Mini-Review
Oxaliplatin-induced hypersensitivity reaction: underlying mechanisms and management Francesca Aroldi, Tiziana Prochilo, Paola Bertocchi, Alberto Zaniboni UO di Oncologia, Fondazione Poliambulanza, Brescia, Italy Hypersensitivity reactions are rare but feared drugs adverse effect. These reactions are not uncommon with anticancer drugs, such as taxanes, monoclonal antibodies, and platinum compounds. Oxaliplatinum, a third-generation platinum compound, one of the mainstay drugs in the treatment of many gastrointestinal cancers, can give rise to hypersensitivity reactions, sometimes with fatal outcomes. In this paper, we reviewed the incidence and mechanisms underlying the occurrence of this event, highlighting the most recent advances concerning the pathogenesis of the reaction and also reporting possible risk factors identified and the most effective treatment in preventing the onset of this event. Keywords: Oxaliplatin, Hypersensitivity reactions, Treatment and prevention
Introduction Hypersensitivity reactions are commonly associated with the use of certain anticancer drugs, including platinum compounds, taxanes, asparaginase, procarbazine, monoclonal antibodies, and epipodophyllotoxins.1 With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered.2 Oxaliplatinum is a thirdgeneration platinum agent approved for the treatment of stage III colorectal cancer (CRC), as adjuvant chemotherapy, and advanced CRC, used in combination with fluorouracil or capecitabine. Oxalipaltin-based chemotherapy has beneficial effects with response rates as high as 53%. The therapeutic potential of oxaliplatin also extends to other cancers such as breast, ovarian, non-small cell lung, prostate, and stomach cancer. Among known oxaliplatin doselimiting toxicities are common neurological (paraesthesia and dysaesthesia of the hands, feet and perioral region), haematopoietic and gastrointestinal toxicities, and more rarely, hypersensitivity infusion reactions.3 These hypersensitivity reactions are often mild or moderate, but sometimes can be serious and can cause patient death, as in the case of anaphylaxis reactions.4 It is often necessary to stop the treatment or to decrease the speed of infusion. Therefore, the prevention and management of acute infusion reactions and the identification of patients at high risk for oxaliplatin hypersensitivity reactions are important issues. In this article, we review the mechanism Correspondence to: A. Zaniboni, UO di Oncologia, Fondazione Poliambulanza, Via Bissolati 57, 25124 Brescia, Italy. Email: zanib@nu merica.it
ß 2015 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947814Y.0000000204
underlying these reactions in order to improve the management of this important oxaliplatin side effect.
Materials and Methods A MEDLINE search for recent and past studies, case reports, meta-analysis, and reviews pertaining to oxaliplatin-related hypersensitivity reactions was performed. Particular attention was paid to severe reactions, and reports on the incidence, risk factors, and management of oxaliplatin-related side effects.
Results and Discussion From the review of literature, we report the main identifying characteristics of oxaliplatin hypersensitivity reactions, particularly with regard to their incidence, clinical features, underlying immunological mechanisms, risk factors, and management.
Characteristics and incidence of oxaliplatin hypersensitivity reaction A hypersensitivity drug reaction is a state of altered reactivity in which the body reacts with an increased immune response to what is perceived as a foreign substance. Oxaliplatin is characterized by acute reactions that occur during the first infusion but also after repeated exposures. The clinical features associated with oxaliplatin hypersensitivity reactions typically consist of rigors, fever, rash, tachycardia, and dyspnea, but also include urticaria, angioedema, rhinoconjuntivitis, and bronchospasm.5,6 The incidence in patients with CRC is around 15% and occurs after infusion in patients with prior exposure to oxaliplatin. Severe and potential fatal hypersensitivity reactions are heralded by bronchospasm, angioedema, hypotension, and anaphylaxis and occur in 2%
Journal of Chemotherapy
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NO.
