Title: CIRRHOSIS IN INTRAHEPATIC CHOLANGIOCARCINOMA: PROGNOSTIC
IMPORTANCE AND IMPACT ON SURVIVAL
Version: 3 Date: 12 Jun 2022
Reviewer's report:
Major issues
More transparency is needed in the study methods. In addition, the potential limitations need to
be acknowledged. First, the authors need to describe the data source. The NCDB is a national
hospital-based cancer registry. The authors should describe what percent of cancers diagnosed/
treated in the US are included and from which states. Like other cancer registries, it codes
cancers using ICD-O codes, which include morphologic codes and topographical codes. This
is briefly mentioned but needs to be explained this in more detail for the readers who are less
familiar with cancer registries. Second, the ICD-O codes used to identify cases need to be
shared with the readers (Ex- C221 represents intrahepatic bile duct cancer etc). Is there a reason
why 8161/3 was not used for identifying intrahepatic CCA cases? This should be explained.
Third, the authors need to clearly states what the inclusion and exclusion criteria were (if any),
as well as the study period in the methods section (the 2004-2017 NCDB was used but the
study period was 2010-2017 and this should be clearly stated in the methods section to avoid
confusion). In the statistical analysis section, they need to state the statistical tests that were
used to determine differences in demographic, tumor, and treatment characteristics by cirrhosis
status, the level of statistical significance that was used (p<0.05), and how they determined which
variables to include in their multivariable model. Did they first perform univariate analysis to
identify variables with a certain threshold of significance? Or did they use forward or backward
selection? Which variables were potential confounders? Why did they not include any of the
tumor characteristics in their multivariable model (like tumor grade, stage, and size)? I think
more detail about how they constructed their multivariable model is needed.
The authors need to discuss the potential limitations of their study more clearly. They only
state one limitation of their study (lines 227-229) when, in fact, there are several other potential
limitations and this deserves its own paragraph. One important limitation to this study is the
potential for misclassification of intrahepatic cholangiocarcinoma, which is not mentioned.
Previous US and worldwide studies have discussed the potential for misclassification of CCA
subtypes based on ICD-O coding algorithms. Specifically, it has been shown that perihilar CCA
is frequently misclassified as intrahepatic CCA when in fact it is perihilar (extrahepatic). For
example, a US study by Welzel et al examining cancer registry data from 1992-2000 found
that 91% of pCCA were incorrectly coded as iCCA, resulting in an overestimation of iCCA
incidence. The fact that 63.4% (33,160/53,054) of the patients with CCA had intrahepatic CCA
suggests the possibility of misclassification as, historically, perihilar CCA is felt to be the most
common subtype and intrahepatic CCA felt to represent 10-20% of CCA cases in the US. The
authors need to mention this important limitation and how it may affect the interpretation of
their results. Another important limitation is the potential for selection bias. This study only
includes patients who had a liver biopsy (which is appropriate in order to correctly identify
cirrhosis status), which only represented 10.9% of patients with intrahepatic CCA. There may be
systematic differences between patients who did and did not have a liver biopsy and this should
be mentioned. Maybe those who had a liver biopsy were more likely to be surgical candidates,
as liver biopsies are often performed intra-operatively at the time of staging/resection. They also
need to mention the potential limitations of using a cancer registry, which include the potential
for miscoding, missing data, and lack of patient-level data.
In terms of the survival analysis, it would be interesting to stratify by treatment type and/or
tumor stage. While this is not necessary, I think it would be interesting and would strengthen
the paper. The treatment of choice for intrahepatic CCA is surgical resection, therefore, it would
be interesting to stratify the survival analysis by resection status (those who underwent surgery
vs didn’t undergo surgery).
The presentation of the survival results is not clear. In the abstract and throughout the manuscript,
the authors reference the short-term survival, overall survival, and long-term survival whereas in
Table 5, they present the results as overall and long-term survival. In the methods section, they
only define long-term survival but never define short-term survival (is it assumed to be survival
< 60 months after date of diagnosis?). In addition, the median survival was only presented for a
subset of the study population (3,030 as opposed to 3,644) and this needs to be mentioned and
discussed. Why were 614 patients not included in the calculation of median OS?
In addition, the authors discuss in great detail the need for increased utilization of palliative care
services but how is palliative care utilization measured/defined in the NCDB database. Would
recommend discussing how the NCDB database defines palliative care utilization (ex- following
with a palliative care specialist, receiving palliative chemoradiation therapy, etc) if you want to
include this as a key message in the paper.
