Reviewer's report
Title:Should women with chronic pelvic pain have adhesiolysis? Results and
lessons learnt from a prematurely discontinued randomized controlled trial (RCT)
of adhesiolysis versus diagnostic laparoscopy.
Version:2Date:23 December 2013
Reviewer: David Wiseman
Reviewer's report:
General comments
Thank you for inviting me to review this important paper that deals with a problem
crying out for resolution. The authors have tackled the problem with a nicely
designed study. Unfortunately, as the authors point out, the study was terminated
early for reasons stated and many of the analyses have suffered as a result.
Nevertheless the work deserves publication, given the importance of this
question.
In the light of the paper's main and acknowledged deficiency regarding sample
size it is all the more important that the paper be tightened up in a number of
respects. For this reason I have labelled many of the revisions as "major" but I
expect that these can be easily accomplished and that once done the paper
should be in excellent shape for publication.
I do feel statistical review is worthwhile, especially regarding the post hoc pooling
with the Swank data, as well as the covariance issue.
I was very pleased to see this work appear in preliminary abstract form several
months ago and communicated my willingness to write an editorial for the full
manuscript version. I reiterate now this offer given the importance of this subject.
A: Discretionary Revisions
Introduction
A1Cost of health care resources. I would add that these are likely to be
underestimates.
A2 Lamvu (quoting other papers) says that 12% of the 600,000 or so
hysterectomies are done with a primary indication for surgery = 72,000. The cost
of a hysterectomy is about $30,000 giving a cost of $2,160 million (ie $2.16 US
billions), a figure not fully accounted for in the $881 million number
Lamvu, G. Role of hysterectomy in the treatment of chronic pelvic pain. Obstet
Gynecol. 2011 May; 117(5):1175-8
It is worth mentioning the cost of performing adhesiolysis. Our own analysis puts
this figure at over $5b for 430,000 procedures in the US in 2009.
http://www.adhesions.org/IAS2012-AHRQAdhesiolysis.pdf
Adhesiolysis: A reanalysis of the AHRQ Report on Chronic Pelvic Pain
Wiseman, DM. Nov 30 2012. International Adhesions Society, Dallas, TX.
www.synechion.com/IAS2012-AHRQAdhesiolysis.pdf (see attached)
A3 “and the clinical benefit of adhesiolysis in the context of CPP is still unclear
[10, 11]” ADD “and controversial”
A4 I would delete the last two sentences of the first paragraph for the following
reasons:
1. The issue of complications is a distraction and self evident, if anything I would
put this in the discussion about the risks/benefits of lysis. The references cited do
not particularly enhance the point being made (Chapron does not specifically
analyse complications associated with lysis, and from the abstract the Jansen
paper seems not to either. A better paper to enhance the point about
complications is ten Broek et al. Ann Surg. 2013; 258:98, although this deals with
abdominal adhesiolysis).
2. The issue of barriers is also a distraction from the point being made, again I
would put this in the discussion after you have weighed the risks/benefits of lysis
without barriers and then speculate on how the use of barriers may or may not
change that equation. When you do include this I would suggest changing “there
is currently no effective way of preventing adhesions from reforming once they
have been removed” to “current methods to limit adhesion reformation have
limited efficacy.”
3. You need to get straight to the point about what studies have been done
related to your primary question. Adding “and controversial” as described above
gets you there.
A5 Second paragraph “Only one randomized controlled trial….etc.”
The Peters study (ref 24) deserves mention at this point as it contributes to (and
was probably the first real effort in trying to understand this problem) what we
currently know about lysis and pain. It suffers from the fact that lysis was by
laparotomy and of course was not blinded, but it should be mentioned here
before the Swank study.
A6 A much more detailed critique of the Swank study and its deficiencies is
needed as a number of papers have now quoted this and erroneous information
is getting into the literature. See my review at:
http://www.adhesions.org/IAS2012-AHRQAdhesiolysis.pdf
B Minor Essential Revisions
B1 Abstract: are the figures in elipses ranges or confidence intervals? Needs to
be specified in methods section of abstract.
Introduction
B2 First line: Should spell out and then abbreviate ie: Chronic Pelvic Pain (CPP)
Methods:
B3 Change “Proportions are compared” to ““Proportions were compared”
B4 References should be provided regarding the use of the McGill, SF12 and
EHP30, preferably in this population (or as close as possible). A brief description
of what each tool (and their domains) measures should be provided.
B5 These tools are mentioned twice in the methods section – in the second and
7th paragraph. Remove duplicate reference in para 7.
B6 Was a statistical package used? SPSS etc. Please specify.
Results
B7 There were 21 patients with no adhesions, but with pain. I am curious to know
if you tracked their pain after the diagnostic laparoscopy, what treatments did
they then employ?
B8 “Five women were loss to contact” change to “Five women were lost to
contact”
B9 Change: “Adhesiolysis were completed in all the women in the study group” to
“Adhesiolysis was completed in all the women in the study group”
B10 Figure 2: Key to symbols needs to be provided (squares = control, circles =
lysis)
B11 Fig 2b = y axis label – “physical”
B12 “we reanalyzed the results based on the number of women with a 50%
improvement of pain in each group.”
