Made to Measure: Personalised cancer medicine

Doctors have long known that two patients with the same type of cancer may respond very differently to the same treatment; a person’s susceptibility to a disease as well as treatment success or resistance can vary from one person to another, even within family groups. But a greater understanding of our genetic information at the individual level is facilitating new approaches in the detection, treatment, and prevention of cancer and other diseases, which are more tailored to the needs of each patient.

The ‘one size fits all’ approach where a patient’s therapy was selected based on average results from randomised clinical trials is increasingly being replaced by targeted therapeutics and their related molecular diagnostics. The age of personalised medicine, first signalled in the 60s, is here and now and offering new hope for cancer patients.

The mapping of the human genome, completed in 2003, and recent advances in genome technologies have laid the groundwork for understanding the roles of genes in disease development. All diseases have a genetic component, whether inherited or resulting from the body's response to environmental stresses like viruses or toxins. Detecting these subtle mutations, or biomarkers, is a complex and ongoing challenge.

Most types of cancers are not single diseases. There can be over a dozen subtypes within a breast cancer diagnosis, for example. An ever-growing number of molecular diagnostic tests are becoming available commercially, aimed at identifying genetic mutations within a particular cancer that might be treatable with certain drugs. These gene tests can also detect errant genes in people at risk of developing certain cancers.

Using this genetic information to develop targeted cancer therapies is revolutionising how drugs are being designed and how patients are being treated.

“Put simply, personalised medicine is about making the treatment as individualised as the disease,” capsulates Dr David Gallagher, a medical oncologist and medical geneticist who returned to Ireland from the world-renowned Memorial Sloan-Kettering Cancer Centre in New York in 2010. He established the Cancer Genetics Clinic at the Mater Private Hospital, which opened in February 2011.

“Cancer genetics and personalised cancer medicine are closely related but not exactly the same thing. Personalised medicine is about individualising therapy for patients: taking a biopsy of a patient’s tumour and looking for molecular changes; genetic mutations and different expressions of proteins within the tumour that may allow you to select a tailored treatment for the individual based on the molecular makeup of their actual tumour.

“This is often what people are referring to when they talk about personalised medicine and it forms a major part of my daily work as a medical oncologist. Cancer genetics focuses largely on prevention; genetic testing for potential abnormalities before an individual gets cancer. If we find these genetic ‘red flags’ we can initiate a strategy of either early detection, which involve regular screening, or cancer prevention, which involves chemo prevention or surgical prevention.

“This personalised approach to cancer diagnosis and treatment is increasingly where medical oncology is trying to go and genetics is at the very centre of that. I dual trained as both a geneticist and an oncologist because that’s where I think the future of this field lies,” he tells Cancer Professional.

“In the oncology clinic, when a person is diagnosed with cancer, depending on their diagnosis there may or may not be a treatment that is available for their particular cancer subset. We can test for a protein marker or genetic marker that may influence their response to a drug, and if the individual has this biomarker they will go down one treatment paradigm, and if they don’t they may go down a different treatment route.”

The first step toward more individualised drug treatment for patients was taken over half a century ago with the identification of oestrogen receptors by Elwood Jensen at the University of Chicago in 1958. This discovery was followed by the introduction of the anti-oestrogen drug tamoxifen in the 1970s, which enabled a more individualised approach to the treatment of breast cancer patients.

About a decade later, researchers found that some women who had particularly fast-growing breast cancers expressed extra copies of a gene called HER-2 (Human Epidermal growth factor Receptor 2). The genes were producing many copies of a protein that appeared to be driving the growth of the cancer cells.

This discovery led to the development of another targeted therapy in the 1990s, the monoclonal antibody trastuzumab, which effectively latched onto the HER-2 proteins on the surface of a cancer cell and slowed or stopped cancer-cell growth in the 20% to 25% of breast cancer tumours that contained an amplified HER-2 gene.

Since then, numerous targeted anticancer therapies, covering a wide variety of targets in tumour tissue or the tumour's environment, have become the subject of extensive research and development activities worldwide. Clearly, pharmacogenomics is now a booming industry.

