Correspondence
IN REPLY: We agree with Dr Atkin’s description of the conclu- Angela R. Bradbury and Olufunmilyo I. Olopade
sions from the report of the International Workshop on Screening for
Breast Cancer. 1 The statement reporting a mortality benefit described
for women older than age 40 years is supported by a meta-analysis that
included several randomized trials and specifically evaluated benefits
for women age 40 to 49 years.2 We regret that this additional reference
was not attached to this statement. We agree with Dr Atkins that there
remains uncertainty regarding long-term radiation exposure from
mammography, particularly in high-risk women who begin screening
earlier than age 40 years. As we hoped to convey, we feel that alternative
imaging modalities, such as breast magnetic resonance imaging, which do
not involve radiation exposure may ultimately replace mammography in
individualized programs for breast cancer prevention.3
■ ■ ■
Should Subgroup Analysis of
Randomized Clinical Trials Have a
Direct Impact on Clinical Practice?
TO THE EDITOR: The recent publication in the Journal of Clinical
Oncology of the randomized clinical trial performed by the European
Organisation for Research and Treatment of Cancer Chronotherapy
Group did raise the issue of the clinical reliability of sex subgroup
analysis in clinical trials.1 The primary end point of this large cooper-
ative multicentric phase III trial was 2-year survival, and the sample
size was then calculated to determine a 10% survival difference (from
30% to 40%) in favor of the chronomodulated arm (superiority trial).
Patients were stratified according to performance status, liver involve-
ment, and center. In the abstract (which has to be considered the most
rapid source for a take-home message), the authors conclude that
“both regimens achieved similar median survival times more than 18
months with an acceptable toxicity” and that “chronomodulated
schedule produced a survival advantage in men.”1 A controversy exists
regarding the correct interpretation of subgroup analysis of random-
ized clinical trials, given that the risk to provide misinterpretation
could lead to wrong treatment guidelines. Although the trial is ade-
quately powered for its main end point, it is not able to detect differ-
ences in efficacy between subgroups with adequate power. Moreover,
the sex analysis lead to both a significantly better effect for chrono-
therapy in men, but also a significantly better effect for standard
chemotherapy in women, and this is not mentioned in the abstract
conclusion.1 Actually, in the article a balanced discussion about the
subgroup issues is present. Although the multivariate analysis should
protect over baseline prognostic factors’ interaction (when adequately
studied), the list of the patients’ characteristics, which the authors
decided to consider for subgroup analysis, should be reported in the
article as well. A number of pieces of specific literature have been
published regarding the risk of the erroneous interpretation of sub-
group analyses and the most common conclusions are those analyses
can be overinterpreted and may lead to suboptimal patient care.2 A
sort of methodologic recommendation for subgroup analyses and
their interpretation has been recently produced by Brookes et al3,4—
only previously planned subgroup analyses should be performed; any
trial should be powered taking into account the prespecified subgroup
analyses; notwithstanding all these considerations, any specific analy-
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Copyright © 2007 by the American Society of Clinical Oncology. All rights reserved.
Department of Medicine, Section of Hematology/Oncology, University of
Chicago, Chicago, IL
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.
REFERENCES
1. Fletcher SW, Vlack W, Harris R, et al: Report of the International Workshop
on Screening for Breast Cancer. J Natl Cancer Inst 85:1644-1656, 1993
2. Hendrick RE, Smith RA, Rutledge JH III, et al: Benefit of screening
mammography in women aged 40-49: A new meta-analysis of randomized
controlled trials. J Natl Cancer Inst Monogr 22:87-92, 1997
3. Bradbury A, Olopade OI: The case for individualized screening recommen-
dations for breast cancer. J Clin Oncol 24:3328-3329, 2006
sis is affected by several bias, and the conclusions need to be softened.
In absence of strong common evidence, this is an hypothesis-
generating exercise for further specifically addressed randomized trial.
The risk in subgroup analysis to provide errors has been also quanti-
fied, and seems to be not related to the patient sample size.2
Correctly, Giacchetti et al1 performed a sex-treatment interaction
analysis, and this interaction resulted significantly at the multivariate
analysis. This result is interesting. However, the observed survival
differences by sex could be due to imbalance in unmeasured baseline
prognostic factors (demographic and/or molecular characteristics).
