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• Oncologists increasingly use targeted agents directed at molecular features of cancer cells
• There is increased off label use of these new targeted agents without evidence to support the practice
• A landmark study concludes that off label use of targeted agents show no benefit and should be discouraged
• Professor Gabra, head of cancer at Imperial College, says more research is needed

Despite significant progress in cancer care over the past decade, there remain substantial challenges in the treatment of advanced cancers. This has increased off-label use of newer drugs based on molecular studies of tumours, largely without much evidence to support the practice.

A landmark clinical study, known as SHIVA, led by Christophe le Tourneau, a senior medical oncologist at the Institut Curie in Paris, raised expectations among both doctors and patients, because it is one of the first randomized studies to explore molecularly targeted agents applied outside their indicated use (off-label) among those with advanced cancers for whom standard therapies had failed.
 
Findings, published in Lancet Oncology, September 2015, concluded that, “off-label use of molecularly targeted agents should be discouraged,” since the study detected no improvement in survival rates when compared to treatments selected by clinicians that were not based on such sophisticated DNA profiling. 

What are the implications of the study’s negative findings for personalised medicine?

Christophe le Tourneau

In the videos below Le Tourneau describes the SHIVA trail and some of the challenges it faced.

   

   
    

The context

Cancer is a heterogeneous, complex, and challenging disease to treat. Tumours formerly categorized as a single entity on the basis of microscopic appearance are now known to be diverse in their molecular characteristics. Cancer chemotherapy is on an evolutionary path from non-specific cytotoxic drugs that damage both tumour and normal cells to targeted agents that are directed at unique molecular features of cancer cells, and aims to produce greater effectiveness with less toxicity.
 
Over the past decade our understanding of cancer and the basis of its treatment has been significantly changed by the advent of rapid and cheap DNA sequencing technology. The application of these sophisticated analytic techniques to arrive at a therapy for a particular cancer has been called “personalized oncology.” The idea of personalized cancer care based on molecular characteristics of the tumour promises to expand the boundaries of precision medicine. Numerous case reports and other observations have suggested that therapy targeted at molecular characteristics of a tumour can have significant beneficial effects.
 
These personalized therapeutic strategies have rendered traditional classifications of many cancers redundant, because they have advanced our understanding of the underlying biology and molecular mechanisms of specific cancers. Cancer is no longer considered a single disease entity, and is now being subdivided into molecular subtypes with dedicated targeted and chemotherapeutic strategies. The concept of using information from a patient's tumour to make therapeutic and treatment decisions has changed the landscapes of both cancer care and cancer research.
 

The SHIVA study

The SHIVA study, carried out at eight academic centres in France and conducted in 195 patients with metastatic cancer resistant to standard care, was a proof-of-concept, open-label, randomized controlled study. The patients were randomly assigned to receive either molecularly targeted agents (used off-label) chosen on the basis of the molecular profile of the tumour; or therapy based on the clinician's choice. The median follow-up period was 11.3 months. Findings showed a median progression free survival (PFS) of 2.3 months for patients receiving targeted therapy, versus 2.0 months for patients receiving therapy based on the clinician's choice.

"So far, no evidence from our randomised clinical trial supports the use of molecularly targeted agents outside their indications on the basis of tumour molecular profiling . . . . . Our findings suggest that off-label use of molecularly targeted agents outside their indications should be discouraged, and enrolment into clinical trials encouraged," says Le Tourneau and his colleagues.
 

More research required

Hani Gabra, Professor of Medical Oncology and Head of Cancer, Imperial College London says, "SHIVA is important because it is the first randomized study carried out in this complex area of matching drugs to genomic profiles of tumours. Despite the fact that the results are negative we should continue research in this area because personalised medicine is a relatively new area. One thing to note is that the molecularly targeted agents used in SHIVA were single agents, which could increase resistance and reduce the agent’s efficacy. In clinical practice we tend to use several targeted agents in combination in order to counteract drug resistance. SHIVA tested specific agents and specific targets, which resulted in disappointing findings. This doesn’t necessarily negate the overall strategy, but it does suggest that more research is necessary to test the overall strategy, and this might be more challenging.”
 

Takeaways

SHIVA is one of several on going and proposed studies aimed at defining the role of targeting sequencing of tumours in an endeavour to enhance therapy. The SHIVA study did not uncover any new positive evidence to help in the management of advanced cancers. Le Tourneau and his colleagues suggest further studies in a subset of patients that have tumours with molecular alterations in the chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. Oncologists, while disappointed by SHIVA’S results, still hold out hope for their patients and advocate further studies.

• Cancer results when stem cells divide and mutate uncontrollably
• Whether this is predominantly the result of intrinsic or extrinsic factors is unclear
• Some experts say 65% of cancers result from intrinsic factors and are unavoidable
• Other experts say most cancers result from extrinsic factors and are avoidable
• Cancer strategy should not hide behind ‘bad luck’
• Resources need to be allocated more smartly to prevent cancer

Is cancer the result of bad luck and unavoidable, or is it self-inflicted and prevented by simple lifestyles choices? Two 2015 studies arrive at strikingly different conclusions.
 
One, carried out by researchers from the John Hopkins Kimmel Cancer Centre and published in January 2015 in the journal Science, suggests that two thirds of cancers result from bad luck. Another, carried out by researchers from the Stony Brook Cancer Centre in New York and published in December 2015 in the journal Nature rebuts the findings of the Science paper, and suggests that 70 to 90% of cancer risk is self-inflicted and therefore can be avoided.

Which is right? And, why should this concern us?
 

