Metal-Based Drugs Step Solution 1 2 3 4 5 6 7 8 9 10 11 12 100-fold dilution of ﬁnal target concentration 10-fold dilution of ﬁnal target concentration Concentration was calculated by subtracting the cumulative dose administered in steps 1−8 from the total target dose Table 5: Castells’ 12-step desensitization protocol. Rate (mL/h) Time (in minutes) 2.0 5.0 10.0 20.0 5.0 10.0 20.0 40.0 10.0 20.0 40.0 75.0 15 15 15 15 15 15 15 15 15 15 15 prolonged to complete target dose Volume infused per step (mL) 0.50 1.25 2.50 5.00 1.25 2.50 5.00 10.00 2.50 5.00 10.00 232.50 to the fact that the patient is exposed to very low concentra- tions of “free” platinum during each infusion. The threshold for the manifestation of a reaction is considered to be lowered with each treatment [68, 86]. According to Markman et al., the patient is sensitized during the ﬁrst-line treatment (6 courses), and retreatment with the same drug provides the additional immunological stimulation necessary for a reaction during infusion number 8 [32]. Novel studies have suggested that hypersensitivity to platinum agents is not only caused by their common platinum component but also by their diﬀerent structures and biological targets. According to molecular analyses, cisplatin, carboplatin, and oxaliplatin aﬀect various genes, many of which regulate cell cycle and signal transduction [87, 88]. 5. Symptoms Platinum hypersensitivity symptoms may develop acutely during infusion or within minutes, hours, or days after the infusion [32]. A mild rash may be the ﬁrst manifestation of hypersensitivity, and this will be followed by more severe reactions in 50% of patients. Symptoms of mild hypersensitivity include skin rash, urticaria, ﬂushing, palmar itching, burning, edema of the face and hands, abdominal cramping and diarrhea, back pain, and pruritus. They usually resolve quickly with antihistamines and steroids. More severe reactions manifest with bronchospasm, tachy- cardia, hypotension or hypertension, seizures, and chest pain. Systemic anaphylaxis may be life-threatening [30, 32, 34, 39, 76, 89, 90]. In oxaliplatin-based regimens, dysesthesia with laryngeal spasm may occur during, immediately after, or even hours after the drug administration [86, 91–93]. Respiratory problems may be more severe than initially estimated in 5 many cases, as hypoxemia in oxaliplatin-related reactions is often found with no symptoms of dyspnoea [73]. 6. Treatment Strategies It is recommended that treating physicians inform patients receiving platinum agents of the risks of hypersensitivity, especially after multiple infusions. It is important for patients to be alert and appropriately educated, so that symptoms are promptly recognized. Administration of platinum drugs should take place in a medical setting with all necessary equipment, and the staﬀ should be experienced in treating hypersensitivity reactions. When a reaction occurs, the infusion should be immediately stopped, and normal saline, intravenous antihistamines, and low-dose corticosteroids should be administered (Table 3). The main dilemma is whether the platinum-based regimen should be completely discontinued in future infusions. When the reaction is life- threatening, all platinum compounds are usually excluded from future treatment options. In case of mild-to-moderate hypersensitivity reactions, there is a range of management options [34]. 6.1. Infusion Rate and Premedication. Lowering of infusion rate and use of premedication with corticosteroids and antagonists of histamine receptors have allowed successful readministration of the platinum agent in some case; however there is great risk of recurrence. Some studies actually suggest that in carboplatin patients who still have not exhibited hypersensitivity after a total of 8 infusions, premedication should be given as precaution, and the administration rate should be signiﬁcantly decreased in order to lower the future risk [34]. A retrospective study was most recently conducted by O’Ceabhaill et al. and included 777 patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer retreated with carboplatin. The data showed that an incrementally increasing, 3-hour infu- sion during carboplatin retreatment, along with appropriate premedication, may reduce hypersensitivity reactions, when compared to the standard 30-minute infusion [34]. 6.2. Desensitization Protocols. Various desensitization pro- tocols have been successfully implemented in order to re- administer the same platinum agent, especially in cases where the patient seems to have been beneﬁted by the drug (Table 4). Protocols are based on gradual reintroduction of small amounts of drug antigen while escalating to the full dose, on prolonged infusion and premedication. Successful desensitization protocols are usually time-consuming [30, 32, 33, 38, 50, 53–57, 89–91]. Prolonged desensitization is probably more tolerable when considering the changes caused in the extracellular ﬂuid drug concentration rate [94]. However, rapid protocols that develop desensitization within 4 8 hours have also been attempted [78]. A recent − trial by Castells et al. included 413 cases and reported a 12- step intravenous and intraperitoneal rapid desensitization protocol that can be applied in a wide range of chemotherapy agents (Table 5). The population consisted predominantly