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Date: 10/14/2022 To: "Logan Corey"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1571
RE: Manuscript Number ONG-22-1571
Concurrent Surgery for Locoregional Gynecologic Cancers and Pelvic Floor Disorders in the Medicare Population Dear Dr. Corey:
Thank you for sending us your work for consideration for publication in Obstetrics & Gynecology. Your manuscript has been reviewed by the Editorial Board and by special expert referees. The Editors would like to invite you to submit a revised version for further consideration.
If you wish to revise your manuscript, please read the following comments submitted by the reviewers and Editors. Each point raised requires a response, by either revising your manuscript or making a clear argument as to why no revision is needed in the cover letter.
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Your submission will be maintained in active status for 21 days from the date of this letter. If we have not heard from you by Nov 04, 2022, we will assume you wish to withdraw the manuscript from further consideration.
EDITOR COMMENTS:
Please note the following:
Thank you for your submission.
Clarifications:
1. Line 53: Please define "clinically relevant" rate. This is alluded to again in Results, line 120 "In order to increase clinical relevance", but please explain what you mean/how this is defined in the Methods section.
2. Lines 142-144 - The speculation about reasoning for declining concurrent surgeries should be moved from Results to the Discussion section. It would be appropriate to state that the proportion of patients with POP/UI increased during the study period in the Results, but actually linking this as a potential cause/effect should be moved to Discussion, because there could be potentially other contributing factors as well.
* Help us reduce the number of queries we add to your manuscript after it is revised by reading the Revision Checklist at https://journals.lww.com/greenjournal/Documents/RevisionChecklist_Authors.pdf and making the applicable edits to your manuscript.
* Figure 1: Please upload as a figure file on Editorial Manager.
* Figure 2: Please move the y= data and P for trend to the legend or below the figure. Please upload as a figure file on Editorial Manager.
REVIEWER COMMENTS:
Reviewer #1:
Overall:
View Letter
5 11/1/2022, 10:49 AM
The authors are commended for their assessment of concurrent gynecologic oncology and urogynecologic procedures.
They establish that POP/UI is an important issue for patients with gynecologic malignancies that is currently under- addressed. The study is limited by its retrospective nature. The authors could strengthen their study with perhaps a matched analysis for trends overall in POP/UI surgery to see if what they see in cancer survivors mirrors the general population and could strengthen it with a sensitivity analysis of unmeasured confounding (they describe a sensitivity analysis in the methods, but it is unclear where this is represented in the results).
Grammar:
- Assess for grammar
- Concurrent surgery vs concomitant surgery: choose one way to describe and stick to it.
Abstract:
- I would recommend mention of a sensitivity analysis in the methods.
- Line 24: those "who had a diagnosis of POP/UI at time of initial surgery" meaning they had a pre-existing surgery? Or is this referencing the ~80% of the line preceding this (that had a preexisting diagnosis but didn't get surgery). Overall, there are many groups discussed in this study and it is somewhat difficult to keep them straight.
- Line 28: I wonder the utility of the analysis of the rate of concomitant surgery over the time period given the significant potential for confounding.
Intro:
- Line 43: what are the reasons? Perhaps list some of them or describe them?
- Line 49-50: Is life expectancy increasing the main driver for interest in quality-of-life metrics? Or is it that there is more attention paid now to patient experience than prior? Arguably the life expectancy in this country has not changed so significantly in the last 20 years.
- Lines 51-52: I'm not sure I understand what is meant by lack of long-term follow-up? Do the authors suggest that many cancer survivors do not have long-term follow-up? OR that the POP/UI isn't followed?
Methods:
- Line 69: Define what is meant by "local or regional" for each of the cancer types.
- Line 73: Why were people who did not have a hysterectomy within 6 months excluded? If someone had initially received hormonal therapy (for example) for uterine cancer and then opted to pursue hysterectomy, they could have more than 6 months since diagnosis. I think reasonable to exclude but would include why this timeline was chosen.
- Line 85-97: Include the demographics that will be assessed (including a statement on why race was used as a variable, per journal policy)
- Line 91: why were codes from 2022 used on data that had diagnoses only through 2017?
- Lines 99-100: Not necessary to include Microsoft Office programs.
- Lines 106: Univariate analysis was used due to low numbers? (versus multivariate)?
- Lines 109-111: Perhaps expand upon the description of the sensitivity analysis and what it was used for.
Results
- Lines 118-122: Clarify what is meant by the 1,686 patients who had concomitant surgery in table 1 versus those 1,252 in table 2. Are these distinct patients or is there overlap?
- Line 128: What was the adjusted odds ratio? Describe in the results what it was adjusted by (multiple variables, all variables in the table, etc). In the table legend, you state it was adjusted for the variables univariately associated with the outcome in table 2.
- Line 130: What aOR is reported for age over 74? 0.48 or 0.78?
- Line 143: Save this for the discussion of results. Perhaps a better way to depict the rate of concurrent surgery would be to standardize the denominator.
- Line 157: What is meant by "overall cohort"? The new cohort, the original cohort? Perhaps consider using the "Cohort 1"
and "Cohort 2" naming system more consistently (or if it is a sub-group of one of those cohorts, have an additional naming system).
- Were sensitivity analyses included in the results? If so, a statement such as "Sensitivity analysis demonstrated findings were ___ [robust or not robust]___ to unmeasured confounding" would make it more obvious.
View Letter
2 of 5 11/1/2022, 10:49 AM
Discussion:
- Could include further discussion about the predictors found to be associated in this study, and why the diagnosis before might make an impact (surgical planning etc). Additionally, the authors posit reasons why cervical cancer / chemotherapy may be associated with increased POP/UI, but is there data for this? If so, I recommend citing prior studies.
- I wonder the utility of an analysis of trends in surgery for POP/UI in NON-cancer patients over the same time period—for instance, could those with a cancer diagnosis be matched to non-cancer patients and see if the trends seen in cancer patients mirrored those without a cancer diagnosis for rate of POP/UI surgery overall. This could potentially address the limitation that although the diagnosis of POP/UI was inferred from codes, the severity (therefore necessity of surgery) was not.
