BMJ 1999;318:1073 ( 17 April )
The Di Bella multitherapy trial
Randomised controlled trials may not
always be absolutely needed
Criticism ignores standard
methodology of cancer treatments
Reply from author and statistical
controlled trials may not always be absolutely needed
EDITORWe disagree with Müllner's
editorial1 as it took a very narrow
perspective on a case in which attention should have been paid to
the relations between general methodological principles of cancer
trials and the social context in which the Di Bella story
The editorial might give the (wrong) impression that the Di Bella trial3 was inadequate and could not show
the lack of antitumour activity of Di Bella's multitherapy. In 1982 an editorial in the New
England Journal of Medicine accompanied the publication of a
phase II study of the US National Cancer Institute on another anticancer
"miracle" treatment named laetrile. This said that the
study "closed the book on laetrile."4 Interestingly, that study
adopted the same non-randomised design (and the same negative results)
as the Italian study.
Have general methodological principles of clinical research in oncology
changed so dramatically since then? We do not think so and suspect
that the editorial indicates limited familiarity with phase II
trials in oncology. Too much familiarity with a given research field
may lead to blindness concerning its limitations,5 and the view is
perfectly legitimate that current standards of phase
II oncology trials should be abandoned. But why was not this the main theme of Müllner's
editorial? Why did all criticism exclusively target the Di Bella trial?
To illustrate possible approaches to similar cases in the future a more
general discussion of pros and cons of randomised versus non-randomised
studies in similar cases (in terms of risk of bias, costs, time
needed to get an answer, likelihood that such an answer will be
accepted, acceptability, or randomisation in situations
characterised by high social and political pressure, etc.) would
have been useful. Is strict adherence to the dogma of randomisation
always the best solution in phase II trials, when what matters is to
determine whether a new drug or regimen has sufficient biological
activity to warrant more extensive, costly, and time consuming studies?
Maybe a commentary would have served the purpose better. Are we sure
that insisting that randomised controlled trials are always
absolutely needed for a perfect study will not end up, in the long
run, doing more harm than good to the future of evidence based
health care? We hope that the BMJ will promote a discussion around
Alessandro Liberati, Professor of biostatistics.
Università di Modena, Centro per la Valutazione della Efficacia della
Assistenza Sanitaria Modena, Italy Email firstname.lastname@example.org
Nicola Magrini, Unit
Centro per la Valutazione della Efficacia della Assistenza Sanitaria (CeVEAS) Modena, Italy
Lucio Patoia, Unit head.
CeVEAS Modena, Unità di Medicina Interna e Scienze
Oncologiche, Perugia, Italy
Luigi Pagliaro, Professor
of internal medicine.
Divisione di Medicina Interna, Università di Palermo, Palermo, Italy
- Müllner M. Di Bella's therapy:
the last word? BMJ 1999; 318: 209-210[Free Full Text].
- Turone F. Italy starts trials for controversial
cancer treatment. BMJ 1998; 316: 327[Free Full Text].
Study Group for the Di
Bella Multitherapy Trial. Evaluation of an unconventional
cancer treatment (the Di Bella multitherapy):
results of phase II trials in Italy. BMJ 1999; 318: 224-228[Abstract/Free
- Relman AS. Closing the book on laetrile. N
Engl J Med 1982;
- Simonetti RG, Liberati A,
Angiolini C, Pagliaro
L. Treatment of hepatocellular carcinoma: a
systematic review of randomized controlled trials. Ann Oncol 1997; 8: 117-136[Abstract].
standard methodology of cancer treatments
his editorial on the trials conducted to evaluate the anticancer treatment
known as Di Bella multitherapy,1 Müllner
argues that "the design of the studies is flawed" and that
"the researchers should have conducted randomised controlled
trials." 2 Müllner's
criticism seems to ignore the standard methodology in the
development of cancer treatments.3 This requires that the
activity of a treatment be ascertained by means of phase II trials,
before randomised phase III trials can even be considered. The aim
of phase II trials is to distinguish between drugs with promising
activity warranting further trials, and drugs for which further
trials on human subjects are not justified. Their methodology responds
to the ethical imperative of minimising the number of patients
exposed to useless and potentially harmful treatments as well as the
time needed to identify potentially useful treatments.
In phase II trials of cancer treatments, randomised control groups are
usually not needed because the end point most often used is
"objective response" (defined on the basis of the observed reduction
of tumour size), that seldom occurs spontaneously. Blinding is never
used in cancer trials, mainly because of the obvious toxicity of
most cancer treatments. Indeed, it would have been impossible to
conduct a randomised trial of Di Bella multitherapy in Italy. Given the wide media
coverage and the public's great expectations of high efficacy of
this treatment, and in the face of some 2000 free Di Bella treatments
ordered by the courts, the enrolment of hundreds of patients,
accepting to be assigned at random to a treatment that might not
have been Di Bella multitherapy, was
inconceivable. For all of these scientific, ethical, and practical reasons,
after a thorough discussion, the Italian National Oncology Committee
recommended the immediate start of phase II trials.
