Management of hypersensitivity to platinum- and taxane-based chemotherapy: cepo review and clinical recommendations

taxane-based chemotherapy to patients who have had a hypersensitivity reaction and for whom no other treatment options are available. Considering the available evidence, the Comité de l’évolution des pratiques en oncologie made recommendations for clinical practice in Quebec


INTRODUCTION
Although the incidence of hypersensitivity to antineoplastic agents can increase with the number of treatments, reactions are not predictable and often are not associated with the pharmacologic mechanism of action of the medication 1 .When patients experience hypersensitivity reactions, clinicians can either continue the treatment, at the risk of causing a severe reaction and potentially a fatal anaphylactic shock, or stop the treatment, although it might be the only option available.
The molecular mechanisms of hypersensitivity to anticancer agents are not yet well defined.As in other drug reactions, and based on the results of skin testing, immediate reactions sometimes appear to involve immunoglobulin E. Delayed reactions might be caused by other mechanisms, such as activation of the complement cascade 2 .
The diagnosis of hypersensitivity is based on the patient's medical history and, if possible, the results of diagnostic (skin or challenge) tests 3 .The patient's clinical history can be difficult to evaluate because cancer patients are often receiving multiple medications that can also trigger hypersensitivity reactions.In addition, the proposed chemotherapy might also trigger immune responses not mediated by immunoglobulin E 4 .The cancer itself can also occasionally produce clinical symptoms that resemble a hypersensitivity reaction caused by mast cell activation.Epidemiology studies

Background
Although antineoplastic agents are critical in the treatment of cancer, they can potentially cause hypersensitivity reactions that can have serious consequences.When such a reaction occurs, clinicians can either continue the treatment, at the risk of causing a severe or a potentially fatal anaphylactic reaction, or stop the treatment, although it might be the only one available.The objective of the present work was to evaluate the effectiveness of methods used to prevent and treat hypersensitivity reactions to platinum-or taxane-based chemotherapy and to develop evidence-based recommendations.

Methods
The scientific literature published to December 2013, inclusive, was reviewed.

Results
Premedication with antihistamines, H2 blockers, and corticosteroids is not effective in preventing hypersensitivity reactions to platinum salts.However, premedication significantly reduces the incidence of hypersensitivity to taxanes.A skin test can generally be performed to screen for patients at risk of developing a severe reaction to platinum salts in the presence of grade 1 or 2 reactions, but skin testing does not appear to be useful for taxanes.A desensitization protocol allows for re-administration of either platinum-or taxane-based chemotherapy to some patients without causing severe hypersensitivity reactions.
have shown that certain types of cancer are associated with an increased risk of hypersensitivity 2 .
The objectives of the present work were to review the scientific literature evaluating the effectiveness of methods used to prevent and treat hypersensitivity to taxane-or platinum-based chemotherapy and to make clinical recommendations based on the best available evidence.

METHODS
This article is an updated adaptation of an original clinical guideline available online (http://www.msss.gouv.qc.ca/sujets/prob_sante/cancer/download.php?f=ec531e187f7e1b161079228273b58a18).To begin, the scientific literature published up to April 2013 was searched in PubMed using the keywords "desensitization," "skin test," "platinum salts," "cisplatin," "carboplatin," "oxaliplatin," "taxane," "paclitaxel," "docetaxel," and "hypersensitivity."The literature review was subsequently updated to cover the period from April 2013 to December 2013.Only English-and French-language studies were selected.Economic studies were not considered.Clinical guidelines and consensus statements issued by relevant international organizations and cancer agencies were also identified.
The level of evidence of selected studies and the strength of guideline recommendations were evaluated using the American Society of Clinical Oncology and European Society for Medical Oncology grading system (Table i).The original guideline was developed by a subcommittee of the Comité de l'évolution des pratiques en oncologie (cepo), reviewed by independent experts, and finally adopted by the cepo by consensus.

3.1.1
Incidence Widespread use of platinum antineoplastic agents has led to an increased incidence of hypersensitivity reactions (Table ii).Hypersensitivity is rarely reported during the initial course of treatment.A major feature of hypersensitivity to platinum drugs, compared with other types of agents, is that allergic reactions can appear after a significant number of infusions with no prior clinical signs 10 .Carboplatin-based chemotherapy is often administered over 6 cycles, and hypersensitivity reactions are usually observed during re-treatment, after a period of remission.Hypersensitivity reactions to oxaliplatin are thought to be less frequent, although the growing use of that agent in recent years has led to a reported incidence of approximately 19% 11 .
The incidence of cross-reactivity between platinum drugs has not been fully studied.Allergic crossreactivity between cisplatin and carboplatin has been reported, but the number of cases is insufficient to establish the true incidence 12 .

