Download Cancer-related hospitalisations and `unknown` stage

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ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Cancer related hospitalisations and “unknown” stage prostate
cancer: a population-based record linkage study
Luo, Qingwei; Yu, Xue Qin; Smith, David; Goldsbury, David; CookeYarborough, Claire; Patel, Manish; O'Connell, Dianne
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Cong Chen, Analytical Developer
National Cancer Registration and Analysis Service,
Public Health England,
United Kingdom
27-Sep-2016
This paper describes the incidence of missing data among prostate
cancer records in the 2001-2009 study period and explores possibly
correlated variables using the New South Wales Cancer Registry
and Admitted Patient Data Collection records by reporting relevant
data and cursory statistical analysis. I am happy to recommend it for
publication with minor corrections.
While some attention is given to the non-reporting of cancer (Figure
1, cited on page 7) this is not further discussed. No discussion is
provided of the high number of patients who are diagnosed within
the same time period with both prostate cancer and another cancer,
how the study might distinguish treatments for different cancers, and
the confounding effect the presence of multiple cancers has on
survival analysis and hospital treatments.
The last paragraph of the discussion section on page 14 would be
improved by providing a reference discussing the consequences of
missing data and resulting bias, such as the well-known „Multiple
imputation for missing data in epidemiological and clinical research:
potential and pitfalls‟ BMJ 2009;338:b2393 . The first paragraph on
page 11 suggests that survival outcomes for “unknown” stage
resemble those for certain other stages. Insufficient data is
presented to determine whether this is not a result of “unknown”
being distributed similarly to the known stages and the survival
behaving as some form of average. It would be good if the
speculation could be better grounded.
The clarity of the paper could be improved by a number of small
changes. Stage at diagnosis, as mentioned on page 6 under
Outcome variables, is not clearly defined. The CHeReL data
dictionary (reference 13) does not mention any stage fields for
NSWCR data, and the paragraph is very confusing. In particular,
where do “stage at diagnosis” and “summary stage based on spread
within four months of diagnosis” come from as data and do they in
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
fact refer to the same field? ORs (odds ratios, abstract onwards) and
the ICD-10-AM (Australian Modification, page 7 onwards) are never
written out. ICD-10-AM has a reference given to explain it (reference
13) but ICD classification is not even mentioned on that page
(http://www.cherel.org.au/data-dictionaries, accessed September 26
2016) and a more appropriate reference should be provided.
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Klaus Kraywinkel
Center for Cancer Registry Data,
Robert Koch-Institute, Berlin, Germany
10-Oct-2016
Overall a well designed and performed study, about an important
topic in cancer registration. The manuscript, for most parts, is
intelligibly written. A lot of data are presented, which makes it a little
difficult for the reader to keep track, but at the end the very most of
them seem to be worth being reported. Nevertheless I have some
comments/suggestions:
1. Not being familiar with the Australian health system, I had some
difficulties in understanding how "non hospital reported cases" could
be characterized. Through which sources of information did the
NSWCR become aware of these cases, if their were not "hospital
reported?" Does the term "not hospital reported" specificly mean the
patient was definetly not treated in a hospital, or may there be other
explanations? What exactly are "non-notifying facilities such as
private consulting rooms" (page 12), if there is a mandatory
requirement hat all cancers diagnosed in NSW, ... are notified to the
NSWCR by institutions including public and private hospitals, public
multipurpose health services, radiation oncology departments,
cancer care centres, private day procedure centres, residential aged
care facilities and pathology laboratories" (page 5). At this point I got
a little confused about how any facility could be "non-notifying".
2. In the introduction, you clearly pointed under which circumstances
"missing stage" may occur: either the medical workup was not
complete due to various reasons (including patient related ones like
advanced age and comorbidities), or the workup was done, but did
information somehow did not make it to the NSWCR. In the
discussion you mention a combination of both: there was some
workup, but no RP was performed, and the available staging
information didn't "fit" into the NSWCR staging system (like the T1c
cases you mentioned on page 13). Maybe you could try to be a little
more explicit about your findings to what extend the "missing stage"
could be referred to the above mentioned mechanisms. This would
be especially important because only the second and third
mechanism seems to be susceptible for improvements.
