Newly Diagnosed Multifocal GBM: A Monocentric Experience and Literature Review

Round 1

Reviewer 1 Report

In this manuscript Baro et al present a large mono-institutional retrospective study analyzing multifocal and multicentric Glioblastomas. Authors further perform literature review and combine their findings with the previous reports. The analysis follows the newest WHO 2021 classification for GBM whenever possible and clearly identifies the analysis limits based on previous classifications. The authors show that multifocal GBMs are more frequent than initially reported. Radiotherapy and TMZ was identified as an independent prognostic factors for survival, though the influence of extent of surgical resection is not clear. The manuscript is well written and of interest to the scientific community.

Several improvements should be envisaged:

1. Throughout the manuscript authors compare their recent analysis to previous reports on multifocal/multicentric GBMs. It would be important to analyze and to highlight further in the discussion differences between multifocal GBMs and other GBMs. Currently, it is not clear from the text, which of the findings are specific to multifocal GBMs, and which are the classical characteristics of all GBMs (E.g. surgical resection and treatment modalities as prognostic factors).
2. Authors discuss correctly the confounding patient characteristics that may result in the lack of or limited surgical resection. As the authors show that radiotherapy + TMZ treatment represents an independent prognostic factor, it would be important to discuss whether other parameters linked to patient health prior or during surgery (could) influence lack of follow up RT +TMZ treatment, thus leading to shorter overall survival.
3. Reference 1: Ostrom et al, have released new statistical report in 2020 based on 2013-2017 cases (DOI: 10.1093/neuonc/noaa200). The authors should verify this reference for reported values and cite accordingly.

Author Response

We would like to thank the reviewer for careful and thorough reading of this manuscript and for the thoughtful comments and constructive suggestions, which improved the quality of this manuscript. Our response follows.

Reviewer n.1: Throughout the manuscript authors compare their recent analysis to previous reports on multifocal/multicentric GBMs. It would be important to analyze and to highlight further in the discussion differences between multifocal GBMs and other GBMs. Currently, it is not clear from the text, which of the findings are specific to multifocal GBMs, and which are the classical characteristics of all GBMs (E.g. surgical resection and treatment modalities as prognostic factors).

Response: thank you for your comment. Since our work focused only on multifocal / multicentric glioblastomas we have not enrolled patients with single lesion. Nevertheless, in the introduction section, we included a brief comparison between multiple lesions and single lesions, underlining the greater difficulty of treatment and the worse prognosis of the first ones (page 2, line 73-78).

Authors discuss correctly the confounding patient characteristics that may result in the lack of or limited surgical resection. As the authors show that radiotherapy + TMZ treatment represents an independent prognostic factor, it would be important to discuss whether other parameters linked to patient health prior or during surgery (could) influence lack of follow up RT +TMZ treatment, thus leading to shorter overall survival.

Response: thank you for pointing this out. We added a paragraph with this issue (page 14, line 430-434)

Reference 1: Ostrom et al, have released new statistical report in 2020 based on 2013-2017 cases (DOI: 10.1093/neuonc/noaa200). The authors should verify this reference for reported values and cite accordingly.

Response: Thank you for this comment. We changed the reference and the report in the text acc accordingly (page 2, line 47-48).

Reviewer 2 Report

The authors conducted a monocentric retrospective study on multifocal glioblastoma with the aim to increase our general understanding on this sub-entity and better define the treatment options for these patients. The study is based on a sound methodology and was well executed, with the only caveat that it was conducted with clinical records from only a small number of patients (i.e., based on the inclusion/exclusion criteria of the study, the medical records from only 98 patients diagnosed with multifocal glioblastoma could be analyzed).  One important finding from the study was to confirm the chemoradiation (i.e., TMZ plus RT) as an independent prognostic factor in this patient cohort. More patient data from a much larger multicentric study will be needed in the future for a better understanding of the impact of chemoradiation on the various molecular subtypes of multifocal GBM and the prognostic role of expressed DNA repair MGMT protein in this sub-entity. I found the study very informative and the manuscript well written. I have also found the inclusion of a section discussing the strengths and limitations of the study very helpful. My only (minor) inquiries for the authors are as follows:

1. Could you please clarify whether the complete Stupp protocol scheme (i.e., concurrent chemoradiation followed by adjuvant TMZ cycles) was used in all cases where you indicated in the manuscript that the patient was treated with RP+TMZ? Also, was the RT administered to the patients in the study as WBRT or conformal?
2. What was the reason for treating some of the patients with RT alone? Was this decision solely based on the tumor MGMT status or on additional criteria that were also considered in the decision process? The same question regarding the two patients who received TMZ alone. Regarding the latter, TMZ alone data (but from a much larger patient population) could be very valuable in the future for answering some (still outstanding) questions regarding the radiosensitization potential of TMZ. Lastly, it is both counterintuitive and intriguing that the disease control rate (DCR) in the patients who received RT alone in this study was 0%.

Author Response

We would like to thank the reviewer for careful and thorough reading of this manuscript and for the thoughtful comments and constructive suggestions, which improved the quality of this manuscript. Our response follows.

Reviewer n.2: could you please clarify whether the complete Stupp protocol scheme (i.e., concurrent chemoradiation followed by adjuvant TMZ cycles) was used in all cases where you indicated in the manuscript that the patient was treated with RP+TMZ? Also, was the RT administered to the patients in the study as WBRT or conformal? 

Response: Thank you for this comment. As we have specified in paragraph 3.1 Patient characteristics and in Table 1, not all patients treated with RT + TMZ followed the original Stupp protocol consisting of radiotherapy with concomitant temozolomide followed by 6 cycles of temozolomide. Furthermore, the radiotherapy administered to the patients was conformal. We added this information in paragraph 3.1 Patients characteristics (page 5, line 198).

What was the reason for treating some of the patients with RT alone? Was this decision solely based on the tumor MGMT status or on additional criteria that were also considered in the decision process? The same question regarding the two patients who received TMZ alone. Regarding the latter, TMZ alone data (but from a much larger patient population) could be very valuable in the future for answering some (still outstanding) questions regarding the radiosensitization potential of TMZ. Lastly, it is both counterintuitive and intriguing that the disease control rate (DCR) in the patients who received RT alone in this study was 0%.

Response: thank you for the comment. We add a paragraph assessing this point on page 14, line 415-420.

We agreed about the future perspective of a larger population based study investigating the radiosensitisation potential of TMZ. Further, the fact that the 2 patients who received RT alone had any benefit from the treatment could be related to the confounding factor such as PS and disease dissemination leading to the choice of a palliative and limited treatment.

Round 2

Reviewer 1 Report

I accept the changes made by the authors