Characterizing Variability in Lung Cancer Outcomes and Influence of a Lung Diagnostic Assessment Program in Southeastern Ontario, Canada

Round 1

Reviewer 1 Report

Interessing study, but some data’s are confusing

 

I have several comments

 

Major

1.       the number of patients excluded by exclusion criteria should be reported  in the flow chart (from 2700 to 1832

2.       Definition of level incomes is not reported on methods

3.       I don’t understand in the univariate analysis, why for age, the authors take 80 as reference. Usually we take for reference the majority of the group. I suggest to take 60 y

4.       Same remark for the distance, i suggest to take as referece, < 50

5.       The sentence « We considered the possibility of lead time bias affecting the results of the study on the relationship between LDAP management and favorable outcome for LC. We evaluated this possibility by analyzing survival from the date of first abnormal imaging (rather than from date of diagnosis)….should be move on the method section

6.       Again, I don’t understand why for age, and factors associated with LDAP, authors take as reference 70, I suggest to take 60 as cut off

7.       The sentence ‘However, there was no difference in the likelihood of LDAP management for patients at extremes of age and no difference for other income quintiles compared with  the reference lowest income quintile » »it’s confusing, I think according to the table 1, the âge and incomes are not significantlyly associated with the use of LDAP ? it’s exact ?

8.       Again, same remark for distance, taking intermediate level as reference is confusing

9.       « Influence of LDAP Management on subsequent LC Care (Specialist AssessmentTreatment, and Health Resource Utilization) : standard deviation are not reported,

10.   First Treatments Received for Lung Cancer in LDAP and non-LDAP Cohorts, p values had to be reported and text amended as significantive or no….I am not sure that there is significant differences…

11.   I suggest, , to give also the median OS of each group and to perform analysis on 1-year survival as a sensitivity analysis

12.   First sentence of the discussion shoul be amendaede as 2-year OS

13.   The sentence ‘They similarly found that patients were more likely to be diagnosed in an LDAP if they lived closer to an LDAP [10]…. In the discuss will be exact if close distance was take as reference for the analysis

14.   I suggest to add in the discussion section a paragraph on the impact of incomes on 2-year OS and to discuss with already published study

Minors

1.       After ref 13, the text jump to 28

2.       818 (46%) were managed through the LDAP, while 923 (53%) were from the non-LDAP = 99%, correct for 100%

3.       Stage 0 or unknown 320 patients in the univaraite analyse but 319 in the table 1

4.       Stage Unknown 96 (11.7%) patients in table 1 but 95 in table 3

5.       Table 3 : adenocarcinoma + non adenocarcinom = 95.4% correct to have 100%

6.       Table 3 : whar is stage 0 for lung cancer

7.       What is the definition of treatment ie : systemic and surgical treatments ?

8.       Habous is in reference 10. Check it on the text. I think there is a problem with the references number on the text

Author Response

Reviewer 1

General Comments: Interesting study, but some data’s are confusing. I have several comments.

Response: Thank you for your interest in our study. We hope the data are less confusing by having addressed the comments below.

Major comments: 

Comment #1: The number of patients excluded by exclusion criteria should be reported in the flow chart (from 2700 to 1832.

Response #1: We thank the reviewer for their attention to our Figure and identifying this error. We wish to clarify that Figure 1 is correct in that there were 1,832 cases identified, not 2700.  Rather, 2,700 represents the sum of cases identified from the OCR plus the LDAP database, but there is considerable overlap between these databases such that cases would be counted twice. As such, we corrected the text in the first sentence of the Results section to state that “A total of 1,832 cases were identified…”. Upon additional review in verifying our response to this comment, we noted an inconsistency in our exclusion criteria whereby one patient with stage 0 lung cancer was excluded from the analysis while one remained in the analysis. As such, we have corrected this and included both patients with stage 0 lung cancer in our analysis for consistency.  Figure 1 has been updated to reflect this change, and we added additional details regarding the final breakdown of cases from each cohort to comprise the final study cohort of 1,742 cases, as seen on Page 4.

Comment #2: Definition of level incomes is not reported on methods.

Response #2: Thank you for bringing this to our attention. We have clarified the definition of the income quintiles in the Methods section under 2.5.1 Independent Variables on Page 3, line 151-154 to specify that “Income quintile was determined based on the patient’s postal code and adjusted household income data from Statistics Canada’s (StatCan) census data. Income quintile represents median adjusted household income by family size [18]..”