B13 Do you mean 50% improvement in pain score? Please state. Further, unless
I have missed it, I cannot find reference to this method of presentation in
reference 15.
B14 Part of last sentence of results: “and adhesiolysis was complete in all the
women in the study group” – this duplicates a previous statement.
Discussion:
B15 “analysis based on a 50% improvement in pain did not reveal the same
evidence of benefit”
See B13 –I would remove this completely. I cannot find Swank using this
method, and if he did, you need to cite the comparable figure here.
B16 “degree and evidence of benefit of these treatments remains variable”
change to:
“degree and evidence of benefit of these treatments remains variable and
questionable”
B17 References
Ref 1 – end page/
Reference 10: is repeated as ref 17 and 19: duplicates need to be removed and
references renumbered in text as appropriate
Reference 17 – author needs to be spelled out: J Alexander-Williams
Ref 19 – this is a repeat of ref 17 and 10 (see above)
Reference 14 – check spelling diZerega
Ref 16 – needs author
Ref 21 – needs full citation
Refs 11 and 26 are duplicates
C Major Compulsory Revisions
C1 Stats: Was the Mann-Whitney performed comparing the differences in score
of the two groups, rather than the scores themselves? Please decribe
C2 Regarding the various withdrawals and patient flow - Methods, Figure 1 and
Results need to be harmonized and rewritten to match each other. Terms used
should be clarified (or changed) if necessary as it is not clear which criteria were
applied and when. For example:
1. Which criteria were used to define “eligibility for recruitment”?
2. Did patients consent before the baseline assessment? What did the baseline
assessment consist of? Pain scores?
3. The 5 patients that declined surgery – did these consent but later withdraw?
4. The 6 patients that were removed due to medical reasons, was this simply the
exercise of exclusion criteria 1,2,3 and 5, or other reasons?
5. What were the medical reasons for the 2 patients removed before
randomization – were these part of the criteria or something else? (correct
answer should be the former!)
6. In Results the term “baseline assessments” is used, this needs to be made
consistent)
7. Please standardize “No laparoscopy N=11” (fig 1)”and “11 women withdrew
after enrollment before surgery”
8. “5 had endometriosis and did not wish to be randomized”. It is not clear from
the pre-op type of criteria (see comment below) that endo (ie anywhere, other
that associated with adhesions) is an exclusion criterion. The way this is written
implies that patients were told that they had endo (determined at laparoscopy) –
were they under conscious sedation? Please clarify, especially in the description
of the inclusion/exclusion criteria and also in the patient disposition descriptions
in the results and Fig 1.
C3 “Prior to surgery” – how could adhesion details be obtained before surgery?
Perhaps you mean prior to performance of lysis? In patients allocated to
diagnostic laparoscopy how were the details reliably obtained. Sometimes the
extent and severity of adhesions can only be estimated without lysis, often the
full extent and severity is better known only after lysis. If this is the case, please
state this. I would put this paragraph where is belongs
C4 Inclusion criteria: Non endo-related adhesions – does this mean that the
patient had no endo anywhere, or that at the specific site of adhesions there was
no endo? (see above comment regarding harmonization of terms). Specify that
this was determined by gross inspection (or other means). If endo was
associated with, and buried within an adhesion, how could this be determined in
patients only with diagnostic laparoscopy?
C5 “suitable for laparoscopic adhesiolysis” and “confident they could be
adequately removed” – please specify what criteria were applied to determine
“suitability”?
In patients assigned to adhesiolysis, were all adhesions lysed? Please describe.
What criteria were used to decide if an adhesion was to be lysed (probably same
as previous answer)
In how many patients were adhesions not considered suitable for lysis? What
was their outcome? (is this selection bias?)
C6 Inclusion criterion 3 is really two separate items – please split out.
C7 There are really pre-operative criteria and intraoperative criteria. For clarity I
would point this out and say that once the preop criteria had been satisfied and
the procedure begun the intraoperative criteria were determined.
C8 Then change:
“Randomisation was performed using a computer generated random numbers
and the concealed, opaque unlabeled envelope was opened when adhesions
were diagnosed and the operating surgeon was confident that they could be
adequately removed.”
to:
“Randomisation was performed using a computer generated random numbers
and the concealed, opaque unlabeled envelope was opened after it had been
determined that the patient met the the intraoperative criteria”
C9 Access to patient notes in case of emergency – in how many patients did this
happen and what a priori decision was made as how to deal with data from those
patients?
C10 Power calculation: What was the basis for choosing 10 points as the effect
size? Why is this considered clinically meaningful? Provide references if
possible. How did you arrive at the SD of 18.5?
Results
C11 Since the study was terminated early, please report the actual power
regarding the primary efficacy parameter given the actual sample size.
C12 “None of the participants elected to have a 12-month follow up.” Belongs at
the end of the first paragraph.