Already dozens of targeted agents have been approved for use in specific cancers including drugs that interfere with cell growth signalling (imatinib, gefitinib, etc) or tumour blood vessel development (bevacizumab, sunitinib, etc), as well as drugs that promote the specific death of cancer cells (bortezomib, pralatrexate, etc), stimulate the immune system to destroy specific cancer cells (rituximab, ipilimumab, etc) and deliver toxic molecules to cancer cells (brentuximab vedotin, ibritumomab tiuxetan, etc). 

Oncologists and their patients in Ireland are fortunate to have access to some of the most exciting, lead candidate drugs in cancer through participation in clinical trials directed by the All Ireland Cooperative Oncology Research Group (ICORG).

ICORG’s growing portfolio of member-generated clinical trials of some of top targeted agents from global market leaders, including the GlaxoSmithKline (GSK) B-RAF melanoma study. A total of 600 Irish patients were screened and 140 of these enrolled onto the trial last year. The drug is designed to attack a genetic mutation B-RAF that is found in half of patients with melanoma, and in other cancers such as colon and thyroid.

“In the lab the new treatment had yielded remarkable results, shrinking tumours and keeping them at bay. One Irish patient has also seen remarkable results that started within a week of taking the drug. On returning for the first scan six weeks after taking the drug there was a 50% reduction in the disease in his body and on recent scans there was a further 40% reduction and no new disease,” an ICORG spokesperson told Cancer Professional.

She also revealed that ICORG anticipates it will be working with between eight and ten of the most promising of the new targeted agents by the middle of 2012.

Another illustration of Ireland’s burgeoning leadership in this field is the recent announcement that St James’s Hospital is the leading European site in the crizotinib trial. This news is all the more exciting when examining early data for this drug. In the early phase studies more than 60% of lung cancer patients who received crizotinib were alive after two years, according to data released in June 2011.

“We are increasingly moving away from the ‘one size fits all’ approach to treating cancer, but it still how most patients are treated,” says Dr Gallagher. “However, every year this is changing, more and more. We are crossing the traditional tissue defined definition of cancer to a more molecular defined era of cancer, so breast cancers are being treated like stomach cancers because they have a similar molecular profile. That would never have happened in the past.”

Dr David Gallagher

He points out that even if targeted therapies are available, they cannot be delivered to "the right patient at the right time" without access to sophisticated diagnostic tools, making molecular diagnostics a key driver in personalised medicine.

Dr Gallagher remarks: “Molecular diagnostics is about analysing the tumour for different markers, whereby patients are ‘stratified’ into subgroups according to their biomarker profile and likely response to a specific treatment. Molecular tests are referred to as either predictive markers to guide treatment or prognostic markers that are used to inform prognosis after treatment.”

OncotypeDX, for example, is indicated for women for node negative, hormone receptor positive and HER 2 Neu negative invasive breast cancer, and provides a risk score that helps determine whether a woman should proceed with curative adjuvant chemotherapy in addition to hormone therapy.

The National Cancer Control Programme (NCCP) announced in October 2011 that breast cancer patients could now avail of the benefits of OncotypeDX in the public health service. The clinical data published for the use of this test has indicated that up to 30% of women who would otherwise have received chemotherapy will now be considered as low risk and as a result will be spared the toxicity and long term side effects of treatment. The NCCP expects around 300 women annually to undergo the test, with around 100 women subsequently excluding chemotherapy from their treatment plan.

For most drugs, such as tamoxifen and trastuzumab, the companion diagnostic tests are used to select the patients who are most likely to benefit from treatment; but such tests can also be used to predict toxicity. For example, irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype. Genetic polymorphism of the UGT1A1 gene is related to severe toxicity caused by the drug, such as leukopenia and diarrhoea. In order to identify the group of patients with aberration of the UGT1A1 gene who will need a reduced dose of irinotecan, a pharmacodiagnostic test was developed (Invader® UGT1A1 Molecular Assay). Another, similar genetic test to predict toxicity of 5-fluorouracil or capecitabine, and helps guide physician dosing decisions, was recently introduced (TheraGuide 5-FU).

Investigating mechanisms of sensitivity and resistance to new molecularly targeted cancer drugs is the principle aim of a recently established consortium of scientists, clinicians and industry partners in Ireland. Molecular Therapeutics for Cancer Ireland (MTCI) has already attracted huge investment, including a €6 million award by the EU to investigate possible treatments for difficult-to-treat types of breast cancer.