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of patients receiving oxaliplatin treatment.5 It is very important for physicians to recognize early symptoms of hypersensitivity to avoid severe or fatal events.
Pathophysiology: immunological mechanism underlying hypersensitivity The mechanism underlying the hypersensitivity to oxalipaltin is generally associated with immunoglobulin E (IgE)-mediated hypersensitivity.7 First, the exposure to the antigen represented by drug results in establishment of IgE. Thereafter, the binding of antigen to preformed IgE to mast cells and basophils leads to a release of preformed granules, mediators, and cytokines. Furthermore, it causes a recruitment of neutrophils, mast cells, eosinophils and vasodilatation of blood vessels, increased vascular permeability, glandular secretions, and epithelial damage. All of these effects together lead to oxaliplatin-hypersensitivity syndrome. The pathophysiology of oxaliplatininduced hypersensitivity reactions is unclear, but there are likely many involved mechanisms. Acute reactions such as anaphylaxis are generally associated with immune-mediated effects as evidenced by detection of drug-dependent IgG antibodies with or without complements.8,9 In addition, the important role of inflammation can also be hypothesized, probably mediated by T cells. The drug binds as a hapten to a carrier protein and so can stimulate CD4z and CD8z T cells. Drug haptens are able to stimulate the immune system, in particular dendritic cells that can induce T-cell response and the release of inflammatory mediators.10 In confirmation, some authors reported high levels of interleukin 6 and of tumour necrosis factor alpha, which are pro-inflammatory molecules, and they explain this effect as a massive release of pro-inflammatory molecules.11 Another severe adverse outcome of oxaliplatin is immune-mediated thrombocytopenia that has been identified in 7% of allergic-type reactions in a retrospective analysis.12 Some authors reported the formation of auto-antiantibodies to erythrocytes, platelets, and neutrophils after repeated infusion of oxaliplatin.13 Shao and Hong14 and Sorbye et al.15 reported thrombocytopenia after oxaliplatin-based chemotherapy; in the first case, it was fatal and associated with a large intracranial haemorrhage. In all of these cases, the oxaliplatin-dependent antibodies against GPIIb/IIIa were identified. Teng et al.16 reported fatal pancytopenia with intracranial haemorrhage after oxaliplatin treatment and serious pancytopenia has also been reported by Taleghani et al.17 after the fifteenth oxaliplatin treatment in a patient with advanced colorectal cancer. In another case report,18 an anaphylactic shock immediately after oxaliplatin infusion led to a patient’s death. In all of the above-mentioned case reports, patients had been heavily pre-treated with oxaliplatin. To
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counteract the underlying immune-mediated mechanism, the use of steroids seems to be one of the most cost-effective approaches. In fact, all patients who experienced a fatal outcome had not received steroids. Recently, the involvement of type II and III reactions in the pathophysiology of these reactions has been suggested, but further analysis is necessary to understand the real mechanism underlying these reactions.19
Risk factors and management The identification of risk factors is an important issue for the prevention and related management of these serious adverse events. High neutrophil counts and low monocyte counts were hypothesized as two risk factors for grade 3/4 reactions in oxaliplatin-induced hypersensitivity reactions in Japanese patients by Seki et al.20 However, this relationship was not found in the literature review.21 Some retrospective analyses21 report an increased risk for hypersensitivity reactions in women, younger people and patients repeatedly exposed to oxaliplatin. Kim et al.22 suppose a possible role of hormonal influences. However, repeated exposure to the agent and a history of drug hypersensitivity increase the risk to hypersensitivity reactions.6 Interestingly Chay et al. reported acute reactions in all females treated with this drug.23 As long as the mechanism underlying these reactions are IgE mediated with a component of inflammation, pharmacological prophylaxis with antihistamines, corticosteroids, or both is recommended to reduce the frequency and severity of these reactions.6 Hypersensitivity reactions are unpredictable and can occur despite preventive measures.6 A recent study demonstrated a significant improvement of tolerance with increased doses of dexamethasone and antihistamine.24 Pre-medication strategy proposed by Parel et al. is the use of anti-histamine and/or steroids and reduced infusion flow.21 The use of glucocortisoids is explained with their inhibitory activity on expression of multiple inflammatory genes (cytokines, enzymes, receptors, and adhesion molecules) and their positive activity on the transcription of genes that code for anti-inflammatory proteins, such as lipocortin-1, interleukin-10, receptor antagonist, and neutral endopeptidase.25 Sometimes, these reactions lead to suspension of treatment. Mild-to-moderate reactions to platinum compounds generally do not require treatment discontinuation.6 In many cases, therapy can be continued or be re-challenged with pre-medication. The re-challenge with oxaliplatin is generally less successful than with other drugs: approximately 50% of patients re-challenged with platinum compounds have hypersensitivity reactions, despite premedication.1 Although
Aroldi et al.
