Quality of the diagnostic process in patients presenting with symptoms suggestive of bladder or kidney cancer: a systematic review

Objectives In urological cancers, sex disparity exists for survival, with women doing worse than men. Suboptimal evaluation of presenting symptoms may contribute. Design We performed a systematic review examining factors affecting the quality of the diagnostic process of patients presenting with symptoms of bladder or kidney cancer. Data sources We searched Medline, Embase and the Cochrane Library from 1 January 2000 to 13 June 2019. Eligible criteria We focused on one of the six domains of quality of healthcare: timeliness, and examined the quality of the diagnostic process more broadly, by assessing whether guideline-concordant history, examination, tests and referrals were performed. Studies describing the factors that affect the timeliness or quality of the assessment of urinary tract infections, haematuria and lower urinary tract symptoms in the context of bladder or kidney cancer, were included. Data extraction and synthesis Data extraction and quality assessment were independently performed by two authors. Due to the heterogeneity of study design and outcomes, the results could not be pooled. A narrative synthesis was performed. Results 28 studies met review criteria, representing 583 636 people from 9 high-income countries. Studies were based in primary care (n=8), specialty care (n=12), or both (n=8). Up to two-thirds of patients with haematuria received no further evaluation in the 6 months after their initial visit. Urinary tract infections, nephrolithiasis and benign prostatic conditions before cancer diagnosis were associated with diagnostic delay. Women were more likely to experience diagnostic delay than men. Patients who first saw a urologist were less likely to experience delayed evaluation and cancer diagnosis. Conclusions Women, and patients with non-cancerous urological diagnoses just prior to their cancer diagnosis, were more likely to experience lower quality diagnostic processes. Risk prediction tools, and improving guideline ambiguity, may improve outcomes and reduce sex disparity in survival for these cancers.


GENERAL COMMENTS
This is a well-written systematic review that makes an important contribution to the knowledge base for cancer diagnosis. I have only the following few comments of which comments 1 and 5 need to be addressed as a minimum: Method/search strategy and study inclusion: 1) Searching only Medline and Embase is very restricted. As a minimum this needs to be complemented by a search of the Cochrane library too.
2) Rationale for restricting to 2000 onwards not very strong and suggests you have missed some pre-2000 studies (even if only few).
Could it be improved, e.g., has the technology used in the diagnostic process changed significantly from 2000?
Method/data extraction and quality assessment: 3) From the abstract it is clear that quality appraisal is also performed by 2 authors independently, but this is not clear from the methods section. I suggest including this information here too as it is a strength.
Results: 4) The positive association between haematuria visits and diagnostic delay, I imagine reflects that the more haematuria visits a patient has, the longer the delay is, but I would suggest writing this out in full for clarity, especially in the context of the dose-dependent relationship between haematuria visits and likelihood of referral presented immediately beforehand. 5) You have clearly and explicitly assessed study quality and presented it in Table 1. Nevertheless you have not linked this to the results anywhere else in the results section. Some discussion of it in relation to the validity of the results is necessary in the results section, and I would also suggest adding a summary of that discussion to the actual Discussion section. In systematic reviews this needs to be explicit in all parts of the manuscript (apart from the introduction).
6) Instead of using NS to mean either non-specified (Appendix 2) or non-significant (

GENERAL COMMENTS
This is a nice review of published literature on the timeliness and quality of investigation of symptoms of bladder and kidney cancer.
The review is in narrative form, which makes synthesis of data somewhat more challenging than if a meta-analysis had been caried out -however, this seems to be a reflection of the heterogeneity of the literature rather than a limitation of the review itself.

REVIEWER
Jonathan Gelfond UT Health San Antonio, USA REVIEW RETURNED 06-Jun-2019

GENERAL COMMENTS
The authors present an interesting systematic review of the literatures on the diagnostic evaluation for bladder and kidney cancer. The paper is clearly written. The authors were focused on the quality and the timeliness of the diagnostic evaluation. The applied NICE criterion was appropriate. The authors present a summary of previous findings on the factors associated with lower quality assessment andelay in diagnosis (female gender, urologist vs. general practitioner, etc.). The main findings are nicely summarized in Table 3. There are a couple of minor concerns. 1. Would it have been possible to do a meta-analysis of a subset of the studies or the outcome that were most homogenous? 2.
There was over 15 years of data, which is a strength of the paper, but are there any time trends in these findings? 3.
The studies discussed were mostly retrospective, but there were some prospective intervention studies that were targeting improvements in such diagnostic evaluations. In Table 2 the control vs intervention times in the right columns seem reversed. Could this be made more clear? 4.
Could Table 2 identify the significant differences between men and women?

