Infusion reactions to systemic chemotherapy

INTRODUCTION — Virtually all chemotherapeutic agents have the potential to initiate infusion reactions, defined in this review as unexpected reactions that cannot be explained by the known toxicity profile of the drug. The cytotoxic agents that are most commonly associated with infusion reactions are the taxanes, platinum drugs, pegylated liposomal doxorubicin, asparaginase, procarbazine, etoposide, bleomycin, cytarabine, and ixabepilone. While these are often referred to as "hypersensitivity reactions," many do not have a proven immunologic mechanism. Thus, the term infusion reaction is preferred. In contrast, allergic reactions where a known immunologic mechanism can be demonstrated through blood or skin testing are clearly established for platinum drugs, taxanes, some monoclonal antibodies, and certain other chemotherapy agents, as discussed in this review.

After an introductory section that summarizes the characteristics of infusion reactions and different approaches to classifying them, this review will focus on commonly used conventional cytotoxic drugs with a moderate to high incidence of infusion reactions, and the ways in which these reactions can be treated and/or prevented. Infusion reactions in patients receiving therapeutic monoclonal antibodies for cancer treatment are discussed separately, as are other cutaneous adverse effects associated with chemotherapy. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy" and "Cutaneous adverse effects of conventional chemotherapy agents".)

CHARACTERISTICS OF REACTIONS

Signs and symptoms of infusion reactions — Infusion reactions may affect any organ system in the body. Most are mild in severity, although severe and even fatal reactions occur. The most common signs and symptoms of infusion reactions are:

●Flushing

●Itching

●Alterations in heart rate and blood pressure

●Dyspnea or chest discomfort

●Back or abdominal pain

●Fever and/or shaking chills

●Nausea, vomiting, and/or diarrhea

●Various types of skin rashes

●Throat tightening

●Hypoxia

●Seizures

●Dizziness and/or syncope

In this review, infusion reactions involving these symptoms will be referred to as "standard infusion reactions" or SIRs. These represent the majority of reactions to systemic chemotherapeutic agents.

Signs and symptoms of anaphylaxis — Anaphylaxis is a distinct reaction that is rare with most conventional cytotoxic agents, although it is well established that the platinum drugs and the taxanes can cause anaphylaxis. The most common signs and symptoms of anaphylaxis caused by intravenously-administered medications are the following:

●Cutaneous symptoms – Flushing, itching, urticaria, and/or angioedema (usually of face, eyelids, or lips)

●Respiratory symptoms – Repetitive cough, sudden nasal congestion, shortness of breath, chest tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality (due to laryngeal edema), hypoxia

●Cardiovascular symptoms – Faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss of consciousness

●Gastrointestinal symptoms – Nausea, vomiting, abdominal cramping, and/or diarrhea

●Neuromuscular symptoms – Sense of impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, pelvic pain

The clinical manifestations of anaphylaxis (from all causes) are presented in detail elsewhere. (See "Anaphylaxis: Emergency treatment".)

Although there is overlap between the clinical features of anaphylaxis and those of SIRs, certain signs and symptoms are highly suggestive of anaphylaxis, and they should be specifically sought when evaluating a patient with an infusion reaction: urticaria, repetitive cough, wheeze, throat tightness/change in voice, and hypotension. These stereotypical signs and symptoms result from the release of mediators from mast cells and basophils. In contrast, fever and prominent muscular pain are NOT features of anaphylaxis, and the presence of these signs and symptoms suggests the reaction is an SIR.

It is critical to undress the patient and examine the skin carefully during infusion reactions in order to fully appreciate skin findings, especially urticaria. The neck, trunk, extremities, abdomen, and axillae are the sites where urticaria often appears first.

Timing and risk factors — As a group, infusion reactions (including both SIRs and anaphylaxis) usually occur during or within a few hours of drug infusion. Occasionally, a reaction may occur one to two days after administration, and patients must be adequately informed of symptoms to watch for and the appropriate course of action to take if a problem arises. Although they most commonly occur with the first or second drug administration, infusion reactions are unpredictable and can occur at any time despite preventive measures.

Attempts to identify patients who are likely to develop an infusion reaction have met with limited success, although infusion reactions are generally more common in the following settings [1,2]:

●With IV as compared to oral or intraperitoneal administration

●After multiple cycles of certain agents (see 'Platinum drugs' below)

●In patients with a prior infusion reaction to a drug of the same chemical class

●A history of multiple drug allergies, regardless of drug class

CLASSIFICATION OF INFUSION REACTIONS

National Cancer Institute classification — The most recent version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) for grading adverse reactions during chemotherapy administration has a scale for grading the severity of infusion reactions (table 1) and separate grading scales for allergic reactions (which are appropriate for non-infusional medications) and anaphylaxis (table 2).

Allergists/immunologists have a different approach to classifying infusion reactions, which divides them into reactions with features of mast cell or basophil activation (signifying potential progression to anaphylaxis) and those without such features (ie, standard infusion reactions [SIRs]). This approach is intended to identify patients at risk for anaphylaxis upon re-exposure, regardless of the severity of the initial reaction.

Patients with even mild symptoms of mast cell/basophil activation (eg, urticaria and dyspnea) must be treated with caution, because re-exposure to the causative agent could result in a fulminant and severe anaphylaxis. One of the authors (MC) is aware of unpublished cases in which failure to recognize anaphylaxis and manage it appropriately led to fatalities upon re-exposure to the causative drug, despite the premedications and reduced infusion rates that would have adequately managed most SIRs.

Thus, oncologists and other specialists working with chemotherapy drugs (eg, rheumatologists) should be familiar with the characteristics of anaphylactic reactions and manage these rare reactions differently from SIRs. We recommend that patients with even mild signs or symptoms of anaphylaxis not be re-exposed to the causative agent until they have been evaluated by an allergy specialist with experience in drug allergy and desensitization [3]. In particular, these patients should NOT be considered candidates for additional premedication and an attempt at drug readministration using a slower rate of infusion.

Anaphylaxis — Anaphylaxis is defined as a serious allergic or hypersensitivity reaction that is rapid in onset and may cause death [4,5]. The diagnosis is based on clinical signs and symptoms (table 3) [4]. (See 'Signs and symptoms of anaphylaxis' above and 'Agents associated with anaphylaxis' below.)

A common diagnostic mistake is equating anaphylaxis with anaphylactic shock and failing to recognize milder forms of anaphylaxis. Anaphylactic shock is the extreme end of a spectrum, but the goal should be recognition and appropriate management of anaphylaxis in its milder forms, when it is more amenable to treatment and interventions can be undertaken to prevent subsequent, more severe reactions. For example, a patient who develops limited urticaria and mild wheezing after receiving a cytotoxic agent meets diagnostic criteria for anaphylaxis (table 3).

If an infusion reaction includes signs and symptoms of anaphylaxis, administration of the drug should be stopped immediately. The patient should not be considered a candidate for premedication or drug readministration at a slower rate of infusion [6]. Instead, referral to an allergist should be arranged. In the future, the patient will either need to be changed to a different and non-cross-reacting drug or receive the drug that caused the reaction through a desensitization procedure.

Mechanisms — Anaphylaxis was traditionally defined as a constellation of symptoms and signs that arose from an IgE-mediated reaction that resulted in widespread activation of mast cells and basophils throughout the body and massive release of vasoactive mediators, including histamine and tryptase. However, the definition was subsequently broadened to include any mechanism that causes widespread activation of these cells, which can sometimes involve additional cell types [7].

In classic IgE-mediated anaphylaxis, repeated exposure to a medication, such as a platinum drug, results in sensitization, or the production of drug-specific IgE antibodies, in susceptible individuals. The IgE antibodies then coat the surface of mast cells and basophils, binding to surface IgE receptors. When the drug is given again, the surface-bound IgE binds the drug, resulting in crosslinking of the surface IgE receptors, triggering an activation cascade. IgE-mediated anaphylaxis can also occur with a first exposure, presumedly due to previous IgE sensitization to cross-reactive substance. Carboplatin is an example of a drug that causes classic IgE-mediated anaphylaxis.

In the broader definition of anaphylaxis, mast cells and basophils can become activated through additional non-IgE-mediated mechanisms, or other immune cells, including T lymphocytes and macrophages, may be predominantly responsible, releasing cytokines in addition to vasoactive mediators [7,8]. Examples of chemotherapy agents that cause reactions through these other mechanisms include oxaliplatin and taxanes.

Evaluation of anaphylaxis — Evidence that a reaction was anaphylaxis can be obtained from blood tests collected at the time of the reaction and from skin testing, a technique employed by allergy specialists to identify drugs which are capable of causing mast cell activation, especially through IgE-mediated immune mechanisms. These two diagnostic tools are discussed in this section.

●Serum tryptase to support the diagnosis of anaphylaxis – Mast cells and basophils contain various chemical mediators that are transiently released into the circulation during anaphylaxis. Serum total tryptase is the laboratory test that is most useful because it is nearly exclusively released by mast cells and basophils. An elevation in tryptase following a reaction provides evidence that mast cells and basophils were involved. Tryptase levels usually peak within three hours of the onset of symptoms, so blood should be drawn one to three hours after the reaction occurs. Blood drawn ≤30 minutes from the onset of symptoms may be falsely negative. Blood can be collected in a standard red top tube and serum should be frozen (at zero degrees Celsius) if it cannot be assayed promptly. Tryptase in frozen serum is stable for up to one year. Note that elevations in tryptase are not seen in all episodes of anaphylaxis, so the absence of this finding does not exclude anaphylaxis.

The upper limit of normal for serum total tryptase is approximately 11 ng/mL, depending on the assay system. A clinically significant elevation is defined as a 20 percent increase over baseline + 2 ng. The equation for calculating a significant increase in tryptase is ≥(1.2 x baseline tryptase level + 2 ng) [9]. Elevations in anaphylaxis can range from marginally elevated to greater than 1000 ng/mL. Note that in patients with low normal baseline tryptase levels, a significant elevation can be present even if the post-event tryptase is <11 ng/mL. For example, if a patient's baseline tryptase is 3 ng/mL, any increase above (1.2 x 3 ng/mL + 2 ng/mL) or 5.6 ng/mL is considered significant. The patient's baseline level can be assessed after symptoms have resolved for at least 24 hours. The interpretation of tryptase levels in anaphylaxis is discussed separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

A genetic condition called hereditary alpha tryptasemia, identified in 2014 and present in up to 6 percent of the general population, is associated with more severe anaphylaxis and may be important to identify in patients with chemotherapy-induced reactions. (See "Hereditary alpha-tryptasemia".)

●Skin testing to evaluate anaphylaxis – Skin testing is a technique used by allergy specialists to determine if a drug is capable of activating mast cells in the skin and therefore potentially able to cause anaphylaxis if administered systemically. The utility of skin testing is best established in the evaluation of reactions to the platinum drugs and may be useful in some patients with paclitaxel reactions (although this is not routine practice). If a patient's reaction was suggestive of anaphylaxis but tryptase levels were not elevated, skin testing may still be informative. (See 'Skin testing' below and 'Drug versus vehicle' below.)

USE OF PREMEDICATION TO PREVENT INFUSION REACTIONS — Premedication can help prevent and/or reduce the severity of infusion reactions, particularly standard infusion reactions (SIRs). In contrast, premedication does not prevent anaphylaxis in most cases, although the severity of the reaction may be reduced.