Lastly, the authors should mention that the study protocol was approved by the institution’s IRB
(typically included in the methods section).
Minor issues
• Line 52: Should “short term” survival be overall survival based on how it’s presented in Table 5
• Line 73: Should be Western Europe instead of West Europe
• Lines 76-77: Would say “age-adjusted incidence rates” instead of “age-adjusted rates” for
clarity
• Line 88: Consider rephrasing “significant poor prognosis for OS” to “worse survival” or “worse
prognosis”
• Line 122: Consider rephrasing to say “of the X number of patients with intrahepatic CCA, X
% underwent a liver biopsy, of which X% had cirrhosis”.
• Line 123: What do they mean by “approximately 20% of within either arm”? This sentence
is very confusing.
• Line 124: Would delete the sentence that starts with “Statistically significant differences”.
• Lines 127-129: Would consider rephrasing to say something like “a higher proportion of
patients with cirrhosis were hispanic [12.4 vs 7.5%, p<0.001)]).
• Lines 158-159: This information is not clearly shown in Table 3. In Table 3, would add the total
number of patients with and without cirrhosis at the top of the table, as well as the proportions
who underwent surgery, chemo, and radiation.
• Line 159: Would consider rephrasing “more like to not receive” to “less like to receive”
• Line 237: rephrase “at of”
• Conclusion section: Would not states “in our study of 33,160 patients”, as the results presented
only apply to the 3,644 patients with intrahepatic CCA that underwent a liver biopsy.
Title: CIRRHOSIS IN INTRAHEPATIC CHOLANGIOCARCINOMA: PROGNOSTIC
IMPORTANCE AND IMPACT ON SURVIVAL
Version: 3 Date: 12 Jun 2022
Reviewer's report:
Major issues
More transparency is needed in the study methods. In addition, the potential limitations need to
be acknowledged. First, the authors need to describe the data source. The NCDB is a national
hospital-based cancer registry. The authors should describe what percent of cancers diagnosed/
treated in the US are included and from which states. Like other cancer registries, it codes
cancers using ICD-O codes, which include morphologic codes and topographical codes. This
is briefly mentioned but needs to be explained this in more detail for the readers who are less
familiar with cancer registries. Second, the ICD-O codes used to identify cases need to be
shared with the readers (Ex- C221 represents intrahepatic bile duct cancer etc). Is there a reason
why 8161/3 was not used for identifying intrahepatic CCA cases? This should be explained.
Third, the authors need to clearly states what the inclusion and exclusion criteria were (if any),
as well as the study period in the methods section (the 2004-2017 NCDB was used but the
study period was 2010-2017 and this should be clearly stated in the methods section to avoid
confusion). In the statistical analysis section, they need to state the statistical tests that were
used to determine differences in demographic, tumor, and treatment characteristics by cirrhosis
status, the level of statistical significance that was used (p<0.05), and how they determined which
variables to include in their multivariable model. Did they first perform univariate analysis to
identify variables with a certain threshold of significance? Or did they use forward or backward
selection? Which variables were potential confounders? Why did they not include any of the
tumor characteristics in their multivariable model (like tumor grade, stage, and size)? I think
more detail about how they constructed their multivariable model is needed.
The authors need to discuss the potential limitations of their study more clearly. They only
state one limitation of their study (lines 227-229) when, in fact, there are several other potential
limitations and this deserves its own paragraph. One important limitation to this study is the
potential for misclassification of intrahepatic cholangiocarcinoma, which is not mentioned.
Previous US and worldwide studies have discussed the potential for misclassification of CCA
subtypes based on ICD-O coding algorithms. Specifically, it has been shown that perihilar CCA
is frequently misclassified as intrahepatic CCA when in fact it is perihilar (extrahepatic). For
example, a US study by Welzel et al examining cancer registry data from 1992-2000 found
that 91% of pCCA were incorrectly coded as iCCA, resulting in an overestimation of iCCA
incidence. The fact that 63.4% (33,160/53,054) of the patients with CCA had intrahepatic CCA
suggests the possibility of misclassification as, historically, perihilar CCA is felt to be the most
common subtype and intrahepatic CCA felt to represent 10-20% of CCA cases in the US. The
authors need to mention this important limitation and how it may affect the interpretation of
their results. Another important limitation is the potential for selection bias. This study only
includes patients who had a liver biopsy (which is appropriate in order to correctly identify
cirrhosis status), which only represented 10.9% of patients with intrahepatic CCA. There may be
systematic differences between patients who did and did not have a liver biopsy and this should
be mentioned. Maybe those who had a liver biopsy were more likely to be surgical candidates,
as liver biopsies are often performed intra-operatively at the time of staging/resection. They also
need to mention the potential limitations of using a cancer registry, which include the potential
for miscoding, missing data, and lack of patient-level data.