Cancer

Cancer is a complex group of diseases characterised by the uncontrolled growth and spread of abnormal cells. If this is not checked it can cause death. Nearly 80% of all cancer diagnoses are in people aged 55 or older. Some facts about cancer In 2015 around 1.7m new cancer cases were diagnosed in the US, and about 330,000 in the UK. Each year, there are some 589,430 cancer deaths in the US, and some 162,000 in the UK. The annual treatment cost of cancer for the US is about $90bn and for the UK about £10bn. The causes of cancer include genetic, and lifestyle factors; certain types of infections; and environmental exposures to different types of chemicals and radiation.  Whitfield Growdon, Oncology Surgeon at Massachusetts General Hospital and professor at the Harvard University Medical School describes cancer and the causes of cancer.


         

The Science paper: cancer is unavoidable

The Science paper found that 65% of cancer cases are a result of bad luck: random DNA mutations in tissue cells during the ordinary process of stem cell division; regardless of lifestyle and hereditary factors. The remaining 35% of cancer cases, say the authors, are caused by a combination of similar mutations and some environmental and hereditary factors. One implication of these findings is that preventative strategies will not make a significant difference to the incidence rates of most adult cancers. So accordingly, the optimal way to reduce adult cancers is early detection when they are still curable by surgery.
 
Stem cell division is the normal process of cell renewal, but the extent to which random cell mutations contribute to cancer incidence, compared with hereditary or environmental factors, is not altogether clear. This is what the John Hopkins researchers sought to address with their study. Scientists examined 31 tissue types to discover whether the sheer number of cell divisions increases the number of DNA mutations, and therefore make a given tissue more prone to become cancerous.
 
Researchers developed a mathematical model, which suggested that it is incorrect to assume that cancer may be prevented with “good genes” even though we smoke, drink heavily, and carry excess weight. Their study found that, "the majority [of adult cancer risk] is due to bad luck, that is, random mutations arising during DNA replication in normal, noncancerous stem cells."  And, "this is important not only for understanding the disease, but also for designing strategies to limit the mortality it causes," say the researchers.
 
According to the Science paper bad luck mutations account for 22 of 31 adult cancer types, including ovarian, pancreatic, bone and testicular cancers. The remaining nine, including lung, skin and colorectal cancers, occurred more often than the random mutation rate predicted. This suggests that in these cancers, either inherited genes or environmental factors have a significant influence on cases.
 
“Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue,” says Bert Vogelstein, Clayton Professor of Oncology at the John Hopkins University School of Medicine, and co-author of the study. One example, he says, is in colon tissue, which in humans, undergoes four times more stem cell divisions than small intestine tissue. Likewise, colon cancer is much more prevalent than small intestinal cancer.
 
In a BBC Radio 4 interview Cristian Tomasetti, co-author of the study said: “Let’s say my parents smoked all their lives, and they never got lung cancer. If I strongly believed cancer was only environment, or the genes that are inherited, then since my parents didn’t get cancer, I may think I must have good genes, and it would be OK to for me to smoke. On the contrary, our study says ‘no’, my parents were just extremely lucky, and played a very dangerous game.”

Related Commentaries

Liquid biopsies to detect pancreatic cancer are near 
Full circle in cancer research
Is immunotherapy a breakthrough in cancer treatment?
Is patient engagement the new blockbuster drug? 
We should give up trying cure cancer

The Nature paper: cancer is avoidable

In a BBC interview, Yusuf Hannun, Director of the Stony Brook Cancer Center, Joel Strum Kenny Professor of Cancer Research and one of the authors of the Nature paper, challenged the findings of the ‘bad luck’ study. He suggests that hiding behind ‘bad luck’ is like playing Russian roulette with one bullet; one in six will get cancer. "What a smoker does is add two or three more bullets to the revolver and pulls the trigger. Although there is still an element of luck, because not every smoker gets cancer, they have stacked the odds against themselves. From a public health point of view, we want to remove as many bullets as possible from the revolver," says Hannun.
 
The Nature paper rebuts the John Hopkins ‘bad luck’ thesis. Its lead author, Song Wu, from the Department of Applied Mathematics and Statistics at Stony Brook University, notes that the Science paper had not conducted an alternative analysis to determine the extent to which external risk factors contribute to cancer development, and it assumes that the two variables: intrinsic stem-cell division rates, and extrinsic factors, are independent. “But what if environmental factors affect stem-cell division rates, as radiation is known to do?” asks Wu.
 
Wu and his colleagues provide an alternative analysis by applying four analytical approaches to the data that were used in the earlier Science paper and arrive at a radically different conclusion: that 70 to 90% of adult cancer cases result from environmental and lifestyle factors, such as smoking, drinking alcohol, sun exposure and air pollution. Wu admits that some rare cancers can result from genetic mutations, but suggest that incidence rates of cancers are far too high to be explained primarily by mutations in cell division.
 
According to the Nature paper, if intrinsic risk factors did play a key role in cancer development, the total number of divisions in tissue stem cells would correlate with lifetime cancer risk, and the incidence rates of the disease would be less than it actually is. Wu and his colleagues analyzed the same 31 cancer types as in the earlier Science paper, and evaluated the number of stem cell divisions in each. They then compared these rates with lifetime cancer incidence among the same cancer types. This allowed them to calculate the contribution of stem cell division to cancer risk.
 
Wu et al also pursued epidemiological evidence to further access the contribution of environmental factors to cancer risk. They analyzed previous cancer studies, which show how immigrants moving from regions of low cancer incidence to regions with high cancer incidence soon develop the same tumor rates, suggesting that the risks are environmental rather than biological or genetic.
 
The researchers’ findings suggest that mutations during cell division rarely accumulate to the point of producing cancer, even in tissues with relatively high rates of cell division. In almost all cases, the Nature paper found that some exposure to carcinogens or other environmental factors would be needed to trigger disease, which again suggested that the risks of the most prevalent adult cancers are due to environmental factors. For example, 75% of the risk of colorectal cancer is due to diet, 86% per cent of the risk of skin cancer is due to sun exposure, and 75% of the risk of developing head and neck cancers is due to tobacco and alcohol.
 