Pharmacologic prophylaxis with antihistamines, glucocorticoids, or both is recommended for certain drugs that have a high incidence of infusion reactions (eg, paclitaxel, cabazitaxel, asparaginase). Antihistamines (H1 and H2 receptor antagonists) are used to proactively reduce the effects of histamine, one of the many mediators released by mast cells when they become activated, although they do not prevent mast cell activation and all its other resultant effects. Glucocorticoids suppress the activation and proinflammatory functions of many types of immune cells, although they cannot prevent mast cell activation or anaphylaxis and are not recommended as first-line treatment for anaphylaxis. There is evidence for increased side effects from steroids when used at high doses for the prevention or treatment of anaphylaxis, without demonstrated benefits. Most premedication regimens have been derived empirically rather than established through randomized trials. Because premedication is not completely protective, even for SIRs, it is important to monitor patients closely during and immediately after all chemotherapy infusions. Specific prophylactic regimens that are recommended for individual drugs are discussed below.

PRINCIPLES OF TREATMENT AND RECHALLENGE — Clinicians should be prepared for an infusion reaction to occur during each drug administration, and standing orders should be in place to allow immediate intervention if symptoms occur, without waiting for the clinician [10]. Medical equipment and supplies needed for resuscitation (pharmacologic agents such as epinephrine, antihistamines, intravenous fluids, and aerosolized bronchodilators as well as oxygen, tracheostomy equipment, and a defibrillator) should be readily available in any area where chemotherapy is administered.

Treatment of an infusion reaction and possible rechallenge depends upon the type and severity or the reaction.

Treatment of mild to moderate standard infusion reactions — Mild to moderate standard infusion reactions (SIRs; ie, National Cancer Institute [NCI] grades 1 and 2 and infusion reactions that do not involve symptoms of anaphylaxis (table 1)) are the most commonly encountered reactions. These can usually be managed with temporary interruption of the infusion and symptom management. (See 'Characteristics of reactions' above.)

Rechallenge — After all symptoms have resolved, rechallenge with a reduced infusion rate and additional premedication is usually successful, with the important exception of patients treated with platinum agents. We do not recommend rechallenging patients with platinum agents, even with additional premedications. Instead, we advocate referral to an allergist for skin testing. If skin testing is positive, the patient should either avoid any future exposure to the drug or receive it only through a desensitization protocol.

For patients who have recurrent SIRs despite premedication, desensitization protocols have allowed for continued use of the drug in some cases. Referral to an allergy specialist with experience in drug desensitization is an option for such patients, as a wider range of desensitization techniques can be considered [3].

Treatment of anaphylaxis and severe standard infusion reactions — Reactions with any features of anaphylaxis (table 2) or severe SIRs (NCI grade 3 or higher (table 1)) require discontinuation of the drug infusion and immediate treatment with epinephrine and antihistamines.

Prompt recognition and treatment are critical in anaphylaxis. In series of fatal anaphylaxis from all causes, death typically ensues within 30 minutes from exposure to the trigger. Detailed guidelines for the management of anaphylaxis are available from the Joint Council of Allergy, Asthma, and Immunology, which are summarized in a rapid overview table for adults (table 4) and children (table 5) [4]. Similar recommendations have been made in the American Heart Association (AHA) Advanced Cardiac Life Support (ACLS) guidelines [11]. (See "Anaphylaxis: Emergency treatment".)

The initial management of anaphylaxis includes the following:

●Stop the infusion of the suspect medication

●Placement of the patient in the recumbent position to maintain blood flow to vital organs

●Intramuscular injection of epinephrine  (table 4 and table 5) in the lateral aspect of the quadriceps muscle

●Call for help (summon a resuscitation team in the hospital setting, call 911 or an equivalent service in the community setting)

●Supplemental oxygen

●Volume resuscitation

●Intravenous antihistamines (table 4 and table 5)

Rechallenge after a severe standard infusion reaction — Following a severe SIR (NCI grade 3 or higher (table 1)), rechallenge is usually discouraged. This is particularly true if the SIR included any symptoms suggestive of an allergic reaction, such as urticaria or angioedema [6]. In most cases, the mechanism of severe SIRs is not known, and so it is difficult to predict the best technique for preventing recurrence. If a patient is felt to be a candidate for continuation of therapy because there is potential clinical benefit of further treatment and no other reasonable alternatives exist, then we suggest desensitization, as this technique offers the most graduated and controlled manner of administration. At the author's institution (MC), these reactions are managed in the same manner as anaphylaxis, with uniformly good outcomes [7,12]. (See 'Management after anaphylaxis' below.)

Management after anaphylaxis — Rechallenge should not be attempted for suspected anaphylaxis. The platinum drugs, which are strongly associated with IgE-mediated anaphylactic reactions, cause recurrent reactions upon rechallenge in approximately 50 percent of cases. Instead, we suggest referral to an allergy specialist with experience in drug desensitization [3]. With rare exception [13], oncologists lack the expertise to evaluate and manage these patients by themselves.

Mast cells and basophils, the cells involved in anaphylaxis, can be temporarily hyporesponsive immediately after a reaction and may be unable to be activated further. This phenomenon has probably contributed to the confusion that currently exists in the medical literature about the safety of rechallenge following severe infusion reactions. However, this phenomenon is unpredictable, and the patient is at high risk for a recurrence of anaphylaxis as soon as the cells have recovered their sensitivity, a process which takes days to weeks. Therefore, we do not recommend that patients be rechallenged after a reaction with symptoms of anaphylaxis.

Overview of skin testing — Skin testing (using the prick/puncture and intradermal methods) is the primary diagnostic tool used by allergists to evaluate patients who have experienced an infusion reaction that included any symptoms suggestive of possible anaphylaxis. When indicated, skin testing is generally performed by allergy/immunology specialists, with specific training in the technique, proper interpretation of results, and management of the rare allergic reactions that occur in response to the testing itself.

Skin testing with chemotherapy agents is best characterized for the platinum drugs and taxanes, as discussed below. (See 'Platinum drugs' below and 'Taxanes' below.)

Skin testing with other chemotherapy drugs can also be performed, provided the drug is not a vesicant or known to cause skin necrosis upon extravasation (table 6). In contrast, drugs with irritant properties can be used for skin testing, but this must be done carefully, with dilutions of the drug that have been shown to be nonirritating to the skin. (See "Extravasation injury from cytotoxic and other noncytotoxic vesicants in adults".)

Allergists perform prick/puncture tests first, followed by intradermal tests if the prick/puncture tests are negative. This is done because prick/puncture testing is less likely to induce a systemic allergic reaction in highly sensitive patients and also less likely to produce false positive, irritant responses. If prick/puncture testing is negative, then intradermal testing is performed. Intradermal testing delivers more drug to cutaneous mast cells and is therefore more sensitive than prick/puncture testing. Appropriate positive (eg, histamine) and negative (saline or diluent for the therapeutic agent) must always be included.

In patients who have experienced a significant infusion reaction or anaphylaxis, skin testing is usually deferred for at least one to two weeks, since false negative results are possible immediately after a severe reaction due to hyporeactivity of cutaneous mast cells [14]. However, in patients with nonanaphylactic symptoms, testing may be performed sooner if necessary, since positive tests are still meaningful. The technique of skin testing is discussed in detail separately. (See "Overview of skin testing for IgE-mediated allergic disease".)

●Positive skin test results indicate that the patient is at significant risk for anaphylaxis if the drug is given again without precautions. Desensitization should be performed before readministration of the agent if there is no equivalent substitute therapy.

●Negative skin test results indicate that the drug in question could be readministered through a graded challenge protocol, with additional premedications.

Overview of desensitization — Desensitization involves readministration of the implicated drug in a highly controlled manner using a series of sequential steps in which the dose is gradually increased. Desensitization is indicated for infusion reactions that have features of anaphylaxis. The technique can also be applied to severe SIRs that recur despite slower rates of infusion and premedications. Important points regarding this technique include:

●Desensitization is absolutely contraindicated in patients with a history of chemotherapy-induced blistering or exfoliative dermatitis, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Re-exposure in this setting can induce a fatal recurrence. (See "Cutaneous adverse effects of conventional chemotherapy agents".)

●Desensitization is not effective in preventing the recurrence of other idiosyncratic immunologic reactions such as serum sickness, hemolytic anemia, or drug fever.

●Desensitization should only be carried out under close medical supervision by experienced individuals who are comfortable with emergency management of anaphylaxis. In our view, all desensitization protocols should be performed by allergists, although as noted above, there are rare institutions at which experienced oncologists handle desensitization protocols by themselves [13].

Drug desensitization protocols are based upon stepwise administration of increasing doses of medication, such that exposure begins at very low doses, increases gradually, and is uninterrupted. The protocols presented herein have been performed successfully in published reports, although modifications may be needed in individual cases, and experience with the technique is invaluable. Symptoms during the desensitization procedure are usually mild and occur most often during the final step [12]. Clinicians should avoid altering successful protocols to render them faster or significantly change the time interval between doses. Faster protocols may be acceptable for some types of infusion reactions, but are less likely to be successful in patients with IgE-mediated anaphylaxis [15]. Therefore, the authors suggest not using abbreviated protocols to desensitize to agents (such as the platinum drugs) in which an IgE-mediated mechanism has been implicated in infusion reactions.

Desensitization induces a state of temporary tolerance to a drug that is dependent on continuous exposure. The state of tolerance is lost once the drug is cleared. Therefore, patients must be counseled that they remain allergic to the drug and must be desensitized for each subsequent administration.

At some institutions, initial desensitizations are carried out in the medical intensive care unit, although there is accumulating evidence that desensitizations for any severity of hypersensitivity reaction can be safely performed at outpatient facilities under the care of allergists and experienced nurses [16]. If the procedure is well tolerated, subsequent desensitizations can be performed on standard hospital floors or in hospital-associated infusion units with one-on-one nursing, using established policies and procedures, and after appropriate training of the nursing staff on desensitization procedures. Patients without cardiac comorbidities and with mild initial reactions can undergo their first desensitization in an outpatient facility, under the supervision of the allergist and with one-to-one nursing care.

AGENTS ASSOCIATED WITH ANAPHYLAXIS — The platinum drugs and the taxanes are the chemotherapeutic agents that most commonly cause anaphylaxis. However, any drug can cause anaphylaxis in a susceptible individual, and reactions with features of anaphylaxis have been reported with asparaginase, cytarabine, cyclophosphamide and ifosfamide, procarbazine, and ixabepilone. (See 'Signs and symptoms of anaphylaxis' above.)

PLATINUM DRUGS

Incidence and characteristics of reactions — The platinum drugs have all been associated with anaphylaxis, particularly after repeated cycles. The overall incidence ranges from 10 to 27 percent and typically occurs after the patient has completed an initial course of treatment, experienced a disease recurrence, and resumed therapy with the same platinum agent, or following at least six to seven cycles of continuous treatment.

●Immediate reactions – Most infusion reactions with the platinum drugs (cisplatin, carboplatin, and oxaliplatin) are classic type I IgE-mediated allergic reactions, which are also called immediate reactions. With the platinum drugs in particular, common symptoms of mild immediate reactions are pruritus (especially of the palms and soles), flushing, and sometimes urticaria. More severe immediate reactions can start with these same mild symptoms, but progress to include nausea, abdominal bloating and/or diarrhea, chest tightness, throat tightness, hypotension, and desaturation (table 3).

●Delayed reactions – A few cases of type II (immune-mediated hemolytic anemia or thrombocytopenia) and type III reactions (delayed vasculitic urticaria) have been described with platinum drugs (table 7) [16-25]. Skin testing and desensitization have no role in type II and III reactions, and the causative drug should be avoided in the future.

