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Targeted back pain care is “cheaper and better for patients”, BBC News has reported. The broadcaster says that a new model for assessing the severity of back pain has shown significant improvements compared with current methods, and could also save more than £30 per patient.

In cases of lower back pain not caused by a disease process, GP’s usually uses an escalating approach, with patients given a succession of more intensive treatments when no improvement is seen. Patients are initially taught self-management techniques, and possibly instructed to take a short course of painkillers. If there is no improvement, doctors will then usually discuss with the patient and refer them for the physical therapy that they think is most appropriate for them (e.g. physiotherapy). In this new trial doctors compared existing processes with a new model that used a screening tool to help decide on whether or not they should be referred for further therapy, and if so, which treatment this should be.

The trial demonstrated that the model was slightly more effective at improving patients’ symptoms, and also produced small cost savings compared with using standard practice. The doctors are quoted in the news as saying the research is “very promising”, particularly as the economic assessment demonstrates the approach to be cost effective. However, further testing of this screening tool in clinical practice will now be needed. Also, further follow-up is required to see whether use in wider numbers gives the expected longer-term benefits of reduced disability and improved quality of life for back pain sufferers.

 

Where did the story come from?

The study was carried out by researchers from the Arthritis Research UK Primary Care Centre at Keele University, the School of Population and Public Health at the University of British Columbia, and Vancouver Coastal Health Research Institute. Funding was provided by Arthritis Research UK. The study was published in the peer-reviewed medical journal The Lancet.

In general, BBC News has reflected the findings of this research paper well, although some of the terms used in its news report could be misinterpreted. For example, it is not very accurate to say that current general practice management of lower back pain is a “one size fits all” approach. The management approaches used in this trial (for example physiotherapy with or without a psychological component) are currently included in the pathways of care recommended by the National Institute for Health and Clinical Excellence (NICE) and used in practice.  However, the approach tested in this trial was different in that it used a screening tool to identify which treatment was most appropriate, rather than the current practice where doctors use their clinical judgement when deciding which service they think is most appropriate to refer to. The screening tool used in this trial operates on the principle of stratifying patients into three risk groups and assigning those at greater risk of developing chronic problems to receive more intensive therapy.

 

What kind of research was this?

This was a randomised controlled trial (the STarT Back trial) designed to compare current general practice management of lower back pain with an intervention of “stratified primary care”. In this stratified primary care, people would receive one of three levels of care depending on their perceived prognosis – low-, medium- or high-risk.

Lower back pain is a chronic health problem that not only places a considerable burden on the healthcare system, but also causes a high level of persistent disability among those affected, reduces capacity to work and significantly affects quality of life. The research paper reports that 6-9% of UK adults consult their GP about lower back pain each year, and that 60-80% of them will still be suffering from pain one year later.

The study was concerned with lower back pain that would sometimes be medically termed “non-specific” lower back pain. This means that the cause of pain, tension or stiffness of the lower back is not clear. It is a diagnosis based on the exclusion of specific disease causes of pain such as cancer, fractures, inflammatory conditions, infections or spinal cord compression – all serious causes of lower back pain that must be excluded by a doctor during initial assessment.

Current medical practice follows a stepwise approach to non-specific lower back pain, initially focusing on self-management and then considering referral for further therapy if back pain persists. The first step of management tends to be encouraging the person to remain as active as possible, with the use of short-term painkillers (paracetamol or an anti-inflammatory drug) to control pain if required. If the person does not improve, the GP may then refer them for physical therapy, such as physiotherapy or an exercise programme. In some cases referral may be made for combined physical and psychological treatment. Referral to an orthopaedic consultant for consideration of surgery would be a last resort.

Under current guidance, people who have lower back pain that is associated with nerve root compression or entrapment (for example from a herniated, or ‘slipped’, disc) may sometimes be given an earlier referral for orthopaedic assessment depending on their clinical features. Nerve root compression causes pain going into the legs along the course of the nerve. This is termed radiculopathy (sciatica is the term commonly used when there is compression of the sciatic nerve).

In this trial, the main hypothesis was that using a stratified approach to decide on the most appropriate management option for lower back pain (with or without radiculopathy) would result in better clinical and economic benefit compared with current best practice.

 

What did the research involve?

In 10 GP surgeries near to Stoke-on-Trent in the UK, medical records were searched to identify patients who had consulted their doctor about back pain between June 2007 and November 2008. The researchers excluded patients with any pain caused by serious disease (including those mentioned above), those with serious medical illnesses or mental health conditions, pregnant women and people currently receiving non-GP management of their back pain.

All remaining eligible participants were then assessed using the STarT Back Screening Tool. This is a validated, simple, prognostic screening tool designed for this study which allocates patients into three defined risk groups of low-, medium- or high-risk. The assessment tool takes into account factors such as the level of distress, anxiety, fear or depression that their back pain is causing them. A higher score indicates they are at higher risk of having chronic and persisting back problems.

Participants were randomised into either a control group receiving standard care (283 people) or an intervention group receiving care directed by the screening tool’s results (568 people). The control group received a 30-minute assessment and treatment session from a physiotherapist who gave them exercises and advice (for example about remaining active or about returning to work), with the option of onward referral for further physiotherapy (the decision made at the therapist’s discretion).

Those randomised to the intervention group (568) received the same initial physiotherapy assessment and treatment session, but decisions on further referral were made using the person’s risk classification on the STarT Back Screening Tool. Those patients identified as low-risk only received the initial physiotherapy session, but those in the medium- and high-risk groups were automatically referred for further therapy.

Further therapy was provided by therapists as follows:

• In the control group it was given by physiotherapists who had received general training in physical therapies and some training in more complex psychology-based treatments, but who had received no additional training specific to this trial.
• In the medium-risk intervention group, patients received treatment from physiotherapists who had been given three days of specific training on providing standard physiotherapy to address symptoms and function.
• In the high-risk intervention group, patients received psychologically-informed physiotherapy from therapists who were given nine days of specific training on providing therapy that addressed physical symptoms and function, in addition to tackling the psychological consequences of their back pain and psychological barriers that may hinder recovery.    

The main clinical outcome was improvement of scores in the Roland and Morris Disability Questionnaire (RMDQ) score at 12 months. Scores range from 0 to 24, with higher scores indicating more severe disability.

To perform an economic evaluation, the researchers estimated the incremental quality-adjusted life years (QALYs) gained with the intervention. QALYs are used to measure the health benefits that an intervention gives over standard treatment. They take into account the quality of the person’s life rather than just how much the treatment may extend life. The researchers then looked at the cost of any QALY gained by the intervention.

 

What were the basic results?

The average age of participants in this trial was 50 years, and 59% were women. In the intervention group, 26% of patients were stratified as low-risk, 46% as medium- and 28% as high-risk. Across all people in the trial the average number of treatment sessions received was comparable: 3.8 in the control group and 3.9 in the intervention group. The basic results were as follows:

• Overall, people in the intervention groups experienced an average (mean) improvement of 4.3 RMDQ points by 12 months, while those in the control group experienced an average improvement of 3.3 points. This small difference between the groups, equating to 1.06 points, was statistically significant (95% CI 0.25 to 1.86).
• The researchers then calculated a factor called the “effect size”, which indicates the size of the difference between two treatment groups, with a larger effect size indicating a more effective treatment. The “effect size” for the difference in RMDQ score at 12 months was 0.19, which is quite small.
• At 12 months, the intervention strategy of stratified care was associated with a mean increase of 0.039 additional QALYs compared with standard care and a saving of £41.93 (with the cost in the intervention group being £240.01 versus £274.40 in the control group).

 

How did the researchers interpret the results?

The researchers conclude that a stratified approach to care for lower back pain, which uses a prognostic screening tool to decide whether to refer someone for further physiotherapy (with or without a psychological element) “will have important implications for the future management of back pain in primary care”.

 

Conclusion

This was a large and well-conducted trial that has demonstrated a small effectiveness benefit and a small cost saving when people with lower back pain were stratified using a screening tool. Under the workings of this tool those with the highest levels of distress and problems associated with their pain would be placed in the high-risk group and so referred for physiotherapy with a psychological component, those with medium risk features would have a greater number of physiotherapy sessions and those with the lowest risk would have initial physiotherapy with advice on self-management.

It is important to note that this practice does not differ dramatically from standard general practice care of lower back pain, rather that it applies the use of a simple tool (rather than clinical judgement) to help decide which treatment option would be most suitable. It is incorrect to suggest that the current system is a “one-size-fits-all” approach as patients will already be offered different treatments based on their clinical features (taking into account other medical or mental health problems they may have), and their response to previous treatment. Instead it is probably more accurate to think of the proposed method as a tool that would guide the clinician to which treatment should be given, giving a more standardised approach to care than the current system.

This trial has demonstrated small benefits with this different system. Further testing and validation of this screening tool is now needed in clinical practice, along with further follow-up to see whether use in wider numbers gives the expected longer-term benefits of reduced disability and improved quality of life for back pain sufferers.

