Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme—A Literature Review and Clinical Outcomes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review addresses TMZ in the treatment of GBM. It is compact and yet sufficiently informative. I have a few suggestions.

 

#Introduction

Since this review seems to be based on the WHO classification 2021, the authors probably use the term GBM to refer to glioblastoma, IDH-wildtype, but not to G4 astrocytoma, IDH-mutant, right? The definition of what they mean by ‘GBM’ as well as that of GBM based on the WHO classification 2021 should be clearly mentioned for the readers unfamiliar with brain tumors.

 

#Materials and Methods

This is pertinent to the above. Before the era of the WHO classification 2021, glioblastoma, IDH-wildtype and G4 astrocytoma, IDH-mutant had been lumped together under the name of ‘GBM’; actually, G4 astrocytoma, IDH-mutant had been called ‘GBM’ as well. Thinking this way, I am afraid the keywords they used for searching the literature might have picked up both glioblastoma, IDH-wildtype and G4 astrocytoma, IDH-mutant in the WHO classification 2021. If what the authors mean by ‘GBM’ is glioblastoma, IDH-wildtype, then in a strict sense, G4 astrocytoma, IDH-mutant should have been excluded. This kind of exclusion of the literature has been performed for this review? If there is a hint of the possibility of mixture of both, then, this should be clearly described somewhere in the Ms.

 

#Results

-Is it better to compare TMZ with other commercially and clinically used anti-GBM agents, like Carmustine? This is because I want to know where TMZ could be placed in terms of effects/side effects or how much GBM could be resistant in comparison with other anti-GBM agents.

-3.1.

What is ‘grade 3-4’ hematologic complications? Probably, not a few readers do not know this grading.  

 

#Some further editing (in terms of grammar, style, etc) is necessary.

Ex

#Abstract

-the WHO classification > the WHO classification 2021 (the edition should be described)

-Therapy for patients with glioblastoma multiforme > Therapy for patients with GBM, temozolomide in the treatment of glioblastoma multiforme > temozolomide in the treatment of GBM (This is because the abbreviation for glioblastoma multiforme has already introduced at the very outset of the abstract)

 

-etc, throughout the Ms

Comments on the Quality of English Language

A relatively good English

Author Response

July 07, 2024
MDPI: Current Oncology Journal
Special Issue: Treatment for Glioma: Retrospect and Prospect
Guest Editors: Dr. Andrea Landi, Dr. Valentina Baro, Prof. Dr. Giuseppe Lombardi