- I would include in the limitations that SEER-Medicare covers <30% of diagnoses.
- Line 183-184: I think the results of the sensitivity analysis will be important to distinguish why this study accounts for those and more.
- Lines 201-207: It is difficult to compare year to year if diagnosis patterns changed (versus actually more people were being diagnosed).
Tables:
- Generally, for descriptions below the table I would not abbreviate (for instance: continuous instead of cont. or Minimally invasive surgery instead of "Min. invasive surgery")
Table 1:
- See Green Journal table guidelines; also, rationale for inclusion of race as a variable should be discussed in the methods.
Why were lymphadenectomy / adjuvant therapies included? Is there evidence that this alters surgeon decision-making to do concurrent POP/UI surgery?
- Why was non-metropolitan ~4400? I would state what the actual number was and then have an asterisk/superscript with description below for why it was an estimate.
- Describe again what "Cohort 1" is in the table description.
Table 2:
- Are both row and column percent necessary? The table appears busy.
- Again, why are lymphadenectomy and adjuvant treatment included?
Table 3: Add to text what the adjustedOR was calculated by (i.e., which variables were included and why).
Table 4: Put In the table description which was cohort 2.
Table 5 and 6: similar comments to tables 2 and 3.
Figure 1:
- Define what loco/regional cancer meant (which exact stages)
- Define what was "cohort 1" and "cohort 2" to keep naming consistent throughout the paper and figures Figure 2:
- Don't need equation of line p-trend is sufficient
- The figure legend is unclear. For part a, this is assessing the trends in concurrent year among the overall cohort (which one, #1 or #2) and among the select patients who had a pre-existing POP/UI diagnosis? And part b is showing percent of diagnosis of POP/UI out of what—total people diagnosed with cancer? Age-based rate?
Reviewer #2:
General Comments to the Authors:
The authors nicely describe the frequency of concomitant surgery addressing pelvic organ prolapse (POP) and/or urinary incontinence (UI) in patients undergoing surgery for locoregional gynecologic cancers using a retrospective cohort design.
Interestingly, while the early diagnosis of POP/UI has improved/increased over 17 years, the rate of concomitant procedures being performed has gone unchanged (~5.5%), suggesting an opportunity to intervene in more women to address conditions which may substantially negatively impact their quality of life. Use of the SEER-Medicare dataset allows for the study of a robust number of patients, and the decision to stop with index surgery in 2017 permits a 5-year follow- up. They acknowledge weaknesses inherent to the retrospective use of a population-based dataset in addition to lack of knowledge re: POP/UI symptom severity; the possible decision to manage pelvic floor disorders conservatively; and possible coding errors that could have occurred with the transition of ICD-9 to ICD-10. Additional commentary re:
predictors of concomitant surgery (in particular, that Non-Hispanic Blacks and Others are significantly less likely to undergo POP/UI repair compared to Whites) would be welcomed. Overall, this was well-written with a clear presentation of the data in both the text and tables.
View Letter
5 11/1/2022, 10:49 AM
Specific Comments to the Authors:
Structure:
This paper is clearly laid out with all key elements present: abstract, introduction, methodology, results, and conclusions.
The TITLE accurately and succinctly describes the content of the paper.
The ABSTRACT accurately reflects the content of the article well.
The INTRODUCTION describes what the authors hoped to achieve, but, space permitting, you should consider expanding upon one of your referenced citations:
1. The report that "A majority of women diagnosed with a gynecologic malignancy report experiencing symptoms related to POP/UI before and during their cancer treatment" was surprising to me. Add a sentence or two to clarify/quantify. Upon reviewing Bretschneider's 2016 paper, the claim that "a majority" reported symptoms seems inflated; they describe that 40.9% reported UI, and the prevalence of "severe" UI was more like 10%. And this paper—a questionnaire-based survey—
did not attempt to quantify POP on exam and did not query re: bulge symptoms.
The METHODS were clear. The study's design was a retrospective cohort. Eligibility criteria are well-defined and easily understood using Figure 1.
2. Please provide confirmation that this was considered exempt from IRB review.
RESULTS:
3. In Figure 2a, the legend needs to add a description/definition of the black vs. blue trend lines DISCUSSION:
4. In my opinion, it's worth highlighting and commenting on the racial disparity identified: i.e., compared with Non- Hispanic Whites, the Non-Hispanic Blacks and Others are significantly less likely to undergo concomitant POP/UI surgery.
Do the other references you've cited re: combined cancer + PFD surgery identify the same discrepancy? Why do you think Black patients are less likely to be offered concomitant surgery?
5. Similarly, can you speculate on why non-metropolitan location is more associated with concomitant surgery? I'd have predicted the opposite—or perhaps no effect of urban/rural. Do other references find a similar effect?
Reviewer #3: Review of Manuscript ONG-22-1571 "Concurrent surgery for locoregional gynecologic cancers and pelvic floor disorders in the Medicare population"
A manuscript that utilizes SEER data from 2000-2017 in an attempt to evaluate the potential of concomitant surgery for pelvic organ prolapse/urinary incontinence in addition to surgical management for presumed locoregional gynecologic cancers (ovarian, uterine and cervical) has been presented. In addition to evaluating patients from Cohort 1 those which had surgery including a small proportion of those which underwent a POP/UI procedure, they also evaluated a second cohort of patients that did not have a concomitant POP/UI procedure with their hysterectomy but a portion then underwent said surgery. In general the manuscript is well written, although owing to the nature of the SEER database the oncologic details, some of which may have been know or expected preoperative are sparse or lacking and thus not fully informative of pre-op decisions. I have the following questions and comments.
Title - Note this is from the SEER database.
Précis - I would state it potentially presents a missed opportunity for many of the limitations you mentioned at the end of the manuscript.
Abstract - Line 24 - if this is referring to Cohort 2 please add the N.
Introduction
- Line 45 - Is there data on the potential impact of adjuvant therapy on success rates for these combined procedures from an incontinence standpoint?
- Line 54 - I think you are referencing the lack of widely metastatic disease. Regional SEER status includes spread to regional lymph nodes, which many would in fact consider metastatic disease.
