[Return to Clinical Futures index]

Chapter 4 - Cancer

Karol Sikora

Introduction

The majority of people who develop cancer are over 60 years old. The biggest global demographic change predicted for the next 25 years is a dramatic shift in the number of people over this age. Inevitably this will lead to a rise in cancer incidence (Tables 4.1, 4.2). The UK Government Actuary's Department predicts that the number of people over 65 will have risen from 9.4 million in 1992 to 11.8 million in 2020.1 The WHO estimates that over the next 25 years there will be over a 100% increase in the number of people over 60 years in 31 countries. Although health education, screening and possibly new prevention strategies could reduce the risks of lung, skin and oropharyngeal neoplasms, the age shift is likely to dwarf all other factors affecting cancer incidence. Cancer is thus becoming a major health problem all over the world. This year more than ten million people will develop the disease. Half will live in countries that between them have less than 5% of the world's cancer treatment resources. By the year 2020 the number of new patients each year will be a frightening 20 million. Developing and implementing a strategy to reduce the untold suffering this will cause is a daunting but urgent challenge to which cancer prevention is the obvious key.

Cancer prevention

The world is a constantly changing place. Cancer care, like airline travel, petrochemicals, and telecommunications, has become a truly international endeavour. It is costly - often way beyond the purchasing power of many countries whose people earn low incomes. There are many misconceptions even among specialists of the relative effectiveness of many interventions. Increasingly sophisticated techniques are becoming available to measure the relative benefits of different approaches. We now have many currencies of suffering: person years of life lost - PYLL; quality adjusted life years - QALY and disability adjusted life years - DALY, all with their protagonists and innate value judgements. But epidemiologists are like voyeurs at a scene of mass destruction. However precise the body count they cannot bring back the lost lives or reduce the suffering caused.

Our track record in the control of infectious diseases is impressive. The eradication of smallpox and the rapid decline in poliomyelitis are public health triumphs of our times on par with John Snow's removal of the Broad Street pump handle in 1854. Better sanitation, education and the extended programme of immunisation, which now reaches 80% of the world's children, have had a great impact on global health. We even seem able to meet new infectious challenges as diverse as AIDS and Ebola fever. Cancer cannot be contained or eradicated in the same way but we will need to place far more emphasis on the role the individual can take, albeit with the support of health-care professionals, in improving their health. Smoking, poor diet, and alcohol account for 68% of the risk factor in cancer in the western world, meaning that with enough education and, crucially, with enough support, individuals can be helped to make an enormous impact on cancer incidence. Indeed our success in other areas of public health has led to increased longevity and thus cancer and other degenerative illnesses have soaring global incidence. The failure of medicine to control cancer and degenerative disease will make imperative a complete revolution in "health creation" through major governmental healthy living initiatives starting in the late 1990s. Indeed our success in other areas of public health has lead to increased longevity and thus cancer's soaring global incidence.

Optimal use of current knowledge could reduce the overall cancer incidence by at least 3 million. Tobacco control is the most urgent need. We need to look for long-term solutions here. The politics of tobacco is a complex conspiratorial web of industrialists, farmers, manufacturers, politicians and the pensions business all looking after their own interests. Reduce cigarette consumption in many countries and the economy simply collapses. Governments are naturally cautious. In democracies they are subject to intense lobbying. In less democratic societies corruption, using the massive profits generated by the industry, usually achieves the desired end-point. How can we simply stand back and watch western merchants of death so blatantly exploit the young of the developing world, associating images of sex, success and wealth with their lethal wares? With forceful and concerted international action against cigarette promotion we could reduce cancer incidence by 20% by the year 2020.

Dietary modification could result in a further 20% reduction across the board. The problem is refining the educational message and getting it right in different communities. Changing our current high fat, low fibre diet with a low fruit and vegetable intake to a wholefood diet rich in fruits, vegetables, grains, pulses are common themes for cancer prevention. But many features of the modern western diet are now being adapted globally as branded fast food makers seek out new markets. Again political will is necessary to reduce the costs to the public of healthy foods and education and incentives need to be given to schools, factories and public health institutions to help them improve the quality of food and information given to pupils, students, and patients. We now have evidence that those with healthy lifestyles and low meat diets have between 40% and 50% lower cancer mortality.2 More data will come forward from the European Prospective Investigation into Diet and Cancer (EPIC) study currently in progress. This is a good example where painstaking data and serum collection on 400 000 Europeans could, over the years, provide a vast resource for investigating prospectively the complex interrelationships between diet and cancer. Cancer incidence varies enormously across Europe providing an excellent natural laboratory for such studies. And interventional epidemiology using rigorous controlled studies could produce the evidence that could lead to major changes.

