Infusion reactions to systemic chemotherapy

Authors
Mariana C Castells, MD, PhD
Ursula A Matulonis, MD

Section Editors
Reed E Drews, MD
N Franklin Adkinson, Jr, MD

Deputy Editors
Diane MF Savarese, MD
Anna M Feldweg, MD

Last literature review version 18.2: Maio 2010 |This topic last updated: Maio 7, 2010 (More)

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, L-asparaginase, procarbazine, etoposide, bleomycin, cytarabine, and ixabepilone. While these are often referred to as "hypersensitivity reactions", many do not have an allergic component. Thus, the term infusion reaction is preferred.

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 reactions to therapeutic monoclonal antibodies used for cancer therapy"and "Cutaneous complications 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
  • Hypoxia
  • 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, and/or loss of consciousness
  • Gastrointestinal symptoms: nausea, vomiting, abdominal cramping, and/or diarrhea
  • Neurological symptoms: sense of impending doom, tunnel vision, dizziness, and/or seizure

The clinical manifestations of anaphylaxis (from all causes) are presented in detail elsewhere. (See "Anaphylaxis: Rapid recognition and 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, and throat tightness/change in voice. 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, 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

NCI classification—The most recent NCI Common Toxicity Criteria (NCI-CTC) for grading adverse reactions during chemotherapy administration distinguishes between allergic/hypersensitivity reactions, and acute infusion reactions induced by cytokine release (table 1)[3]. Both types of reactions can vary in severity from grade 1 (mild) to grade 5 (fatal):

  • Mild to moderate (grade 1 or 2) reactions are characterized by pruritus, flushing, rash, urticaria, fever, chills, dyspnea, and mild hypotension
  • Severe (grade 3 or 4) reactions are associated with angioedema, bronchospasm, and hypotension, requiring immediate and urgent treatment.

The NCI Common Toxicity Criteria emphasize the severity of symptoms. However, 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, SIRs). The severity of the reaction is considered separately. This approach is intended to identify patients at risk for anaphylaxis upon reexposure, 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 reexposure 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 reexposure to the causative drug, despite the premedications and reduced infusion rates that would have adequately managed most SIRs.

Another criticism of the NCI Common Toxicity Criteria is the inclusion of fever as a possible sign of an allergic reaction, since fever is not a manifestation of mast cell/basophil activation, and the prominence of fever during an infusion reaction is more indicative of an SIR.

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 reexposed to the causative agent until they have been evaluated by an allergy specialist with experience in drug allergy and desensitization [4]. In particular, these patients should NOT be considered candidates for additional premedication and an attempt at drug readministration using a slower rate of infusion.

Definition of anaphylaxis—Anaphylaxis was traditionally defined as a constellation of symptoms and signs that arose from an IgE-mediated allergic reaction which resulted in explosive release of vasoactive mediators from mast cells and basophils throughout the body. However, the definition of anaphylaxis has been broadened in recent years to include any reaction that leads to widespread activation of mast cells and basophils [5]. Anaphylaxis is now diagnosed based upon clinical signs and symptoms (table 2)[6]. This more inclusive definition emphasizes the common endpoint of mast cell/basophil activation and the severity of the reactions that can result, and places less importance on the mechanism by which the cells are activated. In addition, clinicians should not equate anaphylaxis with anaphylactic shock, as the latter represents the severe end of a spectrum. The goal should be early recognition and appropriate management of anaphylaxis in its milder forms. (See "Anaphylaxis: Rapid recognition and treatment".)

All reactions with features of anaphylaxis should be considered potentially severe, because of the tendency of anaphylaxis to recur and worsen with reexposure. As an example, a patient who develops limited urticaria and mild wheezing after receiving a cytotoxic agent should be diagnosed with possible anaphylaxis and should not be considered a candidate for premedication and drug readministration at a slower rate of infusion. Instead, referral to an allergist and use of a desensitization protocol should be pursued. (See 'Agents associated with anaphylaxis'below.)

In this topic review, as mentioned previously, anaphylaxis will be referred to as such, and all other infusion reactions will be grouped under the term standard infusion reactions (SIRs).

