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PEER REVIEW HISTORY
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are provided with free text boxes to elaborate on their assessment. These free text comments are
reproduced below.
ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Association between ischemic bowel syndromes and androgendeprivation therapy in prostate cancer patients: a retrospective
cohort study
Chung, Chi-Jung; Chiang, I-Ni; Huang, Chao-Yuan; Pu, YeongShiau; Chang, Chao-Hsiang; Muo, Chih-Hsin; Wang, Ruey-Yun;
Young, Tai-Horng
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Nishi Karunasinghe
University of Auckland
New Zealand
18-Aug-2016
The content of this manuscript is interesting and will add value to the
scientific literature. Most Western and some Eastern studies indicate
that prostate cancer management with ADT has implications on
cardiovascular risk, diabetes, stroke etc. On the contrary, this study
from Taiwan shows no such risk with ADT except a marginal trend
on ischemic bowel syndrome (IBS).The strength of this study is due
to data collection from a population (n=7160) based on the
Longitudinal Health Insurance Database for Catastrophic Illness
Patients in Taiwan.
I have very little knowledge to comment on the statistical analyses of
this manuscript. The following comments are therefore made
assuming statistical testing is appropriate.
However, this paper requires language edition (some of which are
mentioned in the attached document). Please have a thorough check
of language throughout the paper.
There are a few other technical issues with this manuscript that
needs correction or explanation before this manuscript is published.
The content of this manuscript is interesting and will add value to the
scientific literature. Most Western and some Eastern studies indicate
that prostate cancer management with ADT has implications on
cardiovascular risk, diabetes, stroke etc. On the contrary, this study
from Taiwan shows no such risk with ADT except a marginal trend
on ischemic bowel syndrome (IBS).The strength of this study is due
to data collection from a population (n=7160) based on the
Longitudinal Health Insurance Database for Catastrophic Illness
Patients in Taiwan.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
I have very little knowledge to comment on the statistical analyses of
this manuscript. The following comments are therefore made
assuming statistical testing is appropriate.
However, this paper requires language edition (some of which are
mentioned below).
Please have a thorough check of language throughout the paper.
There are a few other technical issues with this manuscript that
needs correction or explanation1. When men treated with the LHRH agonists were retrieved from the
database, did you eliminate those treated with combined androgen
blockade (that is men receiving both LHRH agonists and antiandrogens).If not if there were anti-androgen treatments within the
LHRHa treatment regimes, it is not completely correct to claim that
the outcome was based on the LHRHa. If combined LHRHa and antiandrogens(AA) were used by some, while others had LHRHa or AA
as single treatments, it is better to look at all three regimens
separately.
2. Please note that you have categorised leuprorelin (ATC code
L02AE02), goserelin (L02AE03), and triptorelin (L02AE04) as LHRH
antagonists. They are LHRH agonists not antagonists.
3. You have not stratified the data for tobacco smoking as mentioned
in your text. Please note that this could have implications in your
analysis. Studies indicate that those exposed to tobacco smoke and
carrying a genotype that is prominent among Asian communities
(and found in a lower frequency among Caucasians) viz the aldoketo reductase 1C3 (AKR1C3) rs12529 G allele is associated with
lower serum PSA levels indicating that they may also have lower
1
androgen levels . Therefore, ADT effects could be different between
smokers and non-smokers. Is there any way you can collect tobacco
smoking data for both ADT and non-ADT groups and make
corrections to the current analysis?
4. Please check whether the mean age recorded for both groups in
your study are comparable with statistics from the rest of the world. If
not could it be that men in your location are diagnosed with prostate
cancer at a later age? Mean age at prostate cancer diagnosis in
2
National statistics in New Zealand is around 68y . Median Age of
Cancer Patients at Diagnosis during 2009-2013 according to the
SEER statistics is 66y for all races from the US.
(http://seer.cancer.gov/csr/1975_2013/results_merged/topic_med_ag
e.pdf#search=mean+age+at+prostate+cancer+diagnosis)
It is a possibility that late age prostate cancer diagnosis at your
location could be masking the ADT effects as the risk of
cardiovascular, stroke and diabetes increases with age.
Abstract line 27
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with newly diagnosis of- Change to newly diagnosed with
We enrolled 7160 male patients- If you have extracted data from a
database, not correct to say that you enrolled patients.
ICD-9-CM 185 - Better to note somewhere in the manuscript that this
is the same as 2016 ICD-10-CM C61
Even after adjusting potential risk factors- Change to- Even after
adjusting for potential risk factors.