It is likely that current work going on to identify key plant phytochemicals involved in protecting individuals from cancer - namely phytates, protease inhibitors, isoflavinoides and isoflavones, limonene, lycopene, plant phenols, aromatic isothiocyanates, methylated flavones, coumarines, and plant sterols - will progress and that very specific preventive and treatment regimens may develop from improved knowledge about the mechanisms of actions of these substances.

Infection causes around 15% of cancer worldwide and is potentially preventable (Table 4.1). Hepatitis B immunisation in children has significantly reduced the incidence of infection in China, Korea, Egypt, and West Africa. Shortly we will see if it has reduced the incidence of hepatoma, which begins by the third decade of life in endemic regions. The unconfirmed trends are already encouraging. Hepatitis C may also be involved in the production of hepatoma. Cancer of the cervix, the commonest women's cancer in parts of India and Latin America, is clearly associated with certain subtypes of human papillomavirus. Vaccines are now becoming available and entering trial. Helicobacter pylori is associated with stomach cancer. Here, without any intervention, there has been a remarkable downward trend in incidence worldwide. Dissecting out the complex factors involved including food storage, preparation and content is a considerable challenge. Other cancer causing infections are Epstein-Barr virus (nasopharyngeal cancer and Burkitt's lymphoma), schistosomiasis (bladder cancer), the liver fluke (a rare type of cancer affecting the bile ducts), the human T-cell leukaemia virus, and the ubiquitous HIV (lymphoma and anal cancer). Although geographically localised, their prevention by lifestyle change and vaccination programmes are realistic short-term goals. A major challenge is to identify, quantitate and reduce the cofactors involved in the link between infection and carcinogenesis. In some examples nearly the whole population carries the infection yet only a proportion will get cancer. Cofactors may have both positive and negative effects, making the analysis difficult.

The key to success in cancer prevention is careful targeting. Clearly there is little point telling the dark-skinned village fishermen of Southern India to avoid sunbathing on the beach. Targeted prevention programmes are very cost effective and can be shared by different countries with similar cancer patterns. Countries with limited resources need not keep reinventing the wheel. Prevention packages can be tailored and adapted widely. To do this we need good data of incidence in relation to geography. Descriptive epidemiology provides a fertile hunting ground for patterns of carcinogenesis. Relating genetic changes in cancer to their cause and geography - the emerging discipline of molecular epidemiology - will complete the circle and point the way to specific interventions.3 The future of prevention will almost surely be about using such techniques to carefully target preventive strategies to those who would benefit most. In the postgenomic era it is likely that cancer prevention programmes, at least in developed countries, will be completely individualised - a combination of genetic, environmental and lifestyle data will be used to construct very specific personalised messages.4 One of the biggest problems is education. The media often exaggerate cancer risks, diluting the real public message that is needed.

Screening

Screening for cancer is a potentially important tool. Careful targeting is required - breast cancer is simply not a major problem in many parts of the world. Again the cost of the technology required must match the gain. Low cost direct inspection techniques for oral and cervical cancer by health workers seem attractive to achieve tumour downstaging and hence better survival results. Unfortunately the evaluation of such programmes in India, China and Russia have shown surprisingly poor results in terms of overall effectiveness. A major cost in instituting any screening procedure is simply getting the message to the people and then developing the logistics, often under difficult conditions. Cultural barriers may be insurmountable without better education, especially of girls, who as mothers will become responsible for family health. Low technology tests have low specificity so flooding already hard pressed secondary care facilities with patients with non-life-threatening abnormalities.

Genetic predisposition

Evidence that genetic background can increase the risk of developing cancer comes from three sources. First the risk of cancer is greater amongst family members of patients with cancer. This is currently the most difficult observation to examine mechanistically as the number of genes involved and their functional abnormalities are diverse. Second there are specific families with a very high incidence of particular forms of tumours. Such cancer families may contain mutated specific genes which increase cancer risk through various mechanisms. Some of the genes have been identified such as TP53 in the Li-Fraumeni syndrome. Finally there are specific recognisable inherited clinical syndromes associated with rare cancer types, such as multiple endocrine neoplasia 1 with its high incidence of parathyroid, endocrine pancreatic and anterior pituitary tumours (Table 4.3). A common feature in all types of familial cancer is its tendency to occur at an earlier age, to be multiple, and to occur bilaterally when paired organs exist.5

Until now genetic risk assessment for cancer has been confined to the relatively rare inherited syndromes. This is likely to change dramatically over the next few years.6 Gene hunting has already uncovered sets of genes which if mutated may result in increased cancer risk. Table 4.4 lists examples of such genes for breast cancer.