 

Comment #3: I don’t understand in the univariate analysis, why for age, the authors take 80 as reference. Usually, we take for reference the majority of the group. I suggest to take 60 y.

Response #3: Thank you for this feedback. We had selected the oldest age group to provide as a reference for the other age groups. We note that the reviewer suggested taking the reference for the majority of the group and suggests taking 60 as the reference age group.  We note that the largest group is the 71-80 age group, which does not align with the reviewer’s suggestion to take 60 as the reference age group.  Based on our interpretation of the reviewer’s comment, we understood this to mean that we should take the 18-60 group as the reference age range, which we think will make the analysis easier as it is the youngest age group to which the other groups can be compared. This is reflected in Table 2A & 2B, on Page 7-8. If we have misunderstood this comment, please let us know.

Comment #4: Same remark for the distance, I suggest to take as reference, < 50

Response #4: We have updated the analysis such that <50km from the LDAP is now the reference group, as seen in Table 2A & 2B, on Page 7-8.

Comment #5: The sentence « We considered the possibility of lead time bias affecting the results of the study on the relationship between LDAP management and favorable outcome for LC. We evaluated this possibility by analyzing survival from the date of first abnormal imaging (rather than from date of diagnosis) ….should be move on the method section.

Response #5: Thank you for this suggestion. We agree that this statement is better situated in the Methods section and have this change, as seen in Section 2.7 Statistical Approach on Page 4 line 221-224. 

Comment #6: Again, I don’t understand why for age, and factors associated with LDAP, authors take as reference 70, I suggest to take 60 as cut off

Response #6: This comment was addressed in Response #3 with the appropriate revisions seen in Tables 2A and 2B, Pages 7-8.

Comment #7: The sentence ‘However, there was no difference in the likelihood of LDAP management for patients at extremes of age and no difference for other income quintiles compared with the reference lowest income quintile » »it’s confusing, I think according to the table 1, the age and incomes are not significantly associated with the use of LDAP ? it’s exact ?

Response #7: Thank you for raising this concern. We agree that the language is confusing. By incorporating the reviewer’s feedback to reference the age group 18-60, we clarify that age and income are significant factors associated with LDAP management.  This can be seen in Section 3.3 Factors associated with LDAP management on Page 9, where we state “Patients aged 61-70 were more likely to be LDAP-managed than younger patients (HR 1.56, p=0.0122) as were patients that were not in the lowest income quintile (p=0.0209)."

Comment #8: Again, same remark for distance, taking intermediate level as reference is confusing

Response #8: This has been addressed in our Response to Comment #4 above.

Comment #9: Influence of LDAP Management on subsequent LC Care (Specialist Assessment Treatment, and Health Resource Utilization): standard deviation are not reported. 

Response #9: Thank you for bringing this to our attention. We have added the standard deviations to both the text on Page 10-11 and Figure 2 A-D on Page 11. 

Comment #10: First Treatments Received for Lung Cancer in LDAP and non-LDAP Cohorts, p values had to be reported and text amended as significance or no….I am not sure that there is significant differences…

Response #10: Thank you for this suggestion. We have further analysed the data and added statement on Page 11-12 reflecting this data that reads: “Overall, patients with LC in the LDAP cohort had a higher probability of receiving treatment compared to those in the non-LDAP cohort (p < 0.0001). Furthermore, when analyzing each stage of LC, patients in stage I, stage IV and unknown stage categories were more likely to receive treatment if managed through LDAP (p < 0.0001) (Table 4).

Comment #11: I suggest to give also the median OS of each group and to perform analysis on 1-year survival as a sensitivity analysis.

Response #11: Thank you for your suggestion. We have conducted the recommended analysis as suggested and included it below for the reviewer’s consideration. The results of the 1-year analysis were consistent with the existing findings and we did not feel that they provide any additional information beyond the 2-year OS and the median OS. Rather, we felt that the additional information cluttered the Table and made it harder to interpret. To that end, we have decided not to include the 1-year survival data in the final manuscript.

Table 2A. Factors Associated with Overall Median 1- and 2-Year Survival - Unadjusted Analysis and Adjusted Analysis from Diagnosis.

