Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma

Round 1

Reviewer 1 Report

This paper follows up on the results of a previous report by the authors and evaluates the outcomes of the Histone deacetylase inhibitor Belinostat (PXD-101) in addition to conventional radiation therapy and TMZ.

Although the overall results show that the add-on effect of Belinostat is limited, the paper is valuable in showing which patients benefited from the treatment and how it can be improved in the future.

Some comments are as follows

It should be clearly stated whether the amount of radiation dose received in the Control and Belinostat groups was different, and if possible, it should be shown in the Table.

In the second paragraph from the bottom of the Discussion, the authors mention that additional doses during maintenance therapy can be expected to improve outcomes, but they should not be too definitive.

It would be better to indicate what the limitations are.

Table: Move the word "Toxicities (Grade)" to the left.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

The objective of this article was to share the clinical outcomes of a pilot study to assess the performance of belinostat on 13 patients with GBM  in comparison to GBM controls that received radiation therapy and TMZ.  The significance of this study is high because the development of the GBM is aggressive and the median overall survival remains at 16 months.  This study offered a 50 month follow of each participant group. The goal and focus of the study is strong and the work is meaningful; upon review, there is necessary work to be done to strengthen the presentation of the outcomes of the work.

Major Comments

Please reference the parameters used for each sequence. This is standard for articles that include MRI as a tool.

Figure 3 should be redone. The left side of the head for the person is cut off in Fig3a Pre-RT.  Could you make the regional contours slightly thicker?  Please mention why there slices were chosen over other axial slices. 

• Registration was mentioned to be performed but in some of the images, the patient's head is titled
• This is visible in Figure 3A
• Why wasn't CHo/NAA shown for reoccurrence? Was the sequence not rerun?
• The slide comparisons are not showing the same anatomy in Figure 3a

Figure 4 mentions out of field but it would help to see in-field images to better understand table A2.

Minor comments:

• Figure 2: Adapt the charts to show where the mean median measurements are located
• Would Figure 2b make the interpretation that if belinostat were prescribed in month 9, that we'd see a difference?
• Table A2 would be better in the main part of the paper instead of the appendices. In addition, please explain the statistics and what is meant by the percentage increases to the voxel-wise comparisons.  It's confusing as it is currently presented and I'm not aware of what 100% refers to. Table A2 should be referenced before Figure 3
• Figure 4:  The contrast of the Pre-RT and Recurrence need to be modified to the same scale.
• In the caption of this figure, reexplain what the PTV1, PTV2, and rPTV mean in terms of the margins. This was placed in the methods but would improve the readability of the document by replacing in the comments.
• line 117 should reference Table A2.
•  

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

This article describes a single-center prospective study testing the contribution of an HDAC inhibitor to conventional management by radiochemotherapy of glioblastoma.
Below are some comments/suggestions:

Chapitre 2/ Materials and Methods

Line 75-85 :

The authors describes their method of contouring and dose protocols for glioblastomas. It would have been interesting to quote the reference for this choice of dose and contouring given that this do not correspond to the guidelines of both RTOG (Colman doi:10.1016/j.ijrobp.2006.05.021), the ESTRO (10.1016/j. radonc.2015.12.003) or more recently from the NRG (10.1007/s11060-019-03152-9); in particular for the choice of prescribing two different dose.

Line 81-84 : « Margins of 5 to 10 mm were added to generate clinical tumor volumes (CTVs) and 3 to 5 mm to generate planning treatment volumes (PTVs) to account for microscopic disease spread and treatment setup uncertainty, respectively. PTV1 is the FLAIR abnormal volume receiving 51 Gy while PTV2 is the T1w-CE volume receiving 60 Gy »

It seems  that the two volumes are processed in VMAT in an integrated boost manner: PTV1 51Gy in 30 fractions of 1.7Gy and 60Gy in 30 fractions to the PTV2.

Line 93-94 : « PFS is reported for patients based on time to radiologic confirmation of disease progression from the date of surgery. Data are right censored for patients who were lost to follow-up. Kaplan-Meier curves for OS were generated. »

The criteria used to define the progression should be specified. Are the RANO criteria been used  (10.1007/s00234-017-1899-7) or others?

Chapter 4/ Discussion

Line 232-238

The place of new imaging modalities in the contouring of glioblastomas is an important element in improving the management of these patients.

A chapter integrating current progress in this theme would have been relevant . 

The three patients illustrated here are particularly interesting in this respect. A retrospective analysis of the recurrences with this Cho/NAA Imaging for both arms could have been useful.

Finally, as all patients have been treated according to the same contouring and fusion imaging protocol, it seems difficult to see in this an explanation for the lack of efficacy of the experimental arm. 

Line 225-231 and 257-268
The potential role of radiosensitization by the HDAC inhibitor that might be provided by
- the results comparable to a dose escalation study
- the loss of difference beyond 6 months
- the different recurrence patterns with fewer recurrences in high dose areas
makes it all the more interesting to discuss the choice to make 2 dose levels rather than a single volume at 60Gy in this protocol.

In the end, this research protocol, although bringing non-significant results, makes it possible to ask questions of contouring and imaging of fusion in the management.

Author Response

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Author Response File: Author Response.docx