The human genome project continues to provide detailed sequencing data.7 It is estimated that the whole genome will be completed by 2005. Novel assays for DNA mutations which can be rapidly applied to tiny samples of human tissue are being developed. Finally, advances in information technology will lead to more powerful computer storage and retrieval of sequence-based information.8

There is considerable public concern at genetic risk assessment. The use of genetic information for life assurance, health insurance and job selection are areas of profound ethical debate. Further- more, preimplantation diagnosis for known inherited cancer pre- disposing genes is already possible. As our knowledge of the human genome increases exponentially over the next decade it is likely that selection of low cancer incidence embryos will be feasible. Genetic information will be useful in identifying individually tailored screening programmes, lifestyle advice, and, if necessary, preventive interventions to individuals. The latter may include gene therapy in a prophylactic setting as well as ablative surgery and chemoprevention.

As well as determining the risk of developing cancer, similar technology will be used to assess prognosis and the choice of therapy. The pathway a tumour will envolve is determined by the somatic genetic changes that led to the malignant cell in the first place. "Molecular stamp collecting" and long-term computer analysis will almost certainly revolutionise clinical decision making, especially in choosing how aggressive to be to prevent recurrence.

Surgery

The last two decades have seen an increasing trend to conservation surgery, with organ preservation in several parts of the body. This has been driven by a combination of technological improvements, clinical trials, and patient preference. Thus, breast, rectal, bone, skin and head and neck surgical excisions are now far less extensive and destructive, both physically and psychologically.9 Molecular analysis of biopsy samples is likely to provide an effective profile of tumour behaviour in an individual patient. Novel imaging techniques will give a better understanding of the anatomical relationships between tumour and normal tissue making the optimal plane of dissection clearer. Computerisation and robotics will allow cancer surgery to be planned in advance and carried out at least in part by non-manually controlled devices further enhancing tissue conservation.10 The surgeon of the next century will be a highly skilled technician, expert in robotics and computer-driven image reconstruction systems. Like radiologists already, surgeons will work from locations remote from the patient, carrying out highly specialised tasks by remote control.11

Virtual reality will combine information from touch during surgical procedures with real-time three-dimensional imaging, especially in those parts of the body such as the brain where tumour resection with minimal normal tissue is the crucial objective. Surgery for metastatic disease will become increasingly successful in selected patients.12 The precise tailoring of adjuvant systemic therapies, together with immune system resetting, will reduce the recurrence rate in those patients whose primary tumours can be resected. With increasing success in detecting precancerous lesions will come more opportunities for non-surgical interventions and surgery may eventually become a rare treatment modality. Good evaluation strategies for new surgical procedures are essential before routine use is made of them.

Because of the great fear surrounding cancer and the strong desire of medical professionals to move swiftly from diagnosis to treatment, patients currently experience complex demanding and frightening treatments before they have properly adjusted to the diagnosis of cancer, and thought through the implications of their treatments. Patients treated in a state of shock, fear and resistance have markedly less good outcomes from treatment, with greater postoperative complication rates, and it is important that the delivery of more sophisticated care and treatment involves medical teams "bringing the patient with them" in the medical process. This will involve making sure patients are really ready to embark upon their treatment having understood what is happening to them, adjusted to their new situation, been fully involved in treatment decisions and become positively motivated towards the treatment, having had the opportunity to prepare psychologically and physically with the use of counselling, stress reduction techniques, and nutritional improvement. Over-zealous and rushed treatment programmes leave severe psychological scars in cancer patients, which does not need to happen if adequate care, attention and time are given prior to treatment taking place. Time lost in the treatment process in this way is more than compensated for by having the patient prepared, motivated and actively involved in their treatment process.

Radiotherapy

Radiotherapy has a 100-year history. There are essentially two ways in which its effects can be enhanced to eradicate localised cancer. The first is physical - ensuring that the radiation targets the tumour as precisely as possible. The second is biological - utilising information on the differential biological sensitivity of tumour and normal tissue to design an optimal fractionation scheme for radiation delivery.13

Physical improvements are likely to be driven by developments in the power of computing. The large amount of mathematical data contained in CT and MRI scans will be used more effectively by new planning systems. Technological developments such as rapidly responsive multileaf collimation will allow the shape of the radiation beam to be changed rapidly and precisely even during treatment delivery, so making conformal therapy the standard practice for all radical radiotherapy treatment plans. Computer technology and robotics will almost certainly take over most of the planning, optimisation, simulation and execution phases of radiation delivery.14

A greater understanding in the pathways of DNA repair will make the ability to predict radiation responsiveness a realistic possibility. The functional evaluation of radiation response genes - often discovered in other species - may allow the development of rapid and cheap assays from very limited amounts of tissue. Designer fractionation, optimising the timing of radiation delivery to each patient, will be planned from molecular measurements on tumour and normal fine needle aspirates.