Methods
- Line 69 - Did you consider looking only a local disease spread for perhaps a more homogeneous group of patients with a very low risk of adjuvant therapy?
- Line 80 - as written it almost sounds like all women in Cohort 2 had incontinence surgery but in fact this was less than 450 patients (Table 4).
Results
- Line 118 - While most did not receive adjuvant therapy, the number that did is not insignificant.
View Letter
4 of 5 11/1/2022, 10:49 AM
- Line 131 - Can you comment on how the receipt of adjuvant therapy, a decision likely not made until after all pathology had returned may have been impactful on various surgical decisions?
Discussion
- Line 167 - What is the proposed metric for proportion of women that undergo a concomitant procedure? Clearly 0 is too low and 100 is too high, what though may be a reasonable number that can be considered feasible?
- Line 212 - Do you think the higher likelihood of adjuvant therapy for ovarian cancer patients may have impacted this too?
Tables - For Table 1 and 4 did you consider combining for possible comparisons?
Table 2 & 5 - No comments
Table 3 & 6 - Did you consider using ( ) for the upper and lower 95% CI?
Figures - No comments.
STATISTICAL EDITOR COMMENTS:
- How many were excluded based on < 5 yrs follow-up and why were those not included, but treated as censored data? If more than 10% of the final cohort, then should at least include those as a sensitivity analysis and report the data.
- General: Why was BMI not included among the baseline characteristics? If available, should be included. Need to enumerate any missing data in Tables.
- Table 1: Need units for age. Should show the subsets of POP/UI surgery type as a Venn diagram in order to show the reader the relationship among the groupings.
- Table 2, 4: Need units for age.
- Table 3, 5: Need units for age. Should consolidate CIs with point estimates into one column. Should include a column of unadjusted ORs for contrast with the aORs in Table 3.
- Table 6: Need units for age. As in Table 3, should consolidate point estimates with their CIs into one column and include unadjusted ORs to contrast with aORs.
- General: The cohorts with POP/UI surgery, both overall and in the POP/UI diagnosis subsets are relatively small. Given the differences in baseline characteristics, should corroborate the multivariable regression analysis with matching algorithm. There would appear to be more than enough controls with which to match.
-- Sincerely,
Vivian W. Sung, MD, MPH Deputy Editor, Gynecology‒Elect The Editors of Obstetrics & Gynecology
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View Letter
5 of 5 11/1/2022, 10:49 AM
EDITOR COMMENTS:
Please note the following:
Thank you for your submission.
Clarifications:
1. Line 53: Please define "clinically relevant" rate. This is alluded to again in Results, line 120 "In order to increase clinical relevance", but please explain what you mean/how this is defined in the Methods section.
Agree .Will remove as it does not add to the manuscript.
2. Lines 142-144 - The speculation about reasoning for declining concurrent surgeries should be moved from Results to the Discussion section. It would be appropriate to state that the proportion of patients with POP/UI increased during the study period in the Results, but actually linking this as a potential cause/effect should be moved to Discussion, because there could be potentially other contributing factors as well.
Agree. This has been removed from the Results section.
* Help us reduce the number of queries we add to your manuscript after it is revised by reading the Revision Checklist
at https://journals.lww.com/greenjournal/Documents/RevisionChecklist Authors.pdf and making the applicable edits to your manuscript.
* Figure 1: Please upload as a figure file on Editorial Manager.
* Figure 2: Please move the y= data and P for trend to the legend or below the figure. Please upload as a figure file on Editorial Manager.
Julie and Randall to Answer
The p-trend is now added below the figure.
REVIEWER COMMENTS:
Reviewer #1:
Overall:
The authors are commended for their assessment of concurrent gynecologic oncology and urogynecologic procedures. They establish that POP/UI is an important issue for patients with gynecologic malignancies that is currently under-addressed. The study is limited by its retrospective nature. The authors could strengthen their study with perhaps a matched analysis
for trends overall in POP/UI surgery to see if what they see in cancer survivors mirrors the general population and could strengthen it with a sensitivity analysis of unmeasured
confounding (they describe a sensitivity analysis in the methods, but it is unclear where this is represented in the results).
Grammar:
- Assess for grammar Grammar reviewed.
- Concurrent surgery vs concomitant surgery: choose one way to describe and stick to it.
Updated to “concurrent” throughout the manuscript.
Abstract:
- I would recommend mention of a sensitivity analysis in the methods.
Julie and Randall to Answer
A sensitivity analysis was not performed; a subset analysis was performed. This wording has been revised in the manuscript methods and reads as:
Previous sentence:
“A sensitivity analysis was done for subset of individual with only a POP/UI diagnosis that mirrored exactly the statistical methodology used for the overall study cohort.”
Revised:
“A subset analysis was done among individuals with a POP/UI diagnosis for each cohort to evaluate if similar results were seen for this group compared to the entire study population; the statistical methodology mirrored that used for the entire study population of each cohort.”
- Line 24: those "who had a diagnosis of POP/UI at time of initial surgery" meaning they had a pre-existing surgery? Or is this referencing the ~80% of the line preceding this (that had a preexisting diagnosis but didn't get surgery). Overall, there are many groups discussed in this study and it is somewhat difficult to keep them straight.
These are patients who had a diagnosis related to POP/UI, but did NOT have a concurrent surgery.
Patients with any surgery for POP/UI before their cancer diagnosis were excluded from all cohorts. We have standardly used the terms “cohort 1” and “cohort 2” to hopefully make the groups understudy more clear.
- Line 28: I wonder the utility of the analysis of the rate of concomitant surgery over the time period given the significant potential for confounding.
Julie and Randall to Answer
While there is always room to evaluate for potential confounding, there is utility in displaying the rate of concurrent surgeries over time to allow the data to speak for the population it represents, and to provoke reason surrounding this observed flat trend in our study population.
Intro:
- Line 43: what are the reasons? Perhaps list some of them or describe them?
Commonly cited reasons inserted. Correct citation applied.
- Line 49-50: Is life expectancy increasing the main driver for interest in quality-of-life metrics?
