A 51-year-old woman with relapsed epithelial ovarian cancer presents to the clinic for cycle 7 of carboplatin/docetaxel. Approximately 20 minutes into the carboplatin infusion, her palms feel warm and she develops flushing and pruritus. The infusion is stopped, and the nurse administers 25 mg of diphenhydramine just as the patient begins coughing and reports that her chest feels tight. Vital signs reflect an increase in heart rate of 15 beats/minute, and blood pressure and oxygen saturation are normal. After 5 minutes, her cough and chest tightness resolve but she remains flushed and swollen.
Infusion reactions are common with all cancer therapies, but when is it time to change the treatment plan?
Hospitalists play a key role in the care of oncology patients. In addition to managing complications of cancer, hospitalists are often the supervising physicians during inpatient chemotherapy. Given the frequency of adverse drug effects, the ability to recognize and treat infusion reactions rapidly is important. The decision to discontinue current therapy or re-challenge a patient after a reaction depends on many clinical factors, including severity of reaction and efficacy of alternative therapies. Until recently, hypersensitivity reactions (HSRs) prevented patients from receiving first-line therapies, but rapid desensitization protocols have been proven effective. With close physician supervision, these high-risk procedures can be done safely.
Adverse reactions to chemotherapeutic agents may involve any organ system in the body and can range from mild to anaphylactic. Symptoms may include flushing, increased heart rate, alterations in blood pressure, dyspnea, chest tightness, back pain, fever, itching, nausea, and rash. Although the incidence of severe reactions is less than 5%, deaths have been reported (1, 2). Thus, prompt assessment and astute management are required. Understanding the underlying pathophysiology and terminology used to describe these reactions can help hospitalists intervene appropriately and make an important difference in patient outcomes.
“Infusion reaction” is a term used to describe adverse reactions that occur during or immediately after administration of a medication. In general, most reactions are mild to moderate in severity and may represent irritant effects. In many cases, these are anticipated and can be managed with temporary interruption of the infusion and symptom management with steroids, antihistamines, antiemetics, and possibly anxiolytics. Generally, the infusion is completed without progression to a severe reaction, albeit at slower rate and with greater reliance on supportive medications. Such reactions are common during administration of paclitaxel, a taxane, and mild reactions are attributed to the vehicle (3).
HSRs are a subgroup of adverse drug reactions that are unexpected and are characterized by objectively reproducible signs and/or symptoms at doses that are normally tolerated. Immediate HSRs appear within 1 hour of an infusion. Delayed HSRs occur any time thereafter and often include macular papular rashes and Stevens-Johnson syndrome (4).
Most immediate HSRs are IgE mediated, although non-IgE-mediated mechanisms have also been described. Once activated, mast cells and basophils release vasoactive mediators including histamine, leukotrienes, prostaglandins, and cytokines. Manifestations may affect any part of the body, but cutaneous findings are most common, followed by cardiovascular and respiratory symptoms. Symptoms and signs concerning for an HSR should be specifically sought when evaluating a patient with an infusion reaction. In particular, urticaria, angioedema, cough, wheeze, throat tightness, hoarseness, and cardiovascular changes warrant immediate attention.
HSRs represent a minority of infusion reactions and are most commonly seen with the platinums, particularly after multiple cycles of therapy (3, 5). For example, the overall incidence of infusion reactions to carboplatin is about 12%. The incidence increases with repeated drug exposure and more than doubles to nearly 25% in women who received more than 7 cycles (6).
Unlike most infusion reactions, which are mild in severity and lack characteristics suggestive of rapid progression, manifestations of HSRs are a contraindication for re-challenge. It can be difficult to assess what manifestations are likely to progress. For this reason, the National Cancer Institute (NCI) developed terminology for grading adverse reactions to help guide management (see Table 1) (7). If the reaction is mild or moderate (NCI grade 1 or 2) and signs or symptoms suggestive of progression to anaphylaxis are absent, re-challenge may be appropriate. Patients with severe infusion reactions (NCI grade ≥3) should have the drug discontinued immediately and should be treated with epinephrine, antihistamines, and systemic steroids.
Supervising physicians should be prepared for an infusion reaction to occur at any time, and standing orders should be in place for immediate intervention by nursing to prevent delay. Medical equipment and supplies for resuscitation such as epinephrine, antihistamines, intravenous fluids, oxygen, bronchodilators, and defibrillators should be readily available (see Figure).
There are ongoing attempts to identify patients at greatest risk for HSRs. Risk factors include repeated exposure to the agent, history of drug sensitivity, preparation/additives, concurrent autoimmune disease, and intravenous administration (8). At some centers, skin testing is used to help assess risk for an HSR. If skin testing is positive or if the prior reaction is consistent with an immediate HSR, the patient should not be re-challenged but may be a candidate for desensitization.
Knowledge of the characteristic HSRs for the specific chemotherapeutic agent employed will facilitate prompt and appropriate interventions (see Table 2). HSRs are most common with the following agents, in order of descending incidence: platinums (carboplatin, oxaliplatin, cisplatin), taxanes (paclitaxel, docetaxel), L-asparaginase, epipodophyllotoxins (teniposide, etoposide), and procarbazine (2, 8, 9).
Like chemotherapy, the administration of monoclonal antibodies is commonly associated with infusion reactions, some of which can be severe. Immediate reactions to monoclonal antibodies usually provoke a characteristic infusion syndrome, occurring within a few minutes to hours of the first infusion. Most reactions are mild to moderate and present with fever, chills, rigors, nausea, headache, and rash; they are usually immediate, although 10% to 20% of infusion reactions to monoclonal antibodies are delayed, suggesting close observation is necessary for each patient during every infusion (5).
