Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment

Round 1

Reviewer 1 Report

As the title precisely indicates, this review of Triarico et al. summarizes knowledge and references about mechanisms, risk factors and strategies of prevention and treatment of Vincristine-induced peripheral Neuropathy (VIPN) in pediatric patients. After an introduction to the use of Vincristine for chemotherapies and its neuropathological effects and assessment approaches, the knowledge about its pharmacokinetics and pharmacological mechanisms are summarized. This is followed by an overview of the related pathological mechanisms including a summarizing figure. Also patient-related and treatment related risk factors for children are summarized and an overview on the available experience for the prevention and treatment is provided, including a summarizing table.

In my understanding, the intended contribution of this review is exactly this specific overview as a reference for clinicians to recognize risk factors for pediatric patient specific decisions on the use of therapeutics. It may also be a reference for further research into this subject.

General comments:

The review is relatively short, easily readable and the nice figure and table are helpful for a quick comprehension of the content. Besides its potential as a reference for clinicians, this summarizing overview including the figure 2 could stimulate the development of Adverse Outcome Pathways for regulatory neuro-toxicology (https://aopwiki.org/), which is a high priority field of work at OECD level. These aspects are clearly strengths of the paper.

In order to understand how comprehensive the review intends to be, a paragraph explaining the applied literature search strategy would be useful.

It seems that the review intends to focus on VIPN in pediatric patients. Sections 2, 3 and partly also section 4 appear not to be specific for pediatric patients. Some explanation could be interesting, if/in which aspects we can expect -from a mechanistic point of view- some differences between adults and children in Vincristine pharmacokinetics, pharmacodynamics, pathogenesis and the patient related risk factors. The non-pediatric specific information may be available also in other reviews, e.g. in a similar structure in Gui-zhou Li et al. 2020 https://doi.org/10.1016/j.neuro.2020.10.004? In contrast sections 5 and 6 appear to focus on evidence available for children regarding treatment related risk factors and prevention/treatment strategies. Here it could be interesting, if/why evidence available in adults could be/could not be relevant in children. In summary, in could be worth some paragraph of summarizing discussion, what is special about children, and do we need to differentiate between children of different age.

In the abstract, in section 6 and in the conclusions it is mentioned that there is a lack of consensus on strategies for VIPN prevention and treatment. Could this be referenced and explained, via which organizations/working groups or else, such consensus could ideally/practically develop?

Would you have any specific recommendation for further research, as indicated in the last sentence?

Specific comments:

Line 184, Figure 2: The relations between “structures affected” and “type of damage” do not coincide with the discussion in the text above. “Microtubules” and “Mitochondria” should exchange their place.

A table summarizing the information in section 5 about treatment related risk factors could be useful (Similar to table 1 for section 6)

Line 367, Table 1: It could be useful to include the age of the children covered with these references.

 

Editorial comments:

Line 19: … both and treatment-related risk factors…

Line 114, Figure 1: The legend to figure 1 may be amended to indicate the meaning of the complete figure, not just the lower part of the figure.

Line 128: … it is very neurotoxic

Line 133: special regard should be performed… (not sure, if this is correct English)

Line 135 … produces poor myelosuppression  … (not sure, if this is correct English)

Line 152: The term “Wallerian degeneration” is also used in the figure without any explanation. Therefore, I suggest to explain, in the text, the term with few words and put it in brackets.

Line 199: … in younger children than older ones…

Line 372: … related both by patient-related risk factors…

Author Response

As the title precisely indicates, this review of Triarico et al. summarizes knowledge and references about mechanisms, risk factors and strategies of prevention and treatment of Vincristine-induced peripheral Neuropathy (VIPN) in pediatric patients. After an introduction to the use of Vincristine for chemotherapies and its neuropathological effects and assessment approaches, the knowledge about its pharmacokinetics and pharmacological mechanisms are summarized. This is followed by an overview of the related pathological mechanisms including a summarizing figure. Also patient-related and treatment related risk factors for children are summarized and an overview on the available experience for the prevention and treatment is provided, including a summarizing table.

In my understanding, the intended contribution of this review is exactly this specific overview as a reference for clinicians to recognize risk factors for pediatric patient specific decisions on the use of therapeutics. It may also be a reference for further research into this subject.

 

Thank you so much for the comment.

This work arises from the need to deepen our knowledge on VIPN in pediatric age in order to better manage our patients. We are very happy if this review will be useful to other clinicians in managing their patients.

General comments:

The review is relatively short, easily readable and the nice figure and table are helpful for a quick comprehension of the content. Besides its potential as a reference for clinicians, this summarizing overview including the figure 2 could stimulate the development of Adverse Outcome Pathways for regulatory neuro-toxicology (https://aopwiki.org/), which is a high priority field of work at OECD level. These aspects are clearly strengths of the paper.

In order to understand how comprehensive the review intends to be, a paragraph explaining the applied literature search strategy would be useful.

