Covering letter
Dear Ms April Rada,
Regarding the paper named A comparison between type 3 excision of the
Transformation Zone by Straight Wire Excision of the Transformation Zone
(SWETZ) and Large Loop Excision of the Transformation Zone (LLETZ): a
randomized study here goes the answers to the questions pointed in your e-mail dated
October, 1st, 2014, and, following, to the questions pointed by the three referees.
Please, consider the new version of the paper submitted today and there is a remaining
question that we would like to hear from you: the 3rd referee asked to remove the Youtube
URL to procedures examples. Our intention was to, beyond the written description, give a
full picture of the procedures. We don’t know if the journal uses webappendix and had
decided to mention the URL of these Youtube videos. They were specially prepared by us
for this purpose and are not public yet. We prefer to let the decision to maintain this way, to
treat them as webappendixes or to simply remove them to you.
Editor’s comments:
-Being a prospective study, the author(s) did not mention any data about follow-up
among the independent comparisons of margin status in both groups. What were the
post-LLETZ and SWETZ cytologic and colposcopic findings? Did the author(s) quantify
the risk of persistence of malignancy with positive margins at follow-up?
The authors: This was not a prospective study. Our outcomes were only the ones that
could be measured during the procedures or in the specimen analysis. Accessing the followup data that we have now, many women showed no data on cytology or colposcopy after
the procedures, because they were sent to basic units as part of our routine care. We are
begging a new study, in which we will invite these women to reassume follow-up with us
and gather data of the 2-year follow-up period of the ones that remained in our unit to
prepare another paper addressing residual/recurrent disease and late complications like
stenosis. This one will not be ready until the next year.
-What were the exclusion criteria for this study?
The authors: As this paper is a result of the unification of two original ones, the exclusion
criteria were partially exposed in lines 151-152 and in the Figure, where they were listed
concerning each analysis (surgical outcomes analysis or margin analysis). In order to make
this clear, I’ve made some additions to the original. Please, see new attached document
(lines 154-162).
-What was the prevalence of cervical stenosis (Defined as difficulty in obtaining an
endocervical brush smear) in both groups?
The authors: As mentioned above, this was not a prospective study and this outcome will
be investigated in later papers.
-Depth of cervical tissue excised in both groups.
The authors: As said in lines 176-177, “the purpose to remove 20-25mm depth of the
endocervical epithelium”, but, in line 203, we say that we used one of two loop electrodes,
both with 20mm of height. We made some corrections to make it clearer. Please see new
attached document (lines 176-181 and 209-213).
Referee 1:
the two treatment modalities comparison is not giving the complete picture as it is
comparing only type 3 TZ. If the author had data on type 1&2 TZ the value would have
been enhanced.
The authors: Although some cases had type 2 TZ, all procedures were type 3 excisions.
There is no data on less extensive excisions because this was not our purpose.
Include more references specially rlated to complications and follow up of LLETZ.
The authors: We’d inserted a paragraph on this matter in the Introduction. Please see new
attached document (lines 105-108).
It is also not clear that the study was performed by one surgeon or more and whether
they have comparable expertise. The authors may include a line or two on surgeon’s
clinical experience on the procedures.
The authors: We’d included this information on line 177.
Only a partial picture of intra-operative complications is given. More details of
complications may be included for example, if there was any burn injury or not.
The authors: The complications are described to each method on lines 289-295 and we’d
included a few more details. Please see new attached document.
Post operative and follow up complications such as secondary haemorrhage ,infections ,
burn ,long term follow up like abortions ,preterm labour etc can be included as is an
important aspect of these type of surgical managements that can be included in the
paper.
The authors: As said above, this is not a prospective study and some of these questions
will be adressed in a future paper.
Conclusion stating both technique showed low morbidity is incorrect major surgical
complications like perforation etc with a complication rate of 5,6 % is not low or more
explanation is needed.
The authors: We had modified the phrase. Please see new attached document (lines 365367).
Minor essential revisions:
There are many mistakes in the paper the paper needs to be revised thoroughly for
language and other corrections some of the suggestions enlisted below
1.Introduction - para2 :Please check the ref no2 it is incomplete as the web page contains
information about mortality statistics and not treatment modalities.
The authors: This reference was incorrectly used. We’d excluded it.
2. Introduction para 1 : Please provide website of ref 1 if available. Please double
check with the figure 15.33.