It is likely that complex physical and biological parameters will be used in conjunction with treatment algorithms to draw together multiple data sources so that beam configuration and fractionation schedules can be optimised on an individual basis. The therapist will use virtual reality reconstruction systems to assess progress during treatment by direct observation of tumour shrinkage.

Chemotherapy

The major problem in cancer treatment is undetected metastatic disease at the time of primary therapy. For many of the common tumours our systemic treatments are inadequate and there have been essentially few advances over the last 50 years (Table 4.5). Table 4.6 examines the current status of chemotherapy in patients with a variety of metastatic tumours.

The key problem in the effective treatment of patients with solid tumours is the similarity between tumour and normal cells. Local therapies such as surgery and radiotherapy can succeed, but only if the malignant cells are confined to the area treated. This is so in around one-third of cancer patients. For the majority, some form of systemic selective therapy is required. While there are many cytotoxic drugs available, only a small proportion of patients are actually cured by their use. The success stories of Hodgkin's disease, non-Hodgkin's lymphoma, childhood leukaemia, chorio- carcinoma and germ cell tumours have just not materialised for the common cancers such as those of the lung, breast or colon.15 Despite enormous efforts in new drug development, clinical trials of novel drug combinations, the addition of cytokines, high-dose regimens and even bone marrow rescue procedures, the gains in survival have been marginal. Against this disappointing clinical backdrop we have seen an explosion of information on the molecular biology of cancer. Although our knowledge of growth control is still rudimentary, we have at last had the first glimpse of its complexity. This has brought a new vision with which to develop novel selective mechanisms to destroy tumours.16 This does, however, raise the question over the fact that currently 70% of the cancer budget is being spent in the last 6 months of patients' lives, often on fairly ineffective, expensive chemotherapeutic regimens. A hard but necessary decision will need to be taken to invest more of this money in the earlier phases of the illness in provision of support measures to help strengthen the individual's coping style, and in increasing involvement of patients in the promotion of their own health, well-being, and quality of life. Improvements in mental state and positive involvement in self-help programmes will make it easier for patients to say no to "last ditch" medical interventions, due to their greatly improved quality of life and peace of mind.

The next decade should see a new golden age of drug discovery. This will not be based on empirical screening programmes as in the past, but on logical drug design using molecular graphics to produce novel structures that will interfere with specific biological processes vital for growth. These will include blocking and stimulating therapies for signal transduction pathways; inactivators of oncogene products; the use of high throughput screens to discover small molecules to mimic tumour suppressor genes; transcription control inhibitors for specific genes; selective activators of apoptosis; cell cycle inhibitors and effective antimetastatic drugs.17 These processes have evolved to use very similar pathways in a wide range of organisms. Thus studying the molecular genetics of a specific functional process in yeast or the worm often will shed light on the human equivalent. The construction of knockout or transgenic animals, where a specific genetic change is artificially created, allows the exploration of that gene's precise function. It is also likely that model systems will be developed to explore the use of direct genetic intervention for the treatment and perhaps even prevention of cancer prior to clinical trials.

Gene therapy

The main problem facing the gene therapist is how to get new genes into every tumour cell. If this cannot be achieved then any malignant cells that remain unaffected will emerge as a resistant clone. Presently we do not have ideal vectors. Despite this drawback, there are already nearly 300 protocols accepted for clinical trial in over 4000 cancer patients worldwide, the majority in the USA. The ethical issues are fairly straightforward with oncology providing some of the highest possible benefit-risk ratios. There are several strategies currently under investigation.

Genetic tagging

The use of a genetic marker to tag tumour cells may help in making decisions on the optimal treatment for an individual patient. The insertion of a foreign marker gene into cells from a tumour biopsy and replacing the marked cells into the patient prior to treatment can provide a sensitive new indicator of minimal residual disease after chemotherapy. The commonest marker is the gene for neomycin phosphotransferase - the neo R gene, an enzyme which metabolises the aminoglycoside antibiotic G418. This gene, when inserted into an appropriate retroviral vector, can be stably incorporated into the host cell's genome. Originally detected by antibiotic resistance, it can now be picked up more sensitively by means of the polymerase chain reaction. In this way as few as one tumour cell among one million normal cells can be identified. This procedure has helped in the design of aggressive chemotherapy protocols in leukaemia and neuroblastoma.18 It has also proven valuable in elucidating the reasons for relapse after autologous bone marrow or stem cell transplantation where recurrent tumour samples can be examined for tagged genes inserted into donor infusions.

