 details, for example. the distribution of cancer research projects suppor t ed in Br i ta in in 1974.19 T h e overwhelming majority of these are studies directed at investigating the behaviour of the cancer cell and to a much lesser extent the response of the host. The identification and distribution of determinants in human populations are largely ignored. By 1980 epidemiology accounted for only 4 per cent of about 800 projects supportedin Britain by the Cancer Research Campaign.20 An Interactive Model

The study of the response of the organism to cancer has heen limited to a consideration of immunologic processes. The more general nature of the biologic capacity for the


MAINTENANCE OF

INTERNAL MILIEU e-g. Immunologic processes

ENVIRONMENTAL

AGENT(S)

Malignant . transformation

Cell Malignant cell Eliminate

Figure 2. A minimally Reactive Model of Carcinogenesis ("Rx" means treatment)

I Cell biology

8 pathological Clinical

J Immunology

Biochemistry

Carcinogenesis 8 molecular biology

Radiobiology

b Epidemiology

20 40 60 80 100 120 140 160

Figure 3. Numbers of Cancer Campaign UK 1974

maintenance of the internal milieu is an a d d i t i o n a l a n d use fu l concep t , t h e applicability of which we might explore in relation to the aetiology and treatment of cancer. If endocrine and neurologic systems, for instance, are known to be involved in the maintenance of the internal milieu, it is not unreasonable to suppose that they may be involved in the protection of the body against malignant changes in its constituent cells.

Research Projects Supported bv Cancer Research Source: Ref. 19

There are some data to support this contention, including evidence that some kinds of psychiatric disorder seem to be associated with a reduced risk of cancer.2' Certainly the hormonal changes of pregnancy are important in reducing risk of breast cancer - and there is some evidence that the e n d o c r i n e c h a n g e s o r p e r h a p s t h e immunologic changes of pregnancy may effect a more generalized protection against


malignant transformation.22,23 Most cancer research is carried out on other

species or isolated cells. Little effort is expended on the much more useful study of the interaction of various environmental and internal biologic responses in humans themselves. Most medical scientists fee1 that they can only get answers by manipulating one variable at a time in animal models, often of doubtful applicability to the human questions. In the real world. however, there arc? “natural experiments” taking place which allow us, if we become careful observers, to make sensible judgments in regard to cancer in humans.

Such observations allow the broadening of the model from the direct effect of agents on cells to a more generalized study of the interaction of environment and biology in humans. It was the epidemiology of lung cancer in relation t o cigarettes which initiated the moves to reduce consumption, not the effects of smoking on beagles or the isolation of individual carcinogens in laboratory systems.

Ep idemio logy , p a r t i c u l a r l y a n a l y t i c epidemiology, which looks for associations at the individual level between exposures, behaviours, or biologic variation and the risk of disease, provides an appropriate set of

HUMAN BEHAVIOUR

K COLLECTIVE

e.g. Environmental standards

INDIVIDUAL

e.g. Specific 1 carcinogenic behaviour

/ e.g.Maladapted or e.g. Social equality or inequality

adapted lifestyle

INTERNAL MAINTENANCE e.g. Immunologic processes

? Neurologic processes Endocrine

ENVIRONMENTAL Malignant.

or mat ion-

Malignant Cell Rx=Eliminate \

HUMAN POPULATIONS + ? ? ?

Figure 4: An Interactive Model of Carcinogenesis

POTTER 138 COMMUNITY HEALTH STUDJES

tools for undertaking observational studies. The final addition to this now interactive

model is human behaviour - that active component which allows u s to make recommendations to people which they may undertake to consciously protect themselves against the development of cancer. Human behaviour is also the component which allows us to describe why certain kinds of cancers are a problem at all - for example lung cancer, skin cancer.

Human behaviour of the collective variety influences both the presence and absence of potential cancer-initiating substances, for example environmental and industr ia l exposures and food are factors over which we can have some collective control. We also influence the general capacity of self and others by the maintenance or change of societal structures and strictures. At an individual level we appear to make choices not only about specific carcinogenic behaviours but also in regard to the degree of adaptation to our environment, and therefore directly or indirectly about our health- maintaining functions (Figure 4).

How does such a model help? First of all, it allows reorientation of research priorities so that factors other than external agents (for example viruses, carcinogens] and a small area of the biologic response to external agents (for example immunology] are given due regard. For instance, we might begin to explore more seriously the relationship between the nervous system and chronic disease - do interruptions to nerve function, changes in mood, or mental illness affect disease rates? And what about positive deviance: do those whose mental or emotional equilibrium is above average experience a different risk? Similar questions may be asked about the influence of other systems on carcinogenesis or more generally on the initiation of chronic disease. It may need to be emphasized here that what is envisaged here is a redress of the balance of research priorities. The active agent-passive victim a n d t h e min ima l ly r e a c t i v e mode l s necessarily restrict work to a small number of disciplines. The interactive model allows a much broader base for research. It is not suggested that disciplines which may elicit causal explanations should be neglected. Both laboratory and clinical disciplines on the one hand and population sciences such as

POTTER 139

sociology and epidemiology will allow insights into causal mechanisms. Both, but particularly the latter, are also pertinent to cancer prevention.