3. Introduction - para 1-line 2 to figure regarding incidence of new cases seems to be
incorrect, please include correct figure.
The authors: The website was provided in the new document (unfortunately it’s in
portuguese). The figure is correct. It is really much higher in Brasil than in most developed
countries.
4. Give full form of abbreviations when they appear in text for the first time. Brackets
should be applied appropriately.
The authors: A full review of the text was done and some correction made. Please see new
attached document.
5 Methods- para-7 - line-1 : the term sedation may used rather then narcosis.
The authors: Done.
6. Results- Para 3- reframe line 5th to 7th. - not clear.
The authors: Done.
6. Results - para 6 correction needed in language you may replace ‘once only
‘with ‘one out of every’.
The authors: Done.
Results- para 4th - line 5- risk reduction replace with ARR (absolute riskreduction).
The authors: Done.
In discussion section first present your essential key findings then build up the discussion
and do the comparisons.
The authors: The key findings were mentioned in the new version in the first paragraph of
Discussion in order of importance. The other paragraphs were reordered concerning the
order in which the findings were mentioned.
Discussion- para 3- first line- mentioned other studies without giving the references.
The authors: These studies were mentioned above. The references were now mentioned.
Discussion: Clearly specify limitations of the study.
The authors: Done. Please see lines 378-397.
Tables give p values up to one decimal place.
The authors: Done in most cases.
Table1 No need to be given in column of total and both % or SD in single column not
relevant
The authors: They were removed in the new version.
Table 2 You can give median time of surgery
The authors: Done.
Table 2 first row blood loss Give <20 first then in next row give 20-100 – change order
The authors: Done to this row and for the other categories of comparison.
Table 3 column % cases and total of cases may be deleted .
The authors: Done.
Table 4 &5 also total and % column be deleted.
The authors: Done.
There is no need to give figure (Flow chart) you can incorporate the values in text.
The authors: The flowchart is a recommendation of Consort statement and gives an idea of
the development of the study and it’s difficulties at a glance*. Although this study, as most
trials, has a simple design, it has two analyses with different withdrawals. The flowchart
has the intention to make these things clear to the reader.
Discretionary Revisions:
Proper framing of para merge the two /three line para with the other para improve
presentation
The authors: A full revision of the text was done in order to reduce the number of
paragraphs. Please, see new version.
In methodology section define all the three types of TZ or at least give some references.
The authors: Done.
incorporated the results of type 2 TZ - also define clearly from objective and title.
The authors: By the time this trial was conducted, we were not used to use this
classification as the excision type was incorporated to International Colposcopy
Nomenclature in 2011. That’s why we treated all type 2-3 TZ with conization (type 3 TZ).
Also, the patients with type 2 TZ were too few to make any subgroup analysis. So, We’d
stated at the purpose of the study (in the final paragraph of Introduction) that the patients
had type 2 or 3 TZ, but all the excisions were type 3. Mentioning this feature in the title
will make it too long.
Referee 2:
1. study enrollment was from January 2008 - February 2012, only thereafter, in
June 2013the trial was registered at clinical trials.gov - thus making registration
senseless.....
The authors: In fact the register in ClinicalTrials.gov occurred after the recruitment of
women.
Our study is a continuation of the previous study, mentioned in the paper, by Camargo and
colleagues, including two of us. In her study, she had several difficulties that interfered
with the recruitment and prevented to reach sample size. It took place from November 1999
to December 2004. After finishing their analysis, in which was clear the lack of Power to
*
Altman 2001. The revised CONSORT statement for reporting randomized trials: explanation and
elaboration. Ann Intern Med. 2001 Apr 17;134(8):663-94.
important outcomes, we decided do reassume the protocol trying to avoid the previous
difficulties. That’s why we used the first study as a reference to estimate sample size, as
mentioned in Material and Methods’ section.
The ClinicalTrials.gov register of the previous study (NCT00995020) was first received in
June 16, 2009 and it’s last update, reporting final results, was done in October 15, 2012.
Only after that it was possible to create another register to recruit new subjects with some
protocol modifications.
Although it seems that the register was senseless, we know that no serious journal would
publish a clinical trial without a register and our register was done only when it was
possible. As ClinicalTrials.gov does accept registers after the recruitment had been
completed, we did so.
We know the fact that clinical trials registers are important to let reviewers know the
ongoing studies, but, unfortunately, it was not possible in our case.
However, the approval of ethics committee happened before the recruitment, as explained
ahead.
