Medical and Pediatric Oncology 31:522–524 (1998)
CANCER CONTROVERSIES
Clinical Trials Confirm But Don’t Innovate—Con
David J. Girling, MD*
Randomised clinical trials became an essential part of
clinical research in the 1940s. They have led to many
important innovations in treatment in all areas of medi-
cine, not least in oncology. Those of us involved in clini-
cal research are aware, however, that the ways we are
constrained to publish our results can create a misleading
impression. The standard structure of a clinical scientific
article—introduction, patients and methods, results, dis-
cussion—and the way it is written can all too often give
the impression that clinical research is more inductive
than innovative. This constraint can conceal the explor-
atory nature of hypotheses that are being tested and our
genuine uncertainty about the likely outcomes of a ran-
domised trial at the time it is planned. It also obscures the
sense of discovery that can prevail as we conduct the trial
and analyse the results. I therefore make my case against
this motion on the basis of the way clinical research
happens in practice, using a number of examples from
our own and others’ research. These examples come
mainly, but not exclusively, from the field of oncology.
Small cell lung cancer (SCLC) is highly sensitive to
chemotherapy. In the 1970s, however, there was genuine
uncertainty and disagreement within the medical com-
munity about whether chemotherapy had a role in the
treatment of SCLC. The drug combinations then in use
were considered highly toxic, and toxicity was not as
well controlled as it is today. Some clinicians were con-
vinced that those using chemotherapy could be killing as
many patients as they were helping and were probably
curing none. The view was also expressed at the time that
even if a minor survival benefit could be demonstrated, it
would not justify the toxicity. In contrast, other clinicians
were enthusiastic advocates of chemotherapy in the light
of their own experiences.
We therefore conducted a multicentre randomised trial
comparing multidrug chemotherapy versus selective pal-
liative treatment, in which supportive care, radiotherapy,
and minimal single-drug chemotherapy could be given as
and when required to control symptoms. We made the
comparison in terms of survival, adverse reactions, and
quality of life, recognising the importance of all these
endpoints [1]. The trial showed that with immediate mul-
tidrug chemotherapy, there was a large survival benefit (a
doubling of median survival), better control of metasta-
ses, acceptable toxicity, and better quality of life in terms
© 1998 Wiley-Liss, Inc.
of clinicians’ assessments of breathlessness, level of ac-
tivity, and overall condition. The important issue here is
that this trial was not simply confirming what everyone
thought to be the case before it was conducted. If that had
been so, its ethics could have been questioned and we
would certainly not have been able to enlist the level of
collaboration that we achieved. This was one of a number
of trials that established the role of chemotherapy in the
management of SCLC and led to major changes in clini-
cal practice.
It was followed by trials that established the appropri-
ate duration of chemotherapy. But these, again, were not
trials that simply confirmed previous prejudices. There
was no way of knowing in advance what the best dura-
tion would be. Indeed, the level of genuine uncertainty is
evident from the wide range of durations that was stud-
ied, from 3 to 14 courses of chemotherapy at intervals of
3 weeks, and even then, some clinicians were suggesting
before the trials were conducted that chemotherapy
should be continued indefinitely in patients who were
still considered to be responding. These trials showed
that six courses were sufficient and fewer for patients
with poor performance status in whom the primary aims
of chemotherapy were palliative.
The first placebo-controlled, randomised trial of zid-
ovudine in patients with advanced AIDS-related complex
(ARC) or AIDS showed that with zidovudine there was
significant reduction in mortality and in the frequency of
opportunistic infections [2]. The important question then
arose whether zidovudine might have a role in the man-
agement of HIV-infected people who were well and
symptom-free. The dilemma was real. If the drug were to
be given early in the course of infection, it might delay
disease progression and so improve survival, and it might
even abort the infection altogether in its earliest stages.
Alternatively, it might have no beneficial effects at this
stage. It might, in contrast, serve as a constant reminder
Medical Research Council Cancer Trials Office, Cambridge, United
Kingdom
*Correspondence to: David J. Girling, M.D., Medical Research
Council Cancer Trials Office, 5 Shaftesbury Rd., Cambridge CB2
2BW, UK.
Received 19 May 1998; Accepted 5 June 1998

of a person’s HIV-positive status and cause unacceptable
toxicity, substantially worsening quality of life. More-
over, it might also induce viral resistance, thereby mak-
ing further use of the drug ineffective, once ARC or
AIDS had supervened. The toxicity of zidovudine in pa-
tients with AIDS was already well documented and could
be life-threatening. Which was the better policy?
