Reviewer’s report
Title: 
Chemotherapy-based gonadotoxicity risk evaluation as a predictor of
reproductive outcomes in cancer survivors: A prospective cohort
Version: 
0 
Date: 
27 May 2020
Reviewer's report:
The aim of this study was to evaluate long term reproductive outcomes in cancer
survivors according to gonadotoxcity risk estimation of the chemo-radiotherapy
regimens received using a retrospective cohort study design. Post-pubertal
patients referred for fertility preservation between 1997 and 2017 was
performed, though it is unclear whether only those patients who completed
ovarian tissue cryopreservation (vs. oocyte/embryo cryopreservation) were
included. This is an important topic that is a key survivorship issue for many
patients of reproductive age. However, the writing and presentation leave me a
bit confused about what the study entailed. Further, the authors are
recommended to do a more thorough job of presenting the literature (in the
Introduction) and incorporating the unique value of these results. On the one
hand, further data on reproductive outcomes following gonadotoxic treatment is
important. However, the authors do not present how these results compare to
other studies and other cohorts and with a relatively small sample size, it is
unclear how to extrapolate these findings to counsel patients. 
Intro
- Suggest authors clarify radiation therapy effects on fertility - does this refer to
radiation to the abdominal area? The authors only mention damage to ovaries,
but damage to uterus will also impact family-building options.
- At this point, this is not a new area of research with several risk-based
calculations and guidelines already published. These are referenced later in the
Methods but should be referenced and described here as well. It is recommended
that the authors more thoroughly represent the work that has already been done
to quantify gonadotoxicity of treatments and risk categories. What does this
study add? 
- "The 14 overall risk for ovarian insufficiency in patients who underwent
gonadotoxic treatment, 15 was shown to be 30% after a mean follow up of 50
months [7]." In addition, there are other seminal studies that should be cited here
for quantifying the risk associated with gonadotoxic treatments.
- Suggest the authors present more background on ovarian tissue
cryopreservation (OTCP) including representation of worldwide use (in the US,
it is still considered experimental). The advantages are presented, but what about
disadvantages or risks?
- It is unclear if the objective of this study is related to OTCP. Is this secondary
analysis of a larger study? If so, this should be stated. If not, why would OTCP
pts only - and not all patients who received gonadotoxic treatments - be
included?
Methods
- Were study methods approved by an IRB or reviewed by an human protections
governing body?
- "Oncologists in our institution discuss fertility preservation with their adult 19
patients before initiating cancer treatment and refer those who wish to freeze
ovarian 20 tissue or oocytes to our unit." It was stated that one of the benefits of
OTCP was that it may be most appropriate for prepubertal pts. Why then are
post-pubertal adult patients included in this study?
- It is unclear what patient population was studies here. In the Intro, it appears
this was limited to OTCP pts. However, in Participants, it seems that any patient
with cryopreserved reproductive material was included - implying that this may
include oocyte and embryo cryopreservation, right? 
- "Absence of menstrual cycle for at least 3 cycles or 6 months was defined as
amenorrhea." It is unclear what this means. 3 cycles consecutively? Or within a 6
month period?
Results
- Why were data not available for some patients? 
- In the text, it reads, "The mean age at follow-up was 23.7±6.3 years." However,
in Table 1, this is reported as the Age at OTCP. 
- What is the average time since diagnosis/treatment and current age and ranges,
if the above is not correct?
- Do the IVF pregnancies refer to patients using their own fresh or frozen
gametes or donated gametes?
Discussion
- The results include: "No significant differences were found in age at treatment,
chemotherapy prior to OTCP, 11 GnRHa treatment during chemotherapy or
follow-up time (years from treatment to 12 questionnaire) between the low,
moderate and high-risk groups." - this appears to be counter to the literature. The
authors may explain why this might be the case in the discussion.
- "Our risk evaluation is easily designated…" - it is unclear to me that the authors
developed their own risk evaluation. It seems as though they were following
previously published guidelines, as described in the Methods, no? It seems
references 14-16 were followed to create risk categories.
- "Women need to be aware that fertility preservation may not be an insurance
against 5 infertility but rather that it might add to the chance of achieving
parenthood in the future. 6 Women should also be informed that, although
natural conception may be possible, they 7 are at risk of premature menopause as
a consequence of the cancer treatment." This is not a new idea in the world of
oncofertility. What addition to the literature does this study provide in
counseling patients? Might clinicians use the estimates provided here? Or how
do clinicians incorporate the limitations of this study to still use the results in
counseling patients?
- "This further highlights the paramount importance of multidisciplinary
management 18 and close collaboration between the oncology and reproductive
professionals in the 19 management of these patients." - the barriers to
reproductive healthcare, including patients' ability to access fertility preservation,
certainly vary by country and health systems. The authors should comment on
this. Having providers make referrals is not the only barrier. In the US, these
procedures are often not covered by insurance and are quite expensive for
patients. 
- The authors highlight the "relatively large" sample size as a strength of the
study, when in fact I might argue the sample size was relatively small. In
comparison, ref 15 (Green et al.) reported a sample size of hundreds to establish
risk groups.
- The lack of validated measures of patient reported outcomes is also a limitation.
How informed did patients feel about their reproductive and family-building
options? Were they concerned? Distressed? 
- Overall, I am still confused about what patients this study included - only those
with a history of OTCP or all cancer patients who received gonadotoxic therapy?
If the former, then where does egg/embryo freezing exist within this?
There are grammar and some spelling mistakes throughout. 
Are the methods appropriate and well described?
If not, please specify what is
required in your comments to the authors.
Unable to assess
Does the work include the necessary controls?
If not, please specify which
controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not,
please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review
is recommended, please specify what aspects require further assessment in your
comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the
manuscript:
Needs some language corrections before being published
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