Treatment of Older Adult Patients with Glioblastoma: Moving towards the Inclusion of a Comprehensive Geriatric Assessment for Guiding Management

Round 1

Reviewer 1 Report

I would like to commend the authors on a well-written and interesting article. I enjoyed reading "Treatment of older adult patients with glioblastoma: Moving 2 towards the inclusion of a comprehensive geriatric assessment 3 for guiding management" and the topic is of great interest to the neurosurgical and neuro-oncology community as the population continues to age and the incidence of GBM increases in the elderly population.

I have a few suggestions/questions that may help improve the paper:

- In the Introduction, I suggest the authors really highlight how the standard of care for GBM has been established from studies that outright excluded elderly patients (e.g. inclusion criteria for Stupp trial was < 70 years old). The authors address this throughout the paper but I think the introduction should emphasize this point as it is critical when considering the evidence for the extrapolating the standard of care to an elderly patient.

-Are there any additional studies that describe the correlation between KPS and the frailty metrics other than the one mentioned on p. 10 lines 397-401? I think the authors can highlight this poor correlation between KPS and frailty even more to point out KPS is not a marker of frailty.

- Can authors expand on pros and cons of CGA compared to a more simple frailty metrics, like the mFI-5 score? Given the lack of consensus for what metrics are included in a CGA and the time such metrics take patients to complete, maybe the authors can state what items they feel should be included in a CGA and why that's superior to a shorter scoring metric.

- I suggest adding a summary table for the trials discussed in the Body of the paper that make up the evidence for adjuvant XRT, chemo, combined therapy, and CGA screening in older GBM patients as it would be useful for the reader to reference.

- I did not find Figure 1 particularly useful, as nearly each decision algorithm ended with numerous treatment options ranging in aggressiveness. Perhaps the authors could add a column after the last branch point with average survival for each treatment strategy based on the best available data.

- Can the authors add a discussion or future directions paragraph on any biologic measures of frailty (e.g. telomere length, sarcopenia, etc.) and how they could be used to measure biological age (rather than chronological age)?

Author Response

Thank you to the reviewer for their insightful comments. Please see below for a response to each comment. 

• In the Introduction, I suggest the authors really highlight how the standard of care for GBM has been established from studies that outright excluded elderly patients (e.g. inclusion criteria for Stupp trial was < 70 years old). The authors address this throughout the paper but I think the introduction should emphasize this point as it is critical when considering the evidence for the extrapolating the standard of care to an elderly patient.
  • I have incorporated this change
• Are there any additional studies that describe the correlation between KPS and the frailty metrics other than the one mentioned on p. 10 lines 397-401? I think the authors can highlight this poor correlation between KPS and frailty even more to point out KPS is not a marker of frailty.
  • I have incorporated this change
• Can authors expand on pros and cons of CGA compared to a more simple frailty metrics, like the mFI-5 score? Given the lack of consensus for what metrics are included in a CGA and the time such metrics take patients to complete, maybe the authors can state what items they feel should be included in a CGA and why that's superior to a shorter scoring metric.
  • There is no data using simple frailty metrics. This is problematic because patients have inherent functional limitations as a result of their disease so a CGA would be more robust.
• I suggest adding a summary table for the trials discussed in the Body of the paper that make up the evidence for adjuvant XRT, chemo, combined therapy, and CGA screening in older GBM patients as it would be useful for the reader to reference.
  • I have created a table (now table 1) highlighting the pivotal trials that provide evidence for adjuvant treatment. CGA screening data thus far in GBM is very heterogenous and doesn't fit well in a table. 
• I did not find Figure 1 particularly useful, as nearly each decision algorithm ended with numerous treatment options ranging in aggressiveness. Perhaps the authors could add a column after the last branch point with average survival for each treatment strategy based on the best available data.
  • We have opted to keep figure 1 in, however the editors can remove it at their discretion if they are in agreement with the reviewer. 
• Can the authors add a discussion or future directions paragraph on any biologic measures of frailty (e.g. telomere length, sarcopenia, etc.) and how they could be used to measure biological age (rather than chronological age)?
  • We have added a statement regarding sarcopenia in the discussion.

Thank you again for your review. 

Manik Chahal

Reviewer 2 Report

The main topic is to assess a good score for eligible patients;

• The topic is original and relevant;
• The comparison of different scores is useful;
• because it is a review report I do not think the other information are needed;
• the conclusions are correct;
• the references are very extensive (except for the two potential - recommended ones);
• I do not have other comments.

For more complete references I suggest to insert these papers (considering that it is a review paper)

• Di Cristofori, B. Zarino, C. Fanizzi, GA Fornara, G. Bertani, P. Rampini, G. Carrabba, M. Caroli. Analysis of factors influencing the access to concomitant chemo-radiotherapy in elderly patients with high grade gliomas : role of MMSE, age and tumor volume. J Neurooncol 2017
• B Zarino, MA Sirtori, T Meschini, GA Bertani, M Caroli, C Bana, L Borellini, M Locatelli, G Carrabba. Insular lobe surgery and cognitive impairment in gliomas operated with intraoperative neurophysiological monitoring. Acta Neurochirurgica: https://doi.org/10.1007/s00701-020-04643-9

Author Response

Thank you to the reviewer for their comments and suggestions.

We have incorporated the 2nd reference paper, but felt that the first reference paper did not fit naturally into the review. 

Thank you again for your review. 

Manik Chahal