Page 8 Line 56We collected 24464 male patients- Do you mean to say- We
collected medical records of.....
Page 9- Line 7
Patients with following exclusion were excluded- Do you mean to say
'Patients with following criteria were excluded.
Page 9- Line 7-10
1. with androgen deprivation therapy (ADT) before the date for
prostate cancer diagnosis
How can patients receive ADT before prostate cancer diagnosis?
Page 9- Line 16-18
5. with follow-up year < one year.
Please make it clearer. Is it <1y following prostate cancer diagnosis?
Page 9 22-24hormone-releasing hormone (LHRH) antagonists containing
leuprorelin (ATC code L02AE02), goserelin (L02AE03), and
triptorelin (L02AE04).None of these are LHRH antagonists. They are all LHRH agonists.
Page 9 Line 97
HNI program or the end of 2011 which first coming.- Do you mean to
say ' HNI program or the end of 2011 whichever came first.
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Page 10, Line 10All statistical analyses were performed to use SAS software version
9.4- Do you mean to say all statistical analyses were performed
using SAS software version 9.4
Page 10- line 12
The significant level was set p < 0.05 at two-tailed test. Do you mean
to say 'The statistical significant level was set at p < 0.05 with twotailed testing?
Page 10- Lines 12-24- The difference of age group (< 65, 65-69, 7074, 75-79, and 80+ years-old), and baseline comorbidity between
ADT and non-ADT group was used chi-square test. The different of
mean age and the duration between ADT treatment and prostate
cancer was used t-test. Please rewrite this part. It is not clear
enough.
Page 11 Line 4We all selected 7160- Correct as We selected 7160....
Page 11 Line 11-16There were no differences of age and the duration between the date
for ADT treatment and prostate cancer between ATD cohort and
non-ADT cohort.
Do you refer to the duration between the date of ADT treatment and
the date of prostate cancer diagnosis for the ADT group? What was
taken as the duration for the non-ADT group? Is it the time difference
between prostate cancer detection and the time you screened the
database.
Page 11 Line 16-21Please note thatIt is quite unusual for Caucasian men receiving ADT to have a lower
3
cardiovascular risk than the non-ADT group . However, among Asian
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4
men it is controversial .
5
ADT is usually associated with diabetes . However your data is
showing results contrary to what is observed with the normal
Caucasian groups. This is interesting but needs more explanation
and possibly a correction for tobacco exposure as mentioned before.
Page 11 line 361000 person-years respective- change to respectively
Page 11 lines 50-53
Patients with late ADT treatment was a higher IBS incidence than
non-ADT cohort
(1.23 vs. 0.89 per 1000 person-years), but….- Change was to show
#
In table 3 what is meant by next to rate?
Page 14 line 56Change IBD to IBS
1.
Karunasinghe N, Lange K, Han D, et al. Androgen pathway
related gene variants and prostate cancer association in Auckland
men Curr Pharmacogenomics Person Med 2013; 11 (1): 22-30.
2.
Wang A, Obertova Z, Brown C, et al. Risk of fracture in men
with prostate cancer on androgen deprivation therapy: a populationbased cohort study in New Zealand. BMC Cancer 2015; 15: 837.
3.
Tsai HK, D'Amico AV, Sadetsky N, Chen MH, Carroll PR.
Androgen deprivation therapy for localized prostate cancer and the
risk of cardiovascular mortality. J Natl Cancer Inst 2007; 99(20):
1516-24.
4.
Teoh JY, Ng CF. Cardiovascular risk after androgen
deprivation therapy for prostate cancer: an Asian perspective. Int
Urol Nephrol 2016; 48(9): 1429-35.
5.
Wang H, Sun X, Zhao L, Chen X, Zhao J. Androgen
deprivation therapy is associated with diabetes: Evidence from metaanalysis. J Diabetes Investig 2016; 7(4): 629-36.
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Handoo Rhee
Department of Urology
Princess Alexandra Hospital
Brisbane, Australia
30-Aug-2016
Thank you kindly for your invitation to review this article. In this
population based retrospective cohort study, the risk of ischemic
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bowel syndrome and associated risk factors have been reviewed
against the use of androgen deprivation therapy. Control group was
determined randomly. ADT cohort was less likely to have important
co-morbidities such as CAD, diabetes, stroke and hypertension. The
difference may be secondary to case selection for the use of ADT e.g. patients with significant co-morbidities may have not been
prescribed ADT in anticipation of metabolic adverse effects. This
places patients without ADT with higher pre-test probability of having
IBS. This article would benefit from propensity score matching or
adjustments for co-morbidities. There is a need for minor correction
of english.