Dear Editors and Reviewers,
At the beginning we would like to thank You sincerely for the possibility to re-submit our 
revised manuscript Temozolomide (TMZ) in the treatment of glioblastoma multiforme—A 
Literature Review and Clinical Outcomes for consideration as an article in Special Issue 
Treatment for Glioma: Retrospect and Prospect. Thank You very much for considering it for 
potential publication. We would like to thank You for the very thorough reviews and for the 
advices and constructive criticism, which have been valuable for improving the paper. All of 
Your suggestions for changes and improvements were very helpful to us, and we have 
revised the manuscript according to the recommendations made in the reviews. All of the 
changed, deleted and added portions of the manuscript are marked by using Track Changes.
We have attached a proposition of Graphical Abstract, according to the Editor’s suggestion.
According to the reviewers’ instructions we corrected our manuscript point-by-point as 
follows:
Reviewer 1
At the beginning we would like to thank You very much for reviewing our manuscript 
Temozolomide (TMZ) in the treatment of glioblastoma multiforme—A Literature Review and 
Clinical Outcomes for consideration as an article in Special Issue Treatment for Glioma: 
Retrospect and Prospect. We also would like to thank You very much for Your opinion that 
our manuscript is “compact and yet sufficiently informative”. Our team tried to prepare this 
TMZ review basing on the latest scientific data and to present it in the most relevant version. 
Thank You so much, that You noticed and appreciated it. Thank You.
1. “#Introduction. Since this review seems to be based on the WHO classification 2021, the 
authors probably use the term GBM to refer to glioblastoma, IDH-wildtype, but not to G4 
astrocytoma, IDH-mutant, right? The definition of what they mean by ‘GBM’ as well as that of 
GBM based on the WHO classification 2021 should be clearly mentioned for the readers 
unfamiliar with brain tumors.”
Dear Reviewer, 
We sincerely thank You for noticing this problem. In the Introduction section, we included an 
explanation of the WHO classification, both the current one with the differentiation into IDHwt and IDH-mutant GBM, and the previous state before 2021, where the aforementioned 
GBM subtypes were not distinguished. The definition of what we mean by 'GBM' in our 
paper is described in the Materials and Methods section. Thank You.
2. “#Materials and Methods. This is pertinent to the above. Before the era of the WHO 
classification 2021, glioblastoma, IDH-wildtype and G4 astrocytoma, IDH-mutant had been 
lumped together under the name of ‘GBM’; actually, G4 astrocytoma, IDH-mutant had been 
called ‘GBM’ as well. Thinking this way, I am afraid the keywords they used for searching the 
literature might have picked up both glioblastoma, IDH-wildtype and G4 astrocytoma, IDHmutant in the WHO classification 2021. If what the authors mean by ‘GBM’ is glioblastoma, 
IDH-wildtype, then in a strict sense, G4 astrocytoma, IDH-mutant should have been excluded. 
This kind of exclusion of the literature has been performed for this review? If there is a hint 
of the possibility of mixture of both, then, this should be clearly described somewhere in the 
Ms.”
Dear Reviewer, 
Thank You very much for that comment. Indeed, as You suggested, not specifying the criteria 
for including articles in the analysis would have caused inaccuracies. The Materials and 
Methods section includes an explanation of the definition of GBM that was used in our 
article. The exclusion of the literature You mentioned was not performed because of the 
similar therapeutic approach with TMZ in these tumors. Marking MGMT methylation status 
(a criterion that differentiates IDH-wt from IDH-mutant GBM) is not yet standard in all 
centers as of today and was not before 2021. Given that much of the literature on TMZ dates 
from before 2021, distinguishing TMZ therapies for each GBM subtype separately might not 
allow the article to provide a comprehensive overview. We believe that the analysis of 
studies both before 2021 and after this year will allow us to show the results of the therapy 
of the described TMZ in a broader scope. Once again, thank You for providing such an 
accurate comment. Thank You.
3. “#Results. -Is it better to compare TMZ with other commercially and clinically used antiGBM agents, like Carmustine? This is because I want to know where TMZ could be placed in 
terms of effects/side effects or how much GBM could be resistant in comparison with other 
anti-GBM agents.”
Dear Reviewer,
Thank You very much for this suggestion. Other alkylating chemotherapeutics are obviously 
very important in complementary therapy to TMZ treatment. However, in this study, 
carmustine was not the object of our interest. According to PMID: 32589560, in terms of side 
effects carmustine "(...) have high associated toxicity (mainly causing myelosuppression and 
respiratory alterations) that limits their use and even leads to treatment discontinuation 
(...)," while TMZ "(...) has predictable side effects, and its toxic effects are usually reversible 
and only mild or moderate (...)," as we have described in the TMZ side effects paragraph. The 
combined use of the two chemotherapeutics is highlighted in some studies, and we have 
added the relevant information about this in the text. However, according to e.g. PMID: 
30459887, such a combination may result in alternative side effects. Thank You again for 
pointing out the issue related to carmustine, but it would go beyond the scope of our article 
in which we focused mainly on TMZ itself.
3.1. “What is ‘grade 3-4’ hematologic complications? Probably, not a few readers do not 
know this grading.”
Dear Reviewer,
Thank You so much for noticing that issue. We have clarified the classification of adverse 
effects in general and added specific values for lymphopenia. This grading should be clear in 
its current form. Thank You.
4. “#Some further editing (in terms of grammar, style, etc) is necessary.”
Dear Reviewer,
Thank You very much for this remark. The manuscript has undergone English editing with 
attached certificate. Thank You.
5. “#Abstract. -the WHO classification > the WHO classification 2021 (the edition should be 
described), -Therapy for patients with glioblastoma multiforme > Therapy for patients with 
GBM, temozolomide in the treatment of glioblastoma multiforme > temozolomide in the 
treatment of GBM (This is because the abbreviation for glioblastoma multiforme has already 
introduced at the very outset of the abstract), -etc, throughout the Ms”
Dear Reviewer,
Thank You for noticing that issue. Relevant phrases have been replaced by abbreviations and 
the year has been clarified at the WHO classification
We believe that the presented article will interest physicians and researchers in subject of 
neuro-oncology and glioma management. The type of submitted manuscript is a review article, 
and the style and format have been prepared according to MDPI guidelines. All authors have 
read the amendments and agreed to publication. Thank You for reviewing our manuscript and 
considering it for potential publication in Current Oncology Journal. We appreciate Your time 
and look forward to Your response.