Factor	N	Overall Survival			Unadjusted		Adjusted
		1-year	2-year	Median (months)	HR (95% CI)	p	HR (95% CI)	p
Age
18 - 60	279	54.8%	41.9%	15.8	referent	0.0062	referent	<.0001
61 - 70	563	51.2%	37.9%	12.7	1.12 (0.93, 1.35)		1.26 (1.05, 1.53)
71 - 80	623	47.5%	35.1%	11.1	1.24 (1.03, 1.49)		1.60 (1.33, 1.93)
> 80	276	44.1%	32.6%	8.9	1.41 (1.14, 1.74)		1.78 (1.43, 2.21)
Sex
Female	920	55.5%	43.0%	15.8	0.68 (0.61, 0.77)	<.0001	0.79 (0.70, 0.89)	0.0001
Male	821	42.4%	29.7%	8.6	referent		referent
Distance from CCSEO (kms)
< 50	652	54.4%	41.8%	15	referent	0.0045	referent	0.3302
50 - 100	909	46.4%	34.7%	10.2	1.22 (1.07, 1.39)		1.10 (0.95, 1.26)
> 100	180	46.1%	28.9%	10.1	1.28 (1.04, 1.56)		0.99 (0.80, 1.23)
Income Quintile
1 (lowest)	324	42.5%	31.1%	8.4	2.27 (1.53, 3.36)	0.0004	2.01 (1.35, 3.01)	0.0026
2	522	51.0%	38.2%	12.4	1.79 (1.21, 2.62)		1.56 (1.05, 2.33)
3	541	49.2%	34.8%	11.2	1.89 (1.28, 2.77)		1.75 (1.17, 2.61)
4	288	48.7%	39.4%	11.7	1.81 (1.22, 2.70)		1.69 (1.13, 2.53)
5 (highest)	66	74.2%	56.1%	33.2	referent		referent
Histology Type (OCR histology)
Adenocarcinoma	675	63.7%	53.1%	29.3	referent	<.0001	referent	<.0001
Squamous cell carcinoma	296	53.6%	37.1%	14.3	1.45 (1.21, 1.73)		1.49 (1.24, 1.80)
Poorly differentiated carcinoma	517	34.2%	22.3%	4.1	2.55 (2.21, 2.96)		2.13 (1.82, 2.48)
Small cell	171	27.3%	12.0%	6.7	2.66 (2.18, 3.24)		1.75 (1.43, 2.14)
Other	82	57.2%	42.9%	16.5	1.27 (0.93, 1.73)		1.19 (0.87, 1.62)
Stage (OCR best stage)
0/I	381	87.9%	75.8%	-	0.16 (0.13, 0.20)	<.0001	0.16 (0.13, 0.20)	<.0001
II	106	77.3%	62.1%	-	0.24 (0.17, 0.32)		0.27 (0.19, 0.37)
III	267	54.4%	31.8%	14	0.50 (0.42, 0.59)		0.51 (0.43, 0.61)
IV	668	24.7%	14.9%	4.4	referent		referent
unknown	319	41.3%	30.6%	6.0	0.71 (0.61, 0.83)		0.63 (0.53, 0.74)
LDAP
No	924	41.0%	29.8%	7.5	referent	<.0001	referent	<.0001
Yes	817	58.9%	44.7%	18.5	0.61 (0.54, 0.69)		0.76 (0.67, 0.87)

*Note: One patient with two primaries of adenocarcinoma and squamous cell carcinoma was not included.

 

Table 2B. Factors Associated with Overall Survival - Unadjusted Analysis and Adjusted Analysis from First Abnormal Imaging.

