Title: The effect of menopausal hormone therapy on gastrointestinal cancer risk and mortality
in South Korea: a population based cohort study
Version: 3 Date: 21 May 2021
Reviewer's report:
This study by Nam et al. entitled “The effect of menopausal hormone therapy on gastrointestinal
cancer risk and mortality in South Korea: a population based cohort study” aims to evaluate
the association between menopausal hormone therapy and gastrointestinal cancer risk. They
utilize data from the NHIS Sample Cohort of Korea and conduct a propensity-matched cohort
study. They report a decreased risk of colorectal cancer and gastric cancer, although estimates
for cancer sites other than colorectal are hampered by statistical imprecision. Hence, the
study confirms the existing literature within this field. There are some limitations to take into
consideration.
1. The rationale for including all gastrointestinal cancers in one study is not well justified. Much
evidence exists with respect to colorectal cancer which has a very different pathogenesis than,
for instance, gastric cancer. The authors should explain in more details why they want to study
all gastrointestinal cancers in the same study.
2. With respect to the propensity score matching, the authors need to describe the methods for this
matching in more details. It is also unclear why they adjust for the factors they matched on and
why they did not include all covariates in the propensity score matching. Furthermore, it seems
as if only non-users who did not receive hormone therapy during follow-up were considered
eligible. If this is true, they have excluded matched non-users who became users during follow-
up. This is inappropriate and could lead to biased estimates. Finally, in the methods section, the
terminology ‘cases and controls’ is used, whereas the terms ‘hormone users’ and ‘non-users’ are
applied in the rest of the study. The latter is to be preferred.
3. An analysis of the impact of duration of MHT use is warranted. For studies on cancer risk,
analyses that confirm increasing risk with increasing duration of use are pivotal. Accordingly,
an analysis for discontinuation of use would also strengthen the paper.
4. In the results section, the authors use Kaplan-Meier estimates and incidence rates to compare
users and non-users. This should be avoided. The comparison of risk between users and non-
users is what the Cox Regression should be used for. Kaplan-Meier estimates and incidence
rates should be used only to describe absolute risks of cancer. In addition, it is unclear why they
report Kaplan-Meier survival curves for outcomes that are not related to survival. Suggest that
they provide cumulative incidence curves for cancer and treat death as competing risk, unless
death is part of the outcome definition.
5. In tables 2 and 3, it is unclear why the authors include estimates for covariates. The study
cohort is defined by hormone therapy users and non-users and, as such, estimates for these
covariates are not particularly relevant. Instead, it would be interesting to evaluate incidence of
hormone therapy use stratified by, for instance, age and Charlson Comorbidity Index (although
data might be sparse).
Title: The effect of menopausal hormone therapy on gastrointestinal cancer risk and mortality
in South Korea: a population based cohort study
Version: 3 Date: 21 May 2021
Reviewer's report:
This study by Nam et al. entitled “The effect of menopausal hormone therapy on gastrointestinal
cancer risk and mortality in South Korea: a population based cohort study” aims to evaluate
the association between menopausal hormone therapy and gastrointestinal cancer risk. They
utilize data from the NHIS Sample Cohort of Korea and conduct a propensity-matched cohort
study. They report a decreased risk of colorectal cancer and gastric cancer, although estimates
for cancer sites other than colorectal are hampered by statistical imprecision. Hence, the
study confirms the existing literature within this field. There are some limitations to take into
consideration.
1. The rationale for including all gastrointestinal cancers in one study is not well justified. Much
evidence exists with respect to colorectal cancer which has a very different pathogenesis than,
for instance, gastric cancer. The authors should explain in more details why they want to study
all gastrointestinal cancers in the same study.
2. With respect to the propensity score matching, the authors need to describe the methods for this
matching in more details. It is also unclear why they adjust for the factors they matched on and
why they did not include all covariates in the propensity score matching. Furthermore, it seems
as if only non-users who did not receive hormone therapy during follow-up were considered
eligible. If this is true, they have excluded matched non-users who became users during follow-
up. This is inappropriate and could lead to biased estimates. Finally, in the methods section, the
terminology ‘cases and controls’ is used, whereas the terms ‘hormone users’ and ‘non-users’ are
applied in the rest of the study. The latter is to be preferred.
