Botulinum Neurotoxin A in the Treatment of Pharyngocutaneous Fistula after Salvage Surgery in Head and Neck Cancer Patients: Our Preliminary Results

Round 1

Reviewer 1 Report

The authors showed that injection of neurobotulinum toxin A in the parotid glands of head and neck cancer patients affected by salivary fistulas after salvage surgery decreased the subjective perception of the saliva flow, which has an effect on the spontaneous closure of fistulas. Anyway, I have a few questions:

1. The authors stated that the follow-up period lasted 12 weeks. What is the reason for that?

2. In the limitations of the study, it is necessary to state that the measurement of the amount of saliva is a subjective data and that it should be objectified.

3. Do the authors have experience with the use of certain drugs that affect hyposalivation?

4. Do the authors have experience with the use of the Montgomery tube in preventing the occurrence of PCF?

Author Response

C1. The authors stated that the follow-up period lasted 12 weeks. What is the reason for that?

A1. Thank you for the opportunity to clarify this issue. We followed patients for 12 weeks because it is a length of time that correlates well with that of the observed duration of botulinum effect (Blitzer, A., & Sulica, L. (2001). Botulinum toxin: basic science and clinical uses in otolaryngology. The Laryngoscope, 111(2), 218–226. https://doi.org/10.1097/00005537). The results of basic science studies on botulinum toxin effect agree that one to 3 days usually pass before any clinical effect is seen, followed by a period of marked effect for a week or 2, which levels off to a more moderate plateau lasting until nerve recovery is complete at approximately 3 months. This typical pattern is not well understood, but is likely related to the process of nerve recovery (Brin MF. Botulinum toxin therapy: basic science and overview of other therapeutic applications. In: Blitzer A, Binder WJ, Boyd JB, Carruthers A, eds. Management of Facial Lines and Wrinkles. Philadelphia: Lippincott Williams & Wilkins, 2000:279–302.).

C2. In the limitations of the study, it is necessary to state that the measurement of the amount of saliva is a subjective data and that it should be objectified.

A2. Thank you for this comment. It was added at the end of the discussion, in the limits of the study.

C3. Do the authors have experience with the use of certain drugs that affect hyposalivation?

A3. We previously used Amitriptyline oral solution which has well known hyposalivation effects. However, Amitriptyline therapeutic indications are represented by the treatment of major depressive disorder, neuropathic pain, chronic tension type headache (CTTH) and prophylactic treatment of migraine in adults. The use of Amitriptyline, which is a sedative drug, to reduce salivation is off-label, with the risk of undesirable effects because of the systemic effects (cardiological and vascular effects, dizziness, dry mouth, blurred vision, constipation, weight gain etc.)

C4. Do the authors have experience with the use of the Montgomery tube in preventing the occurrence of PCF?

A4. The incidence of PCF is very rare in our LT patients. We don’t use systematically invasive method to prevent PCF. We do not have direct experience with the use of the Montgomery tube, except for one previous case who didn’t tolerate the tube after surgery, which was then removed.

Reviewer 2 Report

This is a small case series describing the use of BoNT-A in patients with pharyngocutaneous fistulas. While there is a potential interest in the research question the authors trying to address (does BoNT-A improve clinical outcomes for these patients?) the study design and the extremely low number of patients limit its ability to address this, dramatically. 

Specifically, the authors have no control group so the outcomes cannot be compared and the impact of the intervention, if any, cannot be estimated. Also, they include 12 TL cases and 1 TPL. This "treatment" arm would be more informative if it included either only TLs or a descent amount of TPLs as well.

Another major concern that needs to be addressed is the fact that the authors do not report an IRB approval. Did the authors seek IRB approval?

This could be a very promising article. While there are also other edits/comments, I maintain that the aforementioned comments/concerns have to be addressed before this work is considered for publication. 

Author Response

C1. This is a small case series describing the use of BoNT-A in patients with pharyngocutaneous fistulas. While there is a potential interest in the research question the authors trying to address (does BoNT-A improve clinical outcomes for these patients?) the study design and the extremely low number of patients limit its ability to address this, dramatically.

A1. We know that the sample size is an important limitation of our study as we have described in discussion. The number of our cases is in any case proportional to that of the incidence of a rare complication (the pharyngocutaneous fistula) in a rare pathology (laryngeal tumor subjected to total laryngectomy). The number is representative of all cases with that complication in our eight years study period, and we aim to increase the sample in the future.

C2. Specifically, the authors have no control group so the outcomes cannot be compared and the impact of the intervention, if any, cannot be estimated. Also, they include 12 TL cases and 1 TPL. This "treatment" arm would be more informative if it included either only TLs or a descent amount of TPLs as well.

A2. Thanks for the comment; the study lacks a control group but we compared the results obtained in our sample with those of a previous study from our clinic which had a sample with characteristics comparable to ours. In the discussion we reported the differences in the results obtained from the administration of BoNT-A compared to that study group. In discussion we write: “the limitations of this study are the small number of cases, the comparison based on our previous cases series and the literature’s data because of the lack of a control group”.

C3. Another major concern that needs to be addressed is the fact that the authors do not report an IRB approval. Did the authors seek IRB approval?

A3. The information about the IRB approval is in the paragraph “Institutional Review Board Statement” of the manuscript. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Fondazione Policlinic (protocol code 0041313/21).