Evidenced Based Medicine and Research Methods

Randomised controlled trials

Tutor notes

Aims of session

 To become familiar with a systematic approach (CASP framework) in critically appraising a

randomised controlled trial (RCT).
 To interpret a meta-analysis forest plot and the role of heterogeneity in systematic reviews.

Learning objectives

 To consider the strengths and weaknesses of an RCT in relation to the study question.
 To consider the role of bias and confounding in interpretation of the findings.
 To interpret and explain the data.
 To consider the applicability of an RCT to the clinical question.

Key Learning Points

 If feasible, an RCT is the best study design to examine the effectiveness of an intervention.
 There are a number of issues concerning eligibility criteria, randomisation method, allocation
concealment, blinding and follow-up that need to be examined when considering whether the
findings are valid, and if the findings are applicable to a clinical situation (see end for further
details on these issues).
 When one reads a trial with a positive result, always ask whether the finding can be explained
by chance, bias or confounding.

Instructions given to students

Core pre-session work: Watch the lecture ‘How do we measure the effectiveness of
treatments: randomised controlled trials’ (60 mins). Then read the paper and think about the
CASP using the CASP checklist for RCTs below (60 mins). You will then have the
opportunity to discuss the CASP items in breakout groups in the tutorial and will be asked to
discuss your responses to the CASP questions.

Allow 2 hours to watch the recorded lecture and prepare for this session.

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Instructions for the session

1. Ask students whether there were any particular issues arising from the lecture – it is
likely that there will be an opportunity to address these during the session.
2. Introduce the scenario and ask whether they would recommend exercise to the woman
(5 mins)
3. Put students into breakout rooms to work through the CASP. (30 mins)
4. Go through the CASP items (30 mins)
5. Part 2: as a group discuss questions 2.1-2.4. (10-15 mins)
6. Look at the meta-analysis findings (questions 2.5-2.8) (10-15 mins)
7. Consider possible causes of the heterogeneity – question 2.9 (could do in breakout
groups if time) (15 mins)
8. Questions 2.10-2.12 (10 mins)

Background details about colorectal cancer

Colorectal cancer is the third most common cancer in the UK after breast and lung cancer, with
approximately 40,000 new cases registered each year. Colorectal cancer is the second most common
cause of cancer death in the UK (Cancer Research UK).

Occurrence is strongly related to age, with almost three-quarters of cases occurring in people aged
65 or over.

Risk factors include a family history of colorectal cancer, familial adenomatous polyposis,
inflammatory bowel disease, hormonal factors, a diet rich in red meat and fat, a sedentary lifestyle,
obesity, smoking, high alcohol consumption, diabetes and a family history of small bowel cancer,
endometrial cancer, breast cancer and ovarian cancer.

The most common presenting symptoms and signs of colorectal cancer or large polyps are rectal
bleeding, persisting change in bowel habit and anaemia. However, the presentation depends on the
site of the cancer:

 Right colon cancers are more likely to present with weight loss, anaemia, occult bleeding, mass
in right iliac fossa, disease more likely to be advanced at presentation.

 Left colon cancers are more likely to present with colicky pain, rectal bleeding, bowel
obstruction, tenesmus, mass in left iliac fossa, early change in bowel habit, less advanced disease
at presentation.

 Stage IIA (T1-T2, N0, M0): The cancer has grown through the muscularis mucosa into the
submucosa (T1) or it may also have grown into the muscularis propria (T2). It has not spread to
nearby lymph nodes or distant sites. The 5-year survival is 72-75%.

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Clinical scenario

John, a 55-year-old white male in previously good health, is found to have a colon cancer. He
undergoes a left hemicolectomy. The histology confirms that the resection margins are clear and
there is no evidence of metastases. John is relieved that his wound has healed well and that he
didn’t need a colostomy. He has been told that the chance of cure is high, but he is still worried
about future recurrence. Although he starts to feels better he is aware that his energy and
enthusiasm levels are still low. He wonders what he can do to improve his health and to feel ‘back to
normal’. He does some research on the internet and comes across an article which suggests that
exercise might be helpful for cancer survivors. He makes an appointment to see his GP to discuss
whether there might be a local exercise programme he could join.