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
James Hanley
McGill University
Canada
26-Sep-2016
The motivation for studying this outcome is not all that well
described.
The follow-up ends 5 years ago. In view of the small no.of IBS
events, and wide CIs for hazard ratios, the data should be brought
up to date.
The statistical analysis is a bit rudimentary, and suspect in a few
places. I know we should not make much of small differences in
Table 1, especially as the n's are large, but the p-value for age does
not fit with the reported means and SDs.
The stage composition and treatments received are not reported.
These would give a better sense of what the samples look like. E.G.
How many had radiation? surgery?
The numbers of deaths from Pr Ca and other causes would also fill
out the picture.
As would a description of when the person years start for each
compared group.
And the timing of the IBS events vis a vis the start of ADT , and in
relation to how long it was given, would help too.
It is not enough to just report in the abstract that there was no sig,
difference in IBS rates when the numbers (25 and 35 ) are so small
and the CIs so wide. One needs to say what rate ratios are being
ruled in/out.
I would not expect hazards to be proportional. The increased risk
would not be immediate, would it?
The additional no.s of events would help tighten the CIs and allow
more subdivisions.
The English writing is quite poor, and would need to be carefully
edited. In several places I was guessing, and did not understand.
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VERSION 1 – AUTHOR RESPONSE
To Reviewer#1:
Thank you for reviewing our manuscript and the excellent remarks. The manuscript has been revised
point-by-point according to your suggestions and comments. The major revisions are written in red
font for your convenience.
Comments:
1. When men treated with the LHRH agonists were retrieved from the database, did you eliminate
those treated with combined androgen blockade (that is men receiving both LHRH agonists and antiandrogens).If not if there were anti-androgen treatments within the LHRHa treatment regimes, it is not
completely correct to claim that the outcome was based on the LHRHa. If combined LHRHa and antiandrogens (AA) were used by some, while others had LHRHa or AA as single treatments, it is better
to look at all three regimens separately.
Reply: Thank you for your comment. Among 24464 PC patients, only 257 (1.05%) patients received
LHRH as single treatments; thus, we could not disregard patient with combined anti-androgens. In the
revised manuscript, we considered considering anti-androgens as a risk factor and further adjusted
this factor in multivariable models or in the combination analysis. However, in the combination
analysis, a small sample size of IBS event was considered, and we opted not to show the table of
combination analysis in the final version. Therefore, we revised the information on anti-androgens in
Table 1 and added sentences to discuss the issue in the Results and Discussion section.
Table X1. Distribution of antiandrogen between prostate cancer with and without ADT treatment
ADT
n = 7160 Non-ADT
n = 7160
n % n % p-value
Antiandrogen 6743 94.2 5513 77.0 <0.0001
Chi-square and t-test
Table X2. Incidence and hazard ratio for IBS in different ADT treatment compared to non-ADT
patients
ADT Antiandrogen n Event no. Person–years Rate IRR (95% CI) p-value Adjusted
HR (95% CI) p-value
No No 1647 8 10088 0.79 1.00 1.00
No Yes 5513 27 29075 0.93 1.71 (0.53–2.58) 0.69 1.00 (0.45–2.23) 0.99
Only Orchiectomy No 225 1 1006 0.99 1.25 (0.16–10.0) 0.83 1.02 (0.13–8.27) 0.98
Only LHRH No 186 0 793 0.00 NA NA
Both No 6 0 21 0.00 NA NA
Only Orchiectomy Yes 1529 6 6568 0.91 1.15 (0.40–3.32) 0.79 1.05 (0.36–3.05) 0.93
Only LHRH Yes 4524 17 1775 0.96 1.21 (0.52–2.79) 0.66 1.24 (0.53–2.91) 0.62
Both Yes 690 1 2796 0.36 0.45 (0.06–3.61) 0.45 0.46 (0.06–3.71) 0.47
Adjusted for age, CAD, diabetes, stroke, hypertension, hyperlipidemia, lower leg fracture or surgery,
asthma, chronic obstructive pulmonary disease, prostatectomy, and radiotherapy
2. Please note that you have categorized leuprorelin (ATC code L02AE02), goserelin (L02AE03), and
triptorelin (L02AE04) as LHRH antagonists. They are LHRH agonists not antagonists.
Reply: Thank you for your reminders. We checked and revised the words in the revised manuscript.