Or is it that there is more attention paid now to patient experience than prior? Arguably the life expectancy in this country has not changed so significantly in the last 20 years.
Both are likely. Life expectancy for cancer survivors has increased.
- Lines 51-52: I'm not sure I understand what is meant by lack of long-term follow-up? Do the authors suggest that many cancer survivors do not have long-term follow-up? OR that the POP/UI isn't followed?
Agree that the use of “follow-up” is unclear. We meant to emphasize that the current literature examining patients with Gyn Cancer and POP/UI doesn’t examine long-term outcomes. Edited for clarity.
Methods:
- Line 69: Define what is meant by "local or regional" for each of the cancer types.
This is established by the SEER database in order to standardize the data and is cited in the manuscript.
The definitions for specific anatomical sites can be found in the URL below. We felt listing these in the primary body of the manuscript would be too cumbersome.
https://seer.cancer.gov/tools/ssm/SSM2018-FEMALE-GENITAL-SYSTEM.pdf
- Line 73: Why were people who did not have a hysterectomy within 6 months excluded? If someone had initially received hormonal therapy (for example) for uterine cancer and then opted to pursue hysterectomy, they could have more than 6 months since diagnosis. I think reasonable to exclude but would include why this timeline was chosen.
We believed 6 months was enough time to allow for coordinating concurrent surgeries and that extending beyond 6 months would potentially include patients who may have been lost to follow-up, or patients who were prompted to have their hysterectomy due to cancer progression.
- Line 85-97: Include the demographics that will be assessed (including a statement on why race was used as a variable, per journal policy)
Added.
- Line 91: why were codes from 2022 used on data that had diagnoses only through 2017?
Julie and Randall to Answer
While individuals had a cancer diagnosis only though 2017, this study looked at their claims after hysterectomy for up to 5 years for POP/UI procedures. Additionally, codes used to identify adjuvant treatments needed to extend past their cancer diagnosis and hysterectomy.
The sentence “Standard codes as of March 23rd, 2022 were used as recommended from the National Cancer Institute…” represents codes lists in total and not just those relevant for 2022. To clarify, we have revised this sentence as follows:
“Standard code lists for the entire study period as of March 23rd, 2022 were used as recommended from the National Cancer Institute…”
- Lines 99-100: Not necessary to include Microsoft Office programs.
Deleted.
- Lines 106: Univariate analysis was used due to low numbers? (versus multivariate)?
Julie and Randall to Answer
We did both a descriptive univariate analysis and a multivariate logistic regression model. A univariate analysis was used to see greater detail/granularity of our data (frequencies/cell counts, percentages, etc.…) AND to assess the univariate association between predictors/risk factors and mains outcomes.
The significant univariate associations ultimately determined the variables added to the multivariate logistic regression models.
- Lines 109-111: Perhaps expand upon the description of the sensitivity analysis and what it was used for.
Julie and Randall to Answer
We incorrectly used the term sensitivity analysis in the methods and have updated that (please see response above).
Results
- Lines 118-122: Clarify what is meant by the 1,686 patients who had concomitant surgery in table 1 versus those 1,252 in table 2. Are these distinct patients or is there overlap?
There is overlap. 1,252 of patients with a POP/UI diagnosis had POP/UI surgery. Edited for clarity.
- Line 128: What was the adjusted odds ratio? Describe in the results what it was adjusted by
(multiple variables, all variables in the table, etc). In the table legend, you state it was adjusted for the variables univariately associated with the outcome in table 2.
All of the variables found significant in the univariate analysis were adjusted for in the multivariate analysis. These ones presented in Table 3. So: Age group, Race/Ethnicity, Marital Status, Urban Rural Indicator, Cancer Site, SEER Summary Stage, Charlson Comorbidity Count, POP/UI diagnosis on or before hyst date, Surgery Type (route), Presence of lymphadenectomy, Presence of adjuvant treatment (any type).
- Line 130: What aOR is reported for age over 74? 0.48 or 0.78?
This has been edited for clarity.
- Line 143: Save this for the discussion of results. Perhaps a better way to depict the rate of concurrent surgery would be to standardize the denominator.
Agree.
- Line 157: What is meant by "overall cohort"? The new cohort, the original cohort? Perhaps consider using the "Cohort 1" and "Cohort 2" naming system more consistently (or if it is a sub- group of one of those cohorts, have an additional naming system).
Agree. Edited for clarity.
- Were sensitivity analyses included in the results? If so, a statement such as "Sensitivity analysis demonstrated findings were ___ [robust or not robust]___ to unmeasured confounding" would make it more obvious.
Julie and Randall to Answer
See previous comment regarding sensitivity analysis.
Discussion:
- Could include further discussion about the predictors found to be associated in this study, and why the diagnosis before might make an impact (surgical planning etc). Additionally, the authors posit reasons why cervical cancer / chemotherapy may be associated with increased POP/UI, but is there data for this? If so, I recommend citing prior studies.
The strongest predictor by far was the presence of a history of POP/UI diagnosis. Generally, this does not seem to be well addressed by clinicians. Therefore, we stress that pre-operative evaluation for POP/UI diagnoses in these patients is essential and should be the standard of care.
There are data that cervical cancer surgery radicality and chemotherapy may affect future pelvic floor function. Citations added.
- I wonder the utility of an analysis of trends in surgery for POP/UI in NON-cancer patients over the same time period—for instance, could those with a cancer diagnosis be matched to non- cancer patients and see if the trends seen in cancer patients mirrored those without a cancer diagnosis for rate of POP/UI surgery overall. This could potentially address the limitation that although the diagnosis of POP/UI was inferred from codes, the severity (therefore necessity of surgery) was not.
We agree that an analysis using non-cancer patient data would insightful, however that is currently outside the scope of the current data/analysis.
- I would include in the limitations that SEER-Medicare covers <30% of diagnoses.
Julie and Randall to Answer This limitation is now added to discussion.
Our analysis using the SEER-Medicare dataset only included women over the age of 65 who lived in one of the SEER registries catchment areas at the time of their diagnosis, and therefore these results may not be generalizable to the entire US population. There may be different trends among young cancer patients that is worth exploring in future studies.