re-treatment with oxaliplatin is not recommended for patients who have severe hypersensitivity reactions, desensitization protocols have been successfully implemented in patients with grade 3 hypersensitivity.5 This protocol basically consists of administration of a sequence of serial dilutions over extended infusion periods. Nowadays, the importance of antioxidant agents is increasing; in particular the attention is focused on glutathione. This antioxidant agent can be used to prevent and treat neuropathy induced by oxaliplatin, but it has also an anti-inflammatory role that inhibits transcription factor NF-kappaB, which regulates the transcription of several inflammatory genes.26 It is also essential for innate and adaptive immune functions and important for T-lymphocyte proliferation,27 phagocytic activity of polymorphonuclear neutrophils, dendritic cell functions,28 and antigen presentation by antigen-presenting cells.26
Conclusion The importance of oxaliplatin in the treatment of colorectal cancer and other cancers is clear, but as with all anticancer drugs, it is necessary to understand and be able to deal with its side effects, even those that are less common. Oxaliplatin administration is burdened in 15% of cases by the onset of hypersensitivity reactions, which in 2% of cases have proven to be fatal. Some reactions are so severe that they can lead to patient death as a result of anaphylaxis or thrombocytopenia. Management of oxaliplatin hypersensitivity reactions remains an important issue above all because of the severity of these reactions, but also because oxaliplatin is an effective drug, and due to these reactions, it is often necessary to stop treatment. A recent study20 demonstrated the efficiency of pre-medication and the improvement of tolerance with increased doses of dexamethasone and antihistamine. Therefore, there is not a uniform approach, but as reported in a recent study by Parel et al., the reintroduction of oxaliplatin using an appropriate pre-medication strategy is possible, e.g. using antihistamine and/or steroids and reduced infusion flow in grade I or II reactions. Parel et al. encourage prevention with reinforced premedication in patients who have risk factors. The literature focuses on three possible risk factors for these reactions: female gender, age, and repeated exposure to oxaliplatin. However, more epidemiological and scientific support is needed. The mechanisms underlying these reactions are different: IgE mediates the release of histamines, leukotrienes, and cytokines that are responsible for urticaria, angioedema rhinoconjunctivitis, bronchospasm, and anaphylaxis, but also inflammation with unclear mechanisms and development of antibodies. So for
Oxaliplatin hypersensitivity reaction
management of these reactions, corticosteroids and antihistamines drugs play important roles. Recently, it was hypothesized that type II and III reactions could be involved. Glutathione, used to manage neuropathy induced by oxaliplatin, may play an interesting role even in the treatment of hypersensitivity reactions. The association between certain HLA-B alleles and the development of certain drug reactions is known for the carbamazepine, but nowadays it is not for the oxaliplatin.11 To understand oxaliplatin adverse events, reactions underlying mechanisms new studies are recommended.
Disclaimer Statements Contributors All authors have contributed to the paper. Funding None. Conflicts of interest The authors have declared no conflicts of interest for this article. Ethics approval Ethical approval was not required.
