Oxaliplatin-Related Hypersensitivity Reactions: A Single Institution Series and Literature Review
, Alessandra Panichi, Gianluca Tomasello, Claudia Bareggi, Barbara Galassi, Nerina Denaro, Fiorella Ruatta, Carolina Cauchi, Maria Grazia Rossino and Ornella Garrone *
Stefano Cordio
Round 1
Reviewer 1 Report
In relation to the aim of the paper submitted by Dr Barbin and others to describe the dimension of the problem related to Oxaliplatin-related hypersensitivity reactions (HSRs), I appreciated the robust analysis of the amount of the literature data which are heterogeneus with a clear prevalence of papers retrospective in nature and modest sample size and frequenty papers are consistent in case reports.
The sample size of this series of the Oncology Medical Unit of University of Milan described in this paper is quite modest in comparison to the series published in the literature; however they applied a meticolous description of the characteristics of the population analysed both in term of subjective and clinical signs as in order to therapeutic management of single HSR; in particular a clear message showed by authors concern the types of premedications and fast management at time of infusion and the follow -up of these infusions reactions confirming the good expertise of the group.
The weakness of the discussion is in order to following points:
1. I suggest if is possible to better review the mechanism and pathophysiology of the HSRs expecially in terms of immunological dimension such as monocytes-macrophages, dendritic cells and antigen-presenting cells which are the components of the innate immune system; in particular is important to better clarify the items of the relationship between treatment with platinum agents and their activation and stimulation of cytokines and other co-stimulating molecules that provide signals to activate the resting T cells.
2. Furthermore, another aspect of improvement of this work concerning the importance of the levels of eosinophil and WBCs count although this item seems very controversial for the frequent lack of basal assessment of this parameters before the start of platinum treatment; moreover serum albumin which is a common parameter utilized as a marker of nutritional status and the malnutrition degrades both the innate and adaptive immune system so low serum albumin levels increases vascular permeability and increases interstitial volume, which potentiates immediate HSR.
3) The discussion does not provide informations about the feasibility of oxaliplatin-desensitization procedure which is used in some Institutions which is a important topic in this setting. The procedures of oxaliplatin-desensitization are described in the literature both after HSRs to carboplatin and oxaliplatin. The reintroduction of oxaliplatin can be done after skin testing for oxaliplatin sensitivity or using a 12-step desensitization protocol. Finally another point of potential improvement of this review regarding the development of type II hypersensitivity; this reaction manifesting with severe thrombocytopenia and immune haemolysis and must be considered especially when oxaliplatin is rechallenged. So is important to remember the importance of promptly recognizing the association between oxaliplatin-induced hypersensitivity reaction and immune-mediated thrombocytopenia.
Author Response
- I suggest if is possible to better review the mechanism and pathophysiology of the HSRs…
In the Discussions chapter, the following paragraph has been added: HSRs can be classified as ‘Type B’ reactions, based on the European Medicines Agency (EMA) definition of adverse drug reactions (ADRs): non-dose related, unpredictable and usually not related to drug’s mechanism of action and usually resolving when treatment is terminated. Type B reactions are divided into immune-mediated reactions and non-immune reactions. Gell and Combs defined a more specific classification of these reactions, recognizing four hypersensitivity states. Type I reactions are immunoglobulin E (IgE) mediated reactions, such as anaphylaxis; Type II reactions are antibody-mediated reactions such as thrombocytopenia, hemolytic anemia and blood transfusion reactions; Type III reactions are immune-complex-mediated hypersensitivity reactions, such as vasculitis and serum sickness; Type IV reactions are delayed T cell-mediated reactions, such as erythema multiforme, toxic epidermal necrolysis, allergic contact dermatitis. According to the onset of symptoms, the European Network for Drug Allergy (ENDA) has categorized HSRs into two types of reactions: immediate, with symptoms onset within 1-6 hours from the drug exposure, typically IgE-mediated, and non-immediate, with symptoms onset at any time, from 1 hour after the initial exposure to many days after the end of the exposure. These reactions are usually delayed T cell-mediated allergic reactions [27]. It is known that platinum agents, together with their direct cytotoxic effects, also impact the immune system and can lead to immune cells activation [28].