The interactive model offers a second advantage. Acting on the patterns we observe, we may begin to institute preventive programs. Without taking account of collective and individual human behaviour, prevent ive programs are meaningless. Preventive efforts in relation to cancer are made at present largely to encourage early diagnosis, for example with screening or regular checkups, despite the fact that we already have some information that is relevant and about which people might make decisions - for example, the effect of reproductive and sexual behaviour on the risk of breast and cervical cancer might ptoperly help inform decisions about sexual lifestyle and reproduction.24

Thirdly, the interactive model allows us to think about other therapeutic methods which are largely ignored at present. As suggested earlier, there are doubts as to whether the current high-technology clinical approach is the only appropriate one to cancer treatment. Because we have asked limited questions. our understanding of the cancer process is limited and our major approach to its treatment has been the elimination of the malignant tissue by surgery or other means, many Fequiring highly specialized techniques and staff. Our preoccupation with an outdated model of the genesis of cancer has not allowed us to explore some alternative modes of therapy.

A specific theoretical example would be the use of fasting in treatment. It is known, for instance, that prolonged fasting inhibits the development of many tumours in animals, perhaps by impairing certain responses of the humoral immunologic system - antibodies - but not those of the cellular component. The cellular elements are those which may act against cancers while some antibodies may actually protect cancers against cellular activity.25 Other techniques which could be e x p l o r e d i n c l u d e p s y c h o t h e r a p e u t i c techniques, medi ta t ion, and physical training, all of which measurably affect the function of some physiological parameters and might reasonably be presumed to be involved in the maintenance of the internal milieu.

These apparently non-specific techniques


were employed by our medical forebears, perhaps (as we in our technologic superiority might believe) because they could do little else, but perhaps also because they had an understanding of the necessary interaction of h u m a n s wi th the i r envi ronment . Our spectacular success with antibiotics and emergency surgery should not blind us to the spectacular failure that the transplanation of these techciques into the treatment of cancer has proved.

Perhaps the most important aspect of this model is that it allows, or even insists on, social responses. If the initiation of a majority of cancers has an environmental component then the source of those environmental fispects is a proper subject for cancer research. I f , a s the evidence suggests, the presence of environmental agents is largely the result of collective or individual human activity, then collective human activity must be called into response - whether by establishing that certain behaviours have become socially unacceptable (for example, smoking), enacting legislation to eliminate hazards from the workplace or the living space, drawing drawing up guidelines for appropriate eating, or embarking on social re form to ensu re jus t and equ i t ab le distribution of goods and services.

Finally, it is worthwhile here to briefly describe the process of carcinogenesis at the level of the individual cell. The development of a particular cancer at any site is the result of a complex sequence of events, each of which will bear on the final development of a malignancy. A cell may undergo a series of changes from a normally functioning entity through various levels of impaired function as cellular controls (DNA] are altered, to a f ina l ly , f rankly mal ignant cell wh ich reproduces itself more-or-less indefinitely and whose metabolic functions are grossly aberrant. At any stage during this sequence, the cell may undergo a series of changes from a normally functioning enti ty through

various levels of impaired function as cellular controls (DNA) are altered, to a finally, frankly malignant cell which reproduces itself more-or-less indefinitely and whose metabolic functions are grossly aberrant. At any stage during this sequence, the cell may undergo genetic changes which are lethal, may continue to survive as an abnormal but non-malignant cell or possibly even undergo some further modification which makes it behave more like a normal cell. Thus carcinogenesis is a complex sequential process and not a simple two-valuedoutcome for any cell or individual.

The more restricted mechanistic models, by their emphasis on external agents, focus largely on the initiation stages of cancer and largely ignore those factors which influence whether the damagedcell survives to produce a tumour. These latter influences have been termed promotional factors and appear frequently to be related to lifestyle and social factors. Thus there is a distortion of the understanding of the time-flow of cancer development with those influences which are perhaps most amenable to preventive manipulation being most ignored. Reduction of alcohol consumption (a known tumour promoter] and increase of vitamin A (a tumour inhibitor] a re examples. This approach is more readily facilitated by an interactive model. We do not need nineteenth century science and twentieth century high technology for the study and treatment of cancer. We need a wider base in research, particularly the exploration of patterns of human health and disease (and tha t means multi-causal, interactive thinking), radical hygiene and conservative therapeutics rather than the reverse, along with exploration of the capacities within the human system for the prevention, suppression and even elimination of cancer, and political and social action to eliminate or reduce those factors which we have already identified a s carcinogenic.

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cancer: nineteenth century science — twentieth century technology

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