“At present, there is a lack of targeted therapies for two poor-prognosis subtypes of breast cancer namely ‘triple negative’ breast tumours and invasive lobular carcinomas of the breast,” says MTCI Investigator Professor William Gallagher, an Associate Professor of Cancer Biology in the UCD School of Biomolecular & Biomedical Science and a UCD Conway Institute, who is leading this research. “Together these subtypes make up almost 25% of all breast cancers. Our research will explore the role of kinases – the key regulators of cell function - in these types of breast cancer in order to develop therapeutic targets that may inhibit the rate of activation of kinases in cancer sufferers.”

Other national developments include the establishment of Ireland’s first Breast Cancer Tissue Bio Resource in 2010, which should enable speedier discoveries and ultimately more effective and personalised treatments for patients. In addition, a Germline DNA Bio Bank has just been set up at the Cancer Genetics Clinic in the Mater Private. The Clinic also expects to launch a new prostate cancer screening study in early 2012.

Although Irish efforts with regard to investigating and promoting more personalised cancer treatment is laudable, European health authorities see considerable scope for improvement throughout the EU. The Health Research Directorate of the European Commission organised a series of workshops on personalised medicine in 2010, culminating in a two-day conference in Brussels last year, where key opinion leaders addressed recent achievements in health related research leading to personalised medicine and identified priorities for future actions needed at the European level.

Arising from this, the European Commission is currently exploring whether a French cancer initiative could be applied in other EU countries. Under the French programme all cancer patients can be tested, free of charge, for the molecular characteristics of their particular tumours. Once tested, patients can be prescribed with the most appropriate medicine as soon as possible. This initiative is now in its sixth year.

Dr Fabien Calvo, Deputy Director-General and Director of Research at the French National Cancer Institute, explains: “The goal of the French programme is to offer each cancer patient access to a molecular test as soon as possible following the regulatory approval of a new targeted cancer therapy. For example, in 2008 the institute allocated €2.5 million for KRAS testing in colorectal cancer. This was not long after regulatory authorities approved cetuximab and panitumumab for patients with colorectal cancer with the non-mutated (wild-type) KRAS gene.

“Similarly in 2009, the institute allocated €1.7 million to the regions to test patients with activating mutations of the epidermal growth factor receptor (EGFR) in their tumours. This followed regulatory approval of gefitinib for metastatic non-small cell lung cancer in patients with activating mutations of EGFR.

“Although there is a cost to the government in offering these tests, there has also been a savings on the cost of medicines,” he stresses. Dr Calvo says that EGFR testing for patients with lung cancer has saved a massive €69 million for the health insurance system because only those patients who could benefit from gefitinib have received the treatment. 

Mr John Dalli, Commissioner for Health and Consumer Policy, European Commission, agrees that the high costs for personalised medicine should be offset by efficiency gains. He told the conference: “By offering personalised medicines to patients, healthcare providers can avoid trial and error and reduce adverse reactions. This offers the potential for major benefits to patients and to the healthcare system as a whole. At the moment, this potential is largely unexploited. Efforts by academia and industry need to be stepped up.”

The first article ever published that coined the term ‘personalised medicine’ (the Wall Street Journal/the Oncologist, 1999) predicted, “The race is on to come up with tailor-made drugs that will treat people based on their individual genetic makeup.” After many years of development, personalised health care is increasingly moving into clinical practice. Apple CEO Steve Jobs and maverick author Christopher Hitchens, who both recently succumbed to cancer, were among a select few patients to have their entire genomes sequenced in the hope of tailoring each man's cancer treatment to their specific genetic mutations within the cancer. Even still, the attempted treatments fell short of cures.

The era of personalised medicine is here, albeit in its infancy, and we have already seen the first important results. The promise of  “targeting drugs for each unique genetic profile” as outlined in the 1999 article is tantalisingly close but as of yet, far from being fulfilled.

A jab in the right direction

The involvement of pharmacists in Ireland in the seasonal flu vaccination programme is a recent and welcome development. Community pharmacists are well placed to overcome many obstacles to increasing vaccination rates and Government officials estimate that transferring the administration of the flu vaccine from GPs to pharmacists will trim between €5 million and €13 million every year off the State immunisation bill.