3. You have not stratified the data for tobacco smoking as mentioned in your text. Please note that
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
this could have implications in your analysis. Studies indicate that those exposed to tobacco smoke
and carrying a genotype that is prominent among Asian communities (and found in a lower frequency
among Caucasians) viz the aldo-keto reductase 1C3 (AKR1C3) rs12529 G allele is associated with
lower serum PSA levels indicating that they may also have lower androgen levels1. Therefore, ADT
effects could be different between smokers and non-smokers. Is there any way you can collect
tobacco smoking data for both ADT and non-ADT groups and make corrections to the current
analysis?
Reply: The lack of data on tobacco smoking in the Longitudinal Health Insurance Database in Taiwan
is a critical limitation. Asthma and COPD were considered risk factors for ischemic bowel syndrome;
therefore, we used asthma and COPD variables as proxy indicators for tobacco smoking and further
adjusted them in the multivariable models. Finally, the association between ADT therapy and IBS risk
remains insignificant even when we included tobacco smoking-related asthma and COPD adjustment
in the models.
4. Please check whether the mean age recorded for both groups in your study are comparable with
statistics from the rest of the world. If not could it be that men in your location are diagnosed with
prostate cancer at a later age? Mean age at prostate cancer diagnosis in National statistics in New
Zealand is around 68y2. Median Age of Cancer Patients at Diagnosis during 2009-2013 according to
the SEER statistics is 66y for all races from the US.
(http://seer.cancer.gov/csr/1975_2013/results_merged/topic_med_age.pdf#search=mean+age+at+pr
ostate+cancer+diagnosis)
It is a possibility that late age prostate cancer diagnosis at your location could be masking the ADT
effects as the risk of cardiovascular, stroke and diabetes increases with age.
Reply: The average age in 24464 male PC patients was about 74 years, which fitted the previous
studies as follows:
Chung, S. D., Liu, S. P., Lin, H. C., Wang, L. H. Increased risk of pneumonia in patients receiving
gonadotropin-releasing hormone agonists for prostate cancer. PLoS One 2014; 9 (6): e101254.
Chen, C. H., Tzai, T. S., Huang, S. P., Wu, H. C., Tai, H. C., Chang, Y. H., Pu, Y. S. Clinical outcome
of Taiwanese men with metastatic prostate cancer compared with other ethnic groups. Urology 2008;
72 (6): 1287-1292.
5. Abstract line 27
with newly diagnosis of- Change to newly diagnosed with
Reply: We revised the sentence in the Abstract section according to your suggestion.
We enrolled 7160 male patients- If you have extracted data from a database, not correct to say that
you enrolled patients.
Reply: We revised the sentence in the Abstract section according to your suggestion.
ICD-9-CM 185 - Better to note somewhere in the manuscript that this is the same as 2016 ICD-10-CM
C61
Reply: Thank you for your suggestions. We revised and added ICD-10-CM C61 in the Methods
section of the revised manuscript.
Even after adjusting potential risk factors- Change to- Even after adjusting for potential risk factors.
Reply: Thank you for your suggestions. We revised the sentence in the Abstract section.
6. Page 8 Line 56
We collected 24464 male patients- Do you mean to say- We collected medical records of.....
Reply: Thank you for your reminders. We revised and rewrote the sentence in the Methods section of
the revised manuscript.
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7. Page 9- Line 7
Patients with following exclusion were excluded- Do you mean to say 'Patients with following criteria
were excluded.
Reply: Thank you for your reminders. We revised the word in the Methods section of revised
manuscript.
8. Page 9- Line 7-10
1. with androgen deprivation therapy (ADT) before the date for prostate cancer diagnosis. How can
patients receive ADT before prostate cancer diagnosis?
Reply: Thank you for your comment. Clinically, patients are coded with prostate cancer in the
database after prostate biopsy yielded pathological results stating prostate adenocarcinoma. ADT
would be given to patients with advanced or metastatic disease. However, certain conditions must be
met before we would provide ADT before prostate biopsy. For example, if the patients received bone
fracture surgery and bone pathology suggested possible prostate cancer, ADT may be prescribed to
the patient before prior to prostate biopsy. Patients with extremely high PSA (>100 ng/dL) and positive
image findings would also possibly receive ADT before the definite pathology report and diagnosis
coding. To prove the relationship between cause and effect, we set up the criteria to exclude the
patients receiving ADT prior to prostate cancer diagnosis.
9. Page 9- Line 16-18
5. with follow-up year < one year.- Please make it clearer. Is it <1y following prostate cancer
diagnosis?
Reply: Thank you for your reminders. We revised this sentence in the Methods section of the revised
manuscript.
