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Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. 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. Downloaded from http://bmjopen.bmj.com/ on May 14, 2017 - Published by group.bmj.com 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 These include: References This article cites 15 articles, 2 of which you can access for free at: http://bmjopen.bmj.com/content/7/1/e014259#BIBL Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. 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