ACADEMY PUBLIC POLICIES

Why Don't We All Have Cancer?

World Health Organization _ Cancer

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Politics of cancer care

There are clearly many angles to the politics of cancer care, and these are linked closely to the economics of the disease. For the purposes of this chapter, I will focus on the differences in cases diagnosed and death rates and how they drive the politics of the disease, using breast and prostate cancer to illustrate gender differences and breast and lung cancer to illustrate social class effects.

In many ways, prostate cancer is the male counterpart of breast cancer. The similarities extend to a number of levels: both organs have a role in sexuality and reproduction; both change during life in response to hormone levels; both cancers can be treated by changes in the hormone environment; and treatments for the cancers arising in the respective organs cause profound changes in sexual function.

Politically, the powerful sexual and emotional imagery of the breast has been used to great effect to channel research and treatment funds into breast cancer for many decades. This has resulted in steady and progressive improvement in outcomes for women with breast cancer, reflected both in improved survival and reduced damage from successful treatment. For example, women are increasingly offered less mutilating surgery or breast reconstructions rather than radical mastectomy. On the drug funding issue, women have again been very effective at campaigning for new treatments - witness the rapid uptake of trastuzumab (better known as Herceptin) across the European and North American healthcare systems.

Until recently, despite the biological parallels, there was no analogous movement to support men with prostate cancer or campaigning to improve treatments and outcomes. As recently as 1995, for example, spending on prostate cancer research in the UK was only one-tenth that on breast cancer. In the last 10 years, this has changed, partly driven by the PSA test. This shifted the spectrum of prostate cancer substantially to the ‘left’, with a decrease in late cases and increase in early cases for which the treatment options are more varied and the possibility exists for cure or prolonged survival with the disease. This historical lack of public health and research interest is particularly surprising given the general concentration of political and economic power in the hands of men of middle age and above - those most at risk of the disease and with very little risk of breast cancer (though men can get it). The difference appears to be rooted in the differing psychologies of men and women – it’s fine for women to talk about breast cancer, and women are not seen as diminished but often rather strengthened by it - witness Kylie Minogue’s world tour. On the other hand, it has previously been very difficult for men to talk about the disease, particularly when treatments carry ‘unmacho’ risks such as impotence and incontinence, quite apart from the fundamentally embarrassing route needed for diagnosis (via the rectum). Coupled with most men’s general ‘ostrich’ approach to all matters related to health, the result has been a price paid by men living shorter, less healthy lives than women.

More recently, however, there has been a shift in public and economic policies, with more money spent on treatment for men and research into the disease. This has been driven no doubt in part by the pharmaceutical industry’s belated realization that there is a lot of money to be made from one of the biggest male cancer killers in the West. There has also been a change in that major public figures such as Colin Powell, Roger Moore, and Rudolph Giuliani have been prepared to talk about their treatment for the disease.

Finally, the issue of smoking and public policy is worth mentioning in the context of the politics of cancer care, as this has varied widely across the world and over the decades. Not too long ago, tobacco companies actually ran adverts with the strap-line that a particular cigarette was the preferred brand for doctors. The linkage of smoking to increased risk of various cancers has been one of the triumphs of epidemiological research, and has resulted in massive reductions in the rates of smoking and diseases linked to it in the developed world. A range of measures has driven this, from legal (smoking bans) through educational (advertising and sponsorship bans, health warnings) through to fiscal (tax the stuff, which has the additional benefit of paying for the healthcare needed to pick up the consequences for smokers). In the developing world, things are different, however: smoking is still seen as ‘cool’, underpinned by advertising and marketing to young people, rather than the pariah activity banished to chilly doorways it has increasingly become in Europe and North America.

Furthermore, the money brought in to developing countries by the big multinational tobacco companies carries with it much political clout, and this can used to tone down the public health assault on the habit that has occurred in the West. Coupled with the young age structures of developing countries, an epidemic of developing world smoking-related cancers – lung, bladder, throat, mouth - can be anticipated in the coming years. In countries like China which are rapidly modernizing and improving living standards and life expectancy, this can be expected to result in particularly large increases in these cancers.

How does cancer develop?

In order to understand how cancer develops, it is necessary to include a little background on basic cell biology. The cell is the basic building block that makes up all living things. The human body, in common with all animals from the smallest such as yeast to the largest blue whale, is composed of cells. Some animals - yeast, for example - are made of single cells; others, ourselves included, are made of many different sorts of cells – blood, bone, brain, kidney, and so on. All cells in an organism have their own carefully controlled life cycle. Cancer occurs when the control of this cycle goes wrong, leading to unregulated growth of a group of cells which can spread and damage other structures in the body. This chapter will focus on how cancer develops and also on some of the underlying biology needed to understand this. I will also illustrate how an understanding of the causes can be used to define treatment strategies.

The key component of the cell for understanding cancer is the nucleus, which holds the DNA that contains the genetic code. Cancer is caused fundamentally by damage to the DNA leading to abnormal, unregulated growth of cells. Remarkably, although different cells may differ markedly in their appearance and function (for example, nerve cells, muscle cells, and blood cells), all the cells in a given organism share the same DNA code. DNA is clustered into long strands called chromosomes. There are 23 pairs in each human cell. Within each chromosome, the DNA is arranged in genes, each one coding for a single protein. We can think about genes and chromosomes as being like a library of books, with each of the 23 chromosomes an individual volume and each of the 21,000 genes a page of instructions in that volume. It is easy to see conceptually how damage to a page of instructions can lead to alterations in the properties of a cell.

We will run through how these different structures work and interact, and how they can go wrong to lead to the development of a cancer. Everyone starts life as a single fertilized egg that develops first into a ball of identical cells and then, progressively, grows, organizes, and develops into a complete complex individual. The process by which cells develop from this initial group into highly specialized subtypes is one of the most incredibly complex processes in nature and yet is happening constantly all around us and within us.

This clearly requires an intricate network of checks and balances. It requires that cells communicate with their neighbours to ensure that the right development path is followed at the right time. It requires that cells no longer required are deleted and eliminated with the minimum of disruption (a process called apoptosis, from the Greek word meaning ‘a falling off of petals’). As organs develop, they must grow their own blood supplies and maintain them in response to damage. It requires that organ systems communicate with each other, for example nerves connecting with the muscles they control. Endocrine (hormone) glands are coordinated to produce their products in cycles (for example, the ovaries) or in response to stress (the adrenal glands). This is achieved by genes being switched on and off in a coordinated fashion as individual organ systems grow and develop. Once the growth process is complete and the animal is formed, tissues must be maintained, damage repaired, and general housekeeping kept ticking over – nutrients supplied and processed, waste products eliminated, and so on. The more one thinks about the mind-blowing complexity of all these tasks, the remarkable thing is that the processes run so reliably for so many years in most people, and that cancer – essentially, unregulated cell division – does not occur more frequently than it does.

DNA structure and function

As already mentioned, the genetic code is stored in human cells in 23 pairs of chromosomes. Each chromosome comprises a very long molecule of DNA containing the genes, which are interspersed with spacer sequences. Each gene is flanked by regions of DNA that control when a particular gene is switched on or off. For example, the gene coding for the protein myosin, a key component of muscle cells, will be switched on where needed – in muscle – but off in other tissues where it is not required, such as nerve cells. The network of on and off switches is clearly critical to regulation of the behaviour of cells, and study of these controls is a major feature of cancer research – if the controls do not work, cells can grow in an unregulated fashion, as occurs in cancers.

To understand how cells carry out all these functions, it is necessary to understand a bit more about the structure of DNA and how the code embedded in the DNA molecule is translated into the end product that is the functioning organism. DNA is an abbreviation for deoxyribose nucleic acid. It had been known for some time before the famous discovery of its double helical structure by Crick and Watson in 1953 that DNA contained the genetic code. The DNA molecule is a long spine of two alternating building blocks – a sugar (called deoxyribose) and a phosphate group linked to four molecules named adenine, guanine, cytosine, and thymine (abbreviated to A, G, C, T) and referred to as bases. These bases are arranged along the spine of the DNA molecule and form two complementary pairs, A with T and C with G, that can bond to each other. The double helical nature of DNA results from one strand (the positive or sense strand) being matched by a complementary antisense strand with an A paired with every T, C with every G, and so on. The A-T and C-G bonds thus provide the ‘glue’ that maintains the double helical structure of the DNA strands. The complementary nature of the bond process means that if the two strands are pulled apart and each used as a template for two new strands, the result is two identical copies of the first DNA molecule.

This inherent property of DNA, whereby it can make identical copies of itself, is one of the fundamental properties of all life on Earth. The structure of DNA is very tightly conserved across the whole spectrum from the simplest to the most complex. The fidelity of the duplication process is also extremely high. The error rate is so low that it takes many generations to accumulate significant differences – the rate of genetic ‘drift’ – and is one of the bases for evolutionary biology. Coming back to the genetic books in the library: each time a cell divides, a complete set of the 23 pairs of volumes with their 21,000 genes (‘pages’ of information) must be ‘typed’ by the cell. From time to time, a comma, letter, or full stop will be mistyped. Mostly, as in a book, this will not alter the meaning, but sometimes, changes will be critical, with consequent alteration to how the daughter cell carrying the change (called a mutation) functions. Parenthetically, the number of small random differences can be tracked across the evolutionary tree to allow estimates of when a given pair of species diverged from each other.

Genes and control of gene expression

The fundamental unit that the DNA is organized around is the gene. A gene contains the code for a single protein. Proteins can have many functions ranging from structural, for example a protein called tubulin which makes the cell’s internal ‘skeleton’, to functional, such as forming the parts of muscles that contract. This flow of information, whereby information in DNA is transcribed into a message (in RNA) and then into a single protein, is one of the central concepts of biology.

Proteins are the key building blocks of cells, responsible for all the key activities. Other components of cells, such as fats and sugars, are manufactured as a result of actions of proteins. Proteins clearly have to have a range of functions, therefore. These include: signaling both within and between cells; structure (a sort of microscopic scaffolding); and, very importantly, proteins called enzymes, which act on other biological molecules to bring about the formation of new molecules. This process can be destructive – for example, the enzymes in digestive secretions (and washing powders!) which break down food; or constructive – the enzymes involved in the manufacture of new molecules for the cell.

The production of a protein from a gene involves the transcription of the gene into a messenger ribose nucleic acid (mRNA) molecule within the nucleus of the cell. The RNA molecule has a structure like DNA but differs in key respects. Firstly, the deoxyribose sugar (the D in DNA) in the backbone is replaced by ribose (the R in RNA). Secondly, the molecule is single-stranded. And thirdly, the thymine (T) base is substituted by uracil (U), though the pairing remains the same. In order to make RNA, the DNA double helix is temporarily ‘unzipped’ into two single strands. A complementary RNA molecule then assembles and is transported out of the nucleus into the cytoplasm and the DNA then zips itself back up again. This process, another key part of biology, is called transcription.

Once in the cytoplasm, this messenger RNA must be converted into protein, the second key part of the translation of the code embedded in the DNA into functional proteins. A second sort of RNA – called transfer RNA – provides the link between the messenger RNA and the building blocks of protein. Key to this translation process is the triplet code embedded in the DNA. Proteins, like DNA, are made up of chains of simpler molecules. The protein building blocks, called amino acids, can be linked together to form effectively endless chains. The basic amino acid molecule has three key features – termed a carboxy terminus and an amino (hence the name) terminus, plus a variable side branch which gives each amino acid its distinct properties.