3.1.2
Risk Factors Risk factors for developing hypersensitivity to platinum drugs, especially cisplatin and oxaliplatin, have to be better identified.An existing hypersensitivity to certain drugs and environmental factors has been associated with an increased risk of developing symptoms from carboplatin 13 .Among patients receiving carboplatin, the number of treatments and the total lifetime exposure to platinum drugs have been associated with the risk of developing hypersensitivity to carboplatin 10 .The interval between the last cycle of the initial course of treatment and the first cycle of the second course is a predictive variable 13 .In this regard, Schwartz et al. 14 showed that the risk of a severe reaction during carboplatin treatment was 47% if the interval between courses was more than 24 months and 6.5% when the interval was less than 12 months (n = 36).
When carboplatin forms part of combination chemotherapy, the incidence of hypersensitivity seems to be affected by the antineoplastic agent with which carboplatin is being combined.The calypso study showed that hypersensitivity occurred more often among patients receiving a carboplatin-paclitaxel combination than among those receiving carboplatin combined with pegylated liposomal doxorubicin (18.8% vs. 5.6%) 15 .In a Southwest Oncology Group study, Markman et al. 16 showed that, compared with single-agent carboplatin, the combination of pegylated liposomal doxorubicin and carboplatin reduced the frequency of hypersensitivity reactions (0% vs. 30%).
Hypersensitivity reactions have been observed for all routes of administration, including intravenous, intraperitoneal, and intravesical 17,18 .

Incidence
Hypersensitivity symptoms generally develop within the first 10-15 minutes after infusion (78% within the first 10 minutes) 19 .In 95% of cases, reactions occur during the first or second infusion 20 , but reactions can appear during subsequent infusions (3%) 19,20 .Some patients also develop skin reactions several days or up to a week after infusion.The incidence of paclitaxel and docetaxel hypersensitivity varies between 8% and 50% (Table ii).
Paclitaxel and carboplatin are often administered concomitantly, and so it can be difficult to distinguish which drug has triggered a hypersensitivity reaction.Diagnosis is facilitated by the clinical presentation and the time of appearance because the reactions are different for and specific to each agent.

3.2.2
Risk Factors In the case of paclitaxel, hypersensitivity reactions occur more often in patients with a history of atopy 4 .For both docetaxel and paclitaxel, a history of mild skin reactions during earlier treatments; the presence of respiratory dysfunction, overweight, or obesity; and menopausal or postmenopausal status have also been reported as risk factors [21][22][23] .
Whether hypersensitivity can be attributed to the taxanes themselves or to their formulation vehicles has not yet been established [24][25][26] .Paclitaxel is administered in a solution of ethanol and Kolliphor el (formerly Cremophor el: BASF, Ludwigshafen, Germany), which is also used as a vehicle for other compounds known potentially to cause hypersensitivity (cyclosporine, teniposide, diazepam, propofol, and vitamin K) 25,27 .However, studies have shown that Kolliphor used without paclitaxel and without premedication does not trigger hypersensitivity reactions 28 .
The reaction to docetaxel has been attributed to its vehicle, polysorbate 80, which is also used for etoposide 29 .However, data have shown that the drug itself might be the cause of hypersensitivity 30,31 .