Factor	N	Overall Survival			Unadjusted		Adjusted
		1-year	2-year	Median (months)	HR (95% CI)	p	HR (95% CI)	p
Age
18 - 60	271	59.4%	42.9%	17.5	referent	0.0247	referent	<.0001
61 - 70	539	53.8%	38.6%	14.5	1.13 (0.93, 1.36)		1.33 (1.09, 1.61)
71 - 80	593	51.9%	38.1%	13	1.21 (1.00, 1.45)		1.64 (1.36, 1.99)
> 80	258	46.7%	34.2%	11.3	1.38 (1.11, 1.71)		1.80 (1.44, 2.25)
Sex
Female	875	59.7%	45.3%	19.1	0.67 (0.60, 0.76)	<.0001	0.78 (0.69, 0.89)	0.0001
Male	786	45.4%	30.9%	10.3	referent		referent
Distance from CCSEO (kms)
< 50	630	56.8%	43.5%	17.1	referent	0.0074	referent	0.6509
50 - 100	864	50.5%	36.6%	12.4	1.20 (1.05, 1.37)		1.03 (0.90, 1.19)
> 100	167	50.8%	29.9%	12.1	1.30 (1.05, 1.60)		0.94 (0.75, 1.17)
Income Quintile
1 (lowest)	302	45.7%	33.3%	10	2.18 (1.46, 3.26)	0.0019	2.02 (1.34, 3.04)	0.0048
2	499	55.1%	38.9%	14.5	1.78 (1.20, 2.64)		1.63 (1.08, 2.44)
3	519	52.2%	36.6%	13	1.88 (1.27, 2.78)		1.84 (1.22, 2.76)
4	277	53.2%	42.0%	14.5	1.74 (1.16, 2.62)		1.64 (1.09, 2.48)
5 (highest)	64	75.0%	59.4%	35.4	referent		referent
Histology Type (OCR histology)
Adenocarcinoma	648	66.8%	54.5%	31.4	referent	<.0001	referent	<.0001
Squamous cell carcinoma	291	58.0%	39.1%	16.4	1.43 (1.19, 1.71)		1.45 (1.20, 1.76)
Poorly differentiated carcinoma	483	37.4%	24.1%	5.9	2.48 (2.13, 2.88)		2.10 (1.79, 2.46)
Small cell	162	30.8%	12.1%	7.5	2.82 (2.30, 3.44)		1.78 (1.45, 2.19)
Other	77	61.0%	46.5%	22.6	1.21 (0.87, 1.67)		1.13 (0.82, 1.57)
Stage (OCR best stage)
0/I	374	90.1%	77.2%	.	0.15 (0.12, 0.18)	<.0001	0.15 (0.12, 0.19)	<.0001
II	105	79.0%	63.8%	.	0.22 (0.16, 0.30)		0.25 (0.18, 0.35)
III	261	58.1%	32.1%	14.9	0.49 (0.41, 0.58)		0.51 (0.43, 0.61)
IV	627	28.1%	15.7%	5.4	referent		referent
unknown	294	44.9%	33.7%	8	0.63 (0.53, 0.75)		0.56 (0.47, 0.67)
LDAP
No	844	43.5%	31.4%	9.2	referent	<.0001	referent	0.0161
Yes	817	62.8%	45.9%	20.6	0.61 (0.54, 0.69)		0.72 (0.63, 0.82)

*Note: 80 patients with no imaging study identified in OCR were excluded and one patient with synchronous diagnoses of adenocarcinoma and squamous cell carcinomas is excluded.

Comment #12: First sentence of the discussion should be amended as 2-year OS.

Response #12: We appreciate the suggestion. In response to feedback from Reviewer 3, we have revised the introductory paragraph of the Discussion. We have clarified that we are speaking to 2-year OS in the second sentence in this revised paragraph and have made this amendment on Page 13, line 645-646.

Comment #13: The sentence ‘They similarly found that patients were more likely to be diagnosed in an LDAP if they lived closer to an LDAP [10] …. In the discussion will be exact if close distance was take as reference for the analysis

Response #13: Thank you for your comment. We wish to clarify that this sentence refers to the Habbous et al paper, which found that patients were more likely to be diagnosed in an LDAP if they lived closer to an LDAP.  Now that we have changed the analysis such that the reference group is the one with patients residing <50km from the LDAP, we more easily see the effect of increased distance from LDAP on LDAP management. As such, we have kept this sentence in the paper to better reflect this.

Comment #14: I suggest to add in the discussion section a paragraph on the impact of incomes on 2-year OS and to discuss with already published study.