Premedication — Most centers do not routinely administer premedication before infusion of cisplatin, carboplatin, or oxaliplatin because of the lack of data demonstrating that any premedication regimen successfully prevents infusion reactions. However, with oxaliplatin, the available data regarding benefit from a prophylactic regimen are conflicting:

●In one series of 272 patients receiving oxaliplatin, 48 patients (18 percent) developed infusion reactions despite the use of a primary prevention regimen of famotidine and dexamethasone (8 mg) prior to all treatment cycles (with the addition of diphenhydramine after cycle 4) [26].

●Other investigators have suggested benefit from higher doses of dexamethasone in conjunction with an H1 plus an H2 receptor blocker [27]. In a retrospective cohort study of 181 patients receiving oxaliplatin plus short-term infusional FU (the FOLFOX regimen) for colon cancer, one cohort received standard premedication (dexamethasone 8 mg plus granisetron) prior to chemotherapy while a second cohort received higher doses of dexamethasone (20 mg) plus diphenhydramine (50 mg) and famotidine (20 mg) in addition to granisetron, starting with the sixth cycle of chemotherapy. The cohort receiving additional premedication had a lower incidence of hypersensitivity reactions (7 versus 20 percent), and the median number of treatment cycles increased from 9 to 12.

Although increased premedication with dexamethasone may decrease the rate of hypersensitivity reactions, patients who react to oxaliplatin need to be skin tested and evaluated for desensitization because increased premedication does not prevent anaphylaxis.

Carboplatin and cisplatin — The overall incidence of infusion reactions (of all types) with carboplatin is approximately 12 percent [1]. The incidence is higher with repeated courses of therapy. The characteristics of infusion reactions to carboplatin are typical of anaphylaxis, with pruritus (particularly of the palms and soles), flushing, urticaria, facial swelling, wheezing, chest tightness, dyspnea, abdominal cramping, and hypotension [1,28-30]. Patients may also report "not feeling right" or a sense of impending doom. One series described a case in which isolated chest pain progressing to cardiac arrest was the only detectable symptom [31]. We have had two similar cases referred to our center, in which patients reacted to carboplatin infusions with flushing and syncope followed by cardiac arrest (unpublished data).

The incidence of infusion reactions with cisplatin is not as well reported. In early trials, incidence rates were between 5 and 14 percent [32,33]. As with carboplatin, the incidence is higher in patients who receive a greater number of courses [34] and possibly in those undergoing concomitant cisplatin-based chemoradiotherapy, for unclear reasons [35]. Some authors suggest that incidence rates have declined over time [36]. Multiple factors may have contributed:

●Current regimens commonly include pretreatment glucocorticoids as a routine component of the antiemetic regimen, particularly with cisplatin. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

●In common diseases such as lung cancer, there is an appreciation that patients require fewer cycles of cisplatin and/or carboplatin to achieve therapeutic end points than the number they may have received in the past. Many patients receive no more than four to six cycles of treatment, which is associated with a lower rate of infusion reactions [1].

Higher-risk groups — Patient groups at higher risk for reactions to carboplatin include individuals with relapsed disease, those with BRCA mutations, and children with brain tumors.

●Patients with relapsed disease – The incidence of infusion reactions increases with repeated drug exposure [1]. A common scenario is a reaction developing after a patient with epithelial ovarian cancer has completed a first course of therapy (often six cycles of a platinum-containing regimen), and restarted treatment with the same regimen at the time of a disease recurrence. Typically, this corresponds to the seventh to tenth exposure to the drug [1,12,28,37,38]. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

One center described an approach that appeared to prevent/delay infusions reactions to carboplatin in women without a history of platinum-induced infusion reactions, but who were at high risk because they required retreatment with platinum drugs for relapsed ovarian and related cancers [39]. In this retrospective series, patients received carboplatin using a graduated infusion protocol that was essentially a short desensitization (1 percent of the total dose in the first hour, 9 percent in the second hour, and 90 percent in the third hour), combined with premedications [39]. Premedications consisted of dexamethasone 20 mg the night before and again the morning of infusion, with diphenhydramine and ranitidine (each 50 mg intravenously [ranitidine is no longer available in the United States]) given immediately before infusion. In an analysis of 707 patients treated over a 10-year period in the outpatient setting, the incidence, timing, and severity of infusion reactions in 174 patients given the three-hour protocol with premedication were compared with those of 533 patients who continued to receive the usual 30-minute infusion. Infusion reactions occurred in a lower percentage of patients receiving the three-hour infusion (3.4 versus 11 percent) and the time to first infusion reaction was longer (16 versus 9 treatments).

Prospective confirmation of these results is needed to assess the true impact of these measures in an unselected high-risk patient population. Whether this approach reduces the previously noted high rates of infusion reactions in patients with inherited mutations in one of the genes associated with hereditary breast and ovarian cancer syndrome (BRCA 1 or 2) is unknown. (See 'Carboplatin and cisplatin' above.)

However, for patients requiring re-exposure to carboplatin for treatment of recurrent ovarian cancer, empiric use of this protocol is an alternative to continuing with a standard 30 minute platinum infusion. This approach has been adopted at a number of institutions. If the patient develops a hypersensitivity reaction with any symptoms suggestive of anaphylaxis despite this approach, rechallenge should not be attempted. Instead, the patient should be referred to an allergist with experience in drug desensitization or to an oncology center that can perform formal desensitizations. (See 'Risks of rechallenge without desensitization' below.)

●Patients with BRCA mutations – Clinicians should have a heightened sense of awareness for infusion reactions in women with inherited mutations in one of the genes associated with hereditary breast and ovarian cancer syndrome (BRCA 1 or 2), as they appear to have a higher risk for carboplatin infusion reactions, and reactions occur at a lower cumulative exposure [40,41]. This was shown in an analysis of 87 patients with ovarian cancer treated with carboplatin plus olaparib on two different clinical trials [40]. Of the total 29 patients who developed an infusion reaction while receiving carboplatin, 93 percent had a deleterious BRCA mutation. When patients were categorized according to BRCA status, 48 percent of those with a deleterious mutation had a history of an infusion reaction compared with 6 percent of those without a BRCA mutation. Mutation carriers also had an onset of carboplatin infusion reaction at significantly lower cumulative dose exposure (figure 1). (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)

●Children with brain tumors – A 42 percent incidence of infusion reactions has been noted in children receiving carboplatin for brain tumors [37].

Oxaliplatin — The incidence of infusion reactions with oxaliplatin seems to be increasing over time, perhaps the result of increasing clinical use for colorectal cancer [26,42,43]. Oxaliplatin infusion reactions may occur within minutes of drug administration and with any cycle of therapy. However, as with cisplatin and carboplatin, the incidence increases with multiple courses of therapy [19,24,44]. Most of the severe reactions represent anaphylaxis. Milder reactions can present as pruritus, fever, chills, and urticaria [25].

In several large series, acute infusion reactions were reported in 12 to 25 percent of patients treated with oxaliplatin; up to one-third were severe (ie, grade 3 or worse (table 1)) [24,26,42,45-47]. In the largest report, 308 of 1224 (25 percent) patients developed symptoms compatible with an oxaliplatin reaction, as verified by the development of similar symptoms on rechallenge [24]. Observations based on this series included:

●Most reactions occurred after the first five treatment courses (median nine, range 1 to 24).

●The majority of patients (63 percent) had mild reactions, characterized by pruritus and small area of erythema developing during the infusion or within several hours of receiving treatment. All patients with mild reactions were able to tolerate continued treatment with additional premedication.

●Severe reactions occurred in 37 percent and were characterized by diffuse erythroderma, facial swelling, chest tightness, bronchospasm, and decrease in blood pressure, which developed within minutes of drug infusion. Although rechallenge with a lower rate of drug infusion and two to three days of premedication was attempted in these patients, fewer than one-half tolerated an additional two to four courses of therapy; the remaining patients required treatment discontinuation because of recurrence of severe reactions. Desensitization was not attempted.

Other apparently immune-mediated reactions have also been reported with oxaliplatin, including acute immune thrombocytopenia, immune hemolytic anemia, Evans syndrome, and possible drug-induced thrombotic microangiopathy [24,25,48,49] (see "Drug-induced thrombotic microangiopathy (DITMA)"). Collectively, fewer than 65 such reactions have been reported. Patients may develop fever, chills, lower back pain, hematuria, and/or bleeding, most commonly during or within 24 hours of the last infusion. Reported laboratory abnormalities include thrombocytopenia, anemia, increased bilirubin and creatinine, low haptoglobin, and proteinuria. Direct Coombs tests and antiplatelet antibodies are variably positive [49]. Following immediate oxaliplatin discontinuation, fluids, and glucocorticoids, some patients recovered over days to weeks, while others required transfusions of platelets or red blood cells, or hemodialysis, and followed a more protracted course. A small number of fatalities have been described [20,50-52]. It is not clear if there are common pathogenic mechanisms underlying these reactions, but an awareness of this spectrum of disorders related to oxaliplatin is important. Patients with these types of reactions should not receive oxaliplatin again.

It is also important to keep in mind that reactions during oxaliplatin therapy may be caused by concomitantly administered drugs. Many protocols administer oxaliplatin concurrent with fluorouracil and leucovorin (eg, oxaliplatin plus leucovorin and short-term infusional fluorouracil [FU], the FOLFOX regimen). In these regimens, leucovorin and oxaliplatin are usually administered simultaneously. In some cases, a presumed oxaliplatin infusion reaction in fact represents a hypersensitivity reaction to leucovorin. Referral to a drug allergy expert for skin testing and possible drug provocation testing is advised for patients treated with concurrent oxaliplatin and leucovorin if the results would alter the treatment plan. This might be the case if continuation of oxaliplatin with a different chemotherapy partner such as capecitabine would be considered if leucovorin was deemed responsible for the infusion reaction, or if a second-line chemotherapy regimen is being considered that also contains leucovorin (eg, irinotecan plus leucovorin and short term infusional FU, FOLFIRI). (See 'Leucovorin' below and "Initial systemic therapy for metastatic colorectal cancer", section on 'Capecitabine doublets' and "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'The cytotoxic chemotherapy backbone'.)

There is some evidence that exposure to oxaliplatin caused patients to become sensitized to carboplatin and/or cisplatin, and cross-reactivity has been demonstrated among the three platinum agents (although cisplatin has been safely administered to patients with carboplatin hypersensitivity) [53]. It is not recommended to switch platinum agents after a reaction to one without assessing skin test reactivity [54]. (See 'Cross-reactivity among platinum drugs' below.)

Risks of rechallenge without desensitization — In most (but not all [30]) reports, at least 50 percent of patients who develop an infusion reaction to a platinum agent will react again if rechallenged, even after additional premedication [37,42-44], and fatalities have been reported [55,56]. In our view, patients with any symptoms suggestive of anaphylaxis should not be rechallenged, but instead, be referred to an allergist with experience in drug desensitization or to an oncology center with similar experience (see below).

Rechallenge should be restricted to patients with mild to moderate reactions that do not include features of anaphylaxis. However, even mild reactions can escalate to severe reactions, underscoring the need for close monitoring during rechallenge. Rechallenge can be preceded by premedication with glucocorticoids plus an H1- (eg, diphenhydramine, 50 mg) and H2-histamine receptor blocker (eg, famotidine 20 mg) 30 minutes prior to infusion. In addition, a slower infusion rate (over three to six as compared to two hours) should be used [26,45].

Evaluation and management of patients with possible anaphylaxis — Patients receiving platinum drugs who have infusion reactions with any features of anaphylaxis should not receive further drugs until they have been evaluated by an allergy specialist with experience in drug allergy, skin testing, and desensitization [3]. If referral to an experienced allergist is not possible, then the oncologist may either refer the patient to an oncology center with experience in skin testing and desensitization or change the patient's therapy to an alternative agent, if a reasonable alternative exists.