In terms of the survival analysis, it would be interesting to stratify by treatment type and/or
tumor stage. While this is not necessary, I think it would be interesting and would strengthen
the paper. The treatment of choice for intrahepatic CCA is surgical resection, therefore, it would
be interesting to stratify the survival analysis by resection status (those who underwent surgery
vs didn’t undergo surgery).
The presentation of the survival results is not clear. In the abstract and throughout the manuscript,
the authors reference the short-term survival, overall survival, and long-term survival whereas in
Table 5, they present the results as overall and long-term survival. In the methods section, they
only define long-term survival but never define short-term survival (is it assumed to be survival
< 60 months after date of diagnosis?). In addition, the median survival was only presented for a
subset of the study population (3,030 as opposed to 3,644) and this needs to be mentioned and
discussed. Why were 614 patients not included in the calculation of median OS?
In addition, the authors discuss in great detail the need for increased utilization of palliative care
services but how is palliative care utilization measured/defined in the NCDB database. Would
recommend discussing how the NCDB database defines palliative care utilization (ex- following
with a palliative care specialist, receiving palliative chemoradiation therapy, etc) if you want to
include this as a key message in the paper.
Lastly, the authors should mention that the study protocol was approved by the institution’s IRB
(typically included in the methods section).
Minor issues
• Line 52: Should “short term” survival be overall survival based on how it’s presented in Table 5
• Line 73: Should be Western Europe instead of West Europe
• Lines 76-77: Would say “age-adjusted incidence rates” instead of “age-adjusted rates” for
clarity
• Line 88: Consider rephrasing “significant poor prognosis for OS” to “worse survival” or “worse
prognosis”
• Line 122: Consider rephrasing to say “of the X number of patients with intrahepatic CCA, X
% underwent a liver biopsy, of which X% had cirrhosis”.
• Line 123: What do they mean by “approximately 20% of within either arm”? This sentence
is very confusing.
• Line 124: Would delete the sentence that starts with “Statistically significant differences”.
• Lines 127-129: Would consider rephrasing to say something like “a higher proportion of
patients with cirrhosis were hispanic [12.4 vs 7.5%, p<0.001)]).
• Lines 158-159: This information is not clearly shown in Table 3. In Table 3, would add the total
number of patients with and without cirrhosis at the top of the table, as well as the proportions
who underwent surgery, chemo, and radiation.
• Line 159: Would consider rephrasing “more like to not receive” to “less like to receive”
• Line 237: rephrase “at of”
• Conclusion section: Would not states “in our study of 33,160 patients”, as the results presented
only apply to the 3,644 patients with intrahepatic CCA that underwent a liver biopsy.
Please review this paper.
user
Title: CIRRHOSIS IN INTRAHEPATIC CHOLANGIOCARCINOMA: PROGNOSTIC
IMPORTANCE AND IMPACT ON SURVIVAL
Version: 3 Date: 12 Jun 2022
Reviewer's report:
Major issues
More transparency is needed in the study methods. In addition, the potential limitations need to
be acknowledged. First, the authors need to describe the data source. The NCDB is a national
hospital-based cancer registry. The authors should describe what percent of cancers diagnosed/
treated in the US are included and from which states. Like other cancer registries, it codes
cancers using ICD-O codes, which include morphologic codes and topographical codes. This
is briefly mentioned but needs to be explained this in more detail for the readers who are less
familiar with cancer registries. Second, the ICD-O codes used to identify cases need to be
shared with the readers (Ex- C221 represents intrahepatic bile duct cancer etc). Is there a reason
why 8161/3 was not used for identifying intrahepatic CCA cases? This should be explained.
Third, the authors need to clearly states what the inclusion and exclusion criteria were (if any),
as well as the study period in the methods section (the 2004-2017 NCDB was used but the
study period was 2010-2017 and this should be clearly stated in the methods section to avoid
confusion). In the statistical analysis section, they need to state the statistical tests that were
used to determine differences in demographic, tumor, and treatment characteristics by cirrhosis
status, the level of statistical significance that was used (p<0.05), and how they determined which
variables to include in their multivariable model. Did they first perform univariate analysis to
identify variables with a certain threshold of significance? Or did they use forward or backward
selection? Which variables were potential confounders? Why did they not include any of the
tumor characteristics in their multivariable model (like tumor grade, stage, and size)? I think
more detail about how they constructed their multivariable model is needed.