Links To The Headlines

Targeted back pain care ‘cheaper and better for patients’. BBC News, September 29 2011

Links To Science

Hill JC, Whitehurst DGT, Lewis M et al. Comparison of stratified primary care management for low back pain with current best practice (STarT Back): a randomised controlled trial. The Lancet, Early Online Publication, 29 September 2011

“Eating just three eggs a week increases chance of men getting prostate cancer,” reported the Daily Mail. The story went on to say that “experts in the US claimed that men who consume more than two-and-a–half eggs on a weekly basis were up to 81% more likely to be killed by the disease”.

This research examined the association between eating red meat, poultry and eggs and the risk of developing lethal prostate cancer (which the researchers defined as either dying from the disease or having metastatic disease that had spread to other organs). The study was in a large group of 27,607 healthy men, of whom 199 developed lethal prostate cancer over 14 years of follow-up. The researchers calculated that the men who ate the most eggs were at significantly higher risk than those who ate fewer eggs. No significant association was found with any other food item.

This large cohort study has some strengths, such as its large size and the fact that information on the participants’ diet was continually updated over the course of the study. However it also has several limitations, and only a small number of lethal cancers actually occurred, which could suggest that this association is due to chance. Furthermore, these results are inconsistent with previous research, which found no significant association between eggs and prostate cancer. The findings will need to be confirmed in more robust studies before any firm conclusions can be drawn.

 

Where did the story come from?

The study was carried out by researchers from the Harvard School of Public Health, the University of California in San Francisco, Brigham and Women’s Hospital and Harvard Medical School. Funding was provided by the US National Institute of Health.
 
The study was published in the peer-reviewed medical journal, Cancer Prevention Research.

The media generally reported the study accurately. However, the Daily Mirror’s suggestion that “a clear link between eggs and prostate cancer” has been found may be misleading, as the researchers say that their results contradict previous findings into the association and that more research is needed. But the Mirror does point out that men in the study who ate the most eggs differed from the rest of the participants in important ways, such as weight and smoking status.

 

What kind of research was this?

This was a prospective cohort study that investigated whether there is an association between eating red meat, poultry and eggs and the risk of developing lethal prostate cancer in healthy men. A subgroup analysis was carried out afterwards, in the men from this cohort who went on to develop prostate cancer. The researchers wanted to see whether eating habits after prostate cancer diagnosis were associated with the risk of the disease progressing and becoming fatal.

The researchers’ theory was based on the findings from previous research, which found:

• an increased risk of developing lethal prostate cancer in healthy men who ate red meat
• an increased risk of progression to lethal disease in men with prostate cancer who ate eggs and skin-on poultry after their diagnosis

Participants were recruited from an ongoing cohort study that began in 1986. This study was comprised of American male health professionals, who were between the ages of 40 and 75 in 1986. Men in this study completed a questionnaire every two years with information on their medical conditions, physical activity, weight, medications and smoking status. They provided information regarding their eating habits every four years.

Prospective cohort studies are an appropriate design for answering this type of research question. Assessing eating habits at the beginning of a study reduces the risk that people will inaccurately recall their dietary habits, which can arise when you ask people to remember what they ate over a long period of time. It also ensures that the exposure (eating certain foods) precedes the outcome (developing and dying of prostate cancer).

 

What did the research involve?

In 1994, the researchers recruited 27,607 men from the existing cohort study in the US. The men did not have prostate or other forms of cancer (except non-melanoma skin cancer [which are rarely aggressive]). They had also had a prostate specific antigen (PSA) test (PSA screening is not performed in the UK, as higher PSA levels can indicate cancer but are not specific for it. For example, raised levels can also occur with benign enlargement, infection or inflammation).

In this study:

• Information on the men’s eating habits was collected every four years.
• Information regarding prostate cancer diagnosis was collected every two years.
• From men who had been diagnosed with prostate cancer, information of treatment and disease progression was collected every two years.

The researchers defined lethal prostate cancer as disease that had spread to distant organs (metastatic cancer) or death due to prostate cancer during the study’s follow-up period (1994 to 2008).

The researchers followed up the cohort for 14 years and analysed the associations between eating different amounts of red meat, poultry and eggs and the risk of developing lethal prostate cancer. The researchers grouped each participant according to the average amounts of each type of food they ate per week. For red meat, the subgroups included less than three servings, 3 to 4 servings, 5 to 7 serving and over 8 servings per week. For poultry, the subgroups were defined as less than 1.5 servings, 1.5 to 2.5 servings, 2.5 to 3.5 servings, or over 3.5 servings for week. For eggs, the subgroups were less than half an egg, 0.5 to 1.5 eggs, 1.5 to 2.5 eggs, or over 2.5 eggs. To determine which subgroup each participate would be allocated to, the researchers averaged their responses from all of the dietary questionnaires the participants had completed up until their diagnosis, or until the end of the study (for those who were not diagnosed).

To determine the amount of each food eaten, they averaged the reported amounts over all of the questionnaires that were completed before diagnosis. During the analysis, the researchers controlled for possible confounding factors, such as age, amount of food eaten, body mass index (BMI, which is an indicator of obesity), smoking status and physical activity levels.

The researchers also analysed the risk of dying from prostate cancer in the men who were diagnosed with it during the course of the study, based on their eating habits after diagnosis. The researchers only included men who were diagnosed with localised cancer (cancer that had not spread beyond the prostate). During the analysis, they controlled for possible confounding factors such as age at diagnosis, time since diagnosis, disease stage, treatment type, BMI, activity level, smoking status and pre-diagnosis diet.

 

What were the basic results?

Of the 27,607 men included, 199 died of prostate cancer during the study. When the researchers analysed the association between eating habits and risk of lethal prostate cancer when using data up to the point of initial diagnosis, they found that:

• Men who ate an average of 2.5 or more eggs per week had an 81% higher risk of lethal prostate cancer compared to those who ate an average of less than half an egg per week (Hazard Ratio [HR] 1.81, 95% CI 1.13 to 2.89, p=0.01).
• The association between average amount of eggs eaten per week and risk of lethal prostate cancer became non-significant when the researchers analysed data collected up to the point of development of a lethal form of the disease (that is, disease progression or death).
• There was no significant association between the average amount of red meat eaten and the risk of lethal prostate cancer.
• Men who consumed more red meat or eggs tended to exercise less and have a higher BMI, and were more likely to smoke and have a family history of prostate cancer.

Of the 3,127 men who developed prostate cancer during the course of the study, 123 died of it during follow-up. Further analysis of the men who died found no significant association between eating habits after diagnosis and risk of the disease progressing from localised prostate cancer to lethal prostate cancer.

 

How did the researchers interpret the results?

The researchers conclude that: “Eating eggs may increase risk of developing a lethal form of prostate cancer among healthy men,” and that although “additional large prospective studies are needed, caution in egg intake may be warranted for adult men”.

 

Conclusion

This was a large prospective cohort study that examined the impact of lifestyle on the risk of developing and dying from advanced prostate cancer.

In addition to its large size, another strength of the study is that the information regarding exposure (eating habits) and possible confounders (medical conditions, activity levels, weight, medications and smoking status) were continually updated over the study’s course. However, updating information on eating habits every four years may still introduce a significant level of recall bias, and accurately remembering what you ate over the previous four years is likely to be difficult.

The study and data analysis also has several limitations. First, the number of deaths and cases of lethal prostate cancer were small (only 199 out of 27,607 men in the whole cohort, and 123 out of 3,127 in the case-only cohort [those who initially developed localised disease]). This small number increases the likelihood that the results are due to chance. Second, the researchers say that the group of men included in the study generally ate low amounts of the foods of interest, which limits the ‘power’ (or ability to detect a difference) of the analysis.

Furthermore, while the researchers controlled statistically for a number of possible confounders, it is difficult to say whether other factors could account for this relationship. The researchers say that men in the study who consumed more red meat or eggs tended to have a higher BMI, exercise less and were more likely to smoke and have a family history of prostate cancer. Additionally, it is probably difficult to control completely for other dietary effects and focus the analysis on a single component of a person’s diet.

This study points to possible associations between diet and risk of prostate cancer. The aforementioned limitations, however, weaken the strength of these conclusions, in addition to the fact that previous research has looked at this question and found no association. While an 81% increased risk sounds like a high and definitive figure, it is probably best to wait for more conclusive research before cutting eggs out of your diet. There are existing dietary and lifestyle guidelines for reducing cancer risk, such as limiting your consumption of energy-dense foods such as meat and increasing your consumption of fruits, vegetables and wholegrains.

Links To The Headlines

Eating just three eggs a week ‘increases chance of men getting prostate cancer’. Daily Mail, September 30 2011

Prostate cancer linked to eggs, say researchers. Daily Mirror, September 30 2011

Just 3 eggs a week ‘raises the prostate cancer risk’. Daily Express, September 30 2011

 

Links To Science

Richman EL, Kenfield SA, Stampfer MJ et al. Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate specific antigen-era: incidence and survival. Cancer Prevention Research, Published Online First September 19 2011

The Daily Telegraph reported that a “vaccine could reduce HIV to ‘minor infection’”. The news story reports on a phase I clinical trial that assessed the safety of a new HIV vaccine in a small group of people in Spain.