3. Speaking of improvements: In my view you seem a bit
restrained/less specific regarding your conclusions: Following your
argumentation on page 13:
"The staging system used by the NSWCR does not allow for stage
to be assigned from a needle biopsy alone, so low risk patients
diagnosed by a core needle biopsy alone due to elevated PSA,
unlike that used in the USA SEER system (classified as T1c stage),
will be recorded as “unknown” stage ..."
wouldn't it be consistent to suggest that the NSWCR should
somehow adapt their system of collecting stage information, at least
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
for prostate cancer? It seems that relevant information that is
actually there is getting lost to the cancer registry because it does
not fit to the NSWCR system, which seems somewhat unnecessary
(and you mention that the other cancer registries like SEER have
more appropiate ways to collect this information). In general terms, I
would like to learn a little more about what you think could be done
to improve completeness of stage information. A statement like
"Particularly, the potential issues in relation to the cancer notification
systems in public and private hospitals identified in this study may
need further attention to improve the completeness of stage data in
the NSWCR" seems a little bit weak/inconcrete.
4. Referring to the possible bias in survival rates introduced by
missing stage information (page 14), you state: "For example, when
examining differences in survival between stages, the results will be
biased towards the null if cases with “unknown” stage are simply
grouped with the localised, regional or distant stage cases."
I don't know of any analysis performed that way. Normally, either
survival of those with missing stage is not given at all (which I think
is not a good idea), or it is presented as an own category. The more
severe problem may be that the survival by stage itself may be
biased (towards higher figures) because the cases with stage
information represented a positive selection of patients that are "fit"
enough for the medical workup, or for an RP. Your results seem to
indicate that this is not really the case at least for those patients who
get some kind of treatment. Nevertheless I found these analyses to
be very informative, but would not exactly share your conlusions.
VERSION 1 – AUTHOR RESPONSE
Reviewer: 1
Reviewer Name: Cong Chen, Analytical Developer Institution and Country: National Cancer
Registration and Analysis Service, Public Health England, United Kingdom Please state any
competing interests or state „None declared‟: None declared
Please leave your comments for the authors below This paper describes the incidence of missing
data among prostate cancer records in the 2001-2009 study period and explores possibly correlated
variables using the New South Wales Cancer Registry and Admitted Patient Data Collection records
by reporting relevant data and cursory statistical analysis. I am happy to recommend it for publication
with minor corrections.
While some attention is given to the non-reporting of cancer (Figure 1, cited on page 7) this is not
further discussed.
Authors‟ response:
We thank the reviewer for this comment and agree that cancer care provided by NSWCR “nonnotifiers” as presented in Figure 1 should be discussed further. In our original submission, this point
was further discussed this in the first paragraph of the Discussion on page 12 and in the second
paragraph on page 13, and we now cite Figure 1 in the relevant context in the first paragraph of the
Discussion on page 12.
No discussion is provided of the high number of patients who are diagnosed within the same time
period with both prostate cancer and another cancer, how the study might distinguish treatments for
different cancers, and the confounding effect the presence of multiple cancers has on survival
analysis and hospital treatments.
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
Authors‟ response:
This study included all men with a first diagnosis of prostate cancer and 2% of this cohort were
diagnosed with another cancer during the same time period. To distinguish the treatments for different
cancers, only prostate cancer specific procedures were identified by the procedure codes in the
Medicare Benefits Schedule-Extended classification of the ICD-10-AM (please see “Hospital prostate
cancer procedures” in the Methods section on page 7). In order to rule out the confounding effect of
the presence of multiple cancers on the survival analysis, we accounted for the comorbidity scores
which included cancers other than prostate cancer (please see “Comorbidities” in Methods section on
page 8 and 9).
