Groeneveldt et al “A mixed exercise training programme…”
Response to Reviewers
1
Please note that all changes are marked in red on the revised manuscript
Reviewer: Saskia Persoon
Reviewer's report:
We are pleased to hear that this reviewer considers our results will make a positive
contribution to the field.
Major Compulsory Revisions
1. Patients and Methods, Results and Discussion
My first concern relates to the primary aim of the study. The primary aim as stated in this
article is to assess the feasibility and acceptability of the exercise program. However, the
outcomes feasibility and acceptability are not further defined in the introduction or method
section and also the results are missing.
- We have now included a section in the Methods (page 6) on the outcomes used
to assess feasibility and acceptability. These outcomes are now clearly stated in
the Results section, page 7-8.
Still in the discussion it is mentioned that “The principal finding of this study is that a tailored
EP is safe and feasible in treated MM patients”. What is the basis for this conclusion?
- Safety is now defined in the Methods (page 6), and the outcomes in the Results
(page 9).
I have some doubts about the feasibility of this exercise program, as it included aerobic
exercise, and in the fourth paragraph of the discussion it becomes clear that many of the
patients included in this study were actually not fit enough for aerobic programs. These
points need clarification.
– This point was confusing, as it was a general point about myeloma sufferers.
We have now removed this statement. In fact, an inclusion criterion for our
study was the ability to undertake aerobic exercise.
2. Introduction – second paragraph
This part should be updated. The authors refer to reviews that were all published before
2007. This research field expands quickly with new studies and reviews published regularly.
- We have now updated the Introduction (page 3) to include a reference to 4 new
publications in the area (references 10-13).
3. Patients and Methods – Study Outcomes – second paragraph
If I understand it correctly, cardiorespiratory fitness was preferably assessed with a
submaximal single stage treadmill walking test. If however patients were unable to perform
this test another test was used. I think it would have been better, if across all patients
cardiorespiratory fitness was assessed in a similar way and I am therefore curious why the
authors chose a different approach? Furthermore the second method/test to assess
cardiorespiratory fitness should be explained in more detail, is this a reliable and validated
method/test?
- This is a valid point, however, we only realized mid-way through the study
that some patients were not able to perform the treadmill walking test. We
chose to use the bicycle ergometer instead, and have now included details of
the make and design, and the software used (page 6-7). As ours was a
feasibility study, this would be one of the findings that will inform the design
of a future RCT, a point we have mentioned in the Discussion (page 11).
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Also more information should be given about the hand grip strength and leg press
measurements (for instance, was the 1-RM for the leg press determined and if so, was that
done indirectly or directly)?
- These details are now included in the Methods section (page 6-7).
4. Results – Baseline assessments
In this section a comparison is made between the results of the patient population and the
healthy population. I suggest to move this comparison to the discussion, or to announce
this comparison in the method section. In addition, I think the paragraphs ‘Participants,
recruitment’ and ‘Baseline assessments’ can be combined.
– This comparison is announced in the Methods section, and the Results section
has been re-organised as suggested.
–
5. Results
The information on numbers of patients, dropouts and reasons for dropping out is spread all
over the result section. It would be more convenient for the readers if all this information is
given in the first paragraph of this section.
- This information is now given in the first section of the Results, under the
heading “Study uptake, screening and progression through the study” (page78).
6. The scores for the HADS questionnaire are missing. I would advise to include the results
in the text or in table 2 or 3.
- These are now included in the Results section (page 9).
7. Results - Changes form baseline to 6 months
The authors state here that improvements in all parameters were maintained or further
increased between three and six months. It is not clear to me how this statement is
substantiated, as no statistical test seems to be done to test for differences between the
results on three and six months.
- We have done these statistical tests, and the results are included in the Results
section where appropriate (page 9).
8. Results – Predictive factors
This paragraph is completely unexpected, as there was no mention of predictive factors in
the introduction or methods section. Also the statistical analysis was not pre-described in
the ‘Analysis’ paragraph. This point should be addressed.
- We agree, and have now removed this section, as the numbers are too small for
any meaningful analyses.
9. The methods and results of the focus group sessions are minimally described and I don’t
think that in this way, this part adds a lot to the current paper. Maybe it is better to leave the
qualitative part out of this article.
- We believe that the Focus group findings add valuable information about the nature
and magnitude of the benefit that the exercise programme had on the lives and
experiences of the participants and are keen to leave this section in.