10. Page 9- Line 22-24
hormone-releasing hormone (LHRH) antagonists containing leuprorelin (ATC code L02AE02),
goserelin (L02AE03), and triptorelin (L02AE04).- None of these are LHRH antagonists. They are all
LHRH agonists.
Reply: Thank you for your reminders. We checked and revised the word terminology in the Methods
section of the revised manuscript.
11. Page 9- Line 97
HNI program or the end of 2011 which first coming.- Do you mean to say ' HNI program or the end of
2011 whichever came first.
Reply: Thank you for your reminders. We revised the sentence in the Methods section of the revised
manuscript.
12. Page 10- Line 10
All statistical analyses were performed to use SAS software version 9.4- Do you mean to say all
statistical analyses were performed using SAS software version 9.4
Reply: Thank you for your reminders. We revised the sentence in the Methods section of the revised
manuscript.
13. Page 10- Line 12
The significant level was set p < 0.05 at two-tailed test. Do you mean to say 'The statistical significant
level was set at p < 0.05 with two-tailed testing?
Reply: Thank you for your suggestions. We revised the sentence in the Methods section of the
revised manuscript.
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14. Page 10- Line 12-24
The difference of age group (< 65, 65-69, 70-74, 75-79, and 80+ years-old), and baseline comorbidity
between ADT and non-ADT group was used chi-square test. The different of mean age and the
duration between ADT treatment and prostate cancer was used t-test. Please rewrite this part. It is not
clear enough.
Reply: Thank you for your suggestions. We revised these sentences in the Methods section of the
revised manuscript.
15. Page 11- Line 4
We all selected 7160- Correct as We selected 7160....
Reply: Thank you for your suggestions. We revised the sentence in the Results section of the revised
manuscript.
16. Page 11- Line 11-16
There were no differences of age and the duration between the date for ADT treatment and prostate
cancer between ATD cohort and non-ADT cohort.
Do you refer to the duration between the date of ADT treatment and the date of prostate cancer
diagnosis for the ADT group? What was taken as the duration for the non-ADT group? Is it the time
difference between prostate cancer detection and the time you screened the database.
Reply: Thank you for your suggestions. As you described, the non-ADT group was frequency
matched according to age and index year of receiving ADT treatment in the ADT group. Therefore,
the duration varies between prostate cancer diagnosis and the time we screened the database.
17. Page 11- Line 16-21
Please note thatIt is quite unusual for Caucasian men receiving ADT to have a lower cardiovascular risk than the nonADT group3. However, among Asian men it is controversial4.
ADT is usually associated with diabetes5. However your data is showing results contrary to what is
observed with the normal Caucasian groups. This is interesting but needs more explanation and
possibly a correction for tobacco exposure as mentioned before.
Reply: Thank you for your comment. All diagnosis of vascular disease, such as CAD, diabetes,
stroke, and other, was based on the data retrieved during the timing of prostate cancer diagnosis.
Thus, all comorbidity is more likely to be the underlying diseases of these patients. During data
analysis, we evaluated these variables as risk factors and adjusted them in the multivariable models.
18. Page 11- Line 36
1000 person-years respective- change to respectively
Reply: Thank you for your suggestions. We revised the word in the Results section of the revised
manuscript.
19. Page 11- Line 50-53
Patients with late ADT treatment was a higher IBS incidence than non-ADT cohort (1.23 vs. 0.89 per
1000 person-years), but….- Change was to show
Reply: Thank you for your suggestions. We revised the word in the Results section of the revised
manuscript.
In table 3 what is meant by # next to rate?
Reply: Thank you for your reminder. We added the footnote and deleted the symbol # in Table 3.
20. Page 14- Line 56
Change IBD to IBS
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Reply: Thank you for your suggestions. We changed the acronym in the Discussions section of the
revised manuscript.
To Reviewer#2:
Thank you for reviewing our manuscript and the excellent remarks. The manuscript has been revised
point-by-point according to your suggestions and comments. The major revisions are written in red
font for your convenience.
Comments:
1. Thank you kindly for your invitation to review this article. In this population based retrospective
cohort study, the risk of ischemic bowel syndrome and associated risk factors have been reviewed
against the use of androgen deprivation therapy. Control group was determined randomly. ADT
cohort was less likely to have important comorbidities such as CAD, diabetes, stroke and
hypertension. The difference may be secondary to case selection for the use of ADT e.g. patients with
significant comorbidities may have not been prescribed ADT in anticipation of metabolic adverse
effects. This places patients without ADT with higher pretest probability of having IBS. This article
would benefit from propensity score matching or adjustments for comorbidities. There is a need for
minor correction of English.
