10 December 2014
Dafne Solera, Ph.D., Executive Editor
BMC Cancer
BioMed Central
236 Gray's Inn Road
London WC1X 8HB UK
Dear Dr. Solera:
Thank you for sending me the reviewers’ comments.
I have responded to them and have revised my manuscript, tables, and figures in accordance with their
suggestions.
Please refer to the table named ‘Response to reviewers’ as described below.
The revisions have been submitted through the Author Center.
I look forward to receiving your reply.
Yours sincerely,
Mitsukuni Suenaga
Department of Gastroenterology, Cancer Institute Hospital of the
Japanese Foundation for Cancer Research
3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
Phone Number: +081-3-3520-0111,
Fax Number: +081-3-3520-0141
Email Address: m.suenaga@jfcr.or.jp
Response to reviewers
BMC
Rev.1
Major1
Comment
Response
The authors decided to exclude from the study
Enrollment in this study was limited to patients of the wild-type
patients with a UGT1A1* 28 or UGT1A1*6
or heterozygous group for UGT1A1*28 and *6 polymorphisms
genotypes or compound heterogzygous due to
to ensure the safety of subjects based on the following: as
their higher risk of developing toxicity. This
described on page 7, line 13 Satoh et al. reported that
represents a limit for the study that should be
irinotecan could be used safely in Japanese patients of the wildacknowledged.
type or heterozygous for UGT1A1*28 and *6 polymorphisms;
In fact American and European guidelines for
and the approved dose of irinotecan for Japanese patients is
pharmacogenetic testing (ww.pharmgkb.org/
150mg/m2.
Dutch Pharmacogenetics Working Group)
recommend to use a 25% reduction of irinotecan As you pointed out, this regimen with a reduced starting dose
dose in these patients instead of not treating the of irinotecan may provide an antitumor benefit for Japanese
patients.
patients homozygous for UGT1A1*28 and *6 polymorphisms.
These patients could by the way be at higher
Thus, our study future prospectives have been additionally
chance of tumor response according to some
described in the sentence on page 22, line 11, “ We consider it
authors. I would consider to extend the study also necessary in future to determine appropriate doses irinotecan
to this class of patients, with a 25% lower starting and evaluate the efficacy and safety in Japanese patients of the
dose, at least as study future perspectives.
homozygous group for UGT1A1*28 and *6 polymorphisms.”.
Rev.1
Major2
I would perform an additional statistical analysis
to compare the outcome of patients who
discontinued first line treatment for toxicity or for
tumor progression
“The outcome of patients who discontinued first line treatment
for toxicity or for tumor progression” has been additionally
described in the paragraph starting on page 16, line 14, ” The
outcome was compared between patients who discontinued
the first-line oxaliplatin-based treatment due to progression of
the primary disease and those who discontinued it due to
adverse events: the response rate, PFS, and OS were 8.7% (95%
CI: 2.4-20.8%), 3.8 months (95% CI: 2.5-4.7 months) and 12.4
months (95% CI: 8.9-15.1 months), respectively, in the former,
while they were 11.6% (95% CI: 3.9-25.1%), 6.6 months (95% CI:
5.6-9.4 months) and 17.0 months (95% CI: 12.7-23.3 months),
respectively, in the latter.”.
Rev.1
Major3
When performing a statistical analysis to compare
PFS and OS between patients pre-treated or not
pre-treated with bevacizumab the authors should
perform a multi-variate analysis including covaraites as age, sex, PS, tumorsite,…. In the OS
analysis they should also add as a co-variate the
post-FOLFIRI/beva treatment.
The results of Cox multivariate regression analysis including age,
sex, PS, primary tumor site and pre-treatment or not pretreatment with bevacizumab as covariates have been added on
page 16, line 10, “ Additional multivariate analysis including sex,
age, ECOG PS, primary tumor site, and pre-treatment with
bevacizumab as covariates resulted in HR for OS of 3.773
(p<0.001) and for PFS of 2.237 (p=0.008).”.
Despite your recommendation, “the post-FOLFIRI/beva
treatment” was not included as a covariate in the OS analysis
because it was a time-dependent covariate and may have been
affected by the effect of treatment due to the study regimen
itself, making it difficult to interpret the result.
Rev.1
The outcome of beva pre-treated patients is quite
Discretionary worse than for not pre-treated patients and this
1
could be a limitation for the treatment of these
patients. This in my opinion should be highlighted
in the study conclusion
Investigation of possible differences in efficacy with and
without bevacizumab pre-treatment was an exploratory
objective of this study. Thus, this point is described in the
Discussion (page 20, line 1) rather than in the Conclusion.
Rev.1
In the discussion when mentioning Kras tumor
We cannot mention Nras, Braf, PI3K and PTNE loss because
Discretionary status the authors could consider also other well these markers were not determined in this study.
2
acknowledged prognostic tumor markers for CRC
as Nras, Braf status, PI3KCA and PTNE loss
Editorial
Request
1.) Kindly include the full names of the
Institutional Review Boards that approved study
- Please update your ethics statement to include
the name of the ethics committee that approved
your study.
Is it absolutely necessary to include the full names of all IRBs
that approved this study? This was a multicenter study and was
approved by the IRB of each participating institution as clearly
described in the section of Methods.