Enhancing tumour immunogenicity

The presence of an immune response to cancer has been recognised for many years. The problem is that human tumours seem to be predominantly weakly immunogenic. If ways could be found to elicit a more powerful immune stimulus, then effective immunotherapy could become a reality. Several observations from murine tumours indicate that one reason for weak immunogenicity of certain tumours is the failure to elicit a T helper cell response. This in turn releases the necessary cytokines to stimulate the production of cytolytic T cells which can destroy tumours. The expression of cytokine genes such as interleukin 2 (IL2), tumour necrosis factor (TNF) and interferon in tumour cells has been shown to bypass the need for T helper cells in mice. Similar clinical experiments are now in progress. Melanoma cells have been prepared from biopsies and infected with retrovirus containing the IL2 gene. These cells are being used as a vaccine to elicit a more powerful immune response.19

Vectoring cytokines to tumours

Cytokines such as the interferons and interleukins have been actively explored for their tumoricidal properties. Although there is evidence of cytotoxicity, their side effects are profound which limits the dose that can safely be administered. It is possible to insert cytokine genes into cells that can potentially home in on tumours and so release a high concentration of their protein product locally. TNF genes have been inserted into tumour infiltrating lymphocytes from patients with melanoma and given systemically. These experiments are controversial for two reasons. First, it appears from in vitro studies that the amount of TNF expressed from such cells was unlikely to be sufficient to cause a significant cytotoxic effect and, second, the insertion of a foreign gene limits the ability of the lymphocyte to target into tumour masses.20 Over 20 patients have so far been treated at the US National Cancer Institute and formal publication of the results is eagerly awaited.

Inserting drug-activating genes

The main problem with existing chemotherapy is its lack of selectivity. If drug-activating genes could be inserted which would only be expressed in cancer cells then the administration of an appropriate prodrug could be highly selective. There are now many examples of genes preferentially expressed in tumours. In some cases, their promoters have been isolated and coupled to drug activating enzymes. Examples include alphafetoprotein in hepa- toma, prostate-specific antigen in prostate cancer, and c-erbB2 in breast cancer21 (Table 4.7).

Such promoters can be coupled to enzymes such as cytosine deaminase or thymidine kinase, thereby producing unique retroviral vectors which are able to infect all cells but can only be expressed in tumour cells. These suicide (or Trojan horse) vectors may not have absolute tumour specificity, but this may not be essential - it may be possible to perform a genetic prostatectomy or breast ductectomy, so effectively destroying all tumour cells as well as certain normal tissue.

Suppressing oncogene expression

The downregulation of abnormal oncogene expression has been shown to revert the malignant phenotype in a variety of in vitro tumour lines. It is possible to develop in vivo systems such as the insertion of genes encoding for complementary (antisense) mRNA to that produced by the oncogene. Such anti-genes specifically switch off the production of the abnormal protein product. Mutant forms of the c-ras oncogene are an obvious target for this approach. Up to 75% of human pancreatic cancers contain a mutation in the twelfth amino acid of this protein and reversal of this change in cell lines leads to the restoration of normal growth control. Clearly the major problem is to ensure that every single tumour cell gets infected. Any cell which escapes will have a survival advantage and produce a clone of resistant tumour cells. For this reason it may be that future treatment schedules will require the repetitive administration of vectors in a similar way to fractionated radiotherapy or chemotherapy.

Replacing defective tumour suppressor genes

In cell culture malignant properties can often be reversed by the insertion of normal tumour suppressor genes such as RB-1, TP53, and DCC.22 Although tumour suppressor genes were often identified in rare tumour types, abnormalities in their expression and function are abundant in common human cancers. As with anti-gene therapy, the difficulty in this approach lies in the delivery of actively expressed vectors to every single tumour cell in vivo. Nevertheless clinical experiments are in progress in lung cancer where retroviruses which encode TP53 genes are being administered bronchoscopically. Tumour regressions have been reported.23 A total of 187 gene therapy protocols for cancer are now active (Table 4.8).

Immunological approaches

The last 10 years have seen dramatic advances in our understanding of how human T lymphocytes recognise and in some situations destroy cancer cells. Major efforts are going into the development of various types of cancer vaccine using peptide, glycoprotein, antitumour antibody idiotype antigens as well as autologous or allogeneic tumour cell lines.24 Polynucleotides encoding for various tumour-specific peptides have been claimed to raise a powerful immune response under certain situations.