The incidence of these reactions seems highest with rituximab and trastuzumab (9). The exact mechanism is not well understood and appears to be multifactorial, including IgE-mediated phenomenon and cytokine-release syndromes. Although HSRs are less common with cetuximab, fatal anaphylaxis has been reported. This is particularly true in the southeastern United States due to regional triggers leading to preexisting IgE antibodies to the galactose-alpha-1, 3-galactose portion of the cetuximab molecule (10).
For patients who experience recurrent infusion reactions despite appropriate pre-medication and slower infusion rates, or for those with severe reactions, options are limited. Some oncologists advocate discontinuing the offending chemotherapy and choosing alternative regimens. Others refer patients for drug desensitization. The appropriate course is usually chosen on the basis of factors related to the severity of the reaction, the circumstances of the patient, the disease, and the chemotherapy options and outcomes.
When a drug that has provoked an immediate HSR is clearly indicated and alternative medications are less desirable, drug desensitization is an option to re-introduce the offending medication in a relatively safe manner. Desensitizations induce temporary tolerance of the offending agent through mechanisms that remain elusive. Participation of an allergist with expertise in these high-risk procedures is essential to determine whether the patient is an appropriate candidate and to tailor existing protocols.
The key issues are the clinical status of the patient and whether the reaction was immediate or delayed. Immediate HSRs are generally amenable to desensitization. The positive and negative predictive values of skin tests to chemotherapeutic agents remain unclear. Skin testing with these cytotoxic agents can be prohibitively expensive and technically difficult. Thus, allergists may or may not pursue skin tests as part of the risk assessment. For patients with history of asthma or other lung disease, pulmonary function tests are advisable. In otherwise healthy individuals, peak flow monitoring may suffice. Safe and successful desensitization protocols require seamless coordination among treating physicians from allergy, oncology, and hospitalist teams, as well as pharmacists, nurses, and respiratory therapists.
Classic drug desensitization protocols start with 1/10,000th of the target dose, and subsequent doses are doubled or tripled until the goal dose is obtained. Until recently, most desensitizations involved antibiotics or aspirin. However, groundbreaking work by Castells and colleagues has demonstrated the safety and efficacy of protocols for chemotherapeutic agents (9, 11). The success of these protocols has permitted the widespread availability of these high-risk procedures. More recently, modified protocols are emerging from other centers (12).
Return to the case
In ovarian cancer, platinum agents are first-line therapy, and alternative treatments are clearly inferior. For this reason, our patient was referred to an allergist for desensitization. The key elements of the reaction were consistent with an immediate HSR, including flushing, shortness of breath, chest tightness, facial swelling, mild tachycardia, and mild tachypnea. At consultation, she had a normal exam and normal screening spirometry. The desensitization protocol was adapted from published data (11) and tailored to her specific dose. (See Table 3)
Although patients are generally pre-medicated with an H1 and possibly an H2 antihistamine, most do not require additional steroid dosing beyond the usual protocol for the desired chemotherapy. However, higher-risk patients may benefit from additional pre-medication. When needed, generally low to moderate doses of steroids are sufficient (e.g., 40 mg of methylprednisolone) with or without a leukotriene inhibitor such as montelukast.
The key to successful desensitization is continuous monitoring and an order set that enables the early identification of HSR and immediate initiation of appropriate therapy. Allergists must be available during the procedure to assist with recognition and management of adverse reactions. Patient safety relies on continuous monitoring with one-to-one nursing and frequent assessments by treating physicians, as well as immediate access to all supportive medications.
One very significant difference from typical chemotherapeutic infusions is that even minor reactions warrant interruption of the infusion and prompt intervention. Once the patient is at baseline, the offending dose may be re-introduced successfully and the desensitization can be completed. In preparation for adverse reactions, appropriate rescue medications should be at the bedside. The algorithm for management of adverse reactions is analogous to that described for infusion reactions (see Figure). It is important to note that infusion reactions may occur at any point in the protocol, including the final phases of the last step (11).
Desensitization must be repeated for each subsequent cycle of chemotherapy. These protocols induce a state of temporary tolerance that does not last until the next administration; therefore, they must be repeated each cycle. It is paramount to patient safety to recognize and be prepared for adverse reactions even after multiple uneventful desensitizations. If reactions occur, subsequent desensitization may require adjustments to the protocol (11). Adjustments can be made when patients have reactions during the protocol.
Our patient tolerated the desensitization without adverse reaction until she developed angioedema at the very end of the infusion. Accordingly, we altered the protocol for the next infusion. Specifically, we increased pre-medication and extended the infusion time to minimize recurrence. Interval steps were increased to 20 minutes, and an additional serial dilution was added. Subsequent infusions were well tolerated without HSR manifestations.
Virtually all chemotherapeutic agents have the potential to cause infusion reactions, including transient adverse effects and true HSR. Although severe reactions are rare, mild to moderate reactions are very common. Manifestations can range from pruritus and flushing to life-threatening hypotension and bronchospasm. Despite risk of anaphylaxis, desensitization protocols are a safe and effective way to offer first-line therapies to patients who have experienced significant reactions. However, these high-risk procedures require clinical vigilance and interdisciplinary coordination and care. Hospitalists are playing an increasing role in the care of oncology patients undergoing chemotherapy. Accordingly, they must acquire the requisite skills to identify and manage HSRs to these agents.