The last paragraph of the discussion section on page 14 would be improved by providing a reference
discussing the consequences of missing data and resulting bias, such as the well-known „Multiple
imputation for missing data in epidemiological and clinical research: potential and pitfalls‟ BMJ
2009;338:b2393 .
Authors‟ response:
We have revised the final paragraph of the Discussion (first paragraph on page 15) to further explore
the implications of missing data on statistical analyses and have added the reference as suggested
(reference 30).
The first paragraph on page 11 suggests that survival outcomes for “unknown” stage resemble those
for certain other stages. Insufficient data is presented to determine whether this is not a result of
“unknown” being distributed similarly to the known stages and the survival behaving as some form of
average. It would be good if the speculation could be better grounded.
Authors‟ response:
We agree that the data available for this study are insufficient to determine whether the survival
pattern is a result of “unknown” stage being distributed similarly to the known stages or that the
survival behaves as some form of average. Unfortunately we cannot obtain detailed clinical
information from the cancer registry, and as a result, we cannot identify the composition of “unknown”
stage. However, we have added some further discussion about the possible mixture of stages to the
last paragraph of the Discussion on page 14.
The clarity of the paper could be improved by a number of small changes. Stage at diagnosis, as
mentioned on page 6 under Outcome variables, is not clearly defined. The CHeReL data dictionary
(reference 13) does not mention any stage fields for NSWCR data, and the paragraph is very
confusing. In particular, where do “stage at diagnosis” and “summary stage based on spread within
four months of diagnosis” come from as data and do they in fact refer to the same field? ORs (odds
ratios, abstract onwards) and the ICD-10-AM (Australian Modification, page 7 onwards) are never
written out. ICD-10-AM has a reference given to explain it (reference 13) but ICD classification is not
even mentioned on that page (http://www.cherel.org.au/data-dictionaries, accessed September 26
2016) and a more appropriate reference should be provided.
Authors‟ response:
We have revised the manuscript to consistently use „stage at diagnosis‟, which refers to the data field
„Degree of spread at diagnosis‟ provided in the NSWCR data. We have revised the „stage at
diagnosis‟ definition on page 6 under „Outcome variables‟ and added a specific reference (the
NSWCR data dictionary, reference 15). We used the term stage at diagnosis instead of degree of
spread so that the term is in line with other international publications.
We have added the definition of ORs at the first mention in the Abstract on page 1.
We have added a new reference (reference 18) to explain the first mention of the International
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
Classification of Diseases 10th revision Australian Modification (ICD-10-AM) (see the first paragraph
on page 7).
Reviewer: 2
Reviewer Name: Klaus Kraywinkel
Institution and Country: Center for Cancer Registry Data, Robert Koch-Institute, Berlin, Germany
Please state any competing interests or state „None declared‟: „None declared‟
Please leave your comments for the authors below Overall a well designed and performed study,
about an important topic in cancer registration. The manuscript, for most parts, is intelligibly written. A
lot of data are presented, which makes it a little difficult for the reader to keep track, but at the end the
very most of them seem to be worth being reported. Nevertheless I have some
comments/suggestions:
1. Not being familiar with the Australian health system, I had some difficulties in understanding how
"non hospital reported cases" could be characterized. Through which sources of information did the
NSWCR become aware of these cases, if there were not "hospital reported?" Does the term "not
hospital reported" specifically mean the patient was definitely not treated in a hospital, or may there
be other explanations? What exactly are "non-notifying facilities such as private consulting rooms"
(page 12), if there is a mandatory requirement that all cancers diagnosed in NSW, ... are notified to
the NSWCR by institutions including public and private hospitals, public multipurpose health services,
radiation oncology departments, cancer care centres, private day procedure centres, residential aged
care facilities and pathology laboratories" (page 5). At this point I got a little confused about how any
facility could be "non-notifying".