2. essential facts are missing in the paper (authors should adhere to CONSORT
guidelines for publishing an RCT)
mention time of enrollment
who performed the surgery (were the authors involved in the surgical
procedures=major bias!)?
The authors: We’d made a full revision of the paper and submitted in to the Consort
check-list (Altman 2001). Please, see it at the end of this letter.
Regarding who were the surgeons, it’s now described in the paper (line 177): they were,
most of the times, residents in their 2nd or 3rd year or other post-graduation students with
different level of expertise, under close supervision of two of the authors (FR and MJC).
All procedures were performed in a clinical setting as they would be done if no clinical trial
was taking place. Actually, the procedures continued to be performed after recruitment was
closed by the same categories of surgeons under the same kind of supervision, as would be
done in other clinical settings.
We don’t consider it a relevant source of bias because the primary outcome (compromised
surgical margins) was measured by a pathologist not aware of patient allocation. Other less
important outcomes could be biased, as the surgeon, knowing patient allocation could,
theoretically, decide to make the excision in more than one piece, but rather than a
methodological flaw, it would be an ethical issue.
Blood loss and geometric ambition could be biased, but the differences in these outcomes
did not reach statistical significance.
Time of surgery was measured in the same way by nurses in the operating room,
independently of which procedure was taking place, and complications were reported as
usual to all procedures.
We’d mentioned these limitations in the new version.
discuss the extremely poor incomplete resection rate in the LLETZ group (nearly 50%; in
the literature you would find appr. 20%)
The authors: Actually, as you can see in Table 3, incomplete excision, infered from
compromised margin was 16.7% for ectocervical and 27.8% for endocervical margin in the
LLETZ-cone group, and, in SWETZ group these numbers were 7.7 and 13.5%,
respectively. The percentage mentioned includes impaired margins what is really high (and
already mentioned in the original paper), but usually not mentioned in other papers. We
think that’s a feature of specimens resulting from electrosurgical excisional procedures,
systematically reported by our pathologists. In our case, although this high prevalence of
reported thermal artifact, it did not interfere with final diagnosis (Table 4). We had inserted
a few lines about this in the paper (lines 337-339) and suppressed Table 4 as requested by
another referee.
Although impaired margin is not the same as compromised one, clinically it has the same
significance to the follow-up. That’s why we decided to make one analysis adding these
two outcomes in Table 3.
provide more details about ethics approval, what year?
The authors: this study is a resumption of a previous one, trying to get over some of it’s
flaws. The protocol of the first one was approved by our institutional ethics committee
(Comitê de Ética em Pesquisa – CEP/IFF) and our national ethics commission (Comissão
Nacional de Ética em Pesquisa – CONEP) (see the two scanned documents at the end of
this letter) before their recruitment had begun. The review of the national commission was
necessary because the protocol included a foreign institution: the Coombe Women’s
Hospital (Ireland). As you can see in it’s firts lines, the protocol was presented in May, 20th,
1999, it’s approval was decided by CEP/IFF in September, 10th, 1999, and in October, 25th,
1999 by CONEP.
When we decided to reassume the protocol, CEP/IFF considered it the same protocol
because it had the same questions and the same researchers. So, they decided that it was not
necessary to submit it again.
3. check the tables for flaws: two times "ectocervical" and never "endocervical"
The authors: Sorry. This happened because of multiple editions and translation. The
corrections were made in Table 3.
Referee 3:
Minor changes:
English language: The authors will need to improve the language in several parts
of the manuscript, for example:
Abstract (background), line 310, 318-319 etc.
The authors: Sorry. As English is not our native language, we requested a full translation by
a third part that is familiar to American English. Some corrections were made following
Referee’s 1 suggestions. Abstract was revised. Also, lines 310 and 318-319 were reviewed.
Inappropriate reference-please change: line 100-reference 2.
The authors: it was removed.
Major changes:
Material and Method:
1) The study time period has not been mentioned.
The authors: It’s now mentioned.
2) Line number 174 (description of SWETZ): How was hemostasis achieved at the end of
procedure? Was ablation done in the crater of cervix?
The authors: After specimen removal, the crater was fully fulgurated with a ball electrode.
We’d inserted this information in the paper.
3) How many surgeons (colposcopists) were doing the excisional procedures and what
was the level of their experience as they had some very serious complications leading to
hysterectomy? Were the results practitioner dependent and could the experience have
introduced a bias in the results?
