Looking at research

Finding and choosing research papers

More and more people with cancer are looking for information about treatments for themselves. Many people use the Internet to try to find out about new treatments.  But you have to think about what you read.  There is cancer research going on all over the world.  You can’t read one research paper in isolation and expect it to give you the whole picture about research into that particular type of cancer.
Each time a new treatment makes it through all the stages of research and clinical trials, it will have a large number of published research papers to its name.  Mostly these will have shown it to be a useful new treatment that may contribute to slowing down, or curing a cancer.  But amongst those papers, there are likely to be one or two that showed that it didn’t work better than the existing treatment it was compared to.  These results that seem opposite to the others may have happened by chance.  Or there may have been problems with the patient group that was selected.  Or there may have been difficulties with giving the treatment.

What the doctors are looking for is evidence that on balance the treatment is an improvement.  Sometimes statisticians will gather together all the results of all the trials and do a ‘meta-analysis’.  This is an academic paper that compares all the results to give a broader picture.

The point that we are trying to make is that reading any one of these papers is unlikely to give you the broader picture.  You probably can’t rely on research results that come from just one study.

Understanding statistical tests

We can’t give you a crash course in understanding statistical analysis here.  If you read academic papers, you will be faced with the names of statistical tests and results claiming ‘95% confidence intervals’.

The statistical tests, for example, ‘T tests’ and ‘chi squared tests’ are ways of mathematically comparing results to show if there really is a difference between two treatments.  ‘Confidence intervals’ are used to show the likelihood of a result happening by chance.  For example, if a result is declared with 95% confidence, then it means the researchers are pretty sure that the result is OK and has not happened by chance.

If you understand statistics then you may find reading the results helpful.  If not, don’t worry.  Read the discussion at the end of the paper you are looking at.  This part usually makes the claims in the rest a bit clearer!

Questions to ask when reading research reports

There are a few important points you may like to bear in mind when looking at research.  Here are a few questions you might ask

• What type of cancer is being investigated?  If it is not the type you have, then the treatment is unlikely to be helpful to you. 
• What stage are the patients in the study?  Is it a treatment for advanced cancer, or an adjuvant treatment to try to stop the cancer coming back?  
• How many patients were involved in the study?  The bigger the numbers, the more likely the results are accurate.  The fewer there are, the more likely the results happened by chance.  The most accurate studies use thousands, often in many countries.  
• What was the aim of the trial?  You need to be looking at phase 3 clinical trials which are the ones where a new treatment is compared with the current treatment.  
• Was it a controlled trial?  This means the treatment was compared with standard treatment (which might be no treatment).  Patients were allocated one or other treatment at random to prevent ‘bias’ (eg a treatment seeming better because the doctors used it for all the healthy patients and gave the other treatment to all the sick patients).  
• How much did the new treatment help?  Sometimes a new treatment seems really promising when you read the reports.  But when you look at how much it extended survival, it turns out be a matter of weeks.

It is fine to pursue a new treatment if you know the answer to all these questions and decide it is still for you.  But it is important to understand clearly what you are likely to gain.

Especially when looking at alternative treatments, an important source of information is case studies, which are detailed (often technically-written) stories patients who have been given the treatment. 

Phase 1, 2, 3 and 4 trials

Phase 1 (phase I)

These are the earliest trials in the life of a new drug or treatment. They are usually small trials, recruiting anything up to 30 patients (often a lot less). The trial may be open to people with any type of cancer.

When laboratory testing shows a new treatment might help treat cancer, phase 1 trials are done to find out

• The safe dose range        
• The side effects        
• How the body copes with the drug        
• If the treatment shrinks cancer

The first patient to take part will be given a very small dose of the drug. If all goes well, the next person will get a slightly higher dose. With each patient taking part, the dose will gradually be increased and the effect that has will be monitored. Any side effects will be recorded. In a phase 1 trial, you may have lots of blood tests, as the researchers look at how the drug is affecting you. And at how your body copes with, and gets rid of the drug.

People entering phase 1 trials often have advanced cancer and have usually had all the treatment available to them.  This is because they may benefit from the new treatment in the trial, but many won’t.  The aim of the trial is to look at doses and side effects.  This work has to be done first, before we can test the potential new treatment to see if it works.  Phase 1 trials are important because they are the first step in finding new treatments for the future.

Phase 2 trials (phase II)

About 7 out of every 10 (70%) new treatments tested at phase 1 make it to phase 2 trials. These trials may be done on people who all have same type of cancer, or with several different types of cancer. Phase 2 trials are done to find out

• If the new treatment works well enough to test in phase 3        
• Which types of cancer it is effective against        
• More about side effects and how to manage them        
• More about the most effective dose to use

Although these treatments have been tested at phase 1, you may still have side effects that are not known about. Drugs can affect people in different ways.

