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Correspondence

Findings from the meta-analysis


by the Early Breast Cancer Trialists
Collaborative Group (EBCTCG)1 seem
to have settled the debate about the
role of postmastectomy radiotherapy
in patients with low axillary nodal
burden. In this study, 1 patients
with breast cancer with one to
three positive nodes were reported
to benefit from postmastectomy
radiotherapy in terms of locoregional
recurrence, overall recurrence, and
disease-specic mortality.
However, after 20 years, radiotherapy was not associated with
improved overall survival; a survival
gain from breast cancer of 79% only
translated into a non-significant
3% gain in overall survival. 1 This
nding continues to suggest that in
patients with a low nodal burden,
other causes of death, particularly
cardiovascular mortality, might
counteract the gains of breast cancer
survival conferred by radiotherapy.2
Loss of these gains is problematic in
populations with a high prevalence
of risks for cardiovascular disease,
such as in southeast Asia,3,4 and in
resource-restricted settings with low
technologically advanced facilities
for radiation (heartlung sparing
treatment). In these settings, the
balance between the benefits and
harms of radiotherapy in terms of
overall survival could be tipped to the
opposite direction.
In the era of personalised
medicine, indications for adjuvant
treatment should not only be based
on cancer-specific characteristics,
but also should take into account
the cardiovascular risk profile of
patients and the heartlung sparing
capabilities of treatment with
radiation. Development of rules for
clinical predictions incorporating
breast cancer-specific factors 5 and
cardiovascular risk profiles, ethnic
origin, and radiation techniques could
be the way forward in prediction of
the absolute overall survival gains
conferred by adjuvant radiotherapy.
We declare no competing interests.

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*Nirmala Bhoo-Pathy,
Jean-Philippe Pignol,
Helena M Verkooijen
ovenjjay@gmail.com
Julius Centre University of Malaya, Faculty of Medicine,
50603 Kuala Lumpur, Malaysia (NB-P); Department of
Radiation Oncology, Erasmus MC Cancer Institute,
Netherlands (J-PP); and Imaging Division, University
Medical Center Utrecht, Utrecht, Netherlands (HMV)
1

EBCTCG (Early Breast Cancer Trialists


Collaborative Group). Eect of radiotherapy
after mastectomy and axillary surgery on
10-year recurrence and 20-year breast cancer
mortality: meta-analysis of individual patient
data for 8135 women in 22 randomised trials.
Lancet 2014; 383: 212735.
Harris EER, Correa C, Hwang W, et al. Late
cardiac mortality and morbidity in early-stage
breast cancer patients after breast-conservation
treatment. J Clin Oncol 2006; 24: 410006.
Reid CM, Yan B, Wan Ahmad WA, et al. The Asia
Pacic Evaluation of Cardiovascular Therapies
(ASPECT) collaborationimproving the
quality of cardiovascular care in the Asia Pacic
Region. Int J Cardiol 2014; 172: 7275.
Selvarajah S, Hani J, Kaur G, et al. Clustering
of cardiovascular risk factors in a
middle-income country: a call for urgency.
Eur J Prev Cardiol 2013; 20: 36875.
Mukesh MB, Duke S, Parashar D, Wishart G,
Coles CE, Wilson C. The Cambridge
post-mastectomy radiotherapy (C-PMRT)
index: a practical tool for patient selection.
Radiother Oncol 2014; 110: 46166.

Authors reply
Our meta-analysis 1 of individual
patient data from trials in women
given mastectomy and axillary
clearance to at least level ll showed
that radiotherapy reduced mortality
from breast cancer by 20% in women
with one to three positive lymph
nodes (rate ratio [RR], irradiated
vs not, 080, 95% CI 067095;
2p=001) and by 13% in women with
at least four positive lymph nodes
(RR 087, 95% CI 077099; 2p=004).
Little reason of how radiotherapy
works exists to think that this
treatment for breast cancer has any
appreciable abscopal effect and so,
as Ismail Jatoi suggests, these results1
showed that a proportion of the
deaths avoided by radiotherapy would
have arisen from cells localised within
the areas targeted by radiotherapy
(ie, the chest wall and, for most trials,
the regional lymph nodes).
We agree with Rajni Sethi and
colleagues that doctors who use these
results1 in clinical practice need to take

account of the low absolute risk of


recurrence in women being considered
for postmastectomy radiotherapy
today compared with the women who
participated in these trials. However,
the proportional reductions in risk that
we noted could reasonably be applied
to women today who have between
one and three positive nodes if they
have appreciable risk of recurrence. We
also agree with Nirmala Bhoo-Pathy
and colleagues that clinical prediction
rules incorporating both breast
cancer-specic and other factors might
be helpful in the future.
We noted that in any node positive
disease, about one death due to
breast cancer was avoided in the
20 years after radiotherapy for every
15 breast cancer recurrences of any
type (ie, locoregional or distant)
avoided during the rst 10 years. This
results differs from our estimate of
one death due to breast cancer avoided
by 15 years for every four recurrences
avoided in the first 10 years in
the trials of radiotherapy after
breast-conserving surgery.2 However,
the women with node positive disease
in the trials of postmastectomy
radiotherapy generally had more
advanced cancers and more extensive
radiotherapy than did the women
in the trials of radiotherapy after
breast-conserving surgery.
Information about recurrence
available for analysis in these
trials is the time to first recurrence
and whether that recurrence was
locoregional or distant in the patient.
This availability of such information
enables estimations to be made of the
size of the effect of radiotherapy on
breast cancer recurrence of any type
(ie, locoregional or distant) of cancer.
However, women who are at a high risk
of locoregional recurrence (eg, because
they have more aggressive cancers)
are also at an increased risk of distant
recurrence, so rates of locoregional
and distant recurrence are correlated,
and additional analyses cannot
remove this correlation. Radiotherapy
substantially reduces the rate of local
www.thelancet.com Vol 384 November 22, 2014

Correspondence

We declare no competing interests.