Cytotoxic agents implicated in anaphylaxis—Anaphylaxis has been best established with the platinum drugs and the taxanes. Anaphylaxis to other cytotoxic agents is rare, although the possibility of anaphylaxis exists with any medication. (See 'Platinum drugs'below and 'Taxanes'below.)

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 tests that support the diagnosis of anaphylaxis — Mast cells and basophils contain various chemical mediators that are transiently released into the circulation during anaphylaxis. Some of these are unique to these cell types and, if elevated, can help confirm that the reaction was anaphylaxis.

The laboratory test that is most useful in this setting is a serum total tryptase level. Tryptase levels usually peak within three hours of the onset of symptoms, so blood should be drawn one to two 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.

The upper limit of normal for serum total tryptase is approximately 11 ng/mL, depending on the assay system. Elevations in anaphylaxis can range from marginally elevated to greater than 100 ng/mL. Any elevation in serum tryptase is consistent with anaphylaxis, although a normal tryptase level does not exclude anaphylaxis because tryptase elevations are not seen in all anaphylactic reactions or may have resolved before the blood was collected. The interpretation of tryptase levels in anaphylaxis is discussed separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

If a patient's reaction was suggestive of anaphylaxis but tryptase levels were not elevated, skin testing may still be informative.

  • 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. (See 'Platinum drugs'below.)

USE OF PREMEDICATION TO PREVENT INFUSION REACTIONS—Premedication can help prevent and/or reduce the severity of infusion reactions, particularly SIRs. In contrast, anaphylaxis is generally not prevented by premedication, although the severity of the reaction may be reduced in some cases.

Pharmacologic prophylaxis with antihistamines, glucocorticoids, or both is recommended for certain drugs that have a high incidence of infusion reactions (eg, paclitaxel, denileukin diftitox). However, these regimens have been derived empirically rather than established through randomized trials. Furthermore, they are not completely protective, even for SIRs. Therefore, even with premedication, patients must be monitored 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 [7]. 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 SIRs—Mild to moderate SIRs (ie, infusion reactions that do not involve symptoms of anaphylaxis) 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.

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 [4].

Treatment of anaphylaxis and severe SIRs—Reactions with ANY features of anaphylaxis and severe SIRs (grade 3 or 4, (table 1), require discontinuation of the drug infusion and immediate treatment with epinephrineand 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 3) and children (table 4)[6]. Similar recommendations have been made in the American Heart Association (AHA) Advanced Cardiac Life Support (ACLS) guidelines [8]. (See "Anaphylaxis: Rapid recognition and treatment".)

The initial management of anaphylaxis includes the following:

  • Stop the infusion of the suspect medication
  • Intramuscular injection of epinephrine(table 3and table 4)
  • Call for help (summon a resuscitation team in the hospital setting, call 911 or an equivalent service in the community setting)
  • Placement of the patient in the recumbent position (if tolerated) to maintain blood flow to vital organs
  • Supplemental oxygen
  • Volume resuscitation
  • Intravenous antihistamines (table 3and table 4)

Rechallenge after a severe SIR—Following a severe SIR, rechallenge is usually discouraged. 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 [9]. (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 [4]. With rare exception [10], 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 with most chemotherapy agents is of limited value because the positive and negative predictive values are not known. An important exception to this is skin testing with the platinum drugs, which is useful in the evaluation of infusion reactions with features of allergic reactions. (See 'Platinum drugs'below.)

Skin testing with other chemotherapy drugs is considered investigational. Many chemotherapy agents can cause irritation and necrosis upon extravasation, and these should not be used for skin testing (table 5). However, if investigational skin testing with other agents is undertaken and a positive result is obtained, then desensitization should be performed before readministration of the agent if there is no equivalent substitute therapy.

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 exfoliative dermatitis, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Reexposure in this setting can induce a fatal recurrence. (See "Cutaneous complications 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 [10].

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 [9]. Clinicians should avoid altering successful protocols to render them faster or significantly change the time interval between doses.