Reviewer: 1
Please leave your comments for the authors below I would like to thank the authors for writing a well thought out review which is very much needed and relevant.
I have a few minor query: Although the author's do justify why the search started from 1st January 2000 due to their prior knowledge it would be good if they could justify this on a non subjective basis i.e. by inserting a reference which indicates for instance technological advances where not available or papers were not available etc.
Thank you Reviewer 1 for your positive comment.
We have cited the 2017 Ngo review on diagnostic timeliness of haematuria, which found 2 (relatively small) studies in the 1980s from Sweden and Denmark. However, we have supplemented our rationale for focusing on the year 2000 and beyond, mainly due to the knowledge that the two-weekwait/fast-track referral system was introduced in 2000, and that clinical practice, diagnostic quality and timeliness would have been affected by this.
"We restricted our search to studies published from 2000 due to prior knowledge that there were few early relevant studies 9 , and that the quality of the diagnostic process for cancer might have been affected by the introduction of national initiatives such as the fast-track referral pathways in the United Kingdom (UK) in 2000." Reviewer: 2 This is a well-written systematic review that makes an important contribution to the knowledge base for cancer diagnosis. I have only the following few comments of which comments 1 and 5 need to be addressed as a minimum: Method/search strategy and study inclusion: 1) Searching only Medline and Embase is very restricted. As a minimum this needs to be complemented by a search of the Cochrane library too.
2) Rationale for restricting to 2000 onwards not very strong and suggests you have missed some pre-2000 studies (even if only few). Could it be improved, e.g., has the technology used in the diagnostic process changed significantly from 2000?
Method/data extraction and quality assessment: 3) From the abstract it is clear that quality appraisal is also performed by 2 authors independently, but this is not clear from the methods section. I suggest including this information here too as it is a strength.

Results: 4) The positive association between
Thank you Reviewer 2 for your helpful and constructive feedback. We have made several substantial improvements to the study, especially with regards to the search strategy, as detailed below. 1) We have now performed a search of the Cochrane library from inception to 13 th June 2019, in addition to updating the original search to 13 th June 2019.
2) As per response to Reviewer 1, we have strengthened the rationale for performing our search from 2000.

3)
We have added this in Methods, Data Extraction and Quality assessment: "Quality appraisal was performed using a modified version of the Critical Appraisal Skills Programme (CASP) checklist for cohort studies by both authors (Table 1 Footnote) 13 . " 4) We have amended the sentence in question under haematuria visits and diagnostic delay, I imagine reflects that the more haematuria visits a patient has, the longer the delay is, but I would suggest writing this out in full for clarity, especially in the context of the dosedependent relationship between haematuria visits and likelihood of referral presented immediately beforehand.
5) You have clearly and explicitly assessed study quality and presented it in Table 1. Nevertheless you have not linked this to the results anywhere else in the results section. Some discussion of it in relation to the validity of the results is necessary in the results section, and I would also suggest adding a summary of that discussion to the actual Discussion section. In systematic reviews this needs to be explicit in all parts of the manuscript (apart from the introduction).
6) Instead of using NS to mean either nonspecified (Appendix 2) or non-significant (Table 3), pick a different abbreviation for Appendix 2 such as NSp to avoid misunderstanding Results, Presenting Symptoms, 2 nd paragraph last sentence: "…and a high-quality US study involving claims review found that increasing number of haematuria visits was associated with diagnostic delay for bladder cancer patients 24 ." 5) We described the size and type of the studies in the Results section, but have now also added a paragraph about the quality of the studies in the Results section: The main bias and applicability concerns related to the suboptimal identification and/or adjustment for confounders in 18 of the studies, 6 of which were studies using questionnaires [14][15][16][17][18][19] , 10 were retrospective cohort studies providing descriptive statistics mainly, using record reviews (n=5) 20-24 and electronic health records (n=5) 25-29 , 1 was a case-control study 30 and 1 an ecological study 31 .
We also added a sentence to first paragraph of the Strengths and Limitations section, within Discussion: " Although some of the studies did not adjust for all the confounders, the descriptive sections related mainly to the diagnostic intervals and appropriate statistical analyses were performed for examining the factors affecting these intervals, where relevant." 6) We have changed NS in Appendix 2 to "Either" to avoid any confusion.

Reviewer: 3
This is a nice review of published literature on the timeliness and quality of investigation of symptoms of bladder and kidney cancer.
The review is in narrative form, which makes synthesis of data somewhat more challenging than if a meta-analysis had been caried out -however, this seems to be a reflection of the heterogeneity of the literature rather than a limitation of the review itself.
Thank you for your feedback.