Skin Testing
Skin testing was developed to predict immunoglobulin E-mediated allergic reactions, and certain precautions for the use of skin testing have been reported in the literature 32 .Indeed, patients with cardiovascular disease and elderly patients can be at risk of complications from testing.As with any medication, the patient's general condition must be considered if complications could occur and require attention.Furthermore, patients presenting with dermographism, urticaria, eczema, or cutaneous mastocytosis can have false-positive skin tests.Patients with improperly controlled asthma and reduced pulmonary function, and those with a history of severe hypersensitivity when exposed to weak doses of antigens, can be at risk of developing an anaphylactic reaction to skin testing.
Certain medications can affect skin-test reactivity 32 .The time interval between drug discontinuation and skin testing vary with the drug (Table iii).The use of muscle relaxants and antiemetics with antihistaminic properties can reduce skin-test reactivity, as can the use of tricyclic antidepressants and phenothiazines.Because many of those drugs have a long half-life or often cannot be interrupted for clinical reasons (or both), skin testing often proceeds in spite of their presence.If testing triggers a weak or negative reaction, interference can therefore be considered.Use of decongestants, inhaled beta-agonists, or cromolyn has no effect on skin-test results.
Some authors recommend that all patients receiving carboplatin be tested before each treatment after the 6th 4,34 .Patients who experience hypersensitivity symptoms and a positive skin-test result should undergo a desensitization protocol.Markman et al. 35 reported that 6 of 7 patients with a positive skin-test result for carboplatin developed an anaphylactic reaction during re-treatment with carboplatin.
Skin testing can be used to evaluate the potential for cross-reactions between two platinum drugs [36][37][38] .If indicated, patients with negative skin-test results for a particular platinum agent might be able to continue treatment with a different agent without premedication 39 .Compared with patients having a negative skin-test result, those with a positive result have a greater risk of experiencing cross-reactivity between platinum salts 40 .
Although used to identify a potential allergic reaction, skin testing can be used in patients who have had symptoms of anaphylaxis 2 ; however, 2-6 weeks should elapse after the anaphylactic reaction and before the test to avoid generating a false-negative result because of mast cell hyporeactivity 37,41 .If testing occurs earlier, a positive result is always significant.

Infusion Time and Premedication Infusion Time:
O'Cearbhaill et al. 10 noted that administration of a 3-hour carboplatin infusion together with premedication (instead of the standard 30-minute infusion) could reduce the risk of hypersensitivity (3.4% vs. 21%).
A meta-analysis evaluated the impact of paclitaxel infusion time and showed no difference in the risk of developing hypersensitivity when treatment was administered over 3 or 24 hours (risk ratio: 1.86; 95% confidence interval: 0.63 to 5.52) 42 .Furthermore, Hainsworth et al. 43 noted no difference in activity between 1-day and 3-day paclitaxel schedules in which each dose was administered by 1-hour infusion.
Premedication: Routine premedication with antihistamines and steroids is not recommended before commencement of platinum-based therapy 8,12,44,45 .A small retrospective study showed that premedication (diphenhydramine, dexamethasone, granisetron, and famotidine vs. dexamethasone and granisetron) reduced hypersensitivity reactions associated with modified folfox6 (leucovorin, 5-fluorouracil, oxaliplatin) 46 .In the case of a grade 1 or 2 hypersensitivity reaction, it is possible to continue oxaliplatin treatment without reducing the infusion rate if the patient is premedicated with dexamethasone 47 .Administration of premedication with corticosteroids and a histamine receptor antagonist has allowed some patients to be re-treated with platinum drugs without desensitization 9 ; however, there is always a risk of recurrence of the reaction.
Routine premedication with glucocorticoids can diminish the incidence of hypersensitivity during paclitaxel or docetaxel therapy from 30% to 3% 20,48 .With premedication, the incidence of hypersensitivity reactions to paclitaxel is between 1% and 3% regardless of infusion time (1, 3, or 24 hours).Kwon et al. 49 showed that, compared with a single administration 30 minutes before treatment, administration of dexamethasone 12 and 6 hours before infusion of paclitaxel led to fewer hypersensitivity reactions; another study showed no difference 50 .Premedication with dexamethasone (8 mg for 3 days starting the day before infusion) can reduce the incidence of grade 3 or 4 hypersensitivity reactions to docetaxel to about 2% 51,52 .As a result, the median cumulative dose administered before the incidence of severe symptoms increased (from 490 mg/m 2 to 790 mg/ m 2 ) [53][54][55] .Chouhan et al. 56 showed that a single dose of dexamethasone 30 minutes before docetaxel infusion was sufficient to prevent hypersensitivity reactions.

3.3.3
Treatment of Hypersensitivity Symptoms Early recognition of hypersensitivity reactions is essential for the patient's well-being and can, in some cases, save lives.Patients must be informed of adverse events so that they can contact medical personnel as soon as possible 57 .
Treatment must be interrupted immediately when a patient develops a hypersensitivity reaction.Depending on the symptoms, it might be necessary to administer medication.Antihistamines, corticosteroids, and if necessary, epinephrine and bronchodilators should be administered, and oxygen should be readily available 57 .In the case of a severe reaction, treatment should not be continued.However, with a mild reaction, treatment can be resumed the same day [57][58][59] .In many cases, a mild-to-moderate reaction will resolve after a brief interruption of treatment and administration of appropriate medication 60 .
Re-treatment has the potential to have serious consequences, and close monitoring is therefore essential during the next cycle.