Response #14: We thank the reviewer for the suggestion. We agree that social determinants impact lung cancer survival outcomes and have added discussion and literature demonstrating that income has been shown to influence lung cancer survival. As such, we have added the following paragraph to the Discussion on Page 14, lines 712 - 722: “Previous studies have highlighted the impact of social determinants of health on LC outcomes [6,14]. Patients of lower socioeconomic status are almost twice as likely to be diagnosed with LC and tend to have more advanced disease at diagnosis [6]. Even when diagnosed at an earlier stage, patients of lower income groups are less likely to receive curative treatments, which ultimately impacts survival outcomes [6]. Our study suggests a complex relationship between income quintile and distance from LDAP; lower income quintile and increased distance from the LDAP were associated with lower likelihood of LDAP management and higher probability of death, however in the adjusted analysis with LDAP as a variable, distance from LDAP was no longer significant while income remained significant, raising the possibility that higher income quintile may overcome the barrier of distance from LDAP.”

Minor Comments

Comment #15: After ref 13, the text jump to 28

Response #15: We thank the reviewer for this observation. We have carefully reviewed and updated all citations and references in a sequential manner as per the suggestion. We have ensured that all the references are cited accurately and consistently throughout the manuscript.

Comment #16: 818 (46%) were managed through the LDAP, while 923 (53%) were from the non-LDAP = 99%, correct for 100%

Response #16: Thank you for noticing this. We realize that we did not round up the value from 46.99% to 47%. We have made this change, which can be seen on Page 1, Line 25 and Page 4, Line 213.  

Comment #17: Stage 0 or unknown 320 patients in the univaraite analyse but 319 in the table 1.

Response #17: We appreciate bringing this to our attention and apologize for the confusion. We have clarified in the Methods section that Stage 0 is defined as Tis(carcinoma in situ)N0M0. We have therefore included patients with Stage 0 lung cancer with the Stage 1 group in Table 1.  As clarified in Response #1 above, we have included two patients with stage 0 lung cancer (instead of excluding one). We have updated this in Table 1, page 6. In doing so, the number of patients in the Unknown group remains 319, but the number of patients in the Stage 0/1 group has increased by 1. We also amended Figure 1 removing the exclusion of the Stage 0 patient from the data.

Comment #18: Stage Unknown 96 (11.7%) patients in table 1 but 95 in table 3.

Response #18: This has been corrected as described above, as seen in Table 1, page 5.

Comment#19: Table 3 : adenocarcinoma + non adenocarcinom = 95.4% correct to have 100%  – they should not be added since N (%) represents number and proportion of adenocarcinoma/non-adenocarcinoma patients with LDAP..

Response#19: Thank you for your comment. We suspect the reviewer may have misinterpreted the data in this Table. This Table summarizes factors associated with LDAP management and demonstrates that 51.3% of patients with adenocarcinoma received LDAP management while 44.1% of patients with a non-adenocarcinoma diagnosis received LDAP management. These data are not additive.   

Comment #20: Table 3 : whar is stage 0 for lung cancer

Response #20: Thank you for your question. We have defined Stage 0 in the Methods section 2.5 Definitions on Page 3, Line 174-175, stating: “LC stage was defined as per TNM 8^th edition classification with stage 0 representing Tis(carcinoma in situ)N0M0.”

Comment #21: What is the definition of treatment ie: systemic and surgical treatments?

Response #21: Thank you for this question. We acknowledge the lack of clarity of definitions in our initial manuscript and have revised the Methods section to provide clearer definitions and variables. We have added the following paragraph in our Methods section under 2.5 Definitions to answer this question on Page 3, lines 177-182: “The first treatment modality was defined as the initial anticancer treatment received by patients. The treatment modalities included the following: surgical treatment, where the patient's initial treatment was resection; systemic therapy, which included targeted therapy, cytotoxic chemotherapy, or immunotherapy; radiation therapy, which included initial radiation to the chest and/or site of metastases; and chemoradiation, which was defined as a concurrent combined modality as the initial treatment.”

Comment #22: Habous is in reference 10. Check it on the text. I think there is a problem with the references number on the text.

Response #22: Thank you for your comment. We have carefully reviewed and updated the references.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors assess the factors that may contribute to the variability of lung cancer outcomes in Southeast Ontario, Canada. In particular, they evaluate the influence of LDPA availability on LC care. The negative effect of increasing distance from LDPA on LC management and as an independent factor for influencing LC survival is analyzed. While similar studies have been conducted previously, this paper stands for its design ad focus.

 

A  few more graphs based on Tables 2A, 2B, 4 would make the data easier to understand the relationships between the variables.