10. Abstract-results/Discussion-first paragraph
It is mentioned that the adherence rate was high in this study. However only 20 of the 28
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logbooks were returned at 6 months; this means that 29% of the data is missing and this
might bias the results. I would advise to discuss this point in the article.
- During the second 6 months, patients were not dutiful in returning log books,
however they had 100% attendance in the 4-weekly gym classes, hence the
method of assessing adherence only on log-book returns may under-estimate
the real data. We have included a statement in the Discussion about methods
to increase log-book compliance (page 11).
11. Discussion – Second paragraph
“An important feature of our study was the inclusion of such patients, the demonstration of
benefit from the programme, and the lack of adverse events”. The strength of a study is
more dependent on the study design and not on the results found.
– This sentence was misleading in its wording and have removed it. We were not
referring to the strength of study design, but to the clinical impact of our
admittedly preliminary findings.
12. Abstract - Purpose
In this part the authors state that there is limited evidence about exercise programs in
patients with multiple myeloma because of the high prevalence of lytic bone disease and
perceived fracture risk. Of course the lytic bone disease and perceived fracture risk makes
it more difficult to study standardized exercise programs in these patients, but I think the
statement is not substantiated. Is it not also possible that evidence is limited because of the
small number of patients with multiple myeloma relative to the number of patients with for
instance breast cancer?
– Yes, agree.
- Minor Essential Revisions - We have addressed all these and made the requisite
changes.
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Groeneveldt et al “A mixed exercise training programme…”
Response to Reviewers
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Reviewer: Freerk Baumann
Reviewer's report:
Major Compulsory Revisions:
(1) The authors are right in their remark that the special group of multiple myeloma patients
has not been studied sufficiently. It is however not correct that these patients have not been
considered in any studies. Schmitz et al. 2010 (ASCM) accentuate in their guidelines that
feasibility studies have shown that haemato-oncological patients can take part in
therapeutic exercises and that these are safe. The main question of a feasibility study is
therefore almost obsolete.
– We have now included a reference to studies in Haemato-oncology patients in the
Introduction (page 3), and described the information that exists on myeloma patients.
Myeloma patients differ importantly from other Haemato-oncology patients because
of their intrinsic bone disease, and poorer functionality, hence the need for a
feasibility study, before we can conduct large meaningful studies, that this reviewer
acknowledges are still missing.
(2) The work has some methodological weaknesses: missing control group (effects are
measured as well!), missing randomization; all though a randomization is not necessary in
feasibility study.
(3) Due to the missing control group, the reduction in pain cannot be interpreted
– yes, it is a single arm pilot feasibility study, thus we cannot ascribe the reduction in
pain to the exercise programme, here we are simply presenting the results
(4) Details about the exercise program are missing and there is only little information on
exercise intensity, duration, etc. An individualized exercise program is pointed out however
detailed information is missing. Especially in a feasibility study it is important to describe the
exact exercise dosage.
- We have now included details on the exercise study, including intensity, duration,
and what factors were taken into account in the individualized programme (page 5-6).
Furthermore, information on exercise adherence cannot be found: how many exercise
sessions were actually completed by the patients? Is the adherence rate comparable in the
supervised and the home-based program?
- Adherence is now defined in the Methods section under ‘Study outcomes’ and
the data given in the Results section. A lower proportion of patients returned
their log-books in the second 3 months, but the adherence rates, as scored
from the returned log-books was not significantly different from the rates in
the first 3 months. This point was also brought up by reviewer 1 and was
discussed above.
(5) The discussion is poor because analyses are rare. To what extent are theresults of this
study important for the rehabilitation of multiple myeloma? Which mechanisms could be
responsible for the reduction of fatigue? Possible theories that give the reader something to
think about are missing.
– We have now included these points in the Discussion (pages 11-12).
Minor Essential Revisions:
(6) The study was conducted between 2006 and 2007. Why was the manuscript only
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submitted now? Treatment regimens for oncological patients change very fast, therefore the
currentness of the data can be questioned.
- Despite recent advance in the use of proteasome inhibitors and IMiDs in the therapy
of myeloma patients, this cancer remains incurable, and no major advances have
had a meaningful impact on bone destruction, most of which occurs at the time of
diagnosis. The rehabilitation needs of patients and the impact of bone disease on
QOL remain unchanged over the years. In fact, with more patients living longer,
these needs are more urgent.
(7) Important information on how the resistance test was performed is missing. Was the test
dynamic, static, maximum etc.?