References 1 Zanotti KM, Markman M. Prevention and management of antineoplastic induced hypersensitivity reactions. Drug Saf. 2001;24:767–79. 2 Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol. 2009;102(3):179–87. 3 Gowda A, Goel R, Berdzik J, Leichman CG, Javle M. Hypersensitivity Reactions to oxaliplatin: incidence and management. Oncology (Williston Park). 2004;18(13):1671–5. 4 Wang JH, King TM, Chang MC, Hsu CW. Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis. World J Gastroenterol. 2012;18(38):5427–33. 5 Brandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, Mordenti P, et al. Hypersensitivity reactions related to oxaliplatin (OHP). Br J Cancer. 2003;89:477–81. 6 Lee MY, Yang MH, Liu JH, Yen CC, Lin PC, Teng HW, et al. Severe anaphylactic reactions in patients receiving oxaliplatin therapy: a rare but potentially fatal complication. Support Care Cancer. 2007;15:89–93. 7 Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12(5):601–9. 8 James E, Podoltsev N, Salehi E, Curtis BR, Saif MW. Oxaliplatin-induced immune thrombocytopenia: another cumulative dose-dependent side effect? Clin Colorectal Cancer. 2009;8:220–4. 9 Bautista MA, Stevens WT, Chen CS, Curtis BR, Aster RH, Hsueh CT. Hypersensitivity reaction and acute immunemediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature. J Hematol Oncol. 2010;3:12. 10 Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127(Suppl 3):S74–81. 11 Koutras AK, Makatsoris T, Paliogianni F, Kopsida G, Onyenadum A, Gogos CA, et al. Oxaliplatin-induced acuteonset thrombocytopenia, hemorrhage and hemolysis. Oncology. 2004;67:179–82. 12 Maindrault-Goebel F, Andre T, Tournigand C, Louvet C, Perez-Staub N, Zeghib N, et al. Allergic-type reactions to oxaliplatin: retrospective analysis of 42 patients. Eur J Cancer. 2005;41(15):2262–7. 13 Curtis BR, Kaliszewski J, Marques MB, Saif MW, Nabelle L, Blank J, et al. Immune-mediated thrombocytopenia resulting from sensitivity to oxaliplatin. Am J Hematol. 2006;81:193–8. 14 Shao YY, Hong RL. Fatal thrombocytopenia after oxaliplatinbased chemotherapy. Anticancer Res. 2008;28:3115–7.
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15 Sorbye H, Bruserud Y, Dahl O. Oxaliplatin-induced haematological emergency with an immediate severe thrombocytopenia and hemolysis. Acta Oncol. 2001;40:882–3. 16 Teng CJ, Hsieh YY, Chen KW, Chao TC, Tzeng CH, Wang WS. Sudden-onset pancytopenia with intracranial hemorrhage after oxaliplatin treatment: a case report and literature review. Jpn J Clin Oncol. 2011;41:125–9. 17 Taleghani BM, Meyer O, Fontana S, Ahrens N, Novak U, Borner MM, et al. Oxaliplatin-induced immune pancytopenia. Transfusion. 2005;45(5):704–8. 18 Wang JH, King TM, Chang MC, Hsu CW. Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis. World J Gastroenterol. 2012;18(38):5427– 33. 19 Syrigou E, Syrigos K, Saif MW. Hypersensitivity reactions to oxaliplatin and other antineoplastic agents. Curr Allergy Asthma Rep. 2008;8(1):56–62. 20 Seki K, Senzaki K, Tsuduki Y, Ioroi T, Fujii M, Yamauchi H, et al. Risk factors for oxaliplatin-induced hypersensitivity reactions in Japanese patients with advanced colorectal cancer. Int J Med Sci. 2011;8:210–5. 21 Parel M, Ranchon F, Nosbaum A, You B, Vantard N, Schwiertz V, et al. Hypersensitivity to oxaliplatin: clinical
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22 23 24
25 26 27 28
