Review Reports

Round 1

Reviewer 1 Report

The authors presented in « Rationale and Design of BeatNF2 trial: A Clinical Trial to Assess the Efficacy and Safety of Bevacizumab in Patients with Neurofibromatosis Type 2 Related Vestibular Schwannoma. »

The BeatNF2 trial is the first randomized controlled trial designed to assess the efficacy and safety of bevacizumab in patients with NF2 associated VS. This trial began in October 2019 and is now ongoing.

Bevacizumab is used now world wide for NF2 associated VS but no trial has compared BEvacizumab vs control treatment. The results will be of great interest.

 

I have 2 minors remarks on the protocol

Inclusion criteria : « A hearing test of the affected ear demonstrates both a maximum WRS of 80% or

less and pure-tone averages of less than 100 db ». The authors will thus include patient with a very bad hearing (PTA>100dB). Is it not too restrictive ? The authors did not mention the lenght of the hearing loss and if they will include patients with hearing loss following surgery on this VS for example.

I would like thus to have clarification on hearing inclusion criteria.

 

NF2 severity score is a genetic score based on mutation. No interest to use it for the follow-up.

Insted, NFTI-QOL is a scoring of the quality of life that should be used to evaluate the impact of the treament on the quality of life.

Author Response

Comment #1: Inclusion criteria : « A hearing test of the affected ear demonstrates both a maximum WRS of 80% or less and pure-tone averages of less than 100 db ». The authors will thus include patient with a very bad hearing (PTA>100dB). Is it not too restrictive ?

• We have reviewed previous reports of clinical trials thoroughly before deciding the inclusion criteria of our study. According to a retrospective review report of 31 patients of the United States by Plotkin S et al. (reference #21), two patients with maximum WRS of 0% had remarkable hearing function improvement following the treatment. Therefore, it may not be reasonable to exclude severe hearing dysfunction cases based upon maximum WRS sores. Moreover, a multi-institution, open-label phase II trial (reference #38), which was the only prospective clinical trial at the time point of designing our clinical trial, did not exclude severely affected hearing patients as well. Thus, we set the lowest hearing level of the inclusion criteria to be at a level considered as "total loss of hearing," which is PTA>100 dB. In this study, we are expecting to demonstrate how low hearing cases can benefit from the treatment.

Comment #2: The authors did not mention the lenght of the hearing loss and if they will include patients with hearing loss following surgery on this VS for example. I would like thus to have clarification on hearing inclusion criteria.

• In this study, patients who underwent resection of vestibular schwannomas are eligible as long as they fulfill the other criteria, such as a specific postoperative duration, hearing function criteria, etc.
• We did not set a criterion regarding the period of hearing disturbance since there have been no clear evidence regarding it.

Comment #3: NF2 severity score is a genetic score based on mutation. No interest to use it for the follow-up. Insted, NFTI-QOL is a scoring of the quality of life that should be used to evaluate the impact of the treament on the quality of life.

• The NF2 severity score mentioned in this manuscript is a scoring system used in Japan, based on criteria of symptoms associated with patients' QOL (reference #2). It does not include any genetic criteria.

Reviewer 2 Report

In this clinical trial the authors present  the project and aims of the first randomized double blind multicenter trial to assess both efficacy and safety of bevacizumab for neurofibromatosis type 2.

Overall, the final endpoint is to undesrtand if bevacizumab is useful to improve hearing function.

It's well known that NF2 associated VS are more likely to become symptomatic respect to isolated VS; for this reason finding an effective solution to preserve hearing function is very important in these patients.

I suggest 

• to better clarify the flowchart where is showed as patients are allocated in two arms and to explain deeply the first time point of 24 weeks and what this time point means in the global evaluation
• to simplify SECONDARY OUTCOME MEASURES
• to introduce, explaining the use of 5 mg/kg bevacizumab, the evidence that 10 mg/kg  seems to be no more effective (Scott R et al, MULTICENTER, PROSPECTIVE, PHASE II AND BIOMARKER..." Journal of clinical oncology, ASCO 3446 Volume 37, Issue 35
• to add notions about previewed toxicities

Author Response

Comment #1: to better clarify the flowchart where is showed as patients are allocated in two arms and to explain deeply the first time point of 24 weeks and what this time point means in the global evaluation

• We added a few changes to the flow charts (Figures 2 and 3) to make them clearer.

Comment #2: to simplify SECONDARY OUTCOME MEASURES

• Since there is no maximum limit for the word count, we request the to allow us to submit the secondary outcomes unchanged since simplifying it may affect the literature's clarity.

Comment #3: to introduce, explaining the use of 5 mg/kg bevacizumab, the evidence that 10 mg/kg  seems to be no more effective (Scott R et al, MULTICENTER, PROSPECTIVE, PHASE II AND BIOMARKER..." Journal of clinical oncology, ASCO 3446 Volume 37, Issue 35

• We added the reference mentioned above to the manuscript as mentioned above.

Comment #4: to add notions about previewed toxicities.

• A list of the possible bevacizumab-related toxicities is already mentioned in section 3.3.4. Since this is a design report, we did not include literature details.

Reviewer 3 Report

Literature reports which 27% of vestibular shwannomas (VS) patients suffered of hearing loss within 2 years of diagnosis of NF2 shwannoma related. Hearing can decline in ears during a variable interval of time also without a measurable tumoral mass growth. Morbidity of surgery or radiation treatment of VS is highly dependent on tumor size. Lots of pilot study offer some good suggestions about bevacizumab rechallenge in order to demonstrate that administering repeated or interrupted doses of bevacizumab could impair tumor progression but there is not a clinical trial until this study. It was also demonstrated that higher dosage (7,5 mg/kg) could give an improvement in NF2-related QOL and reduction in tinnitus-related distress (data  reported in 30% and 60% of participants - children and adults) (Plotkin et at). Author could insert some variation in dosages in future both in initial phase and in rechallenge phase. I recommend the paper for publication.

Author Response

Comment #1: Author could insert some variation in dosages in future both in initial phase and in rechallenge phase.

•           Thanks for the suggestion, but due to the limited timeline and limited budget, we cannot include other dosages and hope it will be addressed in future trials.