By Fran Boyle
Breast News: Newsletter of the NHMRC National Breast Cancer Centre
Vol. 6, No. 1, Spring 2000
While the world's first randomised trial to demonstrate a survival advantage for
patients on high-dose chemotherapy stem cell support is a fake, Dr Fran Boyle
argues that clinical trials are still the best way to improve treatment for
women with breast cancer.
In January this year, a team of American oncologists went to Johannesburg, South
Africa to audit records from Professor Werner Bezwoda's randomised trial 1, 2
which purported to compare two cycles of high-dose chemotherapy with stem cell
support, with standard adjuvant chemotherapy (CAF) in patients with high-risk
primary breast cancer.
While Professor Bezwoda's study differed in strategy from United States and
European trials that employ a single high-dose cycle after standard chemotherapy
3, there was considerable interest in replicating his approach. In an area of
oncology awash with phase II studies, and many disappointments, this was the
only randomised trial to demonstrate a survival advantage for patients on the
high-dose arm.
In February Professor Bezwoda acknowledged he had "committed a serious breach of
scientific honesty and integrity" by misrepresenting the results of the trial 4.
The following month the Lancet published an auditor's report 5 and revealed the
study had not been reviewed or approved by an Institutional Ethics Committee.
Professor Bezwoda has subsequently admitted that control patients received a
different chemotherapy protocol than that reported at American Society of
Clinical Oncology (ASCO) (Cyclophosphamide, mitoxantrone and vincristine rather
than CAF) and that he had falsified this because a previous trial in metastatic
disease had been criticised on the basis that the same control arm was
considered substandard therapy.
But this development should not alter the clinical practice guideline
recommendations which state that there is insufficient evidence to justify the
use of high-dose chemotherapy outside of clinical trials. If anything, these
findings strengthen the practice recommendations.
The auditors have recommended that the Bezwoda "trial" should not be used as a
basis for further studies 5. This was their brief from the US National Cancer
Institute. The University of Witwatersrand has fired Bezwoda and claims that
this is "misconduct by an individual, not an institution" 6.
The research community has taken a broader view of this event. In an
accompanying commentary 7, Lancet Editor, Richard Horton, questions the role of
Bezwoda's colleagues and the Institutional Ethics Committee (IEC) processes in
Johannesburg, given the publicity this trial has attracted in the past year. But
this is not just an internal South African problem. Why did noone reviewing
these abstracts for oral presentation at prestigious international meetings
question that a study as large as this had a single author (ASCO), or that the
numbers of patients in each arm in the abstract do not add up to the total
(European Society for Clinical Oncology)?
In seeking possible solutions, Horton notes that it is not current practice to
submit source data for review prior to acceptance of an abstract or paper.
Implementing this routinely would paralyse the publication system. Given the
priority that evidence-based medicine places on randomised trials, an
international register has been proposed 8, in order to allow closer scrutiny of
these "gold standard" activities.
Single-institution, investigator-sponsored studies are probably the most
vulnerable to the kind of difficulties uncovered here, and could be targeted for
external audit resources. Strengthening support for the largely voluntary
activities of IECs in reviewing earlier phase trials should also be considered;
education, administrative support and identification of conflicts of interest
will be required, but will cost.
Nevertheless, it would be a disaster if public confidence in the ethical conduct
of large international and Australian cooperative group studies in 2000 was
undermined by this event. Violations of this magnitude would be impossible in
that setting. The recently completed IBCSG study 15 tests a similar approach to
that of Bezwoda, and its data and conclusions will be intensely scrutinised well
before publication.
Improving the care of women with breast cancer requires a commitment to clinical
trials. The field of high-dose chemotherapy demonstrates amply that randomised
trials have been required to assess the true role of this expensive and
potentially toxic approach that offered so much hope in earlier phase trials 3.
Bezwoda wanted it to work. We all did. We may have to look elsewhere for a
strategy, but in the end, unless its penicillin, we will still need a randomised
trial to give the answer.
Source :
http://pandora.nla.gov.au/nph-arch/2000/H2000-Sep -1/http://www.nbcc.org.au/pages/info/resource/nbccpubs/brnews/00spr/spr4.htm