features and risk factors. BMC Pharmacol Toxicol. 2014;15(1):1. Kim BH, Bradley T, Tai J, Budman DR. Hypersensitivity to oxaliplatin: an investigation of incidence and risk factors, and literature review. Oncology. 2009;76(4):231–8. Chay WY, Chew L, Yeoh TT, Tan MH. An association between transient hypokalemia and severe acute oxaliplatinrelated toxicity predominantly in women. Acta Oncol. 2010;49:515–7. Kidera Y, Satoh T, Ueda S, Okamoto W, Okamoto I, Fumita S, et al. High-dose dexamethasone plus antihistamine prevents colorectal cancer patients treated with modified FOLFOX6 from hypersensitivity reactions induced by oxaliplatin. Int J Clin Oncol. 2011;16(3):244–9. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanism. Clin Sci (Lond). 1998;94(6):557–72. Ghezzi P. Role of glutathione in immunity and inflammation in the lung. Int J Gen Med. 2011;4:105–13. Hadzic T, Li L, Cheng N, Walsh SA, Spitz DR, Knudson CM. The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion. J Immunol. 2005;175(12):7965–72. Kuppner MC, Scharner A, Milani V, von Hesler C, Tschop KE, Heinz O, et al. Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion. Blood. 2003;102(10):3668–74.
Oxaliplatin-induced hypersensitivity reaction: underlying mechanisms and management Francesca Aroldi, Tiziana Prochilo, Paola Bertocchi, Alberto Zaniboni UO di Oncologia, Fondazione Poliambulanza, Brescia, Italy Hypersensitivity reactions are rare but feared drugs adverse effect. These reactions are not uncommon with anticancer drugs, such as taxanes, monoclonal antibodies, and platinum compounds. Oxaliplatinum, a third-generation platinum compound, one of the mainstay drugs in the treatment of many gastrointestinal cancers, can give rise to hypersensitivity reactions, sometimes with fatal outcomes. In this paper, we reviewed the incidence and mechanisms underlying the occurrence of this event, highlighting the most recent advances concerning the pathogenesis of the reaction and also reporting possible risk factors identified and the most effective treatment in preventing the onset of this event. Keywords: Oxaliplatin, Hypersensitivity reactions, Treatment and prevention
Introduction Hypersensitivity reactions are commonly associated with the use of certain anticancer drugs, including platinum compounds, taxanes, asparaginase, procarbazine, monoclonal antibodies, and epipodophyllotoxins.1 With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered.2 Oxaliplatinum is a thirdgeneration platinum agent approved for the treatment of stage III colorectal cancer (CRC), as adjuvant chemotherapy, and advanced CRC, used in combination with fluorouracil or capecitabine. Oxalipaltin-based chemotherapy has beneficial effects with response rates as high as 53%. The therapeutic potential of oxaliplatin also extends to other cancers such as breast, ovarian, non-small cell lung, prostate, and stomach cancer. Among known oxaliplatin doselimiting toxicities are common neurological (paraesthesia and dysaesthesia of the hands, feet and perioral region), haematopoietic and gastrointestinal toxicities, and more rarely, hypersensitivity infusion reactions.3 These hypersensitivity reactions are often mild or moderate, but sometimes can be serious and can cause patient death, as in the case of anaphylaxis reactions.4 It is often necessary to stop the treatment or to decrease the speed of infusion. Therefore, the prevention and management of acute infusion reactions and the identification of patients at high risk for oxaliplatin hypersensitivity reactions are important issues. In this article, we review the mechanism Correspondence to: A. Zaniboni, UO di Oncologia, Fondazione Poliambulanza, Via Bissolati 57, 25124 Brescia, Italy. Email: zanib@nu merica.it
ß 2015 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947814Y.0000000204
underlying these reactions in order to improve the management of this important oxaliplatin side effect.