The researchers recruited 30 people who did not have HIV and gave 24 of them three injections of the new HIV vaccine, which was based on a smallpox vaccine. The other six people received placebo injections. The researchers followed the volunteers for 48 weeks.

The researchers found that the vaccine appeared to be well-tolerated over this time and there were no serious side effects. More than three-quarters of the volunteers had a detectable immune response to the vaccine. However, the primary aim of this preliminary study was to assess safety not effectiveness. It is not known whether the immune response caused by the vaccine would be sufficient to protect against HIV infection or lower HIV levels in people who are already HIV positive. It is likely that further safety trials in a larger group of people will be performed before the effectiveness of this vaccine is assessed.

 

Where did the story come from?

The study was carried out by researchers from The Hospital Clinic-IDIBAPS, Barcelona, Spain, the CentroNacional de Biotecnologia, CSIC, Madrid, Spain and other Spanish, Swedish, Swiss and British research institutions. It was funded by three Spanish research foundations, FIPSE, FIS and HIVACAT.

The study was published in the peer-reviewed medical journal Vaccine.

The research was covered well by The Daily Telegraph, the Daily Mail and the Daily Mirror, which all said that further tests would need to be carried out. The Daily Telegraph detailed what the researchers had said the next steps would be.

 

What kind of research was this?

This was a phase I clinical trial to assess the safety of an HIV/AIDS vaccine and how well it could provoke an immune response, which is a sign that a vaccine is having an effect. Phase I studies are studies that test the preliminary safety of a treatment in a small group of people. Often these types of studies do not have a control group. In this case, there were 24 people who received the vaccine and six who received a placebo. Importantly, this type of trial is not designed to test effectiveness and the researchers were not trying to assess how well the vaccine would protect people from contracting HIV. However, they did look at how strong the immune response to the vaccine was. Immune response is a marker for eventual success of the vaccine and a sign that the vaccine is having an effect.

The vaccine was based on a smallpox vaccine that had been adapted with HIV genes. The vaccine was called MVA-B. The idea was that the vaccine would prime the body to recognise HIV so that it would mount a rapid immune response. If used to treat people who have already contracted HIV, this would potentially allow the body to clear the HIV to levels that don’t cause disease. If used to prevent people from getting HIV, it would hopefully prevent the virus from entering cells in the first place.

 

What did the research involve?

The study was carried out in Spain. The researchers recruited 30 men and women who were free from HIV and at low risk of infection. The participants were between 18 and 55 years of age, and 24 were men. The participants had no history of a previous smallpox vaccination. The researchers randomly allocated six people to receive placebo and 24 people to receive the vaccine.

The 24 people received three injections of the vaccine into their muscle, and the control group received placebo injections. Both groups received these injections at the start of the study, after four weeks and after 16 weeks. The participants were then followed for 48 weeks.

The participants were asked to use an effective method of contraception with their partner from 14 days prior to the first vaccination until four months after the last one.

The primary endpoints (the measures considered to be most important by the researchers) were serious side effects and how well the body mounted an immune response. They looked, in particular, at a type of immune cell called a T-cell. The researchers also took into account less severe side effects and how well the body produced antibodies against the vaccine.

Screening for side effects was performed throughout the study. Blood tests were performed at the study start and at weeks four, eight, 16, 20 and 48. The participants were given safe sex counselling and an HIV test at the screening interview and at weeks four, 16 and 48.

 

What were the basic results?

The researchers said that, overall, the vaccine was well-tolerated. A total of 169 adverse events were reported during follow-up. Five of these were grade-three adverse events, which would be considered serious. However, although the five serious adverse events were all in the vaccination group, these were not considered to be related to the study drug. For example, one volunteer had tonsillitis, one volunteer had a traffic accident, one volunteer had both pneumonia and two asthmatic attacks. Of the 145 reported milder adverse events (grade one and two), 52 were considered to be definitely related to the vaccination. The most common mild adverse events were pain at the site of the injection and headaches.

The researchers found that positive T-cell immune responses were detected in 75% of volunteers and that these were maintained until week 48 in 68% of the participants. The proportion of responders increased after the second dose. Ninety-five per cent of the participants had antibodies against the vaccine at week 18 and 72% had antibodies at week 48.

 

How did the researchers interpret the results?

The researchers say that in this first phase I trial with the HIV/AIDS vaccine candidate MVA-B in healthy volunteers the vaccine was safe and well-tolerated and elicited strong and durable T-cell responses in 75% of volunteers. They say that their data support further exploration of MVA-B as an HIV vaccine candidate.

 

Conclusion

This phase I trial showed that this HIV vaccine was well-tolerated and did not lead to serious adverse effects in a small group of healthy volunteers. The vaccine was also shown to cause a T-cell immune response in 75% of the 24 participants and to cause antibody responses in 95%.

These results are encouraging and will probably mean that the researchers go on to look at safety and immune response to this vaccine in a larger group of people. There are two potential ways in which vaccines could be used to fight HIV. A vaccine may either be used as a prophylactic to stop people being infected with the virus, or therapeutically, to help the body to lower HIV levels once a person has already been infected. The aim of therapeutic use would be to reduce disease symptoms. This study did not look at the effectiveness of the vaccine, including how well it could protect against infection with HIV or lower HIV levels in the body of people already infected.

Further research is needed to test the vaccine in these two areas – preventing HIV infection or reducing the number of virus particles in infected people. Also, other studies are looking at potential HIV vaccines, and research will be needed to test how well this vaccine compares to these.

Links To The Headlines

New HIV vaccine could turn deadly condition into ‘minor infection like herpes’. The Daily Telegraph, September 29 2011

Vaccine could reduce HIV to ‘minor infection’. The Daily Telegraph, September 29 2011

HIV vaccine could turn condition into "minor chronic infection" like herpes, experts claim. Daily Mirror, September 29 2011

Links To Science

García F, López Bernaldo de Quirós JC, Gómez CE, et ak. Safety and immunogenicity of a modified pox vector-based HIV/AIDS vaccine candidate expressing Env, Gag, Pol and Nef proteins of HIV-1 subtype B (MVA-B) in healthy HIV-1-uninfected volunteers: A phase I clinical trial (RISVAC02). Vaccine 2011

An anti-smoking drug called Tabex may “boost a person’s chances of ditching cigarettes three-fold,” The Sun has today reported.

The smoking cessation drug, also known as cytisine, has been available in some Eastern European and former Soviet countries, such as Russia, for more than 40 years. However, the researchers of this study said that the drug has not previously been tested in a way that would meet modern regulatory standards, which all drugs must satisfy before they can be marketed in the UK. To test the effectiveness of the drug the researchers performed a study using 740 volunteers who were either given the drug or a dummy (placebo) drug for 25 days. They found that 12 months after treatment, 8.4% of participants taking cytisine had successfully quit, compared to 2.4% of participants taking placebo. This equated to an extra 6% of people giving up smoking, a performance comparable to existing approved treatments.

As well as producing promising results, the drug is reported to be inexpensive, which singles it out as a potential future treatment within the UK. However, given that the trial was relatively small and short it is likely that more research will be needed to confirm its effectiveness and safety before regulators can approve its use.

 

Where did the story come from?

The study was carried out by researchers from University College London, the UK Centre for Tobacco Control Studies and the Cancer Centre and Institute of Oncology, Poland. It was funded by the UK’s National Prevention Research Initiative and published in the peer-reviewed New England Journal of Medicine. The trial itself was conducted at the smoking cessation clinic of the Maria Sklodowska-Curie Memorial Cancer Centre in Warsaw, Poland.

The news coverage of this story was mainly accurate. However, it should be noted that while cytisine has not been “banned” as one headline said, it does not have a licence to market in the UK.

 

What kind of research was this?

This was a randomised, double-blind placebo-controlled trial. The researchers said that cytisine has been available in Bulgaria since 1964 and is commercially available in countries such as Poland and Russia for approximately US $6-$15 per course of treatment. However, they said that despite the drug’s widespread use there have not yet been any large placebo-controlled trials that would adhere to modern regulatory standards. This study was performed to fulfil this requirement.

 

What did the research involve?

The researchers enrolled 740 individuals who smoked 10 or more cigarettes per day, and who were willing to attempt to stop smoking permanently. They were randomised to receive either cytisine or a placebo pill (370 in each group). The participants took cytisine or the placebo for 25 days, and were then assessed 6 and 12 months after the treatment period had ended, to determine whether they had managed to give up smoking or if they had relapsed. The participants agreed prior to the trial not to take any other medications to stop smoking. Both groups received a minimal amount of counselling during the study.