- Line 183-184: I think the results of the sensitivity analysis will be important to distinguish why this study accounts for those and more.
Julie and Randall to Answer
Please see above comments on the reported sensitivity analysis.
- Lines 201-207: It is difficult to compare year to year if diagnosis patterns changed (versus actually more people were being diagnosed).
Agree. We found this was a notable finding and although we cannot definitively say which reflects the reality, we wanted to present it.
Tables:
- Generally, for descriptions below the table I would not abbreviate (for instance: continuous instead of cont. or Minimally invasive surgery instead of "Min. invasive surgery")
Edited.
Table 1:
- See Green Journal table guidelines; also, rationale for inclusion of race as a variable should be discussed in the methods. Why were lymphadenectomy / adjuvant therapies included? Is there evidence that this alters surgeon decision-making to do concurrent POP/UI surgery?
Lymphadenectomy may be associated with the radicality of surgery and therefore we thought warranted evaluation and wanted to present the results we found.
Adjuvant therapy, including chemotherapy and especially radiation, is known to affect tissue integrity and has been hypothesized to influence the development of POP/UI.
Additionally, if a clinician believes a patient may need adjuvant radiation treatment they may be more likely to avoid concurrent POP surgery. This is speculation and deserves further
investigation.
- Why was non-metropolitan ~4400? I would state what the actual number was and then have an asterisk/superscript with description below for why it was an estimate.
Julie and Randall to Answer
The SEER-Medicare DUA’s Cell Suppression Policy does not allow for any reported data of less than 11, including categories were that number could be determined using math. Therefore, approximations are a necessary solution as described here: CMS Cell Suppression Policy | Guidance Portal (hhs.gov).
Table 1 now includes the below footnote (as seen in table 5) :
“**Cell size suppressed to comply with Seer-Medicare confidentially rules”, - Describe again what "Cohort 1" is in the table description.
Added.
Table 2:
- Are both row and column percent necessary? The table appears busy.
Julie and Randall to Answer
We wanted to display the data that suits the informational needs of various readers without need for computation. If necessary, row columns should remain as these percentages cannot be calculated by a reader in subset analyses without further information.
- Again, why are lymphadenectomy and adjuvant treatment included?
Explained above.
Table 3: Add to text what the adjustedOR was calculated by (i.e., which variables were included
and why).
Variables included in adjusted OR were the variables found to be significant in the univariate analyses.
Table 4: Put In the table description which was cohort 2.
Added.
Table 5 and 6: similar comments to tables 2 and 3.
Answered above
Figure 1:
- Define what loco/regional cancer meant (which exact stages)
This varies by anatomical site and is likely too cumbersome for the manuscript body. It is well defined by SEER in the following URL and has been purposefully developed to standardize cancer staging across different anatomical sites. It is listed in citation number 11:
https://seer.cancer.gov/tools/ssm/SSM2018-FEMALE-GENITAL-SYSTEM.pdf
- Define what was "cohort 1" and "cohort 2" to keep naming consistent throughout the paper and figures
This has been edited for clarity throughout the paper.
Figure 2:
- Don't need equation of line p-trend is sufficient Julie and Randall to Answer
The equation of the trend line has been removed.
- The figure legend is unclear. For part a, this is assessing the trends in concurrent year among the overall cohort (which one, #1 or #2) and among the select patients who had a pre-existing
experiencing symptoms related to POP/UI before and during their cancer treatment" was surprising to me. Add a sentence or two to clarify/quantify. Upon reviewing Bretschneider's 2016 paper, the claim that "a majority" reported symptoms seems inflated; they describe that 40.9%
reported UI, and the prevalence of "severe" UI was more like 10%. And this paper—a questionnaire-based survey—did not attempt to quantify POP on exam and did not query re:
bulge symptoms.
We were basing that statement on this sentence from their Results section:
“More than half of women reported symptoms of SUI (59.5 %)”.
We can also add one more citation that stated this in the abstract if necessary:
“More than half of the patients with cancer reported baseline urinary incontinence (UI) and 10.9% felt a bulge from their vagina.”
Thomas, Sajeena G., Holly R. N. Sato, J. Christopher Glantz, Paula J. Doyle, and Gunhilde M.
Buchsbaum. 2013. “Prevalence of Symptomatic Pelvic Floor Disorders among Gynecologic Oncology Patients.” Obstetrics and Gynecology 122 (5): 976–80.
The METHODS were clear. The study's design was a retrospective cohort. Eligibility criteria are well-defined and easily understood using Figure 1.
2. Please provide confirmation that this was considered exempt from IRB review.
Added.
RESULTS:
3. In Figure 2a, the legend needs to add a description/definition of the black vs. blue trend lines Julie and Randall to Answer
These figures have been revised and additional description has been added to the footnote as described above.
DISCUSSION:
4. In my opinion, it's worth highlighting and commenting on the racial disparity identified: i.e., compared with Non-Hispanic Whites, the Non-Hispanic Blacks and Others are significantly less likely to undergo concomitant POP/UI surgery. Do the other references you've cited re:
combined cancer + PFD surgery identify the same discrepancy? Why do you think Black patients are less likely to be offered concomitant surgery?
There are few large database studies of Gyn cancer surgery and POP/UI. The only one that included race did not find a statistical significance on univariate analysis. Multivariate analysis was not done.
McConnell, Nicole J., J. Ryan Stewart, Alexandra Martin, Jeremy T. Gaskins, and Erin E.
Medlin. 2018. “The Safety and Feasibility of Gynecologic Cancer Surgery Combined With Surgery for Pelvic Floor Dysfunction.” Female Pelvic Medicine & Reconstructive Surgery, October. https://doi.org/10.1097/SPV.0000000000000621.
The discussion has been expanded to include this disparity.
5. Similarly, can you speculate on why non-metropolitan location is more associated with concomitant surgery? I'd have predicted the opposite—or perhaps no effect of urban/rural. Do other references find a similar effect?
No other study has evaluated this. We don’t think our dataset can be used to draw these inferences and more research into these specific questions is needed.