Materials and Methods A MEDLINE search for recent and past studies, case reports, meta-analysis, and reviews pertaining to oxaliplatin-related hypersensitivity reactions was performed. Particular attention was paid to severe reactions, and reports on the incidence, risk factors, and management of oxaliplatin-related side effects.
Results and Discussion From the review of literature, we report the main identifying characteristics of oxaliplatin hypersensitivity reactions, particularly with regard to their incidence, clinical features, underlying immunological mechanisms, risk factors, and management.
Characteristics and incidence of oxaliplatin hypersensitivity reaction A hypersensitivity drug reaction is a state of altered reactivity in which the body reacts with an increased immune response to what is perceived as a foreign substance. Oxaliplatin is characterized by acute reactions that occur during the first infusion but also after repeated exposures. The clinical features associated with oxaliplatin hypersensitivity reactions typically consist of rigors, fever, rash, tachycardia, and dyspnea, but also include urticaria, angioedema, rhinoconjuntivitis, and bronchospasm.5,6 The incidence in patients with CRC is around 15% and occurs after infusion in patients with prior exposure to oxaliplatin. Severe and potential fatal hypersensitivity reactions are heralded by bronchospasm, angioedema, hypotension, and anaphylaxis and occur in 2%
Journal of Chemotherapy
2015
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27
NO.
2
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Aroldi et al.
Oxaliplatin hypersensitivity reaction
of patients receiving oxaliplatin treatment.5 It is very important for physicians to recognize early symptoms of hypersensitivity to avoid severe or fatal events.
Pathophysiology: immunological mechanism underlying hypersensitivity The mechanism underlying the hypersensitivity to oxalipaltin is generally associated with immunoglobulin E (IgE)-mediated hypersensitivity.7 First, the exposure to the antigen represented by drug results in establishment of IgE. Thereafter, the binding of antigen to preformed IgE to mast cells and basophils leads to a release of preformed granules, mediators, and cytokines. Furthermore, it causes a recruitment of neutrophils, mast cells, eosinophils and vasodilatation of blood vessels, increased vascular permeability, glandular secretions, and epithelial damage. All of these effects together lead to oxaliplatin-hypersensitivity syndrome. The pathophysiology of oxaliplatininduced hypersensitivity reactions is unclear, but there are likely many involved mechanisms. Acute reactions such as anaphylaxis are generally associated with immune-mediated effects as evidenced by detection of drug-dependent IgG antibodies with or without complements.8,9 In addition, the important role of inflammation can also be hypothesized, probably mediated by T cells. The drug binds as a hapten to a carrier protein and so can stimulate CD4z and CD8z T cells. Drug haptens are able to stimulate the immune system, in particular dendritic cells that can induce T-cell response and the release of inflammatory mediators.10 In confirmation, some authors reported high levels of interleukin 6 and of tumour necrosis factor alpha, which are pro-inflammatory molecules, and they explain this effect as a massive release of pro-inflammatory molecules.11 Another severe adverse outcome of oxaliplatin is immune-mediated thrombocytopenia that has been identified in 7% of allergic-type reactions in a retrospective analysis.12 Some authors reported the formation of auto-antiantibodies to erythrocytes, platelets, and neutrophils after repeated infusion of oxaliplatin.13 Shao and Hong14 and Sorbye et al.15 reported thrombocytopenia after oxaliplatin-based chemotherapy; in the first case, it was fatal and associated with a large intracranial haemorrhage. In all of these cases, the oxaliplatin-dependent antibodies against GPIIb/IIIa were identified. Teng et al.16 reported fatal pancytopenia with intracranial haemorrhage after oxaliplatin treatment and serious pancytopenia has also been reported by Taleghani et al.17 after the fifteenth oxaliplatin treatment in a patient with advanced colorectal cancer. In another case report,18 an anaphylactic shock immediately after oxaliplatin infusion led to a patient’s death. In all of the above-mentioned case reports, patients had been heavily pre-treated with oxaliplatin. To