His GP says she will track down the original journal article and suggests that he makes an
appointment in a fortnight’s time.

The GP obtains the paper:

Courneya KS, Friedenreich CM, Quinney HA, Fields AL, Jones LW, Fairey AS. A randomized trial of
exercise and quality of life in colorectal cancer survivors. European Journal of Cancer Control
2003;12(4):347–57.

She decides that this would be a good opportunity to formally appraise the paper as part of her
continuing professional development and plans to share the findings with her colleagues at their
monthly educational meeting. She downloads the CASP checklist for randomised controlled trials
(RCTs) and works through the questions.

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Part 1: Critical Appraisal

Use the CASP framework provided to critically appraise the Courneya et al (2003) study.

11 questions to help you make sense of a

randomised controlled trial

How to use this appraisal tool

 Three broad issues need to be considered when appraising the report of a randomised
controlled trial:

Are the results of the study valid? (Section A)

What are the results? (Section B)

Will the results help locally? (Section C)

The 11 questions on the following pages are designed to help you think about these issues
systematically.

 The first three questions are screening questions and can be answered quickly. If the answer to
all three is "yes", it is worth proceeding with the remaining questions.

 There is a degree of overlap between several of the questions.

 You are asked to record a "yes", "no" or "can't tell" to most of the questions.

 A number of hints are given after each question. These are designed to remind you why the
question is important.

©CASP This work is licensed under the Creative Commons Attribution - NonCommercial-ShareAlike
3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-
sa/3.0/. www.casp-uk.net

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A) Are the results of the study valid?
Screening questions
1. DID THE TRIAL ADDRESS A CLEARLY FOCUSED ISSUE? X Yes  No  Can’t tell
HINT: Please consider the following sub-questions:

a. Was the population studied clearly defined?

Population – people diagnosed with colorectal cancer within the past 3-months, “recovered from
surgery” and had no contraindications to exercise (measured by the rPAR-Q , which asks about
symptoms on exercising such as chest pain and light-headedness).

b. Was the intervention studied clearly identified?

Intervention – 30 min fitness consultation and personalised exercise prescription for next 16 weeks
with aim of achieving 20-30 mins 3-5 times/week of exercise at a particular intensity.

c. Was the comparator studied clearly identified?

Comparator – Asked not to begin a structured exercise programme until after the 16 week trial was
over, then offered the consultation (known as a waiting list control).

d. Are the outcomes considered relevant for you?

Outcomes – primary – quality of life measured by the FACT-C (Functional assessment of cancer
therapy-Colorectal Scale) which has been shown to be “reliable, valid and responsive”.

Lots of secondary outcomes: anxiety, depression, satisfaction with life, fatigue, cardiovascular
fitness, flexibility, self-reported exercise.

Key point alert: What do we mean by “reliable, valid and responsive”?

Reliable: ability to produce consistent, reproducible estimates of true effect.

Valid: measures the construct that it claims to measure

Responsiveness of a patient-reported outcome deals with the extent to which changes in the scores
are associated with changes in the underlying clinical status of the subject

Potential additional questions for students:

Who delivered the intervention?

It doesn’t say clearly, but implies it is the project director who also made the weekly phone calls.

Why did they measure the amount of exercise?

To see whether the intervention and control groups actually did what was asked. This is described as
a process measure as it measures the mechanism by which we expect the intervention to work. If
the intervention does lead to an improvement in QoL, the researchers also need to see an increase
in amount of exercise to support their hypothesis.

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2. WAS THE ASSIGNMENT OF PARTICIPANTS TO TREATMENTS RANDOMISED?

X Yes  No  Can’t tell

a. How was this carried out?

Researchers use a random numbers table and allocated people on a 2:1 basis to intervention and
control (twice as many people allocated to the intervention group).