Substitution of Therapy
A new formulation of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) avoids the use of Kolliphor as a vehicle, and thus premedication is not required 61,62 .No hypersensitivity reactions were reported in several phase i, ii, and iii studies that used this agent 28,[62][63][64] , and administration of nab-paclitaxel was well tolerated in 5 patients who had previously experienced hypersensitivity reactions to paclitaxel 65 .However, one phase iii study indicated that nab-paclitaxel can cause hypersensitivity reactions 28 .

3.3.5
Desensitization Protocols Desensitization is indicated when no alternative therapy exists or when the available alternative is less effective than the treatment being used.Desensitization protocols involve inducing a temporary tolerance to a treatment by gradually reintroducing a small amount of the antigen over a relatively short period of time until the total scheduled dose has been administered 41,66,67 .Because a desensitization protocol induces only a temporary tolerance, it must be carried out every time the patient receives the treatment 1,41,66 .
A 12-step desensitization protocol has been developed by the Dana-Farber Cancer Institute and the Brigham and Women's Hospital 41,57,67,68 .Unlike most of the other protocols, it is the only one to have been successfully used during several hundred desensitizations for multiple antineoplastic agents.The protocol involves the preparation of three different solutions with escalating concentrations of the drug (Table iv).The infusion rate changes every 15 minutes, and the volume infused is approximately double that of the preceding step.As reported in three publications, use of this 12-step protocol resulted either in no hypersensitivity reaction or in a less-severe Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).reaction than the reaction that originally led to the need for desensitization (Table v).
In 2005, Feldweg et al. 57 reported the results of paclitaxel and docetaxel desensitization for patients admitted to a desensitization protocol because of severe hypersensitivity reactions (dyspnea, laryngeal edema, bronchospasm, oxygen desaturation, chest pain, significant change in blood pressure, or loss of consciousness) during prior treatment.During desensitization, 4 patients developed a reaction.The reactions were less severe than the original ones (palmar-plantar erythema, abdominal pain, burning sensation in the chest, and moderate flushing).Treatment was interrupted, and the patients received diphenhydramine.One patient had complications warranting readmission to hospital.That patient opted for a change in treatment; the other three underwent subsequent desensitizations using the standard or a modified protocol without any reactions.
In 2005, Lee et al. 67 reported the results of desensitization to carboplatin, paclitaxel, and four other agents (docetaxel, trastuzumab, doxorubicin, and mesna).To be eligible, patients had to have experienced a hypersensitivity reaction to chemotherapy less than 6 hours after infusion, with the need to continue on the same agent.All patients completed their desensitization protocols.A total of 225 desensitizations (88.2%) were completed without any symptoms, and in 18 patients (30 desensitizations), symptoms were less severe than the initial ones during the first (n = 13), second (n = 3), third (n = 1), or fourth (n = 1) desensitization.Skin reactions in those 18 patients were treated with antihistamines (n = 8), and chest pain and shortness of breath were treated with antihistamines either alone or combined with oxygen.In 6 patients, treatments given in addition to antihistamines included albuterol for dyspnea; corticosteroids for symptoms persisting more than 5 minutes; a beta-blocker for chest pain, tachycardia, and hypertension; and intramuscular epinephrine for throat tightness and hypotension.Once the hypersensitivity symptoms were managed, all patients completed their treatment and received subsequent desensitizations on a modified protocol.
In 2008 and 2010, Castells et al. 41 and Limsuwan and Castells 68 published the results of desensitizations for carboplatin, paclitaxel, cisplatin, oxaliplatin, and other treatments (rituximab, liposomal doxorubicin, and doxorubicin).To be eligible, patients had to have experienced a hypersensitivity reaction during or within 48 hours after infusion.Of all the desensitizations, 94% produced a mild reaction or no reaction.All reactions were controlled by interrupting treatment and administering appropriate medication, with epinephrine needed for 1 patient.Overall, 7% of reactions occurred during steps 1-4, 18% during steps 5-8, and 75% during steps 9-12, with 51% of reactions occurring during the last step of the desensitization protocol.All patients received their treatment at full dose.

