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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 of clinicians’ assessments of breathlessness, level of ac-
clinical research in the 1940s. They have led to many tivity, and overall condition. The important issue here is
important innovations in treatment in all areas of medi- that this trial was not simply confirming what everyone
cine, not least in oncology. Those of us involved in clini- thought to be the case before it was conducted. If that had
cal research are aware, however, that the ways we are been so, its ethics could have been questioned and we
constrained to publish our results can create a misleading would certainly not have been able to enlist the level of
impression. The standard structure of a clinical scientific collaboration that we achieved. This was one of a number
article—introduction, patients and methods, results, dis- of trials that established the role of chemotherapy in the
cussion—and the way it is written can all too often give management of SCLC and led to major changes in clini-
the impression that clinical research is more inductive cal practice.
than innovative. This constraint can conceal the explor- It was followed by trials that established the appropri-
atory nature of hypotheses that are being tested and our ate duration of chemotherapy. But these, again, were not
genuine uncertainty about the likely outcomes of a ran- trials that simply confirmed previous prejudices. There
domised trial at the time it is planned. It also obscures the was no way of knowing in advance what the best dura-
sense of discovery that can prevail as we conduct the trial tion would be. Indeed, the level of genuine uncertainty is
and analyse the results. I therefore make my case against evident from the wide range of durations that was stud-
this motion on the basis of the way clinical research ied, from 3 to 14 courses of chemotherapy at intervals of
happens in practice, using a number of examples from 3 weeks, and even then, some clinicians were suggesting
our own and others’ research. These examples come before the trials were conducted that chemotherapy
mainly, but not exclusively, from the field of oncology. should be continued indefinitely in patients who were
Small cell lung cancer (SCLC) is highly sensitive to still considered to be responding. These trials showed
chemotherapy. In the 1970s, however, there was genuine that six courses were sufficient and fewer for patients
uncertainty and disagreement within the medical com- with poor performance status in whom the primary aims
munity about whether chemotherapy had a role in the of chemotherapy were palliative.
treatment of SCLC. The drug combinations then in use The first placebo-controlled, randomised trial of zid-
were considered highly toxic, and toxicity was not as ovudine in patients with advanced AIDS-related complex
well controlled as it is today. Some clinicians were con- (ARC) or AIDS showed that with zidovudine there was
vinced that those using chemotherapy could be killing as significant reduction in mortality and in the frequency of
many patients as they were helping and were probably opportunistic infections [2]. The important question then
curing none. The view was also expressed at the time that arose whether zidovudine might have a role in the man-
even if a minor survival benefit could be demonstrated, it agement of HIV-infected people who were well and
would not justify the toxicity. In contrast, other clinicians symptom-free. The dilemma was real. If the drug were to
were enthusiastic advocates of chemotherapy in the light be given early in the course of infection, it might delay
of their own experiences. disease progression and so improve survival, and it might
We therefore conducted a multicentre randomised trial even abort the infection altogether in its earliest stages.
comparing multidrug chemotherapy versus selective pal- Alternatively, it might have no beneficial effects at this
liative treatment, in which supportive care, radiotherapy, stage. It might, in contrast, serve as a constant reminder
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 Medical Research Council Cancer Trials Office, Cambridge, United
quality of life, recognising the importance of all these Kingdom
endpoints [1]. The trial showed that with immediate mul- *Correspondence to: David J. Girling, M.D., Medical Research
tidrug chemotherapy, there was a large survival benefit (a Council Cancer Trials Office, 5 Shaftesbury Rd., Cambridge CB2
doubling of median survival), better control of metasta- 2BW, UK.
ses, acceptable toxicity, and better quality of life in terms Received 19 May 1998; Accepted 5 June 1998
© 1998 Wiley-Liss, Inc.
Cancer Controversies—Con 523

of a person’s HIV-positive status and cause unacceptable II disease to radical prostatectomy (RP), plus either pla-
toxicity, substantially worsening quality of life. More- cebo (P) or 5 mg daily of diethylstilboestrol (DES); those
over, it might also induce viral resistance, thereby mak- with stages III and IV to P or DES alone or with orchi-
ing further use of the drug ineffective, once ARC or dectomy [5]. Much against expectations, DES in a daily
AIDS had supervened. The toxicity of zidovudine in pa- dose of 5 mg did not improve survival because of an
tients with AIDS was already well documented and could excess hazard of cardiovascular death.
be life-threatening. Which was the better policy? In the late 1980s and early 1990s, single-drug oral
The Concorde trial: a randomised, double-blind, pla- etoposide daily for 5 or more days in 3-week cycles was
cebo-controlled trial comparing immediate versus de- being increasingly used as palliative chemotherapy for
ferred zidovudine in people with symptom-free HIV in- SCLC on the basis of reports of its efficacy and relatively
fection was conducted to answer the better policy ques- low toxicity in nonrandomised studies. Intake to the first
tion [3]. At the time it was planned, it attracted vigorous randomised trial comparing oral etoposide versus stan-
criticism from some quarters on the basis that its double- dard intravenous multidrug chemotherapy had to be
blind, placebo-controlled design was unethical (now that stopped prematurely. This followed the recommendation
zidovudine was known to be active against HIV), that it of an independent Data Monitoring and Ethics Commit-
contravened the 1964 Declaration of Helsinki, and that tee, when 370 of the planned intake of 450 patients had
when a patient’s treatment was chosen at random, the been randomised. A planned interim analysis had shown
physician was abandoning personal responsibility to the that oral etoposide was associated with a higher risk of
patient. The critics lost sight of the genuine uncertainty hematologic toxicity, lower response rates, and worse
about the better treatment policy. They assumed that zid- survival [6]. This trial was confirmatory only in the sense
ovudine must be beneficial whenever it was given in the of confirming the imprudence of giving new treatment
course of HIV infection. They made the fundamental regimens without their having been reliably assessed in
error of supposing that the Concorde trial was simply innovative randomised trials.