Recently the successful cloning of cytolytic T cells (CTL) has led to the identification of a series of antigenic peptides degraded from intracellular proteins and ending up in the clefts of major histocompatibility complex (MHC) molecules on the external surface of the cell. Three approaches have been used in their identification. Target cells transfected with cDNA libraries have been used to analyse the specificity of CTL clones. This genetic approach was used to identify the MAGE series of melanoma antigens as well as MART, tyrosinase and Melan-A. A biochemical strategy has been the separation and characterisation of peptides from purified MHC molecules. A third approach has been the construction and analysis of the response to synthetic peptides that bind to MHC class I determinants.25

Phase I clinical trials are now in progress using several vaccine strategies (Table 4.9). Most involve direct peptide injection with immunological adjuvant, but enhanced responses may be obtained by using autologous dendritic cells pulsed with peptide antigens. Assays are available to measure the immunological effectiveness of such vaccines so that optimisation can be achieved before moving to larger scale phase II trials aimed at determining efficacy.

Psychosocial care

The quality of psychosocial care currently available to patients is patchy. There is good evidence of variation not only in the skills and technology available in many hospitals, but also in the clinical outcomes.26 Psychological support, counselling, complementary therapies and genuine dialogue between patient and health-care professionals are not ubiquitous.

The next decade is likely to see an inexorable rise in patient power. This will lead to increased sharing of information about treatments and their impact on the quality of life. Already the internet provides an amazing plethora of essentially uncontrolled information on cancer frequently accessed by computer-literate patients and their families. Society is seeing the deglorification of professionals whether in law, government or medicine. The media will become even more ruthless in dealing with inconsistencies and varied standards currently in use. At the same time traditional support structures, such as organised religion, the family unit, and social services, are declining in their impact. Consumerism will develop in cancer care. Already we can see this with the use of complementary therapies.27

Complementary therapies have been widely used by cancer patients for many years. The failure of modern medical science to live up to its expectation to cure the majority of common cancers, together with an increasing self empowerment of those with life-threatening illness, have resulted in a dramatic increase in interest in both complementary and alternative treatments for cancer, as well as holistic self-help approaches.

There is a wide spectrum of belief in complementary medicine. In the past it has been seen by some as a true alternative to orthodox medicine. Surgery, radiotherapy and chemotherapy were regarded as evil - cutting, burning and poisoning. Zealots holding this view did untold damage dissuading people from having potentially helpful treatment. Often these views emanated from charismatic practitioners who were far from holistic - indeed they usually pursued single treatment modalities such as electrical and crystal therapies, extreme diets with detoxification or semi-secret organic remedies. At the other end of the spectrum, and equally damaging, was the patronising paternalism of establishment medicine - readily dismissing the potential of complementary medicine to help people. Over the last decade we have seen the two opposing extremes come together to share a middle ground, where by pooling knowledge and understanding, patients can gain immensely. Table 4.10 examines currently used therapies.28

The pharmacological therapies are especially popular in the USA where a vast information network has been established initially through specialist book publishers and more recently on the internet. They are much less popular in Britain, although vitamins and homoeopathy are widely utilised. There are considerable difficulties surrounding the use of pharmacologically based therapies in an orthodox clinical setting. It would be illogical not to apply the same scrutiny for, say, sharks cartilage or high-dose vitamin therapy as for any anticancer agent. And yet the beneficial results often claimed are extreme but with only anecdotal evidence. Some practitioners of such treatments may well promise cure from the disease often at considerable expense. The psychological therapies also have extreme variants which may pose considerable dangers to some patients, especially if carried out by inexperienced practitioners. These include the more extreme forms of psychic surgery and rebirthing experiences which can lead to longlasting and damaging psychotic reactions.

Many cancer centres in Britain are developing programmes of supportive care using some of these treatments. Most are avoiding the pharmacological and more extreme psychological and physical therapies. A major problem is the lack of high quality research showing benefit. Most of us believe that complementary therapies are helpful in improving the quality of life of many cancer patients. It may even have a small but measurable effect on disease-free and absolute survival of many different cancer types. The problem is proving it through rigorous and preferably randomised clinical trials. This area of research is extremely challenging. Different levels of patient motivation, together with the problems in assessing quality of life, make things very difficult for the investigator. Indeed the gold standard of the randomised clinical trial may often be an inappropriate tool for this type of research which may need new paradigms for its analysis. It is easy for those involved in purchasing services to use the lack of good conventional data showing benefit as an excuse to turn down applications for funding.

There has now been a tremendous evolution in our understanding of the application of the holistic approach to health and illness, which revolves primarily around involving patients in the promotion of their own health through therapies and self-help techniques which strengthen them in body, mind, and spirit. There is now greater understanding and tolerance of the role of complementary therapies in support and symptom control in cancer, and genuine understanding of the need of some patients to seek more extreme alternative treatments in the face of crushing medical statistics. There has been a great settling down of earlier fears that holistic practitioners and centres were trying in some way to take patients away from their orthodox treatments, or that they were even trying to actively exploit patients, but these fears have largely been allayed through better communication and ongoing mutual educative processes. Sometimes patients and practitioners involved in holistic approaches do place too much emphasis on the potential role the individual may have in the aetiology and treatment of their cancer, and care must be taken to give the right level of weighting to these approaches so that individuals do not become over responsible and self-blame if they do not become well.