The Nature paper concludes that bad luck, or intrinsic factors, only explain 10 to 30% of cancer cases, while 70 to 90% of adult cancer cases result from environmental and lifestyle factors. "Irrespective of whether a subpopulation or all dividing cells contribute to cancer, these results indicate that intrinsic factors do not play a major causal role," say the authors. This suggests that many adult cancers may be more preventable than previously thought. 
 

Preventing cancer 

Even the Science study concedes that extrinsic factors play a role in 35% of the most common adult cancers, including lung, skin and colorectal cancers. This, together with the Nature study, and the rising incidence of avoidable cancers, should be a wake-up call because a substantial proportion of cancers can be prevented.
 
Hannun is right! Whatever the causes of cancer, we should not ‘hide behind bad luck’.  We should act on evidence, which suggests that it is within everyone’s capabilities to make simple lifestyle changes that can prevent common adult cancers.  Although maintaining a healthy lifestyle is no guarantee of not getting cancer, the Nature paper underlines the fact that a healthy lifestyle stacks the odds in your favor.  The paper supports preventative cancer strategies.
 
In 2015, tobacco smoking caused about 171,000 of the estimated 589,430 cancer deaths in the US. The Nature paper suggests that the overwhelming majority of these could have been prevented. In addition, the World Cancer Research Fund has estimated that up to 33% of the cancer cases that occur in developed countries are related to being overweight or to obesity, physical inactivity, and/or poor nutrition, and thus could also be prevented.
 
It seems reasonable to suggest that the risk of cancer can be significantly reduced by: (i) a cessation of smoking, (ii) drinking less alcohol, (iii) protecting your skin from the sun, (iv) eating healthily, (v) maintaining a healthy weight, and (vi) exercising regularly.
 

The UK Position

Everyone understands the enormity of the burden of cancer, and what to do to reduce its risk. In the UK, as in other wealthy countries, there is no lack of money, no lack of resources, and no lack of expertise for cancer care. The annual spend on cancer diagnosis and treatment alone in the UK is about £10 billion. The UK also has a government appointed Cancer Czar charged with producing a national cancer plan to bring Britain's cancer survival rates up to those of European levels. Despite our understanding and all these resources, a 2014 study published in the Lancet suggests that cancer survival rates in the UK still lag more than 20 years behind many other European countries, and that people are dying needlessly.  Why is this?
 

Fear of preventative medicine 

Writing in The Times in January 2016, Sir Liam Donaldson, a former UK Chief Medical Officer, suggested that although preventative healthcare strategies are vital “to provide safe, high quality care without running out of money”, governments avoid helping the public to mitigate the risks of modern living, which can cause cancer, because of  “two primal political forces: the mortal dread of being labeled a ‘nanny state’, and a fear of removing people’s perceived pleasures.”
 
During Donaldson’s tenure between 1998 and 2010, the government rejected his recommendation for a minimum unit price for alcohol, and for the same reasons in 2014, the government rejected a tax on sugar recommended by Public Health England. Excess sugar increases the risk of cancer, heart disease and diabetes. According to Donaldson, without effective government action to lower the vast and escalating burden of cancer, and other chronic diseases, the NHS is unsustainable.
 
The missing link in preventative strategies is behavioral techniques that engage people who are at risk and help them change their behaviors. Such techniques have been demonstrated to be successful in both the UK and US. They explain how people behave, and encourage them to reduce unhelpful influences on their health, and change the way they think and act about important health-related issues such as diets, lifestyles, screenings and medication-management. See: Behavioral Science provides the key to reducing diabetes
 

Takeaway 

It is crucial that the UK government now embraces behavioral techniques to curb the curse of cancer.  Donaldson is right: if cancer, and other chronic diseases, which together consume the overwhelming percentage of healthcare expenditure, are not prevented the NHS will become unsustainable.

Diabetes wars

• Failing diabetes services are waisting money
• Too many people with diabetes develop avoidable complications
• No one is held accountable for poor diabetes service performance
• The NHS payment systems do not effectively incentivise the delivery of recommended standards of diabetes care
• Appropriate incentives for diabetes services could improve diabetes outcomes and save the HNS £170m per year

National Audit Office v. NHS

A war is being waged between the NHS and the UK’s National Audit Office (NAO) over the state of adult diabetes services in the UK. Two NAO reviews found that doctors are failing to meet nationally agreed standards of diabetes care, and that they are neither effectively incentivised to deliver and sustain quality services nor accountable for poor service. 

The NHS says it is committed to supporting doctors to deliver high-quality care to people with and at risk of diabetes, but the NAO is not convinced.  It recommends that monies for diabetes services and doctors’ remuneration should be linked more directly to desired patient outcomes in order to promote and sustain accountability, responsibility, learning and the strengthening of local capacity. 

 

Adult or type 2 diabetes (T2DM) is an avoidable chronic condition, which occurs when the body does not produce enough insulin to function properly, or the body’s cells do not react to insulin. This means that glucose stays in the blood, and is not used as fuel for energy. There are currently 3.9 million people living with diabetes in the UK, with 90% of those affected having T2DM. Diabetes is a cause of serious long-term health problems, which include blindness, kidney failure, lower limb amputation, and cardiovascular disease, such as a stroke. Roni Sharvana Saha, Consultant in Acute Medicine, Diabetes and Endocrinology at St Georges University Hospital, London describes why weight control is important for the management of T2DM.

         
            (click on the image to play the video) 

Local responsibility for adult diabetes services 

In England the responsibility for diabetes services and support rests with local Clinical Commissioning Groups (CCGs) and GPs. In 2003 the UK government gave primary care trusts the responsibility for commissioning local services on behalf of their local populations, and freedom to decide how to best deliver diabetes services. It is for GP practices to ensure that people with diabetes receive all the nine recommended care processes each year in accordance with agreed clinical guidance (see below). In 2004 the Quality and Outcomes Framework (QOF) was introduced as part of the new GP contract, which includes payments for undertaking specified clinical activities and achieving set clinical indicators.