Health Minister James Reilly is also convinced that this new convenient and cheaper service offered by pharmacists will achieve greater penetration into the community of vaccine uptake, which will consequent reduce the annual winter surge in hospital admittances and in busy GP surgeries.

Influenza is a highly infectious acute respiratory illness that is self-limiting and short lived in most healthy adults but in high-risk patients, including the very young and the elderly, the effects of influenza can be severe and can cause serious illness and death. 

In such patients, serious respiratory complications can develop, including pneumonia and bronchitis. Tragically, between 300 and 400 people die annually from influenza and its complications.

Prevention is the key; influenza immunisation prevents between 70 to 90% of influenza-specific illness among healthy adults and reduces severe illnesses and complications by up to 60%, and deaths by 80%, in the elderly.

Health Minister James Reilly (and halo)

Minister Reilly’s announcement last July of plans to introduce a new pharmacist-led influenza vaccination service was widely welcomed by the general public and healthcare professionals, although the Irish Medical Organisation, which represents most of the country’s doctors, voiced some reservations concerning aspects of the new regulations that allow pharmacists to deliver the flu vaccine.

The profession of pharmacy was more than ready and willing to embrace this new challenge and expanded role. Following the Minister’s announcement almost 1,000 pharmacists enrolled in accredited national vaccination training courses. In fact, hundreds of pharmacists had already received this training in the 12 months prior to the Minister’s formal confirmation of their involvement in the 2011/2012 seasonal flu campaign.

The Boots pharmacy chain had tested the proverbial waters in 2010 with what was effectively viewed by health authorities as a ‘pilot’ flu vaccination service in its 60 stores nationwide.

A subsequent satisfaction survey revealed that almost 100% of people who received their flu jab from Boots pharmacists were delighted with the service. Significantly, about a third stated they wouldn’t have received the vaccination but that the option to “drop in” to a local pharmacy for the flu shot was too convenient to miss.

“The skill set of pharmacy and the spread of pharmacy - the penetration into the community – have long been underutilised in our health services, but I think we’re beginning to see that this is changing for everyone’s benefit,” says Mary Rose Burke, Director of Pharmacy at Boots Retail (Ireland) and a member of the National Pharmacy Reference Group which advises the Pharmaceutical Society of Ireland (PSI) on practice development policy.

Although the necessary legislative amendment was only introduced in mid October last year, which permitted pharmacists in Ireland to administer the flu jab, Boots Ireland was able to introduce its new service in 2010 through a Patient Group Direction (PGDs).

A PGD is a written direction relating to the supply and or administration of a prescription only medicine (subject to specific inclusions and exclusions) and is developed, authorised and signed by the Boots Medical Director, Dr Graham Marshall.

“We put between 6 to 12 months of work into defining a flu vaccination service and developing it to higher clinical governance standards because we knew obviously it would come under a lot of scrutiny. We looked at best international practice, examining the protocols, training and experience of other countries that offer a pharmacy-led vaccination service was introduced, such as in the UK and Portugal, and determined a framework that we felt was consistent with Irish legislation. We set ourselves to be the gold standard that any change in regulation would model itself on the way we had done it,” explains Ms Burke.

She is quick to point out that this early initiative by Boots and the recent involvement of pharmacists nationwide in the influenza vaccination programme by no means reinvents the wheel; “all protocols and procedures are identical to receiving the vaccine in your GP surgery, except that you don’t necessarily need an appointment and our opening hours are more flexible. It’s all about ensuring broader uptake of the flu vaccine so that those who need it can get it.”

Under the Medicinal Products (Prescription and Control of Supply) (Amendment) Regulations 2011, registered pharmacists can now supply and administer the seasonal influenza vaccine to patients, and if necessary adrenaline injections for the emergency treatment of anaphylactic shock arising from the flu jab – although this latter provision is a very rare occurrence with the Irish Medicines Board reporting that only three patients out of millions who had received the “ordinary” seasonal flu vaccine (excluding the ‘09/’10 pandemic swine-flu jab) suffered anaphylactic-type reactions over the past decade, and there have been no related death during that period.