Transcription

Whilst in theory an infinite number of types of amino acids are possible, only 20 are found in living organisms. The DNA code is arranged in triplets called codons. There are 64 possible three-letter codes using A, T/U, C, and G. Each triplet has a specific meaning and can either refer to an amino acid or, in effect, form a punctuation mark. For example, within this coding system, AUG means ‘start here’ (termed a ‘start codon’); UAG, UGA, and UAA mean ‘stop here’; while the remainder are linked to specific amino acids – for example, cysteine is UGU or UGC. As there are 64 possible combinations in the triple code but only 20 amino acids, it follows that some amino acids have more than one triplet code. It can easily be seen, therefore, that a mutation which changes a single base can fundamentally alter the resultant protein. For example, a change from UGC (cysteine) to UGA (the stop signal) will shorten the resultant protein, with a possible major change in function.

Amino acids and protein structure

As already mentioned, the core code of the gene is flanked by complex regulatory machinery to ensure genes are switched on and off at the correct times. It is this regulation of gene function that is often faulty in the cancer cell.

Regulation of gene expression requires the interaction of a complex series of events. To understand this, a little more detail on gene structure is required. On both sides of the coding portion of a gene are the control regions. As with a mutation in the coding region described already, it can easily be understood how changes to the regulation of the gene or the processing of the messenger RNA can result in over- or under-production of a protein or the generation of an abnormal protein with undesirable properties. These control regions are themselves regulated by other genes, called transcription factors, which turn gene expression up or down like a volume control. The transcription factors are the key regulators of the whole process, and it is therefore unsurprising that many of the genes involved in cancer turn out to be from this family of proteins.

The hallmarks of cancer

Having covered the basics of the machinery, we can now turn to the ways in which the processes go wrong to produce a cancer. In 2000, two leading cell biologists, Douglas Hanahan and Robert Weinberg, published a seminal paper entitled ‘The Hallmarks of Cancer’ summarizing the changes that are both necessary and sufficient to produce a cancer. A cancer cell differs from normal cells in that it divides in an unregulated fashion. In addition, cancer cells have the ability to spread to and invade other parts of the body. Hanahan and Weinberg summarized the processes that must occur in the cell in order for it to be transformed from a normal, law-abiding member of cellular society into a dangerous outlaw. These changes are characterized as:

Self-sufficiency in positive growth signals;

Lack of response to inhibitory signals;

Failure to undergo ‘programmed cell death’ to eliminate faulty cells;

Evasion of destruction by the immune system;

The ability to grow in and destructively invade other tissues;

Ability to sustain growth by generating new blood vessels.

The first two of these are reasonably self-explanatory and lead to unregulated growth. The third is less obvious and is linked to the development process. If all cells simply grew and divided, it would not be possible, for example, to form hollow tubular structures such as the gut or blood vessels. To do this, certain cells must be deleted from the growing organism as the needs of the growing structure dictate.

This process, already mentioned, is called apoptosis, and is a key cellular function. Apoptosis is also a method that the organism uses to get rid of faulty or malfunctioning cells such as those nearing the end of their lifespan that need replacing. Cancer cells are by definition abnormal and thus should be self-deleting. Failure to undergo apoptosis is thus key to the transformation from an abnormal cell into one with limitless replicative potential. A further feature of apoptosis is that cells damaged by chemotherapy or radiotherapy are frequently not killed outright, but merely ‘mortally wounded’. The subsequent death of the cell is often by apoptosis, illustrating that the evasion mechanism is not completely shut down, even in the cancer cell. Increasing resistance to apoptosis is, however, one way in which the cancer cell evades destruction by chemotherapy or radiotherapy.

Understanding apoptosis is unsurprisingly therefore one of the major areas of cancer research.

Further distinguishing features of cancers are their ability to grow and to invade other tissues in the body while avoiding destruction themselves by the immune system. The immune system can be regarded as a sort of cellular police force that identifies intruders such as bacteria and eliminates them. As cancer cells are abnormal, the immune system should be able to identify and destroy them.

Evasion of this process is therefore essential to the cancer. As already indicated, the growth and development of cells, tissues, and organs is very finely regulated to ensure the correct sort of cell grows in the correct place and time in the organism. One key aspect of cancer growth is the acquisition of the ability to grow in the wrong place, and this is a feature that distinguishes a malignant tumour from a benign one, which can grow but not spread or invade. It should be noted that benign tumours can still present severe consequences, for example an acoustic neuroma is a benign tumour of the auditory nerve that transmits signals from the inner ear to the brain. The tumour will progressively enlarge, causing deafness and balance problems, without ever spreading elsewhere.

The final hallmark of cancer is the ability to grow a new blood supply. Any collection of cells larger than around one-tenth of a millimetre across needs a blood supply. As the new tumour grows, it must therefore acquire the ability to stimulate blood vessel growth. The blood vessel growth of tumours is often haphazard and turns out to use genes not involved in the maintenance of normal blood vessels.

The process is known as tumour angiogenesis, and because it differs from normal angiogenesis, it has become an important target for cancer drug development. If it is possible to knock out the blood supply of the cancer, further growth is prevented. One of the most successful of the new generation of targeted molecular therapies, bevacizumab (Avastin), works by targeting this process.

Cancer Research UK

MediLexicon International -What Is Cancer? What Causes Cancer?

Carcinogenesis – how cancers start

As already indicated, cancer results when the changes required for the hallmarks of cancer have occurred. To understand how cancer develops, we now need to turn to how external factors bring about cancer - a process known as carcinogenesis. Fundamentally, cancer results from damage to DNA. All agents that damage DNA therefore are potential carcinogens – agents that cause cancer. The reverse is not true, however; not all agents that help cause cancer themselves directly damage DNA, though this always lies at the end of the process. Examples of cancer-causing substances that do not directly damage DNA include alcohol and the sex hormones involved in causing breast and prostate cancer. There are many sorts of carcinogens and many are well known – cigarette smoke and ionizing radiation, for example. Taking cigarette smoking, we know that typically it is necessary to smoke many cigarettes for many years for cancer to develop. This suggests that the process of carcinogenesis is slow and potentially has more than one step. From the discussion above, it would be predicted that mutations would be necessary in different sets of genes to cause the hallmark changes described by Hanahan and Weinberg. Such a chain of events was also postulated in the early 1990s and is now often referred to as the ‘Vogelstein cascade’, with each step in the chain representing a new mutation.

Dr Vogelstein’s group studied inherited bowel cancer, a condition in which there are a number of recognized pre-cancerous (also called pre-malignant) steps that could be identified in patients  They collected tissues from patients and set about identifying which genes were abnormal in the various steps along the pathway from normal bowel lining to a clinically obvious cancer. It turned out to be possible to identify candidate genes that need to be damaged for each step of the cascade to occur. Subsequent work has demonstrated that similar cascades of events apply to all tumour types, though the individual genes involved and the sequence of damage vary.

One fruitful way to identify genes has been to study families with so-called ‘inherited’ cancers. The term is a bit of a misnomer as the cancer is not inherited in the same way as, say, a diamond necklace, that is, as an intact, fully formed object. What is inherited is a greatly increased risk of developing a disease early, often in a very florid, aggressive form. One such disease is called adenomatous polyposis coli (APC). Patients with the disease develop multiple benign adenomas from an early age. In time, some of these progress to cancer, and without treatment death typically occurs in the early 40s from bowel cancer. Studies of patients with the disease showed that they had abnormalities in a particular gene, which was named APC. The identification of the APC gene in these patients led to further study of the function of the gene, which turns out to function as an ‘off-switch’. If it is knocked out, an important check on cell growth is removed and adenomas form. As is often the way with inherited cancers, the much commoner, non-inherited cancers turned out to share similar abnormalities. Studies of non-inherited bowel cancer confirm that the APC gene is malfunctioning in around 80% of these sporadic cases, so the gene clearly has a key function in regulating the normal growth of the bowel lining.

Studies of inherited cancers thus often shed important light on the causation of the non-inherited counterpart disease. Study of these ‘cancer families’ helped identify key cancer-related genes such as APC, RB (linked to retinoblastoma, a rare childhood eye tumour), p53 (linked to Li-Fraumeni syndrome, in which patients develop multiple different cancers), and VHL (linked to von Hippel Lindau syndrome, a complex disorder that includes kidney cancer). In addition, examination of the varying natural history of the inherited disease helps us to understand what the normal function of these genes may be. All of the genes mentioned above are termed ‘tumour-suppressor’ genes, but this is a misnomer as this is not their primary role in the organism. As may be predicted from the APC gene, these genes are key regulators of the cell cycle (the first two aspects of the hallmarks mentioned above), and damage or deletion of function leads to uncontrolled growth. Examining the normal functions of these genes has shed important light on how the cell cycle is regulated. As lack of control of the cell cycle is a hallmark of cancer, many cancer treatments work by interfering with the cell cycle genes that are misfiring in the cancer cell. In addition, a new generation of cancer drugs, the targeted molecular therapies, is currently hitting the clinics and the news headlines.

These drugs work by targeting specific molecules known to be misfiring in the cancer. Not all inherited cancer genes are directly involved in the cell cycle, however. A good example is the VHL gene, originally identified in patients with von Hippel Lindau syndrome. Sufferers develop multiple abnormalities from an early age, including cysts in the nervous system, in particular the cerebellum (part of the brain involved in balance and coordination), spinal cord, and retina, together with kidney tumours both benign and malignant. The kidney tumours are typically bilateral, multiple, and occur from a young age. As for APC, the patient inherits one non-functioning gene; a single hit to the remaining gene leaves no functioning VHL protein in the cell. Given that renal tumours are relatively rare but are common in patients with VHL, this tells us that the chances of a given gene suffering one hit are relatively high, but suffering two hits takes much longer, hence sporadic tumours are single and have a much later age of onset.

Detailed study of the VHL gene has revealed that it is involved in sensing the oxygen levels in the cell. If oxygen is low, this leads to the production of signals to surrounding cells to start growing new blood vessels. In other words, it regulates angiogenesis, a key hallmark of cancer.

Further studies have shown that these changes are sufficient to drive the cancer cell in the test tube, and the replacement of the VHL gene in these models will reverse the cancerous characteristics of the cells. Furthermore, the kidney tumour type found in VHL patients, called renal cell carcinoma, is characteristically very rich in blood vessels, as may be predicted from the gene function. Study of sporadic (non-inherited) renal cell carcinomas has revealed that VHL is mutated in around 70% of cases, making the VHL/angiogenesis pathway an attractive target for therapy. Research into new VHL-based treatments for kidney cancer, a notoriously difficult cancer to treat once it has spread, has proved very fruitful, with six agents licensed since 2006 and several more pending for a disease for which only two agents had been licensed in the previous 25 years. All of these agents target aspects of the pathway identified by the genetic research summarized above.

Non-inherited cancer

While inherited cancers shed important light on the classes of genes involved in cancer, the majority of cases of cancer do not result from an obvious inherited predisposition. As we have seen in the major causes of cancer death worldwide arise from tumours in the lung, stomach, liver, colon, and breast. Of these cancers, lung cancer is strongly linked to cigarette smoking, and liver cancer to infection with the hepatitis B virus, with a significant role for alcohol consumption. Cancers of the digestive tract are presumed to be linked to diet, but the precise causation is still poorly understood. Likewise, breast cancer (and prostate cancer in men) is clearly linked to both dietary and hormonal factors. How may these diverse influences act to produce the changes required to generate a cancer described above?

Lung cancer is the best understood example of how a carcinogen in the environment can interact to generate a cancer. The risk is clearly linked to amount of tobacco consumed – there is a dose effect – and the duration of consumption. Smokers who give up tobacco before getting cancer have a decreasing risk of developing the disease after stopping. In terms of a model like the Vogelstein cascade, smoking must be responsible for inducing the first steps of the cascade and continued smoking must also induce the subsequent steps. In older models of carcinogenesis, the initial step was often referred to as initiation and the subsequent steps as promotion of tumour growth, with a final step termed transformation. These terms still have value and in the laboratory, agents that convert non-malignant cell growths into cancerous ones are often referred to as transforming the cells.