Allocation done prior to the fitness test – not usual practice, especially as ability to pass the fitness
test was one of the eligibility criteria. One would normally do all baseline assessments before the
randomisation and allocation procedures. However, the person doing the fitness test was blinded.

b. Was the allocation sequence concealed from researchers and patients?

There is no detail about method of allocation concealment (sealed envelopes, telephone

randomisation etc, which are well regarded methods of allocation concealment). One consequence
of non-concealed allocation is that selection bias creeps in and one ends up with baseline
imbalances between the two study arms.

They give detail about consent to the fitness test, but don’t actually describe consent to the trial. It is
therefore difficult to be sure that allocation was concealed from the researcher taking consent.
However, the potential participants were given consent forms prior to attending for the fitness test,
which were given to the project director. It is probable that consent was taken before the fitness
test and by the project director.

Key point alert: what is selection bias?

Selection bias can occur when people are asked to take part in a trial based on a knowledge of which
study group they will be allocated to; e.g. the recruiter knows that a potential participant is
depressed and unlikely to comply with the exercise programme and the recruiter knows that the
next allocation is to the exercise intervention. The recruiter decides to not invite the person to take
part or may discourage their participation by being negative about the study.

We can identify risk of selection bias by an imbalance between groups in baseline characteristics.
Ways to prevent selection bias are to ensure that the randomisation sequence is truly random and
that the person recruiting and allocating the potential participant to a trial has no idea what study
arm the person will be allocated to (allocation concealment).

3. WERE ALL OF THE PARTICIPANTS WHO ENTERED THE TRIAL PROPERLY ACCOUNTED FOR AT ITS
CONCLUSION? X Yes  No  Can’t tell

a. Was the trial stopped early?

No. The trial wasn’t stopped early.

b. Were patients analysed in the groups to which they were randomised?

See figure 1. What happened to participants is well described, 91.3% follow-up, which is good, and
the reasons for those lost to follow- up are given: 7 lost from intervention group and 2 from control
group.

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Patients were analysed in the groups to which they were allocated. This is good practice. However 7
participants in the intervention and 2 participants in the control group were lost to follow-up, so this
is not a full intention to treat analysis.

For full intention to treat (ITT) analyses, all participants who did not receive the assigned
intervention according to the protocol as well as those who were lost to follow-up are included in
the analysis. This means that missing follow-up data has to be imputed (i.e. a scientifically plausible
value for the follow-up data has to be created. This could range from the last value carried forward,
to using more complex techniques that take account of the characteristics of these participants to
create a value at follow-up that is based on outcome data from other people in the same group and
with similar characteristics (age, gender, ethnicity, quality of life etc)).

Key point alert: consider attrition rates

Are losses to follow-up similar in both groups? If higher in the intervention group there may be
issues with side-effects or acceptability. If losses to follow-up are very high one would be concerned
that the outcome will be better than that seen when the intervention is rolled out more generally.

Key point alert: confounding and ITT

The strength on an intention to treat (ITT) analysis is that it preserves the effect of random allocation
of participants into different branches of the trial; the equal distribution of confounders is
maintained by an ITT analysis. Another advantage of this type of analysis is that it mirrors the real-
world situation where patients don’t follow the prescribed treatment.

If the answers to Questions 1, 2 and 3 are negative, then it would not be worth continuing
reading the paper for your purpose. Otherwise, read on.

Detailed questions

4. WERE PATIENTS, HEALTH WORKERS AND STUDY PERSONNEL ‘BLIND’ TO TREATMENT?

 Yes X No  Can’t tell
a. Patients

Not blinded – they were told their allocation, either they would have an exercise consultation now
or in 4 months time. If in the control group they were asked not to start an exercise programme. It is
almost impossible to blind participants to this type of intervention.

b. Health workers

The intervention appears to have been delivered by the research team. We don’t know anything
about the regular team looking after the patient’s malignancy.

c. Study personnel

The project director was not blinded and he made weekly phone calls to participants to find out how
much exercise they were doing. No mention of blinding of other outcomes such as the person doing
the treadmill test, although it may well be the same blinded fitness instructor who undertook the
baseline assessment.

