Reviewer 1
1. Statistical heterogeneity of RR across the studies is explored with the Cochran’s
Q2 test and I2 Statistic. Why didn’t you apply the Cochran’s Q2 test?
In the originally submitted version of the manuscript we intended to use both methods were
appropriate [1, 2]. However, we only used and reported on the method of DerSimonian and
Laird [2]. Correction was made.
2. One way sensitive analysis is used to investigate the influence of each study on
the overall estimate by calculating a pooled RR omitting each estimate one at a
time. Did you do this?
This method of sensitivity analysis was not used considering the significant heterogeneity
that was indicated in the discussion section to be one of the main limitations of the current
meta-analysis. In the revised version, meta-regression analysis was performed to determine
to what extent the heterogeneity is explained by effects of variables, e. g. age at HL
diagnosis, follow-up duration, study’ size, etc.
3. To study the heterogeneity Meta regression model is utilized. The Meta
regression explains the heterogeneity in terms of study level covariates. Did you
do this?
Please see above.
4. Please, better explain in the text and, also in the figure 1, the overlapping and
non-overlapping studies. 25 studies are non-overlapping and 9 are overlapping?
This point it’s not clear.
Details of overlapping studies were given in the third paragraph of the results section.
Moreover, we also indicated in Table 1’s footnote “Overlapping studies were shaded
together”.
5. The fixed-effect model or the statistical heterogeneity tests showed a significant
heterogeneity of RR across the studies? Please, clarify this.
Please see above concerning heterogeneity.
6. RR and Follow Up latency and RR vs. age HL diagnosis and FU latency. Did you
use Fixed or Random model? Please better explain in the text.
Although all figures’ legends indicate the method used, we added this information to the
text – where not mentioned - as suggested by the reviewer.
7. RR and treatment modality: The fixed-effect model or the statistical
heterogeneity tests showed a significant heterogeneity of RR across the studies?
Please, clarify this.
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Female breast cancer following Hodgkin’s lymphoma
Heterogeneity of the RR vs. treatment modalities was explored and added to the revised
version. Moreover, because of the few number of studies that analyzed the combination of
RT with either alkylating or on alkylating agents, we created one subgroup for all patients
who received the combined therapy regardless of the nature of chemotherapy regimens.
8. Please, explain in the first row what does it means, STROBE criteria met/app.; FU
(y). All abbreviations for to better understand the Table 1.
All abbreviations were already included in the footnote of Table 1. Due to complexity of the
table and limited space, some abbreviations have to be used. However, we managed to
decrease the number of abbreviated terms.
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Female breast cancer following Hodgkin’s lymphoma
Reviewer 2
1. The authors do a nice job identifying all current literature on second
breast cancers in HL survivors. I think that while the overall conclusions
about age and time since treatment are consistent with what is known,
for the purposes of a meta-analysis the absence of significant treatment
data in many studies makes claims about associations between specific
treatment variables (mantle RT (2 studies), RT alone (3 studies). Maybe
useful to state the number of cases covered rather than number of
studies. If too small, then consider different presentation of data.
Very useful comment. The exact numbers of patients vs. treatment modality were detailed
in additional table (new Table 1), while other relevant details were given in Table 2.
2. Recommended considering a consistent term throughout the text for what
you refer to as latency, follow-up, etc. (consider time since diagnosis or
time since treatment completion).
Latency and follow-up periods were reported since completion of therapy. However, time
since data of HD diagnosis is self-explained. Correction was made.
3. Abstract: In results, extra word To at the beginning of sentence 4.
Corrected.
4. Background: would remove word disease before stage in paragraph 1.
Corrected.
5. Methods/Selection criteria: missing word "that" before developed in par 2,
sentence 3.
Corrected.
6. Discussion: paragraph 1: would re-word sentence number 3. it needs to be
clearer Paragraph 3: would add "increase in risk" after (RR=14.08). Would add
"the" before RT field in line Paragraph 4: would change term combining of RT
and alkylating CT to "the combination" of RT and alkylating CT.
All were corrected.
7. Page 13: Paragraph 3. End sentence at therapy in second to last line and leave
last line as a separate sentence.
Corrected.
8. Page 13: paragraph 4: in line two, add "are" before inherent.
Corrected.
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Female breast cancer following Hodgkin’s lymphoma
Reviewer 3
1. A wide range of risk estimates (0.5 to over 70-fold) have been reported and
while there is clearly an association, the very high amount of heterogeneity (Isquared=96%) makes assessment of the size of risk difficult. Presently although
the authors state in the methods that reasons for heterogeneity were explored,
it is unclear what methods were employed and there is insufficient information
as to whether the heterogeneity could be explained.
We fully agree that the range of RRs have been wide and the heterogeneity has been
considered as a limitation of this meta-analysis. A meta-regression analysis was performed
to determine to what extent the heterogeneity could be explained by different covariates.
The dependent variable used was the natural logarithm of RR weighted for the inverse of
variance.
2. Ideally, the influence of study design and clinical factors on the pooled risk
estimate and heterogeneity should be assessed using meta-regression (this is
best done in consultation with a statistician experienced in meta-regression and
as there is no meta-regression available in Review Manager, another package
such as Stata would be required).
Please see above. A statistician consultation was though and we have used the IBM SPSS
statistical package v.19.
3. Predictive intervals rather than confidence intervals should be presented as the
large amount of variation between studies is not taken into account with
confidence intervals and predictive intervals give a better view of where the risk
of a new study would lie.