Analysis of tobacco smoke has revealed a host of agents that will result in transformation in cell culture systems. Detailed study of these smoke constituents has revealed the precise molecular mechanisms at work, down to the mode of interaction with the DNA double helix. One of the key culprits is called benzopyrene, and careful research has demonstrated it will bind to the DNA helix, damaging the structure. As mentioned above, there is clearly a need for DNA damage – an initiating event followed by a generally prolonged period of further damage accumulation, sometimes referred to as promotion – before a final transforming event turns the pre-cancerous lesion into a full-blown cancer. In the case of tobacco, the process appears to be driven by continuous exposure to tobacco smoke, which has direct DNA-damaging properties. For other diseases, in particular breast and prostate cancers, the role of promoter is taken by the individual’s own hormones. As indicated, risk of breast cancer is influenced by duration of exposure of the breast to cyclical female hormones – hence early menarche and fewer pregnancies with no breast-feeding results in increased risk. The inference of this is that the continued cycles of changes in the breast induced by the menstrual cycle magnify any initial DNA damage done by some form of environmental carcinogen. A similar effect is seen in  prostate cancer, in that men castrated early in life (for example, eunuchs) have a very low risk of prostate cancer compared to their peers who presumably are exposed to the same environmental carcinogens. A similar role is played by alcohol in liver disease. Alcohol, as already noted, is not a direct carcinogen – it will not damage DNA. However, heavy long-term abuse of alcohol induces cycles of damage and repair in the liver, with increased cell turnover. As with the cyclical changes in the breast, this continual increased activity serves to magnify the harm done by the DNA-damaging agents which must also be present, increasing the opportunity for accumulation of further DNA damage and the development of cancer.

In the case of liver cancer, we also have detailed knowledge of the most frequent carcinogen – hepatitis B infection. The disease is a massive cause of suffering worldwide, but particularly in China and other parts of Asia where up to 10% of the population is chronically infected. There are lower rates in India and the Middle East, with rates less than 1% in Europe and North America. The risk of developing chronic infection is highest in those infected in infancy. Since 1982, a vaccine to HBV has been available. With vaccine programmes in place in various countries for some years, this has allowed scientists to complete the final test of the link between a virus and cancer – if the link were causal, preventing infection should and did prevent the disease. The precise molecular mechanism whereby the virus causes cancer is still being studied, but, as with smoking, the evidence for causation is now compelling.

Moving on to another cancer linked to infection – cervical cancer – we can see a similar story emerging. It was observed in the 1920s that cervical cancer was more common in women who had had high numbers of sexual partners, in particular prostitutes, and it was rare in nuns (except for those who had been previously sexually active), suggesting an infective, sexually transmitted cause. The disease was shown to be linked to infection with the human papillomavirus (HPV) by Harald Zur Hausen in 1976. Dr Zur Hausen found HPV DNA in both genital warts and cervical cancer. He received the Nobel Prize for Medicine for this discovery and his subsequent work in the field, which demonstrated the precise molecular links between the virus and the cancer. The virus produces various proteins which interact with two genes called Rb and p53, both key controllers of the cell cycle, providing an obvious route for generating a cancer.

The development of a vaccine against HPV and hence cervical cancer has proved more technically challenging than the HBV vaccine. However, the linkage between chronic viral infection and cancer allowed the study of the pre-malignant stages of cervical cancer. This led to the discovery that these could be identified in smears of cells taken with a wooden spatula from the cervix and then examined under the microscope. Identification of the pre-cancer stage, called cervical intra-epithelial neoplasia (CIN) or carcinoma-in-situ (CIS), allowed preventative treatment. Most European and North American countries have comprehensive screening based on the cervical smear test. These programmes have been estimated to have saved many thousands of lives. More recently, a vaccine against the varieties of HPV linked to cervical cancer became available in 2006 and is beginning to appear in public health vaccine programmes for girls as a way of preventing infection, with consequent reduction in cancer risk. There is some controversy about the vaccine as some interpret it as a way of protecting against the risks of promiscuity. However, protection against one sexually transmitted disease does not lower risks from others such as HIV. In addition, the vaccine will protect women against the risks of prior promiscuity in their partners, something they have no control over whatsoever. It will, however, take 10 to 20 years for this benefit to be seen, as this is the typical time lag between HPV infection and the development of cancer.

How is cancer treated?

Cancer treatment is complex and typically will involve input from a number of different groups, ranging from a wide assortment of doctors, including general practitioners (family doctors), surgeons, oncologists, pathologists, radiologists, palliative care specialists, as well as a huge number of other trained personnel – nurses, radiographers, physiotherapists, technicians in laboratories and radiotherapy departments, theatre orderlies, the list goes on and on. The details of organization for these different groups vary enormously from country to country and are a function of both the politics and economics of healthcare.

To try and get around this problem, I will present the organization of cancer treatment as a journey from symptoms to diagnosis, treatment, follow-up, and palliative care for those experiencing incurable recurrence. Different healthcare systems will process these events in a variety of ways, but by and large, the underlying principles are pretty universal. The final part of the chapter gives an overview of the main different classes of treatment, such as surgery, chemotherapy, and radiotherapy.

Initial diagnosis and investigations

Most patients still present with symptoms such as a persistent cough or problems such as blood appearing in the urine. Significant numbers are also picked up by screening programmes, either organized on a systematic basis (for example, for breast and cervical cancer) or more informally (such as PSA testing for prostate cancer). Some cases are picked up as incidental findings in the course of investigation for some other problem. For example, an abdominal scan may detect an asymptomatic tumour in a kidney. I will return to these groups of patients later.

Most patients will present to their doctor with some sort of symptom they have noticed and which they are worried about. Although symptoms, like people, come in an unlimited number of varieties, they can mostly be grouped into those causing disruption of normal function, such as a brain tumour disrupting normal movement, or abnormal symptoms due to damage by the tumour, such as bleeding, pain, or cough. The period between initial symptoms and diagnosis of cancer may be very short or may sometimes run to years. Sometimes the delay in diagnosis is down to misinterpretation of symptoms by health professionals, sometimes deliberate self-neglect or self-deception by patients, and sometimes a mixture of the two.

Unsurprisingly, the perception that an opportunity to make an early diagnosis has been missed can cause severe subsequent problems in the relationship between the patient and their doctor, often at a time when they need them most. Family doctors have a tough time in this respect. For example, headache and backache are common symptoms, and in the vast majority of cases have benign causes that may need symptomatic remedies but do not need extensive investigation. Occasionally, of course, these symptoms may indicate an underlying brain or spinal tumour. Another example is the presence of blood in the bowel motions. All medical students know that this may indicate bowel cancer. All family doctors will know that for patients in the ‘at risk’ age range for bowel cancer, the presence of conditions like haemorrhoids (an irritating condition of the lower anus that can bleed) are virtually universal. How do they then set about distinguishing the banal from the severe (but rare) without grossly over-investigating their patients? The answer often lies in another basic skill taught in medical school – the art of taking an accurate history. Thus, a sudden and unexpected change such as severe bleeding mixed in with motions is much more likely to be due to a cancer than a small quantity of bright red blood being seen smeared on the toilet paper occurring over a period of years.

Screening for cancer

In an ideal world, we would be able to offer tests that picked up cancer before it reached the more serious stages, allowing early intervention and a much greater prospect of cure. Such a process is called screening and is now available for a number of cancers: breast, uterine, cervix, and bowel. In addition, the PSA blood test is a potential screening test for prostate cancer, but its use remains controversial. It is helpful to describe the characteristics of an ideal screening test and then examine how these tests shape up in practice.

This is illustrated in the following example:

Features of an ideal screening test (Source: WHO)

 • The target disease should be a common form of cancer, with high associated death rate

• Effective treatment, capable of reducing the risk of death if applied early enough, should be available

• Test procedures should be acceptable, safe, and relatively inexpensive In addition, we need to consider:

• True positive rates: Sick people correctly diagnosed as sick

• False positive rates: Healthy people wrongly identified as sick

• True negative rates: Healthy people correctly identified as healthy

• False negative rates: Sick people wrongly identified as healthy

Relation between results of liver scan and correct diagnosis

 Thus the sensitivity (Patients with liver disease and abnormal scans/all patients with a positive scan) = 231/231+31 = 0.88 and the specificity (Patients with normal scans and no disease/all patients with normal scans) =54/(27+54) = 0.67

A further measure is the positive predictive value (the proportion of patients with abnormal scans who have liver disease) = 231/(231+27) = 0.89 and the negative predictive value of a negative scan (the proportion of patients with normal scans who have no liver disease) = 54/(32+86) = 0.45

For a test in the clinic, this is pretty good – a positive scan in someone suspected of having liver disease is a pretty good indicator that the person has the disease. How does this fare as a screening test, then?

To illustrate the difference between using a test for diagnosis in someone already known to be ill and screening for disease in people with no symptoms, we can look at the figures for breast cancer. Let us suppose that the rate of missed cases (the specificity) in those who we test is 10% and that the level of early, undetected disease is 1 in 500 people. If we now test 100,000 subjects, an ideal test would yield 200 positive tests in the cancer sufferers and 999,800 negative tests in those without the disease. However, our test, though good, is not perfect and will only detect 180 of the 200 cases, leaving 20 people wrongly reassured. Conversely, the test is also not completely specific. Let us say that 95% of those without the disease will test negative but 5% will wrongly test positive. When we apply this to our screening population, we see that this means that 5% of the 99,800 without the disease will falsely test positive. This works out as 4,999 false positive tests in people without the disease. This means that only a minority (180/4,999 = 4%) of those with a positive test actually have the disease, but 4,999 – 180 = 4,819 people have had a nasty scare. Furthermore, 20 have been falsely reassured and will go on to present with cancer anyway, possibly detected late as they may ignore the symptoms, believing themselves to be cancer-free. However, the overwhelming majority of those with a negative test (99,800 – more than 99%) really were free of the disease, so a negative test is pretty reassuring.

These worked examples are important, as they illustrate the limitations of screening tests which at first sight sound pretty good. In point of fact, the figures above are the best figures available – sensitivity and specificity fall in younger women (probably because their breast tissue is denser, making it harder to see abnormal lumps), leading to more incorrectly categorized cases. Furthermore, while the cost of the test itself is small, the cost of chasing up the false positives is much larger and needs to be factored into the costs of the screening programme.

There is a further problem when working out the benefit of screening. In our example above, we will identify cases of cancer earlier than would have happened without screening, potentially improving treatment prospects. However, with breast cancer, the cure rates are good, with three-quarters of diagnosed women being long-term survivors. This leaves the quarter who are destined to do badly, who are the main potential beneficiaries of screening. This is a relatively small number in relation to the numbers of tests carried out, and the downside is over-investigation of healthy women without breast cancer.

Investigating suspected cancer

Whether the patient has been picked up by a screening programme or has presented to their doctor with worrisome symptoms, the next step is to carry out further tests to confirm or exclude the diagnosis. Diagnosis is usually based on a tissue sample (biopsy) of the affected organ, preceded by clinical examination by a doctor, imaging, and blood tests. Ideally, cancer would be investigated using non-invasive imaging tests. In practice, in almost all cases the diagnosis needs to be confirmed by examining a tissue sample in the laboratory. Imaging is key to deciding where and how to obtain tissue. Modern cross-sectional imaging either with X-rays – computed tomography, or CT, scans – or using magnetic resonance imaging (MRI) can give remarkably detailed pictures of internal organs and suspected tumours. However, even the best imaging is unable to show with certainty whether a mass is cancerous and also, even if the diagnosis of cancer is highly likely, exactly what sort of cancer. Occasionally the imaging is sufficient. For example, an elderly, frail, life-long heavy smoker with suspected lung cancer on a chest X-ray and who is unfit for any treatment may be spared the discomfort of a confirming biopsy. One or two other scenarios may also not require a biopsy – patients with extensive cancer deposits in bone (a common site of spread for prostate cancer) on imaging and a grossly elevated serum prostate specific antigen (PSA) can be reliably diagnosed as having widespread prostate cancer with no biopsy. In all of these cases, the abnormalities are evident. However, even for radiologically obvious lesions such as these, a biopsy is generally required to determine the exact cancer type and hence the appropriate treatment.