C13 Table 2: text references Table 2, but no table provided
C14 The text that follows mixes up ideas that are in the next paragraph. The flow
of ideas needs to be improved here, for example:
“There was no difference in the baseline characteristics between the study and
control group
except the adhesion score in the study group” – this is referred to again in the
next paragraph, please clean this up.
C15 The paper uses several post hoc analyses not described in the methods.
These should be clearly demarcated and explained. Eg “The adhesion scores
were not correlated with VAS at any visit (baseline, 3 month & 6 month), and
neither were the differences from baseline to 3 or 6 months” – what procedures
were used to determine this? Was this a covariance analysis? Please clarify.
C16 There are two sections that deal with the changes in the various scores. The
first is in the paragraph beginning “Figure 2 and 3”. Then the discussion
digresses to a post hoc analysis. Then the discussion of scores begins again with
“In women who underwent…” It is not clear why this is broken up. Please
consolidate this and make it more understandable what is going on here and
whether we are talking about changes in scores, or comparisons of the changes
in scores between the groups.
A table comparing the changes in scores would be helpful.
C17 Lastly, since there does appear to be a difference in VAS at baseline (albeit
non-significant, but this might be attributed to the small sample size), a
covariance analysis of score change vs baseline score might be useful. The
discussion has the comment:
“Despite this being a randomised controlled trial, due to the small sample size,
there was disparity in the baseline characteristics of adhesion and VAS score,
which may have inadvertently, confounded the results.”
Doing a covariance may help you qualify better your statement in the discussion.
Discussion
C18 “There are many proposed hypotheses to substantiate the ‘myth’ that
adhesions can cause pain. “ suggest change to:
“There are two main mechanisms by which adhesions may cause pain.”
C19 “Our study”… this belongs with the paragraph before the previous one about
baseline disparity. A similar idea is repeated in the last para – these need to be
consolidated.
C20 The statement “our study demonstrated that this group of women benefited
most from adhesiolysis” suggests that you did some sort of covariance analysis –
did you?
C21 Some discussion about the change in scores between 3 and 6 months is
needed, as well as a discussion as to why scores were reduced in the diagnostic
group.
C22 Comment about Adept: Aside from the fact that the cited paper (25) deals
with de novo adhesions, it shows that Adept is no better than Lactated Ringers
(LRS). An earlier paper on Adept (Brown et al. Adept (icodextrin 4% solution)
reduces adhesions after laparoscopic surgery for adhesiolysis: a double-blind,
randomized, controlled study. Fertil Steril. 2007; 88:1413) appears also to be
silent on the issue of reformation.
C23 Having said this, there may be a small effect of the Adept (or LRS if it had
been used) on reformation.
C24 (The Brown study also includes some data on pain reduction after Adept
and LRS CPP patients – worth comparing and contrasting these data)
C25 Pooled data with Swank. This requires much more discussion to compare
and contrast the populations from the two studies. Swank included some men, it
looked at abdominal pain etc. (see
http://www.adhesions.org/IAS2012-AHRQAdhesiolysis.pdf) You need to detail
the method used in this analysis to extact and pool the data. I would add a
section in methods and results for post hoc analyses.
Level of interest: An article of outstanding merit and interest in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
Have you in the past five years received reimbursements, fees, funding, or salary
from an organisation that may in any way gain or lose financially from the
publication of this paper, either now or in the future?
I am the President and owner of Synechion, Inc. which provides consulting and
R&D services. Together with a patient oriented web site we own (adhesions.org),
we focus on the science and business of adhesion prevention. Our clients
include companies and other commercial entities interested in the field of
adhesions and their prevention. The question posed by this paper is of critical
interest to our clients as well as the patients we serve through the adhesions.org
web site.
I am also president and owner of KevMed, LLC, which markets a device,
PainShield MD, for the treatment of pain, including pelvic pain and pain
associated with adhesions.
Do you hold any stocks or shares in an organisation that may in any way gain or
lose financially from the publication of this paper, either now or in the future?
I or my family may hold stocks in companies described above.
Do you hold or are you currently applying for any patents relating to the content
of the manuscript? Have you received reimbursements, fees, funding, or salary
from an organization that holds or has applied for patents relating to the content
of the manuscript? Yes, see above.
Do you have any other financial competing interests? No.
Do you have any non-financial competing interests in relation to this paper?
I have a long standing interest in the subject matter of this paper. While
remaining open to the question as to "whether adhesiolysis should be performed
for pain?", I have published my objection to the interpretation of work that
concludes that it should not (eg see
http://www.adhesions.org/IAS2012-AHRQAdhesiolysis.pdf - attached). Even if
adhesiolysis does prove to be of benefit in treating otherwise unexplained pain,
our own work on PainShield MD suggests that for unexplained abdominal or
pelvic pain in the absence of bowel obstruction, PainShield MD should be used
before adhesiolysis is conducted, since it is a non-invasive, inexpensive
alternative with few risks than surgery.