Phase 2 trials are often larger than phase 1. There may be up to 50 people taking part. If the results of phase 2 trials show that a new treatment may be as good as existing treatment, or better, it then moves to phase 3.

Phase 3 (phase III)

These trials compare new treatments with the best currently available treatment (the standard treatment). They may compare

• A completely new treatment with the standard treatment     
• Different doses or ways of giving a standard treatment     
• A new radiotherapy schedule with the standard one

Phase 3 trials are usually much larger than phase 1 or 2. This is because differences in success rates may be small. So, you would need many patients in the trial to show the difference.

For example, 6% more people get a remission with a new treatment compared to standard treatment. If a phase 3 trial gave the new treatment to 50 people and the standard treatment to 50, on average, there may be 3 more remissions in the new treatment group. The 2 groups would not look that different. If they gave each treatment to 5,000 people, there could be 300 more remissions in the new treatment group.

Sometimes phase 3 trials involve thousands of patients in many different hospitals and even different countries.

Randomization

Phase 3 trials are usually randomized. This means the researchers put the people taking part into 2 groups at random. One group gets the new treatment and the other the standard treatment. 

Overviews

Trial overviews are studies that combine all the results from phase 3 trials of a new treatment. They are sometimes called meta-analyses. The idea is to get a broader picture of how well a treatment works. The more data (information) you have, the more accurate the results are likely to be.

Phase 4 (phase IV)

Phase 4 trials are done after a drug has been shown to work and has been granted a license.  So they are looking at drugs that are already available for doctors to prescribe, rather than new drugs that are still being developed.

The main reasons pharmaceutical companies run phase 4 trials are to find out

• More about the side effects and safety of the drug     
• What the long term risks and benefits are     
• How well the drug works when it’s used more widely than in clinical trials

About randomized trials

What randomization is

Phase 3 trials compare one treatment with another, to find out which is better.  Most phase 3 trials are randomized.  This means that there are at least 2 different groups in the trial and those taking part are put into one or other group at random.  This ‘randomization’ is usually done by a computer.

Each group in the trial will receive a different treatment.  If there are 2 groups, one group will have the new treatment being tested and the other the standard treatment that they would have to treat their cancer if not in the trial.  Those having the standard treatment are called the ‘control group’.  A randomized trial that has a control group is called a ‘randomized controlled trial’.

There may be more than 2 groups.  Some trials test more than one new treatment or they may test variations in one particular new treatment – for example different doses of a drug.  There will still be a control group who have the standard treatment that they would have if not in the trial.

Sometimes control groups are given a dummy treatment, called a placebo.  This is only done if there is no standard treatment available.

Why randomize?

Randomization is done because researchers need to be sure that the results they get are correct and not biased for any reason.

Of course, researchers are unlikely to be deliberately biased.  But it is possible to be biased without realizing it.  Supposing a new treatment is being tested that has quite bad side effects.  The doctors running the trial might subconsciously avoid putting sicker patients into the new treatment group.  So as the trial went on, the control group would have more and more of the sickest patients in it.  The less sick people in the new treatment group might do better than the control group.  So, when the trial results come out, the new treatment looks as if it works better than the standard treatment.  But really it doesn’t.

The placebo effect
Patients can also be biased.  Many of us feel better if we believe we have taken something to make us feel better.  Even if we’ve only taken a tablet made of chalk or sugar.  This is called the placebo effect.
Phase 3 trials could compare a new treatment with no treatment at all.  But then, the people getting the new treatment might feel better, even if the new treatment didn’t work.  They would be showing the placebo effect.  The others, getting no treatment, would of course not feel any better.
Some trials compare a new treatment with a dummy treatment called a placebo.  The dummy treatment looks exactly like the new treatment – the same shape or color of pill, or size of injection for example.  The two groups of patients cannot be biased, because they won’t know if they are getting the placebo or the new treatment.

Using a placebo is not very common in cancer clinical trials.  It is not ethical to give a placebo to group of people who really needed a treatment for cancer.  So the research ethics committee would not give permission for a trial designed in that way.  A placebo would only be used if there was no standard treatment and the patient would not receive any treatment if not in the trial.

Blind trials

A blind trial is a trial where the people taking part do not know which treatment they are getting.  They could be getting the new treatment.  Or they could be getting standard treatment or a placebo, depending on the design of the trial.  All patients will receive identical injections or tablets so they cannot tell.