confirmatory in character. In any event, affected people Innovative analyses of collated data from randomised
were eager to join the trial, which accrued 1,749 subjects trials have contributed greatly to knowledge of, for ex-
in 3 years. The results showed that, contrary to the preju- ample, prognostic factors, survival expectations, acute
dices of some, the early use of zidovudine was not ben- and long-term toxicity risks, and rare adverse effects of
eficial. There was no statistically significant difference in treatment. They have also led to improved and clinically
clinical outcome between the two treatment policies de- more relevant staging definitions. In no sense are such
spite the large difference in the amount of zidovudine analyses and trials-associated research merely confirma-
received by the two patient groups and the fact that the tory. On the contrary, they contribute substantially to
number (347) of clinical endpoints (AIDS and death) was new knowledge and better understanding.
larger than the sum of those in all other published trials Randomised trials also need to be innovative in their
in early HIV infection at the time. Six participants expe- methodology. For example, we increasingly appreciate
rienced life-threatening adverse events, five while receiv- the value of comparing quality of life (QL) between treat-
ing zidovudine, one while receiving placebo. These re- ment groups. A number of well-validated QL instruments
sults were, for some, counterintuitive. are available, but big questions remain about when to
It is not uncommon for the results of a randomised apply them, how to define QL endpoints, and how best to
trial to be counterintuitive, for a trial to be the very op- analyse and present the data collected. The assessment of
posite of confirmatory in character. This is because the palliation, for example, is an essential component of
uncontrolled and biased evidence on which all too many many treatment comparisons. Yet there is no consensus
clinical decisions are based leads to misleading and er- on its precise definition. As well as relief of symptoms,
roneous conclusions. A few examples of counterintuitive this could embrace time to onset, duration, and degree of
results follow. symptom control and prevention. Using data from a large
In the 1960s and early 1970s, the hope was that the randomised trial, we have, therefore, investigated differ-
long-term administration of alkylating agents following ent methods of defining and analysing palliation [7]. We
surgical resection of nonsmall cell lung cancer would found that not only the degree, but even the direction of
improve survival. A meta-analysis of five randomised between-treatment differences could vary with the meth-
trials involving 2,145 patients designed to answer this ods used. There is nothing ‘‘confirmatory’’ here; indeed,
question showed that surgery alone was the better treat- the findings emphasise the need for innovation to reach
ment policy, postoperative chemotherapy being associ- agreed definitions to be specified in published reports.
ated with a 15% increase in the risk of death [4]. Of course, there are circumstances in which it is de-
In the Veterans Administration’s first large ran- sirable to conduct a genuinely confirmatory randomised
domised trial of the treatment of cancer of the prostate, trial (a trial designed to assess whether a treatment effect
2,314 patients were randomised: those with stages I and seen in a previous randomised trial is real and important)
524 Girling

[8]. These include differences in the interpretation of therapy compared with selective palliative treatment for small-cell
results of a randomised trial. Such can arise from differ- lung cancer. Resp Med 83:51–58, 1989.
2. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding
ences in prior beliefs about the efficacy of the treatments
PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley
under comparison and prior skepticism about the clinical RT, Jackson GG, Durack DT, King D, and the AZT Collaborative
worth of a treatment in question. Such differences are not Working Group: The efficacy of azidothymidine (AZT) in the
uncommon after publication of a single trial, unless the treatment of participants with AIDS and AIDS-related complex: A
trial is very large. That they exist at all confounds any double-blind, placebo-controlled trial. N Engl J Med 317:185–
191, 1987.
notion that clinical trials are in general no more than
3. Concorde Coordinating Committee: Concorde: MRC/ANRS ran-
confirmatory. domised double-blind controlled trial of immediate and deferred
In conclusion, properly designed, clinically relevant, zidovudine in symptom-free HIV infection. Lancet 343:871–881,
randomised trials can be highly innovative. They and 1994.
associated research lead to reliable comparisons between 4. Non-small Cell Lung Cancer Collaborative Group: Chemotherapy
treatment policies, accurate assessments of the size of for non-small cell lung cancer: A meta-analysis using updated data
on individual patients from 52 randomised clinical trials. Br Med
differences, and important changes in clinical practice
J 311:899–909, 1995.
from which patients benefit. They have come a long way 5. Byar DP: The Veterans Administration Cooperative Urological
from coin-tossing randomisation and simple comparisons Research Group’s studies of cancer of the prostate. Cancer 32:
of proportions to be sophisticated research instruments 1126–1130, 1973.
requiring highly specialised methodologic, statistical, 6. Medical Research Council Lung Cancer Working Party: Compari-
and computing expertise. It is essential that the clinical son of oral etoposide and standard intravenous multidrug chemo-
therapy for small-cell lung cancer: A stopped multicentre ran-
community appreciate their value and importance.
domised trial. Lancet 348:563–566, 1996.
7. Stephens R, Hopwood P: Response to palliative treatment: the case
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