Factors Influencing the Timeliness and Completeness of Appropriate Staging Investigations for Patients with Stage I–III Lung Cancer in Southeastern Ontario

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The theme is important considering lung cancer incidence and current trends concerning survival; interesting analysis exploring the influence of various demographic/financial/geographic/clinical factors on the completeness of lung cancer setting. Such topic might be of particular interest to pneumologists, oncologists, general practitioners and various policy makers. The methodology is clearly presented, the results are complex and properly presented; statistic methods seem sound. The discussion is result focused and conclusions seem logical.

One suggestion - It might be interesting to explore if the results might be extrapolated to other regions/care systems.

Author Response

Reviewer 1

Comment 1: The theme is important considering lung cancer incidence and current trends concerning survival; interesting analysis exploring the influence of various demographic/financial/geographic/clinical factors on the completeness of lung cancer setting. Such topic might be of particular interest to pneumologists, oncologists, general practitioners and various policy makers. The methodology is clearly presented, the results are complex and properly presented; statistic methods seem sound. The discussion is result focused and conclusions seem logical.

One suggestion - It might be interesting to explore if the results might be extrapolated to other regions/care systems. 

Response 1: We thank the reviewer for their positive feedback. The reviewer raises an interesting question as to whether the results might be extrapolated to other regions and care systems. While it is possible that other rural healthcare regions may experience similar barriers and impacts on care, further research would be needed to explore this.  To emphasize the importance of this point, the Discussion section has been revised to include a sentence stating: “Future research should explore the extent to which comparable care models can address similar barriers to timely staging in other health systems.”  [page 9, paragraph 4, lines 271-273].

Reviewer 2 Report

Comments and Suggestions for Authors

Clarity on location of S.E. Ontario would be helpful for readers not all familiar with different locales in Ontario.  One would have thought that Toronto and Ottawa - both very large and sophisticated centres - would be included in S.E. Ontario.  Some commentary about non-inclusion of small-cell lung cancer in this analysis is needed.  Also, the question of stage migration is not addressed.  Patients may be thought to have Stage I or II then found to have Stage III or IV.  Is the concept of "variable adjustment"  same as multivariate analysis?  It would be helpful if the patient outcomes (TTF, OS) were compared between the LDAP group and the non-LDAP group.  I'm not convinced a 1 week delay in the non-LDAP group means so much.  Possibly means more in high-grade disease vs. well differentiated cancers.

Author Response

Reviewer 2

Comment 1: Clarity on location of S.E. Ontario would be helpful for readers not all familiar with different locales in Ontario.  One would have thought that Toronto and Ottawa - both very large and sophisticated centres - would be included in S.E. Ontario.  

Response 1: Thank you for this request. We have added clarifying information to Section 2.1 Local Context stating that “Southeastern Ontario (SE Ontario) is largely rural region situated to the east of Toronto and southwest of Ottawa along the northeastern shore of Lake Ontario in Canada. Its largest city, Kingston, had a population of ~135,000 in 2017, at which time the population of the entire region was estimated at 500,000 people, or 3.6% of the Ontario population” [page 2, section 2.1, line 69-71]. 

 

Comment 2: Some commentary about non-inclusion of small-cell lung cancer in this analysis is needed.  

Response 2: Thank you for your comment. We would like to clarify that patients with small-cell lung cancer were included in our analysis and were categorized under the category "non-adenocarcinoma", with other more aggressive lung cancer subtypes. We realize that we could have more explicitly clarified this grouping. We have thus updated the manuscript with the following statement added to the Section 2.3 Case Definitions, Demographics, and Study Outcomes for clarification: “In the analysis, lung cancer histology was categorized into adenocarcinoma and non-adenocarcinoma subtypes (including squamous cell, poorly differentiated carcinoma, small cell carcinoma, large cell carcinoma, neuroendocrine not other specified, and other)”. [page 3, section 2.3, lines 107-110].

 

Comment 3: Also, the question of stage migration is not addressed.  Patients may be thought to have Stage I or II then found to have Stage III or IV. 

Response 3: Thank you for raising this important point. While we address this point in our Limitations section, we recognize that we should bring this forward in the Methodology section as well. While we acknowledge that patients may have undergone stage migration during the diagnostic process, it is impossible to identify whether this occurred with available data. To clarify this, we added a statement in the Methods section: “We also excluded patients with stage IV or unknown LC stage due to the lack of data regarding stage migration and inability to differentiate patients who had stage IV disease at the time of first clinical assessment from those who were found to have stage IV disease only after completing staging”. [page 3, section 2.3, lines 114-117].

 

Comment 4: Is the concept of "variable adjustment" same as multivariate analysis?

Response 4: Thank you for your comment. Our manuscript does not use the term “variable adjustment” but refers to “multivariate analysis”. To ensure clarity, we have revised the initial mention to explicitly state: "multivariate regression models" [page 7, paragraph 2, section 3.3.1, line 192]. All subsequent references to the analysis model maintain the term "multivariate analysis" as originally stated.

 

Comment 5: It would be helpful if the patient outcomes (TTF, OS) were compared between the LDAP group and the non-LDAP group. 

I'm not convinced a 1-week delay in the non-LDAP group means so much.  Possibly means more in high-grade disease vs. well differentiated cancers. 

Response 5: We thank the reviewer for this comment. We reported on lung cancer survival outcomes in a prior publication in Current Oncology using this same database.  

AlGhamdi, S., Kong, W., Brundage, M., Eisenhauer, E. A., Parker, C. M., & Digby, G. C. (2023). Characterizing Variability in Lung Cancer Outcomes and Influence of a Lung Diagnostic Assessment Program in Southeastern Ontario, Canada. Current Oncology. 30(5), 4880–4896. https://doi.org/10.3390/CURRONCOL30050368

In that study, we found that LDAP management was associated with a lower probability of dying at 2 years (HR 0.76 vs. non-LDAP, p < 0.0001). Our current study builds on this prior work to further elucidate the system factors that contribute to this observed difference in patient outcomes.

Regarding the question as to whether a 1-week delay in the non-LDAP group is likely to influence outcomes, our data suggest that this is not the only contributing factor, as LDAP managed patients were also much more likely to complete optimal staging (OR 2.29, p <0.0001). As such, according to our data, LDAP management significantly improves completeness and timeliness of staging investigations, and their respective impact on outcomes are intertwined. 

Thanks to the reviewer’s comment, we see the opportunity to elaborate on this in the Discussion section and have added a section stating that: “Not only did LDAP managed patients undergo faster staging by an average of 1 week, but they were also more likely to complete staging investigations. While a 1-week delay in completing staging may seem minor, it can be critical in the context of an aggressive cancer such as LC where delays in care are associated with worse outcomes [26,27]. Together with the observed increase in completeness of staging, these results may in part explain the finding from our prior study of this cohort that LDAP management is associated with a lower probability of dying at 2 years”. [page 10, paragraph 2, lines 293-299]

This is reiterated in the Conclusion: Given that lung cancer is an aggressive disease and that delays in staging have been associated with stage progression, delayed treatment, and worse outcomes, our finding that LDAP management significantly increases the likelihood of completing staging investigations and undergoing faster staging may in part explain our prior finding that LDAP management is associated with improved 2-year lung cancer survival. [page 11, paragraph 1, lines 330-334].