DISCUSSION
Hypersensitivity reactions to chemotherapy are unpredictable adverse events with potentially lethal consequences.Among the agents most likely to cause this type of reaction are platinum drugs and taxanes.Literature on this subject often comes from case studies and populations consisting of a limited number of patients.Further research is needed to validate the reported information.
According to the U.S. National Cancer Institute grading system, grade 1 hypersensitivity reactions allow treatment to be continued without any modification, and grade 2 reactions might require modification.Depending on the drug being administered, modifications such as substituting therapy, using steroid and antihistamine premedication, and reducing the infusion rate are a possibility.Optimal treatment is determined using clinical judgment based on the presenting symptoms.In the case of grade 3 or 4 reactions, patients should not be given the same treatment without modifications.In the event of mild-to-moderate reactions, any reintroduction of the drug could lead to a severe or even lethal reaction 72 .In such cases, a desensitization protocol should be planned 2 .
Premedication is ineffective with platinum drugs, but using premedication with taxanes can diminish the risk of hypersensitivity reactions 8,12,44 .
Modifying the infusion time seems to have an effect on the risk of having a reaction to some agents, but additional research is needed to clarify this issue 42,43,73,74 .
The utility of skin testing in clinical practice remains a contentious issue 9 .However, its use could help to diagnose or predict a hypersensitivity reaction or to evaluate the potential for cross-reactions between two platinum drugs.It is important to note that even patients with a negative result are not immune to hypersensitivity reactions.Experts often underscore the fact that skin testing can be useful when the risk for hypersensitivity is high 9 .Indeed, some reports have shown that, unlike reactions to taxanes, for which skin testing is unreliable, hypersensitivity reactions to platinum agents can be identified with such testing 2,75 .In the case of carboplatin, close monitoring is needed, particularly after the 6th cycle 2,25,[75][76][77] .However, the recommendation to systematically conduct skin testing after a predetermined number of cycles varies depending on the source.In the presence of a hypersensitivity reaction, it is recommended that an allergist, medical oncologist, or any medical specialist with desensitization experience be consulted to determine the most appropriate course of treatment.
Skin testing must be carried out by skilled personnel specially trained to perform the technique, interpret the results, and manage the allergic reactions that could arise during the test itself.The use of appropriate controls allows for the results to be properly interpreted.Additional research is needed to clarify the role of skin testing and to establish guidelines.On the other hand, a positive result should be considered significant and must be taken into account.
The various desensitization protocols reported in the literature have often been used in a limited number of cases and a limited number of desensitizations.In most cases, efficacy and safety results

e637
Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
are nonexistent or minimal.The desensitization protocols for platinum drugs and taxanes discussed earlier in this article were administered to 15 or more patients 40,41,57,67,70,71 and are based on administering treatment in numerous dilutions and gradual steps.The associated success rate is nearly 100%, with no severe hypersensitivity reactions in most cases.The large-scale studies reported by the Dana-Farber Cancer Institute and Brigham and Women's Hospital describe a 12-step protocol tested on a larger group of patients undergoing a significant number of desensitizations involving platinum drugs and taxanes 41,57,67,68 .In every case, the planned therapy was successfully administered, with no hypersensitivity reactions or with just mild reactions, all of which were less severe than the initial ones.Premedication was administered before desensitization for both platinum drugs and taxanes.When hypersensitivity reactions occurred during the desensitization protocol, administration of antihistamines and interruption of treatment successfully controlled the symptoms in most cases and allowed the protocol to be completed.During subsequent desensitizations, a modified protocol allowed for all patients to receive the scheduled number of treatment cycles.
It is important to emphasize that successful application of a desensitization protocol depends on the experience of the team in charge of its administration and the team's ability to accurately assess the risks 41,57,67,68 .All personnel involved must be trained to recognize hypersensitivity reactions and to respond immediately.Emergency medicationsincluding epinephrine, antihistamines, bronchodilators, and oxygen-must be at the patient's bedside to ensure quick administration if needed.Patients must be educated to recognize early symptoms and to immediately inform the medical staff.