3. An analysis of the impact of duration of MHT use is warranted. For studies on cancer risk,
analyses that confirm increasing risk with increasing duration of use are pivotal. Accordingly,
an analysis for discontinuation of use would also strengthen the paper.
4. In the results section, the authors use Kaplan-Meier estimates and incidence rates to compare
users and non-users. This should be avoided. The comparison of risk between users and non-
users is what the Cox Regression should be used for. Kaplan-Meier estimates and incidence
rates should be used only to describe absolute risks of cancer. In addition, it is unclear why they
report Kaplan-Meier survival curves for outcomes that are not related to survival. Suggest that
they provide cumulative incidence curves for cancer and treat death as competing risk, unless
death is part of the outcome definition.
5. In tables 2 and 3, it is unclear why the authors include estimates for covariates. The study
cohort is defined by hormone therapy users and non-users and, as such, estimates for these
covariates are not particularly relevant. Instead, it would be interesting to evaluate incidence of
hormone therapy use stratified by, for instance, age and Charlson Comorbidity Index (although
data might be sparse).
Please review this paper.
user
Title: The effect of menopausal hormone therapy on gastrointestinal cancer risk and mortality
in South Korea: a population based cohort study
Version: 3 Date: 21 May 2021
Reviewer's report:
This study by Nam et al. entitled “The effect of menopausal hormone therapy on gastrointestinal
cancer risk and mortality in South Korea: a population based cohort study” aims to evaluate
the association between menopausal hormone therapy and gastrointestinal cancer risk. They
utilize data from the NHIS Sample Cohort of Korea and conduct a propensity-matched cohort
study. They report a decreased risk of colorectal cancer and gastric cancer, although estimates
for cancer sites other than colorectal are hampered by statistical imprecision. Hence, the
study confirms the existing literature within this field. There are some limitations to take into
consideration.
1. The rationale for including all gastrointestinal cancers in one study is not well justified. Much
evidence exists with respect to colorectal cancer which has a very different pathogenesis than,
for instance, gastric cancer. The authors should explain in more details why they want to study
all gastrointestinal cancers in the same study.
2. With respect to the propensity score matching, the authors need to describe the methods for this
matching in more details. It is also unclear why they adjust for the factors they matched on and
why they did not include all covariates in the propensity score matching. Furthermore, it seems
as if only non-users who did not receive hormone therapy during follow-up were considered
eligible. If this is true, they have excluded matched non-users who became users during follow-
up. This is inappropriate and could lead to biased estimates. Finally, in the methods section, the
terminology ‘cases and controls’ is used, whereas the terms ‘hormone users’ and ‘non-users’ are
applied in the rest of the study. The latter is to be preferred.
3. An analysis of the impact of duration of MHT use is warranted. For studies on cancer risk,
analyses that confirm increasing risk with increasing duration of use are pivotal. Accordingly,
an analysis for discontinuation of use would also strengthen the paper.
4. In the results section, the authors use Kaplan-Meier estimates and incidence rates to compare
users and non-users. This should be avoided. The comparison of risk between users and non-
users is what the Cox Regression should be used for. Kaplan-Meier estimates and incidence
rates should be used only to describe absolute risks of cancer. In addition, it is unclear why they
report Kaplan-Meier survival curves for outcomes that are not related to survival. Suggest that
they provide cumulative incidence curves for cancer and treat death as competing risk, unless
death is part of the outcome definition.
5. In tables 2 and 3, it is unclear why the authors include estimates for covariates. The study
cohort is defined by hormone therapy users and non-users and, as such, estimates for these
covariates are not particularly relevant. Instead, it would be interesting to evaluate incidence of
hormone therapy use stratified by, for instance, age and Charlson Comorbidity Index (although
data might be sparse).
assistant