The role of the pathologist in cancer diagnosis

The pathologist assesses small tissue samples taken, for example, via a needle – biopsies. Occasionally, for example in renal cancer, the initial material may be from a surgically removed organ, such as the diseased kidney. Mostly, this is done by mounting very thin slices of the removed tumour on slides and then carrying out a range of stains which highlight particular features of interest. The stained slides are then examined by the pathologist using a microscope. A commonly used stain is haematoxylin and eosin (usually called H&E) which highlights the various components of the cell such as the nucleus. Increasingly specialized stains are used which help further characterize the tumour. An example would be staining for the oestrogen receptor in breast cancer which helps predict the response of the cancer to both chemotherapy and hormone therapy. There are a rapidly growing number of available tests, mostly based on monoclonal antibodies (which are also increasing rapidly as a form of treatment). In addition, tests can also be done to look for changes in the expression of particular genes or to look for the presence of particular mutations or rearrangements in chromosomes.

The primary question for the pathologist is: ‘is it cancer?’ If the answer is ‘yes’, then secondary questions include the specific type – in other words, in which organ did it start and which subtype. In addition, cancers are graded in terms of aggressiveness, typically on a scale of one (low) to three (high). Some cancers, for example prostate cancer, lymphoma (cancer of the lymph glands), and sarcomas (cancers of the connecting and structural tissues such as bone, muscle, or cartilage), have different grading systems, but the same principles apply. All of these systems are based on the size and shape of the cancer cells and how they compare to the normal cells in the organ in which they originated.

More recently, and increasingly, additional sub classification is based on molecular markers present on the cancer. These can be defined as characteristic features based on excessive levels of particular markers either in the tumour itself or circulating in blood (or sometimes present in urine). Probably the best-known example of a molecular marker is HER2 in breast cancer. This was initially described as a marker of poor outcome in breast and ovarian cancer by Dr Denis Slamon from UCLA in the late 1980s. This led to the development of the drug trastuzumab (Herceptin), intended to target cells with excessive amounts of the protein (termed over-expression). Landmark trials, initially in patients with advanced disease and subsequently in newly diagnosed patients, showed that the drug significantly improved outcomes for the 25% of women with tumours with high levels of the HER2 protein. Staining tumour samples for HER2 expression thus gives important information about prognosis (treatment outcomes) and also helps guide the choice of treatment.

The other major role for the pathologist in cancer care is the assessment of specimens resulting from surgical removal of organs containing cancer. In addition to the questions posed above, which will be reassessed with the larger specimen, the pathologist is also addressing issues such as:

• Is the tumour confined to the organ that has been removed at surgery?

• Are the surgical resection margins (the edges of the specimen) free of tumour?

• Is there spread to other associated structures such as lymph glands?

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Treatment decision-making

Having carried out a biopsy and appropriate imaging, a decision has to be made about the treatment approach for the patient. An important initial decision is whether or not cure is feasible. If treatment is going to be essentially palliative, this must be factored into decision-making – quality of life becomes paramount. If treatment is potentially curative, then different considerations apply – research has shown that patients will endure considerable side effects in return for a chance of cure. Whether the aim is cure, life prolongation, or palliation of symptoms, a range of approaches are available and may be used either alone or in combination. Decisions need to be reviewed on a regular basis and treatment adapted in accordance with side effects and tumour response – that is, whether or not things are improving.

Increasingly, in major healthcare systems, these decisions are not made by individual doctors but by a multi-disciplinary team, usually abbreviated to MDT (in the UK, this is now mandatory if the hospital is to receive reimbursement for cancer therapy). Typically, these teams will comprise surgeons, radiation and medical oncologists, radiologists, pathologists, and specialist nurses. The MDT will review the baseline information (termed staging information) prior to the consultation with the patient to review the various test results. Generally, these decisions will be based on national or international guidelines on best practice. The results and treatment options will then be discussed with the patient in the clinic, and the clinical plan finalized.

The various treatment modalities will be dealt with in turn, but before doing so, it may be helpful to give a broad breakdown of the relative importance of the treatment modalities. . For example, bladder cancer can be managed either by surgery to remove the bladder (cystectomy) or by radiotherapy to destroy the tumour, with surgery reserved for salvage of radiotherapy failures. In the USA, very few patients are managed electively with radiotherapy, which is reserved mostly for palliation (symptom control) in the elderly and frail. In contrast, in the UK, around two-thirds of patients are managed with primary radiotherapy, with surgery focused on the younger, fitter patients. These differences in practice stem largely from the differences in the UK and US health economies rather than any evidence-driven differences. The essential principle underlying the distribution is that around 30% of cases are only very locally invasive – for example, basal skin cancers (commonly called rodent ulcers) – and require a very limited local therapy, usually surgery but occasionally radiotherapy. Of the rest, around 40% of patients end up with widespread cancer and 30% have locally advanced cancer, which can be eradicated by local/regional treatments such as surgery or radiotherapy. As already indicated the precise split varies in part by geography but also varies with anatomical site. For example, cancer of the colon is best treated with surgery rather than radiotherapy, as a normal large bowel is relatively intolerant of radiotherapy, and also targeting a mobile structure is clearly problematical. On the other hand, cancer of the uterine cervix (neck of the womb) is now predominantly treated by radiotherapy combined with simultaneous chemotherapy, with surgery reserved for salvage cases plus a limited role in assessing the disease for local spread.

Of the patients who end up with advanced cancer, around half present with this in the first place, the other half start out with apparently localized disease but then subsequently relapse with more widespread problems. Of patients who develop advanced (usually called metastatic) cancer, the majority will have essentially incurable disease. These will be diseases like advanced lung, bowel, breast, prostate, or liver cancer – the major cancer killers. A minority will have potentially chemocurable diseases such as testicular cancer, lymphoma, leukaemia, or certain childhood cancers.

It can be seen from this breakdown that the majority of patients cured of cancer in the 21st century are treated with modalities developed initially in the 19th century – surgery and radiotherapy. The major drug treatment advances, which drive so many of the news headlines, started in the mid-20th century and mostly extend lives in advanced disease rather than actually curing patients. This fact is well known to public health doctors but less well appreciated by the general public. It follows from this that in poorer economies; the maximum impact on cancer will be obtained by putting in place good basic surgery and radiotherapy. The best illustration of this is the survival rates worldwide for rectal cancer, for which the best results are obtained in Cuba, renowned for its well-organized medical care but with very limited access to the more expensive new drugs. Where resources are limited, cancer chemotherapy is best focused on the rare chemocurable cancers such as childhood leukaemia and testicular cancer. As these cancers mostly occur in younger people, the impact from drug spend in this area on life years saved is disproportionately high compared to spending on end-of-life cancer drugs in older patients. Drug therapy for advanced disease occurring in later life tends to have a much smaller impact on cure rates. Even if cures were common, the patients themselves are older and thus have more limited life expectancy anyway.

Surgery

Surgery clearly dates back millennia, but the era of cancer surgery really dates back to the development of effective anaesthesia in the mid-19th century, which moved surgery from the ghastly, last-ditch ‘gore-fest’ of emergency amputations to controlled dissections. As already discussed, surgery to remove the tumour is one of the mainstays of cancer therapy (together with radiotherapy), and despite advances in drug treatment seems set to remain so for the foreseeable future. Increasingly, surgeons are developing minimally invasive (often called keyhole) techniques to operate without performing large incisions. These have the advantage of rapid postoperative recovery, but do increase operation times and are technically challenging. These techniques do allow older, frailer patients to be operated on due to the faster recovery times. They are also more generally attractive to all patient groups as they are less painful in the recovery period and rehabilitation to full normal function is quicker. Against this, operating via long metal tubes whilst peering down a modified telescope has been likened to tying your shoelaces with chopsticks, making exponents of open surgery claim that the key cancer outcomes – completeness of tumour removal, for example – may be compromised. Assessment of this aspect of care is made by the pathologist – a key member of the cancer team. A recent development in minimal access surgery is the robot assisted procedure. In a robotic operation, the instruments are inserted manually and then fixed into the robot arms. Viewing ports are inserted and the surgeon operates at a console separate from the patient – essentially using computer games technology to manipulate the instruments remotely. There are potential downsides to this exciting technology – for example, the set-up time for the robot instruments is longer than directly manipulated ‘keyhole’ instruments. Also, the machines themselves cost around £1,000,000 to buy and approximately £150,000 per year to run. This is a considerable additional outlay over and above all the general infrastructure of operating theatres, wards, anaesthetic departments, and so on. Whether ultimately this will turn out to be both clinically and cost effective clearly remains to be seen. Certainly in the USA, there is now very strong consumer/patient demand for robotic surgery that may ultimately override the colder clinical considerations. Radiotherapy

Radiotherapy is another 19th-century technology still going strong in the 21st century. Roentgen made the key observations underpinning modern radiotherapy in 1895 when he observed that invisible rays (which he called X-rays’) were produced when electrons were fired at a target in a vacuum – revealed by their ability to blacken photographic film. It was rapidly realized that X-rays were transmitting energy and that this energy could be potentially focused for treatment as well as imaging. Within a matter of months, the first patients with skin tumours were treated – a breathtaking rate of innovation. The technologies of both imaging and therapy have gradually been refined and improved over the last century or so, and now form key components of modern cancer therapy. Indeed, as already noted, the most effective parts of modern cancer therapy remain surgery and radiotherapy, with the additional gain from drug treatment in terms of cure rates being relatively marginal. In wealthy first-world economies, drug treatments can clearly be funded over and above these two key planks of therapy. However, in poorer countries, where difficult choices have to be made, very few drugs offer good value for money in curative terms compared to surgery and radiotherapy.

After the initial observations of the effects of X-rays, either electrically generated or produced by using radioactive isotopes, the technology has been progressively refined. Initial technology based on the vacuum tubes described by Roentgen in the 19th century gave a beam which could penetrate to internal organs but which deposited considerably more of the dose nearer the skin. In the 1950s, much more powerful, so-called mega-voltage machines became available. These were based on the artificial isotope Cobalt-60, now superseded by an electrically based device called a linear accelerator, usually abbreviated to linac. These latter machines used the magnetron valve developed in the Second World War for radar. The pulsed energy can be used to ‘shove’ electrons into the target at much higher energies with much better properties for treating deep-seated tumours – a sort of electronic ploughshare from a high-tech sword.

Modern radiotherapy can be very precisely targeted by integrating treatment delivery with detailed imaging. Side effects arise in two ways. In structures such as skin, gut lining, and the mouth, the effects can be likened to sunburn, with severity depending on the dose received. Effects experienced depend on the site treated and may include diarrhoea with lower bowel treatment, or sore mouth, hair loss, and reddening in treated skin, and so on. A second group of side effects is experienced in solid structures such as lung and kidney. In these organs, there is little immediate effect, but if critical dose constraints are exceeded, the irradiated tissue will progressively fail. Dose to critical organs adjacent to the target tumour is thus a key restriction on the delivery of radiotherapy – a certain amount of toxicity will be worth accepting in order to treat the cancer, but clearly there comes a point when the damage may outweigh the benefit. Improved radiotherapy such as intensity-modulated radiotherapy (IMRT), involving very sophisticated dose distributions which appear to ‘bend’ dose around critical structures, is increasingly becoming available but increases costs and complexity of delivery. A linked development is on-board imaging in treatment machines which can be used to give image-guided radiotherapy (IGRT) where the treatment tracks movements in the tumour from day to day. The combination of IMRT and IGRT has the potential to both increase tumour control (by ensuring treatment is on target) and decrease side effects by better sparing of uninvolved tissues.