Double blind trials

A double blind trial is a trial where neither the researchers nor the patients know what they are getting.  The computer gives each patient a code number.  And the code numbers are then allocated to the treatment groups.  Your treatment arrives with your code number on it.  Neither you, nor your doctor knows whether it is the new treatment or not.

The list of patients and their code numbers is kept secret until the end of the trial.  In an emergency the researchers would be able to find out which trial group a patient was in, but generally no one would know until the trial had finished.

Pilot studies

Pilot studies (or feasibility studies) are small scale versions of larger trials.  The format is the same but they only recruit a small number of people, so are quicker to do.

Not all trials need to have a pilot study first.  But they can be a useful way of testing to see if the trial design works.  If necessary, the trials team can then make changes to the design before the larger trial starts.

Pilot studies are often too small to say for sure if one treatment is better than another.  But they give the research team a good idea of how things will go when they do the larger trial.

Screening trials

Screening means testing the general population for a particular cancer.  The aim is to pick up cancers early, before they have started to cause symptoms.  Researchers may plan screening trials to see if new tests are reliable enough to detect particular types of cancer.  Or to see if there is an overall benefit in picking up the cancer early.

Screening trials can be done on the general population.  Or they can be done on a group of people who have a higher than normal risk of developing a disease.

Prevention trials

Prevention trials see whether a particular treatment can prevent cancer developing.  The people taking part do not have cancer.  As with screening trials they can be carried out on the general population, or on a specific ‘high risk’ group.

Epidemiology trials

Epidemiology is the study of causes and patterns of disease.  So an epidemiological study investigates whether a particular factor causes cancer or not.  Most epidemiological studies are observational.

Observational studies

There are three types of observational studies:

• Cohort study  
• Case control study
• Cross sectional study

Cohort study

A ‘cohort’ is a group of people, and so cohort studies look at groups of people.  The research team will recruit a number of people who do not have cancer.  Some of them will have been exposed to certain factors, and some won’t.

The researchers then collect detailed information on all the people taking part for a number of years.  They see who in the group develops cancer and who doesn’t.  They then look at for a link between certain factors and developing cancer.
An example of a cohort study is the European Prospective Investigation into Cancer (EPIC) study.  This study recruited many thousands of people from across Europe in the mid to late 1990s.  The researchers are collecting data on several factors including what the group eat and drink.  And they will record who develops cancer and who doesn’t.  We already have some early results.  In time, the study will tell us more about what aspects of our diet cause (or prevent) cancer.
Another example is the British Doctors Study of the 1950s.  This first showed the link between smoking and lung cancer.  The late Sir Richard Doll and colleagues recruited 40,000 British male doctors in 1951, and followed them for 50 years.  The results showed that many more doctors who smoked went on to develop lung cancer than those who did not smoke.
Cohort studies are very useful to find out more about risk factors.  But they are expensive and time consuming.  They can be used when it wouldn’t be possible to test a theory any other way.  You couldn’t make a group of people smoke in a randomized trial, for example.

Case control study

Case control studies work the opposite way to cohort studies.  The research team will recruit a group of people with cancer (cases) and a group of people without cancer (controls).  They then look back to see how many people in each group were exposed to a certain risk factor.  To make the results as reliable as possible, the researchers may try to match cases and controls for a variety of general factors, such as age and sex.

An example of a case control study would be to recruit a group of people who have lung cancer and a group of people who don’t.  And then ask them all if they smoke, and how much.  You can then look at how many people in each group smoke to see if there is a link between smoking and lung cancer.

Case control studies are useful, and they are quicker and cheaper than cohort studies.  But the results may be less reliable.  The research team often have to rely on people thinking back and recalling if they were exposed to a certain risk factor or not.  But people may over or under estimate things, and this can affect the results.

Another issue is the difference between association and cause.  Just because there is an association between a factor and a disease, it doesn’t mean that the factor causes the disease.  For example, a case control study may show that people with a lower income are more likely to develop cancer.  But it doesn’t mean that the level of income itself causes cancer.  It may mean that they have a poor diet or are more likely to smoke, for example.

Cross sectional study

A cross sectional study is carried out at one point in time, or over a short period of time.  They find out who has been exposed to a risk factor and who has developed cancer, and see if there is a link.

An example of a cross sectional study would be to see how many out of a certain number of people smoke, and how many people have lung cancer.

Cross sectional studies are quick and cheap to do.  But the results can be less useful.  This is partly because cancers usually develop over many years, so looking the number of people who smoke and the number of people with lung cancer at any one point in time will not give us the full picture.  Some of those recorded as not having cancer may go on to get it in the future.  Sometimes researchers will do a cross sectional study first to find a possible link.  Then they go on to do a case control or cohort study to look at it in more detail.