 

The nine basic processes of diabetes care are: (i) blood glucose level measurement (HbA1c), (ii) blood pressure measurement, (iii) cholesterol level measurement, (iv) retinal screening, (v) foot and leg check, (vi) kidney function testing (urine),  (vii) kidney function testing (blood), (viii) weight check, (ix) smoking status check.
 

Failing incentives

QOF awards for GPs initially improved diabetes outcomes in primary care. However, recently there has been little improvement, and according to the NAO the current payment system for GPs is not driving the required patient outcomes. GPs are paid for each individual diabetes test they carry out rather than being rewarded for ensuring that all nine tests are delivered. Similarly, the Payment by Results tariff system for English hospitals does not incentivize the multi-disciplinary care required to treat a complex long-term condition such as diabetes. According to the NAO the NHS needs to review and enhance its payment systems to ensure that they effectively incentivise good care and better outcomes for people with diabetes.
 

National Audit Office’s First Review (2012)

In May 2012 the NAO’s first review of adult diabetes services in England found that the NHS was not delivering value for money, and that it was underestimating its annual spend on diabetes services by some £2.6 billion. “There is poor performance in expected levels of diabetes care, low achievement of treatment standards, and 24,000 people die each year from avoidable causes relating to diabetes”, said the report.

The NAO findings included the following:

    1. "Fewer than one in five people with diabetes in England are being treated to recommended standards, which reduce their risk of diabetes-related complications
    2. Many people with diabetes develop avoidable complications
    3. NHS accountability structures fail to hold commissioners of diabetes service providers to account for poor performance
    4. No one is held accountable for poor performance, despite the fact that performance data exist
    5. The NHS is not effectively incentivising the delivery of all aspects of recommended standards of care through the payments systems
    6. There is a lack of clarity about the most effective way to deliver diabetes services
    7. Payment mechanisms available to GPs are failing to ensure sustained improvements in outcomes for people with diabetes
    8. The NHS does not clearly understand the costs of diabetes
    9. Effective management of diabetes-related complications could save the NHS £170 million a year"

The NAO Recommendation

The NAO recommended that the system of incentives for doctors be renegotiated to improve outcomes for people with diabetes in accordance with agreed clinical practice. GPs should only be paid for diabetes care if they ensure all nine care processes are delivered to people with diabetes. Also the NAO recommended that the thresholds at which GPs are remunerated for achieving treatment standards should be reviewed regularly.
 

Public Accounts Committee Chair: “Depressing report”

Margaret Hodge, chair of The House of Commons Committee on Public Accounts, which took oral and written evidence on the NAO Report, said, “This was one of the most depressing Reports I’ve read. Everybody understands the enormity of the problem; nobody is arguing with the figures; everybody accepts both the nature of the checks, and the treatments to prevent complications that should be done; money or lack of it has not been an issue; there appears to be a structure within the Department of Health with a tsar and a group of people whose job it is—and yet we are failing.”
 

Public Accounts Committee’s Conclusion: Higher costs, poorer services

The conclusions of Public Accounts Committee echoed its chair’s opening remarks, “Although there is consensus about what needs to be done for people with diabetes, progress in delivering the recommended standards of care and in achieving treatment targets has been depressingly poor. There is no strong national leadership, no effective accountability arrangements for commissioners, and no appropriate performance incentives for providers. We have seen no evidence that the Department of Health will ensure that these issues are addressed effectively . . . . Failure by it to do so will lead to higher costs to the NHS as well as less than adequate support for people with diabetes.”
 

Action for Diabetes: the NHS’s Defence (2014)

In January 2014 the NHS defended its services in Action for Diabetes, a report prepared by its Medical Directorate, which sets out the activities NHS England is undertaking as a direct commissioner of GP and other primary care services, and as a support to secondary and community care commissioners to improve outcomes for people with and at risk of diabetes. The report stated that between 1996 and 2002 there was a, “marked reduction in excess mortality in those with diabetes”, and the UK’s diabetes-related mortality rates were better than 19 other developed economies. 

Action for Diabetes reaffirmed that the NHS was committed to supporting CCGs to deliver high-quality care to people with and at risk of diabetes, and will:

      • “Provide tools and resources to support commissioners in driving quality improvement
      • Ensure robust and transparent outcomes information, and align levers and incentives to facilitate delivery of integrated care across provider institutional boundaries
      • Empower patients with information to support their choices about their own health and care, and support the development of IT solutions that allow sharing of information between providers and between providers and people with diabetes
      • Look to the future of the NHS to deliver continued improved outcomes for people with or at risk of diabetes.” 

In a foreword to Action for Diabetes Professor Jonathan Valabhji, the UK government’s National Clinical Director for Obesity and Diabetes, said the NHS needs, “new thinking about how to provide integrated (diabetes) services in the future in order to give individuals the care and support they require in the most efficient and appropriate care settings, across primary, community, secondary, mental health and social care, and in a safe timescale”.
 

National Audit Office’s Second Review (2015) 

In October 2015, the NAO published a follow-up review of NHS adult diabetes services, and criticised (I) the still low rates of the delivery of basic diabetes care processes, and (ii) the low rates of attainment of diabetes treatment goals. The NAO pointed to the escalation of avoidable complications, such as amputation, blindness, kidney failure and stroke that consume about 70% of the annual treatment costs of the NHS on diabetes.  The report commented:  “The improvements in the delivery of key care processes have stalled, . . . and this is likely to be reflected in a halt to outcomes improvement for diabetes patients . . . There are still 22,000 people estimated to be dying each year from diabetes-related causes that could potentially be avoidable”.

Ineffective payment systems

The NAO’s 2015 report criticized the way that the NHS distributes money, and sets local incentives for improving the delivery diabetes services. Economists have long argued that bureaucrats distributing monies with loose conditions is not an effective way to achieve transformative change. According to the NAO, “Current financial incentives, funding mechanisms and organisational structures of health services do not support the delivery of integrated diabetes care”. The NAO recommends that the NHS should, “Ensure that its payment systems effectively incentivise good care and better outcomes for people with diabetes”. 