We trust that exploring heterogeneity would certainly address the variations.
4. Given the heterogeneity, it would be clearer to state that a random-effects
model was used for all analyses.
Not all analyses ware based on random-effects model (Figure 5 was based on fixed-effects).
We re-emphasized the nature of the used models in the text and legends.
5. The authors present interesting discussion with respect to age at diagnosis of HL
and SBC, latency and treatment. Heterogeneity may be influencing the pooled
findings here as each subgroup does not contain the same studies. The different
pooled risks between subgroups may reflect the differences between the studies
included in each group rather than true differences between subgroups.
Done using meta-regression.
6. For similar reasons, I would not present pooled risks for Table 2.
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Female breast cancer following Hodgkin’s lymphoma
Data related to Table 2 (now Table 4) were re-done excluding the pooled analysis. The
limitation attributed to the few studies available was included and highlighted.
7. Results (page 8, paragraph 3, sentence 3) state “The heterogeneity was
attributed to diverse RR and wide CIs among small-sized studies as compared
with larger studies”- this is inaccurate as large studies with their narrower CIs
may have less overlap with CIs from other studies and so contribute more to the
heterogeneity.
We fully agree. The statement was deleted.
8. Some study design factors are presented in Supplementary Table 1 but sources
of Hodgkin patients and methods for identification of breast cancer, whether
incidence or mortality, etc. should be added.
Detailed Tables 1 and 2 were added to the revised manuscript. All SBC cases were incidence
events and not mortality. This was made cleared in the revised text. Analysis of SBC
mortality would definitely be confounded by the mortality from HL itself or its therapyrelated effects, the age of diagnosis of HL or SBC, length of follow-up, etc. This important
comment was added to the revised submission.
9. The authors conclude that this meta-analysis may inform breast cancer
screening recommendations for HL patients. It is not clear what is
recommended. Could this review also inform how to decrease chances of SBC?
An interesting comment. The paragraph was re-written and a short statement about ways
to decrease the incidence of SBC was added.
10. Minor modifications:
In the first sentence of the introduction, please indicate the time period when HL
became curable.
Done.
On page 8 paragraphs 1 & 2, it would be better to present the range of follow-up
times, ages and latency, AERs across studies rather than 95% CI of medians.
Also please specify number of studies with data rather than `several’ or `few’.
Done.
In the methods, please give the time period for literature selection in the first
paragraph. Also specify the time selection period in the abstract along with
summary of study location and ranges for age. Please add a summary of study
locations to the start of discussion.
Done.
The results suggest that case-control studies were excluded- please state this as
exclusion criteria in methods.
A statement was added to the methods section.
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Female breast cancer following Hodgkin’s lymphoma
In the results, it is not necessary to list the overlapping studies as these are
nicely highlighted in Table 1. If there are exceptions to the most recent study
being used, please indicate this in the text.
Statements about overlapping studies were already highlighted in the text.
On page 8, paragraph 4, sentence 2 it would be better to say “There was no
difference in mean age at neither diagnosis nor mean latency since diagnosis
between institutional and population-based studies.”
Corrected.
Please give 95% CI/PI and I-squared when reporting pooled risks in the text,
for example on page 8 and 9 when considering age at HL diagnosis and on page
10 when discussing time period.
Done.
Please clarify in the first sentence of page 13 what the comparison group was to
the protective effect of pelvic RT found in De Bruin- confusing since the risk is
increased in Table 2.
The following sentence was added “Table 4 also shows the potential protective role of pelvic
RT as reported by De Bruin et al [3], where those who received that modality showed the
risk was not as high as compared with those who did not”.
On occasions, the authors state there was a lower risk but it would be better to
say that the risk was not as high if the risk greater than 1.
Corrected.
In page 13 paragraph 2, the role of splenectomy on risk is unclear as two studies
found no change in risk, and one found a higher risk.
Agree, the limitation of the evidence was highlighted and the pool analysis was removed.
In the forest plots, please report only the study reference, RR and 95% CI. If it is
possible, please add the number of observed and expected SBC, and no of HL
cases to the plots. Also consider adding boxes proportional to study size around
the risk estimate.
Adding the reference to the Forest plots is useful for readers considering the large number
of included studies. The plots were generated by REVMAN which is one of the known world
standards. Studies’ weights are already shown.
Please clarify in Table 1 that the column labeled year is year of HL diagnosis.
Done.
There are 35 studies in Table 1 and 24 included- please check that the results
and figure 1 report consistent numbers.
Attributed to overlapping studies (shaded and explained in the text).
On page 3, paragraph 3, sentence 4 “young females” but “aged 30+ at HL”please check.
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Female breast cancer following Hodgkin’s lymphoma
Thanks, corrected.
In paragraph 2 page 7 “reaming” should be “remaining”. Page 11, paragraph 2,
sentence 2 “prove” instead of “proof”.
Corrected.
References
1.
2.
3.
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Mantel N, Haenszel W: Statistical aspects of the analysis of data from
retrospective studies of disease. J Natl Cancer Inst 1959, 22(4):719-748.
DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986,
7(3):177-188.
De Bruin ML, Sparidans J, van't Veer MB, Noordijk EM, Louwman MW, Zijlstra JM,
van den Berg H, Russell NS, Broeks A, Baaijens MH et al: Breast cancer risk in
female survivors of Hodgkin's lymphoma: lower risk after smaller radiation
volumes. J Clin Oncol 2009, 27(26):4239-4246.
Female breast cancer following Hodgkin’s lymphoma