In the process of evaluating anticancer treatments,
"uncontrolled" phase II trials (yet under controlled conditions) are
far from being "studies of weak design" and provide
direct, objective, verifiable, and rapid evaluations. This
represents the real interest of patients. In past decades, many
anticancer treatments with a preclinical evidence of activity or a
therapeutic rationale much stronger than those of Di Bella multitherapy were excluded from further trials
(and from clinical use) solely on the basis of the results of
"uncontrolled" phase II trials that showed insufficient activity.
In any case, the claim that in studies on Di Bella multitherapy "we do not know whether
controls would have done better or worse" contrasts with the
observed response rate (<1%) and poor survival.1 We consider these
findings sound enough to prevent vulnerable cancer patients and
desperate relatives from pursuing hopeless treatments.
Head of pharmacoepidemiology unit.
D Greco, Head of epidemipology department.
S Spila-Alegiani, Biostatistician.
G Traversa, Epidemiologist.
G Benagiano, Director.
Istituto Superiore di Sanità, I-00161 Rome, Italy
P Bruzzi, Head of clinical epidemiology unit.
Istituto Nazionale Ricerca sul Cancro, I-16132 Genova, Italy
Study Group for the Di
Multitherapy Trials. Evaluation of an
unconventional cancer treatment (the Di Bella Multitherapy): results of phase II trials in Italy. BMJ
1999; 318: 224-228[Abstract/Free
- Müllner M. Di Bella's therapy:
the last word? BMJ 1999; 318: 208-209[Free Full Text].
Vita VT, Hellman S, Rosenberg SA. Cancer:
principles and practice of oncology. 5th ed. In: New York: Lippincott-Raven , 1997.
a on behalf of the Editorial
Committee of the Italian Study Group for the Di Bella Multitherapy Trials
Reply from author
and statistical adviser
EDITORIt is unfortunate that my editorial
has been misinterpreted as suggesting that the trial of the Di Bella therapy was "useless."
The BMJ does not publish a paper if its results are believed
to be invalid. It does publish papers where, although the evidence
is not up to the standards that might be desirable, the evidence is
the best available on a topic of importance. Most readers may well
be able to decide for themselves whether the present results give
strong enough evidence against the claims of the Di Bella multitherapy. In our opinion, the trial provided good
evidence that Di Bella's therapy did not match up to the unreasonable
claims made for itLiberati et al1 quote Di Bella as
claiming that he can cure 100% of cancers. We believe, however, that
this study was not of the best possible scientific quality, although
some readers adopt a more drastic point of view.2 It is a matter of opinion as to whether the
study was a phase II trial in the usual sense or not. It can be
argued that this therapy was not in the early stage of a screening
process but that a confirmatory trial was required. There certainly
are randomised and controlled phase II trials, even in cancer,
although we agree that they are frequently uncontrolled in that
clinical area. It is understandable that, in the emotional and
political situation like the one in Italy an uncontrolled study was
the most or only practical option available to test Di Bella's therapy. This
does not mean that in scientific terms an uncontrolled study would
always provide the best answer. Raschetti's
response3 implies that the current practice
of uncontrolled phase II studies cannot be questioned. Liberati et al take a more liberal view and state that
it is legitimate to challenge present methodology, but the editorial
did not make a general statement. Did it miss this opportunity of a
more general debate of advantages and disadvantages of randomised controlled
trials in similar settings? We think not: these issues were
addressed as part of the editorial, and the present discussion is a
good example of an evolving debate. The BMJ website, allowing rapid
response and flexibility, is a suitable platform, and the forum is
now open for discussion. It is time to rethink: the published last
word is gone.
Marcus Müllner, Editorial
Stephen J W Evans, Statistical adviser.
BMJ, London WC1H 9JR
A, Magrini N, Patoia
L, Pagliaro L. Missing the forest while
looking at the tree. eBMJ
www.bmj.com/cgi/eletters/318/718/208#EL3 [16 Feb 1999].
- Reyes JL. Compared to what? eBMJ
www.bmj.com/cgi/eletters/318/7178/208#EL1 [22 January 1999].
- Raschetti R, Bruzzi P, Greco D,
Maggini M, Menniti-Ippolito
F, Spila-Alegiani S, et
totally disagree with Müllner's view. eBMJ www.bmj.com/cgi/eletters/318/7178/208#EL2 [8 Feb 1999].
© BMJ 1999
Related editorials in BMJ:
NHS: possibilities for the endgame.
BMJ 1999 318: 209-210. [Full text]
Other related articles in BMJ:
Evaluation of an unconventional cancer treatment (the Di Bella multitherapy):
results of phase II trials in Italy.
Italian Study Group for the Di Bella Multitherapy Trials
BMJ 1999 318: 224-228. [Abstract] [Full text] [extra: Data Supplement]
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