Hormone therapy

Although chemotherapy now dominates cancer drug therapy, it was a hormone-based drug therapy that was the first successful medicinal cancer treatment. Hormone therapy for cancer dates back to the 1940s following observations made by Charles Huggins, an American urologist, on patients with advanced prostate cancer.

The pioneers of hormone therapy reasoned that if the ‘parent’ tissue needed normal hormone levels, then the abnormal tumour derived from the tissue may retain this dependence. Trials of castration in advanced prostate cancer produced dramatic results, with rapid and substantial improvements in symptoms such as pain from cancer deposits in bone. Following this, administration of female hormones, which of course suppress male characteristics, was attempted, again with dramatic results. Sadly, these endocrine effects, while substantial, would last for only 1 or 2 years, the disease then recurring. Similar effects were observed in pre-menopausal women with breast cancer following removal of the ovaries. The subsequent decades have seen the development of a whole range of hormone-based medications for both prostate cancer and breast cancer in particular. One of these drugs, the oestrogen blocker tamoxifen, is probably responsible for saving more lives than any other anticancer drug. More than half a century on, new drugs targeting the hormone pathways are still appearing in the clinic.

Chemotherapy

If members of the public are asked to name the class of drugs most associated with cancer treatment, they will say chemotherapy. The term covers a wide range of different agents with diverse origins from antibiotics to plant extracts to synthetic chemicals based on DNA. All interfere with the mechanics of cell division and, as many tissues have dividing cells, this leads to the typical side effects such as nausea and vomiting (partly from damage to the gut lining, partly from a direct effect on the brain), hair loss (damage to hair follicles), and risk of infection (damage to the production of white blood cells needed to defend against infection). We are all familiar with the images of billiard ball bald patients ‘fighting’ cancer (to use the tabloid press term). Whilst this does occur with chemotherapy, the reality is more varied, with much chemotherapy given in the outpatient setting producing little nausea or hair loss. Hair loss is hard to prevent, but it is not a uniform property of all chemotherapy drugs. Nausea and vomiting are now pretty largely preventable, allowing the administration of drugs hitherto considered too toxic, even to quite elderly patients. This is important because much chemotherapy is given for palliation of symptoms, hence quality of life is of paramount importance. There is arguably little point to life prolongation if the quality of that life is poor. The first chemotherapy drugs were based on chemicals derived from mustard gas, used extensively to ghastly effect in the First World War. It was noted that soldiers exposed to these agents who survived would experience drops in their white blood cells (the cells in the blood that are responsible for defense against infection). There is, of course, a cancer of the white blood cells – usually termed leukaemia. Trials were carried out of mustard gas derivatives such as mustine in both leukaemia and a second related group of cancers called lymphoma. Patients in these trials experienced for the first time remissions of what had previously been untreatable conditions. With drugs used singly, unfortunately these remissions turned out to be temporary. However, further drugs followed, and trials established that using these drugs in combinations could lead to cures for patients with leukaemia and lymphoma. A wave of new chemotherapy drugs followed, and in the 1970s and 1980s it was widely assumed that these would in turn lead to curative therapies for most cases of advanced cancer. These drugs came from a variety of sources. Plant extracts (vincristine, docetaxel, paclitaxel), complexed heavy metals (cisplatinum, carboplatin), and antibiotics (doxorubicin, mitomycin) proved to be fruitful areas of discovery leading to large-scale laboratory screening programmes looking for promising chemicals in a whole range of plant and bacterial extracts. Another area of discovery was compounds derived from the components of DNA or other building blocks of the cell division process, the best example being 5-fluoro-uracil, which is a derivative of uracil, one of the components of RNA. The extra fluorine atom in the molecule allows 5FU to interact with DNA and RNA but not to be processed normally – a molecular ‘spanner’ in the works.

In the 1970s and 1980s, further notable successes followed; in particular advanced testicular cancer was transformed from a lethal to a highly curable condition. The magnitude of this success is best illustrated by seven-times Tour de France champion Lance Armstrong who was diagnosed with very extensive disease, including brain involvement. After successful extensive chemotherapy, he went on to win his first Tour, followed by a record-breaking six further triumphs. Similar successes have been seen in the leukaemias and a range of childhood cancers. Sadly, however, the major cancer killers have proved to be more resistant to chemotherapy, with cures elusive, although most tumour types will respond to chemotherapy to a degree. It was suggested that the problem may have been that insufficiently large doses of chemotherapy were being given. However, a round of trials in the 1990s showed that even extreme doses of combination chemotherapy together with a bone marrow transplant were unable to cure major killers such as advanced breast cancer.

This realization has led to a change of emphasis. The observation that advanced disease, while incurable, would respond to chemotherapy for a while led to the testing of chemotherapy in the setting of early disease, as had previously been done with hormone therapy. It was known that many patients with no obvious disease nonetheless later developed recurrence. This suggested that there must be very small amounts of cancer lurking undetected. The hypothesis was that giving chemotherapy early may work better than waiting for detectable relapse. Initial trials were disappointing but with hindsight were simply too small to detect the benefits. When trial results were pooled in breast cancer, it was realized that there was a benefit to early chemotherapy, with women receiving it relapsing later and surviving longer compared to those for whom chemotherapy was saved as a ‘salvage’ treatment. This is called adjuvant therapy and works on the principle that so-called ‘micro-metastatic’ disease may be eradicable; whereas once the disease is visible on a scan it is incurable. Essentially, modern scanners, whilst very sensitive, are unable to detect tumours smaller than a few millimeters across. Hence we cannot distinguish between people who have been cured by initial surgery or radiotherapy and those who have apparently normal scans but in reality harbour small residual tumour deposits destined to cause relapse in the future. Subsequent studies have refined the drug combinations used and also the groups of women deriving most benefit. The problem with adjuvant therapy is that many women will do well just with surgery and radiotherapy, and thus derive no benefit from the chemotherapy, only toxicity and potential harm. This risk is greatest for those with lowest risk of disease recurrence, either due to less aggressive disease or high risk of death from other causes (for example, the very elderly).

More recently, greater emphasis has been placed on the role of chemotherapy in palliation of symptoms. This may seem like an oxymoron – giving toxic drugs to reduce suffering. However, improved symptom control, in particular with drugs that prevent the severe nausea previously associated with chemotherapy, has transformed the value of these agents for palliation. The survival gains seen are often relatively modest – typically a matter of months – leading to researchers developing methods for measuring quality of life. This allows comparison of toxic drugs producing benefit, for example by reducing pain, with alternatives often described under the blanket term of ‘best supportive care’ – painkillers, radiotherapy, and so on.

These two trends – adjuvant and palliative use – have greatly increased the cancer drug bill in the developed world (see Chapter 5) as, although the gains are relatively small, the numbers who can benefit are enormous, and this has resulted in widespread use of chemotherapy in relatively elderly cancer patients.

Monoclonal antibodies

Antibodies are a key component of the body’s immune defences. Each antibody comprises a constant region and a variable region. The variable region is responsible for the binding of the antibody to its target. The normal function of antibodies is to bind to invading infectious organisms – viruses, bacteria, and so on. When exposed to a new infection, the body’s white blood cells identify it and select the cells (called lymphocytes) with the antibody-variable region best able to stick to and disable the invader. Production of the relevant cells is massively increased, followed by increased production of antibodies able to bind to the invader. Once bound, other immune cells identify the antibody-coated invaders and ingest them, using the antibody-constant region as a ‘hook’ for pulling them out of the circulation. The development of an immune system is one of the key evolutionary steps necessary for the existence of complex multicellular organisms. Those born with inherited defects in their immune systems struggle to survive childhood, underlining the importance of this function.

In the 1970s, technology was developed to exploit the ability of the immune system by manufacturing antibodies against ‘artificial’ targets such as cancer cells. These engineered targeted antibodies are called monoclonal antibodies – antibodies made by a single clone of cells – and can be made to stick to pretty much any chosen target. By picking targets on cancer cells, these natural molecules can be own right. When they first appeared, it was thought that monoclonal antibodies would be the ‘magic bullet’ that would eradicate advanced cancer by being custom-made to order for each tumour. The reality sadly proved to be less dramatic, but 30 years on, monoclonal antibodies are now hitting the clinics in increasing numbers.

The best-known monoclonal antibody is probably trastuzumab, more often referred to by its trade name of Herceptin. The drug targets a protein on the surface of cancer cells known as HER2, part of a family of what are called growth factor receptors. These are best thought of as on/off switches regulated by circulating proteins (in this case called heregulin). Around one-third of breast cancers have an abnormal form of HER2 on the cell surface, essentially resulting in the switch being turned permanently ‘on’. Breast tumours that are HER2-positive grow faster and more aggressively than those that are HER2-negative. Targeting HER2 on the cell surface thus seemed a logical strategy and monoclonal antibodies a good way of going about it. Initial studies were carried out in women with HER2-positive tumours and confirmed that the approach worked, with the drug being licensed in 2002. Although results were positive, with shrinkage of tumours seen, they were not as dramatic as may have been hoped for. Nonetheless, further trials were deemed worthwhile, this time using Herceptin in conjunction with chemotherapy for advanced disease. These trials produced more striking results, with women receiving Herceptin surviving around 50% longer than those receiving just chemotherapy.

The next stage of development proved to be even more interesting. Having shown benefit in incurable disease, the next step was to test the drug in patients with earlier disease at a potentially curable stage, a strategy that had already proved successful with hormone therapy and chemotherapy. The Herceptin adjuvant trials were an oncological triumph, with a halving of the relapse risk and the possibility that some of the previously incurable women were actually cured. There was a catch, however. Most women with early HER2-positive breast cancer actually already had a good outlook just with surgery, radiotherapy, and chemotherapy. If a woman is already cured by these treatments, she clearly cannot benefit from any further treatment (and may indeed be harmed, as Herceptin carries a risk of heart disease).

Conversely, some women will still die despite all current therapies, and therefore they too will benefit relatively little. In between are the real winners, converted from those destined to relapse to those potentially cured. This means that in the adjuvant (preventative) setting, the number needed who must be treated to benefit one of the real winners is high, maybe as many as 20. As the cost of Herceptin is substantial (around £30,000 per year), the effective cost per woman saved can be estimated as around 20 × 30,000 = £600,000. Unsurprisingly, therefore, when the drug was licensed for adjuvant use, a further storm of controversy followed – how much is it reasonable to spend to save one life?

Targeted molecular therapies

The DNA revolution and the sequencing of the entire human genome always promised that the benefits would result in better medicines. As more and more genes were cloned, it became possible to map the genes that were abnormal in cancer cells compared to normal cells. Once a key gene is identified, it then became possible to design drugs to target the abnormal gene or, more precisely, its associated protein product. One way to target therapies is with antibodies, as described above. The other way, now generating large numbers of new drugs, is to produce chemicals that interfere with the function, either of the abnormal protein itself or of one of the other elements of the same pathway in the cell. The first and probably best example of the first strategy is the leukaemia drug imatinib (Glivec). A form of leukaemia called chronic lymphocytic leukaemia (CLL) has long been known to be characterized by the presence of a so-called ‘Philadelphia chromosome’. This abnormal chromosome is a fusion of two different chromosomes and results in the production of an abnormal protein derived from two different genes – called the bcr-abl fusion protein. Detailed molecular biology studies established that bcr-abl was both necessary and sufficient (the key conditions for a candidate new drug development) to drive the CLL cells, making it an ideal target. The drug imatinib was the first drug to successfully hit the target and it transformed the prognosis for CLL, with prolonged remissions occurring in patients resistant to the chemotherapy drugs previously used. Sadly, however, the remissions, while lengthy, were not permanent – the cancer cells eventually became resistant. This has been a feature of the targeted small molecular therapies – they are often exquisitely effective, with low side effects compared to chemotherapy, but generally do not lead to cures. However, as already noted in the chemotherapy section with leukaemia, initial use of these drugs singly also only produced remissions but not cures, so hopefully combination use will prove similarly beneficial. Time will tell.