Tryptase is elevated in all the cases of anaphylaxis to carboplatin and it is a very useful marker if desensitization is being considered. If serum tryptase was collected at the time of the reaction and is elevated above the patient's baseline, then it can be assumed that the patient had had anaphylaxis. Elevated tryptase indicates mast cell activation with or without IgE, and such patients may not need skin testing and should only receive the platinum agent again using a desensitization protocol. (See 'Evaluation of anaphylaxis' above.)

Skin testing — In patients who have had an infusion reaction (of any severity), skin testing reliably predicts the majority of anaphylactic reactions to platinum-type drugs, and patients who have a positive skin test should not be rechallenged without use of a desensitization protocol because the next reaction could be more severe.

Skin testing protocols have been developed to identify patients who are at risk for platinum-induced anaphylaxis and are most useful in centers at which allergists and oncologists collaborate closely [29,57-62]. Skin testing is generally performed by allergy/immunology specialists, with specific training in the technique, proper interpretation of results, and management of the rare allergic reactions that occur in response to the testing itself. (See "Overview of skin testing for IgE-mediated allergic disease".)

Techniques and timing — Prick/puncture testing is performed first. If this is positive, then reactivity is confirmed and no further skin testing is required. If prick/puncture testing is negative, then intradermal testing is performed with 0.02 mL of the same drug concentration used for prick/puncture initially. If this is negative, it is followed by 0.02 mL of a 10-fold stronger concentration. Concentrations for each platinum drug are specified below:

●For carboplatin, prick/puncture testing is performed with 10 mg/mL, which is equivalent to the concentration at which the drug is infused. If the patient's history suggests extreme sensitivity, prick/puncture testing is performed with lower concentrations first (eg, 1 mg/mL or lower) [29,63]. If prick/puncture is negative, intradermal testing is then performed with 1 mg/mL. If this is negative, intradermal testing is performed with 10 mg/mL, although some protocols use maximal concentrations of 3 or 5 mg/mL, and the optimal concentration has not been determined.

●For cisplatin skin testing, maximal concentrations of 1 mg/mL are used for both prick/puncture testing and intradermal testing [12].

●For oxaliplatin skin testing, maximal concentrations of 3 to 5 mg/mL are used for both prick/puncture testing and intradermal testing [12,64].

●The timing of skin testing is important because two different errors are possible [65,66]. After a severe reaction, which involves massive mast cell degranulation, the patient's mast cells may be temporarily desensitized or significantly less reactive while intracellular granules are refilling with mediators, resulting in false negative skin test results. Thus, it is best to wait at least four weeks after a severe reaction to perform skin testing. However, if the testing is performed sooner and is positive, the results should be reliable. It is also important not allow too much time to elapse after a reaction before performing skin testing, because drug-specific IgE can drop to low levels over time, also yielding false negative skin tests [67]. Therefore, we try to perform skin testing no longer than six months from the time of the reaction. For patients with very severe reactions and skin testing that was negative but was performed more than six months after the reaction, we worry that the result could be falsely negative, and we give the next dose using a graded challenge protocol, for added safety, as described in the next section.

Interpretation — In patients with past immediate infusion reactions to platinum drugs, the results of skin testing, combined with the severity of the past reaction, are used to determine future management [59,60]:

●A positive supports the diagnosis of platinum-induced anaphylaxis. Nearly all patients with past reactions that were consistent with moderate to severe IgE-mediated immediate allergy will have a positive skin test. Although not every patient with a positive skin test will react if given the drug again [68], we believe that all patients with positive skin testing should only receive the drug by desensitization in the future because platinum hypersensitivity reactions can be severe and even fatal [55,56]. (See 'Desensitization protocols' below.)

Once a patient has developed an immediate allergy to a platinum drug, the allergy generally persists. If the patient is not exposed to the drug for several years but then requires it again for relapsed disease, we perform skin testing again before administration if there is time. The skin test may have converted to negative, and if this is the case, the patient can receive the drug normally for the first one or two cycles. However, the patient must be watched carefully for recurrent allergy (even mild symptoms), because it is likely to reappear after two or three cycles of treatment, at which point skin testing should be performed again to guide further treatment.

●The negative predictive value of skin testing was estimated at 92 percent for platinum drugs in general in one large study [14]. It was 100, 89, and 87 percent for cisplatin, oxaliplatin, and carboplatin, respectively. However, if more than six months has elapsed between the reaction and skin testing, the negative predictive value is lower [67]. (See 'Techniques and timing' above.)

If the patient's past infusion reaction was moderate to severe and suggestive of anaphylaxis, but skin testing to the platinum drug involved was negative, the details of the case should be re-examined carefully to determine if another agent may have been given in close proximity to the platinum (eg, leucovorin). If so, an infusion reaction to the other drug should be considered. (See 'Leucovorin' below.)

If no other agent can be implicated, we recommend empiric desensitization to the platinum drug.

If no other agent can be implicated and the past reaction was mild, then patients with negative skin tests can receive the platinum drug again using a graded challenge (also called a drug provocation test). (See 'Graded challenge (drug provocation testing)' below.)

Utility of skin testing in patients without reactions — At a few centers, skin testing has been performed in patients who have received multiple courses of carboplatin therapy but have not actually had an infusion reaction, in an effort to identify patients who may react in the future [58,59]. This is not our approach. Although a positive skin test result with platinum drugs may identify patients at higher risk to develop a later infusion reaction, not all patients with positive skin tests will develop reactions, and we have been able to manage patients safely by intervening only after symptoms have appeared. Patients who have been exposed to other platinum agents and need to be treated with a different one need skin testing before exposure due to potential cross-reactivity, as described above.

The largest study of this approach included 126 patients who were skin tested with an intradermal injection of 0.02 mL of an undiluted aliquot of the carboplatin preparation for infusion, performed 30 minutes prior to each planned dose [59]. All patients had gynecologic malignancies and had received at least six cycles of platinum-based chemotherapy. A positive skin test was defined as a wheal ≥5 mm in diameter with a surrounding flare (although allergy specialists typically define a positive test as a wheal ≥3 mm larger than the negative control).

Thirty-nine patients (31 percent) had a positive skin test. Six of seven patients (86 percent) with a positive skin reaction who elected to proceed with carboplatin infusion developed an infusion reaction, compared with only 7 of 87 (8 percent) who had a negative skin test. Of the 39 patients with positive skin tests, seven others elected to undergo rechallenge using a desensitization protocol, of which six were successful. Thus, a negative test was associated with the absence of a reaction with subsequent administration, while a positive test result indicated increased risk for an infusion reaction with subsequent doses [58,59].

Graded challenge (drug provocation testing) — At the authors' institutions, graded challenges are performed by giving patients 1/10 of a full dose (at normal concentrations and at the normal infusion rate), without premedications, followed by 30 minutes of observation. If no symptoms develop, the remaining 9/10 of the dose is given normally. If this is tolerated, it proves that the patient is not allergic at that point in time, and can continue to receive the drug normally in the future, although providers should remain vigilant for signs of reactions in these patients, particularly after multiple exposures. Other centers have published results of a similar but simplified approach, in which the challenge was not graded [68], although we believe a graded approach is safer because fatalities have been reported with re-exposure to these drugs [55,56]. (See 'Rechallenge' above.)

If skin testing is not available — If a patient has experienced an infusion reaction to a platinum drug and evaluation by an allergy specialist is not possible, then the patient should be assumed to be at risk for anaphylaxis. The patient should either be treated with an alternative chemotherapy agent or only receive subsequent doses of the platinum drug in question using a formal desensitization protocol. If evaluation by an allergy specialist is not possible, and there is no reasonable alternative drug, then patients with infusion reactions that have any features of anaphylaxis (regardless of severity), patients with severe (ie, grade 3 or worse (table 1)) standard infusion reactions (SIRs), and patients with mild/moderate SIRs that recurred despite premedication and slower rate should be assumed to be at risk for anaphylaxis and only receive subsequent doses of the platinum drug in question using a formal desensitization protocol.

Desensitization protocols — Clinical indications and general principles of desensitization are discussed above. As mentioned previously, desensitization induces a temporary state of tolerance and must be repeated each time the patient requires the same drug in the future. (See 'Overview of desensitization' above.)

Patients with positive skin testing after an infusion reaction to a platinum drug should only receive that platinum drug again using a desensitization protocol. Desensitization protocols for platinum drugs have been developed independently by allergists (table 8) [12,29,63] and by oncologists (table 9A-B) [1,34,69-71]. The authors do not suggest using abbreviated protocols for platinum drugs [15], and longer protocols (or more dilute starting solutions) may occasionally be needed [72]. Although there is less experience, desensitization protocols modeled upon those used for carboplatin have been used successfully to permit continued oxaliplatin treatment [23,46,57,73,74].

Cross-reactivity among platinum drugs — Cross-reactivity based on clinical reactivity and/or skin testing between carboplatin and oxaliplatin has been estimated to be between 37 and 45 percent, while the cross-reactivity between cisplatin and the other two agents appears to be much lower [14,75]. Based on these findings, patients who have reacted to either carboplatin or oxaliplatin have the lowest risk of a repeat reaction if switched to cisplatin, provided the patient has never received cisplatin in the past [75]. However, one of the authors (MC) has encountered exceptions to this observation and performs skin testing to the platinum agent that is desired for the patient's future treatment in this situation, followed by desensitization if the skin test result is positive [76]. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Retreatment with carboplatin and risk of hypersensitivity reactions'.)

TAXANES — Paclitaxel and docetaxel are among the most widely used cytotoxic drugs. Premedication is routinely recommended to prevent infusion reactions. (See 'Premedication regimens' below.)

Paclitaxel and docetaxel

Characteristics of infusion reactions — Clinically, acute reactions to paclitaxel are characterized by dyspnea (with or without bronchospasm), urticaria, hypotension (or sometimes hypertension), and an erythematous rash (which may not begin until after the patient has returned home following drug infusion) [6]. Severe back, pelvic, chest, and crushing abdominal pain may also occur.

The clinical characteristics of docetaxel-related infusions reactions in a series of 102 cases included the following [77]:

●Facial flushing (80 percent)

●Chest discomfort/pain (67 percent)

●Back pain (51 percent)

●Tachycardia (45 percent)

●Erythematous rash (36 percent)

●Hypotension (25 percent)

●Pruritus/urticaria (20 percent)

●Facial swelling (18 percent)

With both drugs, symptoms usually develop within the first 10 to 15 minutes of drug infusion, and nearly 90 percent occur during the first or second drug infusion [30,34,78]. The timing of these reactions suggests that they are mediated by a direct release of mast cell mediators such as histamine and tryptase. These reactions can occur with later infusions, even if they have not occurred with previous doses [78].

Delayed reactions — An estimated 10 to 15 percent of hypersensitivity reactions to taxanes present as delayed cutaneous reactions, beginning a few days to 10 days after taxane infusion [14,79]. The use of premedications may impact when symptoms appear, with more extensive premedication resulting in a greater delay until symptoms appear. Delayed taxane reactions can range from mildly pruritic maculopapular eruptions to urticaria and angioedema to (less commonly) dyspnea. Most resolve in several days with symptomatic treatment.

It is important to ask about delayed reactions because they can be the prelude to subsequent acute infusion reactions, including anaphylaxis [6]. For this reason, significant delayed reactions, not only those involving urticaria and angioedema, but also maculopapular rashes, should be evaluated by allergists before the drug is readministered. Both types of delayed reactions have been observed in patients that subsequently develop severe infusion reactions.