According to article’s results, “Patients’ characteristics according to
sex were well balanced except for age and PS. Age ⱕ 50 years and PS of
1 or 2 were more frequent in women than in men (21% v 14%; and
59% v 46.5%, respectively). After stratification for age and PS, the
interaction tests were not found significant (P ⬎ .1).” If not due to
imbalance, the difference of outcome between males and females
could be a true difference or could be due to statistical chance alone,
especially because not only sex but a long list of patient characteristics
has been analyzed. So, in our opinion, more caution should be used
when authors decide to put the results of secondary, exploratory
analyses in the abstract of an article.
Emilio Bria
Department of Medical Oncology, Regina Elena National Cancer Institute,
Rome, Italy
Massimo Di Maio
National Cancer Institute, Naples, Italy
Federica Cuppone, Cecilia Nisticò, and Francesco Cognetti
Department of Medical Oncology, Regina Elena National Cancer Institute,
Rome, Italy
Diana Giannarelli
Biostatistics, Regina Elena National Cancer Institute, Rome, Italy
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.
REFERENCES
1. Giacchetti S, Bjarnason G, Garufi C, et al: Phase III trial comparing 4-day
chronomodulated therapy versus 2-day conventional delivery of fluorouracil,
leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal
cancer: The European Organisation for Research and Treatment of Cancer
Chronotherapy Group. J Clin Oncol 24:3562-3569, 2006
2. Lagakos SW: The challenge of subgroup analyses–reporting without distort-
ing. N Engl J Med 354:1667-1669, 2006
605
 Correspondence
3. Brookes ST, Whitley E, Peters TJ, et al: Subgroup analyses in randomized
controlled trials: Quantifying the risks of false-positives and false-negatives.
Health Technol Assess 5:1-56, 2001
■ ■ ■
IN REPLY: In their Conclusion, Bria et al emphasize that more
caution is needed in reporting the effects of sex on survival and toler-
ability that were derived from the European Organisation for Research
and Treatment of Cancer phase III trial 05963.1 Their comment is
based on the controversy regarding the generation and the interpreta-
tion of subgroups analyses. Indeed, we strongly believe that the ab-
stract serves the purpose of delivering the most clinically relevant
findings with honesty. This is why we wrote, “In women, the risk of an
earlier death on ChronoFLO4 was increased by 38% compared with
FOLFOX2. . . .In men, the risk of death was decreased by 25% on
ChronoFLO4. . . .” So, we agree with Bria et al that the abstract is the
most rapid source for a take home message, but we mean the whole
abstract, not the conclusion only.
For treatment interaction tests, we considered factors related to pa-
tient characteristics (age, sex, WHO performance status [PS] 0 v ⬎ 0),
baseline hematologic and biochemical data (leukocyte, granulocyte and
platelet counts, alkaline phosphatases, gamma glutamyltransferase,
transaminases, carcinoembryonic antigen, and CA 19-9), and tumor
characteristics (primary site, Duke’s stage, liver involvement, number of
metastatic sites). At the exception of sex, no other factor displayed any
strongly significant interaction with the delivery schedule (P ⬍ .01).
As mentioned in the article, an imbalance between women and men
was found for PS and age. After stratification for age and PS, the interac-
tion tests were not found significant (P ⬎ .1) because of a lack of power,
but presented the same trend for a higher efficacy in men treated by
infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chrono-
modulated FLO4) in the different age and PS strata. Indeed, the difference
between men and women could be a true difference or statistical chance.
However, in a Cox proportional hazards model a sex x schedule
interaction term was found significant in presence of PS, age,
number of metastatic sites, and percentage of liver involvement
(Table 4).1 This supports that sex effect is a true difference.
Lagakos recommends being cautious with subgroups analysis.