The authors: This information was inserted in the paper as requested by another referee.
As said above, the surgeons were, most of the times, residents in their 2nd or 3rd year or
other post-graduation students with different level of expertise, under close supervision of
two of the authors (FR and MJC). The major complication was a consequence of a less
experienced surgeon performing the procedure. All procedures were performed in a clinical
setting as they would be done if no clinical trial was taking place. Actually, the procedures
continued to be performed after recruitment was closed by the same categories of surgeons
under the same kind of supervision, as it would be done in other clinical settings.
We don’t consider it a relevant source of bias because the primary outcome (compromised
surgical margins) was measured by a pathologist not aware of patient allocation. Other less
important outcomes could be biased, as the surgeon, knowing patient allocation could,
theoretically, decide to make the excision in more than one piece, but rather than a
methodological flaw, it would be an ethical issue.
Blood loss and geometric ambition could be biased, but the differences in these outcomes
did not reach statistical significance.
Time of surgery was measured in the same way by nurses in the operating room,
independently of which procedure was taking place, and complications were reported as
usual to all procedures.
These considerations had been mentioned in the new version.
4) Please mention if patients gave you their informed consent.
The authors: Yes, we’d mentioned it in the new version.
5) Line 169: Why did you set as an objective to remove 20-25 mm in depth and not
anything less?
The authors: Actually, the objective was to remove 20mm in depth (as mentioned in the
new version), but not less than this measure, because most of the cases had a type 3
transformation zone and we followed Prendiville’s recommendation to excise this depth to
remove de endocervical disease†.
6) Line 174: 1 cm length straight electrode and 0.2 of straight section….. . My question is
0.2 of what?
The authors: Mm. It’s stated in the new version.
†
Prendiville 2003. The Treatment of grade 3 cervical intraepithelial neoplasia. In Prendiville W, Ritter J, Tatti
S, Twiggs L. Colposcopy - Management Options. London: Saunders. 2003. Pages 131-132.
7) Please remove all youtube video url addresses !!!!
The authors: That’s a question. Our intention was to, beyond the written description, give
a full picture of the procedures as recommended in the Consort guidelines in reporting
clinical trials. We don’t know if the journal uses webappendix and had decided to mention
the URL of these Youtube videos. They were specially prepared by us for this purpose and
are not public yet. We prefer to let the decision to maintain this way, to treat them as
webappendixes or to simply remove them to the editors.
Results:
1) Table 4 and Table 5 do not need to be included. The description in the text is enough.
The authors: Done.
Discussion:
1) Line 313: how was cervicometry performed?
The authors: It was done using a hysterometer. It’s in the new version.
2) Line 328: Please provide any literature reference for the shrinkage of tissue samples
after fixation with formalin.
The authors: It was included. See reference 18.
3) The discussion section has 12 paragraphs. Please limit the number of paragraphs
by integrating some in one paragraph.
The authors: we tried to be more concise. Please see new version.
4) What are the strengths and limitations of your study? Please clarify.
The authors: As requested by other referee, it was clearly shown in the new version.
5) I would like to have seen a comment on the depth of cones and oncologic versus
obstetric risk as some patients in the study were of reproductive age. Perhaps a subgroup
analysis for women under 45 years old would have been useful to see if SWETZ is also a
superior technique for them without leading to such deep cones and therefore exposing
them to a future obstetric risk.
The authors: This is an important matter. It’s now mentioned at Introduction. However, all
women had a type 3 excision of the TZ because they had type 3 TZ (except for a few ones),
even the ones under 45 years-old. Such subgroup analysis would be fruitless and without
enough Power to demonstrate any difference.
6) If the mean depth between SWETZ and LLETZ is the same (see Table 2), how do the
authors explain the finding of less positive endocervical margins with SWETZ
technique? Have these results been adjusted for specimen fragmentation as a
confounder?
The authors: That is a central question. If the two procedures remove the same amount of
tissue, why one of them offers less compromised margins? Probably, as you point out, other
factors are responsible for fewer diagnoses of compromised margins in the SWETZ arm.
Fragmentation is one of them. The other can be thermal artifact, that was different between
groups, favoring SWETZ, but without statistical significance. Because of the absence of
statistical association between allocation and thermal artifact in this sample, we could not
test the hypothesis of confounding. Concerning fragmentation, which was related to
allocation, none of the remaining cases after exclusions had more than one segment in the
SWETZ arm, impairing the analysis of confounding to this factor. We’d added this point to
the Discussion.