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Key point alert: What is detection bias?

Detection bias occurs when there are systematic differences between groups in how outcomes are
determined. This is prevented by the blinding of outcome assessment.

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Potential additional questions for students:

If the patients know which group they are in might this affect the response they give to
questionnaire asking about quality of life and psychological status?

Quite possibly – people might be disappointed about having to wait for the intervention and this
might affect how they are feeling.

Do you think the control group are likely to do what they are asked?

There is a high risk of contamination here; the control group might start exercising anyway. This issue
is a real problem in trials of exercise interventions.

Can you think of any way the participants could have been blinded?

Sham intervention such as relaxation or gentle stretching exercises

5. WERE THE GROUPS SIMILAR AT THE START OF THE TRIAL?  Yes X No  Can’t tell
Look at other factors that might affect the outcome such as age, sex, social class

Key point alert: we are checking for selection bias here.

Sometimes there is poor reporting, where only the characteristics of those who completed the trial
are shown in table 1, as has happened here.

Potential additional questions for students:

What factors do the students think may be associated with QoL in people with colorectal cancer?

Baseline balance is a matter of judgement. Look at the characteristics in table 1. There are no
statistically significant differences in characteristics between the study groups, but, with a small
sample differences have to be huge to reach statistical significant and the CONSORT statement says
that you shouldn’t do significance testing of baseline characteristics. You should look particularly
hard at those characteristics that might influence the outcome. Things that might affect QoL include
stage of disease, type of treatment (chemo and radiotherapy can make you feel dreadful), people
who are married may have more support than those living alone...

Some of the characteristics that have a difference of about 10% or more between the groups are:
sex, marital status, education, income, % at stage 3 or 4.

6. ASIDE FROM THE EXPERIMENTAL INTERVENTION, WERE THE GROUPS TREATED EQUALLY?
X Yes  No  Can’t tell

All participants had weekly phone calls to ask about exercise levels.

Chemotherapy and radiotherapy proportions are fairly similar – not perfect...

We don’t have much other information and we are not told anything about their care from the
surgeon or oncologist.

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Key point alert: what is performance bias?
Performance bias occurs where there are systematic differences between groups in the care that is
provided, or in exposure to factors other than the intervention of interest.
Performance bias can be reduced by blinding the participants and people treating the participant.

(B) What are the results?

7. HOW LARGE WAS THE TREATMENT EFFECT?

a. What outcomes were measured?

Look at table 3. (Discuss table 4 later in part 2. If students ask why we are leaving out table 4, it is
because it is not an intention to treat analysis)

The primary outcome is (FACT-C). There are lots of secondary outcomes reported.

b. Is the primary outcome clearly specified?

The primary outcome (FACT-C) was clearly specified in both the methods and in the table.

c. What results were found for each outcome?

Potential additional questions for students:

Would one of the students like to talk through the results for the primary outcome measure?

In the exercise group the FACT-C increased from a score of 106 at the start to 107.4 at the 16 week
follow-up point. The comparable figures for the control group are 107 and 109.8. The intervention
group actually had a smaller improvement score from baseline to follow-up. The difference in
change scores between the groups was -1.3 points (favouring the control group). BUT the difference
was not statistically significant.

What does a change of 1.4 points from baseline to follow-up mean? Is it clinically worthwhile?

No, in the discussion the minimally clinically important difference (MCID) for the FACT-G is
mentioned – it is 4 points. This means that if someone reports an improvement of 4 points they are
likely to experience an improvement in how they feel. Smaller differences are not associated with
feeling different. It is likely that the MCID for the FACT-C won’t be hugely different from the FACT-G,
but it is not known.

What about the findings for the secondary outcomes?

There are no statistically significant results.