Authors‟ response:
We thank the reviewer for this comment, and have added some clarification on the health service
facilities that are not mandatory notifiers to the NSWCR to the Methods section, second paragraph on
page 5:
'However, mandatory notifiers do not include the private consulting rooms of individual general
practitioners or specialists (including urologists). '
We have revised the description on hospital-reported prostate cancer diagnosis in the first paragraph
on page 7 to clarify that only patients with a prostate cancer-related hospitalisation will have a hospital
reported diagnosis. Patients are not reported to the NSWCR, and are considered “non-hospital
reported cases”, when they received hospitalisations that were not related to prostate cancer. The
term “not hospital reported” can be interpreted as the patient was not treated for prostate cancer in a
hospital during the study period. For these cases, the only notification to the NSWCR is likely to be
the pathology report confirming the cancer diagnosis. This was discussed in the second paragraph of
the Discussion on page 13.
2. In the introduction, you clearly pointed under which circumstances “missing stage" may occur:
either the medical workup was not complete due to various reasons (including patient related ones
like advanced age and comorbidities), or the workup was done, but the information somehow did not
make it to the NSWCR. In the discussion you mention a combination of both: there was some workup,
but no RP was performed, and the available staging information didn't "fit" into the NSWCR staging
system (like the T1c cases you mentioned on page 13). Maybe you could try to be a little more explicit
about your findings to what extent the "missing stage" could be referred to the above mentioned
mechanisms. This would be especially important because only the second and third mechanism seem
to be susceptible for improvements.
Authors‟ response:
We have revised the second paragraph on page 13 to be more explicit about our findings on the
possible reasons by adding the percentages of patients who did not receive surgical treatment or
active treatment within four months after diagnosis, as shown below:
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
'We found that 95% of prostate cancer patients with “unknown” stage received no surgical treatment,
and that half of these patients received no other active treatment up to four months after diagnosis.'
However, as we do not have clinical data relating to the medical workup, such as clinical stage
assessment performed at private consulting rooms of general practitioners or specialists (e.g.
urologists), we cannot provide any more explicit information on patients whose stage was not
recorded by the NSWCR (e.g. low risk patients diagnosed by a core needle biopsy alone due to
elevated PSA, or patients who had a bone scan or imaging outside a hospital and then went onto
watchful waiting or androgen deprivation therapy, which was not captured in the APDC data).
3. Speaking of improvements: In my view you seem a bit restrained/less specific regarding your
conclusions: Following your argumentation on page 13:
"The staging system used by the NSWCR does not allow for stage to be assigned from a needle
biopsy alone, so low risk patients diagnosed by a core needle biopsy alone due to elevated PSA,
unlike that used in the USA SEER system (classified as T1c stage), will be recorded as “unknown”
stage ..."
Wouldn‟t it be consistent to suggest that the NSWCR should somehow adapt their system of
collecting stage information, at least for prostate cancer? It seems that relevant information that is
actually there is getting lost to the cancer registry because it does not fit to the NSWCR system, which
seems somewhat unnecessary (and you mention that the other cancer registries like SEER have
more appropriate ways to collect this information). In general terms, I would like to learn a little more
about what you think could be done to improve completeness of stage information. A statement like
"Particularly, the potential issues in relation to the cancer notification systems in public and private
hospitals identified in this study may need further attention to improve the completeness of stage data
in the NSWCR" seems a little bit weak/inconcrete.
Authors‟ response:
We have revised the second paragraph on page 13 of the Discussion section to reflect the differences
between the NSWCR and SEER systems and why we couldn‟t suggest the adoption of SEER staging
rules in the NSWCR. Unlike the USA SEER system which includes detailed clinical information
including diagnostic information and TNM stage, there is no clinical information in the NSWCR to
identify the patients who were diagnosed by a core needle biopsy alone due to elevated PSA levels
(low risk cases), or who had a bone scan or imaging outside a hospital and then went onto watchful
waiting or androgen deprivation therapy (advanced disease cases) due to the absence of clinical
information. However, in the last paragraph on page 15, we described the newly established NSW
Prostate Clinical Cancer Registry which intends to collect clinical stage and PSA levels from
clinicians.