Reply: Thank you for your comments. Although we did not use propensity score matching, we tried
our best to use age matching between ADT and non-ADT groups and adjustments for all potential
comorbidities, such as CAD, CVD, DM, HT, hyperlipidemia, and lower leg fracture or surgery, in the
longitudinal health insurance database. Therefore, the statistical results should be acceptable. In
addition, we had the revised manuscript edited by Knowledge Growth Support
(http://www.kgsupport.com). We uploaded the certification in the attachment file field.
To Reviewer#3:
Thank you for reviewing our manuscript and the excellent remarks. The manuscript has been revised
point-by-point according to your suggestions and comments. The major revisions are written in red
font for your convenience.
Comments:
1. The motivation for studying this outcome is not all that well described.
Reply: Thank you for your suggestions. We revised and added a paragraph to explain the rationale of
our study purpose.
2. The follow-up ends 5 years ago. In view of the small no. of IBS events, and wide Cis for hazard
ratios, the data should be brought up to date.
Reply: Thank you for your comments. The present data (2000–2011) is the most recent version to link
the incidence of IBS. We revised and added the sentences to discuss this issue in the Discussion
section.
3. The statistical analysis is a bit rudimentary and suspect in a few places. I know we should not make
much of small differences in Table 1, especially as the n's are large, but the p value for age does not
fit with the reported means and SDs.
Reply: Thank you for your reminder. We rechecked the data and revised the typing error in the
revised Table 1.
4. The stage composition and treatments received are not reported. These would give a better sense
of what the samples look like. E.G. How many had radiation? Surgery?
Reply: Thank you for your suggestions. The lack of clinical data on stage and grade in the
Longitudinal Health Insurance Database in Taiwan is a critical limitation. We discussed this fact in the
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Limitation section. In addition, we reanalyzed and revised the data on treatments, including
prostatectomy and radiotherapy in all revised tables. Even when these treatments were considered,
no significant association between ADT therapy and IBS risk was observed in our results.
5. The numbers of deaths from Pr Ca and other causes would also fill out the picture.
Reply: Thank you for your suggestions. We revised and added the information on the death of cohort
patients in the Discussions section.
6. As would a description of when the person years start for each compared group.
Reply: Thank you for your suggestions. We revised and added the information on the characteristics
of cohort patients in the Results section.
7. And the timing of the IBS events vis a vis the start of ADT, and in relation to how long it was given,
would help too.
Reply: Thank you for your suggestions. We revised and added the information on the characteristics
of cohort patients in the Results section.
8. It is not enough to just report in the abstract that there was no sig, difference in IBS rates when the
numbers (25 and 35) are so small and the CIs so wide. One needs to say what rate ratios are being
ruled in/out.
Reply: Thank you for your suggestions. Considering the word numbers requested in the Abstract
section, we revised and added the discussion in the Discussion section of the revised manuscript.
9. I would not expect hazards to be proportional. The increased risk would not be immediate, would
it?
Reply: Thank you for your suggestions. We used the scaled Schoenfeld residuals to test the
assumption of Cox proportional hazard, and the result showed no violation (p = 0.87).
10. The additional no.s of events would help tighten the CIs and allow more subdivisions.
Reply: Thank you for your suggestions. We showed the possible conditions for all study population in
the follow-up:
Event ADT
n = 7160 Non-ADT
n = 7160
None 3682 (51.4%) 4579 (64.0%)
IBS 25 (0.35%) 35 (0.49%)
Death 3453 (48.2%) 2546 (35.6%)
Duration between ADT to IBS occurred, year 3.48 (SD = 1.99) 4.24 (SD=2.48)
The assumption of Cox proportional hazard was not violated, and we tried to further reanalyze the
association between ADT treatment and IBS incidence by considering competing risk for death. The
result listed as follows remained insignificant. We revised and added the discussion in the Discussion
section.
Table 2. Incidence and hazard ratios for IBS in ADT cohort compared with those of non-ADT cohorts
ADT Non-ADT
Event no. Person–
years Rate Event no. Person–
Years Rate IRR (95% CI) p Adjusted
HR (95% CI) p Adjust
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SHR (95% CI) p
Overall 25 28959 0.86 35 39163 0.89 0.97 (0.58–1.61) 0.89 1.08 (0.64–1.82) 0.78 0.82 (0.49–1.38)
0.46
Adjusted for age, CAD, diabetes, stroke, hypertension, hyperlipidemia, lower leg fracture or surgery,
asthma,
chronic obstructive pulmonary disease, prostatectomy, and radiotherapy
Rate, per 1000 person–years
SHR, subdistribution hazard ratio in Cox proportional hazard regression with competing risk for death
adjusted for age, CAD,
diabetes, stroke, hypertension, hyperlipidemia, lower leg fracture or surgery, asthma, chronic
obstructive pulmonary disease,
prostatectomy, and radiotherapy
11. The English writing is quite poor, and would need to be carefully edited. In several places I was
guessing, and did not understand.