8. HOW PRECISE WAS THE ESTIMATE OF THE TREATMENT EFFECT? Look at the confidence limits.

Look at the confidence intervals: for the FACT-C the mean difference is -1.3, 95% CIs: -7.8 to 5.1.

Ask someone to explain what this means

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The true population mean difference is likely to lie somewhere between -7.8 and 5.1 points. i.e. it
could encompass both a clinically meaningful difference in favour of either the control or
intervention group!

Key point alert: Was there a power calculation?

No and there should have been.

(C) Will the results help locally?

9. CAN THE RESULTS BE APPLIED IN YOUR CONTEXT (OR TO THE LOCAL POPULATION?)
X Yes  No  Can’t tell
Do you think that the patients covered by the trial are similar enough to the patients to whom you
will apply this? if not how do they differ?

How do these patients compare to our patient and to the epidemiology of colorectal cancer
patients in general?

75% of people with bowel cancer in the UK are aged over 65 years, so this is a slightly younger
population (mean age 60 years).

The participants were recruited from a specialist cancer unit in Canada. One would need to consider
whether there is any differences in the stage of presentation between the UK and Canada (more
screening?) and whether standard treatment pathways differ.

Probably OK to use these results in the UK context. Alberta gets very cold in winter and this could
affect adherence to a walking programme.

This is very much a matter of opinion, there are no hard and fast rules to help with this judgement.

Key point alert: The concept being described here is GENERALISABILITY or EXTERNAL VALIDITY
A research finding may be entirely valid in one setting, or in one type of patient but not in another.
Generalisability describes the extent to which research findings can be applied to settings and
patients other than that in which they were originally tested. The sort of issues that can affect
generalisability include the age and gender of patients, the severity of the disease, the presence of
other co-morbidities and the setting (e.g. patients from primary or secondary care). If the
participants are not representative of the profile of patients with a condition, then the trial results
are unlikely to be broadly generalizable.

10. WERE ALL CLINICALLY IMPORTANT OUTCOMES CONSIDERED? X Yes  No  Can’t tell
a. Is there other information you would like to have seen? Consider outcomes from the point of
view of the:

i. individual
ii. policy maker and professionals
iii. family/carers
iv. wider community

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Mostly. Again this is a matter of opinion and depends on your perspective. If you are a patient with
colorectal cancer there may be an outcome that the research team never thought would be
important. This is why we now involve patients in helping us design research studies.

Key point alert: Were there any side-effects reported? What side-effects could result from an
exercise intervention?

Exercise could lead to musculoskeletal problems, falls... Actually walking is pretty safe.

b. If not, does this affect the decision?

Not relevant.

11. ARE THE BENEFITS WORTH THE HARMS AND COSTS?  Yes X No  Can’t tell

Even if this is not addressed by the study, what do you think?

We don’t know anything about the costs, but the intervention didn’t work.

However, because so many of the control group started exercising it isn’t possible to say that
exercise has no effect.

Brief summary of the main biases in RCTs

Type of bias Description What should we be looking for?

Selection bias Systematic differences between  Random sequence generation
baseline characteristics of the  Allocation concealment
groups that are compared
Performance bias Systematic differences between  Blinding of participants and
groups in the care that is personnel.
provided, or in exposure to
factors other than the
interventions of interest
Detection bias Systematic differences between  Blinding of outcome
groups in how outcomes are assessment
determined

Attrition bias Systematic differences between  Incomplete outcome data

groups in withdrawals from a
study
Reporting bias Systematic differences between  Selective outcome reporting;
reported and unreported some outcomes have been
findings measured but results not given
Adapted from the Cochrane Handbook of systematic reviews version 5.1.9

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Part 2: The Systematic Review

The scenario continues....

The GP reads the paper and is confused about what the paper is really saying. How should she
interpret Table 4 (Association between change in fitness and change in quality of life)?

Consider the findings of table 4:

2.1) What have the researchers done?

They’ve abandoned the randomised comparator and compared participants who increased their
fitness with those who didn’t. i.e. they have not used intention to treat analysis here.