The second approach to targeted therapy is to aim for the pathway that is linked to the ‘core’ abnormality. The best example of this is the recent transformation of kidney cancer therapy. Until recently, advanced kidney cancer was all but untreatable, with only two drugs licensed, interferon and interleukin-2, both of very limited effectiveness. Most kidney cancers occur ‘spontaneously’, that is to say, no other family members develop the same cancer. It had been observed many years ago that rare families developed the same tumours, often at a very young age. One such inherited syndrome was described by von Hippel and Lindau and now bears their names. Patients with von Hippel Lindau (VHL) syndrome develop multiple early kidney cancers

as part of the disease. Microscopically, the VHL cancers resembled the much more common, noninherited cancers, so it was suspected that abnormalities in the VHL gene may be present in the spontaneous cancers, and this did indeed turn out to be the case. However, the problem in patients with VHL syndrome is that the normal function in the VHL protein is missing; hence targeting the VHL protein itself would only make the problem worse. Study of the VHL pathway revealed that as a result of VHL under activity, proteins normally suppressed by the VHL protein became overactive. These include proteins driving the cells to divide and a further family of molecules driving the production of new blood vessels. Drugs were developed which targeted members of this pathway, either up- or downstream of the misfiring VHL protein, including three small molecular therapies, sunitinib, sorafenib, and temsirolimus, and a monoclonal antibody called bevacizumab.

Trials of these drugs have resulted in the treatment of advanced kidney cancer being revolutionized, with all four drugs licensed since 2006 and a further raft of additional drugs also heading into the clinic. As with CLL, however, although for the first time large advanced tumours could be made to shrink, the drugs do not result in cures in most cases, and treatment resistance develops with time. Trials are now focusing on adjuvant therapy, sequencing, and combinations in the hope that further survival gains can be made.

As with the Herceptin story above, the drugs have caused huge controversy due to their cost – patients need to be treated continuously rather than with a limited course of treatment, as was previously the norm with treatments such as chemotherapy. The drugs are expensive – around £25,000–£30,000 per year of treatment – with consequent variations in access. Unlike with Herceptin and breast cancer, however, purchasing authorities in a range of countries, including Canada, Australia, Scotland, and England, have been more resistant to funding treatments for a group of predominantly elderly male patients than they were for the very vocal women’s breast cancer lobby.

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Drugs used for symptom control

Although not directly treating the cancer, a range of supportive care drugs have contributed to big improvements in cancer treatments over the last 10 to 15 years. The improved anti-sickness drugs have already been mentioned. Also related to chemotherapy safety and delivery are the growth factors, in particular granulocyte colony stimulating factor (G-CSF) which boosts white blood cell counts, reducing infection risks. A second related product called GM-CSF (granulocyte-macrophage colony stimulating factor), initially developed for the same purpose, has turned out to have a valuable role in releasing blood cell precursors called stem cells into the circulation. This somewhat esoteric observation has allowed the harvesting of stem cells prior to high-dose chemotherapy intended to destroy the normal bone marrow. Previously patients needed a bone marrow transplant to ‘rescue’ them from such treatment, but it turns out that harvested stem cells do the same job but more quickly and with a much easier pre-treatment harvesting procedure, extending the range of patients suitable for these high-dose therapies.

Another area of recent research has been bone-protecting agents. Many cancers spread into bone with devastating consequences, including pain, fracture, and paralysis due to spinal column damage. Research demonstrated that the body ‘over-reacting’ to the cancer led, paradoxically, to increased damage. Drugs initially developed for osteoporosis (bone thinning) turned out to reduce this collateral, self-inflicted damage. The initial drugs available, such as clodronate, were relatively low in potency but later drugs, such as zoledronate and ibandronate, are many times more effective and can substantially reduce bone damage in patients with advanced cancer. Even more intriguingly, in adjuvant trials in high-risk breast cancer, zoledronate also appeared to reduce soft tissue disease, suggesting these agents may in addition have direct anticancer properties.

The improvements in cancer treatment seen in the last 100 years have been dramatic and have transformed the outcomes for millions of people across the world. Cancer treatment in the early 21^st century is safer, more effective, and less toxic than it was 50 or 100 years ago. Surgery and radiotherapy continue to be refined and improved, with better targeting and minimal access technologies increasingly available. The ancillary imaging and pathology services will also continue to improve and allow better selection of treatment options in the future. The range of drugs and the effectiveness of those drugs are increasing rapidly, and this will generate further improvements in the coming years. The main problem with all this, is the escalating cost, but grappling with this issue is better than not having the options available.

Cancer research

As we have already seen, the mainstays of cancer therapy remain surgery and radiotherapy, both of which date from the 19th century but which have undergone a process of continual technical improvement, which is still ongoing. Drug treatments for cancer are comparatively much more recent.

The first successful cancer drug therapy was the use of synthetic female hormones to treat prostate cancer in the 1940s. Successful curative chemotherapy really dates from the 1970s with the development of treatments for leukaemias and lymphomas (cancers of the bone marrow and lymphatic system), although interestingly, the chemicals on which these treatments are based were previously developed for more nefarious purposes (as we have seen, mustine, one of the first successful drugs in this area, is based on the active ingredient of mustard gas). The development of new treatments and the improvement of existing ones clearly require a process of research. This text will describe some of the ways in which research happens, in particular the differences between the rules for drugs and those for devices (such as radiotherapy machines) or techniques (surgery). These contrasts will be explored in some detail, as there are important differences, with significant anomalies resulting. The text will focus mostly on where new treatments come from, but similar trial structures apply to testing existing treatments against each other or for research into techniques of symptom control.

The development process for new surgical and radiotherapy techniques differs significantly from that applying to drugs. Typically, a surgical improvement will be a small technical change (for example, a better way to control bleeding) that does not fundamentally conceptually alter the underlying technique. Such improvements are often licensed essentially on a ‘fitness for purpose’ basis (that is, does it really help control bleeding?). Similar arguments apply to technical radiotherapy improvements (for example, better ways of targeting radiation to spare normal tissues). In general, it has been taken as self-evident that improvements of these sorts must be better and their implementation will follow. In fact, the improvements may be illusory and commercial pressure rather than any sound evidence base may drive their implementation. I will illustrate how and why this may arise using robotic surgical techniques and intensity-modulated radiotherapy as examples.

Drug treatments, on the other hand, have to meet fundamentally different criteria. Generally, an improvement in survival rates compared to the previous standard of care is required by regulatory authorities such as the Food and Drug Administration (FDA) in the USA. This means a new drug treatment requires testing in a series of clinical trials involving large numbers of patients. Broadly, these can be divided into three categories termed phases 1 to 3.

Phase 1 trials establish the safety and side-effect profile of a drug. Typically, these will involve small numbers of patients, for cancer drugs usually those who have run out of standard options and who will have had multiple previous treatments. Drugs with less dramatic effects, for example blood pressure drugs, will often be tested first on healthy volunteers.

Phase 2 trials are larger and will often involve patients earlier in the ‘cancer journey’ than phase 1 studies, and they aim to confirm that a drug has useful activity against the target cancer. For a drug that looks promising, the final phase 3 trial will compare it with whatever is considered the standard of care.

A phase 3 trial will involve many hundreds or even thousands of patients. There are a range of problems inherent in this design, ranging from consent and cost to legislative burdens. Phase 3 licensing trials are now almost always international affairs and have to comply with legislative frameworks from multiple countries, in particular the USA. The costs of such trials are enormous and explain the very high costs of new drugs - around $1 billion from synthesis to registration of a new cancer drug. The licensing process – which gives a company the lucrative right to market a drug or product – is tightly regulated by national or transnational bodies such as the FDA. This theme of regulation will be developed further in the next text - arguably, the high level of trial regulation protects the individual participant in a trial from possible harm at the expense of society at large by slowing the pace of improvement and driving up the costs of new drugs to the point when access is increasingly restricted, even in the most wealthy of economies.

Developing new cancer drugs

Basic science

Clearly, a massive body of biological research underpins cancer research. There have been huge advances made in the last 50 years, particularly the unraveling of the structure of DNA and the so-called ‘central dogma’ of biology – the relationship between DNA, RNA, and protein. Previous generations of cancer drugs were developed largely by observing the effects of chemicals on cells, looking for drugs that were particularly effective at killing cancer cells. This research produced the chemotherapy drugs that appeared in large numbers in the 1970s and 1980s. Although new chemotherapy agents are still being produced, there is a sense of diminishing returns from more recent drugs compared to the huge advances of previous decades.

More recent research has focused on the evolving knowledge of the molecular signatures of cancer discussed in the previous chapter in relation to targeted small molecules and monoclonal antibodies. The human genome was sequenced in the late 20th century. The initial sequencing technology was cumbersome and slow, and the first complete sequence took many years to complete. Having completed this task, and with the overall structure of the human genome now known, it has become possible to sequence the genomes of specific cancers and to compare the cancer DNA to the patient’s normal DNA extracted from their blood cells. This now takes teams in specialized laboratories a few weeks and costs are falling rapidly. The technology, time required, and costs are likely to improve dramatically over the next few years such that it will soon be possible to individually determine the DNA sequence of each patient’s cancer as part of the diagnostic work-up. For the time being, this work is experimental, and remarkable results are emerging from this new field of study.

The human cell contains around 21,000 genes arranged in 23 chromosomes. Research comparing the DNA sequence of the entire 21,000 genes with the normal DNA of the patients has now been done for a number of cancers, and the results illustrate how small the line is between normal and cancerous cells. On average, experiments of this sort reveal abnormalities in around 40 to 60 genes. Put another way, if we picture the human genome as a library of 23 books (the chromosomes) each of around 1,000 pages (genes), there will be a total of 40 to 60 typographic errors in the entire cancer cell version of the ‘library’. Furthermore, many of these genetic ‘typos’ will not actually alter the ‘sense’ of the gene - the protein produced will retain normal function. The number of key drivers of the cancer process boils down to around 12 pathways. The genes mutated or misfiring in cancers studied in this way all belong to one of these pathways and appear to be present in all cancers studied. This work points the way to the next stage of cancer drug development. The recent round of small molecules and monoclonals have largely (but not entirely) focused on single molecules such as HER2 being targeted by Herceptin. This recent whole genome work highlights the need to target pathways of multiple genes rather than single members. Drug screens in the future are likely to focus on this aspect of cancer biology, in tandem with whole genome screens to pinpoint the key mutated genes in particular cancers. It also opens the possibility that the drugs of tomorrow will be known to work in the presence of particular genetic signatures. Therefore, linking whole genome sequencing to diagnosis points the way to one of the ‘holy grails’ of cancer medicine - the personalized selection of drug therapies.