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counteract the underlying immune-mediated mechanism, the use of steroids seems to be one of the most cost-effective approaches. In fact, all patients who experienced a fatal outcome had not received steroids. Recently, the involvement of type II and III reactions in the pathophysiology of these reactions has been suggested, but further analysis is necessary to understand the real mechanism underlying these reactions.19
Risk factors and management The identification of risk factors is an important issue for the prevention and related management of these serious adverse events. High neutrophil counts and low monocyte counts were hypothesized as two risk factors for grade 3/4 reactions in oxaliplatin-induced hypersensitivity reactions in Japanese patients by Seki et al.20 However, this relationship was not found in the literature review.21 Some retrospective analyses21 report an increased risk for hypersensitivity reactions in women, younger people and patients repeatedly exposed to oxaliplatin. Kim et al.22 suppose a possible role of hormonal influences. However, repeated exposure to the agent and a history of drug hypersensitivity increase the risk to hypersensitivity reactions.6 Interestingly Chay et al. reported acute reactions in all females treated with this drug.23 As long as the mechanism underlying these reactions are IgE mediated with a component of inflammation, pharmacological prophylaxis with antihistamines, corticosteroids, or both is recommended to reduce the frequency and severity of these reactions.6 Hypersensitivity reactions are unpredictable and can occur despite preventive measures.6 A recent study demonstrated a significant improvement of tolerance with increased doses of dexamethasone and antihistamine.24 Pre-medication strategy proposed by Parel et al. is the use of anti-histamine and/or steroids and reduced infusion flow.21 The use of glucocortisoids is explained with their inhibitory activity on expression of multiple inflammatory genes (cytokines, enzymes, receptors, and adhesion molecules) and their positive activity on the transcription of genes that code for anti-inflammatory proteins, such as lipocortin-1, interleukin-10, receptor antagonist, and neutral endopeptidase.25 Sometimes, these reactions lead to suspension of treatment. Mild-to-moderate reactions to platinum compounds generally do not require treatment discontinuation.6 In many cases, therapy can be continued or be re-challenged with pre-medication. The re-challenge with oxaliplatin is generally less successful than with other drugs: approximately 50% of patients re-challenged with platinum compounds have hypersensitivity reactions, despite premedication.1 Although
Aroldi et al.
re-treatment with oxaliplatin is not recommended for patients who have severe hypersensitivity reactions, desensitization protocols have been successfully implemented in patients with grade 3 hypersensitivity.5 This protocol basically consists of administration of a sequence of serial dilutions over extended infusion periods. Nowadays, the importance of antioxidant agents is increasing; in particular the attention is focused on glutathione. This antioxidant agent can be used to prevent and treat neuropathy induced by oxaliplatin, but it has also an anti-inflammatory role that inhibits transcription factor NF-kappaB, which regulates the transcription of several inflammatory genes.26 It is also essential for innate and adaptive immune functions and important for T-lymphocyte proliferation,27 phagocytic activity of polymorphonuclear neutrophils, dendritic cell functions,28 and antigen presentation by antigen-presenting cells.26