Incidence with paclitaxel — In early trials, acute infusion reactions developed in up to 30 percent of patients receiving paclitaxel and were dose-limiting. After the introduction of methods to diminish the incidence and severity of infusion reactions (eg, prolonging the drug infusion, and premedication with antihistamines and glucocorticoids), the rate of severe reactions was reduced to 2 to 4 percent [78,80-82].

With appropriate premedication, the incidence of infusion reactions is approximately the same (1 to 3 percent) whether paclitaxel is administered over 24, three, or one hour [83,84]. However, the incidence may be higher with infusion times under one hour [85]. Even with appropriate premedication, mild reactions (skin rash, flushing) still occur in a substantial number of patients. (See 'Premedication regimens' below.)

Incidence with docetaxel — Based on differences in formulation, it was thought that the rate of infusion reactions with docetaxel would be less than with paclitaxel (see 'Mechanisms of infusion reactions' below). However, 30 percent of patients receiving docetaxel without premedication developed reactions [86]. Furthermore, even with standard premedication, potentially life-threatening infusion reactions occur in approximately 2 percent of docetaxel-treated patients [77,87,88]. Docetaxel-related fluid retention, which is not a true infusion reaction, is also discussed below (see 'Other idiosyncratic reactions' below).

Mechanisms of infusion reactions — The taxanes can cause both standard infusion reactions (SIRs) and anaphylaxis. To further complicate matters, there is evidence that both the taxane component and the vehicles used to solubilize these agents are capable of causing various types of infusion reactions. (See 'Drug versus vehicle' below.)

Among the proposed mechanisms underlying paclitaxel infusion reactions are complement activation, direct mast cell/basophil activation, and classic IgE-mediated anaphylaxis [89]. The mechanism underlying acute docetaxel infusion reactions is less well characterized [90].

Drug versus vehicle — It is uncertain whether the taxanes themselves or the vehicles in which they are dissolved are responsible for the majority of infusion reactions [91,92].

Paclitaxel is formulated in Cremophor, a vehicle that is common to other drugs that cause infusion reactions, such as cyclosporine, diazepam, propofol, and vitamin K [92]. Paclitaxel should probably be avoided in patients who have had a severe reaction to one of these drugs (although nabpaclitaxel may be used) (see 'Nabpaclitaxel' below). There is also some evidence that incomplete mixing of paclitaxel and Cremophor before administration may be at least partly responsible for first exposure reactivity [93].

There are multiple potential mechanisms for reactions to the taxane drugs, and this issue remains unresolved. Reactions to docetaxel have been attributed to the vehicle, polysorbate 80, the same vehicle used for etoposide [94] (see 'Etoposide' below). In animal models, polysorbate has been shown to induce histamine release and cause hypersensitivity reactions [95]. The United States Prescribing Information for docetaxel lists reactions to other drugs containing polysorbate 80 as a contraindication to administration. However, the drugs themselves may be capable of initiating infusion reactions, independent of the solvent [96,97].

Skin testing has been used for risk stratification, and patients with positive skin testing are candidates for desensitization. There is evidence that paclitaxel-sensitized patients can react to docetaxel, indicating a common sensitizing mechanism, and that patients reactive to paclitaxel need to be skin tested for both paclitaxel and docetaxel to be able to use docetaxel [79]. In addition, patients with positive skin testing to paclitaxel may react to non-Cremophor-containing paclitaxel preparations (eg, nabpaclitaxel). (See 'Nabpaclitaxel' below.)

Other idiosyncratic reactions

●Pneumonitis – In addition to the infusion reactions described above, there are multiple reports of acute, bilateral, transient pulmonary infiltrates developing during, within a few hours, or up to two weeks after paclitaxel administration. In one case in which the patient was subjected to intense investigation, paclitaxel (and not Cremophor) was judged responsible, and the mechanism appeared to be a cell-mediated (type IV) delayed reactions (table 7) [98]. A similar reaction has been reported rarely with docetaxel. (See "Taxane-induced pulmonary toxicity".)

●Docetaxel and fluid retention – Unlike paclitaxel, docetaxel has been associated with a fluid retention syndrome that is attributed to capillary leakage [82,99,100]. Fluid retention is cumulative.

Glucocorticoid premedication (dexamethasone 8 mg twice daily for 24 hours before and 48 hours following each docetaxel dose) reduces the incidence of severe cases of fluid retention from 20 to 6 percent, reduces the number of patients discontinuing treatment because of this adverse effect from 32 to 3 percent, and increases the median cumulative dose to onset of moderate to severe fluid retention from 490 mg/m² to 790 mg/m² [36,100,101]. Lower doses are needed for weekly treatment (see 'Premedication regimens' below).

●Docetaxel cutaneous toxicity – Docetaxel also causes skin toxicity that appears similar to acral erythema [102]. A unique variant, termed fixed erythrodysesthesia plaque, develops as a fixed, solitary plaque proximal to the infusion site that does not involve the palms or soles. It usually resolves with desquamation, leaving hyperpigmentation five to six weeks later.

These effects are more likely manifestations of direct skin toxicity than infusion reactions. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

Premedication regimens — Premedication with a glucocorticoid, as well as an H1 and H2 receptor antagonist, is recommended prior to paclitaxel. Premedication with a glucocorticoid alone is recommended prior to docetaxel.

Premedication with a glucocorticoid reduces but does not eliminate the risk of infusion reactions in patients receiving paclitaxel or docetaxel. At least one fatality despite premedication has been reported [103].

Paclitaxel

●Every three week regimens – For paclitaxel being administered every three weeks, conventional practice is to administer 20 mg of dexamethasone orally 12 and 6 hours prior to drug administration, with H1 and H2 receptor antagonists administered IV 30 minutes prior to drug infusion [104]. Using this approach, the rate of severe infusion reactions is only 1 to 2 percent, compared to 2 to 5 percent without treatment [105]. The nonsedating agent cetirizine may be substituted for diphenhydramine after the first two courses of treatment in the absence of an infusion reaction. At least some data suggest that prophylactic use of pemirolast, an oral mast cell stabilizing agent, may further decrease the incidence of paclitaxel-induced infusion reactions [106]. However, additional data are required to assess the role of this approach, and oral pemirolast is not available in the United States.

While this empirically derived three drug regimen has been a standard premedication for paclitaxel since its early development [80], there are no published trials that support benefit for an H2-receptor antagonist to prevent infusion reactions to paclitaxel. Benefit was called into question by a prospective but nonrandomized pre-post interventional noninferiority study of 366 Dutch patients undergoing a first cycle of outpatient paclitaxel for treatment of cancer; 183 initiating therapy between October 2018 and April 2019 were premedicated with a standard regimen containing ranitidine (a drug which has been withdrawn from the US market), while a subsequent cohort treated between April and December 2019 were treated without ranitidine [107]. The rate of infusion reactions of any grade was actually less in the group treated without ranitidine (20 versus 12 percent) as was the rate of severe infusion reactions ≥grade 3 (4.4 versus 1.6 percent). Whether these data apply to other regimens (eg, those containing famotidine) is unclear. In our view, the data are insufficient to be practice-changing.

Alternative glucocorticoid regimens have been proposed to reduce glucocorticoid exposure. The two-dose oral glucocorticoid regimen is preferred for most patients receiving the drug on an every three week basis unless there are extenuating circumstances. However, a single 20 mg dose of dexamethasone plus antihistamines can be administered intravenously 30 minutes prior to paclitaxel [91,108-110]. This shorter prophylactic regimen has been widely adopted. A single randomized trial demonstrated no difference in either the rate of infusion reactions or severe infusion reactions with a single-dose IV versus two-dose oral dexamethasone regimen [111], and another large retrospective analysis failed to find any correlation between dexamethasone dose and incidence of hypersensitivity reactions to either paclitaxel or docetaxel [112]. However, at least one direct comparison study showed a 10 percent higher rate of infusion reactions with one-dose IV compared with the two-dose oral regimen (17.3 versus 7.5 percent, respectively), although the majority were not severe [83]. Furthermore, a meta-analysis of six studies (including the single randomized trial [111]; the remainder were retrospective comparisons) concluded that the two-dose oral glucocorticoid regimen was associated with fewer severe infusion reactions as compared with a single IV dose [113].

●Weekly regimens – Patients who receive paclitaxel on a weekly administration schedule have the potential to receive substantial doses of dexamethasone; ongoing glucocorticoid treatment is unnecessary for most [36,114,115]. One approach is to administer a lower dexamethasone dose (10 mg IV) with an H1 and H2 receptor blocker 30 minutes prior to the first administration of weekly paclitaxel. Glucocorticoid doses can then be safely tapered by weekly 2 mg decrements after the third or fourth week in patients without infusion reactions and then discontinued [116,117].

Docetaxel

●Every three week administration – For patients receiving docetaxel every three weeks, dexamethasone (8 mg orally twice a day for three consecutive days) is begun 24 hours before the docetaxel infusion. This regimen is effective for reducing both the incidence/severity of infusion reactions and fluid retention [99].

●Weekly docetaxel – The optimal schedule of glucocorticoid administration in patients receiving weekly docetaxel is unclear, and practice is variable [118].

At least two studies reported a low incidence of infusion reactions (3 percent in both studies) with dexamethasone 8 mg the night before, just prior to, and the evening after the weekly dose (24 mg per week) [36,119]. Alternatively, a phase II trial of weekly docetaxel in 54 patients with metastatic breast cancer reported no infusion reactions with a single dose of 8 mg of dexamethasone prior to each weekly dose of docetaxel [120].

However, in at least one other trial, there was a higher incidence of infusion reactions with the first dose of weekly docetaxel when patients were premedicated with a single dose of 10 mg of dexamethasone immediately prior to the infusion [121]. The authors recommended dexamethasone 8 mg orally twice a day for 24 hours before the docetaxel infusion prior to the first two weekly doses, with a switch to the single dose regimen thereafter if there was no reaction after the first two weekly doses. We agree with this approach.

●Patients with hormone refractory prostate cancer receiving prednisone – For men receiving docetaxel plus prednisone for hormone refractory prostate cancer, the United States Prescribing information recommends dexamethasone 8 mg orally at 12, 3, and 1 hour before each docetaxel dose.

Test dosing (not recommended) — Test dosing does not predict which patients will develop initial or recurrent infusion reactions to taxanes and most oncologists do not perform it. "Screening" for hypersensitivity to taxanes by means of a test dose (prior to the first dose) was studied in a series of 206 patients receiving an initial dose of either docetaxel or paclitaxel, 90 of whom received a test dose (1 mg of either paclitaxel or docetaxel administered in 3 mL of normal saline over two to five minutes by IV push, at least 30 minutes after premedications) [122]. Of the 22 patients who had an infusion reaction, only one of the five who required hospitalization was from the test dose group. Compared to patients who did not receive a test dose, the severity of the reaction after a test dose was significantly less (1.5 versus 3.3 on a scale of 1 to 4), and there was less need for acute hospitalization. However, others suggest that test doses are unreliable and argue against their routine use [89]. Test dosing is not a widely accepted practice.

Retreatment after an infusion reaction

Rechallenge — Patients experiencing major infusion reactions have been successfully rechallenged after premedication with high dose glucocorticoids plus H1 and H2 receptor antagonists and taxane administration at a slower infusion rate, with or without desensitization [30,34,68,89,123,124]. In a series of 107 infusion reactions to paclitaxel, 80 patients were successfully rechallenged without undergoing desensitization [30]. Clinical indications and general principles of desensitization are discussed above. (See 'Overview of desensitization' above.)