Author Response

Reviewer 2

Comment #1: A few more graphs based on Tables 2A, 2B, 4 would make the data easier to understand the relationships between the variables.

Response #1: We thank the reviewer for the suggestion. We agree that a Figure helps to better display the data for Table 4 and have included a stacked bar chart to demonstrate the data visually, which can be seen on Page 13, Figure 3. Another reviewer had asked that we add median survival data. In doing so, the data in Tables 2A and B became too complex to be able to generate a meaningful figure. 

Author Response File: Author Response.docx

Reviewer 3 Report

Dear Authors,

 

The article makes an interesting contribution to the field of regional health programs for rapid assessment in clinics that accelerate the management of patients with suspected lung cancer and improve patient survival. However, I have a few comments to the authors before the manuscript could be considered for publication.  

 

Aim of the study

1. The aim of the study in the Abstract is different from the aim in the main text (lines 68-71). Please, note that the aim of the study should be identical in the abstract and in the main text.

 

Material and Methods

2. The Materials and Methods need to be organized better, and should be prepared in more understandable way. Please put in order, revise and re-edit information in paragraphs following up: Study design (or Study design and settings), Data collection, Study participants, Study variable, Definitions, Statistical analysis, and describe them more precisely.

3. Dependent and independent variables with their categories should be well defined in a separate Study variable section.

4. Study Outcomes listed in row 99 should be more clearly formulated.

5. In the Statistical analysis, more information is needed on the Cox-model approach, composition of statistical models, HR and OR with interpretation, and the level of statistical significance, as well as the software used for the analysis.

 

Results

6. Some variables in Table 1 are not discussed, therefore its description needs to be expanded.

7. Results of the study listed in lines 150-151 and 25-26; 175 and 27; 177; 261-262 do not coincide with the tables. Why are their values incorrect?

 

Discussion

8. In the beginning in the Discussion should appear the clearly separated paragraph on the Main findings.

9. In line 345, is underlined “Prior studies have shown…”, but citations are not given. Please complete it.

 

Key words

10. According to the reviewer, "mortality", and “Ontario” should be added to the keywords.

 

Please, highlight the changes to the revised version, using a different colour.

Author Response

Reviewer 3

General Comment: The article makes an interesting contribution to the field of regional health programs for rapid assessment in clinics that accelerate the management of patients with suspected lung cancer and improve patient survival. However, I have a few comments to the authors before the manuscript could be considered for publication. 

Response: We thank the reviewer for their interest in our study. We hope that the revisions we have made address the comments raised.

Comment #1: The aim of the study in the Abstract is different from the aim in the main text (lines 68-71). Please, note that the aim of the study should be identical in the abstract and in the main text.

Response #1: We thank the reviewer for noting this inconsistency. We have revised the abstract to ensure that it accurately reflects the aim stated in the main text. As a result, some small edits were made to the abstract to ensure we adhered to the word count limit.

Comment #2: The Materials and Methods need to be organized better and should be prepared in more understandable way. Please put in order, revise and re-edit information in paragraphs following up: Study design (or Study design and settings), Data collection, Study participants, Study variable, Definitions, Statistical analysis, and describe them more precisely.

Response #2: We agree with the reviewer that the addition of these subsections to the Materials and Methods section improves organization and clarity. To address this, we have re-organized this section for more logical flow and edited the paragraphs accordingly. These changes can be seen on Page 2-4.

Comment #3: Dependent and independent variables with their categories should be well defined in a separate Study variable section.

Response #3: Thank you for this suggestion. We have included a separate section called Study Variables and Data Collection in the Methods section on Page 3, where we have defined the independent and dependent variables and described how these data were obtained. Minor changes were made to the other sections of the Materials and Methods to minimize repetition.

Comment #4: Study Outcomes listed in row 99 should be more clearly formulated.

Response #4: Thank you for this feedback. In addressing Comment #2 to re-organize the Materials and Methods Section, we added a subsection “2.6 Study Outcomes”, where these are better defined. This can be found on Page 3, lines 165 - 167.

Comment #5: In the Statistical analysis, more information is needed on the Cox-model approach, composition of statistical models, HR and OR with interpretation, and the level of statistical significance, as well as the software used for the analysis.