During the 25-day treatment period, the participants followed a treatment schedule that has been licensed in several European countries, where the number of tablets decreased over time:

• 1-3 days: six 1.5mg tablets a day (one tablet every two hours)
• 4-12 days: five tablets a day for 9 days
• 13-16 days: four tablets a day for 4 days,
• 17-20 days: three tablets a day for 4 days
• 21-25 days: two tablets a day for 5 days

Participants were contacted 6 and 12 months after their treatment had ended and asked whether they had managed to give up smoking. A “relapse” was defined as self-reported smoking of five or more cigarettes during the specified follow-up period (the previous 6 or 12 months). The carbon monoxide concentration in exhaled breath was measured for participants who reported that they had given up smoking, to confirm their reports.

Participants were also asked whether they had experienced any side-effects, and if so, to describe them. The researchers then coded the responses they received.

The researchers then analysed their results on the “intention-to-treat principle”, meaning that they analysed their results based on all the people that were originally randomised in the study, rather than just those they could contact. They considered treatment to have failed in any participants that they could not contact at the follow-up points.

 

What were the basic results?

Results after 12 months showed that 8.4% of the participants randomised to receive cytisine had not relapsed (in other words, had successfully quit smoking), compared to 2.4% of the participants randomised to receive placebo. This was a difference of 6% (95% CI 2.7% to 9.2%), which equated to people taking cytisine being 3.4 times more likely to give up than those taking a placebo (95% CI 1.7 to 7.1).

The researchers report that this increase in rate of giving up smoking is higher than that reported for the existing drug vareniciline (smokers taking varenicline are 2.3 times more likely to quit than those taking a placebo) and nicotine-replacement therapy (1.6 times more likely). However, the absolute difference in rate (in this case 6%) was lower than that shown for vareniciline, and similar to that shown for nicotine-replacement therapy. Some of these differences may be due to the length of the treatment period, which was only 4 weeks in this trial but 8 weeks for nicotine-replacement therapy and 12 weeks for vareniciline.

Gastrointestinal (stomach and intestine) side effects, predominantly stomach-ache, dry mouth, dyspepsia and nausea, were reported significantly more frequently in participants receiving cytisine (13.8%) than those receiving placebo (8.1%). There were no other side effects, which were significantly more frequent in the group receiving cytisine. The two groups experienced similar rates of drug discontinuation and dose reduction.

Although this study only lasted 12 months and was not large enough for an assessment of uncommon adverse events, the researchers report that the latest Periodic Safety Update Report provided to the European Authorities, based on more than 7 million exposed persons, did not identify any safety signals: in other words, the drug is considered safe.

 

How did the researchers interpret the results?

The researchers said: “In this single-centre study, cytisine was more effective than placebo for smoking cessation. The lower price of cytisine, as compared with that of other pharmacotherapies for smoking cessation, make it an affordable treatment to advance smoking cessation globally.”

 

Conclusion

In this promising 12-month trial (involving a treatment period of 25 days), 8.4% of participants taking cytisine (brand name Tabex) managed to give up cigarettes, compared to 2.4% of participants taking placebo. This means that the participants taking cytisine were more than three times more likely to give up.

Although individuals in the group receiving cytisine experienced more gastrointestinal side-effects, the researchers said that other uncommon side effects are unlikely as this drug has been available in other countries for more than 40 years.

Other points to note are that:

• The trial was not large enough to assess the uncommon adverse events that could occur with the drug. Because the drug is in the same class as others linked to neuropsychiatric side effects and suicidal ideas the researchers recommend continued surveillance of the 7 million people reported to be taking it.
• Compared to the therapies currently available in the UK, the number of extra people who are able to quit after taking cytisine is similar to those who can quit with nicotine-replacement therapy, although the course of treatment tested here is shorter. Specific research to compare it against treatments currently available in the UK may be warranted, along with studies of longer courses of the drug.
• In this study, the participants were given minimal behavioural support, such as counselling. The researchers suggest that combining cytisine with more intensive behavioural support could potentially increase the absolute quit rates.

Overall, this paper will generate discussion about how cytisine might fit into the range of treatments currently available, although more research is likely to be needed before the drug is approved.

Links To The Headlines

Quit smoking for six quid. The Sun, September 29 2011

Smokers get chance to beat the habit with 12p tablets. The Guardian, September 29 2011

Banned: The 12p ‘cure’ for smokers not to be made available in Britain. The Metro, September 29 2011

Links To Science

West R, Zatonski W, Cedzynska M et al. Placebo-Controlled Trial of Cytisine for Smoking Cessation. New England Journal of Medicine 2011; 365:1193-1200, September 29 2011

A painkiller taken by millions can increase the risk of heart attack and stroke by 40%, the Daily Mail has today reported. The newspaper says that researchers are calling for the drug, called diclofenac, to be available on prescription only.

The news is based on a large review that looked at the cardiovascular risks associated with a class of widely used painkillers called non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs in high-dose formulations are usually only available on prescription, but some low-dose NSAIDs, including ibuprofen, naproxen and diclofenac, can be bought over the counter.

The review found that diclofenac raised the risk of heart problems by 22% when taken at over-the-counter doses and by 40% at prescription strength. Naproxen and low-dose ibuprofen were least likely to increase the risk of heart attacks and strokes.

While previous research has highlighted the cardiovascular risks of some NSAIDs, this review of observational studies provides some important new information about the risks associated with all currently available NSAIDs at different doses. As such, its findings will no doubt be important to future decisions about how these drugs should be used and regulated.

However, it is important to note that for a healthy individual who takes diclofenac, the increased risk to the heart is still very small. Because of the nature of this research, it is not possible to estimate accurately how small this risk is, but some experts have suggested that it is in the region of a 0.4% increase in risk. Anyone who is concerned about taking NSAIDs should not stop taking these drugs but should consult their doctor.

 

Where did the story come from?

The study was carried out by researchers affiliated with Hull York Medical School, the Institute for Clinical Evaluative Sciences, the University of Toronto in Canada and the University of Newcastle in Australia. It received no external funding. The study was published in the peer-reviewed journal PLoS Medicine.

The research was covered fairly in most newspapers. In its print version of the story the Daily Mail featured a large front-page headline warning of a “Painkiller heart alert”, which may have been alarming. However, within the article itself the Daily Mail did feature prominent messages that patients should not panic and should not stop taking their medication. Both the Daily Mail and The Daily Telegraph reported that, for most healthy people, the increased risk of heart and other problems from diclofenac was small, and the reports featured in the Daily Mail, The Daily Telegraph and the Daily Express all included comments and advice from independent experts.

 

What kind of research was this?

This was a systematic review comparing the risks of individual NSAIDs taken at typical doses by people at home, rather than in hospital. The researchers say that there are concerns about the risk associated with non-prescription NSAIDs available in low-dose forms, such as ibuprofen, naproxen and diclofenac.

The researchers point out that while some randomised trials have highlighted the cardiovascular risk of some NSAIDs, little is known about how the risks of individual drugs compare when used at different doses, for different lengths of time and in different populations. For this reason the researchers set out to examine the outcomes seen in controlled observational studies, which would better reflect the risks associated with the typical domestic use of NSAIDs rather than the risks associated with their use in the idealised setting of a clinical trial. To date, randomised trials of NSAIDs have reported only small numbers of heart and stroke problems.

 

What did the research involve?

The researchers searched a wide range of electronic databases for relevant studies published between 1985 and 2010 that had reported on the cardiovascular risks associated with the use of individual NSAIDs in population settings. They included only non-randomised, controlled observational studies in their literature search,these observational studies included case control, cohorts and case-crossover studies. They then assessed the methodological quality of the selected studies. From a total 459 potentially relevant papers, 51 studies met their criteria.

From the studies gathered, the researchers extracted and pooled information about the risk of major cardiovascular events associated with individual NSAIDs. They also assessed subsets of studies that provided relevant information to examine the risk of NSAIDs in different doses and in people with low and high existing risk of heart problems. To compare different drugs they carried out a further type of analysis, called a pair-wise comparison, where they indirectly compared each drug against another in turn, taking the results from separate trials.

The overall analyses included data from 30 case-control studies and 21 cohort studies involving more than 2.7 million individuals and featuring a total of 184,946 cardiovascular events.

 

What were the basic results?

The researchers looked at the drugs where there were 10 or more studies.  Of drugs where there were 10 or more studies, researchers found that the highest overall risks were seen with rofecoxib and diclofenac, and the lowest with ibuprofen and naproxen. Compared with not using any NSAIDs the researchers found:

• rofecoxib increased the risk of heart problems by 45% (95% CI 1.33 to 1.59)
• diclofenac increased the risk by 40% (95% CI 1.27 to 1.55)
• ibuprofen increased the risk by 18% (95% CI 1.11 to1.25)

In a subset of studies that looked at risk associated with lower doses they found:

• low doses of rofecoxib increased the risk by 37% (95% CI 1.20 to 1.57)
• low doses of celecoxib increased the risk by 26% (95% CI 1.09 to 1.47)
• low doses of diclofenac increased the risk by 22% (95% CI 1.12 to 1.33)

It is important to note that the drug rofecoxib has already been withdrawn from the market because of its association with a raised risk of cardiovascular events. Including it in the study allows the risk associated with other drugs to be compared with the risks of rofecoxib.