Mary Rose Burke

In 2010, more than 5,000 people received their flu vaccine in Boots pharmacies around the country. While this figure wasn’t sufficient to detect any measurable impact on hospital attendances for influenza-related complications, Ms Burke notes that it will be interesting to see what the overall outcome of the first national pharmacy-led flu vaccination campaign has had on uptake levels and hospitalisations.

“If somebody isn’t sick it can be hard to get them into a doctor’s surgery. A flu vaccination is one of those things that a person could just keep putting off, even thought they know it’s very important. But if you make it so easy and so accessible and convenient and at a time of their choosing, there’s a far greater chance that these at-risk groups will get their flu shots.

“We saw this in our Boots campaign; about a third of the people who received their flu vaccination in our pharmacies said they wouldn’t have got them otherwise. If this pattern is repeated in the new national flu vaccination programme, we could see an increase in uptake levels of more than 30%. In fact, that figure could be higher because it’s even more convenient now that there are so many more pharmacies involved.”

The lower cost should also prove an incentive. While there is no set price in pharmacy for the flu vaccine – the Competition Authority prohibits price setting among independent enterprises such as pharmacies – the overall fee for the vaccine and consultation ranges from €20 to €35 approximately. Of course, the flu vaccine in pharmacies is free of charge for people over 65 years of age with a valid Medical Card, GP Visit Card or Health Amendment Act (HAA). Customers over 65 years of age not eligible for any of those schemes will be asked to pay a reduced amount of approximately €15. This charge is for administering the vaccine, as the flu vaccine is free to all at-risk groups.

“I think there is a huge scope for pharmacists within the vaccination area. It’s pretty much straight forward; there is no diagnosis involved and most vaccinations are part of national programmes so I believe pharmacists can play a significant role in making sure that as a country we meet the WHO hurdles of penetration rates. Pharmacists could successfully offer other vaccination programmes such as for cervical cancer, possibly even childhood immunisations, although that may be somewhere further down the road, not least because you’d need waiting room facilities and the infrastructure in pharmacy would need to be right for that, but there’s no reason why we wouldn’t look at all of those services,” says Ms Burke.

More than 1,600 pharmacists have now received training in vaccination techniques from Hibernian Healthcare, which was initially commissioned by Boots in 2010 to provide training for their pharmacists on vaccination consultation, administration of the vaccine and post vaccination issues and complications. The training company’s programme was devised in conjunction with the Irish Pharmacy Union and is accredited by the School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin.

However, the pharmacy flu vaccination service hit a bump on the road early on when it emerged towards the end of November that an inadequate dose of the vaccine had been administered in error, requiring about 800 people – approximately 20% of patients vaccinated by pharmacists at that time – to be recalled to receive a booster jab.

“Unfortunately some pharmacists who attended a particular training course by Hibernian Healthcare were shown a DVD on how to administer the vaccine but which demonstrated the paediatric dose not the adult dose. As soon as this error came to light, within Boots, and I believe replicated around the country, we went back to our records, identified which pharmacists were at the training day, and ascertained from those pharmacists if they followed that incorrect procedure or not,” recounts Ms Burke.

“Many had realised that what they were shown didn’t make sense and had corrected their technique so we identified the pharmacists involved, pulled the records of any of the vaccinations they had administered, contacted the patients and invited them to come back. Many patients had seen the news reports and they understood the issue, so most of them came back in the next couple of days for revaccination.

“It’s a very unfortunate and regrettable incident but I think we have a lot to learn from that, and fortunately nobody came to harm, everybody was contacted. It has demonstrated the robust method of record keeping as we were able to do a very rapid follow up and contact the patients to get them back in very, very quickly. But absolutely we need to recognise that there was a number of issue that led to this happening and we need to address these and ensure that, for the next service that develops in pharmacy, we build in steps that would make sure that something like this would not happen again with something potentially more serious.”

As Director of Pharmacy at Boots (Ireland), Ms Burke leads all pharmacy activities in Boots, including future strategy and development. She maintains that travel vaccination is a potential new service that could be accessed through pharmacies in the near future.

“This is certainly an area that Boots is looking very seriously at. The growing popularity of long haul holidays means that more people may need these travel vaccinations, but often they can get swept away with the excitement and glamour of their trip and may neglect to think about the various vaccines they need.

