Di Bella's therapy: the last word?
BMJ 1999; 318 doi: https://doi.org/10.1136/bmj.318.7178.208 (Published 23 January 1999) Cite this as: BMJ 1999;318:208All rapid responses
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Editor - The January 23rd issue of the "British Medical Journal"
published the results of the phase II trials conducted in Italy to
evaluate the anticancer treatment known as "Di Bella Multitherapy" (1). In
an accompanying editorial (2), Dr. M. Müllner argued that "the design of
the studies is flawed" and that the "the researchers should have conducted
randomised controlled trials" allocating patients "to different treatments
(or, in this case, placebo)".
We totally disagree. The criticism concerning the lack of a control
group is a major one because it promotes the idea that, even at the phase
II level, only randomised, double-blind, placebo controlled studies are
appropriate for evaluating anticancer therapies. Although in theory this
approach sounds fascinating, it is the opposite of current practice in
clinical cancer research.
Indeed, the currently adopted standard methodology in the development
of cancer treatments (3) requires that the active nature of a treatment be
ascertained by means of phase II trials, before randomised phase III
trials can even be considered. In a phase II trial randomised-control
groups are usually not needed because the endpoint most often used in
these trials is "objective response" (defined on the basis of the observed
reduction of tumour size). Objective responses seldom occur spontaneously,
and when a pre-established number of objective responses are observed
following the administration of a treatment, a cause-effect relationship
can be confidently assumed. Moreover, double-blind phase II studies are
never used in cancer trials, mainly because of the obvious inherent
toxicity of most cancer treatments; thus attempts to "blindly" evaluate a
treatment would be impossible, unless placebos capable of reproducing the
same toxic effects of the experimental anticancer treatments were
identified.
The main objective of phase II trials in cancer treatment is to
distinguish between drugs with promising activity, worthy of further
trials, and drugs the activity of which is insufficient to justify further
trials on human subjects. The necessary step of conducting phase II trials
responds to the ethical imperative of minimising, not only the number of
patients exposed to useless and potentially harmful therapies, but also
the overall time needed to identify therapies that could be potentially
useful.
Moreover, it should be stressed that the size of the study group is
estimated on the basis of a clinically interesting level (P1) which
incorporates the best available knowledge about the expected response rate
with current therapeutic alternatives for the specific type of cancer (4).
Perhaps Dr. Müllner considers phase II trials without a control group
to be useless, because they are intrinsically prone to flaws; yet it
should be emphasised that these studies are important tools in acquiring
knowledge about "activity" during the entire cycle of the development of
new drugs. In any case, "a posteriori" it is wrong to claim that in our
studies on Di Bella Multitherapy "we do not know whether controls would
have done better or worse". We know, in fact, that the observed response
rate has been close to the null effect: so how could controls have done
worse?
The fact of the matter is that, even if all of the editorial's
criticisms were well founded (which, in our opinion, they are not), in the
case of Di Bella Multitherapy, conducting a randomised trial for each of
the conditions under study would have been physically impossible, at least
in Italy. The enrolment of hundreds of patients, accepting to be randomly
assigned to Di Bella Multitherapy or a conventional treatment, in the face
of some 2000 court ordered free Di Bella treatments, simply could not have
been achieved. Given the wide coverage by mass media and the public's
great expectations of high efficacy of this new treatment would have made
it inconceivable to ask patients to agree to be assigned at random to a
treatment that might not have been Di Bella Multitherapy.
For all of these reasons following a long and painful debate, the Italian
National Oncology Committee considered the immediate start of phase II
trials to be the only ethical and feasible approach.
In the overall process of evaluating anticancer therapies, phase II
trials without a control group (yet under controlled conditions), are far
from being "studies of weak design" and respond to need to acquire a
direct, open, objective, verifiable and rapid evaluations. This represents
the real interest of patients though from an abstract, academic point of
view, the evidence obtained with the phase II Di Bella trials may be
considered "not perfect" (and it would be interesting to know when a
clinical investigation produces a perfect evidence), we consider the
findings sound enough to prevent vulnerable cancer patients and desperate
relatives from pursuing hopeless therapies.
The Editorial Committee of the Italian Study group for the Di Bella
Multitherapy Trials
R. Raschetti (Istituto Superiore di Sanità, Roma), P. Bruzzi
(Istituto Nazionale Ricerca sul Cancro, Genova), D. Greco, M. Maggini, F.
Menniti-Ippolito, S. Spila-Alegiani, G Traversa and G. Benagiano (Istituto
Superiore di Sanità, Roma)
References:
1) Italian Study Group for the Di Bella Multitherapy Trials.
Evaluation of an unconventional cancer treatment (the Di Bella
Multitherapy): results of phase II trials in Italy. BMJ 1999; 318:224-228.
2) Müllner M. Di Bella's therapy: the last word? BMJ 1999; 318: 208-
209.
3) De Vita VT, Hellman S, Rosenberg SA. Cancer: principles and
practice of oncology (5th edition). Lippincott - Raven publishers, New
York, 1997.
4) Levental BG, Wittes RE. Research methods in clinical oncology.
Raven press, New York, 1988.
Competing interests: No competing interests
What was Di Bella's therapy compared to? Nothing! It would have been
most instructive to compare Di Bella to conventional therapy as well as
untreated controls. In dismissing Di Bella as dangerous and ineffective,
are we saying that there is safe, effective treatment for such as
metastasized malignant melanoma? It appears that the research was intended
to erect a straw figure which could be easily demolished. Bad science wins
again!