Ibuprofen only posed a risk when taken at a higher dose and naproxen had no significant risk at any dose.

They say the increase in risk was proportional for both high- and low-risk groups. This means that, relative to their risk if not using NSAIDS, the risks for both groups increased to the same extent. The risk of cardiovascular problems also rose early in the course of treatment. For some NSAIDs, risk was found to increase within the first month of taking the drug.

 

How did the researchers interpret the results?

The researchers say the results of their review “are robust enough to inform clinical and regulatory decisions”.

• They call for “regulatory action” on diclofenac, as it is currently available without prescription.
• They say the limited data on etoricoxib “raises serious concerns” about safety, particularly as similar drugs such as rofecoxib have been withdrawn.
• They say that, in the case of ibuprofen, labelling warnings should be strengthened to stop patients who are already at high risk of cardiovascular problems from exceeding the maximum recommended dose.
• They question the continued use of indomethacin.

 

Conclusion

This large review has published some important information on the cardiovascular risks associated with NSAIDs, including the risk associated with different doses and in populations at both high and low risk of cardiovascular events. It raises concerns about some of these risks, in particular the risk associated with the widely used non-prescription drug diclofenac.

As its authors point out, it had some limitations.

• It had to rely on observational studies (rather than randomised controlled trials), which are subject to bias, especially in terms of other factors (confounders) that might influence results. However, the researchers did take steps to minimise this risk.
• The data in the studies mainly came from large administrative databases and electronic health records, and may not have been comprehensive, especially concerning key information such as use of non-prescription NSAIDs and aspirin, or information about people’s risk of heart problems.
• The review suffered from ‘heterogeneity’. This means that many of the studies varied in their design, their methods and how they analysed results. Heterogeneity makes it harder to combine the results of different studies accurately and can, therefore, throw doubt on the findings of systematic reviews.

Patients using NSAIDs who are worried about side effects should not stop taking them, but instead consult their doctor.

Links To The Headlines

Painkiller heart alert: Don’t stop taking pills, but do talk to your GP, British scientists urge. Daily Mail, September 28 2011

Common painkillers can raise heart risk. The Daily Telegraph, September 28 2011

Health alert over common painkiller. Daily Express, September 28 2011

Links To Science

McGettigan P, Henry D. Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies. PLoS Medicine 8(9)

The Daily Mail reported today that, “thousands of lives could be saved if the age at which men are screened for bowel cancer is lowered by 10 years.”

This news story is based on a large Austrian study that aimed to determine the correct age to screen men and women for bowel cancer. It found that the number of screening colonoscopies needed to detect one case of bowel cancer (called the number needed to screen or NNS) was significantly lower in men compared to women across all ages. The NNS in men who were 55-59 years old was similar to women 10 years older (75.0 versus 81.8 colonoscopies respectively). This and other similar findings led the authors to suggest a need to reduce the screening age in men by approximately 10 years.

This robust study provides important information about the difference in prevalence of bowel cancer in men and women of different ages who took part in a national colonoscopy screening programme.

The applicability of the findings from this Austrian study to the UK is limited in some ways. For instance, in Austria, men and women aged 50 are invited to be screened for bowel cancer using a procedure called a colonoscopy where a camera is used to examine the bowel. In the UK, screening does not take place until men and women reach age 60, at which point screening is performed using a different sort of test called a faecal occult blood (FOB) test, which can be done at home. Doctors then use these test results to decide whether further investigation is needed. Colonoscopy is frequently used to investigate patients who have an abnormal FOB test result.

Nevertheless, this is a valuable study for policy makers in the UK. While the UK does not have a national colonoscopy screening programme in the same way as Austria, this study improves knowledge about the pattern of abnormalities found. A similar study of the UK programme could help identify if the same sex and age differences exist for people who are being investigated for signs of bowel cancer by colonoscopy after a positive FOB test.

 

Where did the story come from?

The study was carried out by researchers from the University of Vienna, Austria. Funding was provided by the Fund for Preventative Check-ups and Health Promotion.
 
The study was published in the peer-reviewed medical journal Journal of the American Medical Association (JAMA).

The coverage of this story was generally good with both the Mail and the Telegraph acknowledging that the UK does not have the same national screening programme as used in the study, but that the results may still be helpful. They also point out that both men and women are screened from 60 years of age in England, 10 years later than is the standard in the Austrian study. Both reports also highlight that people in Scotland are already screened at a lower age (50 years) than in England and include quotes from the “Beating Bowel Cancer” campaign group who advocate lowering the age limit to 50 years of age across the entire UK.

 

What kind of research was this?

This was a cohort study using adult participants of a national screening colonoscopy programme over a four year period (2007 to 2010) in Austria.

The researchers state that the typical age for screening for colorectal cancer (bowel cancer) in many countries (including the US and Austria) is 50 years for both men and women. The goal of bowel cancer screening is to find and remove abnormal growths in the bowel known as polyps. Once removed, the polyps can be tested in the lab to see if they are small and harmless (adenomas), slightly larger and potentially harmful (advanced adenoma), or already cancerous.

The authors say that previous research has suggested that men typically develop more advanced adenomas and have a higher prevalence of bowel cancer, so it has been suggested that men should be screened earlier than women should.

This research aimed to determine the correct age to screen men and women for bowel cancer.

 

What did the research involve?

This study followed 44,350 participants aged between 50 and 79 years old who were screened over a period of four years (2007 to 2010) as part of the national screening colonoscopy programme in Austria. Colonoscopy is the screening method used in Austria to detect early signs of bowel cancer. A colonoscopy is when a flexible tube attached to a small camera and light is used to examine your entire bowel.

The results of the colonoscopies, including laboratory tests, video and photo documentation, were reviewed for signs of adenoma, advanced adenoma and colorectal cancer (bowel cancer).

If more than one adenoma was found they were characterised (either as: harmless, potentially harmful or cancerous) by the most advanced one identified.

The researchers analysed their results in five-year age band separately for men and women. The prevalence and number needed to screen (NNS) were calculated. NNS was used to predict the number of colonoscopies that would need to be undertaken to detect one case of adenoma, advanced adenoma or bowel cancer. These were calculated separately for men and women at different five year age-bands ranging from 30-34 to over 95 years old. Most of those screened were aged between 50 and 79 years old.
This type of analysis is appropriate for this sort of study, and because it takes into account the different number of people screened in each age band, the NNS is a better assessment of the efficiency of the programme than the raw number of cancers detected.

 

What were the basic results?

A total of 22,598 (51%) women and 21,752 (49.0%) men were screened during the four-year period. The average age (median) for men and women was similar at 60.7 and 60.6 years respectively and ranged from 54.5 years to 67.6 years. Relatively few adults under 50 years old were screened.

Small abnormal growths (polyps) in the colon were found in 34.4% of individuals, colon cancer in 0.4% and rectal cancer in 0.2%.

Adenomas

Adenomas were found more frequently in men (24.9%) compared with women (14.8%) for all ages groups combined, suggesting that men have an extra 10% absolute risk of having adenomas. The prevalence of adenomas in 50 to 54-year-old men was 18.5%, significantly greater than the prevalence among women in the same age group, but similar to the prevalence among 65 to 69-year-old women (17.9%).

The NNS to detect adenomas was 4.0 (95% confidence interval [CI] 3.9 to 4.1) for men and 6.7 (95%CI 6.6 to 7.0) for women. In 50 to 54-year-old women, the NNS was nearly twice as high as the NNS in men of the same age (9.3 versus 5.4). The NNS among 45 to 49-year-old men (5.9) was similar to that in women aged 60-64 (6.0).

Advanced adenomas

The prevalence of advanced adenomas was much higher in men (8.0%) than women (4.7%) for all age groups combined. The prevalence of advanced adenoma in men aged 50-54 (5.0%) was higher then women of the same age (2.9%) but was similar to women 10 years older (5.1%).

NNS to find an advanced adenoma were 21.5 (95%CI 20.3 to 22.8) for women and 12.6 (95%CI 12.0 to 13.2) for men.

Bowel cancer

The prevalence of bowel cancer was twice as high in men compared to women (1.5% versus 0.7% respectively) for all age groups combined. The number of colonoscopies needed to detect one case of bowel cancer was significantly lower in men compared to women for all ages combined (66.7 versus 137.0 respectively). The NNS in men who were 55-59 years old was again similar to women in the group 10 years older (75.0 versus 81.8 respectively).

 

How did the researchers interpret the results?

The authors concluded that being male was a significant risk factor in the development of bowel cancer, and that this indicates that ‘new sex-specific age recommendations for screening’ should be considered. They suggest that it may be important to start screening men earlier than 50 years to avoid early abnormalities being missed that could later develop into the observed higher prevalence of cancer in men. They also discuss the idea that women could be screened later due to their lower risk and prevalence of bowel cancer.