"I think pharmacy would have a big role to play in making travel vaccinations available to people in a way that fits in with the planning of their holiday. Again, it’s the convenience factor that makes it easier for them to access this service as pharmacy has a higher penetration rate into the community so that everyone who is going abroad to those high-risk destinations would firstly know that they need to get vaccinated and secondly, we’d make it easy for them to avail of it,” she says.

Pharmacists in Ireland are expected to inject new vigour into the national flu vaccination programme, with the involvement of pharmacy in other immunisation programmes increasingly likely in the future as health authorities explore options for the safe, efficient and cost-effective delivery of public health services. This and similar service development will no doubt see pharmacy change over the coming years from community drugstores to community health destinations.

X-Ray: the invisible files

Professor Wilhelm Röntgen

A German physicist experimenting with his newly discovered invisible ray chanced to pass his hand through the beam. On the adjacent screen, the flesh of his hand had seemingly melted away, becoming a ghostly shadow through which only the bones were visible. Had Professor Wilhelm Röntgen any inkling in that heart-stopping moment on 8th November 1895 that he had just stumbled upon one of the most important discoveries in medical history?

Prof Röntgen delivered a paper detailing his findings in December that year, admitting that the precise nature of these new rays was unknown to him, and calling them X-rays, "for the sake of brevity" as "x" is the mathematical symbol for the unknown.

This new ray, unlike any others known at that time, was able to penetrate solid objects, even the thick walls of his laboratory, but it was the skeletal hand that captured the imagination of the public and of doctors, who immediately recognised that this discovery could transform medical practice forever. The science of medical radiology was born.

More than a century later, medical imaging has evolved into a vastly more sophisticated art form, yet it is still based on the principles that different parts of the body absorb a beam of X-rays according to their density, producing an image in which internal structures can be identified as well as any abnormalities indicative of injury and diseases.

X-rays are electromagnetic waves, like light waves but with a wavelength about one thousand times smaller. Because of this very short wavelength, X-rays can easily penetrate low-density material, such as flesh, but are still reflected or absorbed by high-density material, such as bone. The picture made by an X-ray machine shows the denser materials as dark areas.

For example, in a chest X-ray image, the calcium density of the spine and ribs blocks the most X rays, leaving white areas on a film. The water densities of the stomach and liver appear grey as they block less of the X-ray beam than bones. The fat density of muscles is less than that of the water so they look only slightly darker; finally, the air spaces in the lungs allow penetration of most of the X-ray beam and look almost black on the films.

While it sounds straightforward enough, X-ray films require a highly trained eye to recognise the distinction between superimposed ‘shadows’ of varying shades from back to white, interpret the results and make a diagnosis.

“Plain film radiograph, or x-ray, is the oldest, simplest and most common form of medical imaging. It’s basically a two dimensional representation of a three dimensional structure,” explained Dr Eoin Kavanagh, a consultant radiologist at the Mater Misericordiae Hospital and Cappagh National Orthopaedic Hospital, and senior lecturer at UCD School of Medicine and Medical Science.

“There are a million indications for X-rays: does the patient have a broken bone? Is there a foreign object in the body? Do they have a chest infection? The list goes on and on. Pretty much every patient who enters the hospital system will get some form of X-ray examination performed.

“This is the most standard of all our procedures, where you shine the X-ray beam through the patient and onto an image detector and then we interpret the resulting film. I would say in the Mater hospital we do a couple of hundred X-ray examinations every day. In Cappagh, where I work also, we do many thousands every month,” he added.

Besides diagnostic applications, interventional radiologists, such as Dr Kavanagh, use X-ray and other imaging techniques to guide “real time” procedures, such as needle biopsies. “This afternoon, for example, I’ll see about ten patients for joint injections during which I’ll use X-ray guidance that we call fluoroscopy, which is low dose X-ray, to guide the needle tip into various joints. Not all of our image-guided procedures involve X-rays; we use ultrasound and some MRI also.”

The inventor Thomas Edison is credited with developing the fluoroscope in 1896, a calcium tungstate coated screen that glowed when X rays hit it, allowing direct viewing of any part of the anatomy.