Early Breast Cancer Trialists


Collaborative Group
bc.overview@ctsu.ox.ac.uk
Early Breast Cancer Trialists Collaborative Group
Secretariat, Clinical Trial Service Unit, Oxford
OX3 7LF, UK
1

EBCTCG (Early Breast Cancer Trialists


Collaborative Group). Eect of radiotherapy
after mastectomy and axillary surgery on
10-year recurrence and 20-year breast cancer
mortality: meta-analysis of individual patient
data for 8135 women in 22 randomised trials.
Lancet 2014; 383: 212735.
EBCTCG (Early Breast Cancer Trialists
Collaborative Group). Eect of radiotherapy
after breast-conserving surgery on 10-year
recurrence and 15-year breast cancer death:
meta-analysis of individual patient data for
10 801 women in 17 randomised trials. Lancet
2011; 378: 170716.
Department of Error. Lancet 2014; 384: 1848.

www.thelancet.com Vol 384 November 22, 2014

EMAs transparency
seems to be opaque
The European Medicines Agency (EMA)
has now adopted its policy about
access to clinical trial data,1 more than
a year after the release of the rst draft
for public consultation.2 Although
intended to boost accountability
and trust in medical research, the
policy does not seem to meet such
expectations. 3 The main concern
is with respect to which data and
documents can be accessed. The policy
applies only to dossiers submitted
through the centralised procedures
from 2015. Pharmacovigilance
data are not deemed in the policy.
Before publication, the holder of
marketing authorisation could edit
clinical overviews, study summaries,
and reports to delete commercially
confidential informationdisclosure
of such information might undermine
a companys economic interest.
This redaction process could be
assumed to only apply to trade
secrets (eg, formulae, processes,
and molecules), but might include
advice offered by non-European
regulatory authorities, plans for clinical
development, or protocols agreed
with non-European authorities and
marketers. The proprietary nature
of any assay developed for analysis
of a given product is a pretext not
to release pharmacodynamic and
pharmacokinetic data, as such
information might give competitors
a substantial advantage. Even
information that helps to make
the calculation for sample size
(eg, estimates of endpoint variability,
screening, and retention rates) might
be condential.
Misinterpretation of what is meant
by commercially confidential could
make it possible to conceal key
information, for instance, negative
results from a clinical trial or safety
alerts that could, if published,
possibly tarnish the image of a
product, and therefore the owners
economic interests.

Postponement of the release of


individual patient data to a so-called
second phase is disappointing.
Present marketing authorisation
applications do not regularly
include individual patient data
for subsequent scientific review
(not even by the EMA). The risk of
re-identification, however negligible
for anonymised or de-personalised
data, and the boundaries of a
patients informed consent seem to
offer another reason for restriction of
access to data. If a company informs
study participants that their personal
data from the commercial trial will
not be used in any possible future
research, this would prevent access
to this information.
The EMAs policy was expected
to mainly pursue the interests of
patients and public health and
at the same time, preserve the
industrys intellectual property rights
and protecting patients privacy.
Confidential information about
drugs seems to keep being protected
by hiding of clinical data and not
only with patents. Clinical data are
public goods because they belong
rst to trial participants, researchers,
medical sta, but also to taxpayers
who fund most of the investigators,
infrastructures, and facilities included
in clinical research.

Mark Thomas/Science Photo Library

recurrence; therefore, many patients


in the group allocated to radiotherapy
who would otherwise have had first
a local and then a distant recurrence
had their local recurrence prevented
or at least delayedand hence their
distant recurrence came first. This
increase in the number of women
whose distant recurrence came first
is a well recognised eect and should
not be mistaken for an adverse eect
of radiotherapy on the rate of distant
recurrence. Radiotherapy actually
decreases the rate of distant recurrence,
as is shown by its favourable eect on
breast cancer mortality. This point is
discussed further in the appendix of our
2014 report.1
By contrast, analyses of the number
of women with local recurrence as
a first event will suggest favourable
results for patients only if radiotherapy
really does reduce the rate of local
recurrence, and can therefore be
informative. Analyses of local
recurrence are, however, affected by
the association between local and
distant recurrence so decreases in
the number of women with local
recurrence usually slightly exaggerates
the eect of radiotherapy on the rate
of local recurrence of breast cancer.
The appendix of our Article1 has been
corrected3 to include some additional
analyses of local recurrence; all analyses
previously provided are unchanged.

We thank Judith Baggott for editing our letter.


We declare no competing interests.

*Rita Banzi, Vittorio Bertele,


Silvio Garattini
rita.banzi@marionegri.it
IRCCS-Istituto di Ricerche Farmacologiche Mario
Negri, Milan 20156, Italy
1

European Medicines Agency. European


Medicines Agency policy on publication of
clinical data for medicinal products for
human use. 2014. www.ema.europa.eu/
docs/en_GB/document_library/
Other/2014/10/WC500174796.pdf (accessed
Oct 11, 2014).
European Medicines Agency. Draft policy 70:
publication and access to clinical trial data.
June 2013. www.ema.europa.eu/docs/en_GB/
document_library/Other/2013/06/
WC500144730.pdf (accessed Oct 11, 2014).
Banzi R, Bertele V, Demotes-Mainard J, et al.
Fostering EMAs transparency policy.
Eur J Intern Med 2014; 25: 68184.

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