7) Do you have any information on the cytology follow-up of these patients treated with
SWETZ versus LLETZ at 6 months and 12 months to see if the failure rate is the same or
different?
The authors: As mentioned above, this was not a prospective study. Our outcomes were
only the ones that could be measured during the procedures or in the specimen analysis.
Accessing the follow-up data that we have now, many women showed no data on cytology
or colposcopy after the procedures, because they were sent to basic units as part of our
routine care. We are beginning a new study, in which we will invite these women to
reassume follow-up with us and gather data of the 2-year follow-up period of the ones that
remained in our unit to prepare another paper addressing residual/recurrent disease and late
complications like stenosis. This one will not be ready until the next year.
References:
Only 11 references have been provided. I would have expected many more in such an
article. Please provide more references (if any) on the following:
1) NETZ versus LLETZ (line 121)
2) CKC versus LLETZ (line 182)
The authors: Although there are many studies addressing these comparisons, we’d decided
to use information from metanalysis, because of the level of evidence of such articles.
Concerning NETZ, we’d decided to mention only randomized clinical trials, but we had
added three other observational references to the new version.
Hoping to had answered all questions in a satisfactory way,
Yours,
Fábio Russomano.
Checklist of Items To Include When Reporting a Randomized Trial‡
Paper Section and
Topic
Title and abstract
Introduction
Descriptor
Reported on lines …
How participants were allocated to interventions
3 and 54
Background
Methods
Scientific background and explanation of rationale.
95-139
Participants
Eligibility criteria for participants and the settings
and locations where the data were collected.
Precise details of the interventions intended for each
group and how and when they were actually
administered.
Specific objectives and hypotheses.
Clearly defined primary and secondary outcome
measures and, when applicable, any methods used to
enhance the quality of measurements (e.g., multiple
observations, training of assessors).
How sample size was determined and, when
applicable, explanation of any interim analyses and
stopping rules.
143-153
Method used to generate the random allocation
sequence, including details of any restriction (e.g.,
blocking, stratification).
Method used to implement the random allocation
sequence (e.g., numbered containers or central
telephone), clarifying whether the sequence was
concealed until interventions were assigned.
Who generated the allocation sequence, who enrolled
participants, and who assigned participants to their
groups.
Whether or not participants, those administering the
interventions, and those assessing the outcomes were
blinded to group assignment. If done, how the
success of blinding was evaluated.
Statistical methods used to compare groups for
primary outcome(s); methods for additional analyses,
such as subgroup analyses and adjusted analyses.
170-175
Flow of participants through each stage (a diagram is
strongly recommended). Specifically, for each group
report the numbers of participants randomly
assigned, receiving intended treatment, completing
the study protocol, and analyzed for the primary
outcome. Describe protocol deviations from study as
planned, together with reasons.
Dates defining the periods of recruitment and followup.
Figure
Interventions
Objectives
Outcomes
Sample size
Randomization
Sequence generation
Allocation
concealment
Implementation
Blinding (masking)
Statistical methods
176-200
131-135
201-217; 226-233
163-169
170-175
170-175
220-221
234-241
Results
Participant flow
Recruitment
‡
248
Altman DG et al. The revised CONSORT statement for reporting randomized trials: explanation and
elaboration. Ann Intern Med. 2001 Apr 17;134(8):663-94.
Baseline data
Numbers analyzed
Outcomes and
estimation
Ancillary analyses
Adverse events
Discussion
Interpretation
Generalizability
Overall evidence
Baseline demographic and clinical characteristics of
each group.
Number of participants (denominator) in each group
included in each analysis and whether the analysis
was by “intention to treat.” State the results in
absolute numbers when feasible (e.g., 10 of 20, not
50%).
For each primary and secondary outcome, a
summary of results for each group and the
estimated effect size and its precision (e.g., 95%
confidence interval).
Address multiplicity by reporting any other analyses
performed, including subgroup analyses and adjusted
analyses, indicating those prespecified and those
exploratory.
All important adverse events or side effects in each
intervention group.
257-269 and Table 1
Interpretation of the results, taking into account
study hypotheses, sources of potential bias or
imprecision, and the dangers associated with
multiplicity of analyses and outcomes.
Generalizability (external validity) of the trial
findings.
General interpretation of the results in the context of
current evidence.
320-367; 372-397
254-256
248-250
270-317; 375-377
289-295
404-406
400-404