Conclusion The importance of oxaliplatin in the treatment of colorectal cancer and other cancers is clear, but as with all anticancer drugs, it is necessary to understand and be able to deal with its side effects, even those that are less common. Oxaliplatin administration is burdened in 15% of cases by the onset of hypersensitivity reactions, which in 2% of cases have proven to be fatal. Some reactions are so severe that they can lead to patient death as a result of anaphylaxis or thrombocytopenia. Management of oxaliplatin hypersensitivity reactions remains an important issue above all because of the severity of these reactions, but also because oxaliplatin is an effective drug, and due to these reactions, it is often necessary to stop treatment. A recent study20 demonstrated the efficiency of pre-medication and the improvement of tolerance with increased doses of dexamethasone and antihistamine. Therefore, there is not a uniform approach, but as reported in a recent study by Parel et al., the reintroduction of oxaliplatin using an appropriate pre-medication strategy is possible, e.g. using antihistamine and/or steroids and reduced infusion flow in grade I or II reactions. Parel et al. encourage prevention with reinforced premedication in patients who have risk factors. The literature focuses on three possible risk factors for these reactions: female gender, age, and repeated exposure to oxaliplatin. However, more epidemiological and scientific support is needed. The mechanisms underlying these reactions are different: IgE mediates the release of histamines, leukotrienes, and cytokines that are responsible for urticaria, angioedema rhinoconjunctivitis, bronchospasm, and anaphylaxis, but also inflammation with unclear mechanisms and development of antibodies. So for
Oxaliplatin hypersensitivity reaction
management of these reactions, corticosteroids and antihistamines drugs play important roles. Recently, it was hypothesized that type II and III reactions could be involved. Glutathione, used to manage neuropathy induced by oxaliplatin, may play an interesting role even in the treatment of hypersensitivity reactions. The association between certain HLA-B alleles and the development of certain drug reactions is known for the carbamazepine, but nowadays it is not for the oxaliplatin.11 To understand oxaliplatin adverse events, reactions underlying mechanisms new studies are recommended.
Disclaimer Statements Contributors All authors have contributed to the paper. Funding None. Conflicts of interest The authors have declared no conflicts of interest for this article. Ethics approval Ethical approval was not required.
References 1 Zanotti KM, Markman M. Prevention and management of antineoplastic induced hypersensitivity reactions. Drug Saf. 2001;24:767–79. 2 Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol. 2009;102(3):179–87. 3 Gowda A, Goel R, Berdzik J, Leichman CG, Javle M. Hypersensitivity Reactions to oxaliplatin: incidence and management. Oncology (Williston Park). 2004;18(13):1671–5. 4 Wang JH, King TM, Chang MC, Hsu CW. Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis. World J Gastroenterol. 2012;18(38):5427–33. 5 Brandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, Mordenti P, et al. Hypersensitivity reactions related to oxaliplatin (OHP). Br J Cancer. 2003;89:477–81. 6 Lee MY, Yang MH, Liu JH, Yen CC, Lin PC, Teng HW, et al. Severe anaphylactic reactions in patients receiving oxaliplatin therapy: a rare but potentially fatal complication. Support Care Cancer. 2007;15:89–93. 7 Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12(5):601–9. 8 James E, Podoltsev N, Salehi E, Curtis BR, Saif MW. Oxaliplatin-induced immune thrombocytopenia: another cumulative dose-dependent side effect? Clin Colorectal Cancer. 2009;8:220–4. 9 Bautista MA, Stevens WT, Chen CS, Curtis BR, Aster RH, Hsueh CT. Hypersensitivity reaction and acute immunemediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature. J Hematol Oncol. 2010;3:12. 10 Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127(Suppl 3):S74–81. 11 Koutras AK, Makatsoris T, Paliogianni F, Kopsida G, Onyenadum A, Gogos CA, et al. Oxaliplatin-induced acuteonset thrombocytopenia, hemorrhage and hemolysis. Oncology. 2004;67:179–82. 12 Maindrault-Goebel F, Andre T, Tournigand C, Louvet C, Perez-Staub N, Zeghib N, et al. Allergic-type reactions to oxaliplatin: retrospective analysis of 42 patients. Eur J Cancer. 2005;41(15):2262–7. 13 Curtis BR, Kaliszewski J, Marques MB, Saif MW, Nabelle L, Blank J, et al. Immune-mediated thrombocytopenia resulting from sensitivity to oxaliplatin. Am J Hematol. 2006;81:193–8. 14 Shao YY, Hong RL. Fatal thrombocytopenia after oxaliplatinbased chemotherapy. Anticancer Res. 2008;28:3115–7.
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