2 1945 [30]. Hypersensitivity reactions in patients receiving cisplatin were ﬁrst described in the 1970s in patients who had been retreated with the drug [31]. Since then, all platinum agents have been associated with such reactions. The aim of this paper is to provide recent data con- cerning hypersensitivity reactions to platinum-containing chemotherapy agents. We will present the characteristics and pathogenetic mechanisms of this hypersensitivity, as well as the basic management options available to date. 2. Incidence Extensive use of platinum compounds in chemotherapy during the last decade has led to a signiﬁcant increase in the incidence of hypersensitivity reactions (Table 1). Hypersensitivity to carboplatin is rarely observed during the ﬁrst course of treatment. In fact, the most striking diﬀerence of carboplatin hypersensitivity, when compared to nonplat- inum agents, is the fact that most allergic reactions are reported after the patient has received a signiﬁcant number of infusions although he has exhibited no hypersensitivity up until then [32–37]. Half of the reactions observed are moderate to severe [32]. During the ﬁrst ﬁve cycles, the overall risk is less than 1% [38]; it rises sharply to 6.5% with the sixth cycle [39] and has been reported as high as 27% in patients receiving more than seven cycles of treatment [32, 40, 41]. The overall incidence of carboplatin hypersensitivity reaches 44% in the third-line retreatment setting [32, 42]. Reactions to carboplatin are usually observed after a median number of eight infusions [32, 33, 39]. Markman et al. were the ﬁrst to report that peak incidence of carboplatin reaction is observed during cycle 2 in the second-line setting [32]. The incidence of cisplatin hypersensitivity exhibits similar characteristics to those observed with carboplatin. It seems to range from 5% to 20% and increases with concomitant radiation [43]. Oxaliplatin-related hypersensitivity reactions were originally considered less common, but with the growing use of this drug during the last years, it has been found that reactions occur at a frequency as high as 18.9% [44, 45]. However, severe grade 3 or 4 events occur in only 1.6% of patients [46]. These reactions usually develop after six drug infusions [47]. Severe anaphylaxis is rarely observed and is mostly described in case reports [48, 49]. To the best of our knowledge, there have still been no reports of hypersensitivity reactions associated with newer platinum compounds (i.e., satraplatin, picoplatin). This, however, may be partly attributed to the fact that for some of the trials conducted, known hypersensitivity to platinum- containing compounds was an exclusion criterium. The prevalence of hypersensitivity to these agents remains to be explored in larger studies in the future. 3. Risk Factors Factors predictive of hypersensitivity reactions to platinum agents are yet to be clariﬁed. HLA phenotype and intensity of exposure inﬂuence the possibility of sensitization in reﬁnery workers [67]. Prior history of allergy to drugs and various Metal-Based Drugs Table 1: Incidence and severity of hypersensitivity to platinum agents. Drug Cisplatin Overall incidence % 5−20 Carboplatin 1−44 Oxaliplatin 10−18.9 Characteristics/Severity (i) Occurs within minutes of infusion start (ii) Mostly between 4th−8th course (iii) Increases with concomitant radiation (i) Occurs within minutes or days from infusion (ii) less than 1% during cycles 1 5 − (iii) 6.5% in cycle 6 (iv) 27% in cycle 7 or more (v) 44% in 3rd-line retreatment Half of all reactions observed are moderate to severe (i) Occurs within minutes/hours from infusion (ii) Mostly after 6th course (iii) Grade 3-4 in only 1.6% (iv) Severe anaphylaxis mostly in case reports environmental factors are associated with greater risk [68, 69]. In patients receiving carboplatin, the number of prior platinum treatments and total lifetime exposure is associated with possibility of hypersensitivity [32, 34, 69–72], but it is not clear whether lowering individual doses during retreatment would reduce the risk [34]. The interval between the last infusion of ﬁrst-line chemotherapy and retreatment is an independent predictive variable [69]. High rate of drug infusion also seems to be vital [16] whereas selection of ﬁrst-line and retreatment regimens is not inﬂuential [69]. Most recently, Sugimoto et al. showed that patients with carboplatin-free interval >13 months was related to a 22- fold higher risk of hypersensitivity and that a maximum dose/body of carboplatin >650 mg is also an independent risk factor [40]. Navo et al. observed that carboplatin hypersensitivity is more frequent in patients with ovarian cancer [70]. A retrospective study by Lafay-Cousin et al. in pediatric patients with low-grade glioma concluded that hypersensitivity reactions occurred signiﬁcantly earlier in children receiving weekly carboplatin infusions as compared to children on a monthly schedule. Being a girl was identiﬁed as a risk factor. The cumulative risk of allergic reactions increased with the number of infusions, and there was no evidence of a plateau [17]. It has also been found that the eosinophilic number and ratio during the previous cycle of allergy and on the day of an allergic reaction are not helpful in predicting a hypersensitivity response [73]. The incidence of carboplatin hypersensitivity also seems to be associated with the type of antineoplastic drugs it is