Why did they do this?

Contamination in the control group – they increased their exercise levels (it is easy to do and they
knew what the trial was about)

Poor adherence in the intervention group (only 76% reported 60+ minutes of moderate or vigorous
exercise per week)

2.2) Why might the research team have chosen fitness?

Because self-report might be influenced by the participant’s knowledge of the group to which they
were allocated. Those in the intervention group may over-report their activity to try to please the
researcher, and those in the control group might under-report because they were meant to not
increase their exercise. These would be examples of reporting biases. Fitness is more objective and is
influenced by how much exercise you have actually done.

2.3) What are the results of the analyses by fitness?

People who increased their fitness during the trial improved their QoL, those who didn’t increase
their fitness had a small reduction in QoL. There was a statistically significant difference between the
groups. This improvement was consistent across a lot of the secondary outcomes.

2.4) Which results should the GP believe?

The secondary analysis is not randomised and comes with all the problems of observational studies.
There is likely to be residual confounding that can’t be adjusted for (such as attitudes to health and
fitness, other aspects of a healthy lifestyle). The researchers do report that the two groups
categorised by fitness did not differ in relation to important characteristics. However, we don’t have
the figures and can’t see how the groups differ. The trial results are important and should make us
cautious about rolling out such an intervention (as policy makers or commissioners of health
services).

Where does this study come in the hierarchy of evidence?

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The RCT evidence is high (but below a well conducted systematic review), however the observational
analysis is lower (more like a cohort study)

The GP decides to see if there have been any further trials published as the paper was published in
2003. She comes across a Cochrane review of exercise interventions on quality of life in patients
who have had cancer:

Mishra SI, Scherer RW, Geigle PM, Berlanstein DR, Topaloglu O, Gotay CC, Snyder C. Exercise
interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev. 2012
Aug 15;8:CD007566. doi: 10.1002/14651858.CD007566.pub2.

The review includes 40 trials, 22 in breast cancer survivors and 12 in patients with a range of other
cancers (two colorectal). In 30 trials the patients had completed the active treatment for their
cancer. The exercise intervention varied by mode (walking, cycling, gym etc), setting (at a centre or
home-based), level of supervision, intensity and duration of programmes.

The meta-analysis for the main outcome, difference between groups in the change in health related
quality of life (HRQoL) from baseline to follow-up, is reproduced below:

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2.5) Interpret the meta-analyses of the Cochrane Review
Focus on the top meta-analysis – ‘up to 12 weeks follow-up’. (Don’t forget that in year 2 students
learned how to interpret a forest plot of a meta-analysis, so this should be revision!)

There are 3 subgroup analyses summarising the results by length of follow-up. I suggest the students
focus on the top one – ‘up to 3 months follow-up’.

2.6) Take the study by Cho (2006) and explain the box and whisker plot

This is the mean difference between intervention and control group QoL for one study with its 95%
confidence interval.

2.7) What does the diamond at the bottom represent?

The diamond is the summary statistic for the effect estimate. In this case it is the standardised mean
difference (SMD) because different QoL measures have been combined.

SMDs are hard to interpret, they are actually units of standard deviation. The important issue here is
that the confidence intervals do not cross the line of no effect.

2.8) What does the I2 mean?

The I2 statistic - ranging from 0-100%, measures the degree of inconsistency across studies in a meta-
analysis that is not accountable by chance.

Interpreting I2

I2 = 0% no heterogeneity; I2 ≥25% low heterogeneity; I2 ≥50% moderate / substantial heterogeneity;

I2 ≥75% high heterogeneity.

Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless
we know how consistent the results of studies are, we cannot determine the generalisability of the
findings of the meta-analysis. Inconsistency of studies' results in a meta-analysis reduces the
confidence of recommendations about the intervention or treatment. In an attempt to establish
whether studies are consistent, reports of meta-analyses commonly present tests of heterogeneity
to determine whether there are genuine differences underlying the results of the studies
(heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity).
The I2 is one such test. You may also come across the Chi2.