Comment: Reasons for failure

According to market economists aid is at best wasteful, and at worst creates a damaging culture of dependency. Also, aid is often subject to vested interests, and fails to change people’s behaviors and improve wellbeing.
 
Institutions responsible for delivering diabetes services in England have not learned these lessons, and as a consequence poorly incentivized diabetes service providers fail to propel people living with diabetes towards self-management, and fail to slow the onset of devastating and costly complications. 
 

Effective incentives are key for improving diabetes outcomes

This Commentary has suggested that without appropriate incentives diabetes service providers have become chronically dependent on their paymasters, which has stifled innovation, made service providers less focused on patient outcomes, and less likely to innovate and prioritize the generation of other resources. Current incentives for diabetes service providers should be renegotiated.
 
A previous Commentary suggested that effective patient outcomes occur when people and communities are engaged and assume greater responsibility for their own wellbeing. Tried and tested behavioral techniques successfully used by the Cameron and Obama administrations need to be embedded in a range of diabetes services to create offerings that people want and that actually lower the risk of T2DM, propel those living with the condition into self-management, and slow the onset of devastating and costly complications; see Behavioral Science provides the key to reducing diabetes.
 
A related issue, which needs to be addressed to improve patient outcomes further, is the need to reduce the power of the bureaucracies that control the provision of diabetes services and to increase competition among diabetes service providers. Current bureaucratic diabetes service providers present a significant barrier for new entrants, and thereby discourage investments in innovations and new technologies. This will be the subject of a future Commentary.

• Detecting pancreatic cancer early is a significant advance
• 80% of people with pancreatic cancer are diagnosed late
• Only 3% of pancreatic cancer patients survive 5 years after diagnosis
• 12% of pancreatic cancer is associated with obesity
• MD Anderson blood test is 100% accurate at detecting pancreatic cancer
• Urine test 90% accurate at detecting pancreatic cancer
• Both tests could be in the clinic in a few years

Liquid biopsies are poised to detect pancreatic cancer early, which is a significant advance.

This is important because the clinical symptoms arise late in people with this cancer. Eighty per cent of people with the disease are diagnosed when it has already spread, so they are not eligible for surgery to remove the tumour, which currently is the only potential cure. Only about 3% of patients diagnosed with pancreatic cancer survive five years after diagnosis.
 

The pancreas is an organ that sits close behind the stomach, and has two main functions: (i) producing digestive enzymes, which break down food so that it can be absorbed, and (ii) producing insulin, which regulates blood sugar levels. Pancreatic cancer occurs when cells are produced in the pancreas in an uncontrolled fashion. This can lead to a number of health risks. Almost half of all new cases of cancer of the pancreas are diagnosed in people aged 75 and over, and is uncommon in people under 40. This year, an estimated 48,960 adults in the US and some 9,000 in the UK will be diagnosed with pancreatic cancer. It is estimated that 40,560 US deaths, and about 9,000 deaths in the UK from this disease also will occur this year. Those at higher risk include people with a family history of the cancer, heavy smokers, and obese people. There is some suggestion that pancreatic cancer is a risk for people over 50 who are newly diagnosed with diabetes.
 

Pancreatic cancer and diabetes

Type-2 diabetes is considered to be associated with pancreatic cancer, but it is not altogether clear whether diabetes is a risk factor or a symptom. Two studies published in 2011; one in the British Journal of Cancer, and the other in the Annals of Oncology confirm the hypothesis that, “increased BMI and abdominal obesity are associated with increased pancreatic cancer risk.” One of the studies estimates that about 12% of all pancreatic cancers in the UK are attributable to overweight and obesity. Fatty tissue in overweight people produces more hormones and growth factors than those in people of a healthy weight. High levels of some of these hormones, including insulin, which is produced in the pancreas, can increase the risk of pancreatic cancer.

Dr Roni Sharvanu Saha, a consultant in acute medicine, diabetes and endocrinology at St George's Hospital, London, opines on the possible relationship between diabetes treatment and pancreatic cancer, and says that, “the jury is out” about the link. 


            
                

Blood test for pancreatic cancer 

Pancreatic cancer is devastating, it usually shows no signs or symptoms, and presents late. Being able to detect the disease early is considered life enhancing for patients. Scientists from the University of Texas MD Anderson Cancer Center believe they are close to developing a blood test to detect pancreatic cancer, which they describe as "a major advance". Early results, published in 2015 in the journal Nature, showed the test was 100% accurate. Experts said the findings were striking and ingenious, but required refinement before they could be used in the clinic.
 

Major advance

A wall of fat marks the boundary of every cell in the human body. The MD Anderson test hunts for tiny spheres of fat, called exosomes, which are shed by the cancers. Scientists looked for unique signatures of cancer in these fatty exosomes, and noticed that a protein called proteoglycan glypican-1 was found in much higher levels in people with pancreatic cancer. Further blood tests on 270 people showed it was 100% accurate at distinguishing between cancers, other pancreatic disorders and healthy tissue.

The need for such a test is huge. According to Dr Raghu Kalluri, one of the MD Anderson researchers, the test is, "not too far" from the clinic. "We think the ability to identify and isolate cancer exosomes is a major advance and provides the possibility of immensely benefiting our patients," says Kalluri.
 

Urine test for pancreatic cancer

Scientists from Barts Cancer Institute, Queen Mary College, London, have developed a simple urine test to detect pancreatic cancer. The UK-Spanish study, published in Clinical Cancer Research in 2015, showed that out of 1,500 proteins found in the urine samples of 500 people, three were seen to be at much higher levels in the pancreatic cancer patients. This provided a "protein signature" that could identify the most common form of the disease, and distinguish between this cancer and the inflammatory condition chronic pancreatitis, which can be hard to tell apart. The signature was found to be 90% accurate. More research is now planned, and scientists will focus particularly on people whose genes put them at particular risk of pancreatic cancer.
 

