Docetaxel with prednisone or prednisolone for the treatment of ...

over to receive additional mitoxantrone after they
had progressed or remained stable for at least
6 weeks on prednisone therapy. However,
crossovers were not permitted in either the
CALGB 9182 trial or in the trial by Berry and
colleagues.
Including crossovers in intention-to-treat (ITT)
analyses can result in ‘dilution’ of the true effects
of a treatment, as patients are analysed as
randomised. For example, if mitoxantrone plus
prednisone is more effective than prednisone
alone, then any analyses would be less conclusive.
This is because in that situation, it is likely that
there would be a number of patients randomised
to receive prednisone alone crossing over and
receiving mitoxantrone also later in the trial. If
any of these patients who crossed over then
responded to the mitoxantrone therapy, they
would still be analysed as randomised, i.e. to
prednisone alone. This therefore would attribute
an effect to prednisone rather than mitoxantrone,
thus diluting the true estimate of the treatment
effect of mitoxantrone. However, in this case the
study that allowed crossovers had a stronger
treatment effect in favour of mitoxantrone plus
prednisone than the two studies that did not allow
crossovers.
Hydrocortisone was used in CALGB 9182
The CALGB 9182 trial used hydrocortisone,
whereas both CCI-NOV22 and the trial by Berry
and colleagues used prednisone. However, both
hydrocortisone and prednisone are forms of
corticosteroid, both similar to a natural hormone
produced by the adrenal glands. They both relieve
inflammation and are used to treat certain types of
cancer. Both hydrocortisone and prednisone cause
similar side-effects such as stomach irritations,
headaches and insomnia. In all three trials, the
dosages of hydrocortisone and prednisone were
equivalent and administered in the recommended
manner. 18 Therefore, given these similarities,
hydrocortisone and prednisone will be classed as
equivalent corticosteroids.
Differences in the populations
In any meta-analysis and estimation of a pooled
treatment effect, differences in the populations of
the individual studies must be carefully
considered. Trials can differ significantly especially
with respect to patient selection and baseline
characteristics. These differences may mean that
combining the results from one trial conducted in
a specific set of patients and the results from
another trial conducted in a completely different
patient population is inappropriate.
© Queen’s Printer and Controller of HMSO 2007. All rights reserved.
Health Technology Assessment 2007; Vol. 11: No. 2
One of the key factors causing differences in the
populations between trials is the varying inclusion
criteria for each trial. The inclusion criteria for the
trial by Berry and colleagues restricted eligibility
to men with asymptomatic disease, CCI-NOV22
required patients to be symptomatic with
symptoms including pain and disease progression,
whereas CALGB 9182 required patients only to
have metastatic disease – no restrictions on
symptoms were imposed, meaning that this trial
included a varied population – with both
symptomatic and asymptomatic patients.
The impact of this means that the baseline
characteristics and prognosis for patients in each
of the trials may not be comparable and therefore
combining the results from each trial may be
inappropriate. In particular, looking at the overall
median survival of the patients in each trial, it
appears that the patients in the trial by Berry and
colleagues had longer life expectancies at baseline
than the patients in CALGB 9182 and CCI-
NOV22.
All of the patients included in the trial by Berry
and colleagues were asymptomatic and 38% of
patients included in CALGB 9182 had no
analgesic requirement at baseline; however,
patients without pain and analgesic requirements
were ineligible for inclusion in the CCI-NOV22
trial. Patients included in the trial by Berry and
colleagues had better performance status scores
than those in CALGB 9182 and CCI-NOV22 at
baseline; 99% of patients in the trial by Berry and
colleagues 87% of patients in CALGB 9182 and
63% of patients in CCI-NOV22 had a performance
status score of 0 or 1.
Patients had lower PSA levels at baseline in the
trial by Berry and colleagues compared with
CALGB 9182 and CCI-NOV22. The median
baseline PSA levels for those receiving
mitoxantrone were 56.7, 209 and 150 ng/ml,
respectively, and for those receiving a
corticosteroid the median baseline PSA levels were
71.0, 158 and 141 ng/ml, respectively. The
number of prior treatments also varied between
the studies; for example, patients in CALGB 9182
had a greater prior exposure to antiandrogens
compared with those in CCI-NOV22 (72%
compared with 42%).
However, as all of the trials administered
chemotherapy, all had to include men with
mHRPC who were fit and healthy enough to
receive chemotherapy. This means that the trials
were conducted in a restricted subset of men with
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