Reviewer #3: Review of Manuscript ONG-22-1571 "Concurrent surgery for locoregional gynecologic cancers and pelvic floor disorders in the Medicare population"
A manuscript that utilizes SEER data from 2000-2017 in an attempt to evaluate the potential of concomitant surgery for pelvic organ prolapse/urinary incontinence in addition to surgical management for presumed locoregional gynecologic cancers (ovarian, uterine and cervical) has been presented. In addition to evaluating patients from Cohort 1 those which had surgery including a small proportion of those which underwent a POP/UI procedure, they also evaluated a second cohort of patients that did not have a concomitant POP/UI procedure with their hysterectomy but a portion then underwent said surgery. In general the manuscript is well written, although owing to the nature of the SEER database the oncologic details, some of which may have been know or expected preoperative are sparse or lacking and thus not fully
informative of pre-op decisions. I have the following questions and comments.
Title - Note this is from the SEER database.
Added.
Précis - I would state it potentially presents a missed opportunity for many of the limitations you mentioned at the end of the manuscript.
Added.
Abstract - Line 24 - if this is referring to Cohort 2 please add the N.
Introduction
- Line 45 - Is there data on the potential impact of adjuvant therapy on success rates for these combined procedures from an incontinence standpoint?
There is a dearth of data on this topic. Fears of placing mesh in patients with presumed poor wound healing are definitely evident. Interestingly, the below study found no difference in mesh complications in patients with a history of pelvic radiation compared to those without.
Painter, Caitlyn E., Julia Geynisman-Tan, Navendu Samant, Debbie Postlethwaite, and Olga Ramm. 2021. “Mesh Complication Rates Following Pelvic Radiation Therapy in Women With History of Synthetic Midurethral Sling Implantation.” Female Pelvic Medicine & Reconstructive Surgery 27 (2): e476–80.
- Line 54 - I think you are referencing the lack of widely metastatic disease. Regional SEER status includes spread to regional lymph nodes, which many would in fact consider metastatic disease.
Agree. SEER does an excellent job of trying to standardize their “staging” across anatomical sites and has the benefit of combining multiple anatomic sites in studies such as this one. Also, many patients with positive lymph nodes (who undergo surgery) don’t have overtly obvious positive nodes and their positive lymph node status is not known until after surgery. Therefore, we felt appropriate to include Regional disease in this study.
Methods
- Line 69 - Did you consider looking only a local disease spread for perhaps a more homogeneous group of patients with a very low risk of adjuvant therapy?
Yes. However, we found it may have narrowed our scope too much given that many patients found to have positive lymph node status do not have clinically evident positive lymph nodes when planning for their index cancer surgery.
- Line 80 - as written it almost sounds like all women in Cohort 2 had incontinence surgery but in fact this was less than 450 patients (Table 4).
Agree. This has been edited for clarity. Thank you for pointing this out.
Results
- Line 118 - While most did not receive adjuvant therapy, the number that did is not insignificant.
Agree.
- Line 131 - Can you comment on how the receipt of adjuvant therapy, a decision likely not made until after all pathology had returned may have been impactful on various surgical decisions?
Clinicians may be prepared to treat a patient with adjuvant treatment even heading into their initial surgery (certain histologies of uterine cancer, certain sizes of cervical cancer, other higher risk factors like LVSI on biopsy, etc). The effects of planning for radiation and radiation’s effects on tissue integrity may impact surgical decisions. This can be hypothesized by in our study that found that patients who undergo radiation have a lower aOR for undergoing POP/UI treatment in the subsequent five years.
Discussion
- Line 167 - What is the proposed metric for proportion of women that undergo a concomitant procedure? Clearly 0 is too low and 100 is too high, what though may be a reasonable number that can be considered feasible?
We know in this population the incidence of POP/UI diagnosis is too low based on the prevalence found in many studies of validated surveys. We also know from our study that only 5.5% of the entire population undergoes concurrent surgery. So, if we conservatively assume half of the patients with POP/UI are undiagnosed we think a proposed metric would be 10% of this total population (medicare age, locoregional gyn cancer) would be expected to undergo concurrent POP/UI surgery.
In future investigations, we plan to investigate this question.
- Line 212 - Do you think the higher likelihood of adjuvant therapy for ovarian cancer patients may have impacted this too?
Definitely. Also possibly patient-directed factors as well (feeling of overwhelmed perhaps being more associated with ovarian cancer diagnosis than endometrial cancer diagnosis given general mortality differences, etc).
Tables - For Table 1 and 4 did you consider combining for possible comparisons?
Julie and Randall to Answer
For the purposes of this study, we did not think necessary to access or draw-attention to demographic differences between cohorts.
Table 2 & 5 - No comments
Table 3 & 6 - Did you consider using ( ) for the upper and lower 95% CI?
Julie and Randall to Answer
Confidence intervals are now reported with parenthesis in place of upper and lower 95% Cls.
Figures - No comments
- Table 6: Need units for age. As in Table 3, should consolidate point estimates with their CIs into one column and include unadjusted ORs to contrast with aORs.
Julie and Randall to Answer
Units have been added for ages. CIs are now consolidated into one column.
Unadjusted ORs are not included in table 6 because the statistical significance and direction of effect (less than or greater than 1) of an unadjusted OR can be taken away from the detail provided in table 5.
- General: The cohorts with POP/UI surgery, both overall and in the POP/UI diagnosis subsets are relatively small. Given the differences in baseline characteristics, should corroborate the multivariable regression analysis with matching algorithm. There would appear to be more than enough controls with which to match.
Julie and Randall to Answer
We feel that the demographic differences among those who had a concurrent surgery is one of the main findings of this analysis. Our main conclusion is that dedicated efforts must be made to identify patients who would most benefit from concurrent surgeries. Matching on any of those differential demographic variables would obscure the findings we would like to highlight.
Date: 11/18/2022 To: "Logan Corey"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1571R1
RE: Manuscript Number ONG-22-1571R1
Concurrent Surgery for Locoregional Gynecologic Cancers and Pelvic Floor Disorders in the Medicare Population: A SEER Database Study
Dear Dr. Corey:
Thank you for submitting your revised manuscript. After review, we will not be able to move forward with further revisions until you have addressed and performed the Statistical Editor’s fourth question (Q4) below. We invite you to submit a second revision of the manuscript.