 

Conclusion

This study showed that the prevalence of adenoma, advanced adenoma and bowel cancer was significantly higher in men than in women of comparable age in Austrian adults taking part in a national colonoscopy screening programme.

This difference was shown using a large group of individuals within the age range that is currently screened for in Austria and the US. While the study’s size is a strength, it is important to acknowledge that it also has some limitations.

• The study of prevalence only looked at differences in cancer prevalence between ages and sex. It did not look at whether other influences such as family history of bowel cancer, diet or ethnicity affected the age-sex relationship. Further studies with appropriate adjustment for these, and other potentially influencing factors, are warranted before the age-sex differences can be generalised with some confidence to different groups of people.
• Only a relatively small number (n= 1,630) of people under the age of 50 years old were screened. Hence, the results obtained from these younger groups were more prone to uncertainty than larger, older groups.
• This study tested screening for bowel cancer using colonoscopy; this is not the standard method in all countries. In England, Wales and Northern Ireland, patients over 60 years old are invited to be screened using a faecal occult blood (FOB) test kit that can be done at home. Those in Scotland can be screened from the age of 50 years old. The FOB tests for blood in the faeces. If blood is detected, an invitation of further investigation into the cause of the bleeding, which may include a colonoscopy, is made.
• The age and sex differences for screening using the FOB test are not considered in this study and these findings are not as applicable to the UK as they would be to countries with a national colonoscopy screening programme such as Austria and the US.

This robust study provided important information about the difference in the prevalence of adenoma, advanced adenoma and bowel cancer in men and women of different ages taking part in a national colonoscopy screening programme in Austria. While the UK does not have a national colonoscopy screening programme exactly like this, this study adds to what is known about bowel cancer risk and the information may be valuable in helping policy makers make decisions about the future of the screening programme here.

Links To The Headlines

Lower bowel cancer screening age for men, study suggests. The Daily Telegraph, September 28 2011

‘Screen men at 50 for bowel cancer’ and save thousands of lives, says charity. Daily Mail, September 28 2011

Links To Science

Ferlitsch M, Reinhart K, Pramhas S, et al. Sex-Specific Prevalence of Adenomas, Advanced Adenomas, and Colorectal Cancer in Individuals Undergoing Screening Colonoscopy. JAMA 2011; 306: 1289-1395

The Daily Mail has reported that doctors do not support giving life-extending drugs to patients with terminal cancer. The newspaper says that a new report has said the treatments “give false hope and are too costly for the public purse”.

The news story is based on an extensive international report that examined the cost and value of cancer care in developed countries. The report suggests policy changes that could be made to make cancer care more affordable to both patients and society. The report was based on the opinion of many experts, including physicians, patient advocates and economists, and provides examinations of a range of key issues. However, the report does not actually suggest that life-extending drugs should be withheld from terminal cancer patients, rather that there is a greater need to understand whether treatments at this stage will actually extend life, and whether resources would be better directed at improving patients’ quality of life through options such as palliative care. The report also suggests several policy areas that could be targeted to improve quality of care while reducing its cost.

This report is likely to stimulate discussions on policy relating to cancer care, but it is not policy itself. The report is of great interest but would need a broad agreement within the health service if it was to change the manner in which care is provided in the UK.

 

Where did the story come from?

The report was created by researchers from a variety of institutions from the UK, US, Australia, Canada and across Europe. These institutions include King’s College London, CancerPartnersUK, North of England Cancer Network, Northumbria Healthcare, the Institute of Nuclear Medicine, the Association of the British Pharmaceutical Industry, the University of London and Oxford University.

The commission was funded by the Conquer Cancer Foundation and the Greenwall Foundation for Bioethics, the University of California Los Angeles, Belgium’s Herculesstichting and Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, and the UK’s National Institute for Health Research (NIHR) Biomedical Research Centre and Department of Health.

The study was published in the journal The Lancet Oncology. However, it was published as an opinion piece and was not subject to the peer-review process.

The media focused on futile care, which is a particular issue highlighted in the report. This is addressed under the issue of ‘overutilisation’ in general, and is not the primary focus of the report. That said, the report does recommend that special attention should be paid to end of life cancer care. They say that improving the ability to predict the effectiveness of treatment could spare patients side effects and false hope from ineffective care, and also spare the healthcare system the cost of ineffective care. However, some life-extending drugs are valuable for people with terminal illness and the authors do not say that all of these give false hope or are too expensive.

 

What kind of research was this?

This is a discursive policy report written by a panel of international cancer experts. The report is intended to guide public debate on cancer care in developed countries, including the UK. The report attempts to identify the drivers of high-cost cancer care, as well as to propose solutions for these issues.

The extensive report looks at many of the different factors that drive the cost of cancer care. It gathers opinions from a variety of experts, including clinicians, patient advocates, policy makers and cancer survivors. The authors examined the cost and effectiveness of cancer care, and identified issues that drive up the cost of care but that may not provide great improvements in health outcomes. Among the issues examined are the economics of cancer care, the individual and societal impact of cancer treatments, areas where new technology could be improved or developed, predicted rates of cancer in the years to come and whether current methods for evaluating evidence are appropriate.

 

What did the research involve?

The authors collected opinions from a wide variety of experts on the status of cancer care costs and the effectiveness of cancer treatment in developed countries. It examined the role that cost drivers, evolving patterns of disease and trends in the provision of care play in determining the amount of money spent on cancer care. They then examined the value of cancer care from various perspectives, including the role played by:

• health research and research into cost-effectiveness
• available treatment options, such as surgery, radiation and imaging technologies
• the possibilities offered by new testing technologies, including genetic testing
• anti-cancer drugs, the pharmaceutical industry and the processes for developing new drugs
• patients’ involvement in treatment and their ability to express their wishes

They also examined current approaches to addressing the affordability of cancer care in different countries.

The authors say that there are several areas that could be addressed to reduce cost and improve the quality of cancer care:

 

Cost of care

The authors first examined the cost of cancer care, and specifically ‘cost drivers’. These are those interventions that account for most of the costs. They examined the cost of cancer from the perspective not only of the price paid for treatments, but also in terms of the economic impact of patients not being able to function normally due to illness or early death.

 

Burden of disease

The authors also looked at the patterns of disease, the complexity of illness and how research accounted for these patterns. They then examined how this burden of disease translates into the cost of treating individual patients, and in turn the cost of treating cancer in society as a whole.

 

Technological development

The authors next highlight the process by which technologies are developed and the cost of this process, and suggest ways in which these costs could be reduced without forfeiting benefits in terms of health outcomes.

 

Overutilisation

The report looks at how ‘overutilisation’ of cancer technologies and services can drive costs without adding any additional benefit in terms of health outcomes, for example the use of expensive diagnostic tests that provide no greater benefit than cheaper alternatives. The authors identified areas of care that could be reduced without reducing health outcomes.

 

What were the basic results?

The study is extensive so the following section only provides a very brief overview of its findings. The authors identified multiple sources of high cancer costs, and outlined recommendations for improving care and reducing costs in each of the identified areas.

 

Cost of care

The authors found that the absolute amount spent on cancer care is increasing in all developed countries, and that the rate of this increase is going up year by year. They say that this is not simply due to the increasing number of cancer cases seen, but that the rise is also driven by factors such as the use of increasingly individualised treatments that are expensive to develop and the use of inappropriate cancer products (although they say this is more of an issue in the US than in the UK). They found that in 2009-2010, the NHS spent £5.86 billion on cancer care, which is 5.6% of the UK’s total health spend.

They recommend that countries attempt to drive the development of new low-cost technologies by increasing the use of off-patent products and rethinking the pathway of care that patients follow when they have cancer.

 

Burden of disease

The report says that one of the main drivers of cancer care costs is the ageing population (more people are being diagnosed with cancer) and the increasing complexity of disease, including patients with multiple illnesses. They say that the increase in cancer care costs is due both to the amount spent per patient and the number of patients diagnosed.

The authors found that this current clinical research often fails accurately to reflect the burden of disease seen in the real world. Patients with multiple illnesses are often excluded from clinical trials, so that the evidence base for new technologies does not accurately reflect the way in which cancer occurs and will be treated in the real world. The researchers recommend that clinical research into new treatments be reflective of this real-world burden of disease for society, and take into account patient frailty and multiple illnesses.

 

Technology development

The authors found that many technologies that provide little additional benefit are taken all the way through the technology development phase, which becomes increasingly expensive the further along it goes. They recommend that the technology development process be changed, and that the design of early clinical trials be improved. They say that technologies that show little additional benefit should be halted earlier in the development process so that they do not reach the most expensive phases. The researchers say that this should result not only in reduced research costs, but also in more rigorous standards of evidence.

 

Overutilisation

The report found that overutilisation of cancer services is an issue in all areas of care. The authors say that the need to treat cancer promptly plays a role in overutilisation as it may be quicker and easier for medical staff to discuss a plan for treatment than to discuss why other treatments may not be suitable for use. They say that clinicians are also increasingly relying on technology and scans to assess new symptoms rather than physical examinations, but that the costs of using imaging techniques are also increasing per patient. The sheer amount of information on new technologies may also prevent clinicians from thoroughly understanding the evidence base needed to decide on the most appropriate treatment plan for a patient.