Statistical heterogeneity may be caused by:

clinical differences between studies
methodological differences between studies
unknown study characteristics

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2.9. Given the information provided above about the review, what factors might explain the
different results for QoL for the different trials (i.e. the high level of heterogeneity)?

You might like to split the students into groups to think about (i) the interventions and (ii) the
patient populations.

a. the interventions
 Exercise may only have an effect if people achieve a certain level of intensity (which may be
more likely if the exercise is supervised)
 Exercise in groups may have the benefits of group support helping people feel better
because of the social interaction, not actually the exercise
 People exercising in certain situations may be more likely to adhere (coming to centre vs
doing it at home)

b. the patient populations

Exercise may have different effects depending on:
 the type of cancer, its severity and spread
 the stage of treatment (if still having chemo or radiotherapy the participants may have felt
worse trying to exercise)
 The age of people affected
 The type of treatment and where sited, may find it easier to exercise after breast rather than
abdominal surgery for example.
 The motivation of people taking part, highly motivated people may exercise more intensively
and get a better outcome. They may not reflect the general population.

Trial design: time of follow-up, if there is an effect on Qol it may reduce over time from the end of
the intervention, so when the follow-up is done is also important.

2.10) A major problem with the Courneya trial and other trials within the Cochrane review are the
issue of contamination and the lack of blinding. How might one alter the design to try to address
this problem?

Could have a control group with a sham intervention e.g. relaxation, stretching or yoga. BUT these
might be therapeutic in their own right.

2.11) So what’s the bottom line? This is what the Cochrane review authors said:

This systematic review finds that exercise interventions may have beneficial effects on overall HRQoL
and HRQoL domains including cancer-specific concerns (e.g. breast cancer), body image/self-esteem,
emotional well-being, sexuality, sleep disturbance, social functioning, anxiety, fatigue, and pain at
varying follow-up periods among cancer survivors who are beyond active treatment for their primary
or recurrent cancer. Exercise programs could be considered as an integral component for the
management of HRQoL among cancer survivors.

The positive results must be interpreted cautiously owing to the heterogeneity of mode of exercise
programs, measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials.
Further, a lack of understanding about important elements of exercise programs (mode, frequency,
duration of sessions and programs, and intensity) for optimal effects on HRQoL and HRQoL domains
would preclude informed decision making in clinical settings and limit practical applicability of
findings.

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2.12) What should the GP tell the patient?

It might well be beneficial, it is unlikely to do any harm.

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Eligibility criteria: What criteria did the researchers set for patient eligibility to the trial? This
might have implications for the generalisability of a study. If the criteria mean that only a very
select group (e.g. people with severe disease) are included then the findings won’t be
generalisable to all patients with that condition.

Randomisation method: this refers to how the randomisation was actually done. How was list
produced? – e.g. referring to a random number table, using a computer random number
generator, coin tossing, drawing lots and something quite sophisticated called ‘minimisation’ done
by computer. Taking alternate people or allocating people by day of the week or birthdate is not
random.

Concealment of allocation: if done adequately the researcher taking consent and the participant
should not be able to tell which group the participant will be assigned to. Ideally the person taking
consent would phone an independent person after baseline measures and consent if taken to find
out which group the participant has been allocated to. It can also be done with consecutively
numbered sealed opaque envelopes or sequentially numbered identical drug containers.

Blinding: This occurs when the person who is blinded does not know which study group the
person is in. Several people can be blinded: the patient, the clinician/researcher providing usual
care or the intervention, researchers taking any clinical measurements for outcome assessment
and the statistician.

Incomplete outcome data: loss to follow-up is always a problem in research. In trials one wants to
know how those lost to follow-up compare to those who remained in the study as high losses will
affect the generalisability of the findings and whether or not we can believe the results at all. If
losses are unequal between the study groups this is also a cause for concern as people who drop-
out are generally different from those who stay in. They may be sicker (or sometimes healthier)
and are usually less health conscious.

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