Reply: Thank you for your comment. We had the revised manuscript edited by Knowledge Growth
Support (http://www.kgsupport.com). We uploaded the certification in the attachment file field.
VERSION 2 – REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Nishi Karunasinghe
University of Auckland,
New Zealand
19-Nov-2016
I have no expertise to comment on the statistical aspects of this
manuscript.
Although the current status of the manuscript made me tick yes
boxes for most of the questions, this manuscript needs further
improvement before being published.
I attach my comments and once the authors work on these issues
and improve the standard of this manuscript, editors can decide on
its acceptability.
The reviewer also provided a file with additional comments. Please
contact the publisher for full details.
REVIEWER
REVIEW RETURNED
Handoo Rhee
Department of Urology
Princess Alexandra Hospital
Australia
09-Nov-2016
GENERAL COMMENTS
Revisions made, accept.
VERSION 2 – AUTHOR RESPONSE
To Reviewer#1:
Thank you for reviewing our manuscript and the excellent remarks. The manuscript has been revised
point-by-point according to your suggestions and comments. The major revisions are written in red
font for your convenience.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Comments:
1. Although COPD has a positive association with tobacco asthma occurs both in smokers and non
smokers. Therefore, be careful to consider both Asthma and COPD as proxies to tobacco smoking.
Reply: Thank you for your comment. Our previous reply was not very precise. In fact, we only used
the COPD variables as proxy indicators for tobacco smoking and adjusted the variable in the
multivariable models. We discussed this topic in the previous version (Discussion section on page
17). Meanwhile, asthma was confirmed by previous literature as a risk factor for bowel syndrome
(Introduction section on page 7). Therefore, we considered this variable in Table 1. However, we did
not observe any significant difference in asthma distribution between the ADT and non-ADT cohorts.
2. It is a possibility that late age prostate cancer diagnosis at your location could be masking the ADT
effects as the risk of cardiovascular, stroke and diabetes increases with age. This is the reason that it
is useful that you discuss the age difference in prostate cancer diagnosis between Caucasian
populations and yours.
Reply: Thank you for your reminders. We revised and added discussions in the Discussion section of
the revised manuscript.
3. Page 8 Line 56
We collected 24464 male patients- Do you mean to say- We collected medical records of..... I cannot
see this fixed.
Reply: Thank you for your comment. We revised the sentence in the Methods section of the revised
manuscript.
In the original version: “We collected 24464 male patients with prostate cancer diagnosis [The
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), 185] in
2000-2008.”
In the first revised version: “We approved 24464 male patients that were newly diagnosed with PC by
using the code of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM), 185 or C61 in ICD-10-CM during 2000–2008 in LHID-CIP database.”
In the present revised version: “We recruited 24464 male patients newly diagnosed with PC by
reviewing their medical records and using the code of International Classification of Diseases, Ninth
Revision, Clinical Modification (ICD-9-CM), 185 or C61 in ICD-10-CM for 2000–2008 in the LHID-CIP
database.”
4. Page 11- Line 11-16
There were no differences of age and the duration between the date for ADT treatment and prostate
cancer between ATD cohort and non-ADT cohort.
Do you refer to the duration between the date of ADT treatment and the date of prostate cancer
diagnosis for the ADT group? What was taken as the duration for the non-ADT group? Is it the time
difference between prostate cancer detection and the time you screened the database. This is not yet
clear enough.
Reply: Thank you for your reply. We answer this question through the following illustration. We first
selected the ADT group and acquired the index year of ADT treatment. Based on the same index
year, we chose the non-ADT users who were PC patients but were not treated with ADT. Therefore,
the duration was between the date of PC diagnosis and index year of ADT treatment for both cohorts.
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5. It is not yet corrected in Table 3.
Reply: Thank you for your comment. We carefully rechecked and revised the footnote of Table 3.
Additional remarks1. We evaluated medication history in our series, and 94.2% of the patients with ADT had used
antiandrogens. Also note that 77% on no ADT also received antiandrogens.
Reply: Thank you for your suggestions. We added this information in the Discussion section of the
revised manuscript.