Response #5: To address this comment, we have added further description of the statistical analysis in the Methods section on Page 4, lines 194-204, which now reads:
“We used a Cox-model to complete a time-to-event analysis whereby we evaluated the effect of LDAP-management on overall survival from time of diagnosis, after adjusting for other patient and disease characteristics associated with LC survival. Logistic regression was performed to assess the factors associated with LDAP management. Backward elimination analysis, with LDAP retained, was used to select explanatory factors and eliminate insignificant variables in logistic model and Cox model analyses. We considered the potential impact of lead time bias affecting the results of the study on the relationship between LDAP management and favorable outcome for LC. We evaluated this possibility by analyzing survival from the date of first abnormal imaging (rather than from date of diagnosis). SAS for Windows 9.4 TS1M6 (Cary, NC, USA) was used to conduct statistical analyses.”

Comment #6: Some variables in Table 1 are not discussed, therefore its description needs to be expanded.

Response #6: Thank you for your suggestion. We have expanded our description to discuss all variables in Table 1. This can be seen on page 5, lines 236 -238.

Comment #7: Results of the study listed in lines 150-151 and 25-26; 175 and 27; 177; 261-262 do not coincide with the tables. Why are their values incorrect?

Response #7: We thank the reviewer for bringing this to our attention. Our analysis has been updated and changes have been made to ensure the text is consistent with our tables. These changes can be seen in lines 27, 283, Table 2A and 684.

Comment #8: In the beginning in the Discussion should appear the clearly separated paragraph on the Main findings.

Response #8: Thank you for this feedback. We agree with the reviewer that we did not clearly summarize the main findings of our study at the beginning of the Discussion. The first paragraph has been revised to address this, on Page 13, and reads… “Many patient and disease factors are likely to influence LC survival. We found that, while various patient and disease characteristics influence 2-year overall LC survival in SE Ontario, management of patients suspected of having LC through a specialized rapid-access clinic (the LDAP) is an independent factor influencing survival. We also found that increasing distance from the LDAP had the greatest negative association with LDAP management, however, was not a factor influencing survival.  These results suggest a complex interplay between health system characteristics and patient factors that collectively influence survival.”

Comment #9: In line 345, is underlined “Prior studies have shown…”, but citations are not given. Please complete it.

Response #9: Thank you for pointing this out. We were referring to Habbous et al’s study and added the citation in question. This can be seen on Page 15, Line 818-819.

Comment #10: According to the reviewer, "mortality", and “Ontario” should be added to the keywords.

Response #10: We have made the requested additions.

Comment #11: Please, highlight the changes to the revised version, using a different colour.

Response #11: We acknowledge the reviewer’s request, but the Journal instructions were to use Track Changes to show where the revisions were made. These appear in a different colour throughout and we have added referenced to the Page and Line number to help the reviewer identify where the revisions are made.

Author Response File: Author Response.docx

Reviewer 4 Report

The authors showed that the LDAP plays important role in diagnosis and management of lung cancer. I think they showed the very important findings to management of lung cancer. 

I have several minor concerns.

#1. line 272 , I think "foung" is misspelling, "found" is correct.

#2.Table 4   I thinks the authors should describe "combined chemorads" in detail although they describe one of example "i.e. chemoradiation" in discussion part.   And if possible, I think it is better to include the treatment for the comorbid diseases, such as COPD. 

Author Response

Reviewer 4

General Comment: The authors showed that the LDAP plays important role in diagnosis and management of lung cancer. I think they showed the very important findings to management of lung cancer. I have several minor concerns.

 

Response: We thank the reviewer for their positive remarks. We hope we have addressed the raised concerns through the revisions summarized below.

Comment #1: line 272, I think "foung" is misspelling, "found" is correct.

Response #1: Thank you for noticing this spelling error. We have corrected it on Page 14, line 706.  

Comment #2: Table 4  I thinks the authors should describe "combined chemorads" in detail although they describe one of example "i.e. chemoradiation" in discussion part.   And if possible, I think it is better to include the treatment for the comorbid diseases, such as COPD. 

Response #2: Thank you for your comments. We have clarified the definitions of the various therapies received by patients in the Methods section on Page 3, lines 156-161. We have clarified the language by changing “combined chemorads” to “chemoradiation, defined as concurrent combined modality as the initial treatment”.