In a separate email from Morgan Musselman ([email protected]), you will be receiving a version of your manuscript that has been edited for style by the Manuscript Editor. Please use this version when making the requested changes above. Please also address the queries within this version when you submit your updated revision in Editorial Manager.
Your submission will be maintained in active status for 14 days from the date of this letter. If we have not heard from you by Dec. 2, 2022, we will assume you wish to withdraw the manuscript from further consideration.
Thank you for your attention to this and we look forward to receiving your revised version.
STATISTICAL EDITOR COMMENTS:
Q1: The question regarding the number excluded (should express as n (%) of total) was not answered.
Q2: Since BMI was not included in SEER database, but could potentially be an important confounder, should state this in Discussion among limitations to interpreting this study.
Q3: Regarding addition of univariate unadjusted ORs in Tables 3, 5. These should be added in main text of article as an important source of context for the adjusted ORs. It is important for the reader to see how adjustment enhanced or mitigated the strength of association indicated by the unadjusted analysis. By combining the point estimates with their CIs into a single column, this could easily be formatted in one Table.
Q4: Regarding matching in addition to multivariable adjustment. The Authors establish that the cohorts have multiple differences in identified baseline characteristics, have used multivariable adjustment methodology to account for the differences, yet do not want to match on differences because "Matching on any of those differential demographic variables would obscure the findings we would like to highlight." The Authors need to corroborate their findings and present all the evidence supporting or refuting their hypotheses, including appropriate matching.
In more detail:
Cohort 1 had 30,862 patients, of whom 5.5% underwent concurrent surgery. This is shown well in Fig 2a, with a NS trend over time. Fig 2b shows the rate of diagnosis of POP/UI, which increased (per the linear regression provided) at ~ .5% per year on average. Fig 2a also shows the proportion of cases with POP/UI who underwent concurrent surgery, which decreased by ~ 1% per year (again reading from the linear regression provided). In other words, the increase in diagnosis of POP/UI was offset by a decrease in those cases (POP/UI) undergoing concurrent surgery, with no apparent net change in the overall rate of concurrent surgery.
So, although the first question was directly answered, it is reasonable to ascertain what else may have changed during this time period to influence the rate of concurrent surgery. These could include age, race, year of cancer diagnosis (since there is a significant trend in POP/UI over time), not to mention the other factors related to cancer diagnosis and its treatment.
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1 of 2 12/2/2022, 9:23 AM
The Authors compared in Table 2 the entire cohort of 30,862 (in terms of who did/did not have concurrent surgery) and separately the cohort of those who had the
diagnosis of POP/UI (5,923), whose respective rates of concurrent surgery were 5.4%
and 21.1%. Within each group (all vs POP/UI), age distribution, race/ethnicity, marital status, cancer site etc were compared. While these comparisons are important, the comparisons should also include comparing those with POP/UI vs
those without, rather than comparing POP/UI vs all. This would allow the reader to judge the extent to which differences in age and the other characteristics modified likelihood of concurrent surgery for each subset. Of note, 434 patients underwent concurrent surgery in the non-POP/UI cohort, out of 24,939 patients, or a rate of 1.7%, compared to a rate of 21.1% among the POP/UI, resulting in 5.4% overall. So Table 2 should be revised to include analysis for the subset with no POP/UI.
Table 3, which compares the various factors that were associated with concurrent surgery, again in the subset with POP/UI and the entire group (both POP/UI and non POP/UI), is difficult to interpret. Most of the cases of concurrent surgery (1252/1686, or
~ 74%) occurred among those with POP/UI. That is, it is clearly POP/UI that had the strongest association (unadjusted OR ~ 15, i.e., comparing 21.1% vs 1.7%) with concurrent surgery, and thus dominates analysis of concurrent rates when both subsets are aggregated. Should compute aORs in Table 3 based on the POP/UI group, then the non-POP/UI group. Then, should compare those aORs for each characteristic, in order to show the reader which characteristics (besides POP/UI)
were associated with concurrent surgery, both for the POP/UI group and the nonPOP/UI group. For example, in the present format for Table 3, the aORs for age group
vs concurrent rates show less association as age increases for both POP/UI and “All”
but the aORs at each age stratum are essentially the same. However, “All” is dominated by POP/UI in terms of concurrent surgery outcomes, so the OR's are biased by the POP/UI group. At least judging by the proportions (and therefore the unadjusted OR's), any age effect is negligible for the non-POP/UI group. If that is true for the aORs, then that would seem to be an important distinction.
The Authors then examined the rates of concurrent surgery over the 5 yrs following the initial surgery, in Cohort 2, which was comprised of 16,054 patients, of whom 2,436 were diagnosed with POP/UI and overall 2.8% had subsequent surgery, 5.5% among those with POP/UI and 310/13618, or 2.3% among those without POP/UI, so now with an unadjusted OR = 2.55, so still an important association, but almost an order of magnitude less strong than in the original group. Table 6 should also be revised to include comparison of the non-POP/UI (rather than all) in terms of aORs. In turn, those corresponding aOR (by age stratum etc) should be compared in order to demonstrate for the reader whether the same factors are associated with subsequent surgery for the POP/UI group vs others.
In summary, I suggest that it would be of interest to approach the evaluation of rate of concurrent surgery (Cohort 1) as the output in multi variable regression using the following: (1) diagnosis of POP/UI, year of cancer diagnosis, then all of the relevant characteristics and variables in Table 1. It is not clear from the present analysis which characteristics are most important. Separately, if of interest, could repeat the analysis separately on the POP/UI subset and the non-POP/UI subset.
The same approach could be taken to evaluate subsequent surgery rates (Cohort 2).