2. In men, higher testosterone is inversely correlated to low-density lipoprotein cholesterol (LDL) and
associated with lower high-density lipoprotein cholesterol (HDL) amount 20. ADT increase both HDL
and total cholesterol21.
The above can be edited asIn a population based study of men with no diabetes, higher testosterone is inversely correlated to
with low-density lipoprotein cholesterol (LDL) and positively associated correlated with lower
highdensity lipoprotein cholesterol (HDL) amount 20. Meanwhile, ADT is known to increase both HDL
and total cholesterol in prostate cancer patients21. This means that androgen suppression with ADT
has a variable influence on HDL testosterone correlation compared to that of the non-diabetic men.
Reply: Thank you for your suggestions. We revised this sentence in the Discussion section of the
revised manuscript.
3. O’Farrell et al. assessed the risk of thromboembolic disease in PC patients undergoing ADT and
noticed the incidence of deep vein thrombosis and pulmonary embolism would increase with
prolonged ADT usage and suggested that only men with a relevant indication should receive systemic
ADT.
Also add the fact that O'Farrell study also showed higher risk of thrombosis on those switched from
antiandrogen therapy to GNRH, although your analysis has not looked into that fact.
Reply: Thank you for your suggestions. We revised this sentence in the Discussion section of the
revised manuscript.
4. Longstreth et al. also found that acute large bowel ischemia is independently associated with
COPD (adjusted odds ratio 3.13)10.
Your data shows that non-ADT group had a significantly higher COPD% indicating COPD could be
confounding the different IBS rates among the two groups compared. Add this to your discussion.
Reply: Thank you for your suggestions. The control selection in the study of Longstreth et al. differs
from that of the present work. The controls of Longstreth et al. were derived from the general
population. By contrast, the controls of the present study were PC patients. In general, PC patients
with good clinical conditions received ADT treatment. Therefore, the ADT group in the present study
attained a lower prevalence of CAD, diabetes, stroke, hypertension, and COPD. We considered these
factors in the multivariate regression models. We added this sentence in the Discussion section of the
revised manuscript (Discussion section on page 16).
5. Second, all PC patients in our study possessed an average age of 74 years and exhibited high
mortality during follow-up (48.2% in ADT group and 35.6% in non-ADT group).
Are these mortality rates significantly different? It is possible that due to the high mortality rates
observed in the ADT group, IBS recording would have been affected in that group. It is recorded that
prostate cancer patients carrying a certain genotype (AKR1C3 rs12529 CC) has increased mortality
risk after being treated with ADT (Yu et al 2013 PMID 23359804 ) and do not sufficiently benefit by
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ADT and retain prostate cancer symptoms after ADT (Karunasinghe et al 2016 PMID:27485119). This
could mean that your analysis had confounding effects of IBS recording due to genetic variability. You
can add these to the discussion.
Reply: Thank you for your suggestion. We modified this sentence in the Discussion section of the
revised manuscript (Discussion section on page 17).
This document still needs language edition at places.
1. line 47 page 9
PC patients were grouped into two groups based on receiving ADT treatment: ADT and non-ADT
comparison group. This can be better written asPC patients were stratified into two groups based on those who have received ADT or not.
Reply: Thank you for your suggestions. We revised this sentence in the Discussion section of the
revised manuscript.
2. page 10 line 56- Not yet clear enough.
Reply: Thank you for your suggestions. We revised this sentence in the Methods section of the
revised manuscript.
3. page 11 line 47-53- Not yet clear enough.
Reply: Thank you for your suggestion. We revised this sentence in the Result section of the revised
manuscript.
4. page 12 line 24-32- Not clear
Reply: Thank you for your suggestion. We revised this sentence in the Discussion section of the
revised manuscript.
5. page 13-14
We evaluated medication history in our series, and 94.2% of the patients with ADT had used
antiandrogens. This can be better written as- We evaluated medication history in our records, and
94.2% of the patients who were on ADT also received antiandrogens.
Reply: Thank you for your suggestion. We revised this sentence in the Discussion section of the
revised manuscript.
Downloaded from http://bmjopen.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Association between ischaemic bowel
syndromes and androgen deprivation therapy
in patients with prostate cancer: a
retrospective cohort study
I-Ni Chiang, Chao-Yuan Huang, Yeong-Shiau Pu, Chao-Hsiang Chang,
Chih-Hsin Muo, Chi-Jung Chung, Ruey-Yun Wang and Tai-Horng Young
BMJ Open 2017 7:
doi: 10.1136/bmjopen-2016-012950
Updated information and services can be found at:
http://bmjopen.bmj.com/content/7/2/e012950
These include:
References
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