The Concorde trial: a randomised, double-blind, pla-
cebo-controlled trial comparing immediate versus de-
ferred zidovudine in people with symptom-free HIV in-
fection was conducted to answer the better policy ques-
tion [3]. At the time it was planned, it attracted vigorous
criticism from some quarters on the basis that its double-
blind, placebo-controlled design was unethical (now that
zidovudine was known to be active against HIV), that it
contravened the 1964 Declaration of Helsinki, and that
when a patient’s treatment was chosen at random, the
physician was abandoning personal responsibility to the
patient. The critics lost sight of the genuine uncertainty
about the better treatment policy. They assumed that zid-
ovudine must be beneficial whenever it was given in the
course of HIV infection. They made the fundamental
error of supposing that the Concorde trial was simply
confirmatory in character. In any event, affected people
were eager to join the trial, which accrued 1,749 subjects
in 3 years. The results showed that, contrary to the preju-
dices of some, the early use of zidovudine was not ben-
eficial. There was no statistically significant difference in
clinical outcome between the two treatment policies de-
spite the large difference in the amount of zidovudine
received by the two patient groups and the fact that the
number (347) of clinical endpoints (AIDS and death) was
larger than the sum of those in all other published trials
in early HIV infection at the time. Six participants expe-
rienced life-threatening adverse events, five while receiv-
ing zidovudine, one while receiving placebo. These re-
sults were, for some, counterintuitive.
It is not uncommon for the results of a randomised
trial to be counterintuitive, for a trial to be the very op-
posite of confirmatory in character. This is because the
uncontrolled and biased evidence on which all too many
clinical decisions are based leads to misleading and er-
roneous conclusions. A few examples of counterintuitive
results follow.
In the 1960s and early 1970s, the hope was that the
long-term administration of alkylating agents following
surgical resection of nonsmall cell lung cancer would
improve survival. A meta-analysis of five randomised
trials involving 2,145 patients designed to answer this
question showed that surgery alone was the better treat-
ment policy, postoperative chemotherapy being associ-
ated with a 15% increase in the risk of death [4].
In the Veterans Administration’s first large ran-
domised trial of the treatment of cancer of the prostate,
2,314 patients were randomised: those with stages I and
Cancer Controversies—Con 523
II disease to radical prostatectomy (RP), plus either pla-
cebo (P) or 5 mg daily of diethylstilboestrol (DES); those
with stages III and IV to P or DES alone or with orchi-
dectomy [5]. Much against expectations, DES in a daily
dose of 5 mg did not improve survival because of an
excess hazard of cardiovascular death.
In the late 1980s and early 1990s, single-drug oral
etoposide daily for 5 or more days in 3-week cycles was
being increasingly used as palliative chemotherapy for
SCLC on the basis of reports of its efficacy and relatively
low toxicity in nonrandomised studies. Intake to the first
randomised trial comparing oral etoposide versus stan-
dard intravenous multidrug chemotherapy had to be
stopped prematurely. This followed the recommendation
of an independent Data Monitoring and Ethics Commit-
tee, when 370 of the planned intake of 450 patients had
been randomised. A planned interim analysis had shown
that oral etoposide was associated with a higher risk of
hematologic toxicity, lower response rates, and worse
survival [6]. This trial was confirmatory only in the sense
of confirming the imprudence of giving new treatment
regimens without their having been reliably assessed in
innovative randomised trials.
Innovative analyses of collated data from randomised
trials have contributed greatly to knowledge of, for ex-
ample, prognostic factors, survival expectations, acute
and long-term toxicity risks, and rare adverse effects of
treatment. They have also led to improved and clinically
more relevant staging definitions. In no sense are such
analyses and trials-associated research merely confirma-
tory. On the contrary, they contribute substantially to
new knowledge and better understanding.
Randomised trials also need to be innovative in their
methodology. For example, we increasingly appreciate
the value of comparing quality of life (QL) between treat-
ment groups. A number of well-validated QL instruments
are available, but big questions remain about when to
apply them, how to define QL endpoints, and how best to
analyse and present the data collected. The assessment of
palliation, for example, is an essential component of
many treatment comparisons. Yet there is no consensus
on its precise definition. As well as relief of symptoms,
this could embrace time to onset, duration, and degree of
symptom control and prevention. Using data from a large
randomised trial, we have, therefore, investigated differ-
ent methods of defining and analysing palliation [7]. We
found that not only the degree, but even the direction of
between-treatment differences could vary with the meth-
ods used. There is nothing ‘‘confirmatory’’ here; indeed,
the findings emphasise the need for innovation to reach
agreed definitions to be specified in published reports.
Of course, there are circumstances in which it is de-
sirable to conduct a genuinely confirmatory randomised
trial (a trial designed to assess whether a treatment effect
seen in a previous randomised trial is real and important)
524 Girling
[8]. These include differences in the interpretation of
results of a randomised trial. Such can arise from differ-
ences in prior beliefs about the efficacy of the treatments
under comparison and prior skepticism about the clinical
worth of a treatment in question. Such differences are not
uncommon after publication of a single trial, unless the
trial is very large. That they exist at all confounds any
notion that clinical trials are in general no more than
confirmatory.
In conclusion, properly designed, clinically relevant,
randomised trials can be highly innovative. They and
associated research lead to reliable comparisons between
treatment policies, accurate assessments of the size of
differences, and important changes in clinical practice
from which patients benefit. They have come a long way
from coin-tossing randomisation and simple comparisons
of proportions to be sophisticated research instruments
requiring highly specialised methodologic, statistical,
and computing expertise. It is essential that the clinical
community appreciate their value and importance.
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