Advantages of urine over blood 

Lead researcher, Dr Tatjana Crnogorac-Jurcevic, said: "We've always been keen to develop a diagnostic test in urine as it has several advantages over using blood. It's an inert and far less complex fluid than blood, and can be repeatedly and non-invasively tested.  We're hopeful that a simple, inexpensive test can be developed, and be in clinical use within the next few years."

"For a cancer with no early stage symptoms, it's a huge challenge to diagnose pancreatic cancer sooner, but if we can, then we can make a big difference to survival rates," says co-author and Director of Barts Cancer Institute, Professor Nick Lemoine.
 

Takeaways

Although there is a significant amount of work still to do before these tests appear in clinics, the levels of accuracy reported by the researchers are striking, and suggest that, in principle, a liquid biopsy has been found for this devastating cancer, which is good news for patients suspected of having the disease.

Is patient engagement the new blockbuster drug? 

• Patient engagement improves outcomes
• The future is not a continuation of population based medicine
• Personalized medicine requires effective patient engagement
• Doctors are the main obstacle to enhanced patient engagement

If patient engagement were a drug, it would be front-page news, and malpractice for doctors not to use it. A significant and growing body of opinion believes that an effective way to scale care, and enhance outcomes is to develop patient engagement, but this requires a cultural and behavioral change on the part of doctors, which is not happening fast enough.
 

Low patient engagement means poor outcomes 

Each year payers spend billions on treating avoidable chronic lifetime diseases, yet the incidence of such diseases continue to escalate inflicting devastating personal, and social hardships on people and communities. Some wealthy regions of the world, such as the United Arab Emirates, where diabetes is spiraling out of control, have invested in “cathedrals” of diabetes healthcare staffed by experts, but still do not have the costly burden of diabetes under control. See, Diabetes threatens the future stability of the UAE
 

Tackling causes 

In other regions of the world, the treatment costs alone for avoidable chronic lifetime diseases are expected to bankrupt healthcare systems in the near future. The reason for this is simple. Despite eye watering investments in state-of-the-art treatment strategies, and despite some doctors’ initiatives to engage patients, no healthcare system yet has effectively engaged large proportions of patients living with lifetime chronic diseases, and successfully nudged them towards changing their diets and lifestyles, which are the root causes of a substantial proportion of such conditions. 

Dr Seth Rankin Managing Partner of a London based NHS primary care clinic, describes his efforts to engage patients living with diabetes in order to improve outcomes:

       
               (click on the image to play the video) 
 

Behavioral techniques 

Rankin’s endeavors to engage patients benefit from behavioral techniques, which explain how people behave, and encourages them to reduce unhelpful influences on their health, and change the way they think and act about important health related issues such as diets, lifestyles, screenings and medication management. See: Behavioral Science provides the key to reducing diabetes

“Our new pathway of care borrows from the behavioral sciences and engages patients living with diabetes. It’s based on very simple technology, which can provide huge reach at low cost. We are keen to extend our pathway to other NHS Clinical Commissioning Groups, and would welcome support from well capitalized diabetes agencies,” says Rankin.
 

Doctors’ support critical

Rankin insists that, “Only when patients are meaningfully engaged in their own health will they continuously learn how to improve care for themselves”. Effective patient engagement enhances the connectivity between doctors and patients, and is a sound foundation for behavioral change. However, for patient engagement to be scalable and effective, it has to be supported by appropriate IT, and patient-generated healthcare information. 
 

Doctors control patient engagement

Patients gather healthcare information from the Internet, and this encourages and supports self-management, and enhanced understanding of prevention and risk. However, the quality of online healthcare information is patchy, and patients have difficulty differentiating between legitimate and bogus information. This is resolved when doctors’ engage with patients to help them with the interpretation. Some doctors welcome this opportunity, while others object. This gives doctors the upper hand. Even if the situation is improved by enhancing patients’ access to premium and reliable medical information, doctors still decide whether such information is introduced into patient care pathways. 
 

Improved healthcare

Objections from doctors suggest that online health information results in longer and fraught doctor-patient relationships, which are a costly waste of time. But this is not necessarily so. Evidence, such as that published in 2008 in Telemedicine and eHealth, suggests the opposite: that patient-generated healthcare information, and effective patient engagement can lead to better understanding of specific conditions and treatment options, enhanced medication management, reduced complications, reduced face-time with doctors, and reduced visits to A&E. Specifically, the 2008 paper’s findings report that online healthcare information resulted in: (i) 19.74% reduction in hospital admissions, (ii) 25.31% reduction in bed days of care, and (iii) 20 to 57% reduction in the onset of complications.
 

Takeaways

Despite evidence to suggest that patient engagement enhances outcomes and reduces costs, it is not happening at a rate and quantum to render it effective. The main obstacle is the attitudes of doctors who fear an erosion of their status. Only a significant cultural and behavioral shift on the part of doctors will change this, and open the door to the many other professional disciplines, such as behavioral economists, software designers, community leaders, data scientists and risk managers, who are well positioned to help healthcare and medicine deliver better outcomes for patients. 

The future of healthcare is not a continuation of population-based medicine with its one-size-fits-all therapies mediated by general practitioners. The future of healthcare is personalized medicine, which recognizes that patients and medicines are complex and adaptive, which require smart and adaptive systems. This includes greater patient engagement.

The end of doctors 

• A second technology revolution threatens the future of healthcare
• Healthcare systems that ignore evolving technologies will collapse
• Most healthcare systems are trapped by three basic failures
• Doctors are the interpreters and not the processors of medical knowledge
• Will a computer decide to turn off a life support machine?
• Who owns the medical information on the Internet?