The public interest in complementary therapies and self help has spawned a vast information network about conventional as well as complementary therapies. The internet carries a huge amount of unverified cancer information increasingly accessed by patients and families.29 Clearly if handled correctly, such technologies could become the educational tools of the future. However, it must be realised that at present the use of complementary and self-help approaches gives invaluable tools through which patients' "fighting spirit" can be channelled. There is strong evidence that fighting spirit improves prognosis in cancer30 and patients do need safe ways of feeling involved in the management and control of their cancer. Therefore, even if there is weak evidence about the benefits of these approaches per se, it is crucial that patients are encouraged and not discouraged from getting involved in measures which will help them to feel in control and actively fighting. It is also clear that patients often get very strong placebo effects from being involved in alternative and complementary therapies, as well as a great deal of tender, loving care. There is also increasing evidence for the role of support and self-help techniques in extending survival as well as purely quality of life.31^,32 The next 25 years will see a great refinement in our understanding of which are the intrinsic beneficial elements of complementary and self-help approaches which have predictable and repeatable clinical benefits in allopathic terms, and which are non-specific benefits which are mediated through the effect on coping style, mental state, and placebo.

Cancer planning

The optimal organisation of cancer treatment services is vital if they are to be most effective. Hub and spoke models are clearly the way forward, modified to accommodate the geographical and economic factors of a particular country. Developing a national cancer plan which anticipates technology moving forward is essential for all countries. WHO has developed a series of guidelines in this area which can be adapted widely.33 At present less than 40% of United Nations member states have an effective cancer plan. This must include prevention, early detection and education programmes as well as coordinated facilities for disease management.

The services available to people with cancer in Britain have been under intense review over the last 3 years. In the late 1980s it was clear that Britain lagged behind survival statistics for several of the common cancers. At first the data was not considered firm enough - different collection methods, varying pathological classification, and a plethora of staging systems were all confounding factors. However new data such as those produced by the EUROCARE study are convincing.34 Furthermore there is considerable variation in outcome now clearly demonstrable between different hospitals. In 1993, an Expert Advisory Group on Cancer was established to help reshape cancer services in England and Wales. It consisted of 15 members from different backgrounds, its task was to produce a plan to overhaul cancer services.

The framework produced35 essentially calls for a series of cancer centres as hubs linked to a series of spokes - the cancer units - at general hospitals. The idea is simple. If you have cancer then the quality of care should be the same wherever you present - a sort of oncological Macdonalds. The problem now is its implementation in an increasingly fragmented, competitive and dispirited NHS. There have been many local and regional meetings to set the agenda for change. It is likely that a new pattern of cancer care will be established by the end of the decade.

On a global scale, around 60 of the 191 member states of the United Nations have some form of cancer plan. As the numbers of patients grows with increasing longevity it is vital that coordinated prevention, education, early detection and care plans are drawn up appropriate to the epidemiological distribution of cancer types and the economic background of the country. WHO is assisting counties to do this, in some cases using almost no resources.

Conclusion

It is clear that there is tremendous potential for some very exciting advances in the prevention, diagnosis and treatment of cancer over the next few years. Never before has so much information been available about the disease at a basic level. Getting the best possible treatment to each patient will require concerted and imaginative planning of the structure of the services provided. Such plans will need to be specifically adapted to the geographical, economic and cultural factors; the plans should also be fluid enough to cope with changes in both society and technology. Looking 50 years ahead is difficult. By then the human genome project will be completed with rapid DNA sequence comparisons routinely possible by GPs using arrays of gene chips in their offices. Patients will seize control of their health both for prevention and treatment. The global burden of cancer will start reducing by the year 2015, although the number of new patients will be increasing through the effects of ageing. As we go in to the second half of the next century, cancer will be a relatively rare illness in the developed world, although sadly it will continue to increase in poorer countries.

1 Our vision for cancer. Imperial Cancer Research Fund, London, 1995.

2 Thorogood M et al. Dietary habits and mortality in 11 000 vegetarians and health conscious people: results of a 17-year follow-up study. Br Med J 1996; 313: 775-9.