The report recommends six indicators of when interventions may be suitable for reduction, where cutting the use would have minimal effect on health outcomes. These include interventions that:

• provide no benefit
• result in little increased benefit
• have no clearly defined benefit
• are not desired by patients
• are duplicates of other tests or service
• are more expensive than an equally effective alternative treatment

 

How did the researchers interpret the results?

The authors say that “in general, there are two primary mechanisms to control costs. We can lower the cost of cancer-care services or interventions, or we can reduce [their use]”. They say that examining current policy can result in decreased utilisation of ineffective services, and increased utilisation of effective services. This, they say, is the way to improve efficiency and value of cancer care. They further say that rethinking how research, policy and clinical practice interact can result in reduced costs and improved quality of cancer care.

 

Conclusion

This is an extensive expert opinion piece looking at the high cost of cancer care. The authors examined cost drivers from a variety of policy and clinical perspectives – from epidemiology to research to technology development and health economics. The report identifies key areas that they feel could be addressed to reduce the cost and improve the quality of cancer care. Although the paper discusses specific treatments and national healthcare systems (including the NHS) it is not a specific analysis of where changes in individual systems would be beneficial. Instead, the document raises many issues pertaining to whether cancer care strategies need to be examined and reformed in terms of both cost-effectiveness and clinical benefit.

However, the media generally focused on one specific recommendation outlined in the report – the suggestion that attempts to use cancer-fighting therapies to lengthen the lives of terminal-stage cancer patients may not always be appropriate. Newspaper coverage may not fully reflect the tone and context of the study, which arguably raises questions on the issue rather than attempting to provide a definitive verdict on the current situation.

For example, rather than suggesting that medical care should be withdrawn from cancer patients within their last few weeks of life, the report says that continuing care strategies such as chemotherapy may be problematic for patients, and that focusing on palliative care may improve their quality of life and possibly prolong their survival. In short, the researchers question whether spending could be directed at cheaper, potentially better methods for helping people with late-stage cancer, and (contrary to some news coverage) do not suggest that they should not be helped at all.

The researchers also suggest that there is a need for clinical measures that can accurately determine which late-stage patients would and would not benefit from further disease-fighting therapy, highlighting that they are not advocating the withdrawal of appropriate care options for terminal patients.

The authors say that each health system now needs to consider how much is spent on cancer care and prevention compared with other healthcare priorities. This should include funding the most effective interventions, and insistence on a strong evidence base before adopting newly available medical technology.

The authors say that focusing on areas of care that provide little or no benefit, increasing the use of low-cost technologies and refocusing care pathways on high-quality, cost-effective and value-based care can reduce the cost of cancer care without sacrificing benefits. They also say that countries could further address cancer care costs by developing new ways of financing cancer care, including evaluating the pricing of drugs.

Overall, this is a valuable and intriguing exploration of the nature of current cancer treatment and, contrary to the impression given by media reports, these authors do not suggest that all end of life care should be stopped. Instead the report focuses on value, saying that the benefits of cancer care should be weighed from both an individual and societal perspective, and that the cost of care (in terms of price as well as side effects) should be balanced against the benefits (including quality as well as extension of life).

Links To The Headlines

Dying cancer patients should not be given ‘futile’ drugs. The Daily Telegraph, September 27 2011

Don’t give out cancer drugs if it’s just to extend life: Treatment costs can’t be justified, say experts. Daily Mail, September 27 2011

Cancer cost ‘crisis’ warning from oncologists. BBC News, September 27 2011

Links To Science

Sullivan R, Peppercorn J, Sikora K et al. Delivering affordable cancer care in high-income countries. The Lancet Oncology, Volume 12, Issue 10, Pages 933 – 980, September 2011

“Women who drink two or more cups of coffee a day are less likely to get depressed,” said the BBC today, explaining that the caffeine in coffee may alter the brain’s chemistry.

The story comes from a study of over 50,000 women looking at whether those who drank more coffee were at less risk of getting depressed. It found that the more caffeinated coffee women drank, the lower their risk of developing depression. The same effect was not found for decaffeinated coffee.

This large study has some strengths, but it also has several limitations and is not robust evidence that coffee can prevent depression. It is possible the results are a case of ‘reverse causation’ and that the women who were depressed avoided drinking coffee. Also, it is possible that other factors such as family history or other circumstances influenced the risk of depression, although researchers tried to take account of these.

Overall, this study is not a reason to start drinking more coffee and further research is required to explore the possibility that caffeinated coffee may reduce the risk of depression.

 

Where did the story come from?

The study was carried out by researchers from Harvard School of Public Health, Brigham and Women’s Hospital, Harvard Medical School and Columbia University, US. It was funded by the National Institutes of Health.

The study was published in the peer-reviewed medical journal Archives of Internal Medicine.

Overall, the research was accurately reported by the papers and other media outlets. Both the BBC and The Telegraph pointed out the study has some limitations, the main one being that this type of observational study cannot prove cause and effect, in other words that coffee lowers risk of depression. The BBC also reported comments from an independent expert. The Mirror did not report any of the study’s limitations.

 

What kind of research was this?

This was a prospective cohort study that followed a total of 50,739 women for 10 years, to find out if their intake of caffeine had any association with their risk of developing depression. This type of study is often used to investigate possible links between lifestyle interventions (such as coffee consumption) and health outcomes. The study was prospective and followed people over time, and so is thought to be more reliable than a study in which researchers investigate lifestyle habits retrospectively, or by questionnaire once the outcome (depression or not) is known.

The researchers point out that caffeine is the world’s most widely used stimulant and that 80% of caffeine is consumed through drinking coffee. They also say that previous studies in men have found that caffeine consumption decreases the risk of depression.

However, relatively few studies have examined this possible relationship. Furthermore, the possible association between caffeine use and the risk of depression, a chronic illness that affects twice as many women as men, is poorly understood.

 

What did the research involve?

Data from a large US cohort study was used to examine the possible association between caffeine and depression risk. The original research involved 121,700 American female nurses who were aged 30 to 55 when they enrolled in 1976. They provided researchers with updated information about their health and lifestyle every two years through mailed questionnaires.

The current study began in 1996 and looked at data on coffee consumption and depression from this date onwards. The researchers excluded women who could have had depression in the past, and anyone who had incomplete depression histories or whose data may have been incomplete or incorrect. This left them with 50,739 women, with an average age of 63 years, who were considered free of depressive symptoms at that time.

This group was followed up until 2006. Their consumption of coffee and other drinks, both caffeinated and non-caffeinated, was measured using validated questionnaires that the participants had completed every two years from 1980 through to 2004. Participants were asked about their coffee, tea, soft drinks, and chocolate consumption for the previous year.

The researchers classified participants into five categories of coffee drinking, ranging from one cup a week or less, to four cups a day or more. They used food composition data from official sources to calculate the amount of caffeine in a cup of coffee.

They then looked at whether the women had reported suffering depression from 1996 onwards. This was carried out through the questionnaire asking the women if they had been newly diagnosed with the condition by a doctor or had started using antidepressants regularly. This information was collected from 2000 and updated every two years until 2006.

The researchers also collected information about other factors that might have affected the results including lifestyle, medical history, age, weight, smoking status, exercise and social community group involvement.

Using the women’s reports of caffeine consumption, the researchers computed their average consumption of caffeine and other drinks. To investigate whether there was an association between caffeine consumption and depression, they allowed for a two-year ‘latency period’. For example, data on caffeine consumption from 1980 through to 1994 was used to look at new episodes of depression from 1996 to 1998, while data on consumption from 1980 to 1998 was used to look at new episodes from 2000 to 2002.

The analysis used standard statistical methods and the researchers adjusted their results for other factors that might affect the risk of depression, such as marital status, social involvement, smoking status, physical activity and other medical disorders.

 

What were the basic results?

During 10 years of follow-up (1996-2006), 2,607 new cases of depression were identified.

• women consuming two to three cups of caffeinated coffee daily had 15% less risk of depression (95% confidence interval[CI], 0.75 to 0.95), and those consuming four cups or more daily, had a 20% lower risk (95% CI 0.64 to 0.99) than women consuming one cup or less a day
• of the five caffeine consumption categories, women with the highest caffeine intake (500mg/d or more) had 20% less risk of depression than those consuming less than 100mg/day (95% CI, 0.68 to 0.95)
• decaffeinated coffee was not associated with depression risk
• there was no relationship between caffeine from non-coffee sources and depression risk

 

How did the researchers interpret the results?

The researchers say they found that depression risk decreased with increasing consumption of caffeinated coffee. They say that further investigations are needed to confirm this finding and to determine if caffeinated coffee can help to prevent depression.

 

Conclusion

The strengths of this well-conducted study include its large sample size, its prospective design and its use of a validated food frequency questionnaire, which was sent out seven times over 22 years.