The role of doctors is about to change more than it has in the past two centuries, as the technology revolution enters a new era. 
 

Radical change 

This is the conclusion of Richard and Daniel Susskind in their book, The Future of Professions, published on 22^nd October 2015 by Oxford University Press. They argue that, over the next 20 years, “the second future”, dominated by artificial intelligence (AI) and the Internet, will drive radical changes in healthcare systems, which will involve the transformation of how medical knowledge is made available.

Today, computer systems can delve into vast amounts of patient data, identify trends and make more accurate predictions than doctors. Machines such as IBM’s Watson, which can attain high levels of intelligent behavior is already being used in medicine. In parallel, the Internet provides people with new and effective ways to build communities and share healthcare information. 
 

Never too big to collapse 

Some doctors argue that their activity will never change because it depends on deep expertise, creativity and strong interpersonal skills; none of which can be replaced by computer systems. Earlier, managers of global companies that dominated world markets made similar claims before there enterprises grew obsolete and collapsed.

Twenty years ago, the failure of global companies to meet transformational challenges resulted in 74% of them leaving the Fortune 500 as new technologies and innovations opened the way for agile start-ups and entrepreneurs. The list is long, but here are a few examples. Digital Equipment and Wang Laboratories, once leading computer firms, disappeared completely. Even resurgent giants such as Apple and IBM stared into the abyss of irrelevance, and made painful changes before clawing their way back to the top.
 

In the 1980s the advent of digital photography, software, file sharing, and third-party apps ended Eastman Kodak’s world market domination, during which time Kodak made breakthrough technologies, which included the Brownie camera in 1900, Kodachrome colour film, the handheld movie camera, and the easy-load Instamatic camera. Motorola, another global giant, that developed and built the world's first mobile phone, and dominated that market until 2003, failed to focus on smartphones that could handle email and other data; and as a consequence, rapidly lost share to newcomers such as Apple, LG, and Samsung.

 

Dr Devi Shetty, world-renowned heart surgeon, founder, philanthropist, and chairman of Narayana Health, India’s largest hospital group is viewed as the person who will have the biggest influence on 21^st healthcare. Here he describes how information technology is set to radically change healthcare:

    
        (click on the image to play the video) 
 

Healthcare systems not immune

The Susskind’s agree with Shetty, and believe that healthcare systems, predicated upon antiquated patient-doctor technologies, face a similar demise to that of large companies that failed to adapt and change. The more successful healthcare systems will be those, that copy large companies who survived by collaborating with smaller, agile firms either as suppliers or partners. Rigid bureaucratic healthcare systems that find it more difficult to innovate will fail.
 

Three reasons for failure 

Failure to address three major challenges accounts for the failure of most healthcare systems. The first is the continued investments in failing antiquated systems, and the consequent failure to pursue fresher, more relevant ones. The second is psychological: healthcare systems and doctors fixate on what made them successful in the past, and fail to notice when something new is replacing it. The third challenge is strategic: healthcare systems that only focus on today, and fail to anticipate the future will fail.

Previous HealthPad Commentaries have illustrated these three failures by the billions spent on failing diabetes education programs over the past decade, while the incidence of the condition escalated. This is because diabetes education and awareness programs fixate on antiquated systems, and fail to embrace, smarter and more effective ones. See: Behavioral Science provides the key to reducing diabetes
 

The concentration of medical expertise

A doctor’s raison d'être is to provide solutions to problems that people do not have sufficient specialist knowledge themselves to solve. Previously doctors were the ‘processors’ of medical knowledge, but with medical information becoming ubiquitous, increasingly doctors are becoming the ‘interpreters’ of medical knowledge. Doctors are gateways to specialist medical information.

In most healthcare systems, doctors are a huge and increasing expense, a large proportion of them use antiquated methods, and the expertise of the best doctors is only enjoyed by a few. This is changing by technological innovators finding ways to make medical expertise more widely available. Also, technology is enabling clinical expertise to be broken down into smaller tasks, which can be better achieved with a machine; telemedicine is just one example.
 

Who owns medical knowledge?

Online healthcare information empowers patients and threatens doctors by providing people with medical knowledge that previously resided in the minds of doctors. Such knowledge, which can help to diagnose illnesses, is free, increasingly common, and controlled by users. An important unresolved question is, who owns this medical knowledge?
  

Takeaways

Doctors exist to provide solutions to medical problems. If technology provides better more reliable solutions, the need for doctors dissolves. However, the most convincing objection for the displacement of doctors is an ethical one. Is it morally wrong to leave the decision to turn off a life support machine to another machine?

The debate is just beginning. 

Smart insulin and new hope for type-1 diabetes

• A new smart insulin could improve the lives of people with type-1 diabetes 

• The smart insulin is easier, faster, and more effective than current therapies

• The new compound automatically activates in response to rising blood sugar

A new compound, Ins-PBA-F, referred to as ‘smart insulin’, could spare people living with type-1 diabetes the burden of frequently injecting, and constantly monitoring their blood sugar levels.

The new compound, developed by scientists from the University of Utah, USA, and reported in a 2015 edition of the Proceedings of the National Academy of Science, automatically activates when your blood sugar level soars, brings it back to normal, and remains in circulation for up to 24 hours. In the future, people with type-1 diabetes could inject the smart insulin once a day, or even less frequently, overcoming the need for constant self-monitoring, and insulin top-ups after meals.
 

Easier, faster and more effective

Researchers suggest that the speed, and chemical reactions of Ins-PBA-F normalizing blood sugar in diabetic mice is the same as in healthy mice responding to blood sugar changes with their own insulin. Ins-PBA-F could give a faster, more effective response to lowering blood sugar than the current long-acting insulin drug, and could be tested in humans in two to five years.
 