Regarding the treatment of comorbid diseases, such as COPD, the OCR database unfortunately does not contain treatment information for these comorbid diseases, and this evaluation is outside the scope of this paper. However, we agree that the optimization of COPD is important in this patient population, and have published regarding a local Quality Improvement project to optimize the management of COPD in LDAP patients, which is cited below:

Digby GC, Robinson, AG. Optimizing the Management of Chronic Obstructive Pulmonary Disease in Patients with Lung Cancer: A Quality Improvement Initiative. J Oncol Pract. 2017; 13(11): e957-e965. DOI: 10.1200/JOP.2017.022228.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

no more comment, thanks for your responses

Author Response

Reviewer 1

General Comments: no more comment, thanks for your responses.

Response: We thank the reviewer for taking the time to review our manuscript.

Reviewer 3 Report

Dear Authors,

After checking the manuscript, I believe that the manuscript has improved considerably now, but I can see that, unfortunately, some of my comments have not been addressed. I would request to respond to the following points from Review 1:

 

1.      In my previous comment No. 3, I recommended, that all variables with their categories should be well defined. This should be described, ie. “Age was stratified into following age groups: 18-60, 61-70, 71-80, and >80 years, with the range of 18-60 years consider as reference”. The same should be done with the other variables included in analysis.

2.      In the paragraph Statistical Approach I have not found an explanation for HR and OR with interpretation, and the level of statistical significance – please complete it.  

3.      The manuscript needs explanations for abbreviations, ie. HR, OR, CCSEO, and moreover below all tables and figures should be explained abbreviations, that appear them.    

 

I expect to read a proper revision.

Author Response

Reviewer 3

General Comments:After checking the manuscript, I believe that the manuscript has improved considerably now, but I can see that, unfortunately, some of my comments have not been addressed. I would request to respond to the following points from Review 1:

Response: Thank you for clarifying the comments for which additional revisions are requested.

Comment #1: In my previous comment No. 3, I recommended, that all variables with their categories should be well defined. This should be described, ie. “Age was stratified into following age groups: 18-60, 61-70, 71-80, and >80 years, with the range of 18-60 years consider as reference”. The same should be done with the other variables included in analysis.

Response #1: Thank you for clarifying this requested revisions. We have further defined the variables as suggested on Page 3, Lines 128-144, which now reads:
“Descriptive data were collected, including patient characteristics such as: age, which was stratified into age groups (18-60, 61-70, 71-80, and >80 years), with the 18-60 age group used as reference; sex, which was stratified into male and female, with male used as reference group; geographic distance from the LDAP, which was stratified by distance (<50 kms, 50-100 kms, and >100 kms), with <50kms used as reference group; and income quintile stratified into five groups 1 (lowest) – 5 (highest) with lowest income quintile used as reference group. Income quintile was determined based on the patient’s postal code and adjusted household income data from Statistics Canada's (StatCan) census data; income quintile represents median adjusted household income by family size [18].

 

Data regarding disease characteristics included histologic subtype, which was stratified into adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, small cell carcinoma, large cell carcinoma, neuroendocrine not otherwise specified (NOS) and other, with adenocarcinoma subtype representing the reference group; and stage at diagnosis, which was stratified as stage I,II,III, IV and unknown with stage IV considered as the reference group.”

Comment #2: In the paragraph Statistical Approach I have not found an explanation for HR and OR with interpretation, and the level of statistical significance – please complete it.  

Response #2: Thank you for clarifying the requested revision. We have further explained these in the Statistical Approach, which reads as follows: “Hazard ratio (HR) and odds ratio (OR) were used to describe the effect of factors in model-based analyses on mortality (Tables 2A and 2B) and LDAP management (Table 3), respectively. A value of HR or OR > 1 indicates increased hazard of mortality or odds of LDAP management, for a specific level of the factor as compared to the reference level, with specified magnitude; a value of HR or OR < 1 indicates an effect of opposite direction. A threshold of 0.05 was chosen to determine statistical significance. A p-value < 0.05 was deemed as statistically significant.”

This can be found on Page 4, Lines 241-247.

Comment #3: The manuscript needs explanations for abbreviations, ie. HR, OR, CCSEO, and moreover below all tables and figures should be explained abbreviations, that appear them.

Response #3: We agree with the reviewer that abbreviations require definitions throughout the manuscript and in the Table and Figure legends. We have provided these.

Author Response File: Author Response.docx