Pre-clinical phase

The first step in the development of new drugs is the identification of suitable compounds for study in human beings. Increasingly, this result from the sort of research work on cancer pathways described above. This search at present can take many forms, from screening of random compounds to the targeted synthesis of drugs to hit pre-specified abnormalities in the cancer cell. The drugs currently used in the clinic come from a range of sources, and some of these have been described in the previous chapter. The initial testing of a candidate drug will involve experiments with cancer cells in the laboratory. These cancer cells come from a variety of sources, ranging from human cancers to artificial tumours generated in laboratory animals. Some of the human cell lines were grown by taking fragments of a surgically removed cancer and placing it in cell culture medium in the laboratory. The process is conceptually attractive – you can test your drug on the ‘real’ cancer. There is many such cell lines, possibly the most famous is the HeLa cell line. This was grown from a fragment of cervical cancer taken from a woman called Henrietta Lacks (also sometimes referred to as Helen Lane or Helen Larson in an attempt early on to preserve her privacy), and the cells are very widely used in laboratories around the world. Parenthetically, neither she nor her family gave their consent or permission for this process, resulting in a famous court case in California in 1990 in which it was decided that, in the USA, such a process was lawful. In the UK and other countries, the position is different and informed patient consent for tissue collection is now enforced by legislation. It has been calculated that so many HeLa cells have been cultured that they outnumber many times over the ‘normal’ cells produced by Ms Lacks in her lifetime, giving her a curious form of immortality. The problem with cell lines, however, is that most attempts to grow tumour cells from patients are unsuccessful. Hence the cell lines we have may be as unrepresentative of the typical cancer as HeLa cells are of the person that was Henrietta Lacks. Nonetheless, despite this limitation, human cancer cell lines remain a key component of cancer research and drug testing.

The second form of cell lines used is derived from animal tumours, mostly arising in mice. Many of these tumours are artificially engineered. A good example of this is an engineered cell line used in prostate cancer research. Mice do not get prostate cancer in the way that humans do. However, it is possible to identify genes that are expressed in mouse prostate and to use the promoter regions of those genes to drive the production of proteins that cause cancer. In the case of mice, a gene with the curious name of ‘large-T’ from a cancer-causing virus called SV40 is used.

Parenthetically, while many genes have names that are strings of unmemorable letters and numbers (there are 21,000 human genes alone after all – a lot to name), a subset have names varying from the odd (large-T) to the odder (hedgehog, notch less) to downright amusing – a pair of genes involved in cell signaling are called ‘mad’ and ‘Max’!

In order to have mice develop prostate tumours, the hybrid gene containing the prostate specific gene promoter and the SV40-T gene must be inserted into a fertilized mouse egg. If the insertion is successful, a transgenic mouse results and the growing mice will now express the foreign gene in their prostate glands. As would be predicted, these mice go on to develop multiple prostate tumours. A number of these cancer-prone mice were bred, and the strain is called the Transgenic

Adenocarcinoma of the Mouse Prostate (TRAMP) model. These mice have proved useful in a number of ways. As the mice reliably develop tumours, they can be used to test cancer-preventing strategies such as dietary interventions. Secondly, the tumours can be used to test drug treatments for effectiveness. Thirdly, tumour cells arising in TRAMP mice have been successfully cultured in the lab and these cell lines can be used for experiments, either alone or re-implanted into adult animals from the same mouse strain - quicker and more reproducible than waiting for the tumours to develop in the TRAMP mice themselves. It is again obvious from the above discussions that such models are only representations of aspects of the human disease, not perfect replications of it. Hence, while useful, drugs must ultimately be tested in humans.

Before a drug can be administered to human subjects, a further phase of pre-clinical testing is required - toxicity testing. While animal models and cell culture provide valuable indications of whether a drug may be active in man, they do not tell us whether it is safe. We also need to know whether it is likely that we can achieve drug levels in patients that will be high enough to realistically have an impact on the cancer. The standard way of exploring this is to give escalating drug doses to groups of animals until we start to see animals dying from drug side effects. There are a number of rather grisly standard measures, such as the dose of drug that will kill a proportion of the test subjects – termed the lethal dose (LD) test. Measures such as LD50 (the dose that kills 50% of the animals) and LD10 (10% death rate) are widely used and attract much controversy from anti-vivisection groups. I don’t propose to examine the ethics of animal testing per se – it seems to me to be something you believe is right or believe is wrong. If you fall in the latter category, then no amount of argument will generally alter opinions. I do believe it is worth critically examining the scientific basis of animal testing to try and minimize unnecessary suffering. There are many very obvious problems with LD50 testing – for example, the LD50 will vary widely for different species for a given compound and hence may still expose human subjects to risks. Nonetheless, compounds that turn out to be very toxic in LD50 tests at levels well below the necessary therapeutic levels are unlikely to be safe or worthwhile to test in humans. Whatever the rights and wrongs and limitations of pre-clinical toxicity testing, at present regulatory authorities require such testing on at least two species, one of which must be a non-rodent species such as the dog, before any human testing of a drug can begin.

Phase 1 trials

Having produced a candidate drug and completed the necessary pre-clinical testing package, the next step is testing in human subjects. Logically enough, this is termed a phase 1 trial. For many drugs, for example blood pressure pills, this testing will take place in ‘normal’, usually paid, volunteers. In general, these will be fit young men (not women, due to the risk of inadvertent damage to a foetus). For cancer drugs, which are often very toxic and frequently carcinogenic, this is clearly not an appropriate route, and phase 1 trials usually take place in patients who have exhausted standard treatment options. The classical phase 1 trial format is that the initial three patients are treated at a conservatively low dose and the effects observed. If no unacceptable toxicity occurs, then a further three patients will be treated at a higher dose, and so on. Clearly, for most drugs, eventually a dose level will be reached at which unacceptable side effects occur (termed ‘dose-limiting toxicity’, or DLT). If a patient experiences a DLT, additional patients are treated at the same dose level. If two or more out of six experience a DLT, then the ‘maximum tolerated dose’ (MTD) for the drug is reached and the trial ends. The dose level below the MTD will be used for further study. The classical phase 1 trial has the merit of simplicity, but there are clearly limitations as well. Firstly, different patients will have varying susceptibility to potentially dose-limiting side effects. If the trial includes too many side-effect-prone patients, the estimated maximum tolerated dose will be too low, and vice versa. Secondly, not all drugs need to be used at the maximum tolerated dose. For example, a drug blocking a hormone receptor only needs to be given in sufficient quantity to block the target. Any additional drug given above this level is only adding toxicity with no benefit. For trials with drugs of this sort, it is therefore important to specify the endpoint required to avoid unnecessary drug exposure to participants.

The main problem with phase 1 trials relates to the needs of the patients. Mostly, these studies are happening in patients who have exhausted all standard therapy options and who are clearly desperate for further viable therapies. By its very nature, the phase 1 trial is mostly delivering drug below the likely therapeutic range with a consequent low chance of benefit. Furthermore, at least two of the last six patients entered in a study will receive too high a dose and will experience a high level of side effects. Finally, most drugs entering phase 1 will actually turn out to be of little therapeutic value due to either unforeseen problems preventing delivery of sufficient drug or simply a lack of efficacy against the target cancers. For most patients, therefore, entering a phase 1 trial needs to be seen largely as an act of altruism, and it is indeed true that many patients entering trials will say things like ‘well if it helps people after me, it will be worth it’. Nonetheless, ethics committees and doctors must be careful to protect vulnerable and desperate patients from harm in these trials.

Phase 2

If an agent performs well in phase 1 – in other words, side effects are manageable and acceptable, usually with some evidence of a positive effect on the cancer, then a phase 2 trial will follow. The aim of phase 2 studies is to study the efficacy of the drug in more detail. The drug will be tested at the optimal dose defined in phase 1 in a group of patients assessed as likely to benefit from the drug. This is clearly different to phase 1 as the risk of under- or overdosing is much reduced, though it still remains, due to the limitations of the dose-finding mechanisms in phase 1 discussed above.

Furthermore, as the patients are selected on the basis of likely benefit, the risk/benefit ratio for participants is much better. Typically, up to 40 or 50 patients will enter a phase 2 trial, and the endpoints will be efficacy, and of course safety, in the more defined, usually somewhat fitter, patient population.

Defining efficacy is a major problem. Generally, agents that produce tumour shrinkage are defined as active, and this has led to standardized ways of defining how much shrinkage constitutes a worthwhile response. The most widely used method is the RECIST (Response Evaluation Criteria In Solid Tumors) system, first published in 2000 and updated in January 2009.

• Disease responses are broadly classified as follows:
• Complete response: all assessable disease disappeared;
• Partial response: reduction in size by pre-specified amount of all assessable disease;
• Stable disease: insufficient change to be put in another category;
• Progressive disease: worsening of disease by pre-specified amount or appearance of new cancer deposits.
• The principle underlying this system of assessment is simple; the application in practice is complex.
• As with many things, the devil is in the detail - the following is a list of tricky issues (not comprehensive) to illustrate the difficulties:
• How much should a tumour grow before it counts as progression?
• How much should it shrink to count as a response to treatment?
• What if some lumps shrink but not others?
• When should you carry out the response measurements (too early and you may under-report; too late and patients may have started relapsing)?
• How do you assess tumour deposits in tissues such as bone or pleura (the lining around the lung) where there is no discrete lump that can be measured?

This last point is a particular problem with certain diseases such as prostate cancer that mainly affect bone. Therefore, while response to treatment remains an important test of drug activity, a second set of measures based on how long a patient takes to start getting worse - termed the ‘time to progression’ - is increasingly used. This has proved particularly important with the new targeted molecular therapies for diseases like renal cancer. With this disease, large masses often shrink but by less than the standard RECIST criteria. On review of the scans in these patients, it became obvious that the tumours changed in appearance, with the centre appearing to be less ‘active’ than before - borne out when lumps were removed and found to have dead tissue in the middle. In parallel, tumour related symptoms often improved. For these patients, therefore, prolonged ‘stable’ disease becomes a very worthwhile outcome. Improved time to progression is therefore frequently used as a means of assessing activity of an agent. Finally, of course, agents can be assessed for their effect on overall survival times. This is not frequently used in phase 2 as the principal outcome for a variety of reasons, mainly time - the aim is to establish as quickly as possible which agents to take forward for phase 3 licensing trials.

Phase 3 trials

If an agent shows encouraging activity in phase 2 with acceptable toxicity, it will then proceed into phase 3 trials in which the agent is compared to the current standard of care. Where the agent is a new drug, this will generally involve the drug company discussing the trial with the regulatory organizations such as the UK Medicines and Healthcare Regulatory Agency (MHRA), European Medicines Agency (EMA), and the US Food and Drug Administration (FDA). These bodies will have an opinion as to the appropriate comparator treatment and also the outcome required to obtain a licence. The comparator may be an existing drug or combination of drugs, or it may be what is termed ‘best supportive care’. This latter option is chosen when there is no clear-cut standard therapy - patients receive whichever palliative measures the clinician thinks appropriate.

The hallmark feature of phase 3 trials is that the patients are randomly assigned between the reatment options. This ensures that patients will be evenly distributed between the various arms of the trial and minimizes the risk of differences in outcomes arising due to patients with a better or worse prognosis being concentrated in one arm of the trial. Whilst the design makes good scientific sense and is regarded as the ‘gold standard’ method of assessment, as always there are limitations.

Firstly and most obviously, where the control arm is best supportive care or worse still a placebo medication, there is understandable reluctance on the part of patients. Careful explanation and support is clearly required, particularly to make the point that if there is no other proven alternative, then treatment outside the trial will be no different to the control arm. Often, however, a phase 3 trial is not comparing the new drug with placebo but with the current standard therapy. This is generally a much easier discussion in the clinic as everyone receives treatment and the new medicine may be less good than the old one - we don’t know until we do the trial. Even if the control is placebo, it is by no means a given that the new drug will turn out better – there are plenty of examples of trials in which the drug was no better than placebo, and even examples when the drug was worse – the drug was both toxic and ineffective.

Secondly, most new medicines will be only a little better than the existing ones, hence the likely differences between the trial arms will be small. In order to detect small differences, large sample sizes are necessary to ensure statistical confidence in the outcomes. Statistics is a much mocked, maligned, and misunderstood science, so it is helpful to illustrate why sample sizes need to be big with a simple example. Suppose we want to assess whether a coin used for a coin toss is evenly balanced or biased to either heads or tails. If we toss once, then we get either heads or tails (ignoring the possibility that the coin balances on its edge!). If we toss again and get the same, we have (say) 100% heads, 0% tails. No one would say the coin was biased on this size of sample, though. Suppose we carry on and get to 10 tosses - 6 heads, 4 tails - would we be confident that the coin was biased?

