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BMJ 1999;318:1073 ( 17 April )

Letters

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 adviser

Randomised controlled trials may not always be absolutely needed

EDITOR---We 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 took place.2

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 these topics.

Alessandro Liberati, Professor of biostatistics

Università di Modena, Centro per la Valutazione della Efficacia della Assistenza Sanitaria Modena, Italy Email
alesslib@tin.it

Nicola Magrini, Unit head

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


  1. Müllner M. Di Bella's therapy: the last word? BMJ 1999; 318: 209-210[Free Full Text]. (23 January.)
  1. Turone F. Italy starts trials for controversial cancer treatment. BMJ 1998; 316: 327[Free Full Text].
  1. Italian 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 Full Text]. (23 January.)
  1. Relman AS. Closing the book on laetrile. N Engl J Med 1982; 299: 236.
  1. 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].

Criticism ignores standard methodology of cancer treatments

EDITOR---In 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.

Raschetti, Head of pharmacoepidemiology unit. 
D Greco, Head of epidemipology department. 
Menniti-Ippolito, Biostatistician
Spila-Alegiani, Biostatistician
G Traversa, Epidemiologist
Benagiano, Director. 

Istituto Superiore di Sanità, I-00161 Rome, Italy

Bruzzi, Head of clinical epidemiology unit

Istituto Nazionale Ricerca sul Cancro, I-16132 Genova, Italy


  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[Abstract/Free Full Text]. (23 January.)
  1. Müllner M. Di Bella's therapy: the last word? BMJ 1999; 318: 208-209[Free Full Text]. (23 January.)
  1. De 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

EDITOR---It 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 it---Liberati 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 registrar
Stephen J W Evans, Statistical adviser
BMJ, London WC1H 9JR


  1. Liberati 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].
  1. Reyes JL. Compared to what? eBMJ www.bmj.com/cgi/eletters/318/7178/208#EL1 [22 January 1999].
  1. Raschetti R, Bruzzi P, Greco D, Maggini M, Menniti-Ippolito F, Spila-Alegiani S, et al. We totally disagree with Müllner's view. eBMJ www.bmj.com/cgi/eletters/318/7178/208#EL2 [8 Feb 1999].

© BMJ 1999

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The NHS: possibilities for the endgame.

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[Full text]  

Other related articles in BMJ:

Papers
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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