At that time, X-ray techniques were advancing apace but it soon became apparent that, while low doses of x-ray appeared to have a good affect on many skin diseases, repeated exposure to high-dose x-rays –a source of radiation – was dangerous and could prove deadly.

One of the earliest X-ray machines

Edison dropped X-ray research around 1903 after Clarence Dally, his assistant in X-ray research, died of extreme and repeated X-ray exposure. X-rays had already caused severe burns on his face, hands, and arms, resulting in several amputations.

In the early 20^th century, the problem of looking within body structures was finally addressed when it was found that liquids opaque to X-rays could be ingested or placed within a patient, which allowed the viewing of structures, blockages, ulcers, cancers, and other defects.

One such material was the common mineral barium sulphate, which could be ground up and swallowed to outline the oesophagus, stomach, and small intestine. Barium sulphate could also be inserted as an enema to visualise the large intestine. It is still used to this day, most often in imaging of the gastrointestinal tract during what is colloquially known as a “barium meal”.

Other radio-contrast agents were also developed that could be used with the kidneys, the brain and spinal canal, the circulatory system and the lungs.

In the 1970s, diagnostic radiology made a huge leap into cross-sectional imaging when medical engineers added computers to the equation, developing the technique known as computerised axial tomography (CAT or CT scanning), in which multiple cross-sectional x-ray views are combined by a computer to create three dimensional images of the body's internal structures.  

Around the same time that CT scanning was becoming a practical tool, a less harmful and more revealing imaging technology appeared on the scene that did not rely on X-rays: Magnetic resonance imaging (MRI), which uses powerful magnets and radio waves to create pictures of the body.

While X-rays can shown only the anatomical structures and nothing else, the advent of positron emission tomography (PET) in the mid-70s allowed doctors to study metabolic activity using a short-lived radioactive substances to produce three-dimensional coloured images of how those substances are functioning within the body.

“The more recent advances in X-ray have been in areas like developing system which are filmless: digital transfer of images, reading them of monitors and so on. In terms a future developments in X-ray, it is probably a technology which has evolved as far as it will go,” said Dr Kavanagh. “In terms of radiology, however, we’re looking at fusing CAT scanning with MRI; that’s going to be a massive area of development. Also, a PET MRI scan where a patient has a PET and a MRI scan at the same time, so that you can identify “hot spots” and then map them onto the MRI scan. That’s a very attractive option because the CT scan comes with quite a high radiation dose, and it would be better to avoid that.”

In this age of personalised medicine, molecular imaging is delivering on the promise of providing patient-specific information that allows treatment to be tailored to the exact biological characteristics of both the disease and the patient.

Molecular imaging shows how individual tissues are functioning, as opposed to conventional X-ray and other imaging techniques, which provide anatomical and structural pictures of organs and tissues.

“Imaging can be anatomic, which is where we’re looking inside the body purely anatomically, or it can be functional. With functioning imaging or molecular imaging we can actually see molecular process that are happening in the body.

“What are the functions of the underlying cells? What cells are different in this patient’s body, what is dividing at the wrong rate? This lump in the lung, has it got a high metabolic rate? Could it be a tumour? Do we need to biopsy it? Molecular imaging can help us answer those questions,” said Dr Kavanagh.

The development of novel radiotracers in molecular medicine is an area of rich promise. Different radiotracers can hone in on specific chemical activities in the body. At present, with PET scans for example, a glucose tracer is used to map metabolic activity. “Wouldn’t it be great is we had a radiotracer that could be mapped to prostate cancer, lets say, then you could inject the patient with the material do a scan and see if they have any prostate cancer cells in their body,” said Dr Kavanagh. “That’s the future of radiology, molecular imaging and personalised medical imaging for each patient.”

A wide range of imaging technologies is required to optimally visualise as much of the anatomical structures, and physiological and pathological processes, as possible. Dr Kavanagh illustrated this point with a patient example, a man who has had a bone biopsy, a knee MRI, an MRA (magnetic resonance angiography) of his lower limbs, a nuclear medicine isotope bone scan, and about 15 X-rays in the past year.

“X-ray has an important place in our arsenal when we are diagnosing or following up a patient but we have far more detailed imaging techniques these days. It would be fair to say that the discover of X-ray really got the ball rolling for radiology more than 100 years ago, and it hasn’t stopped since.”