Probably not. However, if we get to 100 tosses with 60 heads and 40 tails, or 1,000 tosses with 600 heads and 400 tails, we would have increasing confidence that the coin was indeed biased. The reverse of the problem is more difficult: if we got 501 versus 499, would we say the coin was biased? Again, probably not, but how about 510 versus 490? 520 versus 480? How similar can the numbers be in order that the difference is probably by chance rather than due to a biased coin? Even a big difference like 600 versus 400 can occur by chance with an unbiased coin, but would be very unlikely. The statistics plan for a trial is therefore key and will specify how many patients will be needed to reliably detect the minimum difference deemed to be clinically important in advance of the trial starting. For a trial testing a new drug in advanced cancer, this will be along the lines of an average improvement in survival of at least three months. As with our coin flip, this could arise by chance so the trial statistician will calculate how many patients are needed to show (or exclude) this difference reliably - usually defined (largely arbitrarily) as the chance result occurring fewer than 1 in 20 times. For most modern trials, there will be a committee (usually called the Independent Data Monitoring Committee, IDMC, or Data and Safety Monitoring Committee, DSMC) set up to independently

monitor the results as they accrue. This is in place to protect patients primarily - if there are unforeseen toxicity problems, for example, the trial may be stopped early. Later on in the trial, the IDMC can end the study if the predefined endpoints are met early. This allows early dissemination of the data and allows other patients access to the drug earlier. Conversely, the IDMC can also determine that the trial is never likely to show significant differences and stop the trial early on grounds of futility.

Endpoints in trials are controversial. Trials are expensive, often $100 million plus, and hence drug companies want them to be as small and quick as possible. Conversely, regulators want the most reliable outcome measures and hence longer follow-up periods or larger sample sizes.

Society at large has needs somewhere in between. We all want better medicines, and if we’ve got cancer, we want them now. Equally, we want them to be safe. Also, the larger and longer the trial, the more the drug company has to charge for the drug in order to pay back the higher development costs for a more detailed discussion of this issue. As health budgets grow, so pressure to reduce drug costs rises, making availability of new drugs increasingly restricted for cancer patients in poorer economies. As a way out of these conflicting tensions, increasingly, researchers are looking for what are called ‘surrogate’ endpoints. The aim is to pick an early endpoint that will accurately predict the final outcome of the trial. The response rate in a phase 2 trial is an example of a surrogate endpoint used to select a drug for phase 3 study. The problem is that the correlation between response rate and the sort of endpoints regulators require, such as improved survival, is not sufficiently good to allow a high response rate in phase 2 to lead directly to a licence. The same will generally apply to comparisons of the response rates in randomized trials.

In order to get away from using survival-based comparisons, which clearly take a long time, investigators must show that some earlier measure reliably predicts the final outcome. An example of such a measure is the ‘time to progression’ mentioned above. This is the time taken for the tumour to grow or spread by pre-specified amounts and is commonly used as a registration trial endpoint in early breast cancer. In some disease settings, for example, PSA in prostate cancer, the candidate marker is unreliable, and drugs in prostate cancer are still currently stuck with needing to show improved survival to get a licence. In prostate cancer, studies are currently evaluating a novel method of response which is counting the number of circulating tumour cells. Typically, these are present in tiny numbers - around 5 per 7.5 milliliters of blood is the key cut-off level - a very tiny number of needles in a massive haystack of tens of millions of blood cells. If validated, such a test could greatly accelerate the pace of cancer drug development in diseases like prostate cancer currently stuck with overall survival endpoints. As shorter trials are cheaper, it could also reduce the price of the drug when licensed.

Comparisons of existing treatments

The phase 1-3 schema described above can broadly be fitted to any new technique or drug combination, however requirements differ in different countries. Trials comparing existing drugs in novel combinations are often undertaken by academic organizations such as Cancer Research UK or the US National Cancer Institute. Using the template above will give reliable results that can influence practice and are the gold standard for advancing medical practice in general. The system becomes much less clear with surgical techniques, radiotherapy equipment, other devices, and biomarkers, though. For example, new technologies such as robotic surgery are introduced as incremental improvements. These ‘improvements’ are treated as self-evident; when in fact they may be nothing of the sort. For example, comparing open with robot-assisted surgery: access routes to the body are different; the tactile connection between the surgeon’s hands and the tissues is lost in robot-assisted surgery; control of bleeding or complications such as bowel perforation may present different risks, possibly requiring conversion from robot-assisted to an open conventional operation; theatre times may be longer when surgeons are training, and so on. It is clearly entirely plausible that each of these factors may substantially affect outcomes. In addition, there is the massive issue of cost. A surgical robot costs over £1 million, with another £100,000–£150,000 annual running costs. Even if the outcomes are better, how much is it worth paying for, say, and earlier discharge from hospital?

One might expect that the introduction of such a technique, for example for prostate removal, would require the same sort of trials that new drugs for prostate cancer require, with equivalence or better in outcomes. No such trial has ever been carried out, yet surgical robots are working in major surgical centers across the world, particularly in the USA. Why the massive discrepancy? In essence, new devices simply have to demonstrate safety and fitness for the purpose for which they are designed. Where changes are genuinely small and incremental clearly a massive trial to show that a new scalpel is slightly better would be impractical and probably meaningless. At some point, the change ceases to be incremental and surgical robots seem to me to be a good example of this, yet are still treated as if they were simply a slightly better scalpel. In the USA in particular, buying a surgical robot has become an essential part of the marketing of a hospital – it is an iconic piece of kit – what go-ahead institution would want to be without one? Grappling with this issue is likely to become more and more important as healthcare systems struggle with rising costs. Conceivably, of course, new technologies may actually save costs. Sticking with the robots, it is not implausible that the claimed shorter learning curve, shorter hospital stay, and reduced complication rates could pay back the capital and running costs. At present, however, we simply don’t know.

Similar arguments apply to tests such as imaging and other diagnostic tests. Again, there is an element of not needing to do research to validate the obvious – a scan with a sharper image is likely to be better than a fuzzy one! However, when we look more closely, things get more tricky. For example, one of the key drivers to decision-making is whether the cancer has spread to a particular organ. In general, if a scan looks abnormal in a particular area known to be at risk, it is likely that this represents disease. The converse is not the case, however – a negative scan could be negative or could mean the disease is below the threshold for detection. This is illustrated by the hypothetical liver scan. A good example of this sort of problem is the detection of cancer in lymph nodes. As lymph nodes are normal structures and cancer in lymph nodes is of similar density (and therefore imaging appearance) to the normal tissue, imaging can only tell us if nodes are of normal or abnormal dimensions – typically, the cut-off size is around 5 millimeters. Clearly, if we have a 4-millimetre cancer deposit replacing the bulk of a node, it will therefore look ‘normal’. Suppose a potentially better imaging test for node disease is developed, how should it be evaluated?

Such a test would fall into the same sort of regulatory route as surgical devices - we need to show safety and fitness for purpose. Safety is straightforward - the phase 1/2 route clearly works fine, but how do we demonstrate ‘fitness for purpose’? The answer is some form of clinical trial, but the question of endpoints is very tricky – how many ‘normal’ lymph nodes harboring small cancers do we need to detect to be worthwhile? How many are we allowed to miss? How do we evaluate the ‘true’ positive and negative rates? Should we move to broader clinical outcomes rather than counting lymph nodes – for example, does the application of the test result in better clinical results, for example longer survival times, than the standard way of managing the patient?

These are all very difficult issues when applied to imaging technology when the acquisition costs of new scanners are very high. Even for technologies that augment existing scanners, for example new contrast medium drugs, the issues are substantial, and there is not a single consistent route across the globe.

Similar arguments apply to diagnostic tests. Again, at first sight, the problem would seem simple - if we have a blood test that correlates with the cancer, then we should use it as part of the basis for clinical decisions. However, if we examine the literature, we find many examples of tests that correlate with presence or absence of disease but very few are actually used clinically - why should this be? The principal answer to this is that the test has to give additional information over what we know already. For example, there are a whole range of urine tests that correlate with the presence of bladder cancer but none are used in the UK. Patients with suspected bladder cancer need a cystoscopy to confirm the diagnosis. The available urine tests are not reliable enough to exclude patients from a cystoscopy. Once the bladder has been examined, if a tumour is seen, a biopsy is needed. Again, the tests are not sufficiently reliable to obviate the need for biopsy. In addition, the excision biopsy is also part of the treatment, so however good the test, the patient still needs the operation. How about predicting prognosis? Again, the urine test is good but not as good as the pathological study of the removed tumour, so again it adds nothing. Given the above, the correct test for a diagnostic procedure is its effect on outcomes - can the test spare invasive procedures or predict which of a range of treatment options is best? This requires large-scale trials similar to those needed to license a drug and is the reason there are so few established tests or markers used in the clinic as decision aids.

There are examples of markers that correlate well with the disease and can be used to predict clinical events in advance of clinical symptoms or obvious scan changes. Examples of such markers include PSA in prostate cancer, CA125 in ovarian cancer, and AFP and HCG in testicular cancer. Even when good markers exist, they cannot necessarily replace other clinical methods of assessment. For example, while changes in PSA largely reflect changes in disease status, some treatments that affect the clinical outcomes (the bone-hardening drugs called bisphosphonates are a good example) have very little effect on PSA levels despite helping prevent bone damage by the cancer. Even more surprisingly, a recent huge study in ovarian cancer and the use of markers produced very counterintuitive results. A rising level of CA125 in the blood accurately predicts clinical relapse. One might expect that treating relapse early would be better than waiting until symptoms developed. The study compared a policy of marker-driven treatment (that is, treatment for relapse started with rising marker levels) with clinical symptom-driven treatment. A total of around 1,500 women took part in the study, and the earlier introduction of treatment in women with more intensive monitoring did not affect survival times. Even more surprisingly, quality of life and anxiety levels were better in the women with the clinically driven treatment - tighter monitoring and earlier treatment were actually therefore inferior overall.

A huge focus of current research is individualized therapy – identifying markers that allow treatment to be tailored to the individual. There are many ways tumours can be characterized - by their DNA mutations, by their patterns of protein expression, by looking at the activities of different enzymes.

However, while it is relatively easy to identify patterns that correlate with different outcomes, it will be obvious from the above discussion that this will not be sufficient to allow treatment to be altered. To demonstrate clinical value will require clinical trials comparing the candidate marker-driven policy with standard care. As the ovarian cancer example above shows, even having a good marker does not guarantee the expected result. A further problem that may emerge is that the numbers of candidate markers being developed may exceed the capacity of research teams to carry out trials, possibly many times over. Furthermore, markers effectively change a disease from being a homogenous entity to a number of distinct sub entities. As good trials need large numbers, this makes doing trials more difficult – the disease effectively becomes rarer. This is illustrated by recent changes in renal cancer. A number of pathological variants had been described some time ago but until the advent of targeted small molecules, this made no difference to treatment options. As already discussed, the abnormalities in clear cell renal cancer (around 70% of the total) lead to new treatments. What then for the remaining 30%? Several different further subtypes make up this 30%, hence trials now become difficult as each is really rather uncommon. As a result, we don’t really know how to manage these subgroups. These so-called ‘orphan’ diseases will become increasingly common and problematical as there will be little in the way of trial data to inform treatments, and trials will be difficult due to lack of numbers.

The coming years will see many exciting developments in new cancer drugs, new biomarkers, and exciting and futuristic technology such as surgical robots. How we incorporate these developments in practice will depend in large measure on clinical research to underpin their use. However, new technologies in particular will have a tendency to be introduced via the marketing rather than trials route. How we license, regulate, and fund these devices will become increasingly problematical as healthcare budgets come under pressure with an ageing population and the massive debt overhang of the credit crunch.