The authors need to discuss the potential limitations of their study more clearly. They only
state one limitation of their study (lines 227-229) when, in fact, there are several other potential
limitations and this deserves its own paragraph. One important limitation to this study is the
potential for misclassification of intrahepatic cholangiocarcinoma, which is not mentioned.
Previous US and worldwide studies have discussed the potential for misclassification of CCA
subtypes based on ICD-O coding algorithms. Specifically, it has been shown that perihilar CCA
is frequently misclassified as intrahepatic CCA when in fact it is perihilar (extrahepatic). For
example, a US study by Welzel et al examining cancer registry data from 1992-2000 found
that 91% of pCCA were incorrectly coded as iCCA, resulting in an overestimation of iCCA
incidence. The fact that 63.4% (33,160/53,054) of the patients with CCA had intrahepatic CCA
suggests the possibility of misclassification as, historically, perihilar CCA is felt to be the most
common subtype and intrahepatic CCA felt to represent 10-20% of CCA cases in the US. The
authors need to mention this important limitation and how it may affect the interpretation of
their results. Another important limitation is the potential for selection bias. This study only
includes patients who had a liver biopsy (which is appropriate in order to correctly identify
cirrhosis status), which only represented 10.9% of patients with intrahepatic CCA. There may be
systematic differences between patients who did and did not have a liver biopsy and this should
be mentioned. Maybe those who had a liver biopsy were more likely to be surgical candidates,
as liver biopsies are often performed intra-operatively at the time of staging/resection. They also
need to mention the potential limitations of using a cancer registry, which include the potential
for miscoding, missing data, and lack of patient-level data.
In terms of the survival analysis, it would be interesting to stratify by treatment type and/or
tumor stage. While this is not necessary, I think it would be interesting and would strengthen
the paper. The treatment of choice for intrahepatic CCA is surgical resection, therefore, it would
be interesting to stratify the survival analysis by resection status (those who underwent surgery
vs didn’t undergo surgery).
The presentation of the survival results is not clear. In the abstract and throughout the manuscript,
the authors reference the short-term survival, overall survival, and long-term survival whereas in
Table 5, they present the results as overall and long-term survival. In the methods section, they
only define long-term survival but never define short-term survival (is it assumed to be survival
< 60 months after date of diagnosis?). In addition, the median survival was only presented for a
subset of the study population (3,030 as opposed to 3,644) and this needs to be mentioned and
discussed. Why were 614 patients not included in the calculation of median OS?
In addition, the authors discuss in great detail the need for increased utilization of palliative care
services but how is palliative care utilization measured/defined in the NCDB database. Would
recommend discussing how the NCDB database defines palliative care utilization (ex- following
with a palliative care specialist, receiving palliative chemoradiation therapy, etc) if you want to
include this as a key message in the paper.
Lastly, the authors should mention that the study protocol was approved by the institution’s IRB
(typically included in the methods section).
Minor issues
• Line 52: Should “short term” survival be overall survival based on how it’s presented in Table 5
• Line 73: Should be Western Europe instead of West Europe
• Lines 76-77: Would say “age-adjusted incidence rates” instead of “age-adjusted rates” for
clarity
• Line 88: Consider rephrasing “significant poor prognosis for OS” to “worse survival” or “worse
prognosis”
• Line 122: Consider rephrasing to say “of the X number of patients with intrahepatic CCA, X
% underwent a liver biopsy, of which X% had cirrhosis”.
• Line 123: What do they mean by “approximately 20% of within either arm”? This sentence
is very confusing.
• Line 124: Would delete the sentence that starts with “Statistically significant differences”.
• Lines 127-129: Would consider rephrasing to say something like “a higher proportion of
patients with cirrhosis were hispanic [12.4 vs 7.5%, p<0.001)]).
• Lines 158-159: This information is not clearly shown in Table 3. In Table 3, would add the total
number of patients with and without cirrhosis at the top of the table, as well as the proportions
who underwent surgery, chemo, and radiation.
• Line 159: Would consider rephrasing “more like to not receive” to “less like to receive”
• Line 237: rephrase “at of”
• Conclusion section: Would not states “in our study of 33,160 patients”, as the results presented
only apply to the 3,644 patients with intrahepatic CCA that underwent a liver biopsy.
assistant