Competing interests: No competing interests
Missing the forrest while looking at the tree
Missing the forrest while looking at the tree:
considerations around the Editorial on the
"Di Bella multitherapy trial"
Editor- As italian physicians deeply involved in promoting Evidence-
Based Health Care (EBHC) we read with great concern M Mullner's editorial
(1) accompanying the results of the "Di Bella multitherapy trial" (2).
We will not argue further on specific aspects of the trial as Raschetti
and co-workers have already done it, in our opinion, effectively and
exaustively (3). Rather, we challenge the "appropriateness" of an
Editorial that handled very narrowly a case where careful attention should
have been paid to the relationships between general methodology principles
of cancer trials and the social context where the "Di Bella story" took
place (4).
Mullner's editorial (1) both in its title:" The Di Bella therapy: the last
word ?" - and later on the last paragraph:".. the design of the study is
flawed….."can legitimate the wrong impression that the trials' results
published in the same issue of the BMJ was insufficient to show the lack
of antitumour activity of the Di Bella multitherapy.
It may be of interest to go back, for comparison, to the title of the
editorial that in 1982 accompanied the publication of the phase II study
of Laetrile. "Closing the book on Leatrile", stated Relman in the New
England Journal of Medicine's editorial that in 1982 accompanied the
publication of the US National Cancer Institute study which adopted the
same non-randomized design and had the same negative results as the
italian study (5).
Have general principles changed so drammatically to justify the
differences between these two editorials? We do not think so.
Mullner’s
editorial was, in our view, inappropriate as it indicates limited
"familiarity" with the world of phase II trials in oncology. We understand
that being "too familiar" with a given research field may mean "blindness"
as to its limitations (6-8), and it may indeed be perfectly legitimate to
hold the view that current standards of phase II oncology trials should be
abandoned. Unfortunately we did not find any such general statement in
Mullner's editorial whose criticisms were, all and exclusively, targeted
to the Di Bella trial. It is no wonder that it was immediately quoted and
welcomed by some Di Bella's supporters in a largely broadcasted national
TV show that took place a few days ago.
If Mullner was interested in discussing how to approach "future similar
cases" a much more appropriate contribution would have come from a more
general debate of pros and cons of randomized vs non randomized 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
randomization in situations characterized by high social and political
pressure, etc.). More specifically, we’d like to see a discussion on
whether the "uncertainty principle" can be simply put into place by ill
informed popular pressure such as the one created by Di Bella’s
supporters.
Is strict adherence to the "dogma" of randomization always the best
solution even in phase II trials where what really matters is to determine
whether a new drug or regimen has sufficient biological activity to
warrant more extensive, costly and time-consuming studies? One should not
forget that during his March 1998 hearing in front of the European
Parlament Prof Di Bella stated that he can cure 100% cancers! It is not
clear from Mullner’s editorial whether he feels that the Italian Institute
of Health trial has satisfactorily accomplished this goal.
Was all this too much for an editorial? Perhaps so, but then a Commentary
- something that the BMJ sometimes uses in addition to Editorials- would
have (probably better) served the purpose.
We wonder whether insisting that RCT are always absolutely needed for a
"perfect study" may not, in the long run, do more harm than good to the
future of EBHC.
Is the BMJ still interested in promoting a discussion around these topics?
We hope so as we believe it is legitimate to expect it from a Journal that
has so often been at the forefront of controversial issues.
Alessandro Liberati,
University of Modena and Italian Cochane Centre at Mario Negri Institute,
Milano, Italy
E-mail alesslib@tin.it.
Nicola Magrini,
Unit of Pharmacoepidemiology and Health Services Evaluation
Azienda Sanitaria Locale, Modena, Italy
Lucio Patoia,
Unit of Pharmacoepidemiology and Health Services Evaluation , Azienda
Sanitaria Locale, Modena, and
Internal Medicine and Oncologic Science Unit, Perugia, Italy
Luigi Pagliaro,
Division of Internal Medicine,University of Palermo, Italy
REFERENCES
1.Mullner M. The Di Bella's therapy: the last word? BMJ 1999; 318:209-210
2. Italian Study Goup 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;318:224-8
3.Raschetti R et al.
We disagree
eBMJ
4. Turone F.
Italy starts trials for controversial cancer treatments
BMJ 1998;316:327
5. Relman AS
Closing the book on Laetrile.
N Engl J Med 1982;299:236
6. Nicolucci A, Grilli R, Alexanian A et al
Quality, evolutyion and clinical implication of randomized control
trials on the treatment of lung cancer: a lost opportunity for meta-
analysis
JAMA 1989; 262:2101-7
7. Marsoni S, Torri V, Taiana A et al
Critical review of the quality and develpment of randomized control
trials and their influence on the
treatment of advanced epithelial ovarian cancer
Ann Oncol 1990; 1:343-53
8.Simonetti R. Liberati A, Angiolini C. Pagliaro
Treatment of hepatocellular carcinoma. A systematic review of
randomized control trials
Ann Oncol 1997; 8:117-36
Alessandro Liberati is a member of the international Advisory Board
of the BMJ.
Luigi Pagliaro is member of the "Commissione Unica per il Farmaco"
(National Drug Control Committee).
None of the Authors of this letter had an official role in the
planning and execution of the italian Di Bella trial
Competing interests: No competing interests