We have also revised the last paragraph of the paper to incorporate the reviewer‟s comment on more
specific argument regarding the improving the completeness of stage information (see the last
paragraph on page 15 and the first paragraph on page 16). We highlighted that both incorporating the
clinical disease information from clinicians and reducing the differences in cancer notifications by
geographical location and private facilities will contribute to the improvement of completeness of stage
data in the NSWCR.
4. Referring to the possible bias in survival rates introduced by missing stage information (page 14),
you state: "For example, when examining differences in survival between stages, the results will be
biased towards the null if cases with “unknown” stage are simply grouped with the localised, regional
or distant stage cases."
I don't know of any analysis performed that way. Normally, either survival of those with missing stage
is not given at all (which I think is not a good idea), or it is presented as an own category.
Authors‟ response:
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
We agree that in general analyses do not group cases with “unknown” stage with those cases with a
known stage. We have deleted this sentence (see the last paragraph on page 14).
The more severe problem may be that the survival by stage itself may be biased (towards higher
figures) because the cases with stage information represented a positive selection of patients that are
"fit" enough for the medical workup, or for an RP. Your results seem to indicate that this is not really
the case at least for those patients who get some kind of treatment. Nevertheless I found these
analyses to be very informative, but would not exactly share your conclusions.
Authors‟ response:
We acknowledge that the paragraph regarding the possible bias in survival rates introduced by
“unknown” stage on page 14 in our first submission was not very clear. We found that the group of
prostate cancer cases who did not receive surgical treatment (e.g. RP) consisted of both those
patients who were not well enough to undergo RP or other definitive staging assessments, and a
group of low risk cases who were diagnosed by a core needle biopsy alone due to elevated PSA
levels, the prostate cancer patients with “unknown” stage are likely to be a mixture of stages. As a
result, the direction of bias introduced by “unknown” stage can be towards or away from the null,
depending on the variation in the composition of this mixture of stages. We have added more detailed
discussion of this to the Discussion, in the last paragraph on page 14.
VERSION 2 – REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Cong Chen
National Cancer Registration and Analysis Service, Public Health
England, United Kingdom
11-Dec-2016
I am happy that the revision has adequately addressed issues with
the previous version of the paper and recommend that it be
accepted for publication.
If the authors are inclined it may help to include the quoted
paragraph in the body of the paper, including the 2%, that only
prostate cancer specific procedures were extracted and rewording
"excluding prostate cancer and metastatic tumors", to make it clear
what was excluded (presumably not metastatic tumors in general). I
would also appreciate a little clarification on "first diagnosis of
prostate cancer".
Authors‟ response:
This study included all men with a first diagnosis of prostate cancer
and 2% of this cohort were diagnosed with another cancer during
the same time period. To distinguish the treatments for different
cancers, only prostate cancer specific procedures were identified by
the procedure codes in the Medicare Benefits Schedule-Extended
classification of the ICD-10-AM (please see “Hospital prostate
cancer procedures” in the Methods section on page 7). In order to
rule out the confounding effect of the presence of multiple cancers
on the survival analysis, we accounted for the comorbidity scores
which included cancers other than prostate cancer (please see
“Comorbidities” in Methods section on page 8 and 9).
Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Klaus Kraywinkel
Center for Cancer Registry Data
at the Robert Koch-Institute
Germany
14-Dec-2016
From my perspective, the recommendations of both reviewers are
adequately implemented in the revised manuscripts.
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Cancer-related hospitalisations and
'unknown' stage prostate cancer: a
population-based record linkage study
Qingwei Luo, Xue Qin Yu, David Paul Smith, David Eamon Goldsbury,
Claire Cooke-Yarborough, Manish Indravadan Patel and Dianne Lesley
O'Connell
BMJ Open 2017 7:
doi: 10.1136/bmjopen-2016-014259
Updated information and services can be found at:
http://bmjopen.bmj.com/content/7/1/e014259
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