One study readministered paclitaxel to seven patients with past severe reactions and one with a mild reaction, using a protocol of escalating infusion rates, combined with premedication [34]. The calculated total dose was mixed in 1000 cc, and the infusion was initiated at 3 to 6 cc/hour, and increased by 6 cc/hour every 10 to 15 minutes until reaching a maximum rate of 42 cc/hour. For patients who had only a mild reaction, treatment was initiated at 21 cc/hour for one hour, then if tolerated, the infusion was increased to 42 cc/hour. Seven of the eight patients were successfully treated using this approach.

Skin testing — Skin testing is positive in over 30 percent of patients with severe taxane hypersensitivity reactions and is recommended to assess the risk of further reactions in future treatments [79,96]. The negative predictive value of skin testing with taxane drugs was 100 percent in one large study [14].

The concentrations used for paclitaxel skin testing at the author's clinic are 1 mg/mL for prick/puncture testing. If prick puncture testing is negative, it should be followed by 0.001 mg/mL and then 0.01 mg/mL paclitaxel administered intradermally [79]. For docetaxel, the concentration for prick/puncture testing is 0.4 mg/mL in normal saline. If negative, it is 0.04 mg/mL and then 0.4 mg/mL docetaxel administered intradermally. If skin test results to any step are positive, the patients should receive any further doses of paclitaxel or docetaxel using a desensitization protocol. If negative, the patient can be rechallenged with premedications and a slower infusion rate.

Taxane desensitization — For patients with recurrent infusion reactions despite premedication and a slower infusion rate, and for those with symptoms suggestive of anaphylaxis and positive skin test results, desensitization may allow continued taxane administration [77,125]. In one series, 17 patients with documented infusion reactions to taxanes who needed continued treatment underwent a desensitization similar to that used for the platinum drugs prior to each subsequent taxane dose (table 8) [125]. Only five minor reactions were observed in 77 subsequent administrations. In another series, five patients were successfully desensitized with a protocol that began with a 1:100,000 dilution of the standard preparation [77]. The mechanism of "desensitization" in such cases is unclear since the vast majority of studied patients had negative skin tests to the taxanes.

Desensitization must be repeated each time the drug is given.

Related agents — Nanoparticle albumin-bound paclitaxel (nabpaclitaxel) and cabazitaxel are additional taxane preparations.

Nabpaclitaxel — Nabpaclitaxel (Abraxane) does not use Cremophor as the vehicle. Infusion reactions have not been reported in phase I, II, or III studies of nabpaclitaxel, despite the omission of routine premedication [126-128]. In addition, this formulation can be administered over 30 minutes without the need for special tubing.

However, although the reported risk of an infusion reaction to nabpaclitaxel is lower than with solvent-based taxanes [129], one of the authors (MC) has seen two patients who developed severe infusion reactions involving back pain, dyspnea, and desaturation. Desensitization was not attempted because the diluent for Abraxane could not be obtained.

Nabpaclitaxel has also been used in patients who experienced paclitaxel-associated infusion reactions in the past [130], although one of the authors (MC) has seen several patients who were reactive to both paclitaxel and nabpaclitaxel. Thus, we do not recommend administering a full dose of nabpaclitaxel to patients with past infusion reactions to paclitaxel. Instead, we administer nabpaclitaxel to such patients in the following manner: We give one-tenth of the dose and wait 30 minutes, then one-fourth, one-half, and then the rest of the dose, with each step separated by 30-minute intervals. If this process is tolerated, then the patient can receive the next scheduled dose normally. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Taxanes'.)

Cabazitaxel — Cabazitaxel, a semisynthetic taxane derivative, has been associated with infusion reactions, especially during the first and second doses. Symptoms may include generalized rash/erythema, hypotension and bronchospasm. Premedication with a glucocorticoid and an H1 as well as H2 receptor antagonist is recommended prior to each dose to prevent infusion reactions.

The overall incidence of infusion reactions is unclear. In a phase I study of single agent cabazitaxel, in which no patient received premedication, only 2 of 25 patients developed a grade 1 infusion reaction with flushing, dizziness and chest tightness; symptoms did not reoccur on retreatment despite the absence of premedication [131]. On the other hand, in a phase II study of 71 patients receiving single agent cabazitaxel, and premedicated only with diphenhydramine, four (6 percent) had an infusion reaction, three severe (grade 3 or 4) [132]. The phase III TROPIC trial of cabazitaxel in men with advanced prostate cancer utilized pretreatment with dexamethasone 8 mg, as well as an H1 and H2 receptor blocker, and no infusion reactions were observed [133]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Males who have received prior docetaxel'.)

It is unclear whether the infusions reactions seen with cabazitaxel are attributable to the drug or its vehicle, polysorbate 80. The United States prescribing information lists reactions to other drugs containing polysorbate 80 (eg, docetaxel, etoposide) as a contraindication to use of cabazitaxel. The drug should be discontinued in the event of a severe reaction.

ANTHRACYCLINES AND RELATED AGENTS

●Incidence and characterization – Generalized infusion reactions are rare with free doxorubicin but more common with liposomal anthracyclines. A localized skin reaction (flare) may develop around the infusion site, particularly after the first treatment, and usually does not cause generalized symptoms. It must be distinguished from drug extravasation. Premedication to prevent infusion related reactions is not recommended for either free doxorubicin, pegylated liposomal doxorubicin, or other anthracycline-related agents. When they occur, recurrent reactions can be lessened by pretreatment with diphenhydramine and glucocorticoids, by reconstituting the drug in saline, and by limiting the initial infusion rate to ≤1 mg/min.

Drugs of the anthracycline class (including doxorubicin administered by the intravesical route [134,135]) and related agents rarely cause infusion reactions [136]. More often, a localized skin flare (erythema, pruritus, and localized urticaria at or adjacent to the site of drug administration) may follow the first intravenous (IV) infusion of anthracycline drugs, but it does not progress to a generalized reaction and anaphylaxis. Sometimes, this localized reaction may be confused with drug extravasation [137]. (See "Extravasation injury from cytotoxic and other noncytotoxic vesicants in adults".)

When infusion reactions occur, signs and symptoms may include flushing, dyspnea, facial edema, headache, chills, back pain, tightness of the chest or throat, presyncope, and hypotension [12,136].

The incidence of generalized infusion reactions is higher with liposomal daunorubicin and pegylated liposomal doxorubicin (9 to 14 percent [105,138]) than with free drug. Infusion reactions to liposome-encapsulated formulations may involve a non-IgE-mediated mechanism, possibly directed against the liposomes [139]. Most reactions are mild, and symptoms resolve when the infusion rate is slowed; for this reason, the initial infusion rate should not exceed 1 mg/min. More severe reactions should be treated as possible anaphylaxis, including reactions that involve more than one organ system (eg, flushing and chest pain, hypotension and dyspnea, other combinations).

●Premedication and prevention – Both the localized flare reaction and generalized infusion reaction can be successfully blocked by pretreatment with diphenhydramine and glucocorticoids [140]. Reconstitution of doxorubicin in saline rather than distilled water seems to decrease the frequency of local flare reactions. (See "Cutaneous adverse effects of conventional chemotherapy agents".)

Although data are limited, for severe reactions, desensitization using the same protocol employed for the platinum agents and taxanes was reported to be successful in six patients, despite negative skin tests (table 8) [12]. Desensitization must be repeated each time the drug is given.

ASPARAGINASE — Asparaginase, a polypeptide of bacterial origin, is an important component of treatment for acute lymphoblastic leukemia.

●Formulations – There are currently five formulations of asparaginase: the original Escherichia coli (E. coli) asparaginase derivative (Elspar), which was discontinued in the United States in 2013 but is still available in Canada and elsewhere (Kidrolase); two other short-acting asparaginase products include bacterially derived Erwinia chrysanthemi asparaginase (Erwinase) and recombinant Erwinia chrysanthemi asparaginase (Rylaze), both of which can be used for patients with hypersensitivity to E. coli-derived asparaginase. Bacterially derived Erwinia chrysanthemi asparaginase is no longer available in the United States and Canada as of 2022, but remains available in the United Kingdom and the European Union.

There are also two long-acting asparaginase products including pegaspargase (Oncaspar) and calaspargase (Asparlas), both of which are E. coli-derived. The pegylated products have longer half-lives (5 to 12 days [141-143] and 13 to 17 days [143], respectively). Pegaspargase has a more convenient schedule (eg, every 14 or 21 days instead of three times per week), is less expensive, and is most commonly used in treatment protocols for newly diagnosed patients. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

The half-life of asparaginase whether pegylated or not decreases precipitously in patients with anti-asparaginase antibodies (see below) [144].

For patients who develop hypersensitivity to the E. coli-derived products, bacterially-derived Erwinia is costly, and there have been sporadic global shortages since 2017 [145]. These issues prompted the development of the recombinant formulation which was approved by the US Food and Drug Administration in July 2021 for individuals who have developed hypersensitivity to E. coli–derived asparaginase.

●Infusion reactions – Hypersensitivity reactions with asparaginase range in severity from localized, transient erythema and rash at the site of injection to acute life-threatening anaphylaxis. The most common symptoms are pain, tenderness, swelling, and erythema at the injection site when given intramuscularly (IM), and dyspnea, bronchospasm, pruritus, skin rash, and urticaria when given intravenously (IV); uncommon symptoms include angioedema, laryngospasm, and hypotension [10,146]. Most reactions, usually following the second to fourth infusion, occur within minutes, but they can occur one to several hours after administration, or even later [147]. Delayed hypersensitivity reactions are more common with pegaspargase due to slow release of the primary antigen [148].

Infusion reactions are more common with IV administration compared with IM or subcutaneous (SC) administration [148-151]. For this reason, the more immunogenic, nonpegylated forms are frequently given SC or IM, while the pegylated products are often given IV to minimize painful medication administration.

•Incidence

-Nonpegylated products – The risk of a hypersensitivity reaction appears to be similar between the E. coli-derived products. Elspar was commonly used in the United States and has similar reaction rates to Kidrolase, the currently available asparaginase preparation. Prior to premedication, infusion rates ranged from 5 to 8 percent per administered dose, increasing with the number of doses; up to one-third or more of patients experience an infusion reaction by the fourth dose [152-157]. Fewer than 10 percent of reactions are "serious" (ie, accompanied by hypotension and/or respiratory distress).

Erwinia asparaginase was developed for individuals with hypersensitivity to E. coli-derived asparaginase. However, infusion reactions can also occur. As an example, hypersensitivity reactions after the use of recombinant Erwinia asparaginase occurred in 25 percent of patients in clinical trials, although they were severe in only 2 percent [158]. For bacterially-derived Erwinia asparaginase, the rate of severe grade 3 or 4 reactions is approximately 5 percent [159]. The rate of other side effects (pancreatitis, thrombosis, etc) is approximately the same among all available forms of asparaginase.

-Pegylated products – Although pegaspargase is the least immunogenic of the available formulations and has a lower rate of severe reactions, less severe infusion reactions still occur in up to 30 percent of patients over the duration of therapy [145,160-165]. Similarly, with IV calaspargase pegol, grade 3 and 4 hypersensitivity reactions, including anaphylaxis, have been reported in 7 to 27 percent of patients [143,165,166]. All pegylated products are E. coli-derived.