3 Eeles R, Ponder B, Easton D, Horwich A, eds. Genetic predisposition to cancer. Chapman and Hall, London, 1996.

4 Plummer S, Casey G. Are we any closer to genetic testing for common malignancies? Nature Med 1996; 2: 156-8.

5 Ponder BA. Genetics of malignant disease. Brit Med Bull 1994; 50: 517-752.

6 Markham AF, Coletta PL, Robinson PA et al. Screening for cancer predisposition. Eur J Cancer 1994; 30: 2015-29.

7 Strachan T. The human genome. Bios Scientific, Oxford, 1994.

8 Farzaneh F, Cooper DN. Functional analysis of the human genome. Bios Scientific, Oxford, 1995.

9 Gullick W, Handyside A. Preimplantation diagnosis of inherited predisposition to cancer. Eur J Cancer 1994; 30: 2030-2.

10 Brady LW, Mieszkalski G. Cancer cure with organ preservation using radiation therapy. Frontiers Radiation Ther Oncol 1993; 27: 245-9

11 Brown TH, Irving MH. Introduction to minimal access surgery. BMJ Publishing, London, 1995.

12 Buckingham RA, Buckingham RO. Robots in operating theatres. Br Med J 1995; 311: 1479-82.

13 Price P, Macmillan T. Radiotherapy in the 21st century; a forward look. In: Tobias JS, Thomas PR, eds. Current radiation oncology, 1994, pp. 382-400.

14 Price A. Molecular targets of radiotherapy. In: Lemoine N, Neoptolemos J, Cooke T, eds. Cancer - a molecular approach. Blackwell Scientific, Oxford, 1994, pp. 315-34.

15 Sikora K, Price P. Treatment of cancer. Chapman and Hall, London, 1995.

16 Varmus H, Weinberg RA. Genes and the biology of cancer. Scientific American Library, New York, 1993.

17 Sporn M. The war on cancer. Lancet 1996; 347: 1377-81.

18 Brenner MK, Rill DR, Moen RC et al. Gene marking to trace origin of relapse after autologous bone marrow transplantation. Lancet 1993; 341: 85-6.

19 Fearon ER, Pardoll DM, Itaya T et al. Interleukin 2 production by tumour cells bypasses the T helper cell function in the generation of an antitumour response. Science 1991; 254: 713-16.

20 Rosenberg SA. Gene therapy for cancer. JAMA 1992; 268: 2416-19.

21 Harris J, Guttierez A, Hurst H, Sikora K, Lemoine N. Gene therapy for cancer using tumour specific drug activation. Gene Ther 1994; 1: 170-7.

22 Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild type p53. Science 1990; 249: 912-15.

23 Roth JA. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nature Med 1996; 2: 985-91.

24 James N, Sikora K. Clinical immunology, 4th edn. In: Lachmann P, Peters K, Walport M, eds. Blackwell Scientific Publications, Oxford, 1993, pp 1773-84.

25 Lewis JJ, Houghton AN. Definition of tumour antigens suitable for vaccine construction. Sem Cancer Biol 1995; 6: 321-7.

26 Faulkner A, Maguire P. Talking to cancer patients and their relatives. Oxford University Press, Oxford, 1994.

27 Lerner M. Choices in healing. MIT Press, Cambridge, 1994.

28 Bell L, Sikora K. Complementary therapies and cancer care. Comp Ther Nurs Midwif 1996; 2: 57-8.

29 Pallen M. The world wide web. Br Med J 1995; 311: 1552-6.

30 Greer et al. Psychological response to breast cancer and 15-year outcome. Lancet 1990; i: 49-50.

31 Fawzy FI, Fawzy NW, Hyun CD et al. Malignant melanoma, effects of an early structured psychiatric intervention, coping and affective state on recurrence and survival six years later. Arch Gen Psychiatr 1993; 50: 681-9.

32 Spiegel D. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 1989; ii: 888-91.

33 National Cancer Control Programmes. Policies and managerial guidelines. WHO, Geneva, 1995.

34 Berrino F, Sant M, Verdecchia A et al. Survival of cancer patients in Europe. IARC Scientific Publications, Lyon, 1995.

35 A policy framework for commissioning cancer services - a report by the expert advisory group on cancer services. Department of Health, London, 1995.
 
 

The following colleagues were invited to act as commentators on early drafts:

Rosy Daniel
Medical Director, Bristol Cancer Help Centre, Bristol, UK

Nicholas Lemoine
Professor of Molecular Pathology, Imperial College School of Medicine, Hammersmith Hospital, London, UK

Indraneel Mittra
Surgeon and Scientist, Tata Memorial Hospital, Mumbai, India

Maurice Slevin
Consultant Medical Oncologist, The London Clinic, London, UK

Masaaki Terada
Director, National Cancer Centre Research Institute, Tokyo, Japan

[Return to Clinical Futures index]