To explain our search strategy, we have added this sentence in the text: “We have searched for papers dedicated to VIPN in the pediatric age performing a Pubmed-based retrieval of articles using the search terms “vincristine”, “Vinka alkaloid”, “neurotoxicity”and “peripheral neurotoxicity” matched with “children”, “childhood”, and “pediatric”. After the original search, we used filters to select articles available in English language and articles with available full texts. The final search retrieved 85 articles, of which 43 were exclusively related to pediatric patients.”

It seems that the review intends to focus on VIPN in pediatric patients. Sections 2, 3 and partly also section 4 appear not to be specific for pediatric patients. Some explanation could be interesting, if/in which aspects we can expect -from a mechanistic point of view- some differences between adults and children in Vincristine pharmacokinetics, pharmacodynamics, pathogenesis and the patient related risk factors. The non-pediatric specific information may be available also in other reviews, e.g. in a similar structure in Gui-zhou Li et al. 2020 https://doi.org/10.1016/j.neuro.2020.10.004? In contrast sections 5 and 6 appear to focus on evidence available for children regarding treatment related risk factors and prevention/treatment strategies. Here it could be interesting, if/why evidence available in adults could be/could not be relevant in children. In summary, in could be worth some paragraph of summarizing discussion, what is special about children, and do we need to differentiate between children of different age.

In section 2, "Pharmacokinetics and pharmacodynamics of vincristine", we analyzed the pharmacodynamic and pharmacokinetic characteristics of vincristine. Regarding the pharmacokinetic characteristics, we focused almost exclusively on data referring to pediatric patients (references 5, 15, 25) while for information on pharmacodynamics we evaluated studies based on preclinical data that cannot be differentiated by age. Also in section 3 most of the data analyzed derives from preliclinical studies and we did not find different data between pediatric and adult patients. In section 4, however, we tried to emphasize that age represents a risk factor for the onset of VIPN and we analyzed the possible causes of this difference (lines 188-204). In the same section we also analyzed the gene polymorphisms that can facilitate the appearance of VIPN; for some of these there are currently only reports in adult patients.

Through our research, we have not been able to find any work comparing pediatric and adult patients with VIPN.

In the abstract, in section 6 and in the conclusions it is mentioned that there is a lack of consensus on strategies for VIPN prevention and treatment. Could this be referenced and explained, via which organizations/working groups or else, such consensus could ideally/practically develop?

Would you have any specific recommendation for further research, as indicated in the last sentence?

This review is the result of our need for more information on the pathogenesis of VIPN, prevention and treatment. It also represents the starting point for a research work on the clinical features of VIPN in our patients. It is a research project that we are trying to carry out but which is still in the design phase and for this reason we have not included further information in the text.

Specific comments:

Line 184, Figure 2: The relations between “structures affected” and “type of damage” do not coincide with the discussion in the text above. “Microtubules” and “Mitochondria” should exchange their place.

As indicated by the reviewer, in Figure 2 we made a mistake. We corrected the figure and added a new version.

A table summarizing the information in section 5 about treatment related risk factors could be useful (Similar to table 1 for section 6)

We have added a table to summarize the treatment related risk factors.

Line 367, Table 1: It could be useful to include the age of the children covered with these references.

Table 1 now is Table 2. We include the age of the children.

 

Editorial comments:

Line 19: … both and treatment-related risk factors…

Line 114, Figure 1: The legend to figure 1 may be amended to indicate the meaning of the complete figure, not just the lower part of the figure.

Line 128: … it is very neurotoxic

Line 133: special regard should be performed… (not sure, if this is correct English)

Line 135 … produces poor myelosuppression  … (not sure, if this is correct English)

Line 152: The term “Wallerian degeneration” is also used in the figure without any explanation. Therefore, I suggest to explain, in the text, the term with few words and put it in brackets.

Line 199: … in younger children than older ones…

Line 372: … related both by patient-related risk factors…

We have corrected the text following the suggestions of the reviewer.

In line 114 we added this sentence “The first part of the figure shows the interaction between Vincristine and the tubuin dimers. The second part shows the Vincristine concentration-dependent action: the arrest of polymerization at low dose and amplification of depolymerization at a high dose.”

In line 152 we added this sentence “By binding to microtubules, vincristine causes changes of neuron shape and stability, preventing the retrograde and anterograde axonal transport with consequent Wallerian degeneration, which consists in the reabsorption of the distal segment of a nerve after it has been damaged, and also causes the alteration of nerve impulse transmission and neuronal death”.

Reviewer 2 Report

This paper summarizes the mechanisms, risk factors, prevention and treatment of vincristine-induced peripheral neuropathy in pediatric patients with cancer . I think there is no other paper focusing on children about vincristine-induced peripheral neuropathy.  This review is useful information for advances in cancer chemotherapy for pediatric tumors.

Author Response

We hope this review will be useful in the management of pediatric patients with VIPN.

Thanks so much for the comments.