Title: Skin testing and hypersensitivity reactions to oxaliplatin
Abstract: Oxaliplatin (L-OHP) is a third-generation platinum (Pt) analogue where the Pt atom is linked to a diaminocyclohexane structure joined to oxalic acid. It has been found to be active as a single agent in advanced colorectal cancer [1.Lévi F. Perpoint B. Garufi C. et al.Oxaliplatin activity against metastatic colorectal cancer. A phase II study.Eur J Cancer. 1993; 29A: 1280-1284Abstract Full Text PDF PubMed Scopus (210) Google Scholar], to synergise with5-fluorouracil (5-FU) and folinic acid (FA) [2.Lévi F. Zidani R. Misset J.L. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer.International Organization for Cancer Chronotherapy. Lancet. 1997; 350: 681-686Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar], and to have a cumulative sensitive neuropathy as the dose-limiting toxicity. Allergic reactions to L-OHP have been described in the literature, including skin rashes and itching, redness of the face, dizziness, shortness of breath and anxiety [3.Larzillieri I. Brandissou S. Breton P. et al.Anaphylactic reaction to oxaliplatin: a case report.Am J Gastroenterol. 1999; 94: 3387-3388Crossref Scopus (21) Google Scholar, 4.Santini D. Tonini G. Salerno A. et al.Idiosyncratic reaction after oxaliplatin infusion.Ann Oncol. 2001; 12: 132-133Abstract Full Text PDF PubMed Scopus (55) Google Scholar]. The incidence rate of this important side-effect in clinical practice is reported to be between ∼2% and up to 12% [5.Meyer L. Zuberbier T. Worm M. et al.Hypersensitivity reactions to oxaliplatin: cross-reactivity to carboplatin and the introduction of a desensitization schedule.J Clin Oncol. 2002; 20: 1146-1147Crossref PubMed Scopus (80) Google Scholar]. As with carboplatin and cisplatin, allergic reaction happens after many courses of therapy, indicating that prolonged exposure to this agent has a role in the patient becoming sensitized. Another factor that limits this incidence rate is that patients do not usually receive more than 10–12 courses of L-OHP, due to drug interruption for progression of disease or for neurotoxicity. In a recent paper, Zanotti et al. [6.Zanotti K.M. Rybicki L.A. Kennedy A.W. et al.Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy.J Clin Oncol. 2001; 19: 3126-3129Crossref PubMed Scopus (147) Google Scholar] described the use of a skin-testing protocol for carboplatin hypersensitivity reactions (HR). In order to screen patients for risk of HR they used a standardized skin test: injecting 0.02 ml aliquots of a carboplatin preparation s.c. into patients undergoing chemotherapy with carboplatin. The study confirmed the predictive value of the positive and negative results of this skin test to identify patients at risk of carboplatin HR. We have studied 20 patients with advanced colorectal cancer treated with a 5-FU, FA and L-OHP combination. Patient data are shown in Table 1. We applied the skin testing to five patients who had symptoms that were consistent with the diagnosis of L-OHP HR to confirm the allergic basis of their clinical profiles. As a control group, the same test was applied to 15 patients with no history of previous HR to L-OHP. In order to verify the allergic nature of these reactions, prick tests and intradermal tests were performed. Prick tests were performed in both groups of patients with a drop of a solution containing L-OHP diluted to 3 mg/ml in 5% glucose (which is the concentration we currently use to deliver this drug). Intradermal tests with 0.1 ml of the same solution were injected s.c. on the planar surface of the arm. Prick tests and intradermal tests were also performed with solutions of cisplatin, carboplatin, and of two Pt salts (hexachloroplatinic acid and potassium tetrachloroplatinate) that are known to cause allergic reactions in occupational workers [7.Santucci B. Valenzano C. de Rocco M. Cristaudo A. Platinum in the environment: frequency of reactions to platinum-group elements in patients with dermatitis and urticaria.Contact Dermatitis. 