- Static – details of the resistance tests are now included in the Methods section
(page 6-7).
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Reviewer: HAN-I WANG
Reviewer's report:
We are pleased that this reviewer finds that our research question was well defined and the
data sound. We are grateful for the several constructive criticisms, especially regarding the
statistics.
Major Compulsory Revisions
1. Statistical analysis Some inconsistencies / confusions were observed in regards to the statistical analysis
employed. Based on the results presented in Table 2 and Table 3, the authors used the
Wilcoxon matched pairs method to analyse the changes in the FACT-G and the fatigue
scores, while they used the student paired t-test for the changes in muscles strength. This
implied that the muscle strength data fitted the normal distribution, while FACT-G and the
fatigue scores did not. However, at later sections (predictive factor section), the authors
used univariate linear regressions for the FACT-G and fatigue scores and muscle strength,
which suggests that all these health outcomes were actually normally distributed (i.e. the
linear regression fails if the data violates the assumption of normal distribution). To make
the analysis results sounder, it is suggested that the distribution of each health outcome
could be checked in order statistical methods to be selected accordingly and more
consistently. Also, the information could be possibly presented more clearly if the authors
could mention the type of the statistical analysis method used, as well as the reasons for
selecting them, in the Method section.
- We have undertaken a review of the statistics. We have confirmed that the data
are normally distributed. Moreover, we have also checked by performing each
comparison using Student’s t-test or Wilcoxon matched pairs test, and found
that the level of significance is similar. We have now presented all statistical
data using parametric tests.
- We have omitted the predictive factors analysis and section, as the numbers are
too small for any meaningful or reliable conclusions.
2. Predictive factors (Multivariate linear regression) Univariate linear regression assumes the response variable is influenced only by one factor.
However, this is normally not the case in the real world. Therefore, a multivariate linear
regression is normally carried out after the univariate analysis.In this study, the authors only
employed the univariate analysis to explore the potential predictive factors. It would be,
thus, helpful if the authors could justify why solely the univariate analysis was employed in
this work.
- see response above
Minor Essential Revisions
3. Figures 3a and 3b It is suggested that it could be more appropriate to use a table for the presentation of the
regression results (such as coefficients and p values) than presenting it using figures. This
is because a table could provide more information about the regression results and a
clearer view of the impact of each factor.
– see response above
4. Maintenance treatments As shown in Table 1, around 20% of the study population were on the maintenance
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treatments. Since there was no control group in this study, it is unclear whether the
changes in health outcomes (e.g. QoL and fatigue score) were caused by the EP or by the
maintenance treatment. It could be helpful if the authors could further clarify this.
- Maintenance treatment is very unlikely to improve QOL or Fatigue scores, as the
main aim of maintenance treatment is to delay disease progression, not
improve disease response or wellbeing.
Discretionary Revisions
Discussion It is suggested that some excessive details of previous studies in the 2nd paragraph of the
Discussion could be trimmed down, especially if the purpose of this part of article is to
explain why the study population is unique from previous studies and important to the
findings.
- We have done this.
6. Discussion The main idea of the 3rd and 4th paragraphs in the ‘Discussion’ section paragraphs was to
justify why the resistance exercises were applied instead of the aerobatic exercises to the
myeloma patients. However, this is not entirely relevant to the discussion of the findings.
Therefore, it is suggested that these two paragraphs could be combined and moved either
to the ‘Method’ or the ‘Introduction’ sections.
- We have done this
7. Predictive factors for attendance/adherence Alongside the predictive factors of QoL improvement, it might be also worthwhile checking
the predictive factors of attendance / adherence. This could provide further information
about who / how to apply the suggested exercise programme in order to make it ‘feasible’ to
other myeloma patients.
- We have omitted any analysis of predictive factors, as the numbers would be
too small for any meaningful conclusion
8. Dropping-out Since the patients who dropped out (n=12) and declined (n=15) accounted for more than
one third of the original study population (n-75), it is considered important to justify that
these patients were not the ones whose health outcomes (e.g. QoL and fatigue scores)
could not be improved by the training programme. Therefore, a simple statistical analysis
could be conducted to demonstrate that there was no characteristic difference between the
dropping out and the actual study population (n=37).
- We only have health outcomes on patients who dropped out after baseline
assessments (8), and our data indicate that these are similar to the FACT-G and
Fatigue scores of the actual study participants. These data are now given in the
results section (page 8), although the numbers are too small to draw any conclusion.
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