It appears that there are multiple factors influencing the surgical rates, even though the aggregate rate for Cohort 1 did not vary over the course of the study. Besides the multivariable regression approach, a complementary approach would be to match POP/UI with non-POP/UI patients on year of study, age etc using propensity score matching, then test for any difference in concurrent surgery rates. The same could be done for subsequent surgery rates as the outcome of interest for Cohort 2
Sincerely,
Vivian Sung, MD, MPH
__________________________________________________
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2 of 2 12/2/2022, 9:23 AM
diagnosis of POP/UI (5,923), whose respective rates of concurrent surgery were 5.4%
and 21.1%. Within each group (all vs POP/UI), age distribution, race/ethnicity, marital status, cancer site etc were compared. While these comparisons are important, the comparisons should also include comparing those with POP/UI vs
those without, rather than comparing POP/UI vs all. This would allow the reader to judge the extent to which differences in age and the other characteristics modified likelihood of concurrent surgery for each subset. Of note, 434 patients underwent concurrent surgery in the non-POP/UI cohort, out of 24,939 patients, or a rate of 1.7%, compared to a rate of 21.1% among the POP/UI, resulting in 5.4% overall. So Table 2 should be revised to include analysis for the subset with no POP/UI.
Table 3, which compares the various factors that were associated with concurrent surgery, again in the subset with POP/UI and the entire group (both POP/UI and non POP/UI), is difficult to interpret. Most of the cases of concurrent surgery (1252/1686, or
~ 74%) occurred among those with POP/UI. That is, it is clearly POP/UI that had the strongest association (unadjusted OR ~ 15, i.e., comparing 21.1% vs 1.7%) with concurrent surgery, and thus dominates analysis of concurrent rates when both subsets are aggregated. Should compute aORs in Table 3 based on the POP/UI group, then the non-POP/UI group. Then, should compare those aORs for each characteristic, in order to show the reader which characteristics (besides POP/UI)
were associated with concurrent surgery, both for the POP/UI group and the nonPOP/UI group.
For example, in the present format for Table 3, the aORs for age group
vs concurrent rates show less association as age increases for both POP/UI and “All”
but the aORs at each age stratum are essentially the same. However, “All” is dominated by POP/UI in terms of concurrent surgery outcomes, so the OR's are biased by the POP/UI group. At least judging by the proportions (and therefore the unadjusted OR's), any age effect is negligible for the non-POP/UI group. If that is true for the aORs, then that would seem to be an important distinction.
The Authors then examined the rates of concurrent surgery over the 5 yrs following the initial surgery, in Cohort 2, which was comprised of 16,054 patients, of whom 2,436 were diagnosed with POP/UI and overall 2.8% had subsequent surgery, 5.5% among those with POP/UI and 310/13618, or 2.3% among those without POP/UI, so now with an unadjusted OR = 2.55, so still an important association, but almost an order of magnitude less strong than in the original group. Table 6 should also be revised to include comparison of the non-POP/UI (rather than all) in terms of aORs. In turn, those corresponding aOR (by age stratum etc) should be compared in order to demonstrate for the reader whether the same factors are associated with subsequent surgery for the POP/UI group vs others.
In summary, I suggest that it would be of interest to approach the evaluation of rate of concurrent surgery (Cohort 1) as the output in multi variable regression using the following: (1) diagnosis of POP/UI, year of cancer diagnosis, then all of the relevant characteristics and variables in Table 1. It is not clear from the present analysis which characteristics are most important. Separately, if of interest, could repeat the analysis separately on the POP/UI subset and the non-POP/UI subset.
The same approach could be taken to evaluate subsequent surgery rates (Cohort 2).
It appears that there are multiple factors influencing the surgical rates, even though
the aggregate rate for Cohort 1 did not vary over the course of the study. Besides the multivariable regression approach, a complementary approach would be to match POP/UI with non-POP/UI patients on year of study, age etc using propensity score matching, then test for any difference in concurrent surgery rates. The same could be done for subsequent surgery rates as the outcome of interest for Cohort 2
In reviewing the feedback provided by the statistical reviewer, we realize we misunderstood the original suggestion on matching. We thought the recommendation was to match between what is now consistently labeled as cohort 1 (all women with gyn cancer) and cohort 2 (those who did not undergo a concurrent surgery and had 5 years of follow-up). We now see that the recommendation was to match those women with a POP-UI diagnosis and those without (or more appropriately stated, women with an insurance claim documenting POP-UI and those without). One of the limitations of using claims data for research is that certain diagnoses may not be listed on a patient insurance claim though a patient has the condition. We hypothesized that this is true for POP-UI conditions as these are often not addressed by either the physician or the patient (as cited in the literature and in the manuscript). The data we present here also supports this as 434 women without an insurance claim documenting POP-UI underwent a procedure to correct the condition. In a perfect world, we would have only performed this analysis on women who we knew had POP-UI. However, that cannot be determined with claims data and is a limitation of this study. To clarify this detail to the reader we have stated that we use POP-UI claims as a proxy for POP-UI diagnosis: “POP-UI Medicare claims were used as a proxy for POP-UI diagnosis”. We have also added as a limitation in the discussion that… “A limitation of using claims data for research is that some conditions may not be listed on insurance claims and this is likely true for POP-UI, especially if the condition was not treated. We are not able to identify the true population of women with POP-UI only the subset who had a claim documenting the diagnosis.”
Additionally, the variables we have available for this study are not good predictors for determining who had a POP-UI claim. In evaluating the reviewer’s suggestion for creating a non-POP- UI propensity-matched dataset, although there were statistically significant variables between diagnosis groups, the regression model indicated that we could not create meaningfully matched groups. We noted that the R-squared from the logistic regression model including the covariates age, race, cancer site, stage, comorbid conditions count, surgery type, year of cancer diagnosis, and treatment variables was only 0.02.
We believe it is likely there is both an increased awareness (and thus increased diagnosis/caims) of a previously underdiagnosed condition (POP-UI) while at the same time,
concurrent surgery for it is less common (as surgeons specialize more and more, and OR time becomes more difficult to coordinate). However, the data available to us does not allow us to answer this question as thoroughly as it deserves and we have ongoing investigations into this specific topic. With the data available we believe we were able to answer our proposed research question in depth,
“what is the rate of concurrent surgeries in a population-based sample of gyn onc patients?”