Type-1 diabetes

According to the WHO, in 2014, 9% of all adults have diabetes, and an estimated 10% of these have type-1 diabetes, a significant proportion of which are children. Type-1 diabetes is an autoimmune disease in which the body kills off all its pancreatic beta cells, which produce insulin that regulates blood sugar. Without beta cells, the body’s sugar levels fluctuate wildly. Dr Sufyan Hussain, Senior Lecturer in Diabetes, Endocrinology and Metabolism at Imperial College, London, describes type-1 diabetes:

       
 

Unrelenting regimen

While insulin injections or infusion allow a person with type-1 diabetes to stay alive, and lead a full and active life, they neither cure the disease, nor necessarily prevent the possibility of the disease’s serious effects, which may include: kidney failure, blindness, nerve damage, heart attack, stroke and pregnancy complications. Traditional insulin therapies are a constant management challenge. Patients must carefully balance insulin doses with eating and other activities multiple times a day and night. Hussain describes the genesis, and benefits of insulin therapy:

    
 

Advantages of ‘smart insulin’

Without insulin, the body has no mechanism for moving sugar out of the blood and into cells, where it is used for energy. People with type-1 diabetes are completely dependent on their daily insulin injections for their survival, and have to check their blood-glucose level by pricking their fingers several times a day to assess how much insulin to inject. Any lapse or miscalculation in this unrelenting regimen can run the risk of dangerous high and low blood-glucose levels; both of which can be life threatening.

“In theory, with Ins-PBA-F there would be none of these glucose problems,” said co-author Dr Danny Chou, “A smart insulin drug that automatically activates in response to rising blood sugar would get rid of the need for top-up injections of insulin, and eliminate the danger of incorrect dosing”.
 

Takeaways

Ins-PBA-F closely mimics the way bodies return their blood sugar levels to normal after eating. According to Chou, “This is an important advance in insulin therapy. Diabetic patients still need to guess to some extent how much insulin they need. With Ins-PBA-F you would just inject it, and it wouldn’t matter if you overshot because its activity would stop when glucose levels get too low. Our smart insulin derivative appears to control blood sugar better than anything that is available to diabetes patients right now.”

• Promising animal study suggests a vaccine for type-1 diabetes
• Harvard’s Dana Faber Cancer Institute endorses the study
• Lab spent years detailing the molecular immune system's response to insulin
• The therapy for type-1 diabetes is insulin, but there’s no cure
• Living with type-1 diabetes is a constant challenge

A molecule that prevents type-1 diabetes in mice has provoked an immune response in human cells, according to scientists from the National Jewish Health and the University of Colorado. The findings, published in the 2015 Proceedings of the National Academy of Sciences, suggest that a mutated insulin fragment could be used to prevent type-1 diabetes in humans.
 

Strategies that work in mice often fail in humans 

Previously, researchers tried administering insulin to people at risk of the disease as a form of immunotherapy similar to allergy injections, but this didn’t provoke an effective response. John Kappler, Professor of Biomedical Research at National Jewish Health says, "Our findings provide an important proof of concept in humans for a promising vaccination strategy." In 2011, researchers from Harvard University’s Dana Farber Cancer Institute reported that Kappler’s strategy prevented type-1 diabetes in mice. However, strategies that work in mice often fail in humans.
 

Promising findings

Kappler’s findings suggest that an insulin fragment with a change to a single amino acid could provoke an immune response. The idea comes from work in Kappler's laboratory detailing the molecular immune system's response to insulin. This suggests that mutating one amino acid in an insulin fragment, and then presenting the insulin to the immune system, might provoke better recognition by the immune system.

Researchers mixed a naturally occurring insulin fragment, and the mutated insulin fragment with separate cultures of human cells. They found that human T-cells responded minimally to the naturally occurring insulin fragment, but relatively strongly to the mutated one. The human T-cells produce both pro-inflammatory and anti-inflammatory chemicals known as cytokines, and scientists believe that healthy immune responses balance pro- and anti-inflammatory factors. Autoimmune disease occurs when the pro-inflammatory response dominates.
                           

Type-1 diabetes

Type-1 diabetes is an autoimmune disease in which a person’s pancreas stops producing insulin, a hormone that enables individuals to get energy from food. It occurs when the body’s immune system attacks and destroys the insulin producing cells in the pancreas, called beta cells. The causes of type-1 diabetes are not fully understood, but scientists believe that both genetic and environmental factors are involved. Dr Sufyan Hussain of Imperial College, London explains:


     

      (click on the image to play the video) 

Type-1 diabetes most typically presents in early age with a peak around the time of puberty. Historically the condition has been most prevalent in populations of European origin, but is becoming more frequent in other ethnic groups. Kuwait, for example, now has an incidence of 22.3/100,000. India and China have relatively low incidence rates, but account for a high proportion of the world’s children with type-1 diabetes because of their large populations. 
 

Living with type1 diabetes

Living with type-1 diabetes is a constant challenge. People with the condition must carefully balance insulin doses (either by multiple injections every day or continuous infusion through a pump) with eating and other activities throughout the day. They must also measure their blood-glucose levels by pricking their fingers for blood six or more times a day. Despite this constant attention, people with type-1 diabetes run the risk of high or low blood-glucose levels, both of which can be life threatening. People with type-1 diabetes overcome these challenges on a daily basis. While insulin injections or infusions allow a person with the condition to stay alive, they don’t cure the disease, nor do they necessarily prevent the possibility of the disease’s complications, which may include kidney failure, blindness, nerve damage, heart attack, stroke, and pregnancy complications. Richard Lane, President of Diabetes UK, and a person living with type-1 diabetes, describes some of the lifestyle changes associated with the condition:

       

        (click on the image to play the video)
 

Takeaways

While Kappler’s results don’t prove that the mutated insulin fragment will work as a vaccine in humans, they do demonstrate a response in humans consistent with the vaccination response in mice. "The new findings confirm that the painstaking work we have done to understand the unconventional interaction of insulin and the immune system has relevance in humans and could lead to a vaccine and a treatment for diabetes," says Kappler.