A variety of life-threatening dermatologic adverse events may occur in association with cancer drug therapies. Here, we discuss the recognition and management of three types of such toxicities: type I hypersensitivity/anaphylaxis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms.
Type I Hypersensitivity/Anaphylaxis
Type I, IgE-mediated, allergic reactions are the most common hypersensitivity reactions to chemotherapeutic agents, develop within minutes of exposure to the causative agent, and can be life-threatening. These reactions are characterized by cutaneous signs such as urticaria, angioedema, pruritus, and flushing. In more severe cases, anaphylaxis can occur, where systemic manifestations such as hypotension, tachycardia, bronchospasm, and abdominal pain are present in conjunction with cutaneous signs.
Anticancer drugs such as platinum compounds, intravenous etoposide, teniposide (Vumon), procarbazine (Matulane), and asparginase (Elspar) are associated with type I hypersensitivity reactions.1 The risk of a type I hypersensitivity reaction typically increases with increasing exposure to a drug. Taxanes are associated with anaphylactoid reactions, which clinically resemble type I IgE-mediated reactions, but are caused by direct nonspecific degranulation of mast cells or basophils.2
In the acute setting, discontinuation of the offending drug is necessary. Symptoms can be treated with systemic corticosteroids and antihistamines. In the case of anaphylaxis, subcutaneous epinephrine is used. It is helpful to confirm the presence of a hypersensitivity reaction by obtaining a tryptase level within a few hours of the reaction.3
Type I hypersensitivity reactions do not necessarily preclude the continuation of therapy with a causative drug. If the benefits of continued therapy outweigh the risks, three options exist: premedication (acetaminophen, diphenhydramine, and/or corticosteroids), desensitization, or use of a different therapeutic agent.
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening mucocutaneous blistering disorders characterized by erosions on at least two mucosal surfaces and cutaneous lesions with central dusky necrosis and a rim of erythema (Fig. 1).4,5
Drug exposure is the most common cause of SJS and TEN. The most common culprits are sulfonamide antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol, many of which are commonly used in conjunction with chemotherapeutic agents. Although a variety of chemotherapeutic agents are reported in the literature to be associated with Stevens-Johnson syndrome or toxic epidermal necrolysis, attributing causality to a specific anticancer drug is difficult given the frequent use of multiple anticancer agents, coadministration with known trigger drugs, and underreporting in the literature.6
These disorders typically occur 1 to 4 weeks after drug exposure. There is often a prodrome of fever and malaise before the appearance of the characteristic rash and subsequent exfoliation. When less than 10% of body surface area is involved, the reaction is termed Stevens-Johnson syndrome, whereas when greater than 30% of body surface area is involved, it is called toxic epidermal necrolysis. For reactions of intermediate severity, the term SJS/TEN overlap syndrome is used.7
Treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis requires discontinuation of the offending agent. Skin-directed therapy is important to encourage wound healing, minimize water loss, and decrease the risk of infection. As SJS and TEN are hypercatabolic states similar to large burns, parenteral fluid, electrolyte, and nutrient resuscitation may be necessary.8,9 Treatment should occur in an ICU or burn unit familiar with managing SJS and TEN.
Short-term treatment with corticosteroids (< 5 days) is still controversial but has been shown to be beneficial for early presentations of TEN; longer courses or initiation later in the disease course are associated with an increased risk of infection.10,11 Treatment with granulocyte colony-stimulating factor (G-CSF, Neupogen) may be indicated for TEN-associated neutropenia.12-15 High-dose intravenous immunoglobulin (2 gm/kg) is most widely used for the treatment of toxic epidermal necrolysis, although the exact mechanism of benefit is unclear.16-21
Drug Rash With Eosinophilia and Systemic Symptoms
Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare and potentially life-threatening syndrome characterized by a combination of morbilliform rash, facial or acral edema, fever, lymphadenopathy, eosinophilia, and internal organ involvement.22 Mortality is as high as 10%, usually due to visceral involvement, most commonly fulminant hepatitis.23-27
The onset of the DRESS syndrome typically occurs 2 to 6 weeks after exposure to the causative drug.26,28 The cutaneous signs of DRESS are often nonspecific, but typically manifest as generalized morbilliform erythema and associated edema of the face and upper extremities. The cutaneous signs are accompanied by systemic signs of fever, lymphadenopathy, and visceral involvement.
The mechanism of this disorder is unknown, but it is thought to be due to altered metabolism of certain drugs, notably anticonvulsants and allopurinol, and decreased clearance of toxic metabolites. Reactivation of herpesvirus infection (especially HHV-6) in conjunction with a drug hypersensitivity reaction is specific for DRESS.29-33
There are no accepted treatment regimens for DRESS syndrome, though high-dose systemic steroids are frequently used when visceral involvement is severe.34-37 Discontinuation of the causative agent is vital. Treatment of the rash includes topical steroids for milder cases and hospitalization for fluid, electrolyte, and nutrition support in more severe cases.
Cutaneous and systemic symptoms can persist for weeks to months after discontinuation of the offending agent, though most patients make a full recovery. Patients should be followed after resolution to monitor for delayed-onset autoimmune disease, most notably hypothyroidism, diabetes mellitus, and cardiomyopathy.38,39 ■
Disclosure: Ms. Barklund and Dr. Anadkat reported no potential conflicts of interest.
References
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Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments.