He advises to perform planned subgroups analysis, appropriate anal-
ysis with interaction tests, and to give magnitude of the treatment
difference with corresponding confidence interval instead of the P
value.2 Bria et al acknowledge that we followed these recommenda-
tions, including interaction test and Forrest plot of interaction be-
tween schedule and sex. However, we could not plan the subgroups
analyses since such effect was largely unknown when we initiated this
trial. Thus, a consistent impact of sex on chemotherapy toxicity or
patient outcome started to arise in the literature once accrual to our
trial was completed.3
We feel that clinical research should aim at discovering new
prognostic and predictive factors, new treatments, better treatment
schedules, and new strategies. Through the use of chronomodulated
delivery of chemotherapy, our group first demonstrated the activity of
oxaliplatin against colorectal cancer,4 then the relevance of liver me-
tastases surgery for the survival of patients with downstaged previously
unresectable metastases.5,6 Both of these findings initially encountered
great scepticism, yet they now have profoundly modified the current
treatment of colorectal cancer worldwide. Thus we share the opinion
of Lagakos that avoiding any presentation of subgroup analysis be-
606
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Copyright © 2007 by the American Society of Clinical Oncology. All rights reserved.
4. Brookes ST, Whitely E, Egger M, et al: Subgroup analyses in randomized
trials: Risks of subgroup-specific analyses; power and sample size for the
interaction test. J Clin Epidemiol 57:229-236, 2004
cause of their history of being overinterpreted would have been a steep
price to pay. Rather than advocating for a ready change in clinical
practice which could imply the delivery of FOLFOX (2-hour infusion
of oxaliplatin and leucovorin on day 1 and 2-hour infusion of leuco-
vorin on day 2, which intercalculated 22-hour constant infusion
rate of fluorouracil on days 1 and 2) in women and that of chrono-
modulated FLO4 in men as standard best practice, we proposed to
investigate the mechanisms through which optimal scheduling of
chemotherapy differs between men and women. Indeed, increased
attention is currently being paid by the medical and scientific commu-
nity to the role of sex for treatment toxicities and patient outcome in
cancer and other diseases.
Our correspondence (Bria et al and our reply) emphasizes the need
for studies testing new chemotherapy and chronotherapy associations
with targeted molecules and a priori planning of effects of sex or other
factors identified in subgroup analyses. Already a sex dependency of tox-
icity and survival has been recently found by our group for two separate
studies, including one with cetuximab.7,8 We are currently developing
new protocols aimed at the determination of the best schedule in women
with metastatic colorectal cancers. Moreover, to better understand the
mechanism of the sex effect, translational research projects of molecular
clock determinants of optimal schedule are also ongoing.
The challenge ahead of us is the administration of tailored chro-
notherapy (ie, the determination of the right drugs at the right doses
and at the right time in the right patient).
Sylvie Giacchetti
INSERM U 776 and Hôpital Paul Brousse, Assistance Publique-Hôpitaux de
Paris, Paris, France
Thierry Gorlia
Data Center, European Organisation for Research and Treatment of Cancer,
Brussels, Belgium
Carlo Garufi
Istituto Regina Elena, Roma, Italy
Francis Lévi
INSERM U 776, University Paris Sud, and Hôpital Paul Brousse, Assistance
Publique-Hôpitaux de Paris, Paris, France
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.
REFERENCES
1. Giacchetti S, Bjarnason G, Garufi C, et al: Phase III trial comparing 4-day
chronomodulated therapy versus 2-day conventional delivery of fluorouracil,
leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal
cancer: The European Organisation for Research and Treatment of Cancer
Chronotherapy Group. J Clin Oncol 24:3562-3569, 2006
2. Lagakos SW: The challenge of subgroup analyses–reporting without distort-
ing. N Engl J Med 354:1667-1669, 2006
3. Neugut AI, Jacobson JS: Women and lung cancer: Gender equality at a
crossroad? JAMA 296:218-219, 2006
4. Lévi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical
trial with 5-fluorouracil, folinic acid and oxaliplatinum using an ambulatory
multichannel programmable pump: High antitumor effectiveness against meta-
static colorectal cancer. Cancer 69:893-900, 1992
JOURNAL OF CLINICAL ONCOLOGY