2000; 43: 333-338Crossref Scopus (79) Google Scholar].Table 1Patient characteristicsPatients with HR (n = 5)Patients without HR (n = 15)Gender Male1 (20%)8 (54%) Female4 (80%)7 (46%)Median age (years)54.553Performance status (WHO) 03 (60%)11 (73%) 11 (20%)4 (27%) ≥21 (20%)0No. of metastatic sites 13 (60%)9 (60%) ≥22 (40%)6 (40%)Primary tumor Colon4 (80%)11 (73%) Rectum1 (20%)4 (27%)No. of previous chemotherapy treatments 13 (60%)11 (73%) ≥22 (40%)4 (27%)Median cumulative L-OHP dose (mg/m2)600945Median no. of L-OHP courses712HR, hypersensitivity reactions; L-OHP, oxaliplatin. Open table in a new tab HR, hypersensitivity reactions; L-OHP, oxaliplatin. In the five patients with clinical manifestations due to L-OHP HR, prick tests gave negative results. Intradermal tests withL-OHP elicited an immediate positive reaction in four out offive patients. Prick tests and intradermal tests performed with solutions of cisplatin, carboplatin, and the two Pt salts all gave negative results. In the patient with a negative intradermal skin test, L-OHP rechallenge was attempted, but it resulted in a severe HR, which required the patient’s admission to hospital. A subsequent prick test was performed, which now became positive. In all five patients, L-OHP was stopped and the patients continued therapy with 5-FU and FA without any further problems (Table 2). The same tests were carried out in 15 other subjects undergoing therapy with 5-FU–FA–L-OHP without any skin reactions: no false-positive test was found.Table 2Hypersensitivity reactions to oxaliplatin (L-OHP), and skin testing resultsPatient no.SexL-OHP(mg/m2)Coursesbefore HRSymptoms and signsPrick test/intradermalreactionL-OHPdiscontinuation1Female6006Erythematous pomphoid lesions, intense itching, edema of the inferior lipneg/posyes2Male6007Erythematous pomphoid lesions extended over the bodyneg/posyes3Female85010Erythema of the face, pruritusneg/posyes4Female100010Burning sensation, extreme weakness, itching, redness of the face, anxietyneg/posyes5Female5106Erythema of the face, itching, edema of the tongue, bronchospasmneg/negyesHR, hypersensitivity reactions. Open table in a new tab HR, hypersensitivity reactions. Through this experience, we have shown that an intradermal skin test with L-OHP confirmed the clinical diagnosis of L-OHP HR in four out of five patients, 80%. The test was negative in all the 15 patients with no previous history of L-OHP HR. The characteristics of the clinical manifestations suggest a type 1 HR, i.e. IgE mediated. The mechanisms by which L-OHP can cause HR need to be established. We did not test for specific anti-Pt antibodies, 1,2-diaminocyclohexane or oxalic acid. The lack of HR to other Pt salts seems to indicate that the whole molecule of L-OHP, rather than just the Pt, plays a pivotal role in eliciting immediate HR. We have previously demonstrated that an immunological response is the basis of haemolytic anaemia caused byL-OHP [8.Garufi C. Vaglio S. Brienza S. Immunohemolytic anemia following oxaliplatin administration.Ann Oncol. 2000; 11: 497Abstract Full Text PDF PubMed Scopus (52) Google Scholar], and it may be speculated that the binding of L-OHP to cutaneous receptors alters or modifies some ligands and promotes an immunological response. These data partly confirm the findings described by Meyer et al. [5.Meyer L. Zuberbier T. Worm M. et al.Hypersensitivity reactions to oxaliplatin: cross-reactivity to carboplatin and the introduction of a desensitization schedule.J Clin Oncol. 2002; 20: 1146-1147Crossref PubMed Scopus (80) Google Scholar]. They report a cross-reactivity with carboplatin, which was not the case in our series. Moreover, they stated that L-OHP reintroduction did not lead to any severe reaction, whereas, in our only patient with a false negative test, the subsequent dose of L-OHP necessitated the patient’s admission to hospital. We can conclude that for patients with a suspected L-OHP HR an intradermal skin test with L-OHP can be performed in order to confirm the allergic basis of reported symptoms. The exact mechanism underlying HR needs to be clarified in order to prevent or decrease the extent of HR and to allow continuation of this important drug. The predictive use of this test in patients with a cumulative L-OHP dose >600 mg/m2 could be tested in a prospective study in order to identify patients at risk of HR.
Publication Year: 2003
Publication Date: 2003-03-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
Access and Citation
Cited By Count: 60
AI Researcher Chatbot
Get quick answers to your questions about the article from our AI researcher chatbot