•Mechanism – Patients who develop hypersensitivity reactions to E. coli-derived asparaginase can be shown to have developed antibodies against the drug. Both anti-asparaginase and anti-polyethylene glycol antibodies have been demonstrated [167,168]. The presence of these antibodies correlates to both the development of hypersensitivity reactions and to inactivation of the drug and loss of therapeutic effect. However, antidrug antibody levels are neither sensitive nor specific for loss of asparaginase activity [169,170]. Antidrug antibodies also have not correlated with survival if patients are switched to a different preparation of asparaginase after the allergic reaction [146]. Additionally, some patients without clinical hypersensitivity reactions develop drug-inactivating antibodies, a phenomenon commonly referred to as "silent inactivation" [169].

Therapeutic drug monitoring (TDM) involves measuring the level of serum asparaginase directly. Trough serum asparaginase levels above 0.1 international units/mL assure sufficient asparaginase activity to be effective [171]. Institutions vary in their use of TDM. Some institutions, including that of one of the authors (TH), perform TDM for all patients receiving E. coli-derived asparaginase. Because the incidence of silent inactivation is low (<2 percent), other sites choose to employ TDM only after an allergic reaction, particularly a grade 1/2 reaction of unclear etiology (late onset, atypical symptoms). Patients being treated with one of the pegylated asparaginase products who are shown to have low asparaginase levels can be switched to an Erwinia preparation, which results in improved outcomes [172,173]. It has wide interpatient variability, although the same threshold of >0.1 international units/mL is considered effective [171].

•Prevention – Many institutions have initiated universal premedication for all E. coli-derived asparaginase formulations including acetaminophen, an H1 blocker such as diphenhydramine, and an H2 blocker (famotidine), with or without a glucocorticoid, given 30 to 60 minutes before each asparaginase infusion or IM injection [174]. With universal premedication, the asparaginase reaction rate has fallen to less than 10 percent [174].

This practice has not been widespread. However, in 2021 the pegaspargase United States Prescribing Information was updated to recommend premedication of all patients with acetaminophen, an H1-receptor blocker, and an H2-receptor blocker administered 30 to 60 minutes prior to each dose [175]. The label for calaspargase has also been similarly updated to recommend routine premedication prior to each dose [176].

Premedication is not required prior to Erwinia asparaginase, either the bacteria-derived or recombinant preparations. However, for patients with a prior history of anaphylaxis, it is often utilized, depending on the institution.

•Treatment – Due to the high incidence of infusion reactions, asparaginase should only be administered in a facility that is capable of treating anaphylaxis if it occurs. The clinician must assume that each dose is capable of precipitating an infusion reaction and be prepared to deal with that possibility (ie, IV access and epinephrine, hydrocortisone, and diphenhydramine immediately available for use). General guidelines for immediate treatment of anaphylaxis in adults and children are outlined in the tables (table 5 and table 4). (See "Anaphylaxis: Emergency treatment".)

•Options for retreatment – For patients who develop a hypersensitivity reaction to one of the E. coli-derived pegylated asparaginase formulations, continued therapy is possible by switching to an Erwinia formulation [153,155,172,177-179]; cross-reactivity is unlikely with the E. coli and Erwinia derivatives of asparaginase because the two are antigenically distinct. The incidence rate of cross-reactivity is 3 to 33 percent [171]. Given the ongoing international shortage of bacterially-derived Erwinia asparaginase, strategies to minimize the need for it were developed [145]. These include universal premedication to minimize the number of patients developing hypersensitivity reactions to pegylated asparaginase products, and TDM to detect patients who have undergone silent inactivation [174,180].

For patients who develop hypersensitivity reactions to pegylated asparaginase, TDM should be performed based on the severity of the reaction [145,171]:

-For grade 1 and 2 reactions, monitor serum asparaginase activity three to seven days after asparaginase administration to identify inactivation and the need to switch to Erwinia asparaginase.

-For a grade 3 reaction, institutional policies vary. For a grade 4 reaction, switch to the Erwinia preparation, without definite need to check asparaginase activity.

These issues have become less relevant with the availability of recombinant Erwinia asparaginase, but this drug is expensive and not yet widely available.

Desensitization to pegaspargase is another option if a recombinant Erwinia preparation is not available or the patient also reacts to Erwinia asparaginase [181,182]. At least two small series have shown that it is possible to use a rapid desensitization protocol to allow the administration of pegaspargase, with subsequent levels of asparaginase above the threshold of 0.1 international units/mL. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

BLEOMYCIN — Several idiosyncratic reactions have been described in patients receiving bleomycin, although most do not appear to be allergic in nature. Routine premedication to prevent these reactions is not usually recommended.

●Hyperpyrexia syndrome – Between 50 and 60 percent of patients receiving bleomycin have a self-limited mild febrile reaction without any other symptoms [183]. The incidence of fever decreases with subsequent doses, particularly if prophylactic antipyretics are administered.

However, approximately 1 percent of patients receiving bleomycin (predominantly for lymphoma) develop a high fever followed by excessive sweating. This may be accompanied by wheezing, mental confusion, anuria, and hypotension. A small number of these patients progress to disseminated intravascular coagulation and die from this complication (fulminant hyperpyrexia) [184-186]. This idiosyncratic reaction may be immediate or delayed several hours to days following the dose. The incidence is highest after the first and second doses.

In most cases, this syndrome appears to involve the release of pyrogenic cytokines and resembles the systemic inflammatory response syndrome (SIRS) (table 10) more than a typical infusion reaction [187]. The observation that bleomycin did not induce histamine release, tachycardia, or hypotension in a dog model also argues against an IgE-mediated mechanism [95]. (See 'Characteristics of reactions' above and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

•Prevention and treatment – A test dose (intravenous [IV] injection of ≤2 units of bleomycin followed by monitoring of vital signs every 15 minutes for a minimum of one hour) followed by administration of the remainder of the dose is recommended by the manufacturer prior to the first one to two doses of bleomycin in patients with lymphoma. However, many institutions (including that of the authors) do not do this because of the very low likelihood of a reaction, particularly after pretreatment with acetaminophen and diphenhydramine. Furthermore, whether a reaction to the test dose implies a contraindication to further bleomycin is unclear. Given that the reaction is almost always seen only after the first or second doses, successful rechallenge is usually possible with premedication.

Anecdotal reports suggest that the hyperpyrexia syndrome can be treated with temporary drug discontinuation, hydration, glucocorticoids, antipyretics, and H1 receptor antagonists [185]. Treating preexisting fever with acetaminophen also may increase the patient's "margin" for tolerating drug-induced hyperpyrexia [184].

●Hypersensitivity pneumonitis – Although bleomycin is more often associated with interstitial pneumonia and pulmonary fibrosis, it may cause acute hypersensitivity pneumonitis, presenting as dyspnea, cough, and rash. This syndrome is radiographically and clinically similar to the more common interstitial pneumonitis, except that it occurs at lower cumulative doses, is associated with peripheral eosinophilia, and lung biopsy is more consistent with a hypersensitivity reaction. Drug rechallenge has not consistently produced a recurrence of the syndrome, suggesting that it is not immune-mediated. (See "Bleomycin-induced lung injury".)

●Acute chest pain – Chest pain during infusion may represent another manifestation of acute bleomycin toxicity, although the mechanism appears to be an acute pleuropericarditis rather than an infusion reaction [188].

●Other rare reactions – One fatal case of fulminant angioedema to bleomycin has been reported [189]. This reaction was preceded by eosinophilia, developed 48 hours after the end of a course of bleomycin, and involved angioedema and a generalized punctate, hemorrhagic rash that was not responsive to glucocorticoids.

CARFILZOMIB — Carfilzomib is a second-generation proteasome inhibitor that is used in the treatment of relapsed/refractory multiple myeloma. It is administered once or twice weekly when given in combination with dexamethasone, or twice weekly as monotherapy. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors' and "Multiple myeloma: Treatment of first relapse", section on 'Refractory to lenalidomide and daratumumab'.)

Infusion-related reactions can include fever, chills, arthralgias, myalgias, facial flushing/edema, vomiting, weakness, dyspnea, hypotension, syncope, chest tightness, angina, and/or rigors; symptoms may develop immediately or be delayed up to 24 hours after drug administration. The United States prescribing information recommends that for combination antineoplastic regimens that include dexamethasone, the dexamethasone (either 20 or 40 mg, depending on the regimen schedule) be administered 30 minutes to 4 hours prior to each carfilzomib dose. For carfilzomib monotherapy, dexamethasone 4 or 8 mg (depending on the dosing regimen chosen for carfilzomib) should be administered orally or intravenously 30 minutes to 1 hour before each carfilzomib dose during the first cycle, and thereafter, as needed to help prevent infusion-related reactions. With this low-dose concomitant premedication, however, the incidence of fever and dyspnea during therapy is still high (19 to 28 percent in one phase II trial [190]).

CYTARABINE

●Incidence and characteristics – Up to one-third of patients receiving cytarabine for acute myeloid leukemia (most of whom have had prior exposure to the drug) develop a characteristic "cytarabine syndrome" within 6 to 12 hours of drug infusion [191-195]. This flu-like syndrome consists of fever, rigors, diaphoresis, myalgias, arthralgias, conjunctivitis, a macular skin eruption, and occasionally, hypotension [196]. While the etiology is unclear, it is probably related to cytokine release rather than immune-mediated [194,195], although at least one study reports the presence of circulating immune complexes [196].

In contrast, IgE-mediated reactions (anaphylaxis with angioedema, urticaria, hypotension) are reported rarely [197-199]. Patients with suggestive signs and symptoms should be referred to an allergist with experience in drug desensitization if continued therapy is indicated [3].

Other types of skin reactions are reported:

•Dose-related acral erythema (hand-foot syndrome) is characterized by intense, painful erythema predominantly involving the palms and soles, which may progress to bullae and desquamation. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

•Neutrophilic eccrine hidradenitis is another dermatologic condition that may represent a hypersensitivity reaction [200], although it is more likely the result of direct cutaneous drug toxicity. The characteristic skin lesions are erythematous plaques or nodules that may be tender or pruritic. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Neutrophilic eccrine hidradenitis'.)

●Prevention and rechallenge – Cytarabine is typically administered as a multiday regimen. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Initial therapy'.)

The United States Prescribing Information for cytarabine does not recommend premedication prior to each day's cytarabine dose. However, a dose of acetaminophen prior to and following each day's drug infusion may reduce the frequency of the cytarabine syndrome. Glucocorticoids may also be beneficial for both treatment and prevention of the cytarabine syndrome [191,194].

Retreatment after cytarabine syndrome can usually be safely accomplished with increased premedication, even in patients with multiple reactions [201,202].

CYCLOPHOSPHAMIDE AND IFOSFAMIDE — Premedication to prevent infusion reactions is not generally recommended with either cyclophosphamide or ifosfamide.

Cyclophosphamide has rarely been associated with anaphylaxis [203-206]. The antigenic compound appears to be the active metabolite rather than the parent compound, which explains why reactions may develop up to 16 hours after drug administration [205].

Infusion reactions are also reported with MESNA, which may be given with high-dose regimens to prevent hemorrhagic cystitis [206,207]. A desensitization protocol was effective one case report [205].

Ifosfamide is rarely reported to cause anaphylaxis; in all cases, it was given with MESNA [208,209].

ETOPOSIDE — Approximately 1 to 3 percent of patients who receive intravenous (IV) etoposide develop angioedema, chest discomfort, bronchospasm, and/or hypotension, usually within minutes of starting the drug infusion [210,211]. Although the mechanism is unclear, the clinical pattern is consistent with anaphylaxis.

The reaction is thought due to the vehicle rather than the drug. The vehicle, polysorbate-80, is the same as that used for docetaxel (see 'Mechanisms of infusion reactions' above). Additional support for this hypothesis is provided by the lack of allergic reactions in patients receiving oral etoposide, which does not contain polysorbate-80. However, there are at least two case reports of hypersensitivity reactions with an alternative formulation of etoposide, etoposide phosphate, which does not contain polysorbate-80 [212].