CONCLUSIONS AND RECOMMENDATIONS
When a hypersensitivity reaction occurs, the dilemma is whether treatment should be stopped, continued, or modified for the patient's well-being.In many cases, implementing effective preventive measures can ensure that the patient is offered the best treatment available.Considering the evidence available to date, the cepo makes these recommendations: • With respect to platinum drugs (cisplatin, carboplatin, oxaliplatin): x Routine premedication with antihistamines and steroids to prevent hypersensitivity reactions is not recommended (grade B recommendation).x Whenever possible, skin testing (prick and intradermal) should be considered for patients with suspected hypersensitivity to platinum drugs (grade B recommendation).
Skin testing must take place at least 2-6 weeks after a hypersensitivity reaction.x In the case of a positive skin test, a desensitization protocol should be considered when treatment cannot be substituted or interrupted (grade B recommendation).x In the case of a negative skin test, a risk of reaction remains; the decision to continue treatment or to administer a desensitization protocol is based on clinical judgment (grade D recommendation).x Skin testing should be performed by a multidisciplinary team specially trained to perform the technique, interpret the results, and manage the rare allergic reactions that can occur during the test itself (grade D recommendation).
• With respect to taxanes (paclitaxel, docetaxel): x Premedication with glucocorticoids and H1 and H2 antagonists should routinely be administered to reduce the risk of hypersensitivity reactions (grade A recommendation).x Skin testing is not recommended for identifying hypersensitivity reactions to taxanes (grade B recommendation).
• With respect to desensitization: x A multi-step desensitization protocol can be used in the case of a positive skin test for platinum drugs or a type i hypersensitivity reaction if treatment cannot be substituted and if stopping treatment would affect the patient's survival (grade B recommendation).The 12-step protocol developed by Castells et al. 41 is supported by the best evidence.x The desensitization protocol must be carried out under appropriate supervision and closely monitored, with all necessary equipment at hand (grade D recommendation): • Medical personnel in attendance must have been trained to recognize hypersensitivity reactions and must be prepared to respond immediately.• Emergency medications (epinephrine, H1 and H2 antihistamines, bronchodilators, and oxygen) must be at the patient's bedside to ensure quick administration as needed.x Patients should be educated to recognize the initial symptoms of hypersensitivity and to immediately inform attending personnel (grade D recommendation).x Premedication must be administered before any desensitization protocol (grade D recommendation).
x If a hypersensitivity reaction should occur during the protocol (grade D recommendation), then • the infusion must be interrupted and the symptoms controlled by appropriate medication.
• the protocol must be adjusted such that the full dose can be administered if possible.• the protocol must be modified for subsequent desensitizations.• a desensitization protocol must be conducted every time the patient subsequently receives treatment.
Based on the foregoing recommendations, the cepo proposed two algorithms for the management of hypersensitivity reactions to platinum drugs and taxanes (Figures 1 and 2).

ACKNOWLEDGMENTS
The cepo is a group of specialists in oncology that reports to the Institut national d'excellence en santé et en services sociaux (inesss).The inesss provided financial support for the present manuscript, which

CONFLICT OF INTEREST DISCLOSURES
The authors have no financial conflicts of interest to declare.
is an adaptation of the original cepo clinical practice guideline, published in July 2013 and freely available in its French version at http://www.msss.gouv.qc.ca/sujets/prob_sante/cancer/download.php?f=e c531e187f7e1b161079228273b58a18.The québécoise de cancérologie of the Ministère de la Santé et des Services sociaux du Québec provided financial support for the original guideline.The cepo thanks Paul Bessett m d, Hôpital Fleurimont (chus); Jean-Luc Dionne md, Hôpital Maisonneuve-Rosemont; Andrew David Moore md, Hôpital Charles-LeMoyne (CSSS Champlain-Charles-LeMoyne); Mireille Poirier bpharm msc bcop, Hôtel-Dieu de Québec (chu de Québec); and Fanny Silviu-Dan md, Montreal General Hospital (muhc) as external reviewers of the original clinical practice guideline.

figure 1
figure 1 Management algorithm for hypersensitivity reactions to platinum agents.a Apply clinical judgment according to observed symptoms.Consider consultation with an allergist, a medical oncologist, or any specialist with desensitization experience; an increase in the infusion time; use or avoidance of premedication; and use of a desensitization protocol.b Desensitization must be conducted under adequate supervision and with the necessary equipment present.po = orally; iv = intravenously.

figure 2
figure 2 Management algorithm for hypersensitivity reactions to paclitaxel and docetaxel.a Use protocol with oral administration when possible.b This product or equivalent.c Apply clinical judgment according to observed symptoms.Consider consultation with an allergist, a medical oncologist, or any specialist with desensitization experience; an increase in the infusion time; use or avoidance of premedication; and use of a desensitization protocol.d Desensitization must be conducted under adequate supervision and with the necessary equipment present.po = orally; iv = intravenously; bid = twice daily.

table i
Levels of evidence and grades of recommendations (adapted fromCook et al., 1992 7 ) v Evidence demonstrated by means of case series without controls

table ii
Hypersensitivity reactions to platinum-and taxane-based chemotherapy (adapted from Syrigou et al., 2010 8 and Makrilia et al., 2010 9 ) Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table iii
33 )rval between drug discontinuation and skin testing (adapted from Brockow and Romano33 ) Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table iv
57 )ral principles of the 12-step desensitization protocol (adapted from Feldweg et al.57 ) Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).