Your Sincerely,
Marcin Jezierzański, Authors

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

the authors review the utilization of TMZ in patients with GBM. The review is comprehensive and well done. A few discrepancies should be corrected: 

line 39 is contradictory: if median survival is 15 months, more than 40% of patients survive longer than a year. This should be corrected. 

I would caution the authors to review the 2021 WHO classification of CNS tumors, as some times glioblastoma and WHO grade IV glioma is used interchangeable, when differences exist and should be mentioned. For instance, line 153-: anapestic glioma is grade III and, thus, not a glioblastoma. 

Comments on the Quality of English Language

needs minor editing. 

Author Response

July 07, 2024
MDPI: Current Oncology Journal
Special Issue: Treatment for Glioma: Retrospect and Prospect
Guest Editors: Dr. Andrea Landi, Dr. Valentina Baro, Prof. Dr. Giuseppe Lombardi

Dear Editors and Reviewers,
At the beginning we would like to thank You sincerely for the possibility to re-submit our 
revised manuscript Temozolomide (TMZ) in the treatment of glioblastoma multiforme—A 
Literature Review and Clinical Outcomes for consideration as an article in Special Issue 
Treatment for Glioma: Retrospect and Prospect. Thank You very much for considering it for 
potential publication. We would like to thank You for the very thorough reviews and for the 
advices and constructive criticism, which have been valuable for improving the paper. All of 
Your suggestions for changes and improvements were very helpful to us, and we have 
revised the manuscript according to the recommendations made in the reviews. All of the 
changed, deleted and added portions of the manuscript are marked by using Track Changes.
We have attached a proposition of Graphical Abstract, according to the Editor’s suggestion.
According to the reviewers’ instructions we corrected our manuscript point-by-point as 
follows:
Reviewer 2
At the very beginning we would like to thank You very much for reviewing our manuscript 
Temozolomide (TMZ) in the treatment of glioblastoma multiforme—A Literature Review and 
Clinical Outcomes for consideration as an article in Special Issue Treatment for Glioma: 
Retrospect and Prospect. Thank You also for stating that “(...) The review is comprehensive 
and well done. (…)”. Our team tried to prepare this TMZ review basing on the latest scientific 
data and to present it in the most relevant version. Thank You so much, that You noticed and 
appreciated it. Thank You.
1. “line 39 is contradictory: if median survival is 15 months, more than 40% of patients 
survive longer than a year. This should be corrected.”
Dear Reviewer,
We thank You immensely for noticing this issue. The relevant sentence in the text has been 
corrected. Thank You.
2. “I would caution the authors to review the 2021 WHO classification of CNS tumors, as 
some times glioblastoma and WHO grade IV glioma is used interchangeable, when 
differences exist and should be mentioned. For instance, line 153-: anapestic glioma is grade 
III and, thus, not a glioblastoma.”
Dear Reviewer,
Thank You so much for noticing that major issue. In line 153, we presented the CANTON 
study (PMID: 28801186), which included patients with anaplastic glioma grade III according 
to the WHO pre-2021 classification. Anaplastic glioma G3 per se is not GBM, whereas in this 
study the authors considered cases of tumors with molecular features of GBM. Since TMZ is 
a chemotherapeutic agent that acts at the molecular level, and the study focused on 
comparing the effect of adding TMZ to RT therapy, we thought it was worth discussing 
whether the molecular features of GBM themselves respond to TMZ therapy. In the next 
paper we cited (PMID: 35275197), other authors already considered this tumor as GBM "(...) 
A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt 
(...)". We believe that the updated WHO 2021 guidelines allow us to include both of the 
above articles in the review under the topic of GBM. Thank You so much once again for 
noticing that inaccuracy. Thank You.
3. (Comments on the Quality of English Language) “needs minor editing.”
Dear Reviewer,
Thank You very much for this suggestion. The manuscript has undergone English editing with 
attached certificate. Thank You.
We believe that the presented article will interest physicians and researchers in subject of 
neuro-oncology and glioma management. The type of submitted manuscript is a review article, 
and the style and format have been prepared according to MDPI guidelines. All authors have 
read the amendments and agreed to publication. Thank You for reviewing our manuscript and 
considering it for potential publication in Current Oncology Journal. We appreciate Your time 
and look forward to Your response.

Your Sincerely,
Marcin Jezierzański, Authors

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors edited the manuscript appropriately, now appreciating the nuances of the 2021 WHO classification.