Premedication to prevent infusion reactions is not routinely recommended prior to IV etoposide. When it occurs, etoposide hypersensitivity may be managed by pretreatment with a glucocorticoid and antihistamines [200,213], several reports indicate that switching to etoposide phosphate is safe in patients who develop an infusion reaction with IV etoposide [214,215].

IXABEPILONE — Ixabepilone is a microtubule inhibitor in the epothilone class that has been approved for treatment of patients with metastatic breast cancer. Like paclitaxel, it is formulated in Cremophor.

Infusion reactions, including anaphylaxis, are reported in approximately 1 percent of patients. Ixabepilone is contraindicated in patients with prior reactions to paclitaxel in Cremophor. As with the taxanes, treatment with ixabepilone requires premedication with H1 as well as H2 receptor antagonists approximately one hour prior to chemotherapy administration. (See 'Premedication regimens' above.)

Patients who experience a hypersensitivity reaction despite antihistamines require the addition of corticosteroids (eg, dexamethasone 20 mg intravenously 30 minutes before infusion, or orally 60 minutes before infusion) to the premedication regimen. Notably, if dexamethasone, a strong cytochrome P450 3A4 (CYP3A4) inducer, is used, the United States Prescribing Information for ixabepilone recommends adjusting the ixabepilone dose gradually up to 60 mg/m² (as a four-hour infusion), with careful monitoring. If the dexamethasone is discontinued, reduce the ixabepilone dose to the dose used prior to initiation of dexamethasone.

LEUCOVORIN — Leucovorin is commonly administered simultaneously with oxaliplatin or irinotecan for the treatment of gastric and colorectal cancers, in regimens such as fluorouracil (FU) plus leucovorin and short-term infusional oxaliplatin (ie, FOLFOX) or FU plus leucovorin and irinotecan (ie, FOLFIRI).

As noted above, some patients who develop infusion reactions during administration of these regimens are commonly presumed to be reacting to oxaliplatin or irinotecan. However, some of these reactions represent hypersensitivity to leucovorin. (See 'Oxaliplatin' above.)

Infusion reactions due to leucovorin appear to be rare, although they may be under-recognized and mistakenly attributed to a co-administered agent, particularly oxaliplatin [216,217]. In the largest series of five patients, symptoms appeared 10 to 70 minutes after the start of the combined-drug infusions and included facial erythema, urticaria, itching, angioedema, dyspnea, and chest pain [217]. These five patients were derived from a cohort of 44 patients who were assessed after suffering a hypersensitivity reaction to a chemotherapy regimen containing leucovorin (35 FOLFOX and 9 FOLFIRI). Four were receiving FOLFOX, and one, FOLFIRI. One patient had chills, fever, back pain, and elevated blood pressure. Two patients reacted to the first administered dose, while the others had received repeated doses prior to reacting. The mechanism(s) underlying these infusion reactions is not known. Skin testing was performed, although it was not positive in any of the five patients, and the diagnosis was made with leucovorin provocation, which reproduced the symptoms.

These reactions have all occurred in patients receiving racemic (D,L) leucovorin, the most commonly used formulation. Given the lack of published reports of hypersensitivity to the L-isomer of leucovorin (LEVOleucovorin) three of the five patients described above who had presumed hypersensitivity reactions to racemic leucovorin during FOLFOX or FOLFIRI chemotherapy were subsequently challenged with LEVOleucovorin and also reacted, suggesting a high rate of cross-reactivity [217]. One patient opted to continue leucovorin using a rapid desensitization protocol, which allowed FOLFIRI to be continued without recurrent symptoms. The desensitization protocol used is described elsewhere. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

METHOTREXATE AND PEMETREXED — Infusion reactions to methotrexate are rare [218]. Premedication is not routinely recommended prior to each dose. Patients who develop recurrent reactions for whom other therapeutic options are not available may benefit from a desensitization protocol [219-221].

Infusion reactions are also rare with pemetrexed, although at least one case of urticarial vasculitis has been reported [222]. Early studies noted a high rate of maculopapular skin rash with pemetrexed (15 percent overall, severe in approximately 1 percent). Both the incidence and severity of skin rash have been reduced with dexamethasone premedication. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Exanthematous (maculopapular) eruptions'.)

TEMSIROLIMUS — Temsirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR) and is the first agent of this drug class to be used clinically for the treatment of renal cell cancer (RCC). (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)

Although allergic reactions are described, their nature and severity are poorly documented [223-225]:

●In a phase II trial of temsirolimus as a single agent in advanced RCC, six patients (8 percent) had an "allergic reaction" but the specific symptoms, severity, and management were not described [223].

●The final report of a phase III trial compared temsirolimus versus interferon versus both drugs in the treatment of advanced RCC did not note any grade 3 or 4 allergic reactions in patients receiving temsirolimus [224]. However, unpublished observations indicate that 5 percent of patients had an allergic reaction, none severe [225]. Reported symptoms were flushing, sensation of warmth, and headache.

●The United States prescribing information also lists anaphylaxis, dyspnea, and chest discomfort as potential symptoms of an allergic reaction, but does not specify their incidence or severity.

●Reactions may be attributed to the drug or its vehicle, polysorbate 80, an agent that has been associated with infusion reactions with other drugs (docetaxel, etoposide).

The manufacturer recommends pretreatment with an H1 receptor blocker (eg, diphenhydramine) before the start of each infusion and avoidance of temsirolimus in patients who have had a history of hypersensitivity to the related drug sirolimus.

Guidelines for management of an infusion reaction include the following:

●Stop the infusion and observe the patient for at least 30 to 60 minutes.

●At the clinician's discretion, treatment may be resumed with the administration of an H1 receptor antagonist, if not previously administered, and/or an H2 receptor blocker (intravenous famotidine 20 mg) approximately 30 minutes before restarting the infusion. The infusion may be resumed at a slower rate (up to 60 minutes).

SUMMARY AND RECOMMENDATIONS

●General aspects – Virtually all chemotherapeutic agents have the potential to initiate infusion reactions. Certain drugs (eg, platinum agents and taxanes) are associated with anaphylaxis, which arises from sudden and widespread activation of mast cells and/or basophils. (See 'Introduction' above.)

Infusion reactions range in severity from mild pruritus and flushing to life-threatening hypotension and bronchospasm. Most are mild and occur during or within one hour of drug administration. (See 'Characteristics of reactions' above.)

The National Cancer Institute (NCI) system of classifying infusion reactions is based on severity (table 1). However, allergists emphasize the differentiation of anaphylaxis from all other types of standard infusion reactions (SIRs). Although there is some overlap, characteristic symptoms of anaphylaxis include urticaria, wheezing, hypotension, and gastrointestinal symptoms, but not fever. Anaphylaxis is likely to recur despite premedication and can typically become more severe upon re-exposure, regardless of the severity of the initial symptoms. (See 'Classification of infusion reactions' above.)

●Prevention – Premedication can help prevent and/or reduce the severity of infusion reactions, although it is not effective in preventing anaphylaxis. Specific premedication regimens for individual agents are addressed in the individual sections above. (See 'Use of premedication to prevent infusion reactions' above.)

The role of skin testing to screen patients before they develop an infusion reaction remains uncertain, and most institutions do not routinely perform them. (See 'Skin testing' above and 'Retreatment after an infusion reaction' above.)

●Immediate treatment – Despite the use of premedication, clinicians must be prepared for an infusion reaction to occur during each drug administration. Standing orders should be in place to allow immediate intervention without waiting for the clinician to arrive. Medical equipment and supplies needed for resuscitation should be readily available. (See 'Principles of treatment and rechallenge' above.)

Immediate management is tailored to the clinical situation. The following represent general guidelines for management of a patient who is suspected of having an infusion reaction to a chemotherapeutic agent.

•Mild to moderate reaction – If the reaction is limited to mild or moderate symptoms of SIR (grades 1 or 2 (table 1)), without features suggestive of anaphylaxis, drug infusion should be temporarily stopped and assessment of airway, breathing, circulation, and mentation accomplished rapidly. Intravenous (IV) administration of 50 mg of diphenhydramine may provide symptomatic relief. Once symptoms have resolved, resumption of the drug infusion at a slowed rate may permit treatment continuation with close monitoring.

•Severe reaction or anaphylaxis – Severe SIRs (grades 3 or 4 (table 1)) or reactions with any features of anaphylaxis (eg, generalized urticaria, wheezing, hypotension, and angioedema) require prompt recognition and treatment. In fatal anaphylaxis, death typically ensues within 30 minutes from exposure to the trigger. (See 'Treatment of anaphylaxis and severe standard infusion reactions' above.)

Initial management of anaphylaxis is summarized in a rapid overview table for adults (table 4) and children (table 5) is covered in detail elsewhere and includes the following (see "Anaphylaxis: Emergency treatment"):

-Immediately discontinue drug infusion

-Place the patient in the supine position with legs elevated (if tolerated)

-Assess airway, breathing, circulation, and adequacy of mentation

-Call for help (summon a resuscitation team in the hospital setting, call 911 or an equivalent service in the community setting)

-Administer intramuscular epinephrine into the anterolateral thigh (0.3 to 0.5 mg aqueous epinephrine, 1:1000 dilution)

-Establish IV access with two 14 to 16 gauge catheters

-Administer both an H1 (eg, 50 mg of diphenhydramine) and an H2 (eg, 20 mg of famotidine) antihistamine IV

-Systemic administration of a glucocorticoid (eg, 40 to 80 mg methylprednisolone IV) may not help acutely, although it may prevent a prolonged or recurrent reaction

●Rechallenge – The decision to attempt retreatment after resolution of the acute event depends upon the specific drug, the severity of the reaction, the cancer being treated and the intent of treatment (ie, potentially curative or palliative), and whether there are reasonable treatment alternatives:

•For most drugs, if the reaction was mild or moderate (NCI grades 1 or 2) and lacking signs or symptoms to suggest anaphylaxis, rechallenge is often possible with premedication (glucocorticoids, antihistamines) and a slower rate of infusion. However, for patients treated with a platinum agent, retreatment should not be attempted, even with additional premedications. Instead, we suggest referral to an allergy or oncology center with experience in drug desensitization. (see 'Principles of treatment and rechallenge' above)

•For severe SIRs (NCI grade 3 or higher) and any reactions with symptoms of anaphylaxis, retreatment should not be attempted. Instead, we suggest referral to an allergy or oncology center with experience in drug desensitization [34,186]. (See 'Anaphylaxis' above.)

•Skin testing may be helpful in the evaluation of SIRs, especially with the platinum drugs and taxanes. If skin testing is positive, then the patient should not be rechallenged. If there is no equivalent substitute drug, then such patients should be given that medication only through desensitization in the future. The negative predictive value of skin testing with platinum drugs and taxanes is high, and patients with a negative result can receive the drug again using a graded challenge. (See 'Overview of skin testing' above.)

●Desensitization – Desensitization protocols have been developed at centers with expertise in drug allergy, and they have been most successfully applied to taxanes and platinum drugs. However, experience with desensitization is not widespread, and the success of these protocols in other settings has not been reported. (See 'Platinum drugs' above and 'Taxanes' above.)

Desensitization should only be carried out under close medical supervision by experienced individuals who are prepared to deal with emergency management of anaphylaxis. Most, if not all desensitization protocols are performed by allergists. Desensitization must be repeated each time the patient requires the drug in the future. (See 'Overview of desensitization' above.)