However, the study had several limitations, as the authors acknowledge, which could affect its results.

• It relied on women remembering and self-reporting their consumption of coffee and other drinks over the previous year.
• It also relies on women self-reporting their diagnoses of depression, rather than using other more reliable sources such as medical records.
• Although researchers tried to control for other factors (called confounders) that might influence the risk of depression, it is possible that these some confounders were not taken into account and affected the results.It is possible that ‘reverse causation’ played a role in the results – in other words women who were depressed (but had not been diagnosed), might also be likely to drink less coffee. The authors tried to minimise this possibility by excluding at the start 10,280 women with severe depression and they also applied a two-year latency period when they computed the cumulative average of caffeinated and non-caffeinated drinks.

Overall, further research is required to explore the possibility that caffeine may reduce the risk of depression.

Links To The Headlines

Coffee may prevent depression, scientists say. BBC News, September 27 2011

Women who drink 4 or more cups of coffee a day are less likely to be depressed. Daily Mail, September 27 2011

Coffee ‘lowers depression risk’. The Daily Telegraph, September 27 2011

Four cups of coffee a day help women beat depression, study claims. Daily Mirror, September 27 2011

Links To Science

Lucas M, Mirzaei F, Pan A, et al. Coffee, Caffeine, and Risk of Depression Among Women. Archives of Internal Medicine 2011; 171: 1571-1578

“Scientists believe they may have discovered the secret of restoring lost memory,” the Daily Express has reported.

The claim is based on research in mice that has identified a molecule called miR-34c that appears to be involved in learning and memory. Through various tests researchers found that blocking the action of miR-34c improved learning in mice with both an Alzheimer’s-like brain condition and in old mice that typically experience age-related memory problems. However, it did not “restore memories”, rather it improved the mice’s ability to learn from their environment.

This type of research in mice is valuable as human brain tissue is not always easy to obtain, and early tests of new treatments need to be carried out in animals before they can be tested in humans. However, there are differences between the species that mean that results in mice may not be representative of what would happen in humans. In particular, Alzheimer’s disease is a complex disease, and mouse models may not be fully representative of its complexity.

However, when analysing tissue samples from people with Alzheimer’s and healthy elderly people the researchers found that those with Alzheimer’s disease had increased levels of miR-34c in a region of the brain important to memory. This supports the theory that miR-34c could play a role in learning and memory in humans as well, although much more research will be needed to determine if this is the case.

 

Where did the story come from?

The study was carried out by researchers from the European Neuroscience Institute in Germany and other research centres in Germany, Switzerland, Brazil and the US. It was funded by the European Science Foundation, the ERA-Net Neuron Epitherapy Project, the Hans and Ilse Breuer Foundation, the Schramm Foundation and the German Research Foundation.

The study was published in the peer-reviewed European Molecular Biology Organization (EMBO) Journal.

The Daily Express reported on this study. Although its report does correctly state that the study was in mice, its suggestion that memories were “restored” by the experimental treatment is not strictly accurate. Rather than enabling the mice to recall lost memories the treatment improved their ability to learn a “cue” from their environment and avoid a painful stimulus (a small electrical shock). As yet, we do not know whether the approach tested in this study would be effective or safe for humans.

 

What kind of research was this?

This was animal and laboratory research looking at the presence and action of certain molecules in a region of the brain called the hippocampus. The researchers wanted to look at the hippocampus because this area of the brain is important in forming memories. It is reported to be one of the first brain regions affected by ageing and forms of dementia such as Alzheimer’s disease.

The researchers were interested in understanding the actions of types of molecules called microRNAs or miRNAs. These play a role in helping to control which genes are able to produce proteins. This study aimed to identify all of the miRNAs within the hippocampus, and identify those that are particularly abundant in this area of the brain, as these miRNAs might play a role related to the formation of memories.

This type of study is easier to perform in mice because of difficulties in obtaining suitable human brain tissue samples. Differences between the species mean that the results may not be directly applicable to humans. In this study the researchers tested whether the miRNAs they identified in mice were also found in brain tissue from humans with and without Alzheimer’s disease.

 

What did the research involve?

The researchers extracted all the very small RNA molecules from mouse hippocampus tissue, and determined their genetic sequence. They then compared the levels of the various miRNAs in the mouse hippocampi and brain tissue as a whole. They also looked at which miRNAs were present at the highest levels in the hippocampus.

The genetic sequence of each miRNA determines which genes it targets and helps to regulate. They looked at what genes the most abundant hippocampal miRNAs might target, and whether these genes were likely to be involved in nerve cell function. They also looked at whether the genes targeted by these miRNAs were switched on (or ‘activated’) in mice’s brains in response to a fear conditioning task, which involves learning to associate an environmental “cue” with an unpleasant stimulus (a mild electrical shock to the foot). If these genes became activated in response to this task it would suggest that they were involved in learning.

Through these tests the researchers identified a particular miRNA molecule called miR-34c that looked like it could be involved in regulating nerve cell function, and performed a number of tests focused on its actions. First they looked at its levels in the hippocampi of older mice (24 months old), which provide a model of age-related memory impairment. They also looked at its levels in mice genetically modified to develop amyloid deposits in their brains, similar to those seen in Alzheimer’s disease. They also looked at the level of miR-34c in brain tissue from postmortems of six people with Alzheimer’s disease and eight age-matched control individuals.

The researchers then looked at whether changing the levels of miR-34c in the brains of regular mice could influence their learning and memory. First, they injected mice with a molecule that acts like miR-34c, and looked at the effect on their learning in the fear conditioning task, and in two other behavioural tests, including a test of memory (the water maze test) and an object recognition task.

They also injected the brains of the Alzheimer’s mouse model and old mice with either a chemical that would block miR-34c or a control chemical, and looked at their performance in the fear conditioning task, memory test and object recognition task.

 

What were the basic results?

The researchers found that 23 known miRNAs were present at high levels in the hippocampus, accounting for 83% of the miRNAs identified.

There were similarities in the miRNAs found in mouse whole-brain tissue and those found in the hippocampus. However, some miRNAs that were only found at low levels in whole-brain tissue were present at high levels in the hippocampus, most notably miR-34c.

The miRNA miR-34c molecule was predicted to target genes involved in nerve cell function, and these genes were found to be switched on in mice’s brains after the fear conditioning task, supporting the theory that they might be involved in learning. The miRNA miR-34c was also found to be present at high levels in the hippocampus of older mice with age-related memory problems and a mouse model of Alzheimer’s disease.

Testing of human tissue samples showed that levels of miR-34c were higher in the hippocampi of people with Alzheimer’s disease than in age-matched controls.

Injecting mice’s brains with a molecule that acts like miR-34c impaired their ability to learn in the fear conditioning task, and their memory in the water maze and object recognition tasks.

Injecting the Alzheimer’s model mice with a chemical that would block miR-34c led to them showing similar performance in the fear conditioning task to similarly-aged normal mice. Injecting them with a control chemical had no effect, with the mice showing the expected problems with their memory. Similar results were seen in mice with memory problems due to old age.

 

How did the researchers interpret the results?

The researchers conclude that “miR-34c could be a marker for the onset of cognitive disturbances linked to [Alzheimer’s disease] and indicate that targeting miR-34c could be a suitable therapy”.

 

Conclusion

This research has identified a specific microRNA molecule that appears to be involved in learning and memory in mice. Blocking the action of this microRNA seems to improve learning in mouse models of Alzheimer’s disease and age-related memory loss.

This type of research in mice is valuable, as suitable human brain tissue is not easy to obtain, and early tests of new treatments need to be carried out in animals before they can be tested in humans. However, there are differences between the species that may mean that results in mice may not be representative of what would happen in humans. In particular, Alzheimer’s disease is a complex disease, and mouse models may not be fully representative of its complexity. Also, the delivery method used in the mice in this study – regular injections directly into the brain – would not be suitable for clinical use.

The researchers’ tests suggest that the miR-34c is present in human hippocampi, and at higher levels in those with Alzheimer’s disease than age-matched controls. This does support a potential role for the microRNA in humans as well, but much more research will be needed to determine if this is the case.

This future research could include the examination of further human tissue samples to verify differences between people with Alzheimer’s and healthy individuals. However, before any testing in live humans could be contemplated there would need to be a great deal more research in mouse models of Alzheimer’s disease, which would need to determine how blocking miR-34c might have an effect in learning and memory, and whether it has an effect on the progressive brain changes that occur in the disease. They will also determine whether blocking miR-34c results in long-lasting improvements in memory, and what effects it might have.

There is a need for new treatments for forms of dementia such as Alzheimer’s disease, so research into potential new treatments is important. However, developing new treatments is a long process, and not always guaranteed to be successful.

Links To The Headlines

Secret of restoring dementia victims’ memory. Daily Express, September 25 2011

Links To Science

Zovoilis A, Agbemenyah HY, Agis-Balboa RC, et al. microRNA-34c is a novel target to treat dementias. The EMBO Journal 2011, September 23 2011