- Furthermore, another aspect of improvement of this work concerning the importance of the levels of eosinophil…
When the dataset has been created, serum albumin levels were defined as a variable to analyze, but it was available only for one patient because it is not routinely investigated.
- The discussion does not provide information about the feasibility of oxaliplatin-desensitization procedure…
Concerning desensitization protocol and skin testing, they are not used in the clinical practice of our institution, for this reason we do not feel confident in discussing their feasibility and efficacy. Furthermore, they seem useful, but some reactions have been noted still.
In the population analyzed, only one patient has thrombocytopenia G1 from baseline assessment throughout the treatment administration. After rechallenge, no patients suffered from thrombocytopenia, for this reason it has not been evidenced in the review.
Reviewer 2 Report
Some comments to authors:
1. The introduction summarizes what is available in the literature; please add a few sentences to highlight the novelty of this approach and how it differs from previous reports.
2. please revise "Steroids and antihistamines were administered to stop symptoms and as preventive strategy for rechallenge"
3. English language needs careful consideration and revisions to eliminate typos, grammar, and scientific inaccuracy
4. Please add a paragraph on the novelty of the work and what sets it apart from what is available in the literature
5. could the authors comment on the clinical severity scale of immediate reactions of hypersensitivity
6. What is the role of hypersensitivity reactions to antineoplastic agents
7. there should be some figures or at least one figure
8. several reports have been missed from the review and they are highly related such as
-https://www.nature.com/articles/6601155
-https://ar.iiarjournals.org/content/32/12/5521
-https://doi.org/10.1016/j.clinthera.2015.03.012
-https://doi.org/10.1517/14740338.5.5.687
Author Response
- The introduction summarizes what is available in the literature; please add a few sentences…
The following sentence has been added to the Introduction: Based on models founded in literature, this work gives updated data and information about oxaliplatin-related HSRs and their safe management, which are still an open issue in cancer treatment.
- Please revise "Steroids and antihistamines were administered to stop symptoms …
The sentence has been modified accordingly: Steroids and antihistamines were administered to reduce hypersensitivity symptoms and prevent further reactions.
- English language needs careful consideration and revisions to eliminate typos…
English revision has been performed.
- Please add a paragraph on the novelty of the work and what sets it apart from what is available…
The following paragraph has been added to the Discussion chapter: This work is based on studies, reviews and case reports already present in literature, but available data are heterogeneous and controversial. At our institution, we do not use desensitization protocol. Grade 3 HSRs have been safely rechallenged with the strategy of intense premedication, not only during the infusion but also in the days preceding the treatment administration. Furthermore, since HSRs are unpredictable and unexpected reactions as per their definition, no randomized trials can be done to investigate their causes and nature. The analyses of more recent and updated data available through retrospective studies is an important instrument to characterize and improve HSRs management.
- Could the authors comment on the clinical severity scale of immediate reactions…
The following paragraph has been added in Materials and Methods paragraph: More in details, allergic reaction/hypersensitivity is defined as a disorder characterized by an adverse local or general response from exposure to an allergen. Intervention is indicated based on grade of reaction: no intervention for grade 1, oral intervention for grade 2, intravenous and urgent intervention for grade 3 and 4 respectively. Anaphylaxis is defined as a disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. Parenteral intervention and urgent intervention are indicated for grade 3 and 4 respectively [20].
- What is the role of hypersensitivity reactions to antineoplastic agents
The following paragraph has been added to the Introduction: Once HSRs occur, the decision to re-administer the agent and to continue and complete the therapy is to be wisely considered [9]. Because of their unpredictable nature and severity, HRSs to antineoplastic agents frequently lead to the prospect of abandoning the treatment and switching to a another that can be less effective [10].
- there should be some figures or at least one figure
We have added a graphic representation of HSRs symptoms in the Results paragraph.
- several reports have been missed from the review and they are highly related such as
-https://www.nature.com/articles/6601155
Round 2
Reviewer 2 Report
Thank you for addressing my comments
